Updated on 2024/10/03

Information

 

写真a

 
OTSUBO KOHEI
 
Organization
Faculty of Medical Sciences Department of Clinical Medicine Assistant Professor
School of Medicine Department of Medicine(Concurrent)
Title
Assistant Professor
Profile
呼吸器内科診療 呼吸器内科学、臨床腫瘍学の研究
External link

Degree

  • Ph.D in Medicine

Research Interests・Research Keywords

  • Research theme:Development of treatment for lung cancer for lung cancer with interstitial pneumonia

    Keyword:Lung cancer, Interstitial pneumonia

    Research period: 2017.4 - 2021.3

  • Research theme:Functional analysis of Hippo pathway-related genes in the lung cancer

    Keyword:Hippo pathway, Lung cancer

    Research period: 2017.4 - 2020.3

  • Research theme:Development of treatment for lung cancer targeting cancer stem cells.

    Keyword:Lung cancer, Cancer stem cell

    Research period: 2014.4 - 2017.3

  • Research theme:Functional analysis of Hippo pathway-related genes in the lung

    Keyword:Hippo pathway, Lung

    Research period: 2011.4 - 2017.3

Papers

  • Nintedanib plus chemotherapy for non-small cell lung cancer with IPF: a randomized phase 3 trial. Invited Reviewed International journal

    Otsubo K, Kishimoto J, Ando M, Kenmotsu H, Minegishi Y, Horinouchi H, Kato T, Ichihara E, Kondo M, Atagi S, Tamiya M, Ikeda S, Harada T, Takemoto S, Hayashi H, Nakatomi K, Kimura Y, Kondoh Y, Kusumoto M, Ichikado K, Yamamoto N, Nakagawa K, Nakanishi Y, Okamoto I.

    Eur Respir J   2022.12

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Real-world data on NGS using the Oncomine DxTT for detecting genetic alterations in non-small cell lung cancer: WJOG13019L. Invited Reviewed International journal

    Sakata S, Otsubo K (corresponding author), Yoshida H, Ito K, Nakamura A, Teraoka S, Matsumoto N, Shiraishi Y, Haratani K, Tamiya M, Ikeda S, Miura S, Tanizaki J, Omori S, Yoshioka H, Hata A, Yamamoto N, Nakagawa K.

    Cancer Sci   2022.1

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Risk factors for disease progression in Japanese patients with COVID-19 with no or mild symptoms on admission. Invited Reviewed International journal

    Ninomiya T, Otsubo K (corresponding author), Hoshino T, Shimokawa M, Nakazawa M, Sato Y, Mikumo H, Kawakami S, Mizusaki S, Mori Y, Arimura H, Tsuchiya-Kawano Y, Inoue K, Uchida Y, Nakanishi Y.

    BMC Infect Dis   2021.8

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Paired genetic analysis by next-generation sequencing of lung cancer and associated idiopathic pulmonary fibrosis Invited Reviewed International journal

    Otsubo K., Iwama E., Ijichi K., Kubo N., Yoneshima Y., Inoue H., Tanaka K., Osoegawa A., Tagawa T., Nakanishi Y. & Okamoto I.

    Cancer Science   2020.7

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Genetic Profiling of Non–Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA Invited Reviewed International journal

    2019.8

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Treatment rationale and design for J-SONIC: a randomized study of carboplatin plus nab-paclitaxel with or without nintedanib for advanced non–small cell lung cancer with idiopathic pulmonary fibrosis Invited Reviewed International journal

    2018.1

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer Reviewed International journal

    Otsubo K, Nosaki K, Imamura CK, Ogata H, Fujita A, Sakata S, Hirai F, Toyokawa G, Iwama E, Harada T, Seto T, Takenoyama M, Ozeki T, Mushiroda T, Inada M, Kishimoto J, Tsuchihashi K, Suina K, Nagano O, Saya H, Nakanishi Y, Okamoto I

    Cancer Science   108   1843 - 1849   2017.9

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    Language:English   Publishing type:Research paper (scientific journal)  

  • MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. Reviewed International journal

    Otsubo K, Goto H, Nishio M, Kawamura K, Yanagi S, Nishie W, Sasaki T, Maehama T, Nishina H, Mimori K, Nakano T, Shimizu H, Mak TW, Nakao K, Nakanishi Y, Suzuki A

    Oncogene   2017.3

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    Language:English   Publishing type:Research paper (scientific journal)  

  • A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells

    Hikasa, H; Kawahara, K; Inui, M; Yasuki, Y; Yamashita, K; Otsubo, K; Kitajima, S; Nishio, M; Arima, K; Endo, M; Taira, M; Suzuki, A

    CANCER SCIENCE   2024.8   ISSN:1347-9032 eISSN:1349-7006

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    Language:English   Publisher:Cancer Science  

    The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/β-catenin/TCF- and IL-1β/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and β-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.

    DOI: 10.1111/cas.16316

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  • Prediction of prognosis in lung cancer using machine learning with inter-institutional generalizability: A multicenter cohort study (WJOG15121L: REAL-WIND)

    Fujimoto, D; Hayashi, H; Murotani, K; Toi, Y; Yokoyama, T; Kato, T; Yamaguchi, T; Tanaka, K; Miura, S; Tamiya, M; Tachihara, M; Shukuya, T; Tsuchiya-Kawano, Y; Sato, Y; Ikeda, S; Sakata, S; Masuda, T; Takemoto, S; Otsubo, K; Shibaki, R; Makino, M; Okamoto, I; Yamamoto, N

    LUNG CANCER   194   107896   2024.8   ISSN:0169-5002 eISSN:1872-8332

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    Language:English   Publisher:Lung Cancer  

    Objectives: Predicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis. Materials and Methods: This multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities. Results: Overall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9–17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88–0.91), 0.85 (0.84–0.87), 0.83 (0.81–0.85), and 0.85 (0.82–0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84–0.92), 0.84 (0.78–0.88), 0.84 (0.76–0.89), and 0.84 (0.75–0.90) at 180, 360, 720, and 1,080 days, respectively. Conclusion: This study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings.

    DOI: 10.1016/j.lungcan.2024.107896

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  • Tracheomediastinal fistula induced by concurrent chemoradiotherapy in small cell lung cancer: A case report and literature review

    Yamamoto, Y; Shibahara, D; Mori, T; Otsubo, K; Shiraishi, Y; Yoneshima, Y; Iwama, E; Tanaka, K; Oda, Y; Okamoto, I

    THORACIC CANCER   15 ( 13 )   1106 - 1111   2024.5   ISSN:1759-7706 eISSN:1759-7714

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    Language:English   Publisher:Thoracic Cancer  

    Tracheomediastinal fistula is a rare but life-threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features.

    DOI: 10.1111/1759-7714.15270

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  • Therapeutic strategies to target connective tissue growth factor in fibrotic lung diseases

    Isshiki, T; Naiel, S; Vierhout, M; Otsubo, K; Ali, P; Tsubouchi, K; Yazdanshenas, P; Kumaran, V; Dvorkin-Gheva, A; Kolb, MRJ; Ask, K

    PHARMACOLOGY & THERAPEUTICS   253   108578   2024.1   ISSN:0163-7258 eISSN:1879-016X

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    Language:English   Publisher:Pharmacology and Therapeutics  

    The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-β. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach.

    DOI: 10.1016/j.pharmthera.2023.108578

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  • Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling

    Yanagihara, T; Tsubouchi, K; Zhou, Q; Chong, M; Otsubo, K; Isshiki, T; Schupp, JC; Sato, S; Scallan, C; Upagupta, C; Revill, S; Ayoub, A; Chong, SG; Dvorkin-Gheva, A; Kaminski, N; Tikkanen, J; Keshavjee, S; Paré, G; Guignabert, C; Ask, K; Kolb, MRJ

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   207 ( 11 )   1498 - 1514   2023.6   ISSN:1073-449X eISSN:1535-4970

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    Language:English   Publisher:American journal of respiratory and critical care medicine  

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-β1 (transforming growth factor-β1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2, in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.

    DOI: 10.1164/rccm.202109-2174OC

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  • Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade

    Takada, K; Buti, S; Bersanelli, M; Shimokawa, M; Takamori, S; Matsubara, T; Takenaka, T; Okamoto, T; Hamatake, M; Tsuchiya-Kawano, Y; Otsubo, K; Nakanishi, Y; Okamoto, I; Pinato, DJ; Cortellini, A; Yoshizumi, T

    EUROPEAN JOURNAL OF CANCER   172   199 - 208   2022.9   ISSN:0959-8049 eISSN:1879-0852

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    Language:English   Publisher:European Journal of Cancer  

    Background: We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. Materials and methods: We evaluated the prognostic ability of a “drug score” computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Results: Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Conclusions: Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

    DOI: 10.1016/j.ejca.2022.06.002

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  • A propensity score-matched analysis of the impact of statin therapy on the outcomes of patients with non-small-cell lung cancer receiving anti-PD-1 monotherapy: a multicenter retrospective study

    Takada, K; Shimokawa, M; Takamori, S; Shimamatsu, S; Hirai, F; Tagawa, T; Okamoto, T; Hamatake, M; Tsuchiya-Kawano, Y; Otsubo, K; Inoue, K; Yoneshima, Y; Tanaka, K; Okamoto, I; Nakanishi, Y; Mori, M

    BMC CANCER   22 ( 1 )   503   2022.5   eISSN:1471-2407

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    Language:English   Publisher:BMC Cancer  

    Background: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood. Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients’ backgrounds. Results: The Kaplan–Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome. Conclusions: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes.

    DOI: 10.1186/s12885-022-09385-8

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  • Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy

    Takada, K; Takamori, S; Shimokawa, M; Toyokawa, G; Shimamatsu, S; Hirai, F; Tagawa, T; Okamoto, T; Hamatake, M; Tsuchiya-Kawano, Y; Otsubo, K; Inoue, K; Yoneshima, Y; Tanaka, K; Okamoto, I; Nakanishi, Y; Mori, M

    ESMO OPEN   7 ( 1 )   100348   2022.2   eISSN:2059-7029

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    Language:English   Publisher:ESMO Open  

    Introduction: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. Methods: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan–Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. Results: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan–Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. Conclusion: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

    DOI: 10.1016/j.esmoop.2021.100348

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Professional Memberships

  • 日本内科学会

  • 日本呼吸器学会

  • 日本臨床腫瘍学会

Research Projects

  • Functional analysis and novel therapeutic development for Apelin-APJ signaling in idiopathic pulmonary fibrosis

    Grant number:24K23319  2024.7 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity Start-up

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    Grant type:Scientific research funding

    CiNii Research

  • 間質性肺炎合併肺癌を対象とした治療の開発

    2018.8

  • 肺癌におけるHippo経路関連遺伝子の機能解析

    2018.8

  • 非小細胞肺癌におけるHippo経路分子MOB1の機能解析

    Grant number:18K15926  2018 - 2020

    日本学術振興会  科学研究費助成事業  若手研究

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    Authorship:Principal investigator  Grant type:Scientific research funding