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Featured researches published by Tatsuma Okazaki.


The EMBO Journal | 2003

NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death

Sachiko Sakon; Xin Xue; Mutsuhiro Takekawa; Tomonari Sasazuki; Tatsuma Okazaki; Yuko Kojima; Jian-Hu Piao; Hideo Yagita; Ko Okumura; Takahiro Doi; Hiroyasu Nakano

NF‐κB downregulates tumor necrosis factor (TNF)‐induced c‐Jun N‐terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor‐associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF‐κB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen‐activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild‐type MEFs, indicating that TRAF‐mediated NF‐κB activation normally suppresses the TNF‐induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death


Biochemical and Biophysical Research Communications | 2003

Phosphorylation of serine 276 is essential for p65 NF-κB subunit-dependent cellular responses

Tatsuma Okazaki; Sachiko Sakon; Tomonari Sasazuki; Hiroaki Sakurai; Takahiro Doi; Hideo Yagita; Ko Okumura; Hiroyasu Nakano

Phosphorylation of several serine residues especially in the transactivation (TA) domain of p65 NF-kappaB subunit has been suggested to be important for its transcriptional activity. However, the responsible phosphorylation site of p65 remains controversial. To investigate the biological significance of phosphorylation and to determine the critical phosphorylation sites of p65, we reconstituted murine embryonic fibroblasts (MEFs) from p65(-/-) mice with various serine to alanine (SA)-substituted mutants of p65. Unexpectedly, mutants in the TA domain, including S529A, S536A, and S529A/S536A, completely rescued the defect of p65(-/-) MEFs as assessed by tumor necrosis factor (TNF)- or interleukin-1 (IL-1)-induced IL-6 production and protection from TNF-induced cell death. On the other hand, S276A mutant had an impaired ability to rescue these responses. Moreover, TNF-induced phosphorylation of p65 was severely impaired in S276A mutant, indicating that S276 is the major phosphorylation site of p65 and its phosphorylation is essential for p65-dependent cellular responses.


Journal of Clinical Oncology | 2006

Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

Hiroyasu Yasuda; Mutsuo Yamaya; Katsutoshi Nakayama; Takahiko Sasaki; Satoru Ebihara; Akio Kanda; Masanori Asada; Daisuke Inoue; Tomoko Suzuki; Tatsuma Okazaki; Hidenori Takahashi; Motoki Yoshida; Tomohiro Kaneta; Kota Ishizawa; Shinsuke Yamanda; Naoki Tomita; Miyako Yamasaki; Akiko Kikuchi; Hiroshi Kubo; Hidetada Sasaki

PURPOSE To investigate the efficacy and safety of nitroglycerin plus vinorelbine and cisplatin in patients with previously untreated stage IIIB/IV non-small-cell lung cancer (NSCLC) as the experimental arm for the next phase III trial. PATIENTS AND METHODS One hundred twenty patients with stage IIIB/IV NSCLC were randomly assigned to vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, with transdermally applied nitroglycerin (25 mg/patient daily for 5 days; arm A) or with placebo patch (arm B) every 3 weeks for a maximum of four cycles in a double-blind and controlled trial. Primary efficacy end points were the best confirmed response rate and time to disease progression (TTP). RESULTS The response rate in arm A (72%; 43 of 60 patients) was significantly higher than that for patients in arm B (42%; 25 of 60 patients; P < .001). Median TTP in arm A was longer than that in arm B (327 v 185 days). No severe adverse effect was recognized for either arm. The rate of grade 1 to 2 headache in arm A (30%; 18 of 60 patients) was significantly higher than that in arm B (2%; one of 60 patients; P < .001, chi(2) test). CONCLUSION Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.


Journal of the American Geriatrics Society | 2005

Capsaicin Troche for Swallowing Dysfunction in Older People

Takae Ebihara; Hidenori Takahashi; Satoru Ebihara; Tatsuma Okazaki; Takahiko Sasaki; Aya Watando; Miyako Nemoto; Hidetada Sasaki

Objectives: To determine whether oral capsaicin troche supplementation with every meal upregulates the impairment of upper respiratory protective reflexes such as the swallowing reflex and the cough reflex.


Journal of Biological Chemistry | 2002

Identification of a Novel Transcriptional Activator, BSAC, by a Functional Cloning to Inhibit Tumor Necrosis Factor-induced Cell Death

Tomonari Sasazuki; Taisuke Sawada; Sachiko Sakon; Toshio Kitamura; Takuma Kishi; Tatsuma Okazaki; Mitsuo Katano; Masao Tanaka; Mamoru Watanabe; Hideo Yagita; Ko Okumura; Hiroyasu Nakano

Tumor necrosis factor (TNF) is a multifunctional cytokine, which induces proliferation or death in a cell type-dependent manner. We previously showed that murine embryonic fibroblasts (MEFs) from TNF receptor-associated factor 2 (Traf2) and Traf5double-deficient (double knockout (DKO)) mice were highly susceptible to TNF-induced cell death. By functional cloning to rescue DKO MEFs from TNF-induced cell death, we have identified a novel gene,Bsac. BSAC is composed of N-terminal basic, SAP (SAF-A/B, Acinus, PIAS), and coiled-coil domains. BSAC is a nuclear protein, and overexpression of BSAC potently activates promoters containing A + T-rich sequences named CArG boxes. Domain mapping analysis revealed that both N-terminal basic and C-terminal proline-rich sequence are required for the transcriptional activity. Overexpression of BSAC in DKO MEFs partially inhibited TNF-induced cell death by suppressing activation of caspases. Interestingly, inhibition of TNF-induced cell death was not observed in DKO MEFs transfected with either N-terminal or C-terminal deletion mutant of BSAC, revealing an intimate correlation between transcriptional activity and antiapoptotic function. Recently, a human homologue of BSAC named MAL/MKL1(megakaryocytic acuteleukemia/megakaryoblasticleukemia-1) was identified as a fusion transcript generated by t(1,22) translocation in acute megakaryoblastic leukemia. Collectively, BSAC is a novel transcriptional activator with antiapoptotic function, which may be involved in the leukemogenesis.


Journal of Immunology | 2005

Macrophage Colony-Stimulating Factor Induces Vascular Endothelial Growth Factor Production in Skeletal Muscle and Promotes Tumor Angiogenesis

Tatsuma Okazaki; Satoru Ebihara; Hidenori Takahashi; Masanori Asada; Akio Kanda; Hidetada Sasaki

Although M-CSF has been used for myelosuppression due to chemotherapy in patients with solid tumors, the effect of exogenous M-CSF on tumor angiogenesis has not been studied. In this study we showed that M-CSF has the ability to accelerate solid tumor growth by enhancing angiogenesis with a novel mechanism. M-CSF accelerated intratumoral vessel density in tumors inoculated into mice, although it did not accelerate the proliferation of malignant cells and cultured endothelial cells in vitro. In both the absence and the presence of tumors, M-CSF significantly increased the circulating cells that displayed phenotypic characteristics of endothelial progenitor cells in mice. Moreover, M-CSF treatment induced the systemic elevation of vascular endothelial growth factor (VEGF). VEGFR-2 kinase inhibitor significantly impaired the effect of M-CSF on tumor growth. In vivo, M-CSF increased VEGF mRNA expression in skeletal muscles. Even after treatment with carageenan and anti-CD11b mAb in mice, M-CSF increased VEGF production in skeletal muscles, suggesting that systemic VEGF elevation was attributed to skeletal muscle VEGF production. In vitro, M-CSF increased VEGF production and activated the Akt signaling pathway in C2C12 myotubes. These results suggest that M-CSF promotes tumor growth by increasing endothelial progenitor cells and activating angiogenesis, and the effects of M-CSF are largely based on the induction of systemic VEGF from skeletal muscles.


Blood | 2009

Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade.

Shinsuke Yamanda; Satoru Ebihara; Masanori Asada; Tatsuma Okazaki; Kaijun Niu; Takae Ebihara; Akemi Koyanagi; Noriko Yamaguchi; Hideo Yagita; Hiroyuki Arai

Delta-like 4 (DLL4) is one of the Notch ligands and plays an important role in vascular development. DLL4 blockade inhibits tumor growth by promoting nonproductive angiogenesis, which is characterized by an increase in vascular density and decrease in tissue perfusion. However, a detailed mechanism remains unclear. In this study, newly developed neutralizing antibodies against mouse and human DLL4 were used to investigate the possible involvement of VEGF-DLL4-ephrinB2 cascade in nonproductive angiogenesis caused by DLL4 blockade. DLL4 blockade and soluble ephrinB2 treatment suppressed tumor growth and induced nonproductive angiogenesis. DLL4 was expressed in subcutaneous tumors, and DLL4 blockade suppressed ephrinB2 expression in the tumors. DLL4 blockade significantly promoted human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and the effect was additive to that of VEGF. Both DLL4 blockade and VEGF significantly increased cord length and branch points in a tubular formation assay. Expression of ephrinB2 in HUVECs was enhanced by VEGF alone, and the enhancement was inhibited by DLL4 blockade. Moreover, when we studied the effect of ephrinB2 RNA interference on HUVEC tubular formation, knockdown of ephrinB2 mimicked the effect of DLL4. These results suggest that ephrinB2 plays a crucial role in nonproductive angiogenesis caused by DLL4 blockade.


Journal of Immunology | 2001

Impairment of Bleomycin-Induced Lung Fibrosis in CD28-Deficient Mice

Tatsuma Okazaki; Atsuhito Nakao; Hiroyasu Nakano; Fumiyuki Takahashi; Kazuhisa Takahashi; Osamu Shimozato; Kazuyoshi Takeda; Hideo Yagita; Ko Okumura

Lung fibrosis is an important pulmonary disease with a high mortality rate, but its pathophysiological mechanism has not been fully clarified. Various types of cells have been implicated in the development of lung fibrosis, including T cells. However, the contribution of functional molecules expressed on T cells to the development of lung fibrosis remains largely unknown. In this study, we determined whether costimulation via CD28 on T cells was crucial for the development of lung fibrosis by intratracheally administering bleomycin into CD28-deficient mice. Compared with wild-type mice, the CD28-deficient mice showed markedly impaired lung fibrosis after injection with low doses of bleomycin, as judged by histological changes and hydroxyproline content in the lungs. In addition, bleomycin-induced T cell infiltration into the airways and production of several cytokines and chemokines including IL-5 were also impaired in the CD28-deficient mice. Furthermore, adoptive transfer of CD28-positive T cells from wild-type mice recovered the impaired bleomycin-induced lung fibrosis in CD28-deficient mice. These findings suggest that the CD28-mediated T cell costimulation plays a critical role in the development of lung fibrosis, possibly by regulating the production of cytokines and chemokines in the lung. Thus, manipulation of the CD28-mediated costimulation could be a potential therapeutic strategy for the prevention of lung fibrosis.


Journal of the American Geriatrics Society | 2004

Effect of temperature on swallowing reflex in elderly patients with aspiration pneumonia

Aya Watando; Satoru Ebihara; Takae Ebihara; Tatsuma Okazaki; Hidenori Takahashi; Masanori Asada; Hidetada Sasaki

To the Editor: We read with interest the study by Ricauda et al. describing a home hospital (HH) model of care for patients with acute stroke because it highlights important issues related to defining a HH. A wide variety of models of care has been described in the international literature under the HH umbrella, engendering controversy over the definition of HH and the effectiveness of the model. These models include the outpatient infusion centerwhere patients receive an intravenous infusion or other treatment; the physicians’ office intravenous service where patients predominantly self-infuse their medications and are reviewed in physicians’ offices; the delivery of home-based care by hospital, or hospital contracted, staff or in the United States by a home health agency to patients in their own homes; early discharge schemes, mostly for postsurgical patients in which patients early in the postoperative period are discharged home and receive postoperative nursing supervision and skilled therapies at home, again with little organized input from physicians; and a clinical unit model that delivers acute hospital-level medical care in the patient’s home and substitutes entirely for an acute hospital admission. Physician and nursing care are provided in the home, as well as appropriate diagnostic and therapeutic care and technologies. The study of HH for acute stroke by Ricauda et al. is an excellent example of a clinical unit model of HH. This HH model possessed three elements we consider to be key features that define a HH. (1) It provides care that substitutes entirely for an inpatient acute hospital admission. (2) It provides an intensity of care, including medical and nursing care, similar to that provided in the hospital appropriate to the severity of the illness treated. (3) It provides care that cannot be provided by usual community-based home care services. Defining HH in this manner relates to the underlying rationale of the model. The main reasons for developing HH include reducing iatrogenic complications including functional decline, honoring patients’ wishes for their care, and reducing expenses. Given this, substitution for an acute hospital inpatient stay is essential in satisfying the HH care model to its fullest extent. Postdischarge programs and nursing programs that do not substitute for a hospital admission entirely expose the patient to the acute hospital environment, may not satisfy patient preference to avoid the hospital, and probably are not as economically efficient as possible. To substitute entirely for an inpatient admission, HH should provide an intensity of care similar to that provided in the hospital to ensure proper evaluation and treatment of the acutely ill patient. This means that 24-hour access to hospital-level medical and nursing care and appropriate diagnostic and therapeutic modalities must be available to the care of the patient. This has generally not been available in the community setting or in many models claiming to be HH. Provision of HH needs to be care that typical community-based home care services cannot provide. HH programs that become blurred with other community-based programs run a high risk of subsequent failure, simply because the skills and organization are different from those required for non-HH community-based care provision. In terms of economics, labeling typical community-based home care services as HH care may simply undermine the economic rationale for the model if expensive HH care is provided to patients who do not require it. Finally, in terms of research and evaluation, blurred boundaries between HH and more typical home care services may result in substantial heterogeneity of patients and care requirements and ensure that outcome studies trend towards equivalence. We hope that focusing the definition of HH will facilitate further development and research on this emerging model of care.


British Journal of Pharmacology | 2005

A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity

Hidenori Takahashi; Satoru Ebihara; Tatsuma Okazaki; Masanori Asada; Hidetada Sasaki; Mutsuo Yamaya

Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg−1 day−1), dalteparin (75 units kg−1 day−1) or danaparoid (50 units kg−1 day−1). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours.

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Kaijun Niu

Tianjin Medical University

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