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1.  Cancer-associated mesenchymal stem cells aggravate tumor progression 
Mesenchymal stem cells (MSCs) have both stemness and multi-modulatory activities on other cells, and the immunosuppressive and tumor-promotive mechanisms have been intensively investigated in cancer. The role of MSCs appears to be revealed in tumor aggravation, and targeting MSCs seems to be a promising strategy for treating cancer patients. However, it is still impractical in clinical therapy, since the precise MSCs are poorly understood in the in vivo setting. In previous studies, MSCs were obtained from different sources, and were prepared by ex vivo expansion for a long term. The inconsistent experimental conditions made the in vivo MSCs obscure. To define the MSCs in the host is a priority issue for targeting MSCs in cancer therapy. We recently identified a unique subpopulation of MSCs increasing in mice and human with cancer metastasis. These MSCs are specifically expanded by metastatic tumor cells, and promote tumor progression and dissemination accompanied by immune suppression and dysfunction in the host, more powerfully than normal MSCs growing without interference of cancer. In this review, we summarize current knowledge of the role of MSCs in tumor aggravation, along with our new findings of the bizarre MSCs.
PMCID: PMC4381695  PMID: 25883937
mesenchymal stem cell; cancer; metastasis; epithelial-to-mesenchymal transition; immunosuppression
2.  Annual Decline in Pentraxin 3 Is a Risk of Vascular Access Troubles in Hemodialysis Patients 
Pentraxin 3 (PTX3), a multifunctional modulator of the innate immunoinflammatory response, is higher in patients undergoing hemodialysis than healthy control. Our study focused on annual change in PTX3 levels in patients with chronic hemodialysis, because regularly undergoing hemodialysis for many years modifies vascular inflammatory status. To demonstrate whether annual change in PTX3 is associated with vascular events, we measured blood levels of pentraxins (PTX3 and high-sensitivity C-reactive protein (hsCRP)) at baseline and in the next year in 76 hemodialysis patients and observed 20 patients with vascular access troubles during follow-up years. The annual decline in PTX3, but not hsCRP, is a significant risk of the incidence of vascular access trouble that is a critical and specific complication for hemodialysis patients (hazard ratio; 0.732 per +1 ng/mL/year in PTX3, *P = 0.039). This study is the first to focus on the annual change of pentraxins in a hemodialysis cohort.
PMCID: PMC4283416  PMID: 25587447
3.  Budget impact analysis of chronic kidney disease mass screening test in Japan 
Our recently published cost-effectiveness study on chronic kidney disease mass screening test in Japan evaluated the use of dipstick test, serum creatinine (Cr) assay or both in specific health checkup (SHC). Mandating the use of serum Cr assay additionally, or the continuation of current policy mandating dipstick test only was found cost-effective. This study aims to examine the affordability of previously suggested reforms.
Budget impact analysis was conducted assuming the economic model would be good for 15 years and applying a population projection. Costs expended by social insurers without discounting were counted as budgets.
Annual budget impacts of mass screening compared with do-nothing scenario were calculated as ¥79–¥−1,067 million for dipstick test only, ¥2,505–¥9,235 million for serum Cr assay only and ¥2,517–¥9,251 million for the use of both during a 15-year period. Annual budget impacts associated with the reforms were calculated as ¥975–¥4,129 million for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥963–¥4,113 million for mandating serum Cr assay only and abandoning dipstick test.
Estimated values associated with the reform from ¥963–¥4,129 million per year over 15 years are considerable amounts of money under limited resources. The most impressive finding of this study is the decreasing additional expenditures in dipstick test only scenario. This suggests that current policy which mandates dipstick test only would contain medical care expenditure.
PMCID: PMC4271136  PMID: 24515308
CKD; Budget impact; Dipstick test; Mass screening; Proteinuria; Serum creatinine assay
4.  FSTL1 promotes bone metastasis by causing immune dysfunction 
Oncoimmunology  2013;2(11):e26528.
In spite of significant advances in our understanding of the metastatic process, the relationship between the dissemination of primary neoplasms to the bones and antitumor immunity remains poorly understood. We have recently identified follistatin-like 1 (FSTL1), a soluble protein secreted by snail family zinc finger 1 (SNAI1)-expressing cancer cells, as a key determinant of bone metastasis that operates by inducing a systemic state of immune dysfunction.
PMCID: PMC3897500  PMID: 24482748
ALCAM; bone metastasis; FSTL1; mesenchymal stem cell; SNAIL
5.  Improvement of Cancer Immunotherapy by Combining Molecular Targeted Therapy 
Frontiers in Oncology  2013;3:136.
In human cancer cells, a constitutive activation of MAPK, STAT3, β-catenin, and various other signaling pathways triggers multiple immunosuppressive cascades. These cascades result in the production of immunosuppressive molecules (e.g., TGF-β, IL-10, IL-6, VEGF, and CCL2) and induction of immunosuppressive immune cells (e.g., regulatory T cells, tolerogenic dendritic cells, and myeloid-derived suppressor cells). Consequently, immunosuppressive conditions are formed in tumor-associated microenvironments, including the tumor and sentinel lymph nodes. Some of these cancer-derived cytokines and chemokines impair immune cells and render them immunosuppressive via the activation of signaling molecules, such as STAT3, in the immune cells. Thus, administration of signal inhibitors may inhibit the multiple immunosuppressive cascades by acting simultaneously on both cancer and immune cells at the key regulatory points in the cancer-immune network. Since common signaling pathways are involved in manifestation of several hallmarks of cancer, including cancer cell proliferation/survival, invasion/metastasis, and immunosuppression, targeting these shared signaling pathways in combination with immunotherapy may be a promising strategy for cancer treatment.
PMCID: PMC3664832  PMID: 23755373
immunotherapy; immunosuppression; MAPK; STAT3; β-catenin
6.  Cost-effectiveness of chronic kidney disease mass screening test in Japan 
Chronic kidney disease (CKD) is a significant public health problem. Strategy for its early detection is still controversial. This study aims to assess the cost-effectiveness of population strategy, i.e. mass screening, and Japan’s health checkup reform.
Cost-effectiveness analysis was carried out to compare test modalities in the context of reforming Japan’s mandatory annual health checkup for adults. A decision tree and Markov model with societal perspective were constructed to compare dipstick test to check proteinuria only, serum creatinine (Cr) assay only, or both.
Incremental cost-effectiveness ratios (ICERs) of mass screening compared with do-nothing were calculated as ¥1,139,399/QALY (US $12,660/QALY) for dipstick test only, ¥8,122,492/QALY (US $90,250/QALY) for serum Cr assay only and ¥8,235,431/QALY (US $91,505/QALY) for both. ICERs associated with the reform were calculated as ¥9,325,663/QALY (US $103,618/QALY) for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥9,001,414/QALY (US $100,016/QALY) for mandating serum Cr assay and applying dipstick test at discretion.
Taking a threshold to judge cost-effectiveness according to World Health Organization’s recommendation, i.e. three times gross domestic product per capita of ¥11.5 million/QALY (US $128 thousand/QALY), a policy that mandates serum Cr assay is cost-effective. The choice of continuing the current policy which mandates dipstick test only is also cost-effective. Our results suggest that a population strategy for CKD detection such as mass screening using dipstick test and/or serum Cr assay can be justified as an efficient use of health care resources in a population with high prevalence of the disease such as in Japan and Asian countries.
PMCID: PMC3328680  PMID: 22167460
Chronic kidney disease; Cost-effectiveness; Dipstick test; Mass screening; Proteinuria; Serum creatinine
7.  4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines 
Vaccine  2006;24(23):4975-4986.
Recombinant poxvirus vaccines have been explored as tumor vaccines. The immunogenicity of these vaccines can be enhanced by co-expressing costimulatory molecules and tumor-associated antigens. While the B7-CD28 interaction has been most comprehensively investigated, other costimulatory molecules utilize different signaling pathways and might provide further cooperation in T cell priming and survival. 4-1BB (CD137) is a TNF family member and is critical for activation and long-term maintenance of primed T-cells. This study was conducted to determine if a poxvirus expressing the ligand for 4-1BB (4-1BBL) could further improve the immune and therapeutic responses of a previously reported poxvirus vaccine expressing a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3).
Experimental Design
A recombinant vaccinia virus expressing 4-1BBL was generated and characterized in an in vitro infection system. This vaccine was then used alone or in combination with a vaccinia virus expressing CEA, B7.1, ICAM-1, and LFA-3 in CEA-transgenic mice bearing established MC38 tumors. Tumor growth and immune responses against CEA and other tumor-associated antigens were determined. The level of anti-apoptotic proteins in responding T cells was determined by flow cytometry on tetramer selected T cells.
The combination of 4-1BBL with B7.1-based poxvirus vaccination resulted in significantly enhanced therapeutic effects against CEA-expressing tumors in a CEA transgenic mouse model. This was associated with an increased level of CEA-specific CD4+ and CD8+ T cell responses, induction of antigen spreading to p53 and gp70, increased accumulation of CEA-specific T cells in the tumor microenvironment, and increased expression of bcl-XL and bcl-2 in CD4+ and CD8+ T cells in vaccinated mice.
4-1BBL cooperates with B7 in enhancing anti-tumor and immunologic responses using a recombinant poxvirus vaccine model. The inclusion of costimulatory molecules targeting distinct T cell signaling pathways provides a mechanism for enhancing the therapeutic effectiveness of tumor vaccines.
PMCID: PMC1865095  PMID: 16621183
vaccinia; vaccination; TRICOM; CEA; 4-1BBL; costimulation
8.  Multiple Costimulatory Modalities Enhance CTL Avidity 
Recent studies in both animal models and clinical trials have demonstrated that the avidity of T cells is a major determinant of anti-tumor and anti-viral immunity. Here, we evaluated several different vaccine strategies for their ability to enhance both the quantity and avidity of CTL responses. CD8+ T-cell quantity was measured by tetramer binding precursor frequency, and avidity was measured by both tetramer dissociation and quantitative cytolytic function. We have evaluated a peptide, a viral vector expressing the antigen transgene alone, with one costimulatory molecule (B7-1), and with three costimulatory molecules (B7-1, ICAM-1 and LFA-3), with anti-CTLA-4 mAb, with GM-CSF, and combinations of the above. We have evaluated these strategies in both a foreign antigen model employing β-gal as immunogen, and in a “self” antigen model, employing CEA as immunogen in CEA transgenic (Tg) mice. The combined use of several of these strategies was shown to enhance not only the quantity, but, to a greater magnitude, the avidity of T cells generated; a combination strategy is also shown to enhance anti-tumor effects. The studies reported here thus demonstrate multiple strategies that can be employed in both anti-tumor and anti-viral vaccine settings to generate higher avidity host T-cell responses.
PMCID: PMC1924685  PMID: 15879092
Vaccine; Poxvirus; Costimulation; Avidity; CTLA-4

Results 1-8 (8)