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Lin C.-L.,Chang Gung Memorial Hospital at Chiayi | Lin C.-L.,Chang Gung University | Lin C.-L.,Chang Gung Memorial Hospital | Wang F.-S.,Chang Gung University | And 7 more authors.
Diabetes | Year: 2010

OBJECTIVE - Disturbances in podocytes are typically associated with marked proteinuria, a hallmark of diabetic nephropathy. This study was conducted to investigate modulation of Notch-1 signaling in high glucose (HG)-stressed human podocytes and in a diabetic animal model. RESEARCH DESIGN AND METHODS - Expression of the Notch signaling components was examined in HG-treated podocytes, human embryonic kidney cells (HEK293), and kidneys from diabetic animals by RT-qPCR, Western blot analysis, and immunohistochemical staining. The association between the Notch signaling, VEGF expression, and podocyte integrity was evaluated. RESULTS - Notch-1 signaling was significantly activated in HG-cultured human podocytes and HEK293 cells and kidneys from diabetic animals. HG also augmented VEGF expression, decreasing nephrin expression and podocyte number - a critical event for the development of proteinuria in diabetic nephropathy. After use of pharmacological modulators or specific shRNA knockdown strategies, inhibition of Notch-1 signaling significantly abrogated VEGF activation and nephrin repression in HG-stressed cells and ameliorated proteinuria in the diabetic kidney. CONCLUSIONS - Our findings suggest that upregulation of Notch-1 signaling in HG-treated renal podocytes induces VEGF expression and subsequent nephrin repression and apoptosis. Modulation of Notch-1 signaling may hold promise as a novel therapeutic strategy for the treatment of diabetic nephropathy. © 2010 by the American Diabetes Association.


Chen M.-F.,Chang Gung Memorial Hospital at Chiayi | Chen M.-F.,Chang Gung University | Chen P.-T.,Chang Gung Memorial Hospital at Chiayi | Chen P.-T.,Chang Gung University | And 6 more authors.
Molecular Cancer | Year: 2013

Background: The identification of potential tumor markers can improve therapeutic planning and patient management. The aim of this study was to highlight the significance of IL-6 in esophageal squamous cell carcinoma (SCC).Methods: We retrospectively analyzed the clinical outcomes of 173 patients with esophageal SCC, and examined the correlation between IL-6 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after manipulation of IL-6 expression.Results: In clinical outcome analysis, positive IL-6 staining and poor treatment response was significantly associated with shorter survival. Furthermore, the frequency of IL-6 immunoreactivity was significantly higher in esophageal cancer specimens than in non-malignant epithelium, and this staining was positively linked to the development of distant metastasis (p = 0.0003) and lower treatment response rates (p = 0.0001).By ELISA analysis, IL-6 serum levels were significantly elevated in patients developing disease failure.When IL-6 expression was inhibited, aggressive tumor behavior and radiation resistance could be overcome in vitro and in vivo. The underlying changes included increased cell death, less epithelial-mesenchymal transition and attenuated STAT3 activation. IL-6 inhibition was also associated with attenuated angiogenesis in tumor-bearing mice.Conclusions: IL-6 was significantly associated with poor prognosis in patients with esophageal cancer. Targeting this cytokine could be a promising strategy for treatment of esophageal cancer, as evidenced by inhibition of aggressive tumor behavior and treatment resistance. © 2013 Chen et al.; licensee BioMed Central Ltd.


Cheng W.-L.,Chang Gung University | Wang C.-S.,Chang Gung Memorial Hospital at Chiayi | Huang Y.-H.,Chang Gung Memorial Hospital | Tsai M.-M.,Chang Gung University | And 3 more authors.
Annals of Oncology | Year: 2011

Background: The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor CXCR2 are associated with metastasis potential. Our studies were designed to clarify the CXCL1 and CXCR2 expression patterns and to explore their potential role in gastric cancer Design: The expression of CXCL1 was determined in primary gastric cancer specimens using quantitative PCR, immunohistochemistry, and western blotting. To investigate the functional significance of CXCL1 expression, a CXCL1 expression vector and short hairpin RNA targeting the CXCL1 or CXCR2 were transfected into gastric cancer cell lines to examine the biological outcomes of these cells. Results: The expression of CXCL1 and CXCR2 was higher in gastric cancer tissues compared with adjacent noncancerous tissues. The upregulation of CXCL1 correlated significantly with tumor progression, advanced stage of gastric cancer patients, and was one of the independent prognostic factors for patient's survival. Furthermore, cancer cells expressing CXCL1 stably exhibited an increase in their migration and invasion ability, whereas CXCL1 or CXCR2 depletion significantly reduced the migration and invasion ability of each cell line. Conclusions: These results provide strong evidence that CXCL1 plays an important role in gastric cancer progression and migration and suggest that CXCL1 is a promising marker for the detection and prognosis of gastric cancer. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Tsai J.-J.,National Yang Ming University | Kuo H.-C.,Chang Gung University | Lee K.-F.,Chang Gung Memorial Hospital at Chiayi | Tsai T.-H.,National Yang Ming University | And 2 more authors.
International Journal of Molecular Sciences | Year: 2013

Total parenteral nutrition (TPN) is an artificial way to support daily nutritional requirements by bypassing the digestive system, but long-term TPN administration may cause severe liver dysfunction. Glycyrrhizin is an active component of licorice root that has been widely used to treat chronic hepatitis. The aim of this study is to investigate the hepatoprotective effect of glycyrrhizin on TPN-associated acute liver injury in vivo. Liver dysfunction was induced by intravenous infusion of TPN at a flow rate of 20 mL/kg/h for three h in Sprague Dawley rats. The rats were pretreated with Glycyrrhizin (1, 3 and 10 mg/kg intravenously). After receiving TPN or saline (control group) for three h, the rats were sacrificed, blood samples were collected for biochemical analyses and liver tissue was removed for histopathological and immunohistochemical examination. We found that aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and triglyceride (TG) levels were significantly increased in the TPN group without glycyrrhizin pretreatment and decreased in the glycyrrhizin-pretreated TPN group in a dose-dependent manner. The stained liver sections showed that glycyrrhizin relieved acute liver injury. The upregulation of serum protein biomarkers of reactive nitrogen species, including nitrotyrosine and inducible NO synthase (iNOS), were attenuated by glycyrrhizin pretreatment. Levels of endoplasmic reticulum (ER) stress factors, such as phosphorylation of JNK1/2, p38 MAPK and CHOP, were decreased by glycyrrhizin pretreatment. In summary, our results suggest that glycyrrhizin decreases TPN-associated acute liver injury factors by suppressing endoplasmic reticulum stress and reactive nitrogen stress. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Liu J.-L.,St Martin Of Porres Hospital | Liu J.-L.,Chang Gung University | Chen F.-F.,Chang Gung Memorial Hospital at Chiayi | Lung J.,Chang Gung Memorial Hospital at Chiayi | And 4 more authors.
British Journal of Cancer | Year: 2014

Background: Autophagy is a programmed cell survival mechanism that has a key role in both physiologic and pathologic conditions. The relationship between autophagy and cancer is complex because autophagy can act as either a tumour suppressor or as a tumour promoter. The role of autophagy in oral squamous cell carcinoma (OSCC) is controversial. Several studies have claimed that either a high or low expression of autophagy-related proteins was associated with poor prognosis of OSCCs. The aims of the study were to compare autophagy in OSCCs, verrucous hyperplasias, and normal oral mucosas, and to inspect the prognostic role of autophagy in OSCCs. Methods: We used the autophagosome marker, LC3B, and autophagy flux marker, p62/SQSTM1 (p62), by using immunohistochemistry, and examined p62 mRNA by RNA in situ hybridization, to evaluate autophagy in 195 OSCCs, 47 verrucous hyperplasias, and 37 normal oral mucosas. The prognostic roles of LC3B and p62 protein expressions in OSCCs were investigated. Results: We discovered that the normal oral mucosa exhibited limited LC3B punctae and weak cytoplasmic p62 staining, whereas the OSCCs exhibited a marked increase in LC3B punctae and cytoplasmic p62 expression. The expression pattern of LC3B and cytoplasmic p62 of the verrucous hyperplasias were between normal oral mucosas and OSCCs. The normal oral mucosas, verrucous hyperplasias, and OSCCs presented no differences in nuclear p62 expression and the p62 mRNA level. p62 mRNA expression was elevated in a minority of cases. High p62 mRNA expression was associated with high p62 protein expression in the cytoplasm. Increased LC3B punctae, high cytoplasmic p62, and low nuclear p62 expressions in OSCCs were associated with aggressive clinicopathologic features and unfavourable prognosis. In addition, low nuclear p62 expression was an independent prognostic factor for overall and disease-specific survival rates. Furthermore, we disclosed that high cytoplasmic p62 expression accompanied with either a low or high LC3B expression, which indicated autophagy impairment under basal or activated autophagic activity, was associated with aggressive behaviour in advanced OSCCs. Conclusions: We suggested that autophagy was altered during cancer initiation and progression. Autophagy impairment contributed to cancer progression in advanced OSCCs. © 2014 Cancer Research UK.


Tsai C.-C.,Chang Gung University | Huang F.-J.,Chang Gung University | Wang L.-J.,Chang Gung University | Lin Y.-J.,Chang Gung University | And 3 more authors.
Fertility and Sterility | Year: 2011

Objective: To evaluate the clinical outcomes and development of children born after intracytoplasmic sperm injection (ICSI) with extracted testicular sperm or ejaculated extreme severe oligo-astheno-teratozoospermia (OAT) sperm. Design: Retrospective study. Setting: Infertility clinic at Chang Gung Memorial Hospital. Patient(s): A total of 126 ICSI cycles were performed using extracted testicular sperm from men with azoospermia and 65 ICSI cycles using fresh ejaculated sperm from men with extreme severe OAT. Intervention(s): Retrospective analysis of clinical outcomes and development of children born after ICSI with extracted testicular sperm or ejaculated extreme severe OAT sperm. Main Outcome Measure(s): Fertilization rates, number of grade 1 zygotes and number of embryos produced, implantation rate, clinical pregnancy rate, abortion and live birth rate per transfer, perinatal outcomes, and birth defects. Result(s): The demographic and clinical factors, including age, E 2 level on hCG day, number of oocytes retrieved, normal fertilization rate, zygote grade 1 score distribution, number of top-quality embryos transferred, clinical pregnancy rate per transfer, chemical pregnancy rate per transfer, implantation rate, live birth rate per transfer, and abortion rate per transfer, were similar between the groups. Sixty live births resulted from 48 extracted testicular sperm cycles and 21 live births from 19 extreme severe OAT. The obstetric and perinatal outcomes were similar between the groups, and children conceived by using ICSI were healthy and without major psychomotor or intellectual development retardation. One case of tetralogy of Fallot occurred in each group. Conclusion(s): There is no evidence of differences in the clinical outcomes and development of children result after ICSI with extracted testicular sperm or ejaculated extreme severe OAT sperm. Copyright © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.


Lee M.,University of California at Los Angeles | Lee M.,Chang Gung Memorial Hospital at Chiayi | Saver J.L.,University of California at Los Angeles | Chang K.-H.,Chang Gung University | And 3 more authors.
Stroke | Year: 2010

Background and Purpose: Microalbuminuria, a marker of both kidney disease and endothelial dysfunction, may be associated with global vascular risk, but the nature and magnitude of the link between microalbuminuria and incident stroke has not been clearly defined. The purpose of this study was to assess the consistency and strength of the association of microalbuminuria with risk of stroke in prospective studies using meta-analysis. Methods: We conducted a systematic search of electronic databases and bibliographies for studies reporting a multivariate-adjusted estimate, represented as relative risk with 95% CI, of the association between microalbuminuria and stroke risk. Studies were excluded if a majority of study participants had established kidney disease or pre-eclampsia. Estimates were combined using a random-effect model. Results: We identified 12 studies, with a total of 48 596 participants and 1263 stroke events. Overall, presence of microalbuminuria was associated with greater stroke risk (relative risk, 1.92; 95% CI, 1.61 to 2.28; P<0.001) after adjustment for established cardiovascular risk factors. There was evidence of significant heterogeneity in the magnitude of the association across studies (P for heterogeneity <0.001, I=68%), which was partially explained by differences in study population, microalbuminuria definition, and different microalbuminuria-related risk among stroke subtypes. However, in stratified analyses, microalbuminuria was associated with increased risk of subsequent stroke in all subgroups (general population, diabetics, those with known stroke). Conclusions: Microalbuminuria is strongly and independently associated with incident stroke risk. Future studies should explore whether microalbuminuria is just a risk marker or a modifiable risk factor for stroke. © 2010 American Heart Association, Inc.


Tsai M.-M.,Chang Gung University | Wang C.-S.,Chang Gung Memorial Hospital at Chiayi | Tsai C.-Y.,Chang Gung University | Chi H.-C.,Chang Gung University | And 2 more authors.
World Journal of Gastroenterology | Year: 2014

The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identi?ed and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Tsai M.-M.,Chang Gung University | Wang C.-S.,Chang Gung Memorial Hospital at Chiayi | Tsai C.-Y.,Chang Gung University | Chen C.-Y.,Chang Gung University | And 7 more authors.
Cancer Letters | Year: 2014

MicroRNAs (miRNAs) play an important role to contribute carcinogenesis. The aim of the current study was to identify useful biomarkers from miRNAs. Differential miRNA profiles were analyzed using the miRNA qRT-PCR-based assay. Two of the most upregulated miRNAs were selected and validated. The miR-196a/-196b levels were significantly increased in gastric cancer (GC) tissues (n= 109). Overexpression of miR-196a/-196b was significantly associated with tumor progression and poorer 5-year survival outcomes. Overexpression of miR-196a/-196b enhances GC cell migration and invasion. Further, radixin was identified as a target gene of miR-196a/-196b. Elevated miR-196a/-196b expression in GC cells led to reduced radixin protein levels and vice versa. Notably, an inverse correlation between miR-196a/-196b and radixin mRNA and protein expression was observed in GC tissues with in situ hybridization and immunohistochemistry analyses. Together, miR-196a/-196b inhibitory oligonucleotides or overexpression of the radixin may thus have therapeutic potential in suppressing GC metastasis. © 2014 Elsevier Ireland Ltd.


Wu M.-H.,Chang Gung Memorial Hospital at Chiayi | Hsu K.-Y.,Chang Gung Memorial Hospital at Linkou | Hsu K.-Y.,Chang Gung University
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2011

We present a case of a patient with preoperative cutaneous candidiasis, who developed candidal infection during stage revision knee arthroplasty. The patient received intravenous fluconazole for 6 weeks and resection arthroplasty with an amphotericin B-loaded cement spacer and continuous oral fluconazole therapy for 9 weeks. Revision surgery was successful. © 2010 Springer-Verlag.

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