Fe-Lin Lin Wu

Cadherin-11 increases migration and invasion of prostate cancer cells and enhances their interaction with osteoblasts

Cell adhesion molecules have been implicated in the colonization of cancer cells to distant organs. Prostate cancer (PCa) has a propensity to metastasize to bone, and cadherin-11, which is an osteoblast cadherin aberrantly expressed in PCa cells derived from bone metastases, has been shown to play a role in the metastasis of PCa cells to bone. However, the mechanism by which cadherin-11 is involved in this process is not known. Here, we show that expression of cadherin-11 in cadherin-11-negative C4-2B4 cells increases their spreading and intercalation into an osteoblast layer and also stimulates C4-2B4 cell migration and invasiveness. The downregulation of cadherin-11 in cadherin-11-expressing metastatic PC3 cells decreases cell motility and invasiveness. Further, both the juxtamembrane (JMD) and beta-catenin binding domains (CBS) in the cytoplasmic tail of cadherin-11 are required for cell migration and invasion, but not spreading. Gene array analyses showed that several invasion-related genes, including MMP-7 and MMP-15, are upregulated in cadherin-11-expressing, but not in cad11-DeltaJMD-expressing or cad11-DeltaCBS-expressing, C4-2B4 cells. These observations suggest that cadherin-11 not only provides a physical link between PCa cells and osteoblasts but also increases PCa cell motility and invasiveness that may facilitate the metastatic colonization of PCa cells in bone.

Effects of Calcineurin Inhibitors on Sirolimus Pharmacokinetics During Staggered Administration in Renal Transplant Recipients

Study Objective. To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long‐term, staggered administration in kidney transplant recipients.

Recombinant arginine deiminase reduces inducible nitric oxide synthase iNOS-mediated neurotoxicity in a coculture of neurons and microglia.

Modulation of nitric oxide (NO) production is considered a promising approach to therapy of diseases involving excessive inducible nitric oxide synthase (iNOS) expression, such as certain neuronal diseases. Recombinant arginine deiminase (rADI, EC3.5.3.6) catalyzes the conversion of L‐arginine (L‐arg), the sole substrate of NOS for NO production, to L‐citrulline (L‐cit) and ammonia. To understand the effect of the depletion of L‐arg by rADI on NO concentration and neuroprotection, a direct coculture of neuron SHSY5Y cells and microglia BV2 cells treated with lipopolysaccharide (LPS) and interferon‐γ (IFN‐γ) was used as a model of iNOS induction. The results showed that rADI preserved cell viability (4‐fold higher compared with the cells treated with LPS/IFN‐γ only) by the MTT assay, corresponding with the results of neuronal viability by neuron‐specific immunostaining assay. NO production (mean ± SD) decreased from 67.0 ± 1.3 to 19.5 ± 5.5 μM after a 2‐day treatment of rADI by the Griess assay; meanwhile, induction of iNOS protein expression by rADI was observed. In addition, rADI substantially preserved the neuronal function of dopamine uptake in the coculture. The replenishment of L‐arg in the coculture eliminated the neuroprotective and NO‐suppressive effects of rADI in the coculture, indicating that L‐arg played a crucial role in the effects of rADI. These results highlight the important role of L‐arg in the neuron‐microglia coculture in excessive induction of iNOS. Regulation of L‐arg by ADI demonstrated that rADI has a potentially therapeutic role in iNOS‐related neuronal diseases.

Use of Inhaled Corticosteroids in Patients With COPD and the Risk of TB and Influenza: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: The use of inhaled corticosteroids (ICSs) is associated with an increased risk of pneumonia in patients with COPD. However, the risks of other respiratory infections, such as TB and influenza, remain unclear.Methods: Through a comprehensive literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, and ClinicalTrials.gov from inception to July 2013, we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta-analyses by the Peto, Mantel-Haenszel, and Bayesian approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of TB and influenza.Results: Twenty-fi ve trials (22,898 subjects) for TB and 26 trials (23,616 subjects) for influenza were included. Compared with non-ICS treatment, ICS treatment was associated with a significantly higher risk of TB (Peto OR, 2.29; 95% CI, 1.04-5.03) but not influenza (Peto OR, 1.24;95% CI, 0.94-1.63). Results were similar with each meta-analytic approach. Furthermore, the number needed to harm to cause one additional TB event was lower for patients with COPD treated with ICSs in endemic areas than for those in nonendemic areas (909 vs 1,667, respectively).Conclusions: This study raises safety concerns about the risk of TB and influenza associated with ICS use in patients with COPD, which deserve further investigation.

Impact of ezetimibe coadministered with statins on cardiovascular events following acute coronary syndrome: a 3-year population-based retrospective cohort study in Taiwan.

BACKGROUND Conflicting results using the combination of ezetimibe and statins to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS) have been reported. OBJECTIVE The aim of this work was to assess the effectiveness of ezetimibe coadministered with statins in reducing cardiovascular events in patients with ACS. METHODS A retrospective cohort study of patients discharged after hospitalization with ACS was conducted from January 1, 2006, to December 31, 2007, and included those who were prescribed statins alone (n = 37,753) and those who received ezetimibe plus statins (n = 1001) within 365 days after the hospitalization, based on patient data obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. The propensity score method was used to identify a 1:1 matched cohort (n = 2002). Risk of rehospitalization for ACS was analyzed by a multivariable Cox proportional hazards regression model. RESULTS The crude event rate of rehospitalization due to ACS in the original cohort was 13.4 per 100 person-years (268 events) in the combination group and 22.6 per 100 person-years (12,724 events) in the statins-alone group (adjusted hazard ratio [HR] 0.69; 95% CI, 0.62-0.78). The crude event rates of rehospitalization due to ACS in the matched cohort were 13.4 and 20.0 per 100 person-years in the combination group and statins-alone group, respectively (HR 0.62; 95% CI, 0.53-0.73). Compared with statins alone, the adjusted HRs for rehospitalization for percutaneous transluminal coronary angioplasty without stent, with stent, and revascularization for the combination group in the matched cohort were 0.61 (0.50-0.75), 0.62 (0.48-0.81), and 0.62 (0.51-0.76), respectively. CONCLUSIONS Based on the data of Taiwans NHIRD, our findings suggest that patients with ACS on ezetimibe combined with statins had a significantly lower risk of rehospitalization due to ACS, percutaneous transluminal coronary angioplasty, and revascularization than those on statins alone. The generalization of the results is limited because of using claims data of a specific population as the data source.

Statins and the risk of liver injury: a population-based case-control study.

This case‐control study investigated the association between statin use and liver injury using Taiwans National Health Insurance Research Database.

Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Conflicting results have been reported regarding the increased risk of adverse outcomes in the concomitant use of clopidogrel and proton pump inhibitors (PPIs) compared with the use of clopidogrel alone. WHAT THIS STUDY ADDS Our study indicated no statistically significant increase in the risk of rehospitalization for acute coronary syndrome due to concurrent use of clopidogrel and PPIs in an Asian population with higher prevalence of CYP2C19 intermediate and poor metabolizers. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for acute coronary syndrome. AIMS Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel. METHODS We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event. RESULTS The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971-1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066-1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk. CONCLUSIONS Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.

Effects of a National Health Education Program on the Medication Knowledge of the Public in Taiwan

Background: The inappropriate use of medication and inadequate medication knowledge among the general population has long been a concern in Taiwan. One reason for the deficiencies might be the lack of an active role of pharmacists in educating the public. To rectify the situation, in 2002, the Bureau of Pharmaceutical Affairs, Department of Health of Taiwan, began to sponsor a national effort, titled Community Education Program on Medication Use, to involve the expertise of pharmacists in public education. Objective: To evaluate the effects of this education program by analyzing the changes in knowledge of drug therapy among the participating public. Methods: This was a single-group pre- and post-comparison study. Between September 2003 and January 2004, a total of 955 community residents enrolled in the pharmacist-facilitated education program offered at 31 community universities. The medication knowledge of the participants was evaluated before and after the program. Demographic variables that might affect the education outcomes of the program were also examined. Results: Medication knowledge at baseline was positively correlated with education level and negatively correlated with age. Females were more aware of drug-related information than were males. The participants showed a significant improvement in medication knowledge (p < 0.001) at the end of the program. The baseline knowledge score was the most important determinant of the improvement of the posttest score. Conclusions: A national education program facilitated by pharmacists can improve the medication knowledge of the participants. Pharmacists should be encouraged to play a proactive role in large-scale health education programs.

Pharmacokinetics and safety of multiple intravenous doses of daptomycin in a Taiwanese adult population.

Background: The pharmacokinetics (PK) and safety of daptomycin have not yet been studied in an adult Taiwanese population. Methods: A total of 13 healthy adult Taiwanese subjects (7 males and 6 females) were enrolled to receive a 5-day course of multiple intravenous daptomycin infusions at a dose of 4 mg/kg every 24 h. Both single-dose and steady-state serum PK were assessed. Results: PK evaluation showed no relevant accumulation of daptomycin based on the steady-state PK, which could be predicted from the single-dose PK. No gender effect on daptomycin, for either single- or multiple-dose PK, was observed. About 60% of the infused daptomycin was eliminated by the renal system in an unchanged form. Protein binding of daptomycin was about 93.92%. The PK parameters in healthy Taiwanese subjects were similar to those reported in healthy Caucasian subjects. No serious adverse events (AE) or deaths occurred during the study. The most frequently reported AE was leukopenia (3/19, 15.8%), followed by amblyopia (2/19, 10.5%). These AEs were considered to be mild-to-moderate in severity and resolved spontaneously. Conclusion: This study demonstrated similarities between Taiwanese and Caucasian healthy subjects in the PK profiles of daptomycin, and thus the dosage regimen used in Caucasian subjects could be applied to Taiwanese.

Bisphosphonate Use and the Risk of Undergoing Total Knee Arthroplasty in Osteoporotic Patients with Osteoarthritis: A Nationwide Cohort Study in Taiwan

Background: The use of bisphosphonates has been reported to have potential beneficial effects on knee osteoarthritis, but existing studies have limitations. The purpose of this study was to examine the association of bisphosphonate use with the risk of undergoing total knee arthroplasty and with the consumption of pain medication among osteoporotic patients with knee osteoarthritis. Methods: We identified patients who were newly diagnosed with knee osteoarthritis among a cohort of patients with osteoporosis from 2009 to 2012 in the National Health Insurance Research Database in Taiwan. We further categorized these patients into 2 groups: those who were treated with bisphosphonates (bisphosphonate users) and those who were not treated with any anti-osteoporosis drug (nonusers). Bisphosphonate treatment adherence was calculated by the medication possession ratio (MPR) as the proportion of days of bisphosphonate treatment within a fixed duration; an MPR of ≥80% was considered high adherence. The primary and secondary outcomes of interest were undergoing total knee arthroplasty and the use of pain medication, respectively. Analyses using Cox proportional hazard models with propensity-score adjustment were performed to estimate the association between bisphosphonate use and the risk of undergoing total knee arthroplasty. The incremental change in the mean accumulated defined daily doses of pain medications among both bisphosphonate users and nonusers was calculated. Results: We identified 16,276 bisphosphonate users and 123,791 nonusers of any anti-osteoporosis drug among the patients with osteoporosis who were newly diagnosed with osteoarthritis. Bisphosphonate use was significantly associated with a decreased risk of total knee arthroplasty (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69 to 0.83; p < 0.001). In patients with a follow-up period of ≥24 months and an MPR of ≥80%, the effect size was significantly greater (adjusted HR, 0.66; p = 0.048). Over the 5 years of follow-up, we found a significantly greater decrease in the use of pain medication among bisphosphonate users than among nonusers (p < 0.001; Chow test). Conclusions: Among patients with osteoporosis and osteoarthritis, bisphosphonate use was associated with a significantly lower risk of total knee arthroplasty, especially in patients with high adherence and longer treatment duration. A lower consumption of pain medication was also found for bisphosphonate users among the patients with osteoporosis and osteoarthritis. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.