Hisatsugu Goto and Yasuhiko Nishioka : ALK and Others: How Important Are ALK and Other Mutations in the Management of Lung Cancer?, Springer, Jul. 2018.
20.
西岡 安彦 : 過敏性肺炎, 株式会社 医学書院, 2018年1月.
21.
豊田 優子, 西岡 安彦 : ランゲルハンス細胞組織球症, 2017年10月.
22.
埴淵 昌毅, 西岡 安彦 : 分子生物学的にみた間質性肺炎および肺癌, 2017年10月.
23.
後東 久嗣, 西岡 安彦 : 肺胞微石症, 2017年10月.
24.
埴淵 昌毅, 西岡 安彦 : じん肺症(珪肺，アスベスト肺), 2017年7月.
25.
西岡 安彦 : 間質性肺炎の急性増悪, 2017年1月.
26.
西岡 安彦 : 非特異性間質性肺炎(NSIP), 2016年12月.
27.
西岡 安彦 : 特発性肺線維症の基礎, 2016年3月.
28.
西岡 安彦 : 特発性間質肺炎, 2016年1月.
29.
Yasuhiko Nishioka : Pathogenesis of IPF. Is abnomal repair of epithelial damage involved in the basic pathogenesis of this disease?, Springer, 2016.
30.
Yasuhiko Nishioka : Is abnormal repair of epithelial damage involved in the basic pathogenesis of this disease?, Springer,Tokyo, 2016.
Motoki Sugasaki, S Nakamura, K Teramoto, M Urushihara, Y Inoue, T Nakao, Yasuhiko Nishioka and Masataka Sata : Lupus anticoagulant hypoprothrombinemia syndrome with multiple and high-titer antiphospholipid antibodies strongly interfered with coagulation assays, Blood Coagulation & Fibrinolysis, Vol.35, No.3, 149-153, 2024.
Hiroyuki Kozai, Hirokazu Ogino, Atsushi Mitsuhashi, Thi Na Nguyen, Yuki Tsukazaki, Yohei Yabuki, Ryohiko Ozaki, Hiroto Yoneda, Seidai Satou, Masaki Hanibuchi, Tsutomu Shinohara, Hiroshi Nokihara and Yasuhiko Nishioka : Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies., Thoracic Cancer, Vol.15, No.5, 369-378, 2024.
(要約)
5-FU induced cell surface expression of CRT and ATP secretion most efficiently among the several chemotherapeutic agents. This effect was enhanced when it was combined with platinum. In the antitumor vaccination assay in vivo, we found that vaccination with dying-AB1-HA (a murine malignant mesothelioma cell line) cells treated with 5-FU, but neither PEM nor PTX, reduced the tumor growth of living-AB1-HA cells inoculated 1 week after vaccination by recruiting CD3
Hiroto Yoneda, Atsushi Mitsuhashi, Aito Yoshida, Hirokazu Ogino, Satoshi Itakura, Thi Na Nguyen, Hiroshi Nokihara, Seidai Satou, Tsutomu Shinohara, Masaki Hanibuchi, Shinji Abe, K Mika Kaneko, Yukinari Kato and Yasuhiko Nishioka : Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells., Cancer Science, Vol.115, No.2, 357-368, 2024.
(要約)
-f and CTLA-4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.
Eiji Takeuchi, Hirokazu Ogino, Kensuke Kondo, Yoshio Okano, Seiya Ichihara, Michihiro Kunishige, Naoki Kadota, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : An increased relative eosinophil count as a predictive dynamic biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors., Thoracic Cancer, Vol.15, No.3, 248-257, 2024.
(要約)
An increased relative eosinophil count (REC) has potential as a predictive biomarker for a beneficial clinical response and outcome to cancer immunotherapies. Therefore, the present study investigated the impact of an increased posttreatment REC on the prognosis of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). We retrospectively reviewed all 151 patients diagnosed with NSCLC and treated with ICI monotherapy and blood test data between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. A total of 151 patients with a mean age of 69 years were included. REC after 4 weeks of initial ICI monotherapy was higher than pretreatment REC in 87 patients but not in 64. REC after 4 weeks of the ICI treatment with and without an increased REC were 4.4 and 1.8%, respectively (p < 0.001). Disease control rates (DCR) were significantly higher in patients with than in those without an increased REC (84% vs. 47%, p < 0.001). The median overall survival (OS) of lung cancer patients with or without an increased REC were 674 and 234 days, respectively. A Kaplan-Meier univariate analysis revealed a significant difference in OS between the two groups (p < 0.001). A Cox proportional regression analysis identified an increased REC as an independent predictor of OS (p = 0.003). ICI-treated NSCLC patients with an increased REC after 4 weeks of treatment had a better DCR and prognosis than the other patients examined.
For senescent cells, ARV825 induced the expression of an apoptosis marker while reducing the expression of BRD4 and senescence markers. On the other hand, for early passage pre-senescent cells, ARV825 reduced the expression of collagen type 1 and α-smooth muscle actin. In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment.
Yohei Yabuki, Masaki Hanibuchi, Eiji Takeuchi, Takashi Haku, Takanori Kanematsu, Naoki Nishimura, Yuko Toyoda, Atsushi Mitsuhashi, Kenji Otsuka, Seidai Satou, Hisatsugu Goto, Hiroto Yoneda, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : A multicenter, open-label, phase II trial of pemetrexed plus bevacizumab in elderly patients with previously untreated advanced or recurrent nonsquamous non-small cell lung cancer., Thoracic Cancer, Vol.14, No.32, 3232-3239, 2023.
(要約)
The median age at initiating chemotherapy was 80 years old. Almost all patients (92.6%) had adenocarcinoma histology. The median number of cycles administered was 6, and the objective response rate was 40.7%. The median progression-free survival, overall survival and 1-year survival were 8.8 months, 27.2 months and 79%, respectively. The treatment was well-tolerated, and no treatment-related death was observed.
Eiji Takeuchi, Kensuke Kondo, Yoshio Okano, Seiya Ichihara, Michihiro Kunishige, Naoki Kadota, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : Pretreatment eosinophil counts as a predictive biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors., Thoracic Cancer, Vol.14, No.30, 3042-3050, 2023.
(要約)
OS was significantly longer in ICI-treated NSCLC patients with a pretreatment eosinophil count of 100 ≤ Eo <500 than in the other patients and, thus, has potential as a new predictive biomarker.
Saki Harada, Takeshi Imakura, Seidai Satou, Hiroshi Nokihara and Yasuhiko Nishioka : A case of successful treatment with eltrombopag for severe immune-related thrombocytopenia induced by atezolizumab:Case report., The Journal of Medical Investigation : JMI, Vol.70, No.3.4, 516-520, 2023.
(要約)
Immune checkpoint inhibitors (ICIs) have shown impressive anti-tumor effects against multiple types of malignancies. Among the wide variety of immune-related adverse events (irAEs), immune-related thrombocytopenia (ITP) is relatively rare but often clinically significant and life-threatening. However, the appropriate treatment for severe ITP has not been determined. We herein report an 82-year-old male patient with non-small-cell lung cancer who developed severe ITP three weeks after starting the third course of atezolizumab. The initial combination therapy with high-dose prednisolone, intravenous immunoglobulin and platelet transfusion was ineffective. However, additional treatment with eltrombopag, a thrombopoietin receptor agonist, resulted in remarkable improvement in the thrombocytopenia. J. Med. Invest. 70 : 516-520, August, 2023.
(キーワード)
Male / Humans / Aged, 80 and over / Carcinoma, Non-Small-Cell Lung / Lung Neoplasms / Thrombocytopenia / Purpura, Thrombocytopenic, Idiopathic
These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.
Yasuhiko Nishioka, Sakae Homma, Takashi Ogura, Seidai Satou, Naoki Arai, Keisuke Tomii, Koichiro Kamio, Susumu Sakamoto, Yasunari Miyazaki, Hiromi Tomioka, Shu Hisata, Tomohiro Handa and Arata Azuma : Exploratory phase 2 study of the novel oral multi-kinase inhibitor TAS-115 in patients with idiopathic pulmonary fibrosis., Respiratory Investigation, Vol.61, No.4, 498-507, 2023.
(要約)
In this exploratory phase 2 study, IPF patients with a percent predicted forced vital capacity (%FVC) decline ≥5% acquired within the previous 6 months were enrolled. Patients were divided into three pre-treatment cohorts, namely, treatment-naïve, pirfenidone, or nintedanib. TAS-115 was administered orally at 200 mg/day with a 5-day on and 2-day off regimen. After 13 weeks of treatment, patients entered a 13-week extension treatment period where the efficacy was evaluated. The primary endpoint was the difference in slope of %FVC decline at Week 13 from baseline. Safety was also evaluated.
Masaki Hanibuchi, Atsushi Mitsuhashi, Atsuro Saijo, Tatsuya Kajimoto, Seidai Satou, Tetsuya Kitagawa and Yasuhiko Nishioka : A case of atopic cough with aphonia showed a prominent response to a histamine H1 receptor antagonist., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 281-284, 2023.
(要約)
-RA, a diagnosis of AC was made. To the best of our knowledge, this is the first report of an AC patient who presented severe cough with aphonia. J. Med. Invest. 70 : 281-284, February, 2023.
T Na Nguyen, Atsushi Mitsuhashi, Hirokazu Ogino, Hiroyuki Kozai, Hiroto Yoneda, Tania Afroj, Seidai Satou, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor., Cancer Science, Vol.114, No.2, 384-398, 2023.
(要約)
Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer.
Momoyo Azuma, Kazunori Oishi, Yukihiro Akeda, Saeko Morino, Yumi Motoki, Masaki Hanibuchi and Yasuhiko Nishioka : Safety and immunogenicity of sequential administration of PCV13 followed by PPSV23 in pneumococcal vaccine-naïve adults aged 65 years: Comparison of booster effects based on intervals of 0.5 and 1.0 year., Vaccine, Vol.41, No.5, 1042-1049, 2023.
(要約)
The 1.0-y interval provided better booster effects induced by PPSV23 than those of the 0.5-y interval in a sequential administration in pneumococcal vaccine-naïve adults aged 65 years. No difference was found in the safety profile between both intervals.
Masaki Hanibuchi, Atsushi Mitsuhashi, Tatsuya Kajimoto, Atsuro Saijo, Seidai Satou, Tetsuya Kitagawa and Yasuhiko Nishioka : Clinical significance of fractional exhaled nitric oxide and periostin as potential markers to assess therapeutic efficacy in patients with cough variant asthma., Respiratory Investigation, Vol.61, No.1, 16-22, 2023.
(要約)
Our observations indicate the usefulness of FeNO and periostin as potential "therapeutic" markers for CVA. To the best of our knowledge, this is the first report demonstrating the clinical significance of these factors as potential biomarkers to assess therapeutic efficacy in patients with CVA.
Seiya Ichihara, Hirokazu Ogino, Hiroto Yoneda, Keiko Haji, Kozo Kagawa, Kojin Murakami, Masato Mima, Yu Aoi, Atsushi Mitsuhashi, Yuki Tsukazaki, Yohei Yabuki, Ryohiko Ozaki, Seidai Satou, Hiroshi Nokihara and Yasuhiko Nishioka : Immune checkpoint inhibitor-related pneumonitis with atypical radiologic features in a patient with anti-aminoacyl-tRNA synthetase antibody., Respiratory Medicine Case Reports, Vol.41, 101797, 2023.
(要約)
A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features.
Muneo Numasaki, Koyu Ito, Kiyoshi Takagi, Kengo Nagashima, Hirotsugu Notsuda, Hirokazu Ogino, Rika Ando, Yoshihisa Tomioka, Takashi Suzuki, Yoshinori Okada, Yasuhiko Nishioka and Michiaki Unno : Diverse and divergent functions of IL-32β and IL-32γ isoforms in the regulation of malignant pleural mesothelioma cell growth and the production of VEGF-A and CXCL8., Cellular Immunology, Vol.383, 104652, 2023.
(要約)
In this study, we sought to elucidate the roles of the interleukin (IL)-32β and IL-32γ in mesothelioma cell growth, and vascular endothelial growth factor (VEGF)-A and C-X-C motif chemokine ligand 8 (CXCL8) expression. IL-32 elicited a growth-promoting effect against one of the six mesotheliomas lines and exerted diverse regulatory functions in VEGF-A and CXCL8 secretion from mesotheliomas stimulated with or without IL-17A. Retroviral-mediated transduction of mesothelioma lines with IL-32γ resulted in enhanced IL-32β expression, which facilitated or suppressed the in vitro growth, and VEGF-A and CXCL8 expression. Overexpressed IL-32β-augmented growth and VEGF-A and CXCL8 production were mainly mediated through the phosphatidylinositol-3 kinase (PI3K) signaling pathway. On the other hand, overexpressed IL-32β-deceased growth was mediated through mitogen-activated protein kinase (MAPK) pathway. NCI-H2373IL-32γ tumors grew faster than NCI-H2373Neo tumors in a xenograft model, which was associated with increased vascularity. These findings indicate that IL-32 are involved in the regulation of growth and angiogenic factor production in mesotheliomas.
(キーワード)
Humans / Interleukins / Mesothelioma, Malignant / Protein Isoforms / Vascular Endothelial Growth Factor A / Interleukin-8
Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s.e.m.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar.
Kozo Kagawa, Seidai Satou, Kazuya Koyama, Takeshi Imakura, Kojin Murakami, Yuya Yamashita, Nobuhito Naito, Hirohisa Ogawa, Hiroshi Kawano and Yasuhiko Nishioka : The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-β production in regulatory T-cells., PLoS ONE, Vol.17, No.10, e0275987, 2022.
(要約)
These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-β production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis.
Makoto Tobiume, Atsushi Mitsuhashi, Atsuro Saijo, Hirokazu Ogino, Tania Afroj, Hirohisa Ogawa, Hisatsugu Goto, Seidai Satou, Akane Abe, Keiko Haji, Ryohiko Ozaki, Hiromitsu Takizawa and Yasuhiko Nishioka : Analysis of the chemotactic factors for tumor-infiltrating fibrocytes and their prognostic significances in lung cancer., Oncology Letters, Vol.24, No.5, 417, 2022.
(要約)
Fibrocytes, which are bone marrow-derived collagen-producing cells, have been reported to be involved in pathogenesis of pulmonary fibrosis. Our previous study reported that tumor-infiltrating fibrocytes play a role in tumor progression and drug resistance in lung cancer. The present study therefore examined chemotactic factors for fibrocytes in tissues of non-small cell lung cancer (NSCLC) and their prognostic significance. Surgically resected tumor tissues were examined for the expression of chemotactic factors, including C-X-C motif chemokine 12 (CXCL12), CCL2, platelet-derived growth factor (PDGF)-AA and PDGF-BB, as well as tumor-infiltrating fibrocytes by immunostaining. The chemotactic ability of fibrocytes in response to each factor was evaluated using a migration assay by counting the migrated cells microscopically, and expression of receptors for chemotactic factors were analyzed by flow cytometry. The expression of CXCL12, but not CCL2, PDGF-AA, or PDGF-BB, was associated with the number of tumor-infiltrating fibrocytes in lung adenocarcinoma (LUAD), but not lung squamous cell carcinoma (LUSQ). In addition, patients with an increased expression of CXCL12 in LUAD but not LUSQ showed a significantly poorer prognosis compared with those with a decreased expression. However, the expression of CCL2, PDGF-AA and PDGF-BB was not correlated with the prognosis of patients with NSCLC. The number of fibrocytes was associated with a poor prognosis in LUAD. Fibrocytes derived from the peripheral blood of healthy subjects as well as patients with lung cancer expressed higher levels of CXCR4 compared with CCR2, PDGF and receptor-α and receptor-β. Overall, these results suggested that targeting tumor-infiltrating fibrocytes via the CXCL12/CXCR4 axis may be a useful strategy for controlling the progression of NSCLC, particularly LUAD.
Kenji Otsuka, Hiroshi Nokihara, Atsushi Mitsuhashi, Ryohiko Ozaki, Yohei Yabuki, Hiroto Yoneda, Hirokazu Ogino and Yasuhiko Nishioka : Efficacy and safety of second-line chemotherapy for patients with advanced non-small cell lung cancer complicated by interstitial lung disease., Thoracic Cancer, Vol.13, No.21, 2978-2984, 2022.
(要約)
Thirty-five patients received two or more regimens. Thirty-four patients were male and the median age at the initiation of second-line chemotherapy was 70 years. Almost all patients had a smoking history. Fourteen patients had adenocarcinoma and 15 had squamous cell carcinoma histology. Stages III and IV were observed in 20 and 11 patients, respectively. With respect to the type of ILD, 12 patients had usual interstitial pneumonia (UIP). The overall response rate and disease control rate were 11.4 and 68.6%, respectively. The median progression-free and median overall survival were 4.1 and 6.4 months, respectively. The AE of ILD was observed in eight patients, five of whom died. UIP and low percentage vital capacity were detected as significant risk factors for the AE of ILD.
Yasuhiko Nishioka, Yuko Toyoda, Ryoko Egashira, Takeshi Johkoh, Yasuhiro Terasaki, Akira Hebisawa, Kinya Abe, Tomohisa Baba, Yuji Fujikura, Etsuo Fujita, Naoki Hamada, Tomohiro Handa, Yoshinori Hasegawa, Koko Hidaka, Takeshi Hisada, Shu Hisata, Chisato Honjo, Kazuya Ichikado, Yoshikazu Inoue, Shinyu Izumi, Motoyasu Kato, Takumi Kishimoto, Masaki Okamoto, Keisuke Miki, Masamichi Mineshita, Yutaro Nakamura, Susumu Sakamoto, Masaaki Sano, Yoshikazu Tsukada, Mari Yamasue, Yoshimi Bando, Sakae Homma, Koichi Hagiwara, Takafumi Suda and Naohiko Inase : Nationwide retrospective observational study of idiopathic dendriform pulmonary ossification: clinical features with a progressive phenotype., BMJ Open Respiratory Research, Vol.9, No.1, e001337, 2022.
(要約)
Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.
Masaki Hanibuchi, Atsuro Saijo, Atsushi Mitsuhashi, Tatsuya Kajimoto, Tetsuya Kitagawa and Yasuhiko Nishioka : The efficacy of mass screening for chronic obstructive pulmonary disease using screening questionnaires in a medical health check-up population., Respiratory Investigation, Vol.60, No.6, 815-821, 2022.
(要約)
Mass screening for COPD using screening questionnaires, particularly the COPD-PS questionnaire, might be useful to identify the early stages of COPD in a medical health check-up population.
(キーワード)
Humans / Forced Expiratory Volume / Cross-Sectional Studies / Reproducibility of Results / Pulmonary Disease, Chronic Obstructive / Spirometry / Mass Screening / Surveys and Questionnaires
Takashi Ogura, Takafumi Suda, Naohiko Inase, Yasuhiko Nishioka, Arata Azuma, Masaki Okamoto, Ayako Takizawa, Tomohiro Ito, B Klaus Rohr and Yoshikazu Inoue : Effects of nintedanib on disease progression and safety in Japanese patients with progressive fibrosing interstitial lung diseases: Further subset analysis from the whole INBUILD trial., Respiratory Investigation, Vol.60, No.6, 787-797, 2022.
Yoshitoyo Ueno, Saki Harada, Koji Sato, Kazuki Momota, Hiroki Sato, Yusuke Akimoto, Yuta Arai, Toshiyuki Nunomura, Manabu Ishihara, Natsuki Tane, Taiga Itagaki, Yasuhiko Nishioka and Jun Oto : Independent lung ventilation for the management of acute allograft rejection after single-lung transplantation for end-stage emphysema., The Journal of Medical Investigation : JMI, Vol.69, No.3.4, 323-327, 2022.
(要約)
Background : We herein report the use of independent lung ventilation (ILV) for managing acute allograft rejection after single-lung transplantation (SLT) for end-stage emphysema. Case presentation : A 54-year-old woman was transferred to our hospital with severe hypoxemia and respiratory distress due to unilateral lung disease with diffuse alveolar damage in the right donor lung associated with acute allograft rejection and with hyperinflation of the left native lung due to emphysema. She was unresponsive to immunosuppressive medications and conventional ventilation strategies, so different ventilator settings for each lung were required. A double-lumen endotracheal tube (DLT) was inserted, and ILV was initiated. The right lung was ventilated with high positive end-expiratory pressure (PEEP), intended for lung recruitment, and the left lung was ventilated with lung protective strategies using a low tidal volume and low levels of PEEP to avoid hyperinflation. Two days later, her lung function was dramatically improved, and the DLT was replaced with a single-lumen endotracheal tube. Gas exchange was maintained, and she was successfully weaned from mechanical ventilation on intensive-care unit day 15. Conclusions : ILV appears to be effective and safe for managing acute allograft rejection after SLT for emphysema. J. Med. Invest. 69 : 323-327, August, 2022.
Takumi Sakurada, Hiroshi Nokihara, Tadashi Koga, Yoshito Zamami, Mitsuhiro Goda, Kenta Yagi, Hirofumi Hamano, Fuka Aizawa, Hirokazu Ogino, Seidai Satou, Yasushi Kirino, Hisatsugu Goto, Yasuhiko Nishioka and Keisuke Ishizawa : Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids: A Phase II Study., The Oncologist, Vol.27, No.7, e554-e560, 2022.
(要約)
This single-arm, phase II study recruited patients with non-squamous non-small cell lung cancer and malignant pleural mesothelioma scheduled to receive chemotherapy including pemetrexed. Patients received 2 mg of dexamethasone daily from days 2 to 6 after chemotherapy with pemetrexed. The primary endpoint was the 3-week incidence of rash eruptions.
Hiroshi Nokihara, Hirokazu Ogino, Atsushi Mitsuhashi, Kensuke Kondo, Ei Ogawa, Ryohiko Ozaki, Yohei Yabuki, Hiroto Yoneda, Kenji Otsuka and Yasuhiko Nishioka : Efficacy of osimertinib in epidermal growth factor receptor-mutated non-small-cell lung cancer patients with pleural effusion., BMC Cancer, Vol.22, No.1, 2022.
(要約)
A total of 63 patients with EGFR mutated NSCLC were treated with osimertinib; 33 (12 with PE) had no EGFR T790M mutation, while 30 (12 with PE) had EGFR T790M mutation. In EGFR T790M-negative NSCLC, the progression-free survival (PFS) of the patients with PE was comparable to that of the patients without PE (median PFS 19.8 vs. 19.8 months, p = 0.693). In EGFR T790M- positive NSCLC, the PFS and overall survival (OS) of the patients with PE were significantly shorter than those of the patients without PE (median PFS 16.8 vs. 8.3 months, p = 0.003; median OS 44.9 vs. 14.2 months, p = 0.007). In the multivariate analysis, the presence of PE was independently associated with shorter PFS and OS in EGFR T790M-positive NSCLC patients, but not EGFR T790M-negative patients.
Jun Kako, Masamitsu Kobayashi, Kohei Kajiwara, Yasutaka Kimura, Yasufumi Oosono, Mizuki Takegata, Kimiko Nakano, Yoshinobu Matsuda, Naomi Nakamura, Natsuki Kawashima, Yuta Hirano, Misako Kitae, Kakuhiro Yamaguchi, Hiroshi Iwamoto, Noboru Hattori, Hiroyuki Sawatari, Satoshi Shiono, Hirokazu Ogino, Yasuhiko Nishioka, Koji Amano and Janelle Yorke : Validity and Reliability of the Japanese Version of the Dyspnea-12 Questionnaire in Patients With Lung Cancer., Journal of Pain and Symptom Management, Vol.64, No.2, e83-e89, 2022.
(要約)
The Japanese version of the Dyspnea-12 questionnaire is a useful and reliable tool to assess the multi-dimensional aspects of dyspnea in patients with lung cancer.
Hitoshi Nishijima, Mizuki Sugita, Natsuka Umezawa, Naoki Kimura, Hirokazu Sasaki, Hiroshi Kawano, Yasuhiko Nishioka, Minoru Matsumoto, Takeshi Oya, Koichi Tsuneyama, Junko Morimoto and Mitsuru Matsumoto : Development of organ-specific autoimmunity by dysregulated Aire expression., Immunology and Cell Biology, Vol.100, No.5, 371-377, 2022.
(要約)
Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3
Hirohisa Ogawa, Masahiko Azuma, Aya Umeno, Mayuko Shimizu, Kazutoshi Murotomi, Yasukazu Yoshida, Yasuhiko Nishioka and Koichi Tsuneyama : Singlet oxygen -derived nerve growth factor exacerbates airway hyperresponsiveness in a mouse model of asthma with mixed inflammation., Allergology International, Vol.71, No.3, 395-404, 2022.
(要約)
NGF production and hyperinnervation were higher in Mix-in mice than in conventional eosinophilic-asthmatic mice and were positively correlated with AHR. Asthmatic parameters were inhibited by NGF neutralizing Abs and myeloperoxidase (MPO) inhibition. The 10- and 12-(Z,E)-HODEs levels were increased in the lungs and were positively correlated with MPO activity and NGF production. NGF was produced by bronchial epithelial cells in vitro upon stimulation with singlet oxygen.
Hirokazu Ogino, W Jennie Taylor, Takahide Nejo, David Gibson, B Payal Watchmaker, Kaori Okada, Atsuro Saijo, R Meghan Tedesco, Anny Shai, M Cynthia Wong, E Jane Rabbitt, R Michael Olin, L Christopher Moertel, Yasuhiko Nishioka, M Andres Salazar, M Annette Molinaro, J Joanna Phillips, A Nicholas Butowski, L Jennifer Clarke, Ann Bush Nancy Oberheim, L Shawn Hervey-Jumper, Philip Theodosopoulos, M Susan Chang, S Mitchel Berger and Hideho Okada : Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas., The Journal of Clinical Investigation, Vol.132, No.3, 2022.
(要約)
BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.
Yutaka Morita, Atsuro Saijo, Hiroshi Nokihara, Atsushi Mitsuhashi, Hiroto Yoneda, Kenji Otsuka, Hirokazu Ogino, Yoshimi Bando and Yasuhiko Nishioka : Radiation therapy induces an abscopal effect and upregulates programmed death-ligand 1 expression in a patient with non-small cell lung cancer., Thoracic Cancer, Vol.13, No.7, 1079-1082, 2022.
(要約)
T cells, occasionally resulting in a systemic immune response to the tumor outside of the treatment field. The phenomenon of tumor regression at the site distant from irradiated fields is known as the abscopal effect. Several case reports have indicated a potential role of RT in overcoming primary and acquired resistance against immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and melanoma patients. We herein report an NSCLC patient who developed acquired resistance to an RT-induced abscopal effect and subsequently experienced reactivation of the systemic antitumor immune response by pembrolizumab, an antiprogrammed death 1 antibody. In this case, RT not only induced an abscopal effect but also upregulated the programmed death-ligand 1 expression outside of the irradiated field when the patient developed resistance to the abscopal effect. This case can facilitate our understanding of the mechanism underlying the RT-induced systemic immune response against cancer cells and adaptive resistance mechanism of cancer cells from immune surveillance. These findings highlight the promising results of current clinical trials combining RT and immune checkpoint inhibitors. Ongoing clinical trials will further establish evidence supporting combination therapy with RT and immune checkpoint inhibitors.
Tamotsu Tanaka, Kazuya Koyama, Naoko Takahashi, Katsuya Morito, Hanif Ali, Momoyo Azuma, Kozo Kagawa, Hiroshi Kawano, Rumana Yesmin, Mutsumi Aihara and Yasuhiko Nishioka : Lysophosphatidic acid, ceramide 1-phosphate and sphingosine 1-phosphate in peripheral blood of patients with idiophathic pulmonary fibrosis, The Journal of Medical Investigation : JMI, Vol.69, No.3.4, 196-203, 2022.
(要約)
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonias. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are signaling lipids that evoke growth factor-like responses to many cells. Recent studies revealed the involvement of LPA and S1P in the pathology of IPF. In this study, we determined LPA, S1P and ceramide 1-phosphate (C1P) in peripheral blood plasma of IPF patients, and examined correlation to the vital capacity of lung (VC), an indicator of development of fibrosis. Blood plasma samples were taken from eleven patients with IPF and seven healthy volunteers. The lipids of the sample were extracted and subjected to liquid chromatography-tandem mass spectrometry for analysis. Results showed that there is a significant negative correlation between VC and plasma LPA levels, indicating that IPF patients with advanced fibrosis had higher concentration of LPA in their plasma. Average of S1P levels were significantly higher in IPF patients than those in healthy subjects. Although it is not statistically significant, a similar correlation trend that observed in LPA levels also found between VC and S1P levels. These results indicated that plasma LPA and S1P may be associated with deterioration of pulmonary function of IPF patients. J. Med. Invest. 69 : 196-203, August, 2022.
Masahiro Sako, Hiroshi Nokihara, Kensuke Kondo, Atsushi Mitsuhashi, Ryohiko Ozaki, Yohei Yabuki, Akane Abe, Hiroto Yoneda, Hirokazu Ogino, Kenji Otsuka, Hisanori Uehara and Yasuhiko Nishioka : A case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia successfully treated with pembrolizumab., Thoracic Cancer, Vol.13, No.1, 129-132, 2021.
(要約)
Pulmonary pleomorphic carcinoma is often refractory to chemotherapy and follows an aggressive clinical course. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced lung cancer, and a few cases with pleomorphic carcinoma have been reported to show tumor shrinkage after therapy with ICIs. When treating patients with ICIs, patient selection is essential, and monitoring and management of immune-related adverse events, including pneumonitis, are needed. We herein report a case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia treated with pembrolizumab, antiprogrammed cell death 1 antibody. Our report highlights important considerations necessary when treating advanced pleomorphic carcinoma patients complicated with interstitial pneumonia. We also review the literature regarding the use of ICIs in such patients.
Hiroto Yoneda, Hiroshi Nokihara, Atsushi Mitsuhashi, Ryohiko Ozaki, Yohei Yabuki, Hirokazu Ogino, Kenji Otsuka and Yasuhiko Nishioka : Correlation between immune-related adverse events and therapeutic effects of nivolumab in patients with malignant pleural mesothelioma., BMC Pulmonary Medicine, Vol.21, No.1, 2021.
(要約)
Eleven patients received treatment with nivolumab. Objective response rate was 18.2% and the disease control rate was 90.9%. Median PFS was 6.8 months (95% confidence interval, 1.3 to 11.9 months) and median OS was 15.2 months (95% confidence interval, 8.9 to 21.5 months). IrAEs occurred in eight patients (72.7%), and grade ≥ 2 irAEs occurred in six patients (54.5%). PFS and OS were significantly longer in the grade ≥ 2 irAEs group than in grade < 2 irAEs group (median PFS 13.6 vs. 3.8 months, p = 0.0093; median OS not reached vs. 8.6 months, p = 0.0108).
(キーワード)
Aged / Aged, 80 and over / Antineoplastic Agents, Immunological / 女性 (female) / Humans / Immune System Diseases / Male / Mesothelioma, Malignant / Middle Aged / Nivolumab / Retrospective Studies / Survival Analysis / Treatment Outcome
Toshifumi Tezuka, Masahiko Azuma, Hirohisa Ogawa, Mayo Kondou, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi and Yasuhiko Nishioka : A RAS inhibitor reduces allergic airway remodeling via regulating IL-33-derived type 2 innate lymphoid cells., Experimental Lung Research, Vol.47, No.9, 451-463, 2021.
(要約)
The RAS signal pathway plays a crucial role in allergen-induced airway remodeling associated with ILC2s. XRP44X may have therapeutic potential for refractory asthma.
Atsushi Mitsuhashi, Kensuke Kondoh, Kazuki Horikawa, Kazuya Koyama, Thi Na Nguyen, Tania Afroj, Hiroto Yoneda, Kenji Otsuka, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : Programmed death (PD)-1/PD-ligand 1 blockade mediates antiangiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker., Cancer Science, Vol.112, No.12, 4853-4866, 2021.
(要約)
Immune checkpoint inhibitor (ICI) programmed death (PD)-1/PD-ligand 1 (PD-L1) blockade has been approved for various cancers. However, the underlying antitumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti-PD-L1/PD-1 Ab in tumor angiogenesis. In syngeneic mouse models, anti-PD-L1 Ab inhibited tumor angiogenesis and induces net-like hypoxia only in ICI-sensitive cell lines. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, interferon-γ (IFN-γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN-γ stimulation in tumor cell lines correlated with the sensitivity of PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing Ab or CXCL11 silencing in tumor cells inhibited the antiangiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti-PD-1 Ab, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results indicate the antiangiogenic function of PD-1/PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity.
Hirokazu Ogino, Makoto Tobiume, Kozo Kagawa, Hiroshi Kawano, Satoshi Sakaguchi, Atsuro Saijo, Daisuke Matsumoto, Hiromitsu Takizawa, Yuriko Morikawa, Yoshimi Bando, Hisatsugu Goto, Hiroshi Nokihara and Yasuhiko Nishioka : A Case of Radiation-associated Angiosarcoma Presenting as Massive Pleural Effusion., Internal Medicine, Vol.61, No.9, 1393-1397, 2021.
(要約)
A 67-year-old man was admitted to our hospital for massive pleural effusion. He had a history of mandibular gingival carcinoma treated with radiation therapy (RT). Based on the cytology findings of pleural effusion and a thoracoscopic pleural biopsy, we finally diagnosed him with radiation-associated angiosarcoma. Retrospective cell-block immunocytochemistry with pleural effusion also showed potential utility for the diagnosis. This case highlights the importance of considering the possibility of radiation-associated secondary cancer in patients with pleural effusion who have a history of RT.
The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.
Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.
Yasuhiko Nishioka, Sakae Homma, Takahito Okubo and Arata Azuma : Design of phase 2 study of TAS-115, a novel oral multi-kinase inhibitor, in patients with idiopathic pulmonary fibrosis., Contemporary Clinical Trials Communications, Vol.23, 2021.
(要約)
This is an open-label, intra-patient comparison, exploratory phase 2 study of TAS-115 to evaluate the efficacy and safety in idiopathic pulmonary fibrosis (IPF) patients when orally administered at 200 mg once daily on a 5-day on and 2-day off regimen for 13 weeks. This study consists of three cohorts: previously treated with pirfenidone (Cohort P, n = 20), with nintedanib (Cohort N, n = 20), and treatment naïve (Cohort U, n = 10). Male or female patients aged ≥40 to <80 years who were diagnosed with IPF in the preceding five years and having a percent predicted forced vital capacity (%FVC) decline of ≥5% within the previous 6 months were enrolled in this study. The primary endpoint is change in the slope of %FVC decline at Week 13 from baseline. Key secondary endpoints are safety, change in FVC from baseline, proportion of the %FVC responders and change in percent predicted diffusing capacity of the lung carbon monoxide from baseline, which are assessed at Weeks 6, 13 and 26.
Yoshikazu Inoue, Takafumi Suda, Hideya Kitamura, Masaki Okamoto, Arata Azuma, Naohiko Inase, Masataka Kuwana, Shigeki Makino, Yasuhiko Nishioka, Takashi Ogura, Ayako Takizawa, Hiroyuki Ugai, Susanne Stowasser, Rozsa Schlenker-Herceg and Tsutomu Takeuchi : Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial., Respiratory Medicine, Vol.187, 2021.
(要約)
The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were -148.31 (nintedanib) and -240.36 (placebo), adjusted difference: 92.05 (95% CI: -10.69-194.80) and for non-Japanese patients were -67.41 (nintedanib) and -177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97-155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of "acute exacerbation or death" (hazard ratio, 0.30 [95% CI: 0.10-0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14-2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings.
These observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.
Keiko Haji, Seidai Satou, Hiroto Yoneda, Toshihiko Nisisho, Hiroshi Nokihara and Yasuhiko Nishioka : Multidisciplinary treatment of skeletal muscle metastasis from lung cancer: A case of triceps muscle metastasis of lung squamous cell cancer., Respiratory Medicine Case Reports, Vol.33, 2021.
(要約)
A 62-year-old Japanese man presented a hard and painful intramuscular mass in the right upper arm during the chemotherapy for lung squamous cell carcinoma. Initially, this mass containing fluid accumulation was treated by radiotherapy and antibiotics as a muscle metastasis suspected to be complicated with local infection. However, because the swelling and pain of his right arm did not improve, he underwent a surgical debridement of the mass. These local treatments succeeded in relieving the patient's symptoms for a while. However, after temporary remission, the recurrence tumor developed the paralysis of right radial nerve and ulnar nerve in his upper arm. Despite further combined therapy including drainage, additional radiotherapy, and chemotherapy, paralysis made his performance status deteriorated. He was eventually discontinued aggressive treatment due to worsened general condition. We herein report a case of lung cancer followed unusual course due to muscle metastasis in the triceps muscle. Because the paralysis caused by muscle metastasis can be the factor to deteriorate the performance status of patient, the combined therapy including antibiotics, debridement, radiotherapy and chemotherapy as early as possible should be considered to avoid its risk.
Epithelial-mesenchymal transition (EMT)-a fundamental process in embryogenesis and wound healing-promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer.
Seidai Satou, Giin Sy Chong, Chandak Upagupta, Toyoshi Yanagihara, Takuya Saito, Chiko Shimbori, Pierre-Simon Bellaye, Yasuhiko Nishioka and Rj Martin Kolb : Fibrotic extracellular matrix induces release of extracellular vesicles with pro-fibrotic miRNA from fibrocytes., Thorax, Vol.76, No.9, 895-906, 2021.
(要約)
of fibroblasts. Culturing on rigid plates or fibrotic decellularised lung scaffolds increased miR-21-5 p expression compared with soft plates or normal lung scaffolds. Dissolved ECM collected from fibrotic lungs and recombinant TGF-β1 increased miR-21-5 p expression on fibrocytes, and these effects were attenuated on soft plates. Fibrocytes from BALF collected from fibrotic interstitial pneumonia patients showed higher miR-21-5 p expression than those from other patients.
Hiroshi Mukae, Takeshi Kaneko, Yasushi Obase, Masaharu Shinkai, Toshio Katsunuma, Kiyoshi Takeyama, Jiro Terada, Akio Niimi, Hiroto Matsuse, Kazuhiro Yatera, Yoshihiro Yamamoto, Arata Azuma, Hirokazu Arakawa, Takashi Iwanaga, Haruhiko Ogawa, Kiyoyasu Kurahashi, Yasuhiro Gon, Hirokazu Sakamoto, Yoko Shibata, Tsutomu Tamada, Yasuhiko Nishioka, Shusaku Haranaga, Shigeharu Fujieda, Naoyuki Miyashita, Hiroyuki Mochizuki, Akihito Yokoyama, Shigemi Yoshihara and Jun Tamaoki : The Japanese respiratory society guidelines for the management of cough and sputum (digest edition)., Respiratory Investigation, Vol.59, No.3, 270-290, 2021.
(要約)
Cough and sputum are common complaints at outpatient visits. In this digest version, we provide a general overview of these two symptoms and discuss the management of acute (up to three weeks) and prolonged/chronic cough (longer than three weeks). Flowcharts are provided, along with a step-by-step explanation of their diagnosis and management. Most cases of acute cough are due to an infection. In chronic respiratory illness, a cough could be a symptom of a respiratory infection such as pulmonary tuberculosis, malignancy such as a pulmonary tumor, asthma, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, drug-induced lung injury, heart failure, nasal sinus disease, sinobronchial syndrome, eosinophilic sinusitis, cough variant asthma (CVA), atopic cough, chronic laryngeal allergy, gastroesophageal reflux (GER), and post-infectious cough. Antibiotics should not be prescribed for over-peak cough but can be considered for atypical infections. The exploration of a single/major cause is recommended for persistent/chronic cough. When sputum is present, a sputum smear/culture (general bacteria, mycobacteria), cytology, cell differentiation, chest computed tomography (CT), and sinus X-ray or CT should be performed. There are two types of rhinosinusitis. Conventional sinusitis and eosinophilic rhinosinusitis present primarily with neutrophilic inflammation and eosinophilic inflammation, respectively. The most common causes of dry cough include CVA, atopic cough/laryngeal allergy (chronic), GER, and post-infectious cough. In the last chapter, future challenges and perspectives are discussed. We hope that the clarification of the pathology of cough hypersensitivity syndrome will lead to further development of "pathology-specific non-specific therapeutic drugs" and provide benefits to patients with chronic refractory cough.
Susumu Sakamoto, Kensuke Kataoka, Yasuhiro Kondoh, Motoyasu Kato, Masaki Okamoto, Hiroshi Mukae, Masashi Bando, Takafumi Suda, Kazuhiro Yatera, Yoshinori Tanino, Tomoo Kishaba, Noboru Hattori, Yoshio Taguchi, Takefumi Saito, Yasuhiko Nishioka, Kazuyoshi Kuwano, Kazuma Kishi, Naohiko Inase, Shinichi Sasaki, Hajime Takizawa, Takeshi Johkoh, Fumikazu Sakai and Sakae Homma : Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial., The European Respiratory Journal, Vol.57, No.1, 2021.
(要約)
81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in
Nobuhito Naito, Hiroshi Kawano, Yuya Yamashita, Mayo Kondou, Shotaro Haji, Ryosuke Miyamoto, Yuko Toyoda, Yasuhisa Kanematsu, Yuishin Izumi, Yoshimi Bando and Yasuhiko Nishioka : Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy., Modern Rheumatology Case Reports, Vol.5, No.1, 52-57, 2020.
(要約)
A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.
Shun Morizumi, Seidai Satou, Kazuya Koyama, Hiroyasu Okazaki, Yajuan Chen, Hisatsugu Goto, Kozo Kagawa, Hirohisa Ogawa, Haruka Nishimura, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara and Yasuhiko Nishioka : Blockade of Pan-Fibroblast Growth Factor Receptors Mediates Bidirectional Effects in Lung Fibrosis., American Journal of Respiratory Cell and Molecular Biology, Vol.63, No.3, 317-326, 2020.
(要約)
H]thymidine incorporation assays. The expression of FGFR was analyzed using IB or flow cytometry. We also investigated the effect of BGJ398 on pulmonary fibrosis induced by bleomycin in mice. Both lung fibroblasts and AECs expressed FGFRs. BGJ398 significantly inhibited the proliferation and migration of lung fibroblasts stimulated with FGF2. BGJ398 also reduced the proliferation of AECs in response to FGF2. Although the administration of BGJ398 ameliorated pulmonary fibrosis in bleomycin-treated mice, it increased mortality resulting from alveolar injury and inhibition of AEC regeneration. These data suggest that the total inhibition of FGFR signaling can suppress lung fibrosis by inhibiting fibroblast activities, although alveolar injury is simultaneously caused.
Mayo Kondou, Toshifumi Tezuka, Hirohisa Ogawa, Kazuya Koyama, Hiroki Bando, Masahiko Azuma and Yasuhiko Nishioka : Lysophosphatidic Acid Regulates the Differentiation of Th2 Cells and Its Antagonist Suppresses Allergic Airway Inflammation., International Archives of Allergy and Immunology, Vol.182, No.1, 1-13, 2020.
(要約)
These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma.
Naoto Okada, Rie Matsuoka, Takumi Sakurada, Mitsuhiro Goda, Masayuki Chuma, Kenta Yagi, Yoshito Zamami, Yasuhiko Nishioka and Keisuke Ishizawa : Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study., Scientific Reports, Vol.10, No.1, 2020.
(要約)
Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAEs). ICI-related interstitial lung disease (ICI-ILD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. Therefore, early ICI-ILD detection and intervention are important for patient safety. However, a risk assessment method for ICI-ILD has not been established and the prediction of ICI-ILD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ICI-ILD occurrence.
This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014-FY2016 Health and Labor Sciences Research Grant on Intractable Diseases. This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities. The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.
Yuji Minegishi, Akihiko Gemma, Sakae Homma, Kazuma Kishi, Arata Azuma, Takashi Ogura, Naoki Hamada, Hiroyuki Taniguchi, Noboru Hattori, Yasuhiko Nishioka, Kiminobu Tanizawa, Takeshi Johkoh, Takuma Yokoyama, Kazutaka Mori, Yoshio Taguchi, Masahito Ebina, Naohiko Inase, Koichi Hagiwara, Hiroshi Ohnishi, Hiroshi Mukae, Yoshikazu Inoue, Kazuyoshi Kuwano, Hirofumi Chiba, Ken Ohta, Yoshinori Tanino, Fumikazu Sakai and Yukihiko Sugiyama : Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: nationwide surveillance in Japan., ERJ Open Research, Vol.6, No.2, 2020.
(要約)
Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively.
Kenji Otsuka, Atsushi Mitsuhashi, Hisatsugu Goto, Masaki Hanibuchi, Kazuya Koyama, Hirohisa Ogawa, Hirokazu Ogino, Atsuro Saijo, Hiroyuki Kozai, Hiroto Yoneda, Makoto Tobiume, Masatoshi Kishuku, Keisuke Ishizawa and Yasuhiko Nishioka : Anti-PD-1 antibody combined with chemotherapy suppresses the growth of mesothelioma by reducing myeloid-derived suppressor cells., Lung Cancer, Vol.146, 86-96, 2020.
(要約)
The combination of anti-PD-1 antibody with CDDP + PEM may be a promising therapy for MPM via inhibiting the accumulation of MDSCs and vessels in tumors.
Shuichi Abe, Seidai Satou, Yoshinori Aono, Momoyo Azuma, Masami Kishi, Koyama Kazuya, Takahashi Naoki, Kozo Kagawa, Hiroshi Kawano and Yasuhiko Nishioka : Functional analysis of human fibrocytes derived from monocytes reveals their profibrotic phenotype through paracrine effects, The Journal of Medical Investigation : JMI, Vol.67, No.1.2, 102-112, 2020.
(要約)
Fibrocytes, which are bone marrow-derived collagen-producing cells, were reported to play a role in the pathogenesis of pulmonary fibrosis. However, their function in pulmonary fibrosis is unclear. We analyzed their function compared with that of monocytes and localization in fibrotic tissues in patients with idiopathic pulmonary fibrosis (IPF). We compared the gene expression profile of monocyte-derived fibrocytes with that of monocytes by microarray analysis. Proliferation and differentiation into myofibroblasts were examined by 3H-thymidine incorporation assay and Western blotting. We measured the level of growth factors in the culture supernatant of fibrocytes by ELISA. The localization of fibrocytes in lung tissues of patients with IPF was determined by immunofluorescence staining. Compared with monocytes, fibrocytes had higher expression of extracellular matrix- and growth factor-encoding genes, including PDGF-B, FGF-2 and VEGF-B. Although fibrocytes did not proliferate in response to PDGF, co-culture of fibrocytes stimulated the growth of lung fibroblasts through the production of PDGF-BB. In the lung of IPF patients, CD45+Collagen-I+FSP-1+ cells, which have a similar phenotype to fibrocytes, were detected and co-stained with anti-PDGF antibody. This study suggested that fibrocytes function in pulmonary fibrosis partly by producing PDGF in the lungs of IPF patients. J. Med. Invest. 67 : 102-112, February, 2020.
Takeshi Imakura, Yuko Toyoda, Seidai Satou, Kazuya Koyama, Haruka Nishimura, Kozo Kagawa, Naoki Takahashi, Nobuhito Naito, Kojin Murakami, Hiroshi Kawano, Masahiko Azuma, Tsutomu Shinohara and Yasuhiko Nishioka : Distinct improvement of pulmonary function, ground-glass opacity, hypoxia and physical findings in an idiopathic pulmonary fibrosis patient after pirfenidone treatment : a case report with a review of the literature., The Journal of Medical Investigation : JMI, Vol.67, No.3.4, 358-361, 2020.
(要約)
Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients. J. Med. Invest. 67 : 358-361, August, 2020.
Akio Takezaki, Shin-ichi Tsukumo, Yasuhiro Setoguchi, G Julie Ledford, Hisatsugu Goto, Kazuyoshi Hosomichi, Hisanori Uehara, Yasuhiko Nishioka and Koji Yasutomo : A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis., The Journal of Experimental Medicine, Vol.216, No.12, 2724-2735, 2019.
(要約)
promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.
Takashi Ogura, Nagio Takigawa, Keisuke Tomii, Kazuma Kishi, Yoshikazu Inoue, Eiki Ichihara, Sakae Homma, Kazuhisa Takahashi, Hiroaki Akamatsu, Satoshi Ikeda, Naohiko Inase, Tae Iwasawa, Yuichiro Ohe, Hiromitsu Ohta, Hiroshi Onishi, Isamu Okamoto, Kazumasa Ogawa, Kazuo Kasahara, Hiroki Karata, Takumi Kishimoto, Yuka Kitamura, Akihiko Gemma, Hirotsugu Kenmotsu, Hiroyuki Sakashita, Susumu Sakamoto, Katsutoshi Sekine, Yuichi Takiguchi, Yuji Tada, Shinichi Toyooka, Yuko Nakayama, Yasuhiko Nishioka, Koichi Hagiwara, Masaki Hanibuchi, Junya Fukuoka, Yuji Minegishi, Toyoshi Yanagihara, Nobuyuki Yamamoto, Hiromasa Yamamoto, Mina Gaga, M Kwun Fong, A Charles Powell and Katsuyuki Kiura : Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia., Respiratory Investigation, Vol.57, No.6, 512-533, 2019.
(要約)
Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.
Akihiro Yoshimura, Tadaaki Yamada, Yusuke Okuma, Rui Kitadai, Takayuki Takeda, Takanori Kanematsu, Hisatsugu Goto, Hiroto Yoneda, Taishi Harada, Yutaka Kubota, Takahiro Yamada, Koji Date, Shinsuke Shiotsu, Kazuhiro Nagata, Yusuke Chihara, Yoshiko Kaneko, Junji Uchino, Yasuhiko Nishioka and Koichi Takayama : Retrospective analysis of docetaxel in combination with ramucirumab for previously treated non-small cell lung cancer patients., Translational Lung Cancer Research, Vol.8, No.4, 450-460, 2019.
(要約)
Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients.
M Toby Maher, Susanne Stowasser, Yasuhiko Nishioka, S Eric White, Vincent Cottin, Imre Noth, Moisés Selman, B Klaus Rohr, Andreas Michael, Carina Ittrich, Claudia Diefenbach and Gisli R Jenkins : Biomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): a randomised, placebo-controlled study., The Lancet. Respiratory Medicine, Vol.7, No.9, 771-779, 2019.
These results suggest that the β-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs.
In SLE cases, IP primarily occurred in male and elderly patients. In addition to the NSIP pattern, the UIP pattern was evident on HRCT scans of IP-related SLE. The survival of SLE patients was unrelated to IP.
(キーワード)
Adult / Age of Onset / Aged / Disease Progression / Female / Humans / Incidence / Lung Diseases, Interstitial / Lupus Erythematosus, Systemic / Male / Middle Aged / Retrospective Studies / Sex Factors / Tomography, X-Ray Computed / Young Adult
Kazuya Koyama, Hisatsugu Goto, Shun Morizumi, Kozo Kagawa, Haruka Nishimura, Seidai Satou, Hiroshi Kawano, Yuko Toyoda, Hirohisa Ogawa, Sakae Homma and Yasuhiko Nishioka : The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice., American Journal of Respiratory Cell and Molecular Biology, Vol.60, No.4, 478-487, 2019.
(要約)
The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.
Atsuro Saijo, Masaki Hanibuchi, Hirokazu Ogino, Kenji Otsuka, Hisatsugu Goto, Hiroshi Nokihara and Yasuhiko Nishioka : Paclitaxel for relapsed small-cell lung cancer patients with idiopathic interstitial pneumonias., Molecular and Clinical Oncology, Vol.10, No.5, 541-546, 2019.
(要約)
Although first-line chemotherapy is highly sensitive against small-cell lung cancer (SCLC), most patients subsequently experience disease progression. Topotecan is the standard therapy for sensitive-relapsed SCLC patients, and subgroup analysis of a randomized phase III trial suggests that amrubicin is effective for refractory-relapsed SCLC. However, because of the lack of the evidence based on clinical trials, the effectiveness of systemic chemotherapy for relapsed SCLC patients with idiopathic interstitial pneumonias (IIPs) is unclear. In the presentstudy, 17 relapsed SCLC patients with IIPs who received a paclitaxel (PTX)-containing regimen as a second-line chemotherapy were retrospectively reviewed. The overall response rate and the disease control rate of the PTX-containing regimens were 29.4 and 47.1%, respectively. The median progression-free survival and the overall survival of the regimens were 2.7 months [95% confidence interval (CI), 1.6-3.6 months] and 3.6 months (95% CI, 2.3-14.0 months), respectively. Grade 3-4 neutropenia and febrile neutropenia occurred in 12 (70.6%) and 2 (11.8%) patients, respectively. During the treatment period, acute exacerbation (AE) of IIPs was observed in five patients (29.4%). Treatment-associated fatality was observed in 1 patient with febrile neutropenia and in 1 patient with AE of IIPs. PTX had promising anti-tumor activity against refractory-relapsed SCLC with IIPs. However, the survival benefit of the treatment was limited because of the high incidence of AE of IIPs and treatment-related death.
Taichi Murakami, Masanori Tamaki, Seiji Kishi, Kojiro Nagai, Hideharu Abe, Yoshimi Bando, Yuko Toyoda, Hirokazu Ogino, Yasuhiko Nishioka, Sayo Ueda, Toshio Doi and Motokazu Matsuura : Systemic Sarcoidosis Presenting with Renal Involvement Caused by Various Sarcoidosis-associated Pathophysiological Conditions, Internal Medicine, Vol.58, No.5, 679-684, 2019.
(要約)
A 61-year-old man was diagnosed with sarcoidosis involving the lungs, eyes, parotid gland and extrathoracic lymph nodes complicated by chronic kidney injury and hypercalcemia. Kidney biopsy showed non-specific interstitial nephritis and nephrosclerosis. However, immunohistochemical staining of cell surface markers revealed a multinucleated giant macrophage surrounded by T-cells, suggesting granulomatous interstitial nephritis. Corticosteroid improved the kidney function, and reduced the serum levels of calcium and angiotensin-converting enzyme. Sarcoid nephropathy may be caused by the combination of several sarcoidosis-associated pathophysiological conditions and a comprehensive kidney examination should be performed to assess the type of injury when determining a treatment strategy.
Hirokazu Ogino, Masaki Hanibuchi, Satoshi Sakaguchi, Yuko Toyoda, Toshifumi Tezuka, Hiroshi Kawano, Soji Kakiuchi, Kenji Otsuka, Atsuro Saijo, Masahiko Azuma, Hiroshi Nokihara, Hisatsugu Goto and Yasuhiko Nishioka : The clinical features of older patients with lung cancer in comparison with their younger counterparts., Respiratory Investigation, Vol.57, No.1, 40-48, 2019.
(要約)
We should positively consider standard treatments for older patients. However, not only their shorter life expectancy but also their poor PS and multiple comorbidities that sometimes render patients unable to receive standard treatments and several chemotherapy regimens, make their prognosis poor. The standard treatments for older patients, especially in locally advanced stages, require modification.
Masami Kishi, Yoshinori Aono, Seidai Satou, Kazuya Koyama, Momoyo Azuma, Shuichi Abe, Hiroshi Kawano, Jun Kishi, Yuko Toyoda, Hiroyasu Okazaki, Hirohisa Ogawa, Hisanori Uehara and Yasuhiko Nishioka : Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice., PLoS ONE, Vol.13, No.12, 2018.
(要約)
Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of pulmonary fibrosis. Nintedanib, a multi-kinase inhibitor that targets several tyrosine kinases, including PDGF receptor (PDGFR), was recently approved as an anti-fibrotic agent to reduce the deterioration of FVC in patients with idiopathic pulmonary fibrosis (IPF). However, the effects of PDGFR-α or -β on pulmonary fibrosis remain unclear. In an attempt to clarify their effects, we herein used blocking antibodies specific for PDGFR-α (APA5) and -β (APB5) in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. The effects of these treatments on the growth of lung fibroblasts were examined using the 3H-thymidine incorporation assay in vitro. The anti-fibrotic effects of these antibodies were investigated with the Ashcroft score and collagen content of lungs treated with BLM. Their effects on inflammatory cells in the lungs were also analyzed using bronchoalveolar lavage fluid. We investigated damage to epithelial cells and the proliferation of fibroblasts in the lungs. APA5 and APB5 inhibited the phosphorylation of PDGFR-α and -β as well as the proliferation of lung fibroblasts induced by PDGF-AA and BB. The administration of APB5, but not APA5 effectively inhibited BLM-induced pulmonary fibrosis in mice. Apoptosis and the proliferation of epithelial cells and fibroblasts were significantly decreased by the treatment with APB5, but not by APA5. The late treatment with APB5 also ameliorated fibrosis in lungs treated with BLM. These results suggest that PDGFR-α and -β exert different effects on BLM-induced pulmonary fibrosis in mice. A specific approach using the blocking antibody for PDGFR-β may be useful for the treatment of pulmonary fibrosis.
Hirohisa Ogawa, Masahiko Azuma, Takaaki Tsunematsu, Yuuki Morimoto, Mayo Kondo, Toshifumi Tezuka, Yasuhiko Nishioka and Koichi Tsuneyama : Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation., Clinical and Experimental Allergy, Vol.48, No.12, 1715-1725, 2018.
(要約)
The IL-17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.
Masaki Hanibuchi, Soji Kakiuchi, Shinji Atagi, Fumitaka Ogushi, Eiji Shimizu, Takashi Haku, Yuko Toyoda, Masahiko Azuma, Mayo Kondo, Hiroshi Kawano, Kenji Otsuka, Satoshi Sakaguchi, Hiroshi Nokihara, Hisatsugu Goto and Yasuhiko Nishioka : A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non-small cell lung cancer patients with interstitial lung disease., Lung Cancer, Vol.125, 93-99, 2018.
(要約)
A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m
M Toby Maher, Susanne Stowasser, Yasuhiko Nishioka, S Eric White, Vincent Cottin, Imre Noth, Moisés Selman, Zuzana Blahova, Daniel Wachtlin, Claudia Diefenbach and Gisli R Jenkins : Investigating the effects of nintedanib on biomarkers of extracellular matrix turnover in patients with IPF: design of the randomised placebo-controlled INMARK®trial., BMJ Open Respiratory Research, Vol.5, No.1, e000325, 2018.
(要約)
The INMARK® trial is evaluating the effect of nintedanib on the rates of change of biomarkers of ECM turnover in patients with IPF, the value of changes in these biomarkers as predictors of disease progression and whether nintedanib affects the associations between changes in these biomarkers and disease progression. Following a screening period, 347 patients with IPF and FVC ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg two times a day or placebo for 12 weeks, followed by an open-label period in which all patients will receive nintedanib for 40 weeks. The primary endpoint is the rate of change in C reactive protein degraded by MMP-1/8 from baseline to week 12.
Rao Rajeswara Arasada, Konstantin Shilo, Tadaaki Yamada, Jianying Zhang, Seiji Yano, Rashelle Ghanem, Walter Wang, Shinji Takeuchi, Koji Fukuda, Nobuyuki Katakami, Keisuke Tomii, Fumitaka Ogushi, Yasuhiko Nishioka, Tiffany Talabere, Shrilekha Misra, Wenrui Duan, Paolo Fadda, A Mohammad Rahman, Patrick Nana-Sinkam, Jason Evans, Joseph Amann, E Elena Tchekneva, M Mikhail Dikov and P David Carbone : Notch3-dependent -catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC., Nature Communications, Vol.9, No.1, 3198, 2018.
(要約)
EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of -catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which -catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of -catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call "adaptive persisters". We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with -catenin, leading to increased stability and activation of -catenin. We demonstrate that the combination of EGFR-TKI and a -catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and -catenin inhibition in patients with EGFR mutant lung cancer.
Mayo Kondo, Hirokazu Ogino, Hirohisa Ogawa, Tania Afroj, Yuko Toyoda, Satoshi Sakaguchi, Miki Tsuboi, Yoshimi Bando, Hisatsugu Goto, Koichi Tsuneyama and Yasuhiko Nishioka : A case of pulmonary pleomorphic carcinoma with malignant phenotypes induced by ZEB1-associated epithelial-mesenchymal transition., Respiratory Medicine Case Reports, Vol.25, 119-121, 2018.
(要約)
A 60-year-old man was admitted to our hospital with non-small cell lung cancer (NSCLC). Imaging and pathological studies revealed NSCLC, not otherwise specified (NOS), at clinical stage T3N1M0 stage IIIA. We started radiotherapy alone because of obstructive pneumonia and end-stage renal disease, but the tumors progressed rapidly and resulted in death due to air obstruction by pharyngeal metastasis. The cancer was diagnosed as pleomorphic carcinoma in an autopsy. Viable lung tumor cells, which were resistant to radiotherapy, and the pharyngeal metastasis had mesenchymal phenotypes and expressed ZEB1 but not SNAI1. These observations indicated that ZEB1-associated epithelial-mesenchymal transition has malignant features including resistance to radiotherapy and aggressive metastatic potential. ZEB1-associated EMT may be an important mechanism to understand the pathophysiology of pleomorphic carcinoma.
Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.
(キーワード)
Acetylcysteine / Administration, Inhalation / Adrenal Cortex Hormones / Antineoplastic Combined Chemotherapy Protocols / Comorbidity / Disease Progression / Drug Therapy, Combination / Evidence-Based Medicine / Glycine / Humans / Idiopathic Pulmonary Fibrosis / Immunosuppressive Agents / Indoles / Japan / Lung Neoplasms / Meta-Analysis as Topic / Practice Guidelines as Topic / Prognosis / Pyridones / Quality of Health Care / Sulfonamides / Survival Rate
Seiji Kishi, Masanori Minato, Atsuro Saijo, Naoka Murakami, Masanori Tamaki, Motokazu Matsuura, Taichi Murakami, Kojiro Nagai, Hideharu Abe, Yasuhiko Nishioka and Toshio Doi : IgA Nephropathy after Nivolumab Therapy for Postoperative Recurrence of Lung Squamous Cell Carcinoma., Internal Medicine, Vol.57, No.9, 1259-1263, 2018.
(要約)
Immune checkpoint inhibitors (ICIs) are becoming a common and important cancer therapy. ICIs are associated with a unique category of side effects, termed immune-related adverse events (irAEs). We herein report the case of a 72-year-old man with postoperative recurrence of lung squamous cell carcinoma who was treated with nivolumab and who developed proteinuria and a worsening kidney function. A kidney biopsy revealed IgA nephropathy. After drug withdrawal, the proteinuria improved and the deterioration of the patient's renal function was halted. Although renal irAEs are considered to be rare and glomerulonephritis is not typical presentation, physicians need to pay more attention to renal irAEs and glomerular injury.
Atsuro Saijo, Hisatsugu Goto, Nakano Mayuri, Mitsuhashi Atsushi, Yoshinori Aono, Masaki Hanibuchi, Hirohisa Ogawa, Hisanori Uehara, Kazuya Kondo and Yasuhiko Nishioka : Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells., Cancer Letters, Vol.421, 17-27, 2018.
(要約)
Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches.
Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP-induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling.
Hiroyuki Kozai, Yuko Toyoda, Hisatsugu Goto, Jun Kishi, Makoto Tobiume, Yuya Yamashita, Haruka Nishimura, Mayo Kondou, Hiroshi Kawano and Yasuhiko Nishioka : A case of interstitial pneumonia associated with anti-PL-7 antibody in a patient with rheumatoid arthritis., The Journal of Medical Investigation : JMI, Vol.65, No.1,2, 147-150, 2018.
(要約)
A 65-year-old female had been treated rheumatoid arthritis (RA), interstitial pneumonia (IP) and nephrotic syndrome with prednisolone and cyclosporine. She was emergently admitted to our hospital due to the worsening exertional dyspnea and severe hypoxemia. Chest computed tomography (CT) showed new diffuse ground-glass opacities (GGOs) with slight consolidations along with bronchovascular bundle were observed in addition to pre-existing reticular shadows in both lungs with lower lobe-predominance. An acute exacerbation (AE) of pre-existing IP triggered by an infection was suspected, and the treatment with antibiotics and corticosteroid pulse therapy improved her general condition and chest radiological findings. Because some auto-antibodies associated with acute/subacute onset IP have recently become available in clinic, we examined those including anti-aminoacyl tRNA synthetase (ARS) antibodies, and found that she was positive for anti-PL-7 antibody. We diagnosed her anti-synthetase syndrome (ASS) without symptom of myositis, and her IP was considered to be ASS-related. The careful consideration is necessary to precisely diagnose and treat the patients with RA-associated interstitial lung diseases as the several etiologies may be overlapped in the same patient. J. Med. Invest. 65:147-150, February, 2018.
Hitoshi Nishijima, Tatsuya Kajimoto, Yoshiki Matsuoka, Yasuhiro Mouri, Junko Morimoto, Minoru Matsumoto, Hiroshi Kawano, Yasuhiko Nishioka, Hisanori Uehara, Keisuke Izumi, Koichi Tsuneyama, Il-mi Okazaki, Taku Okazaki, Kazuyoshi Hosomichi, Ayako Shiraki, Makoto Shibutani, Kunitoshi Mitsumori and Mitsuru Matsumoto : Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)., Journal of Autoimmunity, Vol.86, 75-92, 2018.
(要約)
Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire.
Hisatsugu Goto, Okano Yoshio, Machida Hisanori, Hatakeyama Nobuo, Ogushi Fumitaka, Haku Takashi, Takanori Kanematsu, Tomoyuki Urata, Souji Kakiuchi, Masaki Hanibuchi, Saburo Sone and Yasuhiko Nishioka : Phase II study of tailored S-1 monotherapy with a 1-week interval after a 2-week dosing period in elderly patients with advanced non-small cell lung cancer., Respiratory Investigation, Vol.56, No.1, 80-86, 2018.
(要約)
S-1 is an oral fluoropyrimidine that is active in the treatment of non-small cell lung cancer (NSCLC); however, an optimal treatment schedule and appropriate dose adjustments of S-1 in elderly patients have not yet been established. We conducted a phase II trial to evaluate the efficacy and safety of a 2-week S-1 monotherapy treatment followed by a 1-week interval as a first-line treatment of elderly NSCLC patients, by adjusting the dose based on the individual creatinine clearance (Ccr) and body surface area (BSA). The primary endpoint was the disease control rate. Forty patients were enrolled. The disease control and response rates were 89.5% (95% confidence interval [CI] = 79.8-99.2) and 7.9% (95% CI = 0.0-16.4), respectively. The median progression-free survival and overall survival times were 4.4 months (95% CI = 4.2-8.5) and 17.0 months (95% CI = 11.2-18.7), respectively. Neutropenia, anorexia, hyponatremia, hypokalemia, and pneumonia of grade ≥ 3 occurred in 5.0%, 7.5%, 5.0%, 2.5%, and 2.5% of patients, respectively. Among the patient-reported outcomes, most of the individual factors in the patients' quality of life, including upper intestine-related symptoms improved with the treatment, except for dyspnea, which slightly albeit continuously worsened throughout the study. In elderly patients with previously untreated advanced NSCLC, a 2-week S-1 monotherapy treatment, tailored to both the Ccr and BSA, with a 1-week interval was well tolerated and demonstrated promising efficacy. This study was registered at the University Hospital Medical Information Network (UMIN) Center (ID: UMIN000002035), Japan.
(キーワード)
Administration, Oral / Aged / Aged, 80 and over / Antimetabolites, Antineoplastic / Body Surface Area / Carcinoma, Non-Small-Cell Lung / Creatinine / Drug Administration Schedule / Drug Combinations / Female / Humans / Lung Neoplasms / Male / Metabolic Clearance Rate / Oxonic Acid / Precision Medicine / Survival Rate / Tegafur / Treatment Outcome
Chikugo Momoko, Sebe Mayu, Rie Tsutsumi, Iuchi Marina, Jun Kishi, Masashi Kuroda, Nagakatsu Harada, Yasuhiko Nishioka and Hiroshi Sakaue : Effect of Janus kinase inhibition by tofacitinib on body composition and glucose metabolism., The Journal of Medical Investigation : JMI, Vol.65, No.3.4, 166-170, 2018.
(要約)
Tofacitinib is the first Janus Kinase (JAK) inhibitor to treat moderately to severely active RA. In this study, we investigated whether the effect of tofacitinib have any effects on body composition in mice and female patients with RA. Female C57BL/6 mice fed with a high-fat diet were treated with 30 mg/kg/day tofacitinib or vehicle for 70 days. Following treatment, trunk muscle, subcutaneous fat, and visceral fats were measured using X-ray computed tomography CT scan. Glucose tolerance and insulin sensitivity were assessed. In female RA patients treated with biological disease modified anti-rheumatic-drugs (biological DMARDs) or tofacitinib (n=4 per group), we also evaluated the body composition after 3 months from the start of treatment initiation using bioelectrical impedance analysis. Treatment with tofacitinib did not affect the body weight, and body composition in C57BL/6 mice. It also did not affect glucose, and insulin tolerance in mice. In patients with RA, treatment with biological DMARDs did not affect the body composition whereas the muscle mass was unchanged after receiving tofacitinib and the fat mass was significantly increased. J. Med. Invest. 65:166-170, August, 2018.
Seidai Satou, Shinohara Shintaro, Hayashi Shinya, Morizumi Shun, Abe Shuichi, Okazaki Hiroyasu, Chen Yanjuan, Hisatsugu Goto, Yoshinori Aono, Hirohisa Ogawa, Koyama Kazuya, Nishimura Haruka, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara and Yasuhiko Nishioka : Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity., Respiratory Research, Vol.18, No.1, 172, 2017.
(要約)
Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear. Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin. Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects. These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.
(キーワード)
Animals / Cell Movement / Cells, Cultured / Dose-Response Relationship, Drug / Fibroblasts / Humans / Indoles / Male / Mice / Mice, Inbred C57BL / Pulmonary Fibrosis / Treatment Outcome / Vascular Endothelial Growth Factor A
Thymidine phosphorylase (TP), a rate-limiting enzyme in thymidine catabolism, plays a pivotal role in tumor progression; however, the mechanisms underlying this role are not fully understood. Here, we found that TP-mediated thymidine catabolism could supply the carbon source in the glycolytic pathway and thus contribute to cell survival under conditions of nutrient deprivation. In TP-expressing cells, thymidine was converted to metabolites, including glucose 6-phosphate, lactate, 5-phospho-α-D-ribose 1-diphosphate, and serine, via the glycolytic pathway both in vitro and in vivo. These thymidine-derived metabolites were required for the survival of cells under low-glucose conditions. Furthermore, activation of thymidine catabolism was observed in human gastric cancer. These findings demonstrate that thymidine can serve as a glycolytic pathway substrate in human cancer cells.
Mika K Kaneko, Shinji Yamada, Takuro Nakamura, Shinji Abe, Yasuhiko Nishioka, Akiko Kunita, Masashi Fukayama, Yuki Fujii, Satoshi Ogasawara and Yukinari Kato : Antitumor activity of chLpMab-2, a human-mouse chimeric cancer-specific antihuman podoplanin antibody, via antibody-dependent cellular cytotoxicity., Cancer Medicine, Vol.6, No.4, 768-777, 2017.
(要約)
Human podoplanin (hPDPN), a platelet aggregation-inducing transmembrane glycoprotein, is expressed in different types of tumors, and it binds to C-type lectin-like receptor 2 (CLEC-2). The overexpression of hPDPN is involved in invasion and metastasis. Anti-hPDPN monoclonal antibodies (mAbs) such as NZ-1 have shown antitumor and antimetastatic activities by binding to the platelet aggregation-stimulating (PLAG) domain of hPDPN. Recently, we developed a novel mouse anti-hPDPN mAb, LpMab-2, using the cancer-specific mAb (CasMab) technology. In this study we developed chLpMab-2, a human-mouse chimeric anti-hPDPN antibody, derived from LpMab-2. chLpMab-2 was produced using fucosyltransferase 8-knockout (KO) Chinese hamster ovary (CHO)-S cell lines. By flow cytometry, chLpMab-2 reacted with hPDPN-expressing cancer cell lines including glioblastomas, mesotheliomas, and lung cancers. However, it showed low reaction with normal cell lines such as lymphatic endothelial and renal epithelial cells. Moreover, chLpMab-2 exhibited high antibody-dependent cellular cytotoxicity (ADCC) against PDPN-expressing cells, despite its low complement-dependent cytotoxicity. Furthermore, treatment with chLpMab-2 abolished tumor growth in xenograft models of CHO/hPDPN, indicating that chLpMab-2 suppressed tumor development via ADCC. In conclusion, chLpMab-2 could be useful as a novel antibody-based therapy against hPDPN-expressing tumors.
Mika K Kaneko, Takuro Nakamura, Ryusuke Honma, Satoshi Ogasawara, Yuki Fujii, Shinji Abe, Michiaki Takagi, Hiroyuki Harada, Hiroyoshi Suzuki, Yasuhiko Nishioka and Yukinari Kato : Development and characterization of anti-glycopeptide monoclonal antibodies against human podoplanin, using glycan-deficient cell lines generated by CRISPR/Cas9 and TALEN., Cancer Medicine, Vol.6, No.2, 382-396, 2017.
(要約)
Human podoplanin (hPDPN), which binds to C-type lectin-like receptor-2 (CLEC-2), is involved in platelet aggregation and cancer metastasis. The expression of hPDPN in cancer cells or cancer-associated fibroblasts indicates poor prognosis. Human lymphatic endothelial cells, lung-type I alveolar cells, and renal glomerular epithelial cells express hPDPN. Although numerous monoclonal antibodies (mAbs) against hPDPN are available, they recognize peptide epitopes of hPDPN. Here, we generated a novel anti-hPDPN mAb, LpMab-21. To characterize the hPDPN epitope recognized by the LpMab-21, we established glycan-deficient CHO-S and HEK-293T cell lines, using the CRISPR/Cas9 or TALEN. Flow cytometric analysis revealed that the minimum hPDPN epitope, in which sialic acid is linked to Thr76, recognized by LpMab-21 is Thr76-Arg79. LpMab-21 detected hPDPN expression in glioblastoma, oral squamous carcinoma, and seminoma cells as well as in normal lymphatic endothelial cells. However, LpMab-21 did not react with renal glomerular epithelial cells or lung type I alveolar cells, indicating that sialylation of hPDPN Thr76 is cell-type-specific. LpMab-21 combined with other anti-hPDPN antibodies that recognize different epitopes may therefore be useful for determining the physiological function of sialylated hPDPN.
Atsuro Saijo, Masaki Hanibuchi, Hisatsugu Goto, Yuko Toyoda, Toshifumi Tezuka and Yasuhiko Nishioka : An analysis of the clinical features of lung cancer in patients with connective tissue diseases., Respiratory Investigation, Vol.55, No.2, 153-160, 2017.
(要約)
LC patients with CTD had a high prevalence of ILD, and the presence of CTD-ILD was significantly associated with poor prognosis.
Yoshiyuki Oyama, Noriyuki Enomoto, Yuzo Suzuki, Masato Kono, Tomoyuki Fujisawa, Naoki Inui, Yutaro Nakamura, Shigeki Kuroishi, Koshi Yokomura, Mikio Toyoshima, Shiro Imokawa, Keiji Oishi, Satoshi Watanabe, Kazuo Kasahara, Tomohisa Baba, Takashi Ogura, Hiroshi Ishii, Kentaro Watanabe, Yasuhiko Nishioka and Takafumi Suda : Evaluation of urinary desmosines as a noninvasive diagnostic biomarker in patients with idiopathic pleuroparenchymal fibroelastosis (PPFE)., Respiratory Medicine, Vol.123, 63-70, 2016.
(要約)
Levels of urinary desmosines were significantly higher in patients with PPFE than those in patients with IPF (48.4 vs. 28.6 ng/mg creatinine, p = 0.034), patients with COPD (8.0 ng/mg creatinine, p < 0.001), or controls (17.4 ng/mg creatinine, p < 0.001). Desmosines discriminated between PPFE and IPF (area under the curve [AUC] = 0.708), and between PPFE and controls (AUC = 0.956). However, levels of desmosines were not correlated with physiological parameters in patients with PPFE.
Soji Kakiuchi, Masaki Hanibuchi, Toshifumi Tezuka, Atsuro Saijo, Kenji Otsuka, Satoshi Sakaguchi, Yuko Toyoda, Hisatsugu Goto, Hiroshi Kawano, Masahiko Azuma, Fumitaka Ogushi and Yasuhiko Nishioka : Analysis of acute exacerbation of interstitial lung disease associated with chemotherapy in patients with lung cancer: A feasibility of S-1., Respiratory Investigation, Vol.55, No.2, 145-152, 2016.
(要約)
Although this was a small retrospective study, its findings showed that S-1 and etoposide may be relatively safe options for the treatment of patients with lung cancer and concomitant ILD.
Yuko Toyoda, Ryohiko Ozaki, Jun Kishi, Masaki Hanibuchi, Katsuhiro Kinoshita, Toshifumi Tezuka, Hisatsugu Goto, Hiroyuki Ono, Kojiro Nagai, Yoshimi Bando, Toshio Doi and Yasuhiko Nishioka : An Autopsy Case of Aortic Intimal Sarcoma Initially Diagnosed as Polyarteritis Nodosa., Internal Medicine, Vol.55, No.21, 3191-3195, 2016.
(要約)
A 61-year-old man had hypertension with stenosis in the left renal artery. When his fever, abdominal pain, and renal dysfunction progressed, he was admitted to our hospital. He was diagnosed with polyarthritis nodosa. His renal function rapidly deteriorated despite immunosuppressive therapy. His digestive tract perforated twice, and he subsequently died. An autopsy revealed that aortic intimal sarcoma caused stenosis in multiple arteries. Both polyarteritis nodosa and aortic intimal sarcoma are very rare diseases and the diagnoses are very difficult. It is very important to consider these entities when making a differential diagnosis of vasculitis.
Yasuhiko Nishioka : Cancer immunotherapy as a promising fourth standard therapy for lung cancer: Beyond 20 years for the development of immunotherapy, Respiratory Investigation, Vol.54, No.5, 297, 2016.
Hirokazu Ogino, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Toshifumi Tezuka, Yuko Toyoda, Makoto Tobiume, Kenji Otsuka, Satoshi Sakaguchi, Hisatsugu Goto, Kokichi Arisawa and Yasuhiko Nishioka : Analysis of the prognostic factors of extensive disease small-cell lung cancer patients in Tokushima University Hospital, The Journal of Medical Investigation : JMI, Vol.63, No.3 4, 286-293, 2016.
(要約)
Small-cell lung cancer (SCLC) presents aggressive clinical behavior, and its prognosis is still poor. Previously, performance status (PS), or the existence of brain, bone, or liver metastasis were reported to be unfavorable prognostic factors. Given the recent progress of treatment modalities such as radiotherapy techniques and bone modifying agents, the prognostic factors might be different from previous findings. Therefore, we analyzed the prognostic factors of extensive disease SCLC (ED-SCLC) in recent years. ED-SCLC patients treated in Tokushima University Hospital between 2010 and 2016 were analyzed. Log-rank test and the Cox proportional hazards regression model was used in univariate and multivariate analysis, respectively. Totally, 79 patients were analyzed. In the univariate analysis, age, PS, interstitial pneumonia (IP), liver metastasis, pleural dissemination, neutrophil counts, hypoalbuminemia, hypercalcemia and several liver and biliary enzymes were identified as poor prognostic factors. In the multivariate analysis, age, PS, IP, and liver and biliary enzymes were identified. Moreover, the PS in patients with liver metastasis was significantly worsened. In this study, we newly demonstrated that IP was a significant poor prognostic factor of ED-SCLC. Although liver metastasis was not extracted in multivariate analysis, it may have an impact on the prognosis of ED-SCLC. J. Med. Invest. 63: 286-293, August, 2016.
K Hasegawa, M Tagawa, K Takagi, H Tsukamoto, Y Tomioka, T Suzuki, Yasuhiko Nishioka, T Ohrui and M Numasaki : Anti-tumor immunity elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1., Cancer Gene Therapy, Vol.23, No.8, 266-277, 2016.
(要約)
Interleukin (IL)-28A/interferon (IFN)-λ2 and IL-29/IFN-λ1 have been demonstrated to elicit direct and indirect anti-tumor actions. In this study, we constructed an adenovirus vector expressing either IL-28A/IFN-λ2 (AdIL-28A) or IL-29/IFN-λ1 (AdIL-29) to evaluate the therapeutic properties of intratumoral injection of recombinant adenovirus to apply for the clinical implementation of cancer gene therapy. Despite the lack of an anti-proliferative effect on MCA205 and B16-F10 cells, a retarded growth of established subcutaneous tumors was observed following multiple injections of either AdIL-28A or AdIL-29 when compared with AdNull. In vivo cell depletion experiments displayed that both NK cells and CD8(+) T cells have a major role in AdIL-28A-mediated tumor growth suppression. A significant increase in the number of infiltrating CD8(+) T cells into the tumors treated with either AdIL-28A or AdIL-29 was observed. Moreover, specific anti-tumor cytotoxic T lymphocyte reactivity was detected in spleen cells from animals treated with either AdIL-28A or AdIL-29. In IFN-γ-deficient mice, anti-tumor activities of AdIL-28A were completely impaired, indicating that IFN-γ is critically involved in the tumor growth inhibition triggered by AdIL-28A. IL-12 provided a synergistic anti-tumor effect when combined with AdIL-28A. These results indicate that AdIL-28A and AdIL-29 could be successfully utilized as an alternative cancer immunogene therapy.
Yuko Toyoda, Masaki Hanibuchi, Jun Kishi, Hiroshi Kawano, Shun Morizumi, Seidai Satou, M Kondo, Terumi Takikura, Toshifumi Tezuka, Hisatsugu Goto and Yasuhiko Nishioka : Clinical features and outcome of acute exacerbation of interstitial pneumonia associated with connective tissue disease., The Journal of Medical Investigation : JMI, Vol.63, No.3,4, 294-299, 2016.
(要約)
Acute exacerbation (AE) of interstitial lung disease is reported to be developed in not only idiopathic pulmonary fibrosis but also connective tissue disease-associated interstitial pneumonia (CTD-IP). As the significance of AE of CTD-IP has not been so widely recognized, its clinical feature is not fully elucidated. In the present study, we investigated the incidence, clinical features and outcome of AE of CTD-IP. We retrospectively reviewed admitted cases in our department with medical record from 2011 to 2015. Among 155 patients with CTD-IP, 10 (6.5%) cases developed AE (6 rheumatoid arthritis, 2 polymyositis/dermatomyositis, 1 systemic lupus erythematosus, 1 Sjögren syndrome), and one died of AE within 30 days. Median survival time after the onset of AE was 169 days in all 10 patients. The treatment with immunosuppressant just before AE onset might improve the prognosis of AE. The median survival time after the onset of AE was significantly longer in patients showing good response to corticosteroid compared with those with poor response to corticosteroid (805 days and 45 days, respectively) (p <0.05), suggesting that there are some cases in CTD-IP, showing the good response to corticosteroid even when AE was complicated. J. Med. Invest. 63: 294-299, August, 2016.
Seidai Satou, Masaki Hanibuchi, Takahashi Mikiko, Fukuda Yuh, Morizumi Shun, Yuko Toyoda, Hisatsugu Goto and Yasuhiko Nishioka : A patient with idiopathic pleuroparenchymal fibroelastosis showing a sustained pulmonary function due to treatment with pirfenidone, Internal Medicine, Vol.55, No.5, 497-501, 2016.
(要約)
The patient was a 68-year-old man presenting with body weight loss and exertional dyspnea. High-resolution computed tomography of the chest showed dense subpleural consolidation with traction bronchiectasis and volume loss predominantly in bilateral apical lesions and upper lobes. A histopathological analysis of a specimen of the right upper lobe showed histological patterns which were consistent with idiopathic pleuroparenchymal fibroelastotis (IPPFE). Treatment with pirfenidone was introduced with the expectation of its potential benefit. The effect of pirfenidone was satisfactory, and a decline in forced vital capacity was inhibited during treatment. This is the first case report suggesting the efficacy of pirfenidone for patients with IPPFE.
A 54-year-old man was referred to our hospital due to a mass shadow noted on a chest X-ray. Thoracoscopic lobectomy yielded a diagnosis of primary pulmonary synovial sarcoma according to the histology and SYT-SSX1 gene analyses. Five months after the thoracic surgery, he developed brain metastasis; therefore, we performed resection of the brain metastatic focus followed by radiotherapy. As a local recurrence in the thoracic cavity concurrently emerged, systemic chemotherapy was also administered. These observations indicated that a multidisciplinary approach may be useful against primary pulmonary synovial sarcoma, although there is presently no established therapeutic strategy due to its rarity and highly aggressive nature.
Muneo Numasaki, Hiroki Tsukamoto, Yoshihisa Tomioka, Yasuhiko Nishioka and Takashi Ohrui : A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells., The Tohoku Journal of Experimental Medicine, Vol.240, No.1, 47-56, 2016.
(要約)
The interleukin (IL)-17 family, consisting of six homodimeric cytokines IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F, mediates a variety of biological activities including regulation of chemokine secretion and angiogenesis. Among the IL-17 family members, IL-17A and IL-17E/IL-25 are angiogenesis stimulators, while IL-17B and IL-17F are angiogenesis inhibitors. Recently, IL-17A/F heterodimer, comprised of the IL-17A and IL-17F subunits, was found as another member of the IL-17 cytokine family. However, to date, it has been unknown whether IL-17A/F has biological actions to affect the angiogenesis-related vascular endothelial functions. Therefore, in this study, we investigated the biological effects of IL-17A/F on the growth, migration and capillary-like tube formation of vascular endothelial cells. Recombinant IL-17A/F protein had no direct effects on the growth of human dermal microvascular endothelial cells (HMVECs), whereas, after 4-hour incubation in a modified Boyden Chemotaxicell chamber, IL-17A/F significantly induced migration of HMVECs over a wide range of doses via the phosphatidylinositol-3 kinase (PI3K) signaling pathway. We further investigated the biological effect of IL-17A/F on capillary-like tube formation using a co-culture system of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs), which mimicked the in vivo microenvironment. In this co-culture system, IL-17A/F significantly promoted capillary-like endothelial tube formation in a dose-dependent fashion via the PI3K and extracellular signal-regulated kinase (ERK) signaling pathways. Additionally, IL-17A/F up-regulated secretion of angiogenic growth factors such as IL-8 and growth-related oncogene (GRO)-α by HDFs. These findings identify a novel biological function for IL-17A/F as an indirect angiogenic agent.
A 27-year-old female was referred to our hospital for further examination of hoarseness, cough, and hemoptysis. Positron emission tomography-computed tomography revealed FDG accumulation in a huge mass in the left lower lobe, lymph nodes in the hilum, mediastinum and right cervical lesion left scapula and vertebral body. Further examination yielded the diagnosis of primary lung adenocarcinoma (cT2aN3M1b : Stage IV) harboring the anaplastic lymphoma kinase (ALK) fusion oncogene. Although her general condition was getting worse due to rapid increase of the pleural effusion, crizotinib promptly diminish the pleural effusion and ameliorated the patient's condition. The adverse events of crizotinib, such as nausea, vomiting and visual disturbance, were generally mild and well tolerable during treatment. These findings suggest that crizotinib is a promising candidate for ALK-positive non-small cell lung cancer patients even with poor performances.
(キーワード)
crizotinib / anaplastic lymphoma kinase / non-small cell lung cancer / performance status
Mitsuhashi Atsushi, Hisatsugu Goto, Atsuro Saijo, Trung The Van, Yoshinori Aono, Hirokazu Ogino, Kuramoto Takuya, Tabata Sho, Hisanori Uehara, Keisuke Izumi, Mitsuteru Yoshida, Kobayashi Hiroaki, Takahashi Hidefusa, Gotoh Masashi, Kakiuchi Soji, Masaki Hanibuchi, Seiji Yano, Yokomise Hiroyasu, Shoji Sakiyama and Yasuhiko Nishioka : Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab, Nature Communications, Vol.6, 8792, 2015.
(要約)
Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy.
Hiroshi Kawano, Hitoshi Nishijima, Junko Morimoto, Fumiko Hirota, Ryoko Morita, Yasuhiro Mouri, Yasuhiko Nishioka and Mitsuru Matsumoto : Aire expression is inherent to most medullary thymic epithelial cells during their differentiation program., The Journal of Immunology, Vol.195, No.11, 5149-5158, 2015.
(要約)
Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire+ mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor knockin mice in which long-term ablation of Aire+ mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs.
K Fukushima, S Nakamura, Y Inoue, Y Higashiyama, M Ohmichi, T Ishida, K Yoshimura, T Sawai, N Takayanagi, C Nakahama, T Kakugawa, K Izumikawa, N Aoki, Yasuhiko Nishioka, O Kosaka and S Kohno : Utility of a sputum antigen detection test in pneumococcal and lower respiratory infectious disease in adults, Internal Medicine, Vol.54, No.22, 2843-2850, 2015.
(要約)
To compare the utility of Gram staining, a urinary antigen detection kit and a sputum antigen detection kit were examined for the rapid and early detection of pneumococcal pneumonia and lower respiratory infectious diseases. A newly developed sputum pneumococcal antigen detection kit (RAPIRUN), Gram staining, and urinary antigen detection kit (BinaxNOW) were comparatively evaluated for their ability to detect Streptococcus pneumoniae in patients with pneumonia or lower respiratory tract infection. Sputum culture results were used as a standard for comparison. Furthermore, the pneumococcus-positive rates in culture and rapid tests were compared using polymerase chain reaction (PCR) as a reference. Of the 169 patients studied, 54 (32.0%) tested positive for S. pneumoniae in culture. S. pneumoniae detection sensitivities for Gram staining, RAPIRUN, and BinaxNOW were 75.9%, 90.7%, and 53.7%, respectively; thus, RAPIRUN had a significantly higher sensitivity than BinaxNOW (p<0.001). For patients with ≥10(5) copies/μg of pneumococcal surface protein A DNA PCR analysis, the detection rates of culture, Gram staining, and RAPIRUN were 85.2%, 72.1%, and 82.0%, respectively, however, the detection rate of BinaxNOW was only 47.5%. Comparisons among 45 patients with culture-positive pneumococcal pneumonia revealed that RAPIRUN had a significantly higher detection rate than BinaxNOW in the mild cases (p<0.006), regardless of the number of days from onset (p<0.03). RAPIRUN is a rapid testing kit that detects S. pneumoniae in sputum with a high sensitivity and specificity. It is a particularly more useful detection kit than BinaxNOW for early and mild community-acquired pneumonia in pre-treatment patients whose sputum specimens can be obtained.
Yukinari Kato, Akiko Kunita, Shinji Abe, Satoshi Ogasawara, Yuki Fujii, Hiroharu Oki, Masashi Fukayama, Yasuhiko Nishioka and Mika K. Kaneko : The chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its neutralizing activity, Oncotarget, Vol.6, No.34, 36003-36018, 2015.
(要約)
Podoplanin (PDPN/Aggrus/T1α) binds to C-type lectin-like receptor-2 (CLEC-2) and induces platelet aggregation. PDPN is associated with malignant progression, tumor metastasis, and poor prognosis in several types of cancer. Although many anti-human PDPN (hPDPN) monoclonal antibodies (mAbs), such as D2-40 and NZ-1, have been established, these epitopes are limited to the platelet aggregation-stimulating (PLAG) domain (amino acids 29-54) of hPDPN. Recently, we developed a novel mouse anti-hPDPN mAb, LpMab-7, which is more sensitive than D2-40 and NZ-1, using the Cancer-specific mAb (CasMab) method. The epitope of LpMab-7 was shown to be entirely different from that of NZ-1, a neutralizing mAb against the PLAG domain according to an inhibition assay and lectin microarray analysis. In the present study, we produced a mouse-human chimeric anti-hPDPN mAb, chLpMab-7. ChLpMab-7 showed high antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Furthermore, chLpMab-7 inhibited the growth of hPDPN-expressing tumors in vivo. Although chLpMab-7 recognizes a non-PLAG domain of hPDPN, it suppressed the hematogenous metastasis of hPDPN-expressing tumors. These results indicated that chLpMab-7 suppressed tumor development and hematogenous metastasis in a neutralization-independent manner. In conclusion, hPDPN shows promise as a target in the development of a novel antibody-based therapy.
Takumi Sakurada, Souji Kakiuchi, Soichiro Tajima, Yuya Horinouchi, Ken Konaka, Naoto Okada, Hirotaka Nishisako, Toshimi Nakamura, Kazuhiko Teraoka, Kazuyoshi Kawazoe, Hiroaki Yanagawa, Yasuhiko Nishioka and Keisuke Ishizawa : Pemetrexed-induced rash may be prevented by supplementary corticosteroids, Biological & Pharmaceutical Bulletin, Vol.38, No.11, 1752-1756, 2015.
(要約)
Pemetrexed, a chemotherapeutic drug, is highly active in non-small cell lung cancer and malignant pleural mesothelioma. Unfortunately, rashes are more commonly associated with pemetrexed than other chemotherapies, and it is recommended that patients receive corticosteroids (8 mg/d of dexamethasone) for 3 d, including the day of pemetrexed administration (day 1). However, the efficacy of corticosteroids in this context has not been fully verified. In this retrospective study, we evaluated the medical records of 78 patients who received pemetrexed between April 2009 and March 2014, to confirm whether supplementary corticosteroids prevented rash development. The incidence of rash was lower in the 47 patients who received supplementary corticosteroids (after day 1) compared with the incidence among the 31 patients who did not receive supplementary corticosteroids (19.1% vs. 38.7%). The average cutoff dosage of supplementary corticosteroids on day 2 and day 3 was 1.5 mg/d of dexamethasone, as calculated using the receiver operating characteristic curve, and the odds ratio was 0.33 (95% confidence interval: 0.12-0.94). Administration of ≥1.5 mg of corticosteroids on day 2 and day 3 significantly reduced the severity of the rash compared to no supplementary treatment (grades 2/3, 13.3% vs. 33.3%, p<0.05). However, increasing the dose of corticosteroids had no additional effect on rash development. These results suggest that ≥1.5 mg of supplementary dexamethasone on day 2 and day 3 (in addition to day 1) may be necessary for preventing pemetrexed-induced rash, but high doses of dexamethasone (e.g., 8 mg/d) are unnecessary.
(キーワード)
Adrenal Cortex Hormones / Adult / Aged / Aged, 80 and over / Anti-Inflammatory Agents / Antineoplastic Agents / Area Under Curve / Dexamethasone / Exanthema / Female / Humans / Male / Middle Aged / Neoplasms / Odds Ratio / Pemetrexed / ROC Curve / Retrospective Studies / Severity of Illness Index / Treatment Outcome
埴淵 昌毅, 西岡 安彦 : Current topics from major journals-英文抄読会から ALK陽性非小細胞肺癌に対する1次治療でのクリゾチニブと化学療法の比較試験, 日本胸部臨床, Vol.74, No.6, 717, 2015年.
124.
Hiroshi Kawano, Masaki Hanibuchi, Yoshijima Terumi, Yuko Toyoda, Jun Kishi, Toshifumi Tezuka and Yasuhiko Nishioka : A case of atypical Takayasu arteritis initially presenting with peripheral artery disease, Case Reports in Clinical Pathology, Vol.2, No.2, 34-40, 2015.
Kojiro Nagai, Jun Kishi, Shun Morizumi, Jun Minakuchi, Yoshimi Bando, Yasuhiko Nishioka and Toshio Doi : Henoch-Schönlein purpura nephritis occurring postpartum in a patient with anti-PL-7 anti-synthetase syndrome., Modern Rheumatology, Vol.28, 1-4, 2015.
(要約)
A 37-year-old pregnant woman developed purpura which was subsequently diagnosed as Henoch-Schönlein purpura (HSP). After childbirth, the patient developed proteinuria and hematuria. Further examination revealed that the HSP nephritis (HSPN) was associated with anti-threonyl-tRNA synthetase anti-synthetase syndrome. The onset of HSPN during pregnancy or after childbirth is rare. Moreover, to our knowledge, this is the first case to describe renal involvement in anti-synthetase syndrome.
A 51-year-old man was admitted to our hospital because of fever and diarrhea. Chest X-ray revealed consolidation in the left lower lung field. Ceftriaxone and minocycline were given empirically, under the suspicion of bacterial or atypical pneumonia. In spite of treatment with antibiotics, the disease rapidly progressed to systemic inflammatory response syndrome. The diagnosis of acute respiratory distress syndrome (ARDS) accompanied with influenza (H1N1) 2009 was made because of positive findings of real-time polymerase chain reaction. While multidisciplinary treatment was performed, his condition was further deteriorated suggesting the excessive pro-inflammatory mediators. To remove them, we conducted polymyxin-B immobilized column-direct hemoperfusion (PMX-DHP), and his general condition recovered successfully. PMX-DHP may be a useful treatment choice for ARDS accompanied with influenza.
Seidai Satou, Y Kawamata, A Takahashi, Y Imai, A Hanyu, A Okuma, M Takasugi, K Yamakoshi, H Sorimachi, H Kanda, Y Ishikawa, S Sone, Yasuhiko Nishioka, N Otani and E Hara : Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice, Nature Communications, Vol.6, 7035, 2015.
(要約)
The p16(INK4a) tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. However, since p16(INK4a) knockout mice die prematurely from cancer, whether p16(INK4a) reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the α-klotho ageing-suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation. Surprisingly, this is due to the restoration of α-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in α-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of α-klotho expression. Indeed, p16(INK4a) represses α-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16(INK4a) are inversely correlated with those of α-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating α-klotho expression during ageing.
H Yamazaki, R Sakai, R Koike, Y Miyazaki, M Tanaka, T Nanki, K Watanabe, S Yasuda, T Kurita, Y Kaneko, Y Tanaka, Yasuhiko Nishioka, Y Takasaki, K Nagasaka, H Nagasawa, S Thoma, M Dohi, T Sugihara, H Sugiyama, Y Kawaguchi, N Inase, S Ochi, H Hagiyama, H Kohsaka, N Miyasaka, M Harigai and Group Study PREVENT : Assessment of Risks of Pulmonary Infection During 12 Months Following Immunosuppressive Treatment for Active Connective Tissue Diseases:A Large-scale Prospective Cohort Study, The Journal of Rheumatology, Vol.42, No.4, 614-622, 2015.
(要約)
Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.
Takumi Sakurada, Souji Kakiuchi, Soichiro Tajima, Yuya Horinouchi, Naoto Okada, Hirotaka Nishisako, Toshimi Nakamura, Kazuhiko Teraoka, Kazuyoshi Kawazoe, Hiroaki Yanagawa, Yasuhiko Nishioka, Kazuo Minakuchi and Keisuke Ishizawa : Characteristics and risk factors of interstitial lung disease induced by chemotherapy for lung cancer, The Annals of Pharmacotherapy, Vol.49, No.4, 398-404, 2015.
(要約)
Drug-induced interstitial lung disease (DILD) is generally a serious adverse effect and almost always necessitates the discontinuation of the offending drug. Cancer pharmacotherapy is strongly associated with DILD, and the risk of DILD has been suggested to be higher in patients with lung cancer because of preexisting pneumonic disease. The aim of this retrospective study was to identify the risk factors and prognostic factors for early death from interstitial lung disease (ILD) induced by chemotherapy for lung cancer. The medical records of 459 patients who underwent chemotherapy for lung cancer between April 2007 and March 2013 were analyzed with regard to patient background and DILD development, initial symptoms, and prognosis. A total of 33 patients (7.2%) developed chemotherapy-induced ILD. The most frequently observed initial symptom was dyspnea (94.3%). Preexisting ILD was identified as a risk factor for DILD (odds ratio [OR] = 5.38; 95% CI = 2.47-11.73; P < 0.01). Among the 33 patients who developed DILD, 10 patients suffered an early death despite steroid therapy. Poor prognostic factors included epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) use (OR = 9.26; 95% CI = 1.05-82.0; P < 0.05) and 2 or more prior chemotherapy regimens (OR = 6.95; 95% CI = 1.14-42.3; P < 0.05). Many lung cancer patients have coexisting ILD, and these patients have a high risk of developing chemotherapy-induced ILD. In addition, patients with DILD who underwent EGFR-TKI therapy and 2 or more prior chemotherapy regimens had a higher risk of fatal outcome.
(キーワード)
Adult / Aged / Aged, 80 and over / Antineoplastic Agents / Female / Humans / Lung Diseases, Interstitial / Lung Neoplasms / Male / Middle Aged / Odds Ratio / Prognosis / Retrospective Studies / Risk Factors
Toshifumi Tezuka, Hirohisa Ogawa, Masahiko Azuma, Hisatsugu Goto, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi, Yamaguchi Yoichi, Fujikawa Tomoyuki, Itai Akiko and Yasuhiko Nishioka : IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators, PLoS ONE, Vol.10, No.3, e0121615, 2015.
(要約)
Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.
Seidai Satou, Masaki Hanibuchi, Makoto Tobiume, Jun Kishi, Yuko Toyoda, Hiroshi Kawano, Mikiko Takahashi, Yuh Fukuda and Yasuhiko Nishioka : A case of IgG4-related interstitial lung disease showing usual interstitial pneumonia pattern: Unusual case for histological features with pathological proof, Case Reports in Clinical Pathology, Vol.2, No.1, 6-11, 2015.
Yoshinori Aono, Masami Kishi, Yuki Yokota, Momoyo Azuma, Katsuhiro Kinoshita, Akio Takezaki, Seidai Sato, Hiroshi Kawano, Jun Kishi, Hisatsugu Goto, Hisanori Uehara, Keisuke Izumi and Yasuhiko Nishioka : Role of PDGF/PDGFR axis in the trafficking of circulating fibrocytes in pulmonary fibrosis, American Journal of Respiratory Cell and Molecular Biology, Vol.51, No.6, 793-801, 2014.
(要約)
Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -β, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-β-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-β was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-β biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.
Michi Tanaka, Ryuji Koike, Ryoko Sakai, Kazuyoshi Saito, Shintaro Hirata, Hayato Nagasawa, Hideto Kameda, Masako Hara, Yasushi Kawaguchi, Shigeto Tohma, Yoshinari Takasaki, Makoto Dohi, Yasuhiko Nishioka, Shinsuke Yasuda, Yasunari Miyazaki, Yuko Kaneko, Toshihiro Nanki, Kaori Watanabe, Hayato Yamazaki, Nobuyuki Miyasaka and Masayoshi Harigai : Pulmonary infections following immunosuppressive treatments during hospitalization worsen the short-term vital prognosis for patients with connective tissue disease-associated interstitial pneumonia, Modern Rheumatology, Vol.25, No.4, 609-614, 2014.
(要約)
Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP. A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model. A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates. Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.
Hirohisa Ogawa, G Julie Ledford, Sambuddho Mukherjee, Yoshinori Aono, Yasuhiko Nishioka, J James Lee, Keisuke Izumi and W John Hollingsworth : Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β., Respiratory Research, Vol.15, 143, 2014.
(要約)
Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.
Taisuke Matsuo, Le Tan Dat, Masato Komatsu, Tetsuro Yoshimaru, Kei Daizumoto, Saburo Sone, Yasuhiko Nishioka and Toyomasa Katagiri : Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes., PLoS ONE, Vol.9, No.11, e113606, 2014.
(要約)
Small cell lung cancer (SCLC) is aggressive, with rapid growth and frequent bone metastasis; however, its detailed molecular mechanism remains poorly understood. Here, we report the critical role of early growth factor 4 (EGR4), a DNA-binding, zinc-finger transcription factor, in cell proliferation of SCLC. EGR4 overexpression in HEK293T cells conferred significant upregulation of specific splice variants of the parathyroid hormone-related protein (PTHrP) gene, resulting in enhancement of the secretion of PTHrP protein, a known mediator of osteolytic bone metastasis. More importantly, depletion of EGR4 expression by siRNA significantly suppressed growth of the SCLC cell lines, SBC-5, SBC-3 and NCI-H1048. On the other hand, introduction of EGR4 into NIH3T3 cells significantly enhanced cell growth. We identified four EGR4 target genes, SAMD5, RAB15, SYNPO and DLX5, which were the most significantly downregulated genes upon depletion of EGR4 expression in all of the SCLC cells examined, and demonstrated the direct recruitment of EGR4 to their promoters by ChIP and luciferase reporter analysis. Notably, knockdown of the expression of these genes by siRNA remarkably suppressed the growth of all the SCLC cells. Taken together, our findings suggest that EGR4 likely regulates the bone metastasis and proliferation of SCLC cells via transcriptional regulation of several target genes, and may therefore be a promising target for the development of anticancer drugs for SCLC patients.
Seidai Satou, Masaki Hanibuchi, Asami Fukuya, Youhei Yabuki, Hiroki Bando, Terumi Yoshijima, Hisatsugu Goto, Hirohisa Ogawa and Yasuhiko Nishioka : Idiopathic pleuroparenchymal fibroelastosis is characterized by an elevated serum level of surfactant protein-D, but not krebs von den lungen-6, Lung, Vol.192, No.5, 711-717, 2014.
(要約)
Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported rare disease entity characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes in idiopathic interstitial pneumonias (IIPs). Because the clinical features of this rare disease are not fully elucidated, we examined the clinical characteristics of IPPFE, especially for serum interstitial biomarkers, surfactant protein-D (SP-D), and Krebs von den Lungen-6 (KL-6). Four consecutive cases of IPPFE who fulfilled the diagnostic criteria were studied. All cases were more than 60 years of age, and were classified as underweight by body mass index. A severe restrictive ventilatory defect was found in all cases on admission. High-resolution computed tomography showed intense pleural thickening associated with fibrosis predominant in upper lobes. Histopathological findings were also confirmed in three out of four cases. Interestingly, the serum level of SP-D was markedly elevated in all cases, while KL-6 was within normal range in three out of four cases. As compared with major IIPs such as idiopathic pulmonary fibrosis and fibrotic nonspecific interstitial pneumonia, IPPFE significantly showed higher frequency of cases with a unique pattern of serum biomarkers, which is characterized by an elevated level of SP-D with a normal range of KL-6. In IPPFE, SP-D might tend to be elevated, while KL-6 was within a normal range. Further study is required to determine the pathogenesis and clinical significance of the elevated SP-D in IPPFE.
Masaki Hanibuchi, SJ Kim, IJ Fidler and Yasuhiko Nishioka : The molecular biology of lung cancer brain metastasis: an overview of current comprehensions and future perspectives, The Journal of Medical Investigation : JMI, Vol.61, No.3,4, 241-253, 2014.
(要約)
Brain metastases occur in 20-40% of patients with advanced malignancies and lung cancer is one of the most common causes of brain metastases. The occurrence of brain metastases is associated with poor prognosis and high morbidity in patients with advanced lung cancer, even after intensive multimodal therapy. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While the biology of brain metastasis is still poorly understood, it is encouraging to see more efforts are beginning to be directed toward the study of brain metastasis. During the multi-step process of metastasis, functional significance of gene expressions, changes in brain vasculature, abnormal secretion of soluble factors and activation of autocrine/paracrine signaling are considered to contribute to the brain metastasis development. A better understanding of the mechanism of this disease will help us to identify the appropriate therapeutic strategies, which leads to circumvent brain metastases. Recent findings on the biology of lung cancer brain metastases and translational leads identified by molecular studies are discussed in this review.
Yuko Toyoda, Sho Tabata, Jun Kishi, Takuya Kuramoto, Atsushi Mitsuhashi, Atsuro Saijo, Hiroshi Kawano, Hisatsugu Goto, Yoshinori Aono, Masaki Hanibuchi, Hideaki Horikawa, Toshihiro Nakajima, Tatsuhiko Furukawa, Saburo Sone, Shin-ichi Akiyama and Yasuhiko Nishioka : Thymidine Phosphorylase Regulates the Expression of CXCL10 in Rheumatoid Arthritis Fibroblast-like Synoviocytes, Arthritis & Rheumatology, Vol.66, No.3, 560-568, 2014.
(要約)
Thymidine phosphorylase (TP) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) is induced by tumor necrosis factor α (TNFα) and other cytokines that have been reported to be major inflammation mediators in RA. We previously demonstrated that TP plays an important role in angiogenesis and tumor growth, invasion, and metastasis. The aim of this study was to investigate whether the role of TP in the pathogenesis of RA is similar to its role in tumors. In FLS obtained from 2 patients with RA, the expression of TP, interferon-γ (IFNγ)-inducible protein 10 (CXCL10), and other cytokines was measured by quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assays. Microarray analysis was performed using FLS transfected with TYMP complementary DNA and treated with a TP inhibitor. The expression of TP in FLS was up-regulated by TNFα, interleukin-1β (IL-1β), IL-17, IFNγ, and lipopolysaccharide. Microarray analysis of FLS overexpressing TP identified CXCL10 as a thymidine phosphorylase-related gene. The expression of CXCL10 was induced by TNFα, and this induction was suppressed by TYMP small interfering RNA and TP inhibitor. Furthermore, the combination of TNFα and IFNγ synergistically augmented the expression of TP and CXCL10. TP-induced CXCL10 expression was suppressed by the antioxidant EUK-8. In the synovial tissue of patients with RA, TP levels were significantly correlated with CXCL10 expression. The combination of TNFα and IFNγ strongly induced the expression of thymidine phosphorylase in RA FLS. The induction of thymidine phosphorylase enhanced the expression of CXCL10, which may contribute to the Th1 phenotype and bone destruction observed in RA.
In the national project Health Japan 21 (2nd edition) put forward in April 2013, the Ministry of Health, Labour, and Welfare specified chronic obstructive pulmonary disease (COPD) as a targeted lifestyle-related disease, in addition to cancer, heart diseases, and diabetes, and concluded that the establishment of COPD management systems is an important issue to maintain Japanese people's healthy lives, as the number of deaths from this disease is likely to rapidly increase in the future. In Tokushima Prefecture, the mortality rate associated with COPD has been stably high over the past years ; the nation' s highest in 2010 and third highest in 2011. In some regions of the western area, particularly mountainous regions, and southern area of the prefecture, the standardized mortality rate among males is double the national mean, highlighting the necessity of rapidly taking countermeasures. Under such circumstances, the Tokushima City Medical Association regarded COPD management as a priority item when developing annual projects this year, and organized the COPD Management and Smoking Cessation Promotion Committee in May. The medical association also presented a tentative plan to conduct association-led individualized COPD assessment at its own expense to the local government of Tokushima, with a view to materializing COPD assessment projects to clarify, evaluate, and analyze the actual situation, including surveys on citizens' recognition of COPD and those conducted by family doctors to examine the statuses of their patients, involving the local government in the future. During deliberations to examine the feasibility of this plan, the local government proposed a new COPD assessment plan based on the conventional mass pulmonary cancer examination system, in order to deal with those at a high risk of COPD ; following some revisions, the new plan was adopted. The plan consisted of the following steps : > Targeting those meeting the 3 diagnostic criteria specified in the pulmonary cancer interview sheet for COPD assessment : 1) age of 60 or over ; 2) previous smoking habit ; 3) presence of at least one of the subjective COPD symptoms (chronic coughing, sputum, and shortness of breath during activity). > Providing these patients with a free-consultation coupon to undergo assessment in a registered primary medical examination institution. > Conducting airway obstruction evaluation in primary medical examination institutions using the mass COPD screening interview sheet (COPD-PSTM) and spirometry. > Conducting insurance-covered medical examinations, such as the respiratory function test, chest XP, and CT scans, in secondary medical examination institutions (chest physicians) to establish a definite diagnosis. > Reporting the results of these examinations to family doctors. > If treatment is necessary, developing initial pharmacotherapy plans as part of the standardized treatment of COPD for approximately 3 months, which are implemented by family doctors. In consideration of the rapidly aging Japanese population, the number of potential COPD patients aged 40 and over is expected to reach nearly 7 million soon. In order to deal with such a large number of COPD patients, it is primary care physicians' duty to provide early diagnosis and treatment, and local medical associations are charged with promoting spirometry through their activities as part of COPD assessment projects, aiming to establish cooperative systems to manage the disease between primary care physicians providing treatment during the stable period and chest physicians providing it during the exacerbation period. As future perspectives, spirometry-promoting seminars to be held in clinical environments are being considered ; participation in these seminars will be a requirement for registered primary COPD examination institutions, and those who have completed such programs will be Tokushima City Medical Association-certified COPD specialists (tentative name). It is expected that these approaches to carry out the nation's first COPD assessment projects will improve clinical environments in communities, such as support for smoking cessation, medical professionals' knowledge of COPD, and the standardization of diagnosis and treatment.
Alcohol-based hand rubs are recommended for use by healthcare staff worldwide. In addition to gel and liquid rubs, ethanol-based foam is available for hand hygiene. Ethanol-based foam was launched as the first alcohol-based foaming hand rub available in Japan in June 2011. Ethanol-based foam has gained attention among healthcare staff because ethanol-based foam does not drip from the hands, and allows good visual coverage. This study compared the effectiveness of ethanol-based gel and foam for bacterial removal and the percentage of areas covered with gel or foam. The Parm-Stamp Test was used to prove that ethanol-based foam has the same efficacy against bacteria as gel. To examine if the hands were fully covered with gel or foam, we used the Black Lights device and fluorescence powder. The results showed that the ethanol-based foam provided significantly improved coverage compared with the gel. According to the questionnaire results, ethanol-based foam has a lot of unique benefits, such as no dripping, easy spreading, good visual coverage, and no sticky feeling. Due to the effective cleaning with excellent skin feel during and after use, ethanol-based hand rub foam is very useful in the clinical setting for hand hygiene among healthcare workers.
Katsuhiro Kinoshita, Yoshinori Aono, Momoyo Azuma, Jun Kishi, Akio Takezaki, Masami Kishi, Hideki Makino, Hiroyasu Okazaki, Hisanori Uehara, Keisuke Izumi, Saburo Sone and Yasuhiko Nishioka : Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice., American Journal of Respiratory Cell and Molecular Biology, Vol.49, No.4, 536-543, 2013.
(要約)
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of -smooth muscle actin induced by transforming growth factor , indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.
Jun Huang, Sho Tabata, Souji Kakiuchi, Trung Van The, Hisatsugu Goto, Masaki Hanibuchi and Yasuhiko Nishioka : Identification of pregnancy-associated plasma protein A as a migration-promoting gene in malignant pleural mesothelioma cells: a potential therapeutic target., Oncotarget, Vol.4, No.8, 1172-1184, 2013.
(要約)
Despite recent advances in treatment, malignant pleural mesothelioma (MPM) remains a deadly disease. Targeted therapy generated broad interests and is highly expected for the treatment of MPM, yet promising preclinical results have not been translated into substantial clinical benefits for the patients. In this study, we tried to identify the genes which play functional roles in cell migration as well as to test whether they can be used as novel targets for molecular targeted therapy for MPM in preclinical model. In our study, pregnancy-associated plasma protein A (PAPPA) was identified as a gene whose expression level is correlated with MPM cell migration by correlation analysis combining MPM cell migration ability and their gene expression profiles. Highly migratory cells were selected from MPM cell lines, MSTO-211H, NCI-H290 and EHMES-1 in vitro and up-regulation of PAPPA in these cells were confirmed. In vitro, PAPPA was demonstrated to stimulate the MPM cell migration via cleavage of insulin-like growth factor-binding protein-4 and subsequent release of IGF-1. Gene silencing of PAPPA in MPM cells led to reduced migration, invasion and proliferation. Furthermore, PAPPA shRNA transfected NCI-H290 when orthotopically inoculated into pleural cavity of severe combined immunodeficiency recipient mice, failed to develop tumors and produce bloody pleural effusion as control shRNA transfected cells did. Our study suggests that PAPPA plays a functional role in promoting MPM cell migration and it might serve as a potential therapeutic target for the treatment of MPM.
Shinji Abe, Yuki Morita, Mika Kato Kaneko, Masaki Hanibuchi, Yuta Tsujimoto, Hisatsugu Goto, Souji Kakiuchi, Yoshinori Aono, Jun Huang, Seidai Sato, Masatoshi Kishuku, Yuki Taniguchi, Mami Azuma, Kazuyoshi Kawazoe, Yoshitaka Sekido, Seiji Yano, Shin-ichi Akiyama, Saburo Sone, Kazuo Minakuchi, Yukinari Kato and Yasuhiko Nishioka : A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody, The Journal of Immunology, Vol.190, No.12, 6239-6249, 2013.
(要約)
Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a(+)) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.
The proportion of bird-related HP was higher than that in the previous epidemiological survey, and the proportions of isocyanate-induced HP and farmer's lung were lower. A crucial step in diagnosing chronic HP is to thoroughly explore the possibility of antigen exposure.
Atsushi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Sho Tabata, Sawaka Yukishige, Shinji Abe, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, G Julie Ledford, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages., The American Journal of Pathology, Vol.182, No.5, 1843-1853, 2013.
(要約)
Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-A-expressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-A-expressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs.
Shino Yuasa, Harutaka Yamaguchi, Yoshinori Nakanishi, Shingo Kawaminami, Ryo Tabata, Nobuhiko Shimizu, Mitsuhiro Kohno, Teruki Shimizu, Junya Miyata, Mayuko Nakayama, Jun Kishi, Yuko Toyoda, Yasuhiko Nishioka and Kenji Tani : Treatment responses and their predictors in patients with rheumatoid arthritis treated with biological agents., The Journal of Medical Investigation : JMI, Vol.60, No.1-2, 77-90, 2013.
(要約)
Biological agents represent an important advancement in for the treatment of rheumatoid arthritis (RA), but there is a subset of patients who do not improve despite therapy. This study aimed to determine the efficacy of biological agents for RA and to identify clinical factors that are associated with their response. We studied 98 patients with RA who started an initiating biological agent which was selected from infliximab, etanercept, adalimumab and tociliximab at 4 medical institutions. Etanercept was the most frequently used biological agent followed by infliximab although there was a difference in the selection of the biological agents among medical institutions. We found that etanercept achieved the highest treatment response, remission rate and drug survival rate. A high disease activity in the baseline disease activity score-c-reactive protein (CRP) was shown to be a negative predictor of the treatment response, and high patient global assessment was significantly less likely to achieve a good response. At week 4, decreases in 28 swollen joint counts and CRP were useful as predictors for sustaining the efficacy up to week 48. These data demonstrate that assessments of the disease activity at baseline and the early treatment response may be useful in predicting the efficacy and drug survival rate of biological agents.
Hideki Makino, Yoshinori Aono, Momoyo Azuma, Masami Kishi, Yuki Yokota, Katsuhiro Kinoshita, Akio Takezaki, Jun Kishi, Hiroshi Kawano, Hirohisa Ogawa, Hisanori Uehara, Keisuke Izumi, Saburo Sone and Yasuhiko Nishioka : Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice., The Journal of Medical Investigation : JMI, Vol.60, No.1-2, 127-137, 2013.
(要約)
Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.
T Yamada, S Takeuchi, N Fujita, A Nakamura, W Wang, Q Li, M Oda, T Mitsudomi, Y Yatabe, Y Sekido, J Yoshida, M Higashiyama, M Noguchi, H Uehara, Yasuhiko Nishioka, Saburo Sone and Seiji Yano : Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations, Oncogene, Vol.32, No.37, 4427-4435, 2012.
(要約)
Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.
Seidai Satou, Masaki Hanibuchi, Takuya Kuramoto, Nodoka Yamamori, Hisatsugu Goto, Hirohisa Ogawa, Atsushi Mitsuhashi, The Trung Van, Souji Kakiuchi, Shin-ichi Akiyama, Yasuhiko Nishioka and Saburo Sone : Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment., Clinical & Experimental Metastasis, Vol.30, No.3, 333-344, 2012.
(要約)
The organ microenvironment significantly affects the processes of cancer metastasis. Elucidating the molecular mechanisms of interaction between tumor cells and the organ microenvironment is crucial for the development of effective therapeutic strategies to eradicate cancer metastases. Macrophage stimulating protein (MSP), an activator of macrophages, regulates a pleiotropic array of effects, including proliferation, cellular motility, invasiveness, angiogenesis, and resistance to anoikis. However, the role of MSP in cancer metastasis is still largely unknown. In this study, the action of MSP on the production of metastases was determined in a multiple-organ metastasis model. The murine MSP gene was transfected into two human SCLC cell lines, SBC-5 and H1048, to establish transfectants secreting biologically active MSP. MSP gene transduction did not affect cell proliferation and motility in vitro. Intravenously inoculated MSP transfectants produced significantly larger numbers of liver metastases than parental cells or vector control clones, while there were no significant differences in bone or lung metastases among them. Immunohistochemical analyses of liver metastases revealed that tumor-associated microvessel density and tumor-infiltrating macrophages were significantly increased in lesions produced by MSP transfectants. MSP could stimulate the migration of murine macrophages and endothelial cells in vitro. Consequently, MSP may be one of the major determinants that affects the properties of tumor stroma and that produces a permissive microenvironment to promote cancer metastasis.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Atsuro Saijo, Souji Kakiuchi, Yoichi Maekawa, Koji Yasutomo, Masaki Hanibuchi, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-Notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, Molecular Cancer Therapeutics, Vol.11, No.12, 2578-2587, 2012.
(要約)
Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-κB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-κB signaling.
Kato Mika Kaneko, Akiko Kunita, Shinji Abe, Yuta Tsujimoto, Masashi Fukayama, Kaoru Goto, Yoshihiko Sawa, Yasuhiko Nishioka and Yukinari Kato : Chimeric anti-podoplanin antibody suppresses tumor metastasis through neutralization and antibody-dependent cellular cytotoxicity., Cancer Science, Vol.103, No.11, 1913-1919, 2012.
(要約)
Podoplanin is a platelet aggregation-inducing factor associated with tumor metastasis, malignant progression, and cancer stem cells. We produced a rat-human chimeric anti-podoplanin mAb, NZ-8, from rat anti-podoplanin mAb (NZ-1). Although both NZ-1 and NZ-8 possess high binding affinities and high neutralizing activities of platelet aggregation, the antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity of NZ-8 were much higher than NZ-1. Furthermore, both NZ-1 and NZ-8 inhibited the growth of podoplanin-expressing tumors in vivo. Both NZ-1 and NZ-8 also suppressed hematogenous metastasis of podoplanin-expressing tumors. These results suggest that anti-podoplanin mAbs suppressed hematogenous metastasis by both neutralization and antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity activities. Targeting therapy to podoplanin-expressing tumors should be useful as a novel immunotherapy.
A52-year-old woman was referred to our hospital for further examination of thoracolumbarpain. As dysesthesia at Th4level was seen in neurological examination, thoracic radiculopathy ormyelopathy was suspected. Blood examination showed elevated level of serum ACE and lysozyme.Lymphadenopathy was evident in bilateral hila and mediastina with marked FDG and Galliumaccumulation in FDG-PET-CT and Gallium scintigraphy, respectively. The number of lymphocytesand the CD4/CD8ratio were increased in the BALF. Histological findings of specimens obtainedfrom the lung and the skin lesion revealed noncaseating epithelioid granuloma, which yielded thediagnosis of sarcoidosis. The cerebrospinal fluid examinations showed elevated level of cell counts,proteins and β2-microglobulin. Taken together, she was diagnosed as neurosarcoidosis with thoracicradiculopathy. Her symptoms were improved with oral administration of prednisolone, butthey were exacerbated when prednisolone dose was tapered to20mg/day. Combined therapy ofmethotrexate and prednisolone was initiated, thereafter her symptoms disappeared completely.
Trung The Van, Masaki Hanibuchi, Hisatsugu Goto, Takuya Kuramoto, Sawaka Yukishige, Souji Kakiuchi, Seidai Sato, Satoshi Sakaguchi, Le Tan Dat, Yasuhiko Nishioka, Shin-ichi Akiyama and Saburo Sone : SU6668, a multiple tyrosine kinase inhibitor, inhibits the progression of human malignant pleural mesothelioma in an orthotopic model, Respirology, Vol.17, No.6, 984-990, 2012.
(要約)
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the mesothelium with high chemotherapeutic resistance. In this study, the preclinical therapeutic activity of the multiple tyrosine kinase inhibitor, SU6668, against MPM was examined. Two human MPM cell lines with different pro-angiogenic cytokine expression, Y-MESO-14 cells that express high levels of vascular endothelial growth factor (VEGF) and MSTO-211H cells that express high levels of basic fibroblast growth factor (bFGF), were orthotopically inoculated into the thoracic cavities of mice with severe combined immunodeficiency. The mice with MPM were treated or not treated with SU6668 (200 mg/kg/day). SU6668 abrogated the proliferation of endothelial cells stimulated by VEGF or bFGF, but did not directly affect the growth of human MPM cells in vitro. In this orthotopic implantation model, treatment with SU6668 effectively reduced tumour weight and pleural effusion volumes, in association with inhibition of the growth of tumour vasculature. More importantly, treatment with SU6668 significantly prolonged survival time in mice with MPM. These findings suggest that SU6668 has a promising therapeutic effect on the progression of MPM in vivo through its anti-angiogenic effects.
Shinji Takeuchi, Wei Wang, Qi Li, Tadaaki Yamada, Kenji Kita, S Ivan Donev, Takahiro Nakamura, Kunio Matsumoto, Eiji Shimizu, Yasuhiko Nishioka, Saburo Sone, Takayuki Nakagawa, Toshimitsu Uenaka and Seiji Yano : Dual inhibition of Met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer., The American Journal of Pathology, Vol.181, No.3, 1034-1043, 2012.
(要約)
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a serious problem in the management of EGFR mutant lung cancer. We recently reported that hepatocyte growth factor (HGF) induces resistance to EGFR-TKIs by activating the Met/PI3K pathway. HGF is also known to induce angiogenesis in cooperation with vascular endothelial growth factor (VEGF), which is an important therapeutic target in lung cancer. Therefore, we hypothesized that dual inhibition of HGF and VEGF may be therapeutically useful for controlling HGF-induced EGFR-TKI-resistant lung cancer. We found that a dual Met/VEGF receptor 2 kinase inhibitor, E7050, circumvented HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer cell lines by inhibiting the Met/Gab1/PI3K/Akt pathway in vitro. HGF stimulated VEGF production by activation of the Met/Gab1 signaling pathway in EGFR mutant lung cancer cell lines, and E7050 showed an inhibitory effect. In a xenograft model, tumors produced by HGF-transfected Ma-1 (Ma-1/HGF) cells were more angiogenic than vector control tumors and showed resistance to gefitinib. E7050 alone inhibited angiogenesis and retarded growth of Ma-1/HGF tumors. E7050 combined with gefitinib induced marked regression of tumor growth. Moreover, dual inhibition of HGF and VEGF by neutralizing antibodies combined with gefitinib also markedly regressed tumor growth. These results indicate the therapeutic rationale of dual targeting of HGF-Met and VEGF-VEGF receptor 2 for overcoming HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.
Sho Tabata, Ryuji Ikeda, Masatatu Yamamoto, Tatsuhiko Furukawa, Takuya Kuramoto, Yasuo Takeda, Katsushi Yamada, Misako Haraguchi, Yasuhiko Nishioka, Saburo Sone and Shin-ichi Akiyama : Thymidine phosphorylase enhances reactive oxygen species generation and interleukin-8 expression in human cancer cells., Oncology Reports, Vol.28, No.3, 895-902, 2012.
(要約)
Thymidine phosphorylase (TP) is an angiogenic factor that plays a pivotal role in tumor angiogenesis. Various kinds of solid tumors express TP and high TP activity is correlated with microvessel density. We have previously reported that TP enhances interleukin-8 (IL-8) expression in KB human epidermoid carcinoma cells. In this study, TP was shown to be involved in enhanced expression of IL-8 in EJ human bladder cancer cells and Yumoto human cervical cancer cells as well as KB human epidermoid carcinoma cells. The enzymatic activity of TP was required for the enhanced expression of IL-8. A degradation product of thymidine was implicated in the enhanced expression of IL-8. TP augmented reactive oxygen species (ROS) generation in KB and Yumoto cells, and the enzymatic activity of TP was again required for the generation of ROS. An antioxidant, N-acetylcysteine (NAC), attenuated the generation of ROS and IL-8 mRNA expression in KB and Yumoto cells, and H2O2 increased IL-8 mRNA expression in Yumoto cells, suggesting that ROS generated by TP caused the increased expression of IL-8 mRNA. Since TP also reduced cellular glutathione levels and transcription of γ-GCS in KB cells, the TP-induced augmentation of ROS may be partially attributed to the decreased glutathione. Our findings suggest that thymidine-derived sugars enhanced ROS generation and consequently increased IL-8 expression.
Adel Gomaa Mohammed Gabr, Hisatsugu Goto, Masaki Hanibuchi, Hirohisa Ogawa, Takuya Kuramoto, Minako Suzuki, Atsuro Saijo, Souji Kakiuchi, Van The Trung, Satoshi Sakaguchi, Yoichiro Moriya, Saburo Sone and Yasuhiko Nishioka : Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression, Clinical & Experimental Metastasis, Vol.29, No.3, 207-216, 2012.
(要約)
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show dramatic antitumor activity in a subset of patients with non-small cell lung cancer who have an active mutation in the epidermal growth factor receptor (EGFR) gene. On the other hand, some lung cancer patients with wild type EGFR also respond to EGFR-TKIs, suggesting that EGFR-TKIs have an effect on host cells as well as tumor cells. However, the effect of EGFR-TKIs on host microenvironments is largely unknown. A multiple organ metastasis model was previously established in natural killer cell-depleted severe combined immunodeficient mice using human lung cancer cells. This model was used to investigate the therapeutic efficacy of erlotinib, an EGFR-TKI, on multiple organ metastases induced by human small cell lung cancer cells (SBC-5 cells) that did not express EGFR. Although erlotinib did not have any effect on the proliferation of SBC-5 cells in vitro, it significantly suppressed bone and lung metastases in vivo, but not liver metastases. An immunohistochemical analysis revealed that, erlotinib significantly suppressed the number of osteoclasts in bone metastases, whereas no difference was seen in microvessel density. Moreover, erlotinib inhibited EGF-induced receptor activator of nuclear factor kappa-B expression in an osteoblastic cell line (MC3T3-E1 cells). These results strongly suggested that erlotinib prevented bone metastases by affecting host microenvironments irrespective of its direct effect on tumor cells.
Yoshinori Aono, Julie G. Ledford, Sambuddho Mukherjee, Hirohisa Ogawa, Yasuhiko Nishioka, Saburo Sone, Michael F. Beers, Paul W. Noble and Jo Rae Wright : Surfactant protein-D regulates effector cell function and fibrotic lung remodeling in response to bleomycin injury., American Journal of Respiratory and Critical Care Medicine, Vol.185, No.5, 525-536, 2012.
(要約)
Surfactant protein (SP)-D and SP-A have been implicated in immunomodulation in the lung. It has been reported that patients with idiopathic pulmonary fibrosis (IPF) often have elevated serum levels of SP-A and SP-D, although their role in the disease is not known. The goal of this study was to test the hypothesis that SP-D plays an important role in lung fibrosis using a mouse model of fibrosis induced by bleomycin (BLM). Triple transgenic inducible SP-D mice (iSP-D mice), in which rat SP-D is expressed in response to doxycycline (Dox) treatment, were administered BLM (100 U/kg) or saline subcutaneously using miniosmotic pumps. BLM-treated iSP-D mice off Dox (SP-D off) had increased lung fibrosis compared with mice on Dox (SP-D on). SP-D deficiency also increased macrophage-dominant cell infiltration and the expression of profibrotic cytokines (transforming growth factor [TGF]-1, platelet-derived growth factor-AA). Alveolar macrophages isolated from BLM-treated iSP-D mice off Dox (SP-D off) secreted more TGF-1. Fibrocytes, which are bone marrow-derived mesenchymal progenitor cells, were increased to a greater extent in the lungs of the BLM-treated iSP-D mice off Dox (SP-D off). Fibrocytes isolated from BLM-treated iSP-D mice off Dox (SP-D off) expressed more of the profibrotic cytokine TGF-1 and more CXCR4, a chemokine receptor that is important in fibrocyte migration into the lungs. Exogenous SP-D administered intratracheally attenuated BLM-induced lung fibrosis in SP-D(-/-) mice. These data suggest that alveolar SP-D regulates numbers of macrophages and fibrocytes in the lungs, profibrotic cytokine expression, and fibrotic lung remodeling in response to BLM injury.
Hirohisa Ogawa, Masahiko Azuma, Hisanori Uehara, Tetsuyuki Takahashi, Yasuhiko Nishioka, Saburo Sone and Keisuke Izumi : Nerve growth factor derived from bronchial epithelium afer chronic mite antigen exposure contributes to airway hyperresponsiveness by inducing hyperinnervaiton, and is inhibited by in vivo siRNA., Clinical and Experimental Allergy, Vol.42, No.3, 460-470, 2012.
(要約)
Bronchial asthma is a chronic allergic airway inflammatory disease. Neurotrophins, including nerve growth factor (NGF), play an important role in the pathogenesis of asthma. However, the effects of NGF derived from epithelium on airway hyperresponsiveness (AHR) after antigen sensitization/exposure remain uncertain. In this study, we examined the role of NGF on AHR after chronic antigen exposure and the effect of inhibiting NGF by in vivo siRNA on AHR exacerbation. We generated chronic mouse models of bronchial asthma using house-dust mite antigen (Dermatophagoides pteronyssinus; Dp). NGF concentrations in bronchoalveolar lavage fluid (BALF), lung histopathology, hyperresponsiveness, and related neuronal peptides and cytokines in supernatants of lung homogenates were determined. NGF in BALF was increased in a dose- and time-dependent manner, and was expressed primarily in bronchial epithelium. Nerve fibres and substance P-positive fibres were detected in subepithelium of Dp-sensitized and challenged mice over 4 weeks of mite antigen exposure. AHR was positively correlated with NGF concentration and nerve fibre innervation. AHR, modulation of innervation, and increased substance P were inhibited by in vivo administration of siRNA that targeted NGF, although the inhibition of NGF did not affect allergic inflammation and subepithelial fibrosis. These findings suggest that NGF derived from bronchial and alveolar epithelium plays an important role in AHR after chronic exposure to mite antigen. NGF inhibition could potentially manage bronchial asthma, including AHR.
Wei Wang, Qi Li, Shinji Takeuchi, Tadaaki Yamada, Hitomi Koizumi, Takahiro Nakamura, Kunio Matsumoto, Naofumi Mukaida, Yasuhiko Nishioka, Saburo Sone, Takayuki Nakagawa, Toshimitsu Uenaka and Seiji Yano : Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer., Clinical Cancer Research, Vol.18, No.6, 1663-1671, 2012.
(要約)
Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed. E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
Keiko Miyake, Kenji Tani, Souji Kakiuchi, Chiyuki Suzuka, Yuko Toyoda, Jun Kishi, Toshifumi Tezuka, Shino Yuasa, Masaki Hanibuchi, Yoshinori Aono, Yasuhiko Nishioka and Saburo Sone : Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats, The Journal of Medical Investigation : JMI, Vol.59, No.1-2, 174-185, 2012.
(要約)
Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiation-induced lung disorders in an experimental model. The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation.
Le T Dat, Taisuke Matsuo, Tetsuro Yoshimaru, Souji Kakiuchi, Hisatsugu Goto, Masaki Hanibuchi, Takuya Kuramoto, Yasuhiko Nishioka, Saburo Sone and Toyomasa Katagiri : Identification of genes potentially involved in bone metastasis by genome-wide gene expression profile analysis of non-small cell lung cancer in mice, International Journal of Oncology, Vol.40, No.5, 1455-1469, 2012.
(要約)
Lung cancer is commonly associated with multi-organ metastasis, and the bone is a frequent metastatic site for lung cancer. However, the molecular mechanism of organ-specific metastasis remains poorly understood. To elucidate this issue, we analyzed in this study genome-wide gene expression profiles of 15 metastatic lesions from three organs (bone, lung and liver) in a mouse model with multi-organ metastasis properties of human non-small cell lung cancer cells (ACC-LC319/bone2), using a combination of laser-microbeam microdissection and DNA microarrays. We identified 299 genes that could potentially be involved in the organ-selective nature of lung cancer metastasis. Among them, 77 were bone-specifically expressed elements, including genes involved in cell adhesion, cytoskeleton/cell motility, extracellular matrix remodeling and cell-cell signaling as well as genes already known to be involved in the bone metastasis of breast cancers. Quantitative RT-PCR confirmed the specific upregulation of eight genes in bone metastasis tumors, suggesting that these genes may be involved in bone metastasis. Our findings should be helpful for a better understanding of the molecular aspects of the metastatic process in different organs, and could lead to molecular target-based anticancer drugs and prevention of metastasis, especially bone metastasis.
A62‐year‐old woman was referred to our hospital for further examination of fever of unknownorigin, splenomegaly and pancytopenia. On admission, she had persistent fever and psychologicalsymptoms. Blood examination showed pancytopenia and elevated level of LDH, soluble IL‐2receptorand ferritin. Computed tomography showed multiple low density areas in the spleen, but no systemiclymphadenopathy. In magnetic resonance imaging of the pons, a low and high intensity area onT1‐and T2‐weighted image, respectively, was detected. Taken together these findings, she wassuspected to have hepatosplentic T-cell lymphoma or intravascular large B-cell lymphoma. To makea definite diagnosis, random skin biopsy was performed. Immunohistochemical stainings revealedthe massive infiltration of CD20‐and CD79α‐positive large lymphoid cells inside the vessels, whichyielded the diagnosis of intravascular large B-cell lymphoma.
(キーワード)
fever of unknown origin / intravascular large B-cell lymphoma / random skin biopsy
Tadaaki Yamada, Hideaki Bando, Shinji Takeuchi, Kenji Kita, Qi Li, Wei Wang, Shiro Akinaga, Yasuhiko Nishioka, Saburo Sone and Seiji Yano : Genetically engineered humanized anti-ganglioside GM2 antibody against multiple organ metastasis produced by GM2-expressing small-cell lung cancer cells., Cancer Science, Vol.102, No.12, 2157-2163, 2011.
(要約)
Small-cell lung cancer (SCLC) grows rapidly and metastasizes to multiple organs. We examined the antimetastatic effects of the humanized anti-ganglioside GM2 (GM2) antibodies, BIW-8962 and KM8927, compared with the chimeric antibody KM966, in a SCID mouse model of multiple organ metastases induced by GM2-expressing SCLC cells. BIW-8962 and KM8927 induced higher antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity than KM966 against the GM2-expressing SCLC cell line SBC-3 in vitro. These humanized antibodies inhibited the production of multiple organ metastases, increased the number of apoptotic cells, and prolonged the survival of the SCID mice. Histological analyses using clinical specimens showed that SCLC cells expressed GM2. These findings suggest that humanized anti-GM2 antibodies could be therapeutically useful for controlling multiple organ metastases of GM2-expressing SCLC.
Qi Li, Wei Wang, Tadaaki Yamada, Kunio Matsumoto, Katsuya Sakai, Yoshimi Bando, Hisanori Uehara, Yasuhiko Nishioka, Saburo Sone, Shotaro Iwakiri, Kazumi Itoi, Teruhiro Utsugi, Kazuo Yasumoto and Seiji Yano : Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network., The American Journal of Pathology, Vol.179, No.3, 1483-1493, 2011.
(要約)
The tumor microenvironment is crucial to the progression of various malignancies. Malignant pleural mesothelioma (MPM), which originates from the pleura, grows aggressively in the thoracic cavity. Here we describe an orthotopic implantation SCID mouse model of MPM and demonstrate that α-SMA-positive fibroblast-like cells accumulate in the tumors produced by the human MPM cell lines MSTO-211H and Y-Meso-14. We assessed the interaction between MPM cells and their microenvironments, focusing on tumor-associated fibroblasts. MSTO-211H and Y-Meso-14 cells produced fibroblast growth factor-2 (FGF-2) and/or platelet-derived growth factor-AA (PDGF-AA); they also enhanced growth, migration, and production of hepatocyte growth factor (HGF) by human lung fibroblast MRC-5 cells. MRC-5 cells stimulated HGF-mediated growth and migration of MSTO-211H and Y-Meso-14 cells in an in vitro coculture system. In the orthotopic model, tumor formation by MSTO-211H and Y-Meso-14 cells was significantly inhibited by TSU-68, an inhibitor of FGF, VEGF, and PDGF receptors; imatinib, an inhibitor of PDGF receptors; and NK4, an antagonist of HGF. Histological analyses of clinical specimens from 51 MPM patients revealed considerable tumor-associated fibroblasts infiltration and expression of HGF, together with FGF-2 or PDGF-AA, in tumors. These findings indicate that MPM instigates tumor-associated fibroblasts, promoting tumor progression via a malignant cytokine network. Regulation of this cytokine network may be therapeutically useful for controlling MPM.
Trung The Van, Masaki Hanibuchi, Souji Kakiuchi, Seidai Sato, Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Yasuhiko Nishioka, Shin-ichi Akiyama and Saburo Sone : The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice., Cancer Chemotherapy and Pharmacology, Vol.68, No.2, 497-504, 2011.
(要約)
Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM. We used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle. The combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice. We demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM.
Rentsenkhand Batmunkh, Yasuhiko Nishioka, Yoshinori Aono, Momoyo Azuma, Katsuhiro Kinoshita, Jun Kishi, Hideki Makino, Masami Kishi, Akio Takezaki and Saburo Sone : CCN6 as a profibrotic mediator that stimulates the proliferation of lung fibroblasts via the integrin β1/focal adhesion kinase pathway., The Journal of Medical Investigation : JMI, Vol.58, No.3-4, 188-196, 2011.
(要約)
Idiopathic pulmonary fibrosis is a progressive and lethal disease of the lung that is characterized by the proliferation of fibroblasts and increased deposition of the extracellular matrix. The CCN6/WISP-3 is a member of the CCN family of matricellular proteins, which consists of six members that are involved in many vital biological functions. However, the regulation of lung fibroblasts mediated by CCN6 protein has not been fully elucidated. Here, we demonstrated that CCN6 induced the proliferation of lung fibroblasts by binding to integrin β1, leading to the phosphorylation of FAK(Y397). Furthermore, CCN6 showed a weak, but significant, ability to stimulate the expression of fibronectin. CCN6 was highly expressed in the lung tissues of mice treated with bleomycin. Our results suggest that CCN6 plays a role in the fibrogenesis of the lungs mainly by stimulating the growth of lung fibroblasts and is a potential target for the treatment of pulmonary fibrosis.
Hisatsugu Goto, Masaki Hanibuchi, Satoshi Sakaguchi, Takanori Kanematsu, Souji Kakiuchi, Hideki Tomimoto, Masahiko Azuma, Toshifumi Tezuka, Hiroya Tada, Yukiyo Miki, Toshimi Nakamura, Saburo Sone and Yasuhiko Nishioka : Investigation of the outpatient chemotherapy for lung cancer patients in Tokushima University Hospital., The Journal of Medical Investigation : JMI, Vol.58, No.3-4, 219-226, 2011.
(要約)
Platinum-doublet regimens and docetaxel as first- and second-line chemotherapy, respectively, are shown to prolong the survival of lung cancer patients in various randomized phase III studies. However, the evidence for the efficacy of chemotherapy for lung cancer in the clinical practice is still insufficient. In the present study, we investigated the effectiveness and safety of outpatient chemotherapy for lung cancer in the clinical practice. Ninety-four lung cancer cases were retrospectively analyzed. Among these cases, 67 (71.3%) were non-small cell lung cancer (NSCLC) and 27 (28.7%) were small cell lung cancer (SCLC). The response rates in SCLC and NSCLC patients were 55.6% (15/27) and 16.9% (11/65), respectively. Objective tumor response rates for the patients were found to decrease substantially with each line of treatment as described previously. All adverse events were well tolerated and no treatment-related death was observed. Median time to treatment failures (TTFs) of first-line treatment were 10.1 months and 4.8 months in SCLC and NSCLC, respectively. These findings indicate that even in the setting of clinical practice, the efficacy and safety of chemotherapy is strictly insured by the appropriate therapeutic management.
(キーワード)
Adult / Aged / Aged, 80 and over / Antineoplastic Agents / Carcinoma, Non-Small-Cell Lung / Carcinoma, Small Cell / Female / Hospitals, University / Humans / Lung Neoplasms / Male / Middle Aged / Outpatients / Retrospective Studies
Ivan S. Donev, Wei Wang, Tadaaki Yamada, Qi Li, Shinji Takeuchi, Kunio Matsumoto, Takao Yamori, Yasuhiko Nishioka, Saburo Sone and Seiji Yano : Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer., Clinical Cancer Research, Vol.17, No.8, 2260-2269, 2011.
(要約)
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET that restores downstream mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells PC-9 and HCC827. We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo. Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model by using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments by considering short half-life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF. These results indicate that transient blockade of PI3K/Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in EGFR mutant lung cancer.
Kenji Yokoi, David Hawke, Carol J. Oborn, Jin-Young Jang, Yasuhiko Nishioka, Dominic Fan, Seung Wook Kim, Sun-Jin Kim and Isaiah J. Fidler : Identification and validation of SRC and phospho-SRC family proteins in circulating mononuclear cells as novel biomarkers for pancreatic cancer., Translational Oncology, Vol.4, No.2, 83-91, 2011.
(要約)
There is an urgent need to develop novel markers of pancreatic cancer to facilitate early diagnosis. Pancreatic carcinoma is characterized by marked stroma formation with a high number of infiltrating tumor-associated macrophages (TAMs) that originate from circulating mononuclear cells (MNCs). We hypothesized that differential analysis of protein expression and phosphorylation in circulating MNCs from healthy nude mice and nude mice bearing orthotopic human pancreatic cancer would identify a surrogate marker of pancreatic cancer. These differences were analyzed by two-dimensional gel electrophoresis followed by Western blot analysis using antibody against phosphorylated tyrosine proteins (pY). Protein and phosphorylated protein spots of interest were identified by mass spectrometry and validated by Western blot analysis as candidate markers for pancreatic cancer. We found that the expression and phosphorylation of Src family proteins were significantly higher in circulating MNCs from mice bearing pancreatic cancer than in circulating MNCs from healthy mice. TAMs in mice with pancreatic tumors also had higher Src family protein expression and phosphorylation than resident macrophages in the pancreas of healthy mice. The expression and phosphorylation of Src family proteins were correlated with tumor weight; however, increased Src expression and phosphorylation also occurred in MNCs from mice with chronic pancreatitis. This is the first report to explore novel pancreatic tumor markers in circulating MNCs. Although the specificity of the marker for pancreatic cancer was low, it could be used to monitor the disease or to select high-risk patients with chronic pancreatitis.
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21461171
Hideki Tomimoto, Masaki Hanibuchi, Fumitaka Ogushi, Yoshio Okano, Tsutomu Shinohara, Hiroyuki Doi, Akiyoshi Yamamoto, Eiji Takeuchi, Akihiko Yamamoto, Masahiko Azuma, Hiroya Tada, Takanori Kanematsu, Souji Kakiuchi, Hisatsugu Goto, Seiji Yano, Yasuhiko Nishioka and Saburo Sone : A multi-institutional phase II study of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer., Oncology Letters, Vol.2, No.3, 465-470, 2011.
(要約)
S-1 is an oral anticancer fluoropyrimidine agent designed to elevate anticancer activity with a decrease in gastrointestinal toxicity. We conducted a phase II study to evaluate the efficacy and safety of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 administered orally at 40 mg/m(2) twice a day for 21 consecutive days, and cisplatin (60 mg/m(2)) infused intravenously on day 8, repeated every 5 weeks. Of the 44 patients enrolled in the study, 40 were assessable for efficacy and safety. The median number of cycles administered was 3 (range 1-9 cycles). Among the 40 assessable patients, 7 partial responses were observed, with an overall response rate (RR) of 17.5% [95% confidence interval (CI), 5.2-29.8]. Patients with squamous cell carcinoma showed a significantly higher RR (55.5%) than those with adenocarcinoma (9.1%) or other types of NSCLC (0%). The median progression-free survival was 4.3 months (95% CI, 3.4-4.9), the median survival time was 17.9 months (95% CI, 15.0-20.8), and the 1- and 2-year survival rates were 63.3 and 27.3%, respectively. Major grade 3-4 hematologic toxicities were leukocytopenia (7.5%), neutropenia (5.0%), anemia (15.0%) and thrombocytopenia (2.5%). No grade 4 non-hematologic toxicity or treatment-related death occurred. These results suggest that combination chemotherapy with S-1 plus cisplatin is a promising therapeutic candidate for patients with advanced NSCLC, particularly squamous cell carcinoma.
The effects of the soy isoflavones, genistein, daidzein and equol, on experimental colitis were examined. Equol severely perpetrated dextran sulfate sodium (DSS)-induced colitis as evaluated by the weight loss. Production of the anti-inflammatory cytokine, IL-10, from T cells was decreased in the equol-treated mice. The results show that the soy isoflavone, equol, played an important role in the inflammatory response in the gastrointestinal tract.
Jun Kishi, Yasuhiko Nishioka, Tomomi Kuwahara, Souji Kakiuchi, Momoyo Azuma, Yoshinori Aono, Hideki Makino, Katsuhiro Kinoshita, Masami Kishi, R Batmunkh, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice., The European Respiratory Journal, Vol.38, No.2, 415-424, 2011.
(要約)
Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.
Malignant pleural mesothelioma (MPM), arises from the mesothelial cells, is difficult to be diagnosed at an early stage, and is refractory to conventional chemotherapy and radiotherapy. Therefore, the establishment of novel effective therapies is necessary to improve the prognosis for many patients with this disease. Recent studies have demonstrated that angiogenesis plays a significant role in MPM progression, suggesting the importance of tumor vessels as therapeutic targets. To explore molecular pathogenesis and evaluate the efficacy of vascular targeting therapy in MPM, we developed orthotopic implantation SCID mouse models of MPM. We found that selective VEGF inhibitors were effective only in the treatment of high-VEGF-producing MPM models. On the other hand, multiple kinase inhibitor E7080, with inhibitory activity against various angiogenic cytokine receptors, suppressed the progression and prolonged survival of both high-VEGF-producing and low-VEGF-producing MPM models. Further understanding of the functional characteristics of tumor angiogenesis may be essential to improve targeting therapies in MPM. In this review, we introduce current status of clinical strategies and novel therapeutic approaches against angiogenesis in MPM.
Yasuhiko Nishioka, Yoshinori Aono and Saburo Sone : Role of tyrosine kinase inhibitors in tumor immunology., Immunotherapy, Vol.3, No.1, 107-116, 2011.
(要約)
Various immune cells are involved in both innate and acquired immunity against tumors. NK cells and cytotoxic T lymphocytes play a role as effector cells to directly kill tumor cells. On the other hand, antigen-presenting cells, particularly dendritic cells, control tumor-specific immune responses. In addition, much focus has been paid on the immune regulatory cells in tumor sites, including CD4(+)CD25(+) regulatory T cells and myeloid-derived suppressor cells. The recent advances in molecular-targeted therapy for cancer have provided small-molecule kinase inhibitors, which are effective for several hematopoietic malignancies as well as solid tumors in the clinical setting. Most drugs generally have inhibitory effects on several kinases, including tyrosine kinases, which are critical molecules for the survival, proliferation, migration and invasion of tumor cells. Since the host immune surveillance against tumors affects tumor progression, it is of interest to understand how these molecular-targeted drugs affect immune function in the tumor-bearing host. Besides this, there are emerging findings that myeloid cells could be involved in tumor angiogenesis. In this article, we address the role of tyrosine kinase inhibitors in tumor immunology by summarizing their effects on myeloid cells, such as antigen-presenting cells and regulatory cells, and their role in tumor immunity and angiogenesis.
Takanori Kanematsu, Masaki Hanibuchi, Hideki Tomimoto, Shoji Sakiyama, Koichiro Kenzaki, Kazuya Kondo, Bando Hiroyasu, Haku Takashi, Yoneda Kazuo, Hirose Toshiyuki, Toyoda Yuko, Hisatsugu Goto, Sakaguchi Satoshi, Katsuhiro Kinoshita, Momoyo Azuma, Kakiuchi Soji, Jun Kishi, Masahiko Azuma, Tada Hiroya, Sumitomo Masayuki, Yasuhiko Nishioka, Seiji Yano and Saburo Sone : Epidemiological and clinical features of lung cancer patients from 1999 to 2009 in Tokushima Prefecture of Japan, The Journal of Medical Investigation : JMI, Vol.57, No.3,4, 326-333, 2010.
(要約)
Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo-radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection.
(キーワード)
Adolescent / Adult / Age Factors / Aged / Aged, 80 and over / Carcinoma, Non-Small-Cell Lung / Carcinoma, Small Cell / Female / Humans / Japan / Kaplan-Meier Estimate / Lung Neoplasms / Male / Middle Aged / Risk Factors / 喫煙 (smoking) / Young Adult
Hirohisa Ogawa, Masahiko Azuma, S Muto, Yasuhiko Nishioka, A Honjo, T Tezuka, Hisanori Uehara, Keisuke Izumi, A Itai and Saburo Sone : IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma, Clinical and Experimental Allergy, Vol.41, No.1, 104-115, 2010.
(要約)
Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) β is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKβ-NF-κB pathway may be an ideal strategy for the management of airway remodelling. We examined the effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-β, via inhibition of IKKβ. IMD-0354 inhibited IL-13 and IL-1β production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness. IKKβ plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKβ inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.
Satoshi Sakaguchi, Hisatsugu Goto, Masaki Hanibuchi, Shinsaku Otsuka, Hirokazu Ogino, Souji Kakiuchi, Hisanori Uehara, Seiji Yano, Yasuhiko Nishioka and Saburo Sone : Gender difference in bone metastasis of human small cell lung cancer, SBC-5 cells in natural killer-cell depleted severe combined immunodeficient mice., Clinical & Experimental Metastasis, Vol.27, No.5, 351-359, 2010.
(要約)
Lung cancer frequently develops multiple organ metastases, which thus makes this disease a leading cause of malignancy-related death worldwide. A gender difference is reported to affect the incidence and mortality of lung cancer; however, whether and how the gender difference is involved in lung cancer metastasis is unclear. This study evaluated the gender difference in multiple organ metastases in human small cell lung cancer (SBC-5) cells by using natural killer cell-depleted severe combined immunodeficient mice. Among multiple organ metastases, only bone metastasis formation significantly increased in female mice in comparison to males, while no significant difference was observed in the metastases to the liver and lungs. The suppression of androgen by castration or androgen receptor antagonist treatment in male mice also induced a significant increase of bone metastases. The number of osteoclasts in the bone metastatic lesions was greater in female mice and in mice with androgen suppression than in control male. However, there was no significant difference in the serum concentration of parathyroid hormone-related protein (PTHrP) associated with gender or androgen suppression. An in vitro study also indicated that sex steroid treatment had no effect on the proliferation or PTHrP production in SBC-5 cells. These results indicate that the balance of sex steroids therefore plays an important role in the formation of bone metastasis in small cell lung cancer, and suggests diverse mechanisms of interaction between cancer cells and host cells in the bone microenvironment.
(キーワード)
Androgens / Animals / Base Sequence / Bone Neoplasms / Carcinoma, Small Cell / Cell Line, Tumor / Cell Proliferation / DNA Primers / 女性 (female) / Humans / Killer Cells, Natural / Lung Neoplasms / Male / Mice / Mice, SCID / Orchiectomy / Parathyroid Hormone-Related Protein / Reverse Transcriptase Polymerase Chain Reaction / Sex Factors
Tadaaki Yamada, Kunio Matsumoto, Wei Wang, Qi Li, Yasuhiko Nishioka, Yoshitaka Sekido, Saburo Sone and Seiji Yano : Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer., Clinical Cancer Research, Vol.16, No.1, 174-183, 2010.
(要約)
The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, in lung cancer. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR.
Tohru Sakai, Sakina Furoku, Mariko Nakamoto, Emi Shuto, Toshio Hosaka, Yasuhiko Nishioka and Saburo Sone : The Soy isoflavone equol enhances antigen-specific IgE production in ovalbumin-immunized BALB/c mice., Journal of Nutritional Science and Vitaminology, Vol.56, No.1, 72-76, 2010.
(要約)
Although an immunomodulatory role of the soy isoflavone genistein has been demonstrated, the effects of other soy isoflavones on induction of antigen (Ag)-specific immune responses are not known. In this study, we therefore investigated the effects of daidzein and equol on ovalbumin (OVA)-specific T cell and B cell responses in BALB/c mice. Mice that had been treated with 20 mg/kg equol showed a significantly higher level of OVA-specific IgE than control mice. Levels of interferon (IFN)-gamma and interleukin (IL)-4 production were not different between the control and equol groups. However, IL-13 production level in mice administered 20 mg/kg equol was significantly higher than that in control mice. Strong induction of OVA-specific IgE production by equol was also observed in ovariectomized BALB/c mice, suggesting that the immunomodulatory effect of equol is not affected by endogenous estrogen.
Kenji Ikuta, Seiji Yano, Van The Trung, Masaki Hanibuchi, Hisatsugu Goto, Qi Li, Wei Wang, Tadaaki Yamada, Hirokazu Ogino, Soji Kakiuchi, Hisanori Uehara, Yoshitaka Sekido, Toshimitsu Uenaka, Yasuhiko Nishioka and Saburo Sone : E7080, a multi-tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles., Clinical Cancer Research, Vol.15, No.23, 7229-7237, 2009.
(要約)
Malignant pleural mesothelioma (MPM) is a biologically heterogeneous malignant disease with a poor prognosis. We reported previously that the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, effectively inhibited the progression of VEGF-high-producing (but not VEGF-low-producing) MPM cells in orthotopic implantation models, indicating the need for novel therapeutic strategies to improve the poor prognosis of this disease. Therefore, we focused on the multi-tyrosine kinase inhibitor E7080 and assessed its therapeutic efficacy against MPM cells with different proangiogenic cytokine production profiles.
Shinsaku Otsuka, Masaki Hanibuchi, Kenji Ikuta, Seiji Yano, Hisatsugu Goto, Hirokazu Ogino, Tadaaki Yamada, Soji Kakiuchi, Yasuhiko Nishioka, Takashi Takahashi and Saburo Sone : A bone metastasis model with osteolytic and osteoblastic properties of human lung cancer ACC-LC-319/bone2 in natural killer cell-depleted severe combined immunodeficient mice., Oncology Research, Vol.17, No.11-12, 581-591, 2009.
(要約)
Lung cancer is commonly associated with multiple-organ metastasis, and bone is a frequent metastatic site for lung cancer. Lung cancer frequently develops osteolytic, and less frequently osteoblastic, metastasis to bone. Osteolytic metastasis models of lung cancer have been reported, but no osteoblastic metastasis model is available for lung cancer. In the present study, we established a reproducible model of human lung cancer with both osteolytic and osteoblastic changes in natural killer cell-depleted severe combined immunodeficient mice. Intravenous inoculation of ACC-LC-319/bone2 cells resulted in the development of metastatic colonies in the lung, liver, and bone of the mice. As assessed sequentially by X-ray photographs, osteolytic bone lesions were observed by day 28, and then osteoblastic lesions were detected by day 35. Histological examination revealed the presence of bony spurs, a hallmark of osteoblastic bone metastasis, where osteoclasts were hardly observed. Treatment with an anti-human vascular endothelial growth factor antibody, bevacizumab, as well as zoledronate, inhibited the number of experimental bone metastases, including osteoblastic changes produced by ACC-LC-319/bone2 cells. These results indicate that our bone metastasis model by ACC-LC319/bone2 might be useful to understand the molecular pathogenesis of osteolytic and osteoblastic metastasis, and to identify molecular targets to control bone metastasis of lung cancer.
Akemi Sugita, Hirohisa Ogawa, Masahiko Azuma, Susumu Muto, Akifumi Honjo, Hiroaki Yanagawa, Yasuhiko Nishioka, Kenji Tani, Akiko Itai and Saburo Sone : Antiallergic and anti-inflammatory effects of a novel IκB kinase β inhibitor, IMD-0354, in a mouse model of allergic inflammation., International Archives of Allergy and Immunology, Vol.148, No.3, 186-198, 2008.
(要約)
BACKGROUND: Nuclear factor (NF)-kappaB is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. I kappaB kinase beta (IKK beta), which is responsible for activation of the NF-kappaB pathway, may be an ideal molecular target to inhibit this process. IMD-0354 [N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide] is an attractive novel IKK beta inhibitor that prevents the production of inflammatory cytokines in various diseases, although it is not known if IMD-0354 is effective against allergic inflammation. This study aimed to elucidate the antiallergic effects of a newly synthesized IKK beta inhibitor, IMD-0354, in a mouse model of allergic inflammation. METHODS: We generated ovalbumin (OVA)-sensitized mice which were then challenged with OVA. IMD-0354 was administered intraperitoneally to therapeutic groups. Lung histopathology and the concentrations of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and supernatants of lung homogenates were determined. RESULTS: Administration of IMD-0354 ameliorated airway hyperresponsiveness and reduced the numbers of bronchial eosinophils and mucus-producing cells in OVA-sensitized mice. The total numbers of cells and eosinophils in BALF were also reduced by treatment with IMD-0354. Treatment with IMD-0354 inhibited the production of Th2 cytokines such as interleukin (IL)-5 and IL-13 and eotaxin in the airways and/or lungs of OVA-sensitized mice, but it did not affect the restoration of Th1 cytokines such as IL-12 and interferon-gamma under the same experimental conditions. IgE production was also inhibited by IMD-0354. CONCLUSION: A specific IKK beta inhibitor, IMD-0354, improved allergic airway inflammation and hyperresponsiveness in mice. IMD-0354 may have therapeutic potential for bronchial asthma.
Kazuhide Yoneda, Junji Ueno, Sadamitsu Nishihara, Tetsuya Tsujikawa, Naomi Morita, Hideki Otsuka, Kaori Furutani, Hiromu Nishitani, Kazuya Kondo and Yasuhiko Nishioka : Postprocessing technique with MDCT data improves the accuracy of the detection of lung nodules, Radiation Medicine, Vol.25, No.10, 511-515, 2007.
(要約)
The aim of this study was to determine whether postprocessing techniques could improve the accuracy of detecting lung nodules. A total of 154 segmented lung volumes of multidetector-row computed tomography (MDCT) data were the subject of the study. Lung nodules were present in 88 volumes and absent in 66 volumes. We prepared four groups: (1) 7- or 10-mm thick-section axial images; (2) 1-mm thin-section axial images; (3) sliding slab maximum intensity projection (MIP) images with a slab thickness of 15 mm; and (4) sliding slab volume rendering (VR) images with a slab thickness of 15 mm. Sixteen physicians reviewed each group in interactive cine mode. The observers' performance in the detection of lung nodule was evaluated by receiver operating characteristic (ROC) analysis. The observers' performance of the MIP and VR groups was significantly better than in other two groups. There was no significant difference statistically between the thin and thick groups. The detectability of lung nodules is improved with the use of sliding slab MIP and VR using thin-section image data. Thin-section volume data are essential for improving diagnostic accuracy, but observation of thin-section images without utilization of image-processing techniques dose not improve diagnostic accuracy.
M. Azuma, Yasuhiko Nishioka, Y. Aono, M. Inayama, H. Makino, Jun Kishi, Masayuki Shono, Katsuhiro Kinoshita, H. Uehara, H. ogushi, K. Izumi and Saburo Sone : Role of 1-acid glycoprorein in theraqeutic antifibrotic effects of imatinib plus macrolides in mice., American Journal of Respiratory and Critical Care Medicine, Vol.176, No.12, 1243-1250, 2007.
(要約)
Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect. To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance. The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice. Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects. AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.
Ali Jalili, Shuji Ozaki, Tomoko Hara, Hironobu Shibata, Toshihiro Hashimoto, Masahiro Abe, Yasuhiko Nishioka and Toshio Matsumoto : Induction of HM1.24 peptide specific cytotoxic T lymphocytes by using peripheral-blood stem-cell harvests in patients with multiple myeloma, Blood, Vol.106, No.10, 3538-3545, 2005.
(要約)
HM1.24 antigen is preferentially overexpressed in multiple myeloma (MM) cells but not in normal cells. To explore the potential of HM1.24 as a target for cellular immunotherapy, we selected 4 HM1.24-derived peptides that possess binding motifs for HLA-A2 or HLA-A24 by using 2 computer-based algorithms. The ability of these peptides to generate cytotoxic T lymphocytes (CTLs) was examined in 20 healthy donors and 6 patients with MM by a reverse immunologic approach. Dendritic cells (DCs) were induced from peripheral-blood mononuclear cells of healthy donors or peripheral-blood stem-cell (PBSC) harvests from patients with MM, and autologous CD8(+) T cells were stimulated with HM1.24 peptide-pulsed DCs. Both interferon-gamma-producing and cytotoxic responses were observed after stimulation with either HM1.24-126 or HM1.24-165 peptides in HLA-A2 or HLA-A24 individuals. The peptide-specific recognition of these CTLs was further confirmed by tetramer assay and cold target inhibition assay. Importantly, HM1.24-specific CTLs were also induced from PBSC harvests from patients with MM and these CTLs were able to kill MM cells in an HLA-restricted manner. These results indicate the existence of functional DCs and HM1.24-specific CTL precursors within PBSC harvests and provide the basis for cellular immunotherapy in combination with autologous PBSC transplantation in MM.
Yoshinori Aono, Yasuhiko Nishioka, Mami Inayama, Jun Kishi, Momoyo Ugai, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Imatinib as a Novel Antifibrotic Agent in Bleomycin-induced Pulmonary Fibrosis in Mice, American Journal of Respiratory and Critical Care Medicine, Vol.171, No.11, 1279-1285, 2005.
(要約)
Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
Yanjmaa Bira, Kenji Tani, Yasuhiko Nishioka, juuya Miyata, Keiko Sato, Akihito Hayashi, Yutaka Nakaya and Saburo Sone : Transforming growth factor β stimulates rheumatoid synovial fibroblasts via the type receptor, Modern Rheumatology, Vol.15, No.2, 108-113, 2005.
(要約)
Transforming growth factor (TGF)-beta regulates the function of fibroblasts, and has been shown to have a role in the pathogenesis of rheumatoid arthritis (RA) because several studies have demonstrated the presence of TGF-beta in the synovial tissue and synovial fluids of RA patients. In this study, we examined the expression of TGF-beta receptors in synovial fibroblasts of patients with RA and demonstrated the significance in functional responses of synovial fibroblasts to TGF-beta in this disorder. Transforming growth factor beta1 stimulated the expression of connective tissue growth factor (CTGF) in fibroblasts of patients with RA more than in those of patients with osteoarthritis (OA). Transforming growth factor beta1 induced the chemotactic migration of RA synovial fibroblasts and inhibited their proliferation significantly more than OA synovial fibroblasts. Both RA and OA synovial fibroblasts expressed detectable amounts of TGF-beta receptor type II mRNA, but the expression was higher in RA patients than in OA patients, as assessed by reverse transcriptase-polymerase chain reaction. There was no significant difference in the expression of TGF-beta receptor type I or type III in synovial fibroblasts between RA and OA patients. These results indicate that synovial fibroblasts of RA patients express the increased TGF-beta receptor type II, which is associated with altered responses to TGF-beta observed in CTGF expression, chemotaxis, and proliferation of RA synovial fibroblasts, and may have an important role in the pathogenesis of RA.
Masaki Hanibuchi, Yuka Matsumori, Yasuhiko Nishioka and Saburo Sone : A case of sarcoidosis accompanying squamous cell carcinoma in the mandibular gingiva, The Journal of Medical Investigation : JMI, Vol.52, No.1-2, 118-121, 2005.
(要約)
A 51-year-old man with a history of gingival cancer two years previously was referred to our hospital for further examination of chest abnormal shadow. Bilateral hilar and mediastinal lymphadenopathy, diffuse small nodular opacities and pleural nodules were observed in chest high resolution CT. Serum angiotensin converting enzyme and lysozyme were elevated. Transbronchial lung biopsy specimens demonstrated non-caseous granuloma. CD4-positive lymphocytes were increased in broncho-alveolar lavage (CD4/CD8 ratio 5.47). The patient was diagnosed as having sarcoidosis. Radiological findings were improved and serum angiotensin converting enzyme level was decreased to within the normal range by corticosteroid therapy (prednisolone 30 mg/day). This is the first report of sarcoidosis accompanying the gingival cancer.
Kazuyoshi Manabe, Yasuhiko Nishioka, Jun Kishi, Mami Inayama, Yoshinori Aono, Yoichi Nakamura, Fumitaka Ogushi, Hiroyasu Bando, Kenji Tani and Saburo Sone : Elevation of macrophage-derived chemokine in eosinophilic pneumonia: a role of alveolar macrophages, The Journal of Medical Investigation : JMI, Vol.52, No.1,2, 85-92, 2005.
(要約)
Macrophage-derived chemokine (MDC/CCL22) and thymus-and activation-regulated chemokine (TARC/CCL17) are ligands for CC chemokine receptor 4. Recently, TARC has been reported to play a role in the pathogenesis of idiopathic eosinophilic pneumonia (IEP). The purpose of this study was to evaluate the role of MDC in IEP and other interstitial lung diseases (ILDs). MDC and TARC in the bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay in patients with ILDs and healthy volunteers (HV). We also examined the expression of MDC mRNA in alveolar macrophages (AM) by real-time quantitative reverse transcriptase-polymerase chain reaction. Both MDC and TARC were detected only in BALF obtained from IEP patients. The concentration of MDC was higher than that of TARC in all cases. The level of MDC in IEP correlated with that of TARC. AM from IEP patients expressed a significantly higher amount of MDC than that from HV at the levels of protein and mRNA. MDC in BALF from IEP dramatically decreased when patients achieved remission. These findings suggest that MDC, in addition to TARC, might be involved in the pathogenesis of IEP, and AM play a role in the elevation of MDC in IEP.
Ning Ge, Yasuhiko Nishioka, Yoichi Nakamura, Yoshio Okano, Kazuo Yoneda, Hirohisa Ogawa, Akemi Sugita, Hiroaki Yanagawa and Saburo Sone : Synthesis and Secretion of Interleukin-15 by Freshly Isolated Human Bronchial Epithelial Cells, International Archives of Allergy and Immunology, Vol.135, No.3, 235-242, 2004.
(要約)
Interleukin-15 (IL-15), which shares many functional activities of IL-2, is proposed as a potential modulator of T and natural killer (NK) cell-mediated inflammatory diseases. Since IL-15 gene is expressed in various cell types including epithelial cells, we examined how proinflammatory modulators affect IL-15 gene expression in both freshly isolated human bronchial epithelial cells (HBECs) and the human bronchial epithelial cell line BEAS-2B. HBECs were obtained from 25 patients with primary lung cancer by bronchial brushing under bronchofiberscopy. The expressions of IL-15 and its receptor were examined using reverse transcription-polymerase chain reaction (RT-PCR), Northern blot analysis and enzyme-linked immunosorbent assay. IL-15 mRNA was constitutively expressed in the cells and was upregulated by several proinflammatory cytokines such as IL-1beta, tumor necrosis factor-alpha, interferon-gamma (IFN-gamma) and lipopolysaccharide. In addition, IFN-gamma but not other cytokines induced the synthesis and secretion of IL-15 protein. Investigation of IL-15 receptor expression using RT-PCR showed that IL-15Ralpha and IL-2Rbeta chains but not IL-2Ralpha or gamma chain were constitutively expressed in these cells. Bronchial epithelial cells may contribute to T and NK cell-mediated airway inflammation through IL-15 production.
Masato Okamoto, Sachiko Furuichi, Yasuhiko Nishioka, Tetsuya Oshikawa, Tomoyuki Tano, Sharif Uddin Ahmed, Kiyoshi Takeda, Shizuo Akira, Yoshiki Ryoma, Yoichiro Moriya, Motoo Saito, Saburo Sone and Mitsunobu Sato : Expression of Toll-Like Receptor 4 on Dendritic Cells Is Significant for Anticancer Effect of Dendritic Cell-Based Immunotherapy in Combination with an Active Component of OK-432, a Streptococcal Preparation, Cancer Research, Vol.64, No.15, 5461-5470, 2004.
(要約)
A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-gamma and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4(-/-)) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4(-/-) mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4(-/-) mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.
Toru Asano, Fumitaka Ogushi, Kenji Tani, Hiroyuki Tamiya, Yasuhiko Nishioka and Saburo Sone : Increased macrophage inflammatory protein-1α and -1β in BAL fluid of bronchiolitis obliterans organizing pneumonia, Respirology, Vol.8, No.4, 461-466, 2003.
(要約)
CC chemokines are mainly chemotactic for monocytes and lymphocytes. The aim of this study was to evaluate the involvement of the CC chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in the pathogenesis of bronchiolitis obliterans organizing pneumonia (BOOP). The concentrations of MIP-1alpha and MIP-1beta in BAL fluid (BALF) obtained from patients with BOOP (n = 13) and control patients (CP, n= 18) were measured by enzyme-linked immunosorbent assay. MIP-1alpha in BALF was significantly higher in patients with BOOP (mean +/- SD; 123.8 +/- 98.0 pg/mL) than in CP (62.5 +/- 46.1 pg/mL). Significantly higher MIP-1beta was also detected in patients with BOOP (51.6 +/- 72.5 pg/mL) than in CP (6.4 +/- 3.7 pg/mL). The concentration of MIP-1alpha significantly correlated with the percentage of lymphocytes in BALF, and the concentration of MIP-1beta significantly correlated with the numbers of lymphocytes, neutrophils and eosinophils in BALF. Both MIP-1alpha and MIP-1beta in BALF were decreased after corticosteroid therapy and this was accompanied by decreased lymphocytes in BALF. This study suggests that MIP-1alpha and MIP-1beta may play important roles in the recruitment of immuno-inflammatory cells into the lungs, and may contribute to the pathogenesis of BOOP.
H Ogawa, N Nishimura, Yasuhiko Nishioka, M Azuma, Hiroaki Yanagawa and Saburo Sone : Adenoviral interleukin-12 gene transduction into human bronchial epithelial cells:up-regulation of pro-inflammatory cytokines and its prevention by corticosteroids, Clinical and Experimental Allergy, Vol.33, No.7, 921-929, 2003.
(要約)
One of the potential effects of IL-12 is to restore Th1/Th2 balance. Therefore, we investigated the possibility of developing a system for local delivery of IL-12 into the airways by examining protein expression in a human bronchial epithelial cell line (BEAS-2B) after adenoviral IL-12 gene transduction. The effects of dexamethasone on the gene-modified cells were also examined. Adenoviral vectors AxCAegfp and Ax1CIhp40ip35 were used to transduce enhanced green fluorescence protein and IL-12 genes, respectively, into BEAS-2B cells. Wild-type and IL-12 gene-transduced BEAS-2B cells were then incubated with or without dexamethasone, and concentrations of IL-12, IFN-gamma, IL-6, IL-8, granulocyte macrophage-colony stimulating factor and chemokines (TARC and RANTES) in the supernatant were measured by ELISA. IL-12 receptor expression was analysed by flow cytometry and RT-PCR. The efficiency of transgene expression in BEAS-2B cells at a multiplicity of infection of 30 was approximately 80%. Gene-modified BEAS-2B cells produced biologically active IL-12, regardless of dexamethasone treatment. While IL-12 gene transduction led to increased production of IL-6 and IL-8 by BEAS-2B cells, expressions of these proteins were suppressed by dexamethasone. Addition of exogenous IL-12 failed to augment BEAS-2B cell IL-6 and IL-8 production, and IL-12 receptor expression by BEAS-2B cells was not detected. Our findings suggest that adenoviral IL-12 gene transduction may be effective in inducing IL-12 expression in the airways, and could be a potential approach in the management of bronchial asthma.
Seiji Yano, Yasuhiko Nishioka, Hisatsugu Goto and Saburo Sone : Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules., Cancer Science, Vol.94, No.6, 479-485, 2003.
(要約)
Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non-sprouting (the enlargement, splitting, and fusion of pre-existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non-small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti-tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti-tumor potential in preclinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials.
Hiroya Tada, Fumitaka Ogushi, Kenji Tani, Yasuhiko Nishioka, Jun-ya Miyata, Keiko Sato, Toru Asano and Saburo Sone : Increased binding and chemotactic capacities of PDGF-BB on fibroblasts in radiation pneumonitis, Radiation Research, Vol.159, No.6, 805-811, 2003.
(要約)
Although pulmonary fibrosis is a frequent and serious consequence of radiotherapy for thoracic malignant diseases such as lung cancer, the pathogenesis of this radiation-induced lung disorder remains unclear. To clarify the mechanisms underlying radiation pneumonitis and pulmonary fibrosis, we investigated the expression of platelet-derived growth factor receptor (PDGFR) on fibroblasts obtained from irradiated rat lungs and on control fibroblasts. Whole lungs of male Wistar rats were irradiated with a single dose of 15 Gy, and lung fibroblasts were isolated at 4 weeks after the irradiation. The chemotactic response of irradiated lung fibroblasts to PDGF-BB was significantly higher than that of control lung fibroblasts, whereas there was no significant difference between irradiated lung fibroblasts and control lung fibroblasts in the response to PDGF-AA. Receptor binding assay showed more specific binding sites for PDGF-BB on irradiated lung fibroblasts than on control lung fibroblasts, and the displacement of (125)I-labeled PDGF binding to fibroblasts by unlabeled PDGF showed that (125)I-labeled PDGF-BB was displaced by PDGF-BB but not by PDGF-AA. These results suggest that the increased binding sites for PDGF-BB on irradiated lung fibroblasts correspond mainly to PDGFRB. Scatchard analysis of the saturation data demonstrated an approximately twofold increase both in the number of PDGF-BB binding sites and in the binding affinity in irradiated lung fibroblasts compared to that in control lung fibroblasts. Those results suggest that the increased chemotactic response of irradiated lung fibroblasts to PDGF-BB is related to the overexpression of PDGFRB, which may have an important role in the pathogenesis of radiation-induced pneumonitis and pulmonary fibrosis.
Yasuhiko Nishioka, Hua Wen, Kayo Mitani, Paul D. Robbins, Michael T. Lotze, Saburo Sone and Hideaki Tahara : Differential effects of IL-12 on the generation of alloreactive CTL mediated by murine and human dendritic cells: a critical role for nitric oxide, Journal of Leukocyte Biology, Vol.73, No.5, 621-629, 2003.
(要約)
We examined the mechanisms involved in interleukin (IL)-12-mediated suppression of cellular immunity in mice using allogeneic mixed leukocyte reaction (MLR) stimulated by dendritic cells (DCs) in vitro and compared the effect of IL-12 on MLR in mice and humans. Although IL-12 stimulated human MLR, the addition of IL-12 or interferon-gamma (IFN-gamma) resulted in a dose-dependent suppression of MLR in mice. The treatment with N(G)-monomethyl-L-arginine (L-NMMA) completely abrogated IL-12- and IFN-gamma-mediated suppression of MLR in mice. Furthermore, IL-12 enhanced the alloreactive cytolytic T lymphocyte (CTL) induction in human MLR, whereas the addition of L-NMMA was required to generate alloreactive CTLs in the presence of IL-12 in mice. Nitric oxide (NO) was detected only in mouse MLR. Murine DCs could produce NO, but neither human CD34(+) cell- nor monocyte-derived DCs produced a detectable amount of NO. These results suggest that NO produced by DCs might play an important role in IL-12-mediated immune suppression in mice but not in humans.
Kayo Mitani, Yasuhiko Nishioka, Kazue Yamabe, Hirohisa Ogawa, Toyokazu Miki, Hiroaki Yanagawa and Saburo Sone : Soluble Fas in malignant pleural effusion and its expression in lung cancer cells, Cancer Science, Vol.94, No.3, 302-307, 2003.
(要約)
Soluble Fas (sFas) has the ability to block Fas-mediated apoptosis, suggesting that sFas at tumor sites might inhibit tumor cell-killing by immune effector cells. We examined the sFas level in pleural effusion associated with lung cancer. The level of sFas in malignant pleural effusion was significantly higher than those in transudate and tuberculous pleural effusion. There was no significant difference in the sFas concentration among various histological types of lung cancer. The cytotoxicity mediated by anti-Fas agonistic antibody against Jurkat cells was inhibited by the addition of malignant pleural effusion, being inversely correlated with the sFas concentration. When Fas expression was examined using flow cytometry, eight of ten (80%) lung cancer cell lines expressed cell surface Fas. On the other hand, sFas protein and mRNA were detected in six of ten (60%) lung cancer cell lines, but there was no correlation between Fas and sFas expression. Furthermore, although the expressions of Fas and sFas were clearly detected in tumor cells derived from malignant effusion, the sFas expression was down-regulated in an in vitro culture. These results suggest that sFas in malignant pleural effusion is at least in part produced by lung cancer cells, and might play a role in local immunosuppression by tumor cells.
Hiroyoshi Sei, Atsuko Sano, Hiromi Ohno, Kazue Yamabe, Yasuhiko Nishioka, Saburo Sone and Yusuke Morita : Age-related changes in control of blood pressure and heart rate during sleep in the rat, Sleep, Vol.25, No.3, 279-285, 2002.
(要約)
The aim of this study was to determine age-related changes in the control of mean arterial pressure (MAP) and heart rate (HR) during sleep, and its relationship to the baroreflex in aging. MAP, HR, body temperature (TP), spontaneous activity (ACT), and sleeping/waking duration were monitored for 24 hours in groups of young (10-12 wk old) and old (23-24 mo old) rats. The sleep laboratory at the University of Tokushima. Subjects were 8 young (10-12 wk old) and 7 old (23-24 mo old) Wistar rats. Reflex control of HR was evaluated by examining various pressure responses to an intravenous bolus injection of phenylephrine and sodium nitroprusside. MAP and TP were recorded by a radiotelemetry system. HR was detected from the AP signal. ACT was counted by a photo-sensor system. In the case of old rats, the sensitivity of baroreflex control of HR was significantly depressed, and the spontaneous increase of MAP and HR during REM sleep and the MAP drop at the end of REM sleep were significantly enhanced. The old rats showed no large deterioration of the circadian profiles of MAP, HR, TP, and the amount of sleep. The baroreflex dysfunction is considered to appear in an early stage of the aging process, and to affect the control of MAP and HR during sleep.
Takashi Itokawa, Hiroki Nokihara, Yasuhiko Nishioka, Saburo Sone, Yukihide Iwamoto, Yuji Yamada, Julie Cherrington, Gerald McMahon, Masabumi Shibuya, Michihiko Kuwano and Mayumi Ono : Antiangiogenic Effect by SU5416 Is Partly Attributable to Inhibition of Flt-1 Receptor Signaling, Molecular Cancer Therapeutics, Vol.1, No.5, 295-302, 2002.
(要約)
Interaction between vascular endothelial growth factor (VEGF) and its cognate receptors, KDR/Flk-1 and Flt-1, of vascular endothelial cells is expected to induce an angiogenesis "switch" in tumors and other angiogenesis-associated diseases. SU5416, a selective inhibitor of the KDR/Flk-1 tyrosine kinase, is known to be a potent inhibitor of tumor angiogenesis. In this study, we first observed that SU5416 inhibited Flt-1 tyrosine kinase activity at similar doses, in addition to inhibiting KDR/Flk-1 tyrosine kinase activity in response to VEGF. SU5416 inhibited cell migration of human vascular endothelial cells expressing both Flt-1 and KDR in response to VEGF and also inhibited the cell migration in response to placenta growth factor (PIGF), a specific ligand for Flt-1. Chemotaxis of monocytes expressing only Flt-1 was also inhibited by SU5416 in a dose-dependent manner. Moreover, SU5416 was found to inhibit tyrosine kinase of Flt-1 in response to PIGF in vitro. And angiogenesis induced by PIGF in a Matrigel plug assay was inhibited by administration of SU5416. The antiangiogenic effects by this VEGF receptor-targeting compound appeared to be mediated through interference not only with KDR/Flk-1 but also with Flt-1. Cell migration of vascular endothelial cells and monocytic cells through Flt-1, thus, might play a key role in VEGF-induced tumor angiogenesis in concert with KDR/Flk-1.
Hirohisa Ogawa, Naoki Nishimura, Yasuhiko Nishioka, Masahiko Azuma, Hiroaki Yanagawa and Saburo Sone : Interleukin(IL)-12 gene transduction and its functional expression into human bronchial epithelial cells (BEAS-2B) by adenovirus vector, The Journal of Medical Investigation : JMI, Vol.49, No.1,2, 74-82, 2002.
(要約)
Interleukin (IL)-12 is known as a cytokine that augments the Th1 type response. Especially in allergic diseases such as a bronchial asthma, IL-12 induced restoration of the balance of the Th1/Th2 type immune response is an attractive strategy. In this study, the functional properties of the human bronchial epithelial cell line (BEAS-2B) transduced by an adenoviral vector encoding the human IL-12 gene were examined. Adenovirus vectors, AxCAegfp and Ax1CIhp40ip35 were transduced into BEAS-2B cells. Wild and gene-transduced BEAS-2B cells were incubated and the concentrations of IL-12 and IFN-gamma produced by co-cultured lymphocytes in the supernatant were measured using ELISA. The expressions of surface adhesion molecules, such as CD54 and CD106 were analyzed using flow cytometry. The efficiency of transgene expression of BEAS-2B cells was in a multiplicity of infection (MOI)-dependent manner and at an MOI of 30, the efficiency was approximately 80%. The gene-modified BEAS-2B cells produced biologically active IL-12 in dose- and time-dependent manners. IL-12 gene transduction did not significantly affect the expression of adhesion molecules (CD 54, CD106 and HLA-A,B,C) by BEAS-2B cells. These results suggest that the IL-12 gene may be successfully transduced into human bronchial epithelial cells by adenoviral vector to express IL-12 activity in vivo.
Yasuhiko Nishioka, Wen Hua, Naoki Nishimura and Saburo Sone : Genetic modification of dendritic cells and its application for cancer immunotherapy, The Journal of Medical Investigation : JMI, Vol.49, No.1,2, 7-17, 2002.
(要約)
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs). DCs pulsed with peptides of tumor-associated antigens (TAA) and tumor lysate have been used in cancer immunotherapy. An early clinical study demonstrated the safety of the use of DCs, but the clinical response was not sufficient. The gene-modification of DCs with TAA and soluble factor genes such as cytokine and chemokine genes has been examined to enhance the antigen-presenting capacity of DCs. Viral vectors including retroviruses and adenoviruses have been reported to be useful to obtain a sufficient transduction efficiency into DCs. TAA gene-transduced DCs could have several advantages compared with TAA peptide-pulsed DCs as follows: 1) The use of TAA gene-modified DCs are not restricted by MHC haplotypes. 2) The gene transduction with TAA genes is likely to present the unknown TAA peptides on DCs. 3) The gene-modified DCs show the prolonged presentation of TAA peptides. The transduction of DCs with cytokine genes including IL-12 and GM-CSF have also been reported to argument the antitumor effects of DCs. Although the results in the experimental systems were promising, the clinical application of gene-modified DCs includes several problems such as the standardization of methods of manipulation and gene-transduction of DCs. Approaches to solve them require further studies.
Y. Suzuki, Hiroaki Yanagawa, Yasuhiko Nishioka, N. Nishimura and Saburo Sone : Effect generation of dendritic cells from alveolar and pleural macrophages as well as blood monocytes with lung cancer, Lung Cancer, Vol.34, No.2, 195-205, 2001.
(要約)
In this study, we investigated the generation of dendritic cells (DCs) from blood monocytes and mature macrophages from untreated primary lung cancer patients. Blood monocytes were separated by adherence from blood mononuclear cells (MNC) from ten lung cancer patients and ten control subjects, and cultured for 7 days in medium with granulocyte/macrophage colony-stimulating factor (GM-CSF) plus interleukin (IL-) 4. In all cases examined, DCs with typical characteristics were obtained even in lung cancer patients after 7 days culture with these cytokines, and there was no significant difference in phenotype and stimulatory activity in allogeneic lymphocyte proliferation between DCs derived from monocytes from lung cancer patients and those from control subjects. Next, we examined whether alveolar and pleural macrophages in malignant pleural effusion separated by magnetic beads could differentiate to immunostimulatory DCs. Conventional culture conditions with GM-CSF and IL-4 did not induce efficient numbers of DCs from mature macrophages, whereas the addition of tumor necrosis factor-alpha (TNF-alpha) to GM-CSF and IL-4 effectively contributed to generate DCs. These findings suggest that both mature macrophages and blood monocytes from lung cancer patients could differentiate to DCs, and might be a useful source of DCs for immunotherapy.
Masaki Hanibuchi, Seiji Yano, Yasuhiko Nishioka, Hiroaki Yanagawa, Toyokazu Miki and Saburo Sone : Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966., Clinical & Experimental Metastasis, Vol.18, No.5, 353-360, 2001.
(要約)
serum against SBC-3/DOX cells to a similar extent compared with parental SBC-3 cells. Pretreatment of human effector cells with various cytokines induced further enhancement of the KM966-dependent ADCC against SBC-3/DOX cells. Intravenous injection of SBC-3 or SBC-3/DOX cells into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice developed metastases in multiple organs (liver, kidneys and lymph nodes). Interestingly, SBC-3/DOX cells produced metastases more rapidly than SBC-3 cells, suggesting more aggressive phenotype of SBC-3/DOX cells than their parental cells in vivo. Systemic treatment with KM966, given on days 2 and 7, drastically inhibited the formation of multiple-organ metastases produced by both SBC-3 and SBC-3/DOX cells, indicating that KM966 can eradicate metastasis by SCLC cells irrespective of MDR phenotype. These findings suggest that the mouse-human chimeric KM966 targets the GM2 antigen, and might be useful for the immunological circumvention of multiple-organ metastases of refractory SCLC.
(キーワード)
Animals / Antibodies, Monoclonal / Antineoplastic Agents / Carcinoma, Small Cell / Cytokines / Doxorubicin / Drug Resistance, Multiple / Drug Resistance, Neoplasm / G(M2) Ganglioside / Humans / Lung Neoplasms / Male / Mice / Mice, SCID
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11467766
Yasuhiko Nishioka, Naoki Nishimura, Yoshihiro Suzuki and Saburo Sone : Human monocyte-derived and CD83(+) blood dendritic cells enhance NK cell-mediated cytotoxicity., European Journal of Immunology, Vol.31, No.9, 2633-2641, 2001.
(要約)
Dendritic cells (DC) are known to be the most potent APC and to stimulate antigen-specific T cell responses. Recently it was reported that murine DC were also capable of modulating the innate immunity by stimulating NK cells through cell-to-cell contact. In the present study, we examined whether human DC could affect NK activity. Both monocyte-derived and CD83(+) blood DC were tested. The addition of DC to cultures of CD56(+) cells resulted in the significant dose-dependent enhancement of the killing activity against various NK-sensitive targets. The resultant activity was comparable to that induced by optimal concentrations of various cytokines, including IL-2, IL-12, IL-15 and IFN-gamma. Interestingly, DC enhanced the cytotoxicity of CD3(-)CD56(+) NK cells, but not that of CD3(+)CD56(+) T cells. Experiments using transwells clearly demonstrated that the enhancement of NK activity by DC was mediated by soluble factors produced by DC. The culture supernatants of DC also stimulated NK activity. The treatment of both DC and their supernatants with anti-human IL-12 or IL-18 antibodies did not block the enhancement of NK cell-mediated cytolysis by DC, indicating that other factor(s) produced by DC were responsible for the enhancement of NK activity. These results suggest that human myeloid DC can modulate innate immunity by enhancing NK activity.
Naoki Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara, Hirohisa Ogawa, Sayaka Yamamoto, Kenji Tani and Saburo Sone : Novel centrifugal method for simple and highly efficient adenovirus-mediated green fluorescence protein gene transduction into human monocyte-derived dendritic cells, Journal of Immunological Methods, Vol.253, No.1-2, 113-124, 2001.
(要約)
Dendritic cells (DC) are professional antigen-presenting cells in the immune system. Gene transduction of DC with tumor-associated antigen (TAA) or other genes that enhance the immune reaction has been considered theoretically useful for DC-based immunotherapy. However, gene transduction of DC generated from human peripheral blood monocytes has been difficult due to its low efficiency, even when adenoviral vector was used at high multiplicity of infection (MOI). In the present study, we examined the effect of centrifugal force to enhance efficiency of adenovirus-mediated gene transduction into human monocyte-derived DC at various rotor speeds at various temperatures for various times. We judged the transduction efficiency using enhanced green fluorescence protein (EGFP)-expressing adenoviral vector, and the best condition for centrifugal transduction was determined as 2000 x g at 37 degrees C for 2 h at an MOI of 10 or greater. At an MOI of 50 without centrifugation, the gene transduction efficiency was about 66% and mean fluorescence intensity (MFI) of EGFP expression was about 150 (at 37 degrees C for 2 h). With centrifugal transduction (2000 x g at an MOI of 50 at 37 degrees C for 2 h), 86% or more DC were gene-modified, and especially, MFI of EGFP expression was highly enhanced (MFI: about 3100 or greater). Centrifugally gene-transduced DC were not damaged and were thoroughly functional as measured by mixed lymphocyte reaction (MLR). The centrifugal method was also applicable to human monocytes and K562 cells. The centrifugal transduction method with adenoviral vector might be helpful for the generation of gene-modified DC.
H Nokihara, Seiji Yano, Yasuhiko Nishioka, M Hanibuchi, T Higasida, T Tsuruo and Saburo Sone : A new quinoline derivative MS-209 reverse multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells, Japanese Journal of Cancer Research, Vol.92, No.7, 785-792, 2001.
(要約)
Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS-209 is a novel quinoline compound, which reverses P-glycoprotein (P-gp)-mediated MDR. We previously reported that MS-209 reversed in vitro MDR of human SCLC (SBC-3 / ADM and H69 / VP) cells expressing P-gp. In the present study, we determined the therapeutic effect of MS-209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC-3 / ADM cells expressing P-gp were highly resistant to etoposide (VP-16), adriamycin (ADM), and vincristine (VCR) in vitro, compared with parental SBC-3 cells lacking P-gp expression. MS-209 restored chemosensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro. Intravenous injection with SBC-3 or SBC-3 / ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3 / ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3 / ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3 / ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3 / ADM cells to multiple organs. These findings suggest that MS-209 reversed the MDR of SBC-3 / ADM cells, but not SBC-3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS-209, may be useful for treatment of refractory SCLC patients with multiorgan metastases.
Naoki Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara and Saburo Sone : Enhanced efficiency by centrifugal manipulation of adenovirus-mediated interleukin 12 gene transduction into human monocyte-derived dendritic cells., Human Gene Therapy, Vol.12, No.4, 333-346, 2001.
(要約)
Transduction of dendritic cells (DCs) with genes encoding tumor-associated antigen or with other genes that enhance immune reaction has been theorized to be potentially useful for enhancing the efficiency of DC-based immunotherapy. However, gene transduction of DCs generated from human peripheral blood monocytes has been of limited use because of the low efficiency. Here, we report that the efficiency of in vitro adenovirus-mediated gene transduction into human monocyte-derived DCs can be dramatically enhanced by centrifugation. The best conditions for centrifugal gene transduction were determined to be as follows: 2000 x g at 37 degrees C for 2 hr at a multiplicity of infection (MOI) of 10 or greater. By this centrifugal method, approximately 88 and 70% of DCs were gene transducible at an MOI of 50 and 10, respectively. Functional analysis showed that DCs transduced with human interleukin 12 (IL-12)-expressing adenoviral vector under the optimal conditions of centrifugation stably produced IL-12 protein at high levels (8.1 ng/10(6) cells/48 hr). IL-12 gene-modified DCs (DC/IL-12) displayed a more mature phenotype than nontransduced DCs, as judged by decreased expression of CD1a and increased expression of CD83, B7.1 (CD80), B7.2 (CD86), and MHC class I and II molecules. DC/IL-12 showed a high phagocytic ability similar to nontransduced DCs and were significantly superior to control DCs in the stimulation of autologous and allogeneic T lymphocyte responses. The centrifugal transduction method with adenoviral vector might be useful for efficient generation of gene-modified DCs because it is very simple, highly efficient, reproducible, and not cytopathic. IL-12 gene-modified human DCs may be therapeutically useful as a good adjuvant in DC-based immunotherapy.
Saburo Sone, Tsutomu Shinohara, Yasuhiko Nishioka and Seiji Yano : Symposium on molecular pathogenesis of respiratory diseases and its clinical implication. 4. Molecular pathogenesis of lung cancer and its molecular targeted therapy, Internal Medicine, Vol.40, No.2, 167-170, 2001.
Hiroshi Nokihara, Hiroaki Yanagawa, Yasuhiko Nishioka, Seiji Yano, Naofumi Mukaida, Kouji Matsushima and Saburo Sone : Natural killer cell-dependent suppression of systemic spread of human lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection in severe combined immunodeficient mice., Cancer Research, Vol.60, No.24, 7002-7007, 2000.
223.
Naoki Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara, Kenji Tani and Saburo Sone : Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation and maturation of human monocytes and bone marrow CD34(+) cells to dendritic cells, International Journal of Immunopharmacology, Vol.22, No.7, 501-514, 2000.
224.
Stephan Lang, Yoshinari Atarashi, Yasuhiko Nishioka, Joanna Stanson, Norbert Meidenbauer and Theresa L. Whiteside : B7.1 on human carcinomas:costimulation of T cells and enhanced tumor-induced T-cell death, The Journal of Molecular and Cellular Immunology, Vol.1, No.2, 132-143, 2000.
225.
Hitoe Torisu, Mayumi Ono, Hiromaro Kiryu, Masutaka Furue, Yasukazu Ohmoto, Juichiro Nakayama, Yasuhiko Nishioka, Saburo Sone and Michihiko Kuwano : Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNFα and IL-1α, International Journal of Cancer, Vol.85, No.2, 182-188, 2000.
(要約)
We examined whether macrophage infiltration is associated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous melanoma. We further examined whether human melanoma cells produce angiogenic factors in response to macrophage-derived cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha). Treatment of melanoma cells with TNFalpha and IL-1alpha in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF, TNF alpha, as well as IL-1alpha, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS-activated monocytes was blocked when anti-TNF-alpha antibody or anti-IL-1alpha antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNFalpha and/or IL-1alpha secreted by activated monocytes/macrophages, influencing both tumor growth and angiogenesis in melanomas.
Masaki Hanibuchi, Yasuhiko Nishioka, Hiroaki Yanagawa, Seiji Yano, Parajuli Prahlad, Bando Masashi and Saburo Sone : Human interferon-gamma enhances expression of ganglioside GM2 on human lung cancer cells and their susceptibility for antiganglioside GM2 monoclonal antibody-dependent cellular cytotoxicity., Oncology Research, Vol.12, No.4, 173-179, 2000.
(要約)
Interferons are known to modulate several cellular functions by the induction of various proteins. In this study, we demonstrated that human interferon-gamma (HuIFN-gamma) enhanced the expression of ganglioside GM2 (GM2), which is a kind of tumor-associated antigen substantially expressed in human lung cancer and that human lung cancer cells expressing GM2 became more susceptible to anti-GM2 monoclonal antibody (mAb)-dependent tumor cell killing mediated by human effector cells after HuIFN-gamma treatment. GM2 expression on human lung cancer cells treated with or without HuIFN-gamma was measured by flow cytometry. The antibody-dependent cellular cytotoxicity (ADCC) activity was assessed by 4-h 51Cr release assay. HuIFN-gamma enhanced GM2 expression on human small-cell lung cancer (SCLC), SBC-3, and human non-small-cell lung cancer (NSCLC), A549 cells in a dose-dependent manner. The optimal concentration of HulIFN-gamma was 1,000 U/ml. The effect of HulFN-gamma reached maximum after 4 days of culture. HulFN-gamma did not have any effect to enhance the expression of other gangliosides in SBC-3 cells. No other cytokines used in this study modulated GM2 expression in SBC-3 cells. Anti-GM2 mAb-dependent ADCC activities induced by lymphocytes and monocytes were more potent against IFN-gamma-treated SBC-3 and A549 cells than nontreated cells. Taken together, HulFN-gamma combined with anti-GM2 mAb may be useful for immunotherapy against GM2-positive human lung cancer.
Yasuhiko Nishioka, Motohiro Hirao, Paul D. Robbins, Michael T. Lotze and Hideaki Tahara : Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12., Cancer Research, Vol.59, No.16, 4035-4041, 1999.
(要約)
Bone marrow-derived dendritic cells (BM-DCs) retrovirally transduced with genes encoding murine interleukin (IL)-12 stably expressed bioactive IL-12 protein at high levels. Intratumoral injection with IL-12 gene-modified BM-DCs resulted in regression of day 7 established weakly immunogenic tumors (MCA205, B16, and D122). This antitumor effect was substantially better than that of IL-12-transduced syngeneic fibroblasts or nontransduced BM-DCs. Furthermore, intratumoral injection with IL-12-transduced dendritic cells (DCs) induced specific TH1-type responses to the tumor in regional lymph nodes and spleen at levels greater than those of IL-12-transduced fibroblasts or nontransduced BM-DCs. Trafficking studies confirmed that intratumorally injected IL-12-transduced DCs, but not fibroblasts, could migrate to the draining lymph node to the same extent as nontransduced BM-DCs. This strategy designed to deliver genetically modified DCs to tumor sites is associated with systemic and therapeutic antitumor immunity and is an alternative approach to those that use delivery of DCs loaded with tumor antigen. These results support the clinical application of IL-12 gene-modified DCs in patients with cancer.
Seiji Yano, Masaki Hanibuchi, Yasuhiko Nishioka, Hiroshi Nishihara, Naoki Nishimura, Takashi Tsuruo and Saburo Sone : Combined therapy with anti-p-glycoprotein antibody and macrophage colony-stimulating factor gene transduction for multiorgan metastases of multidrug-resistant human small cell lung cancer in nk cell-depleted scid mice, International Journal of Cancer, Vol.82, No.1, 105-111, 1999.
(要約)
Our aim was to determine the antimetastatic potential of anti-P-glycoprotein (P-gp) antibodies (Abs) against multidrug-resistant (MDR) human small cell lung cancer (SCLC) cells expressing P-gp. Human SCLC cells H69 (P-gp negative) and its etoposide-resistant variant H69/YP (P-gp positive) were used. H69 and H69/VP cells injected i.v. metastasized to the liver, kidneys and systemic lymph nodes of NK cell-depleted severe combined immunodeficient (SCID) mice. H69/VP cells, but not H69 cells, were resistant to treatments with vindesine. Treatment with mouse-human chimeric anti-P-gp Ab (MH162) and its mouse counterpart (MRK-16) reduced metastasis of H69/VP cells in various organs and prolonged the survival of tumor-bearing mice, although they were less effective if injected at late times (after 28 days). Treatment with another mouse anti-Pgp Ab, MRK-17, was effective only against liver metastasis. MH162 and MRK-16 efficiently induced Ab-dependent cellular cytotoxicity (ADCC) by peritoneal macrophages against H69/VP cells in vitro, but MRK-17 was less effective, in accordance with their in vivo antimetastatic potential. Gene transfection of macrophage colony-stimulating factor (M-CSF) into H69/VP cells to augment macrophage-mediated ADCC resulted in inhibition of metastasis to the liver and lymph nodes, but not kidneys. Combined treatment with a low dose of MRK-16 completely cured metastasis of M-CSF transfectant, but not of the mock transfectant. Our findings suggest that while anti-P-gp Abs had antimetastatic potential against SCLC cells expressing P-gp, combined treatment with M-CSF gene transduction to augment the therapeutic efficacy of anti-P-gp Abs may be beneficial for eradicating metastatic MDR SCLC in humans.
Prahlad Parajuli, Yasuhiko Nishioka, Naoki Nishimura, Sukh Mahendra Singh, Masaki Hanibuchi, Hiroshi Nokihara, Hiroaki Yanagawa and Saburo Sone : Cytolysis of human dendritic cells by autologous lymphokine-activated killer cells: participation of both T cells and NK cells in the killing., Journal of Leukocyte Biology, Vol.65, No.6, 764-760, 1999.
(要約)
Dendritic cells (DC) play a key role in the initiation of immune response by stimulating the naive T cells. The fate of DC after the initiation of immune response is not clearly understood. Although there are few reports implicating natural killer (NK) cells in the elimination of DC, killing of DC by LAK cells, and specifically by T cells, has not been studied. In this study, we observed that DC, generated from monocytes, in vitro in the presence of granulocyte-macrophage colony-stimulating factor, interleukin-4 (IL-4), and tumor necrosis factor alpha were susceptible to cytolysis by lymphokine-activated killer (LAK) cells induced in the presence of IL-2 and IL-15 but not IL-12 alone. However, LAK cells induced by a combination of IL-12 and suboptimal dose of IL-2 were cytotoxic to DC. When purified lymphocytes were activated with IL-2, the CD8+/CD57- fraction (T-LAK), but not the CD8-/CD57+ fraction (NK-LAK) was cytotoxic to autologous DC. However, when unseparated peripheral blood mononuclear cells were used to generate LAK cells, both T-LAK and NK-LAK fractions showed equal cytotoxicity against autologous DC. Monoclonal antibodies against CD54, CD11a, and CD18 significantly inhibited the cytolysis, indicating that the killing involves the engagement of CD54 with its ligands.
Hiroshi Nokihara, Yasuhiko Nishioka, Seiji Yano, Naofumi Mukaida, Kouji Matsushima, Takashi Tsuruo and Saburo Sone : Monocyte chemoattractant protein-1 gene modification of multidrug-resistant human lung cancer enhances antimetastatic effect of therapy with anti-P-glycoprotein antibody in SCID mice, International Journal of Cancer, Vol.80, No.5, 773-780, 1999.
(要約)
Distant metastases and multidrug resistance are critical problems in the therapy of human small cell lung cancer (SCLC). In this study, we investigated whether transduction of the monocyte chemoattractant protein-1 (MCP-1) gene into multidrug-resistant (MDR) human lung cancer cells affected the formation of metastases or their inhibition by the anti-P-glycoprotein (P-gp) monoclonal antibody (MAb) MRK16. MDR human SCLC (H69/VP) cells were transduced with the human MCP-1 gene inserted into the expression vector BCMGSNeo. MCP-1 gene transduction had no effect on drug sensitivity, the expression of surface antigens or the in vitro proliferation of H69/VP cells. Using the metastatic model of NK cell-depleted SCID mice, H69/VP cells transduced with the MCP-1 gene were inoculated intravenously (i.v.) and formed metastatic colonies in the liver, kidneys and lymph nodes, similar to those formed by parent or mock-transduced cells. However, systemic treatment of the mice with MRK16 reduced the metastases of H69/VP cells in the liver, kidneys and lymph nodes, and was significantly more effective in inhibiting the metastases of MCP-1 producing H69/VP than those of mock-transduced cells. MCP-1 gene transduction significantly prolonged the survival of tumor-bearing mice treated with MRK16. Our findings suggest that local production of MCP-1 in the tumor site increases the anti-P-gp antibody-dependent cell-mediated cytotoxicity, and the MCP-1 gene-induced modification of MDR human SCLC cells thereby enhances the antimetastatic effect of therapy with anti-P-gp antibody. Thus, the accumulation of effector cells in the tumor site is a very important factor in the therapy using the anti-P-gp antibody.
Prahlad Parajuli, Seiji Yano, Yasuhiko Nishioka, Hiroshi Nokihara, Masaki Hanibuchi, Naoki Nishimura, Teruhiro Utsugi and Saburo Sone : Therapeutic Efficacy of a New Topoisomerase I and II Inhibitor TAS-103, Against Both P-Glycoprotein Expressing and Non-expressing Drug-Resistant Human Small-Cell Lung Cancer, Oncology Research, Vol.11, No.5, 219-224, 1999.
(要約)
We examined the effect of a novel topoisomerase I and II (topo I and II) inhibitor, TAS-103, on P-glycoprotein (P-gp)-expressing and -nonexpressing drug-resistant human small-cell lung cancer (SCLC) cells in vitro and in vivo. We observed that TAS-103 was effective in inhibiting in vitro proliferation of human SCLC (SBC-3 and H69) cells and their drug-resistant variants SBC-3/ADM or SBC-3/CDDP and H-69/VP, respectively. SBC-3/ADM and H-69/VP expressed high P-gp, whereas SBC-3/CDDP did not. TAS-103 also effectively reduced the tumor growth (more than 50% inhibition) of the parental as well as MDR SCLC cells grown SC in nude mice. Adriamycin (ADM) and cisplatin (CDDP), on the other hand, were effective only against the parental cells, while these drugs failed to inhibit the respective drug-resistant variants in vitro or in vivo. TAS-103 was observed to induce apoptosis dose dependently in the parental as well as drug-resistant SCLC cells as analyzed after 48 h of in vitro treatment, suggesting that the stabilization of cleavable topo I- or II-DNA complexes by topo I and II inhibitors like TAS-103 is followed by apoptosis of the cells. Overall, our study suggests that TAS-103 may have clinical application against drug-resistant human SCLC.
(キーワード)
ATP-Binding Cassette, Sub-Family B, Member 1 / Aminoquinolines / Animals / Antineoplastic Agents / Apoptosis / Carcinoma, Small Cell / Drug Resistance, Neoplasm / Humans / Indenes / Lung Neoplasms / Male / Mice / Mice, Inbred BALB C / Mice, Nude / Neoplasm Proteins / Topoisomerase I Inhibitors / Topoisomerase II Inhibitors / Tumor Cells, Cultured
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10608616
Saburo Sone, Seiji Yano, Masaki Hanibuchi, Hiroshi Nokihara, Naoki Nishimura, Toyokazu Miki, Yasuhiko Nishioka and Tsutomu Shinohara : Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice, Cancer Chemotherapy and Pharmacology, Vol.43, No.Supplement 1, S26-S31, 1999.
(要約)
Lung cancer is a major cause of cancer deaths, most of which can be attributed to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have established novel models of human lung cancer (small cell and non-small cell lung cancer) metastasis in natural killer cell-depleted severe combined immunodeficient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites affects the pattern of lung cancer metastasis in distant organs. Several lung cancer cell lines were genetically engineered to produce human macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph nodes, but not the kidneys. In contrast, MCP-1 gene-modified lung cancer cells and their parent cells had identical metastatic potentials. These findings indicate a possible role for cytokines and suggest that lung cancer has metastatic heterogeneity. Examining ways of controlling human lung cancer metastases, we investigated the antimetastatic effect of chimeric monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the development of distant metastases of lung cancer in a dose-dependent fashion. Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction caused complete inhibition of metastasis of H69/VP cells. The antimetastatic effect of these MAbs in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity reaction mediated by mouse macrophages. These findings suggest that the mouse-human chimeric MAb in combination with cytokine gene transduction may be useful for the eradication of lung cancer metastases in humans.
Takuya Takayama, Yasuhiko Nishioka, Lina Lu, Michael T. Lotze, Hideaki Tahara and Angus W. Thomson : Retroviral delivery of viral interleukin-10 into myeloid dendritic cells markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness, Transplantation, Vol.66, No.12, 1567-1574, 1998.
234.
Masaki Hanibuchi, Seiji Yano, Yasuhiko Nishioka, Hiroaki Yanagawa, Tetsuya Kawano and Saburo Sone : Therapeutic efficacy of mouse-human chimeric anti-ganglioside GM2 monoclonal antibody against multiple organ micrometastases of human lung cancer in NK cell-depleted SCID mice, International Journal of Cancer, Vol.78, No.4, 480-485, 1998.
(要約)
The development of distant metastases to multiple organs is a critical problem in the treatment of human lung cancer. In this study, we evaluated the therapeutic efficacy of a mouse-human chimeric anti-ganglioside GM2 (GM2) monoclonal antibody (MAb), KM966 against metastasis formation of GM2-positive human lung cancer cells inoculated intravenously (i.v.) into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice. GM2-positive human small cell lung cancer (SCLC), SBC-3 cells (1 x 10(6)), injected through a tail vein into NK cell-depleted SCID mice, formed large number of metastatic colonies in the liver, kidneys and lymph nodes by 42 days after inoculation (day 42). KM966, but not control MAb, given on days 2 and 7, almost completely inhibited metastasis formation of SBC-3 cells in the liver, kidneys and lymph nodes in a dose-dependent fashion. Moreover, treatment with KM966 at advanced stages of metastasis (even from day 28) significantly suppressed multiple organ metastases of SBC-3 cells. The anti-metastatic effect of KM966 in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity (ADCC) reaction mediated by macrophages of the SCID mice. Our findings suggest that the mouse-human chimeric anti-GM2 MAb, KM966 may be useful for eradicating multiple organ micrometastases of lung cancer in humans.
Seiji Yano, Hiroaki Yanagawa, Masaki Hanibuchi, Kalpana Pai, Yasuhiko Nishioka, Takashi Tsuruo and Saburo Sone : The role of cyclosporin A on antibody-dependent monocyte-mediated cytotoxicity against human multidrug-resistant cancer cells, The Journal of Medical Investigation : JMI, Vol.44, No.3-4, 185-191, 1998.
(要約)
A P-glycoprotein (P-gp) inhibitor, cyclosporin A (CsA) was found to enhance the susceptibility of multidrug resistant (MDR) cancer cells to anti-P-gp antibody-dependent cellular cytolysis (ADCC) by monocytes, but the exact mechanism is unknown. In this study, we examined whether CsA enhanced the susceptibility of MDR cells through its inhibitory effect of P-gp function by using anti-ganglioside GM2 (GM2) monoclonal antibody (Ab), KM966, instead of anti-P-gp Ab, MRK16. Monocyte-ADCC induced by both KM966 and MRK16 against P-gp positive human MDR ovarian cancer cells was significantly augmented by addition of CsA. KM966, but not MRK16, induced monocyte-ADCC against P-gp negative human ovarian cancer cells and CsA enhanced this ADCC activity, indicating that suppressive effect of P-gp function by CsA was not essential to the enhancement of ADCC. Moreover, pretreatment of tumor cells with CsA augmented their susceptibility to monocyte-ADCC irrespective of P-gp expression. Interestingly, KM966 or MRK16 induced monocyte-ADCC against various human lung cancer cells expressing either GM2 or P-gp, but CsA did not affect these ADCC. These findings suggest that CsA may enhance the susceptibility to the monocyte-ADCC of ovarian cancer cells, but not of lung cancer cells, irrespective of its suppressive effect of P-gp function.
(キーワード)
Antibodies, Monoclonal / Cell Line / Cyclosporine / Cytotoxicity, Immunologic / Drug Resistance, Multiple / Humans / Monocytes / Neoplasms
Yasuhiko Nishioka, Seiji Yano, Fujio Fujiki, Naofumi Mukaida, Kouji Matsushima, Takashi Tsuruo and Saburo Sone : Combined therapy of multidrug-resistant human lung cancer with anti-P-glycoprotein antibody and monocyte chemoattractant protein-1 gene transduction: The possibility of immunological overcoming of multidrug resistance, International Journal of Cancer, Vol.71, No.2, 170-177, 1997.
(要約)
We determined whether transduction of the monocyte chemoattractant protein-1 (MCP-1) gene into MDR human lung cancer cells affected their tumorigenicity and sensitivity to antibody-dependent cellular cytotoxicity (ADCC) reaction mediated by the anti-P-glycoprotein (P-gp) monoclonal antibody MRK16. The human MCP-1 gene inserted into an expression vector (BCMGSNeo) was transfected into MDR human small-cell lung cancer (H69/VP) cells. Monocyte chemotactic activity was found in culture supernatants collected from MCP-1-transfected H69/VP cells, but not in supernatants of parent and mock-transfected cells. In an in vitro experiment, recombinant MCP-1 did not affect monocyte-mediated ADCC against H69/VP cells when added to the monocyte culture in either the activation or the effector phase at sufficient concentrations to attract and activate monocytes. Tumorigenicity and growth rates of MCP-1-producing H69/VP cells in nude mice were similar to those of parental cells and mock-transfected cells. However, systemic treatment with MRK16 was more effective in inhibiting the formation of tumors by MCP-1-gene-transfected cells than by mock-transfected cells. Systemic treatment with MRK16 also inhibited the growth of a mixture (1:1) of MCP-1-producing cells and mock-transfected cells. These results suggest that combination therapy with MRK16 and MCP-1 gene transduction may be a useful immunological strategy to inhibit the growth of human MDR cancer cells expressing P-gp.
Seiji Yano, Yasuhiko Nishioka, Hiroshi Nokihara and Saburo Sone : Macrophage colony-stimulating factor gene transduction into human lung cancer cells differentially regulates metastasis formations in various organ microenvironments of natural killer cell-depleted SCID mice, Cancer Research, Vol.57, No.4, 784-790, 1997.
(要約)
We investigated whether local production of macrophage colony-stimulating factor (M-CSF), responsible for migration and activation of monocytes/macrophages at a tumor growth site, affected the metastatic pattern of lung cancer. For this, highly metastatic human squamous (RERF-LC-AI) or small (H69/VP) cell lung carcinoma cells were transduced with the human M-CSF gene inserted into pRc/CMV-MCSF to establish M-CSF-producing clones (MCSF-AI-9-18, MCSF-AI-9-24, and MCSF-VP-5). M-CSF gene transduction had no effect on the expression of surface antigen or on in vitro proliferation. After s.c. injection into SCID mice, the growth rates of M-CSF-producing cells were slower than those of parent or mock-transduced cells. In the metastatic model in SCID mice depleted of natural killer cells, RERF-LC-AI cells formed metastases mainly in the liver and kidneys, whereas H69/VP cells metastasized mainly to the liver and systemic lymph nodes. The numbers of metastatic colonies of MCSF-AI-9-18 and MCSF-AI-9-24 cells in the liver but not the kidneys were significantly reduced. The development of lymph node metastases of MCSF-VP-5 cells was also less than that of parent or mock-transduced cells. Treatment of SCID mice with anti-human M-CSF antibody resulted in a significant increase in liver metastases of their M-CSF gene transfectants. No significant differences were observed in the distributions in mice or in the in vitro invasive potentials of MCSF-AI-9-18 cells and Neo-AI-3 cells. These findings indicate that the antimetastatic effect of M-CSF may be specific to particular organs, suggesting the influence of heterogeneity of organ microenvironments on the metastasis of lung cancer.
Seiji Yano, Hiroaki Yanagawa, Yasuhiko Nishioka, Naofumi Mukaida, Kouji Matsushima and Saburo Sone : T helper 2 cytokines differently regulate monocyte chemoattractant protein-1 production by human peripheral blood monocytes and alveolar macrophages, The Journal of Immunology, Vol.157, No.6, 2660-2665, 1996.
(要約)
Th2 cytokines, such as IL-4, IL-10, and IL-13, suppress proinflammatory cytokine production by monocytes/macrophages. Since monocyte chemoattractant protein-1 (MCP-1) is presumed to play an important role in monocyte recruitment and activation during inflammatory and immune responses, we examined here the effects of these Th2 cytokines on MCP-1 production by human blood monocytes and alveolar macrophages. Unstimulated, highly purified blood monocytes did not produce MCP-1 spontaneously, while LPS treatment induced the production of MCP-1 and its mRNA expression. All Th2 cytokines tested suppressed LPS-induced MCP-1 production and its mRNA expression, although the suppressive effect of IL-13 was weaker than that of IL-4 or IL-10. In contrast, IL-10, but neither IL-4 nor IL-13, induced unstimulated peripheral blood monocytes to produce biologically active MCP-1 protein within 4 h, reaching a maximal level at 12 h. IL-10-induced MCP-1 production was reduced by pretreatment of IL-10 with anti-IL-10 Ab, negating the involvement of contaminated endotoxin. Moreover, IL-10 induced MCP-1 mRNA expression in unstimulated monocytes, independent of de novo protein synthesis. Furthermore, human alveolar macrophages produced MCP-1 spontaneously, and the production was inhibited by IL-4 or IL-13, but was augmented by IL-10. These findings suggest that IL-10 regulates MCP-1 production by monocytes/macrophages in a different way from other Th2 cytokines, such as IL-4 and IL-13, and contributes to host defense responses.
Seiji Yano, Yasuhiko Nishioka, K Izumi, Takashi Tsuruo, T Tanaka, M Miyasaka and Saburo Sone : Novel metastasis model of human lung cancer in SCID mice depleted of NK cells, International Journal of Cancer, Vol.67, No.2, 211-217, 1996.
(要約)
Metastasis is a critical problem in the treatment of human lung cancer. Thus, a suitable animal model of metastasis of human lung cancer is required for in vivo biological and preclinical studies. In this study, we tried to establish a suitable model for this, using SCID mice. Neither human SCLC H69/VP cells (5 x 10(6)) nor squamous-cell carcinoma RERF-LC-AI cells (1 x 10(6)), injected through a tail vein, formed metastases in untreated SCID mice. Pre-treatment of SCID mice with anti-asialo GM1 serum resulted in only a few metastases of H69/VP cells, but pre-treatment with anti-mouse IL-2 receptor beta chain Ab (TM-beta 1) resulted in numerous lymph-node metastases 56 days after tumor inoculation. H69/VP-M cells, an in vivo-selected variant line, formed significant numbers of lymph-node metastases even in SCID mice pre-treated with anti-asialo GM1 serum. SCID mice depleted of NK cells by treatment with TM-beta 1 showed different patterns of metastasis when inoculated intravenously with the 2 different human lung cancer cell lines (H69/VP and RERF-LC-AI cells): H69/VP cells formed metastases mainly in systemic lymph nodes and the liver, whereas RERF-LC-AI cells formed metastases mainly in the liver and kidneys, with only a few in lymph nodes. A histopathological study showed that the metastatic colonies consisted of cancer cells. The numbers of metastatic colonies formed by the 2 cell lines increased with the number of cells inoculated. TM-beta 1 treatment of SCID mice efficiently removed NK cells from peripheral blood for at least 6 weeks, whereas, after treatment of the mice with anti-asialo GM1 serum, NK cells were recovered within 9 days. These findings suggest that NK-cell-depleted SCID mice may be useful as a model in biological and pre-clinical studies on metastasis of human lung cancer.
Saburo Sone, Takashi Tsuruo, S Sato, Seiji Yano, Yasuhiko Nishioka and Tsutomu Shinohara : Transduction of the macrophage colony-stimulating factor gene into human multidrug resistant cancer cells: enhanced therapeutic efficacy of monoclonal anti-P-glycoprotein antibody in nude mice, Japanese Journal of Cancer Research, Vol.87, No.7, 757-764, 1996.
(要約)
To develop a therapeutic modality for overcoming multidrug-resistant (MDR) cancer with anti-MDR1 antibody, we examined the effect of macrophage colony-stimulating factor (M-CSF) gene transfection into MDR AD10 cells on therapy of MDR cancer with anti-MDR1 antibody (MRK17) in nude mice. MDR human ovarian cancer (AD10) cells were transduced with the human M-CSF gene inserted into an expression vector to establish gene-modified cells capable of producing low (ML-AD10), intermediate (MM-AD10) nd high (MH-AD10) amounts of M-CSF. Systemic administration of MRK17 resulted in significant dose-dependent inhibition of subcutaneous growth of ML-AD10 tumors. In contrast, systemic administration of recombinant M-CSF in combination with MRK17 did not augment the therapeutic efficacy of MRK17 alone, but rather promoted the growth of the parent AD10 cells. To test the efficacy of in vivo M-CSF gene therapy combined with antibody, we mixed the parent AD10 cells with MH-AD10 cells producing a large amount of M-CSF, and inoculated the mixed cells subcutaneously. Treatment with MRK17 inhibited growth of the mixed cells more than that of the parent cells alone. Thus, combined therapy with anti-MDR1 mAb and M-CSF gene modification of MDR cancer cells may provide a new immunotherapeutic modality for overcoming MDR in humans.
Masaki Hanibuchi, Seiji Yano, Yasuhiko Nishioka, Hiroaki Yanagawa and Saburo Sone : Anti-ganglioside GM2 monoclonal antibody-dependent killing of human lung cancer cells by lymphocytes and monocytes, Japanese Journal of Cancer Research, Vol.87, No.5, 497-504, 1996.
(要約)
Ganglioside GM2 (GM2) frequently appears on the cell surface of human cancers of neuroendocrine origin. A mouse-human chimeric monoclonal antibody (mAb), KM966, against GM2 was previously found to promote the lysis of various cancer cells by human blood mononuclear cells (MNC). In this study, we analyzed the effector cells responsible for the chimeric mAb-dependent cell-mediated cytotoxicity (ADCC) against small cell lung cancer (SCLC) cells and examined the enhancing effect of various cytokines on the ADCC activity. The ADCC activity was assessed by 4-h 51Cr release assay. Highly purified lymphocytes (> 99%) and monocytes (> 90%) were separated by centrifugal elutriation from peripheral blood MNC of the same healthy donor. KM966 induced lysis of SCLC cells mediated by both lymphocytes and monocytes to similar extents, in a dose-dependent manner. Pretreatment of lymphocytes with various cytokines [interleukin (IL)-2, IL-12 and interferon-gamma] and that of monocytes with macrophage-colony-stimulating factor significantly augmented the killer activity against SCLC cells in the presence of KM966 mAb. KM966 was also effective for the lysis of non-small cell lung cancer cells in direct proportion to the GM2 expression levels. These findings suggest that combined treatment of KM966 mAb with cytokines may be therapeutically useful for in vivo killing of lung cancer cells expressing GM2 through the ADCC reaction.
Masaharu Kan, Fumihiko Kanai, Mitsuru Iida, Hideaki Jinnouchi, Mikio Todaka, Takanobu Imanaka, Kimio Ito, Yasuhiko Nishioka, Tetsuo Ohnishi, Seika Kamohara, Hideaki Hayashi, Takashi Murakami, Susumu Kagawa, Hiroyuki Sano, Naotake Hashimoto, Sho Yoshida, Hideichi Makino and Yousuke Ebina : Frequency of Mutations of Insulin Receptor Gene in Japanese Patients with NIDDM, Diabetes, Vol.44, No.9, 1081-1086, 1995.
(要約)
To examine the prevalence of abnormalities in the insulin receptor structure gene in Japanese with non-insulin-dependent diabetes mellitus (NIDDM), a population of 51 patients with NIDDM was screened for mutations in this gene. Patient genomic DNAs of both alleles corresponding to 22 exons of the gene were amplified by polymerase chain reaction (PCR). The PCR products on pUC19 were sequenced. Three patients with heterozygous missense mutation Thr831-->Ala831 in exon 13 and one patient with heterozygous missense mutation Tyr1334-->Cys1334 in exon 22 of the beta-subunits were identified. Linkage analysis of one of the families plus statistical studies showed that the mutation Thr831-->Ala831 is possibly responsible for the onset of NIDDM. In COS cells transiently expressing both mutant receptor cDNAs and a cDNA of a M(r) 85,000 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), the mutation Tyr1334-->Cys1334 impaired binding of the receptor with the M(r) 85,000 subunit of PI 3-kinase, but linkage analysis of the family showed that the mutation did not cosegregate with NIDDM in the pedigree. Therefore, one missense mutation (Thr831-->Ala831) in the insulin receptor, as found in three patients, is possibly involved in the etiology of a subset of the 51 NIDDM patients.
(キーワード)
Adult / Aged / Alanine / Amino Acid Sequence / Animals / Base Sequence / Cell Line / Cercopithecus aethiops / Cysteine / DNA / DNA Primers / Diabetes Mellitus, Type 2 / Exons / Female / Genetic Linkage / Humans / Insulin / Japan / Kinetics / Macromolecular Substances / Male / Middle Aged / Molecular Sequence Data / Pedigree / Phosphatidylinositol 3-Kinases / Phosphotransferases (Alcohol Group Acceptor) / Point Mutation / Polymerase Chain Reaction / Receptor, Insulin / Recombinant Proteins / Threonine / Transfection / Tyrosine
Seiji Yano, Saburo Sone, Yasuhiko Nishioka, Naofumi Mukaida, Kouji Matsushima and Takeshi Ogura : Differential effects of anti-inflammatory cytokines (IL-4, IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor., Journal of Leukocyte Biology, Vol.57, No.2, 303-309, 1995.
(要約)
The effect of recombinant human IL-4, IL-10, and IL-13 on the chemotaxis and antitumor activity of human blood monocytes induced by monocyte chemotactic and activating factor (MCAF) was examined. MCAF alone did not induce monocyte-mediated cytotoxicity against human melanoma (A375-M) cells whereas it significantly enhanced the cytotoxicity by norMDP-stimulated monocytes. MCAF, unlike IFN-gamma, had no priming effect on monocyte activation by norMDP. MCAF acted with norMDP or LPS to enhance the production of both IL-1 beta and TNF-alpha. Enhanced cytotoxicity of monocytes stimulated with MCAF plus norMDP was reduced by IL-1 receptor antagonist and anti-TNF-alpha antibody. IL-4, IL-10, and IL-13 suppressed the generation of antitumor activity and cytokine production (IL-1 beta and TNF-alpha) of monocytes stimulated with MCAF plus norMDP or LPS. Chemotaxis of monocytes induced by MCAF was not affected by norMDP or any of the anti-inflammatory cytokines (IL-4, IL-10, and IL-13). Moreover, the pretreatment of monocytes with anti-inflammatory cytokines did not suppress monocyte-chemotaxis. These findings suggest that in vivo recruitment and anti-tumor expression of blood monocytes induced by MCAF may be differently regulated by anti-inflammatory cytokines in vivo.
Roustem Nabioullin, Saburo Sone, Kazuto Mizuno, Seiji Yano, Yasuhiko Nishioka, Takashi Haku and Takeshi Ogura : Interleukin-10 is a potent inhibitor of tumor cytotoxicity by human monocytes and alveolar macrophages, Journal of Leukocyte Biology, Vol.55, No.4, 437-442, 1994.
(要約)
The effects of purified human interleukin-10 (IL-10) on the expression of antitumor activity of human monocytes and alveolar macrophages (AMs) obtained by centrifugal elutriation and bronchoalveolar lavage, respectively, from the same healthy donors were examined. Monocytes and AMs were incubated for 16 h in medium with lipopolysaccharide (LPS) in the presence or absence of IL-10 or IL-4, and then their tumoricidal activity was assayed by measuring 125I-IUdR release from human melanoma (A375) cells. Addition of IL-10 to cultures of monocytes or AMs with LPS resulted in dose-dependent suppression of their cytotoxicity against A375 cells, the suppression of the activity of monocytes being the higher. IL-10 also suppressed the synergistic effects of interferon-gamma and desmethyl muramyldipeptide in activation of monocytes. IL-10 inhibited the early induction phase of monocyte activation but not the effector phase (monocyte-mediated cytotoxicity). IL-10 plus IL-4 inhibited the antitumor activities of AMs and monocytes much more than either IL-10 or IL-4 alone. IL-10 and IL-4 at suboptimal concentrations also showed synergistic inhibitory effects. These findings suggest that IL-10 may be important in vivo in down-regulating the antitumor activities of monocytes and AMs in the lung by inhibiting their productions of antitumor effector molecules.
Saburo Sone, E Orino, Kazuto Mizuno, Seiji Yano, Yasuhiko Nishioka, Takashi Haku, A Nii and Takeshi Ogura : Production of IL-1 and its receptor antagonist is regulated differently by IFN-gamma and IL-4 in human monocytes and alveolar macrophages, The European Respiratory Journal, Vol.7, No.4, 657-663, 1994.
(要約)
Interleukin-4 (IL-4) has previously been found to downregulate interleukin-1 (IL-1) production, but to upregulate the production of IL-1 receptor antagonist (IL-1ra) in human monocytes stimulated with lipopolysaccharide (LPS). In the present study we wanted to determine whether the production of IL-1ra in human monocytes and alveolar macrophages (AMs) is regulated differently at the protein and messenger ribonucleic acid (mRNA) levels by IL-4 and interferon-gamma (IFN-gamma). AMs and monocytes obtained from healthy donors by bronchoalveolar lavage and centrifugal elutriation were stimulated with LPS in the presence or absence of IL-4 or IFN-gamma, and the expression of mRNA for IL-1 and IL-1ra was measured by Northern blot analysis. The production of IL-1 and IL-1ra was quantitated by enzyme immunoassays (EIAs). Spontaneous IL-1ra production was seen in AMs after incubation for 4 h in medium alone, but not in blood monocytes, at both the protein and mRNA levels. The spontaneous expression of the IL-1ra gene in AMs was augmented by incubation with IL-4. Interleukin-1 beta (IL-1 beta) production by LPS-stimulated AMs and monocytes was upregulated by IFN-gamma, but downregulated by IL-4. Interestingly, when stimulated with LPS, IFN-gamma inhibited IL-1ra production by monocytes, but up-regulated its production in human AMs at the protein and mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Seiji Yano, Saburo Sone, Yasuhiko Nishioka, M Naito, Takashi Tsuruo and Takeshi Ogura : Cyclosporin A enhances susceptibility of multi-drug resistant human cancer cells to anti-P-glycoprotein antibody-dependent cytotoxicity of monocytes, but not of lymphocytes, Japanese Journal of Cancer Research, Vol.85, No.2, 194-203, 1994.
(要約)
Cyclosporin A (CsA) was previously found to bind to P-glycoprotein expressed on multidrug-resistant (MDR) cancer cells. In the present study, the effect of CsA on anti-P-glycoprotein monoclonal antibody (mAb)-dependent cell-mediated cytotoxicity (ADCC) against human MDR cells was examined. The ADCC reaction was assessed by 4-h 51Cr-release assay. Highly purified lymphocytes (> 99%) and monocytes (> 99%) obtained from blood mononuclear cells (MNC) of healthy donors were used as effector cells. CsA decreased the cytotoxic activity of MNC against MDR cells, but enhanced their ADCC activity in the presence of anti-P-glycoprotein mAb MRK16. Lymphocyte-mediated ADCC and natural killer activity against MDR cells were also suppressed by addition of CsA. CsA induced a significant dose-dependent increase in monocyte-mediated ADCC activity. Interestingly, pretreatment of MDR cancer cells, but not of monocytes, with CsA significantly enhanced ADCC activity mediated by monocytes, but not by lymphocytes. A CsA analog (PSC833) and FK-506, but not verapamil also increased the sensitivity of MDR cells to ADCC by monocytes. CsA did not affect the binding of monocytes to MDR cells in the presence of MRK16 mAb. These results indicate that CsA may directly enhance the susceptibility of MDR cancer cells to the monocyte-mediated ADCC reaction.
Fumihiko Kanai, Yasuhiko Nishioka, Hideki Hayashi, Seika Kamohara, Mikio Todaka and Yousuke Ebina : Direct demonstration of insulin-induced GLUT4 translocation to the surface of intact cells by insertion of a c-myc epitope into an exofacial GLUT4 domain., The Journal of Biological Chemistry, Vol.268, No.19, 14523-14526, 1993.
248.
Hideki Hayashi, Yasuhiko Nishioka, Seika Kamohara, Fumihiko Kanai, Kazuo Ishii, Yasuhisa Fukui, Futoshi Shabisaki, Tadaomi Takenawa, Hiroshi Kido, Nobuhiko Katsunuma and Yousuke Ebina : The alpha-Type 85-kDa subunit of Phosphatidylinositol 3-Kinase is Phosphorylatedat Tyrosines 368, 580, and 607 by the Insulin Receptor, The Journal of Biological Chemistry, Vol.268, No.10, 7107-7117, 1993.
249.
Hideki Hayashi, Seika Kamohara, Yasuhiko Nishioka, Fumihiko Kanai, Noriaki Miyake, Yasuhisa Fukui, Futoshi Shibasaki, Tadaomi Takenawa and Yousuke Ebina : Insulin treatment stimulates the tyrosine phosphorylation of the alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase in vivo., The Journal of Biological Chemistry, Vol.267, No.31, 22575-22580, 1992.
Yasuhiko Nishioka, Saburo Sone, E. Orino, A. Nii and T. Ogura : Down-regulation by interleukin 4 of activation of human alveolar macrophages to the tumoricidal state, Cancer Research, Vol.51, No.20, 5526-5531, 1991.
252.
Saburo Sone, Eiji Kunishige, Farid Fawzy, Hiroaki Yanagawa, Akihiko Nii, Kenichi Maeda, Shinji Atagi, Yuji Heike, Yasuhiko Nishioka, Kazuhito Mizuno and Takeshi Ogura : Interleukin-2-inducible killer activity and its regulation by blood monocyte from autologous lymphocytes of lung cancer patigents, Japanese Journal of Cancer Research, Vol.82, No.6, 716-723, 1991.
(要約)
The ability of blood lymphocytes of newly diagnosed lung cancer patients to respond to interleukin 2 (IL-2) to become IL-2-activated killer (LAK) cells and its regulation by autologous monocytes were examined. LAK activity was measured by 51Cr release assay. The abilities of lymphocytes among blood mononuclear cells (MNC) of subjects of different ages without malignancies to generate LAK activity against NK-cell resistant Daudi cells and lung adenocarcinoma (PC-9) cells were very similar. The LAK activity of blood MNC of lung cancer patients was also nearly the same as that of blood MNC of control subjects. There was no significant difference in IL-2-inducible LAK activity between MNC of patients with small cell lung cancer (SCLC) and those of patients with non-SCLC. Monocytes and lymphocytes were separated from blood MNC on a one-step Percoll gradient. Monocytes of lung cancer patients were found to augment in vitro induction of LAK activity by IL-2 of autologous blood lymphocytes. In contrast, endotoxin-stimulated monocytes suppressed LAK induction of autologous lymphocytes of cancer patients. These findings suggest that administration of IL-2 and LAK cells induced in vitro may be of benefit in the treatment of lung cancer.
Issei Yagi, Shusuke Yagi, Keisuke Nakanishi, Kazuki Tezuka, K Matsuyama, Y Aibara, T Ishida, H Yoneda, M Yamamoto, Takayuki Ise, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Tetsuya Kitagawa, Yasuhiko Nishioka and Masataka Sata : Critical Limb Threatening Ischemia Due to Severe Polyarteritis Nodosa-A Case Report, Internal Medicine, 2024.
The working committee for the proper use of antibiotics was organized at Tokushima University Hospital in March 2002, and the institutional guidelines for the selection and use of antibiotics were established. The infection control team (ICT) also started monitoring the use of particular antibiotics, including third- and fourthgeneration cephalosporins, calbapenems and anti-MRSA antibiotics, and reported on their use in August 2002. To assess these activities, we examined the status of antibiotic use for injections and compared our findings with the previous data. The results were as follows : 1) the reports required were presented in 47% of the total antibiotics used ; 2) after starting the surveillance, the use of the third- and fourth-generation cephalosporins and calbapenems shifted to the first- and second-generation drugs, while the use of anti-MRSA drugs clearly decreased ; 3) these changes resulted in a savings of more than two million yen in medical expenditures in a month. These results suggest that closely monitoring the use of antibiotics may thus be beneficial not only for promoting the proper use of antibiotics but also for reducing overall medical costs.
(キーワード)
抗生物質 (antibiotics) / anti-MRSA antibiotics / proper use / ICT
Chronic obstructive pulmonary disease (COPD) is a long-standing, crippling disease characterized by the accelerated decline of lung function, commonly brought by aging and long-time inhalation of toxic chemicals such as tobacco smoking. Consequently, most COPD patients suffer from chronic cough, sputum and dyspnea on exertion. Moreover, in addition to the decline of lung function due to the destruction of the alveolar structure, COPD is closely related to other diseases such as osteoporosis, cardiovascular diseases, diabetes, muscle dysfuncion, and lung cancer. Therefore, COPD is currently recognized as a systemic disease that the comprehensive management and care are necessary. Although COPD represents an increasing burden throughout the world and is one of the major causes of death word-wide, the issue has been arisen that the recognition of COPD in the general society is still low, especially in Japan. On the other hand, lung cancer is a life-threatening disease with the leading cause of malignancy-related death world-wide, the etiology of which is also closely related to tobacco smoking. Because the pathogenesis and the mortality of COPD and lung cancer are closely related each other, the action to prevent these diseases could be made simultaneously, primarily by the smoking cessation and the detection survey. In this article, we describe the present situation of COPD and lung cancer, the importance of smoking cessation, and the effort of Tokushima City Medical Association to manage COPD in Tokushima.
(キーワード)
COPD / lung cancer / smoking cessation / detection survey