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.

Potential therapeutic effects of N-butylidenephthalide from Radix Angelica Sinensis (Danggui) in human bladder cancer cells.

BACKGROUND: N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. The effect of BP in bladder cancer treatment is still unclear and worth for further investigate. METHODS: Changes of patients with bladder cancer after Angelica Sinensis exposure were evaluated by analysis of Taiwan's National Health Insurance Research Database (NHIRD) database. The anti-proliferative effect of BP on human bladder cancer cells was investigated and their cell cycle profiles after BP treatment were determined by flow cytometry. BP-induced apoptosis was demonstrated by Annexin V-FITC staining and TUNEL assay, while the expressions of apoptosis-related proteins were determined by western blot. The migration inhibitory effect of BP on human bladder cancer cells were shown by trans-well and wound healing assays. Tumor model in NOD-SCID mice were induced by injection of BFTC human bladder cancer cells. RESULTS: The correlation of taking Angelica sinensis and the incidence of bladder cancer in NHIRD imply that this herbal product is worth for further investigation. BP caused bladder cancer cell death in a time- and dose- dependent manner and induced apoptosis via the activation of caspase-9 and caspase-3. BP also suppressed the migration of bladder cancer cells as revealed by the trans-well and wound healing assays. Up-regulation of E-cadherin and down-regulation of N-cadherin were evidenced by real-time RT-PCR analysis after BP treatment in vitro. Besides, in combination with BP, the sensitivity of these bladder cancer cells to cisplatin increased significantly. BP also suppressed BFTC xenograft tumor growth, and caused 44.2% reduction of tumor volume after treatment for 26 days. CONCLUSIONS: BP caused bladder cancer cell death through activation of mitochondria-intrinsic pathway. BP also suppressed the migration and invasion of these cells, probably by modulating EMT-related genes. Furthermore, combination therapy of BP with a lower dose of cisplatin significantly inhibited the growth of these bladder cancer cell lines. The incidence of bladder cancer decreased in patients who were exposed to Angelica sinensis, suggesting that BP could serve as a potential adjuvant in bladder cancer therapy regimen.

5-alpha-reductase inhibitors and the risk of diabetes mellitus: A nationwide population-based study.

BACKGROUND: This nationwide population-based study investigated the risk of type 2 diabetes mellitus (DM) after 5-alpha-reductase inhibitor (5ARI) therapy for benign prostate hyperplasia (BPH) using the National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: In total, 1,298 adult patients newly diagnosed with BPH and who used more than 28 cumulative defined daily doses (cDDD) of 5ARI were recruited as the therapy group cohort, along with 1,2887 subjects who did not use more than 28 cDDD of 5ARI as a control group from 2002 to 2009. Each patient was monitored for 5 years (from 2003 to 2008) to identify those who subsequently developed type 2 DM. A Cox proportional hazards model was used to compare the risk of type 2 DM between the study and comparison cohorts after adjusting for possible confounding risk factors. RESULTS: Patients who received 5ARI therapy had a lower cumulative rate of type 2 DM than those who did not receive 5ARI during the five-year follow-up period (3.5% vs. 5.3%, P = 0.003). In sub-group analysis, among the BPH patients aged <65 years, the five-year type 2 DM events hazard ratio (HR) of 5ARI users was lower than that of nonusers (HR: 0.47, 95% confidence interval (CI): 0.24-0.91; P = 0.026). CONCLUSIONS: Therapy with 5ARI may decrease the five-year risk of type 2 DM in the BPH patients younger than 65 years. Further mechanistic research is warranted to validate the results.

CCL2 increases αvß3 integrin expression and subsequently promotes prostate cancer migration.

BACKGROUND: Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family which is associated with the disease status and outcomes of cancers. Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. However, the effect of CCL2 on human prostate cancer cells is largely unknown. The aim of this study was to examine the role of CCL2 in integrin expression and migratory activity in prostate cancers. METHODS: Prostate cancer migration was examined using Transwell, wound healing, and invasion assay. The PKCδ and c-Src phosphorylations were examined by using western blotting. The qPCR was used to examine the mRNA expression of integrins. A transient transfection protocol was used to examine AP-1 activity. RESULTS: Stimulation of prostate cancer cell lines (PC3, DU145, and LNCaP) induced migration and expression of integrin αvß3. Treatment of cells with αvß3 antibody or siRNA abolished CCL2-increased cell migration. CCL2-increased migration and integrin expression were diminished by CCR2 but not by CCR4 inhibitors, suggesting that the CCR2 receptor is involved in CCL2-promoted prostate cancer migration. CCL2 activated a signal transduction pathway that includes PKCδ, c-Src, and AP-1. Reagents that inhibit specific components of this pathway each diminished the ability of CCL2 to effect cell migration and integrin expression. CONCLUSIONS: Interaction between CCL2 and CCR2 enhances migration of prostate cancer cells through an increase in αvß3 integrin production. GENERAL SIGNIFICANCE: CCL2 is a critical factor of prostate cancer metastasis.

Anabolic androgens affect the competitive interactions in cell migration and adhesion between normal mouse urothelial cells and urothelial carcinoma cells.

The urothelium is constantly rebuilt by normal urothelial cells to regenerate damaged tissues caused by stimuli in urine. However, the urothelial carcinoma cells expand the territory by aberrant growth of tumor cells, which migrate and occupy the damaged tissues to spread outside and disrupt the normal cells and organized tissues and form a tumor. Therefore, the interaction between normal urothelial cells and urothelial carcinoma cells affect the initiation and progression of urothelial tumors if normal urothelial cells fail to migrate and adhere to the damages sites to regenerate the tissues. Here, comparing normal murine urothelial cells with murine urothelial carcinoma cells (MBT-2), we found that normal cells had less migration ability than carcinoma cells. And in our co-culture system we found that carcinoma cells had propensity migrating toward normal urothelial cells and carcinoma cells had more advantages to adhere than normal cells. To reverse this condition, we used anabolic androgen, dihyrotestosterone (DHT) to treat normal cells and found that DHT treatment increased the migration ability of normal urothelial cells toward carcinoma cells and the adhesion capacity in competition with carcinoma cells. This study provides the base of a novel therapeutic approach by using anabolic hormone-enforced normal urothelial cells to regenerate the damage urothelium and defend against the occupancy of carcinoma cells to thwart cancer development and recurrence.

Cancer risks among patients with type 2 diabetes: a 10-year follow-up study of a nationwide population-based cohort in Taiwan.

BACKGROUND: This study aims to determine cancer risks among patients with type 2 diabetes through a follow-up study on a nationwide population-based cohort that included Taiwanese diabetic patients and general population in Taiwan as well as to estimate the population attributable fraction (PAF) of site-specific cancer risks that can be attributed to type 2 diabetes in Taiwanese population by using standardized incidence ratios (SIRs, 95% CI). METHODS: Subjects with type 2 diabetes consisted of 472,979 patients aged ≥ 20 years, whereas general population consisted of 9,411,249 individuals of the same age limit but are not diabetic. Subjects were identified from 1997 to 1998 and followed up until December 31, 2007 or until the first manifestation of any cancer. RESULTS: Cancer sites with increased risks in men, which were consistent with the main and sensitivity analyses, included pancreas (SIR=1.62; 95% CI=1.53 to 1.72), liver (1.61; 1.57 to 1.64), kidney (1.32; 1.25 to 1.40), oral (1.16, 1.12 to 1.21), and colorectal (1.19, 1.15 to 1.22). Cancer sites with increased risks in women included liver (1.55; 1.51 to 1.60), pancreas (1.44; 1.34 to 1.55), kidney (1.38; 1.30 to 1.46), endometrium (1.36; 1.26 to 1.47), bladder (1.19; 1.11 to 1.27), colorectal (1.16; 1.13 to 1.20), and breast (1.14; 1.09 to 1.18). Overall, PAFs were highest for liver cancer in men (4.0%) and women (3.7%), followed by pancreas (3.4%) and kidney (1.6%) cancers in men, and then for endometrium (1.8%) and kidney (1.8%) cancers in women. CONCLUSION: Our data suggested that increased cancer risks are associated with type 2 diabetes.

Potential therapeutic roles of tanshinone IIA in human bladder cancer cells.

Tanshinone IIA (Tan-IIA), one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer.

D-pinitol inhibits prostate cancer metastasis through inhibition of αVß3 integrin by modulating FAK, c-Src and NF-κB pathways.

Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. D-pinitol, a 3-methoxy analogue of d-chiro-inositol, was identified as an active principle in soy foods and legumes, and it has been proven to induce tumor apoptosis and metastasis of cancer cells. In this study, we investigated the anti-metastasis effects of D-pinitol in human prostate cancer cells. We found that D-pinitol reduced the migration and the invasion of prostate cancer cells (PC3 and DU145) at noncytotoxic concentrations. Integrins are the major adhesive molecules in mammalian cells and have been associated with the metastasis of cancer cells. Treatment of prostate cancer cells with D-pinitol reduced mRNA and cell surface expression of αvß3 integrin. In addition, D-pinitol exerted its inhibitory effects by reducing focal adhesion kinase (FAK) phosphorylation, c-Src kinase activity and NF-kB activation. Thus, D-pinitol may be a novel anti-metastasis agent for the treatment of prostate cancer metastasis.

Age-specific percentile-based prostate-specific antigen cutoff values predict the risk of prostate cancer: A single hospital observation.

Background: Testing for prostate-specific antigen (PSA) is often recommended for men with a potential risk of prostate cancer (PCa) before requiring advanced examination. However, the best PSA cutoff value remains controversial. Object: We compared the predictive performance of age-specific percentile-based PSA thresholds with a conventional cutoff of >4 ng/mL for the risk of PCa. Methods: We included men who received PSA measurements between 2003 and 2017 in a medical center in Taiwan. Logistic regression modeling was used to assess the association between age-specific percentile-based PSA thresholds and PCa risk in age subgroups. We further applied C-statistic and decision curve analysis to compare the predictive performance of age-specific percentile-based PSA with that of a conventional cutoff PSA. Results: We identified 626 patients with PCa and 40 836 patients without PCa. The slope of PSA in patients >60-year-old was almost 3 times that of those <60-year-old (0.713 vs 0.259). The risk effect sizes of the 75th percentile PSA cutoff (<60-year-old: 2.19; 60-70-year-old: 4.36; >70-year-old: 5.84 ng/mL) were comparable to those observed based on the conventional cutoff in all age groups. However, the discrimination performance of the 75th percentile PSA cutoff was better than that of the conventional cutoff among patients aged <60-year-old (C-statistic, 0.783 vs. 0.729, p < 0.05). The 75th percentile cutoffs also correctly identified an additional 2 patients with PCa for every 100 patients with PSA screening at the threshold probability of 20%. Conclusions: Our data support the use of the 75th percentile PSA cutoff to facilitate individualized risk assessment, particularly for patients aged <60-year-old.

Ethnic differences in the age-related distribution of serum prostate-specific antigen values: A study in a Taiwanese male population.

This study investigates age-specific prostate-specific antigen (PSA) distributions in Taiwanese men and recommends reference ranges for this population after comparison with other studies. From January 1999 to December 2016, a total of 213,986 Taiwanese men aged above 19 years old without history of prostate cancer, urinary tract infection, or prostate infection were recruited from the Taiwan MJ cohort, an ongoing prospective cohort of health examinations conducted by the MJ Health Screening Center in Taiwan. Participants were divided into seven age groups. Simple descriptive statistical analyses were carried out and quartiles and 95th percentiles were calculated for each group as reference ranges for serum PSA in screening for prostate cancer in Taiwanese men. Serum PSA concentration correlated with age (r = 0.274, p<0.001). The median serum PSA concentration (5th to 95th percentile) ranged from 0.7 ng/ml (0.3 to 1.8) for men 20-29 years old (n = 6,382) to 1.6 ng/ml (0.4 to 8.4) for men over 79 years old (n = 504). The age-specific PSA reference ranges are as follows: 20-29 years, 1.80 ng/ml; 30-39 years, 1.80 ng/ml; 40-49 years, 2.0 ng/ml; 50-59 years, 3.20 ng/ml; 60-69 years, 5.60 ng/ml; 70-79 years, 7.40 ng/ml; over 80 years, 8.40 ng/ml. Almost no change occurred in the median serum PSA value in men 50 years old or younger, while a gradual increase was observed in men over 50. Taiwanese men aged 60 years above showed higher 95th percentile serum PSA values compared to Caucasian men and men in other Asian countries but were closer to those of Asian American and African American men. Results indicate significantly different PSA levels correlating to different ethnicities, suggesting that Oesterling's age-specific PSA reference ranges might not be appropriate for Taiwanese men. Our results should be further studied to validate the age-specific PSA reference ranges for Taiwanese men presented in this study.

Combined Dynamic Alterations in Urinary VEGF Levels and Tissue ADAM9 Expression as Markers for Lethal Phenotypic Progression of Prostate Cancer.

Recent evidence has demonstrated that detection of changes in the levels of urinary vascular endothelial growth factor (VEGF) and tissue a disintegrin and metalloproteinase 9 (ADAM9) is effective in determining prostate cancer progression. To evaluate the combined application of VEGF and ADAM9 as early progression markers of lethal phenotypic cancer, quantification of urinary VEGF and tissue ADAM9 expression was studied in patients with late stage prostate cancer. Tissue biopsies were collected during palliative transurethral resection of prostate (TURP) surgery, and urine samples were collected before hormone therapy and 3, 6 and 12 months post-TURP. We observed a nearly 100% correlation between increasing urinary VEGF levels over time and prostate cancer progression, but no correlation was observed when comparing urinary VEGF concentrations at a single time point and cancer progression. In addition, we also observed correlation of increasing ADAM9 nuclear positive staining and lethal phenotypic transition. Statistical analysis revealed that both the increase in urinary VEGF level and the presence of the tissue ADAM9 nuclear staining were significantly correlated with the risk of patients with relapse prostate cancer (P < 0.05). Thus, we suggest that combination of detection of changes in urinary VEGF and tissue staining of ADAM9 may be accurate for predicting the mortality of patients with prostate cancer during hormone therapy.

Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan.

Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22-2.18) or absence (HR: 2.31, 95% CI = 1.40-3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.

A study on the impact of poor medication adherence on health status and medical expense for diabetes mellitus patients in Taiwan: A longitudinal panel data analysis.

Medication adherence plays an important role in disease management, especially for diabetes. The aim of this study was to examine the impacts of demographic characteristics on medication nonadherence and the impacts of nonadherence on both health status and medical expenses for diabetic patients in Taiwan.A total of 1 million diabetes mellitus patients were randomly selected from the National Health Insurance Research Database between January 1, 2000 and December 31, 2004. All records with missing values and those for participants under 18 years of age were then deleted. Because many patients had multiple clinical visit records, all records within the same calendar year were summarized into 1 single record for each person. This pre-processing resulted in 14,602 total patients with a combined 73,010 records over the course of 5 years. Generalized estimating equation models were then constructed to investigate the effects of demographic characteristics on medication nonadherence and the effects of nonadherence on patient health status and medical expenses. The demographic characteristics examined for each patient include gender, age, residential area, and socioeconomic status.Our analysis of how demographic variables impacted nonadherence revealed that elderly patients exhibited better overall medication adherence, but that male patients exhibited poorer medication adherence than female patients. Next, our analysis of how nonadherence impacted health status revealed that patients who exhibited medication nonadherence had poorer health status than patients with proper medication adherence. Finally, our analysis of how nonadherence impacted medical expenses revealed that patients who exhibited medication nonadherence incurred more medical expenses than those who exhibited proper medication adherence.This study's empirical results corroborate the general relationships expressed in the current literature regarding medication nonadherence. However, this study's results were statistically more reliable and revealed the precise impact on health status in terms of the Charlson comorbidity index and increased annual medical expenses. This indicates the need to improve patient attitudes toward medication adherence, which can have substantial effects both medically and economically.

Impacts of doctor-shopping behavior on diabetic patients' health: A retrospective longitudinal study in Taiwan.

The aim of this study was to clarify the relationship between doctor-shopping behavior and clinical conditions, and to clearly outline the effects of both the number of clinic visits and the number of doctor changes on patients' health conditions. Data from January 1, 2000 to December 31, 2004 was collected from the National Health Insurance Research Database in Taiwan. After randomly selecting one million people, we extracted 5-year longitudinal data, about the number of clinic visits, number of doctor changes, and changes in self-health status for each patient with diabetes over the age of 18. We developed a relationship among the variables by using the generalized estimating equation. The results revealed that the number of clinic visits on the change of health status is a U curve, suggesting that health condition could be optimal with an appropriate number of clinic visits. The effect of the number of doctor changes is linearly correlated with health deterioration. The results suggest that disease conditions can only be controlled with an adequate number of clinic visits. Excessively frequent clinic visits are not only unfavorable to patients' health status but are also wasteful of limited medical resources. For diabetic mellitus patients, the more they change doctors, the worse their health status. All of these results are important for patients to stay healthy and to save medical resources.

Increased risk of Parkinson disease with diabetes mellitus in a population-based study.

This nationwide population-based study investigated the risk of Parkinson disease (PD) in relation to diabetes mellitus (DM) through the National Health Insurance Research Database in Taiwan.A retrospective study was conducted, consisting of 36,294 patients who were newly diagnosed with DM between January 1, 2000 and December 31, 2006 and 108,882 individuals without DM as healthy controls from insurance claims data from Taiwan's National Health Research Institutes Dataset. The subjects were followed up until December 31, 2011 or until the first manifestation of PD. The hazard ratio (HR) of DM for PD incidence was estimated by Cox proportional hazard regression model.Compared with the non-DM cohort, the incidence density rate of PD was 1.36-fold higher in the DM cohort (1.53 vs 2.08 per 1000 person-years) with an adjusted HR of 1.19 (95% confidence interval = 1.08-1.32) after adjusting for age, sex, comorbidities, and medication use. The adjusted HR of PD for DM with a larger magnitude was observed in females (1.29, 1.12-1.49); individuals age 65 years and older (1.20, 1.06-1.35); those without schizophrenia (1.20, 1.08-1.33), bipolar disorder (1.20, 1.08-1.33), hypertension (1.18, 1.06-1.32), hyperlipidemia (1.21, 1.09-1.34), chronic obstructive pulmonary disease (1.19, 1.06-1.32), coronary artery disease (1.22, 1.09-1.36), stroke (1.23, 1.10-1.37), asthma (1.20, 1.08-1.34), flunarizine use (1.21, 1.08-1.35), zolpidem use (1.16, 1.04-1.30), Charlson comorbidity index score of 0 (1.23, 1.08-1.40), and those using metoclopramide (1.35, 1.14-1.60) and zolpidem (1.46, 1.12-1.90).DM increased the risk of PD during a mean follow-up of 7.3 years. Further mechanistic research on the effect of DM on PD is needed.

Prediction of Mortality in Incident Hemodialysis Patients: A Validation and Comparison of CHADS2, CHA2DS2, and CCI Scores.

BACKGROUND: The CHADS2 and CHA2DS2 scores are usually applied for stroke prediction in atrial fibrillation patients, and the Charlson comorbidity index (CCI) is a commonly used scale for assessing morbidity. The role in assessing mortality with score system in hemodialysis is not clear and comparisons are lacking. We aimed at evaluating CHADS2, CHA2DS2, and CCI scores to predict mortality in incident hemodialysis patients. METHODS: Using data from the Nation Health Insurance system of Taiwan (NHIRD) from 1 January 2005 to 31 December 2009, individuals ≧20 y/o who began hemodialysis identified by procedure code and receiving dialysis for > 3 months were included for our study. Renal transplantation patients after dialysis or PD patients were excluded. We calculated the CHADS2, CHA2DS2, and CCI score according to the ICD-9 code and categorized the patients into three groups in each system: 0-1, 2-3, over 4. A total of 3046 incident hemodialysis patients enrolled from NHIRD were examined for an association between the separate scoring systems (CHADS2, CHA2DS2, and CCI score) and mortality. RESULTS: CHADS2 and CHA2DS2 scores revealed good predictive value for total mortality (CHADS2 AUC = 0.805; CHA2DS2 AUC = 0.790). However, the CCI score did not reveal a similarly satisfying result (AUC = 0.576). CONCLUSIONS: Our results show that CHADS2 and CHA2DS2 scores can be applied for mortality prediction in incident hemodialysis patients.

Androgen receptor facilitates the recruitment of macrophages in tumor microenvironment to promote upper urinary tract urothelial cell carcinoma progression.

Interactions between infiltrating macrophages in the tumor microenvironment (TME) and tumor cells contribute to tumor progression. The potential impacts of recruited macrophages to the upper urinary tract urothelial cell carcinomas (UUTUCs) progression remain unclear. Here we found human UUTUCs might recruit more macrophages than surrounding normal urothelial cells in human clinical specimens and in in vitro co-culture experiments with UUTUC cells and macrophages. The consequences of recruiting more macrophages to UUTUCs might then enhance UUTUC cell growth, migration and invasion. Further investigation found that the androgen receptor (AR) not only enhanced UUTUC cells capacity to recruit more macrophages, it could also promote the macrophages-enhanced UUTUC cells growth, migration and invasion. Downstream AR target cytokine search found AR might function through modulating CCL5 expression to influence UTTUC progression. Interruption of CCL5 partially reversed the AR-regulated macrophage-enhanced UUTUC progression. AR in UUTUC cells also increased tumor formation in vivo. Taken together, these results suggest that macrophages recruitment may enhance UUTUC progression, modulated by AR-CCL5 signal through alterations in chromatin state to establish a tumor microenvironment with recruited macrophages and cytokines to facilitate cell growth, migration and invasion.

Androgen receptor expands the population of cancer stem cells in upper urinary tract urothelial cell carcinoma cells.

Androgen receptor (AR) affects the development and progression of upper urinary tract urothelial cell carcinoma (UUTUC). However, the regulatory mechanism exerted by AR to affect UUTUC cells remains unclear. Here we investigated whether AR promotes UUTUC development and progression, possibly by expanding the population of cancer stem cells (CSCs), which are a particular population of cells within cancer cells responsible for tumor initiation, drug resistance and metastasis. We compared UUTUC cells with or without the addition of AR on their CSC population with flow cytometry, colony formation and sphere formation assay to determine the effect of AR on CSC activity, and real-time PCR was used to detect the expression stemness genes and miRNAs. In vivo tumor formation was evaluated with the implantation of cancer cells in nude mice. We found that the addition of AR in UUTUC cells, significantly increased the population of CSC, clonogenicity, sphere formation and the expression of stemness genes (Oct4, Bmi1 and Nanog), altered CSC-related miRNA profile, as well as promoted epithelial mesenchymal transition (EMT). And AR inhibitor, enzalutamide was shown to suppress AR's effect on tumorsphere formation. Furthermore, in an immune-deficient mouse model, the addition of AR in UUTUC cells also increased the tumor formation capacity. This study will help us better understand the extent to which AR contributes to UUTUC progression by expanding their CSC population and capacity. Our findings could explain high incidence of UUTUC observed in males. And targeting AR may lead to novel therapeutic approaches for genetically diversified urothelial carcinomas in precision medicine era.

CHADS2 Scores as a Predictor of Ischemic Stroke in Patients With Peripheral Artery Disease.

OBJECTIVE: To assess the predictive value of CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke) scores for stroke risk in patients with peripheral artery disease (PAD). PATIENTS AND METHODS: From Taiwan's National Health Insurance Research Database, we identified a total of 479 participants with non-atrial fibrillation PAD diagnoses recorded from January 1, 2002, through December 31, 2009. The CHADS2 score was used to stratify 5-year ischemic stroke risk. All participants were followed up from the date of enrollment until ischemic stroke event, death, or the end of 2009. RESULTS: The 5-year risk of ischemic stroke in the present study was 9.4%. A strong correlation was found between the PAD and CHADS2 score (CHADS2 score of 0-1, 0.4%; CHADS2 score of 2-3, 12.3%; CHADS2 score ≥4, 84.0%; area under the curve = 0.920). After adjustment, CHADS2 score was found to be positively correlated with increased risk of ischemic stroke. CONCLUSIONS: Our results indicate that patients with PAD have a significantly higher risk of ischemic stroke and that the CHADS2 score can be used as an indicator of risk for ischemic stroke. Cardiovascular risk evaluation and management are suggested for patients with PAD and higher CHADS2 scores.

CHADS2 scores as a predictor of ischemic stroke after radical prostatectomy.

Patients with prostate cancer have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. The Charlson Comorbidity Index Score (CCIS) is a widely accepted measure for risk adjustment in administrative claims data sets. This study assesses the predictive value of CHADS2 scores and CCIS for stroke among patients with prostate cancer. The study was conducted based on data taken from Taiwan's National Health Insurance Research Database (NHIRD). We identified a total of 5414 participants with nonatrial fibrillation (AF) prostate cancer diagnoses who underwent radical prostatectomy between 1997 and 2011. CHADS2 scores and CCIS were used to stratify the 5-year ischemic stroke risk. All participants were followed from the date of enrollment until ischemic stroke, death, or the end of the 5-year follow-up period. The 5-year risk of ischemic stroke in the present study was 1.7%. Ischemic stroke has a better correlation with CHADS2 (CHADS2 score = 0 to 1: 0.02%, CHADS2 score = 2 to 3: 13.9%, CHADS2 score ≥ 4: 44.4%; AUC = 0.978) than CCIS (CCIS = 0 to 1: 1.6%, CCIS = 2 to 3: 1.7%, CCIS ≥ 4: 3.8%; AUC = 0.520). Our results show that patients with prostate cancer who underwent radical prostatectomy show significantly higher risk of ischemic stroke in high CHADS2 score patients, and the CHADS2 score could be applied for ischemic stroke prediction. Cardiovascular risks evaluation and management are suggested for prostate cancer patients with higher CHADS2 score.