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Shen H.-N.,Chi Mei Medical Center | Shen H.-N.,National Cheng Kung University | Lu C.-L.,National Cheng Kung University | Li C.-Y.,National Cheng Kung University | Li C.-Y.,China Medical University at Taichung
Critical Care Medicine | Year: 2014

Objectives: Physicians generally have higher disease awareness and easier access to medical care, which may help them reduce risk of developing severe sepsis and associated mortality when they suffer from acute infection. However, the opposite situation may occur due to the presence of potential barriers to healthcare in physicians. We aim to examine the risk of severe sepsis and associated mortality in physicians. Design: A matched cohort study. Setting: Registry of medical professionals and inpatient and outpatient claims data from Taiwan's National Health Insurance Research Database. SUBJECTS: Physicians (n = 29,697) in Taiwan and a group of persons who were demographically and socioeconomically matched (1:1 ratio) and without any medical education and background. All subjects were followed from the index date (January 1, 2000) to the occurrence of endpoint, withdrawal, or December 31, 2008, whichever date came first. Interventions: None. Measurements and Main Results: Primary outcome was development of severe sepsis. Secondary outcome was 90-day mortality following severe sepsis. The overall incidence density of severe sepsis was lower in physicians than in controls (3.25 vs 3.90 per 1,000 person-years, p < 0.001). According to the Cox regression model, severe sepsis develops in physicians 24% less likely than controls after baseline covariates were adjusted (adjusted hazard ratio, 0.76; 95% CI, 0.68-0.85). The 90-day mortality rates were similar between physicians and controls with severe sepsis (46.5% vs 45.7%, p = 0.72). However, after controlling for the baseline and additional covariates, the risk of death was significantly lower in physicians than in controls (adjusted hazard ratio, 0.82; 95% CI, 0.71-0.95). Conclusions: These findings support the hypothesis that physicians are less likely than controls to develop or die of severe sepsis, implying that medical knowledge, higher disease awareness, and easier healthcare access in physicians may help reduce their risk of severe sepsis and associated mortality. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Wu D.-W.,Chung Shan Medical University | Liu W.-S.,Chung Shan Medical University | Wang J.,Taichung Veterans General Hospital | Chen C.-Y.,China Medical University at Taichung | And 3 more authors.
Clinical Cancer Research | Year: 2011

Purpose: DDX3 alteration has been shown to participate in hepatocellular tumorigenesis via p21WAF1/CIP1 (p21) deregulation. We observed that DDX3 and p21 expression in lung tumors was negatively associated with E6 expression. Therefore, the aim of this study was to clarify whether deregulation of p21 by DDX3 via an E6-inactivated p53 pathway would enhance tumor progression in HPV-associated lung cancers. Experimental Design: Real-time PCR, luciferase assays, immunoprecipitation, and chromatin immunoprecipitation (ChIP) were performed to determine whether DDX3 was regulated by p53 to synergistically enhance p21 transcriptional activity. Cell proliferation was examined by cell counting and colony formation assays. DDX3 and p21 expression were evaluated in 138 lung tumors by real-time PCR and immunohistochemistry. The prognostic value of p21 expression on relapse-free survival (RFS) was analyzed by Kaplan-Meier analysis. Results: Real-time PCR, luciferase assays, and ChIP assays indicated that three putative p53 binding sites, located at -1,080/-1,070, -695/-685, and -283/-273 on the DDX3 promoter, were required for DDX3 transcription. DDX3 deregulation by the E6-inactivated p53 pathway could promote cell proliferation and the ability to form colonies via reduced Sp1 binding activity on the p21 promoter. Among tumors, p21 expression was positively associated with DDX3 expression and negatively related with E6 expression, particularly in early-stage (I + II) tumors. Interestingly, low p21 expression was associated with a poor RFS in early-stage lung cancer. Conclusion: The reduction of p21 by the alteration of the p53-DDX3 pathway plays an essential role in early-stage HPV-associated lung tumorigenesis and is correlated with poor RFS of lung cancer patients. ©2011 AACR.


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.


Lee C.-P.,National Chung Hsing University | Lin W.-S.,National Chung Hsing University | Chen Y.-M.,China Medical University at Taichung | Kuo B.-J.,National Chung Hsing University
Expert Systems with Applications | Year: 2011

Recently, microarray technology has widely used on the study of gene expression in cancer diagnosis. The main distinguishing feature of microarray technology is that can measure thousands of genes at the same time. In the past, researchers always used parametric statistical methods to find the significant genes. However, microarray data often cannot obey some of the assumptions of parametric statistical methods, or type I error may be over expanded. Therefore, our aim is to establish a gene selection method without assumption restriction to reduce the dimension of the data set. In our study, adaptive genetic algorithm/k-nearest neighbor (AGA/KNN) was used to evolve gene subsets. We find that AGA/KNN can reduce the dimension of the data set, and all test samples can be classified correctly. In addition, the accuracy of AGA/KNN is higher than that of GA/KNN, and it only takes half the CPU time of GA/KNN. After using the proposed method, biologists can identify the relevant genes efficiently from the sub-gene set and classify the test samples correctly. © 2010 Elsevier Ltd. All rights reserved.


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 2 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.


Wu M.-H.,National Cheng Kung University | Wu M.-H.,China Medical University at Taichung | Hong H.-C.,National Cheng Kung University | Hong T.-M.,National Cheng Kung University | And 3 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Carcinoma-associated fibroblasts (CAFs) in tumor stroma play an important role in tumor progression and have been associated with a poor prognosis in oral squamous cell carcinoma (OSCC). However, how CAFs influence OSCC malignancy and whether normalizing CAFs inhibits cancer progression remain unclear. Experimental Design: The relationship between the expression of Galectin-1 (Gal-1) and alpha-smooth muscle actin (α-SMA, a CAF marker) in OSCC patient samples and primary cultured CAFs was examined by quantitative real-time PCR, Western blotting, and immunofluorescence. To examine the effect of Gal-1 on CAF activation and CAF-mediated tumor invasion and migration in vitro, Gal-1 expression was knocked down by small hairpin RNA. Finally, cancer cells and CAFs were coimplanted into SCID mice to evaluate the effect of Gal-1 on CAF-modulated tumor progression in vivo. Results: Gal-1 expression is positively associated with α-SMA in the stroma of OSCC specimens. Gal-1 knockdown decreases activated CAF characteristics, resulting in a decrease in α-SMA expression and extracellular matrix protein production. Notably, blocking Gal-1 expression significantly inhibits CAF-conditioned medium-induced tumor cell migration and invasion, possibly by reducing the production of monocyte chemotactic protein-1 (MCP-1/CCL2). MCP-1 induces the migration of OSCC cells by binding to the receptor CCR2; adding an MCP-1 antibody to CAF-conditioned medium that inhibits the interaction between MCP-1 and CCR2 abolishes migration. Finally, we found that Gal-1 knockdown in CAFs significantly reduces CAF-augmented tumor growth and metastasis in vivo. Conclusions: Our findings demonstrate that Gal-1 regulates CAF activation and indicate that targeting Gal-1 in CAFs inhibits OSCC metastasis by modulating MCP-1 expression. ©2011 AACR.


Hsieh Y.-H.,China Medical University at Taichung
Influenza and other Respiratory Viruses | Year: 2010

Background: Countries in the southern hemisphere experienced sizable epidemics of pandemic influenza H1N1 in their winter season during May-August, 2009. Methods: We make use of the Richards model to fit the publicly available epidemic data (confirmed cases, hospitalizations, and deaths) of six southern hemisphere countries (Argentina, Brazil, Chile, Australia, New Zealand, and South Africa) to draw useful conclusions, in terms of its reproduction numbers and outbreak turning points, regarding the new pH1N1 virus in a typical winter influenza season. Results: The estimates for the reproduction numbers of these six countries range from a high of 1·53 (95% CI: 1·22, 1·84) for confirmed case data of Brazil to a low of 1·16 (1·09, 1·22) for pH1N1 hospitalizations in Australia. For each country, model fits using confirmed cases, hospitalizations, or deaths data always yield similar estimates for the reproduction number. Moreover, the turning points for these closely related outbreak indicators always follow the correct chronological order, i.e., case-hospitalization-death, whenever two or more of these three indicators are available. Conclusions: The results suggest that the winter pH1N1 outbreaks in the southern hemisphere were similar to the earlier spring and later winter outbreaks in North America in its severity and transmissibility, as indicated by the reproduction numbers. Therefore, the current strain has not become more severe or transmissible while circulating around the globe in 2009 as some experts had cautioned. The results will be useful for global preparedness planning of possible tertiary waves of pH1N1 infections in the fall/winter of 2010. © 2010 Blackwell Publishing Ltd.


Lin T.-I.,National Chung Hsing University | Lin T.-I.,China Medical University at Taichung | Ho H.J.,National Chung Hsing University | Lee C.-R.,National Chung Hsing University
Statistics and Computing | Year: 2013

This paper presents a robust probabilistic mixture model based on the multivariate skew-t-normal distribution, a skew extension of the multivariate Student's t distribution with more powerful abilities in modelling data whose distribution seriously deviates from normality. The proposed model includes mixtures of normal, t and skew-normal distributions as special cases and provides a flexible alternative to recently proposed skew t mixtures. We develop two analytically tractable EM-type algorithms for computing maximum likelihood estimates of model parameters in which the skewness parameters and degrees of freedom are asymptotically uncorrelated. Standard errors for the parameter estimates can be obtained via a general information-based method. We also present a procedure of merging mixture components to automatically identify the number of clusters by fitting piecewise linear regression to the rescaled entropy plot. The effectiveness and performance of the proposed methodology are illustrated by two real-life examples. © 2013 Springer Science+Business Media New York.


Chen P.-M.,Taipei Medical University | Wu T.-C.,Chung Shan Medical University | Wang Y.-C.,Chung Shan Medical University | Cheng Y.-W.,Taipei Medical University | And 3 more authors.
Carcinogenesis | Year: 2013

Magnesium superoxide dismutase (SOD2) has been shown to cause dysfunction of p53 transcriptional activity, whereas, in turn, SOD2 expression is regulated by p53 to modulate lung tumorigenesis. In this study, we found that the level of SOD2 expression in a panel of lung cancer cells was negatively correlated with that of NK2 homeobox 1 (NKX2-1) but was not associated with p53 status. Mechanistic studies indicated that a decrease in NKX2-1 caused by SOD2-activated IKKβ transcription was achieved by derepression of binding of Sp1 to the IKKβ promoter. Immunoprecipitation, glutathione S-transferase pull-down experiments and electrophoretic mobility shift assays demonstrated a direct interaction between NKX2-1 and Sp1, blocking Sp1-mediated IKKβ transcription. SOD2-mediated nuclear factor-kappaB activation, via elevation of IKKβ transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, because of development of the epithelial-to-mesenchymal transition. The expression level of NKX2-1 messenger RNA was negatively associated with the extent of SOD immunostaining and the IKKβ messenger RNA expression level in lung tumors. The extent of SOD2 immunostaining and IKKβ messenger RNA levels may independently predict overall survival and relapse-free survival in lung adenocarcinoma patients. In summary, we found that SOD2 activates nuclear factor-kappaB signaling by increasing IKKβ transcription, which results in progression of lung adenocarcinoma and poorer patient outcomes. We suggest that IKKβ may potentially be targeted to improve outcomes in patients with SOD2-positive tumors. © The Author 2013. Published by Oxford University Press. All rights reserved.


Chou L.-P.,Sin Lau Hospital | Chou L.-P.,National Cheng Kung University | Li C.-Y.,National Cheng Kung University | Li C.-Y.,China Medical University at Taichung | Hu S.C.,National Cheng Kung University
BMJ Open | Year: 2014

Objectives: To explore the prevalence and associated factors of burnout among five different medical professions in a regional teaching hospital. Design: Cross-sectional study. Setting: Hospital-based survey. Participants: A total of 1329 medical professionals were recruited in a regional hospital with a response rate of 89%. These voluntary participants included 101 physicians, 68 physician assistants, 570 nurses, 216 medical technicians and 374 administrative staff. Primary and secondary outcome measures: Demographic data included gender, age, level of education and marital status, and work situations, such as position, work hours and work shifts, were obtained from an electronic questionnaire. Job strain and burnout were measured by two validated questionnaires, the Chinese version of the Job Content Questionnaire and the Copenhagen Burnout Inventory. Results: Among the five medical professions, the prevalence of high work-related burnout from highest to lowest was nurses (66%), physician assistants (61.8%), physicians (38.6%), administrative staff (36.1%) and medical technicians (31.9%), respectively. Hierarchical regression analysis indicated that job strain, overcommitment and low social support explained the most variance (32.6%) of burnout. Conclusions: Physician assistant is an emerging high burnout group; its severity is similar to that of nurses and far more than that of physicians, administrative staff and medical technicians. These findings may contribute to the development of feasible strategies to reduce the stress which results in the burnout currently plaguing most hospitals in Taiwan.


Tang C.-H.,National Dong Hwa University | Lee T.-H.,National Chung Hsing University | Lee T.-H.,China Medical University at Taichung
PLoS ONE | Year: 2013

The protein quality control (PQC) mechanism is essential for cell function and viability. PQC with proper biological function depends on molecular chaperones and proteases. The hypertonicity-induced protein damage and responses of PQC mechanism in aquatic organisms, however, are poorly understood. In this study, we examine the short-term effects of different hypertonic shocks on the levels of heat shock proteins (HSPs, e.g., HSP70 and HSP90), ubiquitin-conjugated proteins and protein aggregation in gills of the Mozambique tilapia (Oreochromis mossambicus). Following transfer from fresh water (FW) to 20‰ hypertonicity, all examined individuals survived to the end of experiment. Moreover, the levels of branchial HSPs and ubiquitin-conjugated proteins significantly increased at 3 and 24 h post-transfer, respectively. Up-regulation of HSPs and ubiquitin-conjugated proteins was sufficient to prevent the accumulation of aggregated proteins. However, the survival rate of tilapia dramatically declined at 5 h and all fish died within 7 h after direct transfer to 30‰ hypertonicity. We presumed that this result was due to the failed activation of gill PQC system, which resulted in elevating the levels of aggregated proteins at 3 and 4 h. Furthermore, in aggregated protein fractions, the amounts of gill Na+/K+-ATPase (NKA) remained relatively low when fish were transferred to 20‰ hypertonicity, whereas abundant NKA was found at 4 h post-transfer to 30‰ hypertonicity. This study demonstrated that the response of PQC in gills is earlier than observable changes in localization of ion-secreting transport proteins upon hypertonic challenge. To our knowledge, this is the first study to investigate the regulation of PQC mechanism in fish and characterize its important role in euryhaline teleost survival in response to hypertonic stress. © 2013 Tang, Lee.


Liang H.-H.,National United University | Chen C.-P.,China Medical University at Taichung | Hwang R.-L.,National United University | Shih W.-M.,National United University | And 2 more authors.
Building and Environment | Year: 2014

The preservation of indoor environmental quality (IEQ) is key to the well-being and productivity of office occupants. In Taiwan, the green building certification system established IEQ criteria to evaluate the performance of buildings in acoustics, lighting, ventilation and decoration but not the performance in delivering thermal comfort. This study investigated and compared the green and conventional office buildings in middle Taiwan on various aspects of IEQ during a period of active air-conditioning use. Among the monitored environmental variables, the levels of noise, illumination, and carbon dioxide in both types of buildings were in compliance with international or Taiwan's regulatory standards, but not that of volatile organic compounds. The degrees of overall IEQ satisfaction as well as the proportion of occupants voting for satisfaction in the green buildings were both greater than their counterparts in the conventional buildings. Of the specific areas of IEQ evaluated, including the acoustics, lighting, perception of thermal comfort of the occupants toward the thermal environment, and indoor air quality, a statistically significant difference was found between the mean score of satisfaction in the green buildings and that in the conventional buildings. The occupants sharing a concern on energy conservation were more amenable to slightly deficient IEQ. The system of green building certification in Taiwan was able to facilitate proper IEQ performance of the buildings, although a re-visit of the current criteria to incorporate thermal comfort-related criteria may be adequate. © 2013 Elsevier Ltd.


Background. Since the emergence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012, more than 1,300 laboratory confirmed cases of MERS-CoV infections have been reported in Asia, North Africa, and Europe by July 2015. The recent MERS-CoV nosocomial outbreak in South Korea quickly became the second largest such outbreak with 186 total cases and 36 deaths in a little more than one month, second only to Saudi Arabia in country-specific number of reported cases. Methods. We use a simple mathematical model, the Richards model, to trace the temporal course of the South Korea MERS-CoV outbreak. We pinpoint its outbreak turning point and its transmissibility via basic reproduction number R0 in order to ascertain the occurrence of this nosocomial outbreak and how it was quickly brought under control. Results. The estimated outbreak turning point of ti D23:3 days (95% CI [22.6-24.0]), or 23-24 days after the onset date of the index case on May 11, pinpoints June 3-4 as the time of the turning point or the peak incidence for this outbreak by onset date. R0 is estimated to range between 7.0 and 19.3. Discussion and Conclusion. The turning point of the South Korea MERS-CoV out- break occurred around May 27-29, when control measures were quickly implemented after laboratory confirmation of the first cluster of nosocomial infections by the index patient. Furthermore, transmissibility of MERS-CoV in the South Korea outbreak was significantly higher than those reported from past MERS-CoV outbreaks in the Middle East, which is attributable to the nosocomial nature of this outbreak. Our estimate of R0 for the South Korea MERS-CoV nosocomial outbreak further highlights the importance and the risk involved in cluster infections and superspreading events in crowded settings such as hospitals. Similar to the 2003 SARS epidemic, outbreaks of infectious diseases with low community transmissibility like MERS-CoV could still occur initially with large clusters of nosocomial infections, but can be quickly and effectively controlled with timely intervention measures. © 2015 Hsieh.


Lee D.-F.,Mount Sinai School of Medicine | Su J.,Mount Sinai School of Medicine | Kim H.S.,Mount Sinai School of Medicine | Chang B.,Mount Sinai School of Medicine | And 11 more authors.
Cell | Year: 2015

Summary In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs. Video Abstract © 2015 Elsevier 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.


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.


Chen C.-L.,National Chung Hsing University | Lin Y.-P.,National Chung Hsing University | Lai Y.-C.,National Chung Hsing University | Chen H.-C.,National Chung Hsing University | And 2 more authors.
Traffic | Year: 2011

The F-actin binding protein adducin plays an important role in plasma membrane stability, cell motility and cell-cell junctions. In this study, we demonstrate that α-adducin is mainly localized in the nucleus of sparsely cultured epithelial cells, whereas it is localized at cell-cell junctions when the cells are grown to confluence. Disruption of cell-cell adhesions induces a nuclear translocation of α-adducin. Conversely, α-adducin is redistributed to the cytoplasm and cell-cell junctions in the process of establishing cell-cell adhesions. We identify that α-adducin contains a bipartite nuclear localization signal (NLS) in its COOH-terminal tail domain and a nuclear export signal in its neck region. The phosphorylation of α-adducin at Ser716 that is immediately adjacent to the NLS appears to antagonize the function of the NLS. Moreover, we show that depletion of α-adducin has adverse effects on cell-cell adhesions and, to our surprise, cell proliferation. The impaired cell proliferation is associated with mitotic defects characterized by disorganized mitotic spindles, aberrant chromosomal congregation/segregation and abnormal centrosomes. Taken together, our results not only reveal the mechanism for α-adducin to shuttle between the cytoplasm and nucleus, but also highlight a potential role for α-adducin in mitosis. © 2011 John Wiley & Sons A/S.


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.


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.


Hsu C.-L.,Chung Shan Medical University | Lin Y.-J.,National Chung Hsing University | Ho C.-T.,Rutgers University | Yen G.-C.,National Chung Hsing University | Yen G.-C.,China Medical University at Taichung
Journal of Agricultural and Food Chemistry | Year: 2013

Chronic inflammation is characterized by the upregulation of proinflammatory cytokines in obese adipose tissue. Accumulations of adipose tissue macrophages enhance a chronic inflammatory state in adipose tissues. Many studies have indicated that the adipocyte-related inflammatory response in obesity is characterized by an enhanced infiltration of macrophages. The aim of this work was to study the inhibitory effects of garcinol and pterostilbene on the change in inflammatory response due to the interaction between 3T3-L1 adipocytes and RAW 264.7 macrophages. In the TNF-α-induced 3T3-L1 adipocyte model, garcinol and pterostilbene significantly decreased the mRNA expression of COX-2, iNOS, IL-6, and IL-1β and IL-6 secretion by suppressing phosphorylation of p-IκBα and p-p65. In a coculture model of 3T3-L1 adipocytes and RAW 264.7 macrophages, pterostilbene suppressed IL-6 and TNF-α secretion and proinflammatory mRNA expression and also reduced the migration of macrophages toward adipocytes. In the RAW 264.7 macrophage-derived conditioned medium (RAW-CM)-induced 3T3-L1 adipocyte and 3T3-CM-induced RAW 264.7 macrophage models, pterostilbene significantly decreased IL-6 and TNF-α secretion and proinflammatory mRNA expression (COX-2, iNOS, IL-6, TNF-α, PAI-1, CRP, MCP-1, resistin, and leptin). Our findings suggest that garcinol and pterostilbene may provide novel and useful applications to reduce the chronic inflammatory properties of adipocytes. We also found that pterostilbene inhibits proinflammatory responses during the interaction between 3T3-L1 adipocytes and RAW 264.7 macrophages. © 2012 American Chemical Society.


Ko A.M.-S.,Max Planck Institute for Evolutionary Anthropology | Chen C.-Y.,Academia Sinica, Taiwan | Fu Q.,Max Planck Institute for Evolutionary Anthropology | Delfin F.,Max Planck Institute for Evolutionary Anthropology | And 5 more authors.
American Journal of Human Genetics | Year: 2014

A Taiwan origin for the expansion of the Austronesian languages and their speakers is well supported by linguistic and archaeological evidence. However, human genetic evidence is more controversial. Until now, there had been no ancient skeletal evidence of a potential Austronesian-speaking ancestor prior to the Taiwan Neolithic ∼6,000 years ago, and genetic studies have largely ignored the role of genetic diversity within Taiwan as well as the origins of Formosans. We address these issues via analysis of a complete mitochondrial DNA genome sequence of an ∼8,000-year-old skeleton from Liang Island (located between China and Taiwan) and 550 mtDNA genome sequences from 8 aboriginal (highland) Formosan and 4 other Taiwanese groups. We show that the Liangdao Man mtDNA sequence is closest to Formosans, provides a link to southern China, and has the most ancestral haplogroup E sequence found among extant Austronesian speakers. Bayesian phylogenetic analysis allows us to reconstruct a history of early Austronesians arriving in Taiwan in the north ∼6,000 years ago, spreading rapidly to the south, and leaving Taiwan ∼4,000 years ago to spread throughout Island Southeast Asia, Madagascar, and Oceania. © 2014 The American Society of Human Genetics.


Chang Y.-C.,National Cheng Kung University | Lee W.-J.,National Cheng Kung University | Wang L.-C.,Cheng Shiu University | Yang H.-H.,Chaoyang University of Technology | And 4 more authors.
Applied Energy | Year: 2014

This study describes a method for reducing the emissions of toxic organic pollutants from heavy duty diesel engines fueled by biodiesel produced from waste cooking oil (WCO). An analytical method was developed to simultaneously measure five pollutants from one exhaust sample, namely polycyclic aromatic hydrocarbons (PAHs), polychlorined dibenzo-. p-dixins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated dibenzo-. p-dioxins and dibenzofurans (PBDD/Fs) and polybrominated diphenyl ethers (PBDEs). As yet, no data regarding PBDD/F emissions from mobile sources has been reported in the literature. The mass concentrations in the exhaust, in order, were PAHs. ≫. PBDEs. ≫. PBDD/Fs. >. PCBs. >. PCDD/Fs, while for the pollutants having dioxin-like toxicity, their toxicity concentrations, in order, were PCDD/Fs. >. PBDD/Fs. >. PCBs. These concentrations were two to four orders higher than those in the atmosphere. Even though the chlorine content in the WCO-based biodiesel was five times higher than that of fossil diesel, the reduction in the emission factors of the aforesaid pollutants increased along with the percentage of biodiesel. For example, B20 achieved a 49-73% and 61-83% reduction in mass and toxicity, respectively. In conclusion, the use of WCO-based biodiesel not only solves the problem of waste oil disposal, but also reduces the toxic organic pollutant emissions from diesel engines. © 2013 Elsevier Ltd.


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.


Lee C.-H.,National Cheng Kung University | Lee C.-H.,China Medical University at Taichung | Wu C.-L.,National Cheng Kung University | Shiau A.-L.,National Cheng Kung University
Journal of Immunotherapy | Year: 2010

Chronic inflammation is a potential risk factor for tumor progression. The molecular mechanisms linking chronic inflammation and tumor growth have proven elusive. Herein, we describe a new role for Toll-like receptor 4 (TLR4) in tumor-associated macrophages (TAMs) in promoting tumor growth. TAMs can remodel tumor microenvironment and promote tumor growth. With the use of mice lacking TLR4 signaling, we show that TLR4 signaling influences tumor growth and that TLR4 signaling is a critical upstream activator of nuclear factor-kappa B (NF-κB) in TAMs. TLR4-deficient TAMs produce neither proinflammatory cytokines nor angiogenic factors, and activate no NF-κB activity in tumor cells. Furthermore, using macrophage/tumor cell coculture system and adoptive transfer of macrophages with functional TLR4 macrophages to TLR4-deficient mice bearing tumors, we demonstrate an essential role for TLR4 signaling in inducing NF-κB activity in tumor cells and enhancing tumor growth. Antibody neutralization experiments reveal that TAMs are stimulated by heat shock proteins derived from tumor cells through TLR4, leading to production of growth factors, which may in turn promote tumor growth via NF-κB signal pathway. Therefore, this signaling cascade may represent a therapeutic target in cancer. © 2009 by Lippincott Williams & Wilkins.


Hsieh C.-Y.,Tainan Sin Lau Hospital | Hsieh C.-Y.,National Cheng Kung University | Chen C.-H.,National Cheng Kung University | Li C.-Y.,National Cheng Kung University | And 2 more authors.
Journal of the Formosan Medical Association | Year: 2015

Background/purpose: The National Health Insurance Research Database, which uses claims data from hospitals contracted with the National Health Insurance (NHI) program in Taiwan, has been widely used for stroke research. The diagnostic accuracy of the NHI claims data with regard to acute ischemic stroke (AIS) has rarely been validated. The aim of this study was to validate the diagnosis of AIS in NHI claims data using the Taiwan Stroke Registry (TSR) as a reference. Methods: We retrieved patients' data with a discharge diagnosis of AIS [five-digit International Classification of Diseases Code, 9th version (ICD-9 code): 433xx or 434xx] in a single medical center from August 2006 to December 2008. We then linked these patients to the TSR to validate their AIS diagnosis in the claims data. The positive predictive value (PPV) and sensitivity were determined. Results: We reviewed the claims data of 1736 consecutive AIS patients, of whom 1299 (74.8%) were linked successfully to the stroke registry database. After reviewing the medical records and imaging results of other patients not linked to the registry database (n=437), 235 patients were found to have had an AIS. The PPV was 88.4% [95% confidence interval (CI): 86.8-89.8%] and sensitivity was 97.3% (95% CI: 96.4-98.1%). Forty-four (21.8%) of the false-positive cases (n = 202) were coded as 433. x0 or 434. x0. Conclusion: The PPV of a diagnosis of AIS in the NHI claims data was high. Using five-digit ICD-9 codes to identify AIS cases will markedly decrease the false-positive rate compared with using the commonly used three-digit method. © 2013.


Wu D.-W.,Taipei Medical University | Tsai L.-H.,Chung Shan Medical University | Chen P.-M.,Chung Shan Medical University | Lee M.-C.,Taichung Veteran General Hospital | And 4 more authors.
American Journal of Pathology | Year: 2012

Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non-small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6-positive tumors than in E6-negative tumors. To explore the possible underlying mechanism, E6-negative TL4 and CL1-0 cells were transfected with an E6 cDNA plasmid. A marked decrease in TIMP-3 expression was caused by promoter hypermethylation via increased DNA (cytosine-5-)-methyltransferase 1 (DNMT1) expression. Mechanistic studies indicated that TIMP-3 loss promoted interleukin-6 (IL-6) production, which led to cell invasion and anchorage-independent growth on soft agar plates. Kaplan-Meier and Cox regression models showed that patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods when compared with patients with high-TIMP-3/low-IL-6 tumors. In summary, loss of TIMP-3 may increase IL-6 production via the tumor necrosis factor α/nuclear factor κB axis, thereby promoting tumor malignancy and subsequent relapse and poor survival in patients with HPV-infected non-small cell lung cancer. © 2012 American Society for Investigative Pathology.


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.


Chuang T.-H.,China Medical University at Taichung | Chen Y.-C.,VaNung University | Pola S.,Kakatiya University
Journal of Organic Chemistry | Year: 2010

A series of disubstituted pyridine derivatives was synthesized from the corresponding acryloyl azides by acetic acid-promoted cycloaddition. This represents a novel and convenient synthetic approach to the symmetric 3,5-disubstituted pyridines. The nature of the substituent on the double bond and the utilized solvent were found to be crucial to the yield of pyridines. The reactivity of the acid-promoted cycloaddition increases with the presence of aryl groups, such as phenyl and pyridinyl. We also explored the comprehensive mechanism by the acid-promoted cycloaddition of 13C-labeled cinnamoyl azide. The symmetric 3,5-disubstituted pyridines were synthesized from acryloyl azides by acetic acid-promoted trimolecular condensation. © 2010 American Chemical Society.


Chin W.-C.,National Chung Hsing University | Lin K.-H.,National Institute of Infectious Disease and Vaccinology | Chang J.-J.,China Medical University at Taichung | Chang J.-J.,Academia Sinica, Taiwan | Huang C.-C.,National Chung Hsing University
Biotechnology for Biofuels | Year: 2013

Background: Though n-butanol has been proposed as a potential transportation biofuel, its toxicity often causes oxidative stress in the host microorganism and is considered one of the bottlenecks preventing its efficient mass production. Results: To relieve the oxidative stress in the host cell, metallothioneins (MTs), which are known as scavengers for reactive oxygen species (ROS), were engineered in E. coli hosts for both cytosolic and outer-membrane-targeted (osmoregulatory membrane protein OmpC fused) expression. Metallothioneins from human (HMT), mouse (MMT), and tilapia fish (TMT) were tested. The host strain expressing membrane-targeted TMT showed the greatest ability to reduce oxidative stresses induced by n-butanol, ethanol, furfural, hydroxymethylfurfural, and nickel. The same strain also allowed for an increased growth rate of recombinant E. coli under n-butanol stress. Further experiments indicated that the TMT-fused OmpC protein could not only function in ROS scavenging but also regulate either glycine betaine (GB) or glucose uptake via osmosis, and the dual functional fusion protein could contribute in an enhancement of the host microorganism's growth rate. Conclusions: The abilities of scavenging intracellular or extracellular ROS by these engineering E. coli were examined, and TMT show the best ability among three MTs. Additionally, the membrane-targeted fusion protein, OmpC-TMT, improved host tolerance up to 1.5% n-butanol above that of TMT which is only 1%. These results presented indicate potential novel approaches for engineering stress tolerant microorganism strains. © 2013 Chin et al.; licensee BioMed Central Ltd.


Chen H.-J.,National Sun Yat - sen University | Su C.-T.,Chinese Culture University | Lin C.-H.,National Sun Yat - sen University | Huang G.-J.,China Medical University at Taichung | Lin Y.-H.,Academia Sinica, Taiwan
Journal of Plant Physiology | Year: 2010

In this report a full-length cDNA, SPCP2, which encoded a putative papain-like cysteine protease was isolated from senescent leaves of sweet potato (Ipomoea batatas). SPCP2 contained 1101 nucleotides (366 amino acids) in its open reading frame, and exhibited high amino acid sequence identities (ca. 68% to 83%) with plant cysteine proteases, including Actinidia deliciosa, Arabidopsis thaliana, Brassica oleracea, Phaseolus vulgaris, Pisum sativa, Vicia faba, Vicia sativa and Vigna mungo. RT-PCR analysis showed that SPCP2 gene expression was enhanced significantly in natural senescent leaves and in dark-, abscisic acid- (ABA-), jasmonic acid- (JA-) and ethephon-induced senescent leaves, but was almost not detected in mature green leaves, stems, and roots. Transgenic Arabidopsis with constitutive SPCP2 expression exhibited earlier floral transition from vegetative to reproductive growth, higher percentage of incompletely developed siliques per plant, reduced average fresh weight and lower germination percentage of seed, and higher salt and drought stress tolerance compared to those of control. Based on these results we conclude that sweet potato papain-like cysteine protease, SPCP2, is a functional senescence-associated gene, and its expression causes altered developmental characteristics and stress responses in transgenic Arabidopsis plants. © 2010 Elsevier GmbH. All rights reserved.


Chang Y.-J.,Central Taiwan University of Science and Technology | Hsieh B.-T.,Central Taiwan University of Science and Technology | Liang J.-A.,China Medical University at Taichung
Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment | Year: 2011

The design of experiment was used to find the optimal composition of N-isopropyl acrylamide (NIPAM) gel. Optical computed tomography was used to scan the polymer gel dosimeter, which was irradiated from 0 to 20 Gy. The study was conducted following a statistical method using a two-level fractional factorial plan involving four variables (gelatin - 5% and 6%, NIPAM - 3% and 5%, Bis - 2.5% and 3%, and THPC - 5 and 10 mM). We produced three batches of gels of the same composition to replicate the experiments. Based on the statistical analysis, a regression model was built. The optimal gel composition for the dose range 015 Gy with linearity up to 1.000 is as follows: gelatin (5.67%), NIPAM (5%), Bis (2.56%), and THPC (10 mM). The dose response of the NIPAM polymer gel attains stability about 24 h after irradiation and remains stable up to 3 months. © 2010 Elsevier B.V.


Chen Y.-C.,Foundation Medicine | Chen Y.-C.,Tzu Chi University | Su Y.-C.,Foundation Medicine | Su Y.-C.,Tzu Chi University | And 4 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 K.-H.,Fooyin University | Chiang H.-L.,China Medical University at Taichung
Journal of Hazardous Materials | Year: 2014

Non-metal fractions of waste printed circuit boards (PCBs) were thermally treated (200-500. °C) under nitrogen atmosphere. Carbon, hydrogen, and nitrogen were determined by elemental analyzer, bromine by instrumental neutron activation analysis (INAA), phosphorus by energy dispersive X-ray spectrometer (EDX), and 29 trace elements by inductively coupled plasma atomic emission spectrometer (ICP-AES) and mass spectrometry (ICP-MS) for raw material and pyrolysis residues. Organic compositions of liquid oil were identified by GC (gas chromatography)-MS, trace element composition by ICP system, and 12 water-soluble ions by IC (ionic chromatography). Elemental content of carbon was >450. mg/g, oxygen 300. mg/g, bromine and hydrogen 60. mg/g, nitrogen 30. mg/g, and phosphorus 28. mg/g. Sulfur was trace in PCBs. Copper content was 25-28. mg/g, iron 1.3-1.7. mg/g, tin 0.8-1.0. mg/g and magnesium 0.4-1.0. mg/g; those were the main metals in the raw materials and pyrolytic residues. In the liquid products, carbon content was 68-73%, hydrogen was 10-14%, nitrogen was 4-5%, and sulfur was less than 0.05% at pyrolysis temperatures from 300 to 500. °C. Phenol, 3-bromophenol, 2-methylphenol and 4-propan-2-ylphenol were major species in liquid products, accounting for >50% of analyzed organic species. Bromides, ammonium and phosphate were the main species in water sorption samples for PCB pyrolysis exhaust. © 2014 Elsevier B.V.


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.


Huang H.-W.,Tamkang University | Shih T.-C.,China Medical University at Taichung | Liauh C.-T.,Kun Shan University
BioMedical Engineering Online | Year: 2010

Background: Pennes Bio Heat Transfer Equation (PBHTE) has been widely used to approximate the overall temperature distribution in tissue using a perfusion parameter term in the equation during hyperthermia treatment. In the similar modeling, effective thermal conductivity (K eff) model uses thermal conductivity as a parameter to predict temperatures. However the equations do not describe the thermal contribution of blood vessels. A countercurrent vascular network model which represents a more fundamental approach to modeling temperatures in tissue than do the generally used approximate equations such as the Pennes BHTE or effective thermal conductivity equations was presented in 1996. This type of model is capable of calculating the blood temperature in vessels and describing a vasculature in the tissue regions.Methods: In this paper, a countercurrent blood vessel network (CBVN) model for calculating tissue temperatures has been developed for studying hyperthermia cancer treatment. We use a systematic approach to reveal the impact of a vasculature of blood vessels against a single vessel which most studies have presented. A vasculature illustrates branching vessels at the periphery of the tumor volume. The general trends present in this vascular model are similar to those shown for physiological systems in Green and Whitmore. The 3-D temperature distributions are obtained by solving the conduction equation in the tissue and the convective energy equation with specified Nusselt number in the vessels.Results: This paper investigates effects of size of blood vessels in the CBVN model on total absorbed power in the treated region and blood flow rates (or perfusion rate) in the CBVN on temperature distributions during hyperthermia cancer treatment. Also, the same optimized power distribution during hyperthermia treatment is used to illustrate the differences between PBHTE and CBVN models. K eff(effective thermal conductivity model) delivers the same difference as compared to the CBVN model. The optimization used here is adjusting power based on the local temperature in the treated region in an attempt to reach the ideal therapeutic temperature of 43°C. The scheme can be used (or adapted) in a non-invasive power supply application such as high-intensity focused ultrasound (HIFU). Results show that, for low perfusion rates in CBVN model vessels, impacts on tissue temperature becomes insignificant. Uniform temperature in the treated region is obtained.Conclusion: Therefore, any method that could decrease or prevent blood flow rates into the tumorous region is recommended as a pre-process to hyperthermia cancer treatment. Second, the size of vessels in vasculatures does not significantly affect on total power consumption during hyperthermia therapy when the total blood flow rate is constant. It is about 0.8% decreasing in total optimized absorbed power in the heated region as γ (the ratio of diameters of successive vessel generations) increases from 0.6 to 0.7, or from 0.7 to 0.8, or from 0.8 to 0.9. Last, in hyperthermia treatments, when the heated region consists of thermally significant vessels, much of absorbed power is required to heat the region and (provided that finer spatial power deposition exists) to heat vessels which could lead to higher blood temperatures than tissue temperatures when modeled them using PBHTE. © 2010 Huang 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.


Hsieh B.-T.,Central Taiwan University of Science and Technology | Wu J.,China Medical University at Taichung | Chang Y.-J.,Central Taiwan University of Science and Technology
IEEE Transactions on Nuclear Science | Year: 2013

A gel dosimeter is a three-dimensional (3-D) device that is used in radiotherapy. It is more efficient than traditional one-dimensional and two-dimensional dosimeters because it can be used in complicated radiation therapy applications. However, the achievement of temporal and spatial stabilities for gel dosimeters remains challenging in clinical applications because the fabrication process affects the polymerization reaction during irradiation. This study investigated the dose profile variation of an N-isopropyl acrylamide (NIPAM) polymer gel dosimeter by using the 3-D optical computed tomography scanner OCTOPUSTM 10X (MGS Research Inc.). Two acrylic containers (diameter = 10 cm, height = 10, and diameter = 15 cm, height = 15 cm) filled with polymer gel (gelatin: 5%, NIPAM: 5%, Bis: 3%, THPC: 5 mM) were irradiated by using intensity-modulated radiotherapy (SIEMENS Oncor Impression, 6 MV Photo beam). The treatment field was a 3 cm × 3 cm square field, and the prescribed dose was 5 Gy. The results of the reconstruction line profile showed that the uncertainty of non-irradiated gel is less than 1.3% when a container with 10 cm diameters cooled in a refrigerator with a water bath. The maximum uncertainties of the irradiated gel at 24 h, 48 h, and 72 h post-irradiation were 2.9%, 2.9%, and 3.1%, respectively. However, the maximum uncertainty of the non-irradiated gel dosimeter increased to 3% when a container with 15 cm diameter was cooled in the same refrigerator. After irradiation, the maximum uncertainties of the irradiated gel at 24 h, 48 h, and 72 h post-irradiation were 13.1%, 13.7%, and 12.95%, respectively. The uncertainty differences for gels at different container sizes were attributed to the different cooling rates that were applied to the gels. The time required for large gel containers to cool in the refrigerator was more than 10 h, whereas the cooling process only took 4.2 h for gels in a small container. The time difference produced different temperature histories for gels and may result in changes in gel sensitivity. Given the thermally induced pre-radiation polymerization, the time difference resulted in a deviation in dose profiles. This study reports that thermal control during gel preparation should be carefully performed for clinical applications to achieve a more accurate dose distribution in 3-D image reconstruction. © 1963-2012 IEEE.


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.


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.


Yin M.-C.,China Medical University at Taichung
BioMedicine (Netherlands) | Year: 2015

Pentacyclic triterpenic compounds including asiatic, betulinic, maslinic, oleanolic and ursolic acid occur naturally in many herbs and plant foods. It is well known that these triterpenoids possess anti-oxidative and anti-inflammatory activities. Furthermore, recent in vitro and in vivo researches indicated that these compounds could inhibit the production of advanced glycation end-products (AGEs). The impact of these triterpenes upon the activity and protein expression of enzymes involved in polyol pathway including aldose reductase and sorbitol dehydrogenase has been examined, and positive results are reported. These studies suggest that certain triterpenes are potent anti-glycative agents, and may benefit the prevention and/or therapy of glycation-related diseases such as diabetes mellitus and Alzheimer's disease. In this review article, the anti-glycative activity and action mode of certain triterpenes are highlighted. These information may promote the anti-glycative application of these natural compounds. © Author(s) 2015. This article is published with open access by China Medical University.


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.


Peng K.-W.,National Chung Hsing University | Liou Y.-M.,National Chung Hsing University | Liou Y.-M.,China Medical University at Taichung
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: Wharton's Jelly cells (WJCs) can be differentiated into adipocytes by cytoskeletal reorganisation in association with changes in the mechanical properties of cells. Methods: WJCs subjected to adipocyte induction were observed changes in the cell morphology and alterations in actin filament formation. Transfection with either small interfering RNAs (siRNAs) against formin-2 (FMN-2), tropomyosin-1 (Tm-1), caldesmon (CaD), and profilin (Pro) or a pcDNA6-gelsolin (GSN)-constructed vector in WJCs was used to establish their regulatory roles in controlling adipogenesis. Phenotypic transformation of the cell shape and changes in cell surface adhesion force were determined in WJCs after transformation. Results: The levels of protein and mRNA expression of β-actin and several key actin binding ptoteins (ABPs) were decreased during the early stage of adipogenic induction but were recovered in the later induction. The siFMN-2, siTm-1, siCaD, and siPro gene knockdown in WJCs caused a widening of the cell shape, while WJCs overexpressing GSN retained a fibroblast cell shape. For both transformations, atomic force microscopy revealed alterations in the biomechanical signals on the cell surface. However, the adipogenic potency was increased after siFMN-2, siTm-1, siCaD, and siPro gene knockdown and decreased during GSN overexpression. Conclusions: siRNA gene knockdown of siFMN-2, siTm-1, siCaD, and siPro enhances the potency for WJCs commitment to adipocyte, while GSN overexpression modulates the PPAR-γ-independent pathway for the adipogenesis of WJCs. General significance: The phenotypic changes associated with decreased ABP gene expression are critical for regulating the adipogenic differentiation of WJCs through the temporal control of actin filament organisation. © 2012 Elsevier B.V. All rights reserved.


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.


Chiou S.-M.,China Medical University at Taichung
World Neurosurgery | Year: 2015

Background A few reports have addressed the sex-related efficacy of deep brain stimulation (DBS) in the subthalamic nucleus (STN) to treat advanced Parkinson disease (PD). The present study evaluates the sex-related prognostic factors for STN-DBS outcomes. Methods Seventy-two consecutive patients (48 men and 24 women) were reviewed retrospectively. Changes in the Unified PD Rating Scale scores were compared between men and women in the 6-month drug-off/DBS-on state relative to the preoperative drug-off baseline. A multivariate linear regression model was used to identify the preoperative factors predictive of motor improvements after surgery. Results Before surgery, the male and female patient groups were comparable in clinical severity, except the women were associated with slightly inferior cognition (P < 0.05) and a relatively better response to levodopa (LD) (P < 0.05) than the men. Both sexes showed similar clinical improvements after STN-DBS therapy. In men, preoperative lower LD requirement and higher motor dysfunction, particularly tremor (adjusted R2 = 0.613, P < 0.001), as well as greater improvement in tremor and rigidity after LD therapy (adjusted R2 = 0.232, P = 0.001) were favorable predictors of surgical outcomes. Women achieved a significant improvement if they performed well in activities of daily living even with higher baseline motor scores (adjusted R2 = 0.620, P < 0.001), or exhibited improvements in akinesia disability after preoperative LD therapy (adjusted R2 = 0.305, P = 0.003). Conclusions STN-DBS therapy is equally beneficial for both sexes. Sex-related differences exist with regard to favorable prognostic predictors for early surgical outcomes. © 2015 Elsevier Inc.


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.


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.


Hsieh Y.-L.,National Taiwan Ocean University | Yao H.-T.,China Medical University at Taichung | Cheng R.-S.,National Taiwan Ocean University | Chiang M.-T.,National Taiwan Ocean University
Journal of Medicinal Food | Year: 2012

Chitosan is a natural product derived from chitin. To investigate the hypoglycemic and anti-obesity effects of chitosan, male Sprague-Dawley rats were divided into four groups: normal control, diabetic, and diabetic fed 5% or 7% chitosan. Diabetes was induced in rats by injecting streptozotocin/nicotinamide. After 10 weeks of feeding, the elevated plasma glucose, tumor necrosis factor-α, and interleukin-6 and lower adiponetin levels caused by diabetes were effectively reversed by chitosan treatment. In addition, 7% chitosan feeding also elevated plasma glucagon-like peptide-1 levels and lowered the insulin resistance index (homeostasis model assessment) in diabetic rats. Lower adipocyte granular intensities and higher lipolysis rates in adipose tissues were noted in the 7% chitosan group. Moreover, chitosan feeding reduced hepatic triglyceride and cholesterol contents and increased hepatic peroxisomal proliferator-activated receptor α expression in diabetic rats. Our results indicate that long-term administration of chitosan may reduce insulin resistance through suppression of lipid accumulation in liver and adipose tissues and amelioration of chronic inflammation in diabetic rats. © Copyright 2012, Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition.


Hsieh M.-T.,China Medical University at Taichung | Shia K.-S.,National Health Research Institute | Liu H.-J.,National Tsing Hua University | Kuo S.-C.,China Pharmaceutical University
Organic and Biomolecular Chemistry | Year: 2012

A highly efficient annulative approach towards the construction of the structurally attractive methylenecyclohexane ring was developed through a convenient 1,4-addition of 4-pentenylmagnesium bromide to 2-cyano-2- cycloalkenones followed by a Pd(ii)-mediated oxidative cyclization of the resulting ω-unsaturated α-cyano ketones. Based on this newly developed protocol, polycyclic adducts bearing various ring sizes and substitutions can be prepared in moderate to high yields. © 2012 The Royal Society of Chemistry.


Huang H.-M.,National Taichung University of Science and Technology | Liaw S.-S.,China Medical University at Taichung | Lai C.-M.,National Taichung University of Science and Technology
Interactive Learning Environments | Year: 2016

Advanced technologies have been widely applied in medical education, including human-patient simulators, immersive virtual reality Cave Automatic Virtual Environment systems, and video conferencing. Evaluating learner acceptance of such virtual reality (VR) learning environments is a critical issue for ensuring that such technologies are used to greatest effect. This research describes the use of high performance real-time interactive software (VR4MAX) to build a prototype 3D VR learning system. A questionnaire survey was distributed to 167 university students to investigate learner attitudes toward learning via VR applications. Experimental results show that immersion and imagination features of VR-mediated course contents have a positive impact on perceived usefulness, and can also predict perceived ease of use, both of which contributors to behavioral intention of learners to use VR learning systems. Overall, this research validates the relationship between three features of VR and learners' behavioral intention to use VR learning. The results could prove helpful in guiding future research related to VR learning. © 2013 Taylor & Francis.


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.


Tang C.-H.,National Dong Hwa University | Lai D.-Y.,National Chung Hsing University | Lee T.-H.,National Chung Hsing University | Lee T.-H.,China Medical University at Taichung
Comparative Biochemistry and Physiology - A Molecular and Integrative Physiology | Year: 2012

Na+/K+-ATPase (NKA) is a primary active pump provides the driving force for ion-transporting systems in the osmoregulatory tissues of teleosts. Therefore, modulation of NKA expression or activity and its regulatory subunit, FXYD protein, is essential for teleosts in salinity adaptation. To understand the mechanisms for modulation of NKA in catadromous fishes, NKA expression and activity, cloning and mRNA expression of FXYD11 (AjFXYD11) were examined in Japanese eel (Anguilla japonica) exposed to fresh water (FW) and seawater (SW; 35‰). Expression and activity of NKA as well as mRNA expression of AjFXYD11 in gills were elevated in SW eel compared to FW eel. Conversely, NKA responses in eel kidneys were higher in FW group than SW group, whereas no significant difference was found in renal AjFXYD11 expression between the two groups. Comparison of NKA activity and AjFXYD11 expression between two osmoregulatory tissues suggested that AjFXYD11 plays a specific, functional role in gills. However, since cortisol plays an important role for regulation of ion transport in teleost SW acclimation and gill AjFXYD11 expression was elevated in SW eel, the organ culture approach was used to study the effect of cortisol on gill AjFXYD11 mRNA expression. Our results revealed that cortisol treatment increased the levels of gill AjFXYD11 transcripts. This finding suggested that cortisol could be involved in the regulation of NKA by altering AjFXYD11 expression during the process of SW acclimation in A. japonica. Taken together, the differential expression of branchial and renal NKA and AjFXYD11 implicated their roles in the osmotic homeostasis of Japanese eel exposed to environments of different salinities. © 2012 Elsevier Inc.


Hui C.Y.,Chungnam National University | Tam P.H.T.,National Tsing Hua University | Takata J.,University of Hong Kong | Kong A.K.H.,National Tsing Hua University | And 4 more authors.
Astrophysical Journal Letters | Year: 2014

We have investigated the X-ray and γ-ray properties of the redback millisecond pulsar PSR J1723-2837 with XMM-Newton, Chandra, and Fermi. We have discovered the X-ray orbital modulation of this binary system with a minimum that coincides with the phases of radio eclipse. The X-ray emission is clearly non-thermal in nature, which can be described well by a simple power law with a photon index of ;1.2. The phase-averaged luminosity is ;9 × 10 31 erg s-1 in 0.3-10 keV, which consumes ;0.2% of the spin-down power. We have detected the γ-ray emission in 0.1-300 GeV from this system at a significance of ;6σ for the first time. The γ-rays in this energy range consume ;2% of the spin-down power and can be modeled by a power law with a photon index of ;2.6. We discuss the high energy properties of the new redback in the context of an intrabinary shock model. © 2014. The American Astronomical Society. All rights reserved..


Tsai L.-P.,Buddhist Tzu Chi General Hospital | Tsai L.-P.,Tzu Chi University | Lee H.-H.,Buddhist Tzu Chi General Hospital | Lee H.-H.,China Medical University at Taichung
Gene | Year: 2012

The RCCX module on chromosome 6p21.3 has 3 possible forms: monomodular, bimodular, and trimodular. Chromosomes with 4 RCCX modules are very rare. In the monomodule, most of the CYP21A1P genes do not exist. However, haplotypes of the RCCX module with more than one CYP21A2 gene were observed. Obviously, the gene located downstream of the XA gene can possibly include the CYP21A2 as well as the CYP21A1P gene. © 2012 .


Kang C.-K.,National Chung Hsing University | Lee T.-H.,National Chung Hsing University | Lee T.-H.,China Medical University at Taichung
Frontiers in Zoology | Year: 2014

Introduction: Villin 1 is an actin-regulatory protein involved in the formation of microvilli of mammalian enterocytes. The microvilli, finger-like protrusions, are more abundant on the apical surfaces of gill ionocytes in various freshwater (FW) teleosts than in seawater (SW) fishes. However, the plasticity in the mechanisms of microvillus formation in the gill ionocytes are poorly understood, and the actin-regulatory proteins involved in the formation of microvilli have not been identified in fishes. The present study used the euryhaline medaka (Oryzias dancena) as a model to explore the role of a homolog of villin 1 in the actin-organization of cellular morphologies induced by decreasing salinities. Results: By ultrastructural observation, there are numerous actin filaments organized on the apical cortex of ion-absorptive ionocytes in the FW-acclimated medaka. From gills of the euryhaline medaka, we have identified the VILL sequence. The phylogenetic tree and functional domains suggest that VILL is the homolog of villin 1 in fishes. Immunofluorescence using a specific antibody revealed that VILL was specifically localized to the apical region of gill ionocytes along with microvilli in the FW medaka, but not in SW fish. The expression levels of Odvill mRNA and VILL protein were higher in the gills of the FW individuals than in the SW group and were induced when fish were transferred from SW to FW. A morpholino oligonucleotide for VILL knockdown eliminated the apical protrusions of ionocytes and pavement cells in the trunk epithelia of embryos. Conclusions: From a novel aspect of cytoskeletal functions, our findings highlighted the important role of VILL protein in the ionoregulation of aquatic vertebrates in response to different osmotic challenges. This study is the first to show that the expression of VILL is associated with the formation of microvilli in the absorptive ionocytes of a euryhaline fish. Loss-of-function experiments showed that the distribution of VILL may represent the molecular link between the cytoskeletal organization and cellular morphology of the absorptive ionocytes during hypoosmotic adaptation in aquatic vertebrates. © 2014 Kang and Lee; licensee BioMed Central Ltd.


Yeh H.-Y.,Hungkuang University | Chuang C.-H.,Hungkuang University | Chen H.-C.,China Medical University at Taichung | Wan C.-J.,Tachia General Lee hospital | And 2 more authors.
LWT - Food Science and Technology | Year: 2014

Ginger, a medicinal herb with bioactive components, is now widely used. This study reports the information of bioactive components in two varieties ginger root (Zingiber officinale Roscoe), Guangdong-ginger (GG) and Chu-ginger (CG) available in Taiwan and compares their bioactive components and antioxidant properties using aqueous and ethanolic extract. The proximate analysis of both ginger rhizomes gave similar profiles. Total contents of organic acids were 37.33 and 91.06 mg/g dry weight for GG and CG, respectively, with oxalic and tartaric acids being two major acids. HPLC analysis revealed gingerols and shogaol in both ginger were similar but curcumin content was higher in GG. The essential oils exhibited similar volatile profiles and 60 and 65 compounds were identified for GG and CG, respectively. Among the essential oils major components were camphene, sabinene, α-curcumene, zingiberene, α-farnesene, β-sesquiphellandrene, neral, and geranial. The antioxidant effect of ginger ethanolic extracts were more effective than aqueous extracts in Trolox equivalent antioxidant capacity and Ferric reducing ability of plasma. Contrarily, ginger aqueous extracts were more effective in free radical scavenging activities and chelating abilities. Based on the results, two ginger rhizomes exerted protective effects and could be used as a flavouring agent and a natural antioxidant. © 2013 Elsevier Ltd.


Chang C.-J.,University of Houston | Hung M.-C.,University of Houston | Hung M.-C.,China Medical University at Taichung
British Journal of Cancer | Year: 2012

Accumulated evidence shows that EZH2 is deregulated in a wide range of cancer types, and it has a crucial role in stem cell maintenance and tumour development. Therefore, blocking EZH2 expression or activity may represent a promising strategy for anticancer treatment. In this review, we address the current understanding of the mechanisms underlying EZH2 regulation alongside the function of EZH2 gene targets that are involved in cancer progression. Finally, we will describe cancer therapies that target EZH2 or its downstream cascades, which could potentially reverse the oncogenic and stemness properties of the tumour cells to suppress cancer progression and recurrence. © 2012 Cancer Research UK All rights reserved.


Moon W.K.,Seoul National University | Lo C.-M.,National Taiwan University | Chang J.M.,Seoul National University | Huang C.-S.,National Taiwan University Hospital | And 2 more authors.
Medical Physics | Year: 2012

Purpose: To develop an ultrasound computer-aided diagnosis (CAD) system using speckle features of automated breast ultrasound (ABUS) images. Methods: The ABUS images of 147 pathologically proven breast masses (76 benign and 71 malignant cases) were used. For each mass, a volume of interest (VOI) was cropped to define the tumor area, and the average number of speckle pixels within a VOI was calculated. In addition, first-order and second-order statistical analyses of the speckle pixels were used to quantify the information of gray-level distributions and the spatial relations among the pixels. Receiver operating characteristic curve analysis was used to evaluate the performance. Results: The proposed CAD system based on speckle patterns achieved an accuracy of 84.4 (124147), a sensitivity of 83.1 (5971), a specificity of 85.5 (6576), and an Az of 0.91. The performance indices of the speckle features were comparable to the performance indices of the morphological features, which include shape and ellipse-fitting features (p-value > 0.05). Furthermore, combining speckle and morphological features yielded an Az that was significantly better than the Az of the morphological features alone (0.96 vs 0.91, p-value 0.0154). Conclusions: The results suggest that the proposed speckle features, while combined with morphological features, are promising for the classification of breast masses detected using ABUS. © 2012 American Association of Physicists in Medicine.


Pan M.-H.,National Taiwan University of Science and Technology | Pan M.-H.,China Medical University at Taichung | Lai C.-S.,National Taiwan University of Science and Technology | Tsai M.-L.,National Kaohsiung Marine University | Ho C.-T.,Rutgers University
Molecular Nutrition and Food Research | Year: 2014

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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.


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.


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.


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.


Wu S.-C.,National Health Research Institute | Wu S.-C.,National Tsing Hua University | Liao C.-W.,National Health Research Institute | Liao C.-W.,A-Life Medical | And 4 more authors.
Cell Host and Microbe | Year: 2012

Local infections can trigger immune responses in distant organs, and this interorgan immunological crosstalk helps maintain immune homeostasis. We find that enterobacterial infection or chemically and genetically stimulating reactive oxygen species (ROS)-induced stress responses in the Drosophila gut triggers global antimicrobial peptide (AMP) responses in the fat body, a major immune organ in flies. ROS stress induces nitric oxide (NO) production in the gut, which triggers production of the AMP Diptericin, but not Drosomycin, in the fat body. Hemocytes serve as a signaling relay for communication between intestinal ROS/NO signaling and fat body AMP responses. The induction of AMP responses requires Rel/NF-κB activation within the fat body. Although Rel-mediated Drosomycin induction is repressed by the AP-1 transcription factor, this repressor activity is inhibited by intestinal ROS. Thus, intestinal ROS signaling plays an important role in initiating gut-to-fat body immunological communication in Drosophila. © 2012 Elsevier Inc.


Ou T.-T.,Chung Shan Medical University | Wang C.-J.,Chung Shan Medical University | Lee Y.-S.,Mackay Memorial Hospital Taitung Branch | Wu C.-H.,China Medical University at Taichung | Lee H.-J.,Chung Shan Medical University
Molecular Nutrition and Food Research | Year: 2010

Scope: Cell cycle regulation is a critical issue in cancer treatment. Previously, gallic acid (GA) has been reported to possess anticancer ability. Here, we have evaluated the molecular mechanism of GA on cell cycle modulation in a human bladder transitional carcinoma cell line (TSGH-8301 cell). Methods and results: Using flow cytometer analysis, exposure of the cells to 40 μM GA resulted in a statistically significant increase in G2/M phase cells, which was accompanied by a decrease in G0/G1 phase cells. GA-treated cells resulted in significant growth inhibition in a dose-dependent manner accompanied by a decrease in cyclin-dependent kinases (Cdk1), Cyclin B1, and Cdc25C, but significant increases in p-cdc2 (Tyr-15) and Cip1/p21 by western blotting. Additional mechanistic studies showed that GA induces phosphorylation of Cdc25C at Ser-216. This mechanism leads to its translocation from the nucleus to the cytoplasm resulting in an increased binding with 14-3-3β. When treated with GA, phosphorylated Cdc25C can be activated by ataxia telangiectasia-mutated checkpoint kinase 2 (Chk2). This might be a DNA damage response as indicated by Ser-139 phosphorylation of histine H2A.X. Furthermore, treatment of the cells with a Chk2 inhibitor significantly attenuated GA-induced G2/M phase arrest. Conclusion: These results indicate that GA can induce cell cycle arrest at G2/M phase via Chk2-mediated phosphorylation of Cdc25C in a bladder transitional carcinoma cell line. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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.


Hsiao H.-B.,National Chung Hsing University | Wu J.-B.,Graduate Institute of Pharmaceutical Chemistry | Lin H.,National Chung Hsing University | Lin W.-C.,China Medical University at Taichung
Shock | Year: 2011

In the present study, we reported that kinsenoside, a major component of Anoectochilus formosanus, inhibited inflammatory reactions in mouse peritoneal lavage macrophages and protects mice from endotoxin shock. In LPS-stimulated mouse peritoneal lavage macrophages, kinsenoside inhibited the inflammatory mediators, such as nitric oxide, TNF-α, IL-1β, monocyte chemoattractant protein 1, and macrophage migration inhibitory factor production. Furthermore, kinsenoside decreased the formation of a nuclear factor κB-DNA complex and nuclear p65 and p50 protein levels. Kinsenoside inhibited nuclear factor κB translocation through both IκBα-dependent and -independent pathway. In contrast, it stimulated anti-inflammatory cytokine IL-10 generation and enhanced the mRNA expression of IL-10 and suppressor of cytokine signaling 3 in the same cells induced by LPS. In an animal model, both pretreatment and posttreatment of kinsenoside increased the survival rate of ICR mice challenged by LPS (80 mg/kg, i.p.). Pretreatment with kinsenoside decreased serum levels of TNF-α, IL-1β, IL-10, monocyte chemoattractant protein 1, and migration inhibitory factor at 1 h after sublethal dose of LPS (40 mg/kg, i.p.) in mice. In contrast, kinsenoside enhanced serum IL-10 level at 24 h after LPS injection in mice. In conclusion, kinsenoside inhibited the production of inflammatory mediators and enhanced anti-inflammatory cytokine generation. Therefore, kinsenoside can alleviate acute inflammatory hazards. Copyright © 2011 by the Shock Society.


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.


Lee C.-H.,China Medical University at Taichung | Hong H.-M.,Chung Shan Medical University | Chang Y.-Y.,Chung Shan Medical University | Chang W.-W.,Chung Shan Medical University
Biochimie | Year: 2012

Heat shock protein (Hsp) 90 is an ATP-dependent chaperone and its expression has been reported to be associated with poor prognosis of breast cancer. Cancer stem cells (CSCs) are particular subtypes of cells in cancer which have been demonstrated to be important to tumor initiation, drug resistance and metastasis. In breast cancer, breast CSCs (BCSCs) are identified as CD24-CD44 + cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Although the clinical trials of Hsp90 inhibitors in breast cancer therapy are ongoing, the BCSC targeting effect of them remains unclear. In the present study, we discovered that the expression of Hsp90α was increased in ALDH + human breast cancer cells. Geldanamycin (GA), a Hsp90 inhibitor, could suppress ALDH + breast cancer cells in a dose dependent manner. We are interesting in the insufficiently inhibitory effect of low dose GA treatment. It was correlated with the upregulation of Hsp27 and Hsp70. By co-treatment with HSP inhibitors, quercetin or KNK437 potentiated BCSCs, which determined with ALDH+ population or mammosphere cells, toward GA inhibition, as well as anti-proliferation and anti-migration effects of GA. With siRNA mediated gene silencing, we found that knockdown of Hsp27 could mimic the effect of HSP inhibitors to potentiate the BCSC targeting effect of GA. In conclusion, combination of HSP inhibitors with Hsp90 inhibitors could serve as a potential solution to prevent the drug resistance and avoid the toxicity of high dose of Hsp90 inhibitors in clinical application. Furthermore, Hsp27 may play a role in chemoresistant character of BCSCs. © 2012 Elsevier Masson SAS. All rights reserved.


Su C.-C.,Changhua Christian Hospital | Su C.-C.,MingDao University | Su C.-C.,China Medical University at Taichung
Experimental and Therapeutic Medicine | Year: 2012

Traditional Chinese herbal medicines are widely accepted as an option for the treatment of colorectal cancers. Danshen (Salviae miltiorrhizae Radix) is widely prescribed in traditional Chinese medicine for cardiovascular diseases. Tanshinone IIA (Tan-IIA) is extracted from Danshen. Our previous studies have shown that Tan-IIA induces apoptosis in Colo205 human colon cancer cells in vitro and inμvivo. In the present study, we investigated the efficacy of Tan-IIA and 5-fluorouracil (5-FU) in a Colo205 cell xenograft model. For inμvivo studies, SCID mice were engrafted with Colo205 cells and from day 10 onwards were randomly divided into 3μgroups and treated with 5-FU plus Tan-IIA, 5-FU plus corn oil, and the vehicle alone. At the end of a 4-week dosing schedule, the SCID mice were sacrificed and xenograft tumors were dissected for protein western blot analysis. Our results showed that the Colo205 xenograft model co-treated with Tan-IIA plus 5-FU caused a reduction in the xenograft tumor volumes and decreased P-glycoprotein (P-gp) and microtubule-associated protein light chain 3 (LC3)-II expression compared to 5-FU alone. Based on these observations, it may be possible to develop Tan-IIA plus 5-FU as therapeutic agents for human colon cancer.


Tseng C.-L.,National Health Research Institute | Leng C.-H.,National Health Research Institute | Leng C.-H.,China Medical University at Taichung
Applied Microbiology and Biotechnology | Year: 2012

Bacterial lipoproteins are crucial antigens for protective immunity against bacterial pathogens. Expression of exogenous lipoproteins in Escherichia coli at high levels is thought to be an extremely difficult endeavor because it frequently results in incomplete or absent lipid modification. Previously, we identified a fusion sequence (D1) from a Neisseria meningitidis lipoprotein that induced a non-lipidated protein, E3 (the domain III of the dengue virus envelope protein), to become lipidated. However, without optimizing the growth conditions, some of the D1-fusion proteins were not lipidated. Here, we report the influence of medium components on the expression of recombinant lipoproteins in E. coli. For high-level expression of mature lipoproteins in the C43 (DE3) strain, M9 medium was better than M63 and the rich medium. Furthermore, we analyzed the influence of other media factors (including nitrogen and carbon sources, phosphate, ferrous ions, calcium, magnesium, and pH) on the levels of lipoprotein expression. The results showed that excess nitrogen sources and phosphate in M9 medium could increase the amount of immature lipoproteins, and glucose was a better carbon source than glycerol for expressing mature lipoproteins. We also found that lipoproteins tended to be completely processed in the alkaline environment, even in the nutrient-rich medium. Additional constructs expressing different immunogens or lipid signal peptides as targets were also utilized, demonstrating that these targets could be expressed as completely mature lipoproteins in the M9 medium but not in the rich medium. Our results provide the useful information for expressing mature exogenous lipoproteins in E. coli. © 2011 Springer-Verlag.


Wang H.-J.,National Tsing Hua University | Cheng W.-C.,National Tsing Hua University | Cheng H.-H.,National Tsing Hua University | Lai C.-H.,National Tsing Hua University | And 2 more authors.
Molecular Microbiology | Year: 2012

Helicobacter pylori infection is an aetiological cause of gastric disorders worldwide. H. pylori has been shown to assimilate and convert host cholesterol into cholesteryl glucosides (CGs) by cholesterol-α-glucosyltransferase encoded by capJ. Here, we show that CapJ-deficient (ΔcapJ) H. pylori resulted in greatly reduced type IV secretion system (TFSS)-associated activities, including the hummingbird phenotype of AGS cells, IL-8 production, CagA translocation/phosphorylation and CagA-mediated signalling events. Complementation of the ΔcapJ mutation with wild type cagJ or by adding CGs-containing lysates or exogenous fluorophore-tagged CGs reversed the mutant phenotypes. We also show that the wild-type but not ΔcapJ H. pylori recruited raft-associated components to sites of bacterial attachment. Fluorescence recovery after photobleaching (FRAP) analysis of AGS cells treated with fluorescence-tagged cholesterol/CGs revealed that there was a higher proportion of CGs associated with immobile fractions. CGs-associated membranes were also more resistant to a cold detergent extraction. Thus, we propose that CGs synthesized by H. pylori around host-pathogen contact sites partition in detergent-resistant membranes (DRMs), alters lateral-phase segregation in membrane and reorganizes membrane architecture. These processes together promote the formation of a functional TFSS and H. pylori infection. © 2011 Blackwell Publishing Ltd.


Tsai Y.,China Medical University at Taichung | Jheng L.-C.,Industrial Technology Research Institute of Taiwan | Jheng L.-C.,National Cheng Kung University | Hung C.-Y.,Industrial Technology Research Institute of Taiwan
Polymer Degradation and Stability | Year: 2010

This study synthesizes a series of cyclohexanedimethanol (CHDM)-based alicyclic/aliphatic copolyesters (PBSCs) using succinic acid, 1,4-butanediol and 1,3/1,4-CHDM at various molar ratios to investigate the effects of these compositions on crystallinity, biodegradability and the mechanical properties of PBSCs. The PBSCs were characterized using proton nuclear magnetic resonance, gel permeation chromatography, wide-angle X-ray diffraction, differential scanning calorimeter and thermogravimetric analysis. Biodegradability was evaluated by enzymatic hydrolysis with a lipase from Pseudomonas cepacia. The mechanical properties of PBSCs were determined using a tensile testing machine. Experimental results reveal that the PBSCs containing 1,3/1,4-CHDM in total diol with less than 50 mol% are crystallizable, while those containing 1,3/1,4-CHDM with more than 50 mol% are amorphous. The biodegradability test results suggest that PBSCs can be classified as surface-eroding polymers with a random endo-type scission. Surface hydrophilicity of PBSCs was the predominant effect on enzymatic hydrolysis, not crystallinity. Crown Copyright © 2009.


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.


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.


Hsiao T.-J.,Taipei Medical University | Hwang Y.,Vita Genomics Inc | Chang H.-M.,Vita Genomics Inc | Lin E.,Vita Genomics Inc | Lin E.,China Medical University at Taichung
Gene | Year: 2014

One particularly interesting single nucleotide polymorphism (SNP), rs6235 (encoding an S690T substitution), in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene has been widely associated with obesity in several European cohorts. The present study was intended to investigate the association between the PCSK1 rs6235 SNP and the prevalence of overweight or obesity, or obesity-related metabolic traits in a Taiwanese population. A total of 964 Taiwanese subjects with general health examinations were analyzed. Our data revealed no association of PCSK1 rs6235 with the risk of obesity or overweight in the complete subjects. However, the PCSK1 rs6235 SNP exhibited a significant association with overweight among the male subjects (P. = 0.03), but not among the female subjects. Furthermore, the carriers of GG variant had a significantly higher waist circumference than those with the CC variant (82.5. ±. 11.5 vs. 81.2. ±. 10.2. cm; P. = 0.01) and those with the CG variant (82.5. ±. 11.5 vs. 81.4. ±. 10.4. cm; P. = 0.021). In addition, the carriers of GG variant had a higher diastolic blood pressure than those with the CC variant (81.9. ±. 14.2 vs. 80.3. ±. 12.9. mm. Hg; P. = 0.023). Our study indicates that the PCSK1 rs6235 SNP may contribute to the risk of overweight in men and predict obesity-related metabolic traits such as waist circumference and diastolic blood pressure in Taiwanese subjects. © 2013 Elsevier B.V.


Cheng K.-C.,National Tsing Hua University | Liao J.-N.,National Tsing Hua University | Lyu P.-C.,National Tsing Hua University | Lyu P.-C.,China Medical University at Taichung
Biochemical Journal | Year: 2012

The daily cycle of melatonin biosynthesis in mammals is regulated by AANAT (arylalkylamine N-acetyltransferase; EC 2.3.1.87), making it an attractive target for therapeutic control of abnormal melatonin production in mood and sleep disorders. Drosophila melanogaster Dat (dopamine N-acetyltransferase) is an AANAT. Until the present study, no insect Dat structure had been solved, and, consequently, the structural basis for its acetyl-transfer activity was not well understood. We report in the present paper the high-resolution crystal structure for a D. melanogaster Dat-AcCoA (acetyl-CoA) complex obtained using one-edge (selenium) single-wavelength anomalous diffraction. A binding study using isothermal titration calorimetry suggested that the cofactor bound to Dat first before substrate. Examination of the complex structure and a substrate-docked model indicated that Dat contains a novel AANAT catalytic triad. Site-directed mutagenesis, kinetic studies and pH-rate profiles confirmed that Glu47, Ser182 and Ser186 were critical for catalysis. Collectively, the results of the present study suggest that Dat possesses a specialized active site structure dedicated to a catalytic mechanism. © 2012 The Author(s).


Tang F.-Y.,China Medical University at Taichung | Pai M.-H.,Taipei Medical University | Chiang E.P.I.,National Chung Hsing University
Journal of Nutritional Biochemistry | Year: 2012

Epidemiologic studies suggest that intake of high-fat diet (HFD) promotes colon carcinogenesis. Epithelial-mesenchymal transition (EMT) and inflammation play important roles during tumor progression of colorectal cancer (CRC). Oncogenic pathways such as phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and mitogen-activated protein kinase (MAPK)/ERK signaling cascades induce EMT and inflammation in cancer. No experimental evidence has been demonstrated regarding HFD-mediated tumor progression including EMT in CRC so far. Our results demonstrated that HFD consumption could induce tumor growth and progression, including EMT and inflammation, in a mouse xenograft tumor model. The molecular mechanisms were through activation of MAPK/ERK and PI3K/Akt/mTOR signaling pathways. HFD induced up-regulation of cyclooxygenase-2, cyclin D1 and proliferating cell nuclear antigen proteins concomitant with increases in expression of nuclear factor-κB p65 (RelA) and β-catenin proteins. Surprisingly, HFD consumption could suppress p21CIP1/WAF1 expression through increases in nuclear histone deacetylase complex (HDAC). Moreover, HFD could mediate the disassembly of E-cadherin adherent complex and the up-regulation of Vimentin and N-cadherin proteins in tumor tissues. Taken together, our novel findings support evidence for HFD-mediated modulation of HDAC activity and activation of oncogenic cascades, which involve EMT and inflammation in CRC, playing important roles in tumor growth and progression in a mouse xenograft model. © 2012 Elsevier Inc.


Chang C.-I.,University of Maryland, Baltimore | Chang C.-I.,National Chung Hsing University | Wu C.-C.,University of Maryland, Baltimore | Chen H.-M.,China Medical University at Taichung | Chen H.-M.,Hungkuang University
IEEE Geoscience and Remote Sensing Letters | Year: 2010

Endmember extraction has received increasing interest in hyperspectral image analysis. One widely used endmember extraction algorithm is pixel purity index (PPI), which finds endmembers via a set of random vectors, called skewers. Several issues arise in its implementation. One is the prior knowledge of the number of skewers K required to be used. Second, due to random nature in skewers, the final results are inconsistent and unreproducible. Third, it needs to know the number of dimensions to be retained after dimensionality reduction. Fourth, it needs to preset a cutoff threshold to extract potential endmembers. Finally, it involves human intervention to manually select final endmembers. This letter derives a random PPI (RPPI) to resolve the aforementioned issues. It considers the result produced by PPI using a random set of initial vectors as skewers as a realization of a random algorithm. From a statistical signal processing view point, if endmembers are crucial in terms of information, they should occur in realizations produced by PPI regardless of what set is chosen for skewers. By virtue of this assumption, the proposed RPPI is developed and validated by experiments. © 2006 IEEE.


Wang B.-S.,Chia Nan University of Pharmacy and Science | Huang G.-J.,China Medical University at Taichung | Tai H.-M.,Chia Nan University of Pharmacy and Science | Huang M.-H.,Chia Nan University of Pharmacy and Science
Food and Chemical Toxicology | Year: 2012

This study investigated the antioxidative and anti-inflammatory activities of aqueous extracts of Schizonepeta tenuifolia Briq. (STE). The results showed that STE displayed radical scavenging and reducing activity, as well as liposome protection activity. In addition, the implementation of an HPLC with a photodiode array detector helped to identify polyphenolic components including hesperidin, luteolin, and diosmetin. STE administration in the range of 125-500. mg/kg showed concentration dependent inhibition on carrageenan induced inflammatory response in mice. The anti-inflammatory effects of STE could be related to tissue NO and tumor necrosis factor a (TNF-α) suppression, and associated with the reduction of lipid peroxidation and an increase in antioxidant enzyme activities including catalase, superoxide dismutase, and glutathione peroxidase in vivo. Overall, the results showed that STE might serve as a natural inhibitor of oxidation and inflammation. © 2011 Elsevier Ltd.


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.


Siu L.K.,National Health Research Institute | Siu L.K.,China Medical University at Taichung | Yeh K.-M.,National Defense Medical Center | Lin J.-C.,National Defense Medical Center | 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.


Tsai M.-T.,Hungkuang University | Lin D.-J.,China Medical University at Taichung | Huang S.,Chung Yuan Christian University | Lin H.-T.,Chung Yuan Christian University | Chang W.H.,Chung Yuan Christian University
International Orthopaedics | Year: 2012

Purpose: The present study was designed to address whether osteoblasts play a synergistic role in promoting mesenchymal stem cell (MSC) osteogenesis in a direct cell-cell contact co-culture model. Methods: Murine C3H10T1/2 and MC3T3-E1 cell lines were mixed and plated onto 12-well culture plates and co-cultured at various ratios of initial cell densities. To compare the possible improvement on osteogenic differentiation, co-culture cells were served with or without osteogenic supplements in culture medium. Results: Weak osteogenesis was induced in MSCs co-cultured in an untreatedmediumwith different ratios of osteoblasts. An osteoblast-dependent increase in osteogenic gene expression of Runx2, type I collagen, and osteocalcin was observed over time. Moreover, both alkaline phosphatase (ALP) activity and calcium deposition were distinctly enhanced at levels that were proportional to the quantity of osteoblasts in the culture. The increases in mRNA expression and ALP activity were greater in co-cultures treated with osteogenic supplements than in untreated cultures. However, the production of ALP activity followed by a distinct matrix mineralization was lower in osteogenic-treated cultures containing greater numbers of osteoblasts. This suggests that a higher density of osteoblasts may lead to weak osteogenesis of MSCs by direct cell-cell contact co-culture in an untreated environment. Furthermore, additional osteogenic supplements may act synergistically with osteoblasts to accelerate matrix mineralization by reducing the process of osteogenic differentiation in osteogenic treated co-cultures. Conclusions: The present work may improve the understanding of MSC osteogenesis and may provide benefits for regenerative medicine. © Springer-Verlag 2011.


Hu R.-M.,Asia University, Taiwan | Liao S.-T.,National Yang Ming University | Huang C.-C.,China Medical University at Taichung | Huang Y.-W.,National Chung Hsing University | Yang T.-C.,National Yang Ming University
PLoS ONE | Year: 2012

Background: Fusaric acid (5-butylpicolinic acid), a mycotoxin, is noxious to some microorganisms. Stenotrophomonas maltophilia displays an intrinsic resistance to fusaric acid. This study aims to elucidate the mechanism responsible for the intrinsic fusaric acid resistance in S. maltophilia. Methodology: A putative fusaric acid resistance-involved regulon fuaR-fuaABC was identified by the survey of the whole genome sequence of S. maltophilia K279a. The fuaABC operon was verified by reverse transcriptase-PCR. The contribution of the fuaABC operon to the antimicrobial resistance was evaluated by comparing the antimicrobials susceptibility between the wild-type strain and fuaABC knock-out mutant. The regulatory role of fuaR in the expression of the fuaABC operon was assessed by promoter transcription fusion assay. Results: The fuaABC operon was inducibly expressed by fusaric acid and the inducibility was fuaR dependent. FuaR functioned as a repressor of the fuaABC operon in absence of a fusaric acid inducer and as an activator in its presence. Overexpression of the fuaABC operon contributed to the fusaric acid resistance. Significance: A novel tripartite fusaric acid efflux pump, FuaABC, was identified in this study. Distinct from the formally classification, the FuaABC may constitute a new type of subfamily of the tripartite efflux pump. © 2012 Hu et al.


Lee C.-Y.,Chung Shan Medical University | Huang C.-C.,National Taiwan University | Shih H.-C.,Chung Shan Medical University | Huang K.-H.,China Medical University at Taichung
European Journal of Preventive Cardiology | Year: 2013

Background: Poor medication compliance with antihypertensive drugs may have a significant impact on clinical outcomes, hospitalisation and healthcare expenditure. This study aims to assess medication compliance and its underlying factors in patients receiving antihypertensive drugs in Taiwan. Methods: This retrospective population-based study was based on data from Taiwan's Longitudinal Health Insurance Database (LHID). All patients (n=78,558) were aged 30 years or more and had received at least one antihypertensive prescription between January 2004 and December 2007. We used the medication possession ratio (MPR) as an index to measure the level of medication compliance. Results: Approximately 53% of the patients had high compliance with antihypertensive medication. Factors that were positively associated with medication compliance included patients being aged 30-44 years, higher comorbidity scores (odds ratio (OR): 1.18; 95% confidence interval (CI): 1.08-1.28), the same prescribing physician being visited and a singledrug therapy being prescribed. Female sex (OR: 0.92; 95% CI: 0.89-0.95) and higher socioeconomic status (OR: 0.91; 95% CI: 0.86-0.96) were negatively associated with drug compliance. In addition, high-compliance patients were less likely to be treated at medical centres, corporations (OR: 0.89; 95% CI: 0.84-0.93) or rural (OR: 0.88; 95% CI: 0.83-0.94) institutions. Conclusion: Several patient- and institution-related factors may influence medication compliance. Therefore, for optimal outcomes, patients' awareness of the need for compliance with antihypertensive therapy must be enhanced, and effective intervention strategies should be developed. © 2012 The European Society of Cardiology.


Yeh W.-L.,National Taiwan University | Yeh W.-L.,CSIC - National Museum of Natural Sciences | Lu D.-Y.,China Medical University at Taichung | Liou H.-C.,National Taiwan University | Fu W.-M.,National Taiwan University
Journal of Cellular Physiology | Year: 2012

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumors. In some occasions, oncogenic changes induce an inflammatory microenvironment that promotes the progression of tumors. In gliomas, the presence of microglia may represent tumor-related inflammation and microglia activation, and subsequent inflammatory responses may influence tumor growth and metastasis. Here, we found that C6 glioma-but not primary astrocyte-derived extracellular matrix (ECM) could activate microglia, including primary microglia and BV-2 cell line, and activated microglia-secreted interleukin (IL)-18, a potent inflammatory cytokine of the IL-1 family, to promote C6 migration. In addition, by coating purified ECM components, it was found that secretion of IL-18 by activated microglia was enhanced when microglia encountered with fibronectin and vitronectin. Furthermore, IL-18-induced C6 migration and microfilament disassembly were antagonized by iNOS inhibitor, guanylate cyclase inhibitor, and protein kinase G inhibitor. Taken together, these results indicate that IL-18 secreted by microglia, which was activated by C6 glioma-derived ECM, enhanced migration of C6 glioma through NO/cGMP pathway. © 2011 Wiley Periodicals, Inc.


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.


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.


Liao S.-F.,National Taiwan University | Yang H.-I.,China Medical University at Taichung | Lee M.-H.,Academia Sinica, Taiwan | Chen C.-J.,Academia Sinica, Taiwan | Lee W.-C.,National Taiwan University
PLoS ONE | Year: 2012

Development of hepatocellular carcinoma (HCC) is a multi-factorial process. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are important risk factors of HCC. Host factors, such as alcohol drinking, may also play a role. This study aims to provide a synthesis view on the development of HCC by examining multiple risk factors jointly and collectively. Causal-pie modeling technique was applied to analyze a cohort of 11,801 male residents (followed up for 15 years) in Taiwan, during which a total of 298 incident HCC cases were ascertained. The rate ratios adjusted by age were further modeled by an additive Poisson regression. Population attributable fractions (PAFs) and causal-pie weights (CPWs) were calculated. A PAF indicates the magnitude of case-load reduction under a particular intervention scenario, whereas a CPW for a particular class of causal pies represents the proportion of HCC cases attributable to that class. Using PAF we observed a chance to reduce around 60% HCC risk moving from no HBV-related intervention to the total elimination of the virus. An additional ~15% (or ~5%) reduction can be expected, if the HBV-related intervention is coupled with an HCV-related intervention (or an anti-drinking campaign). Eight classes of causal pies were found to be significant, including four dose-response classes of HBV (total CPW=52.7%), one independent-effect class of HCV (CPW=14.4%), one HBV-alcohol interaction class (CPW=4.2%), one HBV-HCV interaction class (CPW=1.7%), and one all-unknown class (CPW=27.0%). Causal-pie modeling for HCC helps clarify the relative importance of each viral and host factor, as well as their interactions. © 2012 Liao et al.


Kuo S.-Y.,Taipei Medical University | Chen S.-R.,Taipei Medical University | Tzeng Y.-L.,China Medical University at Heping | Tzeng Y.-L.,China Medical University at Taichung
PLoS ONE | Year: 2014

Background: Depression and anxiety are important mood changes in childbearing women. However, changes in depression and anxiety over time in women who undergo an elective cesarean section (CS) have not yet been elucidated. We aimed to characterize the trajectories of depressive and anxiety symptoms, and patterns of co-occurrence, and examined the associated predictors of depression and anxiety courses. Methods: A prospective longitudinal study of childbearing women (N = 139) who underwent a CS was conducted. Depressive and anxiety symptoms were respectively assessed using the Edinburgh Postnatal Depression Scale and State Anxiety Inventory, in the third trimester and at 1 day, 1 week, and 1 and 6 months postpartum. Results: Group-based modeling identified three distinct trajectories of depressive symptoms: group 1 (low, 30.9%), group 2 (mild, 41.7%), and group 3 (high, 27.3%). Four group trajectories of anxiety symptoms were identified: group 1 (low, 19.4%), group 2 (mild, 44.6%), group 3 (high, 28.8%), and group 4 (very high, 7.2%). Mild symptoms of both depression and anxiety were the most common joint trajectory. Depression trajectories were significantly related to anxiety trajectories (p<0.001). Predictors of the joint trajectory included the pre-pregnant body mass index (odds ratio (OR): 2.42, 95% confidence interval (CI): 1.1∼6.3) and a poor sleep score (OR: 3.2, 95% CI: 1.4∼7.3) in the third trimester. Conclusions: Distinctive trajectories and co-occurrence patterns of depressive and anxiety symptoms were identified. Our findings suggest a need for greater attention to continuous assessment of psychological well-being among women who undergo an elective CS. © 2014 Kuo et al.


Tang F.-Y.,China Medical University at Taichung | Chiang E.-P.,National Chung Hsing University | Pai M.-H.,Taipei Medical University
Journal of Agricultural and Food Chemistry | Year: 2010

Lung cancer is one of the leading causes of cancer death in the world. Human non-small-cell lung carcinoma (NSCLC) accounts for almost 80% of lung cancer cases. Aberrant phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathways play important roles and have been widely observed in the development of NSCLC. Previous studies indicated that garlic extracts such as diallyl disulfide (DADS) and diallyl trisulfide (DATS) could inhibit the proliferation of several types of cancer in vitro. However, the inhibitory effects of S-allylcysteine (SAC) on the growth of NSCLC have not been demonstrated yet. Therefore, this study investigated whether consumption of SAC could prevent the growth of NSCLC in both in vitro and in vivo models. It was found that SAC significantly inhibited the proliferation of human NSCLC A-549 cells in vitro. Treatment of the NF-κB inhibitor, Bay-11-7082, could significantly inhibit the proliferation of NSCLC A-549 cells. The results demonstrated that SAC significantly suppressed the activation of mTOR, NF-κB, and cyclin D1 molecules in vitro. Furthermore, the results demonstrated that consumption of SAC significantly inhibited the growth of highly metastatic human NSCLC cells in tumorbearing mice. Bioluminescence imaging and pathological and immunohistochemical (IHC) staining results also indicated that SAC could effectively suppress the growth and malignant progression of human NSCLC in vivo. The chemopreventive effects of SAC were associated with suppression of mTOR and NF-κB molecules in vivo. These results suggested that SAC could act as an effective agent against the malignant progression of human NSCLC in both in vitro and in vivo models. © 2010 American Chemical Society.


Hwang R.-L.,National United University | Chen C.-P.,China Medical University at Taichung
Indoor Air | Year: 2010

This study investigated the thermal sensation of elderly people in Taiwan, older than 60 years, in indoor microclimate at home, and their requirements for establishing thermal comfort. The study was conducted using both a thermal sensation questionnaire and measurement of indoor climatic parameters underlying the thermal environment. Survey results were compared with those reported by Cheng and Hwang (2008, J. Tongji Univ., 38, 817-822) for non-elders to study the variation between different age groups in requirements of indoor thermal comfort. The results show that the predominant strategy of thermal adaptation for elders was window-opening in the summer and clothing adjustment in the winter. The temperature of thermal neutrality was 25.2°C and 23.2°C for the summer and the winter, respectively. Logistically regressed probit modeling on percentage of predicted dissatisfied (PPD) against mean thermal sensation vote revealed that the sensation votes corresponding to a PPD of 20% were ± 0.75 for elders, about ± 0.10 less than the levels projected by ISO 7730 model. The range of operative temperature for 80% thermal acceptability for elders in the summer was 23.2-27.1°C, narrower than the range of 23.0-28.6°C reported for non-elders. This is likely a result of a difference in the selection of adaptive strategies. Practical Implications: Taiwan in the last decade has seen a rapid growth in the elderly population in its societal structure, and as such the quality of indoor thermal comfort increasingly concerns the elderly people. This study presents the results from field-surveying elders residing in major geographical areas of Taiwan, and discusses the requirements of these elders for indoor thermal comfort in different seasons. Through a comparison with the requirements by non-elders, this study demonstrates the unique sensitivity of elders toward indoor thermal quality and the selection of adaptive strategies that need to be considered when a thermal comfort zone is attempted in a household of members consisting of different age groups. © 2010 John Wiley & Sons A/S.


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.


Han Y.-Y.,University of Pittsburgh | Donovan M.,University of Pittsburgh | Sung F.-C.,China Medical University at Taichung
Chemosphere | Year: 2010

Professional bus drivers are exposed to environments containing air pollution and reactive oxygen species (ROS) that can induce cellular oxidative stress and DNA damage. This study investigated environmental factors associated with oxidative DNA damage in a cohort of long-distance bus drivers. In a comparison study, urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage, was examined in 120 male long-distance bus drivers and 58 male office workers in Taiwan. Multivariate logistic regression was used to analyze association between urinary 8-OHdG levels and environmental factors. Bus drivers had higher urinary 8-OHdG levels (adjusted odds ratio (aOR) = 9.4, 95% confidence interval (CI) = 3.5-28.2) compared with office workers. Increased urinary 8-OHdG level was significantly related to cigarette smoking (aOR = 18.0, 95% CI = 7.1-52.1), consumption of energy drinks (aOR = 5.0, 95% CI = 2.1-12.6), and regular exercise (aOR = 3.8, 95% CI = 1.5-10.2). A strong exposure-response relationship was found between urinary 8-OHdG and urinary cotinine (p < 0.0001). Among nonsmokers, bus drivers (aOR = 3.9, 95% CI = 1.0-17.7) had higher urinary 8-OHdG than office workers. Among both bus drivers and office workers, those who drank energy drinks (aOR = 3.7, 95% CI = 1.2-12.2) had higher 8-OHdG levels than those who did not drink energy drinks. Adjusted for smoking, levels of 8-OHdG were increased in long-distance bus drivers exposed to traffic exhaust and ingested energy drinks. Future studies should explore what aspects of energy drinks may contribute to increased urinary 8-OHdG. © 2010 Elsevier Ltd. All rights reserved.


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.


Liao C.-C.,Cheng Ching Hospital | Liao C.-C.,Chung Shan Medical University | Ou T.-T.,Chung Shan Medical University | Wu C.-H.,China Medical University at Taichung | Wang C.-J.,Chung Shan Medical University
Journal of Agricultural and Food Chemistry | Year: 2013

This study investigated the influence of phenolic caffeic acid on obesity in mice fed a high fat diet and its underlying mechanisms base on adipose and hepatic lipid lipogenesis. C57BL/6 mice were fed a normal diet or a HFD (20% fat, w/w) with or without caffeic acid (0.02% and 0.08%, w/w) for 6 weeks. The effects of caffeic acid on hyperlipidemia, hyperglycemia, visceral fat accumulation, and related enzyme activities in HFD-mice are examined. The supplementation of caffeic acid significantly lowered body weight, visceral fat mass, plasma GOT and GPT levels, FAS activity, and free fatty acid compared to the HFD group. Caffeic acid also lowered triglyceride and cholesterol concentrations in plasma and liver. Furthermore, we showed that caffeic acid efficiently inhibited cholesterol biosynthesis as evidenced by 3-hydroxy-3-methylglutaryl CoA reductase in the liver. Caffeic acid supplementation suppressed the activity of lipogenesis via sterol regulatory element-binding protein 1 c and its target enzyme fatty acid synthase. In addition, caffeic acid resulted in increased phosphorylation of AMP-activated protein kinase and decreased acetyl carboxylase, a downstream target of AMPK, which are related to fatty acid β-oxidation in the liver. In conclusion, these results indicate that caffeic acid exhibits a significant potential as an antiobesity agent by suppression of lipogenic enzymes and hepatic lipid accumulation. © 2013 American Chemical Society.


Lai S.-W.,China Medical University at Taichung | Muo C.-H.,Data Management | Liao K.-F.,Taichung Tzu Chi General Hospital | Sung F.-C.,Data Management | Chen P.-C.,Data Management
American Journal of Gastroenterology | Year: 2011

Objectives: The objective of this study was to assess the risk of acute pancreatitis among patients with type 2 diabetes mellitus (DM) and identify the roles of co-morbidities and anti-diabetic drugs. Methods: From claims data of one million enrollees randomly sampled from a population covered by the Taiwan National Health Insurance, 19,518 adults with type 2 DM diagnosed between 2000 and 2005 were identified. In addition, 78,072 DM-free persons, frequency matched with sex, age, and index year for comparison were identified. Subjects were followed up until the end of 2008 or censored to ascertain incident acute pancreatitis cases and associations with co-morbidities and anti-diabetic drugs. Results: Patients with type 2 DM had 1.95-fold greater incidence of acute pancreatitis compared with non-diabetics (27.7 vs. 14.2 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.89 (95% confidence interval (CI)=1.65-2.18) based on multivariable Cox regression analysis. Additive Poisson regression analysis revealed an absolute risk increase of 14.4 per 10,000 person-years (95% CI=13.4-15.5) among type 2 DM patients. Co-morbid alcoholism, hepatitis C infection, and gallstones yielded additional risk of acute pancreatitis among type 2 DM patients (absolute risk increase ranges 86.3, 41.1, and 23.5 per 10,000 person-years, respectively). Patients taking anti-diabetic drugs had a reduced risk of acute pancreatitis, however. The adjusted HR decreased to 0.31 (95% CI=0.18-0.56) among patients who took five different anti-diabetic drugs. Conclusions: Patients with type 2 DM are at an elevated risk of acute pancreatitis. Alcoholism, hepatitis C infection, and gallstones increase the risk further. However, anti-diabetic drugs reduce the risk as the number of drugs used increases and as the duration of treatment increases. © 2011 by the American College of Gastroenterology.


Wu D.-W.,Chung Shan Medical University | Cheng Y.-W.,Chung Shan Medical University | Wang J.,Taichung Veterans General Hospital | Chen C.-Y.,China Medical University at Taichung | And 2 more authors.
Cancer Research | Year: 2010

Paxillin (PXN) gene mutations are associated with lung adenocarcinoma progression and PXN is known to be a target gene of microRNA-218 (miR-218). On this basis, we hypothesized that PXN overexpression via miR-218 suppression may promote tumor progression and metastasis and that PXN may predict survival and relapse in non-small cell lung cancer (NSCLC). Expression of miR-218 and PXN in 124 surgically resected lung tumors were evaluated by real-time PCR and immunohistochemical analysis. The prognostic value of miR-218 and PXN expression on overall survival (OS) and relapse-free survival (RFS) was analyzed by the Kaplan-Meier test and Cox regression analysis. miR-218 expression in lung tumors was negatively associated with PXN expression. Multivariate analyses showed that PXN and miR-218 might independently predict OS and RFS, respectively, in NSCLC. Moreover, patients with low miR-218 combined with PXN-positive had the worst OS and RFS among the 4 combinations. In a cell model, PXN was negatively regulated by miR-218 and cell proliferation, invasion, and soft agar colony formation were enhanced by PXN overexpression induced by miR-218 suppression. Taken together, our findings suggest that PXN overexpression induced by miR-218 suppression is an independent predictor of survival and relapse in NSCLC, highlighting PXN as a potential therapeutic target to improve clinical outcomes in this disease. ©2010 AACR.


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.


Tsai M.-J.,China Medical University at Taichung | Fu Y.-S.,Kaohsiung Medical University | Lin Y.-H.,Kaohsiung Medical University | Huang Y.-B.,Kaohsiung Medical University | Wu P.-C.,Kaohsiung Medical University
PLoS ONE | Year: 2014

The purpose of the present study was to investigate the effect of nanoemulsions as a carrier vehicle of hydrophilic drug for transdermal delivery. The response surface methodology with a mixture design was used to evaluate the effect of ingredient levels of nanoemulsion formulations including cosurfactant (isopropyl alcohol, 20-30%), surfactant (mixed of Brij 30 and Brij 35, 20-30%), and distilled-water (34.5-50.0%) on properties of the drug-loaded nanoemulsions including physicochemical characters and drug permeability through rat skin. The result showed that the hydrophilic drug in aqueous solution with or without penetration enhancer could not transport across rat skin after 12 h of application. Used nanoemulsions as carrier vehicle, the permeation rate of drug was significantly increased from 0 to 63.23 μg/cm2/h and the lag time was shortened from more than 12 h to about 2.7-4.0 h. Moreover, the drug-loaded nanoemulsion formulation also showed physicochemical stability after 3 month storage at 25°C and 40°C. © 2014 Tsai et al.


Jaakkola J.J.K.,University of Oulu | Hwang B.-F.,China Medical University at Taichung | Jaakkola M.S.,University of Oulu
American Journal of Epidemiology | Year: 2010

The authors assessed the relation between exposure to dampness and molds in dwellings and the development of allergic rhinitis in childhood in a 6-year, population-based prospective cohort study of 1,863 children aged 1-7 years at baseline in 1991 (follow-up rate, 77%) from Espoo, Finland. The studied exposures were history of water damage, presence of moisture and visible mold, and perceived mold odor in the home, based on parent-administered questionnaire. A total of 246 (13.2%) children developed physician-diagnosed allergic rhinitis during the study period, resulting in an incidence rate of 440 cases per 10,000 person-years (95% confidence interval (CI): 387, 499). In logistic regression adjusting for confounding, any mold or dampness exposure indicator at baseline (adjusted odds ratio = 1.55, 95% CI: 1.10, 2.18), at follow-up (adjusted odds ratio = 1.62, 95% CI: 1.21, 2.18), or both (adjusted odds ratio = 1.96, 95% CI: 1.29, 2.98) was an important independent determinant of the risk of allergic rhinitis. Of the individual indicators, water damage and moisture on the surfaces were consistent determinants of allergic rhinitis. The results of this cohort study, which assessed exposure before the onset of allergic rhinitis, strengthen considerably the evidence of the role of indoor dampness problems as determinants of allergic rhinitis in children. © 2010 The Author.


Ho H.J.,Tunghai University | Pyne S.,Dana-Farber Cancer Institute | Lin T.I.,National Chung Hsing University | Lin T.I.,China Medical University at Taichung
Statistics and Computing | Year: 2012

This paper deals with the problem of maximum likelihood estimation for a mixture of skew Student-t-normal distributions, which is a novel model-based tool for clustering heterogeneous (multiple groups) data in the presence of skewed and heavy-tailed outcomes. We present two analytically simple EM-type algorithms for iteratively computing the maximum likelihood estimates. The observed information matrix is derived for obtaining the asymptotic standard errors of parameter estimates. A small simulation study is conducted to demonstrate the superiority of the skew Student-t-normal distribution compared to the skew t distribution. The proposed methodology is particularly useful for analyzing multimodal asymmetric data as produced by major biotechnological platforms like flow cytometry. We provide such an application with the help of an illustrative example. © 2011 Springer Science+Business Media, LLC.


Chao A.-C.,Kaohsiung Medical University | Liu C.-K.,Kaohsiung Medical University | Chen C.-H.,National Cheng Kung University | Lin H.-J.,Chi Mei Medical Center | And 7 more authors.
Stroke | Year: 2014

BACKGROUND AND PURPOSE - : The relationship between the dose of recombinant tissue-type plasminogen activator (r-tPA) and its safety/efficacy for ischemic stroke has not been well evaluated in the East Asian population. We assessed the safety/efficacy of different doses of r-tPA for acute ischemic stroke in Chinese patients. METHODS - : A total of 1004 eligible patients were classified according to the dose of r-tPA received for managing acute ischemic stroke: 0.9 mg/kg (n=422), 0.8 mg/kg (n=202), 0.7 mg/kg (n=199), and 0.6 mg/kg (n=181). The safety outcome was symptomatic intracerebral hemorrhage and death within 3 months. The efficacy outcome was good functional outcome (modified Rankin Scale ≤1) at 3 months. RESULTS - : There was a significant trend for symptomatic intracerebral hemorrhage with age (P=0.002). With multivariate logistic regression analysis, a dose of 0.9 mg/kg was a predictor of symptomatic intracerebral hemorrhage (P=0.0109), and a dose ≤0.65 mg/kg was a predictor of good functional outcome (P=0.0369). In patients aged 71 to 80 years, there was a significant trend of increasing symptomatic intracerebral hemorrhage (P=0.0130) and less good functional outcome (P=0.0179) with increasing doses of r-tPA. There was also a trend of increasing mortality (P=0.0971) at 3 months in these patients. CONCLUSIONS - : These results did not support the dose of 0.9 mg/kg of r-tPA being optimal for all patients in the East Asian population. In elderly patients (71-80 years), a lower dose of 0.6 mg/kg is associated with a better outcome. Confirmation of the results through randomized trial is required. © 2014 American Heart Association, Inc..


Xing Z.,University of Houston | Lin A.,University of Houston | Li C.,University of Houston | Liang K.,University of Houston | And 14 more authors.
Cell | Year: 2014

lncRNAs are known to regulate a number of different developmental and tumorigenic processes. Here, we report a role for lncRNA BCAR4 in breast cancer metastasis that is mediated by chemokine-induced binding of BCAR4 to two transcription factors with extended regulatory consequences. BCAR4 binding of SNIP1 and PNUTS in response to CCL21 releases the SNIP1's inhibition of p300-dependent histone acetylation, which in turn enables the BCAR4-recruited PNUTS to bind H3K18ac and relieve inhibition of RNA Pol II via activation of the PP1 phosphatase. This mechanism activates a noncanonical Hedgehog/GLI2 transcriptional program that promotes cell migration. BCAR4 expression correlates with advanced breast cancers, and therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 strongly suppresses breast cancer metastasis in mouse models. The findings reveal a disease-relevant lncRNA mechanism consisting of both direct coordinated protein recruitment and indirect regulation of transcription factors. © 2014 Elsevier Ltd. All rights reserved.


Liu C.-C.,National Health Research Institute | Chow Y.-H.,National Health Research Institute | Chong P.,National Health Research Institute | Chong P.,China Medical University at Taichung | Klein M.,VaxiBio Inc.
Vaccine | Year: 2014

Enterovirus 71 (EV71), an emerging neurotropic virus and coxsackieviruses (CV) are the major causative agents of hand, foot and mouth diseases (HFMD). These viruses have become a serious public health threat in the Asia Pacific region. Formalin-inactivated EV71 (FI-EV71) vaccines have been developed, evaluated in human clinical trials and were found to elicit full protection against EV71. Their failure to prevent CVA16 infections could compromise the acceptability of monovalent EV71 vaccines. Bivalent FI-EV71/FI-CVA16 vaccines have been found to elicit strong neutralizing antibody responses against both viruses in animal models but did not protect against CVA6 and CVA10 viral infections in cell culture neutralization assay. In this review, we discuss the critical bottlenecks in the development of multivalent HFMD vaccines, including the selection of vaccine strains, animal models to assess vaccine potency, the definition of end-points for efficacy trials, and the need for improved manufacturing processes to produce affordable vaccines. © 2014 Elsevier Ltd.


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.


Wu H.-H.,Chung Shan Medical University | Cheng Y.-W.,Chung Shan Medical University | Chang J.T.,Chung Shan Medical University | Wu T.-C.,Chung Shan Medical University | And 4 more authors.
Oncogene | Year: 2010

Apurinic endonuclease 1 (Ape1) is not only involved in base excision repair, but also activates some transcriptional factors through its redox activity. However, which subcellular localization of Ape1 is involved in the activation of transcriptional factor remains unclear. We first observed that Cox-2 expression was associated with cytoplasmic Ape1 expression in lung tumors and cancer cell lines. We thus hypothesize that nuclear factor (NF)-B is activated by cytoplasmic Ape1 to cause Cox-2 expression. Herein, we generated cytoplasmic and nuclear Ape1 in Ape1-knockdown lung cancer cells by exogenous expression of Ape1 containing various deletions and/or mutations of the nuclear localization sequence. It was observed that cytoplasmic Ape1, but not nuclear Ape1, induced Cox-2 expression through NF-B activation. NF-B activation by cytoplasmic Ape1 was diminished by the Ape1 redox activity inhibitor resveratrol. Cells expressing cytoplasmic Ape1 exhibited tumor progression and metastasis in vitro and in vivo as xenografts, but cells expressing nuclear Ape1 did not. Patients with tumors containing elevated cytoplasmic Ape1 had a poor prognosis and a 3.722-fold risk of tumor recurrence and/or metastasis. Cytoplasmic Ape1 could therefore enhance lung tumor malignancy through NF-B activation, suggesting that combination of cisplatin and specific redox inhibitor could improve chemotherapeutic response in patients with tumors containing elevated cytoplasmic Ape1. © 2010 Macmillan Publishers Limited All rights reserved.


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.


Ling J.,University of Texas M. D. Anderson Cancer Center | Kang Y.,University of Texas M. D. Anderson Cancer Center | Zhao R.,University of Texas M. D. Anderson Cancer Center | Xia Q.,University of Texas M. D. Anderson Cancer Center | And 17 more authors.
Cancer Cell | Year: 2012

Constitutive Kras and NF-κB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-κB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/β inactivation inhibited NF-κB activation and PDAC development in Kras G12D and Kras G12D;Ink4a/Arf F/F mice, demonstrating a mechanistic link between IKK2/β and Kras G12D in PDAC inception. Our findings reveal that Kras G12D-activated AP-1 induces IL-1α, which, in turn, activates NF-κB and its target genes IL-1α and p62, to initiate IL-1α/p62 feedforward loops for inducing and sustaining NF-κB activity. Furthermore, IL-1α overexpression correlates with Kras mutation, NF-κB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/β/NF-κB is activated by Kras G12D through dual feedforward loops of IL-1α/p62. © 2012 Elsevier Inc.


Lo H.-H.,Central Taiwan University of Science and Technology | Cheng W.-S.,Central Taiwan University of Science and Technology | Cheng W.-S.,China Medical University at Taichung
APMIS | Year: 2015

Distribution of virulence factors and association with emm polymorphism or isolation site among beta-hemolytic group G Streptococcus dysgalactiae subspecies equisimilis. Streptococcus dysgalactiae subspecies equisimilis (SDSE), the dominant human pathogenic species among group G streptococci, is the causative agent of several invasive and non-invasive diseases worldwide. However, limited information is available about the distribution of virulence factors among SDSE isolates, or their association with emm types and the isolation sites. In this study, 246 beta-hemolytic group G SDSE isolates collected in central Taiwan between February 2007 and August 2011 were under investigation. Of these, 66 isolates were obtained from normally sterile sites and 180 from non-sterile sites. emm typing revealed 32 types, with the most prevalent one being stG10.0 (39.8%), followed by stG245.0 (15.4%), stG840.0 (12.2%), stG6.1 (7.7%), and stG652.0 (4.1%). The virulence genes lmb (encoding laminin-binding protein), gapC (glyceraldehyde 3-phosphate dehydrogenase), sagA (streptolysin S), and hylB (hyaluronidase) existed in all isolates. Also, 99.2% of the isolates possessed slo (streptolysin O) and scpA (C5a peptidase) genes. In addition, 72.8%, 14.6%, 9.4%, and 2.4% of the isolates possessed the genes ska (streptokinase), cbp (putative collagen-binding protein, SDEG_1781), fbp (putative fibronectin-binding protein, SDEG_0161), and sicG (streptococcal inhibitor of complement), respectively. The only superantigen gene detected was spegg (streptococcus pyrogenic exotoxin Gdys), which was possessed by 74.4% of the isolates; these isolates correlated with non-sterile sites. Positive correlations were observed between the following emm types and virulence genes: stG10.0 and stG840.0 with spegg, stG6.1 and stG652.0 with ska, and stG840.0 with cbp. On the other hand, negative correlations were observed between the following: stG245.0, stG6.1, and stG652.0 types with spegg, stG10.0 with ska, and stG10.0, stG245.0, and stG6.1 types with cbp. The prevalence of emm types of SDSE in central Taiwan was investigated for the first time. Moreover, the distribution of virulence factors among beta-hemolytic group G SDSE isolates, as well as their association with emm types or isolation sites were also examined. © 2014 APMIS. Published by John Wiley & Sons Ltd.


Jean W.D.,National Taiwan University | Huang S.-P.,National Taiwan University | Chen J.-S.,China Medical University at Taichung | Shieh W.Y.,National Taiwan University
International Journal of Systematic and Evolutionary Microbiology | Year: 2012

Two Gram-negative, heterotrophic, aerobic, marine bacteria, designated strains KT1T and KM1T, were isolated from seawater samples collected from the shallow coastal regions of northern Taiwan. Cells grown in broth cultures were non-flagellated rods. NaCl was required for growth. Optimal growth occurred with 2-5% NaCl, at 25-30°C and at pH 8. They grew aerobically and were not capable of anaerobic growth by fermenting D-glucose or other carbohydrates. Q-8 was the only isoprenoid quinone. The major polar lipid detected in strain KT1T was phosphatidylmonomethylethanolamine, whereas those detected in KM1T were phosphatidylmonomethylethanolamine, phosphatidyldimethylethanolamine and an unidentified phospholipid. Cellular fatty acids were nearly all iso-branched, with iso-C15: 0 as the most abundant component (54.6-57.2% of the total). Strains KT1T and KM1T had DNA G+C contents of 43.9 and 46.3 mol%, respectively. The two strains shared 98.1% 16S rRNA gene sequence similarity; levels of similarity with the type strains of species of the genus Kangiella were 95.6-98.4 %. Data from the present taxonomic study conducted using a polyphasic approach revealed that the isolates could be classified as representatives of two novel species of the genus Kangiella, for which the names Kangiella taiwanensis sp. nov. (type strain KT1T=BCRC 80330T=JCM 17727T) and Kangiella marina sp. nov. (type strain KM1T=BCRC 80329T=JCM 17728T) are proposed. © 2012 IUMS.


Manguiat L.S.,National Chung Hsing University | Fang T.J.,National Chung Hsing University | Fang T.J.,China Medical University at Taichung
Food Microbiology | Year: 2013

The microbiological quality of chicken- and pork-based street-food samples from Taichung, Taiwan's night markets (50) and Laguna, Philippines' public places (69) was evaluated in comparison to a microbiological guideline for ready-to-eat foods. Different bacterial contamination patterns were observed between 'hot-grilled' and 'cold cooked/fried' food types from the two sampling locations with 'hot grilled' foods generally showing better microbiological quality. Several samples were found to beunsatisfactory due to high levels of aerobic plate count, coliform, Escherichia coli, and Staphylococcusaureus. The highest counts obtained were 8.2 log cfug-1, 5.4 log cfug-1, 4.4 log cfug-1, and 3.9 logcfug-1, respectively, suggesting poor food hygiene practices and poor sanitation. Salmonella was found in 8% and 7% of Taichung and Laguna samples, respectively, which made the samples potentially hazardous. None of the samples was found to be positive for Listeria monocytogenes and E. coli O157, but Bacillus cereus was detected at the unsatisfactory level of 4 log cfug-1 in one Laguna sample. Antimicrobial resistance was observed for Salmonella, E.coli, and S.aureus isolates. Food preparation, cooking, and food handling practices were considered to be contributors to the unacceptable microbiological quality of the street foods. Hence, providing training on food hygiene for the street vendors should result in the improvement of the microbiological quality of street foods. The data obtained in this study can be used as input to microbial risk assessments and in identifying science-based interventions to control the hazards. © 2013 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.


Chien C.-F.,National Yang Ming University | Wu Y.-T.,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
Biomedical Chromatography | Year: 2011

Herbal medicines have been used to treat liver disorders for thousands of years in the East and have now become a promising therapy internationally for pathological liver conditions. Biological analysis of hepatoprotective herbs is an important issue from the pharmacokinetic perspective in developing new therapeutic managements for liver disease. The biological analysis focuses on the pretreatment methods, separation and quantification of herbal medicines in biological samples. We have compiled and discuss the biological analytical method of six herbal medicines for liver protection containing Silybum marianum(silymarin), Glycyrrhiza glabra, Scutellaria baicalensis, Schisandra chinensis, Salvia miltiorrhiza and Astragalus membranaceus. This review provides a convenient reference for researchers to reduce time-consuming method optimization. © 2010 John Wiley & Sons, Ltd.


Lo H.M.,Chaoyang University of Technology | Chiu H.Y.,Chaoyang University of Technology | Lo S.W.,Chaoyang University of Technology | Lo F.C.,China Medical University at Taichung
Bioresource Technology | Year: 2012

This study aims at investigating the effects of micro-nano municipal solid waste (MSW) incinerator (MSWI) fly ash (FA) and bottom ash (BA) on the MSW anaerobic digestion. Results showed that suitable micro-nano and non micro-nano MSWI ashes addition (FA/MSW 3, 6, 18 and 30gg -1 VS and BA/MSW 12, 36, 60 and 120gg -1 VS) could enhance the biogas production compared to the control. It was particularly found to have the highest biogas production at the micro-nano MSWI BA/MSW ratio of 36gg -1 VS (∼193mLg -1 VS MSW, ∼3.5 times to the control). Micro-nano MSWI FA and BA added bioreactors had the higher biogas production than the corresponding non micro-nano MSWI FA and BA added ones. Suitable MSWI ashes addition could improve the biogas production due to the released metals levels suitable for the MSW anaerobic digestion particularly found in the micro-nano added bioreactors. © 2012 Elsevier Ltd.


Chou C.H.,China Medical University at Taichung
Allelopathy Journal | Year: 2010

Alleopathy is the process whereby plant releases toxic compounds into environment, resulting in a detrimental effect on neighbouring plants or its own sharing the same habitat. The toxic metabolites are released into environment through volatilization, leaching, decomposition of plant residues in soil and root exudation. The phenomenon was earlier found in agricultural practice by Theophrastus (372 to 285 BC), who reported the inhibitory effect of pigweed on alfalfa. In 1832, De Candolle suggested that the soil sickness problem in agriculture might be due to exudates of crop plants. Since then, many scientists had reported the significance of toxic effects of plant residues decomposing in soil, leading to the reduction in crop productivity. The productivity of many crops (Sorghum bicolor, Medicago sativa, Oryza sativa, Asparagus officinalis, Pliaseolus radiants, Saccliarum sinensis, etc.) was reduced significantly after a continuous monoculture. The crop productivity declines due to (i). crops produces phytotoxic substances in soil and (ii). the accumulation of phytotoxins causes the imbalance of microbial population, such as Fusarium oxysporum in soil. These harmful allelopathic effects could be reduced through crop rotation or improving soil drainage in field. In a unique example of pasture and forest intercropping system was demonstrated by the author that an aggressive kikuyu grass (Pennisetum clandestinum), was introduced into the deforested conifer land. The kikuyu grass suppressed the growth of weeds significantly, but was not harmful to the regeneration growth of conifer plants or seeding growth of other hardwood trees. The pasture-forest intercropping system, indeed, benefited the forest management by reducing the use of herbicide, saving expensive manpower, and enhancing forage material for livestock. Finally, the author in recent years have developed a unique system of using the plant parts, leaves, twigs, or roots, of allelopathic plants to make a cocktail of agrochemicals to replace conventional herbicides, fungicides, or insecticides, resulting in avoiding the residual effects of agrochemicals and reducing the environmental deterioration. Using advanced biotechnology, the allelopathic genes can be introduced into crops which possess the allelopathic potential to suppress its competitive weeds in the field. Thus, allelopathy has played important roles in sustainable agriculture.


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.


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.


Yang C.-Y.,National Chung Hsing University | Sheih I.-C.,National Chung Hsing University | Fang T.J.,National Chung Hsing University | Fang T.J.,China Medical University at Taichung
Ultrasonics Sonochemistry | Year: 2012

The application of ultrasound for treating rice hull used as the fermentation substrate for xylooligosaccharides production was investigated. Aspergillus japonicus CY6-1 was selected to produce cellulolytic and xylanolytic enzymes from untreated rice hull (RH) and rice hull treated with ultrasound (USRH-M). The hemicellulose yield was increased to 1.4-fold with ultrasound, and treatment time was greatly shortened from 24 h to 1.5 h at 80°C and 300 W/28 kHz. The morphology of RH from various pretreatments was observed with field emission scanning electron microscope (FESEM), revealing the surface structure of USRH-M smoother than that of RH. USRH-M was much easier to be utilized by fungi, to extend the stability of enzyme activity and to increase activities of CMCase, β-glucosidase, and xylanase compared with those of untreated RH. The final fermentative products were xylotetraose, xylohexaose, and higher molecular weight xylooligosaccharides, achieving xylohexaose yield for USRH-M 80% higher than that for RH group. © 2011 Elsevier B.V. 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.


Huang H.-C.,China Medical University at Taichung | Chang T.-M.,Hungkuang University
World Journal of Microbiology and Biotechnology | Year: 2012

Melanin is a dark pigment produced by melanocytes. Tyrosinase is a key enzyme which catalyzes the rate-limiting step of melanogenesis. However, accumulation of melanin leads to various skin hyperpigmentation disorders. To find a novel skin-whitening agent, the antioxidant capacity of Bifidobacterium adolescentis culture filtrate and inhibitory effect on melanogenesis were investigated. The antioxidant effects of B. adolescentis culture filtrate include 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging capacity, 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid)(ABTS) radical cation scavenging activity and reducing power were measured spectrophotometrically. The reducing power is a useful index for the evaluation of potential antioxidants which carry out reduction of ferricyanide to ferrocyanide. Furthermore, the inhibitory effects of the bacterial culture filtrate on mushroom tyrosinase, B16F10 intracellular tyrosinase activity and melanin content were also determined. The results revealed that B. adolescentis culture filtrate (2. 5, 5. 0 and 7. 5 %; v/v) effectively scavenged DPPH and ABTS radicals, and lower concentrations of the bacterial culture filtrates (0. 5, 1. 0 and 1. 5 %; v/v) showed potent reducing power in a dose-dependent pattern. Additionally, the bacterial culture filtrate suppressed murine tyrosinase activity and decreased the amount of melanin in a dose-dependent manner. Our results demonstrated that B. adolescentis culture filtrate decreases the melanogenesis process of melanoma cells by inhibiting tyrosinase activity, which we suggest may be mediated through its antioxidant activity. © 2012 Springer Science+Business Media B.V.


Huang R.H.H.,National Tsing Hua University | Kong A.K.H.,National Tsing Hua University | Takata J.,University of Hong Kong | Hui C.Y.,Chungnam National University | And 2 more authors.
Astrophysical Journal | Year: 2012

We report on Chandra observations of the black widow pulsar, PSR B1957+20. Evidence for a binary-phase dependence of the X-ray emission from the pulsar is found with a deep observation. The binary-phase-resolved spectral analysis reveals non-thermal X-ray emission of PSR B1957+20, confirming the results of previous studies. This suggests that the X-rays are mostly due to intra-binary shock emission, which is strongest when the pulsar wind interacts with the ablated material from the companion star. The geometry of the peak emission is determined in our study. The marginal softening of the spectrum of the non-thermal X-ray tail may indicate that particles injected at the termination shock are dominated by synchrotron cooling. © 2012. The American Astronomical Society. All rights reserved..


Huang C.-Y.,National Chung Hsing University | Chiang S.-F.,National Chung Hsing University | Lin T.-Y.,China Medical University at Taichung | Chiou S.-H.,National Chung Hsing University | Chow K.-C.,National Chung Hsing University
PLoS ONE | Year: 2012

Human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) has been shown to induce host cell death by increasing the permeability of mitochondrial outer membrane (MOM). The mechanism underlying the damage to the mitochondria by Vpr, however, is not clearly illustrated. In this study, Vpr that is introduced, via transient transfection or lentivirus infection, into the human embryonic kidney cell line HEK293, human CD4 + T lymphoblast cell line SupT1, or human primary CD4 + T cells serves as the model system to study the molecular mechanism of Vpr-mediated HIV-1 pathogenesis. The results show that Vpr injures MOM and causes a loss in membrane potential (MMP) by posttranscriptionally reducing the expression of mitofusin 2 (Mfn2) via VprBP-DDB1-CUL4A ubiquitin ligase complex, gradually weakening MOM, and increasing mitochondrial deformation. Vpr also markedly decreases cytoplasmic levels of dynamin-related protein 1 (DRP1) and increases bulging in mitochondria-associated membranes (MAM), the specific regions of endoplasmic reticulum (ER) which form physical contacts with the mitochondria. Overexpression of Mfn2 and DRP1 significantly decreased the loss of MMP and apoptotic cell death caused by Vpr. Furthermore, by employing time-lapse confocal fluorescence microscopy, we identify the transport of Vpr protein from the ER, via MAM to the mitochondria. Taken together, our results suggest that Vpr-mediated cellular damage may occur on an alternative protein transport pathway from the ER, via MAM to the mitochondria, which are modulated by Mfn2 and DRP1. © 2012 Huang et al.


Chen P.-C.,National Taiwan University | Chen P.-C.,Genomic Health | Huang Y.-Y.,National Taiwan University | Juang J.-L.,Genomic Health | Juang J.-L.,China Medical University at Taichung
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2011

Although the cell-based assay is becoming more popular for high throughput drug screening and the functional characterization of disease-associated genes, most researchers in these areas do not use it because it is a complex and expensive process. We wanted to create a simple method of performing an on-chip cell-based assay. To do this, we used micro-electro-mechanical systems (MEMS) to fabricate a microwell array chip comprised of a glass substrate covered with a photoresist film patterned to form multiple microwells and tested it in two reverse transfection experiments, an exogenous gene expression study and an endogenous gene knockdown study. It was used effectively in both. Then, using the same MEMS technology, we fabricated a complementary microcolumn array to be used as a drug carrier device to topically apply drugs to cells cultured in the microwell array. We tested the effectiveness of microwell-microcolumn on-chip cell-based assay by using it in experiments to identify epidermal growth factor receptor (EGFR) activity inhibitors, for which it was found to provide effective high throughput and high content functional screening. In conclusion, this new method of cell-based screening proved to be a simple and efficient method of characterizing gene function and discovering drug leads. © The Royal Society of Chemistry 2011.


Tang F.-Y.,China Medical University at Taichung | Pai M.-H.,Taipei Medical University | Wang X.-D.,Tufts University
Journal of Agricultural and Food Chemistry | Year: 2011

A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene could prevent the growth and progression of colorectal tumor in a mouse xenograft model. Bioluminescence imaging, histopathological, immunofluorescence (IFC), and immunohistochemical (IHC) staining results indicated that lycopene could effectively suppress the growth and progression of colon cancer in tumor-bearing mice. The results demonstrated that lycopene significantly suppressed the nuclear expression of PCNA and β-catenin proteins in tumor tissues. Consumption of lycopene could also augment the E-cadherin adherent molecule and nuclear levels of cell cycle inhibitor p21 CIP1/WAF1 protein. The chemopreventive effects of lycopene were associated with suppression of COX-2, PGE 2, and phosphorylated ERK1/2 proteins. Furthermore, the inhibitory effects of lycopene were inversely correlated with the plasma levels of matrix metalloproteinase 9 (MMP-9) in tumor-bearing mice. These results suggested that lycopene could act as a chemopreventive agent against the growth and progression of colorectal cancer in a mouse xenograft model. © 2011 American Chemical Society.


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.


Chao M.-R.,Chung Shan Medical University | Hu C.-W.,Chung Shan Medical University | Chen J.-L.,China Medical University at Taichung
Microchimica Acta | Year: 2014

CdTe quantum dots capped with thioglycolic acid (TGA) display a strong turn-on fluorescence response if exposed to solutions of cysteine (Cys). In order to exploit this effect, a molecularly imprinted polymer (MIP) for Cys was covalently linked to the QDs via allyl mercaptan. The resulting nanomaterials (QDs, MIP-coated QDs, and nonimprint-coated QDs) were characterized by FTIR and scanning electron microscopy. The adsorption of Cys was studied in phosphate buffer (pH 7.4) with respect to equilibration times (5, 15, and 40 min, respectively), binding constants [2.98, 2.42, and 0.96 (×104 M-1)], and Langmuir isotherms (R2 = 0.9995, 0.9999, and 0.9983) in the Cys concentration range between 3.33 μM to 500 μM. The method has a detection limit of 0.85 μM (3σ, blank, for n = 10). The selectivity of the MIP-coated QDs for Cys over 19 other amino acids is similar to that of bare QDs, but MIP-QDs afford better recoveries of Cys from solutions also containing bovine serum albumin (90 %) and fetal bovine serum (97 %), respectively, when compared to the recoveries that are obtained with bare (non-imprinted) QDs (135 % and 120 %). This is probably due to the fact that the outer MIP shell largely reduces protein wrapping, dot aggregation, and matrix inclusion. [Figure not available: see fulltext.] © 2014 Springer-Verlag Wien.


Liu T.-T.,Yuanpei University | Yang T.-S.,China Medical University at Taichung
International Journal of Food Microbiology | Year: 2012

Using natural additives to preserve foods has become popular due to consumer demands for nature and safety. Antimicrobial activity is one of the most important properties in many plant essential oils (EOs). The antimicrobial activity of the essential oil of Litsea cubeba (LC-EO) from Taiwan and the antimicrobial impact of individual volatile components in the oil on pathogens or spoilage microorganisms: Vibrio parahaemolyticus, Listeria monocytogenes, Lactobacillus plantarum, and Hansenula anomala in vitro, and the antimicrobial activity of the LC-EO against these organisms in food systems were studied. The "antimicrobial impact" (AI) is a new term that combines the effects of minimal microbicidal concentration (MMC) and quantity of an antimicrobial substance. The AI can quantitatively reflect the relative importance of individual components of the EO on the entire antimicrobial activity of the EO. The MMCs of the LC-EO against V. parahaemolyticus, L. monocytogenes, L. plantarum, and H. anomala were determined as 750, 750, 1500, and 375 μg/g, respectively in vitro. The MMCs of the LC-EO were 3000, 6000, and 12,000 μg/g for L. monocytogenes in tofu stored at 4 °C, 25 °C, and 37 °C, respectively. The temperature affected the bacterial growth which consequently influenced the MMCs of the LC-EO. The MMCs of the LC-EO were 3000, 6000, and 375 μg/g for Vibrio spp. in oysters, L. plantarum in orange-milk beverage, and H. anomala in soy sauce, respectively. Except for soy sauce, the food systems exhibited marked matrix effects on diminishing the antimicrobial activity of the LC-EO. Averagely, citral accounted for ca 70% of the total AI value for all the tested organisms, and the rest of the AI value of the LC-EO was determined by all the tested compounds (ca 4%) and the unidentified compounds (ca 26%). © 2012 Elsevier B.V.


Chan K.-C.,Providence University | Pen P.-J.,Providence University | Yin M.-C.,China Medical University at Taichung
Journal of Food Science | Year: 2012

Astaxanthin at 0.01 or 0.05% of the diet was supplied to diabetic rats for 12 wk. Astaxanthin intake significantly increased its deposit in plasma, and retained glutathione content, reduced the production of reactive oxygen species, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in blood and kidney of diabetic rats (P < 0.05). Astaxanthin treatments also significantly decreased plasma levels of C-reactive protein and von Willebrand factor in diabetic rats (P < 0.05). Astaxanthin intake at 0.05% significantly diminished plasminogen activator inhibitor-1 and factor VII activities, enhanced antithrombin-III and protein C activities in circulation (P < 0.05). These results support that astaxanthin could attenuate diabetes associated coagulatory, oxidative, and inflammatory stress. © 2012 Institute of Food Technologists ®.


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.


Chiang H.-L.,China Medical University at Taichung | Lin K.-H.,Fooyin University | Chiu H.-H.,Fooyin University
Journal of Hazardous Materials | Year: 2012

Biosludge can be reused as an adsorbent after ZnCl2 activation, pyrolysis, washing with HCl and distilled water, and drying. But the pyrolysis exhaust of ZnCl2 immersed sludge can be hazardous to human health and the environment. The chemical composition, including carbon, nitrogen, hydrogen, sulfur and 21 trace elements, as well as the physical characteristics, including specific surface area, pore volume, pore size distribution and pore diameter of pyrolytic residue, were investigated in this work. In addition, the components of pyrolytic exhaust including 30 VOC species and 5 odorous sulfur gases were determined to evaluate the exhaust characteristics. The results indicated that the pyrolytic temperature was higher than 500°C, the specific surface area could be over 900m2/g, and the total pore volume could be up to 0.8cm3/g at 600°C. Exhaust concentration fractions of VOC groups were about 65-71% oxygenated VOCs, 18-21% chlorinated VOCs, 4-6% aromatic VOCs, and 6-10% acrylonitrile and cyclohexane under the specific conditions in this study. © 2012 Elsevier B.V.


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 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.


Tsai J.-H.,National Cheng Kung University | Chang S.-Y.,National Cheng Kung University | Chiang H.-L.,China Medical University at Taichung
Atmospheric Environment | Year: 2012

The exhaust gas constituents of light-duty diesel vehicles (LDDVs), including total hydrocarbon (THC), non-methane hydrocarbon (NMHC), carbon monoxide (CO), nitrogen oxide (NO x), and volatile organic compounds (VOCs) were measured by a dynamometer study following federal test procedure-75 (FTP-75) and highway fuel economy cycle. The average fuel consumption of these LDDVs was 0.126 L km -1 for FTP-75, with about 10% fuel consumption savings for highway driving. The average emission factors of NMHC, CO and NO x for light-duty vehicles were 0.158/0.132 (90% of THC), 1.395/1.138, and 1.735/1.907 g km -1 for FTP-75/Highway, respectively. Styrene, n-propylbenzene, n-undecane, o-ethyltoluene, 1,2,4-trimethylbenzene, toluene, o-xylene, isopropylbenzene, m,p-xylene, and ethylbenzene were the dominant VOCs of LDDV exhaust, and the emission factors were about 10-60 mg kg -1. In addition, formaldehyde, acetaldehyde, acetone, butyraldehyde, and m-tolualdehyde were the major carbonyl species from LDDV exhaust, and the emission factors ranged from 1 to 10 mg km -1. The ozone formation potentials of m,p-xylene, o-ethyltoluene, 1,2,4-trimethylbenzene, o-xylene, n-propylbenzene, styrene, and isoprene were >50 mg-O 3 km -1. In addition, formaldehyde, acetaldehyde, and butyraldehyde revealed high ozone formation potential of carbonyl species, with values ranging from 10 to 95 mg-O 3 km -1. Based on the exhaust constituents and ozone formation potential observed, diesel vehicles could be an important air pollution source for urban and industrial areas. © 2012 Elsevier Ltd.


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.


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 20 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.


Yang C.-Y.,National Chung Hsing University | Chin K.-H.,National Chung Hsing University | Chuah M.L.-C.,Nanyang Technological University | Liang Z.-X.,Nanyang Technological University | And 3 more authors.
Acta Crystallographica Section D: Biological Crystallography | Year: 2011

Cyclic diguanosine monophosphate (c-di-GMP) is a key signalling molecule involved in regulating many important biological functions in bacteria. The synthesis of c - di-GMP is catalyzed by the GGDEF-domain-containing diguanylate cyclase (DGC), the activity of which is regulated by the binding of product at the allosteric inhibitory (I) site. However, a significant number of GGDEF domains lack the RxxD motif characteristic of the allosteric I site. Here, the structure of XCC4471 GGDEF, the GGDEF domain of a DGC from Xanthomonas campestris, in complex with c-di-GMP has been solved. Unexpectedly, the structure of the complex revealed a GGDEF-domain dimer cross-linked by two molecules of c-di-GMP at the strongly conserved active sites. In the complex (c - di-GMP) 2 adopts a novel partially inter-calated form, with the peripheral guanine bases bound to the guanine-binding pockets and the two central bases stacked upon each other. Alteration of the residues involved in specific binding to c-di-GMP led to dramatically reduced K d values between XCC4471 GGDEF and c-di-GMP. In addition, these key residues are strongly conserved among the many thousands of GGDEF-domain sequences identified to date. These results indicate a new product-bound form for GGDEF-domain-containing proteins obtained via (c-di-GMP)2 binding at the active site. This novel XCC4471 GGDEF-c-di-GMP complex structure may serve as a general model for the design of lead compounds to block the DGC activity of GGDEF-domain-containing proteins in X. campestris or other microorganisms that contain multiple GGDEF-domain proteins. © 2011 International Union of Crystallography.


Kim J.-H.,University of Texas | Sharma A.,University of Texas | Dhar S.S.,University of Texas | Lee S.-H.,University of Texas | And 8 more authors.
Cancer Research | Year: 2014

Histone methyltransferases and demethylases reversibly modulate histone lysine methylation, which is considered a key epigenetic mark associated with gene regulation. Recently, aberrant regulation of gene expression by histone methylation modifiers has emerged as an important mechanism for tumorigenesis. However, it remains largely unknown how histone methyltransferases and demethylases coregulate transcriptional profiles for cancer cell characteristics. Here, we show that in breast cancer cells, the histone H3 lysine 27 (H3K27) demethylase UTX (also known as KDM6A) positively regulates gene expression programs associated with cell proliferation and invasion. The majority of UTX-controlled genes, including a cohort of oncogenes and prometastatic genes, are coregulated by the H3K4 methyltransferase mixed lineage leukemia 4 (MLL4, also called ALR, KMT2D, and MLL2). UTX interacted with a C-terminal region of MLL4. UTX knockdown resulted in significant decreases in the proliferation and invasiveness of breast cancer cells in vitro and in a mouse xenograft model. Such defective cellular characteristics of UTX-depleted cells were phenocopied by MLL4 knockdown cells. UTX-catalyzed demethylation of trimethylated H3K27 and MLL4-mediated trimethylation at H3K4 occurred interdependently at cotarget genes of UTX and MLL4. Clinically, high levels of UTX or MLL4 were associated with poor prognosis in patients with breast cancer. Taken together, these findings uncover that coordinated regulation of gene expression programs by a histone methyltransferase and a histone demethylase is coupled to the proliferation and invasion of breast cancer cells.©2014 American Association for Cancer Research.


Chen Y.-J.,National Yang Ming University | Wu C.-Y.,National Yang Ming University | Wu C.-Y.,China Medical University at Taichung | Shen J.-L.,National Yang Ming University | And 3 more authors.
Journal of the American Academy of Dermatology | Year: 2013

Background: Although the link between tuberculosis (TB) and biologics use is well established, the risk of TB among patients with psoriasis exposed to traditional systemic therapies remains elusive. Objectives: The aim is to investigate the association between traditional systemic therapies and TB among patients with psoriasis. Methods: We conducted a retrospective cohort study on the risk of active TB among patients with psoriasis and psoriatic arthritis, using the National Health Insurance Research Database of Taiwan, 1996 through 2008. Standardized incidence ratios of TB were analyzed in comparison with age- and gender-matched general population. Logistic regression was used in a nested case-control analysis to estimate the odds ratios of TB related to exposure to traditional systemic agents during the year before TB development. Results: Among the 81,266 patients in the psoriasis cohort, 497 new active TB cases were identified. The incidence rate of TB was 102 cases per 100,000 person-years among patients with psoriasis (standardized incidence ratio 1.22, 95% confidence interval 1.18-1.33). The risk of TB was higher in patients with severe disease (standardized incidence ratio 1.52, 95% confidence interval 1.46-1.74). To facilitate comparisons with the 497 active TB cases, a total of 1988 matched control subjects were selected for a nested case-control study. Patients taking systemic corticosteroids and nonsteroidal anti-inflammatory drugs were associated with higher incidence of TB, especially frequent users, after adjustment for multiple TB risk factors, drug exposures, hospital visits, and level of urbanization. Stratified analyses of current users and new users of these drugs revealed similar results. Finally, traditional systemic antipsoriatic treatment was not associated with TB on any of the analyses. Limitation: The National Health Insurance Research Database did not contain information regarding severity of psoriasis, smoking status, alcohol use, diet, laboratory parameters, chest radiograph, or history of recent contact with an individual with TB. Misclassification of disease cannot be ruled out in a registry-based database. The accessibility of health care may be associated with the level of urbanization, which could confound the effect of drugs in multivariate analyses. Conclusions: Severe psoriasis may be associated with an elevated TB risk. Traditional systemic therapies do not seem to be strongly associated with TB occurrence. © 2012 by the American Academy of Dermatology, Inc.


Chen P.-N.,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: 2011

The one-pot synthesis of a hetero[3]rotaxane, assembled from five different molecular components under solvent-free conditions, through "self-sorting" of the bead and stopper units during the threading and stoppering processes, is reported. © 2011 American Chemical Society.


Tseng C.-H.,National Taiwan University Hospital | Lee K.-Y.,China Medical University at Taichung | Tseng F.-H.,University of Southern California
Journal of Environmental Science and Health - Part C Environmental Carcinogenesis and Ecotoxicology Reviews | Year: 2015

Incretin-based therapies, including the use of incretin mimetics of glucagon-like peptide-1 receptor (GLP-1R) agonists and incretin enhancers of dipeptidyl-peptidase 4 (DPP-4) inhibitors, are widely used by clinicians for glucose lowering in patients with type 2 diabetes mellitus. These agents have benefits of a lower risk of hypoglycemia, being neutral for body weight for DPP-4 inhibitors and having a potential for weight reduction with GLP-1R agonists. They may also have a neutral or beneficial cardiovascular effect. Despite these benefits, an increased risk of cancer (especially pancreatic cancer and thyroid cancer) associated with incretin-based therapies has been reported. In this article, we reviewed related literature of experimental animal and observational human studies, clinical trials, and meta-analyses published until December 15, 2014. Current studies suggested a probable role of GLP-1R activation on the development of pancreatic cancer and thyroid cancer in rodents, but such an effect in humans is not remarkable due to the lower or lack of expression of GLP-1R on human pancreatic ductal cells and thyroid tissues. Findings in human studies are controversial and inconclusive. In the analyses of the US Food and Drug Administration adverse events reporting system, a significantly higher risk of pancreatic cancer was observed for GLP-1R agonists and DPP-4 inhibitors, but a significantly higher risk of thyroid cancer was only observed for GLP-1R agonists. Such a higher risk of pancreatic cancer or thyroid cancer could not be similarly demonstrated in other human observational studies or analyses of data from clinical trials. With regards to cancers other than pancreatic cancer and thyroid cancer, available studies supported a neutral association in humans. Some preliminary studies even suggested a potentially beneficial effect on the development of other cancers with the use of incretins. Based on current evidence, continuous monitoring of the cancer issues related to incretin-based therapies is required, even though the benefits may outweigh the potential cancer risk in the general patients with type 2 diabetes mellitus. Copyright © 2015 Taylor & Francis Group, LLC.


Lee C.-H.,China Medical University at Taichung
Applied Microbiology and Biotechnology | Year: 2012

One of the primary limitations of cancer therapy is lack of selectivity of therapeutic agents to tumor cells. Current efforts are focused on discovering and developing anticancer agents that selectively target only tumor cells and spare normal cells to improve the therapeutic index. The use of preferentially replicating bacteria as an oncolytic agent is one of the innovative approaches for the treatment of cancer. This is based on the observation that some obligate or facultative anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. Meanwhile, bacteria have been demonstrated to colonize and destroy tumor, and have emerged as biological gene vectors to tumor microenvironment. To improve the efficacy and safety of the bacterial therapy, a further understanding of bacteria between with immune system is required. Furthermore, we want to evaluate how bacterial infection facilitates the "bystander effect" of chemotherapeutic agent and assess if it can be used for additional antitumor effect when combined with chemotherapy. This study may not only evaluate therapeutic efficacy of bacteria for the treatment of cancer but also elucidate the mechanisms underlying antitumor activities mediated by bacteria, which involve host immune responses and the cellular molecular responses. © 2011 Springer-Verlag.


Yu Y.-M.,Chang Jung Christian University | Lin H.-C.,China Medical University at Taichung
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2010

Background and aim: The migration of vascular smooth muscle cells from the tunica media to the subendothelial region is a key event in the development of atherosclerosis. Curcumin, which is consumed daily by millions of people, is a polyphenol derived from the plant Curcuma longa. In this study, we investigated the effects of curcumin on tumor necrosis factor-α (TNF-α)-induced cell migration, the formation of intracellular reactive oxygen species (ROS), the translocation of nuclear factor-κB (NFκB) and the activation and expression of MMP-9 in human aortic smooth muscle cells (HASMCs). Methods and results: The Matrigel migration assay showed that curcumin (10 and 20 μmol/l) effectively inhibited TNF-α-induced migration of HASMCs as compared with the control group. To explain this inhibitory effect, MMP-9 was assayed by gelatin zymography and Western blot. The results indicated that curcumin inhibited MMP-9 activity and expression. Furthermore, the production of ROS and the nuclear translocation of NF-κB p50 and p65 induced by TNF-α were dose-dependently suppressed by curcumin pretreatment. Conclusion: These results indicate that curcumin has anti-inflammatory properties and may prevent the migration of HASMCs by suppressing MMP-9 expression through down-regulation of NF-κB. © 2009 Elsevier B.V. All rights reserved.


Liu Z.-H.,Providence University | Devaraj S.,Providence University | Yang C.-R.,China Medical University at Taichung | Yen Y.-P.,Providence University
Sensors and Actuators, B: Chemical | Year: 2012

A new receptor 1 was developed, and its chromogenic and fluorogenic behaviors toward various di- and tricarboxylate anions were investigated. Receptor 1 shows response exclusively toward citrate anion and also distinguishes citrate anion from other anions by different color change in aqueous solution (DMSO/H 2O = 4/1). In addition, the receptor 1 also exhibits a pronounced citrate-induced fluorescence enhancement. The detection limit for the citrate anion was determined as (0.18 ± 0.01 μM). Thus, the receptor 1 can be used as a colorimetric and fluorescent sensor for the determination of citrate ion. © 2012 Elsevier B.V.


Tsai A.C.,Asia University, Taiwan | Tsai A.C.,China Medical University at Taichung | Lee S.-H.,Asia University, Taiwan
Clinical Nutrition | Year: 2015

Diabetes mellitus is prevalent in many countries around the world, but the potential causal factors are not clearly known. We attempted to determine the risk factors for new-onset diabetes in ≥53-year old Taiwanese. Methods: We analyzed the 1999 and 2003 datasets of the Taiwan Longitudinal Survey on Aging (TLSA). We performed logistic regression analyses to determine the cross-sectional and longitudinal (1999-2003) associations of the sociodemographic, lifestyle, and health-related variables with diabetes and new-onset diabetes, respectively. We excluded those who were diabetic at baseline in the longitudinal analysis. Results: Results of the cross-sectional analysis showed that higher weight, past betel-quid chewing, IADL dependency, hypertension, heart disease, chronic kidney disease and depressive symptoms were positively associated with diabetes while alcohol drinking was negatively associated with diabetes. Longitudinal analysis showed that excessive weight, physical inactivity, depressive symptoms, and hypertension were associated with increased likelihood of new-onset diabetes while higher physical activity was associated with reduced likelihood of new-onset diabetes. Cigarette-smoking and moderate alcohol drinking showed no clear impacts on new-onset diabetes in older Taiwanese. Conclusions: Results show that excessive weight, physical inactivity, hypertension and depressive symptoms are the major risk factors for new-onset diabetes for both Eastern and Western populations, whereas smoking and alcohol drinking have varying impacts among these populations. Better understanding of these relationships should be helpful for planning effective health promotion strategies for reducing the risk of new-onset diabetes in older adults. © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.


Chang S.L.,Asia University, Taiwan | Tsai A.C.,Asia University, Taiwan | Tsai A.C.,China Medical University at Taichung
Preventive Medicine | Year: 2015

Objective: This study investigates the role of gender in the associations of long-term depressive symptoms and leisure-time physical activity (LTPA) with the risk of cognitive decline in elderly Taiwanese. Method: We analyzed 3679 subjects (age ≥. 57) in the 2003 and 2007 datasets of the Taiwan Longitudinal Survey on Aging, of which data were collected via face-to-face interviews by trained interviewers. We excluded proxy respondents. Multivariable logistic regression analysis examined the associations of long-term depressive symptoms (increased symptoms: CES-D10 scores from <. 10 to ≥. 10; decreased symptoms: from ≥. 10 to <. 10) and LTPA (frequency, duration, and intensity) with cognitive decline (a decrease of two or more SPMSQ scores). Results: Women had significant higher percentages of cognitive impairment, compared to men, at the baseline (5.9 vs. 1.5%; χ2=51.24, p<0.001) and end-point (10.8 vs. 5.2%;χ2=39.5, p<0.001). Men with long-term depressive symptoms had 5.28 greater odds of cognitive decline (OR=5.28, 95%CI=2.84-9.82, p<0.001) and men with increased depressive symptoms had 2.09 greater odds (2.09, 1.24-3.51, p=0.006). No such association was observed in women. Men with consistently high LTPA had 65% (0.35, 0.19-0.65, p=0.001) and women with increased LTPA had 43% (0.57, 0.34-0.93, p=0.024) reduction in odds of developing cognitive decline. Conclusion: We found gender differences in the longitudinal association between depressive symptoms and cognitive decline. Long-term LTPA may loosen the association between long-term depressive symptoms and cognitive decline. These findings are useful in the identification of vulnerable elderly in the Taiwanese population and public health interventions should focus on assisting their cognitive aging. © 2015 Elsevier Inc.


Tang F.-Y.,China Medical University at Taichung
BioMedicine (Netherlands) | Year: 2012

Cancer has been a leading cause of death in many countries. Chemoprevention of various types of human cancer using dietary nutrients has received a lot of attention and interest in the past decade. Recently, carotenoids have been shown to prevent tumor growth and progression. Carotenoids demonstrated chemopreventive capability by interrupting several stages of cancer including initiation, promotion, progression, and metastasis. The molecular mechanisms of actions are through the modulation of cell-signaling pathways and gene expression. The results of our study suggested that carotenoids could act as chemopreventive agents against the growth and progression of human cancer cells. © 2012.


Tsai Z.-R.,Asia University, Taiwan | Tsai Z.-R.,China Medical University at Taichung
Expert Systems with Applications | Year: 2014

This paper introduces a robust, adaptive and learning approach, called a nonlinear Log-Artificial-Bee-Colony in ('a','b') color space (Log-ab), for the recognition of colored markers. Log-ab optimizes the Recognition Performance Index (RPI) of the marker's templates by using the proposed on-line Bee-colony method for the purpose of adapting in the varied light environment. Furthermore, Log-ab guides a multidirectional robot accurately to move on a desired path in the dynamic light's disturbance by using Log-ab controller. Simultaneously, the proposed multidirectional robot with Kinect performs pattern recognition as well as measures the depth and orientation of a marker quite precisely. Then, for verification of the effectiveness of dynamic ('a','b') color space, the results of Signal to Noise (S/N) run as well as these results show the advantages of the proposed method over the existing color-based methods. Finally, Tracking Success Rate (TSR) of robot for a specific colorful marker shows the robustness of the proposed case as compared with the popular Scale Invariant Feature Transform (SIFT) and Phase-Only Correlation method (POC). © 2013 Elsevier Ltd. All rights reserved.


Tsai A.C.,Asia University, Taiwan | Tsai A.C.,China Medical University at Taichung | Lai M.-Y.,Asia University, Taiwan
Clinical Nutrition | Year: 2014

Background & aims: Falling is a major issue in geriatric health. Tools that identify individuals at risk of falling can help reduce the risk of falling. The study aimed to determine whether the full and short-form Mini Nutritional Assessment (MNAs) have the ability to predict the risk of falling in older adults. Methods: Subjects were 3118 ≥ 53-year old Taiwanese who completed both the 1999 and 2003 "Taiwan Longitudinal Study on Aging" surveys. We rated these subjects with normalized versions of the MNA and applied the standard cut-offs to define under-nutrition (≤23.5 and ≤11 points, respectively). We used multivariate logistic regression analysis and receiver operating characteristics to evaluate the ability of these tools in predicting the risk of falling three years later. Results: Older adults rated as at risk of malnutrition with the full MNA (OR = 1.87, 95% confidence interval = 1.33-2.63, p < 0.001) or the short-form (1.39, 1.07-1.80, p = 0.014) were associated with increased risk of falling three years later. Both versions significantly predicted the risk of falling and performed slightly better in ≥65-year old persons than in younger (53-64-year old) persons. The short-form performed relatively well compared to the full scale. Conclusions: Results suggest that the full and short-form MNAs, in addition to rating the risk of malnutrition, also predict the risk of falling in older adults. Although the short-form is slightly less effective than the full scale in predicting the future risk of falling, its simplicity, effectiveness and efficiency make it ideal as a multipurpose screening tool in clinical settings. © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.


Liao J.-R.,National Chung Hsing University | Chen C.-M.,National Chung Hsing University | Chen C.-M.,China Medical University at Taichung
Signal Processing | Year: 2014

Frequency estimation for single tone complex sinusoid is a fundamental problem in signal processing. A simple and effective way is to directly interpolate the discrete Fourier transform (DFT) coefficients around the peak of the magnitude spectrum. In this paper, we use theoretical analysis to show that correcting a phase term on the DFT coefficients before interpolation can reduce the estimation bias and improve the accuracy of the estimation significantly. We derive the amount of bias reduction that can be achieved by the phase correction. We then show that the phase correction can be considered as a pre-estimation correction while the effect of the previously proposed post-estimation correction is also to reduce the bias caused by the phase. In the experiments, we find that the phase correction proposed here and the post-estimation correction previously proposed is effective in different regions of frequency offset. We theoretically derive the threshold between the regions and propose a hybrid estimator which uses different corrections in different regions of frequency offset. Experiments show that the hybrid estimator is superior among direct estimators across the entire range of frequency offset at moderate and high SNR. © 2013 Elsevier B.V.


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.


Yin M.-C.,China Medical University at Taichung
BioMedicine (Netherlands) | Year: 2012

Triterpene compounds occur naturally in many herbs and plant foods. Triterpenes such as ursolic, oleanolic, and betulinic acid definitely possess antioxidative and anti-inflammatory activities as well as an inhibitory effect on advanced glycation end-product (AGE) formation. Furthermore, the effects of triterpenes upon the activity and expression of aldose reductase, sorbitol dehydrogenase, and glyoxalase I, enzymes involved in the polyol pathway, have been examined, with positive results reported. These studies indicate triterpenes as potent antiglycative agents, suggesting that they can benefit the prevention of and/or therapy for glycation-related diseases such as diabetes mellitus and Alzheimer's disease. Further studies should examine their impact on receptors of AGE (RAGEs) and AGE-RAGE interaction in order to bolster the antiglycative application of these natural compounds. © 2012.


Hwang S.-L.,Development Institute | Yen G.-C.,National Chung Hsing University | Yen G.-C.,China Medical University at Taichung
Journal of Agricultural and Food Chemistry | Year: 2011

Hesperetin is known to activate estrogen receptors (ERs). Estrogen-mediated neuroprotection could be via both ER and tyrosine kinase receptor (Trk) signaling. This study tested whether hesperetin protected PC12 cells from hydrogen peroxide induced oxidative damage via ER-and/or TrkA-mediated actions. Hesperetin (0.1, 1, and 50 μM) inhibited cell viability decreases and reactive oxygen species, intracellular calcium level, and caspase-3 activity increases in H 2O 2-induced PC12 cells. Such actions were significantly (p < 0.05) suppressed by ICI 182,780 (an ER antagonist) or K252a (a TrkA antagonist) at low concentrations (0.1 or 1 μM) only. Hesperetin also stimulated the activation of Akt, ERK, and CREB as well as induced brain-derived neurotrophic factor, PPARγ coactivator 1α (PGC-1α), and seladin-1 (selective Alzheimer's disease indicator-1) via both ER and TrkA in the cells. This study demonstrates that the neuroprotective effects of hesperetin, at low concentrations, are attributed to its stimulation on receptor signaling. Moreover, ER and TrkA are known to be expressed in most Alzheimer's disease (AD) vulnerable brain regions. This study thus suggests that hesperetin might have potential for intervention in neurodegenerative disorders, particularly for AD. © 2011 American Chemical Society.


Chen J.-L.,China Medical University at Taichung | Huang Y.-J.,Chung Shan Medical University | Pan C.-H.,Institute of Occupational Safety and Health | Hu C.-W.,Chung Shan Medical University | Chao M.-R.,Chung Shan Medical University
Free Radical Biology and Medicine | Year: 2011

A highly sensitive quantitative LC-MS/MS method was developed for measuring urinary malondialdehyde (MDA). With the use of an isotope internal standard and online solid-phase extraction, urine samples can be directly analyzed within 10 min after 2,4-dinitrophenylhydrazine (DNPH) derivatization. The detection limit was estimated as 0.08 pmol. This method was further applied to assess the optimal addition of DNPH for derivatization and to measure urinary MDA in 80 coke oven emission (COE)-exposed and 67 nonexposed workers. Derivatization optimization revealed that to achieve complete derivatization reaction, an excess of DNPH is required (DNPH/MDA molar ratio: 893-8929) for urine samples that is about 100 times higher than that of MDA standard solutions (molar ratio: 10-80). Meanwhile, the mean urinary concentrations of MDA in COE-exposed workers were significantly higher than those in nonexposed workers (0.23 ± 0.17 vs 0.14 ± 0.05 μmol/mmol creatinine, P < 0.005). Urinary MDA concentrations were also significantly associated with the COE (P < 0.005) and smoking exposure (P < 0.05). Taken together, this method is capable of routine high-throughput analysis and accurate quantification of MDA and would be useful for assessing the whole-body burden of oxidative stress. Our findings, however, raise the issue that derivatization optimization should be performed before it is put into routine biological analysis. © 2011 Elsevier Inc.


Shih P.-K.,China Medical University at Taichung
Hernia : the journal of hernias and abdominal wall surgery | Year: 2015

BACKGROUND: Partition technique and component separation techniques are natural methods of fascia-fascia closure. We present our experiences and research the differences between the two techniques.METHODS: From January 2006 to August 2013, 41 patients with complex abdominal wall defects reconstructed with partition (N = 18) or component separation technique (N = 23) alone were enrolled into this study. The related data including gender, age, size of defect, operation time, hospital stay, duration of follow-up, comorbidities, body mass index (BMI) and complications were collected. Nonparametric Mann-Whitney test was used to evaluate the differences between the two groups in continuous data; Chi-square test was used to assess the categorical data.RESULTS: The mean defect size of patients with partition technique (N = 18) was 12.55 cm (range 8.2-18.9 cm) with 148.63 min for average operation time, 8.66 days for hospital stay, and 28.8 months for mean follow-up. There were nine cases with postoperative complications (three cases with skin and soft tissue necrosis; two cases with fascia dehiscence; and three cases with wound infection). One case with fascia dehiscence suffered from pneumonia simultaneously. Four cases received secondary operation (fascia repair and split-thickness skin graft), and the other four cases healed spontaneously with mild wound debridement. The mean defect size of the patients with component separation (N = 23) technique was 9.45 cm (range 5.7-12.6 cm) with 143.27 min for average operation time, 7.43 days for hospital stay, and 34.33 months for mean follow-up. One case with skin and soft tissue necrosis underwent reconstruction with split-thickness skin graft and debridement. Two cases with wound infection healed spontaneously with mild wound debridement. There were no significant differences in gender, age, operation time, hospital stay, duration of follow-up, comorbidities, BMI and long-term postoperative complications between the two groups, except for size of defect and short-term postoperative complications.CONCLUSIONS: The partition technique could close larger abdominal fascia defects than component separation technique, but simultaneously run the higher opportunities for short-term postoperative complications.


Tsai C.-H.,National Taiwan University | Huang J.-H.,National Taiwan University | Hwang B.-F.,China Medical University at Taichung | Lee Y.L.,National Taiwan University
Respiratory Research | Year: 2010

Background: Although studies show that maternal smoking during pregnancy increases the risks of respiratory outcomes in childhood, evidence concerning the effects of household environmental tobacco smoke (ETS) exposure remains inconsistent.Methods: We conducted a population-based study comprised of 5,019 seventh and eighth-grade children in 14 Taiwanese communities. Questionnaire responses by parents were used to ascertain children's exposure and disease status. Logistic regression models were fitted to estimate the effects of ETS exposures on the prevalence of asthma, wheeze, and bronchitic symptoms.Results: The lifetime prevalence of wheeze was 11.6% and physician-diagnosed asthma was 7.5% in our population. After adjustment for potential confounders, in utero exposure showed the strongest effect on all respiratory outcomes. Current household ETS exposure was significantly associated with increased prevalence of active asthma, ever wheeze, wheeze with nighttime awakening, and bronchitis. Maternal smoking was associated with the increased prevalence of a wide range of wheeze subcategories, serious asthma, and chronic cough, but paternal smoking had no significant effects. Although maternal smoking alone and paternal smoking alone were not independently associated with respiratory outcomes, joint exposure appeared to increase the effects. Furthermore, joint exposure to parental smoking showed a significant effect on early-onset asthma (OR, 2.01; 95% CI, 1.00-4.02), but did not show a significant effect on late-onset asthma (OR, 1.17; 95% CI, 0.36-3.87).Conclusion: We concluded that prenatal and household ETS exposure had significant adverse effects on respiratory health in Taiwanese children. © 2010 Tsai et al; licensee BioMed Central Ltd.


Wang K.,Georgia Institute of Technology | Chang Y.-H.,Georgia Institute of Technology | Chen Y.,China Medical University at Taichung | Zhang C.,Georgia Institute of Technology | Wang B.,Georgia Institute of Technology
Materials and Design | Year: 2015

Metamaterials are inherently advantageous in achieving designable auxeticity since their Poisson' ratios are determined by the geometry of their unit cells. A family of auxetic metamaterials was created by computer-aided design (CAD) and dual-material three-dimensional (3D) printing. The effects of material selections and stiff material fraction on the Poisson's ratio, equivalent Young's Modulus, and maximum volume reduction were investigated. The results from finite element analysis (FEA) and mechanical testing indicated that the auxeticity and mechanical properties of this dual-material auxetic metamaterial (DMAM) are distinctly different from those of traditional single-material auxetic metamaterials (SMAMs). The interesting properties of DMAMs could be valuable to various engineering applications such as smart materials, biomedical components, and shock-resistant components. © 2014.


Chang S.-S.,Chang Gung University | 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.


Chen C.-J.,National Taiwan University | Yang H.-I.,China Medical University at Taichung
Journal of Gastroenterology and Hepatology (Australia) | Year: 2011

Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti-HCV), alanine aminotransferase (ALT), and α-fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose-response relationship from <300 (undetectable) to ≥1000000 copies/mL. The biological gradients remained significant (P<0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver-related mortality than HBsAg-seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.


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.


Dang Z.,Duke University | Ho P.,Duke University | Zhu L.,Duke University | Qian K.,University of North Carolina at Chapel Hill | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2013

Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate. © 2013 American Chemical Society.


Chao C.-C.,Changhua Christian Hospital | Lin C.-J.,Changhua Christian Hospital | Lin C.-J.,China Medical University at Taichung
Pediatric Neurology | Year: 2014

Background Pituitary apoplexy is a rare clinical emergency which results from hemorrhage or infarction in the pituitary gland. Patient We present a 14-year-old girl with pituitary apoplexy and review the literature. Results Our patient experienced blurred vision, nausea, and headache. Her best-corrected visual acuity was 20/200 and 20/20. Confrontation test visual field testing revealed bitemporal hemianopsia. Brain imaging demonstrated a suprasellar mass. The microscopic endonasal transsphenoidal approach only found 5-10 mL brownish fluid-like material. Pathology confirmed no malignancy. Pituitary apoplexy was diagnosed. Her nausea and headache gradually improved. Six months after operation, her best-corrected visual acuity had improved to 20/30 and 20/20. Conclusions Although pituitary apoplexy is rare in pediatric patients, prompt evaluation including detailed ophthalmic examination, biochemical evaluation, endocrine workup, and image study are very important. © 2014 Elsevier Inc. All rights reserved.


Chen Y.J.,National Taiwan University | Tsai K.S.,National Taiwan University Hospital | Chan D.C.,National Taiwan University Hospital | Lan K.C.,National Defense Medical Center | 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.


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.


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.


Lee C.-L.,National Sun Yat - sen University | Chang W.-D.,China Medical University at Taichung
International Journal of Women's Health | Year: 2013

Aim: In this study, the effects of cigarette smoking on maximal aerobic capacity, anaerobic capacity, and heart rate variability among female university students were investigated. Materials and methods: Twelve smokers and 21 nonsmokers participated in this study. All participants performed an intermittent sprint test (IST) and a 20 m shuttle run test to measure their anaerobic capacity and maximal aerobic capacity. The IST was comprised of 6×10-second sprints with a 60-second active recovery between each sprint. Heart rate variability was recorded while the participants were in a supine position 20 minutes before and 30minutes after the IST. Results: The total work, peak power, and heart rate of the smokers and nonsmokers did not differ significantly. However, the smokers' average power declined significantly during sprints 4 to 6 (smokers versus nonsmokers, respectively: 95% confidence interval=6.2-7.2joule/kg versus 6.8-7.6joule/kg; P<0.05), and their fatigue index increased (smokers versus nonsmokers, respectively: 35.8% ± 2.3% versus 24.5% ± 1.76%; P<0.05) during the IST. The maximal oxygen uptake of nonsmokers was significantly higher than that of the smokers (P<0.05). The standard deviation of the normal to normal intervals and the root mean square successive difference did not differ significantly between nonsmokers and smokers. However, the nonsmokers exhibited a significantly higher normalized high frequency (HF), and significantly lower normalized low frequency (LF), LF/HF ratio, and natural logarithm of the LF/HF when compared with those of the smokers (P<0.05). Conclusion: Smoking may increase female smokers' exercise fatigue and decrease their average performance during an IST, while reducing their maximal aerobic capacity. Furthermore, smoking reduces parasympathetic nerve activity and activates sympathetic cardiac control. © 2013 Lee and Chang.


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.


Chen T.-H.,National Chung Hsing University | Chan P.-C.,National Chung Hsing University | Chen C.-L.,National Chung Hsing University | Chen H.-C.,National Chung Hsing University | Chen H.-C.,China Medical University at Taichung
Oncogene | Year: 2011

Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. In contrast, substitution of Tyr194 with Glu (Y194E substitution) leads to constitutive activation of FAK. The phosphorylation of FAK on Tyr194 may cause conformational changes in the FERM domain, which disrupts the intramolecular inhibitory interaction between the FERM and kinase domains of FAK. Moreover, substitution of the basic residues in the 216 KAKTLRK 222 patch in the FERM domain with Ala antagonizes the effect of the Y194E substitution on FAK activation, thus suggesting that the interactions between the phosphorylated Tyr194 and the basic resides in the 216 KAKTLRK 222 patch may allow FAK to be activated through relief of its autoinhibition. Collectively, this study provides the first example to explain how FAK is activated by receptor tyrosine kinases. © 2011 Macmillan Publishers Limited All rights reserved.


Leung Y.-M.,China Medical University at Taichung
Pharmacology and Therapeutics | Year: 2012

Voltage-gated K + (Kv) channels serve multiple functions. Besides the most well known function of controlling membrane excitability, they may also play roles in cell death and differentiation. Pharmacological activators and inhibitors of Kv channels therefore offer potential therapeutic treatments for a variety of diseases. Inhibition of Kv channels by classical blockers such as tetraethylammonium and 4-aminopyridine, and toxin peptides such as scorpion toxins, are believed to result from a direct intervention or occlusion of the K + permeation pathway. During prolonged depolarization, most Kv channels undergo a process called slow or C-type inactivation, by which the selectivity filter destabilizes and thus limits K + flux. Increasing amount of evidence shows that there are certain compounds which inhibit Kv currents not by directly obstructing the K + conduction pathway, but by accelerating or intensifying selectivity filter destabilization once the channels open. This mode of block represents an alternative mechanism of Kv channel inhibition. Indeed, some of the classical Kv channel blockers are to some extent, or in certain circumstances, involved in hastening slow inactivation. This review begins with a brief description of structure-functions of Kv channels, and then discusses the multiple mechanisms of Kv channel inhibition by classical blockers and how certain compounds inhibit Kv channels by accelerating C-type inactivation. The pharmacological and therapeutic potentials of these C-type inactivation-dependent Kv channel inhibitors are discussed. © 2011 Elsevier Inc. © 2011 Elsevier Inc. All rights reserved.


Chen P.-M.,Taipei Medical University | Cheng Y.-W.,Taipei Medical University | Wu T.-C.,Chung Shan Medical University | Chen C.-Y.,China Medical University at Taichung | Lee H.,Taipei Medical University
Free Radical Biology and Medicine | Year: 2015

Manganese superoxide dismutase (MnSOD) has been shown to be associated with doxorubicin resistance in gastric cancer cells, but the underlying mechanism of MnSOD in drug resistance remains unclear. A recent study indicated that NF-κB activation by MnSOD promoted tumor malignancy in lung adenocarcinoma. Therefore, we hypothesized that MnSOD-mediated NF-κB activation might confer cisplatin resistance in lung adenocarcinoma via the NF-κB/Bcl-2/Snail pathway. Here, the inhibition concentration of cisplatin with 50% cell viability (IC50) was positively correlated with MnSOD expression and its activity in a panel of lung adenocarcinoma cells. The IC50 value was markedly increased and decreased by MnSOD overexpression and knockdown, respectively, in lung cancer cells. Mechanistically, an increase in Bcl-2 by MnSOD-mediated NF-κB activation confers greater cisplatin resistance than cIAP2, Bcl-xL, Mcl-1, and Snail. MnSOD-mediated cisplatin resistance can be overcome by a Bcl-2 antagonist (ABT-199) or IKKβ inhibitor (curcumin) in cells and xenograft tumors. MnSOD expression was positively correlated with nuclear p65 protein and Bcl-2 mRNA expression in tumors from patients with lung adenocarcinomas. A retrospective study indicated that it was more common for MnSOD-positive, nuclear p65-positive, or high Bcl-2 mRNA tumors to have an unfavorable response to cisplatin-based chemotherapy than their counterparts. Therefore, we suggest that ABT-199 or curcumin may be potentially useful to improve tumor regression and chemotherapeutic response in patients with MnSOD/Bcl-2-positive tumors. © 2014 Elsevier Inc.


Liu T.-T.,Yuanpei University | Yang T.-S.,China Medical University at Taichung
Journal of Food Science | Year: 2010

This study investigated the stability and antimicrobial activity of allyl isothiocyanate (AITC) in medium chain triglyceride (MCT) or soybean oil (SBO) dispersed in an oil-in-water (o/w) system during long-term storage. Oil type, content, and oxidative stability affect the stability and antimicrobial activity of AITC during storage. High oil content is favorable for AITC stability in the emulsion. Notably, AITC with MCT is more stable than AITC with SBO with the same oil content. Consequently, AITC with MCT is more effective than AITC with SBO in inhibiting G(-) bacteria (E. coli O157:H7, Salmonella enterica, and Vibrio parahaemolyticus) and G(+) bacteria (Staphylococcus aureus and Listeria monocytogenes). © 2010 Institute of Food Technologists®.


Yin M.-C.,Asia University, Taiwan | Yin M.-C.,China Medical University at Taichung | Lin M.-C.,Chung Shan Medical University | Mong M.-C.,Asia University, Taiwan