96 results on '"Hitoshi Kitayama"'
Search Results
52. The membrane-anchored metalloproteinase regulator RECK stabilizes focal adhesions and anterior-posterior polarity in fibroblasts
- Author
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Shuliang Shi, Makoto Noda, Hitoshi Kitayama, Tomoko Matsuzaki, David B. Alexander, James Monypenny, and Yoko Morioka
- Subjects
rac1 GTP-Binding Protein ,rho GTP-Binding Proteins ,Cancer Research ,Biology ,GPI-Linked Proteins ,Collagen Type I ,Focal adhesion ,Mice ,Microtubule ,Cell Movement ,Cell polarity ,Genetics ,medicine ,Animals ,Fibroblast ,Cell adhesion ,cdc42 GTP-Binding Protein ,Molecular Biology ,Cells, Cultured ,Focal Adhesions ,Membrane Glycoproteins ,Neuropeptides ,Cell Polarity ,Sarcoma ,Fibroblasts ,Actins ,Cell biology ,Fibronectins ,rac GTP-Binding Proteins ,Fibronectin ,medicine.anatomical_structure ,Biochemistry ,Cdc42 GTP-Binding Protein ,Focal Adhesion Protein-Tyrosine Kinases ,biology.protein ,NIH 3T3 Cells ,Extracellular Matrix Degradation - Abstract
Accumulating evidence indicates that Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored matrix metalloproteinase regulator, plays crucial roles in mammalian development and tumor suppression. Its mechanisms of action at the single cell level, however, remain largely unknown. In mouse fibroblasts, RECK is abundant around the perinuclear region, membrane ruffles and cell surface. Cells lacking Reck show decreased spreading, ambiguous anterior-posterior (AP) polarity, and increased speed and decreased directional persistence in migration; these characteristics are also found in transformed fibroblasts and fibrosarcoma cells with low RECK expression. RECK-deficient cells fail to form discrete focal adhesions, have increased levels of GTP-bound Rac1 and Cdc42, and a marked decrease in the level of detyrosinated tubulin, a hallmark of stabilized microtubules. RECK-deficient cells also show elevated gelatinolytic activity and decreased fibronectin fibrils. The phenotype of RECK-deficient cells is largely suppressed when the cells are plated on fibronectin-coated substrates. These findings suggest that RECK regulates pericellular extracellular matrix degradation, thereby allowing the cells to form proper cell-substrate adhesions and to maintain AP polarity during migration; this mechanism is compromised in malignant cells.
- Published
- 2009
53. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells
- Author
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Jun Ishikawa, Akira Kuriu, James D. Griffin, Takeshi Yonezawa, Toshiharu Tamaki, Yuzuru Kanakura, Yoshio Kanayama, Hitoshi Kitayama, Seiichiro Tarui, and Hirokazu Ikeda
- Subjects
Acute myeloblastic leukemia ,Blotting, Western ,Immunology ,Gene Expression ,In Vitro Techniques ,Hematopoietic Cell Growth Factors ,Proto-Oncogene Mas ,Biochemistry ,Recombinant Human Stem Cell Factor ,Receptor tyrosine kinase ,Proto-Oncogene Proteins ,Proto-Oncogenes ,Tumor Cells, Cultured ,medicine ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Northern blot ,Phosphorylation ,Phosphotyrosine ,Receptor ,Stem Cell Factor ,biology ,Cell Biology ,Hematology ,Blotting, Northern ,medicine.disease ,Molecular biology ,Recombinant Proteins ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Haematopoiesis ,biology.protein ,Tyrosine ,Antibody ,Cell Division - Abstract
The c-kit proto-oncogene encodes a receptor tyrosine kinase that is thought to play an important role in hematopoiesis. In a series of human acute myeloblastic leukemia (AML), the expression of the c-kit proto-oncogene and its product was studied by means of Northern blot and immunoblot analyses. The c-kit mRNA was expressed in 20 of 25 cases of AML, and in those cases the product of the c-kit proto-oncogene was detected by immunoblotting with anti-c-kit antibody. The expression of c-kit transcripts and protein was barely detectable in normal bone marrow cells as a control. The expression of c-kit transcript did not correlate with the French-American-British classification nor clinical manifestations. In 6 of 11 cases that expressed c-kit product, AML cells were found to proliferate in response to recombinant human stem cell factor (rhSCF), the ligand for c-kit, and the synergistic stimulation of AML cells was observed by rhSCF and granulocyte- macrophage colony-stimulating factor. Immunoblotting with anti- phosphotyrosine antibody showed that the c-kit receptor protein was detectably phosphorylated in 7 of 12 cases tested before the stimulation with rhSCF, while the rhSCF treatment resulted in an increased tyrosine phosphorylation of c-kit in AML cells. These results indicate that c-kit proto-oncogene is expressed in most cases of AML and is functional in terms of supporting proliferation.
- Published
- 1991
54. Genetic analysis of the K-rev-1 transformation-suppressor gene
- Author
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Yoji Ikawa, Hitoshi Kitayama, Tomoko Matsuzaki, Yoshikazu Sugimoto, and Makoto Noda
- Subjects
Health, Toxicology and Mutagenesis ,viruses ,Molecular Sequence Data ,Mice, Nude ,Biology ,Transfection ,3T3 cells ,law.invention ,GTP Phosphohydrolases ,chemistry.chemical_compound ,Mice ,In vivo ,law ,GTP-Binding Proteins ,Consensus Sequence ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,Amino Acid Sequence ,Fibroblast ,Gene ,Cell Line, Transformed ,fungi ,GTPase-Activating Proteins ,Genetic Complementation Test ,Public Health, Environmental and Occupational Health ,Proteins ,3T3 Cells ,DNA ,Neoplasms, Experimental ,Fibroblasts ,Molecular biology ,Enzyme Activation ,Transformation (genetics) ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Genes, ras ,rap GTP-Binding Proteins ,chemistry ,ras GTPase-Activating Proteins ,Mutagenesis, Site-Directed ,Suppressor ,Kirsten murine sarcoma virus ,Research Article - Abstract
Flat revertants with reduced malignancy in vivo can be isolated from Kirsten sarcoma virus-transformed NIH 3T3 cells (DT line) following transfection with a normal human fibroblast cDNA expression library. We have recovered from one such revertant a 1.8-kb cDNA clone, K-rev-1, that exhibits an activity of inducing flat revertants at certain frequencies (2-5% of total transfectants) when transfected into DT cells. The K-rev-1 cDNA has the capacity to encode a protein with a calculated molecular weight of 21,000, having strong structural similarity to ras proteins (approximately 50% homology), especially in their guanosine triphosphate/guanosine diphosphate-binding, effector-binding, and membrane-attachment domains. Toward understanding the mechanism of action of K-rev-1 protein, we constructed a series of point mutants of K-rev-1 cDNA and tested their biological activities. Substitutions of the amino acid residues in the putative guanine nucleotide-binding regions (Asp17 and Asn116), in the putative effector-binding domain (residue 38), at the putative acylation site (Cys181), and at the unique Thr61 all decreased the transformation-suppressor activity. On the other hand, substitutions including Gly12 to Val12, Ala59 to Thr59, and Gln63 to Glu63 were found to significantly increase the transformation-suppressor activity of K-rev-1. These findings are consistent with the idea that K-rev-1 protein is regulated like many other G-proteins by guanine triphosphate/guanine diphosphate-exchange mechanism probably in response to certain negative growth-regulatory signals.
- Published
- 1991
55. A Domain Responsible for the Transformation Suppressor Activity in Krev-1 Protein
- Author
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Makoto Noda, Hitoshi Kitayama, Tomoko Matsuzaki, and Yoji Ikawa
- Subjects
Chimeric cDNA ,Cancer Research ,Flat revertant ,A domain ,Chromosome Mapping ,Valine ,KREV-1 Protein ,Chimeric gene ,Biology ,Molecular biology ,law.invention ,Chimera (genetics) ,Genes, ras ,rap GTP-Binding Proteins ,Oncology ,GTP-Binding Proteins ,Cell culture ,law ,Complementary DNA ,Suppressor ,Functional organization ,Rapid Communication ,H‐ras gene - Abstract
Krev‐1 cDNA encodes a ras‐related protein and exhibits an activity of inducing flat revertants at certain frequencies (2‐5% of total transfectants) when introduced into a v‐K‐ras‐transformed mouse NIH3T3 cell line, DT. To explore the functional organization of Krev‐1 protein, we constructed a series of chimeric genes consisting of fragments of H‐ras and Krev‐1 cDNAs, and tested their biological activities in DT cells. The results indicated that the determinant for the transformation suppressor activity resides in the N‐terminal one‐third of the Krev‐1 encoded polypeptide within which a highly conserved, putative effector‐binding domain is present.
- Published
- 1990
56. Elevation of activated platelet-dependent chemokines in patients with anti-CD20 monoclonal antibody (rituximab)-treated non-Hodgkin's lymphoma
- Author
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Nobuhiko Uoshima, Kazuyoshi Ishii, Hitoshi Kitayama, Yuka Kamitsuji, Kunio Hayashi, Shosaku Nomura, and Emiko Ishikawa
- Subjects
0301 basic medicine ,Eotaxin ,Blood Platelets ,Male ,Chemokine ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Antibodies, Monoclonal, Murine-Derived ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Chemotherapy ,biology ,business.industry ,Lymphoma, Non-Hodgkin ,Antibodies, Monoclonal ,Hematology ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,Antigens, CD20 ,Non-Hodgkin's lymphoma ,Lymphoma ,030104 developmental biology ,Immunology ,Monoclonal ,biology.protein ,Cancer research ,Rituximab ,Female ,Chemokines ,business ,medicine.drug - Abstract
ocn.ne.jp. This study measured and compared levels of some chemokines in patients with rituximab-treated non-Hodgkin lymphoma because they may participate in the mechanism of efficacy of rituximab in non-Hodgkin lymphoma patients. Monocytic chemotactant protein-1, RANTES (regulated on activation, normally T-cell expressed and secreted), eotaxin, interleukin-8, neutrophil-activating protein-78, stromal cell-derived factor-1, and growth-regulating oncogene-α in patients with rituximab-treated non-Hodgkin lymphoma were measured by enzyme-linked immunosorbent assay. Levels of RANTES were higher in non-Hodgkin lymphoma patients than in controls. Levels of monocytic chemotactant protein-1, RANTES, and neutrophil-activating protein-78 were significantly elevated before and after chemotherapy with rituximab treatment. However, the level of stromal cell-derived factor-1 did not exhibit a significant change. Before to after chemotherapy without rituximab treatment, all chemokine levels did not exhibit significant changes. These findings suggest that activated platelet-dependent chemokines such as RANTES and neutrophil-activating protein-78 may modulate the efficacy of rituximab in antibody-dependent cellular cytotoxity.
- Published
- 2007
57. Reduced Rap1 Signaling Contributes to Prostate Cancer Progression
- Author
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Thomas L Genetta, Veronica Mwihaki Henderson, Mohamed Ali-Seyed, Carlos S. Moreno, Marie E Csete, and Hitoshi Kitayama
- Subjects
Prostate cancer ,business.industry ,Genetics ,medicine ,Cancer research ,Rap1 ,medicine.disease ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2007
58. Dual effects of the membrane-anchored MMP regulator RECK on chondrogenic differentiation of ATDC5 cells
- Author
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Yoko Morioka, Akihiro Umezawa, Shunya Kondo, Chisa Shukunami, Tadao Atsumi, Akira Kudo, Rei Takahashi, Naoya Matsumoto, Yuji Hiraki, Hitoshi Kitayama, Junseo Oh, and Makoto Noda
- Subjects
Immunoblotting ,Morphogenesis ,Type II collagen ,Cartilage metabolism ,Biology ,Matrix metalloproteinase ,GPI-Linked Proteins ,Cell Line ,Extracellular matrix ,Mice ,Chondrocytes ,Downregulation and upregulation ,medicine ,Animals ,Gene Silencing ,Fluorescent Antibody Technique, Indirect ,In Situ Hybridization ,Membrane Glycoproteins ,Cartilage ,Gene Expression Profiling ,Cell Differentiation ,Cell Biology ,Anatomy ,Chondrogenesis ,Matrix Metalloproteinases ,Cell biology ,Extracellular Matrix ,medicine.anatomical_structure ,Mutation ,Collagen - Abstract
Extracellular matrix (ECM) undergoes continuous remodeling during mammalian development. Although involvement of matrix metalloproteinases (MMPs) in ECM degradation has been well documented, how this process is regulated to allow proper ECM accumulation remains unclear. We previously showed the involvement of a membrane-anchored MMP regulator, RECK (reversion-inducing cysteine-rich protein with Kazal motifs), in vascular development in mice. Here we report that Reck mRNA can be detected in developing cartilage in E13.5∼16.5 mouse embryos and is progressively upregulated during differentiation of a chondrogenic cell line ATDC5 in vitro. In the early phase of ATDC5 differentiation, RECK expression stays low, multiple MMPs are upregulated, and there is ECM degradation at the sites of cellular condensation. In the later phase, RECK is upregulated inside the expanding cartilaginous nodules where type II collagen is accumulated while active ECM degradation persists along the rim of the nodules. Constitutive RECK expression suppressed initial cellular condensation, whereas RECK knockdown suppressed the later ECM accumulation in the cartilaginous nodules. These results suggest that RECK expression at the right place (in the core of the nodules) and at the right time (only in the later phase) is important for proper chondrogenesis and that RECK, together with MMPs, plays a crucial role in regulating dynamic processes of tissue morphogenesis.
- Published
- 2007
59. Identification of Rgl3 as a potential binding partner for Rap-family small G-proteins and profilin II
- Author
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Jiegou Xu, Shuliang Shi, Makoto Noda, Hitoshi Kitayama, and Naoya Matsumoto
- Subjects
Molecular Sequence Data ,Small G Protein ,macromolecular substances ,Biology ,Cell morphology ,Mice ,Profilins ,Cell Movement ,Complementary DNA ,ral Guanine Nucleotide Exchange Factor ,Animals ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Actin ,Cell Line, Transformed ,Activator (genetics) ,Gene Expression Profiling ,rap1 GTP-Binding Proteins ,Cell Biology ,Molecular biology ,Cell biology ,Profilin ,Gene Expression Regulation ,Cytoplasm ,biology.protein ,NIH 3T3 Cells ,ras Proteins ,Rap1 ,Protein Binding ,Subcellular Fractions - Abstract
A cDNA encoding a RalGDS-related protein, Rgl3, was isolated by yeast two-hybrid screening using a small G-protein, Rap1, as a bait. Rgl3 mRNA is commonly detectable in several visceral organs (e.g. kidney, heart, liver, and lung) in the mouse and human. The Rgl3 protein mainly localizes in the cytoplasm when expressed in fibroblasts. Yeast two-hybrid assay indicated that Rgl3 could interact with Rap1, Rap2, H-Ras, N-Ras, and R-Ras but failed to interact efficiently with Ral and Rho. Interestingly, Rgl3 was found to affect cell morphology in two assay systems in culture. First, Rgl3 suppressed cell-spreading induced by Rap1, R-Ras, or C3G-CAAX (a membrane-targeted Rap/R-Ras activator) in HEK-293 cells. Second, Rgl3 enhanced the focus-formation induced by oncogenic H-Ras and N-Ras mutants in NIH3T3 cells. Moreover, we identified profilin II as a potential binding partner for Rgl3 by yeast two-hybrid screening. This interaction requires the characteristic proline cluster in the Rgl3 amino-terminal domain. Profilin II and Rgl3 co-operated in enhancing the N-Ras-induced focus-formation. These findings raise the possibility that Rgl3 mediates interaction between Ras/Rap-family proteins and profilin II, an important activator of actin polymerization.
- Published
- 2007
60. Aggressive surgical and chemotherapeutic treatment of advanced pancreatoblastoma associated with tumor thrombus in portal vein
- Author
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Shinji Hirooka, Masanori Hokim, Takuya Kosumi, Akio Kubota, Hitoshi Kitayama, and Takeo Yonekura
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Pancreatoblastoma ,Mesenteric Vein ,Metastasis ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Mesenteric lymph nodes ,Pericardium ,Combined Modality Therapy ,Humans ,Digestive System Surgical Procedures ,Chemotherapy ,Peripheral Blood Stem Cell Transplantation ,business.industry ,Portal Vein ,Thrombosis ,General Medicine ,medicine.disease ,Surgery ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Child, Preschool ,Lymphatic Metastasis ,Pediatrics, Perinatology and Child Health ,Radiology ,business - Abstract
A 3-year-old boy had pancreatoblastoma arising in the pancreatic head and body, with metastasis in the mesenteric lymph nodes, tumor thrombus in the portal vein, and a small metastatic lesion in the left lung. After preoperative chemotherapy, aggressive surgical treatment including resection and reconstruction of the portal and superior mesenteric veins was performed. Postoperative chemotherapy was followed by high-dose chemotherapy and rescue with peripheral blood stem cell transplantation, and he has now been well for 6 years. This is the first surviving pediatric case of advanced pancreatoblastoma treated by aggressive surgical therapy including reconstruction of the portal vein and high-dose chemotherapy followed by peripheral blood stem cell transplantation.
- Published
- 2006
61. Histone deacetylase inhibitor FK228 suppresses the Ras-MAP kinase signaling pathway by upregulating Rap1 and induces apoptosis in malignant melanoma
- Author
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Hidemi Nakagawa, Yusuke Furukawa, T Murakami, Mamitaro Ohtsuki, Eiji Kusano, Krittaya Sutheesophon, T Kobayashi, Yukiko Kobayashi, Yasuhiko Kano, and Hitoshi Kitayama
- Subjects
Male ,endocrine system ,Cancer Research ,Small interfering RNA ,medicine.drug_class ,MAP Kinase Signaling System ,Apoptosis ,Mice, SCID ,Biology ,medicine.disease_cause ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,Depsipeptides ,Genetics ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Molecular Biology ,Melanoma ,Oligonucleotide Array Sequence Analysis ,Antibiotics, Antineoplastic ,Histone deacetylase inhibitor ,rap1 GTP-Binding Proteins ,medicine.disease ,Up-Regulation ,Histone Deacetylase Inhibitors ,enzymes and coenzymes (carbohydrates) ,Cancer research ,ras Proteins ,Rap1 ,Histone deacetylase ,Signal transduction ,Carcinogenesis ,Signal Transduction - Abstract
Histone deacetylase (HDAC) inhibitors are expected to be effective for refractory cancer because their mechanism of action differs from that of conventional antineoplastic agents. In this study, we examined the effect of the HDAC inhibitor FK228 on malignant melanoma, as well as its molecular mechanisms. FK228 was highly effective against melanoma compared with other commonly used drugs. By comparing the gene expression profiles of melanoma cells and normal melanocytes, we defined a subset of genes specifically upregulated in melanoma cells by FK228, which included Rap1, a small GTP-binding protein of the Ras family. The expression of Rap1 mRNA and protein increased in FK228-treated melanoma cells in both a dose- and a time-dependent manner. A decrease in the phosphorylation of c-Raf, MEK1/2, and ERK1/2 was accompanied by an increase in Rap1 expression in both FK228-treated and Rap1-overexpressing cells. Inhibition of Rap1 upregulation by small interfering RNA (siRNA) abrogated the induction of apoptosis and suppression of ERK1/2 phosphorylation in FK228-treated melanoma cells. These results indicate that the cytotoxic effects of FK228 are mediated via the upregulation of Rap1. Furthermore, we found that Rap1 was overexpressed and formed a complex with B-Raf in melanoma cell lines with a V599E mutation of B-Raf. The siRNA-mediated abrogation of Rap1 overexpression increased the viability of these cells, suggesting that Rap1 is also an endogenous regulator of Ras-MAP kinase signaling in melanomas.
- Published
- 2005
62. The membrane-anchored MMP-regulator RECK is a target of myogenic regulatory factors
- Author
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Michiko Echizenya, Satoshi Kawashima, Shunya Kondo, Hitoshi Kitayama, Rei Takahashi, Makoto Noda, Junseo Oh, and Chiaki Takahashi
- Subjects
Cancer Research ,medicine.medical_specialty ,animal structures ,Angiogenesis ,Blotting, Western ,Muscle Fibers, Skeletal ,Matrix metalloproteinase ,Biology ,medicine.disease_cause ,MyoD ,GPI-Linked Proteins ,Muscle Development ,Extracellular matrix ,Mice ,Downregulation and upregulation ,Internal medicine ,Genetics ,medicine ,Animals ,Muscle, Skeletal ,Promoter Regions, Genetic ,Molecular Biology ,In Situ Hybridization ,MyoD Protein ,Membrane Glycoproteins ,Myogenesis ,Gene Expression Regulation, Developmental ,Matrix Metalloproteinases ,Cell biology ,Endocrinology ,Myogenic Regulatory Factors ,Myogenic regulatory factors ,Carcinogenesis - Abstract
The membrane-anchored MMP-regulator RECK is down regulated in many solid tumors; the extent of RECK down regulation correlates with poor prognosis. Forced expression of RECK in tumor cells results in suppression of angiogenesis, invasion, and metastasis. Studies on the roles and the mechanisms of regulation of the RECK gene during normal development may therefore yield important insights into how the malignant behaviors of tumor cells arise and how they can be controlled. Our previous studies indicate that mice lacking RECK die around E10.5 with reduced tissue integrity. In the present study, we have found that in later stage wild-type embryos, RECK is abundantly expressed in skeletal muscles, especially in the areas where the myoblast differentiation factor MRF4 is expressed. Consistent with this finding, the RECK-promoter is activated by MRF4 in cultured cells. In contrast, a myoblast determination factor MyoD suppresses the RECK-promoter. Myoblastic cells lacking RECK expression give rise to myotubes at higher efficiency than the cells expressing RECK, indicating that RECK suppresses myotube formation. These findings suggest that MyoD down regulates RECK to facilitate myotube formation, whereas MRF4 up regulates RECK to promote other aspects of myogenesis that require extracellular matrix integrity.
- Published
- 2005
63. Role of platelet-derived chemokines (RANTES and ENA-78) after stem cell transplantation
- Author
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Kazuyoshi Ishii, Yuri Kamitsuji, Hitoshi Kitayama, Takao Yoshihara, Shigenori Kanazawa, Nobuhiko Uoshima, Norihito Inami, Hiroyuki Ishida, Shosaku Nomura, and Kunio Hayashi
- Subjects
Blood Platelets ,Male ,Chemokine ,Chemokine CXCL5 ,P-selectin ,Immunology ,Graft vs Host Disease ,Biology ,Transplantation, Autologous ,immune system diseases ,Granulocyte Colony-Stimulating Factor ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,Platelet ,Platelet activation ,Receptor ,Chemokine CCL5 ,Transplantation ,Hematopoiesis ,surgical procedures, operative ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,Female ,Stem cell ,Chemokines ,Chemokines, CXC ,Stem Cell Transplantation - Abstract
Stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy. Some patients seem to have an imbalance of the immune response after SCT and cytokines are known to regulate this response. Recently, platelets have been shown to contain members of the chemokine family, suggesting a role of platelets as inflammatory cells. We measured and compared levels of platelet activation markers, chemokines, and soluble factors in patients undergoing SCT. IL-8 and GROα exhibited a significant elevation in the early phase (1 or 2 weeks) after SCT; this trend was marked after autologous SCT. Furthermore, these levels significantly and positively correlated with the change in G-CSF. In contrast, ENA-78 exhibited a significant elevation in the later phase (3 or 4 weeks) after SCT. In addition, its level negatively correlated with the change in G-CSF. Soluble CD40 ligand and platelet-derived microparticles significantly increased after both auto- and allo-SCT. In addition, ENA-78 positively correlated with the level of platelet-derived microparticles. The increase of RANTES seems to be related to platelet activation, since RANTES was in the dynamic phase similar to soluble CD40 ligand and platelet-derived microparticles. RANTES exhibited changes similar to IL-6, TNFα, and soluble IL-2 receptors, which are GVHD markers. Thus, the platelet-derived chemokines ENA-78 and RANTES exhibited particular changes after SCT. Our results suggest that ENA-78 play a role in hematopoietic conditions in which G-CSF is not involved, and RANTES generation after allo-SCT relates to GVHD.
- Published
- 2005
64. [VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, predonisolone, bleomycin) therapy in elderly patients with aggressive non-Hodgkin lymphoma--a study of efficacy and safety, final report]
- Author
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Kazuyoshi, Ishii, Yoshihisa, Yamamoto, Takashi, Shigeki, Hitoshi, Kitayama, Kunio, Hayashi, Asao, Hirose, Tadanobu, Ohta, Atsuko, Mugitani, Hiroko, Fujino, Toshiya, Yagi, Manabu, Hirai, Hirofumi, Teshima, Tatsuya, Katsurada, Fumiaki, Urase, and Hiroyuki, Kitajima
- Subjects
Male ,Neutropenia ,Lymphoma, Non-Hodgkin ,Remission Induction ,Middle Aged ,Drug Administration Schedule ,Survival Rate ,Bleomycin ,Treatment Outcome ,Vincristine ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,Feasibility Studies ,Humans ,Prednisone ,Female ,Mitoxantrone ,Cyclophosphamide ,Aged ,Etoposide - Abstract
We experienced the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, predonisolone, bleomycin) combination regimen for the treatment of elderly patients with aggressive non-Hodgkin lymphoma (NHL) in a multicenter study by 6 collaborative institutions. Patients were previously untreatedor = 60 years of age and received prophylactic G-CSF. Twenty patients entered this trial, and all of them were evaluated for feasibility, toxicity, and efficacy. The complete remission rate was 75.0%, with a 100% overall response rate; overall survival (OS) rate at 3 years was 79.1% (median follow up 761.5 days), with a 60.7% progression-free 3-year survival (PFS) rate (median follow-up 600.0 days). Our trial was promising and well-tolerated. According to IPI, high/high-intermediate risk was associated with significantly worse OS and PFS than low/low-intermediate risk (2-year OS: 51.8% versus 100.0%, p=0.0118; 2-year PFS: 33.3% versus 80.0%, p=0.0125). Grade 3/4 infections occurred in 3 patients, but no patients experienced it with predonisolone reduced.
- Published
- 2005
65. Isolated non-atherosclerotic coronary stenosis: Surgical angioplasty of the left coronary ostium using an anterior approach
- Author
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Luigi D’Orsogna, Tom R. Karl, and Hitoshi Kitayama
- Subjects
medicine.medical_specialty ,Aorta ,business.industry ,medicine.medical_treatment ,Arteriotomy ,Internal thoracic artery ,medicine.disease ,Ostium ,Stenosis ,surgical procedures, operative ,Left coronary artery ,medicine.artery ,Internal medicine ,Angioplasty ,Ascending aorta ,cardiovascular system ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
In the surgical treatment of isolated non-atherosclerotic ostial stenosis of the left main coronary artery (LMCA), direct patch angioplasty may be superior to saphenous vein or internal thoracic artery grafts. We describe a case of a surgical ostial angioplasty of the LMCA using an anterior approach, employing transection of the aorta and main pulmonary artery. A 13-year-old boy with typical precordial anginal chest pain (New York Heart Association class III) whose coronary angiography demonstrated a discrete stenosis at the origin of the LMCA underwent direct angioplasty. The ascending aorta and main pulmonary artery were transected just above the commissures. An incision was made from the upper margin of the transected aorta, through the ostium of the left coronary artery (LCA), and into the left anterior desending (LAD) branch. A saphenous vein patch was sutured into the arteriotomy to create a wide triangular enlargement of the ostium and proximal LCA. The advantage of this technique is that it provides a perfect view of the LMCA from ostial lesion to bifurcation and may have a better long-term patency rate than intact vascular grafts.
- Published
- 1996
66. Avoiding hypoxemia during unifocalization
- Author
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Hitoshi Kitayama, Juan V. Comas, Tom R. Karl, and Carmelo Mignosa
- Subjects
Heart Septal Defects, Ventricular ,Male ,Pulmonary and Respiratory Medicine ,Pulmonary Circulation ,medicine.medical_specialty ,Collateral Circulation ,Constriction, Pathologic ,Pulmonary Artery ,Hypoxemia ,Severe hypoxemia ,medicine.artery ,Internal medicine ,Occlusion ,medicine ,Humans ,Abnormalities, Multiple ,Hypoxia ,Aorta ,business.industry ,Anastomosis, Surgical ,Infant ,Collateral circulation ,Surgery ,medicine.anatomical_structure ,Pulmonary Atresia ,Pulmonary valve ,Pulmonary artery ,cardiovascular system ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
An 11-month-old child underwent unifocalization of the major aortopulmonary collateral arteries, but did not tolerate occlusion of both vessels simultaneously. Using a Y-shaped homograft tube, we translocated the vessels sequentially and avoided severe hypoxemia.
- Published
- 1996
67. Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK
- Author
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Hitoshi Kitayama, Tere Diaz, Jill M. Ray, William G. Stetler-Stevenson, Junseo Oh, Yvona Ward, Yoko Morioka, Makoto Noda, Dong-Wan Seo, Shuliang Shi, Chiaki Takahashi, and Beiyang Wei
- Subjects
Vascular Endothelial Growth Factor A ,Cancer Research ,Endothelium ,Motility ,Biology ,Matrix metalloproteinase ,GPI-Linked Proteins ,chemistry.chemical_compound ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Melanoma ,Metalloproteinase ,Tissue Inhibitor of Metalloproteinase-2 ,Membrane Glycoproteins ,Tissue Inhibitor of Metalloproteinase-1 ,rap1 GTP-Binding Proteins ,Cell migration ,Molecular biology ,Cell biology ,Endothelial stem cell ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Oncology ,chemistry ,Cell culture ,Endothelium, Vascular - Abstract
The antiangiogenic function of the tissue inhibitors of metalloproteinases (TIMPs) has been attributed to their matrix metalloproteinase inhibitory activity. Here we demonstrate that TIMP-1 but not Ala+TIMP-1 inhibits both basal and vascular endothelial growth factor (VEGF)-stimulated migration of human microvascular endothelial cells (hMVECs), suggesting that this effect is dependent on direct inhibition of matrix metalloproteinase (MMP) activity. In contrast, TIMP-2 and mutant Ala+TIMP-2, which is devoid of MMP inhibitory activity, block hMVEC migration in response to VEGF-A stimulation. TIMP-2 and Ala+TIMP-2 also suppress basal hMVEC migration via a time-dependent mechanism mediated by enhanced expression of RECK, a membrane-anchored MMP inhibitor, which, in turn, inhibits cell migration. TIMP-2 treatment of hMVECs increases the association of Crk with C3G, resulting in enhanced Rap1 activation. hMVECs stably expressing Rap1 have increased RECK expression and display reduced cell migration compared with those expressing inactive Rap1(38N). RECK-null murine embryo fibroblasts fail to demonstrate TIMP-2–mediated decrease in cell migration despite activation of Rap1. TIMP-2–induced RECK decreases cell-associated MMP activity. Anti-RECK antibody increases MMP activity and reverses the TIMP-2–mediated reduction in cell migration. The effects of TIMP-2 on RECK expression and cell migration were confirmed in A2058 melanoma cells. These results suggest that TIMP-2 can inhibit cell migration via several distinct mechanisms. First, TIMP-2 can inhibit cell migration after VEGF stimulation by direct inhibition of MMP activity induced in response to VEGF stimulation. Secondly, TIMP-2 can disrupt VEGF signaling required for initiation of hMVEC migration. Third, TIMP-2 can enhance expression of RECK via Rap1 signaling resulting in an indirect, time-dependent inhibition of endothelial cell migration.
- Published
- 2004
68. Enhanced production of osteopontin in multiple myeloma: clinical and pathogenic implications
- Author
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Yukihiko, Saeki, Toru, Mima, Taeko, Ishii, Atsushi, Ogata, Hideyuki, Kobayashi, Shiro, Ohshima, Tetsushi, Ishida, Yuichiro, Tabunoki, Hitoshi, Kitayama, Masao, Mizuki, Yoshinori, Katada, Hideki, Asaoku, Masayasu, Kitano, Norihiro, Nishimoto, Kazuyuki, Yoshizaki, Masahiro, Maeda, Shigeyuki, Kon, Naokazu, Kinoshita, Toshimitsu, Uede, and Ichiro, Kawase
- Subjects
Reverse Transcriptase Polymerase Chain Reaction ,Sialoglycoproteins ,Blotting, Western ,Paraproteinemias ,Bone Marrow Cells ,Enzyme-Linked Immunosorbent Assay ,Neoplasm Proteins ,Diagnosis, Differential ,Biomarkers, Tumor ,Disease Progression ,Tumor Cells, Cultured ,Humans ,Osteopontin ,Bone Resorption ,Multiple Myeloma ,Neoplasm Staging - Abstract
In this study, we examined osteopontin (OPN) production in myeloma cells and plasma OPN levels in multiple myeloma (MM) patients. We assessed OPN production in bone marrow cells (BMCs) by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA). We also assessed OPN production in various B-cell malignant cell lines, including three myeloma cell lines by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. In addition, we measured plasma OPN concentrations by ELISA in 30 MM patients, 21 monoclonal gammopathy of undetermined significance (MGUS) patients and 30 healthy volunteers. As a result, in an immunocytochemical study, abundant OPN was detected in BMCs from overt MM patients, whereas no OPN was detected in BMCs from patients with other haematological diseases, including MGUS. Cultured BMCs from overt MM patients produced more OPN than those from patients with either smouldering MM or MGUS. Myeloma cell lines spontaneously produced OPN. Plasma OPN levels of MM patients were significantly higher than those of MGUS patients and healthy volunteers (P0.05). Moreover, they correlated with both progression and bone destruction of the disease (P0.05). These suggest that myeloma cells actively produce OPN, which possibly contributes to osteoclastic bone resorption in MM. Plasma OPN levels may be a useful biomarker for assessing bone destruction in MM and distinguishing MM from MGUS or smouldering MM.
- Published
- 2003
69. Possible involvement of Rap1 and Ras in glutamatergic synaptic transmission
- Author
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Makoto Noda, Hitoshi Kitayama, Shunya Kondo, Yukio Imamura, and Naoya Matsumoto
- Subjects
Male ,AMPA receptor ,Neurotransmission ,Biology ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,Glutamatergic ,Organ Culture Techniques ,medicine ,Animals ,Humans ,Rats, Wistar ,Receptor ,Oncogene ,General Neuroscience ,Glutamate receptor ,rap1 GTP-Binding Proteins ,Rats ,medicine.anatomical_structure ,Genes, ras ,nervous system ,Schaffer collateral ,Mutation ,ras Proteins ,NMDA receptor ,Neuroscience - Abstract
Rap1A, first identified as a suppressor of transformed phenotype induced by an activated ras oncogene, is abundantly expressed in the brain. Its neurophysiological function, however, is poorly understood. When an activated Rap1A mutant (Rap1-12V) or a dominant negative H-Ras mutant (Ras-17N) was expressed in CA1 neurons in cultured hippocampal slices using the sindbis virus-mediated gene transfer technique, NMDA receptor current in response to Schaffer collateral stimulation was suppressed. Expression of activated H-Ras mutant (Ras-12V) resulted in the elevation of both NMDA receptor current and AMPA receptor current. These results implicate counteracting functions of Ras and Rap1 in the regulation of NMDA receptor-mediated synaptic transmission and a positive regulatory role of Ras in AMPA receptor-mediated synaptic transmission.
- Published
- 2003
70. RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling
- Author
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Makoto, Noda, Junseo, Oh, Rei, Takahashi, Shunya, Kondo, Hitoshi, Kitayama, and Chiaki, Takahashi
- Subjects
Membrane Glycoproteins ,Matrix Metalloproteinases, Membrane-Associated ,Neovascularization, Pathologic ,Metalloendopeptidases ,Oncogenes ,GPI-Linked Proteins ,Extracellular Matrix ,Matrix Metalloproteinase 9 ,Matrix Metalloproteinase 14 ,Animals ,Humans ,Matrix Metalloproteinase 2 ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Signal Transduction - Abstract
RECK was first isolated as a transformation suppressor gene by cDNA expression cloning in a mouse fibroblast cell line transformed by an activated RAS oncogene. Subsequently, reduced expression of RECK in transformed cells and cancer cells were demonstrated. Moreover, in several types of tumors, positive correlation between RECK expression and survival of patients have been noted. RECK encodes a GPI-anchored glycoprotein harboring three protease inhibitor-like domains. The RECK protein regulates at least three members of the matrix metalloproteinase (MMP) family, MMP-2, MMP-9, and MT1-MMP, in vitro or in cultured cells. Restored expression of RECK in cancer cell lines results in strong suppression of invasion, metastasis, and tumor angiogenesis. Mice lacking RECK die in utero with reduced integrity of blood vessels, the neural tube, and mesenchymal tissues. In these mice, MMP activity is elevated, and the amount of collagen type I greatly reduced. The RECK null phenotype is partially rescued (half day delay of death and marked recovery of tissue integrity) by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo and involvement of other target(s) for RECK in the lethal phenotype. These findings indicate that (i) RECK is an important regulator of extracellular matrix remodeling and that (ii) down-regulation of RECK by oncogenic signaling leads to the excessive activation of MMPs thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis.
- Published
- 2003
71. Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies
- Author
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Ichiro Akiguchi, Hidekazu Tomimoto, Makoto Noda, Hiroshi Shibasaki, Hitoshi Kitayama, Yoko Morioka, Masafumi Ihara, and Makoto Kinoshita
- Subjects
Parkinson's disease ,Cytoplasmic inclusion ,Synucleins ,Nerve Tissue Proteins ,Biology ,Septin ,Transfection ,Biochemistry ,Inclusion bodies ,Cell Line ,GTP Phosphohydrolases ,chemistry.chemical_compound ,Mice ,GTP-Binding Proteins ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Molecular Biology ,Cytoskeleton ,Aged ,Synucleinopathies ,Alpha-synuclein ,Inclusion Bodies ,Cell Death ,Dementia with Lewy bodies ,Intracellular Signaling Peptides and Proteins ,Brain ,Neurodegenerative Diseases ,Parkinson Disease ,Cell Biology ,medicine.disease ,Molecular biology ,Cell biology ,Cytoskeletal Proteins ,chemistry ,Proteasome inhibitor ,alpha-Synuclein ,Lewy Bodies ,Carrier Proteins ,Septins ,medicine.drug - Abstract
alpha-Synuclein-positive cytoplasmic inclusions are a pathological hallmark of several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Here we report that Sept4, a member of the septin protein family, is consistently found in these inclusions, whereas five other septins (Sept2, Sept5, Sept6, Sept7, and Sept8) are not found in these inclusions. Sept4 and alpha-synuclein can also be co-immunoprecipitated from normal human brain lysates. When co-expressed in cultured cells, FLAG-tagged Sept4 and Myc-tagged alpha-synuclein formed detergent-insoluble complex, and upon treatment with a proteasome inhibitor, they formed Lewy body-like cytoplasmic inclusions. The tagged Sept4 and alpha-synuclein synergistically accelerated cell death induced by the proteasome inhibitor, and this effect was further enhanced by expression of another Lewy body-associated protein, synphilin-1, tagged with the V5 epitope. Moreover, co-expression of the three proteins (tagged Sept4, alpha-synuclein, and synphilin-1) was sufficient to induce cell death. These data raise the possibility that Sept4 is involved in the formation of cytoplasmic inclusions as well as induction of cell death in alpha-synuclein-associated neurodegenerative disorders.
- Published
- 2003
72. Bivalvation with bridging for common atrioventricular valve regurgitation in right isomerism
- Author
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Toshihiko Saga, Hidetaka Oku, Junzoh Iemura, Hitoshi Kitayama, and Shirotani H
- Subjects
Heart Defects, Congenital ,Male ,Pulmonary and Respiratory Medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Common atrioventricular valve ,Heart disease ,medicine.medical_treatment ,Right isomerism ,Internal medicine ,Methods ,Humans ,Medicine ,Pulmonary blood flow ,cardiovascular diseases ,Heart valve ,Child ,Cardiac catheterization ,Atrioventricular valve ,business.industry ,medicine.disease ,Heart Valves ,Surgery ,Shunt (medical) ,medicine.anatomical_structure ,cardiovascular system ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
A child with regurgitation in the common atrioventricular valve associated with complex heart disease underwent bivalvation with bridging for common atrioventricular valve regurgitation and arterial-pulmonary shunt for low pulmonary blood flow. Postoperative cardiac catheterization and color Doppler echocardiography revealed elimination of atrioventricular valve regurgitation and ventricular enlargement, reflecting an increase in pulmonary artery blood flow. We describe the concept and technique of bivalvation with bridging for common atrioventricular valve regurgitation.
- Published
- 1994
73. Total cavopulmonary connection using a pedicled pericardial conduit for a patient with apicocaval juxtaposition
- Author
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Hitoshi Kitayama, Terufumi Matsumoto, Hidetaka Oku, and Masahiko Onoe
- Subjects
Pulmonary and Respiratory Medicine ,Heart Defects, Congenital ,Male ,medicine.medical_specialty ,Arterial disease ,Heart Ventricles ,Total cavopulmonary connection ,Inferior vena cava ,Electrical conduit ,Postoperative Complications ,Internal medicine ,medicine.artery ,medicine ,Humans ,cardiovascular diseases ,business.industry ,Heart Bypass, Right ,Suture Techniques ,Angiography ,medicine.disease ,Surgery ,medicine.anatomical_structure ,medicine.vein ,Ventricle ,Atresia ,Child, Preschool ,Pulmonary artery ,cardiovascular system ,Cardiology ,Cardiology and Cardiovascular Medicine ,Pulmonary atresia ,business ,Pericardium - Abstract
A 5-year-old boy, with a double inlet solitary ventricle, pulmonary atresia, and apicocaval juxtaposition underwent an extracardiac total cavopulmonary connection. A pedicled pericardial conduit was placed behind the ventricle to make a straight pathway between the inferior vena cava and pulmonary artery. This report presents a solution for managing patients with complicated heart defects with apicocaval juxtaposition during the completion of a total cavopulmonary connection.
- Published
- 2001
74. Modified ultrafiltration may improve postoperative pulmonary function in children with a ventricular septal defect
- Author
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Hidetaka Oku, Hitoshi Kitayama, Masahiko Onoe, Toshio Kaneda, and Terufumi Matsumoto
- Subjects
Heart Septal Defects, Ventricular ,Male ,medicine.medical_specialty ,Partial Pressure ,Pulmonary Edema ,Respiratory physiology ,Hematocrit ,Pulmonary function testing ,law.invention ,Postoperative Complications ,law ,Internal medicine ,Modified ultrafiltration ,Medicine ,Humans ,Child ,Lung ,Retrospective Studies ,Heart septal defect ,Cardiopulmonary Bypass ,medicine.diagnostic_test ,business.industry ,Infant ,Retrospective cohort study ,General Medicine ,medicine.disease ,Intensive care unit ,Respiratory Function Tests ,Oxygen ,Blood pressure ,Child, Preschool ,Cardiology ,Surgery ,Female ,business - Abstract
To evaluate the effectiveness of modified ultrafiltration (MUF) on ventricular septal defect (VSD) repair in children, we retrospectively examined 10 patients who underwent VSD repair with MUF at the Kinki University School of Medicine hospital between June 1998, and December 1998 (MUF group). These patients were compared with 14 patients who underwent the same procedure without MUF (control group) between January 1997 and June 1998. Systolic blood pressure and hematocrit values increased significantly during MUF. By the time of postoperative transfer to the intensive care unit, PaO2 was higher in the MUF group than in the control group (503.3 +/- 112.2mmHg vs 376.3 +/- 149.2mmHg; P = 0.0491), whereas A-aDO2 was lower in the MUF group than in the control group (171.9 +/- 109.2mmHg vs 301.1 x 150.4mmHg; P = 0.0449). These findings demonstrate that MUF had a beneficial effect on pulmonary function in children who underwent surgery to repair a VSD.
- Published
- 2001
75. Expanded polytetrafluoroethylene monocuspid valve for right ventricular outflow tract reconstruction
- Author
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Masaki Otaki, Hidetaka Oku, Iemura J, and Hitoshi Kitayama
- Subjects
Pulmonary and Respiratory Medicine ,Heart Defects, Congenital ,Male ,Reoperation ,medicine.medical_specialty ,Heart disease ,Adolescent ,medicine.medical_treatment ,Expanded polytetrafluoroethylene ,Prosthesis Design ,Prosthesis ,Ventricular Outflow Obstruction ,medicine ,Methods ,Ventricular outflow tract ,Humans ,Heart valve ,Child ,Polytetrafluoroethylene ,Heart Valve Prosthesis Implantation ,business.industry ,Infant ,Perioperative ,medicine.disease ,Surgery ,Stenosis ,medicine.anatomical_structure ,Treatment Outcome ,Echocardiography ,Child, Preschool ,Heart Valve Prosthesis ,Female ,Transannular patch ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Background . Numerous materials have been used for reconstruction of the right ventricular outflow tract (RVOT) in patients with complex congenital heart defects. Methods . Between January 1982 and March 1999, 19 patients (10 boys and 9 girls; mean age, 8.5 years) with severe RVOT obstruction underwent reconstruction using a transannular patch and expanded polytetrafluoroethylene (ePTFE) monocuspid valve. Results . There were no perioperative deaths. Postoperatively, the mean ± standard deviation RVOT gradient was 12 ± 9 mm Hg. Echocardiography showed good motion of all cusps, and most had no or trivial pulmonary regurgitation. The difference between the preoperative and postoperative mean ratio of right-to-left ventricular peak systolic pressure was significant ( p = 0.0001). In the 8 patients followed for 3 years or longer, pulmonary regurgitation was mild or better in 5 and moderate in 2, and the mean peak systolic RVOT gradient was 16.3 ± 5.9 mm Hg. Five patients had good mobility of the monocusps. Two patients needed reoperation because of stenosis at the distal anastomosis of the transannular patch; 1 patient died. Conclusions . The ePTFE monocuspid valve may be useful in reconstruction of the RVOT.
- Published
- 2000
76. Plasma membrane recruitment of RalGDS is critical for Ras-dependent Ral activation
- Author
-
Shosei Kishida, Yoshiharu Matsuura, Akira Kikuchi, Hitoshi Kitayama, Makoto Noda, and Kenji Matsubara
- Subjects
endocrine system ,Cancer Research ,animal structures ,Recombinant Fusion Proteins ,Rap GTP-binding protein ,Fluorescent Antibody Technique ,Plasma protein binding ,Biology ,Mice ,GTP-binding protein regulators ,GTP-Binding Proteins ,ral Guanine Nucleotide Exchange Factor ,Genetics ,Ral Guanine Nucleotide Exchange Factor ,Animals ,Molecular Biology ,COS cells ,Cell Membrane ,Biological Transport ,3T3 Cells ,Cell biology ,Cell Compartmentation ,enzymes and coenzymes (carbohydrates) ,rap GTP-Binding Proteins ,Ral GTP-Binding Proteins ,Biochemistry ,COS Cells ,ras Proteins ,Rap1 ,ral GTP-Binding Proteins ,Signal transduction ,Protein Processing, Post-Translational ,Protein Binding - Abstract
In COS cells, Ral GDP dissociation stimulator (RalGDS)-induced Ral activation was stimulated by RasG12V or a Rap1/Ras chimera in which the N-terminal region of Rap1 was ligated to the C-terminal region of Ras but not by Rap1G12V or a Ras/Rap1 chimera in which the N-terminal region of Ras was ligated to the C-terminal region of Rap1, although RalGDS interacted with these small GTP-binding proteins. When RasG12V, Ral and the Rap1/Ras chimera were individually expressed in NIH3T3 cells, they localized to the plasma membrane. Rap1Q63E and the Ras/Rap1 chimera were detected in the perinuclear region. When RalGDS was expressed alone, it was abundant in the cytoplasm. When coexpressed with RasG12V or the Rap1/Ras chimera, RalGDS was detected at the plasma membrane, whereas when coexpressed with Rap1Q63E or the Ras/Rap1 chimera, RalGDS was observed in the perinuclear region. RalGDS which was targeted to the plasma membrane by the addition of Ras farnesylation site (RalGDS-CAAX) activated Ral in the absence of RasG12V. Although RalGDS did not stimulate the dissociation of GDP from Ral in the absence of the GTP-bound form of Ras in a reconstitution assay using the liposomes, RalGDS-CAAX could stimulate it without Ras. RasG12V activated Raf-1 when they were coexpressed in Sf9 cells, whereas RasG12V did not affect the RalGDS activity. These results indicate that Ras recruits RalGDS to the plasma membrane and that the translocated RalGDS induces the activation of Ral, but that Rap1 does not activate Ral due to distinct subcellular localization.
- Published
- 1999
77. Reconstruction of right ventricular outflow tract by pedicled pericardial valved conduit
- Author
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Mashaki Otaki, Terufumi Matsumoto, Iemura J, Hidetaka Oku, and Hitoshi Kitayama
- Subjects
Pulmonary and Respiratory Medicine ,Aortic valve disease ,Heart Defects, Congenital ,Male ,medicine.medical_specialty ,Heart Ventricles ,Valved conduit ,Electrical conduit ,Internal medicine ,medicine ,Pericardium ,Ventricular outflow tract ,Humans ,Pedicle flap ,business.industry ,Infant ,Plastic Surgery Procedures ,Surgery ,medicine.anatomical_structure ,Pulmonary valve ,Child, Preschool ,Cardiology ,Congenital disease ,Cardiology and Cardiovascular Medicine ,business - Abstract
A modification of the Rastelli technique using a pedicled autologous pericardial valved conduit was performed on 3 patients aged 10 months to 3 years. Two patients in whom a prosthetic gusset was not used or was partially used showed good recovery during the follow-up period (3 months to 3 years). The pedicled autologous pericardial conduit may be expected to increase its diameter with physical growth.
- Published
- 1998
78. Single lead atrial synchronous ventricular pacing in Japanese patients with complete atrioventricular block
- Author
-
Masaki Otaki, Susumu Nakamoto, Nobuo Wakaki, Toshihiko Saga, Hidetaka Oku, Takehiro Inoue, Terufumi Matsumoto, Masao Ueda, Hiroshi Oka, and Hitoshi Kitayama
- Subjects
Tachycardia ,Adult ,Male ,medicine.medical_specialty ,Pacemaker, Artificial ,Supine position ,Biomedical Engineering ,Medicine (miscellaneous) ,Diaphragmatic breathing ,Bioengineering ,Biomaterials ,Japan ,Internal medicine ,medicine ,Supine Position ,Humans ,cardiovascular diseases ,Heart Atria ,Aged ,business.industry ,P wave ,Cardiac Pacing, Artificial ,Mean age ,General Medicine ,Ventricular pacing ,Middle Aged ,medicine.disease ,Heart Block ,Treatment Outcome ,Single lead ,Anesthesia ,cardiovascular system ,Cardiology ,Female ,medicine.symptom ,business ,Atrioventricular block ,Follow-Up Studies - Abstract
The purpose of this study was to review our experience with atrial synchronous ventricular pacing devices (THERA VDD pacing systems, Medtronic, Inc., U.S.A.) using single atrioventricular leads in Japanese patients with complete atrioventricular block and normal sinus function. Twenty patients with a mean age of 55 +/- 13 years underwent implantation of VDD pacemakers. At implantation the amplitude of atrial signals in the supine position during normal breathing, which was measured directly using an external pacing system analyzer, ranged from 1.8 to 5.8 mV with a mean amplitude of 3.4 +/- 1.4 mV. Atrial amplitudes did not change during deep breathing (3.3 +/- 1.1 mV) or in the semi-Fowler position (3.4 +/- 1.6 mV). Atrial oversensing or undersensing was not observed in any of the patients. During a follow-up period, the percentage of atrial synchronization was >95% in 19 patients, and none of the patients had pacemaker related tachycardia or pacemaker related complications. These results were promising enough to warrant the extension of the clinical use of the VDD pacemaker.
- Published
- 1997
79. Two-directional aortic annular enlargement for aortic valve replacement in the small aortic annulus
- Author
-
Terufumi Matsumoto, Susumu Nakamoto, Masao Ueda, Hidetaka Oku, Hitoshi Kitayama, and Masaki Otaki
- Subjects
Pulmonary and Respiratory Medicine ,Aortic valve disease ,Aortic valve ,Adult ,Male ,medicine.medical_specialty ,Valvula aortica ,Aortic valve replacement ,Internal medicine ,medicine ,Artificial valve ,Humans ,Cardiac skeleton ,Child ,business.industry ,Polyethylene Terephthalates ,Anatomy ,Aortic Valve Stenosis ,Prostheses and Implants ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Aortic Valve ,Heart Valve Prosthesis ,cardiovascular system ,Cardiology ,Surgery ,Functional status ,Female ,Implant ,Cardiology and Cardiovascular Medicine ,business - Abstract
We have encountered 3 patients with a small aortic annulus for whom the conventional posterior enlargement alone was not extensive enough to implant an artificial valve of acceptable size. Therefore, we performed two-directional enlargement, which is a combination of posterior and anterior enlargement. First, the posterior enlargement was done, and then an additional aortotomy was made anteriorly and extended to the ventricular septum. The aortic annulus was enlarged by 68% after the two-directional enlargement. At a follow-up of 31 months, the patients' functional status was New York Heart Association class I.
- Published
- 1997
80. The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells
- Author
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Yuji Matsuzawa, Takashi Kato, Yoko Horikawa, Hiroshi Miyazaki, Hirokazu Ikeda, Jun Ishikawa, Tetsuo Nishiura, Itaru Matsumura, Hitoshi Kitayama, Yuzuru Kanakura, and Yoshiaki Tomiyama
- Subjects
STAT3 Transcription Factor ,Acute myeloblastic leukemia ,Cellular differentiation ,Immunology ,Biology ,Biochemistry ,Megakaryocyte ,NF-E2 Transcription Factor ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,medicine ,Tumor Cells, Cultured ,Humans ,GATA1 Transcription Factor ,Thrombopoiesis ,Phosphorylation ,Receptors, Cytokine ,Thrombopoietin ,Gene Expression Regulation, Leukemic ,Recombinant Human Thrombopoietin ,Cell Differentiation ,Cell Biology ,Hematology ,medicine.disease ,Hematopoietic Stem Cells ,Recombinant Proteins ,Neoplasm Proteins ,DNA-Binding Proteins ,GATA2 Transcription Factor ,Leukemia ,medicine.anatomical_structure ,Cell culture ,Leukemia, Myeloid ,NF-E2 Transcription Factor, p45 Subunit ,Acute Disease ,Cancer research ,Neoplastic Stem Cells ,Trans-Activators ,Erythroid-Specific DNA-Binding Factors ,Interleukin-3 ,Megakaryocytes ,Protein Processing, Post-Translational ,Receptors, Thrombopoietin ,Cell Division ,Transcription Factors - Abstract
Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis. However, the biologic effects of TPO on human acute myeloblastic leukemia (AML) cells are largely unknown. To determine if recombinant human (rh) TPO has proliferation-supporting and differentiation-inducing activities in AML cells, 15 cases of AML cells that were exclusively composed of undifferentiated leukemia cells and showed growth response to rhTPO in a short-term culture (72 hours) were subjected to long-term suspension culture with or without rhTPO. Of 15 cases, rhTPO supported proliferation of AML cells for 2 to 4 weeks in 4 cases whose French-American-British subtypes were M0, M2, M4, and M7, respectively. In addition to the proliferation-supporting activity, rhTPO was found to induce AML cells to progress to some degree of megakaryocytic differentiation at both morphologic and surface-phenotypic level in 2 AML cases with M0 and M7 subtypes. The treatment of AML cells with rhTPO resulted in rapid tyrosine phosphorylation of the TPO-receptor, c-mpl, and STAT3 in all of cases tested. By contrast, the expression of erythroid/megakaryocyte-specific transcription factors (GATA-1, GATA-2, and NF-E2) was markedly induced or enhanced in only 2 AML cases that showed megakaryocytic differentiation in response to rhTPO. These results suggested that, at least in a fraction of AML cases, TPO could not only support the proliferation of AML cells irrespective of AML subtypes, but could also induce megakaryocytic differentiation, possibly through activation of GATA-1, GATA-2, and NF-E2.
- Published
- 1996
81. Role of aspartic acid 814 in the function and expression of c-kit receptor tyrosine kinase
- Author
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Tohru Tsujimura, Hitoshi Kitayama, Yukihiko Kitamura, Masahiro Morimoto, Koji Hashimoto, Yuzuru Kanakura, Yuji Matsuzawa, and Yasuhiro Moriyama
- Subjects
Mutant ,Molecular Sequence Data ,Stem cell factor ,Biology ,Transfection ,Biochemistry ,Polymerase Chain Reaction ,Receptor tyrosine kinase ,Cell Line ,Phosphotransferase ,chemistry.chemical_compound ,Mice ,Tumor Cells, Cultured ,Animals ,Point Mutation ,Amino Acid Sequence ,Mast Cells ,Tyrosine ,Molecular Biology ,DNA Primers ,Aspartic Acid ,Stem Cell Factor ,Base Sequence ,Receptor Protein-Tyrosine Kinases ,Tyrosine phosphorylation ,Cell Biology ,Molecular biology ,Recombinant Proteins ,Rats ,Kinetics ,Proto-Oncogene Proteins c-kit ,chemistry ,biology.protein ,Mutagenesis, Site-Directed ,Phosphorylation ,Tyrosine kinase - Abstract
The c-kit receptor tyrosine kinase (KIT) is constitutively activated in three different types of neoplastic mast cell lines by naturally occurring mutations that result in substitutions of Val or Tyr for Asp814 in the phosphotransferase domain. In an effort to characterize the role of the Asp814 residue, we have investigated the properties of mutant KITs in which the Asp814 residue was deleted or mutated to a series of other amino acids. With the exception of rare instances, mutant KITs with substitutions of Asp814 were found to be constitutively phosphorylated on tyrosine and activated in the absence of the ligand, stem cell factor (SCF), whereas a deletion mutant lacking Asp814 (KITDel-Asp-814) did not exhibit tyrosine phosphorylation and activation even after treatment with SCF. In addition to constitutive activation, furthermore, both highly activated substitution mutants (KITVal-814 and KITTyr-814) and modestly activated substitution mutants (KITGly-814 and KITIls-814) were continuously degraded in the absence of SCF, whereas wild-type KIT (KITWild) required SCF stimulation to undergo degradation. These results suggested that the Asp814 residue may play a crucial role in regulating enzymatic activity and expression of KIT and that various types of mutations at the Asp814 residue may generate oncogenic protein with constitutive activation and degradation.
- Published
- 1996
82. Induction of programmed cell death in human hematopoietic cell lines by fibronectin via its interaction with very late antigen 5
- Author
-
Kenji Oritani, Hiroyuki Ikeda, Jun Ishikawa, Koji Hashimoto, Takuma Furitsu, Yoshio Kanayama, Hiroyuki Sugahara, Yuzuru Kanakura, Hitoshi Kitayama, and Katsuhiko Ishihara
- Subjects
Programmed cell death ,Neutrophils ,Immunology ,Stem cell factor ,Apoptosis ,Biology ,Hematopoietic Cell Growth Factors ,Cell Line ,chemistry.chemical_compound ,Receptors, Fibronectin ,Receptors, Very Late Antigen ,Tumor Cells, Cultured ,Immunology and Allergy ,Humans ,Propidium iodide ,Cells, Cultured ,Extracellular Matrix Proteins ,Stem Cell Factor ,Granulocyte-Macrophage Colony-Stimulating Factor ,Articles ,Cell cycle ,Flow Cytometry ,Hematopoietic Stem Cells ,Molecular biology ,Cell biology ,Fibronectins ,Haematopoiesis ,Kinetics ,chemistry ,Cell culture ,Interleukin-3 ,Collagen ,Laminin ,Signal transduction ,Cell Division ,Thymidine - Abstract
Extracellular matrix (ECM) molecules such as fibronectin (FN), collagens, and laminin have important roles in hematopoiesis. However, little is known about the precise mechanisms by which ECM molecules regulate proliferation of human hematopoietic progenitor cells. In this study, we have investigated the effects of ECM molecules, particularly of FN, on the proliferation of a myeloid leukemia cell line, M07E, which proliferates in response to either human granulocyte/macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). The [3H]thymidine incorporation and cell enumeration assays showed that FN strikingly inhibited GM-CSF- or SCF-induced proliferation of M07E cells in a dose-dependent manner, whereas little or no inhibition was induced by collagen types I and IV. The growth suppression of M07E cells was not due to the inhibitory effect of FN on ligand binding or very early events in the signal transduction pathways from the GM-CSF or SCF receptors. DNA content analysis using flow cytometry after staining with propidium iodide revealed that the treatment of M07E cells with FN did not block the entry of the cells into the cell cycle after stimulation with GM-CSF or SCF, whereas the treatment resulted in the appearance of subdiploid peak. Furthermore, FN was found to induce oligonucleosomal DNA fragmentation and chromatin condensation in the cells even in the presence of GM-CSF or SCF, suggesting the involvement of programmed cell death (apoptosis) in the FN-induced growth suppression. The growth suppression or apoptosis induced by FN was rescued by the addition of either anti-FN antibody, anti-very late antigen 5 monoclonal antibody (anti-VLA5 mAb), or GRGDSP peptide, but not by that of anti-VLA4 mAb or GRGESP peptide, suggesting that the FN effects on M07E cells were mediated through VLA5. In addition, the FN-induced apoptosis was detectable in VLA5-positive human hematopoietic cell lines other than M07E cells, but not in any of the VLA5-negative cell lines. These results suggest that FN is capable of inducing apoptosis via its interaction with VLA5, and also raise the possibility that the FN-VLA5 interaction may contribute, at least in part, to negative regulation of hematopoiesis.
- Published
- 1994
83. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product
- Author
-
Yoshio Kanayama, Hiroyuki Ikeda, Uichi Koshimizu, Hitoshi Kitayama, L K Ashman, Hiroyuki Sugahara, Takuma Furitsu, T Tono, Tohru Tsujimura, and J H Butterfield
- Subjects
Molecular Sequence Data ,Leukemia, Mast-Cell ,Protein tyrosine phosphatase ,Biology ,SH2 domain ,Transfection ,Polymerase Chain Reaction ,Proto-Oncogene Mas ,Receptor tyrosine kinase ,Cell Line ,chemistry.chemical_compound ,Mice ,Proto-Oncogene Proteins ,Proto-Oncogenes ,Receptors, Colony-Stimulating Factor ,Tumor Cells, Cultured ,Animals ,Humans ,Point Mutation ,Amino Acid Sequence ,Tyrosine ,Phosphotyrosine ,DNA Primers ,Base Sequence ,Granulocyte-Macrophage Colony-Stimulating Factor ,Receptor Protein-Tyrosine Kinases ,Tyrosine phosphorylation ,General Medicine ,Molecular biology ,Recombinant Proteins ,Proto-Oncogene Proteins c-kit ,chemistry ,ROR1 ,biology.protein ,Interleukin-3 ,Tyrosine kinase ,Platelet-derived growth factor receptor ,Research Article - Abstract
The c-kit proto-oncogene encodes a receptor tyrosine kinase. Binding of c-kit ligand, stem cell factor (SCF) to c-kit receptor (c-kitR) is known to activate c-kitR tyrosine kinase, thereby leading to autophosphorylation of c-kitR on tyrosine and to association of c-kitR with substrates such as phosphatidylinositol 3-kinase (PI3K). In a human mast cell leukemia cell line HMC-1, c-kitR was found to be constitutively phosphorylated on tyrosine, activated, and associated with PI3K without the addition of SCF. The expression of SCF mRNA transcript in HMC-1 cells was not detectable by means of PCR after reverse transcription (RT-PCR) analysis, suggesting that the constitutive activation of c-kitR was ligand independent. Sequencing of whole coding region of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp. Amino acid sequences in the regions of the two mutations are completely conserved in all of mouse, rat, and human c-kit. In order to determine the causal role of these mutations in the constitutive activation, murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line, 293T cells. In the transfected cells, both c-kitR (Gly-559, Val-814) and c-kitR (Val-814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of c-kitR (Gly-559) or wild-type c-kitR was modest or little, respectively. These results suggest that conversion of Asp-816 to Val in human c-kitR may be an activating mutation and responsible for the constitutive activation of c-kitR in HMC-1 cells.
- Published
- 1993
84. Expression, function and activation of the proto-oncogene c-kit product in human leukemia cells
- Author
-
Yuzuru Kanakura, Hiroyuki Sugahara, Hirokazu Ikeda, Hitoshi Kitayama, and Takuma Furitsu
- Subjects
Cancer Research ,Acute myeloblastic leukemia ,Cellular differentiation ,Leukemia inhibitory factor receptor ,Proto-Oncogene Mas ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Proto-Oncogenes ,medicine ,Cell Adhesion ,CD135 ,Humans ,THP1 cell line ,ABL ,Leukemia ,Chemistry ,Gene Expression Regulation, Leukemic ,Cell Differentiation ,Hematology ,Protein-Tyrosine Kinases ,medicine.disease ,Proto-Oncogene Proteins c-kit ,Oncology ,Cancer research ,Leukemia inhibitory factor ,Cell Division ,Chronic myelogenous leukemia - Abstract
The c-kit proto-oncogene encodes a receptor tyrosine kinase that is considered to play important roles in hematopoiesis. The proto-oncogene c-kit product is expressed on various types of human cell lines derived from leukemic cells of erythroid, megakaryocytic and mast-cell lineages. Also, the c-kit product is detectable in blast cells in most cases of acute myeloblastic leukemia (AML) and in some cases of chronic myelogenous leukemia (CML) in blastic crisis (BC). By contrast, little or no expression of c-kit is observed in human leukemia cell lines of lymphoid lineage and in blast cells in acute lymphoblastic leukemia (ALL). Tyrosine phosphorylation and activation of the c-kit product with the ligand for c-kit (stem cell factor: SCF) results in proliferation of some human leukemia cell lines, such as M07E, and blast cells in a substantial fraction of AML cases. In addition, SCF appears to have an activity in inducing differentiation of certain types of leukemic cells. In some cases, further, the c-kit product is found to be activated in leukemic cells even before the stimulation with SCF. These results suggest that c-kit may be involved in excessive proliferation and aberrant differentiation of human leukemia cells.
- Published
- 1993
85. VNCOP-B (Etoposide, Mitoxantrone, Cyclophosphamide, Vincristine, Prednisolone, Bleomycin) Plus Rituximab Therapy in Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Phase II Study of Efficacy and Safety
- Author
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Toshiya Yagi, Fumiaki Urase, Masaru Shibano, Machiko Tsukaguchi, Masahiro Manabe, Atsuko Mugitani, Kazuyoshi Ishii, Yasuaki Nagare, Hirofumi Teshima, Tatsuya Katsurada, Hitoshi Kitayama, Shosaku Nomura, Kunio Hayashi, and Hidetsugu Kimura
- Subjects
Vincristine ,medicine.medical_specialty ,Chemotherapy ,Performance status ,Combination therapy ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,CHOP ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,International Prognostic Index ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Rituximab ,business ,Febrile neutropenia ,medicine.drug - Abstract
[Background and Objectives] CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety because of agespecific comorbidity, increased toxicities of chemo-agents, and the more aggressive aspect of the lymphoma itself. Zinzani reported that a combination therapy including etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin (VNCOP-B) was effective in elderly aggressive NHL patients (Blood1999;94:33–38). We conducted a phase II multicenter study in 8 collaborative institutions to determine if VNCOP-B plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. The primary endpoint was to detect overall survival (OS). The second endpoint was to detect the response rate (RR) and progression-free survival (PFS). [Patients and Treatment] Eligible patients were those aged over 60 years, with aggressive B-NHL documented as CD20 surface antigen positive, performance status (PS) 0 to 2, clinical stage over II or I with a bulky disease, measurable lesions, no prior chemotherapy nor radiation, no severe complications, no major organ dysfunction, no other active cancer, not a HBV carrier, no central nervous system involvement with lymphoma, and who gave the required written informed consent. VNCOP-B plus rituximab was administered as an induction therapy. This protocol was completed in 8 weeks and consisted of weekly doses of chemotherapy combined with rituximab every two weeks. During the 8 weeks of therapy, granulocyte colony-stimulating factor (G-CSF) was administered on a prophylactic base. Rituximab was administered weekly four times a month as a sequential therapy, following one month after the end of the induction therapy. [Results] Between September 2004 and December 2007, 23 patients, median age 73 years, 50.0% classified as high-intermediate/high risk on the age-adjusted International Prognostic Index (IPI), entered this trial and 21 were evaluated for feasibility, toxicity, and efficacy. Twenty-two patients (95.2%) were diagnosed with diffuse large B-cell lymphoma and one (4.8%) with mediastinal large B-cell lymphoma. The nineteen patients (90.5%) completed the induction therapy and all these then received a sequential rituximab therapy. Complete remission rate was 90.5%, with a 100% overall RR at the end of induction therapy; OS rate at 3 years was 76.4% (median follow-up 744days); with an 82.6% 3-year PFS rate (median follow-up 744days). Average Relative dose intensity (RDI) in MIT was 0.61, no significant difference in survival was found regarding RDI. Although IgG level decreased during the induction therapy, it recovered to the prior level after sequential rituximab (IgG means±standard error: pre-treatment 1355.2±146.4mg/dl, post-induction therapy 785.3±107.0mg/dl, post-sequential rituximab 1010.4±60.2mg/dl). According to the IPI, there was a trend suggesting a lower probability of OS and PFS in high/high-intermediate risk than in low/low-intermediate risk cases (3-year OS: 67.5% versus 100.0%, P=0.51; 3-year PFS: 66.7% versus 100.0%, P NA). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the 21 patients despite prophylactic administration of G-CSF, febrile neutropenia in 30.0%, and thrombocytopenia in 10.0%, respectively. Regarding non-hematologic grade 3/4 toxicities, hepatitis occurred in one patient (5.0%) from HCV reactivation, intestinal perforation involving the lymphoma in one patient (5.0%). There was no treatment-related mortality. We had conducted a phase II study of VNCOP-B therapy in 16 elderly patients with aggressive B-NHL (Gan To Kagaku Ryoho2005;32:39–44, in Japanese). Against this historical comparison, the present protocol seemed better in PFS than that without rituximab (3-year PFS: 82.6% versus 56.0%, P=0.11), although OS was almost the same (3-year OS: 76.4% versus 73.4%, P=0.22). [Conclusion] Although our enrolled patients were quite elderly with a median age of 73 years, and half of them had a poor prognosis index, VNCOP-B combined with rituximab was well tolerated and showed promise.
- Published
- 2008
86. Genetic analysis of the Kirsten-ras-revertant 1 gene: potentiation of its tumor suppressor activity by specific point mutations
- Author
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Makoto Noda, Hitoshi Kitayama, Yoji Ikawa, and Tomoko Matsuzaki
- Subjects
G protein ,Guanine ,Mutant ,DNA Mutational Analysis ,Molecular Sequence Data ,Oligonucleotides ,Biology ,Oncogene Protein p21(ras) ,Transfection ,chemistry.chemical_compound ,Structure-Activity Relationship ,Suppression, Genetic ,GTP-Binding Proteins ,Complementary DNA ,Amino Acid Sequence ,Gene ,Multidisciplinary ,Base Sequence ,Point mutation ,Neoplasms, Experimental ,Oncogenes ,Molecular biology ,Transformation (genetics) ,Cell Transformation, Neoplastic ,rap GTP-Binding Proteins ,chemistry ,Mutation ,HT1080 ,Research Article - Abstract
Kirsten-ras-revertant 1 (Krev-1) cDNA encodes a ras-related protein and exhibits an activity of inducing flat revertants at certain frequencies (2-5% of total transfectants) when introduced into a v-K-ras-transformed mouse NIH 3T3 cell line, DT. Toward understanding the mechanism of action of Krev-1 protein, we constructed a series of point mutants of Krev-1 cDNA and tested their biological activities in DT cells and HT1080 human fibrosarcoma cells harboring the activated N-ras gene. Substitutions of the amino acid residues in the putative guanine nucleotide-binding regions (Asp17 and Asn116), in the putative effector-binding domain (residue 38), at the putative acylation site (Cys181), and at the unique Thr61 all decreased the transformation suppressor activity. On the other hand, substitutions such as Gly12 to Val12 and Gln63 to Glu63 were found to significantly increase the transformation suppressor/tumor suppressor activity of Krev-1. These findings are consistent with the idea that Krev-1 protein is regulated like many other G proteins by the guanine triphosphate/guanine diphosphate-exchange mechanism probably in response to certain negative growth-regulatory signals.
- Published
- 1990
87. Aneurysmal Formation Induced by Membranous Tissue in Infundibular Ventricular Septal Defect
- Author
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Hitoshi Kitayama, Toshiharu Miyake, Tsukasa Takemura, Megumi Ikeoka, Terufumi Matsumoto, and Tohru Shinohara
- Subjects
Adult ,Heart Septal Defects, Ventricular ,Heart septal defect ,medicine.medical_specialty ,business.industry ,medicine.disease ,Child, Preschool ,Internal medicine ,medicine ,Cardiology ,Humans ,Infundibular ventricular septal defect ,Female ,Radiology, Nuclear Medicine and imaging ,Heart Aneurysm ,Ultrasonography ,Cardiology and Cardiovascular Medicine ,business - Published
- 2005
88. Hydrostatic speaker and speaker driver
- Author
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Hitoshi Kitayama and Shuji Asami
- Subjects
Physics ,Acoustics and Ultrasonics ,Amplifier ,Acoustics ,Controller (computing) ,Diaphragm (mechanical device) ,Pressure sensor ,law.invention ,Core (optical fiber) ,Controllability ,Arts and Humanities (miscellaneous) ,law ,Hydrostatic equilibrium ,psychological phenomena and processes ,Position sensor - Abstract
A hydrostatic speaker includes an oscillator, a partition diaphragm disposed in the oscillator to divide the oscillator into two chambers, at least one of which chambers serves as a fluid chamber to cause the partition diaphragm to vibrate in response to external signals from a source, an acoustic sound radiation core connected with the partition diaphragm via a rod, a sensor for detecting fluid pressure in the fluid chamber and another sensor for detecting a movement of the partition diaphragm. The hydrostatic speaker is provided with a speaker driver which includes a fuild pressure controller connected to a pressure source for controlling the fluid pressure in the fluid chamber, and a control amplifier for controlling the fluid pressure controller in accordance with the external signals. Signals detected by the pressure sensor and the position sensor are respectively input as feedback signals to the control amplifier in order to improve controllability, to reduce noises due to pressure fluctuation in the pressure source, and to improve a neutral positioning of the partition diaphragm. The hydrostatic speaker can radiate super low-frequency sound, which has been considered difficult by conventional speakers.
- Published
- 1992
89. Three distinct activities possibly involved in mRNA splicing are found in a nuclear fraction lacking U1 and U2 RNA
- Author
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Kazuta Takemura, Akila Mayeda, Yasumi Ohshima, Kazuaki Tatei, and Hitoshi Kitayama
- Subjects
Cell Nucleus ,Small RNA ,Base Sequence ,Transcription, Genetic ,RNA Splicing ,Intron ,RNA ,RNA-binding protein ,DNA Restriction Enzymes ,Biology ,Ribonucleoproteins, Small Nuclear ,Molecular biology ,Chromatography, DEAE-Cellulose ,Cell biology ,Post-transcriptional modification ,Adenosine Triphosphate ,Ribonucleoproteins ,RNA editing ,RNA, Small Nuclear ,Genetics ,Humans ,RNA, Messenger ,Small nuclear ribonucleoprotein ,Small nuclear RNA ,HeLa Cells - Abstract
A nuclear extract from HeLa cells was fractionated by DEAE-Sepharose chromatography, and the fractions were assayed for the binding activity for a small RNA transcript carrying a splice junction or branch point sequence. The binding activity for the RNA carrying a 5' splice junction was localized in the small nuclear ribonucleoprotein (snRNP) fraction together with binding activity for the RNA carrying a 3' splice junction or branch point sequence. However, stronger binding activities for the 3' splice junction RNA and for the branch point RNA were discovered in the flow-through fraction where no small nuclear RNA were detected. When the flow-through fraction was added to purified U1 ribonucleoprotein, the binding activity for the 5' splice junction RNA was markedly enhanced. We propose that the factors responsible for the three types of activities found in the flow-through fraction play a role in the splicing of mRNA precursor.
- Published
- 1986
90. Possible involvement of two signaling pathways in induction of neuron-associated properties by v-Ha-ras gene in PC12 cells
- Author
-
Makoto Noda, Hitoshi Kitayama, Yoshikazu Sugimoto, and Yoji Ikawa
- Subjects
medicine.medical_specialty ,Inositol Phosphates ,Cellular differentiation ,Adrenal Gland Neoplasms ,Inositol 1,4,5-Trisphosphate ,Pheochromocytoma ,Oncogene Protein p21(ras) ,Biology ,Phosphatidylinositols ,Transfection ,Cell morphology ,Biochemistry ,Dexamethasone ,Diglycerides ,Gene product ,chemistry.chemical_compound ,Internal medicine ,Cyclic AMP ,Tumor Cells, Cultured ,medicine ,Animals ,Nerve Growth Factors ,Phosphatidylinositol ,Promoter Regions, Genetic ,Molecular Biology ,Neurons ,Regulation of gene expression ,Bucladesine ,Inositol trisphosphate ,Oncogene Proteins, Viral ,Cell Biology ,Rats ,Cell biology ,Enhancer Elements, Genetic ,Phenotype ,Endocrinology ,Gene Expression Regulation ,Mammary Tumor Virus, Mouse ,chemistry ,Acetylcholinesterase ,Tetradecanoylphorbol Acetate ,Calcium ,Signal transduction ,Plasmids ,medicine.drug - Abstract
Harvey sarcoma virus induces a number of neuron-associated properties in a nerve growth factor-responsive cell line, PC12 (Noda, M., Ko, M., Ogura, A., Liu, D., Amano, T., Takano, T., and Ikawa, Y. (1985) Nature 318, 73-75). We investigated the mechanism of this phenomenon using PC12 sublines cotransfected with a plasmid containing v-Ha-ras gene under control of a hormone-responsive enhancer/promoter element of the mouse mammary tumor virus long terminal repeat (pM14-1) and a plasmid encoding G418 resistance (pSV2neo). Extent of the expression of neuron-associated properties in several cell clones after the addition of dexamethazone (DEX) seems to correlate well with the levels of the v-Ha-ras gene expression. After the induction of v-Ha-ras expression with DEX in these cell lines, sustained elevation of the levels of cAMP as well as of phosphatidylinositol (PtdIns) metabolites, inositol trisphosphate, and diacylglycerol, is observed. Physiological significance of this phenomenon is confirmed by the observation that dibutyryl cAMP and phorbol-12-myristate 13-acetate synergistically induces the expression of neuron-associated properties in PC12 cells. In control PC12 sublines transfected with pSV2neo alone, DEX shows no effects on their cell morphology and the levels of cAMP and the PtdIns metabolites, although these control cell lines are competent to the effects of dibutyryl cAMP and phorbol ester. The priming activity known to be associated with nerve growth factor is also observed with v-Ha-ras as well as with dibutyryl cAMP plus phorbol ester but not with dibutyryl cAMP or phorbol ester alone. The observations suggest that the role of v-Ha-ras gene product in this system may involved simultaneous activation of the two signaling pathways, those mediated by cAMP and by PtdIns turnover.
- Published
- 1988
91. A ras-related gene with transformation suppressor activity
- Author
-
Makoto Noda, Yoji Ikawa, Yoshikazu Sugimoto, Hitoshi Kitayama, and Tomoko Matsuzaki
- Subjects
Regulation of gene expression ,Base Sequence ,Rap GTP-binding protein ,DNA ,Molecular cloning ,Biology ,Blotting, Northern ,Cell Transformation, Viral ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology ,Rats ,Blotting, Southern ,Genes, ras ,Gene Expression Regulation ,Multigene Family ,Complementary DNA ,Animals ,Humans ,Ras subfamily ,Rap1 ,Amino Acid Sequence ,Northern blot ,Gene - Abstract
A 1.8 kb cDNA clone, Krev-1, with revertant-inducing activity on Kirsten sarcoma virus-transformed NIH/3T3 cells, has been isolated from a human fibroblast cDNA expression library. In Krev-1 transfectants, there is a correlation between the levels of specific mRNA and the degrees of suppression of the transformed phenotype. The cDNA encodes a protein of 21,000 daltons that unexpectedly shares around 50% amino acid identities with ras proteins. The Krev-1 homologs are found in mouse, rat, and chicken DNA, and their transcripts are ubiquitously expressed in many rat organs. Thus, the Krev-1 gene seems to play an important role(s) in a wide variety of tissues, and may be involved in the negative growth regulation of certain cell types.
- Published
- 1989
92. Refractoriness to Platelet Transfusion Following Double Valve Replacement in an ITP Patient Who Had Undergone Splenectomy
- Author
-
Terufumi Matsumoto, Masahiko Onoe, Masaki Otaki, Jyunzo Lemura, Kwansong Ku, Susumu Nakamoto, Hidetaka Oku, Hiroshi Oka, Toshio Kaneda, Takehiro Inoue, and Hitoshi Kitayama
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Splenectomy ,Platelet Transfusion ,Postoperative Hemorrhage ,Postoperative Complications ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Platelet ,Heart Valve Prosthesis Implantation ,Purpura, Thrombocytopenic, Idiopathic ,Platelet Count ,business.industry ,Mitral valve replacement ,Middle Aged ,medicine.disease ,Thrombocytopenic purpura ,Surgery ,Cardiac surgery ,Platelet transfusion ,Aortic Valve ,Anesthesia ,Hemostasis ,Retreatment ,Mitral Valve ,Corticosteroid ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Reports of patients with idiopathic thrombocytopenic purpura (ITP) undergoing cardiac surgery are rare, and almost all of the reported cases required platelet transfusion. ITP patients, especially those having a history of splenectomy or a history of heavy bleeding, may have to undergo multiple platelet transfusions. Such transfusions may induce al-loimmunization against the human leukocyte antigen (HLA) and result in refractoriness to subsequent platelet transfusions. We report a case of a 63-year-old female with ITP, with a history of splenectomy and multiple platelet transfusions, who underwent aortic and mitral valve replacement. Although corticosteroid administration, high-dose immunoglobulin therapy, and repeated platelet transfusion led to a temporary increase in platelet count and successful hemostasis, refractoriness to platelet transfusion occurred postoperatively because of the presence of the anti-HLA antibody. In addition, the patient showed complications of pyothorax. Corticosteroids might have exerted an inhibitory influence on the occurrence of pyothorax.
- Published
- 1985
93. Messenger RNA splicing: role of small nuclear RNA-protein complexes
- Author
-
Kazuaki Tatei, Yasumi Ohshima, Kazuta Takemura, Hitoshi Kitayama, and Akila Mayeda
- Subjects
DNA, Bacterial ,Five-prime cap ,Base Composition ,Base Sequence ,RNA Splicing ,Biophysics ,Intron ,Exonic splicing enhancer ,RNA ,Biology ,Ribonucleoproteins, Small Nuclear ,Biochemistry ,Molecular biology ,Cell biology ,Post-transcriptional modification ,RNA silencing ,Genes ,Ribonucleoproteins ,RNA splicing ,Escherichia coli ,Micrococcal Nuclease ,RNA, Messenger ,Small nuclear RNA - Published
- 1986
94. Detection of genes with a potential for suppressing the transformed phenotype associated with activated ras genes
- Author
-
Robert H. Bassin, Hiroto Okayama, Makoto Noda, Hitoshi Kitayama, Yoji Ikawa, Tomoko Matsuzaki, and Yoshikazu Sugimoto
- Subjects
Transforming virus ,viruses ,Viral Oncogene ,Biology ,Transfection ,Cell Line ,Plasmid ,Suppression, Genetic ,Animals ,Humans ,Gene ,Cells, Cultured ,Multidisciplinary ,RNA ,DNA ,Blotting, Northern ,Molecular biology ,Phenotype ,Blotting, Southern ,Cell Transformation, Neoplastic ,Genes, ras ,Gene Expression Regulation ,Cell culture ,Plasmids ,Research Article - Abstract
Seven morphologically nontransformed (flat) revertants with reduced tumorigenicity in vivo have been isolated from populations of Kirsten sarcoma virus-transformed NIH 3T3 cells transfected with a cDNA expression library of normal human fibroblasts. Each revertant harbors 1-10 recombinant plasmids per cell and retains a rescuable transforming virus as well as high level expression of v-Ki-ras-specific RNA and the viral oncogene product, p21v-Ki-ras. Transformed phenotypes are suppressed in cell hybrids generated by fusing each revertant to v-Ki-ras-transformed NIH 3T3 cells. From two of the revertant lines, plasmids capable of giving rise to flat secondary transfectants have been recovered. Thus, in some, if not all, of the revertants, transfected cDNAs seem to be responsible for the suppression of specific transformed phenotypes.
- Published
- 1989
95. Granulocyte colony-stimulating Factor in Allogeneic Bone Marrow Transplantation
- Author
-
Shigeyuki Ishigami, Fumimaro Takaku, Jun Ishikawa, Akira Hiraoka, Hirotoshi Shibata, Tamotsu Yamagami, Hiroyuki Nakamura, Tohru Masaoka, Hitoshi Kitayama, and Hirofumi Teshima
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Fever ,Graft vs Host Disease ,Pain ,Recombinant Granulocyte Colony-Stimulating Factor ,Granulocyte ,Gastroenterology ,Leukocyte Count ,Colony-Stimulating Factors ,hemic and lymphatic diseases ,Internal medicine ,Granulocyte Colony-Stimulating Factor ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Child ,Bone Marrow Transplantation ,Stomatitis ,Leukemia ,Leukopenia ,business.industry ,Incidence ,Remission Induction ,Myeloid leukemia ,Pneumonia ,General Medicine ,medicine.disease ,Granulocyte colony-stimulating factor ,Survival Rate ,medicine.anatomical_structure ,Oncology ,Immunology ,Absolute neutrophil count ,Drug Evaluation ,Female ,medicine.symptom ,business ,Chronic myelogenous leukemia - Abstract
A Phase II study of recombinant granulocyte colony-stimulating factor (G-CSF) in allogeneic bone marrow transplantation (BMT) was performed. The recovery of leukocytes and neutrophils was markedly accelerated in G-CSF-administered recipients. The days to WBC count greater than 1,000/microliters (11.5 +/- 1.9) and the days to neutrophil count greater than 500/microliters (11.5 +/- 1.4) were significantly shorter than those of the monocyte-CSF (M-CSF) and CSF(-) groups. In the G-CSF group the WBC count at nadir was higher than in other groups, and neutrophil recovery preceded monocyte recovery. After the discontinuation of G-CSF, the WBC count first decreased for a few days and then increased again slowly. The short duration of leukopenia brought about a reduction in the number of febrile (greater than 38 degrees C) days which, until day 30, were 1.8 +/- 1.9 in the G-CSF group, also significantly shorter than in others. Acute graft-versus-host disease (greater than grade II) appeared in two of eight patients from the G-CSF group, this incidence being comparable to those found in the other groups. A side effect of G-CSF-mild bone pain-was observed in one patient, but it was tolerable. Six of eight patients in the G-CSF group survived for between five and 13 months after BMT with a Karnofsky score greater than 90%. No relapses were observed in the six, including one patient with chronic myelogenous leukemia and two with acute non-lymphoblastic leukemia. To determine the final influence of G-CSF on myeloid leukemia, further long-term follow-up studies are needed. G-CSF was well tolerated and seemed promising against allogeneic BMT.
- Published
- 1989
96. Proliferation of human myeloid leukemia cell line associated with the tyrosine-phosphorylation and activation of the proto-oncogene c-kit product
- Author
-
Seiichiro Tarui, Tetsuo Nishiura, Akira Kuriu, Brian Druker, Jun Ishikawa, Yoshio Kanayama, Takeshi Yonezawa, Hirosuke Yagura, Hirokazu Ikeda, Hitoshi Kitayama, Yuzuru Kanakura, and James D. Griffin
- Subjects
Cell growth ,medicine.drug_class ,Immunology ,Myeloid leukemia ,Stem cell factor ,Tyrosine phosphorylation ,Cell Biology ,Hematology ,Biology ,Ligand (biochemistry) ,Biochemistry ,Molecular biology ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,chemistry ,Cell culture ,Cancer research ,medicine ,Phosphorylation - Abstract
We investigated the expression, degree of phosphorylation, and activation of the proto-oncogene c-kit product before and after stimulation with the c-kit ligand in a human factor-dependent myeloid leukemia cell line, MO7E. The culture supernatant of the BALB/3T3 fibroblast cell line, which contains the ligand for the murine c-kit product, was found to stimulate proliferation of the MO7E cell line in a dose-dependent manner. The proliferation was significantly inhibited by a tyrosine kinase inhibitor, genistein. An immunoblot technique with a monoclonal antibody specific for phosphotyrosine, showed that there was rapid, dose-dependent tyrosine-phosphorylation of the c-kit product in response to murine c-kit ligand. Furthermore, the murine c-kit ligand increased autokinase activity of the c-kit product in vitro. Similar results were obtained with human stem cell factor (SCF), a recombinant human ligand for the c-kit product. These results suggest that the phosphorylation and activation of the c-kit product are involved in proliferative signals of some human leukemia cells, as well as of normal hematopoietic cells.
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