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Articles by H Kitamura
Total Records ( 4 ) for H Kitamura
  T Kake , H Kitamura , Y Adachi , T Yoshioka , T Watanabe , H Matsushita , T Fujii , E Kondo , T Tachibe , Y Kawase , K. i Jishage , A Yasoda , M Mukoyama and K. Nakao
 

C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.

  D Wakita , K Chamoto , T Ohkuri , Y Narita , S Ashino , K Sumida , H Nishikawa , H Shiku , Y Togashi , H Kitamura and T. Nishimura
 

3-Methylcholanthrene (MCA)-induced sarcomas have been used as conventional tools for investigating immunosurveillance against tumor development. However, MCA-induced sarcoma is not always an ideal model for the study of the human cancer system because carcinomas and not sarcomas are the dominant types of human cancers. To resolve this problem, we established a novel and simple method to induce mouse squamous cell carcinomas (SCCs). As well known, the subcutaneous injection of MCA caused the formation of sarcomas at 100% incidence. However, we here first succeeded at inducing SCC at 60% of incidence within 2 months by a single intra-dermal injection of MCA. Using this primary SCC model, we demonstrated the critical role of interferon (IFN)--dependent type 1 immunity in immunosurveillance against SCC from the following results: (i) The incidence of SCC was accelerated in IFN--deficient mice compared with that in wild-type mice; (ii) In vivo injection of CpG-oligodeoxynucleotides (CpG-ODN) caused a marked reduction in the incidence of SCC in parallel with the activation of type 1-dependent antitumor immunity and (iii) The antitumor activity of CpG-ODN was significantly decreased in IFN--deficient mice. Thus, our established MCA-induced mouse SCC model could be a powerful tool for evaluating immunosurveillance mechanisms during the development of SCC and might result in a novel strategy to address immunosurveillance mechanisms of human cancer.

  A Yasoda , H Kitamura , T Fujii , E Kondo , N Murao , M Miura , N Kanamoto , Y Komatsu , H Arai and K. Nakao
 

Skeletal dysplasias are a group of genetic disorders characterized by severe impairment of bone growth. Various forms of them add to produce a significant morbidity and mortality, yet no efficient drug therapy has been developed to date. We previously demonstrated that C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is a potent stimulator of endochondral bone growth. Furthermore, we exhibited that targeted overexpression of a CNP transgene in the growth plate rescued the impaired bone growth observed in a mouse model of achondroplasia (Ach), the most frequent form of human skeletal dysplasias, leading us to propose that CNP may prove to be an effective treatment for this disorder. In the present study, to elucidate whether or not the systemic administration of CNP is a novel drug therapy for skeletal dysplasias, we have investigated the effects of plasma CNP on impaired bone growth in Ach mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter or in those treated with a continuous CNP infusion system. Our results demonstrated that increased plasma CNP from the liver or by iv administration of synthetic CNP-22 rescued the impaired bone growth phenotype of Ach mice without significant adverse effects. These results indicate that treatment with systemic CNP is a potential therapeutic strategy for skeletal dysplasias, including Ach, in humans.

  T Tanaka , H Kitamura , A Takahashi , N Masumori and T. Tsukamoto
  Objective

We retrospectively assessed long-term outcomes of chemotherapy for advanced germ cell tumors (GCTs) at our institution.

Methods

Ninety-five consecutive males with advanced GCTs of the testis or extragonadal origin who received chemotherapy between 1980 and 2006 were enrolled. All patients underwent induction chemotherapy including cisplatin.

Results

The median follow-up period was 36.1 months (0 – 288.5) for all patients and 52.6 months (2.2 – 288.5) for the 73 current survivors. Totally, 75 patients (78.9%) achieved complete remission (CR). CR was achieved in 61.1%, 37.9% and 75.0% of the patients after induction therapy, second-line therapy and third-line or more, respectively. As salvage therapy, high-dose chemotherapy was performed in 11 patients (11.7%) and regimens with novel anticancer agents such as paclitaxel and irinotecan were employed for 8 patients (8.5%) from 2003 and later. The era of the treatment, extrapulmonary metastasis and serum -fetoprotein were independent prognostic factors for patients. The 5-year overall survival of patients after 1992 was 83.0%, which was significantly higher than that of those before 1992 (56.3%). CR was never achieved in 20 patients and most of them met the criteria of the poor-prognosis group. Disease recurrence after CR was found in nine patients who were initially classified into the good- or intermediate-prognosis group.

Conclusions

Improvement of medical management during chemotherapy and the development of several regimens for salvage chemotherapy seemed to contribute to improving outcomes of patients with advanced testicular cancer. Newly established chemotherapy regimens are needed for improvement of survival of patients in the poor-prognosis group.

 
 
 
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