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Lin Y.-S.,Chi Mei Foundation Medical Center | Lin Y.-S.,Taipei Medical University | Tsai S.-J.,National Cheng Kung University | Lin M.-W.,National Yang Ming University | And 3 more authors.
American Journal of Reproductive Immunology | Year: 2011

Problem Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder. This study was to evaluate whether insulin receptor substrate (IRS)-2 Gly1057Asp polymorphism influences chronic inflammatory parameters in Taiwanese patients with PCOS. Method of study DNA was extracted from whole blood samples for genotyping and detection of IRS-2 Gly1057Asp polymorphism in 129 PCOS women and 109 control women. Ninety-seven PCOS women accepted metformin treatment for 3months, and low-grade chronic inflammatory markers were assessed. Results The levels of IL-6 were significantly elevated in PCOS women compared with normal women. Among allelic variant of IRS-2, concentrations of IL-6 were greater in IRS-2 homozygous Asp population. Treatment with metformin significantly reduced IL-6, especially in PCOS patients with IRS-2 homozygous Asp variant. Conclusion The results showed that IL-6 may be an early low-grade chronic inflammatory marker among PCOS patients with IRS-2 polymorphism in Taiwanese population. This pharmacologic study in IRS-2 polymorphism may provide more information for preventing long-term complications in PCOS. © 2011 John Wiley & Sons A/S. Source


Hsueh Y.-S.,National Health Research Institute | Chang H.H.,National Cheng Kung University | Chiang N.-J.,National Health Research Institute | Chiang N.-J.,National Cheng Kung University | And 9 more authors.
Oncotarget | Year: 2014

Our previous study demonstrated NVP-AUY922, a HSP90AA1 inhibitor, could enhance mutant KIT degradation in gastrointestinal stromal tumor (GIST) cells through both proteasome- and autophagy-mediated pathways. Herein, we showed rapamycin, a MTOR inhibitor and autophagy inducer, could reduce total and phospho-KIT expression levels and enhance apoptosis in imatinib-resistant GIST cells. The involvement of autophagy in rapamycin-induced KIT downregulation was further confirmed by co-localization of KIT and autophagosome, and partial recovery of KIT expression level by either siRNA-mediated BECN1 and ATG5 silencing or autophagy inhibitors after rapamycin. Rapamycin and NVP-AUY922 synergistically inhibited GIST cells growth in vitro. The combination of low-dose NVP-AUY922 with rapamycin had comparable effects on reducing KIT expression, increasing MAP1LC3B puncta and tumor necrosis, and inhibiting tumor growth as high-dose NVP-AUY922 did in GIST430 xenograft model. Our results suggest the addition of a MTOR inhibitor may reduce NVP-AUY922 dose requirement and potentially improve its therapeutic index in mutant KIT-expressing GISTs. Source


Hsueh Y.-S.,National Cheng Kung University | Hsueh Y.-S.,National Institute of Cancer Research | Yen C.-C.,Taipei Veterans General Hospital | Yen C.-C.,National Yang Ming University | And 8 more authors.
Autophagy | Year: 2013

Gastrointestinal stromal tumor (GIST) is a prototype of mutant KIT oncogene-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Heat shock protein 90 (HSP90AA1) is a chaperone protein responsible for protein maturation and stability, and KIT is a known client protein of HSP90AA1. Inhibition of HSP90AA1 has been shown to destabilize KIT protein by enhancing its degradation via the proteasome-dependent pathway. In this study, we demonstrated that NVP-AUY922 (AUY922), a new class of HSP90AA1 inhibitor, is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the imatinibsensitive GIST882 and imatinib-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phosphorylated KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922- induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange- or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. Therefore, the results not only highlight the potential application of AUY922 for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitorinduced KIT degradation. © 2013 Landes Bioscience. Source


Yang C.-S.,National Cheng Kung University | Chow J.C.,Chi Mei Foundation Medical Center | Tsai J.-J.,National Cheng Kung University | Huang C.-W.,National Cheng Kung University
Epilepsy and Behavior | Year: 2011

Hyperventilation is a traditional seizure-provoking procedure used mainly in idiopathic generalized epilepsy and with a relatively limited role in partial epilepsy. Ictal fear is a rare seizure semiology seen in temporal lobe epilepsy. It has been suggested that the amygdala and anterior hippocampus are involved in generating ictal fear. We describe a rare patient with nonlesional temporal epilepsy who, while hyperventilating during an electroencephalography recording, developed complex partial seizures presenting as ictal fear. The particular sensitivity of the anterior hippocampus (probably the amygdala) to hypocapnia might be an important factor contributing to seizures. To avoid misdiagnosing this unusual condition as a pseudo-seizure, a detailed history and seizure semiology, as well as a concurrent electroencephalography recording, are mandatory. © 2011 Elsevier Inc. Source


Chen J.-Y.,National Health Research Institute | Li C.-F.,Chi Mei Foundation Medical Center | Kuo C.-C.,National Health Research Institute | Tsai K.K.,National Health Research Institute | And 3 more authors.
Breast Cancer Research | Year: 2014

Introduction: Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear.Methods: Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.Results: Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo.Conclusion: Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival. © 2014 Chen et al.; licensee BioMed Central; licensee BioMed Central Ltd. Source

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