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  1. Article ; Online: Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis

    Koichi Ando / Ryo Manabe / Yasunari Kishino / Sojiro Kusumoto / Toshimitsu Yamaoka / Akihiko Tanaka / Tohru Ohmori / Hironori Sagara

    International Journal of Molecular Sciences, Vol 24, Iss 2242, p

    A Network Meta-Analysis

    2023  Volume 2242

    Abstract: Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive ... ...

    Abstract Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.
    Keywords brain metastasis ; ALK rearrangement ; acquired resistance ; network meta-analysis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

    Tohru Ohmori / Toshimitsu Yamaoka / Koichi Ando / Sojiro Kusumoto / Yasunari Kishino / Ryou Manabe / Hironori Sagara

    International Journal of Molecular Sciences, Vol 22, Iss 2, p

    2021  Volume 792

    Abstract: The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase ... ...

    Abstract The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.
    Keywords EGFR-TKIs ; lung injury ; inflammation ; TNF ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610 ; 616
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms

    Toshimitsu Yamaoka / Motoi Ohba / Tohru Ohmori

    International Journal of Molecular Sciences, Vol 18, Iss 11, p

    2017  Volume 2420

    Abstract: Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small-molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, ... ...

    Abstract Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small-molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma of the head and neck. Although these therapies can significantly prolong progression-free survival, curative effects are not often achieved because of intrinsic and/or acquired resistance. The resistance mechanisms to EGFR-targeted therapies can be categorized as resistant gene mutations, activation of alternative pathways, phenotypic transformation, and resistance to apoptotic cell death. Analysis of the processes that modulate EGFR signal transduction by EGFR-targeted inhibitors, such as tyrosine kinase inhibitors and monoclonal antibodies, has revealed new therapeutic opportunities and has elucidated novel mechanisms contributing to the discovery of more effective anticancer treatments. In this review, we discuss the roles of EGFR in cancer development, therapeutic strategies for targeting EGFR, and resistance mechanisms to EGFR-targeted therapies, with a focus on cancer therapies for individual patients.
    Keywords epidermal growth factor receptor ; resistance mechanisms ; cancer ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Receptor Tyrosine Kinase-Targeted Cancer Therapy

    Toshimitsu Yamaoka / Sojiro Kusumoto / Koichi Ando / Motoi Ohba / Tohru Ohmori

    International Journal of Molecular Sciences, Vol 19, Iss 11, p

    2018  Volume 3491

    Abstract: In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, ...

    Abstract In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms.
    Keywords receptor tyrosine kinase ; molecular target inhibitors ; resistance mechanisms ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Up-regulation of Syndecan-4 contributes to TGF-β1-induced epithelial to mesenchymal transition in lung adenocarcinoma A549 cells

    Yoko Toba-Ichihashi / Toshimitsu Yamaoka / Tohru Ohmori / Motoi Ohba

    Biochemistry and Biophysics Reports, Vol 5, Iss C, Pp 1-

    2016  Volume 7

    Abstract: Syndecan-4 (SDC4) is a cell-surface proteoglycan associated with cell adhesion, motility, and intracellular signaling. Here, we present that SDC4 functions as a positive regulator of the transforming growth factor (TGF)-β1-induced epithelial to ... ...

    Abstract Syndecan-4 (SDC4) is a cell-surface proteoglycan associated with cell adhesion, motility, and intracellular signaling. Here, we present that SDC4 functions as a positive regulator of the transforming growth factor (TGF)-β1-induced epithelial to mesenchymal transition (EMT) via Snail in lung adenocarcinoma, A549 cells. TGF-β1 up-regulated the expression of SDC4, accompanied by the induction of EMT. Wound-healing and transwell chemotaxis assay revealed that SDC4 promoted cell migration and invasion. SDC4 knockdown recovered the E-cadherin and decreased vimentin and Snail expression in EMT-induced A549 cells. However, depletion of SDC4 resulted in little change of the Slug protein expression and mesenchymal cell morphology induced by TGF-β1. The double knockdown of SDC-4 and Slug was required for reversal of epithelial morphology; it did not occur from the SDC4 single knockdown. These findings suggest that Snail is a transcriptional factor downstream of SDC4, and SDC4 regulates TGF-β1-induced EMT by cooperating with Slug. Our data provide a novel insight into cellular mechanisms, whereby the cell-surface proteoglycan modulated TGF-β1-induced EMT in lung adenocarcinoma, A549 cells.
    Keywords Syndecan-4 ; Transforming growth factor-β 1 ; Epithelial to mesenchymal transition ; Snail ; Slug ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
    Subject code 500
    Language English
    Publishing date 2016-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Blockade of EGFR Activation Promotes TNF-Induced Lung Epithelial Cell Apoptosis and Pulmonary Injury

    Toshimitsu Yamaoka / Satoru Arata / Mayumi Homma / Tetsuya Homma / Sojiro Kusumoto / Koichi Ando / Ryou Manabe / Yasunari Kishino / Motoi Ohba / Junji Tsurutani / Masafumi Takimoto / Tohru Ohmori / Hironori Sagara

    International Journal of Molecular Sciences, Vol 20, Iss 16, p

    2019  Volume 4021

    Abstract: Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this ... ...

    Abstract Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.
    Keywords TNF ; EGFR ; apoptosis ; lung injury ; transactivation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Inhibition of Virus-Induced Cytokine Production from Airway Epithelial Cells by the Late Addition of Budesonide

    Tetsuya Homma / Yosuke Fukuda / Yoshitaka Uchida / Tomoki Uno / Megumi Jinno / Yasunari Kishino / Mayumi Yamamoto / Hiroki Sato / Kaho Akimoto / Keisuke Kaneko / Akiko Fujiwara / Haruna Sato / Kuniaki Hirai / Yoshito Miyata / Hideki Inoue / Shin Ohta / Yoshio Watanabe / Sojiro Kusumoto / Koichi Ando /
    Shintaro Suzuki / Toshimitsu Yamaoka / Akihiko Tanaka / Tohru Ohmori / Hironori Sagara

    Medicina, Vol 56, Iss 3, p

    2020  Volume 98

    Abstract: Background: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like ... ...

    Abstract Background: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like receptor 3 (TLR3), induced inflammatory chemokines from airway epithelial cells and found prior incubation with corticosteroids diminishes the effect of TLR3 activation. In clinical practice, mild asthma is recommended as-needed budesonide (BUD) when symptoms occur following a viral infection, etc. However, many questions still surround BUD’s usefulness if taken after a virus has already infected airway tissue. Objective: The aim of this study was to investigate the inhibitory effects of BUD on inflammatory cytokines induced by viral infection. Methods : Normal human bronchial epithelial (NHBE) cells were stimulated with poly I:C or infected with human rhinovirus-16 (HRV16) and BUD was added after the initial stimulation. Expression of both thymic stromal lymphopoietin (TSLP) and CCL26/eotaxin-3 was quantified by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Knockdown study was performed. Results : Pre-or post-incubation with BUD inhibited both poly I:C- and HRV16-induced mRNAs and proteins of both thymic stromal lymphopoietin (TSLP) and CCL26 with significance. Knockdown of the glucocorticoid receptor diminished these effects of BUD. Under the same conditions of BUD’s experiment, post-incubation with neither fluticasone propionate nor dexamethasone suppressed expression of both TSLP and CCL26, which induced by poly I:C. Conclusion: Post-addition of BUD inhibited the virus-induced TSLP and CCL26 from the airway epithelial cells. These results suggest that inhalation of BUD after viral infection has beneficial effects on asthma. Conclusion: Late addition of BUD may benefit among patient with viral infection and type 2 allergic airway disease such as asthma.
    Keywords budesonide ; thymic stromal lymphopoietin (tslp) ; rhinovirus ; epithelial cells ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Correlation of Arterial CO 2 and Respiratory Impedance Values among Subjects with COPD

    Tomoki Uno / Tetsuya Homma / Masahiko Shigemura / Yosuke Fukuda / Tomoyuki Kimura / Chihiro Onitsuka / Tomoko Kawahara / Hiroki Sato / Kaho Akimoto / Hiromitsu Suganuma / Ayaka Kashima / Shigenori Yamamoto / Takaya Ebato / Tomohiro Matsunaga / Keisuke Kaneko / Hatsuko Mikuni / Haruna Sato / Yoshitaka Uchida / Akiko Fujiwara /
    Naota Kuwahara / Ryo Manabe / Hitomi Ida / Kuniaki Hirai / Yoshito Miyata / Megumi Jinno / Shin Ohta / Yasunari Kishino / Hideki Inoue / Mayumi Yamamoto / Yoshio Watanabe / Sojiro Kusumoto / Koichi Ando / Shintaro Suzuki / Akihiko Tanaka / Tohru Ohmori / Hironori Sagara

    Journal of Clinical Medicine, Vol 9, Iss 2819, p

    2020  Volume 2819

    Abstract: Chronic obstructive pulmonary disease (COPD) is a respiratory illness characterized by airflow limitation and chronic respiratory symptoms with a global prevalence estimated to be more than 10% in 2010 and still on the rise. Furthermore, hypercapnic ... ...

    Abstract Chronic obstructive pulmonary disease (COPD) is a respiratory illness characterized by airflow limitation and chronic respiratory symptoms with a global prevalence estimated to be more than 10% in 2010 and still on the rise. Furthermore, hypercapnic subject COPD leads to an increased risk of mortality, morbidity, and poor QoL (quality of life) than normocapnic subjects. Series of studies showed the usefulness of the forced oscillation technique (FOT) to measure small airway closure. Traditional findings suggested that hypercapnia may not be the main treating targets, but recent findings suggested that blood stream CO 2 may lead to a worse outcome. This study aimed to seek the relationship between CO 2 and small airway closure by using FOT. Subjects with COPD ( n = 124; hypercapnia 22 and normocapnia 102) were analyzed for all pulmonary function values, FOT values, and arterial blood gas analysis. Student’s t -test, Spearman rank correlation, and multi linear regression analysis were used to analyze the data. COPD subjects with hypercapnia showed a significant increase in R5, R20, Fres, and ALX values, and a greater decrease in X5 value than normocapnic patients. Also, multiple linear regression analysis showed R5 was associated with hypercapnia. Hypercapnia may account for airway closure among subjects with COPD and this result suggests treating hypercapnia may lead to better outcomes for such a subject group.
    Keywords CO 2 ; hypercapnia ; FOT ; Medicine ; R
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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