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Hsu H.-H.,Mackay Memorial Hospital | Hsu H.-H.,Nursing and Management College | Cheng L.-H.,China Medical University at Taichung | Ho T.-J.,China Medical University at Taichung | And 9 more authors.
Tumor Biology | Year: 2014

Despite rapid advances in the diagnostic and surgical procedures, hepatocellular carcinoma (HCC) remains one of the most difficult human malignancies to treat. This may be due to the chemoresistant behaviors of HCC. It is believed that acquired resistance could be overcome and improve the overall survival of HCC patients by understanding the mechanisms of chemoresistance in HCC. A stable HA22T cancer line, which is chronically resistant to a histone deacetylase inhibitor, was established. After comparing the molecular mechanism of apicidin-R HA22T cells to parental ones by Western blotting, cell cycle-regulated proteins did not change in apicidin-R cells, but apicidin-R cells were more proliferative and had higher tumor growth (wound-healing assay and nude mice xenograft model). Moreover, apicidin-R cells displayed increased levels of p-IGF-IR, p-PI3K, p-Akt, Bcl-xL, and Bcl-2 but also significantly inhibited the tumor suppressor PTEN protein and apoptotic pathways when compared to the parental strain. Therefore, the highly proliferative effect of apicidin-R HA22T cells was blocked by Akt knockdown. For all these findings, we believe that novel strategies to attenuate IGF-IR/PI3K/Akt signaling could overcome chemoresistance toward the improvement of overall survival of HCC patients. © 2013 International Society of Oncology and BioMarkers (ISOBM).

Chiu C.-T.,Kaohsiung Memorial Center | Chiang W.-F.,Chi Mei Medical Center Liouying | Chuang C.-Y.,Faculty | Chang S.-W.,Kaohsiung Memorial Center
Journal of Oral and Maxillofacial Surgery | Year: 2010

Purpose: To offer recommendations of risk factors, prevention, and treatment of oral bisphosphonate and steroid-related osteonecrosis of the jaw (BSRONJ) in Taiwan. Materials and Methods: Twelve patients were clinicopathologically proved to have bisphosphonate-related osteonecrosis of the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were concurrently administered long-term steroids. Of the 12 patients, 3 patients were assigned to the first stage of BRONJ; 5 patients were assigned to the second stage, and 4 patients were assigned to the third stage. The patients' symptoms, localization of necrosis, presence of a fistula, and association with possible triggering factors for onset of the lesion were recorded. Results: The radiologic investigations revealed osteolytic areas and scintigraphy demonstrated increased bone metabolism. Microbiologic analysis showed pathogenic actinomycosis organisms in a majority of patients (91.6%). Antibiotic therapy, minor debridement surgery, and combined hyperbaric oxygen therapy were useful in obtaining short-term symptomatic relief. Conclusions: Comorbidities of steroid use along with bisphosphonates may cause osteonecrosis of the jaw to occur sooner, be more severe, and respond more slowly to a drug discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to treat than BRONJ. From the data gained from other published studies of BRONJ and our clinical experience with the series of cases of BSRONJ, we offer recommendations of risk factors, prevention, and treatment of BSRONJ in southern Taiwan. © 2010 American Association of Oral and Maxillofacial Surgeons.

Lan J.,Chang Gung University | Huang H.-Y.,Chang Gung University | Lee S.-W.,Chi Mei Medical Center Liouying | Chen T.-J.,Chi Mei Medical Center | And 8 more authors.
Tumor Biology | Year: 2014

Despite the advances in diagnostic imaging and treatment modalities, the risk stratification and final outcomes in patients with nasopharyngeal carcinomas (NPC) still remain suboptimal. Through data mining from published transcriptomic database, topoisomerase IIα (TOP2A) was first identified as a differentially upregulated gene in NPC tissues, which implicates cell division via selective cleavage, rearrangement, and re-ligation of DNA strands. Given the roles of TOP2A in prognostication and in the frontline therapeutic regimen of common carcinomas, such as breast cancer, we explored TOP2A immunoexpression status and its associations with clinicopathological variables and survival in a well-defined cohort of NPC patients. TOP2A immunohistochemistry was retrospectively performed and analyzed using H-score method for biopsy specimens from 124 NPC patients who received standard treatment without distant metastasis at initial diagnosis. Those cases with H-score larger than the median value were construed as featuring TOP2A overexpression. The findings were correlated with the clinicopathological variables, disease-specific survival (DSS) and distant metastasis-free survival (DMFS). TOP2A overexpression was significantly associated with American Joint of Cancer Committee (AJCC) stages III-IV (p = 0.019) and univariately predictive of adverse outcomes for DSS (p = 0.0078) and DMFS (p = 0.0003). In the multivariate comparison, TOP2A overexpression remained prognostically independent to portend worse DSS (p = 0.047, hazard ratio = 1.732) and DMFS (p = 0.003, hazard ratio = 2.569), together with advanced AJCC stages III-IV. TOP2A expression is upregulated in a subset of NPCs and its increased immunoexpression significantly correlated with advanced stages and tumor aggressiveness, justifying the potentiality of TOP2A as a prognostic biomarker and a novel therapeutic target of NPC. © 2013 International Society of Oncology and BioMarkers (ISOBM).

Lee L.-M.,Taipei Medical University | Tsai T.-C.,Chi Mei Medical Center Liouying | Chung H.-H.,National Cheng Kung University | Tong Y.-C.,National Cheng Kung University | And 2 more authors.
BJU International | Year: 2012

OBJECTIVES To compare agmatine-induced prostatic relaxation in hypertensive and control rats. To investigate the responsible mechanism(s) and the role of the ATP-sensitive potassium channel. Methods Prostate strips were isolated from male spontaneously hypertensive (SH) rats and normal Wistar-Kyoto (WKY) rats for measurement of isometric tension. The strips were precontracted with 1 Âμmol/L phenylephrine or 50 mmol/L KCl. Dose-dependent relaxation of the prostatic strips was studied by cumulative administration of agmatine, 1 to 100 Âμmol/L, into the organ bath. Effects of specific antagonists on agmatine-induced relaxation were studied. Western blotting analysis was used to measure the gene expression of the ATP-sensitive potassium channel in the rat prostate. Results Prostatic relaxation induced by agmatine was markedly reduced in SH rats compared with WKY rats. The relaxation caused by agmatine was abolished by BU224, a selective imidazoline I2-receptor antagonist, but was not modified by efaroxan at a dose sufficient to block imidazoline I1-receptors. The relaxation induced by diazoxide at a concentration sufficient to activate ATP-sensitive potassium channels was markedly reduced in the SH rat prostate. Expressions of ATP-sensitive potassium channel sulphonylurea receptor and inwardly rectifying potassium channel (Kir) 6.2 subunits were both decreased in the prostate of SH rats. CONCLUSION The decrease of agmatine-induced prostatic relaxation in SH rats is related to the change in ATP-sensitive potassium channels. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.

Lee L.-M.,Taipei Medical University | Lin C.-H.,Chi Mei Medical Center Liouying | Chung H.-H.,National Cheng Kung University | Cheng J.-T.,Chi Mei Medical Center | And 2 more authors.
LUTS: Lower Urinary Tract Symptoms | Year: 2013

Objectives: The effect of agmatine on prostate contractility as well as the roles of imidazoline receptors and potassium channels in this action were studied using isolated Wistar rat prostate tissue. Methods: Rat prostate strips were pre-contracted with 1 μmol/L phenylephrine or 50 mmol/L KCl. The relaxation response to agmatine (1-100 μmol/L) was measured. The effects of imidazoline receptor blockers: efaroxan, BU224, KU14R; ATP-sensitive K+ channels (KATP) channel inhibitor: glibenclamide; cyclic AMP (cAMP) phosphodiesterase inhibitor: IBMX; or protein kinase A (PKA) inhibitor: H-89 on the agmatine-induced relaxation were studied. Results: Agmatine produced relaxation in prostate strips pre-contracted with phenylephrine or KCl in a dose-dependent manner. This relaxation was significantly reduced by BU224, a selective I2 imidazoline receptor (IR) blocker, but not by I1 or I3 IR blockers (efaroxan, KU14R respectively). Moreover, the agmatine-induced relaxation was attenuated by glibenclamide and H-89, but enhanced by IBMX. Conclusion: The results suggest that agmatine causes rat prostate relaxation by activation of the I2 IR, which opens KATP channels through cAMP/PKA pathway. © 2012 Blackwell Publishing Asia Pty Ltd.

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