Thiazide-associated hyponatremia increases the risk of major adverse cardiovascular events among elderly Taiwanese patients.

BACKGROUND: Thiazide-associated hyponatremia (TAH) has been supposed to increase the risk of major adverse cardiovascular events (MACE) in the elderly. Therefore, this study aimed to evaluate the association of TAH with the risk of MACE in elderly Taiwanese patients. METHODS: Data from the longitudinal generation tracking database (LGTD 2010) of the Health and Welfare Data Science Center (HWDC) were retrospectively assessed. The TAH study group was defined as using > 30 cumulative daily defined doses (CDDDs) thiazide diuretics within one year before diagnosis of hyponatremia. The control group (1:3 propensity score matching) had no diagnosis of hyponatremia but had used > 30 CDDDs thiazide diuretics within one year. Data on MACE were extracted using International Classification of Diseases codes. Outcomes were assessed using a multivariable Cox proportional hazard model and Kaplan-Meier analysis. RESULTS: A total of 1155 and 3465 individuals were enrolled in the TAH and the control groups, respectively. The rates of MACE (11.1% vs. 7.3%) and death (22.8% vs.12.2%) were significantly higher in the TAH group than the control group. In the TAH group, the adjusted HRs were 1.29 (CI 1.01 ‒ 1.65) for MACE, 1.39 (CI 1.19 ‒ 1.63) for all-cause death, and 1.61 (CI 0.90 ‒ 2.92) for stroke. CONCLUSION: TAH in patients above 65-years-old is associated with a 29% higher risk of MACE, 39% higher risk of all-cause death, and 61% higher risk of stroke. This work suggests that thiazides prescription in elderly patients should be more careful. However, further research is required to confirm our findings.

Isolinderalactone Induces Apoptosis, Autophagy, Cell Cycle Arrest and MAPK Activation through ROS-Mediated Signaling in Colorectal Cancer Cell Lines.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from the root extract of Lindera aggregata, has been reported to exhibit anti-proliferative and anti-metastatic activities in various cancer cell lines. However, the mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation and induced cell cycle G2/M arrest in CRC cells by inhibiting the expression of cyclin B, p-cdc2, and p-cdc25c and up-regulating the expression of p21. In addition, ILL induced mitochondria-associated apoptosis through the up-regulation of cleaved -caspase-9 and -3 expression. ILL induced autophagy by increasing the levels of LC3B in CRC cells, which was partially rescued by treatment with an autophagy inhibitor (chloroquine). Furthermore, ILL increases the accumulation of reactive oxygen species (ROS) and activates the MAPK pathway. Application of the ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited ILL toxicity and reversed ILL-induced apoptosis, cell cycle arrest, autophagy, and ERK activation. Taken together, these results suggest that ILL induces G2/M phase arrest, apoptosis, and autophagy and activates the MAPK pathway via ROS-mediated signaling in human CRC cells.

Association between cirrhosis and herpes zoster in a cohort study in Taiwan.

OBJECTIVES: The aim of the study was to assess if an association exists between cirrhosis and herpes zoster in Taiwan. METHODS: A retrospective cohort study was designed to analyse the 2000-2013 claim dataset of 1 million insured residents who were randomly sampled from the Taiwan National Health Insurance Program. In total, 16 190 subjects aged 20-84 years old with newly diagnosed cirrhosis since 2000 to 2012 were identified as the cirrhosis group and 16 190 sex- and age-matched subjects without cirrhosis were selected as the non-cirrhosis group. Both cirrhosis and non-cirrhosis groups were followed until a new diagnosis of herpes zoster was made or until the end of 2013. The multivariable Cox proportional hazard regression model was applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) for herpes zoster associated with cirrhosis. RESULTS: The incidence rate of herpes zoster was 1.08-fold greater in the cirrhosis group than the non-cirrhosis group (8.33 vs 7.69 per 1000 person-years, 95%CI 1.02-1.15). After adjusting for confounders, the adjusted HR of herpes zoster was 1.11 (95% CI 1.004-1.24) for the cirrhosis group compared with the non-cirrhosis group. The adjusted HR increased to 1.33 (95% CI 1.02-1.74) for the decompensated cirrhosis group compared with the non-cirrhosis group. CONCLUSIONS: Cirrhosis is associated with a small but significant increase in the risk of herpes zoster. Given that the risk of herpes zoster is small and the expense of herpes zoster vaccination is high, whether cirrhotic persons need to be vaccinated should assess the balance of cost and benefit.

The impacts of ambient temperature and ultraviolet radiation on the incidence of herpes zoster: An ecological study in Taiwan.

The aim of the study was to examine the relationship between ambient temperature, ultraviolet radiation, and the development of herpes zoster in Taiwan. An ecological study was conducted to analyse the database of the Taiwan National Health Insurance Programme. Participants aged ≥20 years with newly diagnosed herpes zoster between 2003 and 2012 were selected for analysis. The monthly incidence rate of herpes zoster was measured between 2003 and 2012. Monthly average ambient temperature in Celsius (°C) between 2003 and 2012 was measured according to the official database of the Central Weather Bureau in Taiwan. Monthly accumulated ultraviolet radiation (MJ m-2 ) between 2003 and 2012 was measured according to the official database of the Environmental Protection Administration in Taiwan. The overall incidence rates of herpes zoster ranged from 2.54 to 5.67 per 10 000 persons per month from 2003 to 2012.The monthly average ambient temperature was higher and the monthly accumulated ultraviolet radiation was stronger from May to October. The incidence rates of herpes zoster seemed to be high during the period of high ambient temperature and strong ultraviolet radiation (from May to October).Whenever ambient temperature increased 1°C per month, the incidence rate of herpes zoster increased by 0.072 per 10,000 persons per month. Whenever ultraviolet radiation increased 1 MJ m-2 per month, the incidence rate of herpes zoster increased by 0.313 per 10 000 persons per month. There is a significant association between ambient temperature, ultraviolet radiation, and the development of herpes zoster in Taiwan. The incidence rate of herpes zoster is high during the period of high ambient temperature and strong ultraviolet radiation. Low ambient temperature and weak ultraviolet radiation might be beneficial for the prevention of herpes zoster.

Hispolon Induces Apoptosis, Suppresses Migration and Invasion of Glioblastoma Cells and Inhibits GBM Xenograft Tumor Growth In Vivo.

Hispolon, a polyphenol compound isolated from Phellinus linteus, has been reported to exhibit antioxidant, antiproliferative, and antitumor activities. This study aimed to explore the antitumor effects of hispolon on glioblastoma multiforme (GBM) cells in vitro and in vivo. The results revealed that hispolon significantly inhibited GBM cell proliferation and induced apoptosis through caspase-9 and caspase-3 activation and PARP cleavage. Hispolon also induced cell cycle G2/M phase arrest in GBM cells, as supported by flow cytometry analysis and confirmed by a decrease in cyclin B1, cdc2, and cdc25c protein expressions in a dose- and time-dependent manner. Furthermore, hispolon suppressed the migration and invasion of GBM cells by modulating epithelial-mesenchymal transition (EMT) markers via wound healing, transwell assays, and real-time PCR. Moreover, hispolon significantly reduced tumor growth in DBTRG xenograft mice and activated caspase-3 in hispolon-treated tumors. Thus, our findings revealed that hispolon is a potential candidate for the treatment of GBM.

Risk of herpes zoster among patients with predialysis chronic kidney disease in a cohort study in Taiwan.

BACKGROUND/OBJECTIVE: Patients on chronic dialysis are at risk of developing herpes zoster, but little systematic research focuses on the association between predialysis chronic kidney disease and herpes zoster. The objective of the study was to explore the association between predialysis chronic kidney disease and herpes zoster in Taiwan. METHODS: A nation-based retrospective cohort study was performed using the 2005-2012 database of the Taiwan National Health Insurance Program. There were 16 655 subjects aged 20-84 years with newly diagnosed predialysis chronic kidney disease as the study group and 33 310 randomly selected subjects without chronic kidney disease as the comparison group. Both groups were matched with sex, age, comorbidities and the year of the index date. The incidence rates of herpes zoster in both groups were calculated. The multivariable Cox proportional hazards regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for herpes zoster associated with predialysis chronic kidney disease. RESULTS: The overall incidence rate of herpes zoster was 1.4-fold higher in the predialysis chronic kidney disease group than that in the non-chronic kidney disease group (8.76 vs 6.27 per 1000 person-years, 95% CI 1.27-1.54; P < .001). After controlling for co-variables, the adjusted HR of herpes zoster was 1.38 (95% CI 1.25-1.53; P < .001) for subjects with predialysis chronic kidney disease compared with non-chronic kidney disease subjects. The adjusted HR increased to 1.65 for subjects with predialysis chronic kidney disease and with any comorbidity (95% CI 1.42-1.92; P < .001). CONCLUSIONS: Patients with predialysis chronic kidney disease correlate with approximately 1.4-fold increased hazard of developing herpes zoster.

The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition.

BACKGROUND/AIMS: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. METHODS: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. RESULTS: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. CONCLUSION: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

Tamoxifen usage correlates with increased risk of Parkinson's disease in older women with breast cancer: a case-control study in Taiwan.

BACKGROUND AND OBJECTIVES: Little is known about the association between tamoxifen usage and risk of Parkinson's disease in women with breast cancer. The present study aimed to evaluate the association between tamoxifen usage and Parkinson's disease in older women with breast cancer in Taiwan. METHODS: We conducted a retrospective nationwide case-control study using the database of the Taiwan National Health Insurance Program. In total, 293 female subjects with breast cancer, aged 65 years and above, who were newly diagnosed with Parkinson's disease between 2000 and 2011 were included. Additionally, 1053 female subjects with breast cancer aged 65 years and above without Parkinson's disease were randomly selected as controls. Both cases and controls were matched for age and comorbidities. Ever use of tamoxifen was defined as subjects who had at least a prescription for tamoxifen before the index date, whereas never use of tamoxifen was defined as those who never had a prescription for tamoxifen before the index date. We used the unconditional logistic regression model to calculate the odds ratio (OR) and 95% confidence interval (CI) for the association between tamoxifen usage and risk of Parkinson's disease. RESULTS: After adjusting for confounding variables, the adjusted OR of Parkinson's disease was 3.32 for subjects with ever use of tamoxifen (95% CI, 2.50-4.43), compared with nonusers. Further analysis showed that the adjusted ORs of Parkinson's disease were 3.21 (95% CI, 2.29-4.49), 3.95 (95% CI, 2.77-5.64), and 11.4 (95% CI, 2.63-49.7) for subjects with < 2, 2-6, and ≥ 6 years of cumulative tamoxifen usage, respectively, when compared with nonusers. CONCLUSIONS: Tamoxifen usage was associated with a 3.32-fold increase in the likelihood of having Parkinson's disease among older women with breast cancer in Taiwan.

Using proton pump inhibitors correlates with an increased risk of chronic kidney disease: a nationwide database-derived case-controlled study.

Background: Those taking proton pump inhibitors (PPIs) might have a higher risk of acute kidney injury. The long-term safety, especially the PPI-associated chronic kidney disease (CKD) is the subsequent concern. Objective: This study explores the potential relationship between using PPIs and CKD in Taiwan. Methods: Using a database collated by the Taiwan National Health Insurance programme, we conducted a population-based case-controlled study to identify 16 704 cases of patients aged 20 years or older with newly diagnosed CKD between 2000 and 2013. 16 704 controls were randomly selected and were matched by sex, age and comorbidities. 'Use' of PPIs was defined as when subjects had received at least a prescription for PPIs before the index date. 'Non-use' was defined as subjects who had never received a prescription for PPIs before the index date. The odds ratio (OR) for CKD associated with the use of PPIs was estimated by a logistic regression model. Results: The OR for CKD was 1.41 for subjects using PPIs [95% confidence interval (CI) 1.34, 1.48] compared with subjects who had never used PPIs. Almost all major types of PPIs present a weak association with increased odds of CKD in cumulative duration and dosage regression analysis. The OR in relation to cumulative duration (per month) of PPIs use was 1.02 (95% CI 1.01, 1.02) and the OR in relation to cumulative dosage (per microgram) of PPIs use was 1.23 (95% CI 1.18, 1.28). Conclusions: Using PPIs presented 1.4-fold higher odds of CKD in Taiwan health insurance claims data analysis.

Anti-Tumor and Radiosensitization Effects of N-Butylidenephthalide on Human Breast Cancer Cells.

N-Butylidenephthalide (BP), which is extracted from a traditional Chinese medicine, Radix Angelica Sinensis (danggui), displays antitumor activity against various cancer cell lines. The purpose of this study was to investigate the cytotoxic and radiosensitizing effect of BP and the underlying mechanism of action in human breast cancer cells. BP induces apoptosis in breast cancer cells, which was revealed by the TUNEL assay; the activation of caspase-9 and PARP was detected by western blot. In addition, BP-induced G2/M arrest was examined by flow cytometry and the expression levels of the G2/M regulatory protein were detected by western blot. BP also suppresses the migration and invasion of breast cancer cells, which was tested by wound healing and the matrigel invasion assay; the involvement of EMT-related gene expressions was detected by real-time PCR. Furthermore, BP enhanced the radiosensitivity of breast cancer cells, which was measured by the colony formation assay and comet assay, where the foci of γ-H2AX after radiation significantly increased in BP pretreated cells and was evidenced by immunocytochemistry staining and western blot. The homologous recombination (HR) repair protein Rad51 was down-regulated after BP pretreatment. These results indicate that BP might be a potential chemotherapeutic and radiosensitizing agent for breast cancer therapy.