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Chiu S.C.,Taichung Tzu Chi Hospital | Huang S.Y.,Mackay Memorial Hospital | Chen S.P.,Hualien Tzu Chi Hospital | Su C.C.,Changhua Christian Hospital | And 3 more authors.
Prostate Cancer and Prostatic Diseases | Year: 2013

BACKGROUND:Tanshinone IIA (Tan-IIA) is one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae Radix. We explored the mechanisms of cell death induced by Tan-IIA treatment in prostate cancer cells in vitro and in vivo.METHODS:Cells were treated with Tan-IIA and growth inhibition was assessed. Cell cycle profiles after Tan-IIA treatment were determined by flow cytometry. Expression levels of cell cycle regulatory proteins and apoptosis-related proteins were determined after Tan-IIA treatment. Expression levels of endoplasmic reticulum (ER) stress-regulated genes were determined to investigate their role in Tan-IIA-induced cell death. GADD153 expression was knocked down by small interfering RNA (siRNA) transfection. Rate of cell death and proliferation was obtained by 3-(4,5-dimethyl thizol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Antitumor activity of Tan-IIA was performed in LNCaP xenograft model.RESULTS:Our results showed that Tan-IIA caused prostate cancer cell death in a dose-dependent manner, and cell cycle arrest at G0/G1 phase was noted, in LNCaP cells. The G0/G1 phase arrest correlated with increase levels of CDK inhibitors (p16, p21 and p27) and decrease of the checkpoint proteins. Tan-IIA also induced ER stress in prostate cancer cells: activation and nuclear translocation of GADD153/CCAAT/enhancer- binding protein-homologous protein (CHOP) were identified, and increased expression of the downstream molecules GRP78/BiP, inositol-requiring protein-1 and GADD153/CHOP were evidenced. Blockage of GADD153/CHOP expression by siRNA reduced Tan-IIA-induced cell death in LNCaP cells. Tan-IIA also suppressed LNCaP xenograft tumor growth, causing 86.4% reduction in tumor volume after 13 days of treatment.CONCLUSIONS:Our findings suggest that Tan-IIA causes G0/G1 cell cycle arrest in LNCaP cells and its cytotoxicity is mediated at least partly by ER stress induction. These data provide evidence supporting Tan-IIA as a potential anticancer agent by inducing ER stress in prostate cancer. © 2013 Macmillan Publishers Limited All rights reserved.

Hsu M.-Y.,National Tsing Hua University | Hsu M.-Y.,Taichung Veterans General Hospital | Chen S.-J.,Taipei Veterans General Hospital | Chen K.-H.,National Tsing Hua University | And 3 more authors.
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2015

The purpose of this article is to demonstrate the capacity of paper-based ELISA (P-ELISA) to monitor VEGF in patients requiring treatment for vision-threatening diseases. The most commonly encountered vision-threatening diseases are age-related macular degeneration (AMD) and diabetic retinopathy (DR), both of which may require short-term or life-long anti-VEGF injection treatment therapy. Accurate measurement of VEGF concentration in aqueous humor can provide significant and timely information to diagnose the disease state. Adequate and precise therapy may consequently be provided. At odds with conventional diagnostic approaches is the fact that a maximum of only 200 microliters of aqueous humor can be safely removed from the eye for testing. Fortunately, new diagnostic platforms, such as P-ELISA, require only minute volumes, i.e., approximately 2 microliters per test "well" and approximately 40 microliters total to quantify VEGF levels, and the testing process takes less than an hour. Thus, point-of-care (POC) diagnostics, such as P-ELISA, should be examined and improved upon as needed in order to develop an efficient tool for outpatient clinics and others to obtain semi-quantitative results that might facilitate accurate dosing of anti-VEGF treatment and delay or prevent the progression of AMD and DR. This journal is © The Royal Society of Chemistry 2015.

PubMed | Taichung Veterans General Hospital, National Taiwan University Hospital, Chang Gung Memorial Hospital, Chung Shan Medical University and 5 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Despite the advancement of epidermal growth factor receptor (EGFR) inhibitors in lung cancer therapy, it remains unclear whether EGFR mutation status in familial lung cancers is different from that of sporadic cases. In this multicenter retrospective study, we compared both the EGFR mutation frequency and patterns between familial and sporadic cases. The results explored that family history of lung cancer is an independent predictor for higher EGFR mutation rate in 1713 lung adenocarcinoma patients (Odd ratio 1.68, 95% CI 1.06-2.67, P = 0.028). However, the distribution of EGFR mutation subtypes was similar to that of sporadic cases. Part of our study involved 40 lung cancer families with at least 2 tumor tissues available within each single family (n = 88) and there was no familial aggregation pattern in EGFR mutation subtypes. There were two families harboring the YAP1 R331W germline risk allele and EGFR mutation statuses among YAP1 family members also varied. These phenomena may hint at the direction of future research into lung carcinogenesis and EGFR mutagenesis.

PubMed | China Medical University at Taichung, Chung Shan Medical University, Taichung Tzu Chi Hospital, Changhua Christian Hospital and National Taiwan University Hospital
Type: | Journal: Toxicology and applied pharmacology | Year: 2016

Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic -cells are mostly unclear. In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic -cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo. These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascades and PARP. In addition, ER stress was triggered as indicated by several key molecules of the UPR. Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPK, and GSK3-/. Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPK effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-/ (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects. Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPK each other. Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic -cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways.

Tsai C.-F.,Asia University, Taiwan | Yeh W.-L.,Changhua Christian Hospital | Chen J.-H.,Taichung Tzu Chi Hospital | Lin C.,China Medical University at Taichung | And 2 more authors.
International Journal of Molecular Sciences | Year: 2014

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK) is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP)-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Yang Y.-W.,China Medical University at Taichung | Hsieh T.-F.,Taichung Tzu Chi Hospital | Hsieh T.-F.,Tzu Chi University | Yu C.-H.,Dalin Tzu Chi Hospital | And 4 more authors.
Journal of Psychiatric Research | Year: 2014

Background: This nationwide population-based study investigated the risk of Parkinson's disease (PD) after zolpidem use in patients with sleep disturbance using the National Health Insurance Research Database (NHIRD) in Taiwan. Material and methods: In total, 59,548 adult patients newly diagnosed with sleep disturbance and who used zolpidem were recruited as the study cohort, along with 42,171 subjects who did not use zolpidem as a comparison cohort from 2002 to 2009. Each patient was monitored for 5 years, and those who subsequently had PD were identified. A Cox proportional hazards model was used to compare the risk of PD between the study and comparison cohorts after adjusting for possible confounding risk factors. Results: The patients who received zolpidem had a higher cumulative rate of PD than those who did not receive zolpidem during the 5-year follow-up period (1.2% vs. 0.5%, P<0.001). The adjusted hazard ratios were 1.10 (95% CI, 0.88-1.37), 1.41 (95% CI, 1.17-1.72), and 1.27 (95% CI, 1.05-1.55) for zolpidem use with 28-90, 91-365, and more than 365 cumulative defined daily doses (cDDDs), respectively, compared to those who did not use zolpidem. Conclusions: Among the patients with sleep disturbance, zolpidem use increased the risk of PD after 5 years of follow-up. Further mechanistic research of zolpidem effect in PD is needed. © 2014 Elsevier Ltd.

Hsu M.-Y.,Taichung General Veteran Hospital | Hsu M.-Y.,National Tsing Hua University | Yang C.-Y.,National Tsing Hua University | Hsu W.-H.,National Chung Hsing University | And 8 more authors.
Biomaterials | Year: 2014

The vascular endothelial growth factor (VEGF) level in aqueous humor has been used as an indicator to monitor specific diseases in the retinal ischemic condition. For clinical diagnosis, only about 200μL of aqueous humor can be collected from the anterior chamber before the threat of anterior chamber collapse. It is necessary to develop an inexpensive diagnostic approach with the characteristics of highly sensitive, short operation duration, and requires small clinical sample quantities. To achieve the main objective of this study, we first prepared bevacizumab to be conjugated with HRP. We then deposited 2μL aqueous humor from patients with different diseases onto each test zone of paper-based 96-well plates. After the colorimetric results were performed via ELISA protocol, the output signals were recorded using a commercial desktop scanner for analysis. In this study, only 2μL from the aqueous humor of each patient was required for paper-based ELISA. The mean aqueous VEGF level was 14.4pg/mL from thirteen patients (N=13) with senile cataract as the control. However, the mean aqueous VEGF level from other patients with proliferative diabetic retinopathy (N=14), age-related macular degeneration (N=17), and retinal vein occlusion (N=10) showed VEGF increases to 740.1pg/mL, 383pg/mL, and 219.4pg/mL, respectively. © 2014 Elsevier Ltd.

Huang S.-M.,National Chung Hsing University | Huang S.-M.,Foundation Medicine | Huang S.-M.,Taichung Tzu Chi Hospital | Huang S.-M.,Tzu Chi University | And 11 more authors.
Endocrine-Related Cancer | Year: 2014

Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated withmalignancy in human colon cancer patients. Themigratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of humanGDNF. The expression of vascular endothelial growth factor (VEGF)was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-inducedcancer cell migrationwas reducedby aVEGFRinhibitor. TheGDNF-inducedVEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 α (HIF1α) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1α by a pharmacological inhibitor or dominant-negative mutant reduced theGDNF-inducedmigratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF-VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1α signaling pathways. © 2014 Society for Endocrinology.

Liao W.-L.,Foundation Medicine | Liao W.-L.,China Medical University at Taichung | Chang T.-P.,Taichung Tzu Chi Hospital | Chen H.-J.,Data Management | And 2 more authors.
Journal of Orthopaedic and Sports Physical Therapy | Year: 2015

STUDY DESIGN: A nationwide, population-based, retrospective cohort study. OBJECTIVES: To investigate whether benign paroxysmal positional vertigo (BPPV) is associated with an increased risk of fracture. BACKGROUND: Benign paroxysmal positional vertigo is a brief rotational vertigo induced by head position change that may increase the risk of falls and, therefore, fracture. METHODS: Data from the Taiwan National Health Insurance Research Database were used for this study. We selected a case cohort comprising 3796 patients aged over 20 years who were newly diagnosed with BPPV between 2000 and 2006. In addition, we randomly selected a control cohort of 15 184 individuals without BPPV. Patients with BPPV were matched to individuals in the control group according to sex, age, and index year. A Cox proportional hazard regression was performed to compute the hazard ratio of fracture, after adjusting for demographic characteristics and comorbidities. RESULTS: The prevalence of comorbidities was higher among patients with BPPV. After adjusting for age, sex, and comorbidities, patients with BPPV exhibited a 1.14-fold (95% confidence interval [CI]: 1.04, 1.25; P<.01) higher risk of fracture than those without BPPV. Trunk fracture (vertebra, rib, and pelvis) was the fracture type with the highest adjusted hazard ratio (1.24; 95% CI: 1.06, 1.45; P<.01) in patients with BPPV relative to those without BPPV. An analysis stratified according to demographic factors revealed that men with BPPV exhibited a 1.43-fold (95% CI: 1.22, 1.66; P<.001) higher risk of fracture. Patients with BPPV aged over 65 years exhibited a significantly higher risk of fracture (adjusted hazard ratio = 1.17; 95% CI: 1.03, 1.33; P<.05) than did those without BPPV. CONCLUSION: Patients with BPPV exhibited a higher risk of fracture than did those without BPPV. Copyright ©2015 Journal of Orthopaedic & Sports Physical Therapy® All rights reserved.

Wu M.-S.,Taichung Tzu Chi Hospital | Su S.-F.,Hungkuang University
Journal of Nursing | Year: 2016

Aging frequently induces degenerative changes in the spine. Patients who suffer from lumbar degenerative disease tend to have lower back pain, neurological claudication, and neuropathy. Furthermore, incontinence may be an increasing issue as symptoms become severe. Lumbar spine fusion surgery is necessary if clinical symptoms continue to worsen or if the patient fails to respond to medication, physical therapy, or alternative treatments. However, this surgical procedure frequently induces adjacent segment disease (ASD), which is evidenced by the appearance of pathological changes in the upper and lower sections of the spinal surgical sites. In 1997, ISOBAR TTL dynamic rod stabilization was developed for application in spinal fusion surgery to prevent ASD-related complications. The device has proven effective in reducing pain in the lower back and legs, decreasing functional disability, improving quality of life, and retarding disc degeneration. However, the effectiveness of this intervention in decreasing the incidence of ASD requires further research investigation, and relevant literature and research in Taiwan is still lacking. This article discusses lumbar degenerative disease, its indications, the contraindications of lumbar spine fusion surgery using ISOBAR, and related postoperative nursing care. We hope this article provides proper and new knowledge to clinical nurses for the care of patients undergoing lumbar spine fusion surgery with ISOBAR.

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