Li Shin Hospital

Taoyuan, Taiwan

Li Shin Hospital

Taoyuan, Taiwan
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Lan C.-C.,Foundation Medicine | Lan C.-C.,Tzu Chi University | Peng C.-K.,Tri Service General Hospital | Peng C.-K.,Institute of Undersea and Hyperbaric Medicine | And 5 more authors.
PLoS ONE | Year: 2017

Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary microvascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/ kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression. © 2017 Lan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Chang T.-H.,Graduate Institute of Medical science | Tsai M.-F.,Da - Yeh University | Su K.-Y.,Academia Sinica, Taiwan | Su K.-Y.,Research Center for Medical Excellence | And 12 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: Non-small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown. Objectives: To examine the role of EMT regulators in resistance to gefitinib. Methods: The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistanceinvitro, and a xenograft mouse model was used forinvivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription-polymerase chain reaction. Measurements and Main Results: Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells. Conclusions: Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.


Kumar S.S.,National Central University | Kumar S.S.,University Putra Malaysia | Hsiao J.-H.,National Central University | Ling Q.-D.,National Central University | And 11 more authors.
Biomaterials | Year: 2013

Umbilical cord blood (UCB) is an attractive source of hematopoietic stem and progenitor cells (HSPCs) for transplantation. However, the low number of HSPCs from a single UCB donor limits the direct transplantation of UCB to patients. Because little is known about the effects of the physical microenvironment on HSPC expansion, we investigated the exvivo expansion of HSPCs cultured on biomaterials with different elasticities and grafted with different nanosegments. Polyvinylalcohol-co-itaconic acid (PVA-IA)-coated dishes with different stiffnesses ranging from a 3.7kPa to 30.4kPa storage modulus were used. Fibronectin or an oligopeptide (CS1, EILDVPST) was grafted onto the PVA-IA substrates. High exvivo fold expansion of HSPCs was observed in the PVA-IA dishes grafted with fibronectin or CS1, which displayed an intermediate stiffness ranging from 12.2kPa to 30.4kPa. The fold expansion was more than 1.4 times higher than that cultured in tissue culture polystyrene dishes (TCPS, 12GPa). Furthermore, HSPCs cultured in fibronectin or CS1-grafted PVA-IA-coated dishes with a stiffness of 12.2-30.4kPa generated more pluripotent colony-forming units (CFU-GM and CFU-GEMM) than those in TCPS dishes. This result indicates that both the physical and biological properties of biomaterials affect the exvivo expansion of HSPCs. © 2013 Elsevier Ltd.


Lan C.-C.,Foundation Medicine | Lan C.-C.,Tzu Chi University | Hsu H.-H.,Tri Service General Hospital | Wu C.-P.,Li Shin Hospital | And 3 more authors.
Journal of Surgical Research | Year: 2014

Background Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) cause substantial morbidity and mortality despite improvements in the understanding of lung injury and advances in treatment. Recruitment maneuver (RM) with high sustained airway pressures is proposed as an adjunct to mechanical ventilation to maintain alveolar patency. In addition, RM has been advocated to improve pulmonary gas exchange. However, many factors may influence responses to RM and the effect of pleural effusion (PLE) is unknown. Method There were four groups in this study (n = 6 in each group). Group A was the control group, group B was the PLE group, group C was ARDS with RM, and group D was ARDS with PLE and RM. RM was performed in groups C and D, consisting of a peak pressure of 45 cm H2O with positive end-expiratory pressure of 35 cm H2O sustained for 1 min. Arterial blood gas, systemic and pulmonary hemodynamics, lung water, and respiratory mechanics were measured throughout. Result After the induction of ALI/ARDS, there were significant decreases in partial pressure of oxygen in arterial blood, mean arterial pressure, systemic vascular resistance, and lung compliance. There were also significant increases in the alveolar-arterial O2 tension difference, partial pressure of arterial carbon dioxide, mean pulmonary arterial pressure, pulmonary vascular resistance, and lung water. The RM improved oxygenation, which was attenuated by PLE. Conclusions ALI/ARDS leads to poor oxygenation and hemodynamics. RM results in improved oxygenation, but this improvement is attenuated by PLE. © 2014 Elsevier Inc. All rights reserved.


Higuchi A.,National Central University | Higuchi A.,National Health Research Institute | Higuchi A.,Cathay Medical Research Institute | Shen P.-Y.,National Central University | And 8 more authors.
Tissue Engineering - Part A | Year: 2011

The effect of visible light irradiation on the expression of pluripotent genes (Oct-4, Sox2, and Nanog) in amniotic fluid-derived stem cells (AFSCs) and on the osteogenic differentiation ability of AFSCs was investigated using light-emitting diodes (LEDs) at 0-2mW/cm2 in various wavelengths : [blue (470nm), green (525nm), yellow (600nm), and red (630nm)]. Pluripotent gene expression in AFSCs was up-regulated by visible light irradiation from a LED for more than 6h. Green light irradiation of AFSCs up-regulated the expression of pluripotent genes more significantly than irradiation with other light. The osteogenic differentiation of AFSCs was facilitated by green and blue light irradiation. Facilitated differentiation into osteogenic cells by visible light irradiation was not mediated by reactive oxygen species (ROS); alkaline phosphatase activity (a marker of early osteogenic differentiation) and gene expression of osteopontin (a marker of late osteogenic differentiation) did not change significantly between AFSCs in differentiation medium with or without a ROS scavenger (vitamin C). The mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway, as well as other unknown signaling pathways, may be responsible for the activation of signaling pathways that facilitate the differentiation of AFSCs into osteogenic cells on light irradiation. © Copyright 2011, Mary Ann Liebert, Inc. 2011.


Chen L.-Y.,National Central University | Chang Y.,Chung Yuan Christian University | Shiao J.-S.,National Central University | Ling Q.-D.,Cathay Medical Research Institute | And 9 more authors.
Acta Biomaterialia | Year: 2012

Umbilical cord blood (UCB) is an attractive source of hematopoietic stem and progenitor cells for hematopoietic stem cell (HSC) transplantation. However, the low number of HSCs obtainable from a single donor of UCB limits direct transplantation of UCB to the treatment of pediatric patients. In this study, we investigated the ex vivo expansion of HSCs cultured on biomaterials grafted with several nanosegments, i.e. polyamine, fibronectin, RGDS, and CS1 (EILDVPST), at several surface densities. No direct correlation was found between fold expansion of HSCs and physical parameters of the culture dishes, i.e. surface roughness and water contact angle of the culture dishes. However, a small amount of grafted amino groups, less than 0.8 residual μmol cm -2, on the dishes was effective for the ex vivo expansion of HSCs. A high amount of grafted amino groups hindered the ex vivo expansion of HSCs on the dishes. HSCs cultured on dishes with a high concentration of CS1 (2.40 residual μmol cm -2) showed greater expansion of HSCs and more pluripotent colony-forming units (i.e. colony-forming unit-granulocyte, erythroid, macrophage, and megakaryocyte (CFU-GEMM)) than those on fibronectin-grafted and polyamine-grafted dishes. These data suggest that the specific interaction between HSCs and CS1 helps to maintain the pluripotency of HSCs during the ex vivo expansion of HSCs. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Higuchi A.,National Central University | Higuchi A.,National Health Research Institute | Higuchi A.,Cathay Medical Research Institute | Tamai M.,Tokyo Institute of Technology | And 8 more authors.
Polymer Reviews | Year: 2010

The optical resolution or chiral separation of one specific enantiomer from others is in demand for the production of pharmaceuticals because many pharmaceuticals exist as stereoisomers, with each enantiomer having different biological activity. There is considerable demand for separation techniques appropriate for the large-scale resolution of chiral molecules. Chiral separation of racemic mixtures of pharmaceuticals through chiral or achiral polymeric membranes with or without a chiral selector represents a promising system for future commercial application. This article reviews several polymeric materials for the chiral separation of pharmaceuticals. Several chiral separation membranes were prepared from chiral polymers where enantioselectivity was generated from chiral carbons in the main chain. However, it is rather difficult to generate excellent chiral separation membranes from chiral polymers alone, because racemic penetrants mainly encounter the flexible side chains of the membrane polymers. Therefore, chiral separation membranes were also prepared using polymers with a chiral branch. Furthermore, several molecules have been used for specific interactions between the molecules and specific pharmaceuticals or drugs in chiral separation membranes. Cyclodextrins, crown ether derivatives, albumin, and DNA are commonly used as stereoselective ligands in chiral separation membranes. Finally, this article discusses future trends in polymeric materials for chiral separation membranes.


Lan C.-C.,Foundation Medicine | Chu W.-H.,Taipei zu Chi Hospital | Yang M.-C.,Foundation Medicine | Lee C.-H.,Foundation Medicine | And 2 more authors.
Respiratory Care | Year: 2013

BACKGROUND: Pulmonary rehabilitation (PR) is beneficial for patients with COPD, with improvement in exercise capacity and health-related quality of life. Despite these overall benefits, the responses to PR vary significantly among different individuals. It is not clear if PR is beneficial for patients with COPD and normal exercise capacity. We aimed to investigate the effects of PR in patients with normal exercise capacity on health-related quality of life and exercise capacity. METHODS: Twenty-six subjects with COPD and normal exercise capacity were studied. All subjects participated in 12-week, 2 sessions per week, hospital-based, out-patient PR. Baseline and post-PR status were evaluated by spirometry, the St George's Respiratory Questionnaire, cardiopulmonary exercise test, respiratory muscle strength, and dyspnea scores. RESULTS: The mean FEV1 in the subjects was 1.29 ± 0.47 L/min, 64.8 ± 23.0% of predicted. After PR there was significant improvement in maximal oxygen uptake and work rate. Improvements in St George's Respiratory Questionnaire scores of total, symptoms, activity, and impact were accompanied by improvements of exercise capacity, respiratory muscle strength, maximum oxygen pulse, and exertional dyspnea scores (all P <.05). There were no significant changes in pulmonary function test results (FEV1, FVC, and FEV1/FVC), minute ventilation, breathing frequency, or tidal volume at rest or exercise after PR. CONCLUSIONS: Exercise training can result in significant improvement in health-related quality of life, exercise capacity, respiratory muscle strength, and exertional dyspnea in subjects with COPD and normal exercise capacity. Exercise training is still indicated for patients with normal exercise capacity. © 2013 Daedalus Enterprises.


PubMed | Tri Service General Hospital, Foundation Medicine, Li Shin Hospital and Institute of Undersea and Hyperbaric Medicine
Type: Journal Article | Journal: PloS one | Year: 2016

Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF) has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti-VEGF antibody (bevacizumab, 5mg/kg), IR, IR + preconditioning anti-VEGF antibody (1mg/kg), IR+ preconditioning anti-VEGF antibody (5mg/kg) and IR+ post-IR anti-VEGF antibody (5mg/kg) group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK) were increased in IR-induced ALI. Administration of preconditioning anti-VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti-VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro-inflammatory cytokines, and neutrophilic infiltration into the lung tissues.


PubMed | Tri Service General Hospital, Tzu Chi University, Li Shin Hospital and Institute of Undersea and Hyperbaric Medicine
Type: Journal Article | Journal: The Journal of thoracic and cardiovascular surgery | Year: 2016

Ischemia-reperfusion acute lung injury is characterized by increased vascular permeability, lung edema, and neutrophil sequestration. Ischemia-reperfusion acute lung injury occurs in lung transplantation and other major surgical procedures. Effective regulation of alveolar fluid balance is critical for pulmonary edema. Sodium-potassium-chloride co-transporter regulates alveolar fluid and is associated with inflammation. We hypothesized that sodium-potassium-chloride co-transporter is important in ischemia-reperfusion acute lung injury. Bumetanide, a sodium-potassium-chloride co-transporter inhibitor, is used to treat pulmonary edema clinically. We studied the effect of bumetanide in ischemia-reperfusion acute lung injury.Isolated perfusion of mouse lungs in situ was performed. The main pulmonary artery and left atrium were catheterized for lung perfusion and effluent collection for recirculation, respectively, with perfusate consisting of 1mL blood and 9mL physiologic solution. Ischemia-reperfusion was induced by 120minutes of ischemia (no ventilation or perfusion) and reperfused for 60minutes. Wild-type, SPAK knockout (SPAKIn wild-type mice, ischemia-reperfusion caused lung edema (wet/dry weight 6.300.36) and hyperpermeability (microvascular permeability, 0.290.04), neutrophil sequestration (255.055.8cells/high-power field), increased proinflammatory cytokines, and nuclear factor-B activation (1.330.13). Acute lung injury was more severe in WNK4 mice with more lung edema, permeability, neutrophil sequestration, and nuclear factor-B activation. Severity of acute lung injury was attenuated in SPAKFunctional reduction of sodium-potassium-chloride co-transporter by genetic or pharmacologic treatment to inhibit sodium-potassium-chloride co-transporter resulted in lower severity of acute lung injury induced by ischemia-reperfusion. Sodium-potassium-chloride co-transporter may present a promising target for therapeutic interventions in a clinical setting.

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