Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms ...involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.
Thioamides antithyroid‐drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD‐induced agranulocytosis is important for clinical management. ...We performed a genome‐wide association study (GWAS) involving 20 patients with ATD‐induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single‐nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD‐induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8–103.7; P = 1.3 × 10‐24) and replication (OR = 37; 95% CI = 3.7–367.4; P = 9.6 × 10‐7). HLA‐B*38:02:01 was in complete linkage disequilibrium with rs185386680. High‐resolution HLA typing confirmed that HLA‐B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)‐induced agranulocytosis (OR = 265.5; 95% CI = 27.9–2528.0; P = 2.5 × 10‐14), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA‐B*38:02:01 in predicting CMZ/MMI‐induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
Background Previous reports have indicated that statins could prevent bone loss in ovariectomized (OVX) rats and increase the expressions of osteogenic genes in cultured osteoblasts. In this study, ...we hypothesized that simvastatin might increase osteoblast number and protein expressions of osteogenic markers localized in bones in concomitance with the prevention of bone loss in OVX rats.
Materials and methods Fifty‐four 3‐month‐old OVX and sham‐operated (SHAM) female Sprague–Dawley rats were used. Simvastatin (10–20 mg kg−1 day−1) was administrated orally for 6 weeks. Trabecular volume, osteoblast number and osteogenic proteins including BMP2, collagen type I and osteocalcin on bone sections obtained from lumbar vertebral body, distal femur and proximal tibia were measured.
Results The results showed that SHAM rats had significantly less trabecular bone volume and osteoblast number than that of OVX rats 6 weeks after operation. Oral simvastatin treatment (10–20 mg kg−1 day−1) increased bone volume and osteoblast number in the distal femurs, proximal tibiae and vertebrae of OVX rats. Furthermore, the osteoblastic cells with immuno‐stained BMP2, collagen type I and osteocalcin in vertebral bones were significantly increased by simvastatin treatment (20 mg kg−1 day−1) in OVX rats.
Conclusions This study demonstrates that simvastatin enhances the production of osteogenic proteins in bone and this effect may contribute to the prevention of bone loss in OVX rats.
Summary
This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)‐positive and ...‐negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg‐positive and 104 HBeAg‐negative patients) who were previously treated with TDF and had post‐treatment follow‐up for at least 6 months (median: 55, IQR 36‐85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg‐positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg‐negative patients. Cox regression analysis revealed that the higher end‐of‐treatment HBsAg levels were an independent factor of virological relapse in HBeAg‐positive and HBeAg‐negative patients. The end‐of‐treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg‐positive and HBeAg‐negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg‐positive and HBeAg‐negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off‐therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end‐of‐treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end‐of‐treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg‐positive and HBeAg‐negative CHB patients.
Summary
Background
The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently.
Aim
To ...identify modulating factors for serum ALT levels and to refine its ULN threshold.
Methods
We enrolled 34 346 consecutive subjects who completed the health check‐up at Taipei Veterans General Hospital from 2002 to 2009. ULN was set for healthy ALT level to the 95th percentile of the reference healthy population.
Results
A group of 21 282 subjects were used as a training set to define an ULN with the highest sensitivity; afterwards, this ULN was validated in another set of 13 064 subjects. A reference healthy population was selected from the training set after excluding subjects with any abnormalities in independent risk factors associated with elevated serum ALT level (>40 IU/L) by multivariate analysis like body mass index, waist circumference, glucose, cholesterol, high‐density lipoprotein‐cholesterol, triglyceride, hepatitis B virus surface antigen, anti‐hepatitis C virus antibody and fatty liver. The new ULN of serum ALT level defined as the 95% percentile in the healthy population were 21 IU/L and 17 IU/L for men and women respectively. These cut‐off values had the highest Youden's index and areas under the corresponding receiver operating curves among four widely applied thresholds in both the training and validation sets.
Conclusions
The suggested threshold of upper limit of normal provides better discrimination between healthy and unhealthy status. Viral hepatitis, metabolic syndrome and fatty liver are the major risk factors of elevated serum alanine aminotransferase levels.
Fracture liaison services (FLS), implemented in different ways and countries, are reported to be a cost-effective or even a cost-saving secondary fracture prevention strategy. This presumed favorable ...cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards. This study summarizes the economic impact and cost-effectiveness of FLS implemented to reduce subsequent fractures in individuals with osteoporosis. This systematic review identified studies reporting economic outcomes for FLS in osteoporotic patients aged 50 and older through a comprehensive search of MEDLINE, EMBASE, Cochrane Central, and PubMed of studies published January, 2000 to December, 2016. Grey literature (e.g., Google scholar, conference abstracts/posters) were also hand searched through February 2017. Two independent reviewers screened titles and abstracts and conducted full-text review on qualified articles. All disagreements were resolved by discussion between reviewers to reach consensus or by a third reviewer. In total, 23 qualified studies that evaluated the economic aspects of FLS were included: 16 cost-effectiveness studies, 2 cost-benefit analyses, and 5 studies of cost savings. Patient populations varied (prior fragility fracture, non-vertebral fracture, hip fracture, wrist fracture), and FLS strategies ranged from mail-based interventions to comprehensive nurse/physician-coordinated programs. Cost-effectiveness studies were conducted in Canada, Australia, USA, UK, Japan, Taiwan, and Sweden. FLS was cost-effective in comparisons with usual care or no treatment, regardless of the program intensity or the country in which the FLS was implemented (cost/QALY from $3023–$28,800 US dollars (USD) in Japan to $14,513–$112,877 USD in USA. Several studies documented cost savings. FLS, implemented in different ways and countries, are reported to be cost-effective or even cost-saving. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards.
To investigate the long-term incidence and predictors for hepatitis B surface antigen (HBsAg) loss after nucleoside analogue therapy.
The study included 411 noncirrhotic chronic hepatitis B patients ...(148 hepatitis B e antigen (HBeAg)-positive and 263 HBeAg-negative patients) who were treated with lamivudine (n = 110) or entecavir (n = 301) with posttreatment follow-up of at least 12 months.
In HBeAg-positive patients, the 8-year cumulative rates of virologic relapse, clinical relapse and HBsAg loss were 55.6%, 47.7% and 19.6%, respectively. In HBeAg-negative patients, the rates were 69.3%, 58.9% and 33.1%, respectively. Cox regression analysis showed that hepatitis B virus genotype C and lower end-of-treatment HBsAg levels were independent predictors of HBsAg loss in HBeAg-positive and -negative patients. The 5-year HBsAg loss rate was 47.3% in HBeAg-positive patients with end-of-treatment HBsAg levels <300 IU/mL, while the 8-year HBsAg loss rate was 69.3% in HBeAg-negative patients with end-of-treatment HBsAg levels <200 IU/mL. Five patients experienced hepatitis flares with decompensation after stopping nucleoside analogue therapy, and one died after retreatment. Of the 48 patients who developed off-therapy HBsAg loss, two developed hepatocellular carcinoma.
The rate of HBsAg loss was relatively high and the rate of hepatic events was low in noncirrhotic patients who discontinued nucleoside analogue therapy.
Summary
Background
Data are limited regarding the effectiveness and safety of generic velpatasvir plus sofosbuvir (VEL/SOF) for hepatitis C virus (HCV) in patients with or without human ...immunodeficiency virus (HIV) coinfection.
Aim
To evaluate the effectiveness and safety of generic VEL/SOF‐based therapy for HCV infection in patients with or without HIV coinfection in Taiwan.
Methods
Sixty‐nine HIV/HCV‐coinfected and 159 HCV‐monoinfected patients receiving 12 weeks of generic VEL/SOF with or without ribavirin (RBV) for HCV were prospectively enrolled. The anti‐viral responses and the adverse events (AEs) were compared between the two groups. The characteristics potentially related to sustained virological response 12 weeks off therapy (SVR12) were analysed.
Results
The SVR12 was achieved in 67 HIV/HCV‐coinfected patients (97.1%; 95% CI: 90.0%‐99.2%) and in 156 HCV‐monoinfected patients (98.1%; 95% CI: 94.6%‐99.4%) receiving VEL/SOF‐based therapy, respectively. The SVR12 rates were comparable between HIV/HCV‐coinfected and HCV‐monoinfected patients, regardless of pre‐specified baseline characteristics. One hundred twenty‐two (53.5%) and seven (3.1%) patients had baseline resistance‐associated substitutions (RASs) in HCV NS5A and NS5B regions, but the SVR12 rates were not affected by the presence or absence of RASs. One (1.4%) and five (3.1%) patients in the HIV/HCV‐coinfected and HCV‐monoinfected groups had serious AEs. No patient died or discontinued treatment due to AEs. The eGFR remained stable throughout the course of treatment in HIV/HCV‐coinfected patients receiving anti‐retroviral therapy containing tenofovir disoproxil fumarate (TDF).
Conclusions
Generic VEL/SOF‐based therapy is well‐tolerated and provides comparably high SVR12 rates for HCV infection in patients with and without HIV coinfection.
Background
Whether there is a difference in survival after neoadjuvant chemoradiotherapy plus surgery (CRT‐S) compared with definitive chemoradiotherapy (dCRT) in patients with locally advanced ...oesophageal squamous cell carcinoma (SCC) remains controversial.
Methods
Patients with SCC who underwent curative treatment from 2008 to 2014 were identified from the Taiwan Cancer Registry. Propensity score matching was undertaken to balance pretreatment clinical variables. Overall survival was compared between patients undergoing CRT‐S or dCRT. Univariable and multivariable analyses were performed to identify prognostic factors for overall survival.
Results
A total of 5832 patients with clinical stage II and III oesophageal SCC receiving CRT‐S (1754) or dCRT (4078) were included. After propensity score matching, each group included 1661 patients. The 3‐year overall survival rate for patients treated with CRT‐S was 41·1 per cent compared with 17·9 per cent for those who had dCRT (P < 0·001). In multivariable analysis, treatment modality was an independent prognostic factor in the overall cohort before propensity score matching: hazard ratio 0·45 (95 per cent c.i. 0·40 to 0·51) for CRT‐S versus dCRT (P < 0·001). In separate analyses of patients with clinical stage II and those with stage III disease, CRT‐S was associated with significantly better overall survival than dCRT.
Conclusion
Neoadjuvant chemoradiotherapy and oesophagectomy is associated with better overall survival than dCRT in patients with stage II and III oesophageal SCC.
Surgery indicated after chemoradiation
Aims To evaluate the clinical inference of serum alpha-fetoprotein (AFP) response in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). Materials and ...methods Three hundred and thirteen previously untreated HCC patients were enrolled in the study. The optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA for those with a baseline AFP level of ≥100 ng/ml. The impact of AFP response on prognosis was analysed and prognostic factors were assessed. Results After a median follow-up of 26.7 ± 19.1 months, 49 patients died and 264 patients were alive. The cumulative 5 year survival rates were 75.3 and 57.4% in patients with an initial AFP of <100 ng/ml and ≥100 ng/ml, respectively ( p = 0.003). In the 58 patients with a baseline AFP of ≥100 ng/ml and initial completed tumour necrosis after RFA, the cumulative 5 year survival rates were 62.4 and 25.7% in optimal and non-optimal AFP responders, respectively ( p = 0.001). By multivariate analysis, the prothrombin time international normalized ratio >1.1 ( p = 0.009), non-optimal AFP response ( p = 0.023), and creatinine >1.5 mg/dl ( p = 0.021) were independent risk factors predictive of poor overall survival. Besides, the cumulative 5 year recurrence rates were 83.4 and 100% in optimal and non-optimal AFP responders, respectively ( p < 0.001). Multivariate analysis demonstrated platelet count ≤105 /mm3 ( p = 0.048), tumour size >2 cm ( p = 0.027), and non-optimal AFP response ( p < 0.001) were independent risk factors associated with tumour recurrence after RFA. Conclusions Serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA.
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