Publications by authors named "Hong-Tai Chang"

137 Publications

Multidisciplinary Care after Acute Care for Stroke: A Prospective Comparison between a Multidisciplinary Post-Acute Care Group and a Standard Group Matched by Propensity Score.

Int J Environ Res Public Health 2021 07 20;18(14). Epub 2021 Jul 20.

Department of Business Management, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.

In this large-scale prospective cohort study, a propensity score matching method was applied in a natural experimental design to investigate how post-acute care (PAC) after stroke affects functional status and to identify predictors of functional status. The main objective of this study was to examine longitudinal changes in various measures of functional status in stroke patients and predictors of scores for these measures before and after PAC. A group of patients who had received PAC for stroke at one of two medical centers (PAC group, = 273) was compared with a group who had received standard care for stroke at one of four hospitals (three regional hospital and one district hospital; non-PAC group, = 273) in Taiwan from March, 2014, to October, 2018. The patients completed the functional status measures before rehabilitation, the 12th week and the 1st year after rehabilitation. Generalized estimating equations were used to estimate differences-in-differences models for examining the effects of PAC. The average age was 68.0 (SD = 8.1) years, and males accounted for 57.9%. During the follow-up period, significant risk factors for poor functional outcomes were advanced age, hemorrhagic stroke, and poor function scores before rehabilitation ( < 0.05). Between-group comparisons at subsequent time points revealed significantly higher functional status scores in the PAC group versus the non-PAC group ( < 0.001). Notably, for all functional status measures, between-group differences in total scores significantly increased over time from baseline to 1 year post-rehabilitation ( < 0.001). The contribution of this study is its further elucidation of the clinical implications and health policy implications of rehabilitative care after stroke. Specifically, it improves understanding of the effects of PAC in stroke patients at different follow-up times. Therefore, a policy implication of this study is that standard care for stroke should include intensive rehabilitative PAC to maximize recovery of overall function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18147696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303420PMC
July 2021

Machine Learning Algorithms to Predict Recurrence within 10 Years after Breast Cancer Surgery: A Prospective Cohort Study.

Cancers (Basel) 2020 Dec 17;12(12). Epub 2020 Dec 17.

Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

No studies have discussed machine learning algorithms to predict recurrence within 10 years after breast cancer surgery. This study purposed to compare the accuracy of forecasting models to predict recurrence within 10 years after breast cancer surgery and to identify significant predictors of recurrence. Registry data for breast cancer surgery patients were allocated to a training dataset ( = 798) for model development, a testing dataset ( = 171) for internal validation, and a validating dataset ( = 171) for external validation. Global sensitivity analysis was then performed to evaluate the significance of the selected predictors. Demographic characteristics, clinical characteristics, quality of care, and preoperative quality of life were significantly associated with recurrence within 10 years after breast cancer surgery ( < 0.05). Artificial neural networks had the highest prediction performance indices. Additionally, the surgeon volume was the best predictor of recurrence within 10 years after breast cancer surgery, followed by hospital volume and tumor stage. Accurate recurrence within 10 years prediction by machine learning algorithms may improve precision in managing patients after breast cancer surgery and improve understanding of risk factors for recurrence within 10 years after breast cancer surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765963PMC
December 2020

Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 in patients with metastatic breast cancer: phase II randomized, placebo-controlled study.

J Immunother Cancer 2020 07;8(2)

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA

Purpose: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC).

Methods: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety.

Results: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%).

Conclusion: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2019-000342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380846PMC
July 2020

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

J Clin Oncol 2020 09 17;38(27):3138-3149. Epub 2020 Jul 17.

Graduate School of Medicine, Gunma University, Gunma, Japan.

Purpose: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.

Methods: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).

Results: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% 29.2%; 043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; .0004). The most common all-grade adverse events were diarrhea (N+C 83% L+C 66%) and nausea (53% 42%). Discontinuation rates and HRQoL were similar between groups.

Conclusion: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499616PMC
September 2020

Aberrant DNA Hypermethylation Silenced LncRNA Expression in Gastric Cancer.

Anticancer Res 2019 Oct;39(10):5381-5391

Department of Surgery, Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan, R.O.C.

Background/aim: Long noncoding RNAs (lncRNAs) are noncoding transcripts that are >200 nucleotides in length. However, the biological functions and regulation mechanisms of lncRNAs in gastric carcinogenesis remain unknown.

Materials And Methods: The expression levels of Linc00472 were analyzed by real-time PCR. The DNA methylation status was assessed using Combined Bisulfite Restriction Analysis (COBRA). The biological role of Linc00472 was assessed in AGS cells with Linc00472 overexpression.

Results: Using the next-generation sequencing approach, we identified DNA methylation-associated lncRNAs in gastric cancer cells. Among them, the expression level of Linc00472 significantly decreased in gastric cancer tissues compared to adjacent normal tissues. Furthermore, we observed a more frequent hypermethylation of CpG islands upstream of Linc00472 in gastric cancer tissues. Ectopic Linc00472 expression could significantly inhibit gastric cancer cell growth and migration.

Conclusion: Epigenetically regulated Linc00472 expression plays a crucial role in modulating gastric cancer cell growth and motility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.13732DOI Listing
October 2019

Combination of inductive effect of lipopolysaccharide and in situ mechanical conditioning for forming an autologous vascular graft in vivo.

Sci Rep 2019 07 23;9(1):10616. Epub 2019 Jul 23.

Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.

Autologous vascular grafts have the advantages of better biocompatibility and prognosis. However, previous studies that implanted bare polymer tubes in animals to grow autologous tubular tissues were limited by their poor yield rates and stability. To enhance the yield rate of the tubular tissue, we employed a design with the addition of overlaid autologous whole blood scaffold containing lipopolysaccharides (LPS). Furthermore, we applied in vivo dynamic mechanical stimuli through cyclically inflatable silicone tube to improve the mechanical properties of the harvested tissues. The effectiveness of the modification was examined by implanting the tubes in the peritoneal cavity of rats. A group without mechanical stimuli served as the controls. After 24 days of culture including 16 days of cyclic mechanical stimuli, we harvested the tubular tissue forming on the silicone tube for analysis or further autologous interposition vascular grafting. In comparison with those without cyclic dynamic stimuli, tubular tissues with this treatment during in vivo culture had stronger mechanical properties, better smooth muscle differentiation, and more collagen and elastin expression by the end of incubation period in the peritoneal cavity. The grafts remained patent after 4 months of implantation and showed the presence of endothelial and smooth muscle cells. This model shows a new prospect for vascular tissue engineering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-47054-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650437PMC
July 2019

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells.

Front Pharmacol 2018 9;9:1285. Epub 2018 Nov 9.

School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.

Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood. We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients. Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients. Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.01285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238227PMC
November 2018

Hepatic Arterial Infusion Chemotherapy Is a Feasible Treatment Option for Breast Cancer with Liver-predominant Metastatic Disease.

In Vivo 2018 Nov-Dec;32(6):1635-1641

Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.

Background: Patients with liver metastasis from breast cancer (LMBC) are usually offered systemic therapy. However, for those with progressive liver disease and limited extra-hepatic conditions, local liver management becomes an option. Herein we present our experience with hepatic arterial infusion chemotherapy (HAIC).

Patients And Methods: From 1999 to 2018, 42 patients with LMBC, who had progressive liver metastasis after systemic therapy, were treated with HAIC. A catheter was placed angiographically into the hepatic artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-fluorouracil, folinic acid, and cisplatin. This treatment was repeated at monthly intervals. The medical records were reviewed and analyzed for hepatic tumor response, progression-free survival, overall survival and adverse effects.

Results: Complete response was observed in two patients (5%), partial response in 18 patients (43%) and stable disease in eight patients (19%). Fourteen patients (33%) had progressive disease after HAIC. The median progression-free survival and overall survival were 8.4 and 19.3 months, respectively. There was no death related to HAIC. The patients with response to the treatment had a significant survival benefit (p<0.005).

Conclusion: HAIC can be an option for those with progressive liver disease who are heavily pretreated while their extra-hepatic conditions are minimal or stable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.11425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365741PMC
January 2019

Extracellular Matrix-receptor Interaction Signaling Genes Associated with Inferior Breast Cancer Survival.

Anticancer Res 2018 Aug;38(8):4593-4605

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.

Background/aim: Breast cancer is a common type of cancer in women, and metastasis frequently leads to therapy failure. Using next-generation sequencing (NGS), we aspired to identify the optimal differentially expressed genes (DEGs) for use as prognostic biomarkers for breast cancer.

Materials And Methods: NGS was used to determine transcriptome profiles in breast cancer tissues and their corresponding adjacent normal tissues from three patients with breast cancer.

Results: Herein, 15 DEGs (fold change >4 and <0.25) involved in extracellular matrix (ECM)-receptor interaction signaling were identified through NGS. Among them, our data indicated that high HMMR expression levels were correlated with a poor pathological stage (p<0.001) and large tumor size (p<0.001), whereas high COL6A6 and Reelin (RELN) expression levels were significantly correlated with an early pathological stage (COL6A6: p=0.003 and RELN: p<0.001). Multivariate analysis revealed that high HMMR and SDC1 expression levels were significantly correlated with poor overall survival (OS; HMMR: adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI]=1.10-3.41, p=0.023; SDC1: [aHR] 2.47, 95%CI=1.28-4.77, p=0.007) for breast cancer. Combined, the effects of HMMR and SDC1 showed a significant correlation with poor OS for patients with breast cancer (high expression for both HMMR and SDC1: [aHR] 3.29, 95%CI=1.52-7.12, p=0.003).

Conclusion: These findings suggest that HMMR and SDC1 involved in the ECM-receptor interaction signaling pathway could act as effective independent prognostic biomarkers for breast ductal carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.12764DOI Listing
August 2018

Comprehensive identification of microRNA arm selection preference in lung cancer: miR-324-5p and -3p serve oncogenic functions in lung cancer.

Oncol Lett 2018 Jun 24;15(6):9818-9826. Epub 2018 Apr 24.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, R.O.C.

MicroRNA (miRNA/miR) dysfunction is a hallmark of lung cancer, and results in the dysregulation of tumor suppressors and oncogenes during lung cancer progression. Selection of the 5p and 3p arms of miRNA is a mechanism that improves the modulation of miRNA biological functions and complicates the regulatory network in human types of cancer. However, the involvement of arm selection preference of miRNA in lung cancer remains unclear. In the present study, changes in miRNA arm selection preference were comprehensively identified in lung cancer and corresponding adjacent normal tissues by analyzing The Cancer Genome Atlas. Arm selection was revealed to be consistent in the majority of miRNAs in lung cancer. Only a few miRNAs had significantly altered arm selection preference in lung cancer. Among these, the biological functions of the individual arms of miR-324 were investigated further. The data revealed that miR-324-5p and -3p were significantly overexpressed in lung cancer cells. Ectopic expression of miR-324-5p significantly promoted cell proliferation and invasion in lung cancer cells, while miR-324-3p overexpression significantly increased cell proliferation but did not alter the invasion of lung cancer cells. In conclusion, the arm selection preference of miRNA may be an additional mechanism through which biological functions are modulated. The results of the present study provide a novel insight into the underlying mechanisms of lung cancer and may direct research into future therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2018.8557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958786PMC
June 2018

Isocitrate dehydrogenase 1-snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability.

Breast Cancer Res 2018 04 16;20(1):25. Epub 2018 Apr 16.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan, Republic of China.

Background: The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown.

Methods: In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion.

Results: The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage (p = 0.012), lymph node metastasis (p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08-2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32-4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39-4.50; p = 0.002) in patients with breast cancer.

Conclusion: Our findings revealed that a IDH1/Snail molecular signature could serve as an independent biomarker for poor prognosis in breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-018-0953-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902927PMC
April 2018

Impact of hepatitis C virus infection on long-term mortality after acute myocardial infarction: a nationwide population-based, propensity-matched cohort study in Taiwan.

BMJ Open 2018 01 26;8(1):e017412. Epub 2018 Jan 26.

Critical Care Center and Cardiovascular Medical Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Introduction: The influence of hepatitis C virus (HCV) infection on long-term outcomes of patients with acute myocardial infarction (AMI) is unclear. Therefore, this study aimed to analyse the impact of HCV infection on 12-year mortality rates after AMI using data from the Taiwan National Health Insurance Research Database (NHIRD).

Methods: NHIRD data for approximately 23 000 000 patients between January 2000 and December 2012 were analysed. A total of 186 112 cases of first AMI admission were identified. A total of 4659 patients with HCV infection not receiving interferon therapy were enrolled and divided into those with (n=107) or without (n=4552) cirrhosis. Using one-to-one matching, 4552 matched controls were included in the final analysis.

Results: The 12-year mortality rate was significantly higher in patients with AMI with HCV infection and cirrhosis than in those with HCV infection but without cirrhosis (P<0.0001) or controls (P<0.0001). Patients with HCV infection but without cirrhosis had significantly higher long-term mortality rates than the matched controls (P<0.0001). The HR for mortality was higher in patients with HCV infection (HR 1.12; 95% CI 1.06 to 1.18). HCV influenced outcomes among the subgroups of patients who were male (HR 1.15) and those who had hypertension (HR 1.14).

Conclusions: HCV infection influenced the 12-year mortality rates of patients with AMI, especially those who were male and those who had hypertension. Cirrhosis further increased the long-term mortality rates of patients with AMI with HCV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2017-017412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829782PMC
January 2018

Prevention of Tamoxifen-related Nonalcoholic Fatty Liver Disease in Breast Cancer Patients.

Clin Breast Cancer 2018 08 23;18(4):e677-e685. Epub 2017 Nov 23.

School of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Tamoxifen is commonly used to prevent breast cancer recurrence. Studies have confirmed the association between tamoxifen and nonalcoholic fatty liver disease (NAFLD), with the results indicating the need for aggressive management of this side effect. We assessed the potential risk factors for and identified the possible protective factors of tamoxifen-related fatty liver.

Materials And Methods: We enrolled patients with a history of breast cancer, aged 20 to 70 years, who had received with tamoxifen treatment within the past 5 years. We obtained the initial data and performed a follow-up blood test and ultrasound examination to compare the differences before and after tamoxifen treatment. The patients were divided into relatively normal and fatty liver groups.

Results: Of the 266 enrolled tamoxifen-treated patients, 143 (53.8%) and 123 (46.2%) were in the relatively normal and fatty liver groups, respectively. The initial body weight (57.6 ± 9.3 kg vs. 60.9 ± 10.3 kg; P = .006) and body mass index (BMI; 23.4 ± 3.8 kg/m vs. 25.0 ± 4.2 kg/m; P < .001) were lower in the relatively normal group. An initial BMI of ≥ 22 kg/m was a potential risk factor for tamoxifen-related NAFLD (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.00-2.48; P = .048). In contrast, a weekly exercise duration of ≥ 150 minutes reduced the risk (HR, 0.47; 95% CI, 0.31-0.69; P < .001).

Conclusion: The results from our study suggest that a BMI of ≥ 22 kg/m is a potential risk factor for tamoxifen-related fatty liver and exercise is a possible protective factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clbc.2017.11.010DOI Listing
August 2018

miR-105/93-3p promotes chemoresistance and circulating miR-105/93-3p acts as a diagnostic biomarker for triple negative breast cancer.

Breast Cancer Res 2017 Dec 19;19(1):133. Epub 2017 Dec 19.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20-30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients.

Methods: The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student's t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction.

Results: miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/β-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease.

Conclusions: miR-105/93-3p activates Wnt/β-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-017-0918-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738224PMC
December 2017

An Analysis of Emergency Department Visits and the Survival Rate for Colorectal Cancer Patients: A Nationwide Population-based Study.

Intern Med 2017 Aug 1;56(16):2125-2132. Epub 2017 Aug 1.

Radiation Oncology Department, Kaohsiung Veterans General Hospital, Taiwan.

Objective We examined the general characteristics, survival rate, and most common reasons for visiting the emergency department (ED) among colorectal cancer patients in Taiwan. We performed a population-based retrospective study and used data sourced from the National Health Insurance Research Database (NHIRD). Methods The colorectal cancer patient population, their diagnosis, and their medical management at the ED were identified using the Longitudinal Health Insurance Database 2000 (HV) codes and International Classification of Diseases, Ninth Revision, Clinical Modification system. We investigated their reasons for visiting the ED and the medications used there, analyzed their cumulative survival curves using the Kaplan-Meier method, and compared the survival curves with other colorectal cancer patients who had never visited the ED. Results Between 2000 and 2012, there were 6,532 ED visits by 3,347 colorectal patients, and the number per year increased gradually. The top three most common reasons for visiting ED were ill-defined conditions, abdominal pain, and intestinal obstruction. The overall survival rates of colorectal patients in the ED visit group at 3, 5, and 10 years, were 0.65, 0.56, and 0.47, respectively, without significant differences from the rates among colorectal cancer patients who did not visit the ED (p=0.2072). Conclusion We described the circumstances of ED visitation by colorectal cancer patients in Taiwan. Health care providers and researchers should pay more attention to improve medical care quality and investigate more details to predict the outcome among colorectal cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.7629-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596271PMC
August 2017

The impact of DPP-4 inhibitors on long-term survival among diabetic patients after first acute myocardial infarction.

Cardiovasc Diabetol 2017 07 11;16(1):89. Epub 2017 Jul 11.

Critical Care Center and Cardiovascular Medical Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Background: Previous studies regarding the cardioprotective effects of dipeptidyl peptidase 4 (DPP-4) inhibitors have not provided sufficient evidence of a relationship between DPP-4 inhibition and actual cardiovascular outcomes. This study aimed to evaluate the impact of DPP-4 inhibitors on the survival of diabetic patients after first acute myocardial infarction (AMI).

Methods: This was a nationwide, propensity score-matched, case-control study of 186,112 first AMI patients, 72,924 of whom had diabetes. A propensity score, one-to-one matching technique was used to match 2672 controls to 2672 patients in the DPP-4 inhibitor group for analysis. Controls were matched based on gender, age, and a history of hypertension, dyslipidemia, diabetes, peripheral vascular disease, heart failure, cerebrovascular accident, end-stage renal disease, chronic obstructive pulmonary disease, and percutaneous coronary intervention.

Results: DPP-4 inhibitors improve the overall 3-year survival rate (log rank P < 0.0001), whether male or female. Cox proportional hazard regression showed DPP-4 inhibitor is beneficial in diabetes patients after AMI (HR = 0.86; 95% CI 0.78-0.95), especially in those patients with hypertension (HR = 0.87; 95% CI 0.78-0.97; P = 0.0103) and cerebrovascular disease (HR = 0.83; 95% CI 0.72-0.97; P = 0.018), but without dyslipidemia (HR = 0.78; 95% CI 0.67-0.92; P = 0.0029), without peripheral vascular disease (HR = 0.86; 95% CI 0.78-0.96; P = 0.0047), without heart failure (HR = 0.84; 95% CI 0.73-0.96; P = 0.0106), without end stage renal disease (HR = 0.86; 95% CI 0.77-0.95; P = 0.0035), and without chronic obstructive pulmonary disease (HR = 0.87; 95% CI 0.78-0.97; P = 0.0096).

Conclusions: DPP-4 inhibitor therapy improved long-term survival in diabetic patients after first AMI, regardless of gender.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-017-0572-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505012PMC
July 2017

Analysis of gallstone disease after gastric cancer surgery.

Gastric Cancer 2017 Sep 2;20(5):895-903. Epub 2017 Feb 2.

Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Rd, Zuoying District, Kaohsiung, 81362, Taiwan.

Background: The incidence rate of newly developed gallstone disease after gastrectomy for gastric cancer is thought to be higher than that in the general population. However, the presentation and management of these gallstones remain under debate, and the role of prophylactic cholecystectomy remains questionable.

Methods: Data on adult patients who were diagnosed with gastric cancer and received gastrectomy between 2000 and 2011 were extracted from the Taiwan National Health Insurance Research Database. A patient was excluded if he or she had gallstone disease or received cholecystectomy before the index date. The incidence of newly developed gallstone disease and its subsequent management were recorded. Data were analyzed to evaluate the factors associated with gallstone development and treatment options.

Results: A total of 17,325 gastric cancer patients who underwent gastrectomy were eligible for analysis. During the follow-up period (mean 4.1 years; median, 2.9 years), 1280 (7.4%) patients developed gallstone disease and 560 (3.2%) patients subsequently underwent cholecystectomy. The in-hospital mortality for cholecystectomy was 1.8% (10/560). Development of gallstone disease was associated with older age, total gastrectomy, duodenal exclusion, diabetes, cirrhosis, and more comorbidities. Factors associated with the use of cholecystectomy to treat gallstone disease included younger age, fewer comorbidities, medical center admission, and presentation as cholecystitis.

Conclusions: Although few patients required further gallbladder removal after gastrectomy for gastric malignancy, the increased mortality rate for subsequent cholecystectomy was worth noting. The decision to undergo prophylactic cholecystectomy might be individualized based upon patient characteristics and the surgeon's discretion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10120-017-0698-5DOI Listing
September 2017

Breast Cancer Incidence and Predictors of Surgical Outcome: a Nationwide Longitudinal Study in Taiwan.

Clin Oncol (R Coll Radiol) 2017 Jun 27;29(6):362-369. Epub 2017 Jan 27.

Department of Business Management, National Sun Yat-sen University, Kaohsiung 80607, Taiwan, Republic of China. Electronic address:

Aims: Despite the huge and growing global burden of patients who require breast cancer surgery, high-quality population-based studies of breast cancer trends and outcomes are scarce. The purpose of this study was to explore the incidence of breast cancer and predictors of hospital resource utilisation, mortality and recurrence in a nationwide population of patients who have received surgery.

Materials And Methods: This retrospective study analysed trends and outcomes in a Taiwan population of 77 971 patients after breast cancer surgery during 1996-2010. The Cox proportional hazards model was used for multivariate assessment of both mortality and recurrence predictors.

Results: The data analysis indicated that, during this period, the estimated mean hospital treatment cost and mean length of stay increased by 16.3% and 53.4%, respectively. The estimated mean overall survival time was 138.9 months (standard deviation 0.3 months) and the overall 1, 3, 5 and 10 year survival rates were 97.3, 89.2, 82.2 and 70.1%, respectively. The estimated mean overall recurrence time was 10.8 months (standard deviation 0.2 months) and the overall 1, 3, 5 and 10 year recurrence rates were 0.1, 18.8, 26.6 and 36.0%, respectively. Outcomes were significantly associated with age, Deyo-Charlson comorbidity index score, surgeon seniority, hospital volume, surgeon volume, surgery type, hospital level and baseline comorbidities (P<0.001).

Conclusions: Analyses of these population-based data revealed simultaneous increases in the standard incidence of breast cancer surgery and its associated medical resource utilisation. Notably, healthcare providers and patients should recognise that both patient attributes and hospital attributes may affect breast cancer surgery outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clon.2017.01.005DOI Listing
June 2017

Do racial differences exist in the association between pregnancy-induced hypertension and breast cancer risk?

Hypertens Pregnancy 2017 May 19;36(2):138-144. Epub 2017 Jan 19.

j Department of Surgery , Kaohsiung Veterans General Hospital , Kaoh , Taiwan.

Background: Previous studies investigating the relationship between pregnancy-induced hypertension (PIH) and breast cancer risk have yielded inconsistent results. Unlike numerous Western studies, studies have reported that PIH may be a risk factor for breast cancer in Western Asian women. To confirm these results, we designed a retrospective population-based cohort study to assess the relationship between PIH and subsequent risk for breast cancer in Taiwan.

Methods: Patients with newly diagnosed PIH were selected from the Taiwan National Health Insurance Research Database (NHIRD), and a 1:4 matched cohort of women without PIH based on age and the year of delivery was randomly selected from the same database as the comparison group. The incidence of new-onset breast cancer was assessed in both cohorts.

Results: Among the 23.3 million individuals registered in the NHIRD, 26,638 patients with PIH and 106,552 matched controls were identified. The incidence rate of breast cancer was higher in patients with PIH than in the matched controls (incidence rate ratio = 1.09, 95% confidence interval [CI] = 1.09-1.10, p < 0.0001). However, the Kaplan-Meier analysis revealed a similar cumulative incidence rate of breast cancer between the PIH and comparison cohorts (log-rank p = 0.4303). Moreover, results from a multivariate analysis indicated that PIH was not a statistically significant independent risk factor for breast cancer (adjusted hazard ratio = 1.10, 95% CI = 0.87-1.39, p = 0.4247).

Conclusions: The present study demonstrated no significant temporal relationship between PIH and risk for subsequent breast cancer in Eastern Asian women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10641955.2016.1258411DOI Listing
May 2017

Effect of thymol on Ca²⁺ homeostasis and viability in PC3 human prostate cancer cells.

Chin J Physiol 2017 Feb;60(1):32-40

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.

Thymol is a phenolic compound that affects physiology in different cell models. However, whether thymol affects Ca²⁺ homeostasis in prostate cancer cells is unknown. The action of this compound on cytosolic Ca²⁺ concentrations ([Ca²⁺]i) and viability in PC3 human prostate cancer cells was explored. The results show that thymol at concentrations of 100-1500 μM caused [Ca²⁺]i rises in a concentration-dependent manner. Removal of extracellular Ca²⁺ reduced thymol’s effect by approximately 80%. Thymol-induced Ca²⁺ entry was confirmed by Mn²⁺ entry-induced quench of fura-2 fluorescence, and was inhibited by approximately 30% by Ca²⁺ entry modulators (nifedipine, econazole, SKF96365), and the protein kinase C (PKC) inhibitor GF109203X. In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin abolished thymol-induced [Ca²⁺]i rises. Treatment with thymol also abolished thapsigargin-induced [Ca²⁺]i rises. Thymol-induced Ca²⁺ release from the endoplasmic reticulum was abolished by the phospholipase C (PLC) inhibitor U73122. Thymol at 100-900 μM decreased cell viability, which was not reversed by pretreatment with the Ca²⁺ chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N’,N’-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in PC3 cells, thymol induced [Ca²⁺]i rises by inducing PLC-dependent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ entry via PKC-sensitive store-operated Ca²⁺ channels and other unknown channels. Thymol also induced Ca²⁺-dissociated cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4077/CJP.2017.BAF447DOI Listing
February 2017

MicroRNA-324 in Human Cancer: miR-324-5p and miR-324-3p Have Distinct Biological Functions in Human Cancer.

Anticancer Res 2016 10;36(10):5189-5196

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.

MicroRNAs (miRNAs) are small non-coding RNAs that have crucial regulatory functions in carcinogenesis. miR-324-5p and miR-324-3p are generated from the same hairpin RNA structure, however, both are diverse in their direct target genes and expression levels. We report that expression of miR-324-5p and -3p was frequently observed to be either up-regulated or down-regulated, and the selection preference of miR-324 for 5p and 3p arms significantly varied in various types or human cancer. Overexpression of miR-324-5p or -3p suppressed growth and invasion of breast cancer cells. Overexpression of miR-324-5p reduced the growth and invasive abilities of colorectal cancer cells, whereas miR-324-3p suppressed colorectal cancer cell invasion but did not influence cell growth. We conclude that miR-324-5p and miR-324-3p might have distinct biological functions, further complicating the regulatory network in human cancer. Therefore, the arm selection preference of miR-324 may be a method for modulating its function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.11089DOI Listing
October 2016

Effect of protriptyline on [Ca] and viability in MG63 human osteosarcoma cells.

Toxicol Mech Methods 2016 Oct 28;26(8):580-587. Epub 2016 Oct 28.

e Department of Medical Education and Research , Kaohsiung Veterans General Hospital , Kaohsiung , Taiwan.

Tricyclic antidepressants (TCA) have been clinically prescribed in the auxiliary treatment of cancer patients. Although protriptyline, a type of TCA, was used primarily in the clinical treatment of mood disorders in cancer patients, the effect of protriptyline on physiology in human osteosarcoma is unknown. This study examined the effect of protriptyline on cytosolic free Caconcentrations ([Ca]) and viability in MG63 human osteosarcoma cells. Protriptyline between 50 and 250 μM evoked [Ca] rises concentration-dependently. Protriptyline induced influx of Mn, indirectly implicating Cainflux. Protriptyline-evoked Caentry was inhibited by nifedipine by 20% but was not altered by econazole, SKF96365, GF109203X, and phorbol-12-myristate-13-acetate (PMA). In Ca-free medium, treatment with protriptyline inhibited the endoplasmic reticulum Capump inhibitor thapsigargin-evoked [Ca] rises. Conversely, treatment with thapsigargin inhibited 45% of protriptyline-evoked [Ca] rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter protriptyline-evoked [Ca] rises. Protriptyline at 50-250 μM decreased cell viability, which was not reversed by pretreatment with the Cachelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, our data suggest that in MG63 cells, protriptyline induced [Ca] rises by evoking Carelease from the endoplasmic reticulum and other stores in a PLC-independent manner, and Caentry via a nifedipine-sensitive Capathway. Protriptyline also caused Ca-independent cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15376516.2016.1216208DOI Listing
October 2016

Mechanisms underlying effect of the mycotoxin cytochalasin B on induction of cytotoxicity, modulation of cell cycle, Ca homeostasis and ROS production in human breast cells.

Toxicology 2016 Aug 1;370:1-19. Epub 2016 Oct 1.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC,. Electronic address:

Cytochalasin B, a cell-permeable mycotoxin isolated from the fungus Phoma spp., shows a wide range of biological effects, among which its potent antitumor activity has raised great interests in different models. However, the cytotoxic activity of cytochalasin B and its underlying mechanisms have not been elucidated in breast cells. This study examined the effect of cytochalasin B on MCF 10A human breast epithelial cells and ZR-75-1 human breast cancer cells. Cytochalasin B (10-20μM) concentration-dependently induced cytotoxicity, cell cycle arrest, and [Ca] rises in ZR-75-1 cells but not in MCF 10A cells. In ZR-75-1 cells, cytochalasin B triggered G2/M phase arrest through the modulation of CDK1, cyclin B1, p53, p27 and p21 expressions. The Ca signal response induced by cytochalasin B was reduced by removing extracellular Ca and was inhibited by the store-operated Ca channel blocker 2-APB and SKF96365. In Ca-free medium, cytochalasin B induced Ca release through thapsigargin-sensitive endoplasmic reticulum stores. Moreover, cytochalasin B increased HO levels but reduced GSH levels. The apoptotic effects evoked by cytochalasin B were partially inhibited by prechelating cytosolic Ca with BAPTA-AM and the antioxidant NAC. Together, in ZR-75-1 cells but not in MCF 10A cells, cytochalasin B activated Ca-associated mitochondrial apoptotic pathways that involved G2/M phase arrest and ROS signaling. Furthermore, cytochalasin B induced [Ca] rises by releasing Ca from the endoplasmic reticulum and causing Ca influx through 2-APB or SKF96365-sensitive store-operated Ca entry. Our findings provide new insights into the possible application of cytochalasin B in human breast cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tox.2016.09.006DOI Listing
August 2016

RelA-Mediated BECN1 Expression Is Required for Reactive Oxygen Species-Induced Autophagy in Oral Cancer Cells Exposed to Low-Power Laser Irradiation.

PLoS One 2016 15;11(9):e0160586. Epub 2016 Sep 15.

Department of Stomatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Low-power laser irradiation (LPLI) is a non-invasive and safe method for cancer treatment that alters a variety of physiological processes in the cells. Autophagy can play either a cytoprotective role or a detrimental role in cancer cells exposed to stress. The detailed mechanisms of autophagy and its role on cytotoxicity in oral cancer cells exposed to LPLI remain unclear. In this study, we showed that LPLI at 810 nm with energy density 60 J/cm2 increased the number of microtubule associated protein 1 light chain 3 (MAP1LC3) puncta and increased autophagic flux in oral cancer cells. Moreover, reactive oxygen species (ROS) production was induced, which increased RelA transcriptional activity and beclin 1 (BECN1) expression in oral cancer cells irradiated with LPLI. Furthermore, ROS scavenger or knockdown of RelA diminished LPLI-induced BECN1 expression and MAP1LC3-II conversion. In addition, pharmacological and genetic ablation of autophagy significantly enhanced the effects of LPLI-induced apoptosis in oral cancer cells. These results suggest that autophagy may be a resistant mechanism for LPLI-induced apoptosis in oral cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160586PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025201PMC
August 2017

Effect of NPC15199 on [Ca²⁺]i and viability in SCM1 human gastric cancer cells.

Chin J Physiol 2016 Oct;59(5):268-275

Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.

NPC15199 is a synthesized compound that inhibits inflammation in some models. However, whether NPC15199 affects Ca²⁺ homeostasis in human gastric cancer is unclear. This study examined the effect of NPC15199 on cytosolic free Ca²⁺ concentrations ([Ca²⁺]i) and viability in SCM1 human gastric cancer cells. The Ca²⁺-sensitive fluorescent dye fura-2 was used to measure [Ca²⁺]i. NPC15199 evoked [Ca²⁺]i rises concentration-dependently. The response was reduced by removing extracellular Ca²⁺. NPC15199-evoked Ca²⁺ entry was not inhibited by store-operated channel inhibitors (nifedipine, econazole and SKF96365) and protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate, PMA), or PKC inhibitor (GF109203X). In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) nearly abolished NPC15199-evoked [Ca²⁺]i rises. Conversely, treatment with NPC15199 also nearly abolished thapsigargin or BHQ-evoked [Ca²⁺]i rises. Inhibition of phospholipase C (PLC) with U73122 did not affect NPC15199-evoked [Ca²⁺]i rises. NPC15199 at concentrations of 100-900 μM induced concentration-dependent, Ca²⁺-independent decrease in viability. Together, in SCM1 cells, NPC15199 induced [Ca²⁺]i rises that involved Ca²⁺ entry through PKC-insensitive non-store-operated Ca²⁺ channels and PLC-independent Ca²⁺ release from the endoplasmic reticulum. NPC15199 also induced Ca²⁺-independent cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4077/CJP.2016.BAF421DOI Listing
October 2016

CTMP, a predictive biomarker for trastuzumab resistance in HER2-enriched breast cancer patient.

Oncotarget 2017 May;8(18):29699-29710

Institute of Clinical Medicine, Medical College, National Cheng Kung University, Tainan, Taiwan.

Trastuzumab is regarded as the primary therapy for patients with HER2-enriched breast cancer, but the pathological complete response for advanced cases is less than 30%. The underlying mechanism of trastuzumab resistance remains unclear and there are currently no conclusive biomarkers for patient response to trastuzumab. Identifying predictive biomarkers for trastuzumab response may allow treatments to be individually tailored and optimized multi-target therapies may be developed. CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance. In this study, we examined samples from 369 patients to investigate the correlation between CTMP expression level and patient outcome. Elevated CTMP expression was correlated with adverse outcomes in HER2-enriched patients including overall and disease-free survival as well as trastuzumab resistance. Ectopic expression of varying levels of CTMP in SkBR3 cells dose-dependently attenuated trastuzumab-mediated growth inhibition through AKT activation. In addition, inhibition of AKT signaling by AKT inhibitor IV and Rapamycin reversed CTMP-mediated trastuzumab resistance. In clinical samples, the high expression of CTMP was showed in trastuzumab non-responders and positively correlated with AKT activity. Taken together, we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2-enriched breast cancer. High CTMP expression not only predicted poor prognosis, but may also predict resistance to trastuzumab in HER2-enriched patients. Therefore, CTMP expression may be considered as a prognostic biomarker in HER2-enriched breast cancer and high expression may indicate a utility for AKT-inhibition in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.10719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444696PMC
May 2017

Arm Selection Preference of MicroRNA-193a Varies in Breast Cancer.

Sci Rep 2016 06 16;6:28176. Epub 2016 Jun 16.

Center For Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

MicroRNAs (miRNAs) are short noncoding RNAs derived from the 3' and 5' ends of the same precursor. However, the biological function and mechanism of miRNA arm expression preference remain unclear in breast cancer. We found significant decreases in the expression levels of miR-193a-5p but no significant differences in those of miR-193a-3p in breast cancer. MiR-193a-3p suppressed breast cancer cell growth and migration and invasion abilities, whereas miR-193a-5p suppressed cell growth but did not influence cell motility. Furthermore, NLN and CCND1, PLAU, and SEPN1 were directly targeted by miR-193a-5p and miR-193a-3p, respectively, in breast cancer cells. The endogenous levels of miR-193a-5p and miR-193a-3p were significantly increased by transfecting breast cancer cells with the 3'UTR of their direct targets. Comprehensive analysis of The Cancer Genome Atlas database revealed significant differences in the arm expression preferences of several miRNAs between breast cancer and adjacent normal tissues. Our results collectively indicate that the arm expression preference phenomenon may be attributable to the target gene amount during breast cancer progression. The miRNA arm expression preference may be a means of modulating miRNA function, further complicating the mRNA regulatory network. Our findings provide a new insight into miRNA regulation and an application for breast cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep28176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910092PMC
June 2016

Ca Signaling and Cell Death Induced by Protriptyline in HepG2 Human Hepatoma Cells.

J Biochem Mol Toxicol 2016 Nov 2;30(11):539-547. Epub 2016 Jun 2.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

The effect of protriptyline on Ca physiology in human hepatoma is unclear. This study explored the effect of protriptyline on [Ca ] and cytotoxicity in HepG2 human hepatoma cells. Protriptyline (50-150 μM) evoked [Ca ] rises. The Ca entry was inhibited by removal of Ca . Protriptyline-induced Ca entry was confirmed by Mn -induced quench of fura-2 fluorescence. Except nifedipine, econazole, SKF96365, GF109203X, and phorbol 12-myristate 13 acetate did not inhibit Ca entry. Treatment with the endoplasmic reticulum Ca pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) inhibited 40% of protriptyline-induced response. Treatment with protriptyline abolished BHQ-induced response. Inhibition of phospholipase C (PLC) suppressed protriptyline-evoked response by 70%. At 20-40 μM, protriptyline killed cells which was not reversed by the Ca chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in HepG2 cells, protriptyline induced [Ca ] rises that involved Ca entry through nifedipine-sensitive Ca channels and PLC-dependent Ca release from endoplasmic reticulum. Protriptyline induced Ca -independent cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbt.21820DOI Listing
November 2016

The effect of the phenol compound ellagic acid on Ca(2+) homeostasis and cytotoxicity in liver cells.

Eur J Pharmacol 2016 Jun 30;780:243-51. Epub 2016 Mar 30.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC. Electronic address:

Ellagic acid, a natural phenol compound found in numerous fruits and vegetables, causes various physiological effects in different cell models. However, the effect of this compound on Ca(2+) homeostasis in liver cells is unknown. This study examined the effect of ellagic acid on intracellular Ca(2+) concentration ([Ca(2+)]i) and established the relationship between Ca(2+) signaling and cytotoxicity in liver cells. The data show that ellagic acid induced concentration-dependent [Ca(2+)]i rises in HepG2 human hepatoma cells, but not in HA22T, HA59T human hepatoma cells or AML12 mouse hepatocytes. In HepG2 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by store-operated Ca(2+) channel blockers (2-APB, econazole or SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin abolished ellagic acid-induced [Ca(2+)]i rises. Conversely, incubation with ellagic acid abolished thapsigargin-induced [Ca(2+)]i rises. Inhibition of phospholipase C (PLC) with U73122 also abolished ellagic acid-induced [Ca(2+)]i rises. Ellagic acid (25-100μM) concentration-dependently caused cytotoxicity in HepG2, HA22T or HA59T cells, but not in AML12 cells. Furthermore, this cytotoxic effect was partially prevented by prechelating cytosolic Ca(2+) with BAPTA-AM only in HepG2 cells. Together, in HepG2 cells, ellagic acid induced [Ca(2+)]i rises by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-sensitive store-operated Ca(2+) channels. Moreover, ellagic acid induced Ca(2+)-associated cytotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2016.03.057DOI Listing
June 2016

Analysis of Recurrence Management in Patients Who Underwent Nonsurgical Treatment for Acute Appendicitis.

Medicine (Baltimore) 2016 Mar;95(12):e3159

From the Division of General Surgery (T-JL, S-IL, C-YT, C-HK, H-TC, I-SC), Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung; School of Medicine (S-IL, W-CH, H-TC), National Yang-Ming University, Taipei; and Critical Care Center and Cardiovascular Medical Center (W-CH), Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

The recurrence rate for acute appendicitis treated nonoperatively varies between studies. Few studies have adequately evaluated the management of these patients when appendicitis recurs. We aimed to explore the recurrence rate and management of patients with acute appendicitis that were first treated nonoperatively.We identified patients in the Taiwan National Health Insurance Research Database who were hospitalized due to acute appendicitis for the first time between 2000 and 2010 and received nonsurgical treatment. The recurrence and its management were recorded. Data were analyzed to access the risk factors for recurrence and factors that influenced the management of recurrent appendicitis.Among the 239,821 patients hospitalized with acute appendicitis for the first time, 12,235 (5.1%) patients were managed nonoperatively. Of these, 864 (7.1%) had a recurrence during a median follow-up of 6.5 years. Appendectomy was performed by an open and laparoscopic approach in 483 (55.9%) and 258 (29.9%) patients, respectively. The remaining 123 (14.2%) patients were again treated nonsurgically. Recurrence was independently associated with young age, male sex, percutaneous abscess drainage, and medical center admission by multivariable analysis. In addition, age <18, a (CCI) <2, medical center admission, and a longer time to recurrence were correlated with using laparoscopy to treat recurrence. Neither type of appendicitis, percutaneous abscess drainage, nor length of first time hospital stay had an influence on the selection of surgical approach.In conclusion, a laparoscopic appendectomy can be performed in recurrent appendicitis cases, and its application may not be related to previous appendicitis severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000003159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998395PMC
March 2016
-->