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Chang L.-Y.,Chang Gung University | Lin Y.-C.,Chang Gung University | Mahalingam J.,Chang Gung Memorial Hospital | Huang C.-T.,Chang Gung University | And 11 more authors.
Cancer Research | Year: 2012

Chemokine CCL5/RANTES is highly expressed in cancer where it contributes to inflammation and malignant progression. In this study, we show that CCL5 plays a critical role in immune escape in colorectal cancer. We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (T reg). In mouse cells, RNA interference (RNAi)-mediated knockdown of CCL5 delayed tumor growth in immunocompetent syngeneic hosts but had no effect on tumor growth in immunodeficient hosts. Reduced tumor growth was correlated with a reduction in Treg infiltration and CD8 + T-cell apoptosis in tumors. Notably,we found that CCL5 enhanced the cytotoxicity of T reg against CD8 + T cells. We also found tumor growth to be diminished in mice lacking CCR5, aCCL5 receptor, where a similar decrease in both T reg cell infiltration and CD8 + T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8 + T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-deficient T reg or to enhance their cytotoxic effects against CD8 + T cells. CCR5 signaling blockade also diminished the in vivo suppressive capacity of T reg in inhibiting the antitumor responses of CD8 + T cells, in the sameway as CCL5 signaling blockade. Together, our findings establish that CCL5/CCR5 signaling recruits T reg to tumors and enhances their ability to kill antitumor CD8 + T cells, thereby defining a novel mechanism of immune escape in colorectal cancer. ©2012 AACR. Source


Wang C.-H.,Industrial Technology Research Institute of Taiwan | Hwang Y.-S.,Chang Gung Memorial Hospital | Hwang Y.-S.,Graduate Institute of Clinical Medical Science | Chiang P.-R.,National Tsing Hua University | And 5 more authors.
Biomacromolecules | Year: 2012

The antibody bevacizumab (Avastin) has been used clinically to treat intraocular neovascular diseases based on its antivascular endothelial growth factor (VEGF) character. The anti-VEGF strategy for retinal neovascular diseases is limited by the short half-life of bevacizumab and thus requires frequent injections. This Article reports the sustained release of bevacizumab from a biocompatible material that is composed of a triblock copolymer of poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone)-b-poly(2-ethyl-2- oxazoline) (PEOz-PCL-PEOz). The amphiphilic PEOz-PCL-PEOz triblock copolymer was synthesized in three steps. First, the PEOz was polymerized by methyl p-toluenesulfonate and 2-ethyl-2-oxazoline (EOz), and the living end was terminated by potassium hydroxide methanolic solution. Subsequently, the hydroxyl-PEOz was used as a macroinitiator for the ring-opening polymerization of ε-caprolactone using a Tin(II) octoate catalyst to synthesize the telechelic hydroxylated PEOz-PCL. Finally, the PEOz-PCL-PEOz triblock copolymer was obtained using the 1,6-hexamethylene diisocyanateas a coupling reagent. The PEOz-PCL-PEOz was chemically and molecularly characterized by GPC, 1H NMR, and FTIR, and its aqueous solution (ECE hydrogel) showed a reversible sol (room temperature)-gel (physiological temperature) phase transition, which serves as an easy antibody-packing system with extended release. The biodegradability of ECE hydrogel was assessed by the porosity formation at different periods by scanning electron microscopy. The ECE hydrogel had no in vitro cytotoxicity on the human retinal pigment epithelial cell line by flow cytometry. The histomorphology and electrophysiology of the rabbit neuroretina were preserved after 2 months of intravitreal injection. In conclusion, the ECE hydrogel has a temperature-sensitive sol-gel phase transition and is effective in vitro. Its intraocular biocompatibility demonstrated its great potential to be widely used in biomedical applications for extended drug release. © 2011 American Chemical Society. Source


Chang Y.-L.,Graduate Institute of Clinical Medical Science | Tsai Y.-F.,Chang Gung University | Wu Y.-C.,Chang Gung Memorial Hospital | Hsieh M.-J.,Chang Gung Memorial Hospital
Cancer Nursing | Year: 2014

Background: Little is known regarding the short-term quality of life (QoL) and predictive factors for QoL after esophagectomy for cancer in Eastern countries. Objective: The aims of this study were to assess QoL and symptoms within 1 and 6 months after surgery for esophageal cancer (EC) and to identify factors predictive of QoL within 6 months after esophagectomy in Taiwan. Methods: A longitudinal, prospective design was used, where convenience samples of 99 patients who had undergone esophagectomy for cancer were recruited from 2 medical centers in northern Taiwan. All participants responded to a questionnaire with a QLQ-C30 (Quality of Life Questionnaire-Cancer) core and a QLQ-OES18 (esophageal module of the European Organization for Research and Treatment [EORTC] QLQ-C30) module in structured interviews at baseline and 1 and 6 months after surgery. Results: The results showed significant decline in social function and global QoL; fatigue, insomnia, eating problems, reflux, and dry mouth were major problems within 6 months. Body mass index, body weight loss before surgery, activity performance status, and anastomosis site showed no significant association with the function and symptom aspect of QoL. Surgical complications, advanced cancer, neoadjuvant therapy before surgery, and tumor location other than at the EC junction had significant deleterious effects on several aspects of QoL. Conclusions: This study describes the demographics of EC and short-term changes in QoL and also the predictive impact factor for QoL after surgery for EC. Implications for practice: Knowledge of risk factors for poor postoperative QoL would be useful for health providers in detecting and prioritizing problems and treatment options in a busy clinical site. Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Wong C.H.,Graduate Institute of Clinical Medical Science | Lin L.C.,National Defense Medical Center | Lee H.H.,Taipei Medical University | Liu C.-F.,National Taipei University of Nursing and Health Sciences
Journal of Alternative and Complementary Medicine | Year: 2012

Objectives: Pain induced by surgery is a dynamic symptom, which may be quite variable even in the same surgical procedures. The purpose of this study was to investigate the analgesic effect of far infrared rays on the patients during the postoperative period of total knee arthroplasty (TKA). The selection and application of analgesic methods after the orthopedic surgery are therefore valuable for advanced studies. Design: The quasi-experimental design with a total five consecutive days of far infrared ray (FIR) thermal therapy was employed in this study. Subjects: The study involved 41 participants assigned by register code entry on computer to either the intervention or the control group. Intervention: The FIR pads were applied on the acupoints of ST 37 (Shang Chu Hsu), ST 38 (Tiao Kou), ST 39 (Hsia Chu Hsu), and ST 40 (Feng Lung) of the patients involved in the experimental group from the third day to the fifth day after the TKA. Outcome measures: The analgesic effect was evaluated via the pain intensity of the numeric rating scale (NRS) level and serum concentration of interleukin-6 (IL-6) and endothelin-1 (ET-1). Results: The FIR showed that the significant effects are on relieving pain and lowering the levels of IL-6 and ET-1. The results cannot only be the reference for the postoperative pain relief of TKA, but it can also be the database of another clinical application. Conclusions: This study demonstrated that the FIR can lower the NRS of pain and thus reduce the discomfort experienced by the patient. Findings indicated that effective application of FIR decreased the serum level of IL-6 and ET-1, which represent the subjective indicator of pain. © 2012, Mary Ann Liebert, Inc. Source


Wu C.-K.,National Taiwan University Hospital | Wu C.-K.,National Taiwan University | Lee J.-K.,National Taiwan University Hospital | Chiang F.-T.,National Taiwan University Hospital | And 8 more authors.
Critical Care Medicine | Year: 2011

OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p <.01 for each) were found for tumor necrosis factor-α and E/Em (r =.87) and E/A (r =-0.69), and for interleukin-6 and E/Em (r =.80) and E/A (r =-0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions. Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Source

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