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Wang W.-B.,National Health Research Institute | Yen M.-L.,National Taiwan University Hospital | Liu K.-J.,National Institute of Cancer Research | Liu K.-J.,Taipei Medical University | And 7 more authors.
Stem Cell Reports | Year: 2015

Summary Multipotent human mesenchymal stromal cells (hMSCs) harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A)-secreting T (Th17) lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25 - also known as IL-17E - as well as programmed death ligand-1 (PD-L1), a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.In this article, Yen and colleagues demonstrate that multipotent human mesenchymal stromal cells (hMSCs) suppress interleukin (IL)-17A-secreting T cell (Th17) responses through expression of IL-25, a paracrine factor, and programmed death ligand-1 (PD-L1), a cell surface ligand. The requirement of both factors is explained by IL-25 modulation of PD-L1 expression via JNK and STAT3 to orchestrate an overall effect of suppressing Th17 responses. © 2015 The Authors. Source

Mostafa M.G.,National Institute of Cancer Research | Cherry N.,University of Alberta
International Journal of Environmental Research and Public Health | Year: 2015

In earlier analyses, we demonstrated dose-response relationships between renal and lung cancer and local arsenic concentrations in wells used by Bangladeshi villagers. We used the same case-referent approach to examine the relation of arsenic to biopsy confirmed transition cell cancer (TCC) of the ureter, bladder or urethra in these villagers. As the International Agency for Research on Cancer (IARC) has conclude that arsenic in drinking water causes bladder cancer, we expected to find higher risk with increasing arsenic concentration. We used histology/cytology results from biopsies carried out at a single clinic in Dhaka, Bangladesh from January 2008 to October 2011. We classified these into four groups, TCC (n = 1466), other malignancies (n = 145), chronic cystitis (CC) (n = 844) and other benign (n = 194). Arsenic concentration was estimated from British Geological Survey reports. Odds ratios were calculated by multilevel logistic regression adjusted for confounding and allowing for geographic clustering. We found no consistent trend for TCC with increasing arsenic concentration but the likelihood of a patient with benign disease having CC was significantly increased at arsenic concentrations >100 μg/L. We conclude that the expected relationship of TCC to arsenic was masked by over-matching that resulted from the previously unreported relationship between arsenic and CC. We hypothesize that CC may be a precursor of TCC in high arsenic areas. © 2015 by the authors, licensee MDPI, Basel, Switzerland. Source

Weng C.-C.,National Sun Yat - sen University | Kuo K.-K.,Kaohsiung Medical University | Kuo K.-K.,National Sun Yat - sen University | Su H.-T.,National Sun Yat - sen University | And 8 more authors.
Pancreas | Year: 2016

Objectives: The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling. Methods: The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo. Results: AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGFexpression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion. Conclusion: Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Chen P.-M.,National Health Research Institute | Yen M.-L.,National Taiwan University Hospital | Liu K.-J.,National Institute of Cancer Research | Sytwu H.-K.,Graduate Institute of Microbiology and Immunology | Yen B.-L.,National Health Research Institute
Journal of Biomedical Science | Year: 2011

In recent years, a large number of studies have contributed to our understanding of the immunomodulatory mechanisms used by multipotent mesenchymal stem cells (MSCs). Initially isolated from the bone marrow (BM), MSCs have been found in many tissues but the strong immunomodulatory properties are best studied in BM MSCs. The immunomodulatory effects of BM MSCs are wide, extending to T lymphocytes and dendritic cells, and are therapeutically useful for treatment of immune-related diseases including graft-versus-host disease as well as possibly autoimmune diseases. However, BM MSCs are very rare cells and require an invasive procedure for procurement. Recently, MSCs have also been found in fetal-stage embryo-proper and extra-embryonic tissues, and these human fetal MSCs (F-MSCs) have a higher proliferative profile, and are capable of multilineage differentiation as well as exert strong immunomodulatory effects. As such, these F-MSCs can be viewed as alternative sources of MSCs. We review here the current understanding of the mechanisms behind the immunomodulatory properties of BM MSCs and F-MSCs. An increase in our understanding of MSC suppressor mechanisms will offer insights for prevalent clinical use of these versatile adult stem cells in the near future. © 2011 Chen et al; licensee BioMed Central Ltd. Source

Wu Y.-Y.,Tri Service General Hospital | Wu Y.-Y.,A-Life Medical | Huang T.-C.,Tri Service General Hospital | Tsai T.-N.,A-Life Medical | And 10 more authors.
PLoS ONE | Year: 2016

Objective Trastuzumab-containing treatment regimens have been shown to improve survival outcomes in HER2-positive breast cancer (BC). It is much easier to infuse a fixed one-vial dose to every patient on a regular schedule in the general clinical setting. The aims of this study were evaluating the efficacy of a 440 mg fixed-dose of trastuzumab administered on a monthly infusion schedule, and the risk factors for cardiac events. Patients and methods We retrospectively reviewed data from 300 HER2-positive BC patients in our institute: 208 were early-stage BC patients undergoing adjuvant trastuzumab treatment, and 92 were metastatic BC patients treated with trastuzumab infusions until disease progression. There were 181 patients receiving regular trastuzumab infusions every 3 weeks (Q3W; 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks), and the other 119 patients were treated monthly with a fixed 440 mg dose (QM; fixed 440 mg every 4 weeks). Results The medians of progression-free survival (PFS) and overall survival (OS) in the adjuvant setting were not reached in both treatment groups. In the metastatic setting, there was no significant difference between groups in PFS or OS. The median time to significant cardiovascular (CV) dysfunction was 4.54 months. The incidence of congestive heart failure requiring medication in our cohort was 3.4%. Conclusion In our study, we found that fixed-dose monthly trastuzumab was feasible and effective. In addition, the CV risk was not higher with the fixed-dose protocol. This treatment modality could lower the cost and was easier to implement in clinical practice. Larger prospective randomized studies with longer-term follow up are needed to confirm our results. © 2016 Wu 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. Source

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