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Biomedical subjects

Ryuya Yamanaka

Publications and source records attributed to Ryuya Yamanaka.

At least 19 recordsLinked to original sources
PubMed2006

Increased expression of CCAAT/enhancer binding protein beta correlates with prognosis in glioma patients.

C/EBP beta (CCAAT/enhancer binding protein beta) is a transcriptional factor that belongs to the basic region-leucine zipper class DNA-binding proteins and plays a role in cell differentiation and inflammatory reactions. Although high tissue levels of inflammatory cytokines, such as interleukin (IL)-6, IL-8 and transforming growth factor-beta, have been observed in glioma patients, the mechanisms underlying this phenomenon remain to be elucidated. C/EBP beta induces a variety of cytokines and thus may play a role in the pathogenesis of glioma. In this study, we investigated the relationship between C/EBP beta expression, tumor histology, and prognosis in glioma. The expression of C/EBP beta mRNA was examined with quantitative real-time PCR and protein expression was examined with immunohistochemical techniques in 47 glioma tissue samples. Expression of C/EBP beta mRNA and protein was markedly increased in high grade glioma compared with low grade glioma. Patients whose expression of C/EBP beta mRNA and protein in tumor tissue was lower survived longer than those whose expressions were higher. In vitro, C/EBP beta siRNA inhibited glioma cell proliferation and invasion. Moreover, IL-8 production by glioma cells was inhibited by C/EBP beta siRNA transfection. These data suggest that increased expression of C/EBP beta may contribute to the promotion of tumor invasiveness and progression. The data imply that the comparison of C/EBP beta expression could be a prognostic marker for patients with glioma.

Adolescent↗
PubMed2006

Novel immunotherapeutic approaches to glioma.

Despite advances in radiation, chemotherapy and surgical resectioning, the prognosis of patients with malignant glioma is poor. Therefore, the development of a new treatment modality is extremely important. There are an increasing number of reports that systemic immunotherapy using dendritic cells and peptides is capable of inducing an anti-glioma response. This review highlights progress in dendritic cell- and peptide-based immunotherapy for glioma patients. Dendritic cell- and peptide-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma; the therapy appears to be safe and without major side effects. Biotherapy for malignant glioma with dendritic cells and peptides represents a novel treatment paradigm.

Antigens, Neoplasm↗
PubMed2006

Increased expression of pituitary tumor-transforming gene (PTTG)-1 is correlated with poor prognosis in glioma patients.

Pituitary tumor-transforming gene (PTTG), which is homologous to a mammalian securin, plays a pivotal role in cell transformation and is overexpressed in numerous cancer cell lines and tissues. PTTG functions in the control of mitosis, cell transformation, DNA repair and gene regulation. In the present study, we investigated whether the expression of PTTG1 is correlated with tumorigenicity and prognosis in glioma patients. Expression of PTTG1 was confirmed in three glioma cell lines at the mRNA and protein levels using RT-PCR analysis and Western blotting, respectively. Furthermore, PTTG1 protein was detected in 44 glioma tissue samples using immunohistochemical techniques, markedly increased in high-grade gliomas compared to low-grade gliomas and associated with an unfavorable patient outcome. Moreover, siRNA against the PTTG1 gene inhibited cell proliferation and invasion in glioma cell lines. These data suggest that increased expression of PTTG1 contributes to the tumorigenicity of glioma cells and may be useful as a prognostic marker for glioma patients.

Adult↗
PubMed2006

Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients.

The ECT2 (epithelial cell transforming sequence 2) proto-oncogene encodes a guanine nucleotide exchange factor for Rho GTPases, and regulates cytokinesis. ECT2 plays a critical role in Rho activation during cytokinesis, and thus may play a role in the pathogenesis of glioma. In this study, we investigated relationships between ECT2 expression, tumor histology, and prognosis in glioma patients. ECT2 mRNA expression was examined using quantitative real-time PCR, while its protein expression was examined by immunohistochemistry of 54 glioma tissue samples. Expressions of ECT2 mRNA and protein were markedly increased in high-grade gliomas compared to low-grade gliomas. Patients in whom expression of ECT2 mRNA and protein in tumor tissues was the lowest survived longer than patients who had higher expression. In vitro, ECT2 siRNA inhibited glioma cell proliferation and invasion. These data suggest that increased expression of ECT2 contribute to promotion of tumor invasiveness and progression, implying that evaluation of ECT2 expression is a prognostic marker for glioma patients.

Adult↗
PubMed2005

Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma.

PURPOSE: The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma. EXPERIMENTAL DESIGN: Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For personalized peptide vaccination, prevaccination peripheral blood mononuclear cells and plasma were provided to examine cellular and humoral responses to 25 or 23 peptides in HLA-A24+ or HLA-A2+ patients, respectively; then, only the reactive peptides (maximum of four) were used for in vivo administration. RESULTS: The protocols were well tolerated with local redness and swelling at the injection site in most cases. Twenty-one patients received more than six vaccinations and were evaluated for both immunologic and clinical responses. Increases in cellular or humoral responses specific to at least one of the vaccinated peptides were observed in the postvaccination (sixth) samples from 14 or 11 of 21 patients, respectively. More importantly, significant levels of peptide-specific IgG were detected in the postvaccination tumor cavity or spinal fluid of all of the tested patients who showed favorable clinical responses. Clinical responses were 5 partial responses, 8 cases of stable disease, and 8 cases of progressive disease. The median overall survival for patients with recurrent glioblastoma multiforme in this study (n = 17) was 622 days. CONCLUSIONS: Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.

Adult↗
PubMed2005

Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial.

PURPOSE: To investigate the safety and the immunologic and clinical responses of dendritic cell therapy for patients with recurrent malignant glioma. EXPERIMENTAL DESIGN: Twenty-four patients with recurrent malignant glioma (6 grade 3 and 18 grade 4 patients) were evaluated in a phase I/II clinical study of dendritic cell therapy. All patients were resistant to the standard maximum therapy. The patient's peripheral blood dendritic cells were generated with granulocyte macrophage colony-stimulating factor, plus interleukin 4 with or without OK-432, and pulsed with an autologous tumor lysate. Dendritic cells were injected intradermally, or both intratumorally and intradermally every 3 weeks. RESULTS: The protocols were well tolerated with only local redness and swelling at the injection site in several cases. Clinical responses were as follows: 1 patient with partial response, 3 patients with minor response, 10 patients with stable disease, and 10 patients with progressive disease. The patients whose dendritic cells were matured with OK-432 had longer survival times than the dendritic cells from patients without OK-432 maturation. The patients with both intratumoral and intradermal administrations had a longer survival time than the patients with intradermal administration only. Increased ELISPOT and delayed-type hypersensitivity responses after vaccination could provide good laboratory markers to predict the clinical outcome of patients receiving dendritic cell vaccination. The overall survival of patients with grade 4 glioma was 480 days, which was significantly better than that in the control group. CONCLUSIONS: This study showed the safety and clinical response of autologous tumor lysate-pulsed dendritic cell therapy for patients with malignant glioma. Dendritic cell therapy is recommended for further clinical studies in malignant glioma patients.

Adult↗
PubMed2005

Modified ProMACE-MOPP hybrid regimen with moderate-dose methotrexate for patients with primary CNS lymphoma.

The object of this study was to assess the estimation of 2- and 5-year overall survival and tumor response and the frequency and severity of treatment morbidity with a modified ProMACE-MOPP hybrid protocol in patients with primary CNS lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristine, and methotrexate (500 mg/m(2)) administered in 21-day cycles. Intraventricular 10 mg of methotrexate was given for eight cycles once a week. Patients received 20 Gy of whole brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every 4 months for 2 years. Older patients (aged >60) received a reduced dose of chemotherapeutic agents. Eighteen patients were followed up with neuroimaging and neuropsychological assessments for evidence of CNS toxicity. Sixteen patients completed the regimen as planned. The response rate was 87.5% after the initial chemoradiotherapy. The cumulative survival and progression-free survival rates at 5 years were 56 and 31%, respectively. The median survival time was 68 months. The median progression-free survival time was 39 months. Toxicity included grade 3 or 4 leukopenia in 33% of the cycles administered. There were eight grade 3 or 4 pulmonary toxicities. There were three deaths during chemotherapy: one as a result of sepsis and two of pneumonitis. Three patients (25%) experienced delayed neurologic toxicity while on the complete regimen. Maintaining the dose of methotrexate while adding chemotherapeutic agents improved disease control and overall survival in patients with PCNSL, but early toxicity and delayed neurotoxicity are still a risk of this approach.

Adult↗
PubMed2005

Tumor lysate and IL-18 loaded dendritic cells elicits Th1 response, tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma.

In this study, we demonstrate that tumor lysate-loaded dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumor cells in patients with malignant glioma. CTL from three of five patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts and were variably cytotoxic against the LAK-sensitive cell line Daudi. Also, DCs pulsed normal brain lysate failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two of five patients CD8+ T cells expressed a modest cytotoxicity against autologous glioma cells. CD8+ T cells isolated during these ineffective primings secreted large amounts of IL-10, less amounts of IFN-gamma as detected by ELISA, Type 2 bias in the CD8+ T cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor lysate-loaded DC can be an effective tool in inducing glioma-specific CD8+ CTL able to kill autologous glioma cells in vitro. However, high levels of tumor specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. Moreover, cytotoxic responses were augmented by transfecting DC with the gene for IL-18. For all five patients, CD8+T cells treated with IL18 transfected DC produced Th1 response. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs loaded with total tumor lysate and IL-18 may represent a method for inducing Th1 immunoresponses against the entire repertoire of glioma antigens.

Aged↗
PubMed2005

Induction of antigen-specific immune responses against malignant brain tumors by intramuscular injection of sindbis DNA encoding gp100 and IL-18.

We constructed pSin-SV40-HDV-SV40pA, an improved Sindbis DNA expression vector, and evaluated the potential of this vector system for brain tumor therapy. We investigated whether immunizing mice with xenogeneic DNA encoding human gp100 and mouse IL-18 would enhance the antitumor responses. To study the immune mechanisms involved in tumor regression, we examined tumor growth in B16-gp100-implanted brain tumor models using T-cell subset-depleted and IFN-gamma-neutralized mice. Hugp100/mIL-18 vaccination was also investigated for its antitumor effects against the wild-type murine B16 tumor, which expresses the murine gp100 molecule. Genetic immunization using plasmid pSin 9001 DNA codelivery of human gp100 and mouse IL-18 resulted in enhanced protective and therapeutic effects on the malignant brain tumors. The antitumor and protective effects were mediated by both CD4(+)/CD8(+) T cells and IFN-gamma. Vaccination with hugp100/mIL-18 conferred a significant survival merit to wild-type B16 tumor-harboring mice. Immunogene therapy with the improved Sindbis virus vector expressing xenogeneic gp100 and syngeneic IL-18 may be an excellent approach for developing a new treatment protocol. Thus, the Sindbis DNA system may represent a novel approach for the treatment of malignant brain tumors.

Animals↗
PubMed2005

Isolation and characterization of an N-linked oligosaccharide that is increased in glioblastoma tissue and cell lines.

We have isolated and characterized N-linked oligo-saccharides that are significantly increased in glioblastoma tissue and cell lines. The structures of N-linked oligosaccharides present in 3 human normal brain tissues, 15 patients with glio-blastoma and 3 glioma cell lines were analyzed by partially automated technique for the isolation and fluorescent labeling of N-linked sugar chains from glycoproteins. Characterization of the sugar chains was achieved with the use of a combination of HPLC columns and a highly sensitive fluorescence detector at femtomole levels. By collecting peaks which accounted for 0.1% or more, sixteen different oligosaccharide structures were characterized from glioblastoma tissue and cell lines. The 16 oligosaccharide structures accounted for 48.9% of the total N-linked oligosaccharides present in glioblastoma tissue. The major components of total oligosaccharides were similar to those of normal brain tissue. The amount of a biantennary bigalactosylated structure with one core fucosylation (A2G2F) was present in increased levels in glioblastoma tissue (mean = 2.90%) and glioma cell lines (mean = 5.60%), while being less than 0.1% in normal brain tissue. Expression of highly branched tetra-antennary N-glycans that are usually detected in lungs or hepatocellular cancer was not observed. Tissue glioma cells and cultured cells also displayed strong LCA-lectin binding, which binds to sugar chains with core fucose (including A2G2F), while normal brain tissue did not. Moreover, LCA lectin inhibited proliferation of glioma cells through induction of apoptosis. A2G2F on glioma specimens may provide a novel marker and target for the diagnosis and treatment of glioblastoma, respectively.

Adolescent↗
PubMed2004

Development of improved Sindbis virus-based DNA expression vector.

We have constructed an improved DNA expression vector based on the Sindbis virus. Several DNA-based Sindbis virus vectors were constructed to investigate the efficiency of transgene expression. These vectors, when transfected into mammalian cells, have been used to express heterologous genes. A recombinant genome of Sindbis plasmid DNA, in which the structural genes were replaced by a polylinker cassette to allow for insertion of heterologous genes, was placed under the control of a simian virus (SV 40) promoter with a hepatitis delta virus (HDV) antigenomic ribozyme and a polyadenylation signal. Transfection of mammalian cells with this Sindbis-based plasmid vector, pSin-SV40-HDV-SV40pA, resulted in transient high-level expression of the beta-galactosidase reporter gene. The expression level of beta-galactosidase from pSin-SV40-HDV-SV40pA was more than 16-fold higher than that of pSin-Lux originally reported by Herweijer et al. In vivo expression was also detected after injection of plasmid DNA into mouse quadriceps. In vivo expression was transient and undetectable after day 14. Furthermore, we demonstrate that the transfection of cells with this Sindbis virus vector results in apoptotic death on glioma cells. We have demonstrated a high-level expression of the exogenous beta-galactosidase gene from the pSin-SV40-HDV-SV40pA construct using a Sindbis replication system.

Animals↗
PubMed2004

Gene therapy of brain tumor with endostatin.

Malignant brain tumors are the most vascularized tumors. Despite multimodal treatment approaches, the prognosis remains dismal. Angiogenesis and vascular proliferation are particularly important in the growth and progression of malignant brain tumors and are used as indicators of the degree of malignancy. The continued growth of a brain tumor is dependent on its angiogenic potential. Antiangiogenesis therapy may offer novel strategies for brain tumor therapy. Treatment with Semliki Forest virus-mediated endostatin inhibited the angiogenesis associated with established brain tumors. Gene therapy with endostatin delivered via Semliki Forest virus may be a candidate for the development of a new treatment for brain tumors.

Animals↗
PubMed2004

Alphavirus vectors for cancer gene therapy (review).

Alphaviruses have several characteristics that make them attractive as gene therapy vectors such as transient and high-level expression of a heterologous gene. Alphavirus vectors, Semliki Forest virus (SFV), Sindbis virus (SIN) and Venezuelan equine encephalitis virus (VEE) have been developed as gene expression vectors. Alphaviruses are positive-strand RNA viruses that can mediate efficient cytoplasmic gene expression in mammalian cells. The alphavirus RNA replication machinery has been engineered for high level heterologous gene expression. Since an RNA virus vector cannot integrate into chromosomal DNA, concerns about cell transformation are reduced. Alphavirus vectors demonstrate promise for the safe tumor-killing and tumor-specific immune responses. Recombinant alphavirus RNA replicons may facilitate gene therapy of cancer.

Alphavirus↗
PubMed2004

Advances for the treatment of primary central nervous system lymphoma (review).

Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin's lymphoma arising in the CNS. This review will focus on the recent advances in the treatment of PCNSL. Combined methotrexate-based chemotherapy and radiation therapy is the standard treatment for PCNSL. A median overall survival of 40-60 months is obtained, however, neurotoxicity is a major problem. Preservation of cognitive function appears better after chemotherapy alone, therefore, there are increasing reports that radiotherapy is deferred after chemotherapy. At the moment, the findings of multicenter randomized trials should be awaited to clarify whether deferring radiotherapy in patients responding to chemotherapy allows them to maintain a better quality of life without increasing the risk of local recurrence. The well-designed, multicenter and randomized trials will elucidate the issues, such as best chemotherapy regimen, no brain irradiation in responder and second-line treatment.

Adult↗
PubMed2003

Immunohistochemical analysis of myelination following hemicranial irradiation in neonatal rats.

The mechanism of radiation-induced diffuse brain injury was investigated in a neonatal rat hemicranial irradiation model using immunohistochemistry. Neonatal Fischer 344 rats received hemicranial irradiation with a single dose of 15 Gy, and appropriate combinations of myelin markers were used to assess the myelin damage at various stages of myelin development. Antibodies against myelin basic protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase and myelin oligodendrocyte glycoprotein were used, and the density of the antibody-positive fibers was classified into five categories. Statistical analysis showed significant differences between irradiated and unirradiated hemispheres. The differences decreased and myelination approached normality by postnatal day 70. These results show that myelination in the neonatal rat can recover from the developmental delay caused by a single 15 Gy dose of hemicranial irradiation.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2003

Tumor mRNA-loaded dendritic cells elicit tumor-specific CD8(+) cytotoxic T cells in patients with malignant glioma.

In this study, we demonstrate that tumor mRNA-loaded dendritic cells can elicit a specific CD8(+) cytotoxic T-lymphocyte (CTL) response against autologous tumor cells in patients with malignant glioma. CTLs from three patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts or EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Also, DCs-pulsed normal brain mRNA failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two patients' CD8(+) T cells expressed a modest cytotoxicity against autologous glioma cells. CD8(+) T cells isolated during these ineffective primings secreted large amounts of IL-10 and smaller amounts of IFN-gamma as detected by ELISA. Type 2 bias in the CD8(+) T-cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor mRNA-loaded DC can be an effective tool in inducing glioma-specific CD8(+) CTLs able to kill autologous glioma cells in vitro. However, high levels of tumor-specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs transfected with total tumor RNA may represent a method for inducing immune responses against the entire repertoire of glioma antigens.

Adult↗