Preclinical trial of targeting the Hic-5-mediated pathway to prevent the progression of hepatocellular carcinoma.

The poor prognosis of hepatocellular carcinoma (HCC) was ascribed to metastasis. Targeted therapy aiming at the molecules along the metastatic pathway is a promising therapeutic strategy. Among them, hydrogen peroxide inducible clone-5 (Hic-5) is highlighted. Hic-5, discovered as a reactive oxygen species (ROS)-inducible gene, was identified to be an adaptor protein in focal adhesion and a critical signaling mediator upregulated in various cancers including HCC. Moreover, Hic-5 may regulate epithelial-mesenchymal transition (EMT) transcription factor Snail and its downstream mesenchymal genes including fibronectin and matrix metalloproteinase-9 required for migration and invasion of HCC. However, the comprehensive Hic-5-mediated pathway was not established and whether Hic-5 can be a target for preventing HCC progression has not been validated in vivo. Using whole-transcriptome mRNA sequencing, we found reactive oxygen species modulator (ROMO) and ZNF395 were upregulated by Hic-5 in a patient-derived HCC cell line, HCC372. Whereas ROMO was involved in Hic-5-mediated ROS signaling, ZNF395 locates downstream of Snail for mesenchymal genes expression required for cell migration. Also, ZNF395 but not ROMO was upregulated by Hic-5 for migration in another patient-derived HCC cell line, HCC374. Further, by in vivo knock down of Hic-5 using the Stable Nucleic Acids Lipid nanoparticles (SNALP)-carried Hic-5 siRNA, progression of HCC372 and HCC374 in SCID mice was prevented, coupled with the decrease of the downstream mesenchymal genes. Our study provides the preclinical evidence that targeting Hic-5 is potentially able to prevent the progression of HCCs with Hic-5 overexpression.

Suppressing of Src-Hic-5-JNK-AKT Signaling Reduced GAPDH Expression for Preventing the Progression of HuCCT1 Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a malignant neoplasm of the bile ducts, being the second most common type of cancer in the liver, and most patients are diagnosed at a late stage with poor prognosis. Targeted therapy aiming at receptors tyrosine kinases (RTKs) such as c-Met or EGFR have been developed but with unsatisfactory outcomes. In our recent report, we found several oncogenic molecules downstream of RTKs, including hydrogen peroxide clone-5 (Hic-5), Src, AKT and JNK, were elevated in tissues of a significant portion of metastatic CCAs. By inhibitor studies and a knockdown approach, these molecules were found to be within the same signal cascade responsible for the migration of HuCCT1 cells, a conventionally used CCA cell line. Herein, we also found Src inhibitor dasatinib and Hic-5 siRNA corporately suppressed HuCCT1 cell invasion. Moreover, dasatinib inhibited the progression of the HuCCT1 tumor on SCID mice skin coupled with decreasing the expression of Hic-5 and EGFR and the activities of Src, AKT and JNK. In addition, we found a glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and several cytoskeletal molecules such as tubulin and cofilin were dramatically decreased after a long-term treatment of the HuCCT1 tumor with a high dose of dasatinib. Specifically, GAPDH was shown to be a downstream effector of the Hic-5/Src/AKT cascade involved in HuCCT1 cell migration. On the other hand, TFK1, another CCA cell line without Hic-5 expression, exhibited very low motility, whereas an ectopic Hic-5 expression enhanced the activation of Src and AKT and marginally increased TFK1 migration. In the future, it is tempting to investigate whether cotargeting Src, Hic-5 and/or GAPDH is efficient for preventing CCA progression in future clinical trials.

Targeting Src-Hic-5 Signal Cascade for Preventing Migration of Cholangiocarcinoma Cell HuCCT1.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer with poor prognosis. The deregulation of a lot of oncogenic signaling molecules, such as receptor tyrosine kinases (RTKs), has been found to be associated with CCA progression. However, RTKs-based target therapy showed limited improvement suggesting a need to search for alternative targets for preventing CCA progression. To address this issue, we screened the oncogenic signal molecules upregulated in surgical tissues of CCAs. Interestingly, over-expression of hydrogen peroxide inducible clone-5 (Hic-5) coupled with over-activation of Src, AKT, JNK were observed in 50% of the cholangiocarcinoma with metastatic potential. To investigate whether these molecules may work together to trigger metastatic signaling, their up-and-down relationship was examined in a well-established cholangiocarcinoma cell line, HuCCT1. Src inhibitors PP1 (IC50, 13.4 µM) and dasatinib (IC50, 0.1 µM) significantly decreased both phosphorylated AKT (phosphor-AKT Thr450) and Hic-5 in HuCCT1. In addition, a knockdown of Hic-5 effectively suppressed activation of Src, JNK, and AKT. These implicated a positive cross-talk occurred between Hic-5 and Src for triggering AKT activation. Further, depletion of Hic-5 and inhibition of Src suppressed HuccT1 cell migration in a dose-dependent manner. Remarkably, prior transfection of Hic-5 siRNA for 24 h followed by treatment with PP1 or dasatinib for 24 h resulted in additive suppression of HuCCT1 migration. This suggested that a promising combinatory efficacy can be achieved by depletion of Hic-5 coupled with inhibition of Src. In the future, target therapy against CCA progression by co-targeting Hic-5 and Src may be successfully developed in vivo.

Sex differences in the treatment and outcome of patients with acute coronary syndrome after percutaneous coronary intervention: a population-based study.

BACKGROUND: This study was performed to assess the influence of sex on drug therapy and long-term outcomes in acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI). METHODS: This is a retrospective cohort study of ACS patients who underwent PCI [women (n=8,884) and men (n=23,937)] between January 1, 2006, and December 31, 2007, with at least a 1-year follow-up, based on the National Health Insurance Research Database in Taiwan. Propensity score was used to identify a 1:1 matched cohort (n=17,768) for multivariable adjustment. The influence of sex on drug therapy and outcomes was examined by multivariate logistic regression and multivariable Cox proportional hazards regression. RESULTS: Female patients had an 18% and 12% lower likelihood of receiving aspirin (adjusted odds ratio [OR(adj)]=0.82, 95% confidence interval [CI]=0.77-0.88) and clopidogrel (OR(adj)=0.88, 95% CI=0.81-0.95), respectively, than male patients but had a 17% and 22% higher likelihood of receiving beta-blockers (OR(adj)=1.17, 95% CI=1.10-1.24) and statins (OR(adj)=1.22, 95% CI=1.14-1.29), respectively, than male patients in the matched cohort. The adjusted hazard ratio (HR(adj)) of rehospitalization for revascularization in women was 0.84 (95% CI=0.79-0.90) compared with men after at least a 1-year follow-up in the matched cohort. CONCLUSIONS: Female patients with ACS who underwent PCI were less likely to receive aspirin and clopidogrel but were more likely to receive beta-blockers and statins than male patients. Male sex was associated with a higher risk of rehospitalization for revascularization than female sex.

Age, dementia and care patterns after admission for acute coronary syndrome: an analysis from a nationwide cohort under the National Health Insurance coverage.

BACKGROUND: The number of elderly and the prevalence of dementia have grown considerably in recent years. Little is known about how aging and dementia affect care patterns after discharge for acute coronary syndrome (ACS). OBJECTIVE: This study was designed to assess the impact of dementia on care patterns after admission for patients with ACS across different age groups. METHODS: Of 87,321 patients hospitalized for ACS between 1 January 2006 and 31 December 2007, 1,835 patients with dementia and 3,670 matched patients without dementia (1:2 ratio, matched by age, sex and hospital level) were identified from Taiwan's National Health Insurance Research Database. Use of interventional therapies at hospitalization and guideline-recommended medications post-discharge were compared between patients with and without dementia across different age groups (≤65, 66-75, 76-85, ≥86 years). Multivariate logistic regression models were performed to examine the impact of dementia on care patterns. RESULTS: Overall, dementia was associated with a 27% lower likelihood of receipt of interventional therapies [adjusted odds ratio (OR) = 0.73; 95% CI 0.63, 0.83] and a 22% lower likelihood of guideline-recommended medications (adjusted OR = 0.78; 95% CI 0.68, 0.89) in ACS patients. The use of interventional therapies and guideline-recommended medications decreased with age, and interactions between age and dementia were found. The proportions of patients receiving interventional therapies were 39.4% (without dementia) versus 21.8% (with dementia) in the youngest age group and 18.6% (without dementia) versus 14.5% (with dementia) in the oldest age group. Patients with dementia (age ≤65 years 73.6%; age 66-75 years 82.3%; age 76-85 years 71.8%; age ≥86 years 55.6%) were less likely to receive guideline-recommended medications as compared with those without dementia (age ≤65 years 85.6%; age 66-75 years 87.5%; age 76-85 years 81.2%; age ≥86 years 62.0%). CONCLUSION: Dementia and aging were associated with decreased use of interventional therapies and guideline-recommended medications in ACS patients.

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.

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 Taiwan's 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.

Polypharmacy, aging and potential drug-drug interactions in outpatients in Taiwan: a retrospective computerized screening study.

BACKGROUND: Polypharmacy is common in outpatients and has been identified as a major risk factor for drug-drug interactions (DDIs), which are an important cause of adverse drug reactions. There has been a rapid increase in the number of elderly patients worldwide. However, there have been few studies quantifying the impact of both patient age and the number of concomitant drugs prescribed on the probability of potential DDIs per person in general outpatients. OBJECTIVE: To assess the extent to which polypharmacy and aging are associated with potential DDIs in outpatients at a medical centre in Taiwan. METHODS: The medications of 81,650 outpatients who visited a medical centre in Taiwan between January 2004 and March 2004 were retrospectively screened for potential DDIs using a computerized drug-interaction program. The main inclusion criteria were a minimum of two drug prescriptions and duration of use of 14 or more days. We also analysed the DDI pattern, which included severity, level of documentation and onset of potential DDIs, and assessed the impact of the number of drugs prescribed and of aging on the prevalence of potential DDIs per person. RESULTS: The prevalence of potential DDIs was 25.6% (20,902 of 81,650). The mean ± SD age of the 20,902 patients with potential DDIs was 57.5 ± 16.5 years, and 47.6% of these patients were male. The mean ± SD number of prescribed drugs in patients with potential DDIs was 5.8 ± 2.4, and 67.7% of these patients were prescribed more than four drugs. The majority (55.7%) of DDIs were of the C2 pattern (severity: moderate; documentation: probable). The prevalence of potential DDIs increased in a linear mode with increasing age (p < 0.001) and with the number of drugs prescribed (p < 0.001); furthermore, in addition to being independently associated with potential DDIs, these two factors interacted to increase the risk further. CONCLUSIONS: This study showed that approximately one-quarter of 81,650 outpatients who visited a medical centre in Taiwan over a period of 3 months in 2004 had potential DDIs. We observed independent increases in potential DDIs per person in association with aging and increasing number of prescribed drugs. Furthermore, a significant interaction between these two factors was observed: the effect of aging on the prevalence of potential DDIs increased as the number of prescribed drugs increased. Potential DDIs in outpatients can be reduced by minimizing the number of drugs prescribed following careful consideration of both their benefits and risks, particularly in the aging population.

A mechanism study of light-induced Cr(VI) reduction in an acidic solution.

The mechanisms of photo-catalytic reduction of Cr(VI) were investigated in acidic solutions with and without Fe(III). In a system without Fe(III), no Cr(VI) reduction was observed in dark conditions; conversely, under light conditions, the reduction reaction rate increased to 0.011 and 0.020microM min(-1) at pH 2 and pH 1, respectively, indicating the occurrence of Cr(VI) photo-reduction. The Cr(VI) photo-reduction reaction was induced by the photolysis of water molecules, leading to O(2) production. Upon the addition of Fe(III), the photo-reduction rate of Cr(VI) was significantly enhanced due to the formation of Fe(II), which is the photolytic product of FeCl(2)(+) and the electron donor for Cr(VI) reduction. However, with the same concentration of FeCl complexes, a strong inhibition of Cr(VI) reduction at pH 2 was observed, compared with pH 1. A possible explanation is that FeOH(2+) becomes predominant with increasing pH and that its photolytic product, the OH free radical, is an oxidant for Fe(II) and Cr(III) and can compromise Cr(VI) reduction. The kinetic result of each photo-reduction reaction pathway shows zero-order kinetics, suggesting that the photolysis reaction of H(2)O or FeCl(2+) is the rate-determining step in each pathway. The results also show the potential of developing a homogeneous photo-catalytic method to treat Cr(VI)-containing water.