2021/07/15 更新

写真a

トミダ シュウタ
冨田 秀太
TOMIDA Shuta

学位

  • 博士(工学) ( 名古屋大学 )

研究キーワード

  • バイオインフォマティクス

  • マイクロアレイ

  • 肺癌

  • 腫瘍マーカー

  • バイオマーカー

  • 皮膚マイクロバイオーム解析

  • 比較ゲノム解析

  • マイクロRNA

  • 予後予測

  • 浸潤・転移

  • 発現プロファイリング

  • 遺伝子発現解析

  • クリニカルシーケンス解析

  • 感受性予測

  • パスウェイ解析

  • 再発予測

研究分野

  • その他 / その他  / 病態検査学

  • ライフサイエンス / 心臓血管外科学

  • 情報通信 / 生命、健康、医療情報学

  • ライフサイエンス / 呼吸器内科学

  • ライフサイエンス / 呼吸器外科学

  • ライフサイエンス / 皮膚科学

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経歴

  • 岡山大学   ゲノム医療総合推進センター   准教授

    2019年 - 現在

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  • 岡山大学   医歯薬学総合研究科   准教授(プロジェクト)

    2015年 - 2019年

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  • 近畿大学   医学部   講師

    2013年 - 2015年

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  • カリフォルニア大学ロサンゼルス校

    2009年 - 2013年

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  • 名古屋大学   大学院・医学系研究科   助教

    2006年 - 2008年

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  • 愛知県がんセンター研究所

    2003年 - 2005年

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所属学協会

委員歴

  • 日本癌学会   評議員  

    2018年 - 現在   

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    団体区分:学協会

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論文

  • CEBPγ facilitates lamellipodia formation and cancer cell migration through CERS6 upregulation. 国際誌

    Hanxiao Shi, Atsuko Niimi, Toshiyuki Takeuchi, Kazuya Shiogama, Yasuyoshi Mizutani, Taisuke Kajino, Kenichi Inada, Tetsunari Hase, Takahiro Hatta, Hirofumi Shibata, Takayuki Fukui, Toyofumi Fengshi Chen-Yoshikawa, Kazuki Nagano, Takashi Murate, Yoshiyuki Kawamoto, Shuta Tomida, Takashi Takahashi, Motoshi Suzuki

    Cancer science   112 ( 7 )   2770 - 2780   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ceramide synthase 6 (CERS6) promotes lung cancer metastasis by stimulating cancer cell migration. To examine the underlying mechanisms, we performed luciferase analysis of the CERS6 promoter region and identified the Y-box as a cis-acting element. As a parallel analysis of database records for 149 non-small-cell lung cancer (NSCLC) cancer patients, we screened for trans-acting factors with an expression level showing a correlation with CERS6 expression. Among the candidates noted, silencing of either CCAAT enhancer-binding protein γ (CEBPγ) or Y-box binding protein 1 (YBX1) reduced the CERS6 expression level. Following knockdown, CEBPγ and YBX1 were found to be independently associated with reductions in ceramide-dependent lamellipodia formation as well as migration activity, while only CEBPγ may have induced CERS6 expression through specific binding to the Y-box. The mRNA expression levels of CERS6, CEBPγ, and YBX1 were positively correlated with adenocarcinoma invasiveness. YBX1 expression was observed in all 20 examined clinical lung cancer specimens, while 6 of those showed a staining pattern similar to that of CERS6. The present findings suggest promotion of lung cancer migration by possible involvement of the transcription factors CEBPγ and YBX1.

    DOI: 10.1111/cas.14928

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  • Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression. 国際誌

    Makoto Nakamura, Yusuke Meguri, Shuntaro Ikegawa, Takumi Kondo, Yuichi Sumii, Takuya Fukumi, Miki Iwamoto, Yasuhisa Sando, Hiroyuki Sugiura, Noboru Asada, Daisuke Ennishi, Shuta Tomida, Emi Fukuda-Kawaguchi, Yasuyuki Ishii, Yoshinobu Maeda, Ken-Ichi Matsuoka

    Scientific reports   11 ( 1 )   13125 - 13125   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

    DOI: 10.1038/s41598-021-92526-z

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  • Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. 国際誌

    Akihiro Miura, Daisuke Yamada, Masahiro Nakamura, Shuta Tomida, Dai Shimizu, Yan Jiang, Tomoka Takao, Hiromasa Yamamoto, Ken Suzawa, Kazuhiko Shien, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka, Takeshi Takarada

    International journal of cancer   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

    DOI: 10.1002/ijc.33713

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  • Best practices for the extraction of genomic DNA from formalin-fixed paraffin-embedded tumor tissue for cancer genomic profiling tests. 国際誌

    Hirofumi Inoue, Shuta Tomida, Shigeru Horiguchi, Hironari Kato, Hiromi Matsuoka, Etsuko Sanehira, Masashi Matsuoka, Hiroyuki Yanai, Akira Hirasawa, Shinichi Toyooka

    Pathology international   71 ( 5 )   360 - 364   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, two cancer genomic profiling tests have been approved in Japan and implemented in routine clinical practice: the FDA-approved FoundationOne CDx test, and the OncoGuide NCC Oncopanel test. The quality and quantity of DNA significantly affects the sequencing results; therefore, preparing a sufficient amount of high-quality DNA for clinical cancer genomic profiling tests is important. We examined the best practices for the extraction of cancer genomic DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues of pancreatic, lung and colon cancer specimens. We found that the quality of cancer genomic DNA extracted from 10-μm-thick FFPE samples improved significantly, compared with that from 4-μm-thick FFPE samples, suggesting that 10-μm-thick FFPE samples are preferable for clinical cancer genomic profiling tests. For convenience, we created a quick reference table for calculating the required number of FFPE slides.

    DOI: 10.1111/pin.13086

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  • Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis.

    Daichi Isoshima, Keisuke Yamashiro, Kazuyuki Matsunaga, Makoto Taniguchi, Takehiro Matsubara, Shuta Tomida, Shinzo Ota, Michiyoshi Sato, Yutaka Shimoe, Tatsuo Kohriyama, Zulema Arias, Kazuhiro Omori, Tadashi Yamamoto, Shogo Takashiba

    Odontology   109 ( 1 )   239 - 249   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous plaques from atherosclerosis patients with or without periodontitis to investigate the role of oral bacteria in the formation of atheromatous plaques. We chose four patients with and without periodontitis, who had undergone carotid endarterectomy. Bacterial samples were extracted from the tongue surface, from periodontal pocket (during the oral examination), and from the atheromatous plaques (APs). We investigated the general and oral conditions from each patient and performed next-generation sequencing (NGS) analysis for all bacterial samples. There were no significant differences between both groups concerning general conditions. However, the microbiome patterns of the gingival pocket showed differences depending on the absence or presence of periodontitis, while those of the tongue surface were relatively similar. The microbiome pattern of the atheromatous plaques was entirely different from that on the tongue surface and gingival pocket, and oral bacteria were seldom detected. However, the microbiome pattern in atheromatous plaques was different in the presence or absence of periodontitis. These results suggested that oral bacteria did not affect the formation of atheromatous plaques directly.

    DOI: 10.1007/s10266-020-00524-w

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  • The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. 国際誌

    Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

    Journal of molecular medicine (Berlin, Germany)   99 ( 1 )   131 - 145   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

    DOI: 10.1007/s00109-020-02001-x

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  • Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial. 国際誌

    Hidetoshi Hayashi, Yuichi Takiguchi, Hironobu Minami, Kohei Akiyoshi, Yoshihiko Segawa, Hiroki Ueda, Yasuo Iwamoto, Chihiro Kondoh, Koji Matsumoto, Shin Takahashi, Hisateru Yasui, Toshiyuki Sawa, Yusuke Onozawa, Yasutaka Chiba, Yosuke Togashi, Yoshihiko Fujita, Kazuko Sakai, Shuta Tomida, Kazuto Nishio, Kazuhiko Nakagawa

    JAMA oncology   6 ( 12 )   1931 - 1938   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.

    DOI: 10.1001/jamaoncol.2020.4643

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  • Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. 国際誌

    Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

    Oncology letters   20 ( 6 )   393 - 393   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

    DOI: 10.3892/ol.2020.12256

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  • Diameter Is a Key 3D Characteristic for Assessments of Efficient Inhibitors of Protein-Protein Interactions. 国際誌

    Masakazu Nakadai, Shuta Tomida

    Journal of chemical information and modeling   60 ( 10 )   4785 - 4790   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Three-dimensional (3D) molecular descriptors, including physicochemical and shape properties, for protein-protein interaction (PPI) interface inhibitors have become a topic of discussion. However, the relationships between such properties and binding free energy have not been adequately investigated. In this study, we focused on identifying key 3D molecular descriptors related to the binding free energy and/or the ligand efficiency (LE) of PPI interface inhibitors. A positive correlation was found between the binding free energy and the diameter (D) of cylindrical 3D molecules, in addition to a correlation between LE and D/heavy atom count (HAC). In addition, we showed a correlation between LE and D/HAC for macrocyclic compounds, suggesting that the present findings could be applied during assessments of the potential of macrocyclic PPI interface inhibitors in drug discovery processes.

    DOI: 10.1021/acs.jcim.0c00607

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  • CERS6 required for cell migration and metastasis in lung cancer. 国際誌

    Motoshi Suzuki, Ke Cao, Seiichi Kato, Naoki Mizutani, Kouji Tanaka, Chinatsu Arima, Mei Chee Tai, Norie Nakatani, Kiyoshi Yanagisawa, Toshiyuki Takeuchi, Hanxiao Shi, Yasuyoshi Mizutani, Atsuko Niimi, Tetsuo Taniguchi, Takayuki Fukui, Kohei Yokoi, Keiko Wakahara, Yoshinori Hasegawa, Yukiko Mizutani, Soichiro Iwaki, Satoshi Fujii, Akira Satou, Keiko Tamiya-Koizumi, Takashi Murate, Mamoru Kyogashima, Shuta Tomida, Takashi Takahashi

    Journal of cellular and molecular medicine   24 ( 20 )   11949 - 11959   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

    DOI: 10.1111/jcmm.15817

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  • Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer. 査読 国際誌

    Kosuke Ochi, Ken Suzawa, Shuta Tomida, Kazuhiko Shien, Jui Takano, Shunsaku Miyauchi, Tatsuaki Takeda, Akihiro Miura, Kota Araki, Kentaro Nakata, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Masaomi Yamane, Kazuo Azuma, Yoshiharu Okamoto, Shinichi Toyooka

    Biochemical and biophysical research communications   529 ( 3 )   760 - 765   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

    DOI: 10.1016/j.bbrc.2020.06.077

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  • Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. 査読 国際誌

    Shunsaku Miyauchi, Kazuhiko Shien, Tatsuaki Takeda, Kota Araki, Kentaro Nakata, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Junichi Soh, Shuta Tomida, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka

    Anticancer research   40 ( 5 )   2667 - 2673   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

    DOI: 10.21873/anticanres.14237

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  • DV200 Index for Assessing RNA Integrity in Next-Generation Sequencing. 査読 国際誌

    Takehiro Matsubara, Junichi Soh, Mizuki Morita, Takahiro Uwabo, Shuta Tomida, Toshiyoshi Fujiwara, Susumu Kanazawa, Shinichi Toyooka, Akira Hirasawa

    BioMed research international   2020   9349132 - 9349132   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hindawi  

    Poor quality of biological samples will result in an inaccurate analysis of next-generation sequencing (NGS). Therefore, methods to accurately evaluate sample integrity are needed. Among methods for evaluating RNA quality, the RNA integrity number equivalent (RINe) is widely used, whereas the DV200, which evaluates the percentage of fragments of >200 nucleotides, is also used as a quality assessment standard. In this study, we compared the RINe and DV200 RNA quality indexes to determine the most suitable RNA index for the NGS analysis. Seventy-one RNA samples were extracted from formalin-fixed paraffin-embedded tissue samples (n = 30), fresh-frozen samples (n = 25), or cell lines (n = 16). After assessing RNA quality using the RINe and DV200, we prepared two kinds of stranded mRNA sequencing libraries. Finally, we calculated the correlation between each RNA quality index and the amount of library product (1st PCR product per input RNA). The DV200 measure showed stronger correlation with the amount of library product than the RINe (R 2 = 0.8208 for the DV200 versus 0.6927 for the RINe). Receiver operating characteristic curve analyses revealed that the DV200 was the better marker for predicting efficient library production than the RINe using a threshold of >10 ng/ng for the amount of the 1st PCR product per input RNA (cutoff value for the RINe and DV200, 2.3 and 66.1%; area under the curve, 0.99 and 0.91; sensitivity, 82% and 92%; and specificity, 93% and 100%, respectively). Our results indicate that NGS libraries prepared using RNA samples with the DV200 value > 66.1% exhibit greater sensitivity and specificity than those prepared with the RINe values > 2.3. These findings suggest that the DV200 is superior to the RINe, especially for low-quality RNA, because it is a more consistent assessment of the amount of the 1st NGS library product per input.

    DOI: 10.1155/2020/9349132

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  • YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. 査読

    Takeda T, Yamamoto H, Suzawa K, Tomida S, Miyauchi S, Araki K, Nakata K, Miura A, Namba K, Shien K, Soh J, Shien T, Kitamura Y, Sendo T, Toyooka S

    Cancer science   2019年12月

  • Clinical and immune profiling for cancer of unknown primary site. 査読

    Haratani K, Hayashi H, Takahama T, Nakamura Y, Tomida S, Yoshida T, Chiba Y, Sawada T, Sakai K, Fujita Y, Togashi Y, Tanizaki J, Kawakami H, Ito A, Nishio K, Nakagawa K

    Journal for immunotherapy of cancer   7 ( 1 )   251   2019年9月

  • Proposal of new combination, Cutibacterium acnes subsp. elongatum comb. nov., and emended descriptions of the genus Cutibacterium, Cutibacterium acnes subsp. acnes and Cutibacterium acnes subsp. defendens. 査読

    Dekio I, McDowell A, Sakamoto M, Tomida S, Ohkuma M

    International journal of systematic and evolutionary microbiology   69 ( 4 )   1087 - 1092   2019年4月

  • Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma. 査読 国際誌

    Namba K, Tomida S, Matsubara T, Takahashi Y, Kurihara E, Ogoshi Y, Yoshioka T, Takeda T, Torigoe H, Sato H, Shien K, Yamamoto H, Soh J, Tsukuda K, Toyooka S

    BMC cancer   19 ( 1 )   175 - 175   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas. 査読

    Sakaguchi Y, Yamamichi N, Tomida S, Takeuchi C, Kageyama-Yahara N, Takahashi Y, Shiogama K, Inada KI, Ichinose M, Fujishiro M, Koike K

    Journal of gastroenterology   54 ( 2 )   131 - 140   2019年2月

  • Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells. 査読 国際誌

    Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hidejiro Torigoe, Hiroki Sato, Takahiro Yoshioka, Tatsuaki Takeda, Eisuke Kurihara, Yusuke Ogoshi, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka

    Molecular cancer research : MCR   17 ( 2 )   499 - 507   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.

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  • MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib 査読

    Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Scientific Reports   8 ( 1 )   1955   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation
    however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells
    the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

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  • Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation. 査読

    Nakayama C, Yamamichi N, Tomida S, Takahashi Y, Kageyama-Yahara N, Sakurai K, Takeuchi C, Inada KI, Shiogama K, Nagae G, Ono S, Tsuji Y, Niimi K, Fujishiro M, Aburatani H, Tsutsumi Y, Koike K

    Cancer science   109 ( 12 )   3853 - 3864   2018年12月

  • Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. 査読 国際誌

    Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Shinsuke Oda, Takehiro Matsubara, Hiroki Sato, Ken Suzawa, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Torigoe, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 11 )   3634 - 3642   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

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  • Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. 査読 国際誌

    Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 10 )   3183 - 3196   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

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  • Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. 査読

    Watanabe M, Kagawa S, Kuwada K, Hashimoto Y, Shigeyasu K, Ishida M, Sakamoto S, Ito A, Kikuchi S, Kuroda S, Kishimoto H, Tomida S, Yoshida R, Tazawa H, Urata Y, Fujiwara T

    Cancer science   109 ( 10 )   3263 - 3271   2018年10月

  • Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. 査読

    Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K

    Cancer science   109 ( 10 )   3149 - 3158   2018年10月

  • Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR. 査読 国際誌

    Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Carcinogenesis   39 ( 5 )   719 - 727   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues. Next, we focused on the effect of LRIG1 in NSCLC. For this purpose, we established clones stably overexpressing LRIG1, using EGFR-mutant (HCC827, HCC4011 and NCI-H1975) and wild-type (A549) cells. Transfection of LRIG1 was associated with a decrease in the expression and phosphorylation levels of EGFR in the HCC827, HCC4011 and NCI-H1975 cells. It was also associated with strong suppression of the cell proliferative, invasive, migratory and tumorigenic potential of the HCC827 cells. On the other hand, no such effects were observed in the A549 cells. In addition, LRIG1 also downregulated the expression and phosphorylation levels of other tyrosine kinase receptors, such as HER2, HER3, MET and IGF-1R, and prevented the epithelial-to-mesenchymal transition induced by TGF-β in the HCC827 cells. These findings suggest that LRIG1 exerts important tumor-suppressive effects in EGFR-mutant NSCLC and has the potential to become a novel therapeutic target for EGFR-mutant NSCLC.

    DOI: 10.1093/carcin/bgy044

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  • Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations 査読

    Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Cancer Science   109 ( 5 )   1493 - 1502   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Ltd  

    Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

    DOI: 10.1111/cas.13571

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  • Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers. 査読 国際誌

    Hiroshi Kotani, Yuta Adachi, Hidenori Kitai, Shuta Tomida, Hideaki Bando, Anthony C Faber, Takayuki Yoshino, Dominic C Voon, Seiji Yano, Hiromichi Ebi

    Oncogene   37 ( 13 )   1775 - 1787   2018年3月

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    記述言語:英語  

    BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.

    DOI: 10.1038/s41388-017-0035-9

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  • Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E 査読

    Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G. Kris, Bob T. Li, Marc Ladanyi

    Oncologist   23 ( 2 )   150 - 154   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley-Blackwell  

    We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors’ institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors’, revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. Key Points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling. Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations. In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

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  • CCL28-Deficient Mice Have Reduced IgA Antibody-Secreting Cells and an Altered Microbiota in the Colon. 査読 国際誌

    Kazuhiko Matsuo, Daisuke Nagakubo, Shinya Yamamoto, Akiko Shigeta, Shuta Tomida, Mitsugu Fujita, Takako Hirata, Ikuo Tsunoda, Takashi Nakayama, Osamu Yoshie

    Journal of immunology (Baltimore, Md. : 1950)   200 ( 2 )   800 - 809   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate-induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.

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  • Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma 査読

    Hiroki Sato, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Keisuke Aoe, Kazuhiko Shien, Takahiro Yoshioka, Kei Namba, Hidejiro Torigoe, Junichi Soh, Kazunori Tsukuda, Hiroyuki Tao, Kazunori Okabe, Shinichiro Miyoshi, Harvey I. Pass, Shinichi Toyooka

    Oncogenesis   7 ( 1 )   11   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

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  • Development of novel biologics for cancer metastasis via prevention of extracellular S100A8/A9 function 査読

    Kinoshita Rie, Yamauchi Akira, Shien Kazuhiko, Tomida Shuta, Toyooka Shinichi, Kondo Eisaku, Sakaguchi Masakiyo

    CANCER SCIENCE   109   1017   2018年1月

  • Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer 査読

    Haiyang Chen, Kazuhiko Shien, Ken Suzawa, Kazunori Tsukuda, Shuta Tomida, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kei Namba, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY LETTERS   14 ( 4 )   4349 - 4354   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxelresis-tant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

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  • Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization 査読

    Takehiro Matsubara, Shuta Tomida, Junichi Soh, Takahiro Uwabo, Yoshiko Mori, Mizuki Morita, Yasutomo Nasu, Susumu Kanazawa, Shinichi Toyooka

    BIOPRESERVATION AND BIOBANKING   15 ( 5 )   484 - 486   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MARY ANN LIEBERT, INC  

    DOI: 10.1089/bio.2017.0076

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  • Induction chemoradiotherapy using docetaxel and cisplatin with definitive-dose radiation followed by surgery for locally advanced non-small cell lung cancer 査読

    Hidejiro Torigoe, Junichi Soh, Shuta Tomida, Kei Namba, Hiroki Sato, Kuniaki Katsui, Katsuyuki Hotta, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC DISEASE   9 ( 9 )   3076 - 3086   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AME PUBL CO  

    Background: Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (LA-NSCLC). Typically, around 40-50 Gy of radiation is applied as the induction-dose; however, a definitive-dose (DD) of radiation (60 Gy or higher) is occasionally applied to increase local control. We investigated the impact of induction CRT with DD radiation in LA-NSCLC patients treated with a single regimen of docetaxel and cisplatin.
    Methods: We reviewed 110 patients with LA-NSCLC who underwent induction CRT followed by surgery using a single regimen (docetaxel and cisplatin) between January 1999 and December 2014 at our hospital. The clinical outcomes of a DD group (60 Gy or higher, n= 11) and a non-DD group (less than 60 Gy, n= 99) were investigated using a propensity score (PS)-matched analysis.
    Results: An advanced clinical stage was significantly more common in the DD group than in the nonDD group (P= 0.033). Before and after the PS-matching based on seven factors including clinical stage, there was no significant difference in the rates of postoperative (PO) complication, mortality, 5-year overall survival (OS), or 5-year recurrence-free survival (RFS) between the two groups. After the PS-matching, the pathological complete response (CR) rate was significantly higher in the DD group than in the non-DD group [50% (n= 5/10) vs. 0% (n= 0/10), P= 0.033].
    Conclusions: Induction CRT followed by surgery using docetaxel and cisplatin with DD radiation can be performed safely and is associated with a higher pathological CR rate than that attained using non-DD radiation in LA-NSCLC patients.

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  • PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma 査読

    Yoshihiro Otani, Joji Ishida, Kazuhiko Kurozumi, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Shuta Tomida, Takehiro Matsubara, Tomotsugu Ichikawa, Isao Date

    SCIENTIFIC REPORTS   7 ( 1 )   7391   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.

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  • Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system 査読

    Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY REPORTS   37 ( 5 )   3100 - 3106   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

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  • The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stagedependent manner 査読

    Kazushige Ota, Kit I. Tong, Kouichiro Goto, Shuta Tomida, Akiyoshi Komuro, Zhong Wang, Kazuto Nishio, Hitoshi Okada

    PLOS ONE   12 ( 3 )   e0173713   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Understanding the molecular mechanisms that drive adipogenesis is important in developing new treatments for obesity and diabetes. Epigenetic regulations determine the capacity of adipogenesis. In this study, we examined the role of a histone H3 lysine 27 demethylase, the ubiquitously transcribed tetratricopeptide repeat protein on the X chromosome (Utx), in the differentiation of mouse embryonic stem cells (mESCs) to adipocytes. Using gene trapping, we examined Utx-deficient male mESCs to determine whether loss of Utx would enhance or inhibit the differentiation of mESCs to adipocytes. Utx-deficient mESCs showed diminished potential to differentiate to adipocytes compared to that of controls. In contrast, Utx-deficient preadipocytes showed enhanced differentiation to adipocytes. Microarray analyses indicated that the beta-catenin/c-Myc signaling pathway was differentially regulated in Utx-deficient cells during adipocyte differentiation. Therefore, our data suggest that Utx governs adipogenesis by regulating c-Myc in a differentiation stage-specific manner and that targeting the Utx signaling pathway could be beneficial for the treatment of obesity, diabetes, and congenital utx-deficiency disorders.

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  • Draft Genome Sequence of Bifidobacterium lemurum DSM 28807T Isolated from the Gastrointestinal Tracts of Ring-Tailed Lemurs (Lemur catta) 査読

    Hidehiro Toh, Takehiro Matsubara, Shuta Tomida, Iyo Mimura, Kensuke Arakawa, Takefumi Kikusui, Hidetoshi Morita

    Genome Announcements   5 ( 8 )   2017年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society for Microbiology  

    <title>ABSTRACT</title>

    <named-content content-type="genus-species">Bifidobacterium lemurum</named-content> DSM 28807<sup>T</sup> was isolated from the gastrointestinal tracts of ring-tailed lemurs (<italic>Lemur catta</italic>). Here, we report the first draft genome sequence of this organism.

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer 査読

    Tatsuaki Takeda, Hiromasa Yamamoto, Hirotaka Kanzaki, Ken Suzawa, Takahiro Yoshioka, Shuta Tomida, Xiaojiang Cui, Ramachandran Murali, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kazuhiko Shien, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yoshihisa Kitamura, Shinichiro Miyoshi, Toshiaki Sendo, Shinichi Toyooka

    PLOS ONE   12 ( 2 )   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background
    Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered.
    Methods
    We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients.
    Results
    Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer.
    Conclusion
    Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

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  • Comparative genome analyses of Mycobacterium avium reveal genomic features of its subspecies and strains that cause progression of pulmonary disease 査読

    Kei-ichi Uchiya, Shuta Tomida, Taku Nakagawa, Shoki Asahi, Toshiaki Nikai, Kenji Ogawa

    SCIENTIFIC REPORTS   7   39750   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Pulmonary disease caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Mycobacterium avium is the most clinically significant NTM species in humans and animals, and comprises four subspecies: M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS), M. avium subsp. paratuberculosis (MAP), and M. avium subsp. hominissuis (MAH). To improve our understanding of the genetic landscape and diversity of M. avium and its role in disease, we performed a comparative genome analysis of 79 M. avium strains. Our analysis demonstrated that MAH is an open pan-genome species. Phylogenetic analysis based on single nucleotide variants showed that MAH had the highest degree of sequence variability among the subspecies, and MAH strains isolated in Japan and those isolated abroad possessed distinct phylogenetic features. Furthermore, MAP strains, MAS and MAA strains isolated from birds, and many MAH strains that cause the progression of pulmonary disease were grouped in each specific cluster. Comparative genome analysis revealed the presence of genetic elements specific to each lineage, which are thought to be acquired via horizontal gene transfer during the evolutionary process, and identified potential genetic determinants accounting for the pathogenic and host range characteristics of M. avium.

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  • Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features 査読

    Hiroki Sato, Kazuhiko Shien, Shuta Tomida, Kazuhiro Okayasu, Ken Suzawa, Shinsuke Hashida, Hidejiro Torigoe, Mototsugu Watanabe, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   7   40847   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer. 査読

    Takeda T, Yamamoto H, Kanzaki H, Suzawa K, Yoshioka T, Tomida S, Cui X, Murali R, Namba K, Sato H, Torigoe H, Watanabe M, Shien K, Soh J, Asano H, Tsukuda K, Kitamura Y, Miyoshi S, Sendo T, Toyooka S

    PloS one   12 ( 2 )   e0171356   2017年

  • Draft Genome Sequence of Probiotic Lactobacillus acidophilus Strain L-55 Isolated from a Healthy Human Gut 査読

    Yusuke Fujii, Hidehiro Toh, Takehiro Matsubara, Shuta Tomida, Co Thi Kim Nguyen, Iyo Mimura, Shoji Nakamura, Hidetoshi Morita

    Genome Announcements   4 ( 6 )   2016年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society for Microbiology  

    Probiotic
    <italic>Lactobacillus acidophilus</italic>
    L-55 was isolated from a healthy human gut. Here, we report the draft genome sequence of this organism.

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  • Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway 査読

    Tomoaki Ohtsuka, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Katsuyoshi Takata, Kazuhiko Shien, Shinsuke Hashida, Tomoko Miyata-Takata, Mototsugu Watanabe, Ken Suzawa, Junichi Soh, Chen Youyi, Hiroki Sato, Kei Namba, Hidejiro Torigoe, Kazunori Tsukuda, Tadashi Yoshino, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   6   39557   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

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  • Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer. 査読 国際誌

    Hidenori Kitai, Hiromichi Ebi, Shuta Tomida, Konstantinos V Floros, Hiroshi Kotani, Yuta Adachi, Satoshi Oizumi, Masaharu Nishimura, Anthony C Faber, Seiji Yano

    Cancer discovery   6 ( 7 )   754 - 69   2016年7月

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    記述言語:英語  

    UNLABELLED: KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors. SIGNIFICANCE: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non-small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

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  • Epidermolysis bullosa simplex with mottled pigmentation with noncicatricial alopecia: identification of a recurrent p.P25L mutation in KRT5 in four affected family members 査読

    H. Nagai, N. Oiso, S. Tomida, K. Sakai, S. Fujiwara, Y. Nakamachi, S. Kawano, A. Kawada, K. Nishio, C. Nishigori

    BRITISH JOURNAL OF DERMATOLOGY   174 ( 3 )   633 - 635   2016年3月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

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  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations 査読

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    Cancer Science   107 ( 1 )   45 - 52   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Ltd  

    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. In this study, we demonstrated the antitumor effect of afatinib, as a HER2-targeted therapy, in lung cancers harboring HER2 alterations in vitro and in vivo. Our results strongly suggest that afatinib is a promising therapeutic option for NSCLC patients with HER2-amplification or mutations.

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  • An Intriguing Correlation Based on the Superimposition of Residue Pairs with Inhibitors that Target Protein-Protein Interfaces 査読

    Masakazu Nakadai, Shuta Tomida, Kazuhisa Sekimizu

    SCIENTIFIC REPORTS   6   18543   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Druggable sites on protein-protein interfaces are difficult to predict. To survey inhibitor-binding sites onto which residues are superimposed at protein-protein interfaces, we analyzed publicly available information for 39 inhibitors that target the protein-protein interfaces of 8 drug targets. By focusing on the differences between residues that were superimposed with inhibitors and non-superimposed residues, we observed clear differences in the distances and changes in the solvent-accessible surface areas (.SASA). Based on the observation that two or more residues were superimposed onto inhibitors in 37 (95%) of 39 protein-inhibitor complexes, we focused on the two-residue relationships. Application of a cross-validation procedure confirmed a linear negative correlation between the absolute value of the dihedral angle and the sum of the Delta SASAs of the residues. Finally, we applied the regression equation of this correlation to four inhibitors that bind to new sites not bound by the 39 inhibitors as well as additional inhibitors of different targets. Our results shed light on the two-residue correlation between the absolute value of the dihedral angle and the sum of the Delta SASA, which may be a useful relationship for identifying the key two-residues as potential targets of protein-protein interfaces.

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  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations 査読

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    CANCER SCIENCE   107 ( 1 )   45 - 52   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G(1) arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.

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  • Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer 査読

    Kenichi Suda, Isao Murakami, Kazuko Sakai, Hiroshi Mizuuchi, Shigeki Shimizu, Katsuaki Sato, Kenji Tomizawa, Shuta Tomida, Yasushi Yatabe, Kazuto Nishio, Tetsuya Mitsudomi

    SCIENTIFIC REPORTS   5   14447   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre-and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.

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  • An activating ALK gene mutation in ALK IHC-positive/FISH-negative non-small cell lung cancer. 査読

    Togashi Y, Mizuuchi H, Kobayashi Y, Hayashi H, Terashima M, Sakai K, Bannno E, Mizukami T, Nakamura Y, de Velasco MA, Fujita Y, Tomida S, Mitsudomi T, Nishio K

    Ann Oncol   26 ( 8 )   1800 - 1801   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/annonc/mdv240

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  • Propionibacterium acnes Strain Populations in the Human Skin Microbiome Associated with Acne 査読

    Sorel Fitz-Gibbon, Shuta Tomida, Bor-Han Chiu, Lin Nguyen, Christine Du, Minghsun Liu, David Elashoff, Marie C. Erfe, Anya Loncaric, Jenny Kim, Robert L. Modlin, Jeff F. Miller, Erica Sodergren, Noah Craft, George M. Weinstock, Huiying Li

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   133 ( 9 )   2152 - 2160   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease.

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  • Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome. 査読

    Tomida S, Nguyen L, Chiu BH, Liu J, Sodergren E, Weinstock GM, Li H

    mBio   4 ( 3 )   e00003 - 13   2013年4月

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    出版者・発行元:3  

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  • Analysis of Complete Genomes of Propionibacterium acnes Reveals a Novel Plasmid and Increased Pseudogenes in an Acne Associated Strain 査読

    Gabriela Kasimatis, Sorel Fitz-Gibbon, Shuta Tomida, Marthew Wong, Huiying Li

    BIOMED RESEARCH INTERNATIONAL   2013   918320   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:HINDAWI PUBLISHING CORPORATION  

    The human skin harbors a diverse community of bacteria, including the Gram-positive, anaerobic bacterium Propionibacterium acnes. P. acnes has historically been linked to the pathogenesis of acne vulgaris, a common skin disease affecting over 80% of all adolescents in the US. To gain insight into potential P. acnes pathogenic mechanisms, we previously sequenced the complete genome of a P. acnes strain HL096PA1 that is highly associated with acne. In this study, we compared its genome to the first published complete genome KPA171202. HL096PA1 harbors a linear plasmid, pIMPLE-HL096PA1. This is the first described P. acnes plasmid. We also observed a five-fold increase of pseudogenes in HL096PA1, several of which encode proteins in carbohydrate transport and metabolism. In addition, our analysis revealed a few island-like genomic regions that are unique to HL096PA1 and a large genomic inversion spanning the ribosomal operons. Together, these findings offer a basis for understanding P. acnes virulent properties, host adaptation mechanisms, and its potential role in acne pathogenesis at the strain level. Furthermore, the plasmid identified in HL096PA1 may potentially provide a new opportunity for P. acnes genetic manipulation and targeted therapy against specific disease-associated strains.

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  • Phenotypic and Genomic Analysis of Hypervirulent Human-associated Bordetella bronchiseptica 査読

    Umesh Ahuja, Minghsun Liu, Shuta Tomida, Jihye Park, Puneet Souda, Julian Whitelegge, Huiying Li, Eric T. Harvill, Julian Parkhill, Jeff F. Miller

    BMC MICROBIOLOGY   12   167   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: B. bronchiseptica infections are usually associated with wild or domesticated animals, but infrequently with humans. A recent phylogenetic analysis distinguished two distinct B. bronchiseptica subpopulations, designated complexes I and IV. Complex IV isolates appear to have a bias for infecting humans; however, little is known regarding their epidemiology, virulence properties, or comparative genomics.
    Results: Here we report a characterization of the virulence of human-associated complex IV B. bronchiseptica strains. In in vitro cytotoxicity assays, complex IV strains showed increased cytotoxicity in comparison to a panel of complex I strains. Some complex IV isolates were remarkably cytotoxic, resulting in LDH release levels in A549 cells that were 10- to 20-fold greater than complex I strains. In vivo, a subset of complex IV strains was found to be hypervirulent, with an increased ability to cause lethal pulmonary infections in mice. Hypercytotoxicity in vitro and hypervirulence in vivo were both dependent on the activity of the bsc T3SS and the BteA effector. To clarify differences between lineages, representative complex IV isolates were sequenced and their genomes were compared to complex I isolates. Although our analysis showed there were no genomic sequences that can be considered unique to complex IV strains, there were several loci that were predominantly found in complex IV isolates.
    Conclusion: Our observations reveal a T3SS-dependent hypervirulence phenotype in human-associated complex IV isolates, highlighting the need for further studies on the epidemiology and evolutionary dynamics of this B. bronchiseptica lineage.

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  • An Expanded Multilocus Sequence Typing Scheme for Propionibacterium acnes: Investigation of 'Pathogenic', 'Commensal' and Antibiotic Resistant Strains 査読

    Andrew McDowell, Emma Barnard, Istvan Nagy, Anna Gao, Shuta Tomida, Huiying Li, Anne Eady, Jonathan Cove, Carl E. Nord, Sheila Patrick

    PLOS ONE   7 ( 7 )   e41480   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The Gram-positive bacterium Propionibacterium acnes is a member of the normal human skin microbiota and is associated with various infections and clinical conditions. There is tentative evidence to suggest that certain lineages may be associated with disease and others with health. We recently described a multilocus sequence typing scheme (MLST) for P. acnes based on seven housekeeping genes (http://pubmlst.org/pacnes). We now describe an expanded eight gene version based on six housekeeping genes and two 'putative virulence' genes (eMLST) that provides improved high resolution typing (91eSTs from 285 isolates), and generates phylogenies congruent with those based on whole genome analysis. When compared with the nine gene MLST scheme developed at the University of Bath, UK, and utilised by researchers at Aarhus University, Denmark, the eMLST method offers greater resolution. Using the scheme, we examined 208 isolates from disparate clinical sources, and 77 isolates from healthy skin. Acne was predominately associated with type IA(1) clonal complexes CC1, CC3 and CC4; with eST1 and eST3 lineages being highly represented. In contrast, type IA(2) strains were recovered at a rate similar to type IB and II organisms. Ophthalmic infections were predominately associated with type IA1 and IA2 strains, while type IB and II were more frequently recovered from soft tissue and retrieved medical devices. Strains with rRNA mutations conferring resistance to antibiotics used in acne treatment were dominated by eST3, with some evidence for intercontinental spread. In contrast, despite its high association with acne, only a small number of resistant CC1 eSTs were identified. A number of eSTs were only recovered from healthy skin, particularly eSTs representing CC72 (type II) and CC77 (type III). Collectively our data lends support to the view that pathogenic versus truly commensal lineages of P. acnes may exist. This is likely to have important therapeutic and diagnostic implications.

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  • NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma 査読

    Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

    CANCER CELL   21 ( 3 )   348 - 361   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an "Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.

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  • MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis 査読

    Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutani, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi

    EMBO JOURNAL   31 ( 2 )   481 - 493   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of TTF-1 (also known as NKX2-1 and TITF1), a master regulator of lung development that also plays a role as a lineage-survival oncogene in lung adenocarcinoma development. MYBPH inhibited assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), unexpectedly through its direct physical interaction with Rho kinase 1 (ROCK1) rather than with RLC. Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of TTF-1-positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF-1 expression with favourable prognosis in lung adenocarcinoma patients. The EMBO Journal (2012) 31, 481-493. doi:10.1038/emboj.2011.416; Published online 15 November 2011

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  • Seven-signal proteomic signature for detection of operable pancreatic ductal adenocarcinoma and their discrimination from autoimmune pancreatitis. 査読

    Yanagisawa K, Tomida S, Matsuo K, Arima C, Kusumegi M, Yokoyama Y, Ko SB, Mizuno N, Kawahara T, Kuroyanagi Y, Takeuchi T, Goto H, Yamao K, Nagino M, Tajima K, Takahashi T

    International journal of proteomics   2012   510397   2012年

  • miR-375 Is Activated by ASH1 and Inhibits YAP1 in a Lineage-Dependent Manner in Lung Cancer 査読

    Eri Nishikawa, Hirotaka Osada, Yasumasa Okazaki, Chinatsu Arima, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Yasushi Yatabe, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   71 ( 19 )   6165 - 6173   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. Cancer Res; 71(19); 6165-73. (C)2011 AACR.

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  • Proteasomal Non-catalytic Subunit PSMD2 as a Potential Therapeutic Target in Association With Various Clinicopathologic Features in Lung Adenocarcinomas 査読

    Yasushi Matsuyama, Motoshi Suzuki, Chinatsu Arima, Qin Miao Huang, Shuta Tomida, Toshiyuki Takeuchi, Ryoji Sugiyama, Yasutomo Itoh, Yasushi Yatabe, Hidemi Goto, Takashi Takahashi

    MOLECULAR CARCINOGENESIS   50 ( 4 )   301 - 309   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We previously identified PSMD2, a subunit of the 19S regulatory complex of proteasomes, as a constituent of a signature associated with the acquisition of metastatic phenotype and poor prognosis in lung cancers. In the present study, we found that knockdown of PSMD2 decreased proteasome activity, and induced growth inhibition and apoptosis in lung cancer cell lines. These effects of siRNA-mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with induction of p21. In addition, patients with higher PSMD2 expression had poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, our findings clearly illustrate that lung adenocarcinomas can be divided into two groups; those with and without general upregulation of proteasome pathway genes including PSMD2. This general upregulation was significantly more prevalent in the non-terminal respiratory unit (non-TRU)-type, a recently proposed genetically and clinicopathologically relevant expression profile-defined classification of adenocarcinomas (P &lt; 0.001 by Fisher's exact test). Patients with adenocarcinomas with general upregulation had significantly shorter survival after potentially curative resection (P=0.0001 by log-rank test) independent of disease stage, as shown by multivariate Cox regression analysis. Our results suggest that PSMD2 may be a good molecular target candidate and that other co-regulated proteasome pathway genes and/or their common regulator(s) might also be potential targets, warranting future study including elucidation of the underlying common regulatory mechanism. (C) 2011 Wiley-Liss, Inc.

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  • Novel Metastasis-Related Gene CIM Functions in the Regulation of Multiple Cellular Stress-Response Pathways 査読

    Kiyoshi Yanagisawa, Hiroyuki Konishi, Chinatsu Arima, Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Hirotaka Osada, Takashi Takahashi

    CANCER RESEARCH   70 ( 23 )   9949 - 9958   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Various stresses of the tumor microenvironment produced by insufficient nutrients, pH, and oxygen can contribute to the generation of altered metabolic and proliferative states that promote the survival of metastatic cells. Among many cellular stress-response pathways activated under such conditions are the hypoxia-inducible factor (HIF) pathway and the unfolded protein response (UPR), which is elicited as a response to endoplasmic reticulum (ER) stress. In this study, we report the identification of a novel cancer invasion and metastasis-related gene (hereafter referred to as CIM, also called ERLEC1), which influences both of these stress-response pathways to promote metastasis. CIM was identified by comparing the gene expression profile of a highly metastatic human lung cancer cell line with its weakly metastatic parental clone. We showed that CIM is critical for metastatic properties in this system. Proteomic approaches combined with bioinformatic analyses revealed that CIM has multifaceted roles in controlling the response to hypoxia and ER stress. Specifically, CIM sequestered OS-9 from the HIF-1 alpha complex and PHD2, permitting HIF-1 alpha accumulation by preventing its degradation. Ectopic expression of CIM in lung cancer cells increased their tolerance to hypoxia. CIM also modulated UPR through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress conditions. Our findings shed light on how tolerance to multiple cellular stresses at a metastatic site can be evoked by an integrated mechanism involving CIM, which can function to coordinate those responses in a manner that promotes metastatic cell survival. Cancer Res; 70(23); 9949-58. (C)2010 AACR.

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  • Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer 査読

    Qin Miao Huang, Shuta Tomida, Yuji Masuda, Chinatsu Arima, Ke Cao, Taka-Aki Kasahara, Hirotaka Osada, Yasushi Yatabe, Tomohiro Akashi, Kenji Kamiya, Takashi Takahashi, Motoshi Suzuki

    CANCER RESEARCH   70 ( 21 )   8407 - 8416   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Genomic instability is an important factor in cancer susceptibility, but a mechanistic understanding of how it arises remains unclear. We examined hypothesized contributions of the replicative DNA polymerase delta (pol delta) subunit POLD4 to the generation of genomic instability in lung cancer. In examinations of 158 lung cancers and 5 mixtures of 10 normal lungs, cell cycle- and checkpoint-related genes generally showed mRNA expression increases in cancer, whereas POLD4 showed reduced mRNA in small cell lung cancer (SCLC). A fraction of non-small cell lung cancer patients also showed low expression comparable with that in SCLC, which was associated with poor prognosis. The lung cancer cell line ACC-LC-48 was found to have low POLD4 expression, with higher histone H3K9 methylation and lower acetylation in the POLD4 promoter, as compared with the A549 cell line with high POLD4 expression. In the absence of POLD4, pol delta exhibited impaired in vitro DNA synthesis activity. Augmenting POLD4 expression in cells where it was attenuated altered the sensitivity to the chemical carcinogen 4-nitroquinoline-1-oxide. Conversely, siRNA-mediated reduction of POLD4 in cells with abundant expression resulted in a cell cycle delay, checkpoint activation, and an elevated frequency of chromosomal gap/break formation. Overexpression of an engineered POLD4 carrying silent mutations at the siRNA target site rescued these phenotypes, firmly establishing the role of POLD4 in these effects. Furthermore, POLD4 overexpression reduced intrinsically high induction of gamma-H2AX, a well-accepted marker of double-stranded DNA breaks. Together, our findings suggest that reduced expression of POLD4 plays a role in genomic instability in lung cancer. Cancer Res; 70(21); 8407-16. (C) 2010 AACR.

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  • Erratum: PCNA mono-ubiquitination and activation of translesion DNA polymerases by DNA polymerase α (Journal of Biochemistry (2009) 146:1 (13-21) DOI: 10.1093/jb/mvp043)

    Motoshi Suzuki, Atsuko Niimi, Siripan Limsirichaikul, Shuta Tomida, Qin Miao Huang, Shunji Izuta, Jiro Usukura, Yasutomo Itoh, Takashi Hishida, Tomohiro Akashi, Yoshiyuki Nakagawa, Akihiko Kikuchi, Youri Pavlov, Takashi Murate, Takashi Takahashi

    Journal of Biochemistry   148   261   2010年8月

  • PCNA Mono-Ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymerase alpha 査読

    Motoshi Suzuki, Atsuko Niimi, Siripan Limsirichaikul, Shuta Tomida, Qin Miao Huang, Shunji Izuta, Jiro Usukura, Yasutomo Itoh, Takashi Hishida, Tomohiro Akashi, Yoshiyuki Nakagawa, Akihiko Kikuchi, Youri Pavlov, Takashi Murate, Takashi Takahashi

    JOURNAL OF BIOCHEMISTRY   146 ( 1 )   13 - 21   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Translesion DNA synthesis (TLS) involves PCNA mono-ubiquitination and TLS DNA polymerases (pols). Recent evidence has shown that the mono-ubiquitination is induced not only by DNA damage but also by other factors that induce stalling of the DNA replication fork. We studied the effect of spontaneous DNA replication errors on PCNA mono-ubiquitination and TLS induction. In the pol1L868F strain, which expressed an error-prone pol alpha, PCNA was spontaneously mono-ubiquitinated. Pol alpha L868F had a rate-limiting step at the extension from mismatched primer termini. Electron microscopic observation showed the accumulation of a single-stranded region at the DNA replication fork in yeast cells. For pol alpha errors, pol zeta participated in a generation of +1 frameshifts. Furthermore, in the pol1L868F strain, UV-induced mutations were lower than in the wild-type and a pol delta mutant strain (pol3-5DV), and deletion of the RAD30 gene (pol eta) suppressed this defect. These data suggest that nucleotide misincorporation by pol alpha induces exposure of single-stranded DNA, PCNA mono-ubiquitination and activates TLS pols.

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  • Relapse-Related Molecular Signature in Lung Adenocarcinomas Identifies Patients With Dismal Prognosis 査読

    Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Chinatsu Arima, Keitaro Matsuo, Tetsuya Mitsudomi, Yasushi Yatabe, Takashi Takahashi

    JOURNAL OF CLINICAL ONCOLOGY   27 ( 17 )   2793 - 2799   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    In order to aid the development of patient-tailored therapeutics, we attempted to identify a relapse-related signature that allows selection of a group of adenocarcinoma patients with a high probability of relapse.
    Patients and Methods
    Whole-genome expression profiles were analyzed in 117 lung adenocarcinoma samples using microarrays consisting of 41,000 probes. A weighted voting classifier for identifying patients with a relapse-related signature was constructed with an approach that allowed no information leakage during each training step, using 10-fold cross-validation and 100 random partitioning procedures.
    Results
    We identified a relapse-related molecular signature represented by 82 probes (RRS-82) through genome-wide expression profiling analysis of a training set of 60 patients. The robustness of RRS-82 in the selection of patients with a high probability of relapse was then validated with a completely blinded test set of 27 adenocarcinoma patients, showing a clear association of high risk RRS-82 with very poor patient prognosis regardless of disease stage. The discriminatory power of RRS-82 was further validated using an additional independent cohort of 30 stage I patients who underwent surgery at a distinct period of time as well as with the Duke data set on a different platform. Furthermore, completely separate training and validation procedures using another data set recently reported by the Director&apos;s Challenge Consortium also successfully confirmed the predictive power of the genes comprising RRS-82.
    Conclusion
    RRS-82 may be useful for identifying adenocarcinoma patients at very high risk for relapse, even those with cancer in the early stage.

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  • Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent In silico Analyses 査読

    Hiromichi Ebi, Shuta Tomida, Toshiyuki Takeuchi, Chinatsu Arima, Takahiko Sato, Tetsuya Mitsudomi, Yasushi Yatabe, Hirotaka Osada, Takashi Takahashi

    CANCER RESEARCH   69 ( 9 )   4027 - 4035   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    There is marked disparity with a slight overlap among prognosis-predictive signatures reported thus far for lung cancers. In this study, we aimed at linking poor prognosis with particular pathways and/or functions of the gene sets involved to better understand the underlying molecular characteristics associated with the prognosis of lung adenocarcinomas. Gene set enrichment analysis identified a gene set down-regulated by rapamycin as the most significant, whereas several others responsive to withdrawal of glucose or amino acids, which are related to signaling converging onto mammalian target of rapamycin (mTOR), were also shown to be significantly associated, in addition to those related to DNA damage response and cell cycle progression. We also used connectivity map (C-MAP) analysis, an independent bioinformatics approach, to search for Food and Drug Administration-approved drugs that potentially transform an unfavorable signature to a favorable one. Those results identified inhibitors of phosphatidylinositol 3-kinase (PI3K) and mTOR, as well as unexpected drugs such as phenothiazine antipsychotics and resveratrol as potential candidates. Experimental validation revealed that the latter unexpected agents also inhibited signaling converging onto mTOR and exhibited antitumor activities. In addition, deregulation of multiple signaling converging onto mTOR was shown to be significantly associated with sensitivity to PI-103, a dual specificity PI3K/mTOR inhibitor that is not contained in the C-MAP database, lending further support for the connection. Our results clearly show the existence of gene set-definable, intrinsic heterogeneities in lung adenocarcinomas, which seem to be related to both clinical behavior and sensitivity to agents affecting the identified pathways. [Cancer Res 2009;69(9):4027-35]

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  • Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer 査読

    Hirotaka Osada, Shuta Tomida, Yasushi Yatabe, Yoshio Taternatsu, Toshiyuki Takeuchi, Hideki Murakami, Yutaka Kondo, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   68 ( 6 )   1647 - 1655   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    The proneural basic-helix-loop-helix protein achaete-scute homologue I (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/beta-catenin signaling, E-cadherin, and integrin 01 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.

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  • Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1 査読

    Hisaaki Tanaka, Kiyoshi Yanagisawa, Keiko Shinjo, Ayurnu Taguchi, Ken Maeno, Shuta Tomida, Yukako Shimada, Hirotaka Osada, Takayuki Kosaka, Hideo Matsubara, Tetsuya Mitsudomi, Yoshitaka Sekido, Mitsune Tanimoto, Yasushi Yatabe, Takashi Takahashi

    CANCER RESEARCH   67 ( 13 )   6007 - 6011   2007年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher&apos;s exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.

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  • A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer 査読

    Kiyoshi Yanagisawa, Shuta Tomida, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Takashi Takahashi

    JOURNAL OF THE NATIONAL CANCER INSTITUTE   99 ( 11 )   858 - 867   2007年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS INC  

    Background Among patients with non-small-cell lung cancer (NSCLC), those with poor prognosis cannot be distinguished from those with good prognosis.
    Methods Matrix-assisted laser desorption-ionization mass spectrometry was used to analyze protein profiles of 174 specimens from NSCLC tumors and 27 specimens from normal lung tissue and to derive a prognosis-associated proteomic signature. Frozen resected tissue specimens were randomly divided into a training set (116 NSCLC and 20 normal lung specimens) and an independent, blinded validation set (58 NSCLC and seven normal lung specimens). Mass spectrometry signals from training set specimens that were differentially associated with specimens from patients with a high risk of recurrence (i.e., who died within 5 years of surgical treatment because of relapse) compared with those from patients with a low risk of recurrence (i.e., alive with no symptoms of relapse after a median follow-up of 89 months) were selected by use of the Fisher's exact test, the Kruskal-Wallis test, and the significance analysis of microarray test. These signals were used to build an individualized, weighted voting-based prognostic signature. The signature was then validated in the independent dataset. Survival was assessed by multivariable Cox regression analysis. Proteins corresponding to individual signals were identified by ion-trap mass spectrometry coupled with high-performance liquid chromatography. All statistical tests were two-sided.
    Results From 2630 mass spectrometry signals from specimens in the training cohort, we derived a signature of 25 signals that was associated with both relapse-free survival and overall survival. Among stage I NSCLC patients in the validation set, the signature was statistically significantly associated with both overall survival (hazard ratio [HR] of death for patients in the high-risk group compared with those in the low-risk group = 61.1, 95% confidence interval [CI] = 8.9 to 419.2, P&lt;.001) and relapse-free survival (HR of relapse = 11.7, 95% CI = 3.1 to 44.8, P&lt;.001). Proteins corresponding to signals in the signature were identified that had various cellular functions, including ribosomal protein L26-like 1, acylphosphatase, and phosphoprotein enriched in astrocytes 15.
    Conclusions We defined a mass spectrometry signature that was associated with survival among NSCLC patients and appeared to distinguish those with poor prognosis from those with good prognosis.

    DOI: 10.1093/jnci/djk197

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  • Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors 査読

    T Takeuchi, S Tomida, Y Yatabe, T Kosaka, H Osada, K Yanagisawa, T Mitsudomi, T Takahashi

    JOURNAL OF CLINICAL ONCOLOGY   24 ( 11 )   1679 - 1688   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.
    Methods
    Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR, and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.
    Results
    This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.
    Conclusion
    This study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.

    DOI: 10.1200/JCO.2005.03.8224

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  • A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation 査読

    Y Hayashita, H Osada, Y Tatematsu, H Yamada, K Yanagisawa, S Tomida, Y Yatabe, K Kawahara, Y Sekido, T Takahashi

    CANCER RESEARCH   65 ( 21 )   9628 - 9632   2005年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.

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  • Throwing new light on lung cancer pathogenesis: Updates on three recent topics 査読

    S Tomida, Y Yatabe, K Yanagisawa, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   63 - 68   2005年2月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. it has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.

    DOI: 10.1111/j.1349-7006.2005.00021.x

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  • Reduced expression of Dicer associated with poor prognosis in lung cancer patients 査読

    Y Karube, H Tanaka, H Osada, S Tomida, Y Tatematsu, K Yanagisawa, Y Yatabe, J Takamizawa, S Miyoshi, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   111 - 115   2005年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P = 0.001) appears to be independent of disease stage (P = 0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P = 0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.

    DOI: 10.1111/j.1349-7006.2005.00015.x

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  • Artificial neural network approach for selection of susceptible single nucleotide polymorphisms and construction of prediction model on childhood allergic asthma 査読

    Y Tomita, S Tomida, Y Hasegawa, Y Suzuki, T Shirakawa, T Kobayashi, H Honda

    BMC BIOINFORMATICS   5   120   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Screening of various gene markers such as single nucleotide polymorphism ( SNP) and correlation between these markers and development of multifactorial disease have previously been studied. Here, we propose a susceptible marker-selectable artificial neural network ( ANN) for predicting development of allergic disease.
    Results: To predict development of childhood allergic asthma (CAA) and select susceptible SNPs, we used an ANN with a parameter decreasing method (PDM) to analyze 25 SNPs of 17 genes in 344 Japanese people, and select 10 susceptible SNPs of CAA. The accuracy of the ANN model with 10 SNPs was 97.7% for learning data and 74.4% for evaluation data. Important combinations were determined by effective combination value (ECV) defined in the present paper. Effective 2-SNP or 3-SNP combinations were found to be concentrated among the 10 selected SNPs.
    Conclusion: ANN can reliably select SNP combinations that are associated with CAA. Thus, the ANN can be used to characterize development of complex diseases caused by multiple factors. This is the first report of automatic selection of SNPs related to development of multifactorial disease from SNP data of more than 300 patients.

    DOI: 10.1186/1471-2105-5-120

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  • Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients 査読

    S Tomida, K Koshikawa, Y Yatabe, T Harano, N Ogura, T Mitsudomi, M Some, K Yanagisawa, T Takahashi, H Osada, T Takahashi

    ONCOGENE   23 ( 31 )   5360 - 5370   2004年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Individualized outcome prediction classifiers were successfully constructed through expression pro. ling of a total of 8644 genes in 50 non-small-cell lung cancer (NSCLC) cases, which had been consecutively operated on within a defined short period of time and followed up for more than 5 years. The resultant classifier of NSCLCs yielded 82% accuracy for forecasting survival or death 5 years after surgery of a given patient. In addition, since two major histologic classes may differ in terms of outcome-related expression signatures, histologic-type-specific outcome classifiers were also constructed. The resultant highly predictive classifiers, designed specifically for nonsquamous cell carcinomas, showed a prediction accuracy of more than 90% independent of disease stage. In addition to the presence of heterogeneities in adenocarcinomas, our unsupervised hierarchical clustering analysis revealed for the first time the existence of clinicopathologically relevant subclasses of squamous cell carcinomas with marked differences in their invasive growth and prognosis. This finding clearly suggests that NSCLCs comprise distinct subclasses with considerable heterogeneities even within one histologic type. Overall, these findings should advance not only our understanding of the biology of lung cancer but also our ability to individualize postoperative therapies based on the predicted outcome.

    DOI: 10.1038/sj.onc.1207697

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  • Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival 査読

    J Takamizawa, H Konishi, K Yanagisawa, S Tomida, H Osada, H Endoh, T Harano, Y Yatabe, M Nagino, Y Nimura, T Mitsudomi, T Takahashi

    CANCER RESEARCH   64 ( 11 )   3753 - 3756   2004年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    In this study, we report for the first time reduced expression of the let-7 microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had undergone potentially curative resection could be classified into two major groups according to let-7 expression in unsupervised hierarchical analysis, showing significantly shorter survival after potentially curative resection in cases with reduced let-7 expression (P = 0.0003). Multivariate COX regression analysis showed this prognostic impact to be independent of disease stage (hazard ratio = 2.17; P = 0.009). In addition, overexpression of let-7 in A549 lung adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study represents the first report of reduced expression of let-7 and the potential clinical and biological effects of such a microRNA alteration.

    DOI: 10.1158/0008-5472.CAN-04-0637

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  • Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction 査読

    H Endoh, S Tomida, Y Yatabe, H Konishi, H Osada, K Tajima, T Kuwano, T Takahashi, T Mitsudomi

    JOURNAL OF CLINICAL ONCOLOGY   22 ( 5 )   811 - 819   2004年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose Recently, several expression-profiling experiments have shown that adenocarcinoma can be classified into subgroups that also reflect patient survival. In this study, we examined the expression patterns of 44 genes selected by these studies to test whether their expression patterns were relevant to prognosis in our cohort as well, and to create a prognostic model applicable to clinical practice,
    Patients and Methods Expression levels were determined in 85 adenocarcinoma patients by quantitative reverse transcriptase polymerase chain reaction. Cluster analysis was performed, and a prognostic model was created by the proportional hazards model using a stepwise method.
    Results Hierarchical clustering divided the cases into three major groups, and group B, comprising 21 cases, had significantly poor survival (P = .0297). Next, we tried to identify a smaller number of genes of particular predictive value, and eight genes (PTK7, CIT, SCNN1A, PGES, ERO1L, ZWINT, and two ESTs) were selected. We then calculated a risk index that was defined as a linear combination of gene expression values weighted by their estimated regression coefficients. The risk index was a significant independent prognostic factor (P = .0021) by multivariate analysis. Furthermore, the robustness of this model was confirmed using an independent set of 21 patients (P = .0085).
    Conclusion By analyzing a reasonably small number of genes, patients with adenocarcinoma could be stratified according to their prognosis. The prognostic model could be applicable to future decisions concerning treatment.
    (C) 2004 by American Society of Clinical Oncology.

    DOI: 10.1200/JCO.2004.04.109

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  • Inference of common genetic network using fuzzy adaptive resonance theory associated matrix method 査読

    H Takahashi, S Tomida, T Kobayashi, H Honda

    JOURNAL OF BIOSCIENCE AND BIOENGINEERING   96 ( 2 )   154 - 160   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC BIOSCIENCE BIOENGINEERING JAPAN  

    Inferring genetic networks from gene expression data is the most challenging work in the postgenomic era. However, most studies tend to show their genetic network inference ability by using artificial data. Here, we developed the fuzzy adaptive resonance theory associated matrix (F-ART matrix) method to infer genetic networks and applied it to experimental time series data, which are gene expression profiles of Saccharomyces cerevisiae responding under oxidative stresses such as diamide, heat shock and H2O2. We preprocessed them using the fuzzy adaptive resonance theory and successfully identified genetic interactions by drawing a 2-dimensional matrix. The identified interactions between diamide and heat shock stress were confirmed to be the common interactions for two stresses, compared with the KEGG metabolic map, BRITE protein interaction map, and gene interaction data of other papers. In the predicted common genetic network, the hit ratio was 60% for the KEGG map. Several gene interactions were also drawn, which have been reported to be important in oxidative stress. This result suggests that F-ART matrix has the potential to function as a new method to extract the common genetic networks of two different stresses using experimental time series microarray data.

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  • Analysis of expression profile using fuzzy adaptive resonance theory. 査読

    Tomida S, Hanai T, Honda H, Kobayashi T

    Bioinformatics (Oxford, England)   18   1073 - 1083   2002年8月

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  • Artificial neural network predictive model for allergic disease using single nucleotide polymorphisms data 査読

    S Tomida, T Hanai, N Koma, Y Suzuki, T Kobayashi, H Honda

    JOURNAL OF BIOSCIENCE AND BIOENGINEERING   93 ( 5 )   470 - 478   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC BIOSCIENCE BIOENGINEERING JAPAN  

    The purpose of this study was to develop a novel diagnostic prediction method for allergic diseases from the data of single nucleotide polymorphisms (SNPs) using an artificial neural network (ANN). We applied the prediction method to four allergic diseases, such as atopic dermatitis (AD), allergic conjunctivitis (AC), allergic rhinitis (AR) and bronchial asthma (BA), and verified its predictive ability. Almost all the learning data were precisely predicted. Regarding the evaluation data, the learned ANN model could correctly predict a diagnosis with more than 78% accuracy. We also analyzed the SNP data using multiple regression analysis (MRA). Using the MRA model, less than 10% of patients with the above allergic diseases were correctly diagnosed, while this figure was more than 75% for persons without allergic diseases. From these results, it was shown that the ANN model was superior to the MRA model with respect to predictive ability of allergic diseases. Moreover, we used two different methods to convert the genetic polymorphism data into numerical data. Using both methods, diagnostic predictions were quite precise and almost the same predictive abilities were observed. This is the first study showing the application and usefulness of an ANN for the prediction of allergic diseases based on SNP data.

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書籍等出版物

  • 実験医学(増刊)・皮膚細菌叢のバイオロジー

    冨田 秀太( 担当: 分担執筆)

    羊土社  2014年 

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  • 細胞工学(Vol.32 No.11 2013)・皮膚のマイクロバイオームと疾患

    冨田 秀太( 担当: 分担執筆)

    秀潤社  2013年11月 

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  • 実験医学(増刊)・皮膚のマイクロバイオーム研究最前線

    冨田 秀太( 担当: 分担執筆)

    羊土社  2013年 

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  • 実験医学(増刊)・ 発現プロファイル解析に基づく肺癌の診断・治療の新展開

    羊土社  2004年 

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MISC

  • Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer. 国際誌

    Kohsuke Isomoto, Koji Haratani, Hidetoshi Hayashi, Shigeki Shimizu, Shuta Tomida, Takashi Niwa, Toshihide Yokoyama, Yasushi Fukuda, Yasutaka Chiba, Ryoji Kato, Junko Tanizaki, Kaoru Tanaka, Masayuki Takeda, Takashi Ogura, Tadashi Ishida, Akihiko Ito, Kazuhiko Nakagawa

    Clinical cancer research : an official journal of the American Association for Cancer Research   26 ( 8 )   2037 - 2046   2020年4月

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    記述言語:英語  

    PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

    DOI: 10.1158/1078-0432.CCR-19-2027

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  • Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. 査読

    Makimoto G, Ohashi K, Tomida S, Nishii K, Matsubara T, Kayatani H, Higo H, Ninomiya K, Sato A, Watanabe H, Kano H, Ninomiya T, Kubo T, Rai K, Ichihara E, Hotta K, Tabata M, Toyooka S, Takata M, Maeda Y, Kiura K

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2019年7月

  • Targeting miR-200c/LIN28B Axis in Acquired EGFR-TKI Resistance Non-Small Cell Lung Cancer Cells Harboring EMT Features

    Kazuhiko Shien, Hiroki Sato, Ken Suzawa, Shuta Tomida, Shinsuke Hashida, Hiromasa Yamamoto, Junichi Soh, Hidejiro Torigoe, Kei Namba, Mototsugu Watanabe, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S1267 - S1267   2017年1月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Detection of Multiple Low-Frequency Mutations by Molecular-Barcode Sequencing

    Kei Namba, Shuta Tomida, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S531 - S531   2017年1月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Detection of EGFR mutations in circulating cell-free DNA of non-small cell lung cancer patients by next-generation sequencing

    Ken Suzawa, Shuta Tomida, Takahiro Matsubara, Kadoaki Ohashi, Yuho Maki, Hiromasa Yamamoto, Mizuki Morita, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Katuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin (vol 9, pg 2092, 2015)

    Jared Liu, Riceley Yan, Qiao Zhong, Sam Ngo, Nathanael J. Bangayan, Lin Nguyen, Timothy Lui, Minghsun Liu, Marie C. Erfe, Noah Craft, Shuta Tomida, Huiying Li

    ISME JOURNAL   9 ( 9 )   2116 - 2116   2015年9月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    DOI: 10.1038/ismej.2015.144

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  • NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

    Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

    CLINICAL CANCER RESEARCH   18 ( 10 )   2012年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1078-0432.MECHRES-PR1

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  • NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

    Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-LB-17

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  • MYBPH, a novel transcriptional target of TTF-1/NKX2-1, inhibits ROCK1 and actomyosin assembly, and reduces cell motility and tumor metastasis

    Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutan, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-LB-360

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  • Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features

    Osada Hirotaka, Eri Nishikawa, Chinatsu Arima, Yasumasa Okazaki, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-3992

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  • PCNA Mono-Ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymerase alpha (vol 146, pg 13, 2009)

    Motoshi Suzuki, Atsuko Niimi, Siripan Limsirichaikul, Shuta Tomida, Qin Miao Huang, Shunji Izuta, Jiro Usukura, Yasutomo Itoh, Takashi Hishida, Tomohiro Akashi, Yoshiyuki Nakagawa, Akihiko Kikuchi, Youri Pavlov, Takashi Murate, Takashi Takahashi

    JOURNAL OF BIOCHEMISTRY   148 ( 2 )   261 - 261   2010年8月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    DOI: 10.1093/jb/mvq059

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  • ASH1 gene may be prototypic "lineagesurvival oncogene" and specific therapeutic target for lung cancers with neuroendocrine features

    Hirotaka Sada, Yoshio Tatematsu, Toshiyuki Takeuchi, Shuta Tomida, Hideki Murakami, Yutaka Kondo, Yasushi Yatabe, Yoshitaka Sekido, Takashi Takahashi

    JOURNAL OF GENE MEDICINE   10 ( 4 )   459 - 459   2008年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

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  • In silico screening of differentially expressed microRNAs in lung cancer

    Shuta Tomida, Koyo Tsujikawa, Takashi Takahashi

    MOLECULAR CANCER THERAPEUTICS   6 ( 12 )   3486S - 3486S   2007年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

    S. Tomida, K. Yanagisawa, K. Koshikawa, Y. Yatabe, T. Mitsudomi, H. Osada, T. Takahashi

    ONCOGENE   26 ( 31 )   4600 - 4608   2007年7月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.

    DOI: 10.1038/sj.onc.1210242

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  • Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1

    Hisaaki Tanaka, Kiyoshi Yanagisawa, Keiko Shinjo, Ayurnu Taguchi, Ken Maeno, Shuta Tomida, Yukako Shimada, Hirotaka Osada, Takayuki Kosaka, Hideo Matsubara, Tetsuya Mitsudomi, Yoshitaka Sekido, Mitsune Tanimoto, Yasushi Yatabe, Takashi Takahashi

    CANCER RESEARCH   67 ( 13 )   6007 - 6011   2007年7月

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    記述言語:英語   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher&apos;s exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.

    DOI: 10.1158/0008-5472.CAN-06-4774

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  • A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer

    Kiyoshi Yanagisawa, Shuta Tomida, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Takashi Takahashi

    JOURNAL OF THE NATIONAL CANCER INSTITUTE   99 ( 11 )   858 - 867   2007年6月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

    Background Among patients with non-small-cell lung cancer (NSCLC), those with poor prognosis cannot be distinguished from those with good prognosis.
    Methods Matrix-assisted laser desorption-ionization mass spectrometry was used to analyze protein profiles of 174 specimens from NSCLC tumors and 27 specimens from normal lung tissue and to derive a prognosis-associated proteomic signature. Frozen resected tissue specimens were randomly divided into a training set (116 NSCLC and 20 normal lung specimens) and an independent, blinded validation set (58 NSCLC and seven normal lung specimens). Mass spectrometry signals from training set specimens that were differentially associated with specimens from patients with a high risk of recurrence (i.e., who died within 5 years of surgical treatment because of relapse) compared with those from patients with a low risk of recurrence (i.e., alive with no symptoms of relapse after a median follow-up of 89 months) were selected by use of the Fisher's exact test, the Kruskal-Wallis test, and the significance analysis of microarray test. These signals were used to build an individualized, weighted voting-based prognostic signature. The signature was then validated in the independent dataset. Survival was assessed by multivariable Cox regression analysis. Proteins corresponding to individual signals were identified by ion-trap mass spectrometry coupled with high-performance liquid chromatography. All statistical tests were two-sided.
    Results From 2630 mass spectrometry signals from specimens in the training cohort, we derived a signature of 25 signals that was associated with both relapse-free survival and overall survival. Among stage I NSCLC patients in the validation set, the signature was statistically significantly associated with both overall survival (hazard ratio [HR] of death for patients in the high-risk group compared with those in the low-risk group = 61.1, 95% confidence interval [CI] = 8.9 to 419.2, P&lt;.001) and relapse-free survival (HR of relapse = 11.7, 95% CI = 3.1 to 44.8, P&lt;.001). Proteins corresponding to signals in the signature were identified that had various cellular functions, including ribosomal protein L26-like 1, acylphosphatase, and phosphoprotein enriched in astrocytes 15.
    Conclusions We defined a mass spectrometry signature that was associated with survival among NSCLC patients and appeared to distinguish those with poor prognosis from those with good prognosis.

    DOI: 10.1093/jnci/djk197

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  • Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors

    T Takeuchi, S Tomida, Y Yatabe, T Kosaka, H Osada, K Yanagisawa, T Mitsudomi, T Takahashi

    JOURNAL OF CLINICAL ONCOLOGY   24 ( 11 )   1679 - 1688   2006年4月

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    記述言語:英語   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.
    Methods
    Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR, and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.
    Results
    This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.
    Conclusion
    This study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.

    DOI: 10.1200/JCO.2005.03.8224

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  • Reduced expression of Dicer associated with poor prognosis in lung cancer patients

    Y Karube, H Tanaka, H Osada, S Tomida, Y Tatematsu, K Yanagisawa, Y Yatabe, J Takamizawa, S Miyoshi, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   111 - 115   2005年2月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P = 0.001) appears to be independent of disease stage (P = 0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P = 0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.

    DOI: 10.1111/j.1349-7006.2005.00015.x

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  • Throwing new light on lung cancer pathogenesis: Updates on three recent topics

    S Tomida, Y Yatabe, K Yanagisawa, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   63 - 68   2005年2月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:WILEY-BLACKWELL  

    Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. it has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.

    DOI: 10.1111/j.1349-7006.2005.00021.x

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  • A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation.

    Cancer Res.   65 ( 21 )   9628 - 32   2005年

  • Artificial neural network approach for selection of susceptible single nucleotide polymorphisms and construction of prediction model on childhood allergic asthma

    Y Tomita, S Tomida, Y Hasegawa, Y Suzuki, T Shirakawa, T Kobayashi, H Honda

    BMC BIOINFORMATICS   5 ( 120 )   2004年9月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Screening of various gene markers such as single nucleotide polymorphism ( SNP) and correlation between these markers and development of multifactorial disease have previously been studied. Here, we propose a susceptible marker-selectable artificial neural network ( ANN) for predicting development of allergic disease.
    Results: To predict development of childhood allergic asthma (CAA) and select susceptible SNPs, we used an ANN with a parameter decreasing method (PDM) to analyze 25 SNPs of 17 genes in 344 Japanese people, and select 10 susceptible SNPs of CAA. The accuracy of the ANN model with 10 SNPs was 97.7% for learning data and 74.4% for evaluation data. Important combinations were determined by effective combination value (ECV) defined in the present paper. Effective 2-SNP or 3-SNP combinations were found to be concentrated among the 10 selected SNPs.
    Conclusion: ANN can reliably select SNP combinations that are associated with CAA. Thus, the ANN can be used to characterize development of complex diseases caused by multiple factors. This is the first report of automatic selection of SNPs related to development of multifactorial disease from SNP data of more than 300 patients.

    DOI: 10.1186/1471-2105-5-120

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  • Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction

    H Endoh, S Tomida, Y Yatabe, H Konishi, H Osada, K Tajima, T Kuwano, T Takahashi, T Mitsudomi

    JOURNAL OF CLINICAL ONCOLOGY   22 ( 5 )   811 - 819   2004年3月

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    記述言語:英語   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose Recently, several expression-profiling experiments have shown that adenocarcinoma can be classified into subgroups that also reflect patient survival. In this study, we examined the expression patterns of 44 genes selected by these studies to test whether their expression patterns were relevant to prognosis in our cohort as well, and to create a prognostic model applicable to clinical practice,
    Patients and Methods Expression levels were determined in 85 adenocarcinoma patients by quantitative reverse transcriptase polymerase chain reaction. Cluster analysis was performed, and a prognostic model was created by the proportional hazards model using a stepwise method.
    Results Hierarchical clustering divided the cases into three major groups, and group B, comprising 21 cases, had significantly poor survival (P = .0297). Next, we tried to identify a smaller number of genes of particular predictive value, and eight genes (PTK7, CIT, SCNN1A, PGES, ERO1L, ZWINT, and two ESTs) were selected. We then calculated a risk index that was defined as a linear combination of gene expression values weighted by their estimated regression coefficients. The risk index was a significant independent prognostic factor (P = .0021) by multivariate analysis. Furthermore, the robustness of this model was confirmed using an independent set of 21 patients (P = .0085).
    Conclusion By analyzing a reasonably small number of genes, patients with adenocarcinoma could be stratified according to their prognosis. The prognostic model could be applicable to future decisions concerning treatment.
    (C) 2004 by American Society of Clinical Oncology.

    DOI: 10.1200/JCO.2004.04.109

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  • Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.

    Cancer Res.   64 ( 11 )   3753 - 6   2004年

  • Analysis of expression profile using fuzzy adaptive resonance theory.

    Bioinformatics   18 ( 8 )   1073 - 83   2002年

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産業財産権

  • Fast diagnosis and personalized treatments for acne

    冨田 秀太

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    出願番号:US201261612290P  出願日:2012年3月17日

    公開番号:WO2013142378A9  公開日:2014年1月23日

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  • 細胞増殖阻害剤

    高橋 隆, 山口 知也, 冨田 秀太

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    出願人:国立大学法人名古屋大学

    出願番号:JP2009062975  出願日:2009年7月17日

    公開番号:WO2010-008069  公開日:2010年1月21日

    J-GLOBAL

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  • 肺腺癌患者の術後再発を予測するための方法及び組成物

    高橋 隆, 冨田 秀太, 竹内 俊幸, 谷田部 恭, 光冨 徹哉

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    出願人:国立大学法人名古屋大学, 株式会社Oncomics, 愛知県

    出願番号:JP2008073982  出願日:2008年12月26日

    公開番号:WO2009-084740  公開日:2009年7月9日

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  • 質量分析法を利用した複数癌腫の血液検出のための方法および生物マーカー

    高橋 隆, 柳澤 聖, 冨田 秀太, 竹内 俊幸, 久寿米木, 松尾 恵太郎, 田島 和雄

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    出願人:国立大学法人名古屋大学, 株式会社Oncomics, 愛知県

    出願番号:特願2008-235216  出願日:2008年9月12日

    公開番号:特開2010-066225  公開日:2010年3月25日

    J-GLOBAL

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  • 肺腺癌細胞に対する薬剤の有効性評価法

    高橋 隆, 柳澤 聖, 冨田 秀太

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    出願人:国立大学法人名古屋大学

    出願番号:特願2007-110320  出願日:2007年4月19日

    公開番号:特開2008-263837  公開日:2008年11月6日

    J-GLOBAL

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  • 肺癌患者の術後予後予測のための生物マーカー及びその方法

    高橋 隆, 柳澤 聖, 冨田 秀太, 谷田部 恭, 光冨 徹哉

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    出願人:国立大学法人名古屋大学, 愛知県

    出願番号:特願2006-092568  出願日:2006年3月29日

    公開番号:特開2007-263896  公開日:2007年10月11日

    J-GLOBAL

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  • 癌患者の術後の予後又は転移可能性を予測するための組成物及び方法

    高橋 隆, 冨田 秀太, 柳澤 聖

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    出願人:国立大学法人名古屋大学

    出願番号:特願2005-379867  出願日:2005年12月28日

    公開番号:特開2007-175023  公開日:2007年7月12日

    J-GLOBAL

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  • 肺腺癌患者の術後予後を予測するための方法及び組成物

    高橋 隆, 冨田 秀太, 谷田部 恭, 光冨 徹哉, 竹内 俊幸

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    出願人:国立大学法人名古屋大学, 愛知県, 社団法人バイオ産業情報化コンソーシアム

    出願番号:特願2005-291588  出願日:2005年10月4日

    公開番号:特開2007-097486  公開日:2007年4月19日

    J-GLOBAL

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  • 肺癌組織中の遺伝子発現強度を識別する方法

    高橋 隆, 冨田 秀太, 光冨 徹哉, 谷田部 恭, 小倉 信彦, 染 真人

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    出願人:愛知県, 富士フイルム株式会社

    出願番号:特願2003-415119  出願日:2003年12月12日

    公開番号:特開2005-261201  公開日:2005年9月29日

    特許番号/登録番号:特許第5192632号  発行日:2013年2月8日

    J-GLOBAL

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  • 遺伝子のクラスタリング方法

    小林 猛, 本多 裕之, 花井 泰三, 冨田 秀太

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    出願人:財団法人名古屋産業科学研究所

    出願番号:特願2000-373765  出願日:2000年12月8日

    公開番号:特開2002-175306  公開日:2002年6月21日

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受賞

  • 日本癌学会奨励賞

    2010年   日本癌学会  

    冨田 秀太

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共同研究・競争的資金等の研究

  • ドライバー遺伝子陽性肺癌が依存するパスウェイを標的とした次世代精密医療の開発

    研究課題/領域番号:20H03771  2020年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    冨田 秀太, 豊岡 伸一, 大橋 圭明, 山本 寛斉, 諏澤 憲

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

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  • 分子バーコードを用いた高感度遺伝子変異解析と機能解析

    2017年04月 - 2020年03月

    日本学術振興会  科学研究費補助金(基盤研究(C)) 

    冨田 秀太

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    担当区分:研究代表者  資金種別:競争的資金

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  • Cクラス・Mクラスシグネチャーを統合したECM分類によるがん分子病態の解明

    2016年04月 - 2018年03月

    文部科学省  科学研究費補助金(新学術領域研究(研究領域提案型)) 

    冨田 秀太

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    担当区分:研究代表者  資金種別:競争的資金

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  • 次世代シーケンサーを用いたスキンマイクロバイオームの解析と新規治療法の開発

    研究課題/領域番号:26860902  2014年 - 2015年

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    冨田 秀太

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3770000円 ( 直接経費:2900000円 、 間接経費:870000円 )

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  • 術後再発症例に特異的発現パターンの同定と感受性予測を含む個別化診断手法の構築

    研究課題/領域番号:19790969  2007年 - 2008年

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    冨田 秀太

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3000000円 ( 直接経費:2700000円 、 間接経費:300000円 )

    研究代表者らは、"機能的に関連した一連の遺伝子セット"を解析単位とする解析手法を用いる事によって、肺腺癌の多様性に関する"ターゲットパスウェイ"の抽出に成功した。この"ターゲットパスウェイ"を基にした判別モデルを用いて、独立した肺腺癌データを解析したところ、統計的に有意に、術後予後良好群と予後不良群に分類することができた。また、肺腺癌細胞株を用いた検討により、"ターゲットパスウェイ"に対する阻害活性を持つ薬剤の感受性予測モデルの構築にも成功した。

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担当授業科目

  • バイオメディカルデータサイエンス (2021年度) 第4学期  - 月4~6

  • 臨床医歯科学概論 (2021年度) 集中  - その他

  • バイオメディカルデータサイエンス (2020年度) 第4学期  - その他

  • 臨床医歯科学概論 (2020年度) 集中  - その他