Publications by authors named "Yi-Hui Wu"

72 Publications

COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells.

Oncogene 2021 Jul 11;40(26):4503-4519. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-β3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-β3 antibody. Human tumors with high TGF-β3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-β3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.
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http://dx.doi.org/10.1038/s41388-021-01865-8DOI Listing
July 2021

Prophylactic clipping after endoscopic mucosal resection of large nonpedunculated colorectal lesions: A meta-analysis.

J Gastroenterol Hepatol 2021 Jul 3;36(7):1778-1787. Epub 2021 Mar 3.

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background And Aim: It is not clear whether prophylactic clipping after endoscopic mucosal resection (EMR) of large nonpedunculated colorectal lesions (LNPCLs) prevents delayed bleeding (DB). We aimed to conduct a meta-analysis to clarify the efficacy of prophylactic clipping in prevention of DB following EMR of LNPCLs.

Methods: We searched PubMed, EMBASE, Web of Science, ScienceDirect, Cochrane Library databases, and ClinicalTrials.gov for studies that compared clipping versus (vs) nonclipping in prevention of DB following EMR of LNPCLs. Pooled odds ratio (OR) was determined using a random effects model. The pooled ORs of DB, perforation, and post-polypectomy syndrome in the clipping group compared with the nonclipping group comprised the outcomes. Subgroup analyses based on study design, polyp location, and completeness of wound closure were performed.

Results: Five studies with a total of 3112 LNPCLs were extracted. Prophylactic clipping reduced the risk of DB compared with nonclipping (3.3% vs 6.2%, OR: 0.494, P = 0.002) following EMR of LNPCLs. In subgroup analysis, prophylactic clipping reduced DB of LNPCLs at proximal location (3.8% vs 9.8%, P = 0.029), but not of them at distal location (P = 0.830). Complete wound closure showed superior efficacy to prevent DB compared with partial closure (2.0% vs 5.4%, P = 0.004). No benefit of clipping for preventing perforation or post-polypectomy syndrome was observed (P = 0.301 and 0.988, respectively).

Conclusions: Prophylactic clipping can reduce DB following EMR of LNPCLs at proximal location. Besides, complete wound closure showed superior efficacy to prevent DB compared with partial closure. Further cost analyses should be conducted to implement the most cost-effective strategies.
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http://dx.doi.org/10.1111/jgh.15472DOI Listing
July 2021

Population Monitoring, Egg Parasitoids, and Genetic Structure of the Invasive Litchi Stink Bug, in Taiwan.

Insects 2020 Oct 12;11(10). Epub 2020 Oct 12.

Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

Here we assessed population dynamics, natural enemy fauna (with emphasis on egg parasitoid), and population genetic structure (based on mitochondrial DNA) of the invasive litchi stink bug (LSB), in Taiwan. Our major findings include: (1) fluctuations of LSB in numbers of adults, mating pairs, and egg masses over a 2-year period in Taiwan generally resemble those in the native populations; (2) and are among the most dominant LSB egg parasitoids, with the former consistently outnumbering the latter throughout Taiwan; (3) the presence of two genetically distinct clades suggests LSB in Taiwan most likely derived from multiple invasions. All these data practically improve our understanding of this invasive insect pest, particularly its ecological and genetic characteristics in the introduced area, which represents critical baseline information for the design of future integrated pest management strategies.
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http://dx.doi.org/10.3390/insects11100690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600713PMC
October 2020

Miniaturized Intracerebral Potential Recorder for Long-Term Local Field Potential of Deep Brain Signals.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5188-5191

A miniaturized intracerebral potential recorder for long-term local field potential (LFP) of deep brain signals is proposed. LFP can be recorded by deep brain electrodes. The abnormal beta-band oscillation of LFP in subthalamic nucleus and internal globus pallidus in patients with Parkinson's disease (PD) are associated with the severity of the symptoms. The LFP signal from patients who have been implanted with deep brain electrode can be monitored by our system for at least 24 hours in real time. Graphical user interface has also been developed for use by medical personnel. Imitation experiments and in vivo experiments were performed to successfully verify that our system can measure LFP signals. With 24-hour intracerebral signals, researchers can analyze what is happened in the brain in daily life. In the future, more effective PD treatment can be developed, such as intelligent closed-loop deep brain stimulation.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175384DOI Listing
July 2020

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment.

Front Pharmacol 2020 3;11:206. Epub 2020 Mar 3.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.
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http://dx.doi.org/10.3389/fphar.2020.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063971PMC
March 2020

Risk of Parkinson's disease among patients with herpes zoster: a nationwide longitudinal study.

CNS Spectr 2020 12 13;25(6):797-802. Epub 2019 Dec 13.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.

Objective: Several studies suggested a potential role of viral infection in the pathophysiology of Parkinson's disease (PD). However, the association between herpes zoster and PD was not investigated well till now.

Methods: Using the Taiwan National Health Insurance Research Database, 13 083 patients aged ≥45 years with herpes zoster and 52 332 (1:4) age-/sex-matched controls were enrolled between 1998 and 2008 and followed to the end of 2011. Those who developed PD during the follow-up period were identified.

Results: The Cox regression analysis with adjustment of demographic characteristics, health system utilization, and comorbidities demonstrated that patients with herpes zoster had an increased risk (hazard ratio [HR]: 1.80, 95% confidence interval [CI]: 1.43-2.28) of developing PD in later life compared to the control group. Sensitivity tests after excluding the first year (HR: 1.50, 95% CI: 1.16-1.93) and first 2-year (HR: 1.44, 95% CI: 1.10-1.88) observation periods showed consistent results.

Conclusions: Patients with herpes zoster were more likely to develop PD in later life compared to the controls. Additional studies are necessary for validating our results and to clarify the underlying pathophysiology between herpes zoster and PD.
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http://dx.doi.org/10.1017/S1092852919001664DOI Listing
December 2020

Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.

Cell Death Dis 2019 04 11;10(4):322. Epub 2019 Apr 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPβ), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.
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http://dx.doi.org/10.1038/s41419-019-1555-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459878PMC
April 2019

Implementation of a national quality improvement program to enhance hand hygiene in nursing homes in Taiwan.

J Microbiol Immunol Infect 2019 Apr 28;52(2):345-351. Epub 2018 Sep 28.

Infection Control Center, Chi-Mei Medical Center, Tainan, Taiwan; Department of Nursing, College of Medicine and Life Sciene, Chung Hwa University of Medical Technology, Tainan, Taiwan. Electronic address:

Background/purpose: This study investigated the cause of hand hygiene deficit, and further implemented a quality improvement program using WHO's hand-hygiene strategy to enhance the compliance of hand hygiene in the nursing home in Taiwan.

Methods: This prospective study was conducted in eleven nursing homes in Taiwan from January 2015 to December 2016. After intervention, we monitor the compliance, and accuracy of hand hygiene. In addition, we also calculated the number of episodes of infection per 1000 resident-days in each nursing home in the intervention period (July-December 2015) and post-intervention period (January-October 2016).

Results: Overall, the consumption of alcohol-based handrubs increased from 10.1 ml per resident-day in intervention period to 12.2 ml per resident-day in post intervention period. The compliance of hand hygiene increased from 74% in intervention period to 79% in post-intervention period and the rate of correct hand hygiene increased from 81% in intervention period to 87% in post-intervention period. Most importantly, the infection density decreased from 2.39 per 1000 resident-day in intervention period to 1.89 per 1000 resident-day.

Conclusions: A national quality-improvement program using WHO's hand-hygiene strategy to enhance hand hygiene and reduce healthcare associated infection is effective in nursing homes in Taiwan.
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http://dx.doi.org/10.1016/j.jmii.2018.09.007DOI Listing
April 2019

Human Clinical-Grade Parthenogenetic ESC-Derived Dopaminergic Neurons Recover Locomotive Defects of Nonhuman Primate Models of Parkinson's Disease.

Stem Cell Reports 2018 07 14;11(1):171-182. Epub 2018 Jun 14.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Stem Cell Bank, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Clinical application of stem cell derivatives requires clinical-grade cells and sufficient preclinical proof of safety and efficacy, preferably in primates. We previously successfully established a clinical-grade human parthenogenetic embryonic stem cell (hPESC) line, but the suitability of its subtype-specific progenies for therapy is not clear. Here, we compared the function of clinical-grade hPESC-derived midbrain dopaminergic (DA) neurons in two canonical protocols in a primate Parkinson's disease (PD) model. We found that the grafts did not form tumors and produced variable but apparent behavioral improvement for at least 24 months in most monkeys in both groups. In addition, a slight DA increase in the striatum correlates with significant functional improvement. These results demonstrated that clinical-grade hPESCs can serve as a reliable source of cells for PD treatment. Our proof-of-concept findings provide preclinical data for China's first ESC-based phase I/IIa clinical study of PD (ClinicalTrials.gov number NCT03119636).
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http://dx.doi.org/10.1016/j.stemcr.2018.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067059PMC
July 2018

Cognitive Frailty and Its Association with All-Cause Mortality Among Community-Dwelling Older Adults in Taiwan: Results from I-Lan Longitudinal Aging Study.

Rejuvenation Res 2018 Dec;21(6):510-517

1 Aging and Health Research Center, National Yang Ming University, Taipei, Taiwan.

The definition of cognitive frailty and its prediction for adverse outcome of community-living older adults remains controversial. This study aims to evaluate the association between cognitive frailty and all-cause mortality among community-living older adults. Data of the I-Lan Longitudinal Aging Study (ILAS) were retrieved for study. Frailty was defined by Fried's criteria, and a series of neuropsychological assessments, including the Mini-Mental State Examination, Center for Epidemiology Studies-Depression, the delayed free recall in the Chinese Version Verbal Learning Test, the Boston Naming Test, the category (animal) Verbal Fluency Test, the Taylor Complex Figure Test, the digital backward, and the Clock Drawing Test were performed. All participants received blood sampling after 10-hour overnight fast for various biochemical markers. Cognitive frailty was defined as the concomitant presence of dynapenia and cognitive declines in any domains. Overall, data of 678 participants aged 65 years and older (mean age: 73.3 ± 5.3 years) were obtained for the study. The prevalence of cognitive frailty in this study was 13.3%. People with cognitive frailty were significantly older, having higher multimorbidity burden, more likely to be women, and had less skeletal muscle mass. Adjusted for age and gender, both dynapenia without cognitive impairment (hazard ratio [HR]: 5.402; 95% confidence interval [CI]: 1.463-19.954; p = 0.011) and cognitive frailty (HR: 6.682; 95% CI: 1.803-26.116; p = 0.005) were significantly associated with all-cause mortality. The prevalence of cognitive frailty was 13.3% in Taiwan and was predictive for all-cause mortality. Further study is needed to explore the pathophysiology and reversibility of cognitive frailty.
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http://dx.doi.org/10.1089/rej.2017.2038DOI Listing
December 2018

Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription.

Clin Cancer Res 2018 07 23;24(13):3217-3228. Epub 2018 Feb 23.

Department of Obstetrics & Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. and investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor-binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A NF-κB p65-binding site in the promoter was identified as a major determinant of DBP-dependent promoter activation. This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2943DOI Listing
July 2018

FNIH-defined Sarcopenia Predicts Adverse Outcomes Among Community-Dwelling Older People in Taiwan: Results From I-Lan Longitudinal Aging Study.

J Gerontol A Biol Sci Med Sci 2018 05;73(6):828-834

Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taiwan.

Background: To evaluate the predictive validity of sarcopenia defined by the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project among Asian older adults.

Methods: Data of the I-Lan Longitudinal Aging Study were obtained for analysis. Overall, 1,839 community-dwelling people aged 50 years and older, capable of completing a 6-m walk, with life expectancy of more than 6 months, and not institutionalized at time of data collection were enrolled for study. Data for subjects aged 65 years and older were obtained for study. The outcome measures were all-cause mortality and a composite adverse outcome which includes hospitalizations, emergency department visits, institutionalization, and falls.

Results: Data of 728 eligible elderly participants (73.4 ± 5.4 years; 52.9% males) were analyzed. The prevalence of FNIH-diagnosed sarcopenia was 9.5%: 11.9% males; 6.7% females. Participants having FNIH-defined sarcopenia were considerably older, frailer, more obese, with poorer physical performance than nonsarcopenic subjects (All p < .001); during mean follow-up of 32.9 ± 8.8 months, they also had 3.8 times higher risk of dying, independent of age, sex, multimorbidity, cognitive function, and nutritional status (hazard ratio = 3.8; 95% confidence interval = 1.26-11.45; p = .018). Moreover, sarcopenia defined by grip strength-BMI ratio (WeakBMI) showed stronger association with composite adverse outcomes than traditional handgrip strength (hazard ratio = 1.99; 95% confidence interval = 1.01-3.93; p = .047 vs hazard ratio = 1.80; 95% confidence interval = 0.89-3.62; p = .102 in fully-adjusted model).

Conclusion: Among community-dwelling older people in Taiwan, participants with FNIH-defined sarcopenia had a significantly greater risk of all-cause mortality and composite falls, emergency department visits, institutionalization, and hospitalization.
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http://dx.doi.org/10.1093/gerona/glx148DOI Listing
May 2018

Enhanced Fano resonance in a non-adiabatic tapered fiber coupled with a microresonator.

Opt Lett 2017 Aug;42(15):2956-2959

We achieved enhanced Fano resonance by coupling a bottle resonator with a special non-adiabatic tapered fiber, where there is a high intensity distribution ratio between high-order and fundamental modes in the tapered region, as well as single mode propagation in the waist region. The resonance line shape is theoretically proved to be related to the intensity distribution ratio of the two fiber modes and their phase shift. An enhanced Fano line shape with an extinction ratio over 15 dB is experimentally reached by improving the intensity distribution ratio and tuning the phase shift. The results can remarkably improve the sensitivity of whispering-gallery mode microresonators in the field of optical sensing.
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http://dx.doi.org/10.1364/OL.42.002956DOI Listing
August 2017

Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF-κB-mediated IKKβ expression.

Int J Cancer 2017 12 30;141(11):2305-2317. Epub 2017 Aug 30.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

We have shown that collagen type XI alpha 1 (COL11A1) promotes ovarian cancer progression and is associated with chemoresistance to cisplatin and paclitaxel in ovarian cancer cells. Here, we demonstrate how COL11A1 regulates twist family basic helix-loop-helix transcription factor 1-related protein 1 (TWIST1) to induce chemoresistance and inhibit apoptosis in ovarian cancer cells. Small interfering RNA-mediated reduction in COL11A1 protein levels increased the chemosensitivity to cisplatin and paclitaxel via downregulated TWIST1 expression. TWIST1 messenger RNA levels positively associated with COL11A1 messenger RNA expression levels in ovarian tumors. High TWIST1 expression levels were significantly associated with a progression-free interval of ≤ 6 months (p = 0.001) and death (p = 0.040). In addition, patients with high TWIST1 mRNA levels had significantly shorter 5-year overall-survival (p = 0.004) and progression-free survival (p = 0.009) rates, compared to patients with low TWIST1 levels. Increased TWIST1 expression caused by COL11A1-induced transcription of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) gene occurred via increased SP1 phosphorylation and binding to the IKKβ promoter. COL11A1-mediated nuclear factor-kappa B activation, via transcriptional activation of IKKβ, promoted TWIST1, Mcl-1, and GAS6 expression, which were associated with chemoresistance and anti-apoptosis in ovarian cancer cells. We suggest that IKKβ and TWIST1 can potentially be targeted in patients with COL11A1-positive ovarian cancer.
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http://dx.doi.org/10.1002/ijc.30932DOI Listing
December 2017

Association between using medications with anticholinergic properties and short-term cognitive decline among older men: A retrospective cohort study in Taiwan.

Geriatr Gerontol Int 2017 Apr;17 Suppl 1:57-64

Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan.

Aim: The use of anticholinergic drugs had been strongly linked to adverse health outcomes among older adults, especially in cognitive impairment or dementia. The present study aimed to evaluate the cognitive decline related to the use of anticholinergic drugs among older men living in the veterans' homes in Taiwan.

Methods: This retrospective cohort study was a substudy of The Longitudinal Older Veterans study. A total of 274 residents living in four Taiwan veterans' homes and receiving two consecutive Mini-Mental State Examinations within the interval of 6 months from January 2012 to December 2014 were enrolled in the present study. The medication lists for all participants were reviewed by the same physician, and the anticholinergic properties of the individual medications were evaluated by using the Anticholinergic Cognitive Burden scale. Cognitive decline was defined as the decrease of Mini-Mental State Examinations scores during the study period.

Results: Overall, 139 persons (50.7%) had exposure to anticholinergic drugs at baseline (designated as AC[+]), and the most frequently used anticholinergic drugs were cardiovascular drugs (48.2%), antipsychotics (21.6%), theophylline (20.1%), antidepressants (12.2%), gastrointestinal drugs (11.5%) and antihistamines (8.6%). After adjusting for covariates, AC(+) participants had a significantly higher risk for short-term cognitive decline (OR 2.69, 95% CI 1.36-5.31). After excluding 30 participants using antipsychotics, non-antipsychotics AC(+)participants still had a significantly higher risk for short-term cognitive decline (OR 2.24, 95% CI 1.26-3.99).

Conclusions: Exposure to anticholinergic drugs significantly increased the risk for short-term cognitive decline among older men, and the adverse effects remained similar when antipsychotics were excluded for analysis. A further intervention study is required to evaluate whether reducing anticholinergic burden might improve cognitive function among older adults. Geriatr Gerontol Int 2017: 17 (Suppl. 1): 57-64.
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http://dx.doi.org/10.1111/ggi.13032DOI Listing
April 2017

Predictive factors for dementia and cognitive impairment among residents living in the veterans' retirement communities in Taiwan: Implications for cognitive health promotion activities.

Geriatr Gerontol Int 2017 Apr;17 Suppl 1:7-13

Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan.

Aim: To identify potentially modifiable risk factors for cognitive decline among veterans' home residents in Taiwan METHODS: The present retrospective cohort study was part of the Veteran Affairs-Comprehensive Geriatric Assessment study that retrieved data of the comprehensive geriatric assessment for 946 residents living at four veterans' homes in Taiwan. The study participants were interviewed every 3-6 months from January 2012 and December 2014. Demographic characteristics,multimorbidity by Charlson's Comorbidities Index, physical function by the Barthel Index, cognition by the Mini-Mental State Examination (MMSE), depression by the five-item Geriatric Depression Scale and nutritional status by the Mini-Nutrition Assessment-Short Form were collected for analysis. A generalized estimating equation model was used after it was adjusted for age, educational level, five-item Geriatric Depression Scale, and problem of communication difficulty to identify potential modifiable risk factors for cognitive decline.

Results: The mean age of the participants was 85.7 ± 5.2 years, with a mean follow-up period of 41 ± 21.6 weeks. The prevalence of cognitive impairment (defined by MMSE <24) was 65.6%, whereas 34% of the study participants were positive for depressive symptoms. Approximately one-fifth of the study participants were using psychotropic agents, which was higher among participants with cognitive impairment (23.6% vs 15.6%, P < 0.05) than those without. In the generalized estimating equation model, physical function, nutritional status, depressive symptoms, ex-drinker, multimorbidity and stool incontinence were positively correlated with MMSE score; whereas advanced age, low educational level (<6 years), presence of communication difficulty and use of psychotropic agents were inversely associated with the MMSE score.

Conclusions: Physical function and nutritional status were positively associated with the MMSE score, and use of psychotropic agents was negatively correlated with cognitive function. Further intervention study is required to improve the cognitive health of older adults living in the veterans' retirement communities. Geriatr Gerontol Int 2017: 17 (Suppl. 1): 7-13.
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http://dx.doi.org/10.1111/ggi.13039DOI Listing
April 2017

Association Among Serum Insulin-Like Growth Factor-1, Frailty, Muscle Mass, Bone Mineral Density, and Physical Performance Among Community-Dwelling Middle-Aged and Older Adults in Taiwan.

Rejuvenation Res 2018 Jun 9;21(3):270-277. Epub 2017 May 9.

1 Aging and Health Research Center, National Yang-Ming University , Taipei, Taiwan .

Aging is featured by the complex interrelationship among body composition, frailty status, and physical performance. The main aim of this study was to evaluate the association among serum insulin-like growth factor-1 (IGF-1), body composition, and physical function among community-dwelling middle-aged and elderly population in Taiwan. We conducted a cross-sectional study by using the data of I-Lan Longitudinal Aging Study, which recruited a total of 1833 community-dwelling people aged more than 50 years. Data of lean body mass (LBM), appendicular skeletal muscle mass (ASM), total fat mass (TFM), bone mineral density (BMD) of L-spine/hip, handgrip strength, walking speed, International Physical Activity Questionnaire (IPAQ), Charlson comorbidity index (CCI), serum levels of growth hormone, IGF-1, albumin, total cholesterol, triglyceride, blood urea nitrogen, and creatinine were retrieved for analysis. The mean age of participants was 63.9 ± 9.2 years, and 47.5% were men. The serum IGF-1 level was 140.7 ± 57.6 ng/mL in men and 131.4 ± 54.5 ng/mL in women. The estimated rates of IGF-1 decline with age were 1.88 ng/mL·year in men and 2.13 ng/mL·year in women. The prevalence of frailty was 6.8% and that of prefrailty was 40.4%. After adjusting for age, albumin, IPAQ, and CCI in multiple linear regression models, LogIGF-1 was positively correlated with LBM, ASM, ASM index, height, BMD, and handgrip strength, and was inversely correlated with weakness in both genders. In men, the LogIGF-1 level was positively correlated with weight, body mass index (BMI), waist circumference, and TFM. Higher serum IGF-1 was independently associated with more muscle mass, higher BMD, and better handgrip performance in both genders. The positive association of IGF-1 with BMI, weight, TFM, and waist circumference was found in men only. Further longitudinal study to evaluate the effect of serum IGF-1 on frailty incidence is needed for its causal-effect relationship.
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http://dx.doi.org/10.1089/rej.2016.1882DOI Listing
June 2018

Risk of Epilepsy in Individuals With Posttraumatic Stress Disorder: A Nationwide Longitudinal Study.

Psychosom Med 2017 Jul/Aug;79(6):664-669

From the Department of Psychiatry (Y.-H. Chen, Wei, Bai, Hsu, Huang, Su, Li, Lin, Tsai, M.-H. Chen), Taipei Veterans General Hospital; Division of Psychiatry (Bai, Hsu, Huang, Su, Li, Lin, Tsai, M.-H. Chen), School of Medicine, National Yang-Ming University; Department of Family Medicine (T.-J. Chen), Taipei Veterans General Hospital; Institute of Hospital and Health Care Administration (T.-J. Chen), National Yang-Ming University; Department of Neurology (Wu), and Center for Geriatrics and Gerontology (Wu), Taipei Veterans General Hospital, Taipei; School of Traditional Chinese Medicine (Pan), Chang Gung University; Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety (Pan), College of Human Ecology, Chang Gung University of Science and Technology; Liver Research Center (Pan), Chang Gung Memorial Hospital, Taoyuan; and Division of Psychiatry (Wei), Kunming Branch, Taipei City Hospital, Taipei, Taiwan.

Objective: Several cross-sectional studies have reported a relationship between posttraumatic stress disorder (PTSD) and epilepsy. However, the temporal association between PTSD and epilepsy has rarely been investigated. We hypothesized that the risk of developing epilepsy later in life would be higher in patients with PTSD than in those without PTSD.

Methods: Using the Taiwan National Health Insurance Research Database, 6425 individuals with PTSD and 24,980 age-/sex-matched controls were enrolled between 2002 and 2009 in our study and followed up to the end of 2011. Those who developed epilepsy during the follow-up period were identified.

Results: Individuals with PTSD had a higher incidence of developing epilepsy (2.65 versus 0.33 per 1000 person-years, p < .001), with an earlier onset of epilepsy (37.53 years [15.80 years] versus 48.11 years [23.97 years], p = .002) than did the controls. Individuals with PTSD had an elevated risk of developing epilepsy (hazard ratio [HR] = 3.72, 95% confidence interval [CI] = 2.27-6.11) during the follow-up after adjustment for demographic data and medical and psychiatric comorbidities. Sensitivity analyses after excluding the observation in the first year (HR = 2.53, 95% CI = 1.44-4.47) and the first 3 years (HR = 2.14, 95% CI = 1.15-4.01) revealed consistent results.

Conclusions: These results supported a temporal association between PTSD and the development of epilepsy. Further studies are warranted to investigate the underlying pathophysiological pathways that explain the longitudinal association of PTSD with subsequent epilepsy.
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http://dx.doi.org/10.1097/PSY.0000000000000463DOI Listing
April 2018

Predominance of Clostridium difficile Ribotypes 017 and 078 among Toxigenic Clinical Isolates in Southern Taiwan.

PLoS One 2016 18;11(11):e0166159. Epub 2016 Nov 18.

Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.

Ribotypes and toxin genotypes of clinical C. difficile isolates in Taiwan are rarely reported. A prospective surveillance study from January 2011 to January 2013 was conducted at the medical wards of a district hospital in southern Taiwan. Of the first toxigenic isolates from 120 patients, 68 (56.7%) of 120 isolates possessed both tcdA and tcdB. Of 52 (43.3%) with tcdB and truncated tcdA (tcdA-/tcdB+), all were ribotype 017 and none had binary toxin or tcdC deletion. Eighteen (15%) toxigenic isolates harbored binary toxins (cdtA and cdtB) and all had tcdC deletion, including Δ39 (C184T) deletion (14 isolates), Δ18 in-frame deletion (3 isolates), and Δ18 (Δ117A) deletion (1 isolate). Eleven of 14 isolates with Δ39 (C184T) deletion belonged to the ribotype 078 family, including ribotype 127 (6 isolates), ribotype 126 (4 isolates), and ribotype 078 (1 isolate). Among 8 patients with consecutive C. difficile isolates, these isolates from 6 (75%) patients were identical, irrespective of the presence or absence of diarrhea, suggestive of persistent fecal carriage or colonization. In conclusion in southern Taiwan, ribotype 017 isolates with a tcdA-/tcdB+ genotype were not uncommon and of C. difficile isolates with binary toxin, the ribotype 078 family was predominant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115699PMC
June 2017

[Application of the Peak Area Ratio of STR Loci to Amelogenin Locus in the Estimation of DNA Degradation].

Fa Yi Xue Za Zhi 2016 Apr;32(2):105-8

Objective: To explore the change rules of peak area ratio of STR loci to Amelogenin (AMEL) locus (STR/AMEL), a sex-determining gene in DNA degradation, and to evaluate the application of STR/AMEL value in the estimation of DNA degradation degree.

Methods: DNA was extracted from iliopsoas, and the variations of STR/AMEL value (Penta E/AMEL, Penta D/AMEL, FGA/AMEL) were analyzed after the artificial degradation was made by DNase I, and the changes of these three ratios of the iliopsoas naturally degraded in an outdoor environment were also analyzed. The regression curves were analyzed using the periods of DNA degradation and outside the body as the independent variable (x) and the STR/AMEL value as the dependent variable (y) and three curve equations under two conditions were established.

Results: Both under the conditions of artificial and natural degradation, STR/AMEL value had a negative relationship with the degradation time. The relationship between STR/AMEL and degradation time can be well simulated by the cubic function. R2 was over 0.99 under controlled degradation condition and over 0.86 under natural degradation condition.

Conclusion: The STR/AMEL value (Penta E/AMEL, Penta D/AMEL, FGA/AMEL) is negatively related with the DNA degradation degree, which follows mathematical regression models strictly, and it might be applied to evaluate the DNA degradation degree.
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April 2016

A study of medical device regulation management model in Asia.

Expert Rev Med Devices 2016 Jun;13(6):533-43

b Division of Medical Devices and Cosmetics , Ministry of Health and Welfare , Taipei , Taiwan.

Introduction: With the aging of the post-war baby boomer generation, the increasing demands for healthcare are driving the growth of medical industry and development of new products in order to meet the immense needs from the aging population. However, medical devices are designed to maintain the health and safety of people, therefore, medical devices are undergoing rigorous management by competent health authorities in all countries. In recent years, Asian countries have been reforming their regulations and standards for medical devices with substantial changes.

Areas Covered: The study is a summary of the framework of medical device regulations in Asian countries, including Asian Harmonization Working Party (AHWP), Japan, China, Taiwan, South Korea, India and Singapore. Expert commentary: Asian countries are constantly reforming their medical device regulations. The emergence of brand-new technology and quality management issues arose by global manufacturing have imposed difficulties in harmonizing and reaching consensus between countries. The third-party conformity assessment system for medical devices can reduce the costs for competent health authorities and shorten the review time, which could facilitate the feasibility of harmonization of medical device regulations.
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http://dx.doi.org/10.1080/17434440.2016.1184970DOI Listing
June 2016

Coupled-mode induced transparency in a bottle whispering-gallery-mode resonator.

Opt Lett 2016 Apr;41(8):1825-8

Whispering-gallery-mode (WGM) optical resonators are ideal systems for achieving electromagnetically induced transparency-like phenomenon. Here, we experimentally demonstrate that one or more transparent windows can be achieved with coupled-mode induced transparency (CMIT) in a single bottle WGM resonator due to the bottle's dense mode spectra and tunable resonant frequencies. This device offers an approach for multi-channel all-optical switching devices and sensitivity-enhanced WGM-based sensors.
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http://dx.doi.org/10.1364/OL.41.001825DOI Listing
April 2016

Encoded error calibration for a coded aperture spectrometer based on deconvolution.

Appl Opt 2016 Feb;55(6):1500-6

The principle of a 2D coded aperture spectrometer is described in this paper. The crosstalk of adjacent rows, which is caused by the optical system's point-spread function and the nonuniform illumination of the apertures, is the main source of the system decoded errors. Through the analysis of the effect of the crosstalk and nonuniform illumination on the decoded spectrum, the encoding matrix is modified. Based on the new encoding equation, an algorithm using Gold's deconvolution method is proposed to remove the crosstalk of adjacent rows. In the end, we evaluate the effect of this method through a series of contrast experiments.
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http://dx.doi.org/10.1364/AO.55.001500DOI Listing
February 2016

Antimicrobial susceptibility of clinical Enterobacteriaceae isolates at the emergency department in a regional hospital: A threat of extended spectrum beta-lactamase-producers among nursing home residents.

J Microbiol Immunol Infect 2016 Aug 19;49(4):584-90. Epub 2015 Nov 19.

Department of Internal Medicine, National Cheng Kung University Hospital and Medical Colleague, Tainan, Taiwan. Electronic address:

Background/purpose: The prevalence of extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in nursing home residents has rarely been reported in Taiwan.

Methods: A retrospective study was performed at medical wards of a district hospital at southern Taiwan between July 2009 and June 2011. Patients were included if they were older than 18 years, admitted via the emergency department, and their blood, sputum, or urine culture revealed the growth of Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis. From each patient only the first isolate from the infection site was included. Antimicrobial susceptibility was determined using the disc diffusion method.

Results: Overall, 827 patients were included, with 354 (42.8%) coming from the community and 473 (57.2%) referred from a nursing home. Of the isolates acquired in nursing home, 45.5% (215/473) harbored ESBL. By contrast, 20.6% (73) of 354 isolates acquired in the community exhibited the ESBL production phenotype (p < 0.001). Of the isolates obtained from blood, urine, or sputum, 28.2% (37/131), 36.0% (208/578), or 36.4% (43/118) harbored ESBL, respectively, whereas 41% (211) of 515 E. coli isolates, 34.3% (72) of 210 K. pneumoniae, and 4.9% (5) of 102 P. mirabilis had ESBL. In general, the isolates from a nursing home or those with ESBL had lower antimicrobial susceptibility rates than those from the community or those without ESBL production. Only amikacin, piperacillin/tazobactam, ertapenem, and imipenem/meropenem were active against >90% Enterobacteriaceae isolates, irrespective of ESBL production.

Conclusion: ESBL production was common among clinical Enterobacteriaceae isolates, especially E. coli or those isolated from nursing home residents.
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http://dx.doi.org/10.1016/j.jmii.2015.10.001DOI Listing
August 2016

Analysis of thermo-optic effect-based refractive index dynamic modulation in microspherical resonator.

Appl Opt 2015 Oct;54(28):8363-8

The thermo-optic effect has been utilized to modulate the refractive index dynamically within a whispering gallery mode resonator. Modulation with a large tuning range is mostly performed for mode locking and dynamic control of the optical path at a modulation frequency as low as several hertz, while high-frequency modulation up to megahertz is mainly exploited in optical switching devices with small tuning range. Here, we introduce the response functions theoretically to describe the dynamic response of temperature changes in the mode volume and the resonator body, respectively. This result is verified experimentally in silica microspherical resonators. The dependence of the tuning range on the modulation frequency is achieved. This knowledge could pave the way toward more practical control of refractive index in microresonators.
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http://dx.doi.org/10.1364/AO.54.008363DOI Listing
October 2015

Factors Associated with Blood Culture Contamination in the Emergency Department: Critical Illness, End-Stage Renal Disease, and Old Age.

PLoS One 2015 8;10(10):e0137653. Epub 2015 Oct 8.

Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Blood culture contamination in emergency departments (ED) that experience a high volume of patients has negative impacts on optimal patient care. It is therefore important to identify risk factors associated with blood culture contamination in EDs.

Methodology/principal Findings: A prospectively observational study in a university-affiliated hospital were conducted between August 2011 and December 2012. Positive monomicrobial and negative blood cultures drawn from adult patients in the ED were analyzed to evaluate the possible risk factors for contamination. A total of 1,148 positive monomicrobial cases, 391 contamination cases, and 13,689 cases of negative blood culture were identified. Compared to patients with negative blood cultures, patients in triage levels 1 and 2 (Incidence Rate Ratio, IRR = 2.24), patients with end-stage renal disease (ESRD) (IRR = 2.05), and older patients (IRR: 1.02 per year) were more likely to be associated with ED blood culture contamination.

Conclusions/significance: Critical patients (triage levels 1 and 2), ESRD patients, and older patients were more commonly associated with blood culture contamination in the ED. Further studies to evaluate whether the characteristics of skin commensals contribute to blood culture contamination is warranted, especially in hospitals populated with high-risk patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598129PMC
June 2016

Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells.

J Cancer 2015 22;6(10):1011-9. Epub 2015 Aug 22.

1. Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan.

Solanum incanum extract (SR-T100), containing the active ingredient solamargine, can induce apoptosis via upregulation of tumor necrosis factor receptor expression and activation of the mitochondrial apoptosis pathway, and has therapeutic effects in patients with actinic keratosis. Here, we evaluate the novel molecular mechanisms underlying SR-T100-regulated stemness and chemoresistance. The concentration of SR-T100 that inhibited 50% cell viability (IC50) was lower in ovarian cancer cells than in nonmalignant cells. Furthermore, the SR-T100 IC50 in chemoresistant cells was similar to the IC50 in chemosensitive cells. Additionally, SR-T100 increased cisplatin and paclitaxel sensitivity in chemoresistant cells. SR-T100 downregulated the expression of stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), Notch1, and FoxM1, and reduced sphere formation in ovarian cancer cells. Using microarray analyses, immunoblotting, luciferase activity, and chromatin immunoprecipitation (ChIP) assays, we showed that SR-T100 suppressed the expression of c/EBPβ and COL11A1, and its promoter activity, in resistant cells, but not sensitive cells. SR-T100, paclitaxel, and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, as compared to the vehicle control, and the combination of cisplatin and SR-T100 was more effective than either treatment alone. SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment.
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http://dx.doi.org/10.7150/jca.12738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565851PMC
September 2015

Cognitive Function in Individuals With Physical Frailty but Without Dementia or Cognitive Complaints: Results From the I-Lan Longitudinal Aging Study.

J Am Med Dir Assoc 2015 Oct 28;16(10):899.e9-16. Epub 2015 Aug 28.

Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan; Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan; Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Objective: To investigate if understated cognitive impairment existed in individuals with physical frail or earlier prefrail state but without cognitive complaints and the susceptible cognitive domains to the physical frailty.

Design: A cross-sectional population-based community study.

Setting: I-Lan County of Taiwan.

Participants: A total of 1839 community residents aged 50 years or older in the I-Lan Longitudinal Aging Study.

Intervention: None.

Measurements: Frail status assessments by the Cardiovascular Health Study (CHS) criteria and a series of neuropsychiatric assessments, including the Mini-Mental State Examination (MMSE), the delay free recall in the Chinese Version Verbal Learning Test (CVVLT), the Boston Naming Test (BNT), the category (animal) Verbal Fluency Test (VFT), the Taylor Complex Figure Test (CFT), the digital backward (DB), and the Clock Drawing Test.

Results: After excluding those with significant global cognitive impairment, subjective cognitive complaints, or functional impairment, 1686 persons aged 50 to 89 years (mean 63.4 ± 8.9) were enrolled. The prevalence of prefrail and frail individuals was 40.2% and 4.9%, respectively. The prefrail and frail persons had significantly poorer performance in the MMSE and all neuropsychological tests. Slowness and weakness were the most significant frailty components associated with cognitive impairment. The prefrail and frail individuals showed a more dose-dependent risk for 1 or more cognitive domain impairments than the robust individuals (odds ratio [OR] 1.28 in prefrail individuals versus OR 1.79 in frail individuals). The susceptible cognitive domains in the prefrail state were mainly focused on the nonmemory domains. However, the frail individuals were more likely to have risks for impairment in both memory and nonmemory domains.

Conclusions: Even without subjective cognitive complaints, higher risk of cognitive impairment is presented in the prefrail and frail individuals. The incremental impact of frailty on cognition and the susceptibility of nonmemory domain may provide a new view in evaluating the pathogenesis of the relationship between frailty and cognitive impairment.
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http://dx.doi.org/10.1016/j.jamda.2015.07.013DOI Listing
October 2015

COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization.

Oncotarget 2015 Sep;6(27):23748-63

Department of Obstetrics and Gynaecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan.

Chemoresistance to anticancer drugs substantially reduces survival in epithelial ovarian carcinoma (EOC). Here, microarray analysis showed that collagen type XI alpha 1 (COL11A1) is a chemotherapy response-associated gene. Chemoresistant cells expressed higher COL11A1 and c/EBPβ than chemosensitive cells. COL11A1 or c/EBPβ downregulation suppressed chemoresistance, whereas COL11A1 overexpression attenuated sensitivity to cisplatin and paclitaxel.The c/EBPβ binding site in the COL11A1 promoter was identified as the major determinant of cisplatin- and paclitaxel-induced COL11A1 expression. Immunoprecipitation and immunofluorescence showed that in resistant cells, Akt and PDK1 were highly expressed and that anticancer drugs enhanced binding activity between COL11A1 and PDK1 binding and attenuated PDK1 ubiquitination and degradation. Conversely, chemosensitive cells showed decreased activity of COL11A1 binding to PDK1 and increased PDK1 ubiquitination, which were reversed by COL11A1 overexpression. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and clinical outcome.
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http://dx.doi.org/10.18632/oncotarget.4250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695149PMC
September 2015

All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells.

Carcinogenesis 2015 Apr 5;36(4):498-507. Epub 2015 Mar 5.

Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 704, Taiwan

Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all-trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells.
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http://dx.doi.org/10.1093/carcin/bgv018DOI Listing
April 2015
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