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A method of evaluating if a glioblastoma multiforme (GBM) patient is applicable to be treated with an immunotherapy based on dendritic cell tumor vaccines includes a sample obtaining step to obtain a sample from the GBM patient, a detecting step to detect an expression level of a biomarker, and a comparing step to compare the expression level of the biomarker to a threshold, wherein the GBM patient is applicable to treat with the immunotherapy based on dendritic cell tumor vaccines when the expression level of the biomarker is lower than the threshold. A method of prognosticating a survival rate in the GBM patient after a treatment includes a sample obtaining step, a detecting step, and a comparing step, wherein the GBM patient is determined to have a good prognosis after the treatment when the expression level of the sample from the GBM is lower than the threshold.


A method of evaluating if a glioblastoma multiforme (GBM) patient is applicable to be treated with an immunotherapy based on dendritic cell tumor vaccines includes a sample obtaining step to obtain a sample from the GBM patient, a detecting step to detect an expression level of a biomarker, and a comparing step to compare the expression level of the biomarker to a threshold, wherein the GBM patient is applicable to treat with the immunotherapy based on dendritic cell tumor vaccines when the expression level of the biomarker is lower than the threshold. A method of prognosticating a survival rate in the GBM patient after a treatment includes a sample obtaining step, a detecting step, and a comparing step, wherein the GBM patient is determined to have a good prognosis after the treatment when the expression level of the sample from the GBM is lower than the threshold.


Jung C.-R.,China Medical University at Taichung | Chen W.-T.,National Taiwan University | Lin Y.-T.,China Medical University at Taichung | Hwang B.-F.,China Medical University at Taichung
Environmental Health Perspectives | Year: 2017

Background: Kawasaki disease (KD) is an acute and multi-systemic vasculitis that occurs predominantly in infants and young children. Although the etiological agent of KD remains unclear, limited studies have reported that windborne environmental factors may trigger KD. Objectives: We conducted a time-stratified case-crossover study to assess the associations between air pollutants and KD in Taiwan. Methods: We identified children < 5 years old with a diagnosis of KD from the Longitudinal Health Insurance Database 2000 (LHID2000) between 2000 and 2010. We obtained data regarding carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), particulate matter with aerodynamic diameter < 10 μm (PM10), and sulfate dioxide (SO2) from 70 monitoring stations and used inverse distance weighting to calculate average daily exposures for the residential postal code of each case. We performed conditional logistic regression to estimate associations between KD and each air pollutant according to interquartile range (IQR) increases and quartiles of exposure on the day of hospitalization versus 3–4 reference days during the same month for each case. Additionally, we estimated associations with single-day exposures lagged 1–2 days. Results: We identified 695 KD hospital admissions during the study period. An IQR increase (28.73 ppb) of O3 was positively associated with KD after adjusting for temperature, humidity, northward wind, and eastward wind [adjusted odds ratio = 1.21; 95% confidence interval (CI): 1.01, 1.44]. There were no significant associations between KD and CO, NO2, PM10, or SO2. The association with O3 was limited to exposure on the day of hospitalization and to exposure during the summer months (June–August). Conclusions: Our results provide new evidence that exposure to O3 may increase the risk of KD in children. However, further investigation is needed to confirm the association and identify a potential biological mechanism. © 2017, Public Health Services, US Dept of Health and Human Services. All rights reserved.


Spaggiari M.,China Medical University at Taichung
Transplantation | Year: 2017

BACKGROUND: Pancreas grafts from pediatric donors are still considered “not ideal”. Perceived concerns are related to low islet mass and potential for graft thrombosis. METHODS: The study evaluated all pancreas transplants from January 2000 to May 2015 using the Organ Procurement and Transplant Network (OPTN) database. Comparative analysis of recipient and graft survival was performed between pediatric (≤18 years) and adult donors. In the pediatric group, the outcomes were stratified based on donor age (≤ 6 years; 7-12 years; 13-18 years) and weight (<30 kg; 30-95 Kg; >95 kg). RESULTS: In the selected era, 18 430 pancreas transplants were performed from 4915 (27%) pediatric donors. Short-term graft and patient survivals were comparable between pediatric and adult donors. Ten-year patient and graft survivals were higher in the pediatric donor group: (70% and 54% vs. 68% and 51%; p: 0.001). However, very low weight pediatric donors (<30kg) resulted in worse graft survival in the long-term (44% at 10 years; p:0.006). CONCLUSIONS: Pediatric donor pancreas transplants had comparable patient and graft survival to the adult donor transplants. However, the islet mass of very small donors could influence long-term graft survival if the weights of donors and recipients are not properly matched. Utilization of “very small” pediatric donors was not associated with higher incidence of technical complications or early graft loss. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Chau-Dinh T.,HCMC University of Technology | Nguyen-Duy Q.,POSCO | Nguyen-Xuan H.,China Medical University at Taichung
Acta Mechanica | Year: 2017

An improved three-node triangular plate finite element is presented for plate analysis. The key idea is to enhance the performance of the original MITC3 element with an edge-based strain smoothing technique. To address this derivation, the MITC3 is explicitly formulated to obtain constant gradient matrices. All strain fields are then averaged over edge-based integration domains defined by two nodes of an element’s edge and the centroid(s) of element(s) sharing the element’s edge. A stabilized coefficient factor is also used for the shearing stiffness. We name this element as ES-MITC3, and it is then employed to analyze various plate problems under static loading and free vibration. Numerical results show that the ES-MITC3 element is free of “shear locking” and performs well for static and vibration behaviors. The present element exhibits a good competitor with other several existing three-node triangular plate elements, even the four-node MITC4 element. © 2017 Springer-Verlag Wien


Kung T.-L.,Asia University, Taiwan | Kung T.-L.,China Medical University at Taichung | Hung C.-N.,Da - Yeh University
Theoretical Computer Science | Year: 2017

The exact reliability of a complicated network system is usually difficult to determine, and numerical approximations may play a crucial role in indicating the reliable probability that a system is still operational under a specified suite of conditions. In this paper, we establish upper and lower bounds on the first-order subsystem reliability of bubblesort networks using the probabilistic fault model. Numerical results show that the curves of upper- and lower-bounded reliability are in good agreement, especially when the node reliability is at a low level. © 2017 Elsevier B.V.


Shih C.-T.,China Medical University at Taichung | Wu J.,National Yang Ming University
Medical physics | Year: 2017

PURPOSE: X ray and γ-ray are widely applied in radiology, radiotherapy, and nuclear medicine. Linear attenuation coefficients and linear energy absorption coefficients are essential for dose calculation and image correction. In this study, a method that entails combining the stoichiometric calibration and parametric physical models was developed to convert computed tomography (CT) images into the linear attenuation coefficients and linear energy absorption coefficients.METHODS: A calibration scan was performed using standard tissue-equivalent materials to obtain the characteristics of the x-ray energy spectrum. Subsequently, relationships between CT numbers and tissue parameters were established using standard soft tissue and bone tissue data adopted from the literature. The linear attenuation coefficient and linear energy absorption coefficient were calculated using the parametric fit model.RESULTS: The results showed a linear relationship between CT numbers and tissue parameters. The tissue-equivalent materials differed from real human tissues, leading to considerable errors in estimation of mass attenuation coefficients when the photon energy was lower than 50 keV. Mass attenuation coefficients and mass energy transfer coefficients of five tissues were calculated and validated using clinical CT images. The error was less than ± 5% and ± 8%, compared with the values of the International Commission on Radiation Units (ICRU) 46 report.CONCLUSIONS: The probability of photon interaction with tissues and physical characteristics of tissues can be accurately evaluated by using the proposed method and applied in various clinical applications. © 2016 American Association of Physicists in Medicine.


Chang S.S.,China Medical University at Taichung | Wang X.R.,Yibin University
Numerical Functional Analysis and Optimization | Year: 2017

This article uses the shrinking projection method introduced by Takahashi, Kubota and Takeuchi to propose an iteration algorithm for a countable family of Bregman multi-valued quasi-nonexpansive mappings in order to have the strong convergence under a limit condition in the framework of reflexive Banach spaces. We apply our results to a zero point problem of maximal monotone mappings and equilibrium problems in reflexive Banach spaces. The results presented in the article improve and extend the corresponding results of that found in the literature. © 2017 Taylor & Francis


Chang J.-C.,National Taiwan University | Tseng S.-H.,National Taiwan University | Lai C.-C.,National Chung Hsing University | Lai C.-C.,China Medical University at Taichung | And 3 more authors.
Nature Chemistry | Year: 2017

Daisy chains (DCs) are garlands of flowers that can be worn as bracelets and necklaces. As a result of their beautiful interlocked structures and possible muscle-like motions, cyclic molecular DCs ([cn]DCs, where n is the number of repeating units) have long been attractive synthetic targets for supramolecular chemists. Herein we report artificial molecular muscles that-unlike one-dimensional (1D) biological muscles-contract and stretch in 2D or 3D. These systems have the structures of [c3]- and [c4]DCs with subcomponents that operate as molecular switches, powered through the addition or removal of Zn2+ ions to impart muscle-like behaviour. We assembled these [c3]- and [c4]DCs selectively by exploiting structural rigidity, coordination geometries and bond rotational barriers that disfavoured the formation of smaller homologues. The switching phenomena of our [c3]- and [c4]DCs resulted in the contracted molecular muscles stretching by approximately 23 and 36%, respectively, comparable to the value (27%) for linear biological muscles. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


Yang T.-T.,Yuanpei University | Hsu C.-Y.,National Health Research Institute | Chen Y.-C.,National Health Research Institute | Chen Y.-C.,China Medical University at Taichung | And 3 more authors.
Aerosol and Air Quality Research | Year: 2017

This study investigated PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in order to determine the seasonal changes in total benzo[a]pyrene equivalent (BaPeq) concentrations and to identify contamination sources by using a positive matrix factorization model, a conditional probability function, and characteristic ratios of PAHs in Hsinchu. The sampling period was from September 2014 to August 2015. PM2.5 samplers equipped with 47-mm quartz membrane filters were operated at a flow rate of 16.7 L min-1 for 48 h. The concentrations of 20 PAHs were determined through gas chromatography-mass spectrometry. The results revealed the PM2.5, total PAHs, and BaPeq mass concentrations in the four seasons ranged from 4.91 to 58.5 µg m-3, 0.21 to 8.08 ng m-3, and 0.03 to 0.78 ng m-3, respectively. The PM2.5, total PAHs, and BaPeq mass concentrations were in the order winter > autumn > spring > summer and exhibited significant seasonal variations. The carcinogenic potency of PAHs in winter was approximately 6.21 times higher than that in summer. The major BaPeq contributors were BaP, BbF, INP, and DBA. BaP accounted for 49.0% of BaPeq concentrations in PM2.5 in all four seasons. The annual average lifetime excess cancer risk of PM2.5-bound PAHs (1.60 × 10-5) was higher than that specified in the United States Environmental Protection Agency guidelines (10-6). The two major sources were stationary emission sources and unburned petroleum and traffic emissions, which together accounted for 90.3% of PM2.5-bound PAHs. © Taiwan Association for Aerosol Research.


Lee M.-S.,China Medical University at Taichung | Su T.-Y.,National Pingtung University of Science and Technology | Lien Y.-Y.,National Pingtung University of Science and Technology | Sheu S.-C.,National Pingtung University of Science and Technology
Scientific Reports | Year: 2017

Plant-based food ingredients such as garlic, Chinese leek, Chinese onion, green onion and onion are widely used in many cuisines around the world. However, these ingredients known as the "five forbidden vegetables" (FFVs) are not allowed in some vegetarian diets. In this study, a loop-mediated isothermal amplification (LAMP) assay was developed for the detection of FFVs using five respective LAMP primer sets. The specific primers targeted the ITS1-5.8S-ITS2 nuclear ribosomal DNA sequence regions among the five vegetables. The results demonstrated that the identification of FFVs using the newly developed LAMP assay is more sensitive than the traditional PCR method. Using pepper, basil, parsley, chili and ginger as references, established LAMP primer sets showed high specificity for the identification of the FFV species. Moreover, when FFVs were mixed with other plant ingredients at different ratios (100:0, 50:50, 20:80, 10:90, 5:95, 2:98, and 1:99), no cross-reactivity was evident using LAMP. Finally, genomic DNAs extracted from boiled and steamed FFVs in processed foods were used as templates; the performance of the LAMP reaction was not influenced using validated LAMP primers. Not only can FFV ingredients be identified but commercial foods containing FFVs can also be authenticated. This LAMP method will be useful for the authentication of FFVs in practical food markets in the future. © The Author(s) 2017.


Tseng K.-Y.,National Health Research Institute | Chen Y.-H.,National Health Research Institute | Lin S.,National Health Research Institute | Lin S.,China Medical University at Taichung
Oncotarget | Year: 2017

Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is a member of the tristetraprolin (TTP) family and its role in the aging-related bone loss is currently unknown. We present evidence that ZFP36L1 expression in rat femurs and bone marrow mesenchymal stem cells (bmMSCs) was down-regulated with aging. ZFP36L1 knockdown decreased osteoblastic differentiation of MC3T3-E1 and C3H10T1/2 cells, and increased adipogenic differentiation of 3T3-L1 and C3H10T1/2 cells, whereas ZFP36L1 overexpression did the opposite. The finding that ZFP36L1 overexpression enhanced osteoblastic and repressed adipogenic differentiation was also corroborated by ex vivo experiments. Troglitazone prevented ZFP36L1 from inhibiting adipogenic differentiation, suggesting the significance of PPARγ2 repression in ZFP36L1's inhibitory effect on adipogenic differentiation. ZFP36L1 overexpression repressed the expression of Pparγ2 mRNA, but not the PPARγ promoter activity. Biotin pulldown and electrophoretic mobility-shift assays suggested that ZFP36L1 might interact with endogenous Pparγ2 mRNA by binding to its 3'UTR. The ZFP36L1-containing ribonucleoprotein complexes of ZFP36L1-overexpressing cells contained less Pparγ2 mRNA than those of control cells. In a luciferase reporter construct, replacement of the SV40 poly(A) fragment by the 3'UTR of Pparγ2 mRNA reduced the expression of luciferase transcripts in ZFP36L1-overexpressing cells. Examination of the kinetic expression of Pparγ2 mRNA after transcriptional blockage showed that ZFP36L1 might enhance the degradation of the transcripts. Together, these data imply that ZFP36L1 overexpression might repress adipogenesis at least by down-regulating PPARγ2 expression through post-transcriptional mechanisms. Thus, our findings support the notion that decrease of ZFP36L1 expression in bmMSCs with aging might contribute to the aging-related bone loss.


Tsai C.-W.,China Medical University at Taichung | Lin S.-Y.,China Medical University at Taichung | Kuo C.-C.,China Medical University at Taichung | Huang C.-C.,China Medical University at Taichung
PLoS ONE | Year: 2017

Background: Increasing evidence supports the association between hyperuricemia and incident chronic kidney disease (CKD); however, there are conflicting data regarding the role of hyperuricemia in the progression of CKD. This study retrospectively assessed the longitudinal association between uric acid (UA) level and CKD progression in a Chinese population lived in Taiwan. Methods: Patients with physician diagnosis of hyperuricemia or receiving urate-lowering therapy between 2003 and 2005 were identified in the electronic medical records (EMR) of a tertiary medical center and were followed up until December 31, 2011. Patients were divided into four UA categories at the cut-off 6, 8, and 10 mg/dL. CKD progression was estimated by the change of estimated glomerular filtration rate (eGFR) in the linear mixed models. Kidney failure was defined as an eGFR less than 15 mL/min/1.73 m2 or requiring renal replacement therapy. Results: A total of 739 patients were analyzed. In the full-adjusted model, patients with a baseline UA level ≥6 mg/dL had greater decline in eGFR ((β = -9.6, 95% CI-16.1, -3.1), comparing to those with a UA level less than 6 mg/dL. When stratifying patients into four UA categories, all three hyperuricemia categories (UA6-8, 8-10, ≥10 mg/dL) associated with a greater decline in eGFR over the follow-up period with an increasing dose-response, comparing to the lowest UA category. The risk of progression to renal failure increased 7% (hazard ratio 1.07, 95% CI1.00,1.14) for each 1mg/dL increase in baseline UA level. The influences of hyperuricemia on eGFR decline and the risk of kidney failure were more prominent in patients without proteinuria than those with proteinuria. Conclusion: Our study showed a higher uric acid level is associated with a significant rapid decline in eGFR and a higher risk of kidney failure, particularly in patients without proteinuria. Our findings suggest hyperuricemia is a potential modifiable factor of CKD progression. © 2017 Tsai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hu W.-S.,China Medical University at Taichung | Lin C.-L.,Data Management
International Journal of Cardiology | Year: 2017

Purpose This study aimed to evaluate the predictive role of CHA2DS2-VASc score specifically for the development of ischemic bowel disease (IBD) among atrial fibrillation (AF) patients. Methods Using a nationwide dataset, an AF cohort was established. The study participants were followed up from the index date until they withdrew from the health insurance system, the occurrence of IBD or until the end of 2011. The hazard ratios (HRs) and 95% confidence intervals (CIs) were examined by Cox models to present the subsequent risk of IBD among AF patients by CHA2DS2-VASc score. The area under the receiver operating characteristic (ROC) curve was used to assess the predictive power of CHA2DS2-VASc score for IBD development among AF patients. Results The cumulative incidence of IBD was higher for AF patients with a CHA2DS2-VASc score ≥ 2 than those with a CHA2DS2-VASc score < 2 by 2.30% (p < 0.001) at the end of follow-up. After adjustment for hyperlipidemia, chronic obstructive pulmonary disease, and chronic kidney disease, the AF patients with a CHA2DS2-VASc score ≥ 2 had a 3.35 times higher risk for IBD development compared to those with a CHA2DS2-VASc score < 2 [adjusted HR (aHR) = 3.35, 95% CI = 2.71–4.13]. Among AF patients, the C-statistic of the CHA2DS2-VASc score as a predictor of IBD was 0.56 (95% CI = 0.55–0.57). Conclusions In conclusion, the study is​ the first to investigate the predictive role of CHA2DS2-VASc score specifically for IBD development among AF patients. However, the predictive power was relatively low; further studies are necessary to confirm our findings. © 2017 Elsevier Ireland Ltd


Lin K.-H.,Fooyin University | Lai N.,National Cheng Kung University | Zeng J.-Y.,China Medical University at Taichung | Chiang H.-L.,China Medical University at Taichung
Science of the Total Environment | Year: 2017

Sludge taken from a wastewater treatment plant of the petrochemical industry was dewatered and pyrolyzed to produce liquid oil as an alternative fuel via microwave heating. Element contents of dried sludge were 45.9. ±. 3.85. wt.% carbon, 7.70. ±. 1.43. wt.% hydrogen, 4.30. ±. 0.77. wt.% nitrogen and 3.89. ±. 0.52. wt.% sulfur. Two major thermal degradation peaks of sludge were determined during the microwave pyrolysis process, one at 325-498. K (most of the water was vaporized, and the weight loss was over 85. wt.%) and the other at 548-898. K for sludge constituent decomposition. Zn content was high in the dried raw material and residues. Other toxic elements such as Ni, Cr, Pb, As and Cd contents were 0.61-0.99, 0.18-0.46, 0.15-0.25, 0.018-0.034, and 0.006-0.017. mg/g, respectively. About 14-20. wt.% of oil was produced based on the dried sludge cake, and the oil major elements were C (69-72. wt.%), H (5.7-6.7. wt.%), N (1.9-2.2. wt.%), and S (0.58-0.82. wt.%). The heat values of liquid oils were 8700-9200. kcal/kg at 400-800. °C. © 2017 Elsevier B.V.


Background. Zika virus (ZIKV) transmission has been reported in 67 countries/territories in the Oceania region and the Americas since 2015, prompting the World Health Organization (WHO) to declare ZIKV as a Public Health Emergency of International Concern in February 2016, due to its strong association with medical complications such as microcephaly and Guillain-Barré Syndrome (GBS). However, a substantial gap in knowledge still exists regarding differing temporal pattern and potential of transmission of ZIKV in different regions of the world. Methods. We use a phenomenological model to ascertain the temporal patterns and transmission potential of ZIKV in various countries/territories, by fitting the model to Zika case data from Yap Island and French Polynesia in the Oceania region and 11 countries/territories with confirmed case data, namely, Colombia, Ecuador, French Guiana, Guadeloupe, Guatemala, Mexico, Nicaragua, Panama, Puerto Rico, Saint Martin, and Suriname, to pinpoint the waves of infections in each country/territory and to estimate the respective basic reproduction number R0. Results. Six of these time series datasets resulted in statistically significant model fit of at least one wave of reported cases, namely that of French Polynesia, Colombia, Puerto Rico, Guatemala, Suriname and Saint Martin. However, only Colombia and Guatemala exhibited two waves of cases while the others had only one wave. Temporal patterns of the second wave in Colombia and the single wave in Suriname are very similar, with the respective turning points separated by merely a week. Moreover, the mean estimates of R0 for Colombia, Guatemala and Suriname, all land-based populations, range between 1.05 and 1.75, while the corresponding mean estimates for R0 of island populations in French Polynesia, Puerto Rico and Saint Martin are significantly lower with a range of 5.70-6.89.Wealso fit the Richards model to Zika case data from six main archipelagos in French Polynesia, suggesting the outbreak in all six island populations occurred during the same time, albeit with different peak time, with mean R0 range of 3.09-5.05. Discussion. Using the same modeling methodology, in this study we found a significant difference between transmissibility (as quantified by R0) in island populations as opposed to land-based countries/territories, possibly suggesting an important role of geographic heterogeneity in the spread of vector-borne diseases and its future course, which requires further monitoring. Our result has potential implications for planning respective intervention and control policies targeted for island and land-based populations. © 2017 Hsieh.


Lin C.-H.,Fengyuan Hospital | Wu J.-B.,China Medical University at Taichung | Jian J.-Y.,Central Taiwan University of Science and Technology | Shih C.-C.,Central Taiwan University of Science and Technology
PLoS ONE | Year: 2017

The objective of this study was to evaluate the effects and molecular mechanism of (-)-epicatechin-3-O-β-D-allopyranoside from Davallia formosana (BB) (also known as Gu-Sui-Bu) on type 1 diabetes mellitus and dyslipidemia in streptozotocin (STZ)-induced diabetic mice. This plant was demonstrated to display antioxidant activities and possess polyphenol contents. Diabetic mice were randomly divided into six groups and were given daily oral gavage doses of either BB (at three dosage levels), metformin (Metf) (at 0.3 g/kg body weight), fenofibrate (Feno) (at 0.25 g/kg body weight) or vehicle (distilled water) and a group of control (CON) mice were gavaged with vehicle over a period of 4 weeks. Treatment with BB led to reduced levels of blood glucose, HbA1C, triglycerides and leptin and to increased levels of insulin and adiponectin compared with the vehicle-treated STZ group. The diabetic islets showed retraction from their classic round-shaped as compared with the control islets. The BB-treated groups (at middle and high dosages) showed improvement in islets size and number of Langerhans islet cells. The membrane levels of skeletal muscular glucose transporter 4 (GLUT4) were significantly higher in BB-treated mice. This resulted in a net glucose lowering effect among BB-treated mice. Moreover, BB enhanced the expression of skeletal muscle phospho-AMPK in treated mice. BB-treated mice increased expression of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα) and mRNA levels of carnitine palmitoyl transferase Ia (CPT1a). These mice also expressed lower levels of lipogenic genes such as fatty acid synthase (FAS), as well as lower mRNA levels of sterol regulatory element binding protein 1c (SREBP1c) and liver adipocyte fatty acid binding protein 2 (aP2). This resulted in a reduction in plasma triglyceride levels. BBtreated mice also expressed lower levels of PPARγ and FAS protein. This led to reduced adipogenesis, fatty acid synthesis and lipid accumulation within adipose tissue, and consequently, to lower triglyceride levels in liver, blood, and adipose tissue. Moreover, BB treatment not only displayed the activation Akt in liver tissue and skeletal muscle, but also in C2C12 myotube to cause an increase in phosphorylation of Akt in the absence of insulin. These results demonstrated that BB act as an activator of AMPK and /or regulation of insulin pathway (Akt), and the antioxidant activity within the pancreas. Therefore, BB treatment ameliorated the diabetic and dyslipidemic state in STZ-induced diabetic mice. © 2017 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Chien C.-R.,China Medical University at Taichung | Chen H.-J.,China Medical University at Taichung
Journal of Thoracic Disease | Year: 2016

Novel targeted therapy for patients with non-small-cell lung cancer (NSCLC) and oncogenic mutations along with poor performance status (PS) sometimes evokes a "Lazarus" response. Moreover, for critically ill patients with NSCLC and respiratory failure requiring mechanical ventilation (MV) in the intensive care unit (ICU), only a few case reports have demonstrated positive outcomes with targeted therapy. This perspective review describes in detail the most recently published data in order to highlight the findings and the main pitfalls of targeted therapy for patients with NSCLC in the ICU. © Journal of Thoracic Disease.


Yang T.-S.,China Medical University at Taichung | Liu T.-T.,Yuanpei University | Liu H.-I.,China Medical University at Taichung
Food Hydrocolloids | Year: 2017

Nanostructured lipid carriers (NLC) are a delivery system for drugs or functional substances to control their release and protect them from harmful environmental stresses. The aims of this research were to investigate the effects of chemical structure of aroma compounds, type and composition of lipids as well inhibitors on the lipolysis of NLC in the presence of lipase, and to study the release rate of a functional substance, curcumin, encapsulated in the NLC by a kinetic study. The amount of free fatty acids released from the lipid digestion of NLC was determined by a pH-stat method. Franz diffusion cells were used to study the release rate of curcumin from the digestion of NLC by the lipase in the presence or absence of an inhibitor. The results indicate that the chemical structures of the tested aroma compounds have a marked effect on the inhibition of lipase activity. In addition, the release rate of functional substances such as curcumin encapsulated in the NLC can be controlled by manipulating the lipid type and composition, and using a lipase inhibitor. © 2016


Phung-Van P.,Ghent University | Lieu Q.X.,Sejong University | Nguyen-Xuan H.,China Medical University at Taichung | Abdel Wahab M.,Ghent University
Composite Structures | Year: 2017

This paper presents an effective and simple computational formulation based on isogeometric analysis (IGA) and generalized higher-order shear deformation theory (GHSDT) to study size-dependent analysis of functionally graded carbon nano-reinforced composite (FG-CNTRC) nanoplates. The material properties of FG-CNTRC are assumed to be graded through the thickness direction according to four special distributions of carbon nanotubes (CNTs). The differential nonlocal equations are utilized to take into account size effects. The nonlocal governing equations are approximated according to IGA based on GHSDT, which satisfies naturally the higher-order derivatives continuity requirement in weak form of FG-CNTRC nanoplates. Carbon nanotube volume fraction and nonlocal effects on responses of FG-CNTRC nanoplates with different volume fractions are studied. Numerical results prove high accuracy and reliability of the present method in comparison with other available numerical approaches. © 2017 Elsevier Ltd


Kan Y.-C.,Yuan Ze University | Chen K.-H.,China Medical University at Taichung | Lin H.-C.,China Medical University at Taichung
Computer Methods and Programs in Biomedicine | Year: 2017

Background and Objective Self-management in healthcare can allow patients managing their health data anytime and everywhere for prevention of chronic diseases. This study established a prototype of ubiquitous health management system (UHMS) with healthy diet control (HDC) for people who need services of metabolic syndrome healthcare in Taiwan. Methods System infrastructure comprises of three portals and a database tier with mutually supportive components to achieve functionality of diet diaries, nutrition guides, and health risk assessments for self-health management. With the diet, nutrition, and personal health database, the design enables the analytical diagrams on the interactive interface to support a mobile application for diet diary, a Web-based platform for health management, and the modules of research and development for medical care. For database integrity, dietary data can be stored at offline mode prior to transformation between mobile device and server site at online mode. Results The UHMS-HDC was developed by open source technology for ubiquitous health management with personalized dietary criteria. The system integrates mobile, internet, and electronic healthcare services with the diet diary functions to manage healthy diet behaviors of users. The virtual patients were involved to simulate the self-health management procedure. The assessment functions were approved by capturing the screen snapshots in the procedure. The proposed system development was capable for practical intervention. Conclusion This approach details the expandable framework with collaborative components regarding the self-developed UHMS-HDC. The multi-disciplinary applications for self-health management can support the healthcare professionals to reduce medical resources and improve healthcare effects for the patient who requires monitoring personal health condition with diet control. The proposed system can be practiced for intervention in the hospital. © 2017 Elsevier B.V.


Yeh C.C.,China Medical University at Taichung
Medicine | Year: 2017

RATIONALE: Obesity is considered a relative contraindication to pancreas transplantation due to increased risks of wound-related complications. Robotic surgeries have never been applied for pancreas transplantation in obese recipients though robotic kidney transplantation did and already proved its value in reducing wound-related complications in obese recipients.PATIENT CONCERNS & DIAGNOSES: We performed the first robotic pancreas after kidney transplantation for a 34-year-old Hispanic type 1 diabetic male with class III obesity (BMI = 41 kg/m).INTERVENTIONS: The pancreas graft was procured and benched in the standard fashion. Methylene blue was used to detect any vascular leaks. The operation was completed via two 12-mm ports (camera, laparoscopic bed-side assistance), two 8-mm ports for robotic arms, and a 7-cm epigastric incision for hand port. The portal vein and arterial Y-graft of the pancreas were anastomosed to the recipient's left external iliac vein and artery, respectively. Duodenum-bladder drainage was performed with a circular stapler.OUTCOMES: Duration of warm and cold ischemia was: 45 minutes and 7 hours, respectively. The patient was discharged uneventfully without wound-related complications. Excellent metabolic control was achieved with hemoglobin A1c lowering from 9% before transplantation to 4.4% on day 120. The patient remained in nondiabetic status in 1-year follow-up.LESSONS: In conclusion, robotic pancreas transplantation is feasible in patients with morbid obesity.


Yang L.-C.,China Medical University at Taichung | Lai C.-Y.,China Medical University at Taichung | Lin W.-C.,China Medical University at Taichung
Carbohydrate Polymers | Year: 2017

This study investigated the effects of a type II arabinogalactan from Anoectochilus formosanus (AGAF) on natural killer (NK) cell-mediated cytotoxicity and the possible underlying mechanisms. This study reported that sustained exposure to AGAF increased NK-92MI cell-mediated cytotoxicity in a time- and concentration-dependent manner, as characterized according to the cellular lactic dehydrogenase leakage from K562 leukemia cells. Additionally, antibody neutralization studies have reported that interferon (IFN)-γ, but not perforin or tumor necrosis factor-α, released by NK-92MI NK cells is crucial in enhancing cytotoxicity through an autocrine loop. In this study, AGAF was further demonstrated to induce IFN-γ expression, increasing the susceptibility to NK-92MI cell-mediated cytotoxicity through the toll-like receptor (TLR)-2, TLR4, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB pathways. A pharmacological study revealed that Janus kinase 2/signal transducers and activators of the signal transducers and of transcription 3 signaling are involved in IFN-γ-induced NK cell-mediated cytotoxicity. © 2016


Chen H.-C.,U.S. Food and Drug Administration | Chen H.-C.,China Medical University at Taichung | Chen J.J.,U.S. Food and Drug Administration
BMC Medical Research Methodology | Year: 2013

Background: Two most important considerations in evaluation of survival prediction models are 1) predictability - ability to predict survival risks accurately and 2) reproducibility - ability to generalize to predict samples generated from different studies. We present approaches for assessment of reproducibility of survival risk score predictions across medical centers. Methods. Reproducibility was evaluated in terms of consistency and transferability. Consistency is the agreement of risk scores predicted between two centers. Transferability from one center to another center is the agreement of the risk scores of the second center predicted by each of the two centers. The transferability can be: 1) model transferability - whether a predictive model developed from one center can be applied to predict the samples generated from other centers and 2) signature transferability - whether signature markers of a predictive model developed from one center can be applied to predict the samples from other centers. We considered eight prediction models, including two clinical models, two gene expression models, and their combinations. Predictive performance of the eight models was evaluated by several common measures. Correlation coefficients between predicted risk scores of different centers were computed to assess reproducibility - consistency and transferability. Results: Two public datasets, the lung cancer data generated from four medical centers and colon cancer data generated from two medical centers, were analyzed. The risk score estimates for lung cancer patients predicted by three of four centers agree reasonably well. In general, a good prediction model showed better cross-center consistency and transferability. The risk scores for the colon cancer patients from one (Moffitt) medical center that were predicted by the clinical models developed from the another (Vanderbilt) medical center were shown to have excellent model transferability and signature transferability. Conclusions: This study illustrates an analytical approach to assessing reproducibility of predictive models and signatures. Based on the analyses of the two cancer datasets, we conclude that the models with clinical variables appear to perform reasonable well with high degree of consistency and transferability. There should have more investigations on the reproducibility of prediction models including gene expression data across studies. © 2013 Chen and Chen; licensee BioMed Central Ltd.


Chiang C.-H.,National Taiwan University Hospital | Lee L.-T.,National Taiwan University Hospital | Hung S.-H.,National Taiwan University Hospital | Lin W.-Y.,China Medical University at Taichung | And 6 more authors.
Hepatology | Year: 2014

Limited data exist regarding metabolic risk factors for deaths from hepatocellular carcinoma (HCC) in aging individuals. We investigated the association between diabetes, dyslipidemia, and HCC mortality in those aged 40 years or more (middle-aged and elderly). In this prospective cohort study based on nationwide health screening units, we consecutively followed middle-aged and elderly participants who had no chronic hepatitis B or C virus infection and received health screening from January 1 1998 to December 31 2008. There were 235 deaths from HCC among 50,080 individuals, ascertained by validated death certificates and the national death registry. Diabetes (adjusted hazard ratio [HR], 3.38; 95% confidence interval [CI], 2.35 to 4.86) was positively associated with deaths from HCC. However, hypertriglyceridemia (HR, 0.38; 95% CI, 0.26 to 0.55) and hypercholesterolemia (HR, 0.50; 95% CI, 0.37 to 0.67) were inversely associated with HCC mortality. The above significant associations remained in the lag time analyses, applied to check for reverse causation. Metabolic syndrome, as defined by the American Heart Association / National Heart Lung Blood Institute criteria (HR, 0.63; 95% CI, 0.46 to 0.86) or by the International Diabetes Federation criteria (HR, 0.62; 95% CI, 0.43 to 0.89), was inversely associated with deaths from HCC, especially in men. Conclusion: Middle-aged and elderly individuals, once having diabetes, deserve HCC surveillance to reduce HCC mortality. More research is needed to elucidate why having baseline dyslipidemia relates to lower future HCC mortality. © 2014 by the American Association for the Study of Liver Diseases.


Hsu C.,National Taiwan University Hospital | Hsu C.,National Taiwan University | Tsou H.-H.,National Health Research Institute | Lin S.-J.,Kaohsiung Veterans General Hospital | And 14 more authors.
Hepatology | Year: 2014

Fatal hepatitis B virus (HBV) reactivation in lymphoma patients with "resolved" HBV infection (hepatitis B surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) can occur, but the true incidence and severity remain unclear. From June 2009 to December 2011, 150 newly diagnosed lymphoma patients with resolved HBV infection who were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy were prospectively followed. HBV DNA was checked at baseline, at the start of each cycle of chemotherapy, and every 4 weeks for 1 year after completion of rituximab-CHOP chemotherapy. Patients with documented HBV reactivation were treated with entecavir at a dosage of 0.5 mg/day for 48 weeks. HBV reactivation was defined as a greater than 10-fold increase in HBV DNA, compared with previous nadir levels, and hepatitis flare was defined as a greater than 3-fold increase in alanine aminotransferase (ALT) that exceeded 100 IU/L. Incidence of HBV reactivation and HBV-related hepatitis flares was 10.4 and 6.4 per 100 person-year, respectively. Severe HBV-related hepatitis (ALT >10-fold of upper limit of normal) occurred in 4 patients, despite entecavir treatment. Patients with hepatitis flare exhibited significantly higher incidence of reappearance of HBsAg after HBV reactivation (100% vs. 28.5%; P=0.003). Conclusion: In lymphoma patients with resolved HBV infections, chemotherapy-induced HBV reactivation is not uncommon, but can be managed with regular monitoring of HBV DNA and prompt antiviral therapy. Serological breakthrough (i.e., reappearance of HBsAg) is the most important predictor of HBV-related hepatitis flare. © 2014 by the American Association for the Study of Liver Diseases.


Jao C.-L.,Food and Beverage | Huang S.-L.,National University of Kaohsiung | Hsu K.-C.,China Medical University at Taichung
BioMedicine (Netherlands) | Year: 2012

Bioactive peptides within the original food-derived proteins are inactive but can be activated by releasing them during food processing (by enzymatic hydrolysis or fermentation) or during gastrointestinal (GI) digestion. Among all the bioactive peptides, the antihypertensive peptides attract particular attention owing to the prevalence of high blood pressure, which plays an important role in cardiovascular diseases. These peptides have the ability to act as angiotensin I-converting enzyme (ACE) inhibitors. Previous studies have shown that the ACE inhibitory peptides functioned as competitive, noncompetitive, or uncompetitive inhibitors, and therefore, the structure-activity relationship of the peptides with various inhibition modes needs to be clarified. Besides, the ACE inhibitory activity of these peptides in vitro does not always suggest its antihypertensive effect in vivo, which is based on its fate to encounter GI enzymes and brush-border membrane peptidases, after oral administration. This paper reviews the current literature on ACE inhibitory peptides, focusing on the structure-activity relationship and inhibition mechanisms due to their inhibition modes. In addition, the in vitro-simulated GI digestion for assessing bioavailability and in vivo antihypertensive effects of the peptides are also summarized. © 2012.


Lo Y.-C.,Office of Preventive Medicine | Lo Y.-C.,National Taiwan University Hospital | Ji D.-D.,Center for Research | Ji D.-D.,National Yang Ming University | And 2 more authors.
PLoS Neglected Tropical Diseases | Year: 2014

Background: Sexually transmitted Entamoeba histolytica infection (EHI) has been increasingly recognized among men who have sex with men (MSM). We used the National Disease Surveillance Systems (NDSS) to identify prevalent and incident HIV diagnoses among adults with EHI and to determine the associated factors. Methodology: The NDSS collect demographic, clinical, and behavioral characteristics of case patients through physician reports and public health interviews. EHI was confirmed by polymerase-chain-reaction assays, histopathology, or serology with documented liver abscess. We linked NDSS databases to identify prevalent and incident HIV diagnoses among noninstitutionalized Taiwanese adults with confirmed EHI during 2006–2013. Cox proportional-hazards analysis was used to determine associated factors. Principal findings:: Of noninstitutionalized adults with EHI, we identified prevalent HIV diagnosis in 210 (40%) of 524 males and one (1.7%) of 59 females, and incident HIV diagnosis in 71 (23%) of 314 males. MSM accounted for 183 (87%) and 64 (90%) of prevalent and incident HIV diagnoses in males, respectively. From 2006–2009 to 2010–2013, the prevalence of HIV diagnosis increased from 32% to 45% (P = 0.001) while the incidence of HIV diagnosis increased from 5.4 to 11.3 per 100 person-years (P = 0.001) among males with EHI. Incident HIV diagnosis was independently associated with a younger age, residing in metropolitan areas, hospitalization, previous syphilis, and engagement in oral, anal, or oral–anal sex before illness onset. Conclusions/significance: Prevalent and incident HIV diagnoses were increasingly identified among adult males in Taiwan, preferentially affecting younger urban MSM. Surveillance and risk-reduction interventions are recommended against the interplay of HIV epidemic and sexually transmitted EHI. © 2014 Lo et al.


Wang W.,Peking University | Pan K.,Peking University | Chen Y.,Peking University | Huang C.,China Medical University at Taichung | Zhang X.,Peking University
Nucleic Acids Research | Year: 2012

HBP1 is a sequence-specific DNA-binding transcription factor with many important biological roles. It activates or represses the expression of some specific genes during cell growth and differentiation. Previous studies have exhibited that HBP1 binds to p16 INK4A promoter and activates p16 INK4A expression. We found that trichostatin A (TSA), an inhibitor of HDAC (histone deacetylase), induces p16 INK4A expression in an HBP1-dependent manner. This result was drawn from a transactivation experiment by measuring relative luciferase activities of p16 INK4A promoter with HBP1-binding site in comparison with that of the wild-type p16 INK4A promoter by transient cotransfection with HBP1 into HEK293T cells and 2BS cells. HBP1 acetylation after TSA treatment was confirmed by immunoprecipitation assay. Our data showed that HBP1 interacted with histone acetyltransferase p300 and CREB-binding protein (CBP) and also recruited p300/CBP to p16 INK4A promoter. HBP1 was acetylated by p300/CBP in two regions: repression domain (K297/305/307) and P domain (K171/419). Acetylation of Repression domain was not required for HBP1 transactivation on p16 INK4A. However, luciferase assay and western blotting results indicate that acetylation of P domain, especially K419 acetylation is essential for HBP1 transactivation on p16 INK4A. As assayed by SA-beta-gal staining, the acetylation of HBP1 at K419 enhanced HBP1-induced premature senescence in 2BS cells. In addition, HDAC4 repressed HBP1-induced premature senescence through permanently deacetylating HBP1. We conclude that our data suggest that HBP1 acetylation at K419 plays an important role in HBP1-induced p16 INK4A expression. © 2011 The Author(s).


Huang S.-L.,National University of Kaohsiung | Jao C.-L.,Sudan University of Science and Technology | Ho K.-P.,China Medical University at Taichung | Hsu K.-C.,China Medical University at Taichung
Peptides | Year: 2012

The in vitro DPP-IV inhibitory activity of isolated peptides from of tuna cooking juice hydrolyzed by Protease XXIII (PR) and orientase (OR) was determined. The results showed that the peptide fractions with the molecular weight over 1422 Da possessed the greatest DPP-IV inhibitory activity. The amino acid sequences of the three peptides isolated from PR and OR hydrolysates were identified by MALDI-TOF/TOF MS/MS, and they were Pro-Gly-Val-Gly-Gly-Pro-Leu- Gly-Pro-Ile-Gly-Pro-Cys-Tyr-Glu (1412.7 Da), Cys-Ala-Tyr-Gln-Trp-Gln-Arg-Pro- Val-Asp-Arg-Ile-Arg (1690.8 Da) and Pro-Ala-Cys-Gly-Gly-Phe-Try-Ile-Ser-Gly-Arg- Pro-Gly (1304.6 Da), while they showed the dose-dependent inhibition effect of DPP-IV with IC 50 values of 116.1, 78.0 and 96.4 μM, respectively. In vitro simulated gastrointestinal digestion retained or even improved the DPP-IV inhibitory activities of the three peptides. The results suggest that tuna cooking juice would be a good precursor of DPP-IV inhibitor, and the DPP-IV inhibitory peptides can successfully passed through the digestive tract. © 2012 Elsevier Inc. All rights reserved.


Tsai Y.-G.,National Yang Ming University | Tsai Y.-G.,Chung Shan Medical University | Yang K.D.,Chang Gung University | Niu D.-M.,Taipei Veterans General Hospital | And 3 more authors.
Journal of Immunology | Year: 2010

Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8 + Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8 +CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8 +Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8 +CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8 +CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies. Copyright © 2010 by The American Association of Immunologists, Inc.


Chou E.C.L.,China Medical University at Taichung
Neurourology and Urodynamics | Year: 2010

Aims: This study aims to evaluate the voiding disorder and lower urinary tract symptoms in mentally retarded children. Methods: Fifty-one mentally retarded children (age 7.7 years) was assessed. A volunteer sample comprised of 36 typically developing children (age 6.4 years) served as the comparative group. All participants underwent uroflometric investigation, and residual urine was detected by sonography. Urological history including history of urinary tract infection, incontinence, frequency, and dysurea was collected. In addition, the mentally retarded group was classified according to IQ: severe mentally retarded group (IQ below 40) (n = 11), moderate mentally retarded group (IQ: 41 to 55) (n = 19), mild mentally retarded group (IQ: 56 to 70) (n = 21). Group comparisons were analyzed using Chi-square and Student's t-test. Results: Of the 51 mentally retarded children, 18(35.2%) were found to have voiding dysfunction, which is significantly higher than the control group (8.3%). The incidence of urine incontinence and frequency is also significantly higher in the mentally retarded group. The comparison of the three mentally retarded subgroups showed that the severe mentally retarded group had the highest incidence of voiding dysfunction and urinary incontinence. Overall, the mentally retarded group had higher percentage of small bladder capacity. Conclusions: We concluded that mentally retarded children have a higher incidence of voiding dysfunction and incontinence than the control group. Early detection of voiding dysfunction in an objective, non-invasive manner is important in mentally retarded children, particularly those with severe cognitive impairment. © 2010 Wiley-Liss, Inc.


Hsiao T.-C.,National Central University | Young L.-H.,China Medical University at Taichung | Tai Y.-C.,National Central University | Chen K.-C.,National Central University
Aerosol Science and Technology | Year: 2016

A hygroscopic tandem differential mobility analyzer (H-TDMA) and a hygroscopic coupled DMA and aerosol particle mass (H-DMA-APM) were coupled to examine aqueous film formation and the deliquescence behavior of inorganic nanoparticles. The two systems complement each other because H-DMA-APM measures mass change, while H-TDMA measures mobility diameter (volume) change of nanoparticles upon water uptake. The former mass change was, in particular, more capable to discern minute particle phase changes than the latter size change at moderate RHs. The mass and diameter changes were used to derive the particle effective density for evaluation of aqueous film formation on the nanoparticle surface before and after deliquescence transition. The measurements further showed that approximately 3–5 and 12–20 monolayer equivalents of water molecules formed on the respective surface of 50- and 100-nm inorganic aerosols (ammonium sulfate and sodium chloride) before deliquescence relative humidity (DRH). These findings support the physical basis of the coated-surface model given by Russell and Ming in 2002, and suggest that the phase transition of inorganic nanoparticles near deliquescence is a gradual process instead of an abrupt change. This phenomenon changed the surface energy values, thus confirming the explanation that the DRH of nanoparticles increases as the particle size decreases. This is the first direct observation of nanoparticle deliquescence phase transition using the H-DMA-APM system, and the detailed characterization of aqueous film formation on inorganic nanoparticles is feasible with the presented measurement systems. © 2016 American Association for Aerosol Research © 2016 American Association for Aerosol Research.


Chen T.-Y.,Academia Sinica, Taiwan | Chang Y.-H.,Academia Sinica, Taiwan | Hsu C.-L.,National Chiao Tung University | Wei K.-H.,National Chiao Tung University | And 3 more authors.
International Journal of Hydrogen Energy | Year: 2013

Replacing Pt by earth abundant catalysts is one of the most important tasks toward potential large-scale HER applications. Among many potential candidates, low cost and earth abundant transition metal dichalcogenides such as MoS 2 and WS2 have been promising as good H2 evolution electrocatalysts when they are engineered into the structures with active sites. In this work, we have performed systematic studies on the catalytic reactivity of both MoS2 and WS2 materials produced by one-step and scalable thermolysis from (NH4) 2WS4 and (NH4)2MoS4 precursors respectively. Structural analysis shows that these materials prepared at a higher thermolysis temperature exhibit higher crystallinity. The H 2 evolution electrocatalysts efficiency for the MoS2 prepared at a lower temperature is higher than those at higher temperatures, where amorphous MoS2 or S22- species instead of crystalline MoS2 is the main active site. By contrast, crystalline WS2 prepared at high temperature is identified to be the key reaction site. Both catalysts display excellent efficiency and durability as an electrocatalyst operating in acidic electrolytes. This work provides fundamental insights for further design and preparation of emergent metal dichalcogenide catalysts, beneficial for the development in clean energy. Copyright © 2012, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.


Liu Y.-L.,National Taiwan University Hospital | Yang P.-M.,National Taiwan University Hospital | Shun C.-T.,National Taiwan University Hospital | Wu M.-S.,National Taiwan University Hospital | And 2 more authors.
Autophagy | Year: 2010

Hepatocellular carcinoma (HCC ) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy. © 2010 Landes Bioscience.


Chuang T.-J.,Academia Sinica, Taiwan | Chen F.-C.,National Health Research Institute | Chen F.-C.,National Chiao Tung University | Chen F.-C.,China Medical University at Taichung
Molecular Biology and Evolution | Year: 2014

DNA methylation at CpG dinucleotides can significantly increase the rate of cytosine-to-thymine mutations and the level of sequence divergence. Although the correlations between DNA methylation and genomic sequence evolution have been widely studied, an unaddressed yet fundamental question is how DNA methylation is associated with the conservation of individual nucleotides in different sequence contexts. Here, we demonstrate that in mammalian exons, the correlations between DNA methylation and the conservation of individual nucleotides are dependent on the type of exonic sequence (coding or untranslated), the degeneracy of coding nucleotides, background selection pressure, and the relative position (first or nonfirst exon in the transcript) where the nucleotides are located. For untranslated and nonzero-fold degenerate nucleotides, methylated sites are less conserved than unmethylated sites regardless of background selection pressure and the relative position of the exon. For zero-fold degenerate (or nondegenerate) nucleotides, however, the reverse trend is observed in nonfirst coding exons and first coding exons that are under stringent background selection pressure. Furthermore, cytosine-to-thymine mutations at methylated zero-fold degenerate nucleotides are predicted to be more detrimental than those that occur at unmethylated nucleotides. As zero-fold and nonzero-fold degenerate nucleotides are very close to each other, our results suggest that the "functional resolution" of DNA methylation may be finer than previously recognized. In addition, the positive correlation between CpG methylation and the level of conservation at zero-fold degenerate nucleotides implies that CpG methylation may serve as an "indicator" of functional importance of these nucleotides. © 2013 The Author.


Wu C.-Y.,Taichung Veterans General Hospital | Wu C.-Y.,National Yang Ming University | Wu C.-Y.,China Medical University at Taichung | Wu C.-Y.,National Chung Hsing University | And 12 more authors.
Gastroenterology | Year: 2014

Background & Aims Treatment for hepatitis B virus infection reduces the risk of hepatocellular carcinoma (HCC). However, the long-term protective effects for subgroups of patients with chronic hepatitis B are unclear. Methods We conducted a retrospective nationwide cohort study using data from Taiwan's National Health Insurance Research Database (from January 1, 1997, through December 31, 2010). Cumulative incidences were calculated and multivariable analyses were carried out after adjusting for competing mortality. Propensity scores were used to match 21,595 patients with chronic hepatitis B who received nucleoside analogue therapy for at least 90 days (treated cohort) with 21,595 untreated patients with chronic hepatitis B (controls), who received hepatoprotectants for at least 90 days. Data were collected from the treated cohort for a mean period of 3.46 years and from controls for 5.24 years. Results The treated cohort had a significantly lower 7-year incidence of HCC (7.32%; 95% confidence interval [CI], 6.77%-7.87%) than controls (22.7%; 95% CI, 22.1%-23.3%; P <.001). After adjusting for competing mortality and other confounders, nucleos(t)ide analogue treatment was associated with a reduced risk of HCC, with an adjusted hazard ratio of 0.37 (95% CI, 0.34-0.39; P <.001). Sensitivity analyses confirmed the association between nucleos(t)ide analogue treatment and reduced risk of HCC. Age, sex, cirrhosis, and diabetes mellitus modified this association. Conclusions Based on a retrospective, nationwide study in Taiwan, nucleoside analogue therapy use is associated with reduced risk of HCC in patients with chronic hepatitis B virus infection. © 2014 by the AGA Institute.


Ho P.-J.,National Health Research Institute | Yen M.-L.,National Taiwan University Hospital | Tang B.-C.,National Health Research Institute | Chen C.-T.,National Health Research Institute | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2013

Aims: Mesenchymal stem cells (MSCs) with multilineage differentiation capacity and immunomodulatory properties are novel sources for cell therapy. However, in vitro expansion of these rare somatic stem cells leads to senescence, resulting in declines of differentiation and proliferative capacities. We therefore investigated the mechanisms mediating senescence in human fetal MSCs termed placenta-derived multipotent cells (PDMCs). Results: Long-term cultured PDMCs underwent senescence, with increased levels of hydrogen peroxide (H2O2; a reactive oxygen species), positive β-galactosidase staining, decreased sirtuin-1 expression, increased p21 expression, and cell cycle arrest at the G0/G1 phase. Senescent PDMCs also showed decreased osteogenic capacity. Mechanistically, increased p21 expression and proliferative decline were not due to elevated H2O2 levels nor mediated by p53. Instead, inhibition of protein kinase C (PKC)-α and-β in senescent PDMCs decreased p21 expression and reversed cell cycle arrest. H2O2 was involved in the alteration of differentiation potential, since scavenging of H2O 2 restored expression of c-MAF, an osteogenic and age-sensitive transcription factor, and osteogenic capacity in senescent PDMCs. Innovation: Our findings not only show the effects of senescence on MSCs, but also reveal mechanisms involved in mediating decreased proliferation and differentiation capacity. Moreover, targeting increased levels of H2O2 associated with senescence may reverse the decreased osteogenic capacity of senescent MSCs. Conclusion: Our study suggests that the two biological consequences of senescence, differentiation alteration, and proliferative decline, in fetal MSCs are distinctly regulated by the H2O 2-c-MAF and PKC-p21 pathways, respectively. Antioxid. Redox Signal. 18, 1895-1905. © 2013, Mary Ann Liebert, Inc.


Chien Y.-C.,China Medical University at Taichung | Jan C.-F.,National Taiwan University Hospital | Chiang C.-J.,National Taiwan University | Kuo H.-S.,U.S. Center for Disease Control and Prevention | And 3 more authors.
Hepatology | Year: 2014

Hepatitis B immunization has been documented to prevent fulminant hepatic failure (FHF) and hepatocellular carcinoma (HCC) by historical comparison studies in Taiwan. This study aimed to assess long-term risks and predictors of various liver diseases associated with incomplete immunization in 3.8 million vaccinees. Profiles of the National Hepatitis B Immunization Registry, National Cancer Registry, and National Death Certification Registry were linked to ascertain newly diagnosed cases of HCC and deaths from FHF and chronic liver diseases (CLDs) from infancy to early adulthood of 3,836,988 newborn vaccinees. Cox's proportional hazards models were used to estimate hazard ratios (HRs) for various risk predictors. There were 49 newly developed cases of HCC, 73 deaths from FHF, and 74 deaths from CLDs during the follow-up of 41,854,715 person-years. There were striking differences between unvaccinated and vaccinated newborns after the launch of a national immunization program for HCC incidence (0.293 vs. 0.117 per 100,000 person-years), FHF mortality (0.733 vs. 0.174 per 100,000 person-years), and CLD mortality (2.206 vs. 0.177 per 100,000 person-years). Among vaccinees, incomplete immunization was the most important risk predictor of HCC, FHF, and CLDs, showing an HR (95% confidence interval, P value) of 2.52 (1.25-5.05; P = 0.0094), 4.97 (3.05-8.11; P < 0.0001), and 6.27 (3.62-10.84; P < 0.0001), respectively, after adjustment for maternal hepatitis B serostatus. Conclusion: Hepatitis B immunization can significantly prevent the long-term risk of HCC, FHF, and CLDs from infancy to early adulthood. Incomplete immunization with hepatitis B immunoglobulin or vaccines was the most important risk predictor of the liver disease among vaccinees. (Hepatology 2014;60:125-132) © 2014 by the American Association for the Study of Liver Diseases.


Chen F.-C.,National Health Research Institute | Chen F.-C.,National Chiao Tung University | Chen F.-C.,China Medical University at Taichung | Liao B.-Y.,National Health Research Institute | And 3 more authors.
Molecular Biology and Evolution | Year: 2012

From studies investigating the differences in evolutionary rates between genes, gene compactness and gene expression level have been identified as important determinants of gene-level protein evolutionary rate, as represented by nonsynonymous to synonymous substitution rate (dN/dS) ratio. However, the causes of exon-level variances in dN/dS are less understood. Here, we use principal component regression to examine to what extent 13 exon features explain the variance in dN, dS, and the dN/dS ratio of human-rhesus macaque or human-mouse orthologous exons. The exon features were grouped into six functional categories: expression features, mRNA splicing features, structural-functional features, compactness features, exon duplicability, and other features, including G + C content and exon length. Although expression features are important for determining dN and dN/dS between exons of different genes, structural-functional features and splicing features explained more of the variance for exons of the same genes. Furthermore, we show that compactness features can explain only a relatively small percentage of variance in exon-level dN or dN/dS in either between-gene or within-gene comparison. By contrast, dS yielded inconsistent results in the human-mouse comparison and the human-rhesus macaque comparison. This inconsistency may suggest rapid evolutionary changes of the mutation landscape in mammals. Our results suggest that between-gene and within-gene variation in dN/dS (and dN) are driven by different evolutionary forces and that the role of mRNA splicing in causing the variation in evolutionary rates of coding sequences may be underappreciated. © 2012 The Author.


Chen P.-C.,National Chung Hsing University | Lin T.-H.,Buddhist Tzu Chi General Hospital Taichung Branch | Lin T.-H.,China Medical University at Taichung | Cheng H.-C.,National Chung Hsing University | Tang C.-H.,China Medical University at Taichung
Carcinogenesis | Year: 2012

Nephroblastoma overexpressed (NOV or CCN3) is a secreted matrix-associated protein that belongs to the CCN gene family and is involved in many cellular functions, including growth, differentiation and adhesion. The effect of CCN3 on human prostate cancer cells, however, is unknown. Here, we have shown that CCN3 increased cell migration and intercellular adhesion molecule-1 (ICAM-1) expression in prostate cancer cells. In addition, expression of CCN3 was positively correlated with both cell migration and ICAM-1 expression in human prostate cancer cells. CCN3 activated a signal transduction pathway that included αvβ3 integrin, integrin-linked kinase (ILK), Akt and nuclear factor-kappaB (NF-κB). Reagents that inhibit specific components of this pathway each diminished the ability of CCN3 to effect cell migration and ICAM-1 expression. Moreover, CCN3 increased binding of p65 to an NF-κB-binding element in the ICAM-1 promoter. Finally, knockdown of CCN3 expression markedly inhibited cell migration, tumor growth in bone and bone metastasis. Taken together, our results indicate that CCN3 enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves αvβ3 integrin, ILK, Akt and NF-κB. CCN3 thus represents a promising new target for treating prostate cancer. © The Author 2012. Published by Oxford University Press. All rights reserved.


Yang W.-H.,National Yang Ming University | Lan H.-Y.,National Yang Ming University | Huang C.-H.,Taiwan Advance Biopharm | Huang C.-H.,Hungkuang University | And 8 more authors.
Nature Cell Biology | Year: 2012

Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin. © 2012 Macmillan Publishers Limited. All rights reserved.


Tang C.-H.,China Medical University at Taichung | Yamamoto A.,China Medical University at Taichung | Fong Y.-C.,China Medical University at Taichung | Tan T.-W.,China Medical University at Taichung
Biochemical Pharmacology | Year: 2010

CCL5 (previously called RANTES) was originally recognized as a product of activated T cells, and plays a crucial role in the migration and metastasis of human cancer cells. It has been reported that the effect of CCL5 is mediated via CCR receptors. We found that human chondrosarcoma tissues had significant expression of the CCL5 and CCR5, which was higher than that in normal cartilage. We also found CCL5 increased the migration and matrix metalloproteinases-3 (MMP)-3 expression in human chondrosarcoma cells (JJ012 cells). In addition, MMP-3 small interfering RNA and inhibitor inhibited the CCL5-induced cell migration. Activations of phosphatidylinositol 3-kinase (PI3K), Akt and NF-κB pathways after CCL5 treatment was demonstrated, and CCL5-induced expression of MMP-3 and migration activity was inhibited by the specific inhibitor of PI3K, Akt and NF-κB cascades. Taken together, these results indicate that CCL5 and CCR5 interaction enhanced migration of chondrosarcoma cells through the increase of MMP-3 production. © 2009 Elsevier Inc. All rights reserved.


Chen H.-F.,Far Eastern Memorial Hospital | Chen P.,Central Medicine Hospital Group | Li C.-Y.,China Medical University at Taichung
Hepatology | Year: 2010

We prospectively investigated 615,532 diabetic patients and 614,871 age-matched and sex-matched control subjects selected from National Health Insurance claims for malignant neoplasms of liver and biliary tract (International Statistical Classification of Diseases and Related Health Problems, 9th edition, codes 155 and 156, respectively) between 2000 and 2006. The person-year approach with Poisson assumption was used to estimate the hazard rates. We also evaluated the age-specific and sex-specific relative risks of these two malignancies in relation to diabetes with Cox proportional hazard regression model with adjustment for potential confounders. The overall hazard rate of malignant neoplasm of the liver was 32.76 and 17.41 per 10,000 patient-years, respectively, for diabetic men and women; the corresponding figures for biliary tract neoplasm were much lower at 1.42 and 1.60 per 10,000 patient-years. Compared with control subjects, diabetic patients had a two-fold increased risk of malignant neoplasm of the liver, but this risk was attenuated by adjusting for selected clinical risk factors (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.17-1.25). Additionally, diabetic patients were associated with increased risk of biliary neoplasms with an approximate magnitude of 20%-30%, but the HR was attenuated and became insignificant after adjustment for clinical risk factors (HR 1.07; 95% CI 0.95-1.21). Diabetic patients with cirrhosis had the highest relative risk of liver neoplasm (HR 85.25; 95% CI 76.84-94.58), whereas those with cholangitis had the highest risk of biliary tract neoplasm (HR 70.30; 95% CI 51.95-95.12) compared with control subjects without any clinical risk factors. Conclusion: This population-based study confirms the association of diabetes with liver neoplasm and suggests that diabetic patients with certain clinical risk factors should be educated for strict adherence of liver neoplasm screening. Copyright © 2010 by the American Association for the Study of Liver Diseases.


Lee C.-C.,China Medical University at Taichung | Huang H.-Y.,National Taiwan University | Chiang B.-L.,National Taiwan University | Chiang B.-L.,National Taiwan University Hospital
Human Gene Therapy | Year: 2011

Interleukin (IL)-4 and IL-13 are two key cytokines released from activated T helper type 2 (Th2) cells and strongly associated with asthma and allergic disease. We applied silencing of the IL-4 and IL-13 gene expression by RNA interference delivered by a lentiviral vector to evaluate the therapeutic role of IL-4 and IL13 short hairpin RNAs (shRNAs) in a murine model of asthma. Mice were sensitized with ovalbumin (OVA), and one treatment of IL-4 and IL-13 shRNA lentiviral vector (Lenti-si-IL-4 and Lenti-si-IL-13) was instilled intratracheally 48 hr before challenge. After three challenges of OVA antigen, mice were assessed for airway inflammation and hyperresponsiveness. With infection of Lenti-si-IL-4 and Lenti-si-IL-13 in EL-4 cells, both RNA and protein expressions of IL-4 and IL-13 were obviously abrogated. Furthermore, intratracheal instillation of Lenti-si-IL-4 and Lenti-si-IL-13 in OVA-immunized mice resulted in a strong inhibition of local IL-4 and IL-13 cytokine release. Treatment with Lenti-si-IL-4 and Lenti-si-IL-13 successfully alleviated OVA-induced airway eosinophilia and Th2 cell cytokine release. Finally, to determine airway hyperresponsiveness by enhanced pause and pulmonary resistance in noninvasive and invasive body plethysmography, we found that administration of Lenti-si- IL-4 and Lenti-si-IL-13 markedly decreased airway hyperresponsiveness in OVA-immunized mice. These results suggest that inhibition of IL-4 and IL-13 gene expression by shRNA lentiviral vector markedly inhibits antigeninduced airway inflammation and hyperresponsi eness in mice. © 2011 Mary Ann Liebert, Inc.


Li-Chan E.C.Y.,University of British Columbia | Hunag S.-L.,National University of Kaohsiung | Jao C.-L.,Sudan University of Science and Technology | Ho K.-P.,China Medical University at Taichung | Hsu K.-C.,China Medical University at Taichung
Journal of Agricultural and Food Chemistry | Year: 2012

The dipeptidyl-peptidase IV (DPP-IV)-inhibitory activity of peptides derived from Atlantic salmon skin gelatin hydrolyzed by alcalase (ALA), bromelain (BRO), and Flavourzyme (FLA) was determined. The FLA hydrolysate with the enzyme/substrate ratio of 6% showed the greatest DPP-IV-inhibitory activity. The hydrolysate was fractionated by ultrafiltration with 1 and 2.5 kDa cutoff membranes, and the <1 kDa fraction had the highest DPP-IV-inhibitory activity with an IC 50 value of 1.35 mg/mL. The F-1 fraction further isolated by HPLC showed the IC 50 value against DPP-IV of 57.3 μg/mL, and the peptide sequences were identified as Gly-Pro-Ala-Glu (372.4 Da) and Gly-Pro-Gly-Ala (300.4 Da). The synthetic peptides showed dose-dependent inhibition effects on DPP-IV with IC 50 values of 49.6 and 41.9 μM, respectively. The results suggest that the peptides derived from Atlantic salmon skin gelatin would be beneficial ingredients for functional foods or pharmaceuticals against type 2 diabetes. © 2012 American Chemical Society.


Loan P.T.K.,National Chiao Tung University | Zhang W.,Academia Sinica, Taiwan | Lin C.-T.,Academia Sinica, Taiwan | Wei K.-H.,National Chiao Tung University | And 3 more authors.
Advanced Materials | Year: 2014

The photoluminescence signals of a graphene/MoS2 heterostructural stacking film are sensitive to environmental charges, which allows the single-base sequence-selective detection of DNA hybridization with sensitivity to the level of aM. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Chang Y.-H.,Academia Sinica, Taiwan | Wu F.-Y.,Academia Sinica, Taiwan | Chen T.-Y.,Academia Sinica, Taiwan | Hsu C.-L.,Academia Sinica, Taiwan | And 7 more authors.
Small | Year: 2014

Electroactive MoSx catalysts on porous 3D sponges synthezied by a simple and scalable thermolysis process are proposed. Although no conducting materials are used to host the MoSx catalysts, they still serve as efficient electrodes for hydrogen evolution. The high current density of the MoSx-coated sponges are attributed to the large electrochemical surface area and their S-rich chemical structure. © 2013 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim.


Lin E.,China Medical University at Taichung | Lin E.,Vita Genomics Inc. | Tsai S.-J.,Taipei Veterans General Hospital | Tsai S.-J.,National Yang Ming University
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2016

Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy. © 2015 Elsevier Inc.


Chen H.-C.,U.S. Food and Drug Administration | Kodell R.L.,University of Arkansas for Medical Sciences | Cheng K.F.,China Medical University at Taichung | Chen J.J.,U.S. Food and Drug Administration | Chen J.J.,China Medical University at Taichung
BMC Medical Research Methodology | Year: 2012

Background: Cancer survival studies are commonly analyzed using survival-time prediction models for cancer prognosis. A number of different performance metrics are used to ascertain the concordance between the predicted risk score of each patient and the actual survival time, but these metrics can sometimes conflict. Alternatively, patients are sometimes divided into two classes according to a survival-time threshold, and binary classifiers are applied to predict each patients class. Although this approach has several drawbacks, it does provide natural performance metrics such as positive and negative predictive values to enable unambiguous assessments. Methods: We compare the survival-time prediction and survival-time threshold approaches to analyzing cancer survival studies. We review and compare common performance metrics for the two approaches. We present new randomization tests and cross-validation methods to enable unambiguous statistical inferences for several performance metrics used with the survival-time prediction approach. We consider five survival prediction models consisting of one clinical model, two gene expression models, and two models from combinations of clinical and gene expression models. Results: A public breast cancer dataset was used to compare several performance metrics using five prediction models. 1) For some prediction models, the hazard ratio from fitting a Cox proportional hazards model was significant, but the two-group comparison was insignificant, and vice versa. 2) The randomization test and crossvalidation were generally consistent with the p-values obtained from the standard performance metrics. 3) Binary classifiers highly depended on how the risk groups were defined; a slight change of the survival threshold for assignment of classes led to very different prediction results. Conclusions: 1) Different performance metrics for evaluation of a survival prediction model may give different conclusions in its discriminatory ability. 2) Evaluation using a high-risk versus low-risk group comparison depends on the selected risk-score threshold; a plot of p-values from all possible thresholds can show the sensitivity of the threshold selection. 3) A randomization test of the significance of Somers rank correlation can be used for further evaluation of performance of a prediction model. 4) The cross-validated power of survival prediction models decreases as the training and test sets become less balanced. © 2012 Chen et al.; licensee BioMed central Ltd.


Liu S.-H.,National Yunlin University of Science and Technology | Shu C.-M.,Health 123 | Shu C.-M.,China Medical University at Taichung
Journal of Loss Prevention in the Process Industries | Year: 2015

In 2011, a large petrochemical complex in Taiwan incurred several fire and explosion accidents, which had considerable negative impact for the industry on both environmental and safety issues. Reactive substances are widely used in many chemical industrial fields as an initiator, hardeners, or cross-linking agents of radical polymerization process with unsaturated monomer. However, the unpredictable factors during the process having risk to runaway reaction, thermal explosion, fire, and exposure to harmful toxic chemicals release due to the huge heat and gas products by thermal decomposition could not be removed from the process. This study used differential technology of thermal analysis to characterize the inherent hazard behaviors of azo compounds and organic peroxides in the process, to seek the elimination of the source of the harmful effects and achieve the best process safety practices with zero disaster and sound business continuity plan. © 2014 Elsevier Ltd.


Chien K.-L.,National Taiwan University | Chien K.-L.,National Taiwan University Hospital | Chen P.-C.,China Medical University at Taichung | Hsu H.-C.,National Taiwan University Hospital | And 5 more authors.
Sleep | Year: 2010

Study Objectives: To investigate the relationship between sleep duration and insomnia severity and the risk of all-cause death and cardiovascular disease (CVD) events Design: Prospective cohort study Setting: Community-based Participants: A total of 3,430 adults aged 35 years or older Intervention: None Measurements and Results: During a median 15.9 year (interquartile range, 13.1 to 16.9) follow-up period, 420 cases developed cardiovascular disease and 901 cases died. A U-shape association between sleep duration and all-cause death was found: the age and gender-adjusted relative risks (95% confidence interval [CI]) of all-cause death (with 7 h of daily sleep being considered for the reference group) for individuals reporting ≤ 5 h, 6 h, 8 h, and ≥ 9 h were 1.15 (0.91-1.45), 1.02 (0.85-1.25), 1.05 (0.88-1.27), and 1.43 (1.16-1.75); P for trend, 0.019. However, the relationship between sleep duration and risk of CVD were linear. The multivariate-adjusted relative risk (95% CI) for all-cause death (using individuals without insomnia) were 1.02 (0.86-1.20) for occasional insomnia, 1.15 (0.92-1.42) for frequent insomnia, and 1.70 (1.16-2.49) for nearly everyday insomnia (P for trend, 0.028). The multivariate adjusted relative risk (95% CI) was 2.53 (1.71-3.76) for all-cause death and 2.07 (1.11-3.85) for CVD rate in participants sleeping ≥9 h and for those with frequent insomnia. Conclusions: Sleep duration and insomnia severity were associated with all-cause death and CVD events among ethnic Chinese in Taiwan. Our data indicate that an optimal sleep duration (7-8 h) predicted fewer deaths.


Hou C.-H.,National Taiwan University Hospital | Tang C.-H.,China Medical University at Taichung | Hsu C.-J.,China Medical University at Taichung | Hou S.-M.,Shin Kong Wu Ho Su Memorial Hospital | Liu J.-F.,Shin Kong Wu Ho Su Memorial Hospital
Arthritis Research and Therapy | Year: 2012

Introduction: Osteoarthritis (OA) is the most common degenerative joint disease that is involved in the degradation of articular cartilage. The exact etiology of OA is not completely understood. CCN4 is related to up-regulation in the cartilage of patients with osteoarthritis. Previous studies have shown that CCN4 might be associated with the pathogenesis of OA, but the exact signaling pathways in CCN4-mediated IL-6 expression in synovial fibroblasts (SF) are largely unknown. Therefore, we explored the intracellular signaling pathway involved in CCN4-induced IL-6 production in human synovial fibroblast cells.Methods: CCN4-induced IL-6 production was assessed with quantitative real-time qPCR and ELISA. The mechanisms of action of CCN4 in different signaling pathways were studied by using Western blotting. Neutralizing antibodies of integrin were used to block the integrin signaling pathway. Luciferase assays were used to study IL-6 and NF-κB promoter activity. Immunocytochemistry was used to examine the translocation activity of p65.Results: Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCN4 and the expression was higher than in normal SFs. OASF stimulation with CCN4 induced concentration- and time-dependent increases in IL-6 production. Pretreatment of OASFs with αvβ5 but not α5β1 and αvβ3 integrin antibodies reduced CCN4-induced IL-6 production. CCN4-mediated IL-6 production was attenuated by PI3K inhibitor (LY294002 and Wortmannin), Akt inhibitor (Akti), and NF-κB inhibitor (PDTC and TPCK). Stimulation of cells with CCN4 also increased PI3K, Akt, and NF-κB activation.Conclusions: Our results suggest that CCN4 activates αvβ5 integrin, PI3K, Akt, and NF-κB pathways, leading to up-regulation of IL-6 production. According to our results, CCN4 may be an appropriate target for drug intervention in OA in the future. © 2013 Hou et al.; licensee BioMed Central Ltd.


Huang L.-P.,National Kaohsiung First University of Science and Technology | Lee C.-C.,National Cheng Kung University | Hsu P.-C.,National Kaohsiung First University of Science and Technology | Shih T.-S.,Institute of Occupational Safety and Health | Shih T.-S.,China Medical University at Taichung
Fertility and Sterility | Year: 2011

Objective: To investigate potential associations between semen quality in workers and the concentrations of di(2-ethylhexyl) phthalate (DEHP) in personal air collected from polyvinyl chloride (PVC) plants. Design: Cross-sectional study. Setting: PVC plants in Taiwan. Patient(s): Forty-five male workers employed in two PVC pellet plants. Intervention(s): None. Main Outcome Measurement(s): Sperm concentration, motility, morphology, and chromatin DNA integrity were accessed. Result(s): The workers were divided into low- and high-DEHP-exposed groups in accordance with the median levels of DEHP (23.7 μg/m3) in personal air. In the high-DEHP-exposed group, significant increases were found in the tendency for sperm DNA denaturation (αT) induction, the DNA fragmentation index (DFI), and propensity for coffee drinking. After adjusting for coffee drinking, cigarette smoking, and age, personal air concentrations of DEHP showed positive associations with αT (β = 0.038) and DFI (β = 0.140) and negative associations with sperm motility (β = -0.227). Conclusion(s): This is the first study to demonstrate a link between DEHP concentration in ambient air and the adverse effects in sperm motility and chromatin DNA integrity. Given the current wide use of these PVC products, the implications for phthalates toxicity and occupational health could be considerable. © 2011 by American Society for Reproductive Medicine.


Hsu F.-L.,Taipei Medical University | Huang C.-F.,China Medical University at Taichung | Chen Y.-W.,China Medical University at Taichung | Yen Y.-P.,National Taiwan University | And 5 more authors.
Diabetes | Year: 2013

The therapeutic effect of pterosin A, a small-molecular-weight natural product, on diabetes was investigated. Pterosin A, administered orally for 4 weeks, effectively improved hyperglycemia and glucose intolerance in streptozotocin, high-fat dietfed, and db/db diabetic mice. There were no adverse effects in normal or diabetic mice treated with pterosin A for 4 weeks. Pterosin A significantly reversed the increased serum insulin and insulin resistance (IR) in dexamethasone-IR mice and in db/db mice. Pterosin A significantly reversed the reduced muscle GLUT-4 translocation and the increased liver phosphoenolpyruvate carboxyl kinase (PEPCK) expression in diabetic mice. Pterosin A also significantly reversed the decreased phosphorylations of AMP-activated protein kinase (AMPK) and Akt in muscles of diabetic mice. The decreased AMPK phosphorylation and increased p38 phosphorylation in livers of db/db mice were effectively reversed by pterosin A. Pterosin A enhanced glucose uptake and AMPK phosphorylation in cultured human muscle cells. In cultured liver cells, pterosin A inhibited inducerenhanced PEPCK expression, triggered the phosphorylations of AMPK, acetyl CoA carboxylase, and glycogen synthase kinase-3, decreased glycogen synthase phosphorylation, and increased the intracellular glycogen level. These findings indicate that pterosin A may be a potential therapeutic option for diabetes. © 2013 by the American Diabetes Association.


Cheng J.-C.,China Medical University at Taichung | Yeh Y.-J.,China Medical University at Taichung | Yeh Y.-J.,National Chiao Tung University | Tseng C.-P.,Chang Gung University | And 4 more authors.
Cellular and Molecular Life Sciences | Year: 2012

The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cellbased systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5′-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7bmediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFNα-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy. © Springer Basel AG 2012.


Liao C.-C.,Taipei Medical University Hospital | Liao C.-C.,Taipei Medical University | Lin C.-S.,Taipei Medical University Hospital | Lin C.-S.,Taipei Medical University | And 6 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: The relationship between diabetes and fracture is not completely understood. This study evaluated fracture risk and postfracture mortality in patients with diabetes. RESEARCH DESIGN AND METHODS: We identified 32,471 adults newly diagnosed with diabetes in 2000-2003 using Taiwan's National Health Insurance Research Database. A comparison cohort of 64,942 adults without diabetes was randomly selected from the same dataset, with frequency matched by age and sex. Fracture events in 2000-2008 were ascertained from medical claims. Adjusted hazard ratios (HRs) and 95% CIs of fracture associated with diabetes were calculated. A nested cohort study of 17,002 patients with fracture receiving repair surgeries between 2004 and 2010 calculated adjusted odds ratios (ORs) and 95% CIs of adverse events after fracture in patients with and without diabetes. RESULTS: During 652,530 person-years of follow-up, there were 12,772 newly diagnosed fracture cases. The incidences of fracture for people with diabetes and without were 24.2 and 17.1 per 1,000 person-years, respectively (P < 0.0001). Compared with people without diabetes, the adjusted HR of fracture was 1.66 (95% CI 1.60-1.72) for people with diabetes. The ORs of postfracture deep wound infection, septicemia, and mortality associated with diabetes were 1.34 (95% CI 1.06-1.71), 1.42 (95% CI 1.23-1.64), and 1.27 (95% CI 1.02-1.60), respectively. CONCLUSIONS: Diabetes was associated with fracture. Patients with diabetes had more adverse events and subsequent mortality after fracture. Prevention of fracture and postfracture adverse events is needed in this susceptible population. © 2014 by the American Diabetes Association.


Pan H.-A.,National Chiao Tung University | Hung Y.-C.,China Medical University at Taichung | Sui Y.-P.,National Chiao Tung University | Huang G.S.,National Chiao Tung University
Biomaterials | Year: 2012

Cardiovascular stents require optimised control for the enhancement or inhibition epithelial and smooth muscle cell growth in close contact with the implant. Here we propose that the surface topology in contact with the living cells could be designed to control and optimise the growth and function of such cells. The cardiomyoblast H9c2 was cultured on nanodot arrays with dot diameters ranging between 10 and 200 nm. On the 50-nm nanodot arrays H9c2 showed maximum attachment and proliferation with largest cell area and extended lamellipodia. In contrast, 53.7% and 72.6% reductions of growth were observed on the 100- and 200-nm nanodot arrays after 3 days. Immunostaining indicated that nanodots smaller than 50-nm induced cell adhesion and cytoskeleton organization. Expression of genes associated with fibrosis and hypertrophy was up-regulated in cells grown on 100-nm nanodots. Western blot data showed high levels of expression for vinculin and plasminogen activator inhibitor-1 for cells cultured on 50-nm nanodots. Nanotopography controls cell adhesion, morphology and proliferation. By adjusting the diameter of the nanodots, we could modulate the growth and expression of function-related genes and proteins of H9c2 cardiomyoblasts. The current study provides insights for improved design of artificial implants and parameters that affect biocompatibility. © 2011 Elsevier Ltd.


Hou C.-H.,National Taiwan University Hospital | Hou C.-H.,National Taiwan University | Chiang Y.-C.,China Medical University at Taichung | Fong Y.-C.,China Medical University at Taichung | Tang C.-H.,China Medical University at Taichung
Biochemical Pharmacology | Year: 2011

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins. However, the effect of WISP-1 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that WISP-1 increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells (JJ012 cells). We also found that human chondrosarcoma tissues had significant expression of the WISP-1 which was higher than that in normal cartilage. α5β1 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) inhibited the WISP-1-induced increase of the migration and MMP-2 up-regulation of chondrosarcoma cells. WISP-1 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK and extracellular signal-regulated kinase (ERK). In addition, NF-κB inhibitors also suppressed the cell migration and MMP-2 expression enhanced by WISP-1. Moreover, WISP-1 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-2 promoter. Taken together, our results indicated that WISP-1 enhances the migration of chondrosarcoma cells by increasing MMP-2 expression through the α5β1 integrin receptor, FAK, MEK, ERK, p65 and NF-κB signal transduction pathway. © 2011 Elsevier Inc. All rights reserved.


Liao C.-C.,Taipei Medical University | Liao C.-C.,Taipei Medical University Hospital | Su T.-C.,National Taiwan University Hospital | Sung F.-C.,China Medical University at Taichung | And 4 more authors.
PLoS ONE | Year: 2012

Background: The relationship between hepatitis C virus infection and risk of stroke remains inconsistent. This study evaluates the risk of stroke in association with chronic hepatitis C infection in a longitudinal population-based cohort. Methods: We identified 4,094 adults newly diagnosed with hepatitis C infection in 2002-2004 from the Taiwan National Health Insurance Research Database. Comparison group consisted of 16,376 adults without hepatitis C infection randomly selected from the same dataset, frequency matched by age and sex. Events of stroke from 2002-2008 were ascertained from medical claims (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM, codes 430-438). Multivariate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for potential associated factors including HCV infection, age, sex, low-income status, urbanization, cessation of cigarette smoking, alcohol-related illness, obesity, history of chronic diseases and medication use. Findings: During 96,752 person-years of follow-up, there were 1981 newly diagnosed stroke cases. The HRs of stroke associated with medical conditions such as hypertension, diabetes and heart disease were 1.48 (95% CI 1.33 to 1.65), 1.23 (95% CI 1.11 to 1.36) and 1.17 (95% CI 1.06 to 1.30), respectively, after adjustment for covariates. The cumulative risk of stroke for people with hepatitis C and without hepatitis C infections was 2.5% and 1.9%, respectively (p<0.0001). Compared with people without hepatitis C infection, the adjusted HR of stroke was 1.27 (95% CI 1.14 to 1.41) for people with hepatitis C infection. Conclusion: Chronic hepatitis C infection increases stroke risk and should be considered an important and independent risk factor. © 2012 Liao et al.


Liu J.,Academia Sinica, Taiwan | Yang H.-I.,Academia Sinica, Taiwan | Yang H.-I.,China Medical University at Taichung | Lee M.-H.,National Yang Ming University | And 9 more authors.
Gut | Year: 2014

Background and aims: The associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined by a prospective study using serially measured seromarkers. This study aimed to assess the importance of spontaneous HBeAg, HBV DNA and HBsAg seroclearance in the prediction of HCC risk. Methods: This study included 2946 HBsAg seropositive individuals who were seronegative for antibodies against HCV and free of liver cirrhosis. Serial serum samples collected at study entry and follow-up health examinations were tested for HBeAg, HBV DNA and HBsAg. Cox proportional hazards models were used to calculate the HRs of developing HCC after seroclearance of HBV markers. Results: The HR (95% CI) of developing HCC after seroclearance of HBeAg, HBV DNA and HBsAg during follow-up was 0.63 (0.38 to 1.05), 0.24 (0.11 to 0.57) and 0.18 (0.09 to 0.38), respectively, after adjustment for age, gender and serum level of alanine aminotransferase at study entry. High HBV DNA levels at the seroclearance of HBeAg (mean±SD, 4.35±1.64 log10 IU/mL) may explain the non-significant association between HBeAg seroclearance and HCC risk. Among HBeAg seronegative participants with detectable serum HBV DNA at study entry, the lifetime (30-75-years-old) cumulative incidence of HCC was 4.0%, 6.6% and 14.2%, respectively, for those with seroclearance of both HBV DNA and HBsAg, seroclearance of HBV DNA only, and seroclearance of neither. Conclusions: Spontaneous seroclearance of HBV DNA and HBsAg are important predictors of reduced HCC risk. © 2014, BMJ Publishing Group. All rights reserved.


Siu L.K.,National Health Research Institute | Siu L.K.,China Medical University at Taichung | Yeh K.-M.,Tri Service General Hospital | Lin J.-C.,Tri Service General Hospital | And 2 more authors.
The Lancet Infectious Diseases | Year: 2012

Klebsiella pneumoniae is a well known human nosocomial pathogen. Most community-acquired . K pneumoniae infections cause pneumonia or urinary tract infections. During the past two decades, however, a distinct invasive syndrome that causes liver abscesses has been increasingly reported in Asia, and this syndrome is emerging as a global disease. In this Review, we summarise the clinical presentation and management as well the microbiological aspects of this invasive disease. Diabetes mellitus and two specific capsular types in the bacterium predispose a patient to the development of liver abscesses and the following metastatic complications: bacteraemia, meningitis, endophthalmitis, and necrotising fasciitis. For patients with this invasive syndrome, appropriate antimicrobial treatment combined with percutaneous drainage of liver abscesses increases their chances of survival. Rapid detection of the hypervirulent strain that causes this syndrome allows earlier diagnosis and treatment, thus minimising the occurrence of sequelae and improving clinical outcomes. © 2012 Elsevier Ltd.


Hu S.,Peking University | Hu S.,University of Rochester | Li L.,University of Rochester | Yeh S.,University of Rochester | And 6 more authors.
Molecular Oncology | Year: 2015

Early clinical studies suggested infiltrating T cells might be associated with poor outcomes in prostate cancer (PCa) patients. The detailed mechanisms how T cells contribute to PCa progression, however, remained unclear. Here, we found PCa cells have a better capacity to recruit more CD4(+) T cells than the surrounding normal prostate cells via secreting more chemokines-CXCL9. The consequences of more recruited CD4(+) T cells to PCa might then lead to enhance PCa cell invasion. Mechanism dissection revealed that infiltrating CD4(+) T cells might function through the modulation of FGF11→miRNA-541 signals to suppress PCa androgen receptor (AR) signals. The suppressed AR signals might then alter the MMP9 signals to promote the PCa cell invasion. Importantly, suppressed AR signals via AR-siRNA or anti-androgen Enzalutamide in PCa cells also enhanced the recruitment of T cells and the consequences of this positive feed back regulation could then enhance the PCa cell invasion. Targeting these newly identified signals via FGF11-siRNA, miRNA-541 inhibitor or MMP9 inhibitor all led to partially reverse the enhanced PCa cell invasion. Results from invivo mouse models also confirmed the invitro cell lines in co-culture studies. Together, these results concluded that infiltrating CD4(+) T cells could promote PCa metastasis via modulation of FGF11→miRNA-541→AR→MMP9 signaling. Targeting these newly identified signals may provide us a new potential therapeutic approach to better battle PCa metastasis. © 2014 Federation of European Biochemical Societies.


Lai M.-N.,National Taiwan University | Wang S.-M.,National Taiwan University Hospital | Chen P.-C.,National Taiwan University | Chen Y.-Y.,China Medical University at Taichung | And 2 more authors.
Journal of the National Cancer Institute | Year: 2010

Background: Consumption of Chinese herbs that contain aristolochic acid (eg, Mu Tong) has been associated with an increased risk of urinary tract cancer. Methods: We conducted a population-based case-control study in Taiwan to examine the association between prescribed Chinese herbal products that contain aristolochic acid and urinary tract cancer. All patients newly diagnosed with urinary tract cancer (case subjects) from January 1, 2001, to December 31, 2002, and a random sample of the entire insured population from January 1, 1997, to December 31, 2002 (control subjects), were selected from the National Health Insurance reimbursement database. Subjects who were ever prescribed more than 500 pills of nonsteroidal anti-inflammatory drugs and/or acetaminophen were excluded, leaving 4594 case patients and 174701 control subjects in the final analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multivariable logistic regression models for the association between prescribed Chinese herbs containing aristolochic acid and the occurrence of urinary tract cancer. Models were adjusted for age, sex, residence in a township where black foot disease was endemic (an indicator of chronic arsenic exposure from drinking water [a risk factor for urinary tract cancer]), and history of chronic urinary tract infection. Statistical tests were two-sided. Results: Having been prescribed more than 60 g of Mu Tong and an estimated consumption of more than 150 mg of aristolochic acid were independently associated with an increased risk for urinary tract cancer in multivariable analyses (Mu Tong: at 61-100 g, OR = 1.6, 95% CI = 1.3 to 2.1, and at >200 g, OR = 2.1, 95% CI = 1.3 to 3.4; aristolochic acid: at 151-250 mg, OR = 1.4, 95% CI = 1.1 to 1.8, and at >500 mg, OR = 2.0, 95% CI = 1.4 to 2.9). A statistically significant linear dose-response relationship was observed between the prescribed dose of Mu Tong or the estimated cumulative dose of aristolochic acid and the risk of urinary tract cancer (P <. 001 for both). Conclusions: Consumption of aristolochic acid-containing Chinese herbal products is associated with an increased risk of cancer of the urinary tract in a dose-dependent manner that is independent of arsenic exposure.


Lee Y.L.,National Taiwan University | Wang W.-H.,National Taiwan University | Lu C.-W.,National Taiwan University Hospital | Lin Y.-H.,National Taiwan University | Hwang B.-F.,China Medical University at Taichung
International Journal of Hygiene and Environmental Health | Year: 2011

Literature has shown adverse effects of ambient air pollution exposure on various asthma related outcomes in childhood. However, the associated evidence on pulmonary function effects is still inconsistent.We conducted a population-based study comprised of seventh-grade children in 14 Taiwanese communities. Pulmonary function tests and questionnaires were completed on 3957 subjects. We evaluated the effects of ambient air pollution exposures based on the data collected in 2005-2007 by existing air monitoring stations. Multiple linear mixed effect models were fitted to estimate the relationship between community pollutant levels and pulmonary function indices. After adjustment for individual-level confounders, pulmonary function differed only slightly between communities with different levels of air pollution. We found greater effects of ambient air pollutants on pulmonary function for boys than for girls. Among boys, traffic-related pollutants CO, NOx, NO 2, and NO were generally associated with chronic adverse effects on FVC and FEV 1, and subchronic adverse effects mainly on maximal mid-expiratory flow (MMEF) and peak expiratory flow rate. Among girls, only NOx and NO 2 showed subchronic adverse effects on MMEF. Although effect estimates of SO 2, PM 10, and PM 2.5 were generally negative for boys, none achieved statistical significance.Our data suggests that ambient traffic-related pollution had chronic adverse effects on pulmonary function in schoolchildren, especially for boys. © 2011 Elsevier GmbH.


Yeh C.-C.,China Medical University at Taichung | Liao C.-C.,Taipei Medical University Hospital | Liao C.-C.,Taipei Medical University | Chang Y.-C.,National Taiwan University Hospital | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVE To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries. RESEARCH DESIGN AND METHODSdWith the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes. RESULTSdDiabetes increased 30-day postoperative mortality (odds ratio 1.84 [95%CI 1.46- 2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68-7.28]), liver cirrhosis (3.59 [2.19-5.88]), stroke (2.87 [1.95-4.22]), mental disorders (2.35 [1.71-3.24]), ischemic heart disease (2.08 [1.45-2.99]), chronic obstructive pulmonary disease (1.96 [1.29- 2.97]), and hyperlipidemia (1.94 [1.01-3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88-4.48]) and acute myocardial infarction (3.65 [2.43-5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16-2.44]) and increased medical expenditures (1.32 [1.25-1.40]). CONCLUSIONSdDiabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries. © 2013 by the American Diabetes Association.


Chang S.-S.,Chang Gung University | Chang S.-S.,Chang Gung Memorial Hospital | Hsu H.-L.,Chang Gung University | Cheng J.-C.,China Medical University at Taichung | Tseng C.-P.,Chang Gung University
PLoS ONE | Year: 2011

Background: Bacterial DNA contamination in PCR reagents has been a long standing problem that hampers the adoption of broad-range PCR in clinical and applied microbiology, particularly in detection of low abundance bacteria. Although several DNA decontamination protocols have been reported, they all suffer from compromised PCR efficiency or detection limits. To date, no satisfactory solution has been found. Methodology/Principal Findings: We herein describe a method that solves this long standing problem by employing a broad-range primer extension-PCR (PE-PCR) strategy that obviates the need for DNA decontamination. In this method, we first devise a fusion probe having a 3′-end complementary to the template bacterial sequence and a 5′-end non-bacterial tag sequence. We then hybridize the probes to template DNA, carry out primer extension and remove the excess probes using an optimized enzyme mix of Klenow DNA polymerase and exonuclease I. This strategy allows the templates to be distinguished from the PCR reagent contaminants and selectively amplified by PCR. To prove the concept, we spiked the PCR reagents with Staphylococcus aureus genomic DNA and applied PE-PCR to amplify template bacterial DNA. The spiking DNA neither interfered with template DNA amplification nor caused false positive of the reaction. Broad-range PE-PCR amplification of the 16S rRNA gene was also validated and minute quantities of template DNA (10-100 fg) were detectable without false positives. When adapting to real-time and high-resolution melting (HRM) analytical platforms, the unique melting profiles for the PE-PCR product can be used as the molecular fingerprints to further identify individual bacterial species. Conclusions/Significance: Broad-range PE-PCR is simple, efficient, and completely obviates the need to decontaminate PCR reagents. When coupling with real-time and HRM analyses, it offers a new avenue for bacterial species identification with a limited source of bacterial DNA, making it suitable for use in clinical and applied microbiology laboratories. © 2011 Chang et al.


Yeh C.-C.,China Medical University at Taichung | Lai C.-Y.,China Medical University at Taichung | Hsieh L.-L.,Chang Gung University | Tang R.,Chang Gung Memorial Hospital | And 2 more authors.
Carcinogenesis | Year: 2010

Oxidative stress has been associated with the carcinogenesis of colorectal cancer. Glutathione S-transferases (GSTs) modulate the elimination of free radical.We conducted a case-control study to examine the interaction between oxidative stress and GSTs polymorphisms on colorectal cancer risk. This study recruited 727 pathologically confirmed colorectal adenocarcinoma cases and 736 sex- and age-matched controls. Plasma protein carbonyls, as a parameter of oxidative stress, were measured using enzymelinked immunosorbent assay. Genotypes of GSTM1, GSTT1 and GSTP1 genes were determined using polymerase chain reaction methods. The protein carbonyl levels were significantly higher in cases than in controls and exerted a dose-response relationship (P for trend < 0.001). Compared with the first carbonyl quartile subjects, those in the second, third and fourth quartiles had odds ratios (ORs) of 1.54 [95% confidence interval (CI) = 1.13-2.10], 1.52 (95% CI = 1.11-2.07) and 1.98 (95% CI = 1.46-2.67), respectively. This effect was significantly modified by GSTM1 genotype (P for interaction = 0.037). The three-way interaction analysis revealed that interactions between GSTM1 genotype and cigarette smoking and between GSTT1 genotype and alcohol drinking further modified the oxidative stress contribution for colorectal cancer (p for interaction were 0.067 and 0.054, respectively). The impact of oxidative stress was more prominent among eversmokers with GSTM1-null genotype (OR = 3.45, 95%CI = 1.70- 6.97) and ever-drinkers with GSTT1-present genotype (OR = 3.87, 95% CI = 1.82-8.25). Our results indicate that interaction between oxidative stress and GSTs polymorphisms may play an important role in the pathogenesis of colorectal cancer. © The Author 2009. Published by Oxford University Press.


Hsieh Y.-L.,China Medical University at Taichung
Journal of Tissue Engineering and Regenerative Medicine | Year: 2013

Transplantation of mesenchymal stem cells (MSCs) has been proposed to exert beneficial effects on peripheral nerve regeneration after a peripheral nerve injury, but the functional recovery in the denervated limb is still limited. In this study, we used low-level laser therapy (LLLT) as an adjunct therapy for MSC transplantation on the functional recovery of crushed sciatic nerve in rats. Peripheral nerve injury was induced in 48 Sprague-Dawley rats by crushing the unilateral sciatic nerve, using a vessel clamp. The animals with crushed injury were randomly divided into four groups: control group, with no treatment; MSC group, treated with MSC alone; LLLT group, treated with LLLT alone; and MSCLLLT group, treated with a combination of MSC and LLLT. The sciatic function index (SFI), vertical activity of locomotion (VA) and ankle angle (AA) of rats were examined for functional assessments after treatment. Electrophysiological, morphological and S100 immunohistochemical studies were also conducted. The MSCLLLT group showed a greater recovery in SFI, VA and AA, with significant difference from MSC, LLLT and control groups (p<0.05). Moreover, markedly enhanced electrophysiological function and expression of S100 immunoreactivity, as well as fewer inflammatory cells and less vacuole formation were also demonstrated after nerve crush injury in the MSCLLLT group when compared with the groups receiving a single treatment (p<0.05). MSC transplantation combined with LLLT could achieve better results in functional recovery than a conventional treatment of MSC or LLLT alone. LLLT has a synergistic effect in providing greater functional recovery with MSC transplantation after nerve crush injury. © 2013 John Wiley & Sons, Ltd.


Chen Y.J.,National Taiwan University | Tsai K.S.,National Taiwan University Hospital | Chan D.C.,National Taiwan University Hospital | Lan K.C.,Tri Service General Hospital | And 4 more authors.
Journal of Orthopaedic Research | Year: 2014

Proinflammatory cytokine interleukin-1β (IL-1β) stimulates several mediators of cartilage degradation and plays an important role in the pathogenesis of osteoarthritis (OA). Honokiol, a low molecular weight natural product isolated from the Magnolia officinalis, has been shown to possess anti-inflammatory effect. Here, we used an in vitro model of cartilage inflammation to investigate the therapeutic potential of honokiol in OA. Human OA chondrocytes were cultured and pretreated with honokiol (2.5-10 μM) with or without IL-1β (10 ng/ml). Nitric oxide (NO) production was quantified by Griess reagent. Prostaglandin (PG)E2, metalloproteinase-13 (MMP-13), and interleukin-6 (IL-6) productions were quantified by enzyme-linked immunosorbent assay. The expressions of collagen II, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor κB (NF-κB)-related signaling molecules were determined by Western blotting. Our data showed that IL-1β markedly stimulated the expressions of iNOS and COX-2 and the productions of NO, PGE2, and IL-6, which could be significantly reversed by honokiol. Honokiol could also suppress the IL-1β-triggered activation of IKK/IκBα/NF-κB signaling pathway. Moreover, honokiol significantly inhibited the IL-1β-induced MMP-13 production and collagen II reduction. Taken together, the present study suggests that honokiol may have a chondroprotective effect and may be a potential therapeutic choice in the treatment of OA patients. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:573-580, 2014. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Lin C.-Y.,National Chiao Tung University | Chiou J.-C.,National Chiao Tung University | Chiou J.-C.,China Medical University at Taichung
Solid-State Electronics | Year: 2012

A micro-electro-mechanical system (MEMS)-based image stabilizer is proposed to counteracting shaking in cell phone cameras. The proposed stabilizer (dimensions, 8.8 × 8.8 × 0.2 mm3) includes a two-axis decoupling XY stage and has sufficient strength to suspend an image sensor (IS) used for anti-shaking function. The XY stage is designed to send electrical signals from the suspended IS by using eight signal springs and 24 signal outputs. The maximum actuating distance of the stage is larger than 25 μm, which is sufficient to resolve the shaking problem. Accordingly, the applied voltage for the 25 μm moving distance is lower than 20 V; the dynamic resonant frequency of the actuating device is 4485 Hz, and the rising time is 21 ms. © 2012 Elsevier Ltd. All rights reserved.


Su C.-C.,Changhua Christian Hospital | Su C.-C.,China Medical University at Taichung
Anticancer Research | Year: 2014

Tanshinone IIA (Tan-IIA) is extracted from Danshen (Salviae miltiorrhizae radix). It possesses antitumor activity against a variety of human cancer cells and its induction of apoptosis and inhibition of proliferation of gastric cancer cells are well-documented. However, the molecular mechanisms by which Tan-IIA inhibits gastric cancer have not been well-elucidated. In the present study, we evaluated the cytotoxicity of Tan-IIA against human gastric cancer AGS cells by the (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) MTT assay. The protein expression of tumor necrosis factor-alpha (TNF-α), FAS, p53, p21, cyclin A, cyclin B1, extracellular-related kinase (ERK), phospho extracellularrelated kinase (p-ERK), p38, p-p38, Jun-amino-terminal kinase (JNK), phospho Jun-amino-terminal kinase (p-JNK) and β-actin in AGS cells were measured by western blotting. The cell-cycle distribution was analyzed by flow cytometry. The results showed that Tan-IIA inhibited AGS cells with timeand dose-dependent manners. AGS cells treated with Tan-IIA up-regulated the protein expression of TNFα, FAS, p-p38, p- JNK, p53, p21, caspase-3 and caspase-8 but reduced that of p- ERK, CDC2, cyclin A, and cyclin B1. The results also showed that Tan-IIA dose dependently induced G2/M phase arrest. These findings demonstrate that Tan-IIA can inhibit AGS human gastric cancer cells; one of the molecular mechanisms may be through increasing the protein expression of p-p38 and p-JNK, but decreasing that of p-ERK to induce the activation of p53, followed by increasing the protein expression of p21 to down-regulate CDC2 and cyclin B1 expression which then induces G2/M phase arrest. Another route may be through increasing the protein expression of TNF-α, FAS, caspase-8 and caspase-3 to induce apoptosis.


Lu J.-J.,Chang Gung Memorial Hospital | Lu J.-J.,China Medical University at Taichung | Tsai F.-J.,China Medical University at Taichung | Ho C.-M.,China Medical University at Taichung | And 2 more authors.
Analytical Chemistry | Year: 2012

Rapid identification of community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA), hospital-associated (HA) MRSA, and vancomycin-intermediate S. aureus (VISA) is essential for proper therapy and timely intervention of outbreaks. In this study, peptide biomarkers for rapid identification of methicillin-resistant and vancomycin-intermediate S. aureus strains were discovered by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The results showed that the 1774.1 and 1792.1 m/z peaks corresponding to the phenol-soluble modulin α1 and phenol-soluble modulin α2 peptides, respectively, were present in the majority (95%, 121 of 127) of SCCmec types IV and V isolates, but only in 8% (15 of 185) of SCCmec types I-III isolates. Since SCCmec types I-III isolates are recognized as HA-MRSA and most CA-MRSA isolates belong to SCCmec types IV and V, these two peptides may serve as markers for discrimination between HA-MRSA and CA-MRSA isolates. The 1835.0 and 1863.0 m/z peaks were present in 50% (4 of 8) of heterogeneous VISA and 88% (14 of 16) of VISA isolates. The peptides of these two peaks were identified as proteolytic products of the acyl carrier protein. The results of this study provide the possibility to develop methods for identification of CA-MRSA, HA-MRSA, and vancomycin-resistant S. aureus isolates based on the presence of these peptides. © 2012 American Chemical Society.


Hsu Y.-C.,China Medical University at Taichung | Hsu Y.-C.,I - Shou University | Lin J.-T.,I - Shou University | Lin J.-T.,Fu Jen Catholic University | And 11 more authors.
Hepatology | Year: 2014

Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population-based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8-year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3-2.0%), 9.3% (95% CI, 5.9-12.7%), and 3.3% (95% CI, 2.3-4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1-5.0%), 5.3% (95% CI, 3.0-7.5%), and 6.1% (95% CI, 4.8-7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1-6.1%), 6.6% (95% CI, 3.7-9.5%), and 7.4% (95% CI, 5.9-9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate-adjusted hazard ratios of 0.16 (95% CI, 0.07-0.33%) for ESRD, 0.53 (95% CI, 0.30-0.93) for ischemic stroke, and 0.64 (95% CI, 0.39-1.06) for ACS. Conclusion: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. © 2014 by the American Association for the Study of Liver Diseases.


Tsai S.-W.,National Chiao Tung University | Chiou J.-C.,National Chiao Tung University | Chiou J.-C.,China Medical University at Taichung | Chiou J.-C.,1001 University Road
Sensors and Actuators, B: Chemical | Year: 2011

In situ SiO2-doped SnO2 thin films were successfully prepared by liquid phase deposition. The influence of SiO2 additive as an inhibitor on the surface morphology and the grain size for the thin film has been investigated. These results show that the morphology of SnO2 film changes significantly by increasing the concentration of H 2SiF6 solution which decreases the grain size of SnO 2. The stoichiometric analysis of Si content in the SnO2 film prepared from various Si/Sn molar ratios has also been estimated. For the sensing performance of H2S gas, the SiO2-doped Cu-Au-SnO2 sensor presents better sensitivity to H2S gas compared with Cu-Au-SnO2 sensor due to the fact that the distribution of SiO2 particles in grain boundaries of nano-crystallines SnO 2 inhibited the grain growth (<6 nm) and formed a porous film. By increasing the Si/Sn molar ratio, the SiO2-doped Cu-Au-SnO 2 gas sensors (Si/Sn = 0.5) exhibit a good sensitivity (S = 67), a short response time (t90% < 3 s) and a good gas concentration characteristic (α = 0.6074). Consequently, the improvement of the nano-crystalline structures and high sensitivity for sensing films can be achieved by introducing SiO2 additive into the SnO2 film prepared by LPD method. © 2010 Elsevier B.V. All rights reserved.


Tsai Y.-K.,National Health Research Institute | Fung C.-P.,Taipei Veterans General Hospital | Lin J.-C.,Tri Service General Hospital | Chen J.-H.,Yuanpei University | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

OmpK35 and OmpK36 are the major outer membrane porins of Klebsiella pneumoniae. In this study, a virulent clinical isolate was selected to study the role of these two porins in antimicrobial resistance and virulence. The single deletion of ompK36 (ΔompK36) resulted in MIC shifts of cefazolin, cephalothin, and cefoxitin from susceptible to resistant, while the single deletion of ompK35 (ΔompK35) had no significant effect. A double deletion of ompK35 and ompK36 (ΔompK35/36) further increased these MICs to high-level resistance and led to 8- and 16-fold increases in the MICs of meropenem and cefepime, respectively. In contrast to the routine testing medium, which is of high osmolarity, susceptibility tests using low-osmolarity medium showed that the ΔompK35 mutation resulted in a significant (≥4-fold) increase in the MICs of cefazolin and ceftazidime, whereas a ΔompK36 deletion conferred a significantly (4-fold) lower increase in the MIC of cefazolin. In the virulence assays, a significant (P < 0.05) defect in the growth rate was found only in the ΔompK35/36 mutant, indicating the effect on metabolic fitness. A significant (P < 0.05) increase in susceptibility to neutrophil phagocytosis was observed in both ΔompK36 and ΔompK35/36 mutants. In a mouse peritonitis model, the ΔompK35 mutant showed no change in virulence, and the ΔompK36 mutant exhibited significantly (P < 0.01) lower virulence, whereas the ΔompK35/36 mutant presented the highest 50% lethal dose of these strains. In conclusion, porin deficiency in K. pneumoniae could increase antimicrobial resistance but decrease virulence at the same time. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Hsu Y.-H.,China Medical University at Taichung | Hsu Y.-H.,Foundation Medicine | Muo C.-H.,Data Management | Muo C.-H.,China Medical University at Taichung | And 6 more authors.
Journal of Hepatology | Year: 2015

Background & Aims The relationship between hepatitis C virus (HCV) infection and peripheral arterial disease (PAD) development remains unclear. Methods Health insurance claims data were used to construct a cohort of HCV-infected patients diagnosed during the period 1998-2011. Patients younger than 20 years and those with history of hepatitis B or PAD were excluded. We selected 7641 HCV-infected patients and 30564 matched controls. The adjusted risk of developing PAD was analyzed using a multivariate Cox hazard model. Results The results show that the excess risk of PAD development in HCV-infected patients is 1.43-fold higher (95% CI = 1.23-1.67) compared with non-HCV patients. The adjusted risk of PAD development increases with age; compared with the 20-34 year-old patients, the risk is 3.96-fold higher in HCV-infected patients aged 35-49 years, and 11.7-fold higher in those aged 65 years and above. CKD/ESRD has the highest risk for PAD (HR = 1.80, 95% CI = 1.29-2.53). HCV-infected patients with four comorbidities exhibit a substantially higher risk of developing PAD (HR = 9.25, 95% CI = 6.35-13.5). Excess risk of developing PAD is observed from the first year of follow-up till the third year. Conclusion HCV-infected patients have an independently higher risk of developing PAD. HCV-infected patients with comorbidity have increased risk of developing PAD. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Tang Y.-A.,National Cheng Kung University | Lin R.-K.,Taipei Medical University | Tsai Y.-T.,National Cheng Kung University | Hsu H.-S.,Taipei Veterans General Hospital | And 3 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Overexpression of DNA 5′-cytosine-methyltransferase 3A (DNMT3A), which silences genes including tumor suppressor genes (TSG), is involved in many cancers. Therefore, we examined whether the transcriptional deregulation of RB/MDM2 pathway was responsible for DNMT3A overexpression and analyzed the therapeutic potential of MDM2 antagonist for reversing aberrant DNA methylation status in lung cancer. Experimental Design: The regulation of DNMT3A expression and TSG methylation status by RB/MDM2 was assessed in cancer cell lines and patients. The effects of Nutlin-3, an MDM2 antagonist, on tumor growth in relation to DNMT3A expression and TSG methylation status were examined by xenograft model. Results: We found that RB suppressed DNMT3A promoter activity and mRNA/protein expression through binding with E2F1 protein to the DNMT3A promoter, leading to the decrease of methylation level globally and TSG specifically. In addition, MDM2 dramatically induced DNMT3A expression by negative control over RB. In clinical study, MDM2 overexpression inversely correlated with RB expression, while positively associating with overexpression of DNMT3A in samples from patients with lung cancer. Patients with high MDM2 and low RB expression showed DNMT3A overexpression with promoter hypermethylation in TSGs. Treatment with Nutlin-3, an MDM2 antagonist, significantly suppressed tumor growth and reduced DNA methylation level of TSGs through downregulation of DNMT3A expression in xenograft studies. Conclusions: This study provides the first cell, animal, and clinical evidence that DNMT3A is transcriptionally repressed, in part, by RB/E2F pathway and that the repression could be attenuated by MDM2 overexpression. MDM2 is a potent target for anticancer therapy to reverse aberrant epigenetic status in cancers. © 2012 AACR.


Chen P.-C.,National Taiwan University | Chen H.-F.,Far Eastern Memorial Hospital | Chen H.-F.,University of Taipei | Ko M.-C.,Taipei City Hospital City | And 2 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-This study addresses the strength of association for the bidirectional relationship between type 2 diabetes and depression. RESEARCH DESIGN AND METHODS-We used two cohort studies with the same source of database to determine the link between depression and type 2 diabetes. The data analyzed included a random sample of 1 million beneficiaries selected from the National Health Insurance claims in 2000. The analysis of diabetes predicting the depression onset consisted of 16,957 diabetic patients and the same number of sex- and age-matched nondiabetic control subjects. The analysis of depression predicting diabetes onset included 5,847 depressive patients and 5,847 sex- and age-matched nondepressive control subjects. The follow-up period was between 2000 and 2006, and onset of end points was identified from ambulatory care claims. The Cox proportional hazards regression model adjusted for potential confounders was used to estimate relative hazards. RESULTS-The first cohort analysis notedan incidence density (ID) of 7.03 per 1,000 person-years (PY) and 5.04 per 1,000 PY for depression in diabetic and nondiabetic subjects, respectively, representing a covariate-adjusted hazard ratio (HR) of 1.43 (95% CI 1.16-1.77). The second cohort analysis noted an ID of 27.59 per 1,000 PY and 9.22 per 1,000 PY for diabetes in depressive and nondepressive subjects, respectively. The covariate-adjusted HR was stronger at 2.02 (1.80-2.27) for incident diabetes associated with baseline depression. CONCLUSIONS-The two cohort studies provided evidence for the bidirectional relationship between diabetes and depression, with a stronger association noted for the depression predicting onset of diabetes.© 2013 by the American Diabetes Association.


Lin Y.-H.,China Medical University at Taichung | Huang Y.-C.,Kaohsiung Medical University | Chen L.-H.,Taipei Veterans General Hospital | Chu P.-M.,China Medical University at Taichung
Cancer Chemotherapy and Pharmacology | Year: 2015

Macroautophagy is widely accepted as a cytoprotective mechanism against various environmental stresses. While inhibition of autophagy is generally considered to increase the susceptibility of cancer cells to therapeutic agents, whether it also plays a similar role in tumor stem cells is unclear and still controversial. With increased attention and efforts focused on the cytoprotective feature of autophagy in cancer, it is also essential to understand its role in the biology of cancer stem cells, including self-renewal, differentiation, and tumorigenicity. Although there are very few studies that evaluate autophagy in cancer stem/progenitor cells, understanding the mechanisms governing autophagic responses in various cancer stem cells could provide support for the future development of clinical therapeutics. The present review summarizes current studies that assess the role of autophagy in various types of cancer stem cells and those that evaluate the application of inhibitors of key components within the autophagy pathway in cancer stem/progenitor cells. © 2014 Springer-Verlag Berlin Heidelberg.


Pan H.-A.,National Chiao Tung University | Liang J.-Y.,National Chiao Tung University | Hung Y.-C.,China Medical University at Taichung | Lee C.-H.,National Chiao Tung University | And 2 more authors.
Biomaterials | Year: 2013

Nanotopography controls cell behaviours, such as cell adhesion and migration. However, the mechanisms responsible for topology-mediated cellular functions are not fully understood. A variety of nanopores was fabricated on 316L stainless steel to investigate the effects of spatial control on the growth and function of fibroblasts, the temporal regulation of integrins, and their effects on migration. The NIH-3T3 fibroblast cell line was cultured on the nanopore surfaces, whose pore diameters ranged from 40 to 210 nm. The 40 and 75 nm nanopores enhanced cell proliferation, focal adhesion formation and protein expression of vinculin and β-tubulin after 24 h of incubation. Integrin expression was analysed by qPCR, which showed the extent of spatial and temporal regulation achieved by the nanopores. The protein expression of pERK1/2 was greatly attenuated in cells grown on 185 and 210 nm nanopore surfaces at 12 and 24 h. In summary, the 40 and 75 nm nanopore surfaces promoted cell adhesion and migration in fibroblasts by controlling the temporal expression of integrins and ERK1/2. The current study provides insight into the improvement of the design of stainless steel implants and parameters that affect biocompatibility. The ability to regulate the expression of integrin and ERK1/2 using nanopore surfaces could lead to further applications of surface modification in the fields of biomaterials science and tissue engineering. © 2012 Elsevier Ltd.


Chung W.-S.,China Medical University at Taichung | Lin C.-L.,Data Management | Sung F.-C.,Chinese Institute of Clinical Medicine | Chen Y.-F.,Central Taiwan University of Science and Technology | Kao C.-H.,China Medical University at Taichung
Journal of Rheumatology | Year: 2014

Objective. Studies of the risks of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with Sjögren syndrome (SS) in Asia are scant. We evaluated the effect of SS on the incidences of DVT and PE in a nationwide, population-based cohort in Taiwan. Methods. We identified patients in Taiwan diagnosed with SS between 1998 and 2008 in the Catastrophic Illness Patient Database and the National Health Insurance Research Database. Each patient with SS was matched to 4 control patients based on age, sex, and index year, and all patients were followed up from the index date to December 31, 2010. We calculated the hazard ratios (HR) and 95% CI of DVT and PE in the SS and comparison cohorts by using Cox proportional hazards regression models. Results.We followed 8920 patients with SS and a comparison cohort of 35,680 for about 50,000 and 200,000 person-years, respectively. The mean age of the SS and comparison cohorts was 53.5 and 53.1 years, respectively, and 88.9% of the patients were women. The risks of DVT and PE among the patients with SS were a 1.83-fold and 3.29-fold greater, respectively, than those for the general population after adjusting for age, sex, comorbidities, and frequency of hospitalization. The patients with a secondary SS had a greater risk of PE (adjusted HR: 5.06; 95% CI: 1.22-21.1) than those with a primary SS (adjusted HR: 3.21; 95% CI: 1.96-5.23). Conclusion. Patients with SS have a significantly greater risk of developing DVT or PE than the general population. © 2014. All rights reserved.


Chen Y.-S.,National Chiao Tung University | Hung Y.-C.,China Medical University at Taichung | Lin W.-H.,National Chiao Tung University | Huang G.S.,National Chiao Tung University
Nanotechnology | Year: 2010

To assess the ability of gold nanoparticles(GNPs) to act as a size-dependent carrier, a synthetic peptide resembling foot-and-mouth disease virus(FMDV) protein was conjugated to GNPs ranging from 2 to 50nm in diameter (2, 5, 8, 12, 17, 37, and 50nm). An extra cysteine was added to the C-terminus of the FMDV peptide(pFMDV) to ensure maximal conjugation to the GNPs, which have a high affinity for sulfhydryl groups. The resultant pFMDV-GNP conjugates were then injected into BALB/c mice. Immunization with pFMDV-keyhole limpet hemocyanin(pFMDV-KLH) conjugate was also performed as a control. Blood was obtained from the mice after 4, 6, 8, and 10weeks and antibody titers against both pFMDV and the carriers were measured. For the pFMDV-GNP immunization, specific antibodies against the synthetic peptide were detected in the sera of mice injected with 2, 5, 8, 12, and 17nm pFMDV-GNP conjugates. Maximal antibody binding was noted for GNPs of diameter 8-17nm. The pFMDV-GNPs induced a three-fold increase in the antibody response compared to the response to pFMDV-KLH. However, sera from either immunized mouse group did not exhibit an antibody response to GNPs, while the sera from pFMDV-KLH-immunized mice presented high levels of binding activity against KLH. Additionally, the uptake of pFMDV-GNP in the spleen was examined by inductively coupled plasma mass spectroscopy(ICP-MS) and transmission electron microscopy(TEM). The quantity of GNPs that accumulated in the spleen correlated to the magnitude of the immune response induced by pFMDV-GNP. In conclusion, we demonstrated the size-dependent immunogenic properties of pFMDV-GNP conjugates. Furthermore, we established that GNPs ranging from 8 to 17nm in diameter may be ideal for eliciting a focused antibody response against a synthetic pFMDV peptide. © 2010 IOP Publishing Ltd.


Chang C.-H.,China Medical University at Taichung | Chen S.-J.,Mackay Memorial Hospital Taitung Branch | Chen S.-J.,Tzu Chi University | Liu C.-Y.,National Taipei University of Nursing and Health Sciences
PLoS ONE | Year: 2015

Background & Aims: To evaluate the risk of depressive disorders among patients with Hepatocellular Carcinoma (HCC) using the National Health Insurance Research Database (NHIRD) in Taiwan. Methods: We conducted a retrospective study of a newly diagnosed HCC cohort of 55,973 participants who were selected from the NHIRD. Patients were observed for a maximum of 6 years to determine the rates of newly onset depressive disorders, and Cox regression was used to identify the risk factors associated with depressive disorders in HCC patients. Results: Of the total 55,973 HCC patients, 1, 041 patients (1.86%) were diagnosed with depressive disorders during a mean (SD) follow-up period of 1.1 (1.2) years. The Cox multivariate proportional hazards analysis showed that age of 40-59 (HR 1. 376, 95% CI1.049-1.805, p = 0.021), age of 60-79 (HR 1. 341, 95% CI 1.025-1.753, p = 0.032), women (HR 1.474 95% CI 1.301-1.669, p< 0.001), metastasis (HR 1. 916, 95% CI1.243-2.953, p =0.003), and HCV (HR 1. 445, 95% CI 1.231-1.697, p < 0.001) were independent risk factors for developing depressive disorders. Conclusions: Our study indicated a subsequent risk of depressive disorders in patients with HCC, and the risk increased for those with female gender, aged 40 to 59, aged 60 to 79, with metastasis, or with HCV. Psychological evaluation and support are two critical issues in these HCC patients with the risk factors. Copyright: © 2015 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Chan W.-L.,National Chiao Tung University | Chan W.-L.,China Medical University at Taichung | Yuo C.-Y.,Kaohsiung Medical University | Yang W.-K.,China Medical University at Taichung | And 6 more authors.
Nucleic Acids Research | Year: 2013

Pseudogenes, especially those that are transcribed, may not be mere genomic fossils, but their biological significance remains unclear. Postulating that in the human genome, as in animal models, pseudogenes may function as gene regulators through generation of endo-siRNAs (esiRNAs), antisense RNAs or RNA decoys, we performed bioinformatic and subsequent experimental tests to explore esiRNA-mediated mechanisms of pseudogene involvement in oncogenesis. A genome-wide survey revealed a partial retrotranscript pseudogene ψPPM1K containing inverted repeats capable of folding into hairpin structures that can be processed into two esiRNAs; these esiRNAs potentially target many cellular genes, including NEK8. In 41 paired surgical specimens, we found significantly reduced expression of two predicted ψPPM1K-specific esiRNAs, and the cognate gene PPM1K, in hepatocellular carcinoma compared with matched non-tumour tissues, whereas the expression of target gene NEK8 was increased in tumours. Additionally, NEK8 and PPM1K were downregulated in stably transfected ψPPM1K-overexpressing cells, but not in cells transfected with an esiRNA1-deletion mutant of ψPPM1K. Furthermore, expression of NEK8 in ψPPM1K-transfected cells demonstrated that NEK8 can counteract the growth inhibitory effects of ψPPM1K. These findings indicate that a transcribed pseudogene can exert tumour-suppressor activity independent of its parental gene by generation of esiRNAs that regulate human cell growth. © The Author(s) 2013. Published by Oxford University Press.


Siu L.K.,China Medical University at Taichung | Fung C.-P.,Taipei Veterans General Hospital | Chang F.-Y.,Tri Service General Hospital | Lee N.,Chinese University of Hong Kong | And 3 more authors.
Journal of Clinical Microbiology | Year: 2011

Serotype K1 Klebsiella pneumoniae with multilocus sequence type 23 (ST23) has been strongly associated with liver abscess in Taiwan. Few data regarding the strain types and virulence of this serotype from other Asian countries are available. Serotype K1 K. pneumoniae strains isolated from liver abscess and stool samples from subjects hospitalized in Hong Kong, Singapore, and Taiwan hospitals were examined. Forty-seven serotype K1 isolates were identified: 26 from liver abscess samples and 21 from stool samples. MLST revealed 7 sequence types: 85.1% (40 of 47 isolates) belonged to ST23, 1 isolate belonged to ST163 (a single-locus variant of ST23), and 2 isolates were ST249 (a 3-locus variant of ST23). New STs, namely, ST367, ST425, and ST426, were allocated to 3 of 4 isolates from stool samples. The virulence of these strains was determined by neutrophil phagocytosis and mouse infection models. Except for two ST23 isolates, all Klebsiella pneumoniae isolates were resistant to phagocytosis. Resistance to serum killing varied in isolates of ST23, while all non-ST23 strains were susceptible to serum killing except one with ST249 from a liver abscess. All hypervirulent isolates with a 50% lethal dose of <10 2 CFU were from ST23, were resistant to phagocytosis and serum killing, and also carried both virulence-associated genes, rmpA and aerobactin. Multilocus sequence typing genotype 23 was the most prevalent sequence type among serotype K1 K. pneumoniae isolates from both liver abscess and stool samples in the Asia Pacific region. Serotype K1 K. pneumoniae isolates with capsule expression leading to phagocytic resistance and with the aerobactin gene were associated with hypervirulence. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Chiang C.-H.,National Taiwan University Hospital | Huang K.-C.,China Medical University at Taichung
World Journal of Gastroenterology | Year: 2014

There are limited data regarding the relationship between chronic hepatitis B virus (HBV) infection and metabolic factors. This article aims to highlight the link of metabolic factors with hepatitis B surface antigen (HBsAg) serostatus, HBV load, and HBV-related hepatocellular carcinoma (HCC). Although HBsAg-positive serostatus was positively correlated with a high risk of metabolic syndrome in students, chronic HBV-infected individuals have high serum adiponectin levels. The androgen pathway in HBV carriers with a low body mass index is more triggered which leads to enhanced HBV replication. High HBV load was inversely associated with obesity in hepatitis B e antigen (HBeAg)-seropositive HBV carriers; while in HBeAg-seronegative HBV carriers, high HBV load was inversely related to hypertriglyceridemia rather than obesity. For overweight and obese HBV-infected patients, high HBV load was positively associated with serum adiponectin levels. Several large cohort studies have revealed a positive link of diabetes with incidence of HBV-related HCC. However, the association between incidence of HCC and metabolic factors other than diabetes is still inconclusive. More long-term prospective studies should elucidate the association of chronic HBV infection and its outcomes with metabolic factors in clinical practice. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Ma T.,China Medical University at Taichung | Tien L.,Bureau of National Health Insurance | Fang C.-L.,Bureau of National Health Insurance | Liou Y.-S.,Taipei Veterans General Hospital | Jong G.-P.,Central Taiwan University of Science and Technology
Clinical Therapeutics | Year: 2012

Background: Statins have been linked to new-onset diabetes (NOD); however, the effect of statins on the development of NOD in patients with hypertension and dyslipidemia has not been well studied. Objective: The goal of this study was to investigate the association between statins and NOD. Methods: This was a retrospective cohort study performed by using data from claim forms provided to the central regional branch of the Bureau of National Health Insurance in Taiwan from July 2006 to December 2009. Prescriptions for statins before the index date were retrieved from a prescription database. We estimated the hazards ratios (HRs) of NOD associated with statin use. Nondiabetic subjects served as the reference group. Results: A total of 1360 (8.5%) NOD cases were identified among 16,027 patients with hypertension and dyslipidemia during the study period. The risk of NOD after adjusting for sex and age was higher among users of pravastatin (HR, 1.34 [95% CI, 1.15-1.55]) and atorvastatin (HR, 1.29 [95% CI, 1.16-1.44]) than among nonusers. Patients who took fluvastatin (HR, 0.45 [95% CI, 0.34-0.60]), lovastatin (HR, 0.71 [95% CI, 0.61-0.84]), and rosuvastatin (HR, 0.54 [95% CI, 0.39-0.77]) were at lower risk of developing NOD than nonusers. Simvastatin was not associated with risk of NOD. Furthermore, the risk of NOD after adjusting for concomitant medication usage and mean dose of statins was neutral among users of atorvastatin. Pravastatin, fluvastatin, lovastatin, simvastatin, and rosuvastatin produced similar results as adjusting for sex and age. Conclusions: These outpatients with hypertension and dyslipidemia who took fluvastatin, lovastatin, and rosuvastatin were at lower risk of NOD, whereas patients who took pravastatin were at greater risk. Simvastatin and atorvastatin seemed to have a neutral effect. Our study also demonstrated that atorvastatin has a dose-response effect on NOD risk. Because this was a descriptive study, temporality and subsequent causality of all statins and NOD could not be shown. Further study and independent confirmation of the causality between statin use and NOD in larger clinical trials are warranted. © 2012 Elsevier HS Journals, Inc..


Chang Y.-K.,China Medical University at Taichung | Wu C.-C.,China Medical University at Taichung | Lee L.-T.,National Taiwan University Hospital | Lin R.S.,National Taiwan University Hospital | And 2 more authors.
Chemosphere | Year: 2012

A mass screening of lung function associated with air pollutants for children is limited. This study assessed the association between air pollutants exposure and the lung function of junior high school students in a mass screening program in Taipei city, Taiwan. Among 10,396 students with completed asthma screening questionnaires and anthropometric measures, 2919 students aged 12-16 received the spirometry test. Forced vital capacity (FVC) and forced expiratory flow in 1s (FEV 1) in association with daily ambient concentrations of particulate matter with diameter of 10μm or less (PM 10), sulfur dioxide (SO 2), carbon monoxide (CO), nitrogen dioxide (NO 2), and ozone (O 3) were assessed by regression models controlling for the age, gender, height, weight, student living districts, rainfall and temperature. FVC, had a significant negative association with short-term exposure to O 3 and PM 10 measured on the day of spirometry testing. FVC values also were reversely associated with means of SO 2, O 3, NO 2, PM 10 and CO exposed 1d earlier. An increase of 1-ppm CO was associated with the reduction in FVC for 69.8mL (95% CI: -115, -24.4mL) or in FEV 1 for 73.7mL (95% CI: -118, -29.7mL). An increase in SO 2 for 1ppb was associated with the reductions in FVC and FEV 1 for 12.9mL (95% CI: -20.7, -5.09mL) and 11.7mL (95% CI: -19.3, -4.16mL), respectively. In conclusion, the short-term exposure to O 3 and PM 10 was associated with reducing FVC and FEV 1. CO and SO 2 exposure had a strong 1-d lag effect on FVC and FEV 1. © 2011 Elsevier Ltd.


Yeh T.F.,Childrens Hospital and | Chen C.M.,Taipei Medical University | Chen C.M.,Taipei Medical University Hospital | Wu S.Y.,University of Illinois at Chicago | And 5 more authors.
American journal of respiratory and critical care medicine | Year: 2016

RATIONALE: Bronchopulmonary dysplasia (BPD) is an important complication of mechanical ventilation in preterm infants, and no definite therapy can eliminate this complication. Pulmonary inflammation plays a crucial role in its pathogenesis, and glucocorticoid is one potential therapy to prevent BPD.OBJECTIVES: To compare the effect of intratracheal administration of surfactant/budesonide with that of surfactant alone on the incidence of death or BPD.METHODS: A clinical trial was conducted in three tertiary neonatal centers in the United States and Taiwan, in which 265 very-low-birth-weight infants with severe respiratory distress syndrome who required mechanical ventilation and inspired oxygen (fraction of inspired oxygen, ≥50%) within 4 hours of birth were randomly assigned to one of two groups (131 intervention and 134 control). The intervention infants received surfactant (100 mg/kg) and budesonide (0.25 mg/kg), and the control infants received surfactant only (100 mg/kg), until each infant required inspired O2 at less than 30% or was extubated.MEASUREMENTS AND MAIN RESULTS: The intervention group had a significantly lower incidence of BPD or death (55 of 131 [42.0%] vs. 89 of 134 [66%]; risk ratio, 0.58; 95% confidence interval, 0.44-0.77; P < 0.001; number needed to treat, 4.1; 95% confidence interval, 2.8-7.8). The intervention group required significantly fewer doses of surfactant than did the control group. The intervention group had significantly lower interleukin levels (IL-1, IL-6, IL-8) in tracheal aspirates at 12 hours and lower IL-8 at 3-5 and 7-8 days.CONCLUSIONS: In very-low-birth-weight infants with severe respiratory distress syndrome, intratracheal administration of surfactant/budesonide compared with surfactant alone significantly decreased the incidence of BPD or death without immediate adverse effect. Clinical trial registered with www.clinicaltrials.gov (NCT-00883532).


Huang J.-K.,Academia Sinica, Taiwan | Pu J.,Waseda University | Hsu C.-L.,Academia Sinica, Taiwan | Chiu M.-H.,Academia Sinica, Taiwan | And 7 more authors.
ACS Nano | Year: 2014

The monolayer transition metal dichalcogenides have recently attracted much attention owing to their potential in valleytronics, flexible and low-power electronics, and optoelectronic devices. Recent reports have demonstrated the growth of large-size two-dimensional MoS2 layers by the sulfurization of molybdenum oxides. However, the growth of a transition metal selenide monolayer has still been a challenge. Here we report that the introduction of hydrogen in the reaction chamber helps to activate the selenization of WO 3, where large-size WSe2 monolayer flakes or thin films can be successfully grown. The top-gated field-effect transistors based on WSe2 monolayers using ionic gels as the dielectrics exhibit ambipolar characteristics, where the hole and electron mobility values are up to 90 and 7 cm2/Vs, respectively. These films can be transferred onto arbitrary substrates, which may inspire research efforts to explore their properties and applications. The resistor-loaded inverter based on a WSe2 film, with a gain of ∼13, further demonstrates its applicability for logic-circuit integrations. © 2013 American Chemical Society.


Hsu W.-T.,National Chiao Tung University | Zhao Z.-A.,National Chiao Tung University | Li L.-J.,Academia Sinica, Taiwan | Li L.-J.,China Medical University at Taichung | And 5 more authors.
ACS Nano | Year: 2014

Optical second harmonic generation (SHG) is known as a sensitive probe to the crystalline symmetry of few-layer transition metal dichalcogenides (TMDs). Layer-number dependent and polarization resolved SHG have been observed for the special case of Bernal stacked few-layer TMDs, but it remains largely unexplored for structures deviated from this ideal stacking order. Here we report on the SHG from homo- and heterostructural TMD bilayers formed by artificial stacking with an arbitrary stacking angle. The SHG from the twisted bilayers is a coherent superposition of the SH fields from the individual layers, with a phase difference depending on the stacking angle. Such an interference effect is insensitive to the constituent layered materials and thus applicable to hetero-stacked bilayers. A proof-of-concept demonstration of using the SHG to probe the domain boundary and crystal polarity of mirror twins formed in chemically grown TMDs is also presented. We show here that the SHG is an efficient, sensitive, and nondestructive characterization for the stacking orientation, crystal polarity, and domain boundary of van der Waals heterostructures made of noncentrosymmetric layered materials. © 2014 American Chemical Society.


Chen H.-P.,National Chung Hsing University | Chen H.-P.,National Taiwan University Hospital | Shieh J.-J.,National Chung Hsing University | Shieh J.-J.,Taichung Veterans General Hospital | And 11 more authors.
Gut | Year: 2013

Objective: Type 2 diabetes mellitus is associated with a higher risk of hepatocellular carcinoma (HCC), which is attenuated by the use of metformin. However, there are no studies addressing the effect of metformin on hepatocarcinoma cells from the antitumoural perspective. Design: In the nationwide case-control study, the authors recruited 97 430 HCC patients and 194 860 age-, gender- and physician visit date-matched controls. The chemopreventive effects of metformin were examined by multivariate analysis and stratified analysis. The in vitro effects of metformin on cell proliferation and cell cycle were studied in HepG2 and Hep3B hepatoma cell lines. Results: The OR of diabetes in HCC patients was 2.29 (95% CI 2.25 to 2.35, p<0.001). Each incremental year increase in metformin use resulted in 7% reduction in the risk of HCC in diabetic patients (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001). In the multivariate stratified analysis, metformin use was associated with a reduced risk of HCC in diabetic patients in nearly all subgroups. Cell line studies showed that metformin inhibits hepatocyte proliferation and induces cell cycle arrest at G0/G1 phase via AMP-activated protein kinase and its upstream kinase LKB1 to upregulate p21/Cip1 and p27/Kip1 and downregulate cyclin D1 in a dose-dependent manner, but independent of p53. Combined treatment of oral metformin with doxorubicin functioned more efficiently than either agent alone, in vivo. Conclusions: Use of metformin is associated with a decreased risk of HCC in diabetic patients in a dosedependent manner, via inhibition of hepatoma cells proliferation and induction of cell cycle arrest at G0/G1 phase.


Kuo K.-L.,National Yang Ming University | Kuo K.-L.,Taipei Tzuchi Hospital | Hung S.-C.,Taipei Tzuchi Hospital | Lee T.-S.,National Yang Ming University | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2014

High-dose intravenous iron supplementation is associated with adverse cardiovascular outcomes in patients with CKD, but the underlying mechanism is unknown. Our study investigated the causative role of iron sucrose in leukocyte-endothelium interactions, an index of early atherogenesis, and subsequent atherosclerosis in the mouse remnant kidney model. We found that expression levels of intracellular cell adhesionmolecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and adhesion of U937 cells increased in iron-treated human aortic endothelial cells through upregulated NADPH oxidase (NOx) and NF-κB signaling. We then measured mononuclear -endothelial adhesion and atherosclerotic lesions of the proximal aorta inmale C57BL/6 mice with subtotal nephrectomy, male apolipoprotein E-deficient (ApoE-/-) mice with uninephrectomy, and sham-operated mice subjected to saline or parenteral iron loading. Iron sucrose significantly increased tissue superoxide production, expression of tissue cell adhesion molecules, and endothelial adhesiveness in mice with subtotal nephrectomy. Moreover, iron sucrose exacerbated atherosclerosis in the aorta of ApoE-/- mice with uninephrectomy. In patients with CKD, intravenous iron sucrose increased circulating mononuclear superoxide production, expression of soluble adhesion molecules, and mononuclear-endothelial adhesion compared with healthy subjects or untreated patients. In summary, iron sucrose aggravated endothelial dysfunction through NOx/NF-κB/CAM signaling, increased mononuclear-endothelial adhesion, and exacerbated atherosclerosis in mice with remnant kidneys. These results suggest a novel causative role for therapeutic iron in cardiovascular complications in patients with CKD. Copyright © 2014 by the American Society of Nephrology.


Chou C.-W.,National Taiwan University | Wu M.-S.,National Taiwan University Hospital | Huang W.-C.,China Medical University at Taichung | Chen C.-C.,National Taiwan University
PLoS ONE | Year: 2011

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase which promotes cell proliferation and survival, is abnormally overexpressed in numerous tumors of epithelial origin, including colorectal cancer (CRC). EGFR monoclonal antibodies have been shown to increase the median survival and are approved for the treatment of colorectal cancer. Histone deacetylases (HDACs), frequently overexpressed in colorectal cancer and several malignancies, are another attractive targets for cancer therapy. Several inhibitors of HDACs (HDACi) are developed and exhibit powerful antitumor abilities. In this study, human colorectal cancer cells treated with HDACi exhibited reduced EGFR expression, thereby disturbed EGF-induced ERK and Akt phosphorylation. HDACi also decreased the expression of SGLT1, an active glucose transporter found to be stabilized by EGFR, and suppressed the glucose uptake of cancer cells. HDACi suppressed the transcription of EGFR and class I HDACs were proved to be involved in this event. Chromatin immunoprecipitation analysis showed that HDACi caused the dissociation of SP1, HDAC3 and CBP from EGFR promoter. Our data suggested that HDACi could serve as a single agent to block both EGFR and HDAC, and may bring more benefits to the development of CRC therapy. © 2011 Chou et al.


Siu L.-K.K.,National Health Research Institute | Siu L.-K.K.,China Medical University at Taichung | Chiang T.,Veterans Affairs New Jersey Healthcare System
BMC Infectious Diseases | Year: 2014

Background: KPC-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with high mortality; however, their virulence determinants are not well defined.Methods: We investigated the virulence and plasmid transferability among KPC-containing K. pneumoniae isolates.Results: KPC-2 and -3 were successfully conjugated and retained by a virulent K2 K. pneumoniae recipient isolate. Antimicrobial susceptibility testing showed KPC-2 and -3 donor strains were resistant to more than four classes of antibiotics while the K2 isolate was only initially resistant to ampicillin. After conjugation of KPC-2 and -3, the K2 K. pneumoniae transconjugants became resistant to all beta-lactams. Additionally, the KPC K2 K. pneumoniae transconjugants continued to retain its high serum resistance and murine lethality.Conclusions: Conjugation and retainment of KPC by virulent K2 K. pneumoniae and the ability of the tranconjugants to maintain its high serum resistance and murine lethality after conjugation was demonstrated in this study. These findings are concerning for the potential of KPC-like genes to disseminate among virulent K. pneumoniae isolates. © 2014 Siu et al.; licensee BioMed Central Ltd.


Yen Y.-P.,National Taiwan University | Tsai K.-S.,National Taiwan University | Chen Y.-W.,China Medical University at Taichung | Huang C.-F.,China Medical University at Taichung | And 3 more authors.
Archives of Toxicology | Year: 2012

A pool of myoblasts available for myogenesis is important for skeletal muscle size. The decreased number of skeletal muscle fibers could be due to the decreased myoblast proliferation or cytotoxicity. Identification of toxicants that regulate myoblast apoptosis is important in skeletal muscle development or regeneration. Here, we investigate the cytotoxic effect and its possible mechanisms of arsenic trioxide (As2O3) on myoblasts. C2C12 myoblasts underwent apoptosis in response to As 2O 3 (1-10 μM), accompanied by increased Bax/Bcl-2 ratio, decreased mitochondria membrane potential, increased cytochrome c release, increased caspase-3/-9 activity, and increased poly (ADP-ribose) polymerase (PARP) cleavage. Moreover, As 2O 3 triggered the endoplasmic reticulum (ER) stress indentified through several key molecules of the unfolded protein response, including glucose-regulated protein (GRP)-78, GRP-94, PERK, eIF2α, ATF6, and caspase-12. Pretreatment with antioxidant N-acetylcysteine (NAC, 0.5 mM) dramatically suppressed the increases in reactive oxygen species (ROS), lipid peroxidation, ER stress, caspase cascade activity, and apoptosis in As 2O 3 (10 μM)-treated myoblasts. Furthermore, As 2O 3 (10 μM) effectively decreased the phosphorylation of Akt, which could be reversed by NAC. Over-expression of constitutive activation of Akt (c.a. Akt) also significantly attenuated As 2O 3-induced myoblast apoptosis. Taken together, these results suggest that As 2O 3 may exert its cytotoxicity on myoblasts by inducing apoptosis through a ROS-induced mitochondrial dysfunction, ER stress, and Akt inactivation signaling pathway. © Springer-Verlag 2012.


Hou C.-H.,National Taiwan University Hospital | Hou C.-H.,National Taiwan University | Fong Y.-C.,China Medical University at Taichung | Tang C.-H.,China Medical University at Taichung
Journal of Cellular Physiology | Year: 2011

High mobility group box chromosomal protein 1 (HMGB-1) is a widely studied, ubiquitous nuclear protein that is present in eukaryotic cells, and plays a crucial role in inflammatory response. However, the effects of HMGB-1 on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in HMGB-1-induced IL-6 production in human synovial fibroblast cells. HMGB-1 caused concentration- and time-dependent increases in IL-6 production. HMGB-1-mediated IL-6 production was attenuated by receptor for advanced glycation end products (RAGE) monoclonal antibody (Ab) or siRNA. Pretreatment with c-Src inhibitor (PP2), Akt inhibitor and NF-κB inhibitor (pyrrolidine dithiocarbamate and L-1-tosylamido-2-phenylenylethyl chloromethyl ketone) also inhibited the potentiating action of HMGB-1. Stimulation of cells with HMGB-1 increased the c-Src and Akt phosphorylation. HMGB-1 increased the accumulation of p-p65 in the nucleus, as well as NF-κB luciferase activity. HMGB-1-mediated increase of NF-κB luciferase activity was inhibited by RAGE Ab, PP2 and Akt inhibitor or RAGE siRNA, or c-Src and Akt mutant. Our results suggest that HMGB-1-increased IL-6 production in human synovial fibroblasts via the RAGE receptor, c-Src, Akt, p65, and NF-κB signaling pathways. © 2010 Wiley-Liss, Inc..


Hsu Y.-C.,China Medical University at Taichung | Hsu Y.-C.,E Da Hospital | Hsu Y.-C.,I - Shou University | Ho H.J.,Taichung Veterans General Hospital | And 10 more authors.
Gut | Year: 2015

Objective: To elucidate the association between antiviral therapy and extrahepatic outcomes in individuals infected with HCV. Methods: This nationwide cohort study screened 293 480 Taiwanese residents with HCV infection and excluded those with substantial comorbidity. A total of 12 384 eligible patients who had received pegylated interferon plus ribavirin between 1 October 2003 and 31 December 2010 were enrolled in the treated cohort; they were matched 1: 2 with 24 768 untreated controls in the propensity score and post-diagnosis treatment-free period. The incidences of end-stage renal disease (ESRD), acute coronary syndrome (ACS), ischaemic stroke and catastrophic autoimmune diseases were calculated after adjustment for competing mortality. Results: The treated and untreated cohorts were followed up for a mean (±SD) duration of 3.3 (±2.5) and 3.2 (±2.4) years, respectively, until 31 December 2011. The calculated 8-year cumulative incidences of ESRD, ACS, ischaemic stroke and autoimmune catastrophes between treated and untreated patients were 0.15% vs 1.32% (p<0.001), 2.21% vs 2.96% (p=0.027), 1.31% vs 1.76% (p=0.001) and 0.57% vs 0.49% (p=0.816), respectively. Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of ESRD (HR 0.15; 95% CI 0.07 to 0.31; p<0.001), ACS (HR 0.77; 95% CI 0.62 to 0.97; p=0.026) and ischaemic stroke (HR 0.62; 95% CI 0.46 to 0.83; p=0.001), but unrelated to autoimmune catastrophes. These favourable associations were invalid in incompletely treated patients with duration <16 weeks. Conclusions: Antiviral treatment for HCV is associated with improved renal and circulatory outcomes, but unrelated to catastrophic autoimmune diseases.


Chang C.-W.,National Chiao Tung University | Chiou J.-C.,National Chiao Tung University | Chiou J.-C.,China Medical University at Taichung
Sensors | Year: 2010

This study reports a new stacking method for assembling a 3-D microprobe array. To date, 3-D array structures have usually been assembled with vertical spacers, snap fasteners and a supporting platform. Such methods have achieved 3-D structures but suffer from complex assembly steps, vertical interconnection for 3-D signal transmission, low structure strength and large implantable opening. By applying the proposed stacking method, the previous techniques could be replaced by 2-D wire bonding. In this way, supporting platforms with slots and vertical spacers were no longer needed. Furthermore, ASIC chips can be substituted for the spacers in the stacked arrays to achieve system integration, design flexibility and volume usage efficiency. To avoid overflow of the adhesive fluid during assembly, an anti-overflow design which made use of capillary action force was applied in the stacking method as well. Moreover, presented stacking procedure consumes only 35 minutes in average for a 4 × 4 3-D microprobe array without requiring other specially made assembly tools. To summarize, the advantages of the proposed stacking method for 3-D array assembly include simplified assembly process, high structure strength, smaller opening area and integration ability with active circuits. This stacking assembly technique allows an alternative method to create 3-D structures from planar components. © 2010 by the authors; licensee MDPI, Basel, Switzerland.


Hsieh C.-H.,China Medical University at Taichung | Shyu W.-C.,China Medical University at Taichung | Chiang C.-Y.,China Medical University at Taichung | Kuo J.-W.,National Yang Ming University | And 3 more authors.
PLoS ONE | Year: 2011

Background: Cycling and chronic tumor hypoxia are involved in tumor development and growth. However, the impact of cycling hypoxia and its molecular mechanism on glioblastoma multiforme (GBM) progression remain unclear. Methodology: Glioblastoma cell lines, GBM8401 and U87, and their xenografts were exposed to cycling hypoxic stress in vitro and in vivo. Reactive oxygen species (ROS) production in glioblastoma cells and xenografts was assayed by in vitro ROS analysis and in vivo molecular imaging studies. NADPH oxidase subunit 4 (Nox4) RNAi-knockdown technology was utilized to study the role of Nox4 in cycling hypoxia-mediated ROS production and tumor progression. Furthermore, glioblastoma cells were stably transfected with a retroviral vector bearing a dual reporter gene cassette that allowed for dynamic monitoring of HIF-1 signal transduction and tumor cell growth in vitro and in vivo, using optical and nuclear imaging. Tempol, an antioxidant compound, was used to investigate the impact of ROS on cycling hypoxia-mediated HIF-1 activation and tumor progression. Principal Findings: Glioblastoma cells and xenografts were compared under cycling hypoxic and normoxic conditions; upregulation of NOX4 expression and ROS levels were observed under cycling hypoxia in glioblastoma cells and xenografts, concomitant with increased tumor cell growth in vitro and in vivo. However, knockdown of Nox4 inhibited these effects. Moreover, in vivo molecular imaging studies demonstrated that Tempol is a good antioxidant compound for inhibiting cycling hypoxia-mediated ROS production, HIF-1 activation, and tumor growth. Immunofluorescence imaging and flow cytometric analysis for NOX4, HIF-1 activation, and Hoechst 3342 in glioblastoma also revealed high localized NOX4 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion within the endogenous solid tumor microenvironment. Conclusions: Cycling hypoxia-induced ROS via Nox4 is a critical aspect of cancer biology to consider for therapeutic targeting of cycling hypoxia-promoted HIF-1 activation and tumor progression in GBM. © 2011 Hsieh et al.


Yang J.C.H.,National Taiwan University | Shih J.-Y.,National Taiwan University Hospital | Su W.-C.,National Cheng Kung University | Hsia T.-C.,China Medical University at Taichung | And 13 more authors.
The Lancet Oncology | Year: 2012

Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. Findings: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd.


Hung C.-C.,China Medical University at Taichung | Liou H.-H.,National Taiwan University Hospital
Investigational New Drugs | Year: 2011

The aim of the present study was to evaluate the effect of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) on multidrug resistance. Expression of human Pglycoprotein was assessed by realtime quantitative RT-PCR and western blot. The efflux function of P-glycoprotein was evaluated by rhodamine 123 accumulation and calcein-AM uptake models. The mechanisms of action of YC-1 on different signaling pathways were studied using series of antagonists and the kinetics was also assessed. Cytotoxicity was evaluated by MTT assay. The results demonstrated that increased intracellular accumulation of rhodamine 123 and increased fluorescence of calcein were observed after YC-1 treatment. Furthermore, increased YC-1 concentration resulted in significant decrease in Vmax while K M remained unchanged suggested that YC-1 acted as a noncompetitive inhibitor of P-glycoprotein. Moreover, the inhibition of Pgp efflux function by YC-1 was significantly reversed by NO synthase inhibitor, L-NAME, the sGC inhibitor, ODQ, the PKG inhibitor, Rp-8-Br-PET-cGMPS, and the PKG inhibitor KT5823. In addition, ERK kinase inhibitor PD98059 also significantly restored YC-1 inhibited Pgp efflux function. These results indicated that YC-1 inhibited Pgp efflux via the NO-cGMP-PKG-ERK signaling pathway through noncompetitive inhibition. The present study revealed that YC-1 could be a good candidate for development as a MDR modulator. © Springer Science+Business Media, LLC 2010.


Wu H.-H.,Chung Shan Medical University | Wu J.-Y.,Tzu Chi University | Cheng Y.-W.,Chung Shan Medical University | Chen C.-Y.,China Medical University at Taichung | And 3 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Inhibitors of antiapoptosis protein (IAP) have been implicated in the resistance to cisplatin. Therefore, verifying which pathway is involved in cIAP2 upregulation may be helpful in finding a feasible pathway inhibitor to increase the chemotherapeutic efficacy in human papillomavirus (HPV)-infected lung cancer. Experimental Design: Specific inhibitors of different pathways were used to verify which pathway is involved in cIAP2 transcription. cIAP2 promoter fragments with various deletions and/or mutations were constructed by site-directed mutagenesis. cIAP2, epidermal growth factor receptor (EGFR), and phospho-AKT (p-AKT) expressions in 136 lung tumors were evaluated by immunohistochemistry. Results: Our data show that two NF-κB (-209 to -200 and -146 to -137) and one CREB (cyclic AMP-responsive element binding protein; -52 to -42) binding sites in cIAP2 promoter region were responsible for cIAP2 upregulated by E6 in TL-1 cells. Moreover, CREB was phosphorylated by EGFR/phosphatidylinositol 3-kinase (PI3K) pathway. To test the involvement of cIAP2 on cisplatin resistance, IC50 was lowered to 8.6 μmol/L in TL-1 cells with cIAP2 short hairpin RNA (shRNA) transfection and compared with 39.7 μmol/L in TL-1 cells with nonspecific shRNA. Pretreatment with EGFR or PI3K inhibitor in TL-1 cells diminished the resistance to cisplatin. Among the tumor groups, cIAP2 expression correlated significantly with HPV16/18 E6, EGFR, and p-AKT. We followed up 46 of 136 patients who had tumor recurrence and/or metastasis and underwent chemotherapy. Tumors with cIAP2-positive immunostaining were associated with a poorer tumor response to chemotherapy compared with those with negative immunostaining. Conclusions: cIAP2 upregulated by E6 via EGFR/PI3K/AKT cascades may contribute to cisplatin resistance, revealing that the EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-infected lung cancer. ©2010 AACR.


Hsu Y.-C.,China Medical University at Taichung | Hsu Y.-C.,I - Shou University | Ho H.J.,Fu Jen Catholic University | Wu M.-S.,National Taiwan University Hospital | And 8 more authors.
Hepatology | Year: 2013

Hepatocellular carcinoma (HCC) frequently recurs after surgical resection. This population-based research aimed to investigate the association between postoperative antiviral treatment and risk of recurrent HCC in patients with hepatitis C virus (HCV) infection. By analyzing the Taiwan National Health Insurance Research Database, we initially screened a total of 100,938 patients diagnosed with HCC for the first time between October 2003 and December 2010. Among 2,237 antiviral-naïve HCV-infected patients with curatively resected HCC, there were 213 patients receiving antiviral treatment with pegylated interferon plus ribavirin for 16 weeks or more after surgery (treated cohort). These treated patients were matched 1:4 with 852 controls who were never treated for HCV infection (untreated cohort) by age, gender, cirrhosis, and the elapsed time between surgery and antiviral therapy. Cumulative incidences of and hazard ratios for recurrent HCC were calculated after adjusting for competing mortality. The recurrence rate of HCC was significantly lower in the treated than untreated cohort, with 52.1% (95% confidence interval [CI], 42.0-62.2%) and 63.9% (95% CI, 58.9-68.8%) after 5 years of follow-up, respectively (P = 0.001). The number needed to treat for one fewer recurrent HCC at 5 years was 8. The association between postoperative antiviral treatment and risk of recurrent HCC was independent of adjustment for multiple covariates, with an adjusted hazard ratio of 0.64 (95% CI, 0.50-0.83). Stratified analyses revealed that the attenuation in recurrence risk was greater in patients younger than 60 years and those without cirrhosis or diabetes. Conclusion: Postoperative pegylated interferon plus ribavirin is associated with reduced recurrence of HCC in patients with HCV infection. Age, liver cirrhosis, and diabetes mellitus appear to modify this association. © 2013 American Association for the Study of Liver Diseases.


Liao P.-C.,National Pingtung University of Science and Technology | Tsai C.-C.,Kaohsiung District Agricultural Research and Extension Station | Chou C.-H.,China Medical University at Taichung | Chiang Y.-C.,National Sun Yat - sen University
International Journal of Molecular Sciences | Year: 2012

The landrace strains of Momordica charantia are widely cultivated vegetables throughout the tropics and subtropics, but not in Taiwan, a continental island in Southeast Asia, until a few hundred years ago. In contrast, the related wild populations with smaller fruit sizes are native to Taiwan. Because of the introduction of cultivars for agricultural purposes, these two accessions currently exhibit a sympatric or parapatric distribution in Taiwan. In this study, the cultivars and wild samples from Taiwan, India, and Korea were collected for testing of their hybridization and evolutionary patterns. The cpDNA marker showed a clear distinction between accessions of cultivars and wild populations of Taiwan and a long divergence time. In contrast, an analysis of eight selectively neutral nuclear microsatellite loci did not reveal a difference between the genetic structures of these two accessions. A relatively short divergence time and frequent but asymmetric gene flows were estimated based on the isolation-with-migration model. Historical and current introgression from cultivars to wild populations of Taiwan was also inferred using MIGRATE-n and BayesAss analyses. Our results showed that these two accessions shared abundant common ancestral polymorphisms, and the timing of the divergence and colonization of the Taiwanese wild populations is consistent with the geohistory of the Taiwan Strait land bridge of the Last Glacial Maximum (LGM). Long-term and recurrent introgression between accessions indicated the asymmetric capacity to receive foreign genes from other accessions. The modern introduction of cultivars of M. charantia during the colonization of Taiwan by the Han Chinese ethnic group enhanced the rate of gene replacement in the native populations and resulted in the loss of native genes. © 2012 by the authors; licensee MDPI, Basel, Switzerland.


Manns M.,Hannover Medical School | Manns M.,German Center for Infection Research | Pol S.,Hopital Cochin | Jacobson I.M.,New York Medical College | And 23 more authors.
The Lancet | Year: 2014

Background: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Methods: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. Findings: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). Interpretation: Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferonfree and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. Funding: Bristol-Myers Squibb.


Hsu T.-W.,National Yang Ming University | Liu J.-S.,National Health Research Institute | Hung S.-C.,Buddhist Tzu Chi Hospital Taipei Branch | Kuo K.-L.,Buddhist Tzu Chi Hospital Taipei Branch | And 6 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE: The benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients with advanced chronic kidney disease (CKD) remains undetermined. OBJECTIVE: To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia. DESIGN: Prospective cohort study. SETTING: Taiwan. PARTICIPANTS: From January 1, 2000, through June 30, 2009, we selected 28 497 hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis-stimulating agents. INTERVENTIONS: Users (n = 14 117) and nonusers (n = 14 380) of ACEIs/ARBs. MAIN OUTCOMES AND MEASURES: We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers. RESULTS: In a median follow-up of 7 months, 20 152 patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, 0.91-0.97]) and the composite outcome of long-term dialysis or death (0.94 [0.92-0.97]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, 0.92-1.16]; P = .30). CONCLUSIONS AND RELEVANCE: Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality.


Tseng Y.-L.,China Medical University at Taichung | Chiang M.-L.,Chang Gung Memorial Hospital | Lane H.-Y.,China Medical University at Taichung | Su K.-P.,China Medical University at Taichung | Lai Y.-C.,China Medical University at Taichung
Thrombosis Research | Year: 2013

Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce platelet aggregation induced by ADP. ADP induces platelet aggregation through two purinergic receptors P2Y1 and P2Y12. We characterized the inhibitory properties of SSRIs on ADP-induced platelet aggregation and investigated the effects of SSRIs on the signaling pathways downstream of P2Y1 and P2Y12 receptors. Specific antagonists were used to evaluate which purinergic receptor-mediated aggregation was influenced by SSRIs. The primary phase of ADP-induced aggregation was not inhibited by citalopram. Citalopram failed to influence ADP-induced platelet shape change, intracellular calcium mobilization and the early phosphorylation of PKCα. Differently, citalopram inhibited the secondary phase of ADP-induced platelet aggregation in a concentration-dependent manner. Other SSRIs, including fluoxetine and sertraline, exhibited the same anti-platelet effects. Under P2Y1 blockade, citalopram inhibited platelet aggregation and integrin αIIbβ3 activation in response to ADP, indicating that citalopram inhibited P2Y12-mediated aggregation. Citalopram concentration-dependently inhibited the phosphorylation of Akt, GSK3β, p38 MAPK and Syk induced by ADP, but showed no effect on the decrease of cAMP and VASP phosphorylation. With integrin α IIbβ3 blockade, however, the phosphorylation of Akt triggered by ADP was unaltered by the addition of citalopram. Taken together, under the stimulation of ADP, SSRIs inhibit the amplification of platelet aggregation secondary to the activation of P2Y12 receptor, and subsequently reduce the activation of the downstream molecules of the outside-in signaling pathways. © 2013 Elsevier Ltd.


Srivastava H.M.,University of Victoria | Srivastava H.M.,China Medical University at Taichung
Russian Journal of Mathematical Physics | Year: 2016

Summation, transformation and reduction formulas for various families of hypergeometric functions in one, two and more variables are potentially useful in many diverse areas of applications. The main object of this paper is to derive several substantially more general results on this subject than those considered recently by Neethu et al. [7] in connection with Bailey’s transformation involving the Gauss hypergeometrc function 2F1 (see [1]). The methodology used here is based essentially on some families of hypergeometric generating functions. Relevant connections of the results presented in this paper with those in the earlier works are also pointed out. © 2016, Pleiades Publishing, Ltd.


Lin Y.-K.,National Taiwan University | Ho T.-J.,China Medical University Beigang Hospital | Ho T.-J.,China Medical University at Taichung | Wang Y.-C.,Chung Yuan Christian University
Environmental Research | Year: 2011

Background: This study investigated mortality risks from all causes, circulatory and respiratory diseases for the elderly associated with prolonged exposure to extreme temperatures in four major cities of Taiwan. Methods: Daily average temperatures at the high 99th, 97th, and 95th percentiles were defined as extreme heat, and those at the low 10th, 5th, and 1st percentiles were defined as extreme cold for each city in 1994-2007. Distributed lag non-linear model was used to estimate the relative risk (RR) of mortality associated with 30-day lag temperature, and heat and cold extremes lasting for 3-5, 6-8, and >8 days. The random-effects meta-analysis summarized the risks of temperature and extreme temperatures events. Results: The lowest overall mortality among the elderly was when the temperature was 26. °C on average. Low temperatures caused greater adverse effects than high temperatures, particularly for mortality from circulatory diseases. After accounting for the cumulative 30-day temperature effects, meta-analysis showed that mortality risk slightly increased with strengthened and prolonged heat extremes (≥99th and >3 days; ≥97th and >8 days; and ≥ 95th and >8 days) that RRs ranged from 1.04-1.05, 1.01-1.05, and 1.05-1.13 for mortality from all causes and from circulatory and respiratory diseases, respectively. The corresponding RRs ranged from 0.98-1.01, 0.92-1.06, and 0.97-1.03, respectively, for shorter duration of heat extremes. This study did not identify significant effect for stronger or prolonged cold extremes. Conclusions: Extreme temperatures and their duration cause varied mortality associations in the elderly. Short-term extremely low temperatures exhibit the greatest effect on mortality, and intensified and longer periods of heat extremes also exert a slightly increased effect on mortality. © 2011 Elsevier Inc.


Yang C.-A.,China Medical University at Taichung | Chiang B.-L.,National Taiwan University Hospital | Chiang B.-L.,National Taiwan University
Journal of Autoimmunity | Year: 2015

Inflammasomes are multi-protein complexes composed of a NOD-like receptor (NLR)/an AIM-like receptor (ALR), the adapter molecule apoptosis-associated speck-like protein that contains a CARD (ASC), and caspase-1. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 to IL-1β and IL-18, resulting in inflammation. Genetic mutations in inflammasomes were first recognized to result in autoinflammatory diseases, which are characterized by the absence of both autoantibodies and autoreactive-T/B cells. However, there is increasing attention being placed on genetic polymorphisms that are involved in the components of inflammasomes, and these have implications for innate immunity and the natural history of autoimmune diseases. For example, while the NOD-like receptor family, pyrin domain containing 1 (NLRP1) haplotypes contributes to susceptibility to developing vitiligo; there are other single nucleotide polymorphisms (SNPs) that alters the susceptibility and severity of rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Indeed, there are multiple factors that contribute to lowering the threshold of immunity and inflammasomes play a key role in this threshold. For example, IL-1β and IL-18 further perpetuate Th17 responses and endothelial cell damage, which potentiate a number of autoimmune diseases, including synovitis in RA, cardiovascular disease, and systemic lupus erythematosus (SLE). There is also increasing data on the role of innate immunity in experimental autoimmune encephalomyelitis (EAE), in lupus nephritis, and in a variety of autoimmune pathologies in which activation of the innate immune system is the driver for the adaptive system. Indeed, it is likely that the chronic pathology of autoimmunity is mediated in part by otherwise innocent bystander cells, augmented by inflammasomes. © 2015 Elsevier Ltd.


Tseng F.-Y.,National Taiwan University Hospital | Tseng F.-Y.,National Taiwan University | Lin W.-Y.,National Taiwan University Hospital | Lin W.-Y.,China Medical University at Taichung | And 7 more authors.
Journal of the American College of Cardiology | Year: 2012

This study sought to evaluate the relationship between subclinical hypothyroidism (SCH) and all-cause and cardiovascular disease (CVD) mortality. SCH may increase the risks of hypercholesterolemia and atherosclerosis. The associations between SCH and all-cause or CVD mortality are uncertain, on the basis of the results of previous studies. A baseline cohort of 115,746 participants without a history of thyroid disease, <20 years of age, was recruited in Taiwan. SCH was defined as a serum thyroid-stimulating hormone (TSH) level of 5.0 to 19.96 mIU/l with normal total thyroxine concentrations. Euthyroidism was defined as a serum TSH level of 0.47 to 4.9 mIU/l. Cox proportional hazards regression analysis was used to estimate the relative risks (RRs) of death from all-cause and CVD for adults with SCH during a 10-year follow-up period. There were 3,669 deaths during the follow-up period; 680 deaths were due to CVD. Compared with subjects with euthyroidism, after adjustment for age, sex, body mass index, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, betel nut chewing, physical activity, income, and education level, the RRs (95% confidence interval) of deaths from all-cause and CVD among subjects with SCH were 1.30 (1.02 to 1.66), and 1.68 (1.02 to 2.76), respectively. Adult Taiwanese with SCH had an increased risk for all-cause mortality and CVD death. © 2012 American College of Cardiology Foundation.


Chen S.-H.,China Medical University at Taichung | Tang Y.-B.,National Taiwan University Hospital | Chen H.-C.,China Medical University at Taichung
Journal of the American College of Surgeons | Year: 2013

Background: The aim of this study was to identify the ischemic tolerance of the ileum. In microvascular transfer of autologous bowel segments, the most critical factor for survival is ischemic time. In earlier animal studies, the tolerance of ischemic time was shorter for the ileum than for the jejunum, and an ischemic time of <1 hour was suggested for microvascular transfer of the ileum. It was believed that there are more bacteria in the ileum than in the jejunum and therefore autolysis and necrosis will be triggered sooner after the initiation of ischemia. However, in a clinical scenario, the tolerance for ischemic time of the ileum has not yet been clarified. Study Design: From 1998 to 2011, eight-four cases of microvascular transfer of intestine containing a segment of the ileum were reviewed. Data collected included the ischemia time during surgery, re-exploration, survival, complications, and postoperative functions. Multivariate analysis with exact logistic regression was used to identify the correlation between the ischemic time and necrosis of the transferred segment, as well as other complications. Results: For segmental ileum transfer, the ischemic time >1 hour (but within 2 hours) at room temperature is not a risk factor for flap loss or complications. This contradicts data from animal studies in the literature. Conclusions: Clinically, the ileum segments can tolerate ischemia well within 2 hours. Segmental ileum transfer can be more widely applied in other fields. Care in each step of transfer is mandatory for functional success. © 2013 by the American College of Surgeons.


Wang Y.-J.,National Chiao Tung University | Lin H.-Y.,China Medical University at Taichung | Wu C.-H.,China Medical University at Taichung | Liu D.-M.,National Chiao Tung University
Molecular Pharmaceutics | Year: 2012

We report an efficient therapeutic approach to inhibit the migration and growth of vascular smooth muscle cells (VSMCs) via a low-dose sustained elution of a water-insoluble drug, demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanol chitosan (CHC) nanomatrix. Manipulating the cellular internalization and controlled cytotoxic effect of DMC-CHC nanoparticles over the VSMCs was elucidated. The DMC-CHC nanoparticles, which were systematically characterized in terms of structural morphology, surface potential, encapsulation efficiency, and DMC nanocrystallite distribution, exhibited rapid cellular uptake efficiency and considerably improved cytotoxic potency by 2.8 times compared to the free DMC. Under a cytotoxic evaluation, an improved antiproliferative effect and effective inhibition of VSMC migration as a result of highly efficient intracellular delivery of the encapsulated DMC in comparison to free DMC was achieved, which also was confirmed with a subsequent protein analysis. Cellular drug release and distribution of DMC after internalization into VSMCs was experimentally determined. This work may open a potential intracellular medicinal strategy with improved biological and therapeutic efficacy using the DMC-CHC nanoparticles illustrated in this work. © 2012 American Chemical Society.


Wu C.-Y.,National Yang Ming University | Wu C.-Y.,Taichung Veterans General Hospital | Wu C.-Y.,China Medical University at Taichung | Wu C.-Y.,National Chung Hsing University | And 11 more authors.
JAMA - Journal of the American Medical Association | Year: 2012

Context: Tumor recurrence is a major issue for patients with hepatocellular carcinoma (HCC) following curative liver resection. Objective: To investigate the association between nucleoside analogue use and risk of tumor recurrence in patients with hepatitis B virus (HBV)-related HCC after curative surgery. Design, Setting, and Participants: A nationwide cohort study between October 2003 and September 2010. Data from the Taiwan National Health Insurance Research Database. Among 100 938 newly diagnosed HCC patients, we identified 4569 HBV-related HCC patients who received curative liver resection for HCC between October 2003 and September 2010. Main Outcome Measures: The risk of first tumor recurrence was compared between patients not taking nucleoside analogues (untreated cohort, n=4051) and patients taking nucleoside analogues (treated cohort, n=518). Cumulative incidences and hazard ratios (HRs) were calculated after adjusting for competing mortality. Results: The treated cohort had a higher prevalence of liver cirrhosis when compared with the untreated cohort (48.6% vs 38.7%; P<.001), but lower risk of HCC recurrence (n=106 [20.5%] vs n=1765 [43.6%]; P<.001), and lower overall death (n=55 [10.6%] vs n=1145 [28.3%]; P<.001). After adjusting for competing mortality, the treated cohort had a significantly lower 6-year HCC recurrence rate (45.6%; 95% CI, 36.5%-54.6% vs untreated, 54.6%; 95% CI, 52.5%-56.6%; P<.001). Six-year overall mortalities for treated cohorts were 29.0% (95% CI, 20.0%-38.0%) and for untreated 42.4% (95% CI, 40.0%-44.7%; P<.001). On modified Cox regression analysis, nucleoside analogue use (HR, 0.67; 95% CI, 0.55-0.81; P<.001), statin use (HR, 0.68; 95% CI, 0.53-0.87; P=.002), and nonsteroidal anti-inflammatory drugs or aspirin use (HR, 0.80; 95% CI, 0.73-0.88; P<.001) were independently associated with a reduced risk of HCC recurrence. Multivariable stratified analyses verified the association in all subgroups of patients, including those who were noncirrhotic (HR, 0.56; 95% CI, 0.42-0.76) and diabetic (HR, 0.52; 95% CI, 0.31-0.89). Conclusion: Nucleoside analogue use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection. ©2012 American Medical Association. All rights reserved.


Lin H.-H.,China Medical University at Taichung | Liou H.-H.,Hsin Jen Hospital | Wu M.-S.,National Taiwan University Hospital | Lin C.-Y.,China Medical University at Taichung | Huang C.-C.,China Medical University at Taichung
Nephrology | Year: 2014

Aims: Fibroblast growth factor 23 (FGF23) and Klotho are associated with vascular calcification and cardiovascular disease in dialysis patients. Sevelamer has been shown to reduce progression of vascular calcification. This study aimed to determine the long-term effect of sevelamer treatment on serum FGF23 and Klotho levels in chronic haemodialysis (HD) patients. Methods: In the post-hoc analysis, we measured serum FGF23, Klotho and other biochemical factors (Ca, P, i-PTH, hsCRP, LDL-C) in 50 haemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. Twenty-three patients received sevelamer and 27 patients received calcium carbonate. Results: After 48-week sevelamer treatment, there were significant changes with lower LDL-C (from 2.82 ± 0.78 to 1.65 ± 0.53 mmol/L, P = 0.000), lower FGF23 (from 2465.97 (2568.88) to 795.61 (1098.39), P = 0.000) and higher s-Klotho levels (from 189.35 (161.88) to 252.94 (517.80) pg/mL, P = 0.000). In calcium carbonate group, there were no significant changes of LDL-C and FGF23, but with a borderline significant increase of s-Klotho level (from 142.34 (265.24) to 188.57 (252.38) pg/mL, P = 0.054). Multivariate analysis showed that FGF23 decrement was associated with sevelamer treatment (β = -0.277, P = 0.005), change of serum phosphate (β = 0.609, P = 0.000) and calcium levels (β = 0.635, P = 0.000). The increase of serum Klotho was associated with the decrease of serum phosphate (β = 0.490, P = 0.019). Conclusion: Maintenance HD patients had lower serum FGF23 levels, accompanied with significantly increased serum Klotho levels, after 48-week sevelamer treatment. The FGF23 decrement was associated with sevelamer use, the change of serum phosphate and calcium levels. The serum Klotho increment was proportional to the phosphate-lowering power of the binders. © 2014 Asian Pacific Society of Nephrology.


Gansevoort R.T.,University of Groningen | Correa-Rotter R.,National Medical Science and Nutrition Institute Salvador Zubiran | Hemmelgarn B.R.,University of Calgary | Jafar T.H.,National University of Singapore | And 6 more authors.
The Lancet | Year: 2013

Since the first description of the association between chronic kidney disease and heart disease, many epidemiological studies have confirmed and extended this finding. As chronic kidney disease progresses, kidney-specific risk factors for cardiovascular events and disease come into play. As a result, the risk for cardiovascular disease is notably increased in individuals with chronic kidney disease. When adjusted for traditional cardiovascular risk factors, impaired kidney function and raised concentrations of albumin in urine increase the risk of cardiovascular disease by two to four times. Yet, cardiovascular disease is frequently underdiagnosed and undertreated in patients with chronic kidney disease. This group of patients should, therefore, be acknowledged as having high cardiovascular risk that needs particular medical attention at an individual level. This view should be incorporated in the development of guidelines and when defining research priorities. Here, we discuss the epidemiology and pathophysiological mechanisms of cardiovascular risk in patients with chronic kidney disease, and discuss methods of prevention. © 2013 Elsevier Ltd.


Patent
Sundragon Biomedical Electronics Co. and China Medical University at Taichung | Date: 2015-10-29

The present invention provides a pharmaceutical composition for treating and/or relieving myopia, the pharmaceutical composition comprises a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier; the pharmaceutical composition of the present invention is safe, and can treat and/or relieve myopia by the anti-inflammatory agent. The pharmaceutically acceptable carrier can effectively encapsulate the anti-inflammatory agent at a specific ratio, and the stability and solubility of the pharmaceutical composition can be enhanced.


Wang Y.-J.,National Chiao Tung University | Chien Y.-C.,National Chiao Tung University | Wu C.-H.,China Medical University at Taichung | Liu D.-M.,National Chiao Tung University
Molecular Pharmaceutics | Year: 2011

Encapsulation and release behavior of a water-insoluble drug, magnolol, using a core-shell polysaccharide-based nanoparticle, manipulating the cellular internalization and controlled cytotoxic effect of magnolol-loaded nanoparticles over the A10 vascular smooth muscle cells (VSMCs) was reported. A magnolol-polyvinylpyrrolidone (PVP) core phase was prepared, followed encapsulating by an amphiphilic carboxymethyl-hexanoyl chitosan (CHC) shell to form a magnolol-loaded core-shell hydrogel nanoparticles (termed magnolol-CHC nanoparticles). The resulting magnolol-CHC nanoparticles were employed for evaluation of drug release and controlled cytotoxic inhibition of VSMCs migration in vitro. A sustained release of the magnolol from the nanoparticles was determined. The magnolol-CHC nanoparticles exhibited outstanding cellular uptake efficiency, and under a cytotoxic evaluation, an increased antiproliferative effect and effective inhibition of VSMC migration as a result of efficient intracellular delivery of the encapsulated magnolol in comparison to free magnolol was achieved. We then envision a potential intracellular medication strategy with improved biological and therapeutic efficacy using the magnolol-CHC nanoparticles illustrated in this work. © 2011 American Chemical Society.


Jump A.S.,University of Stirling | Huang T.-J.,China Medical University at Taichung | Chou C.-H.,China Medical University at Taichung
Ecography | Year: 2012

Mountain systems throughout the globe are characterized by high levels of species richness and species endemism. Biodiversity, however, is not distributed evenly with altitude, but often declines from mid to high altitudes. Conversely, endemic species may be over-represented at high altitudes. Upward elevational range shifts of mountain species have been reported in response to ongoing changes in climate, yet the reports are dominated by studies on woody species and mountains at high latitudes. We investigated spatial and temporal changes in the mountain biodiversity in the subtropical island of Taiwan, based on historical survey and resurvey data during the period 1906-2006. We found that upper altitudinal limits of mountain plant distributions have risen by ca 3.6 m yr -1 during the last century, in parallel with rising temperatures in the region. Although species, genus, and family richness decline with altitude, ca 55% of species at the highest altitudes are endemic to the island. Given the steep decline in land area with increasing elevation, these high altitude areas are disproportionately important for plant biodiversity when richness and endemism are standardized by available land area. We argue that the distributional shift that we report, in combination with the altitudinal distribution of plant diversity, is likely to pose a major threat to high mountain species of this highly biodiverse island, a threat that is becoming increasingly evident for high mountain plants throughout the globe. © 2011 The Authors. Ecography © 2012 Nordic Society Oikos.


Huang W.-H.,National Yang Ming University | Chang M.-C.,National Yang Ming University | Chang M.-C.,Taipei Veterans General Hospital | Tsai K.-S.,National Yang Ming University | And 6 more authors.
Oncogene | Year: 2013

Though the early integration of mesenchymal stem cells (MSCs) into tumor-associated stroma of cancer has been demonstrated, the functional contributions and underlying mechanisms of these cells to tumor growth and angiogenesis remain to be clarified. Using a xenograft model, human colorectal cancer cells, MSCs, and their cell mixture were introduced to a subcutaneous site of immunodeficient mice. The tumor growth rate and angiogenesis of each transplantation was then compared. We demonstrate that a variety of colorectal cancer cells, when mixed with otherwise non-tumorigenic MSCs, increase the tumor growth rate and angiogenesis more than that when mixed with carcinoma-associated fibroblasts or normal colonic fibroblasts. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in cancer cells, which induces the activation of Akt and ERK in endothelial cells, thereby enhancing their capacities for recruitment and angiogenesis to tumor. The IL-6/ET-1/Akt or ERK pathway of tumor-stroma interaction can be targeted by an antibody against IL-6 or Lentiviral-mediated RNAi against IL-6 in MSCs, by inhibition or knockdown of ET-1 in cancer cells, or by inhibition of ERK and Akt in host endothelial cells. These demonstrate that attempts to interrupt the interaction of MSCs and cancer cells help to abrogate angiogenesis and inhibit tumor growth in tumors formed by cancer cells admixed with MSCs. These data demonstrate that the tumor microenvironment, namely, MSCs-secreted IL-6, may enrich the proangiognic factors secreted by cancer cells to increase angiogenesis and tumor growth and that targeting this interaction may lead to novel therapeutic and preventive strategies. © 2013 Macmillan Publishers Limited.


Huang T.-C.,China Medical University at Taichung | Wu T.-H.,National Yang Ming University | Lin C.-J.,Taipei Veterans General Hospital | Mok G.S.P.,Macau University of Science and Technology | Guo W.-Y.,Taipei Veterans General Hospital
Journal of Vascular Surgery | Year: 2012

Digital subtraction angiography (DSA) provides detailed hemodynamic information. However, the imaging interpretation is mainly based on the physician's experience and observation. We aimed to quantitatively study the peritherapeutic blood flow changes of a cerebral arteriovenous malformation (AVM) treated by embolization using optical flow estimation on DSA. A 37-year-old woman with an AVM in the right frontal lobe of her brain was enrolled. The optical flow method with a pixel-by-pixel measurement was applied to determine the blood flow in brain vessels on anteriorposterior and lateral DSA views before and after embolization. A return toward normalization of blood flow as a result of embolization was determined semiquantitatively on the posttherapeutic DSA. Optical flow analysis on DSA illustrated the potential of quantifying intracranial blood flows in patients with cerebral vascular disorders and the therapeutic effects. © 2012 Society for Vascular Surgery.


Chang W.-H.,Kaohsiung Medical University | Liu T.-C.,Kaohsiung Medical University | Yang W.-K.,China Medical University at Taichung | Lee C.-C.,Kaohsiung Medical University | And 3 more authors.
Cancer Research | Year: 2011

The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-xs and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib. © 2011 American Association for Cancer Research.


Hsieh H.-M.,Fu Jen Catholic University | Wu W.-M.,Fu Jen Catholic University | Hu M.-L.,National Chung Hsing University | Hu M.-L.,China Medical University at Taichung
Life Sciences | Year: 2011

Aims: We investigated the mechanism of D-galactose (DG)-induced oxidative damage and the neuroprotective action of genistein in PC12 cells. Main methods: PC12 cells were treated with 40 mM DG dissolved in medium containing 85% RPMI1640, 10% HBS and 5% FBS with or without genistein. We measured the protein expression of β-amyloid (Aβ), advanced glycation end products (AGEs), IκB-α and manganese-superoxide dismutase (MnSOD) by western blotting, intracellular reactive oxygen species (ROS) by 2, 7- dichlorofluorescin-diacetate, and the binding activity of nuclear factor kappa B (NF-κB) by electrophortic mobility shift assay. Key findings: DG (40 mM) completely retarded cell growth after incubation for 72 h, and this effect was not due to osmotic changes, as 40 mM mannitol had no effect. Mechanistically, we found that DG increased intracellular ROS starting at 4 h and increased Aβ and AGEs at 24 h. DG treatment for 24 h also increased the binding activity of NF-κB but strongly decreased the expression of IκB-α protein. Furthermore, DG treatment for 48 h increased MnSOD protein expression. All these effects of DG were effectively inhibited by genistein (0.5-10 μM). Significance: The present study indicates that the protection of genistein against DG-induced oxidative stress in PC12 cells, and the effect is likely mediated by decreased intracellular ROS and binding activity of NF-κB. © 2010 Elsevier Inc. All rights reserved.


Hsu C.C.,National Health Research Institute | Hsu C.C.,China Medical University at Taichung | Chang H.Y.,National Health Research Institute | Huang M.C.,Kaohsiung Medical University | And 5 more authors.
Diabetologia | Year: 2012

Aims/hypothesis HbA 1c variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA 1c variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA 1c over 2 years for this risk assessment. Methods Between 2003 and 2005, we recruited 821 middleaged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2 years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30 mg/g (3.4 mg/mmol) or higher. HbA 1c variability was calculated by the SD of serially measured HbA 1c. The Cox proportional hazards model was used to evaluate the association between HbA 1c SD quartile and development of microalbuminuria. Results The incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 personyears for Q1- to Q4-adjusted HbA 1c SD, respectively (p for trend00.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2 year HbA 1c measurements was similar to that from data collection for longer than 4 years. Conclusions/interpretation In addition to mean HbA 1c values, HbA 1c variability, even measured as early as 2 years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes. © Springer-Verlag 2012.


Er T.-K.,Kaohsiung Medical University | Chang J.-G.,Kaohsiung Medical University | Chang J.-G.,China Medical University at Taichung
Clinica Chimica Acta | Year: 2012

High-resolution melting (HRM) analysis is a feasible and powerful method for mutation scanning of sequence variants. Denatured doubled-stranded DNA can be detected in fluorescence changes by increasing the melting temperature and wild-type and heterozygous samples can be easily differentiated in the melting plots. HRM analysis represents the next generation of mutation-scanning technology and offers considerable time and cost savings compared to other screening methods. HRM analysis is a closed-tube method, indicating that polymerase chain reaction amplification and subsequent analysis are sequentially performed in the well, making HRM analysis more convenient than other scanning methodologies. Taken together, HRM analysis can be used for high-throughput mutation screening for research, as well as for molecular diagnostic and clinical purposes. This review summarizes the effectiveness of HRM analysis in the diagnosis of autosomal recessive, dominant, and X-linked genetic disorders. Notably, we will also discuss the limitations of HRM analysis and how to overcome them. © 2012 Elsevier B.V.


Wu D.-W.,Taipei Medical University | Hsu N.-Y.,Taipei Medical University | Wang Y.-C.,Chung Shan Medical University | Lee M.-C.,Taichung Veteran General Hospital | And 3 more authors.
Oncogene | Year: 2015

The dual role of the microRNA-29 (miR-29) family in tumor progression and metastasis in solid tumors has been reported. Evidence for the role of miR-29 in tumor malignancy and its prognostic value in overall survival (OS) and relapse-free survival (RFS) in non-small cell lung cancer (NSCLC) remains conflicting. Mechanistic studies presented herein demonstrated that c-Myc suppressed the expression of miR-29b, promoting soft agar growth and invasion capability in lung cancer cells. Interestingly, the decrease in the expression of miR-29b by c-Myc is responsible for soft agar growth and invasiveness mediated by FHIT loss due to promoter methylation. Among patients, low expression of miR-29b and FHIT was more common in tumors with high c-Myc expression than in tumors with low c-Myc expression. Kaplan-Meier and Cox regression analysis showed that tumors with high c-Myc, low miR-29b and low FHIT expression had shorter OS and RFS periods than their counterparts. In conclusion, the decrease in the expression of miR-29b by c-Myc may be responsible for FHIT loss-mediated tumor aggressiveness and for poor outcome in NSCLC. Therefore, we suggest that restoration of the miR-29b expression using the c-Myc inhibitor might be helpful in suppressing tumor aggressiveness mediated by FHIT loss and consequently improving outcomes in NSCLC patients with tumors with low expression of FHIT. © 2015 Macmillan Publishers Limited All rights reserved.


Chiu H.-F.,Kaohsiung Medical University | Ho S.-C.,Kaohsiung Medical University | Chang C.-C.,National Cheng Kung University | Wu T.-N.,China Medical University at Taichung | And 2 more authors.
American Journal of Gastroenterology | Year: 2011

Objectives: Experimental studies have shown that statins have potential protective effects against cancer. The aim of this study was to investigate whether the use of statins was associated with gastric cancer risk. Methods: We conducted a population-based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National health Insurance Research Database. Cases consisted of all patients who were aged ≥50 years and had a first-time diagnosis of gastric cancer for the period between 2005 and 2008. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. Results: We examined 337 gastric cancer cases and 1,348 controls. We found that ever-use of any statin was associated with a significant decrease in gastric cancer risk (OR=0.68, 95% CI=0.49-0.95). Compared with no use of statins, the adjusted ORs were 0.90 (95% CI=0.60-1.36) for the group having been prescribed statins with cumulative defined daily doses (DDDs) <134.25 and 0.49 (95% CI=0.30-0.79) for the group with cumulative statin use of ≥134.25 DDDs. Also, there was a significant trend toward decreasing gastric cancer risk with increasing cumulative dose (χ 2 for linear trend=7.42, P=0.006). Conclusions: The results of this study are the first to suggest that statins may reduce the risk of gastric cancer. © 2011 by the American College of Gastroenterology.


Lin J.C.-F.,University of Taipei | Lin J.C.-F.,Taipei Medical University Hospital | Liang W.-M.,China Medical University at Taichung
BMC Nephrology | Year: 2015

Abstract Background: Osteoporotic hip fractures cause high mortality and morbidity in elderly adults. Compared to the general population, subjects with end-stage renal disease and hemodialysis often develop mineral bone disorders and have a higher risk for hip fractures. Methods: We conducted a matched cohort study design and used competing risk analysis to estimate the cumulative incidence of the complication rate. Subjects aged greater than 60 years with hip fracture were selected from Taiwan's National Health Insurance Research Database covering a period from 1997 to 2007, and these subjects were followed up until 2009. We used the Kaplan-Meier method to estimate the overall survival and used the log-rank test and multiple Cox proportional hazards model to explore the risk factors for survival. The cumulative incidence of the first complication was estimated using competing risk analysis. Results: Among hemodialysis subjects, the three-month, one-year, two-year and five-year mortality rates were 17.3%, 37.2%, 51.5%, and 80.5%, respectively; the one-year and five-year cumulative incidences of the first surgical complication were 14.2% and 20.6%, respectively; and the three-month cumulative incidence of the first medical complication was 24.1%. Hemodialysis subjects presented a 2.32 times (95% CI: 2.16-2.49) higher hazard ratio of overall death, 1.15 times (95% CI: 1.01-1.30) higher sub-hazard ratio (sub-HR) of surgical complications, and 1.35 times (95% CI: 1.21-1.52) higher sub-HR of the first medical complication than non-hemodialysis controls. Conclusions: The overall mortality and complication rates of hemodialysis subjects after surgery for hip fracture were significantly higher than those of non-hemodialysis subjects. Further prospective studies which include important risk factors are necessary to more precisely quantify the adjusted effect of hemodialysis. © 2015 Lin and Liang.


Weng J.-R.,China Medical University at Taichung | Yen M.-H.,Kaohsiung Medical University
Helvetica Chimica Acta | Year: 2010

The six new dihydro-β-agarofuranoid sesquiterpenes 1-6 and three known compounds were isolated from the whole plant of Celastrus paniculatus. The structures including relative configurations were elucidated by means of spectroscopic analyses. Compounds 1-6 were evaluated for cytotoxicity against a panel of three human-tumor cell lines. © 2010 Verlag Helvetica Chimica Acta AG.


Shaw L.-H.,National Yang Ming University | Lin L.-C.,National Yang Ming University | Lin L.-C.,National Research Institute of Chinese Medicine | Tsai T.-H.,National Yang Ming University | And 2 more authors.
PLoS ONE | Year: 2012

Bu-yang-huan-wu-tang (BYHWT) is one of the most popular formulated traditional Chinese medicine prescriptions, and is widely for prevention of ischemic cardio-cerebral vascular diseases and stroke-induced disability. A specific high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has been developed and validated for simultaneous quantification of the nine main bioactive components, i.e., astragaloside I, astragaloside II, astragaloside IV, formononetin, ononin, calycosin, calycosin-7-O-β-d-glucoside, ligustilide and paeoniflorin in rat plasma after oral administration of BYHWT extract. This method was applied to investigate the pharmacokinetics in conscious and freely moving rats. No significant matrix effects were observed. The overall analytical procedure was rapid and reproducible, which makes it suitable for quantitative analysis of a large number of samples. Among them, three astragalosides and four isoflavones in A. membranaceus, ligustilide in Radix Angelicae Sinensis and Rhizoma Ligustici Chuanxiong and paeoniflorin in Radix Paeoniae Rubra were identified. This developed method was then successfully applied to pharmacokinetic studies of the nine bioactive constituents after oral administration of BYHWT extracts in rats. The pharmacokinetic data demonstrated that astragaloside I, astragaloside II, astragaloside IV and ligustilide presented the phenomenon of double peaks. The other herbal ingredients of formononetin, ononin, calycosin, calycosin-7-O-β-d-glucoside and paeoniflorin appeared together in a single and plateau absorption phase. These phenomenona suggest that these components may have multiple absorption sites, regulation of enterohepatic circulation or the gastric emptying rate, or there is ingredient-ingredient interaction. These pharmacokinetic results provide a constructive contribution to better understand the absorption mechanism of BYHWT and to support additional clinical evaluation. © 2012 Shaw et al.


Lee W.-C.,National Yang Ming University | Tsai T.-H.,National Yang Ming University | Tsai T.-H.,China Medical University at Taichung | Tsai T.-H.,Taipei Medical University Hospital
International Journal of Pharmaceutics | Year: 2010

Coenzyme Q10 (CoQ10) is an endogenous cellular antioxidant that is used as a nutritional supplement and for medicinal purposes. In recent in vivo investigations, cosmetically applied CoQ10 has demonstrated its ability to reduce photoaging, with a corresponding decrease in wrinkle depth. However, the bioavailability of topical CoQ10 is poor; the development of a practical topical formulation is therefore highly desirable. In this study, a liposomal formulation composed of soybean phosphatidylcholine (SPC) and α-tocopherol (Vit E) was utilized to encapsulate CoQ10 for topical application. The liposomes were less than 200. nm in diameter and had a narrow size distribution. Encapsulation of CoQ10 in liposomes composed of SPC and Vit E significantly (p< 0.05) enhanced its accumulation (at least twofold) in rat skin, compared with an unencapsulated suspension. Prolonging the treatment time and increasing the content of CoQ10 in the formulation both raised the amount of CoQ10 in rat skin. However, in skin treated with the highest CoQ10 content formulation, insufficient treatment time limited the amount accumulated. This study demonstrates that liposomal CoQ10 is a promising candidate for the topical application of CoQ10. The treatment duration is the key factor limiting penetration following in vivo topical application. © 2010 Elsevier B.V.


Peng C.-C.,Taipei Medical University | Peng C.-C.,China Medical University at Taichung | Chen K.C.,Taipei Medical University Hospital | Lu H.Y.,China Medical University at Taichung | Peng R.Y.,Hungkuang University
Journal of Biological Regulators and Homeostatic Agents | Year: 2012

Adriamycin nephropathy (AN) or doxorubicin-induced chronic kidney disease (DRCKD) has several strengths as an experimental model of renal diseases involving glomerulosclerosis, tubulointerstitial inflammation and fibrosis. Exercise has shown to be beneficial to many chronic diseases. We hypothesize that treadmill exercise may improve AN, and an investigation was carried out with the AN SD rat model. Treadmill exercise was conducted three times per week, each time for 30 and 60 min. DR induced swelling of glomeruli, collagen deposition in the interstitium and renal cortex, and increased the serum levels of MDA, IL-6, PDGF-BB, MMP-2, MMP-9, TGF-β, p-PDGFR, uric acid, serum cholesterol, triglycerides, BUN, creatinine, blood platelet count, ratio of kidney to body weight, glomerular volume, and urinary BUN and protein. Conversely, levels of serum SOD, TNF-α, p-PI3K, p-Akt, albumin, WBC, RBC, and urinary creatinine were decreased. Treadmill exercise ameliorated most of these damaging effects, better outcome was found for the 60-min exercise training. Conclusively, the endurance exercise is more associated with the normalization of signaling expressions involving TGF-β, PDGF-BB, p-PDGFR, p-PI3K, and p-Akt, which may help CKD patients to restore cell survival, proliferation, and growth. As rehabilitation is a personalized medicine, an appropriate design to fit individual feasibility has to be well figured out. Copyright © by BIOLIFE, s.a.s.


Chen S.-W.,Taipei Medical University Hospital | Chen S.-W.,China Medical University at Taichung | Chen S.-W.,Taipei Medical University | Lin L.-C.,Chi Mei Hospital | And 6 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2014

Purpose This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and was irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation. © 2014 Elsevier Inc. All rights reserved.


Cherng J.-M.,Chung Shan Medical University | Tsai K.-D.,China Medical University at Taichung | Tsai K.-D.,National Chung Cheng University | Yu Y.-W.,Chung Shan Medical University | Lin J.-C.,Centers for Disease Control and Prevention
Radiation Research | Year: 2011

Glycyrrhizic acid has been shown to possess anti-inflammation, antiviral and chemoprotective activity against tumors. We evaluated the protective effects of glycyrrhizic acid in UVB-radiation-induced skin tumor formation in SKH-1 hairless mice and the early molecular biomarkers of these effects. Mice irradiated at 180 mJ/cm 2 twice per week showed 100% tumor incidence in 20 weeks. Feeding with glycyrrhizic acid prior to UVB irradiation caused delays in tumor appearance, multiplicity and size. Feeding with glycyrrhizic acid for 2 weeks before a single UVB irradiation (180 mJ/cm 2) resulted in significant decrease in UVB-radiation-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, and apoptotic sunburn cells together with an increase in p53- and p21/Cip1-positive cell populations in epidermis. Simultaneously, glycyrrhizic acid also significantly inhibited NF-B, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels. Thus glycyrrhizic acid ameliorates UVB-radiation-induced tumorigenesis via downregulation of cell proliferation controls involving thymine dimer, PCNA, apoptosis and transcription factor NF-B and of inflammatory responses involving COX-2, PGE2 and NO while upregulating of p53 and p21/Cip1 to prevent DNA damage and facilitate DNA repair. © 2011 by Radiation Research Society. All rights of reproduction in any form reserved.


Lu D.-Y.,China Medical University at Taichung | Yeh W.-L.,Changhua Christian Hospital | Huang S.-M.,Buddhist Tzu Chi General Hospital | Huang S.-M.,National Chung Hsing University | And 3 more authors.
Neuro-Oncology | Year: 2012

Malignant gliomas are associated with high morbidity and mortality because they are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Osteopontin is abundantly expressed in the brain and is involved in cell adhesion, migration, and invasion. The aim of the present study was to investigate the mechanisms of glioma cell migration. Migration and invasion activity were determined by transwell and wound-healing assays. Gene and protein expressions were analyzed by reverse transcription-PCR, real time-PCR, and Western blotting. Nrf2-DNA binding activity was determined by electrophoretic mobility shift assay. Establishment of migration-prone sublines were performed to select highly migratory glioma. An intracranial xenograft mouse model was used for the in vivo study. Application of recombinant human osteopontin enhanced the migration of glioma cells. Expression of heme oxygenase (HO)-1 mRNA and protein also increased in response to osteopontin stimulation. Osteopontin-induced increase in cell migration was antagonized by HO-1 inhibitor or HO-1 small interfering (si)RNA. Osteopontin-mediated HO-1 expression was reduced by treatment with MEK/ERK and phosphatidylinositol 3-kinase/Akt inhibitors, as well as siRNA against Nrf2. Furthermore, osteopontin stimulated Nrf2 accumulation in the nucleus and increased Nrf2-DNA binding activity. In migration-prone sublines, cells with greater migration ability had higher osteopontin and HO-1 expression, and zinc protoporphyrin IX treatment could effectively reduce the enhanced migration ability. In an intracranial xenograft mouse model, transplantation of migration-prone subline cells exhibited higher cell migration than parental tumor cells. These results indicate that osteopontin activates Nrf2 signaling, resulting in enhanced HO-1 expression and cell migration in glioma cells. © 2012 The Author(s).


Tain Y.-L.,Chang Gung University | Lee W.-C.,Chang Gung University | Hsu C.-N.,Chang Gung University | Hsu C.-N.,Kaohsiung Medical University | And 3 more authors.
PLoS ONE | Year: 2013

Diabetes mellitus complicates pregnancies, leading to diseases in adult life in the offspring. Asymmetric dimethylarginine (ADMA) is increased in diabetes mellitus, kidney disease, and hypertension. We tested whether maternal diabetes causes increased ADMA in rats, resulting in kidney disease and hypertension in the adult offspring, and whether these can be prevented by maternal citrulline supplementation. Newborn female and pregnant Sprague-Dawley rats were injected with streptozotocin (STZ), which made up the nSTZ and STZ models, respectively. For the STZ model, 4 groups of male offspring were killed at age 3 months: the control, STZ, and Cit and STZ+Cit (control and STZ rats treated with 0.25% L-citrulline solution, respectively) groups. The nSTZ rats had lower nephron numbers. The renal level of ADMA was higher in the nSTZ rats than in controls. The STZ group developed kidney injury, renal hypertrophy, and elevated blood pressure at the age of 12 weeks. These conditions were found to be associated with increased ADMA levels, decreased nitric oxide (NO) production, and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in the kidney. In addition, ADMA caused a nephron deficit in cultured rat metanephroi. Maternal citrulline supplementation prevented hypertension and kidney injury, increased the renal DDAH-2 protein level, and restored the levels of ADMA and NO in the STZ+Cit group. Reduced nephron number and increased ADMA contribute to adult kidney disease and hypertension in offspring of mothers with STZ-induced diabetes. Manipulation of the ADMA-NO pathway by citrulline supplementation may be a potential approach to prevent these conditions. © 2013 Tain et al.


Zhang L.,University of Texas M. D. Anderson Cancer Center | Zhang S.,University of Texas M. D. Anderson Cancer Center | Zhang S.,University of Notre Dame | Yao J.,University of Texas M. D. Anderson Cancer Center | And 21 more authors.
Nature | Year: 2015

The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients. © 2015 Macmillan Publishers Limited.All rights reserved.


Liu P.-Y.,Kaohsiung Medical University | Lin Y.-H.,China Medical University at Taichung | Feng C.H.,Kaohsiung Medical University | Chen Y.-L.,Kaohsiung Medical University
Electrophoresis | Year: 2012

A CD-modified CE method was established for quantitative determination of seven hydroxy acids in cosmetic products. This method involved chemometric experimental design aspects, including fractional factorial design and central composite design. Chemometric experimental design was used to enhance the method's separation capability and to explore the interactions between parameters. Compared to the traditional investigation that uses multiple parameters, the method that used chemometric experimental design was less time-consuming and lower in cost. In this study, the influences of three experimental variables (phosphate concentration, surfactant concentration, and methanol percentage) on the experimental response were investigated by applying a chromatographic resolution statistic function. The optimized conditions were as follows: a running buffer of 150 mM phosphate solution (pH 7) containing 0.5 mM CTAB, 3 mM γ-CD, and 25% methanol; 20 s sample injection at 0.5 psi; a separation voltage of -15 kV; temperature was set at 25°C; and UV detection at 200 nm. The seven hydroxy acids were well separated in less than 10 min. The LOD (S/N = 3) was 625 nM for both salicylic acid and mandelic acid. The correlation coefficient of the regression curve was greater than 0.998. The RSD and relative error values were all less than 9.21%. After optimization and validation, this simple and rapid analysis method was considered to be established and was successfully applied to several commercial cosmetic products. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Chen H.-J.,China Medical University at Taichung | Hsu L.-S.,Ming Chuan University | Shia Y.-T.,China Medical University at Taichung | Lin M.-W.,China Medical University at Taichung | Lin C.-M.,Ming Chuan University
Biochemical Pharmacology | Year: 2012

Wnts are secreted glycolipoproteins that play important roles in the regulation of embryonic development and tissue homeostasis. Binding of Wnt to receptors and co-receptors causes inactivation of the β-catenin destruction complex, which leads to the stabilization and nuclear translocation of β-catenin to initiate Wnt-responsive gene expression after associating with TCF in the nucleus. As its deregulation results in serious human diseases, especially cancers, the Wnt signaling pathway serves as a promising platform for screening anti-cancer drugs. Resveratrol was selected based on its ability to inhibit the β-catenin/TCF-mediated transcriptional activity. Resveratrol, a natural phytoalexin found in a variety of plants, possesses health-promoting properties including anti-aging, anti-inflammatory, anti-oxidant, anti-cancer, cardioprotective and neuroprotective activities. We found that resveratrol indeed exhibited dose-dependent suppression of Wnt signaling, reduced the expression of Wnt target genes such as cyclin D1 and conductin, and inhibited the growth of Wnt-stimulated cells and Wnt-driven colorectal cancer cells. Further studies indicated that resveratrol functions downstream of GSK3β. Treatment with resveratrol did not alter the amount of β-catenin and its distribution in the cytoplasm and nucleus, suggesting that resveratrol did not affect the accumulation and nuclear targeting of β-catenin. In contrast, co-immunoprecipitation and in vitro binding analyses substantiated that resveratrol was capable of disrupting the binding between β-catenin and TCF4, contributing to the decreased Wnt signaling. Our discoveries not only reveal a novel target of resveratrol in the Wnt signaling pathway but also show the potential of therapy with harmless resveratrol in colorectal cancer and other Wnt-related diseases.


Weng J.-R.,China Medical University at Taichung | Yen M.-H.,Kaohsiung Medical University | Lin W.-Y.,Kinmen Hospital
Phytochemistry | Year: 2013

Celastrus paniculatus is a traditional medicinal plant with diverse pharmacological activities. To identify its bioactive constituents, three new β-dihydroagarofuranoid sesquiterpenes were isolated from the whole plant, of which the major constituent is (1α,2α,8β,9β)-1, 8-bis(acetyloxy)-2, 9-bis(benzoyloxy)-14-hydroxy-β-dihydroagarofuran. It was assessed for its antiproliferative activity, and it suppressed the viability of MCF-7 breast cancer cells with an IC50 of 17 ± 1 μM. This growth inhibition was, in part, attributable to apoptosis. Moreover, this drug treatment led to LC3B-II accumulation, indicative of autophagy. Western blot analysis established its ability to target a broad range of signaling effectors related to survival and cell cycle progression, including Akt, NF-κB, p53, and MAP kinases. In addition, flow cytometry analysis indicates increased reactive oxygen species production in response to this compound. Taken together, these findings suggest a pleiotropic mode of mechanism that underlies the antiproliferative activity of this compound in MCF-7 breast cancer cells. © 2013 Elsevier Ltd. All rights reserved.


Lee H.-C.,Washington University in St. Louis | Lee H.-C.,Kaohsiung Medical University | Rudy Y.,Washington University in St. Louis | Po-Yuan P.,National Cheng Kung University | And 3 more authors.
Heart Rhythm | Year: 2013

Background Slow delayed-rectifier potassium current (IKs) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. Objective To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs and action potentials (APs) in ventricular myocytes. Methods Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch clamp with and without isoproterenol. Results With 50 μmol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram. Conclusions Amiloride regulates IKs and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia. © 2013 Heart Rhythm Society. All rights reserved.


Yu W.-Y.,Taipei Medical University Hospital | Yu W.-Y.,China Medical University at Taichung | Chen C.-Y.,Taipei Medical University | Chiu W.-T.,Taipei Medical University | Lin M.-R.,Taipei Medical University
International Journal of Epidemiology | Year: 2011

Background: Differences among three helmet types and the ineffectiveness of improper helmet use in preventing head injuries are speculated about but are seldom explored with evidence. A case-control study was conducted to examine how different helmet types and improper helmet use affected protection against head injuries among motorcyclists in Taiwan. Methods: Case motorcyclists comprised 435 persons who sought emergency care due to head injuries at a medical centre in west-central Taiwan over an 8-month period and 23 motorcyclists who died from head injuries at the scene of the crash; 458 motorcyclists who had non-head injuries were used as the control group, and their crashes occurred within 1 hour earlier or later than the corresponding cases. Information on helmet type was validated by interviewing motorcyclists who were refuelling at petrol stations. Results: A conditional logistic regression analysis showed that compared with helmeted motorcyclists, non-helmeted motorcyclists were more than four times as likely to have head injuries [odds ratio (OR) 4.54; 95% confidence interval (CI) 1.25-16.5] and ten times as likely to have brain injuries (OR 10.4; 95% CI 1.82-59.2). Compared with motorcyclists wearing full-face helmets, those wearing halfcoverage helmets were more than twice as likely to have head injuries (OR 2.57; 95% CI 1.50-4.40) and brain injuries (OR 2.10; 95% CI 1.01-4.38). Compared with motorcyclists with firmly fastened helmets, those with loosely fastened helmets increased their risk of head injury (OR 1.94; 95% CI 1.33-2.82) and were more than twice as likely to have brain injuries (OR 2.50; 95% CI 1.47-4.25). Conclusions: Of the three helmet types, half-coverage helmets provided motorcyclists the least protection from head injuries. Furthermore, wearing a loosely fastened helmet may compromise any potential protection. Published by Oxford University Press on behalf of the International Epidemiological Association. © The Author 2011; all rights reserved.


Chen I.-H.,Kaohsiung Medical University | Chang F.-R.,Kaohsiung Medical University | Wu Y.-C.,China Medical University at Taichung | Kung P.-H.,Kaohsiung Medical University | And 2 more authors.
Biochimie | Year: 2015

Triple negative breast cancer (TNBC) exhibits an aggressive clinical course by high metastatic potential. It is known that integrin-mediated cell adhesion and migration are important for cancer metastasis. In the present study, a synthetic compound, 3, 4-methyenedioxy-β-nitrostyrene (MNS), significantly inhibited adhesion of TNBC cell lines to different extracellular matrix (ECM) components. The antimetastatic capacity of MNS was also observed through reducing TNBC cells migration and invasion without affecting cell viability. Confocal microscopy revealed that MNS disrupted the formation of focal adhesion complex and actin stress fiber networks. Consistent with this finding, MNS inhibited phosphorylation of focal adhesion kinase (FAK) and paxillin as detected by Western blot analysis. In exploring the underlying mechanism, we found that MNS inhibited phosphorylation of FAK as a result of reducing β1 integrin activation and clustering. A cell-impermeable dithiol reagent, 2, 3-dimercaptopropane-1-sulfonic acid abrogated all of MNS's actions, indicating that MNS may react with thiol groups of cell surface proteins that are involved in regulation of β1 integrin function as well as cell adhesion and migration. Cell surface protein disulfide isomerase (PDI) has been reported to be essential for the affinity modulation of β integrins. We also demonstrated that MNS inhibited PDI activity both in a pure enzyme system and in intact cancer cells. Taken together, our results suggest that MNS inhibits in vitro metastatic properties of TNBC cells through suppression of β1 integrin activation and focal adhesion signaling. Moreover, inhibition of surface PDI may contribute, at least in part, to the actions of MNS. These results suggest that MNS has a potential to be developed as an anticancer agent for treatment of TNBC. © 2015 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.


Tang J.-Y.,Kaohsiung Medical University | Chang H.-W.,Kaohsiung Medical University | Chang J.-G.,China Medical University at Taichung
DNA and Cell Biology | Year: 2013

Apoptosis is a key mechanism for enhanced cellular radiosensitivity in radiation therapy. Studies suggest that Akt signaling may play a role in apoptosis and radioresistance. This study evaluates the possible modulating role of amiloride, an antihypertensive agent with a modulating effect to alternative splicing for regulating apoptosis, in the antiproliferative effects induced by ionizing radiation (IR) in glioblastoma multiforme (GBM) 8401 cells. Analysis of cell viability showed that amiloride treatment significantly inhibited cell proliferation in irradiated GBM8401 cells (p<0.05) in a time-dependent manner, especially in cells treated with amiloride with IR post-treatment. In comparison with GBM8401 cells treated with amiloride alone, with GBM8401 cells treated with IR alone, and with human embryonic lung fibroblast control cells (HEL 299), GBM8401 cells treated with IR combined with amiloride showed increased overexpression of phosphorylated Akt, regardless of whether IR treatment was performed before or after amiloride administration. The alternative splicing pattern of apoptotic protease-activating factor-1 (APAF1) in cells treated with amiloride alone, IR alone, and combined amiloride-IR treatments showed more consistent cell proliferation compared to that in other apoptosis-related genes such as baculoviral IAP repeat containing 5 (BIRC5), Bcl-X, and homeodomain interacting protein kinase-3 (HIPK3). In GBM8401 cells treated with amiloride with IR post-treatment, the ratio of prosurvival (-XL,-LC) to proapoptotic (-LN,-S) splice variants of APAF1 was lower than that seen in cells treated with amiloride with IR pretreatment, suggesting that proapoptotic splice variants of APAF1 (APAF1-LN,-S) were higher in the glioblastoma cells treated with amiloride with IR post-treatment, as compared to glioblastoma cells and fibroblast control cells that had received other treatments. Together, these results suggest that amiloride modulates cell radiosensitivity involving the Akt phosphorylation and the alternative splicing of APAF1, especially for the cells treated with amiloride with IR post-treatment. Therefore, amiloride may improve the effectiveness of radiation therapy for GBMs. © Mary Ann Liebert, Inc.


Huon L.-K.,Cathay General Hospital | Fang T.-Y.,Cathay General Hospital | Wang P.-C.,Cathay General Hospital | Wang P.-C.,Fu Jen Catholic University | Wang P.-C.,China Medical University at Taichung
Otology and Neurotology | Year: 2012

Objective: To investigate the outcomes of intratympanic (IT) gentamicin sulfate injection to treat intractable Ménière's disease (MD) using evidence-based methods. Data Source: Data were retrieved from a MEDLINE search (January 1995 through January 2011). Study Selection: Selected were English-language articles presenting outcomes of IT gentamicin injection to treat MD that had a prospective study design and an evidence level of II or higher. Data Extraction: The database was searched using Boolean combinations of the keywords intratympanic, gentamicin, and Ménière's disease. Data Synthesis: Dichotomous outcomes (success rate and total deafness) were expressed using a Mantel-Haenszel fixed-effects model. Pretreatment and posttreatment pure-tone audiometry results, and word discrimination scores were summarized using data synthesis techniques. Conclusion: A critical literature appraisal and meta-analysis shows that IT gentamicin injection can control vertigo in patients with MD who have limited hearing injury. The quality of research in this field has improved remarkably over the years. However, a large-scale randomized controlled trial is warranted to confirm the predictive factors for the effectiveness of IT gentamicin injection in treating MD. © 2012, Otology & Neurotology, Inc.


Kozak L.P.,Pennington Biomedical Research Center | Newman S.,Pennington Biomedical Research Center | Chao P.-M.,China Medical University at Taichung | Mendoza T.,Pennington Biomedical Research Center | Koza R.A.,Pennington Biomedical Research Center
PLoS ONE | Year: 2010

While the phenomenon linking the early nutritional environment to disease susceptibility exists in many mammalian species, the underlying mechanisms are unknown. We hypothesized that nutritional programming is a variable quantitative state of gene expression, fixed by the state of energy balance in the neonate, that waxes and wanes in the adult animal in response to changes in energy balance. We tested this hypothesis with an experiment, based upon global gene expression, to identify networks of genes in which expression patterns in inguinal fat of mice have been altered by the nutritional environment during early post-natal development. The effects of over- and under-nutrition on adiposity and gene expression phenotypes were assessed at 5, 10, 21 days of age and in adult C57Bl/6J mice fed chow followed by high fat diet for 8 weeks. Under-nutrition severely suppressed plasma insulin and leptin during lactation and diet-induced obesity in adult mice, whereas over-nourished mice were phenotypically indistinguishable from those on a control diet. Food intake was not affected by under- or over-nutrition. Microarray gene expression data revealed a major class of genes encoding proteins of the caveolae and cytoskeleton, including Cav1, Cav2, Ptrf (Cavin1), Ldlr, Vldlr and Mest, that were highly associated with adipose tissue expansion in 10 day-old mice during the dynamic phase of inguinal fat development and in adult animals exposed to an obesogenic environment. In conclusion gene expression profiles, fat mass and adipocyte size in 10 day old mice predicted similar phenotypes in adult mice with variable diet-induced obesity. These results are supported by phenotypes of KO mice and suggest that when an animal enters a state of positive energy balance adipose tissue expansion is initiated by coordinate changes in mRNA levels for proteins required for modulating the structure of the caveolae to maximize the capacity of the adipocyte for lipid storage. © 2010 Kozak et al.


Huang C.-C.,National Taiwan University | Lin Y.-C.,National Cheng Kung University | Huang Y.-T.,Kaohsiung Medical University | Huang Y.-T.,Chang Gung University | Huang K.-H.,China Medical University at Taichung
BMC Pregnancy and Childbirth | Year: 2014

Background: Limited information is available concerning investigating the separate effect of teenage childbirth on medical issues in the antenatal and perinatal periods. Therefore, this study aimed to assess medical problems in antenatal and perinatal periods among early youth, adolescent and young adult mothers in Taiwan.Methods: This retrospective population-based cohort study was conducted by using data from Taiwan's National Health Insurance Research Database. A total of 335,590 mothers aged less than 25 years who had singleton births were identified between 2002 and 2011. Univariate and multivariate logistic regression analyses were conducted to estimate unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI) of each medical problem category in the antenatal and perinatal periods.Results: Compared with mothers aged 20-24 years, adolescents (16-19 years) and early youth mothers (≤15 years), particularly those aged 10-15, had a significantly higher risk of intrauterine growth retardation (IUGR, OR = 1.37, 95% CI: 1.00-1.89) and preterm delivery (OR = 2.98, 95% CI: 2.48-3.58) after adjusting for demographic characteristics and clinical factors. Additionally, adolescents mothers were at an increased risk of anemia (OR = 1.32, 95% CI: 1.24-1.40), oligohydramnios (OR = 1.21, 95% CI: 1.12-1.32), failed labor induction (OR = 1.33, 95% CI: 1.24-1.43), and fetal distress (OR = 1.20, 95% CI: 1.14-1.26) after adjustment.Conclusions: Not all young mothers in our study experienced the same magnitude of increased medical problems in the antenatal and perinatal periods. However, a sufficiently higher probability of having IUGR and preterm delivery was observed among early youth and adolescent mothers. © 2014 Huang et al.; licensee BioMed Central Ltd.


Liao Y.-C.,Taichung Veterans General Hospital | Liao Y.-C.,National Yang Ming University | Wang Y.-S.,Kaohsiung Medical University | Guo Y.-C.,China Medical University at Taichung | And 4 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives The present study aimed to explore the role of microribonucleic acid (miRNA) Let-7g in regulating endothelial functions. Background Derangement of miRNAs is implicated in the pathogenesis of cardiovascular diseases. Because the transforming growth factor (TGF)-β pathway plays a regulatory role in endothelial functions, miRNAs targeted at TGF-β signal cascade might affect vascular health. Methods Bioinformatics software predicted that Let-7g can influence the TGF-β pathway by targeting 3 genes. The Let-7g's effects on multiple endothelial functions were first tested in endothelial cells (ECs) and then in apolipoprotein E knockout mice. Blood samples from lacunar stroke patients were also examined to further support Let-7g's effects on human subjects. Results Let-7g was experimentally confirmed to knock down the THBS1, TGFBR1, and SMAD2 genes in the TGF-β pathway. PAI-I, one of the downstream effectors of the TGF-β pathway, was also down-regulated by Let-7g. Let-7g decreased EC inflammation and monocyte adhesion and increased angiogenesis via the TGF-β pathway. Furthermore, Let-7g reduced EC senescence through increasing SIRT-1 protein. Venous injection of Let-7g inhibitor into apolipoprotein E knockout mice caused overgrowth of vascular intima-media, overexpression of PAI-1, increased macrophage infiltration, and up-regulation of TGF-β downstream genes in the carotid arteries. Let-7g's beneficial effects on EC were reduced, whereas the TGF-β pathway was suppressed by ribonucleic acid interference. Restoration of the TGF-β pathway also attenuated the effects of Let-7g overexpression. Low serum levels of Let-7g were associated with increased circulating PAI-1 levels. Conclusions Decreased Let-7g levels impair endothelial function and increase the risks of cardiovascular diseases through targeting TGF-β and SIRT-1 signaling. © 2014 by the American College of Cardiology Foundation.


Liaw S.-S.,China Medical University at Taichung | Huang H.-M.,National Taichung University of Education
Computers and Education | Year: 2013

The research purpose is to investigate learner self-regulation in e-learning environments. In order to better understand learner attitudes toward e-learning, 196 university students answer a questionnaire survey after use an e-learning system few months. The statistical results showed that perceived satisfaction, perceived usefulness, and interactive learning environments were all found to predict perceived self-regulation in e-learning environments. Further, perceived usefulness can be influenced by interactive learning environments, perceived self-efficacy, and perceived satisfaction. In addition, perceived satisfaction can be affected by interactive learning environments, perceived self-efficacy, and perceived anxiety. Finally, the study proposes a conceptual model to investigate learner self-regulation in e-learning environments. © 2012 Elsevier Ltd. All rights reserved.


Sun Y.,En Chu Kong Hospital | Chang Y.-H.,National Cheng Kung University | Chen H.-F.,Far Eastern Memorial Hospital | Chen H.-F.,Fu Jen Catholic University | And 4 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - We retrospectively assessed the age- and sex-specific incidence and relative risk of Parkinson disease (PD) in Taiwan's diabetic population. RESEARCH DESIGN AND METHODS - Study cohort included 603,416 diabetic patients and 472,188 nondiabetic control subjects. Incidence rate and relative risk of PD (ICD-9-CM 332.0) were evaluated. RESULTS - The incidence of PD was 3.59 and 2.15 per 10,000 person-years for the diabetic and control group, respectively, representing a covariate adjusted hazard ratio (HR) of 1.61 (95% CI 1.56-1.66), which was substantially reduced to 1.37 (1.32-1.41) after adjusting for medical visits. Diabetes was associated with a significantly elevated risk of PD in all sex and age stratifications except in young women, with the highest HR noted for young men aged 21-40 years (2.10 [1.01-4.42]), followed by women aged 41-60 (2.05 [1.82-2.30]) and >60 years (1.65 [1.58-1.73]). CONCLUSIONS - Diabetes is associated with an increased risk of PD onset in a Chinese population, and the relation is stronger in women and younger patients. © 2012 by the American Diabetes Association.


Lee P.-H.,Taipei Medical University Hospital | Chen J.-J.,China Medical University at Taichung | Tsou Y.-A.,China Medical University at Taichung
Oncology Letters | Year: 2014

Sialolipoma is a rare benign neoplasm and was recently described as a histological variant of intraoral lipoma. In the current report, the case of a of a 65-year-old female with a slow-growing mass in the right parotid gland with recurrence is presented. The initial clinical diagnosis was a benign salivary gland tumor. The tumor was situated between the right parotid gland and the right masseter muscle; therefore, a superficial parotidectomy was performed. Histopathology revealed that the tumor was a sialolipoma of the parotid gland. During the three-month follow-up, a recurrent right parotid tumor was identified in the deep lobe space of the right parotid gland and a deep lobe parotidectomy was performed. The present case demonstrates that although surgical excision is generally sufficient to treat parotid gland sialolipoma, postoperative follow-up is required as multifocal lesions may potentially remain, which could result in recurrence.


Yu J.-S.,Chi Mei Medical Center | Yu J.-S.,Chia Nan University of Pharmacy and Science | Zeng B.-Y.,King's College London | Hsieh C.-L.,China Medical University at Taichung
International Review of Neurobiology | Year: 2013

Acupuncture has been used to treat different conditions for at least 3000 years in China and has gained increasing acceptance worldwide. The acupuncture needle inserted into the muscle layer at the acupoint produces the so-called obtaining qi sensation that causes the excitation of A-δ and C-fibers of the muscle tissue, resulting in afferent signals. The afferent signals pass through the dorsal horn cells of the spinal cord ascending to the brain, such as the hypothalamus, enhancing the release of neuropeptides and hormones, and these afferent signals in the spinal segment may innervate the visceral organ, inducing effect on visceral function. Here, we reviewed the effect of acupuncture stimulation on neuropeptides and hormones, including β-endorphin, serotonin, oxytocin, adrenocorticotropic hormone, gonadotropin-releasing hormone, corticotrophin-releasing hormone, cholecystokinin, and acetylcholine, as well as insulin sensitivity, immunomodulation (anti-inflammation), and autonomic nerve activity. © 2013 Elsevier Inc.


Liaw C.-C.,China Medical University at Taichung | Liaw C.-C.,National Chung Hsing University | Wu T.-Y.,Kaohsiung Medical University | Chang F.-R.,Kaohsiung Medical University | Wu Y.-C.,Kaohsiung Medical University
Planta Medica | Year: 2010

Studies on the Annonaceous acetogenins began after the first cytotoxic acetogenin, uvaricin, was isolated in 1982. This attractive finding made many medicinal and natural product chemists direct their efforts on the isolation and identification of these classes of compounds. As more Annonaceous acetogenins were isolated, more information about them was uncovered. From their structural identification to the total synthesis of natural product analogues and from cell-based screening and molecular-based targeting to animal testing, the mechanisms of action of the Annonaceous acetogenins became clearer. The purpose of this review is to give an account of recent studies on this class of compounds and their analogues, which will aid us not only in clarifying how the Annonaceous acetogenins act but also in establishing principles for the further development of this class of compounds. © 2010 Georg Thieme Verlag KG Stuttgart · New York.


Chen H.-C.,China Medical University at Taichung | Chi H.-S.,National Chiayi University | Lin L.-Y.,Hungkuang University
Molecules | Year: 2013

The volatile components in single-flowered and double-flowered Chinese narcissus were identified by headspace-solid phase microextraction (HS-SPME) coupled with GC and GC/MS. Changes in aroma during the vase-life (days 0, 1, 2, 3, 4, 5 and 6) of two samples were also studied. A total of 35 compounds were identified, of which all were present in single-flowered and 26 in double-flowered samples. The main aroma components were (E)-β-ocimene, and benzyl acetate. Single-flowered narcissus have a higher percentage of benzyl acetate, while double-flowered narcissus have a higher percentage of 1,8-cineole. In vase-life, the total volatile component content peaked on day 2 for single-flowered and day 3 for the double-flowered narcissus. For both single-flowered and double-flowered narcissus flowers, the total content of volatile components had decreased significantly by day 4. © 2013 by the authors.


Barve B.D.,Kaohsiung Medical University | Wu Y.-C.,Kaohsiung Medical University | Wu Y.-C.,China Medical University at Taichung | El-Shazly M.,Kaohsiung Medical University | And 5 more authors.
Organic Letters | Year: 2014

Iron catalyzed oxidative coupling of salicylaldehydes with cyclic ethers proceeded through the direct α-C-H functionalization of ethers, forming the corresponding acetals in moderate to excellent yields. This is the first example of iron catalyzed selective C-O bond formation in the presence of a sensitive aldehyde moiety. © 2014 American Chemical Society.


Tsai C.-L.,Tri Service General Hospital | Lin Y.-C.,A-Life Medical | Wang H.-M.,Kaohsiung Medical University | Chou T.-C.,Tzu Chi University | And 2 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance Baicalein (BE), a phenolic flavonoid extracted mainly from the root of Scutellaria baicalensis Georgi, a Chinese herb, is traditionally used in oriental medicine. Several studies have demonstrated that BE exerts many beneficial effects including anti-inflammatory and antioxidant activities. However, its effect on acute lung injury (ALI) and the molecular mechanisms involved remain unclear and warrant further investigation. The aim of the study is to investigate whether BE improves lipopolysaccharide (LPS, intratracheally, i.t.)-induced ALI in rats, and further study the underlying mechanisms of its activity. Material and methods Rats were administrated with LPS (5 mg/kg/body weight, i.t.) through a 24-gauge catheter to establish the ALI model. The effects of BE on the levels of pro-inflammatory cytokines, nitrite/nitrate in bronchoalveolar lavage fluid, and the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and nuclear factor-kappa B (NF-κB) activation as well as the histopathological changes were evaluated. Results Results showed that BE (20 mg/kg, i.p.) treatment markedly attenuated LPS-induced lung edema, elevation of the levels of IL-1β, TNF-α, IL-6, CINC-3, and nitrite/nitrate in bronchoalveolar lavage fluid accompanied by a remarkable improvement of lung histopathological symptoms. The LPS-enhanced inflammatory cell infiltration and myeloperoxidase activity, O2 - formation and the expression of inducible nitric oxide synthase and nitrotyrosin in lungs were all attenuated by BE. Notably, BE could augment Nrf2/HO-1 cascade, but inhibited NF-κB activation in LPS-instilled lungs that was strongly reversed by blocking HO-1 activity. Conclusion This study is the first to demonstrate that BE protects against LPS-induced ALI in rats. The underlying mechanisms may include inhibition of NF-κB-mediated inflammatory responses and upregulation of Nrf2/HO-1 pathway, which ultimately alleviates the pathological symptoms of ALI. © 2014 Elsevier Ireland Ltd.


Shih P.-H.,National Chung Hsing University | Hwang S.-L.,Food Industry Research and Development Institute | Yeh C.-T.,Taipei Medical University | Yen G.-C.,National Chung Hsing University | Yen G.-C.,China Medical University at Taichung
Journal of Agricultural and Food Chemistry | Year: 2012

Nonalcoholic steatohepatitis (NASH) is caused by an elevation in oxidative stress, which might further lead to hepatic fibrogenesis. Importantly, both peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) play roles in modulating oxidative stress-mediated hepatic dysfunction. The objective of this study was to investigate the mechanisms of the multifunctional effects of cyanidin on regulating antioxidant enzymes and oxidative stress-induced hepatotoxicity. The data indicated that cyanidin-mediated antioxidant enzyme expression involved the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways and Nrf2 activation. Furthermore, the synergistic effect of cyanidin and the PPAR agonist, troglitazone, on Nrf2-PPAR activation, was also observed. Besides, treatment of cyanidin and troglitazone abolished H 2O 2-induced downregulation of genes involved in lipid metabolism. In addition, H 2O 2-mediated cytotoxicity, which was caused by inducing ROS formation and apoptotic cell death, was also ameliorated upon cyanidin and troglitazone stimulation. In conclusion, mitogen-activated protein kinases (MAPKs) and the transcription factor Nrf2 played regulatory roles in cyanidin-mediated antioxidant enzyme activation. Furthermore, the combination of cyanidin and troglitazone activated PPARγ-Nrf2 and improved H 2O 2-mediated perturbation of genes involved in lipid metabolism. These data suggested that cyanidin and PPAR agonists might have synergistic benefits against metabolic dysfunction-related oxidative damage. © 2012 American Chemical Society.


Yeh C.-C.,China Medical University at Taichung | Chen T.-L.,Taipei Medical University Hospital | Chen T.-L.,Taipei Medical University | Hu C.-J.,Taipei Medical University | And 3 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2013

Objective To investigate the associated risk of epilepsy after traumatic brain injury (TBI) in a population-based retrospective cohort study. Methods Using Taiwan's National Health Insurance Research Database of reimbursement claims, we conducted a retrospective cohort study of 19 336 TBI patients and 540 322 non-TBI participants aged ≥15 years as reference group. Data on newly developed epilepsy after TBI with 5-8 years' follow-up during 2000 to 2008 were collected. HRs and 95% CIs for the risk of epilepsy associated with TBI were analysed with multivariate Cox proportional hazards regressions. Results Compared with the non-TBI cohort, the adjusted HRs of developing epilepsy among TBI patients with skull fracture, severe or mild brain injury were 10.6 (95% CI 7.14 to 15.8), 5.05 (95% CI 4.40 to 5.79) and 3.02 (95% CI 2.42 to 3.77), respectively. During followup, men exhibited higher risks of post-TBI epilepsy. Patients who had mixed types of cerebral haemorrhage were at the highest risk of epilepsy compared with the non-TBI cohort (HR 7.83, 95% CI 4.69 to 13.0). The risk of post-TBI epilepsy was highest within the first year after TBI (HR 38.2, 95% CI 21.7 to 67.0). Conclusions The risk of epilepsy after TBI varied by patient gender, age, latent interval and complexity of TBI. Integrated care for early identification and treatment of post-trauma epilepsy were crucial for TBI patients.


Wu C.-R.,China Medical University at Taichung | Tsai C.-W.,China Medical University at Taichung | Chang S.-W.,Da - Yeh University | Lin C.-Y.,China Medical University at Taichung | Huang L.-C.,China Medical University at Taichung
Chemico-Biological Interactions | Year: 2014

The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20 mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of γ-glutamate-cysteine ligase catalytic subunit, γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH-SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c-Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD. © 2014 Published by Elsevier Ireland Ltd.


Liao C.-C.,Taipei Medical University Hospital | Liao C.-C.,Taipei Medical University | Chou Y.-C.,China Medical University at Taichung | Yeh C.-C.,China Medical University at Taichung | And 4 more authors.
Mayo Clinic Proceedings | Year: 2014

Objective: To investigate whether patients with traumatic brain injury (TBI) have an increased risk of stroke or poststroke mortality. Participants and Methods: Using Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study of 30,165 patients with new TBI and 120,660 persons without TBI between January 1, 2000, and December 31, 2004. The risk of stroke was compared between 2 cohorts through December 31, 2008. To investigate the association between in-hospital mortality after stroke and history of TBI, we conducted a casecontrol study of 7751 patients with newly diagnosed stroke between January 1, 2005, and December 31, 2008. Results: The TBI cohort had an increased stroke risk (hazard ratio [HR], 1.98; 95% CI, 1.86-2.11). Among patients with stroke, those with a history of TBI had a higher risk of poststroke mortality compared with those without TBI (odds ratio, 1.57; 95% CI, 1.13-2.19). In the TBI cohort, factors associated with stroke were history of TBI hospitalization (HR, 3.14; 95% CI, 2.77-3.56), emergency care for TBI (HR, 3.37; 95% CI, 2.88-3.95), brain hemorrhage (HR, 2.69; 95% CI, 2.43-2.99), skull fracture (HR, 3.00; 95% CI, 2.42-3.71), low income (HR, 2.65; 95% CI, 2.16-3.25), and high medical expenditure for TBI care (HR, 2.26; 95% CI, 2.09-2.43). The severity of TBI was also correlated with poststroke mortality. Conclusions: Traumatic brain injury was associated with risk of stroke and poststroke mortality. The relationship between TBI and poststroke mortality does not seem to transcend all age groups. This research shows the importance of prevention, early recognition, and treatment of stroke in this vulnerable population. © 2014 Mayo Foundation for Medical Education and Research.


Hsieh C.-H.,China Medical University at Taichung | Hsieh C.-H.,Asia University, Taiwan | Lin Y.-J.,China Medical University at Taichung | Wu C.-P.,Chang Gung University | And 3 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Tumor hypoxia is one of the crucial microenvironments to promote therapy resistance (TR) in glioblastoma multiforme (GBM). Livin, a member of the family of inhibitor of apoptosis proteins, contributes antiapoptosis. However, the role of tumor hypoxia in Livin regulation and its impact on TR are unclear. Experimental Design: Livin expression and apoptosis for tumor hypoxic cells derived from human glioblastoma xenografts or in vitro hypoxic stress-treated glioblastoma cells were determined by Western blotting, immunofluorescence imaging, and annexin V staining assay. The mechanism of hypoxia-induced Livin induction was investigated by chromatin immunoprecipitation assay and reporter assay. Genetic and pharmacologic manipulation of Livin was utilized to investigate the role of Livin on tumor hypoxia-induced TR in vitro or in vivo. Results: The upregulation of Livin expression and downregulation of caspase activity were observed under cycling and chronic hypoxia in glioblastoma cells and xenografts, concomitant with increased TR to ionizing radiation and temozolomide. However, knockdown of Livin inhibited these effects. Moreover, hypoxia activated Livin transcription through the binding of hypoxiainducible factor-1α to the Livin promoter. The targeted inhibition of Livin by the cell-permeable peptide (TAT-Lp15) in intracerebral glioblastoma-bearing mice demonstrated a synergistic suppression of tumor growth and increased the survival rate in standardof- care treatment with radiation plus temozolomide. Conclusions: These findings indicate a novel pathway that links upregulation of Livin to tumor hypoxia-induced TR inGBM and suggest that targeting Livin using cell-permeable peptide may be an effective therapeutic strategy for tumor microenvironment- induced TR. © 2014 American Association for Cancer Research.


Su K.-P.,China Medical University at Heping | Su K.-P.,China Medical University at Taichung | Su K.-P.,King's College London | Lai H.-C.,China Medical University at Heping | And 8 more authors.
Biological Psychiatry | Year: 2014

Background: Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression. Methods: We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis. Results: Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHAtreated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFNinduced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels. Conclusions: EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation. © 2014 Society of Biological Psychiatry.


Wen C.P.,National Health Research Institute | Wen C.P.,China Medical University at Taichung | Wai J.P.M.,National Taiwan Sport University | Tsai M.K.,National Health Research Institute | And 9 more authors.
The Lancet | Year: 2011

The health benefits of leisure-time physical activity are well known, but whether less exercise than the recommended 150 min a week can have life expectancy benefits is unclear. We assessed the health benefits of a range of volumes of physical activity in a Taiwanese population. In this prospective cohort study, 416 175 individuals (199 265 men and 216 910 women) participated in a standard medical screening programme in Taiwan between 1996 and 2008, with an average follow-up of 8·05 years (SD 4·21). On the basis of the amount of weekly exercise indicated in a self-administered questionnaire, participants were placed into one of five categories of exercise volumes: inactive, or low, medium, high, or very high activity. We calculated hazard ratios (HR) for mortality risks for every group compared with the inactive group, and calculated life expectancy for every group. Compared with individuals in the inactive group, those in the low-volume activity group, who exercised for an average of 92 min per week (95 CI 71-112) or 15 min a day (SD 1·8), had a 14 reduced risk of all-cause mortality (0·86, 0·81-0·91), and had a 3 year longer life expectancy. Every additional 15 min of daily exercise beyond the minimum amount of 15 min a day further reduced all-cause mortality by 4 (95 CI 2·5-7·0) and all-cancer mortality by 1 (0·3-4·5). These benefits were applicable to all age groups and both sexes, and to those with cardiovascular disease risks. Individuals who were inactive had a 17 (HR 1·17, 95 CI 1·10-1·24) increased risk of mortality compared with individuals in the low-volume group. 15 min a day or 90 min a week of moderate-intensity exercise might be of benefit, even for individuals at risk of cardiovascular disease. Taiwan Department of Health Clinical Trial and Research Center of Excellence and National Health Research Institutes. © 2011 Elsevier Ltd.


Chan C.-H.,University of Houston | Li C.-F.,Chi Mei Foundational Medical Center | Li C.-F.,National Health Research Institute | Li C.-F.,Southern Taiwan University of Science and Technology | And 16 more authors.
Cell | Year: 2012

Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment. © 2012 Elsevier Inc.


Tsai W.-W.,University of Texas M. D. Anderson Cancer Center | Wang Z.,Sloan Kettering Cancer Center | Yiu T.T.,University of Texas M. D. Anderson Cancer Center | Akdemir K.C.,University of Texas M. D. Anderson Cancer Center | And 13 more authors.
Nature | Year: 2010

Recognition of modified histone species by distinct structural domains within reader proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis. © 2010 Macmillan Publishers Limited. All rights reserved.


Chou L.-W.,China Medical University at Taichung | Kao M.-J.,Taipei City Hospital | Kao M.-J.,National Yang Ming University | Lin J.-G.,China Medical University at Taichung
Evidence-based Complementary and Alternative Medicine | Year: 2012

Myofascial pain syndrome (MPS) has been defined as a regional pain syndrome characterized by muscle pain caused by myofascial trigger points (MTrPs) clinically. MTrP is defined as the hyperirritable spot in a palpable taut band of skeletal muscle fibers. Appropriate treatment to MTrPs can effectively relieve the clinical pain of MPS. Needling therapies, such as MTrP injection, dry needling, or acupuncture (AcP) can effectively eliminate pain immediately. AcP is probably the first reported technique in treating MPS patients with dry needling based on the Traditional Chinese Medicine (TCM) theory. The possible mechanism of AcP analgesia were studied and published in recent decades. The analgesic effect of AcP is hypothesized to be related to immune, hormonal, and nervous systems. Compared to slow-acting hormonal system, nervous system acts in a faster manner. Given these complexities, AcP analgesia cannot be explained by any single mechanism. There are several principles for selection of acupoints based on the TCM principles: "Ah-Shi" point, proximal or remote acupoints on the meridian, and extra-meridian acupoints. Correlations between acupoints and MTrPs are discussed. Some clinical and animal studies of remote AcP for MTrPs and the possible mechanisms of remote effectiveness are reviewed and discussed. © 2012 Li-Wei Chou et al.


Lin J.-T.,New Vision | Cheng D.-C.,China Medical University at Taichung
Polymers | Year: 2014

We present a modeling study of photoinitiated polymerization in a thick polymer-absorbing medium using a focused UV laser. Transient profiles of the initiator concentration at various focusing conditions are analyzed to define the polymerization boundary. Furthermore, we demonstrate the optimal focusing conditions that yield more uniform polymerization over a larger volume than the collimated or non-optimal cases. Too much focusing with the focal length f < f* (an optimal focal length) yields a fast process; however, it provides a smaller polymerization volume at a given time than in the optimal focusing case. Finally, a scaling law is derived and shows that f* is inverse proportional to the product of the extinction coefficient and the initiator initial concentration. The scaling law provides useful guidance for the prediction of optimal conditions for photoinitiated polymerization under a focused UV laser irradiation. The focusing technique also provides a novel and unique means for obtaining uniform photo-polymerization within a limited irradiation time. © 2014 by the authors.


Yao X.,Georgia State University | He W.,Georgia State University | He W.,Peking Union Medical College | Lu C.-D.,Georgia State University | Lu C.-D.,China Medical University at Taichung
Journal of Bacteriology | Year: 2011

Pseudomonas aeruginosa and many other bacteria can utilize biogenic polyamines, including diaminopropane (DAP), putrescine (Put), cadaverine (Cad), and spermidine (Spd), as carbon and/or nitrogen sources. Transcriptome analysis in response to exogenous Put and Spd led to the identification of a list of genes encoding putative enzymes for the catabolism of polyamines. Among them, pauA1 to pauA6, pauB1 to pauB4, pauC, and pauD1 and pauD2 (polyamine utilization) encode enzymes homologous to Escherichia coli PuuABCD of the γ-glutamylation pathway in converting Put into GABA. A series of unmarked pauA mutants was constructed for growth phenotype analysis. The results revealed that it requires specific combinations of pauA knockouts to abolish utilization of different polyamines and support the importance of γ-glutamylation for polyamine catabolism in P. aeruginosa. Another finding was that the list of Spd-inducible genes overlaps almost completely with that of Put-inducible ones except the pauA3B2 operon and the bauABCD operon (β-alanine utilization). Mutation analysis led to the conclusion that pauA3B2 participate in catabolism of DAP, which is related to the aminopropyl moiety of Spd, and that bauABCD are essential for growth on β-alanine derived from DAP (or Spd) catabolism via the γ-glutamylation pathway. Measurements of the pauA3-lacZ and bauA-lacZ expression indicated that these two promoters were differentially induced by Spd, DAP, and β-alanine but showed no apparent response to Put, Cad, and GABA. Induction of the pauA3 and bauA promoters was abolished in the bauR mutant. The recombinant BauR protein was purified to demonstrate its interactions with the pauA3 and bauA regulatory regions in vitro. In summary, the present study support that the γ-glutamylation pathway for polyamine utilization is evolutionarily conserved in E. coli and Pseudomonas spp. and is further expanded in Pseudomonas to accommodate a more diverse metabolic capacity in this group of microorganisms. © 2011, American Society for Microbiology.


Tsai Y.-C.,University of Pennsylvania | Tsai Y.-C.,China Medical University at Taichung | Cooke N.E.,University of Pennsylvania | Liebhaber S.A.,University of Pennsylvania
Nucleic Acids Research | Year: 2016

The relationships of higher order chromatin organization to mammalian gene expression remain incompletely defined. The human Growth Hormone (hGH) multigene cluster contains five gene paralogs. These genes are selectively activated in either the pituitary or the placenta by distinct components of a remote locus control region (LCR). Prior studies have revealed that appropriate activation of the placental genes is dependent not only on the actions of the LCR, but also on the multigene composition of the cluster itself. Here, we demonstrate that the hGH LCR 'loops' over a distance of 28 kb in primary placental nuclei to make specific contacts with the promoters of the two GH genes in the cluster. This long-range interaction sequesters the GH genes from the three hCS genes which co-assemble into a tightly packed 'hCS chromatin hub'. Elimination of the long-range looping, via specific deletion of the placental LCR components, triggers a dramatic disruption of the hCS chromatin hub. These data reveal a higher-order structural pathway by which long-range looping from an LCR impacts on local chromatin architecture that is linked to tissue-specific gene regulation within a multigene cluster. © The Author(s) 2016.


Chen S.-F.,China Medical University at Taichung | Chen S.-F.,Department of National Defence | Nieh S.,Department of National Defence | Jao S.-W.,Tri Service General Hospital | And 5 more authors.
Journal of Pathology | Year: 2013

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related death worldwide. The prognosis of HNSCC is usually poor because of its propensity for extensive invasion, local recurrence and frequent regional lymph node metastasis, even at initial diagnosis. Carcinoma-associated fibroblasts (CAFs), a major type of tumour-surrounding stromal cell, generate mediators through which they interact with tumours and contribute to cancer progression. The orchestration between CAFs and cancer cells is complex. Despite recent studies demonstrating the paracrine effect of stromal cells in the tumour microenvironment on initiation and progression of cancer cells, the major mediator related to CAFs and its underlying mechanism remain unknown. In the present study, we used organotypic culture to investigate CAFs that promote aggressive behaviour of HNSCC cells. Using microarray analysis, we detected abundant expression of interleukin-33 (IL-33) in CAFs and identified IL-33 as a critical mediator in CAF-induced invasiveness. Counteracting IL-33 activity diminished the aggressive phenotype of cancer cells induced by CAFs. Administration of IL-33 promoted cancer cell migration and invasion through induction of epithelial-to-mesenchymal transdifferentiation and increased IL-33 gene expression in cancer cells. In 40 patients with HNSCC, IL-33 expression in CAFs correlated with IL-33 expression in cancer cells. Most cases with a low invasion pattern grading score (IPGS) showed low or no expression of IL-33, whereas most HNSCC cases with high IPGS displayed over-expression of IL-33 in CAFs and cancer cells. High IL-33 expression associated with poor prognosis in terms of nodal metastasis-free survival. These results indicate that CAFs promote cancer invasiveness via paracrine and autocrine effects on microenvironmental IL-33 signalling, and suggest that IL-33 is a potential prognostic biomarker that could be considered in therapeutic strategies for the treatment of patients with HNSCC. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Tseng J.-C.,Perkin Elmer Corporation | Tseng J.-C.,China Medical University at Taichung | Chen H.-F.,China Medical University at Taichung | Wu K.-J.,China Medical University at Taichung
Histology and Histopathology | Year: 2015

Twist1 is an evolutionally conserved transcription factor. Originally identified in Drosophila as a key regulator for mesoderm development, it was later implicated in many human diseases, including Saethre-Chotzen syndrome and cancer. Twist1’s involvement in cancer has been well recognized. Driven by hypoxia-induced factor-1 (HIF-1), Twist1 has been considered as a proto-oncogene and its overexpression has been observed in a wide variety of human cancers. High expression level of Twist1 is closely related to tumor aggressiveness and metastatic potential. In cancer cells, Twist1 has been shown to function as a key regulator of epithelial-mesenchymal transition (EMT), a critical process for metastasis initiation. Twist1 has also been implicated in maintaining cancer stemness for selfrenewal and chemoresistance. This review first summarizes the roles of Twist1 in embryo development and Saethre-Chotzen syndrome followed by a discussion of Twist1’s critical functions in cancer. In particular, the review focuses on the recent discovery of Twist1’s capability to promote endothelial transdifferentiation of cancer cells beyond EMT. © 2015, Histology and Histopathology. All rights reserved.


Tang N.-Y.,China Medical University at Taichung | Liu C.-H.,China Medical University at Taichung | Hsieh C.-T.,Jen Ai Hospital | Hsieh C.-L.,China Medical University at Taichung
American Journal of Chinese Medicine | Year: 2010

Paeoniflorin, a component in Paeonia lactiflora Pall, inhibits nuclear factor-κB expression in chronic hypoperfusion rat and has anti-inflammatory properties. Therefore, the aim of the present study was to investigate the effect of paeoniflorin on cerebral infarct, and the involvement of anti-inflammation. We established an animal model of cerebral infarct by occluding both the common carotid arteries and the right middle cerebral artery for 90 min, followed by reperfusion of 24 hours. The ratios of cerebral infarction area to total brain area, and neuro-deficit score were used as an index to observe the effects of paeoniflorin on cerebral infarct. ED1 (mouse anti rat CD68), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), intercellular adhesion molecular-1 (ICAM-1), myeloperoxidase (MPO) immunostaining and apoptotic cells in the cerebral infarction region also were studied. The results indicated that both pre-treatment and post-treatment with paeoniflorin reduced the ratio of cerebral infarction area; pre-treatment with paeoniflorin also reduced the neurological deficit score. The counts of ED1, IL-1β, TNF-α, ICAM-1 of microvessels and MPO immunoreactive cells and apoptotic cells were increased in the cerebral infarction region; however, these increases were reduced by Paeoniflorin pre-treatment. In conclusion, Paeoniflorin reduced cerebral infarct and neurological deficit in ischemia-reperfusion injured rats, suggesting that paeoniflorin may have a similar effect in humans and might be a suitable treatment for stroke. Paeoniflorin reduced cerebral infarct, at least in part, involves the anti-inflammatory properties. © 2010 World Scientific Publishing Company & Institute for Advanced Research in Asian Science and Medicine.


Ma T.,China Medical University at Taichung | Chang M.-H.,Taichung Armed Forces General Hospital | Tien L.,Bureau of National Health Insurance | Liou Y.-S.,Puli Veterans Hospital | Jong G.-P.,Taichung Armed Forces General Hospital
Drugs and Aging | Year: 2012

Background: HMG-CoA reductase inhibitors (statins) have been linked to new-onset diabetes (NOD). Individual statins may differ in the extent to which they increase the risk for NOD; however, the effect of statins on the development of NOD in elderly hypertensive and dyslipidaemic patients has not been well studied. Objective: The aim of this study was to investigate the relative risk for NOD among elderly (age ≥ 65 years) hypertensive and dyslipidaemic Taiwanese patients who received different statins. Methods: This was a retrospective cohort study performed using data from claim forms provided to the central regional branch of the Bureau of National Health Insurance in Taiwan from July 2004 to December 2009. Prescriptions for statins before the index date were retrieved from a prescription database. We estimated the hazard ratios (HRs) of NOD associated with statin use. Non-diabetic subjects served as the reference group. Results: A total of 2735 NOD cases were identified among 15 637 elderly hypertensive and dyslipidaemic patients during the study period. The risk of NOD after adjusting for sex, age, concomitant medication and mean dose of prescription was lower among users of atorvastatin (HR 0.77; 95% CI 0.71, 0.83) and rosuvastatin (HR 0.65; 95% CI 0.51, 0.82) than among non-users. Patients who took lovastatin (HR 1.38; 95% CI 1.26, 1.50) or simvastatin (HR 1.30; 95% CI 1.14, 1.48) were at higher risk of developing NOD than non-users. Pravastatin and fluvastatin were not associated with increased risk of NOD.


Li R.,Kunming University of Science and Technology | Li R.,University of North Carolina at Chapel Hill | Morris-Natschke S.L.,University of North Carolina at Chapel Hill | Lee K.-H.,University of North Carolina at Chapel Hill | Lee K.-H.,China Medical University at Taichung
Natural Product Reports | Year: 2016

Covering: 1990 to 2015 The clerodane diterpenoids are a widespread class of secondary metabolites and have been found in several hundreds of plant species from various families and in organisms from other taxonomic groups. These substances have attracted interest in recent years due to their notable biological activities, particularly insect antifeedant properties. In addition, the major active clerodanes of Salvia divinorum can be used as novel opioid receptor probes, allowing greater insight into opioid receptor-mediated phenomena, as well as opening additional areas for chemical investigation. This article provides extensive coverage of naturally occurring clerodane diterpenes discovered from 1990 until 2015, and follows up on the 1992 review by Merritt and Ley in this same journal. The distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes are summarized. In the cases where sufficient information is available, structure activity relationship (SAR) correlations and mode of action of active clerodanes have been presented. © 2016 The Royal Society of Chemistry.


Chan C.-H.,University of Houston | Morrow J.K.,University of Houston | Li C.-F.,Chi Mei Foundational Medical Center | Li C.-F.,National Health Research Institute | And 13 more authors.
Cell | Year: 2013

Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression. © 2013 Elsevier Inc.


Lin H.-H.,National Tsing Hua University | Chuang K.-S.,National Tsing Hua University | Lin Y.-H.,Taiwan Power | Ni Y.-C.,Institute of Nuclear Energy Research of Taiwan | And 2 more authors.
Physics in Medicine and Biology | Year: 2014

GEANT4 Application for Tomographic Emission (GATE) is a powerful Monte Carlo simulator that combines the advantages of the general-purpose GEANT4 simulation code and the specific software tool implementations dedicated to emission tomography. However, the detailed physical modelling of GEANT4 is highly computationally demanding, especially when tracking particles through voxelized phantoms. To circumvent the relatively slow simulation of voxelized phantoms in GATE, another efficient Monte Carlo code can be used to simulate photon interactions and transport inside a voxelized phantom. The simulation system for emission tomography (SimSET), a dedicated Monte Carlo code for PET/SPECT systems, is well-known for its efficiency in simulation of voxel-based objects. An efficient Monte Carlo workflow integrating GATE and SimSET for simulating pinhole SPECT has been proposed to improve voxelized phantom simulation. Although the workflow achieves a desirable increase in speed, it sacrifices the ability to simulate decaying radioactive sources such as non-pure positron emitters or multiple emission isotopes with complex decay schemes and lacks the modelling of time-dependent processes due to the inherent limitations of the SimSET photon history generator (PHG). Moreover, a large volume of disk storage is needed to store the huge temporal photon history file produced by SimSET that must be transported to GATE. In this work, we developed a multiple photon emission history generator (MPHG) based on SimSET/PHG to support a majority of the medically important positron emitters. We incorporated the new generator codes inside GATE to improve the simulation efficiency of voxelized phantoms in GATE, while eliminating the need for the temporal photon history file. The validation of this new code based on a MicroPET R4 system was conducted for 124I and 18F with mouse-like and rat-like phantoms. Comparison of GATE/MPHG with GATE/GEANT4 indicated there is a slight difference in energy spectra for energy below 50 keV due to the lack of x-ray simulation from 124I decay in the new code. The spatial resolution, scatter fraction and count rate performance are in good agreement between the two codes. For the case studies of 18F-NaF (124I-IAZG) using MOBY phantom with 1 × 1 × 1 mm3voxel sizes, the results show that GATE/MPHG can achieve acceleration factors of approximately 3.1 × (4.5 ×), 6.5 × (10.7 ×) and 9.5 × (31.0 ×) compared with GATE using the regular navigation method, the compressed voxel method and the parameterized tracking technique, respectively. In conclusion, the implementation of MPHG in GATE allows for improved efficiency of voxelized phantom simulations and is suitable for studying clinical and preclinical imaging. © 2014 Institute of Physics and Engineering in Medicine.


Huang Y.-C.,China Medical University at Taichung | Lin J.-M.,China Medical University at Taichung | Lin H.-J.,China Medical University at Taichung | Chen C.-C.,China Medical University at Taichung | And 4 more authors.
Ophthalmology | Year: 2011

Purpose: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a complex multifactorial pathogenesis. The aim of this study was to identify the susceptibility genes that increase the risk of DR in type 2 diabetes (T2D) and to further elucidate the underlying mechanism of DR pathogenesis. Design: A case-control study. Participants: We included 749 unrelated individuals with T2D (174 with DR and 575 without DR) and 100 nondiabetic controls. Methods: We conducted a genome-wide association study using Illumina HumanHap550-Duo BeadChips. Main Outcome Measures: Compared with the genotypic distribution of single nucleotide polymorphisms (SNPs) between subjects with DR and without DR. Results: Using statistical models, we selected a total of 12 SNPs with P-values <1 × 10-6 that were associated with DR. After controlling for diabetes duration and hemoglobin A1C, 9 of the 12 SNPs located on 5 chromosomal regions were found to be associated with DR. Five loci not previously associated with DR susceptibility were identified in and around the following genes: MYSM1 (Myb-like, SWIRM, and MPN domains 1) located on chromosome 1p (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.03-2.20); PLXDC2 (plexin domain-containing 2) located on the chromosome 10p (OR, 1.67; 95% CI, 1.06-2.65); ARHGAP22 (Rho GTPase-activating protein 22) located on chromosome 10q (OR, 1.65; 95% CI, 1.05-2.60); and HS6ST3 (heparan sulfate 6-O-sulfotransferase 3) located on chromosome 13q (OR, 2.33; 95% CI, 1.13-4.77). The SNPs rs13163610 and rs17376456 located in the unknown gene on chromosome 5q were also associated with DR (OR, 3.63; 95% CI, 1.38-9.58). Conclusions: We identified a genetic association for susceptibility to DR in 5 novel chromosomal regions and PLXDC2 and ARHGAP22, the latter 2 of which are genes implicated in endothelial cell angiogenesis and increased capillary permeability. These findings suggest unsuspected pathways in the pathogenesis of DR. Financial Disclosures: The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2011 American Academy of Ophthalmology.


Cheng W.-J.,China Medical University at Taichung | Cheng Y.,National Taiwan University
International Journal of Drug Policy | Year: 2016

Background: Workplace alcohol policies are crucial for workers' health and safety. The practice of outsourcing is gaining popularity around the world and was found to be associated with poorer health in the working population. This study aimed to examine how outsourcing complicates the implementation of workplace alcohol policies and affects workers' drinking behaviors. Methods: In-depth interviews were conducted with 16 outsource workers, 3 subcontractors and 3 worksite supervisors. Information regarding workers' drinking behaviors, their knowledge, and attitudes toward workplace alcohol policy were analyzed using a qualitative thematic analysis. Results: Factors associated with poor workplace alcohol management included smaller size and private ownership of outsourcers, subcontractors' own drinking behavior and positive attitude to alcohol, and precarious employment conditions of outsourcing workers. The multilateral relationship between outsourcers, subcontractors, and workers complicated and impaired the implementation of workplace alcohol policies. Conclusion: The implementation of workplace alcohol management policies was hampered in outsourcing work conditions due to poor coordination of supervisors in the subcontract chain. The enforcement of alcohol policies in the workplace should be strengthened by consolidating management responsibilities of outsourcers and subcontractors. © 2015 Elsevier B.V.


Huang H.-J.,China Medical University at Taichung | Jian Y.-R.,China Medical University at Taichung | Chen C.Y.-C.,Asia University, Taiwan | Chen C.Y.-C.,China Medical University at Taichung | Chen C.Y.-C.,China Medical University Beigang Hospital
Journal of Biomolecular Structure and Dynamics | Year: 2014

Viral infection by human immunodeficiency virus (HIV) requires integration of viral DNA with host DNA which involves the binding of HIV integrase (IN) with its co-factor lens epithelium-derived growth factor (LEDGF/p75). Since disrupted binding of IN with LEDGF/p75 inhibits proliferation of HIV, inhibition or denaturation of IN is a possible method for inhibiting HIV replication. D77 is a known drug with demonstrated inhibition against HIV by binding to IN. Herein, we utilized D77 as a control to screen for traditional Chinese medicine (TCM) compounds that exhibit similar atomic-level characteristics. 9-Hydroxy-(10E)-octadecenoic acid and Beauveriolide I were found to have higher Dock Scores to IN than D77 through virtual screening. Multiple linear regression (R2 = 0.9790) and support vector machine (R2 = 0.9114) models consistently predicted potential bioactivity of the TCM candidates against IN. The 40 ns molecular dynamics simulation showed that the TCM compounds fulfilled the drug-like criteria of forming stable complexes with IN. Atomic-level investigations revealed that 9-hydroxy-(10E)-octadecenoic acid bound to an important residue A:Lys173, and Beauveriolide I formed stable interactions with the core LEDGF binding site and with Asn256 of the IN binding site on LEDGF. The TCM candidates also initiated loss of α-helices that could affect the functionality of IN. Taken together, the ability of 9-hydroxy-(10E)-octadecenoic acid and Beauveriolide I to (1) form stable interactions affecting IN-LEDGF binding and (2) have predicted bioactivity against IN suggests that the TCM candidates might be potential starting structures for developing compounds that may disrupt IN-LEDGF binding. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:40 © 2013 Taylor & Francis.


Hsieh C.-H.,China Medical University at Taichung | Wu C.-P.,Chang Gung University | Lee H.-T.,Taichung Veterans General Hospital | Liang J.-A.,China Medical University at Taichung | And 2 more authors.
Free Radical Biology and Medicine | Year: 2012

Cycling hypoxia is a well-recognized phenomenon within animal and human solid tumors. It mediates tumor progression and radiotherapy resistance through mechanisms that involve reactive oxygen species (ROS) production. However, details of the mechanism underlying cycling hypoxia-mediated radioresistance remain obscure. We have previously shown that in glioblastoma, NADPH oxidase subunit 4 (Nox4) is a critical mediator involved in cycling hypoxia-mediated ROS production and tumor progression. Here, we examined the impact of an in vivo tumor microenvironment on Nox4 expression pattern and its impact on radiosensitivity in GBM8401 and U251, two glioblastoma cell lines stably transfected with a dual hypoxia-inducible factor-1 (HIF-1) signaling reporter construct. Furthermore, in order to isolate hypoxic tumor cell subpopulations from human glioblastoma xenografts based on the physiological and molecular characteristics of tumor hypoxia, several techniques were utilized. In this study, the perfusion marker Hoechst 33342 staining and HIF-1 activation labeling were used together with immunofluorescence imaging and fluorescence-activated cell sorting (FACS). Our results revealed that Nox4 was predominantly highly expressed in the endogenous cycling hypoxic areas with HIF-1 activation and blood perfusion within the solid tumor microenvironment. Moreover, when compared to the normoxic or chronic hypoxic cells, the cycling hypoxic tumor cells derived from glioblastoma xenografts have much higher Nox4 expression, ROS levels, and radioresistance. Nox4 suppression in intracerebral glioblastoma-bearing mice suppressed tumor microenvironment-mediated radioresistance and enhanced the efficiency of radiotherapy. In summary, our findings indicated that cycling hypoxia-induced Nox4 plays an important role in tumor microenvironment-promoted radioresistance in glioblastoma; hence, targeting Nox4 may be an attractive therapeutic strategy for blocking cycling hypoxia-mediated radioresistance. © 2012 Elsevier Inc. All rights reserved.


Hsu C.-C.,National Taiwan University | Lien J.-C.,China Medical University at Taichung | Chang C.-W.,National Taiwan University | Chang C.-H.,National Taiwan University | And 2 more authors.
Biochemical Pharmacology | Year: 2013

Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47phox and p67phox to the cell membrane. Yuwen02f1 also reverses IκBα degradation and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes. © 2012 Elsevier Inc. All rights reserved.


Tsai T.-Y.,National Taiwan University | Lu T.-W.,National Taiwan University | Kuo M.-Y.,National Taiwan University | Kuo M.-Y.,China Medical University at Taichung | Lin C.-C.,National Taiwan University
Journal of Biomechanics | Year: 2011

Biomechanics of the knee during stair-ascent has mostly been studied using skin-marker-based motion analysis techniques, but no study has reported a complete assessment of the soft tissue artifacts (STA) and their effects on the calculated joint center translation, angles and moments at the knee in normal subjects during this activity. This study aimed to bridge the gap. Twelve young adults walked up a three-step stair while data were acquired simultaneously from a three-dimensional motion capture system, a force plate and a dynamic fluoroscopy system. The "gold standards" of poses of the knee were obtained using a 3D fluoroscopy method. The STA of the markers on the thigh and shank were then calculated, together with their effects on the calculated joint center translations, angles and moments at the knee. The STA of the thigh markers were greater than those on the shank, leading to significantly underestimated flexion and extensor moments, but overestimated joint center translations during the first half of the stance phase. The results will be useful for a better understanding of the normal biomechanics of the knee during stair-ascent, as a baseline for future clinical applications and for developing a compensation method to correct for the effects of STA. © 2011 Elsevier Ltd.


Huang Y.-W.,National Chung Hsing University | Hu R.-M.,Asia University, Taiwan | Lin C.-W.,China Medical University at Taichung | Chung T.-C.,National Chung Hsing University | Yang T.-C.,National Yang Ming University
Antimicrobial Agents and Chemotherapy | Year: 2012

β-N-Acetylglucosaminidase (NagZ), encoded by the nagZ gene, is a critical enzyme for basal-level ampC derepression (ampC expression in the absence of β-lactam challenge) in ampD and dacB mutants of Pseudomonas aeruginosa. Three mutants with a phenotype of basal-level L1 and L2 β-lactamase derepression in Stenotrophomonas maltophilia have been reported, including KJΔDI (ampDI mutant), KJΔmrcA (mrcA mutant), and KJΔDIΔmrcA (ampDI and mrcA double mutant). In this study, nagZ of S. maltophilia was characterized, and its roles in basal-level β-lactamase derepression, induced β-lactamase activities, and β-lactam resistance of KJΔDI, KJΔmrcA, and KJΔDIΔmrcA were evaluated. Expression of the nagZ gene was constitutive and not regulated by AmpR, AmpDI, AmpN, AmpG, PBP1a, and NagZ. Introduction of ΔnagZ into KJΔDI nearly abolished basallevel derepressed β-lactamase activity; conversely, introduction of ΔnagZ into KJΔmrcA did not affect it. At least two activator ligands (ALs) are thus considered responsible for β-lactamase expression in the S. maltophilia system, specifically, the NagZdependent (AL1) and NagZ-independent (AL2) ligands responsible for the basal-level derepressed β-lactamase activities of KJΔDI and KJΔmrcA, respectively. The contributions of AL1 and AL2 to the induced β-lactamase activities may vary with the types of β-lactams. nagZ inactivation did not affect aztreonam-, cefoxitin-, and carbenicillin-induced β-lactamase activities, but it attenuated cefuroxime- and piperacillin-induced β-lactamase activities. Introduction of ΔnagZ into KJ, KJΔDI, KJΔmrcA, and KJΔDIΔmrcA did not significantly change the MICs of the β-lactams tested except that the MICs of cefuroxime and piperacillin moderately decreased in strains KJΔZ and KJΔDIΔZ (nagZ mutants). Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Wu W.-L.,A-Life Medical | Wu W.-L.,Academia Sinica, Taiwan | Lin Y.-W.,China Medical University at Taichung | Min M.-Y.,National Taiwan University | Chen C.-C.,Academia Sinica, Taiwan
Genes, Brain and Behavior | Year: 2010

Sensing external stimulation is crucial for central processing in the brain and subsequent behavioral expression. Although sensory alteration or deprivation may result in behavioral changes, most studies related to the control of behavior have focused on central mechanisms. Here we created a sensory deficit model of mice lacking acid-sensing ion channel 3 (Asic3 -/-) to probe behavioral alterations. ASIC3 is predominately distributed in the peripheral nervous system. RT-PCR and immunohistochemistry used to examine the expression of Asic3 in the mouse brain showed near-background mRNA and protein levels of ASIC3 throughout the whole brain, except for the sensory mesencephalic trigeminal nucleus. Consistent with the expression results, Asic3 knockout had no effect on synaptic plasticity of the hippocampus and the behavioral tasks of motor function, learning and memory. In anxiety behavior tasks, Asic3-/- mice spent more time in the open arms of an elevated plus maze than did their wild-type littermates. Asic3 -/- mice also displayed less aggressiveness toward intruders but more stereotypic repetitive behaviors during resident-intruder testing than did wild-type littermates. Therefore, loss of ASIC3 produced behavioral changes in anxiety and aggression in mice, which suggests that ASIC3-dependent sensory activities might relate to the central process of emotion modulation. © 2010 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society.


Lin M.-C.,Chung Shan Medical University | Yin M.-C.,Asia University, Taiwan | Yin M.-C.,China Medical University at Taichung
Cardiovascular Toxicology | Year: 2013

Preventive effects of ellagic acid against doxorubicin-induced cardiac oxidative, inflammatory and apoptotic stress were examined. This agent at 0.25, 0.5 or 1 % was added in feed and supplied to mice for 8 weeks, and followed by doxorubicin treatment. Ellagic acid intake increased its deposit in heart. Pre-intake of this compound at 0.5 and 1 % significantly attenuated doxorubicin caused increase in plasma creatine phosphokinase activity. Doxorubicin treatment decreased glutathione content, increased reactive oxygen species (ROS), malonyldialdehyde (MDA), interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels, declined glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities, and enhanced xanthine oxidases (XO) activity in heart. Ellagic acid intake dose-dependently reserved glutathione content, lowered ROS and MDA levels, and reduced XO activity. This compound at 0.5 and 1 % retained GPX and SOD activities, and decreased cytokines in heart. Doxorubicin treatment raised cardiac activity and protein production of caspase-3, nuclear factor kappa B (NF-κB) p50 and p65. Ellagic acid dose-dependently lowered caspase-3 activity and cleaved caspase-3 formation, and at 0.5 and 1 % declined activity and protein level of NF-κB. Doxorubicin treatment also up-regulated cardiac expression of p-p38, p-ERK 1/2 and p-JNK, and ellagic acid at 0.5 and 1 % suppressed p-p38 expression and at 1 % down-regulated p-ERK 1/2 expression. These findings suggest that ellagic acid is a potent cardiac protective agent against doxorubicin. © 2013 Springer Science+Business Media New York.


Chiang Y.-C.,China Medical University at Taichung | Lo Y.-N.,Chang Gung University | Chen J.-C.,Chang Gung University
Journal of Neurochemistry | Year: 2013

Previously, we found that chronic methamphetamine treatment altered cannabinoid type 1 receptor (CB1R)-dependent cAMP/PKA/dopamine and cAMP-regulated phosphoprotein of Mr 32 000 (DARPP-32)/T34/PP2B signaling and decreased levels of CB1R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB1R. In this study, we further investigate interactions between CB1R and dopamine D2 receptor (D2R) signaling. Activation of either CB1R or D2R increased extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, while co-stimulation of CB1R and D2R evoked an additive effect on the phospho-ERK1/2 signal. This effect was mediated through a pertussis toxin-sensitive Gαi/o pathway in primary striatal cells. Furthermore, the mRNA level of CB1R was increased via dopamine D2 receptor short form (D2SR) by treatment with D2R agonist quinpirole in D 2SR/C6 glioma cells. This effect could be suppressed by co-treatment with the ERK1/2 inhibitor U0126. To test if D2SR could transcriptionally regulate CB1R, the 5′-untranslated region (5′-UTR) of the cannabinoid receptor 1 (CNR1) gene was sequenced from rat brain. Results showed that the CNR1 gene includes two exons, which contain 375 bp of 5′-UTR and are separated by a 17-kb intron. A luciferase reporter assay showed that the maximal D2SR-responsive promoter activity is located in the -1 to -222 region of CNR1 promoter. Overall, we demonstrate previously unidentified crosstalk between D2R and CB1R via ERK1/2 signaling that enhances the expression of CB1R by modulating its promoter activity. Cannabinoid CB1R and dopamine D2R cross-talk at ERK1/2 signal. Activation of D2SR increases the CB 1R transcription, which is ERK1/2 dependent and enhances CB 1R promoter activity that requires up-stream -1 to -222 region. The results implicate pre-synaptic D2SR could functionally regulate the retrograde cannabinoid signal in the striatum. Cannabinoid CB1R and dopamine D2R cross-talk at ERK1/2 signal. Activation of D 2SR increases the CB1R transcription, which is ERK1/2 dependent and enhances CB1R promoter activity that requires up-stream -1 to -222 region. The results implicate pre-synaptic D2SR could functionally regulate the retrograde cannabinoid signal in the striatum. © 2013 International Society for Neurochemistry.


Chang C.-J.,University of Texas M. D. Anderson Cancer Center | Yang J.-Y.,University of Texas M. D. Anderson Cancer Center | Yang J.-Y.,Stanford University | Xia W.,University of Texas M. D. Anderson Cancer Center | And 9 more authors.
Cancer Cell | Year: 2011

It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs. © 2011 Elsevier Inc.


Lin C.-Y.,Asia University, Taiwan | Yin M.-C.,Asia University, Taiwan | Yin M.-C.,China Medical University at Taichung
Plant Foods for Human Nutrition | Year: 2012

This study analyzed the content of phenolic acids and flavonoids in extracts of guava fruit (Psidium guajava L.), and examined the renal protective effects of guava aqueous extract (GAE) and ethanol extract (GEE) in diabetic mice. GAE had more caffeic acid, myricetin, and quercetin; and GEE had more cinnamic, coumaric and ferulic acids. GAE or GEE at 1 and 2 % was supplied in diet for 12 weeks. GAE or GEE intake at 2 % significantly reduced glucose and blood urea nitrogen levels, increased insulin level in plasma of diabetic mice (p < 0.05). GAE or GEE treatments dose-dependently reserved glutathione content, retained activity of catalase and glutathione peroxidase, and decreased reactive oxygen species, interleukin (IL)-6, tumor necrosis factor-α and IL-1β levels in kidney (p < 0.05). GAE and GEE treatments at 2 % significantly declined renal Nε-(carboxymethyl)lysine, pentosidine and fructose levels (p < 0.05), and suppressed renal activity of aldose reductase (p < 0.05). These findings support that guava fruit could protect kidney against diabetic progression via its anti-oxidative, anti-inflammatory and anti-glycative effects. © 2012 Springer Science+Business Media, Inc.


Mong M.-C.,Asia University, Taiwan | Yin M.-C.,Asia University, Taiwan | Yin M.-C.,China Medical University at Taichung
Journal of Agricultural and Food Chemistry | Year: 2012

Renal protection of s-allyl cysteine (SAC) and s-propyl cysteine (SPC) in diabetic mice against inflammatory injury was examined. Each agent at 0.5 and 1 g/L was added to the drinking water for 10 weeks. SAC or SPC intake significantly reduced the plasma blood urea nitrogen level and increased creatinine clearance (P < 0.05). These treatments significantly lowered the renal level of reactive oxygen species, nitric oxide, interleukin-6, tumor necrosis factor-α, and prostaglandin E 2 in diabetic mice (P < 0.05). Renal mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, protein kinase C (PKC)-α, PKC-β, and PKC-γ was enhanced in diabetic mice (P < 0.05); however, SAC or SPC treatments dose dependently declined mRNA expression of these factors (P < 0.05). Nuclear factor κB (NF-κB) activity, mRNA expression, and protein production in kidney of diabetic mice were significantly increased (P < 0.05). SAC or SPC intake dose dependently suppressed NF-κB activity, NF-κB p65 mRNA expression, and protein level (P < 0.05). Diabetes also enhanced renal protein expression of mitogen-activated protein kinase (P < 0.05). SAC and SPC, only at a high dose, significantly suppressed protein production of p-p38 and p-ERK1/2 (P < 0.05). Renal mRNA expression and protein generation of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ were significantly down-regulated in diabetic mice (P < 0.05), but the intake of SAC or SPC at high dose up-regulated PPAR-α and PPAR-γ (P < 0.05). These findings support that SAC and SPC are potent anti-inflammatory agents against diabetic kidney diseases. © 2012 American Chemical Society.


Iloeje U.H.,Bristol Myers Squibb | Yang H.-I.,China Medical University at Taichung | Chen C.-J.,Academia Sinica, Taiwan | Chen C.-J.,National Taiwan University
Liver International | Year: 2012

Chronic hepatitis B virus (HBV) infection is a serious public health problem because of its worldwide prevalence and potential to cause adverse consequences. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study carried out in Taiwan was used to investigate the natural history of chronic hepatitis B. The REVEAL-HBV study has established an HBV viral load paradigm in the natural history of chronic hepatitis B (CHB). Serum HBV DNA level has been shown to be significantly and independently associated with incidence of hepatocellular carcinoma (HCC) and cirrhosis and liver-related mortality across a biological gradient. It is also a major predictor of HBsAg seroclearance. Genetic features including HBV genotype and basal core promoter A1762T/G1764A mutant, and precore G1896A mutant were documented as predictors of HCC risk. Inactive HBV carriers still had an increased risk on HCC development and liver-related mortality compared with HBsAg -seronegatives. Nomograms focusing on facilitating risk communication between patients and clinicians were developed incorporating non-invasive clinical parameters to predict long-term HCC risk. These will hopefully contribute to evidence-based decisions in the clinical management of CHB patients. A somewhat provocative and novel finding from the REVEAL-HBV study is the association of chronic HBV infection in active replication with an increased pancreatic cancer risk especially in women less than 50 years old. This finding will hopefully spur further research in this area seeking confirmatory evidence. Finally, we hope that the REVEAL-HBV study will continue to be a source of data to answer other important questions in chronic hepatitis B research going forward. © 2012 John Wiley & Sons A/S.


Yang Y.-C.,Asia University, Taiwan | Lii C.-K.,China Medical University at Taichung | Wei Y.-L.,China Medical University at Taichung | Li C.-C.,Chung Shan Medical University | And 3 more authors.
Journal of Nutritional Biochemistry | Year: 2013

We examined the underlying mechanisms involved in n-3 docosahexaenoic acid (DHA) inhibition of inflammation in EA.hy926 cells. The present results demonstrated that pretreatment with DHA (50 and 100 μM) inhibited tumor necrosis factor-alpha (TNF-α)-induced intercellular adhesion molecule 1 (ICAM-1) protein, mRNA expression and promoter activity. In addition, TNF-α-stimulated inhibitory kappa B (IκB) kinase (IKK) phosphorylation, IκB phosphorylation and degradation, p65 nuclear translocation, and nuclear factor-κB (NF-κB) and DNA binding activity were attenuated by pretreatment with DHA. DHA triggered early-stage and transient reactive oxygen species (ROS) generation and significantly increased the protein expression of heme oxygenase 1 (HO-1), induced nuclear factor erythroid 2-related factor 2 (Nrf2) translocation to the nucleus and up-regulated antioxidant response element (ARE)-luciferase reporter activity. Moreover, DHA inhibited Nrf2 ubiquitination and proteasome activity. DHA activated Akt, p38 and ERK1/2 phosphorylation, and specific inhibitors of respective pathways attenuated DHA-induced Nrf2 nuclear translocation and HO-1 expression. Transfection with HO-1 siRNA knocked down HO-1 expression and partially reversed the DHA-mediated inhibition of TNF-α-induced p65 nuclear translocation and ICAM-1 expression. Importantly, we show for the first time that HO-1 plays a down-regulatory role in NF-κB nuclear translocation, and inhibition of Nrf2 ubiquitination and proteasome activity are involved in increased cellular Nrf2 level by DHA. In this study, we show that HO-1 plays a down-regulatory role in NF-κB nuclear translocation and that the protective effect of DHA against inflammation is partially via up-regulation of Nrf2-mediated HO-1 expression and inhibition of IKK/NF-κB signaling pathway. © 2013 Elsevier Inc.


Hung S.-Y.,China Medical University at Taichung | Huang W.-P.,National Taiwan University | Liou H.-C.,National Taiwan University | Fu W.-M.,National Taiwan University
Neuropharmacology | Year: 2015

Autophagy is an intracellular degradation pathway with dynamic interactions for eliminating damaged organelles and protein aggregates by lysosomal digestion. The EGFP-conjugated microtubule-associated protein 1 light chain 3 (EGFP-LC3) serves to monitor autophagic process. Extracellular β-amyloid peptide accumulation is reported as a major cause in Alzheimer's disease (AD) pathogenesis; large numbers of autophagic vacuoles accumulate in patients' brains. We previously demonstrated that extracellular Aβ (eAβ) induces strong autophagic response and α7nAChR acts as a carrier to bind with eAβ; which further inhibits Aβ-induced neurotoxicity via autophagic degradation. In the present study, we overexpressed LC3 in both neuroblastoma cells (SH-SY5Y/pEGFP-LC3) and mice (TgEGFP-LC3) to assess the effect of LC3 overexpression on Aβ neurotoxicity. SH-SY5Y/pEGFP-LC3 cells and primary cortical neuron cultures derived from E17 (embryonic day 17) TgEGFP-LC3 mice showed not only better resistance against Aβ neurotoxicity but also higher α7nAChR expression and autophagic activity than control. Administration of α-bungarotoxin (α-BTX) to block α7nAChR antagonized the neuroprotective action of SH-SY5Y/pECGF-LC3 cells, suggesting that eAβ binding with α7nAChR is an important step in Aβ detoxification. LC3 overexpression thus exerts neuroprotection through increasing α7nAChR expression for eAβ binding and further enhancing autophagic activity for Aβ clearance in vitro and in vivo. © 2015 Elsevier Ltd. All rights reserved.


Chen P.-C.,National Chung Hsing University | Cheng H.-C.,National Chung Hsing University | Tang C.-H.,China Medical University at Taichung | Tang C.-H.,Asia University, Taiwan
Carcinogenesis | Year: 2013

Bone metastasis in patient with advanced-stage prostate cancer, the most commonly diagnosed malignancy in Western countries, increases the risk of intractable bone pain. The nephroblastoma overexpressed (NOV/CCN3) gene, a member of the CCN gene family, is responsible for the secretion of CCN3, a matrixassociated protein involved in many cellular functions. However, the role of CCN3 in prostate cancer metastasis to bone is poorly understood. CCN3 was found to be highly expressed in bone metastasis patients and positively correlated with malignancy in human prostate cancer cells. Prostate cancer conditioned medium-induced osteoclast differentiation was inhibited by neutralizing antibody against CCN3. Specifically, CCN3 was found to induce osteoclastogenesis through the receptor activator of NF-?B ligand (RANKL)-dependent pathway, and the focal adhesion kinase/Akt/p38/NF-?B signal pathway was found to be involved in CCN3-mediated receptor activator of NF-?B expression and RANKL-dependent osteoclastogenesis. In contrast, osteoblasts were observed to play an important role in osteoclast differentiation by paracrine manner, with treatment of osteoblasts with CCN3 found to change the RANKL (osteoclastogenesis):OPG (antiosteoclastogenesis) ratio. Compared with parental PC3 cells, highly invasive PC3-I3 cells markedly enhanced osteoclast activity and bone metastasis in vivo. These results indicate that CCN3 can be used as a novel therapeutic target in the prevention of bone metastasis of prostate cancer. © The Author 2013. Published by Oxford University Press. All rights reserved.


Hsu C.-J.,China Medical University at Taichung | Wu M.-H.,China Medical University at Taichung | Wu M.-H.,National Taiwan University of Physical Education and Sport | Chen C.-Y.,China Medical University at Taichung | And 4 more authors.
Cell Communication and Signaling | Year: 2013

Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein-1α, is a cytokine involved in inflammation and activation of polymorphonuclear leukocytes. CCL3 has been detected in infiltrating cells and tumor cells. Chondrosarcoma is a highly malignant tumor that causes distant metastasis. However, the effect of CCL3 on human chondrosarcoma metastasis is still unknown. Here, we found that CCL3 increased cellular migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. Pre-treatment of cells with the MMP-2 inhibitor or transfection with MMP-2 specific siRNA abolished CCL3-induced cell migration. CCL3 has been reported to exert its effects through activation of its specific receptor, CC chemokine receptor 5 (CCR5). The CCR5 and AMP-activated protein kinase (AMPK) inhibitor or siRNA also attenuated CCL3-upregulated cell motility and MMP-2 expression. CCL3-induced expression of MMP-2 and migration were also inhibited by specific inhibitors, and inactive mutants of AMPK, p38 mitogen activated protein kinase (p38 or p38-MAPK), and nuclear factor κB (NF-κB) cascades. On the other hand, CCL3 treatment demonstrably activated AMPK, p38, and NF-κB signaling pathways. Furthermore, the expression levels of CCL3, CCR5, and MMP-2 were correlated in human chondrosarcoma specimens. Taken together, our results indicate that CCL3 enhances the migratory ability of human chondrosarcoma cells by increasing MMP-2 expression via the CCR5, AMPK, p38, and NF-κB pathways. © 2013 Hsu et al.; licensee BioMed Central Ltd.


Chao C.-Y.,Asia University, Taiwan | Lii C.-K.,Asia University, Taiwan | Lii C.-K.,China Medical University at Taichung | Hsu Y.-T.,China Medical University at Taichung | And 4 more authors.
Carcinogenesis | Year: 2013

Matrix metalloproteinase-9 (MMP-9) plays a critical role in cancer metastasis. Andrographolide (AP) is a diterpene lactone in the leaves and stem of Andrographis paniculata (Burm. f) Ness that has been reported to possess anticancer activity. In this study, we investigated the effect of AP on 12-O-tetradecanoylphorbol- 13-acetate (TPA)-induced MMP-9 expression and invasion in MCF-7 breast cancer cells and the possible mechanisms involved. The results showed that AP dose-dependently inhibited TPAinduced MMP-9 protein expression, enzyme activity, migration and invasion. In addition, AP significantly induced heme oxygenase- 1 (HO-1) messenger RNA (mRNA) and protein expression. Transfection with HO-1 small interfering RNA knocked down the HO-1 expression and reversed the inhibition of MMP-9 expression by AP. HO-1 end products, such as carbon monoxide, free iron and bilirubin, suppressed the TPA-induced MMP-9 mRNA and protein expression, enzyme activity, migration and invasion in MCF-7 cells. Furthermore, TPA-induced extracellular signalregulated kinase (ERK) 1/2 and Akt phosphorylation and the DNA binding activity of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) were attenuated by pretreatment with AP and HO-1 end products. In conclusion, these results suggest that AP inhibits TPA-induced cell migration and invasion by reducing MMP-9 activation, which is mediated mainly by inhibition of the ERK1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways and subsequent AP-1 and NF-κB transactivation. Additionally, induction of HO-1 expression is at least partially involved in the inhibition of TPA-induced MMP-9 activation and cell migration in MCF-7 cells by AP. © The Author 2013. Published by Oxford University Press. All rights reserved.


Chang H.-J.,China Medical University at Taichung | Chang H.-J.,Taichung Veterans General Hospital | Lane H.-Y.,China Medical University at Taichung | Tsai G.E.,University of California at Los Angeles
Current Pharmaceutical Design | Year: 2014

Schizophrenia, a multifactorial mental disorder with polygenic inheritance as well as environmental influences, encompasses a characteristic group of symptoms. Negative and cognitive symptoms which respond poorly to currently available antipsychotics remain a great clinical challenge. Aggressive studies are ongoing to explore the etiological mechanisms of this disease. Among them, one of the primary causal factors is dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews the clinical manifestations of the disease, limitations of current antipsychotics and reconceptualization of the nature of disease and treatment modalities based on the evidence provided by drug models, genetic studies, and clinical trials. The NMDA receptor (NMDAR) model plays a critical role in the revolution of pharmaceutical industry as a new set of drug targets is proposed. Investigations on the modulation of glutamatergic system, particularly the intrinsic NMDA glycine modulatory site, exhibit encouraging results. A group of “NMDA-enhancing agents” either acts directly or indirectly on the glycine modulatory site, showing therapeutic efficacy in preclinical and early clinical trials. A new generation of therapeutic agents targeting the NMDAR shows promise as the next wave of drug development for schizophrenia. © 2014 Bentham Science Publishers.


Huang C.-K.,University of Rochester | Tsai M.-Y.,Chang Gung University | Luo J.,University of Rochester | Kang H.-Y.,Chang Gung University | And 3 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

Bone marrow derived mesenchymal stem cells (BM-MSCs) have been widely applied in several clinical trials of diseases, such as myocardial infarction, liver cirrhosis, neurodegenerative disease, and osteogenesis imperfecta. Although most studies demonstrated that transplantation of BM-MSCs did exert a temporary relief and short-term therapeutic effects, eventually all symptoms recur, therefore it is essential to improve the therapeutic efficacy of transplantation by either elevating the self-renewal of BM-MSCs or enhancing their survival rate. Herein we demonstrated that the BM-MSCs and adipocyte derived mesenchymal stem cells (ADSCs) isolated from the androgen receptor (AR) knockout mice have higher self-renewal ability than those obtained from the wild-type mice. Knockdown of AR in MSC cell lines exhibited similar results. Mechanistic dissection studies showed that the depletion of AR resulted in activation of Erk and Akt signaling pathways through epidermal growth factor receptor (EGFR) activation or pathway to mediate higher self-renewal of BM-MSCs. Targeting AR signals using ASC-J9® (an AR degradation enhancer), hydroxyflutamide (antagonist of AR), and AR-siRNA all led to enhanced self-renewal of MSCs, suggesting the future possibility of using these anti-AR agents in therapeutic approaches. © 2013 Elsevier B.V.


Wu C.-P.,Chang Gung University | Hsieh C.-H.,China Medical University at Taichung | Wu Y.-S.,Tunghai University
Molecular Pharmaceutics | Year: 2011

Chemotherapy is currently one of the most effective ways to treat metastatic cancers. However, of the various mechanisms that are involved in conferring resistance, upregulation of drug efflux ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1), multidrug resistance protein 1 (ABCC1) and ABCG2, has become a major obstacle to cancer chemotherapy and seriously affects the clinical outcome. To date, at least 15 ABC drug transporters have been identified and characterized to transport and confer resistance to practically the entire spectrum of cancer drugs, causing multidrug resistance (MDR) in cancers. Unfortunately, despite decades of research, there is still no real solution to MDR. This review highlights some of the major findings, the roles and problems associated with MDR-linked ABC drug transporters in metastatic cancers and solid tumors, and the current strategies to improve the clinical outcome in cancer chemotherapy. © 2011 American Chemical Society.


Lin C.-H.,China Medical University at Taichung | Lin C.-H.,Chang Gung University | Huang C.-L.,China Medical University at Taichung | Chang Y.-C.,Tamkang University | And 6 more authors.
Schizophrenia Research | Year: 2013

Background: The functional outcome of schizophrenia is affected by multiple factors such as cognitive function and clinical symptoms. The complex relationship among cognitive function (both neuro- and social-cognitions), clinical symptoms, and functional outcome remains unclear. The current study employed structural equation modeling (SEM) to examine whether clinical symptoms mediate the relationship between cognitive function and functional outcome in a large cohort of patients with schizophrenia. Method: Three hundred and two Han-Chinese patients with chronically stable schizophrenia received evaluation of cognitive function (using the Measurement and Treatment Research to Improve Cognition in Schizophrenia [MATRICS] Consensus Cognitive Battery, including 7 domains covering neurocognition and social cognition), clinical symptoms (including positive, negative and depressive symptoms), and functional outcome as assessed by Global Assessment of Functioning Scale and Quality of Life Scale. Results: SEM identified clinical symptoms as a mediator between cognitive function (including all 7 domains of MATRICS) and functional outcome in schizophrenia. The relationship between cognitive function and functional outcome was significant in the basic model. In the mediation model, the link between cognitive function and functional outcome was mediated by clinical symptoms, mainly negative symptoms. Conclusion: This study suggests that clinical symptoms, mainly negative symptoms, mediate the influence of neurocognition and social cognition on functional outcome of schizophrenia. Future studies should explore the impact on other functional outcomes in different ethnicities and various illness phases. © 2013 Elsevier B.V.


Tsai A.C.,Asia University, Taiwan | Tsai A.C.,China Medical University at Taichung | Chi S.-H.,Asia University, Taiwan | Wang J.-Y.,Asia University, Taiwan
Preventive Medicine | Year: 2013

Objective: The objective of this study is to determine the concurrent and longitudinal associations of lifestyle factors including smoking, alcohol drinking, betel quid chewing, tea (. Camellia sinensis) drinking and physical activity with depressive symptoms in older Taiwanese. Methods: The study analyzed Taiwan Longitudinal Study on Aging (TLSA) datasets to determine the association of lifestyle variables with concurrent depressive symptoms in 4122 ≥ 50-year-old Taiwanese at baseline (1999) and with the new development of depressive symptoms 8. years later. Results: Heavy/problem alcohol drinking increased the association with concurrent depressive symptoms (OR = 1.85, 95%CI = 1.02-3.36); frequent tea drinking (OR = 0.63, 95%CI = 0.50-0.79) and frequent physical activity (OR = 0.59, 95%CI = 0.48-0.71) reduced the association; whereas smoking and betel quid chewing showed no significant associations. Smoking (OR = 1.56, 95%CI = 1.06-2.30) increased the development of depressive symptoms 8. years later; past smoking and current betel quid chewing showed similar trends (OR = 1.47, 95%CI = 0.93-2.31); exercising ≥ 3. times/wk reduced the development (OR = 0.77, 95%CI = 0.60-0.99) while alcohol drinking showed no impact. Conclusion: Lifestyle variables can impact the mental wellbeing of older Taiwanese. Interventions to reduce the risk of depressive symptoms in older adults should include strategies aimed at improving these modifiable risk factors. © 2013 Elsevier Inc.


Yang Y.-C.,Asia University, Taiwan | Lii C.-K.,China Medical University at Taichung | Lin A.-H.,Chung Shan Medical University | Yeh Y.-W.,China Medical University at Taichung | And 4 more authors.
Free Radical Biology and Medicine | Year: 2011

Butein and phloretin are chalcones that are members of the flavonoid family of polyphenols. Flavonoids have well-known antioxidant and anti-inflammatory activities. In rat primary hepatocytes, we examined whether butein and phloretin affect tert-butylhydroperoxide (tBHP)-induced oxidative damage and the possible mechanism(s) involved. Treatment with butein and phloretin markedly attenuated tBHP-induced peroxide formation, and this amelioration was reversed by l-buthionine-S-sulfoximine [a glutamate cysteine ligase (GCL) inhibitor] and zinc protoporphyrin [a heme oxygenase 1 (HO-1) inhibitor]. Butein and phloretin induced both HO-1 and GCL protein and mRNA expression and increased intracellular glutathione (GSH) and total GSH content. Butein treatment activated the ERK1/2 signaling pathway and increased Nrf2 nuclear translocation, Nrf2 nuclear protein-DNA binding activity, and ARE-luciferase reporter activity. The roles of the ERK signaling pathway and Nrf2 in butein-induced HO-1 and GCL catalytic subunit (GCLC) expression were determined by using RNA interference directed against ERK2 and Nrf2. Both siERK2 and siNrf2 abolished butein-induced HO-1 and GCLC protein expression. These results suggest the involvement of ERK2 and Nrf2 in the induction of HO-1 and GCLC by butein. In an animal study, phloretin was shown to increase GSH content and HO-1 expression in rat liver and decrease carbon tetrachloride-induced hepatotoxicity. In conclusion, we demonstrate that butein and phloretin up-regulate HO-1 and GCL expression through the ERK2/Nrf2 pathway and protect hepatocytes against oxidative stress. © 2011 Elsevier Inc. All rights reserved.


Lin T.-H.,National Taiwan University | Tang C.-H.,China Medical University at Taichung | Wu K.,Far Eastern Memorial Hospital | Fong Y.-C.,China Medical University at Taichung | And 2 more authors.
Journal of Cellular Physiology | Year: 2011

Collagenase-3 (matrix metalloproteinase, MMP-13) plays an important role in the degradation of cartilage in pathologic conditions. MMP-13 is elevated in joint tissues in both rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, inflammation-stimulated synovial fibroblasts are able to release MMP-13 and other cytokines in these diseases. The peroxisome proliferator-activated receptor-γ (PPARγ) ligands are recently considered as new anti-inflammatory compounds and these ligands were reported to ameliorate inflammatory arthritis. The aim of this study is to evaluate the mechanisms how PPARγ ligands inhibit the inflammatory response in synovial fibroblasts. Two PPARγ ligands, cyclopentenone prostaglandin 15-deoxy-Δ 12,14-prostaglandin-J2 (15d-PGJ2) and synthetic thiazolidinedione compound ciglitazone were examined in this study. Here we found that 15d-PGJ2 and ciglitazone markedly inhibited TNF-α-induced MMP-13 production in human synovial fibroblasts. In addition, activation of nuclear factor κB (NF-κB) is strongly associated with MMP-13 induction by TNF-α and the activation of NF-κB was determined by Western blot, reporter assay, and immunofluorescence. It was found that 15d-PGJ2 markedly attenuated the translocation of NF-κB by direct inhibition of the activation of IKK via a PPARγ-independent manner. Ciglitazone also inhibits TNF-α-induced MMP-13 expression by suppressing NF-κB activation mainly via the modulation of p38-MAPK. Collectively, our data demonstrate that 15d-PGJ2 and ciglitazone attenuated TNF-α-induced MMP-13 expression in synovial fibroblasts primarily through the modulation of NF-κB signaling pathways. These compounds may have therapeutic application in inflammatory arthritis. © 2011 Wiley-Liss, Inc.


Chen K.-C.,China Medical University at Taichung | Chang K.-W.,China Medical University at Taichung | Chen H.-Y.,Asia University, Taiwan | Chen C.Y.-C.,China Medical University at Taichung | And 3 more authors.
Molecular BioSystems | Year: 2011

Based on genome wide association studies (GWAS), the activities of phosphodiesterase 4D (PDE4D) and 5-Lipoxygenase activating protein (ALOX5AP) were suggested as two of the major factors involved in ischemic stroke risks. Uncontrolled PDE4D activities often lead to cAMP-induced stroke and cardiovascular diseases. Overexpression of ALOX5AP, on the other hand, had been shown to play a major role in inflammation pathway that could induce the development of atherosclerosis and stroke. To eliminate the risk factors that lead to stroke, we reported the identification and analysis of dual-targeting compounds that could reduce PDE4D and ALOX5AP activities from traditional Chinese medicine (TCM). We employed world's largest TCM database, TCM Database@Taiwan, for in silico drug identification. We also introduced machine learning predictive models, as well as pharmacophore model, for characterizing the drug-like candidates. Both myristic acid and pentadecanoic acid were identified. The follow-up analysis on molecular dynamics simulation further determined the major roles of the carboxyl group for forming stable molecular interactions. Intriguingly, the carboxyl group demonstrated different bonding patterns with PDE4D and ALOX5AP, through electrostatic interaction and hydrogen bonds, respectively. In addition, the large volume occupied by the ligand hydrophobic regions could achieve inhibition through occupying the vacant spaces in the binding site. These pharmacophores held true for both candidates against each protein targets. Hence, we proposed the presence of the carboxyl group and hydrophobic regions as potent dual targeting features that inhibit both PDE4D and ALOX5AP activities. © The Royal Society of Chemistry 2011.


Hsu C.-M.,China Medical University at Taichung | Yu S.-C.,China Medical University at Taichung | Tsai F.-J.,China Medical University at Taichung | Tsai F.-J.,Asia University, Taiwan | Tsai Y.,China Medical University at Taichung
Carbohydrate Polymers | Year: 2013

Rhubarb is a traditional Chinese medicinal herb, and the ethanolic extract of rhubarb consists of active anthraquinones, which are hydrophobic and have antiproliferative effects on hepatoma cell lines. To increase the aqueous solubility of rhubarb and study the consequent bioavailability, the ethanolic extract of rhubarb was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide that has a hydrophilic outer surface and a hydrophobic central cavity, to form a rhubarb-HP-β-CD complex. This complex was characterized by performing nuclear magnetic resonance spectroscopy, two-dimensional rotating frame spectroscopy and thin layer chromatography to confirm the inclusion of anthraquinones from rhubarb extract in HP-β-CD (weight ratio of rhubarb extract:HP-β-CD = 1:9). We investigated the effects of complexing rhubarb extract with HP-β-CD on the growth of Huh7 and HepG2 cells by performing cytotoxicity analysis, cellular uptake test, and colony formation assay. Our results showed that complexation of rhubarb extract with HP-β-CD increased the aqueous solubility and bioavailability of rhubarb and thus enhanced its effect on hepatoma cells. © 2013 Elsevier Ltd. All rights reserved.


Lee M.-H.,National Yang Ming University | Yang H.-I.,Academia Sinica, Taiwan | Yang H.-I.,China Medical University at Taichung | Liu J.,Academia Sinica, Taiwan | And 10 more authors.
Hepatology | Year: 2013

Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV) patients. This analysis included hepatitis B surface antigen (HBsAg)-seropositive and anti-HCV-seronegative participants from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (R.E.V.E.A.L.-HBV) cohort. Newly developed cirrhosis and HCC were ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds of the participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBV e antigen (HBeAg) serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels, and HBV genotypes. Additionally, the family history was included in the prediction model for HCC. Cox's proportional hazards regression coefficients for cirrhosis and HCC predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA, and HBsAg were all significantly associated with an increased risk of cirrhosis and HCC. The risk scores estimated from the derivation set could accurately categorize participants with low, medium, and high cirrhosis and HCC risk in the validation set (P<0.001). The AUROCs for predicting 3-year, 5-year, and 10-year cirrhosis risk ranged 0.83-0.86 and 0.79-0.82 for the derivation and validation sets, respectively. The AUROC for predicting 5-year, 10-year, 15-year risk of HCC ranged 0.86-0.89 and 0.84-0.87 in the derivation and validation sets, respectively. Conclusion: The risk prediction models of cirrhosis and HCC by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients. © 2013 by the American Association for the Study of Liver Diseases.


Chang S.-S.,China Medical University at Taichung | Huang H.-J.,China Medical University at Taichung | Chen C.Y.-C.,China Medical University at Taichung | Chen C.Y.-C.,China Medical University Beigang Hospital | And 3 more authors.
Molecular BioSystems | Year: 2011

New-type oseltamivir-resistant H1N1 influenza viruses have been a major threat to human health since the 2009 flu pandemic. To resolve the drug resistance issue, we aimed to identify a new type of inhibitors against H1 from traditional Chinese medicine (TCM) by employing the world's largest TCM database (www.tcm.cmu.edu.tw) for virtual screening and molecular dynamics (MD). From the virtual screening results, sodium (+)-isolaricireinol-2 alpha-sulfate, sodium 3,4-dihydroxy-5-methoxybenzoic acid methyl ester-4-sulfate, sodium (E)-7-hydroxy-1,7-bis(4-hydroxyphenyl)hept-5-ene-3S-sulfonate, and 3-methoxytyramine-betaxanthin were identified as potential drug-like compounds. MD simulation of the binding poses with the key residues Asp103 and Glu83, as well as other binding site residues, identified higher numbers of hydrogen bonds than N-Acetyl-d-Glucosamine (NAG), the natural ligand of the esterase domain in H1. Ionic bonds, salt bridges, and electrostatic energy also contribute to binding stability. Key binding residues include Lys71, Glu83, Asp103, and Arg238. Structural moieties promoting H-bond or salt bridge formations at these locations greatly contribute to a stable ligand-protein complex. An available sodium atom for ionic interactions with Asp103 can further stabilize the ligands. Based on virtual screening, MD simulation, and interaction energy evaluation, TCM candidates demonstrate good potential as novel H1 inhibitors. In addition, the identified stabilizing features can provide insights for designing highly stable H1 inhibitors. © 2011 The Royal Society of Chemistry.


Chen Y.-C.,Foundation Medicine | Chen Y.-C.,Tzu Chi University | Su Y.-C.,Foundation Medicine | Su Y.-C.,Tzu Chi University | And 5 more authors.
Kidney International | Year: 2015

The association of chronic hepatitis B virus (HBV) infection with end-stage renal disease (ESRD) is unclear. To help clarify this we conducted a nationwide cohort study to measure the association by analyzing the claims data from the Taiwan National Health Insurance Research Database with ICD-9 codes used to identify diseases. We identified 17,758 adults who had chronic HBV infection and had not taken nucleos(t)ide analogs from 1999 to 2010 and randomly selected 71,032 matched controls without HBV in the same data set. The risk of ESRD was compared between these two cohorts. Cumulative incidences and hazard ratios were calculated after adjusting for competing mortality. The risk of ESRD was significantly higher in the HBV cohort (12-year cumulative incidence, 1.9%) than in the non-HBV cohort (0.49%) with a significant adjusted hazard ratio of 3.85. Multivariable stratified analysis further verified significant associations of ESRD with HBV in men of any age and women under the age of 60 years, but no significant association in women aged ≥60 years. Thus, a large national cohort study indicates that untreated chronic HBV infection is associated with increased risk of ESRD. Hence, high-risk HBV-infected patients should have targeted monitoring for the development of ESRD. © 2014 International Society of Nephrology.


Lin F.-Y.,China Medical University at Taichung | Lin F.-Y.,University of Houston | Chen P.-C.,National Taiwan University | Liao C.H.,China Medical University at Taichung | And 2 more authors.
Sleep | Year: 2014

Study Objective: Few studies have evaluated the hip fracture risk for zolpidem users. We assessed the risk for subjects taking zolpidem. Design: Population-based retrospective cohort study using claims data of a universal insurance system. Participants: We identified 6,978 patients newly prescribed for zolpidem in 2000-2001 age 18 y and older, and 27,848 nonusers frequency matched with sex, age, and date visiting a clinic. Measurements and Results: Both cohorts were followed up to the end of 2008 to measure the hip fracture incidence and risk, which considered factors such as sex, age, occupation, days of drug use, and osteoporosis status. The zolpidem users had a 2.23-fold higher hip fracture incidence than nonusers (3.10 versus 1.39 per 1,000 person-y). The risk increased with age for both cohorts. The elderly users had a 21-fold higher incidence than the younger users, or twofold higher than the elderly nonusers. Among 33 patients (20.4%) with hip fracture occurring during presumed medication days, which was accountable for an incidence of 1,083.0 per 1,000 person-y. Those taking the medicine for 8 days or longer had a moderately higher fracture rate than those taking it for less days (6.02 versus 4.48 per 100 person-times) with a ratio of 1.34 (95% confidence interval 0.42-4.56). Subjects with blue collar occupations were at a higher fracture risk. Conclusion: The hip fracture risk of zolpidem users is higher than that of nonusers. Fracture prevention awareness should be disseminated to the users.


Lin R.-K.,National Cheng Kung University | Hsieh Y.-S.,National Taiwan Normal University | Lin P.,National Health Research Institute | Hsu H.-S.,National Yang Ming University | And 4 more authors.
Journal of Clinical Investigation | Year: 2010

DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in many human diseases, including cancer. The tobacco-specific carcinogen NNK also induces DNA methylation. However, the role of DNMT1-mediated methylation in tobacco carcinogenesis remains unclear. Here we used human and mouse lung cancer samples and cell lines to determine a mechanism whereby NNK induced DNMT1 expression and activity. We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat-containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation. NNK also induced βTrCP translocation to the cytoplasm via the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) shuttling protein, resulting in DNMT1 nuclear accumulation and hypermethylation of the promoters of tumor suppressor genes. Fluorescence immunohistochemistry (IHC) of lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers were characterized by disruption of the DNMT1/βTrCP interaction and DNMT1 nuclear accumulation. Importantly, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. We believe that the NNK-induced DNMT1 accumulation and subsequent hypermethylation of the promoter of tumor suppressor genes may lead to tumorigenesis and poor prognosis and provide an important link between tobacco smoking and lung cancer. Furthermore, this mechanism may also be involved in other smoking-related human diseases.


Chen C.Y.,China Medical University at Taichung | Chen C.Y.,Asia University, Taiwan | Chen C.Y.,Massachusetts Institute of Technology
PLoS ONE | Year: 2011

Rapid advancing computational technologies have greatly speeded up the development of computer-aided drug design (CADD). Recently, pharmaceutical companies have increasingly shifted their attentions toward traditional Chinese medicine (TCM) for novel lead compounds. Despite the growing number of studies on TCM, there is no free 3D small molecular structure database of TCM available for virtual screening or molecular simulation. To address this shortcoming, we have constructed TCM Database@Taiwan (http://tcm.cmu.edu.tw/) based on information collected from Chinese medical texts and scientific publications. TCM Database@Taiwan is currently the world's largest non-commercial TCM database. This webbased database contains more than 20,000 pure compounds isolated from 453 TCM ingredients. Both cdx (2D) and Tripos mol2 (3D) formats of each pure compound in the database are available for download and virtual screening. The TCM database includes both simple and advanced web-based query options that can specify search clauses, such as molecular properties, substructures, TCM ingredients, and TCM classification, based on intended drug actions. The TCM database can be easily accessed by all researchers conducting CADD. Over the last eight years, numerous volunteers have devoted their time to analyze TCM ingredients from Chinese medical texts as well as to construct structure files for each isolated compound. We believe that TCM Database@Taiwan will be a milestone on the path towards modernizing traditional Chinese medicine. © 2011 Calvin Yu-Chian Chen.


Tsai A.C.,Asia University, Taiwan | Tsai A.C.,China Medical University at Taichung | Chang T.-L.,Hsin Yung Ho Hospital
Journal of Nutrition, Health and Aging | Year: 2011

Objective: To determine the impact of dental prosthetic condition on food consumption, risk of malnutrition and follow-up 4-year mortality risk in elderly Taiwanese. Design and setting: Analyzing the data sets of the 1999 and 2003 "Survey of Health and Living Status of the Elderly in Taiwan", a longitudinal cohort study. Participants: A national probability sample of 2766 men and women 65 years of age or older. Measurements: Self-reported intake frequencies of major food categories, masticatory ability, food consumption, and the risk of malnutrition assessed with the Mini Nutritional Assessment (short-form) stratified by dental prosthetic condition. Cox regression was used to compare follow-up mortality risk. Results: Non-denture wearers and removable-denture wearers had poorer masticatory ability and greater nutritional risk and consumed fruits and vegetable less often compared to fixed-denture wearers. Removable-denture wearers also had lower self-perceived nutritional status and BMI compared to fixed-denture wearers. Survival analysis showed that nondenture wearers and removable-denture wearers had lower follow-up 4-year survival. Cox regression analysis showed that removable-denture wearers had increased follow-up 4-year mortality risk compared to fixed-denture wearers adjusted for sociodemographic, lifestyle and health-related factors. Conclusions: Based on data of a national sample of a longitudinal cohort study, dental prosthetic condition is a significant factor of nutritional health in the elderly. It can affect food pattern and the risk of malnutrition and mortality of elderly persons. Dental care should be an important part of geriatric health promotion program and fixed-denture is a preferred choice over removable-denture. © 2011 Serdi and Springer Verlag France.


Yi P.-L.,National Taiwan University | Yi P.-L.,Aletheia University | Chen Y.-J.,National Taiwan University | Lin C.-T.,National Taiwan University | And 2 more authors.
Sleep | Year: 2012

Study Objectives: Controversial sleep disruptions (e.g., poor nighttime sleep and daytime somnolence) are common in epilepsy patients. Sleep is known to be regulated by homeostatic factors, which mediate sleep propensity, and the circadian oscillator, a clocklike mechanism. However, it is unknown how epileptic episodes that occur at different zeitgeber times (ZTs) alter sleep regulation. This study was designed to elucidate the sleep disruptions associated with epilepsy and their underlying mechanisms by delivering kindled epilepsy at different ZTs: ZT0, ZT6, and ZT13. Design: Kindled epilepsy was induced at 3 different ZTs, and sleep-wake activities were analyzed before and after full-blown seizure. Ribonuclease protection assay, radioimmunoassay, and immunohistochemistry were respectively employed to determine the levels of interleukin-1 mRNA, corticosterone, and PER1 protein. Setting: The experiments were performed at Neurophysiology Laboratory at National Taiwan University. Participant and Interventions: Male Sprague-Dawley rats were implanted with electroencephalograph (EEG) electrodes, a bipolar stimulating electrode, and a guide cannula. Kindling stimuli were delivered via a bipolar electrode placed in the right central nucleus of the amygdala. Measurement and Results: Kindled epilepsy occurring at ZT0 and ZT13 predominantly affected homeostatic factors, whereas ZT6-kindling stimuli altered the circadian oscillator. ZT0-kindling decreased rapid eye movement (REM) and non-REM (NREM) sleep, which was mediated by corticotrophin-releasing hormone, but did not alter the rhythm of sleep-wake fluctuation. On the other hand, ZT13-kindling enhanced interleukin-1 and consequently increased NREM sleep without altering the sleep-wake fluctuation. Nevertheless, the expression of PER1 protein in suprachiasmatic nucleus of the hypothalamus and the circadian rhythm of sleep fluctuation were respectively advanced 6 h and 2 h when kindling stimulation was delivered at ZT6. Shifts of sleep circadian rhythm and PER1 oscillation induced by ZT6-kindling were blocked by administration of hypocretin receptor antagonist SB334867 into the SCN, indicating the involvement of hypocretin. Conclusion: These observations suggest that the occurrence of epilepsy at different ZTs alters sleep processes differently.


Chueh P.J.,National Chung Hsing University | Chueh P.J.,China Medical University at Taichung | Chueh P.J.,Asia University, Taiwan | Liang R.-Y.,National Chung Hsing University | And 3 more authors.
Journal of Hazardous Materials | Year: 2014

Gold nanoparticles (AuNPs) possess unique properties that have been exploited in several medical applications. However, a more comprehensive understanding of the environmental safety of AuNPs is imperative for use of these nanomaterials. Here, we describe the impacts of AuNPs in various mammalian cell models using an automatic and dye-free method for continuous monitoring of cell growth based on the measurement of cell impedance. Several well-established cytotoxicity assays were also used for comparison. AuNPs induced a concentration-dependent decrease in cell growth. This inhibitory effect was associated with apoptosis induction in Vero cells but not in MRC-5 or NIH3T3 cells. Interestingly, cDNA microarray analyses in MRC-5 cells supported the involvement of DNA damage and repair responses, cell-cycle regulation, and oxidative stress in AuNP-induced cytotoxicity and genotoxicity. Moreover, autophagy appeared to play a role in AuNPs-induced attenuation of cell growth in NIH3T3 cells. In this study, we present a comprehensive overview of AuNP-induced cytotoxicity in a variety of mammalian cell lines, comparing several cytotoxicity assays. Collectively, these assays offer convincing evidence of the cytotoxicity of AuNPs and support the value of a systematic approach for analyzing the toxicology of nanoparticles. © 2013 Elsevier B.V.


Chang K.-M.,Asia University, Taiwan | Chang K.-M.,China Medical University at Taichung | Liu S.-H.,Chaoyang University of Technology | Wu X.-H.,Chaoyang University of Technology
Sensors | Year: 2012

Surface electromyography (sEMG) is an important measurement for monitoring exercise and fitness. Because if its high sampling frequency requirement, wireless transmission of sEMG data is a challenge. In this article a wireless sEMG measurement system with a sampling frequency of 2 KHz is developed based upon a MSP 430 microcontroller and Bluetooth transmission. Standard isotonic and isometric muscle contraction are clearly represented in the receiving user interface. Muscle fatigue detection is an important application of sEMG. Traditional muscle fatigue is detected from the median frequency of the sEMG power spectrum. The regression slope of the linear regression of median frequency is an important muscle fatigue index. A more negative slope value represents a higher muscle fatigue condition. To test the system performance, muscle fatigue detection was examined by having subjects run on a pedaled-multifunctional elliptical trainer for approximately 30 minutes at three loading levels. Ten subjects underwent a total of 60 exercise sessions to provide the experimental data. Results showed that the regression slope gradually decreases as expected, and there is a significant gender difference. © 2012 by the authors.


You Y.-C.,National Taiwan University | Tzeng M.-C.,National Taiwan University | Lai C.-C.,National Chung Hsing University | Lai C.-C.,China Medical University at Taichung | Chiu S.-H.,National Taiwan University
Organic Letters | Year: 2012

A [2]rotaxane undergoes switching of its bis-p-xylyl-[26]crown-6 (BPX26C6) component away from its guanidinium station toward its 2,2′-bipyridyl and carbamate stations upon the addition and removal of Zn 2+ and PO 4 3- ions, respectively. © 2012 American Chemical Society.


Lai S.-W.,China Medical University at Taichung | Chen P.-C.,Data Management | Chen P.-C.,China Medical University at Taichung | Liao K.-F.,Taichung Tzu Chi General Hospital | And 5 more authors.
American Journal of Gastroenterology | Year: 2012

Objectives: Using population-based representative insurance claims data, the risk of developing hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients, as well as whether DM medications alter the risk of developing HCC were investigated. Methods: From the Taiwan National Health Insurance Research Database, 19,349 newly diagnosed DM patients 20 years and older and 77,396 comparison subjects without DM were identified from claims from 2000 to 2005. The incidences of HCC at the end of 2008 and the risks associated with hepatitis B and hepatitis C were determined. Whether metformin and thiazolidinediones reduce the risk of developing HCC was also measured. Results: The incidence of HCC was twice higher in the DM group compared with the non-DM group (21.0 vs. 10.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.73 (95% confidence interval (CI)=1.47-2.03) using multivariable Cox proportional hazard regression. Male sex, cirrhosis, hepatitis B, and hepatitis C were significant independent factors that predict HCC, with HRs of 2.32, 8.65, 2.52, and 5.61, respectively. In the stratified analysis, the HR increased to 72.4 (95% CI=42.9-122) among patients with DM, cirrhosis, and hepatitis C. HCC risk reduction was greater for diabetics taking metformin than those taking thiazolidinediones (51 vs. 44% reduction). Conclusions: Comorbidity with cirrhosis and/or hepatitis appears to be associated with an extremely increased risk of developing HCC among DM patients. These high-risk patients should be closely monitored for HCC. The use of metformin or thiazolidinediones may reduce the risk of developing HCC. © 2012 by the american College of Gastroenterology.


Niu Y.,University of Rochester | Niu Y.,Tianjin Medical University | Chang T.-M.,University of Rochester | Yeh S.,University of Rochester | And 4 more authors.
Oncogene | Year: 2010

Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormone-refractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR over-expression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells. © 2010 Macmillan Publishers Limited All rights reserved.


Chen C.Y.-C.,China Medical University Beigang Hospital | Chen C.Y.-C.,China Medical University at Taichung | Chen C.Y.-C.,Asia University, Taiwan
Journal of Biomolecular Structure and Dynamics | Year: 2012

Mutant oncogene DJ1 L166P has been linked to a familial form of early-onset Parkinson's disease (PD). The DJ1 mutant deformed C-terminal helices and prevented the formation of a functional DJ1 dimer. Intriguingly, chaperon modulator, BCL2-associated athanogene (BAG1), has been shown to repair DJ1 mutant and restore its functions. Molecular simulation techniques were employed to elucidate protein-protein interactions between BAG1 and DJ1. Interaction of BAG1 with DJ1 showed recovery of disrupted alpha helix structures and H-bonds stabilizing the functional site Cys106. The His126-Pro184 H-bond (hydrogen-bond) critical to maintaining dimer interfaces was also restored and led to the restoration of dimer formation. High conformational to functional DJ1 dimer was confirmed root mean square deviation = 0.74 Å). Results of this suggest several molecular insights on BAG1-DJ1 repair mechanism and may have an impact on advancing PD treatments. Copyright © 2012 Taylor & Francis.


Hsu H.-C.,Asia University, Taiwan | Hsu H.-C.,China Medical University at Taichung
Experimental Gerontology | Year: 2015

Elderly people usually have multiple chronic diseases concurrently. However, studies of multimorbidity patterns over long time periods are scarce. The purpose of this study was to examine the joint trajectories of chronic multimorbidity among the Taiwanese elderly and to examine related factors and to predict later successful aging outcomes. The data used in this study were from a nation-representative panel survey conducted in Taiwan from 1993 to 2007. Those who participated in at least three waves of the survey were included in the analysis (in total 2584 persons and 57,012 observations). The chronic diseases included cardiovascular disease (CVD), chronic non-specific lung disease (CNSLD), arthritis, cancer, gastrointestinal disease (GI), and kidney disease. The multiple group-based trajectories analysis approach was applied to identify the trajectory groups. Four trajectory groups of multimorbidity were identified: low risk (55.51%), CVD risk only (15.55%), GI & CNSLD risk (20.20%), and multiple risks (8.74%). Related factors included age, level of education, physical functioning, depressive symptoms, and undergoing health examinations. The multimorbidity trajectories affected later physical functioning, depressive symptoms, cognitive function, and life satisfaction. Multiple trajectories of multimorbidity show the patterns of health burden and risks to successful aging among the elderly over time. © 2015 Elsevier Inc.


Lin C.-Y.,Asia University, Taiwan | Ni C.-C.,Asia University, Taiwan | Yin M.-C.,China Medical University at Taichung | Lii C.-K.,China Medical University at Taichung
Cytokine | Year: 2012

The preventive effects of four phenolic compounds against cytokines-induced β-cell destruction were assessed in this study. Treatment of INS-1 (832/13) cells with pro-inflammatory cytokine mixtures (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)) resulted in an increased apoptosis. While resveratrol or myricetin failed to prevent cell apoptosis, quercetin or naringenin treatment exhibited an about 40% less in cell death induced by cytokines-mediated damage. This protective effect of quercetin or naringenin might be mediated partially via the activation of the downstream pAkt and pBad pathways, an outcome which was abolished by pretreatment with a specific PI3-kinase inhibitor. Cellular protein levels of p-p38 MAPK and inducible NO synthase (iNOS) were enhanced after cytokines addition; however, the presence of quercetin or naringenin could not suppress their expression. While cytokines induced MnSOD, quercetin or naringnin did not further enhance expression of this protective protein. In addition, the loss of mitochondria membrane potential (MMP) after cytokines treatment might be partially corrected with quercetin or naringenin. However, none of the phenolic compounds tested in this study reversed the blunted glucose-stimulated insulin secretion after cytokines treatment. These results suggest that quercetin or naringenin might possibly be able to protect β-cells from cytokines toxicity by enhancing cell survival through PI3-kinase pathway, independent of p-p38 MAPK or iNOS. © 2012 Elsevier Ltd.


Huang S.-W.,National Taiwan University | Lien J.-C.,China Medical University at Taichung | Kuo S.-C.,China Medical University at Taichung | Huang T.-F.,National Taiwan University
Carcinogenesis | Year: 2012

Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions. © The Author 2012. Published by Oxford University Press. All rights reserved.


Lai H.-C.,China Medical University at Taichung | Lin C.-C.,China Medical University at Taichung | Lin C.-C.,Data Management | Cheng K.-S.,China Medical University at Taichung | And 7 more authors.
Gastroenterology | Year: 2014

Background & Aims The relationship between pyogenic liver abscess (PLA) and gastrointestinal (GI) cancer was first reported more than 20 years ago, yet little is known about this connection. We evaluated this association in a population-based, retrospective, cohort study. Methods Using Taiwan National Health Insurance claims data, we collected data on a cohort of 14,690 patients with PLA diagnosed from 2000 to 2007. A reference cohort of 58,760 persons without PLA (controls) was selected from the same database, frequency matched by age, sex, and index year. Both cohorts were followed up until the end of 2009, and incidences of GI cancer were calculated. Results The incidence of GI cancer was 4.30-fold higher among patients with PLA compared with controls (10.8 vs 2.51/1000 person-years). Site-specific analysis showed that the highest incidence of colorectal cancer was among patients with PLA and diabetes mellitus, followed by patients with PLA without diabetes and controls with diabetes (9.58, 5.76, and 1.49/10,000 person-years, respectively). The PLA cohort also had a high risk of small intestine cancer (adjusted hazard ratio [aHR], 12.7; 95% confidence interval [CI], 5.79-27.7) and biliary tract cancer (aHR, 9.56; 95% CI, 6.68-13.7). Their risk of pancreatic cancer (aHR, 2.51; 95% CI, 1.68-3.76) was also significant. However, patients with PLA did not have an increased risk of gastric cancer compared with controls. Conclusions In a population-based study, we found that the incidence of GI cancer is increased more than 4-fold among patients with PLA compared with controls. PLA might therefore be an indicator of GI cancer. Patients with PLA had the highest incidence of colorectal cancer, followed by cancers of the biliary tract, pancreas, and small intestine. © 2014 by the AGA Institute.


Hwang B.-F.,China Medical University at Taichung | Lee Y.L.,National Taiwan University
Chest | Year: 2010

Background: There were limited studies concerning ambient air pollution exposure on development of bronchitic symptoms among children. These studies provided suggestive but inconclusive results. Therefore, the objective of this study is to assess the association between air pollutants and the prevalence of bronchitic symptoms in the Taiwan Children Health Study. Methods: We conducted a nationwide cross-sectional study of 5,049 Taiwanese children in 2007. Routine air pollution monitoring data were used for sulfur dioxide (SO2), nitrogen dioxides (NO2), ozone (O3), carbon monoxide (CO), and particles with an aerodynamic diameter ≤ 2.5 m m (PM2.5). The exposure parameters were calculated using the between-community 3-year average concentration. The effect estimates were presented as odds ratios (ORs) per interquartile changes for SO2, NO2, O3, CO, and PM2.5. Results: In the two-stage hierarchical model adjusting for confounding, the prevalence of bronchitic symptoms with asthma was positively associated with the between-community 3-year average concentrations of NO 2 (adjusted OR, 1.81 per 8.79 ppb; 95% CI, 1.14-2.86), and CO (OR, 1.31 per 105 ppb; 95% CI, 1.04-1.64). The prevalence of phlegm with no asthma was related to O3 (OR, 1.32 per 8.77 ppb; 95% CI, 1.06-1.63). Conclusions: The results suggest that long-term exposure to outdoor air pollutants, such as NO2, CO, and O3, may increase the prevalence of bronchitic symptoms among children. © 2010 American College of Chest Physicians.


Tsai A.C.,Asia University, Taiwan | Tsai A.C.,China Medical University at Taichung | Chang T.-L.,Hsin Yung Ho Hospital
British Journal of Nutrition | Year: 2011

BMI, mid-arm circumference (MAC) and calf circumference (CC) are anthropometric indicators often included in geriatric health measurement scales. However, their relative effectiveness in predicting long-term mortality risk has not been extensively examined. The present study aimed to evaluate the relative effectiveness of these anthropometrics in predicting long-term mortality risk in older adults. The study prospectively analysed the ability of these indicators in predicting 4-year follow-up mortality risk of a population-representative sample of 4191 men and women, 53 years of age or older in the Survey of Health and Living Status of the Elderly in Taiwan. Cox regression analyses were performed to evaluate the association of follow-up mortality risk with low (<21kg/m2) or high (27kg/m2) BMI, low MAC (<235/22cm for men/women) and low CC (<30/27cm) respectively, according to Taiwanese-specific cut-off points. Results showed that low CC and low MAC were more effective than low BMI in predicting follow-up mortality risk in 65-74-year-old elderly. But low CC and low BMI were more effective than low MAC in75-year-old elderly, and low BMI was more effective than low MAC or low CC in 53-64-year-old persons. High BMI was not effective in predicting mortality risk in any of these age ranges. These results suggest that in elderly adults, CC is more effective than BMI in predicting long-term mortality risk. Thus, more consideration to CC and MAC in designing geriatric health or nutritional measurement scales is recommended. © 2010 The Authors.


Huang G.-J.,China Medical University at Taichung | Deng J.-S.,Asia University, Taiwan | Huang S.-S.,China Medical University at Taichung | Shao Y.-Y.,Shih Chien University | And 2 more authors.
Food Chemistry | Year: 2012

The hepatoprotective potential of antrosterol (ergostatrien-3β-ol, ST1) from Antrodia camphorata (AC) against carbon tetrachloride (CCl 4)-induced liver damage was evaluated in preventive models in mice. Pretreatment with ST1 markedly prevented the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and liver lipid peroxides in CCl 4-treated mice. The activities of antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx)] were significantly increased after treatment with CCl 4 in vivo. In addition, ST1 decreased the level of nitric oxide (NO) production and tumour necrosis factor-alpha (TNF-α) in CCl 4-treated mice. In this study, these results pointed out that ST1 can inhibit lipid peroxidation, enhance the activities of antioxidant enzymes, decreases the TNF-α level, nitric oxide production and inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expressions. Therefore, it was speculated that ST1 protects mice from liver damage through their anti-inflammation capacity. © 2011 Elsevier Ltd. All rights reserved.


Yang H.-I.,Academia Sinica, Taiwan | Yang H.-I.,China Medical University at Taichung | Yuen M.-F.,University of Hong Kong | Chan H.L.Y.,Chinese University of Hong Kong | And 8 more authors.
The Lancet Oncology | Year: 2011

Background: Therapy for chronic hepatitis B reduces the risk of progressing to hepatocellular carcinoma (HCC); however, there is no suitable and accurate means to assess risk. This study aimed to develop and validate a simple scoring system to predict HCC risk in patients with chronic hepatitis B. Methods: The development cohort consisted of 3584 patients without cirrhosis from the community-based Taiwanese REVEAL-HBV study (of whom 131 developed HCC during follow-up), and a validation cohort of 1505 patients from three hospitals in Hong Kong and South Korea (of whom 111 developed HCC during follow-up). We used Cox multivariate proportional hazards model to predict risk of HCC at 3, 5, and 10 years. Variables included in the risk score were sex, age, serum alanine aminotransferase concentration, HBeAg status, and serum HBV DNA level. We calculated the area under receiver operating curve (AUROC) and calibration of predicted and observed HCC risk. Findings: A 17-point risk score was developed, with HCC risk ranging from 0·0% to 23·6% at 3 years, 0·0% to 47·4% at 5 years, and 0·0% to 81·6% at 10 years for patients with the lowest and highest HCC risk, respectively. AUROCs to predict risk were 0·811 (95% CI 0·790-0·831) at 3 years, 0·796 (0·775-0·816) at 5 years, and 0·769 (0·747-0·790) at 10 years in the validation cohort, and 0·902 (0·884-0·918), 0·783 (0·759-0·806), and 0·806 (0·783-0·828), respectively, after exclusion of 277 patients in the validation cohort with cirrhosis. Predicted risk was well calibrated with Kaplan-Meier observed HCC risk. Interpretation: A simple-to-use risk score that uses baseline clinical variables was developed and validated. The score accurately estimates the risk of developing HCC at 3, 5, and 10 years in patients with chronic hepatitis B. Clinicians can use this score to assess risk of HCC in patients with chronic hepatitis B and subsequently make evidence-based decisions about their clinical management. Funding: The Academia Sinica; the National Health Research Institute, Taiwan; and Bristol-Myers Squibb. © 2011 Elsevier Ltd.


Wang Y.-N.,University of Houston | Yamaguchi H.,University of Houston | Hsu J.-M.,University of Houston | Hung M.-C.,University of Houston | And 2 more authors.
Oncogene | Year: 2010

Multiple membrane-bound receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR) and ErbB-2, have been reported to be localized in the nucleus, where emerging evidence suggests that they are involved in transcriptional regulation, cell proliferation, DNA repair and chemo- and radio-resistance. Recent studies have shown that endocytosis and endosomal sorting are involved in the nuclear transport of cell surface RTKs. However, the detailed mechanism by which the full-length receptors embedded in the endosomal membrane travel all the way from the cell surface to the early endosomes and pass through the nuclear pore complexes is unknown. This important area has been overlooked for decades, which has hindered progress in our understanding of nuclear RTKs functions. Here, we discuss the putative mechanisms by which EGFR family RTKs are shuttled into the nucleus. Understanding the trafficking mechanisms as to how RTKs are transported from the cell surface to the nucleus will significantly contribute to understanding the functions of the nuclear RTKs. © 2010 Macmillan Publishers Limited. All rights reserved.


Chou I.-C.,China Medical University at Taichung | Wang C.-H.,China Medical University at Taichung | Lin W.-D.,China Medical University at Taichung | Tsai F.-J.,China Medical University at Taichung | And 4 more authors.
Diabetologia | Year: 2016

Aims/hypothesis: Type 1 diabetes mellitus is a major public health problem of increasing global concern, with potential neurological complications. A possible association exists between type 1 diabetes and subsequent epilepsy. This study evaluated the relationship between type 1 diabetes and epilepsy in Taiwan. Methods: Claims data from the Taiwan National Health Insurance Research Database were used to conduct retrospective cohort analyses. The study cohort contained 2568 patients with type 1 diabetes, each of whom was frequency-matched by sex, urbanisation of residence area and index year with ten patients without type 1 diabetes. Cox proportional hazard regression analysis was conducted to estimate the effects of type 1 diabetes on epilepsy risk. Results: In patients with type 1 diabetes, the risk of developing epilepsy was significantly higher than that in patients without type 1 diabetes (p < 0.0001 for logrank test). After adjustment for potential confounders, the type 1 diabetes cohort was 2.84 times as likely to develop epilepsy than the control cohort was (HR 2.84 [95% CI 2.11, 3.83]). Conclusions/interpretation: Patients with type 1 diabetes are at an increased risk of developing epilepsy. Metabolic abnormalities of type 1 diabetes, such as hyperglycaemia and hypoglycaemia, may have a damaging effect on the central nervous system and be associated with significant long-term neurological sequelae. The causative factors between type 1 diabetes and the increased risk of epilepsy require further investigation. © 2016, Springer-Verlag Berlin Heidelberg.


Lu C.-Y.,China Medical University at Taichung | Yang Y.-C.,Asia University, Taiwan | Li C.-C.,Chung Shan Medical University | Liu K.-L.,Chung Shan Medical University | And 3 more authors.
Biochemical Pharmacology | Year: 2014

Andrographolide, the major bioactive component of Andrographis paniculata, has been demonstrated to have various biological properties including anti-inflammation, antioxidation, and anti-hepatotoxicity. Oxidative stress is considered a major risk factor in aging, inflammation, cancer, atherosclerosis, and diabetes mellitus. NADPH oxidase is a major source of endogenous reactive oxygen species (ROS). In this study, we used EA.hy926 endothelial-like cells to explore the anti-inflammatory activity of andrographolide. Andrographolide attenuated TNFα-induced ROS generation, Src phosphorylation, membrane translocation of the NADPH oxidase subunits p47phox and p67 phox, and ICAM-1 gene expression. In the small hairpin RNA interference assay, shp47phox abolished TNFα-induced p65 nuclear translocation, ICAM-1 gene expression, and adhesion of HL-60 cells. Andrographolide induced the gene expression of heme oxygenase 1 (HO-1) and glutamate cysteine ligase modifier subunit (GCLM) in a time-dependent manner. Cellular glutathione (GSH) content was increased by andrographolide. shGCLM attenuated the andrographolide-induced increase in GSH content and reversed the andrographolide inhibition of HL-60 adhesion. shHO-1 showed a similar effect on andrographolide inhibition of HL-60 adhesion to shGCLM. The mechanism underlying the up-regulation of HO-1 and GCLM by andrographolide was dependent on the PI3K/Akt pathway, and both the Nrf2 and AP-1 transcriptional factors were involved. Our results suggest that andrographolide attenuates TNFα-induced ICAM-1 expression at least partially through suppression of NADPH oxidase activation and induction of HO-1 and GCLM expression, which is PI3K/Akt pathway-dependent. © 2014 Published by Elsevier Inc.


Tsai S.-J.,Chung Shan Medical University | Yin M.-C.,Asia University, Taiwan | Yin M.-C.,China Medical University at Taichung
Food and Chemical Toxicology | Year: 2012

Protocatechuic acid (PCA) at 0.5%, 1% or 2% was supplied to d-galactose (DG) treated mice for 8week. PCA intake at 2% increased its deposit in brain. DG treatment increased brain level of reactive oxygen species, protein carbonyl, carboxymethyllysine, pentosidine, sorbitol, fructose and methylglyoxal (P<0.05). PCA intake, at 1% and 2%, lowered brain level of these parameters (P<0.05). DG treatments enhanced activity and protein expression of aldose reductase (AR) and sorbitol dehydrogenase, as well as declined glyoxalase I (GLI) activity and protein expression (P<0.05). PCA intake at 1% and 2% reduced activity and protein expression of AR (P<0.05), and at 2% restored GLI activity and expression (P<0.05). DG injection also elevated cyclooxygenase (COX)-2 activity and expression, and increased the release of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E2 in brain (P<0.05). PCA intake decreased these cytokines (P<0.05), and at 1% and 2% suppressed COX-2 activity and expression (P<0.05). PCA intake at 1% and 2% also lowered DG-induced elevation in activity, mRNA expression and protein production of nuclear factor kappa B p65 (P<0.05). These findings suggest that the supplement of protocatechuic acid might be helpful for the prevention or alleviation of aging. © 2012 Elsevier Ltd.


Jingling L.,China Medical University at Taichung | Tseng C.,University of Hong Kong | Tseng C.,National Taiwan University
Journal of Experimental Psychology: Human Perception and Performance | Year: 2013

In visual searches, stimuli following the law of good continuity attract attention to the global structure and receive attentional priority. Also, targets that have unique features are of high feature contrast and capture attention in visual search. We report on a salient global structure combined with a high orientation contrast to the background, which actually impairs the search for a local element. In a search display containing 21 × 27 short horizontal element bars, we rotated the orientation of a whole column by 90° so that it stood out as a salient vertical collinear column. Observers searched for a small tilt on one of the elemental bars, and the target only occasionally overlapped with the salient column (overlapping targets) by chance. In other words, the collinear column was not informative about a target search and was task-irrelevant. Our results showed that the target tilt orientation was discerned more slowly and less accurately for overlapping targets than nonoverlapping targets. In five experiments, we demonstrated that collinear grouping on the salient distractor was the major cause of this impairment. Potential mechanisms of how a global structure interacts with perceptual salience are discussed. © 2012 American Psychological Association.


Liu S.-C.,China Medical University at Taichung | Chuang S.-M.,National Chung Hsing University | Hsu C.-J.,China Medical University at Taichung | Tsai C.-H.,China Medical University at Taichung | And 3 more authors.
Cell Death and Disease | Year: 2014

Connective tissue growth factor (CTGF, a.k.a. CCN2) is inflammatory mediator and abundantly expressed in osteoarthritis (OA). Angiogenesis is essential for OA progression. Here, we investigated the role of CTGF in vascular endothelial growth factor (VEGF) production and angiogenesis in OA synovial fibroblasts (OASFs). We showed that expression of CTGF and VEGF in synovial fluid were higher in OA patients than in controls. Directly applying CTGF to OASFs increased VEGF production then promoted endothelial progenitor cells tube formation and migration. CTGF induced VEGF by raising miR-210 expression via PI3K, AKT, ERK, and nuclear factor-?B (NF-?B)/ELK1 pathways. CTGF-mediating miR-210 upregulation repressed glycerol-3-phosphate dehydrogenase 1-like (GPD1L) expression and PHD activity and subsequently promoted hypoxia-inducible factor (HIF)-1α-dependent VEGF expression. Knockdown of CTGF decreased VEGF expression and abolished OASF-conditional mediummediated angiogenesis in vitro as well as angiogenesis in chick chorioallantoic membrane and Matrigel-plug nude mice model in vivo. Taken together, our results suggest CTGF activates PI3K, AKT, ERK, and NF-?B/ELK1 pathway, leading to the upregulation of miR-210, contributing to inhibit GPD1L expression and prolyl hydroxylases 2 activity, promoting HIF-1α-dependent VEGF expression and angiogenesis in human synovial fibroblasts. © 2014 Macmillan Publishers Limited. All rights reserved.


Tang H.-C.,Asia University, Taiwan | Chen Y.-C.,Asia University, Taiwan | Chen Y.-C.,China Medical University at Taichung
RSC Advances | Year: 2015

A study about the physiological regulators of oncogenic growth has recently been published in the literature. When the H-ras gene mutates, the mutant H-ras(G12V) protein causes uncontrolled cell growth. We tried to observe whether there is any difference between the wild type and mutant H-ras protein in terms of the molecular character and structural variation in silico. Our hypothesis is that the H-ras(G12V) protein, accompanied by an altered structure, might be responsible for excess signal transduction and even tumor formation. In this study, we wanted to find a potent compound that could bind to the H-ras(G12V) protein and interfere with the phosphorylation of the substrate protein. By using homology modeling, structure-based docking, candidate screening, and molecular dynamics (MD) simulations, we demonstrated that the structural and molecular character of the H-ras and H-ras(G12V) proteins were different. Abrine could bind to H-ras(G12V) and might interfere with the phosphorylation process. These results provided novel insight for the management of tumors or cancers, which harbor the H-ras(G12V) mutation. © 2015 The Royal Society of Chemistry.


Lang J.-Y.,University of Texas M. D. Anderson Cancer Center | Hsu J.,University of Texas M. D. Anderson Cancer Center | Hsu J.,China Medical University at Taichung | Hsu J.,Asia University, Taiwan | And 12 more authors.
Cancer Cell | Year: 2011

Breast cancer initiating cells (BCICs), which can fully recapitulate the tumor origin and are often resistant to chemo- and radiotherapy, are currently considered as a major obstacle for breast cancer treatment. Here, we show that BIKDD, a constitutively active mutant form of proapoptotic gene, BIK, effectively induces apoptosis of breast cancer cells and synergizes with lapatinib. Most importantly, BikDD significantly reduces BCICs through co-antagonism of its binding partners Bcl-2, Bcl-xL, and Mcl-1, suggesting a potential therapeutic strategy targeting BCICs. Furthermore, we developed a cancer-specific targeting approach for breast cancer that selectively expresses BikDD in breast cancer cells including BCICs, and demonstrated its potent antitumor activity and synergism with lapatinib in vitro and in vivo. © 2011 Elsevier Inc.


Fang L.-Y.,University of Rochester | Izumi K.,University of Rochester | Lai K.-P.,University of Rochester | Liang L.,University of Rochester | And 6 more authors.
Cancer Research | Year: 2013

Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent coculturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition and downregulation of p53/PTEN tumor suppressors. In vivo studies further showed that PTEN/ mice lacking macrophage AR developed far fewer prostatic intraepithelial neoplasia (PIN) lesions, supporting an in vivo role for macrophage AR during prostate tumorigenesis. CCL4-neutralizing antibody effectively blocked macrophage- induced prostate tumorigenic signaling and targeting AR via an AR-degradation enhancer, ASC-J9, reduced CCL4 expression, and xenografted tumor growth in vivo. Importantly, CCL4 upregulation was associated with increased Snail expression and downregulation of p53/PTEN in high-grade PIN and prostate cancer. Together, our results identify the AR-CCL4-STAT3 axis as key regulators during prostate tumor initiation and highlight the important roles of infiltrating macrophages and inflammatory cytokines for the prostate tumorigenesis. © 2013 American Association for Cancer Research.