PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None

Select a Filter Below

Journals
Authors
more »
Year of Publication
1.  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.
doi:10.4161/onci.26528
PMCID: PMC3897500  PMID: 24482748
ALCAM; bone metastasis; FSTL1; mesenchymal stem cell; SNAIL
2.  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.
doi:10.3389/fonc.2013.00136
PMCID: PMC3664832  PMID: 23755373
immunotherapy; immunosuppression; MAPK; STAT3; β-catenin
3.  Cost-effectiveness of chronic kidney disease mass screening test in Japan 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10157-011-0567-1
PMCID: PMC3328680  PMID: 22167460
Chronic kidney disease; Cost-effectiveness; Dipstick test; Mass screening; Proteinuria; Serum creatinine
4.  4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines 
Vaccine  2006;24(23):4975-4986.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1016/j.vaccine.2006.03.042
PMCID: PMC1865095  PMID: 16621183
vaccinia; vaccination; TRICOM; CEA; 4-1BBL; costimulation
5.  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 1-5 (5)