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永野 達也大学院医学研究科 医科学専攻講師
研究活動情報
■ 受賞- 2023年 第17回日本禁煙学会学術総会, 優秀演題賞
- 2021年 日本呼吸器学会, JRS Scientific Award
- 2021年 兵庫県新型コロナウイルス感染症対策本部本部長 感謝状
- 2019年 2019年度 症候別チュートリアル ベストシナリオ賞
- 2019年 Experimental Biology and Medicine (EBM) Outstanding Reviewer Award
- 2013年 第72回臨床アレルギー研究会, 最優秀賞
- 2013年 第1回神緑会Young Investigator Award発表会, 優秀賞
- 2013年 第4回IAA学術集会, IAA Award2013基礎的研究の部 最優秀賞
- BACKGROUND: Chronic obstructive pulmonary disease (COPD) can be complicated by pulmonary hypertension (PH), impacting prognosis and quality of life. Endothelin-1 (ET-1) is implicated in PH development and elevated in COPD patients. The impact of COPD treatments on ET-1 and COPD-related PH remains unclear. This study investigated changes in ET-1 levels after administration of inhaled COPD medications and explored underlying mechanisms. METHODS: Patients underwent pulmonary function tests, COPD Assessment Test, and plasma ET-1 measurement before and 4-12 weeks after treatment initiation. In mice, elastase-induced emphysema was treated with budesonide (BUD), glycopyrronium (GLY), and formoterol (FOR) combinations for 2 weeks. Plasma ET-1 concentration and cytokine expression were analysed. HULEC-5a cells were used to examine ET-1 expression after TNFα stimulation. RESULTS: The study included 33 patients. COPD patients (n = 24) showed higher baseline plasma ET-1 levels compared to controls (n = 9) (2.12 pg/ml vs 1.54 pg/ml, p < 0.001). Plasma ET-1 levels decreased in COPD patients posttreatment (2.12-1.82 pg/ml, p = 0.004), with reductions observed across all disease stages and treatment regimens. Mice showed elevated ET-1 levels and expression of inflammatory cytokines after elastase instillation. BUD/GLY/FOR treatment significantly reduced ET-1 concentration and TNFα expression. Furthermore, TNFα stimulation upregulated ET-1 expression in HULEC-5a cells. CONCLUSIONS: In COPD patients conventional treatment decreased ET-1 concentration. In mouse models TNFα expression was suppressed by BUD/GLY/FOR. In HULEC-5a cells, TNFα stimulation exerted an increased ET-1expression. These findings suggest that the suppressive effect of inhaler therapy on ET-1 expression is due to the anti-inflammatory effects of these drugs.2025年03月, Respiratory medicine, 240, 108027 - 108027, 英語, 国際誌研究論文（学術雑誌）
- Mesothelioma is a highly malignant condition arising from the pleura and peritoneum that is closely related to asbestos exposure. The prognosis for this condition has traditionally been poor due to the difficulty physicians have faced in diagnosing and treating this disease, even in its early phase. Fortunately, recent advances in both the molecular understanding of the development of this disease and innovative and novel treatment modalities have accelerated the discovery of new ways to treat mesothelioma. In this review, we first summarize the mechanism of mesothelioma pathophysiology and then relate it to emerging treatment modalities. These include immunotherapy or immune checkpoint inhibitors (ICIs), molecular targeted therapies, and cell-based therapies (such as CAR-T cells or dendritic cells). The scientific basis for the utilization of these treatment modalities, alongside the current clinical evidence for each option, will be explored in detail later on. The hope is that this review can elucidate how these emerging therapeutic options work clinically to help accelerate further developments in novel mesothelioma treatment modalities.2025年02月, Cancers, 17(4) (4), 英語, 国際誌研究論文（学術雑誌）
- The lung is a vital organ for the body as the main source of oxygen input. Importantly, it is also an internal organ that has direct contact with the outside world. Innate immunity is a vital protective system in various organs, whereas, in the case of the lung, it helps maintain a healthy, functioning cellular and molecular environment and prevents any overt damage caused by pathogens or other inflammatory processes. Disturbances in lung innate immunity properties and processes, whether over-responsiveness of the process triggered by innate immunity or lack of responses due to dysfunctions in the immune cells that make up the innate immunity system of the lung, could be correlated to various pathological conditions. In this review, we discuss globally how the components of lung innate immunity are important not only for maintaining lung homeostasis but also during the pathophysiology of notable lung diseases beyond acute pulmonary infections, including chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.2025年01月, Pathogens (Basel, Switzerland), 14(1) (1), 英語, 国際誌研究論文（学術雑誌）
- There are 4 subtypes of chronic rhinosinusitis (CRS): eosinophilic CRS with nasal polyps (ECRSwNP), ECRS without NPs (ECRSsNP), non-ECRSwNP, and non-ECRSsNP. Most ECRS cases are categorized as ECRSwNP, and the number of patients with ECRSwNP has recently increased. ECRS is associated mainly with helper T-cell type 2 inflammation and eosinophils. Recently, Interleukin-25, -33, or TSLP, helper T-cell type 17, and Group 2 innate lymphoid cells have also been shown to be involved in the molecular mechanism of ECRS. ECRS can lead to several complications including bronchial asthma and/or aspirin intolerance. Conventionally, surgery and corticosteroids have been used to treat ECRS, but biologics have since been applied. Mepolizumab, benralizumab, and tezepelumab have been reported to improve asthma complicated by NPs more than asthma uncomplicated by NPs. Omalizumab, mepolizumab, benralizumab, and dupilumab have been reported to significantly improve Sinonasal Outcome Test-22 scores, nasal polyp scores, and nasal congestion severity in phase III trials. Benralizumab, dupilumab, and tezepelumab have been reported to improve both ECRS and complicated bronchial asthma.2025年01月, Respiratory investigation, 63(1) (1), 35 - 39, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Subacute cough is subdivided and distinguished from chronic cough, because post-infectious cough is considered to be the main cause of subacute cough and differs from acute and chronic cough. However, the details of the spectrum and frequency of causes of subacute cough remain unclear because only two studies on subacute cough have been published. METHODS: Patients who presented with cough that lasted for 3-8 weeks and visited respiratory clinics or hospitals affiliated with the Japan Cough Society during 2 years were studied. RESULTS: A total of 148 patients were prospectively enrolled, and those who did not meet the definition of subacute cough were excluded. Ninety-seven (68.3%) patients with subacute cough progressed to chronic cough, and the main causative diseases were cough variant asthma in 44 patients, atopic cough in 24 patients, sinobronchial syndrome in 13 patients, and post-infectious cough in seven patients. Patients with cough variant asthma complicated by atopic cough and those in whom the cause of subacute cough was unknown tended to develop chronic cough. CONCLUSIONS: This study shows that post-infectious cough is less common than previously thought and the main causes of subacute cough are cough variant asthma, atopic cough, and sinobronchial syndrome and their complications. Cough variant asthma in combination with atopic cough also can be a precursor of refractory chronic cough. The careful diagnosis and treatment of two or more causative diseases is required in patients with subacute cough.2025年01月, Respiratory investigation, 63(1) (1), 74 - 80, 英語, 国際誌研究論文（学術雑誌）
- Previously reported oropharyngeal exercises are long and difficult to perform. Therefore, we created a 10-min daily oropharyngeal exercise program and conducted a study to confirm its effectiveness. Twenty-five participants whose apnoea-hypopnoea index (AHI) values were greater than 5 were enrolled. All of the participants performed 10 min of exercise per day for 12 weeks and were evaluated for AHI values, tongue pressure, lip closure pressure, snoring, and Mallampati scores before and after the exercise. Twenty-two participants (88% of all participants) completed the oropharyngeal exercise. Another patient was unable to attend the last evaluation session due to illness. The AHI value improved significantly from an average of 20.9 to 16.9 times/hour in patients with a pre-exercise AHI of 5 to 30 (P = 0.0317). The AHI improvement group included younger participants than did the AHI deterioration group (P = 0.0498). Although the tongue pressures in the AHI improvement group did not improve significantly (P = 0.354), the lip closure pressures tended to increase from a median of 17.6 N to 21.3 N with oropharyngeal exercises (P = 0.0677). This novel oropharyngeal exercise may be appropriate for younger SAS patients with an AHI less than 30.2024年11月, Scientific reports, 14(1) (1), 28645 - 28645, 英語, 国際誌研究論文（学術雑誌）
- The newly developed portable oxygen concentrator with an auto-demand oxygen delivery system (auto-DODS) automatically switches between 3 sensitivities according to the negative pressure gradient of inhalation and supplies oxygen only during inhalation. The aim of this study was to verify the effectiveness and safety of auto-demand devices compared with a continuous flow oxygen concentrator, during sleep, in a randomized crossover noninferiority trial. We alternatively used an auto-DODS or a continuous-flow oxygen concentrator, all night on separate days for HOT (Home Oxygen Therapy) patients with nocturnal hypoxemic symptoms. The primary endpoints were the mean value of oxygen saturation (SpO2) over the total sleep time. The secondary endpoints included the efficacy endpoints and the safety endpoints. Regarding the primary endpoint, the difference in SpO2 between the auto-DODS and continuous flow was 0.835%. Since the upper limit of this difference did not exceed 2.8, which was set as the noninferiority margin, it was shown that the auto-DODS did not reduce SpO2 by at least 2.8% on average compared to continuous flow. No equipment failure or exacerbation of disease was observed, confirming the safety of the auto-DODS during the night.2024年09月, Scientific reports, 14(1) (1), 20505 - 20505, 英語, 国際誌研究論文（学術雑誌）
- Even with recent advances in pathobiology and treatment options, chronic obstructive pulmonary disease (COPD) remains a major contributor to morbidity and mortality. To develop new ways of combating this disease, breakthroughs in our understanding of its mechanisms are sorely needed. Investigating the involvement of underanalyzed lung cell types, such as endothelial cells (ECs), is one way to further our understanding of COPD. JCAD is a junctional protein in endothelial cells (ECs) arising from the KIAA1462 gene, and a mutation in this gene has been implicated in the risk of developing COPD. In our study, we induced inflammation and emphysema in mice via the global knockout of KIAA1462/JCAD (JCAD-KO) and confirmed it in HPMECs and A549 to examine how the loss of JCAD could affect COPD development. We found that KIAA1462/JCAD loss reduced acute lung inflammation after elastase treatment. Even after 3 weeks of elastase, JCAD-KO mice demonstrated a preserved lung parenchymal structure and vasculature. In vitro, after KIAA1462 expression is silenced, both endothelial and epithelial cells showed alterations in pro-inflammatory gene expression after TNF-α treatment. We concluded that JCAD loss could ameliorate COPD through its anti-inflammatory and anti-angiogenic effects, and that KIAA1462/JCAD could be a novel target for COPD therapy.2024年08月, International journal of molecular sciences, 25(17) (17), 英語, 国際誌研究論文（学術雑誌）
- The respiratory rate is an important factor for assessing patient status and detecting changes in the severity of illness. Real-time determination of the respiratory rate will enable early responses to changes in the patient condition. Several methods of wearable devices have enabled remote respiratory rate monitoring. However, gaps persist in large-scale validation, patient-specific calibration, standardization and their usefulness in clinical practice has not been fully elucidated. The aim of this study was to evaluate the accuracy of 2 wearable stretch sensors, C-STRECH® which is used in clinical practice and a novel stretchable capacitor in measuring the respiratory rate. The respiratory rate of 20 healthy subjects was measured by a spirometer with the stretch sensor applied to 1 of 5 locations (umbilicus, lateral abdomen, epigastrium, lateral chest, or chest) of their body at rest while they were in a sitting or supine position before or after exercise. The sensors detected the largest amplitudes at the epigastrium and umbilicus compared to other sites of measurement for the sitting and supine positions, respectively. At rest, the respiratory rate of the sensors had an error of 0.06 to 2.39 breaths/minute, whereas after exercise, an error of 1.57 to 3.72 breaths/minute was observed compared to the spirometer. The sensors were able to detect the respiratory rate of healthy volunteers in the sitting and supine positions, but there was a need for improvement in detection after exercise.2024年07月, Medicine, 103(29) (29), e38818, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: The efficacy of macrolides in the management of asthma has been studied but remains controversial. We conducted a systematic review and meta-analysis of macrolides in the management of adult patients with asthma. METHODS: Randomized controlled trials of macrolides used in adult patients with asthma were searched for in MEDLINE, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Igaku Chuo Zasshi databases to evaluate the efficacy and safety of macrolides. RESULTS: Seventeen reports with macrolide treatment durations ranging from 6 to 48 weeks were included. Macrolides did not reduce exacerbations requiring hospitalization, severe exacerbations, or rescue use of short-acting beta-2 agonist inhalers; improve lung function; decrease peripheral blood or sputum neutrophil counts; or decrease fractional exhaled nitric oxide compared to placebo. Macrolides statistically improved asthma control and quality of life but by less than the minimal clinically important difference. Peripheral blood eosinophil counts as well as serum and sputum eosinophilic cationic protein concentrations were significantly decreased with macrolides compared to placebo. The improvement of asthma symptoms and airway hyperresponsiveness varied by study. The safety profile of macrolides was comparable to that of placebo. CONCLUSIONS: Although macrolides have some useful clinical aspects, there is not sufficient evidence to recommend their use in the management of adult patients with asthma.2024年07月, Allergology international : official journal of the Japanese Society of Allergology, 73(3) (3), 382 - 389, 英語, 国際誌研究論文（学術雑誌）
- The early detection and treatment of sleep apnea syndrome (SAS) is becoming an important issue in medical practice, as the conventional polysomnography-based method is not only costly, but also demands high expertise from technicians. In this study, we propose a method for diagnosing SAS using noninvasive measurements of oxygen saturation (SpO2), obtained from a pulse oximeter as the input signal, using convolutional neural networks (CNNs). As a result of 10-fold cross-validation, we confirmed that the proposed method yields an 88.99% accuracy.2024年07月, Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, 2024, 1 - 4, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.2024年05月, Respiratory investigation, 62(3) (3), 442 - 448, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non-small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC. METHODS: We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation. RESULTS: A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression-free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013). CONCLUSIONS: The unnecessary use of NSAIDs along with immunotherapy should be discouraged.2024年05月, Thoracic cancer, 15(15) (15), 1228 - 1236, 英語, 国際誌研究論文（学術雑誌）
- (有)科学評論社, 2024年04月, 呼吸器内科, 45(4) (4), 373 - 376, 日本語【希少肺疾患はどこまで解明されたか】肺胞微石症
- BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1β. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.2024年03月, Thoracic cancer, 15(9) (9), 722 - 729, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. AIM: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. METHODS: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. RESULTS: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. CONCLUSIONS: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.2024年, Frontiers in immunology, 15, 1361891 - 1361891, 英語, 国際誌研究論文（学術雑誌）
- OBJECTIVES: : Several studies have reported that oropharyngeal myofunctional therapy (OMT) reduces the severity of obstructive sleep apnea (OSA). However, because OMT protocols are often complicated, they take time and effort to implement. The aim of this study was to determine the therapeutic effect of 8 weeks of simple tongue strength training with a training device. METHODS: : Twenty patients with mild to moderate sleep-disordered breathing were randomized to the control group (n=10) or intervention group (n=10). The patients in the intervention group completed 8 weeks of daily tongue strength training using a training device. After 8 weeks, we evaluated each patient for sleep-disordered breathing by portable monitoring. We also evaluated each patient's body mass index (BMI), neck circumference, Epworth Sleepiness Scale (ESS) score, and tongue pressure. RESULTS: No significant difference was found in the change in apnea hypopnea index (AHI) from baseline to 8 weeks between the control and intervention groups (P=0.44). However, the changes in neck circumference (P=0.02) and maximum tongue pressure (P=0.03) from baseline to 8 weeks were significantly different between the two groups. No significant difference was found for changes in BMI and ESS scores from baseline to 8 weeks between the two groups. CONCLUSIONS: : Tongue strength training in patients with sleep-disordered breathing did not significantly improve AHI as measured by portable monitoring, although significant changes were observed for increased tongue pressure and reduced neck circumference.2024年, Progress in rehabilitation medicine, 9, 20240010 - 20240010, 英語, 国内誌研究論文（学術雑誌）
- BACKGROUND: We have identified and reported a novel antigen, nonprotein-specific secreted EP1-like glycoprotein (51 kDa), for lettuce-related respiratory allergy. OBJECTIVE: We aimed to identify a novel antigen for lettuce-related respiratory allergy that is different from epidermis-specific secreted EP1-like glycoprotein. METHODS: Immunoblotting was performed using an immunoglobulin E-specific antibody. The antigen-antibody reaction was confirmed by means of enzyme-linked immunosorbent assaying. LC-MS/MS analysis was carried out to detect a novel protein found in sera from 3 of 13 patients with lettuce-related respiratory allergy. Finally, we purified a novel protein from Escherichia coli. RESULTS: Immunoblotting assays showed common bands of 17 kDa in the sera of 3 of 13 patients. An enzyme-linked immunosorbent assay confirmed that the patient sera reacted with lettuce latex juice. A 17 kDa protein band that showed antigenic reactivity in 3 of 13 patient sera was identified as a kirola-like protein by LC-MS/MS. In addition, although we purified this protein, we failed to show the inhibitory effect. CONCLUSION: A 17 kDa protein that is a potentially novel antigen of lettuce-associated respiratory allergy was identified. In further studies, we will focus on purifying this novel protein to diagnose lettuce allergy.2023年11月, Immunity, inflammation and disease, 11(11) (11), e1093, 英語, 国際誌研究論文（学術雑誌）
- In acute lung injury (ALI), a severe insult induces a hyperinflammatory state in the lungs. The mortality rate of severe ALI remains high, and novel mechanistic insights are required to improve therapeutic strategies. Endothelin-2 (Edn2), the least studied isoform of endothelin, is involved in lung physiology and development and can be affected by various factors. One of them is inflammation, and another isoform of endothelin, endothelin-1 (Edn1), affects lung inflammatory responses. Considering the importance of Edn2 in the lungs and how Edn2 works through the same receptors as Edn1, we postulated that Edn2 may affect inflammatory responses that are central to ALI pathophysiology. In this study, we performed 24 hours intratracheal lipopolysaccharide (LPS) instillation or PBS control as an in vivo ALI model in eight-week-old conditional Edn2 knockout mice (Edn2-iKO), with Edn2-floxed mice as controls. Bronchoalveolar lavage (BAL) fluid and tissue were collected after exsanguination and analyzed for its cellular, molecular, functional, and histological inflammatory phenotypes. We found that Edn2-iKO mice displayed a reduced pro-neutrophilic inflammatory phenotype even after acute LPS treatment, shown by the reduction in the overall protein concentration and neutrophil count in bronchoalveolar lavage fluids. Further investigation revealed a reduction in mRNA interferon gamma (IFNγ) level of Edn2-iKO lungs and suppression of its downstream signaling, including phosphorylated level of STAT1 and IL-1β secretion, leading to reduced NFĸB activation. To conclude, Edn2 deletion suppressed acute lung inflammation by reducing neutrophil-mediated IFNγ/STAT1/IL-1β/NFĸB signaling cascade. Targeting Edn2 signaling may be beneficial for the development of novel treatment options for ALI.2023年10月, The Kobe journal of medical sciences, 69(3) (3), E96-E105, 英語, 国内誌研究論文（学術雑誌）
- The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets.2023年08月, Nature communications, 14(1) (1), 4956 - 4956, 英語, 国際誌研究論文（学術雑誌）
- Coronavirus disease (COVID-19) often causes persistent symptoms long after infection, referred to as "long COVID" or post-acute COVID-19 syndrome (PACS). This phenomenon has been studied primarily concerning B-cell immunity, while the involvement of T-cell immunity is still unclear. This retrospective study aimed to examine the relationship among the number of symptoms, cytokine levels, and the Enzyme-linked immunosorbent spot (ELISPOT) assay data in patients with COVID-19. To examine inflammatory conditions, plasma interleukin (IL)-6, IL-10, IL-18, chemokine ligand 9 (CXCL9), chemokine ligand 3 (CCL3), and vascular endothelial growth factor (VEGF) levels were analyzed using plasma obtained from COVID-19 recovery patients and healthy controls (HC). These levels were significantly higher in the COVID-19 group than those in the HC group. ELISPOT assays were performed to investigate the correlation between COVID-19 persistent symptoms and T-cell immunity. Cluster analysis of ELISPOT categorized COVID-19 recovery patients in the ELISPOT-high and -low groups, based on the values of S1, S2, and N. The number of persistent symptoms was significantly higher in the ELISPOT-low group than those in the ELISPOT-high group. Thus, T cell immunity is critical for the rapid elimination of COVID-19 persistent symptoms, and its measurement immediately after COVID-19 recovery might predict long-term COVID-19 or PACS.2023年07月, Scientific reports, 13(1) (1), 11071 - 11071, 英語, 国際誌研究論文（学術雑誌）
- A 56-year-old female lettuce farmer was admitted to the hospital with a low-grade fever, worsening cough, and dyspnoea. A blood test revealed eosinophilia and a high serum IgE concentration. The 3-year follow-up showed that her total IgE level increased in December, peaked in May, and suddenly decreased in August. This result was consistent with the lettuce harvest season. A chest x-ray taken on admission showed an infiltrative shadow in the upper lung field. Chest CT revealed patchy ground glass opacity on the upper lung field and thickening of the bronchial wall. The bronchoalveolar lavage fluid contained 8% eosinophils. She was treated with prednisolone, and her symptoms and radiological findings improved. The 37 kDa protein that reacted with the patient's sera was identified by immunoblot analysis.2023年06月, Respirology case reports, 11(6) (6), e01169, 英語, 国際誌研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2023年06月, 肺癌, 63(3) (3), 267 - 268, 日本語多発肝転移を伴う進展型小細胞肺癌の治療経過中に肝不全を来たし死亡した1例
- In-hospital Mortality among Patients with High-flow Nasal Cannulas in the General Ward.High-flow nasal cannulas (HFNCs) have become common devices for patients with respiratory failure who are treated in general wards. Few reports have been published on in-hospital mortality associated with the ratio of oxygen saturation (ROX) index, measured by pulse oximetry/fraction of inspired oxygen to respiratory rate, in patients treated with HFNCs. We aimed to examine in-hospital mortality and associated factors in patients who initiated HFNC use in a general ward. Sixty patients who initiated HFNC use in general wards at Kobe University Hospital between December 2016 and October 2020 were retrospectively enrolled. We assessed in-hospital mortality, comorbidities, and ROX index. The in-hospital mortality was 48.3%, and ROX index values were significantly lower in patients who died than in those who did not (at HFNC oxygen therapy initiation; 6.93 [2.73-18.5] vs. 9.01 [4.62-18.1], p = 0.00861). Although the difference was not statistically significant, the change in ROX index values between HFNC initiation and 12 hours after initiation tended to be greater in the patients who died in the hospital (0.732 [-2.84-3.5] vs. -0.35[-4.3-2.6], p = 0.0536). Lower ROX index values may be associated with the in-hospital death of patients who are treated with HFNCs in general wards.2023年05月, The Kobe journal of medical sciences, 69(1) (1), E33-E39, 英語, 国内誌研究論文（学術雑誌）
- We identified neutralizing monoclonal antibodies against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants (including Omicron variants BA.5 and BA.2.75) from individuals who received two doses of mRNA vaccination after they had been infected with the D614G virus. We named them MO1, MO2, and MO3. Among them, MO1 showed particularly high neutralizing activity against authentic variants: D614G, Delta, BA.1, BA.1.1, BA.2, BA.2.75, and BA.5. Furthermore, MO1 suppressed BA.5 infection in hamsters. A structural analysis revealed that MO1 binds to the conserved epitope of seven variants, including Omicron variants BA.5 and BA.2.75, in the receptor-binding domain of the spike protein. MO1 targets an epitope conserved among Omicron variants BA.1, BA.2, and BA.5 in a unique binding mode. Our findings confirm that D614G-derived vaccination can induce neutralizing antibodies that recognize the epitopes conserved among the SARS-CoV-2 variants. IMPORTANCE Omicron variants of SARS-CoV-2 acquired escape ability from host immunity and authorized antibody therapeutics and thereby have been spreading worldwide. We reported that patients infected with an early SARS-CoV-2 variant, D614G, and who received subsequent two-dose mRNA vaccination have high neutralizing antibody titer against Omicron lineages. It was speculated that the patients have neutralizing antibodies broadly effective against SARS-CoV-2 variants by targeting common epitopes. Here, we explored human monoclonal antibodies from B cells of the patients. One of the monoclonal antibodies, named MO1, showed high potency against broad SARS-CoV-2 variants including BA.2.75 and BA.5 variants. The results prove that monoclonal antibodies that have common neutralizing epitopes among several Omicrons were produced in patients infected with D614G and who received mRNA vaccination.2023年05月, Journal of virology, 97(6) (6), e0028623, 英語, 国際誌研究論文（学術雑誌）
- Genetic information is not transmitted solely by DNA but by the epigenetics process. Epigenetics describes molecular missing link pathways that could bridge the gap between the genetic background and environmental risk factors that contribute to the pathogenesis of pulmonary fibrosis. Specific epigenetic patterns, especially DNA methylation, histone modifications, long non-coding, and microRNA (miRNAs), affect the endophenotypes underlying the development of idiopathic pulmonary fibrosis (IPF). Among all the epigenetic marks, DNA methylation modifications have been the most widely studied in IPF. This review summarizes the current knowledge concerning DNA methylation changes in pulmonary fibrosis and demonstrates a promising novel epigenetics-based precision medicine.2023年03月, Biomedicines, 11(4) (4), 英語, 国際誌研究論文（学術雑誌）
- Purine nucleotides and nucleosides are involved in various human physiological and pathological mechanisms. The pathological deregulation of purinergic signaling contributes to various chronic respiratory diseases. Among the adenosine receptors, A2B has the lowest affinity such that it was long considered to have little pathophysiological significance. Many studies suggest that A2BAR plays protective roles during the early stage of acute inflammation. However, increased adenosine levels during chronic epithelial injury and inflammation might activate A2BAR, resulting in cellular effects relevant to the progression of pulmonary fibrosis.2023年02月, International journal of molecular sciences, 24(5) (5), 英語, 国際誌研究論文（学術雑誌）
- Pulmonary hypertension (PH) is a multi-etiological condition with a similar hemodynamic clinical sign and end result of right heart failure. Although its causes vary, a similar link across all the classifications is the presence of mitochondrial dysfunction. Mitochondria, as the powerhouse of the cells, hold a number of vital roles in maintaining normal cellular homeostasis, including the pulmonary vascular cells. As such, any disturbance in the normal functions of mitochondria could lead to major pathological consequences. The Warburg effect has been established as a major finding in PH conditions, but other mitochondria-related metabolic and oxidative stress factors have also been reported, making important contributions to the progression of pulmonary vascular remodeling that is commonly found in PH pathophysiology. In this review, we will discuss the role of the mitochondria in maintaining a normal vasculature, how it could be altered during pulmonary vascular remodeling, and the therapeutic options available that can treat its dysfunction.2023年02月, Antioxidants (Basel, Switzerland), 12(2) (2), 英語, 国際誌研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2022年11月, 肺癌, 62(6) (6), 655 - 655, 日本語
- Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral angioedema (CholU-PA), 3) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd); 1) and 2) include SAT based on pathogenesis. There have been no studies on differences in the prevalence of bronchial asthma among the subtypes. We analyzed bronchial responsiveness using the methacholine dose indicator Dmin, respiratory symptoms, and exhaled nitric oxide (FeNO). Median log10 Dmin (interquartile range) of patients with conventional SAT-CholU (n = 11), CholU-PA (n = 11), and CholU-Anhd (n = 11) was 0.381 (- 0.829, 1.079), 0.717 (0.249, 0.787), and 1.318 (0.121, 1.699), respectively (p = 0.516). Respiratory symptoms were less frequently observed in CholU-Anhd than in conventional SAT-CholU or CholU-PA. FeNO of patients with conventional SAT-CholU, CholU-PA, and CholU-Anhd was 23 (18.5, 65.0), 39 (32.0, 59.5), and 25 (19.0, 33.0) ppb, respectively (p = 0.237). Nine% of conventional SAT-CholU patients and more than half of CholU-PA patients required treatment for asthma. Log Dmin tended to be lower in patients with SAT-CholU than in those with CholU-Anhd. CholU-PA might be associated with asthma.2022年10月, Scientific reports, 12(1) (1), 18122 - 18122, 英語, 国際誌研究論文（学術雑誌）
- Summary We identified novel neutralizing monoclonal antibodies against SARS-CoV-2 variants (including Omicron) from individuals received two doses of mRNA vaccination after they had been infected with wildtype. We named them MO1, MO2 and MO3. MO1 shows high neutralizing activity against authentic variants: D614G, Delta, BA.1, BA.1.1, BA.2, and BA.2.75 and BA.5. Our findings confirm that the wildtype-derived vaccination can induce neutralizing antibodies that recognize the epitopes conserved among the SARS-CoV-2 variants (including BA.5 and BA.2.75). The monoclonal antibodies obtained herein could serve as novel prophylaxis and therapeutics against not only current SARS-CoV-2 viruses but also future variants that may arise.Cold Spring Harbor Laboratory, 2022年09月
- OBJECTIVES: Oral corticosteroids reduce the antibody titer of the BNT162b2 mRNA vaccine against SARS-CoV-2. To date, the effect of inhaled corticosteroids on antibody titers is unknown. STUDY DESIGN: The design of this study is retrospective study. METHODS: We analyzed the relationship between the clinical features and total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in 320 subjects who had never been infected with Coronavirus disease 2019 (COVID-19) and were vaccinated the second time with the BNT162b2 mRNA vaccine between October 1 to December 28, 2021. RESULTS: Of the 320 subjects, 205 were treated with inhaled corticosteroids. The median antibody titer of patients treated with inhaled corticosteroids was 572 U/mL, which was significantly higher than that of patients treated without inhaled corticosteroids (454U/mL, P = 0.00258). The median antibody titers of smokers, men, and patients aged 65 years and over, were 315.5 U/mL, 385 U/mL, and 425.5 U/mL, respectively. These results are significantly lower than those of patients who never smoked, women, and patients aged less than 64 years (582 U/mL [P < 0.0001], 682.5 U/mL [P < 0.0001], and 717 U/mL [P < 0.0001], respectively). The multivariate analysis revealed that females and age were independent antibody titer-reducing factors (P = 0.0001 and P < 0.0001, respectively). CONCLUSIONS: The use of inhaled corticosteroids did not reduce the antibody titer against SARS-CoV-2 spike protein. Clinicians should continue treatment with inhaled corticosteroids if indicated.2022年08月, Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 18(1) (1), 78 - 78, 英語, 国際誌研究論文（学術雑誌）
- Lung cancer is the leading cause of cancer-related deaths worldwide, and adenocarcinoma is the most common subtype of lung cancer. Endothelin-2 (ET-2) is expressed in the epithelium of alveoli, and its expression is increased in cancer. However, the role of ET-2 in lung adenocarcinoma remains unclear. This study aimed to investigate the pathophysiological functions of ET-2 in A549 human lung adenocarcinoma cells. We analyzed the expression of ET-2 mRNA in lung adenocarcinoma tissues compared with that in nontumor lung tissues using public online databases. The function of ET-2 in A549 cells was investigated using siRNA. ET-2 mRNA level was upregulated in lung adenocarcinoma tissues, and high ET-2 level was associated with poor overall survival in patients with lung adenocarcinoma. ET-2 silencing reduced the proliferation, migration, and invasion, and enhanced apoptosis in A549 cells. Mechanistically, ET-2 silencing reduced the expression levels of X-linked inhibitor of apoptosis and survivin, which are members of the inhibitor apoptosis protein family. In addition, silencing ET-2 inhibited epithelial-mesenchymal transition, which halted migration. Therefore, the specific targeting of ET-2 may be a potential treatment strategy for lung adenocarcinoma.2022年08月, Canadian journal of physiology and pharmacology, 100(8) (8), 818 - 827, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Currently, the prognosis of patients with non-small cell lung cancer (NSCLC) remains unsatisfactory. This current study evaluated the relationship between histology of NSCLC and protein expression of exosomes in the plasma from NSCLC patients, and furthermore investigate the impact of the exosome profile on the tumor, node, metastasis (TNM) classification. METHODS: Plasma samples were collected from 26 NSCLC patients before surgery. The exosomes were extracted from the plasma and liquid chromatography-mass spectrometry (LC/MS) was used to evaluate the expression of the proteins in the exosomes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Cytoscape 3.8.2 software. Multivariate logistic regression and receiver operating characteristic (ROC) curves were used to identify proteins which could effectively distinguish between lung adenocarcinoma and lung squamous cell carcinoma. The relationship between protein expression and the TNM stage was calculated using Spearman rank correlation. RESULTS: The expression levels of ZSWIM9, FYB1, SERPINF1, C1orf68, MASP2, and IGHV3-72 were higher in patients with lung adenocarcinoma compared to patients with lung squamous cell carcinoma. MFGE8 was associated with the occurrence of squamous cell carcinoma. CORO1A was positively correlated with the TNM stage of the patients, and COL4A2 was negatively correlated with TNM stage. GO and KEGG analyses revealed that cholesterol metabolism was important in NSCLC development. CONCLUSIONS: Lung adenocarcinoma may be distinguished from squamous cell carcinoma by the molecular profile of exosomes in the plasma samples. And, proteomics analysis suggested that cholesterol metabolism may play an important role of cancer progress in NSCLC.2022年07月, Translational lung cancer research, 11(7) (7), 1434 - 1452, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression. METHODS: We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes. RESULTS: We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells. CONCLUSION: Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling.2022年06月, Respiratory research, 23(1) (1), 173 - 173, 英語, 国際誌研究論文（学術雑誌）
- CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.2022年05月, International journal of molecular sciences, 23(11) (11), 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Bronchoscopy can be a distress for the patient. There have been few studies on the combination of sedatives and opioids. The aim of this study was to demonstrate the usefulness and safety of administration of the combination of midazolam and pethidine during bronchoscopy. METHODS: In this prospective randomized single (patient)-blind study, we randomly assigned 100 patients who were scheduled to undergo bronchoscopy biopsy to receive treatment with either the midazolam/pethidine combination (combination group) or midazolam alone (midazolam group) during examinations. After the end of bronchoscopy, patients completed a questionnaire and the visual analogue scale was measured. The primary outcome was the patients' acceptance of re-examination assessed by visual analogue scale. We also assessed pain levels, vital signs, midazolam use, xylocaine use, and adverse events. Univariate analyses were performed using Fisher's exact test for categorical data, and the t-test or Mann-Whitney test was carried out for analysis of numeric data. All P-values were two-sided, and values < 0.05 were considered statistically significant. RESULTS: We analyzed 47 patients in the combination group and 49 patients in the midazolam group. The primary outcome was a good trend in the combination group, but not significantly different (3.82 ± 2.3 in combination group versus 4.17 ± 2.75 in midazolam alone, P = 0.400). In the combination group, the visual analog scale score for pain during bronchoscopy was significantly lower (1.10 ± 1.88 versus 2.13 ± 2.42, P = 0.022), and the sedation level score per the modified observer's assessment of alertness/sedation scale was significantly deeper (3.49 ± 0.98 versus 3.94 ± 1.03, P = 0.031). Maximal systolic blood pressure during testing was significantly lower (162.39 ± 23.45 mmHg versus 178.24 ± 30.24 mmHg, P = 0.005), and the number of additional administrations of midazolam was significantly lower (2.06 ± 1.45 versus 2.63 ± 1.35, P = 0.049). There were also significantly fewer adverse events (30 versus 41, P = 0.036). CONCLUSIONS: The combination uses of midazolam and pethidine for sedation resulted in significant improvements in the pain, blood pressure, additional use of midazolam, and safety during bronchoscopy among patients. TRIAL REGISTRATION: This study was registered in the University Medical Hospital Information Network in Japan (UMINCTR Registration number: UMIN000032230 , Registered: 13/April/2018).2022年05月, BMC cancer, 22(1) (1), 539 - 539, 英語, 国際誌研究論文（学術雑誌）
- The SARS-CoV-2 variant Omicron is now under investigation. We evaluated cross-neutralizing activity against Omicron in COVID-19 convalescent patients (n = 23) who had received two doses of an mRNA vaccination (BNT162b2 or mRNA-1273). Intriguingly, after the second vaccination, the neutralizing antibody titers of subjects against SARS-CoV-2 variants, including Omicron, all became seropositive, and significant fold-increases (21.1-52.0) were seen regardless of the disease severity of subjects. Our findings thus demonstrate that two doses of mRNA vaccination to SARS-CoV-2 convalescent patients can induce cross-neutralizing activity against Omicron.2022年05月, The Journal of infectious diseases, 226(8) (8), 1391 - 1395, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Anlotinib demonstrated improved overall survival (OS) and progression-free survival (PFS) compared with placebo as a third-line or subsequent therapy in patients with non-small cell lung cancer (NSCLC) in the ALTER0303 trial. The status of epidermal growth factor receptor (EGFR) mutation, different previous treatment may affect the efficacy of subsequent therapy, and we did this subgroup analysis to characterize the efficacy of anlotinib in patients with and without EGFR mutation. METHODS: The ALTER0303 trial was a randomized, double-blind, phase 3 study of anlotinib in patients with NSCLC who failed at least 2 lines of treatment. In the study, 138 of 437 randomized patients were EGFR mutation positive. A Cox model was used to examine the influence of previous treatment on the efficacy of anlotinib according to EGFR mutation status. RESULTS: For patients with EGFR mutation, the OS was 10.7 and 6.3 months (HR 0.59; 95% CI: 0.38-0.94, P=0.025) in the anlotinib and placebo group, respectively. The PFS was 5.6 and 0.8 months (HR 0.21; 95% CI: 0.13-0.32, P<0.0001) in the anlotinib and placebo group, respectively. For patients without EGFR mutation, the OS was 8.9 months for anlotinib and 6.5 months for placebo (HR 0.73; 95% CI: 0.55-0.97, P=0.029), and the PFS was 5.4 months for anlotinib and 1.6 months for placebo (HR 0.29; 95% CI: 0.22-0.39, P<0.0001). In the anlotinib group, the OS and PFS for patients with and without EGFR mutation was 10.7 and 8.9 months (HR 0.69; 95% CI: 0.50-0.95, P=0.021), 5.6 and 5.4 months (HR 1.00; 95% CI: 0.75-1.34, P=1.000), respectively. The incidence of adverse events was similar in subgroups. CONCLUSIONS: This analysis demonstrated that the benefit of anlotinib as a third-line therapy for patients with NSCLC was independent of EGFR mutation status.2022年05月, Translational lung cancer research, 11(5) (5), 776 - 785, 英語, 国際誌研究論文（学術雑誌）
- 2022年04月, Journal of thoracic disease, 14(4) (4), 809 - 811, 英語, 国際誌
- (一社)日本呼吸器学会, 2022年04月, 日本呼吸器学会誌, 11(増刊) (増刊), 227 - 227, 日本語
- (一社)日本呼吸器学会, 2022年04月, 日本呼吸器学会誌, 11(増刊) (増刊), 249 - 249, 日本語
- BACKGROUND/AIM: Annexin A10 (ANXA10) is a member of the annexin family and a calcium-dependent phospholipid-binding protein. The aim of this study was to clarify the clinical significance of ANXA10 expression in lung adenocarcinoma. MATERIALS AND METHODS: ANXA10 expression was immunohistochemically examined in surgical specimens of lung adenocarcinoma obtained from 74 consecutive patients who underwent complete resection from January 2014 to December 2014. Expression of ANXA10 was down-regulated in A549 cells via siRNA transfection and the effect of ANXA10 on cell migration was assessed by the wound healing assay. Expression of ANXA10 was examined by immunocytochemistry and polymerase chain reaction. RESULTS: High ANXA10 expression was significantly correlated with poor overall survival (p=0.00705). Multivariate analysis with the Cox proportional hazard model demonstrated that ANXA10 expression was an independent prognostic factor. Cell migration was suppressed in ANXA10-down-regulated A549 cell lines. CONCLUSION: ANXA10 has a role in cancer cell migration and high ANXA10 expression is a novel prognostic marker in lung adenocarcinoma.2022年03月, Anticancer research, 42(3) (3), 1289 - 1294, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND/AIM: The gut microbiome plays an important role in the immune system and has attracted attention as a biomarker of several diseases, including cancer. In this study, we examined the relationship between the gut microbiome and lung cancer progression. PATIENTS AND METHODS: Female never-smokers diagnosed with lung adenocarcinoma were consecutively enrolled between May 2018 and August 2019, and fecal samples were collected. Principal coordinate analyses were performed using Bray-Curtis distance matrices to investigate the effects of clinical variables (age, body mass index, Tumor-Node-Metastasis stage, T category, N category, M category, primary tumor size, performance status, and EGFR mutation status) on the gut microbial community. RESULTS: A total of 37 patients were enrolled. T category and primary tumor size were significantly correlated with the gut microbial community (p=0.018 and 0.041, respectively). CONCLUSION: This study identified the gut microbiome as a promising biomarker of lung cancer progression.Anticancer Research USA Inc., 2022年03月, Anticancer Research, 42(3) (3), 1589 - 1598, 英語, 国際誌研究論文（学術雑誌）
- Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK) was first reported in 2007. ALK-rearranged NSCLC accounts for about 3-8% of NSCLC. The first-line therapy for ALK-rearranged advanced NSCLC is tyrosine kinase inhibitors (TKI) targeting ALK. Following the development of crizotinib, the first ALK-TKI, patient prognosis has been greatly improved. Currently, five TKIs are approved by the FDA. In addition, clinical trials of the novel TKI, ensartinib, and fourth-generation ALK-TKI for compound ALK mutation are ongoing. Treatment with angiogenesis inhibitors and immune checkpoint inhibitors is also being studied. However, as the disease progresses, cancers tend to develop resistance mechanisms. In addition to ALK mutations, other mechanisms, including the activation of bypass signaling pathways and histological transformation, cause resistance, and the identification of these mechanisms is important in selecting subsequent therapy. Studies on tissue and liquid biopsy have been reported and are expected to be useful tools for identifying resistance mechanisms. The purpose of this manuscript is to provide information on the recent clinical trials of ALK-TKIs, angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy to describe tissue and liquid biopsy as a method to investigate the mechanisms of resistance against ALK-TKIs and suggest a proposed treatment algorithm.2022年02月, Cancers, 14(5) (5), 英語, 国際誌研究論文（学術雑誌）
- 2022年01月, Sleep & breathing = Schlaf & Atmung, 26(3) (3), 1503 - 1503, 英語, 国際誌
- BACKGROUND/AIM: Measuring the fraction of exhaled nitric oxide (FeNO) is useful in the diagnosis of asthma and cough variant asthma. The aim of this study was to clarify the significance of measuring the FeNO in the differential diagnosis of acute cough. PATIENTS AND METHODS: We analyzed 80 patients who visited the clinic with the chief complaint of acute cough having experienced an asthma-like episode from January 2014 to July 2015. RESULTS: Infectious cough alone was present in 21% of patients, while 30% had asthmatic cough alone and 49% had a combination of infectious and asthmatic cough. The values of FeNO in those with asthmatic cough (30.4±24.7 ppb) and asthmatic/infectious cough (33.2±17.4 ppb) were significantly higher than those with just infectious cough (13.7±3.2 ppb) (p=0.0089 and p<0.0001, respectively). CONCLUSION: FeNO measurement is useful for distinguishing asthmatic diseases, even in the differential diagnosis of acute cough.2022年, In vivo (Athens, Greece), 36(1) (1), 446 - 449, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND/AIM: Although the usefulness of inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) in cough-variant asthma and cough-predominant asthma has been reported, there is no consensus on its starting dose. The aim of this study is to find the optimal dose of ICS/LABA for cough-variant asthma and cough-predominant asthma. PATIENTS AND METHODS: We analysed 112 patients who visited our clinic from January 2009 to December 2012 with the chief complaint of cough that had continued for more than 3 weeks. Cough-variant asthma (n=30) and cough-predominant asthma (n=7) were treated with ICS/LABA. RESULTS: There was no significant difference in cough duration time from starting ICS/LABA in cough-variant asthma and cough-predominant asthma between medium and high doses (14.3% versus 10.9%, respectively) (p=0.192). Moreover, there was no significant difference in cough duration time from starting ICS/LABA in cough-variant asthma between medium and high doses (13.2% versus 11.5%, respectively) (p=0.433). CONCLUSION: The medium starting dose of ICS/LABA is sufficient for treating cough-variant asthma.2022年, In vivo (Athens, Greece), 36(2) (2), 949 - 953, 英語, 国際誌研究論文（学術雑誌）
- Non-small-cell lung cancer (NSCLC) is a major health burden, and novel therapeutic options are needed to help solve this problem. One such option is immunotherapy, which targets immune checkpoint molecules that inhibit cancer cells, decreasing immune system activation, for example, immunotherapies target PD-1, its ligand PD-L1, and CTLA-4. There have been major advances in the development of agents that inhibit these molecules, called immune checkpoint inhibitors, and several of them are already approved for usage in NSCLC patients, especially in advanced stages. In this review, the reasons why immune checkpoint inhibitors could be beneficial and the clinical results of studies using these drugs for advanced or recurrent NSCLC patients are discussed, as is the safety profile of the drugs.2022年, Cancer management and research, 14, 2079 - 2090, 英語, 国際誌研究論文（学術雑誌）
- Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. The emergence of variants of concern (VOCs) has become one of the most pressing issues in public health. To control VOCs, it is important to know which COVID-19 convalescent sera have cross-neutralizing activity against VOCs and how long the sera maintain this protective activity. Methods: Sera of patients infected with SARS-CoV-2 from March 2020 to January 2021 and admitted to Hyogo Prefectural Kakogawa Medical Center were selected. Blood was drawn from patients at 1-3, 3-6, and 6-8 months post onset. Then, a virus neutralization assay against SARS-CoV-2 variants (D614G mutation as conventional strain; B.1.1.7, P.1, and B.1.351 as VOCs) was performed using authentic viruses. Results: We assessed 97 sera from 42 patients. Sera from 28 patients showed neutralizing activity that was sustained for 3-8 months post onset. The neutralizing antibody titer against D614G significantly decreased in sera of 6-8 months post onset compared to those of 1-3 months post onset. However, the neutralizing antibody titers against the three VOCs were not significantly different among 1-3, 3-6, and 6-8 months post onset. Discussion: Our results indicate that neutralizing antibodies that recognize the common epitope for several variants may be maintained for a long time, while neutralizing antibodies having specific epitopes for a variant, produced in large quantities immediately after infection, may decrease quite rapidly.2022年, Frontiers in immunology, 13, 773652 - 773652, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND/AIM: Chloride intracellular channel 1 (CLIC1) is a member of the chloride channel protein family. The aim of this study was to clarify the role of CLIC1 in lung adenocarcinoma. PATIENTS AND METHODS: The expression levels of CLIC1 in 74 patients with completely resected lung adenocarcinoma were analyzed by immunohistochemistry. Overall survival was assessed in relation to the expression level of CLIC1. Moreover, in the lung cancer cell lines A549 and PC9, CLIC1 expression was inhibited by small interfering RNA. The function of CLIC1 was analyzed in these cell lines. RESULTS: High expression of CLIC1 was associated with short overall survival compared to low expression (p=0.0327). Multivariate analysis revealed that CLIC1 expression was an independent prognostic factor. Knockdown of CLIC1 inhibited cell proliferation and migration through suppression of the p38 MAPK signaling pathway in A549 and PC9 cells. CONCLUSION: CLIC1 may be a useful prognostic factor in lung adenocarcinoma.2022年01月, Anticancer research, 42(1) (1), 271 - 277, 英語, 国際誌研究論文（学術雑誌）
- A 73-year-old woman complaining of cough and dyspnea was admitted to our hospital. High-resolution computed tomography chest revealed patchy ground-glass attenuation in the upper lung field. The patient suffered an asthma attack and was diagnosed with allergic pneumonitis; prednisolone was administered for treatment. Bird-related hypersensitivity pneumonitis was suspected, as she had a gray parrot (Psittacus erithacus) and a budgerigar (Melopsittacus undulatus) at home. An immunoblotting analysis with the patient's serum demonstrated IgG-binding fractions to the gray parrot's feathers only; no binding was noted with the budgerigar antigens. The patient was conclusively diagnosed with hypersensitivity pneumonitis related to exposure to a gray parrot.2021年12月, Internal medicine (Tokyo, Japan), 61(14) (14), 2197 - 2202, 英語, 国内誌研究論文（学術雑誌）
- The hedgehog (Hh) pathway is a sophisticated conserved cell signaling pathway that plays an essential role in controlling cell specification and proliferation, survival factors, and tissue patterning formation during embryonic development. Hh signal activity does not entirely disappear after development and may be reactivated in adulthood within tissue-injury-associated diseases, including idiopathic pulmonary fibrosis (IPF). The dysregulation of Hh-associated activating transcription factors, genomic abnormalities, and microenvironments is a co-factor that induces the initiation and progression of IPF.2021年12月, International journal of molecular sciences, 23(1) (1), 英語, 国際誌研究論文（学術雑誌）
- An Investigation on the Consciousness of Patients and Pharmacists Regarding Inhaler Education.Few studies have focused on the awareness of inhaler education in patients and pharmacists who have crucial roles in inhaler education. The aim of this study was to investigate the difference in awareness of inhaler education between patients and pharmacists. We conducted questionnaire-based surveys involving 270 patients with asthma and chronic obstructive pulmonary disease and 139 pharmacists of 13 pharmacies belonging to the same chain dispensing pharmacy in Hyogo prefecture of Japan in July 2011. We obtained valid responses from 230 patients (85.2%) and 139 pharmacists (100%). Although 75% of pharmacists provided inhaler education about the importance of continuation, only 16% of patients felt that they had learned the importance of continuation. Similarly, 95% of pharmacists provided inhaler education about the importance of gargling, however, only 57% of patients felt that they had learned the importance of gargling. This survey clarified the difference in awareness between pharmacists and patients on inhaler education. It proved to be difficult to educate patients on the importance of compliance and gargling.2021年12月, The Kobe journal of medical sciences, 67(4) (4), E119-E124, 英語, 国内誌研究論文（学術雑誌）
- BACKGROUND: Nocturnal desaturation is common in patients with chronic obstructive pulmonary disease (COPD) and impacts disease exacerbation and prognosis. In our previous study, we developed a diagnostic algorithm to classify nocturnal desaturation from SpO2 waveform patterns based on data from patients receiving home oxygen therapy. In this study, we aimed to investigate nocturnal desaturation in patients with COPD based on SpO2 waveform patterns and the associations between the waveforms and clinical data. METHODS: We investigated patients diagnosed with COPD and measured SpO2 and nasal airflow with a type 4 portable long-term recordable pulse oximeter. Then, we classified the SpO2 waveforms with the algorithm and compared the clinical data. RESULTS: One hundred fifty-three patients (136 male and 17 female) were analysed. One hundred twenty-eight of the 153 (83.7%) patients had nocturnal desaturation, with an intermittent pattern (70.6%), sustained pattern (13.1%) and periodic pattern (68.0%). Intriguingly, desaturation with an intermittent pattern was associated with the apnoea-hypopnea index obtained with the portable monitor, and desaturation with a sustained pattern was associated with the cumulative percentage of time at a SpO2 below 90%. CONCLUSIONS: We found that nocturnal desaturation was frequently observed in patients with COPD and could be classified into 3 types of waveform patterns.2021年10月, Respiratory research, 22(1) (1), 276 - 276, 英語, 国際誌研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2021年10月, 肺癌, 61(6) (6), 599 - 599, 日本語
- Background: As of March 2021, Japan is facing a fourth wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To prevent further spread of infection, sera cross-neutralizing activity of patients previously infected with conventional SARS-CoV-2 against novel variants is important but has not been firmly established. Methods: We investigated the neutralizing potency of 81 coronavirus disease 2019 (COVID-19) patients' sera from the first to fourth waves of the pandemic against SARS-CoV-2 D614G, B.1.1.7, P.1, and B.1.351 variants using their authentic viruses. Results: Most sera had neutralizing activity against all variants, showing similar activity against B.1.1.7 and D614G, but lower activity especially against B.1.351. In the fourth wave, sera-neutralizing activity against B.1.1.7 was significantly higher than that against any other variants, including D614G. The sera-neutralizing activity in less severe patients was lower than that of more severe patients for all variants. Conclusions: The cross-neutralizing activity of convalescent sera was effective against all variants but was potentially weaker for B.1.351. The high neutralizing activity specific to B.1.1.7 in the fourth wave suggests that mutations in the virus might cause conformational change of its spike protein, which affects immune recognition of D614G. Our results indicate that individuals who recover from COVID-19 could be protected from the severity caused by infection with newly emerging variants.2021年10月, Open forum infectious diseases, 8(10) (10), ofab430, 英語, 国際誌研究論文（学術雑誌）
- Idiopathic pulmonary fibrosis (IPF), one of the most common fibrosing interstitial lung diseases (ILD), is a chronic-age-related respiratory disease that rises from repeated micro-injury of the alveolar epithelium. Environmental influences, intrinsic factors, genetic and epigenetic risk factors that lead to chronic inflammation might be implicated in the development of IPF. The exact triggers that initiate the fibrotic response in IPF remain enigmatic, but there is now increasing evidence supporting the role of chronic exposure of viral infection. During viral infection, activation of the NLRP3 inflammasome by integrating multiple cellular and molecular signaling implicates robust inflammation, fibroblast proliferation, activation of myofibroblast, matrix deposition, and aberrant epithelial-mesenchymal function. Overall, the crosstalk of the NLRP3 inflammasome and viruses can activate immune responses and inflammasome-associated molecules in the development, progression, and exacerbation of IPF.2021年09月, International journal of molecular sciences, 22(19) (19), 英語, 国際誌研究論文（学術雑誌）
- INTRODUCTION: : When using portable oxygen, a demand oxygen delivery system (DODS), which senses the beginning of inhalation and delivers a bolus of oxygen, is often used. However, conventional DODS may not supply sufficient oxygen when reduced tidal flow fails to trigger the flow sensor. Recently, "auto-DODS," which detects the negative pressure of inhalation and switches among 3 trigger sensitivity levels (standard, high, and extra high), has been developed to improve the efficacy of oxygenation. An auto-DODS can also supply pulsed-flow oxygen when it detects apnea, whereas a conventional DODS has only standard sensitivity. This randomized, open-label, crossover pilot study compared the performance of an auto-DODS with that of a conventional DODS. METHODS: : We recruited patients with chronic obstructive pulmonary disease (COPD) or interstitial pneumonia receiving long-term oxygen therapy. Interventions were performed on 2 different days for each participant. On each day, an auto-DODS or a conventional DODS were tested at rest for 30 minutes and during the 6-minute walk test. The primary outcome was mean oxygen saturation (SpO2). Secondary outcomes were the ratios of time for each sensitivity level and pulsed-flow oxygen when using the auto-DODS, total time desaturated below SpO2 90%, percentage of time desaturated below SpO2 90%, minimum SpO2, mean and maximum pulse rate, six-minute walk distance, recovery time after 6-minute walk test, modified Borg scale, comfort, and discomfort index. RESULTS: : When using the auto-DODS at rest, a high or extra high sensitivity level was observed in addition to standard sensitivity in 6 of 8 participants. During the 6-minute walk test, only standard sensitivity was observed in 6 participants. Mean SpO2 differences between the auto-DODS and conventional DODS at rest and during the 6-minute walk test were -0.6 [-4.5, 3.4] and 0.0 [-2.5, 2.5] ([95% confidence interval]), respectively, neither of which were significant (P = .73 and P = .99). There were no significant differences in secondary outcomes. There were no adverse events when using the auto-DODS. CONCLUSIONS: : This study showed that the auto-DODS did not show superiority in oxygenation either at rest or during exercise compared to a conventional DODS. The auto-DODS was shown to supply oxygen safely and detect inhalations with various trigger sensitivities.2021年09月, Medicine, 100(37) (37), e27191, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: Sleep-disordered breathing is recognized as a comorbidity in patients with idiopathic pulmonary fibrosis (IPF). Among them, nocturnal hypoxemia has been reported to be associated with poor prognosis and disease progression. We developed a diagnostic algorithm to classify nocturnal desaturation from percutaneous oxygen saturation (SpO2) waveform patterns: sustained pattern, periodic pattern, and intermittent pattern. We then investigated the prevalence of nocturnal desaturation and the association between the waveform patterns of nocturnal desaturation and clinical findings of patients with IPF. METHODS: We prospectively enrolled patients with IPF from seven general hospitals between April 2017 and March 2020 and measured nocturnal SpO2 and nasal airflow by using a home sleep apnea test. An algorithm was used to classify the types of nocturnal desaturation. We evaluated the association between sleep or clinical parameters and each waveform pattern of nocturnal desaturation. RESULTS: Among 60 patients (47 men) who met the eligibility criteria, there were 3 cases with the sustained pattern, 49 cases with the periodic pattern, and 41 cases with the intermittent pattern. Lowest SpO2 during sleep and total sleep time spent with SpO2 < 90% were associated with the sustained pattern, and apnea-hypopnea index was associated with the intermittent pattern. CONCLUSION: We demonstrated the prevalence of each waveform and association between each waveform and sleep parameters in patients with IPF. This classification algorithm may be useful to predict the degree of hypoxemia or the complication of obstructive sleep apnea.2021年08月, Sleep & breathing = Schlaf & Atmung, 26(3) (3), 1079 - 1086, 英語, 国際誌研究論文（学術雑誌）
- Objective evaluations of cough frequency are considered important for assessing the clinical state of patients with respiratory diseases. However, cough monitors with audio recordings are rarely used in clinical settings. Issues regarding privacy and background noise with audio recordings are barriers to the wide use of these monitors; to solve these problems, we developed a novel automatic cough frequency monitoring system combining a triaxial accelerator and a stretchable strain sensor. Eleven healthy adult volunteers and 10 adult patients with cough were enrolled. The participants wore two devices for 30 min for the cough measurements. An accelerator was attached to the epigastric region, and a stretchable strain sensor was worn around their neck. When the subjects coughed, these devices displayed specific waveforms. The data from all the participants were categorized into a training dataset and a test dataset. Using a variational autoencoder, a machine learning algorithm with deep learning, the components of the test dataset were automatically judged as being a "cough unit" or "non-cough unit". The sensitivity and specificity in detecting coughs were 92% and 96%, respectively. Our cough monitoring system has the potential to be widely used in clinical settings without any concerns regarding privacy or background noise.2021年05月, Scientific reports, 11(1) (1), 9973 - 9973, 英語, 国際誌研究論文（学術雑誌）
- Background/Aim: The aim of this study was to elucidate the significance of allergic rhinitis and post-nasal drip symptoms in patients with cough-variant and coughpredominant asthma. Patients and Methods: We conducted a retrospective analysis of 91 patients who had cough-variant or cough-predominant asthma and first visited the Nakajima Medical Clinic in Japan between June 2012 and July 2015. Results: Post-nasal drip symptoms were reported in 58 (63.7%) patients. The patients with post-nasal drip symptoms (19.5±8.3 days) had a significantly longer time until cough disappearance than those without post-nasal drip symptoms (11.0±4.8 days) (p=0.000034). Multivariate analysis showed that post-nasal drip symptoms are independent prolonged factors of cough duration. Conclusion: Post-nasal drip symptoms may affect cough control in patients with coughvariant and cough-predominant asthma.International Institute of Anticancer Research, 2021年05月, In Vivo, 35(3) (3), 1799 - 1803, 英語, 国際誌研究論文（学術雑誌）
- INTRODUCTION: Various types of inhalation devices have been released, and it is necessary to acquire the skills for using each of them. The factors that have been previously associated with poor inhalator usage include gender, duration of disease, age, and the type of device. However, it is unclear whether these factors also apply to the Japanese population. The number of education sessions needed to acquire inhaler usage skills is also not established. PATIENTS AND METHODS: We performed a retrospective review of the medical records of selected patients and their subjective assessments of their inhaler usage skills between January 2016 and March 2018. The primary outcome was the effect of inhaler education for each inhaler device. The secondary outcomes were the factors affecting the effectiveness of inhaler education, the effects of inhalation education stratified by age, and the number of inhaler education sessions needed to improve inhaler usage skills. RESULTS: Data from 399 patients were analyzed. Age and the type of delivery device affected the mastery of inhaler usage skills. Approximately half of the patients had acquired inhaler usage skills during baseline evaluation. Approximately 90% of patients acquired inhalation usage skills after two education sessions, regardless of the type of inhalation device. Among the older patients, 35.0% had acquired inhaler usage skills during the baseline evaluation, and 86.8% acquired them after two education sessions. CONCLUSIONS: Inhaler usage skills significantly improved, regardless of the device, after inhalation education, and this was also observed in elderly patients after two education sessions.2021年05月, Respiratory investigation, 59(3) (3), 312 - 319, 英語, 国際誌研究論文（学術雑誌）
- Background: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown. Methods: The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment. Results: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation. Conclusions: Ferroptosis-inducing therapy shows promise in EGFR-activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi) Vorinostat can further promote ferroptosis by inhibiting xCT expression.2021年04月, Translational lung cancer research, 10(4) (4), 1857 - 1872, 英語, 国際誌研究論文（学術雑誌）
- (一社)日本病理学会, 2021年03月, 日本病理学会会誌, 110(1) (1), 284 - 284, 日本語術後補助化学療法施行肺腺癌におけるOCT3の発現と患者予後との関連
- 2021年02月, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 72(4) (4), 723 - 724, 英語, 国際誌研究論文（学術雑誌）
- Asthma is a chronic disease with major public health ramifications owing to its high morbidity and mortality rates, especially in severe and recurrent cases. Conventional therapeutic options could partially alleviate the burden of asthma, yet a novel approach is needed to completely control this condition. To do so, a comprehensive understanding of the molecular mechanism underlying asthma is essential to recognize and treat the major pathways that drive its pathophysiology. In this review, we will discuss the molecular mechanism of asthma, in particular focusing on the type of inflammatory responses it elicits, namely type 2 and non-type 2 asthma. Furthermore, we will discuss the novel therapeutic options that target the aberrant molecules found in asthma pathophysiology. We will specifically focus on the role of novel monoclonal antibody therapies recently developed, such as the anti-IgE, IL-5, IL-5Rα, and IL-4Rα antibodies, drugs that have been extensively studied preclinically and clinically.2021年02月, Respiratory investigation, 59(3) (3), 291 - 301, 英語, 国際誌研究論文（学術雑誌）
- Patients with coronavirus disease 2019 (COVID-19) exhibit a wide clinical spectrum ranging from mild respiratory symptoms to critical and fatal diseases, and older individuals are known to be more severely affected. The underlying mechanism of this phenomenon is unknown. A neutralizing antibody against viruses is known to be important to eliminate the virus. In addition, this antibody is induced at high levels in patients with severe COVID-19, followed by a termination of virus replication. Severe COVID-19 patients exhibit high levels of cytokines/chemokines, even after the disappearance of the virus. This indicates that cytokines/chemokines play significant roles in disease severity. These findings also suggest that antiviral therapy (monoclonal antibody and/or convalescent plasma therapy) should be administered early to eliminate the virus, followed by steroid treatment after viral genome disappearance, especially in patients with severe symptoms.2021年01月, JMA journal, 4(1) (1), 1 - 7, 英語, 国内誌研究論文（学術雑誌）
- Most COVID-19 patients experience asymptomatic/mild symptoms, but some suffer critical symptoms requiring intensive care. It is important to determine how asymptomatic/mild patients react to SARS-CoV-2 infection and suppress virus spread. Innate immunity is important for evasion from the first virus attack, and it may play an important role in the pathogenesis in these patients. We measured serum cytokine levels of 95 COVID-19 patients during the infection's acute phase and are first to report that significantly higher IL-12 and IL-2 levels were induced in asymptomatic/mild patients versus those in the moderate/severe patients, indicating these cytokines' key roles in asymptomatic/mild infections' pathogenesis.2021年01月, The Journal of infectious diseases, 223(7) (7), 1145 - 1149, 英語, 国際誌研究論文（学術雑誌）
- Objective Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe asthma. Although it has been suggested that BT works by reducing airway smooth muscle, the detailed mechanism underlying its effects is still unknown. Methods We performed xenon ventilation computed tomography (Xe-CT) before each BT procedure and six weeks after the third treatment to assess the improvement in lung ventilation at each separate lung region. The air trapping index in each lobe was defined as the mean trapping value (0: none, 1: mild, 2: moderate, and 3: severe) of the included segments. Patients and Materials Four patients were included. Results Asthma symptoms were improved after BT. The comparison of the scores at baseline with those after the third treatment showed that the air trapping index was improved in both the treated and untreated regions. However, neither the pulmonary function nor the exhaled nitric oxide was improved. Conclusion Using Xe-CT, we successfully evaluated the air trapping in patients who underwent BT. The improvement in asthma symptoms by BT may be related to the amelioration of peripheral lung ventilation in both the treated and untreated regions.2021年, Internal medicine (Tokyo, Japan), 60(13) (13), 2027 - 2032, 英語, 国内誌研究論文（学術雑誌）
- Objective Nocturnal desaturation is common in patients with chronic respiratory disease and often worsens the prognosis. Therefore, it should be diagnosed accurately and appropriately treated. The aim of this study was to clarify the diversity of nocturnal desaturation. Methods We prospectively enrolled 58 outpatients diagnosed with chronic respiratory disease receiving home oxygen therapy and measured nocturnal SpO2 using a portable oximeter. We classified nocturnal desaturation (3% decrease in SpO2 from baseline) into three patterns: periodic pattern (desaturation duration of <655 seconds), sustained pattern (desaturation duration of ≥655 seconds), and intermittent pattern (desaturation and recovery of SpO2 repeated with a cycle of several minutes). Results Nocturnal hypoxemia (SpO2≤88% for more than 5 minutes) was found in 23.8% of patients. The percentage of patients with chronic obstructive pulmonary disease (COPD) was significantly higher in the nocturnal hypoxemia group than in the non-hypoxemia group (80% vs. 40.6%, p=0.03). Desaturation with a periodic pattern was found in 81% of patients, desaturation with a sustained pattern was found in 40.5% of patients, and desaturation with an intermittent pattern was found in 59.5% of patients. In patients with COPD, desaturation with a periodic pattern was found in 85.7%, desaturation with a sustained pattern was found in 47.6%, and desaturation with an intermittent pattern was found in 57.1%. Conclusion The SpO2 waveform of nocturnal hypoxemia was able to be classified into three patterns. Suitable treatment for each pattern might improve the prognosis of these patients.2021年, Internal medicine (Tokyo, Japan), 60(19) (19), 3071 - 3079, 英語, 国内誌研究論文（学術雑誌）
- BACKGROUND: Adequate tumor tissue is required to make the best treatment choice for non-small cell lung cancer (NSCLC). Transbronchial biopsy (TBB) by endobronchial ultrasonography with a guide sheath (EBUS-GS) is useful to diagnose peripheral lung lesions. The data of tumor cell numbers obtained by two different sizes of GSs is limited. We conducted this study to investigate the utility of a large GS kit to obtain many tumor cells in patients with NSCLC. METHODS: Patients with a peripheral lung lesion and suspected of NSCLC were prospectively enrolled. They underwent TBB with a 5.9-mm diameter bronchoscope with a large GS. When the lesion was invisible in EBUS, we changed to a thinner bronchoscope and TBB was performed with a small GS. We compared the tumor cell number prospectively obtained with a large GS (prospective large GS group) and those previously obtained with a small GS (small GS cohort). The primary endpoint was the tumor cell number per sample, and we assessed characteristics of lesions that could be obtained by TBB with large GS. RESULTS: Biopsy with large GS was performed in 55 of 87 patients (63.2%), and 37 were diagnosed with NSCLC based on histological samples. The number of tumor cells per sample was not different between two groups (658±553 vs. 532±526, estimated difference between two groups with 95% confidence interval (CI); 125 (-125-376), p = 0.32). The sample size of the large GS group was significantly larger than that of the small GS cohort (1.75 mm2 vs. 0.83 mm2, estimated difference with 95% CI; 0.92 (0.60-1.23) mm2, p = 0.00000019). The lesion involving a third or less bronchus generation was predictive factors using large GS. CONCLUSIONS: The sample size obtained with large GS was significantly larger compared to that obtained with small GS, but there was no significant difference in tumor cell number. The 5.9-mm diameter bronchoscope with large GS can be used for lesions involving a third or less bronchus generation.2021年, PloS one, 16(10) (10), e0259236, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Recent studies have revealed that serpin peptidase inhibitor clade E member 2 (SERPINE2) is associated with tumorigenesis. However, SERPINE2 expression and its role in lung adenocarcinomas are still unknown. METHODS: The expression levels of SERPINE2 in 74 consecutively resected lung adenocarcinomas were analyzed by using immunostaining. Inhibition of SERPINE2 expression by small interfering RNA (siRNA) was detected by quantitative PCR. Cell number assays and cell apoptosis assays were performed to clarify the cell-autonomous function of SERPINE2 in A549 and PC9 lung cancer cells. RESULTS: The overall survival of patients with high SERPINE2 expression was significantly worse than that of patients with low SERPINE2 expression (P = 0.0172). Multivariate analysis revealed that SERPINE2 expression was an independent factor associated with poor prognosis (P = 0.03237). The interference of SERPINE2 decreased cell number and increased apoptosis in A549 and PC9 cells CONCLUSION: These results suggest that SERPINE2 can be used as a novel prognostic marker of lung adenocarcinoma.2020年12月, Respiratory research, 21(1) (1), 331 - 331, 英語, 国際誌研究論文（学術雑誌）
- A Questionnaire Survey of the Inhalation Instruction in Pharmacies.Few studies have focused on the inhalation instruction in pharmacies which have the crucial role on the inhalation instruction. The aim of this study is to evaluate the level of knowledge and the degree of interest for asthma inhalation instruction methods among pharmacists receiving prescription from clinics. We conducted questionnaire surveys to chief pharmacists of 39 consecutive pharmacies belonging to HANSHIN Dispensing Pharmacy in Hyogo, Japan at July 2011. We obtained valid responses from 35 pharmacies. Among them, 14 pharmacies dealt with prescriptions mainly from the clinics (clinic pharmacies) and 21 pharmacies dealt with prescriptions originated from hospitals (hospital pharmacies), including 13 pharmacies that dealt with prescription filled by respiratory physicians (specialty hospital pharmacies). Although the inhalation instruction at the first visit was provided at every pharmacy, only 54.3% of all pharmacies provided inhalation instructions after the second visit. Compared to 0% of the clinic pharmacies, 40% of the specialty hospital pharmacies visually checked the patient's inhalation procedure after the second visit. Visual confirmation of the inhalation technique, especially in the clinic pharmacies, might play an important role in maintaining treatment adherence.2020年11月, The Kobe journal of medical sciences, 66(3) (3), E113-E118, 英語, 国内誌研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2020年10月, 肺癌, 60(6) (6), 644 - 644, 日本語
- (NPO)日本肺癌学会, 2020年10月, 肺癌, 60(6) (6), 700 - 700, 日本語
- BACKGROUND: Cisplatin (CDDP) and vinorelbine as an adjuvant chemotherapy improve the overall survival of patients with completely resected non-small cell lung cancer (NSCLC). However, the treatment completion rate is low due to severe adverse events (AEs). Pemetrexed (PEM) has been used in advanced NSCLC due to its high safety and efficacy. Additionally, the safety of a short hydration method for CDDP administration has been previously reported. Here, we investigated the feasibility of CDDP plus PEM with a short hydration method as adjuvant chemotherapy. METHODS: A total of 21 completely resected nonsquamous NSCLC patients with pathological stage IIA to IIIA disease were enrolled into the study. Adjuvant chemotherapy consisted of four cycles of CDDP (75 mg/m2 ) plus PEM (500 mg/m2 ) every three weeks with a short hydration method. The primary endpoint was the treatment completion rate, and the secondary endpoints included toxicity, the two-year relapse-free survival (RFS) rate, and the outpatient treatment rate. RESULTS: A total of 21 patients (median age: 66 years; 12 males) were enrolled in two centers. All cases were adenocarcinoma with PS0 (71.4%) or PS1 (28.6%). A total of 81.0% of the patients received four cycles of therapy as scheduled and the primary endpoint was met. The rate of outpatient chemotherapy completion after the second cycle was 90.5%. The grade 3 or higher toxicities were anorexia (n = 2) and pulmonary thromboembolism (n = 1). No grade 3/4 hematological toxicities or creatinine level elevations were observed. The two-year RFS rate was 57.3%. CONCLUSIONS: CDDP and PEM with a short hydration is well tolerated in the outpatient setting with limited toxicity. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: CDDP plus PEM adjuvant therapy with a short hydration method is well tolerated in the outpatient setting with limited toxicity. WHAT THIS STUDY ADDS: CDDP plus PEM with a short hydration method has the potential to be one of the options of adjuvant therapy in the future.2020年09月, Thoracic cancer, 11(9) (9), 2536 - 2541, 英語, 国際誌研究論文（学術雑誌）
- In recent years, multitarget drugs for neurological diseases such as Alzheimer's disease have been developed and well researched. Many studies have revealed that multitarget drugs are also useful for lung cancer and respiratory diseases. Pemetrexed is a multitargeted antifolate with strong antitumor activity against mesothelioma and lung adenocarcinoma. Crizotinib is an ATP-competitive tyrosine kinase inhibitor that targets c-MET, ROS1, and ALK. Alectinib is known as an ALK inhibitor but also targets LTK, CHEK2, FLT3, PHKG2, and RET. Sorafenib is a tyrosine kinase inhibitor that targets RAF kinase, KIT, VEGFR, PDGFR1β, FLT3, and RET. Nintedanib is a multiple tyrosine kinase inhibitor that targets FGFR, PDGFR, and VEGFR. In this review, we summarize the mechanisms of action of multitarget therapies and report the results of the latest clinical trials.2020年09月, Molecules (Basel, Switzerland), 25(17) (17), 英語, 国際誌研究論文（学術雑誌）
- Although immunotherapy has led to durable responses in diverse cancers, unfortunately, there has been limited efficacy and clinical response rates due to primary or acquired resistance to immunotherapy. To maximize the potential of immunotherapy, combination therapy with antiangiogenic drugs seems to be promising. Some phase III trials showed superiority for survival with the combination of immunotherapy and antiangiogenic therapy. In this study, we describe a synergistic mechanism of immunotherapy and antiangiogenic therapy and summarize current clinical trials of these combinations.2020年08月, Molecules (Basel, Switzerland), 25(17) (17), 英語, 国際誌研究論文（学術雑誌）
- (一社)日本呼吸器学会, 2020年08月, 日本呼吸器学会誌, 9(増刊) (増刊), 183 - 183, 日本語
- BACKGROUND: Lettuce-associated respiratory allergy has never been reported before. The aim of this study was to clarify the clinical condition of lettuce-associated respiratory allergy and to identify the lettuce antigen which induces allergic symptoms. METHODS: We distributed questionnaires to 1168 lettuce farmers and performed medical examinations in those who exhibited respiratory symptoms related to occupational exposure to lettuce. We analysed specific IgE-binding proteins in the sera of patients through immunoblotting analysis and determined molecular characterization of the IgE-binding bands using liquid chromatography-mass spectrometry. RESULTS: A total of 932 farmers (80%) responded to the questionnaire. Of those, 7% exhibited lettuce-associated respiratory symptoms, during harvesting and packaging. Thirteen patients were diagnosed with allergy to lettuce and agreed to undergo further examinations. The percentage of activated basophils in these patients was significantly higher compared with that reported in negative controls (P < .05). Lettuce-specific IgE (ImmunoCAP® ) and skin prick testing was positive in 46% and 62% of patients, respectively. Notably, occupational lettuce-allergic asthma was detected in one patient through specific bronchial provocation testing. The IgE-binding bands recognized in the sera of >50% of patients were identified as epidermis-specific secreted glycoprotein EP1-like (51 kDa). CONCLUSION: The present analysis identified a novel lettuce allergen. This allergen may have clinically useful applications, such as specific IgE testing and allergen-specific immunotherapy.2020年08月, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 50(8) (8), 932 - 941, 英語, 国際誌研究論文（学術雑誌）
- 2020年08月, Journal of thoracic disease, 12(8) (8), 4561 - 4563, 英語, 国際誌
- The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.2020年05月, International journal of molecular sciences, 21(10) (10), 英語, 国際誌研究論文（学術雑誌）
- Asthma is an important issue not only in health but also in economics worldwide. Therefore, asthma animal models have been frequently used to understand the pathogenesis of asthma. Recently, in addition to acquired immunity, innate immunity has also been thought to be involved in asthma. Among innate immune cells, group 2 innate lymphoid cells (ILC2s) have been considered to be crucial for eosinophilic airway inflammation by releasing T helper 2 cytokines. Moreover, house dust mites (HDMs) belonging to group 1 act on airway epithelial cells not only as allergens but also as cysteine proteases. The production of interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) from airway epithelial cells was induced by the protease activity of HDMs. These cytokines activate ILC2s, and activated ILC2s produce IL-5, IL-9, IL-13, and amphiregulin. Hence, the HDM-induced asthma mouse model greatly contributes to understanding asthma pathogenesis. In this review, we highlight the relationship between ILC2s and the HDM in the asthma mouse model to help researchers and clinicians not only choose a proper asthma mouse model but also to understand the molecular mechanisms underlying HDM-induced asthma.2020年05月, Cells, 9(5) (5), 英語, 国際誌研究論文（学術雑誌）
- INTRODUCTION: Long-term oxygen therapy is reported to improve hypoxemia and survival in patients with respiratory failure. The demand oxygen delivery system (DODS) saves oxygen and extends the usable time of an oxygen cylinder 2- to 3-fold. A portable oxygen concentrator with an auto-DODS has been developed to switch its sensitivity among 3 levels (standard, high, and extra high) and to supply pulsed-flow oxygen when it detects apnea. The aim of this study is to evaluate the efficacy of this newly developed portable oxygen concentrator with auto-DODS compared to the efficacy of conventional DODS in oxygenation. METHODS AND ANALYSIS: Twenty-six patients with chronic obstructive pulmonary disease or interstitial pneumonia will be randomized to use auto-DODS or conventional DODS at rest and during a 6-minute walk test. Primary endpoints are mean oxygen saturation (SpO2) at rest and during the 6-minute walk test. Secondary endpoints are the ratios of the times during which the oxygen concentrator operates at each sensitivity mode (standard, high, and extra high) and at a constant pulse rate to the examination time, the ratio of the times during which SpO2 fall below 90% to the examination time, the lowest value of SpO2 during the examination time, the mean and highest pulse rates during the examination time, 6-minute walking distance, recovery time, Borg scale, comfort, and reliability, which are measured by a numerical rating scale and a questionnaire, respectively. ETHICS AND DISSEMINATION: The study was conducted in accordance with the Declaration of Helsinki and was registered on Aug 23, 2019 (https://jrct.niph.go.jp/en-latest-detail/jRCTs052190041). The results of the study will be presented at academic conferences and submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs052190041.2020年05月, Medicine, 99(19) (19), e20010, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: It has not been determined that demand valve oxygen therapy is effective for nocturnal hypoxia. A portable oxygen concentrator with an auto-demand oxygen delivery system (auto-DODS; standard, high, and extra high) has recently been developed to improve oxygenation and comfort. This oxygen concentrator can supply a pulsed flow when it detects apnoea. The aim of this study is to demonstrate that this newly developed portable oxygen concentrator with an auto-demand function is non-inferior to a continuous-flow oxygen concentrator for nocturnal hypoxemia. METHODS: Twenty patients with chronic obstructive pulmonary disease or interstitial pneumonia will be randomized to receive a portable oxygen concentrator with an auto-DODS or a continuous-flow oxygen concentrator during sleep. The primary endpoint is mean oxygen saturation (SpO2) during the total sleep time. The secondary endpoints are the ratios of time that the oxygen concentrator spends in each sensitivity mode (standard, high, and extra-high) and at a constant pulse rate to the total sleep time, the total time and ratio of time for which SpO2 is less than 90% during the total sleep time, the lowest value of SpO2 during the total sleep time, the mean and highest pulse rate during the total sleep time, the apnoea index during the total sleep time, the total sleep duration itself, and comfort and reliability as measured by numerical rating scale and questionnaires. DISCUSSION: If the auto-DODS demonstrates non-inferiority to continuous flow in oxygenation during sleep, the auto-DODS can be used even at night, and the patient will need only 1 device. TRIAL REGISTRATION: The study was registered on Aug 23, 2019 (jRCTs052190042).2020年05月, Medicine, 99(19) (19), e20031, 英語, 国際誌研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2020年04月, 肺癌, 60(2) (2), 153 - 154, 日本語
- (NPO)日本肺癌学会, 2020年04月, 肺癌, 60(2) (2), 154 - 155, 日本語
- Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A1AR, A2AAR, A2BAR, and A3AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A1AR and A2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A2BAR and A3AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.2020年03月, Cells, 9(3) (3), 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本病理学会, 2020年03月, 日本病理学会会誌, 109(1) (1), 410 - 410, 日本語術後補助化学療法施行肺腺癌におけるATOX1の発現と患者予後との関連
- Purpose: Caspase recruitment domain-containing protein 9 (CARD9) is expressed at high levels in bone marrow cells and has a crucial role in innate immunity. Current studies indicate that CARD9 also plays a key role in tumor progression, but there are few reports on the role of CARD9 in lung cancer. The aim of this study was to clarify the role of CARD9 in lung adenocarcinoma. Patients and Methods: Lung adenocarcinoma tumor samples from 74 patients who underwent complete resection at Kobe University Hospital from January 2014 to December 2014 were analyzed by immunohistochemistry. The role of CARD9 in cancer cells was analyzed using lung cancer cell lines treated with CARD9 siRNA. Results: High expression of CARD9 was observed in 32.4% of tumors, and compared to low expression of CARD9, high expression was associated with poorer overall survival (P = 0.0365). Univariate and multivariate analyses showed that high expression of CARD9 was an independent prognostic factor. Knockdown of CARD9 in lung adenocarcinoma cells inhibited proliferation but did not increase apoptosis. In addition, CARD9 activated the NF-κB pathway in a lung adenocarcinoma cell line. Conclusion: CARD9 was shown to be an independent prognostic factor of poor outcome for lung cancer and may represent a molecular target for treatment.2020年, OncoTargets and therapy, 13, 9005 - 9013, 英語, 国際誌研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2019年11月, 肺癌, 59(6) (6), 772 - 772, 日本語
- (NPO)日本肺癌学会, 2019年11月, 肺癌, 59(6) (6), 860 - 860, 日本語
- (NPO)日本肺癌学会, 2019年11月, 肺癌, 59(6) (6), 902 - 902, 日本語
- A 51-year-old man underwent second-line treatment for non-small-cell lung cancer (NSCLC) with the immune checkpoint inhibitor (ICI) pembrolizumab. On day 2 after two cycles of pembrolizumab, he presented with edema limited to the left third, fourth, and fifth fingers. Based on symptoms, laboratory results, and contrast-enhanced magnetic resonance imaging (MRI) findings, we diagnosed him with tenosynovitis. We prescribed oral prednisolone (0.5 mg/kg/day), and pembrolizumab was continued. Prednisolone immediately relieved the symptoms, and the tumor was still shrinking on day 21 after eight cycles of pembrolizumab. ICI-induced tenosynovitis was managed while continuing ICI usage, suggesting that 0.5 mg/kg/day prednisone might be effective for tenosynovitis without ICI cessation.2019年10月, Internal medicine (Tokyo, Japan), 58(19) (19), 2839 - 2843, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2019年08月, 肺癌, 59(4) (4), 416 - 416, 日本語ペムブロリズマブにより腱滑膜炎をきたした1例
- Immune checkpoint inhibitors (ICIs) have drastically changed the clinical care of cancer. Although cancer immunotherapy has shown promise in various types of malignancies, thus far, the proportion of patients who can benefit from ICIs is relatively small. Immune-related adverse events and high cost are unavoidable problems. Therefore, biomarkers defining patients that are most likely to benefit from ICIs are urgently needed. The expression of programmed cell death-ligand 1 (PD-L1) is a logical biomarker for the prediction of response to anti-PD1/PD-L1 immunotherapies. However, its usefulness is currently debatable because of its varied definition, threshold, and spatial/temporal heterogeneity. Recently, it was reported that the tumor mutational burden, expression of neoantigens, mismatch repair status, and specific gene mutations may be markers for the success of treatment with ICIs. Moreover, it was suggested that the fecal microbiota prior to immunotherapy may play an important role in predicting the efficacy of ICIs. In this review, we focused on these potential biomarkers for cancer immunotherapy reported in recent clinical articles. Further studies are warranted to develop a predictive model using these biomarkers, with the aim of practicing precision medicine in cancer immunotherapy.2019年07月, Cancers, 11(7) (7), 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.2019年05月, International journal of molecular sciences, 20(10) (10), 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Transformation to small cell lung cancer is one phenomenon of acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Few case reports have focused on other types of histological transformation. We report a case of transformation of ALK rearrangement-positive adenocarcinoma to NSCLC with neuroendocrine differentiation during alectinib therapy. A 36-year-old woman presented with a tumor in the left lower lobe and bone metastases. She was diagnosed with ALK rearrangement-positive adenocarcinoma by histopathology of the primary tumor. Alectinib had been effective for 8 months before new lesions appeared. Histopathological re-examination of a recurrent tumor revealed poorly differentiated carcinoma with insulinoma-associated protein 1 (INSM1) expression, which remained ALK-positive. Expression of CD133, BCL-2, and SOX2 was positive in comparison to the initial tumor. Expression of SOX2 became more strongly positive than it was before treatment. The immunohistochemical findings of these markers associated with cancer stem-like cells and/or neuroendocrine differentiation suggest that cancer stem cells play a role in the mechanisms of histological transformation and acquired resistance of ALK rearrangement-positive cancer. To our knowledge, this is the first report to suggest an association between cancer stem-like cells and histological transformation in ALK rearrangement-positive lung cancer.2019年05月, Pathology international, 69(5) (5), 294 - 299, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- AIM: The aim of this study was to identify factors affecting the final diagnosis of cough. MATERIALS AND METHODS: This study recruited 463 consecutive patients who visited five Japanese general hospitals due to cough from October 2006 to September 2007. Of these, 418 patients (90%) who completed a questionnaire designed to acquire data regarding clinical manifestations of cough were included. RESULTS: Most patients with bronchial asthma had cough with seasonal variation and wheezing. Patients with gastro esophageal reflux disease suffered from heartburn and cough without daily or seasonal variation. Cough associated with sinobronchial syndrome was only observed in females and was linked to increased sputum. Patients with whooping cough were bothered by cough interrupting sleep and talking. Patients with cardiogenic cough had exertional dyspnea. CONCLUSION: The specific items on our questionnaire relating to patient characteristics, complications, and triggers of cough, represent useful tools for diagnosing the primary disease producing cough.2019年03月, In Vivo, 33(2) (2), 543 - 549, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Questionnaire Survey for Bronchial Asthma in Elderly Care Facilities.In developed countries such as North America, the decline in mortality from bronchial asthma has ceased since 2006. The decline in mortality rate is also decreasing in Japan, where about 1,500 asthma deaths have been reported. Among these, elderly people aged 65 years or over account for about 90% of cases. Therefore, the treatment of elderly patients with asthma is an important subject. However, few studies have been conducted on asthma in elderly patients. In this survey, we distributed a questionnaire to 253 elderly care facilities in Kobe, Japan. Ninety facilities responded, and 223 patients in 70 out of 90 facilities were diagnosed with asthma. Dry powder inhaler was the most commonly used dosage form of inhaled corticosteroids. Many facilities have patients who need some assistance during inhalation: only 60% of facilities reported that inhalation is performed accurately. While 31 facilities had patients with a history of hospitalization for asthma attacks, only 14 of these facilities were able to provide appropriate initial treatment. Many facilities have difficulty providing assistance with inhalation to elderly patients whose cognitive function has deteriorated. This survey highlights challenges experienced by care facilities in treating asthma in the elderly.2019年02月, The Kobe journal of medical sciences, 64(5) (5), E174-E179, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- BACKGROUND/AIM: Immune checkpoint inhibitors (ICI) are a novel medication for non-small cell lung cancer (NSCLC). Recent reports indicated that baseline tumor size (BTS) relates to the efficacy of ICI therapy for melanoma, but no study exists for NSCLC. This study aimed to evaluate the utility of BTS for ICI therapy. PATIENTS AND METHODS: Data from 58 patients diagnosed with NSCLC who underwent ICI monotherapy, were retrospectively analyzed. Patients were divided into two groups according to BTS (below 101 mm, above 101 mm). The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS). RESULTS: PFS of patients with a large BTS was significantly shorter than that of those with a small BTS (median; 2.07 [95% confidence interval [CI]=0.99-6.77] months versus 6.39 [95%CI=4.17-11.50] months) (p=0.044). OS of patients with large BTS was also significantly shorter (p<0.01). CONCLUSION: BTS is a predictive and prognostic negative factor of ICI therapy for NSCLC.2019年02月, Anticancer Res, 39(2) (2), 815 - 825, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- This paper describes an automatic classification algorithm for nocturnal hypoxemia in patients receiving home oxygen therapy (HOT). Nocturnal hypoxemia is a well-known complication in patients with chronic respiratory disease, and the number of patients receiving HOT has increased in recent years. Many studies have reported that 40% of patients receiving HOT have sleep-related oxygen desaturation. To deal with this situation, a nocturnal pulse oximetry is used to measure oxygen saturation (SpO2) and control the flow rate of highly concentrated oxygen. However, in some cases, the flow rate is not controlled properly and the same flow rate is adopted both during the day and night. There are several types of nocturnal hypoxemia, and it is difficult to classify these types only according to a subjective assessment of a medical doctor. Furthermore, it is difficult to continuously monitor the measurement results of pulse oximetry, although a flexible treatment depending on the state of hypoxemia is desired. To overcome these difficulties, an automatic classification method for SpO2 measured by the nocturnal pulse oximetry is proposed in this paper. The proposed method uses the time domain waveform and the frequency characteristics of SpO2. The classification performance of the method is evaluated by using 48 measured SpO2 values from patients receiving the HOT. The classification results are validated with decisions of ten chest physicians.IEEE, 2019年, Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2019, 3662 - 3665, 英語, 国際誌[査読有り]研究論文（国際会議プロシーディングス）
- Background: The combination of gemcitabine (GEM) and paclitaxel (PTX) was appealing for clinical exploration due to different mechanisms of action and partially non-overlapping toxicities. Purpose: The aim of this study was to elucidate a potential effect of this combination on the proliferation of two non-small cell lung cancer (NSCLC) cell lines, A549 and H520. Materials and methods: Cell lines were treated with GEM and PTX for 48 hours to evaluate the half maximal inhibitory concentration (IC50). To determine the combination index (CI), cell lines were exposed to GEM and PTX, in a constant ratio of IC50, by various combination treatments. GEM`s effect on tubulin was assessed by western blotting and immunofluorescent staining. GEM was combined with nanoparticle albumin-bound-paclitaxel (NP) in evaluating tumor growth inhibition. Results: The IC50 of GEM and PTX in A549 and H520 were 6.6 nM and 46.1 nM, and 1.35 nM and 7.59 nM, respectively. Among the sequences explored (GEM→PTX, PTX→GEM, and GEM plus PTX simultaneously [GEM+PTX]), GEM→PTX produced a mean CI <1 in both cell lines. Western blotting and immunofluorescent staining revealed the intention expressions of acetylated tubulin protein and enhancement of tubulin polymerization within GEM→PTX group. A combination order GEM→NP also worked synergistically to suppress tumor growth. Conclusion: The GEM→PTX sequence may represent a promising candidate regimen for the treatment of NSLCL.2019年, Cancer management and research, 11, 3669 - 3679, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.2019年, OncoTargets and therapy, 12, 3619 - 3624, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Methods: Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) + GEM (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). Results: Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47-79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1-10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6-4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%). Conclusion: The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.2019年, Cancer management and research, 11, 7135 - 7140, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Purpose: Pseudo-progression (PsPD) is a rare phenomenon observed in <5% of cases of non-small cell lung cancer (NSCLC). This event is challenging for both clinicians and patients. Viable biomarkers to distinguish between PsPD and true progressive disease (TPD) are lacking. The aim of our study was to determine the correlation between PsPD and the neutrophil-to-lymphocyte ratio (NLR) in patients with NSCLC treated with immune checkpoint inhibitors (ICIs). Patients and methods: We retrospectively reviewed the clinical records of NSCLC patients treated with ICI monotherapy from December 2015 to October 2018 at Kobe University Hospital, Japan. Twenty-five patients were determined to have either PsPD (n =4) or TPD (n =21). We focused on longitudinal radiological images and NLRs. Results: Here, we report four patients with PsPD. The pre- and post-treatment NLRs were significantly lower in patients with PsPD than in patients with TPD (p = 0.019 and p = 0.007, respectively). The receiver operating characteristic curve according to the pre- and post-treatment NLR showed areas under the curve of 0.82 and 0.94, respectively. The optimal cut-off values for pre- and post-treatment NLR were 4.1 and 3.2, respectively. The pre- and post-treatment NLRs were useful in distinguishing between PsPD and TPD. Both a pre-treatment NLR <4.1 and a post-treatment NLR <3.2 were significantly associated with longer overall survival compared to a pre-treatment NLR ≥4.1 (p < 0.001) and post-treatment NLR ≥3.2 (p = 0.004), respectively. Conclusion: The NLR could be a viable clue for distinguishing between PsPD and TPD. Patients with a high post-treatment NLR in this study all had TPD, suggesting that these subjects should be considered for an early transition to the next drug treatment regimen.2019年, OncoTargets and therapy, 12, 10559 - 10568, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- We herein report the case of a 39-year-old Japanese female with eosinophilic pneumonia associated with natalizumab. The patient with bronchial asthma had multiple sclerosis and was treated using natalizumab. The patient was referred to our department because of a persistent cough. A chest computed tomography (CT) scan revealed bilateral patchy consolidation surrounded by ground-glass opacity. A bronchoalveolar lavage (BAL) was performed. Eosinophil levels in the BAL fluid were increased and the patient was consequently diagnosed as eosinophilic pneumonia associated with natalizumab. Therefore, natalizumab treatment was discontinued. Subsequent chest CT findings showed a remarkable improvement without any treatment.2019年, Therapeutics and clinical risk management, 15, 1283 - 1289, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Hypertrophic pulmonary osteoarthropathy (HPO) is a paraneoplastic syndrome characterized by digital clubbing, arthritis, and periostitis. Tumor removal usually leads to the resolution of these symptoms. We herein report the efficacy of crizotinib treatment for treating the symptoms of HPO associated with c-ros oncogene 1 receptor tyrosine kinase (ROS1)-rearranged lung cancer. A 71-year-old woman presented with a pulmonary tumor and arthritis. She was diagnosed with a ROS1-rearranged lung adenocarcinoma [stage IIIB (cT4N2M0) ] with HPO. Crizotinib dramatically reduced the tumor size and resolved the symptoms. After two months of crizotinib treatment, she underwent lobectomy, and a pathological evaluation revealed ypstage IIIA (ypT3a, ypN1). Crizotinib treatment was effective for reducing the tumor size and improving the symptoms of HPO.2019年01月, Intern Med, 58(10) (10), 1467 - 1471, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- BACKGROUND/AIM: Red cell distribution width (RDW) has been reported to reflect the inflammation and nutrition status and predict prognosis of non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1 (PD-1) antibody. The aim of this study was to analyze the correlation between RDW and prognosis of NSCLC patients. PATIENTS AND METHODS: We collected retrospective data on consecutive NSCLC patients treated with anti-PD-1 antibody from December 2015 to April 2018 at the Kobe University Hospital, Japan. RESULTS: Forty-seven patients were treated. Patients with RDW ≥16% had a significantly shorter OS (p=0.010) compared to those with RDW <16%. In multivariate analysis, RDW ≥16% was an independent factor predicting poor prognosis (p=0.019). CONCLUSION: Pre-treatment RDW ≥16% is an indicator of poor prognosis. RDW is an inexpensive, convenient, and routinely available marker of prognosis.2019年01月, In Vivo, 33(1) (1), 213 - 220, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Background: We have shown that phospholipase Cε (PLCε), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lungBioMed Central, 2019年01月, Respiratory Research, 20(9) (9), 1 - 12, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2019年01月, Respir Res, 20(1) (1), 9, 英語Phospholipase Cε plays a crucial role in neutrophilic inflammation accompanying acute lung injury through augmentation of CXC chemokine production from alveolar epithelial cells[査読有り]研究論文（学術雑誌）
- An Open-Label, Multi-Institutional, Randomized Study to Evaluate the Additive Effect of a Leukotriene Receptor Antagonist on Cough Score in Patients with Cough-Variant Asthma Being Treated with Inhaled CorticosteroidsCough-variant asthma is one of the most common reasons for chronic cough. It is important to treat appropriately cough-variant asthma because 30% to 40% of cough-variant asthma becomes a typical asthma. However, little is known about the treatment of cough-variant asthma except for inhaled corticosteroid (ICS). The aim of this study was to validate the additive efficacy of a leukotriene receptor antagonist (LTRA) on cough score and respiratory function in patients with cough-variant asthma being treated with ICS. A total 28 patients were randomly assigned to either an ICS + LTRA group or an ICS group. There were statistically significant improvements in cough scores in the ICS + LTRA group from 0 weeks (6.7 ± 4.4) to 2 weeks (2.9 ± 3.2) (P < 0.05), 4 weeks (0.7 ± 1.1) (P < 0.001), and 8 weeks (0.8 ± 1.2) (P < 0.001). However similar improvements were not evident in the ICS group from 0 weeks (6.7 ± 4.4) to 2 weeks (5.6 ± 10.0) (P = 0.59), 4 weeks (4.6 ± 7.6) (P = 0.32), and 8 weeks (2.9 ± 5.2) (P = 0.08). On the other hand, no significant changes were evident in the forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC). In conclusion, the LTRA was useful in improving cough in patients with cough-variant asthma, even though it appeared to be ineffective in improving respiratory function.2018年12月, Kobe J Med Sci, 64(4) (4), E134 - E139, 英語, 国内誌[査読有り]研究論文（大学，研究機関等紀要）
- BACKGROUND: Sphingosine kinase phosphorylates sphingosine to generate sphingosine 1 phosphate (S1P) following stimulation of the five plasma membrane G-protein-coupled receptors. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells. METHODS: The effects of S1P on asthma-related genes expression were examined with the human bronchial epithelial cells BEAS-2B and Calu-3 using a transcriptome analysis and siRNA of S1PRs. To clarify the role of CCL20 in the airway inflammation, BALB/c mice were immunized with ovalbumin (OVA) and subsequently challenged with an OVA-containing aerosol to induce asthma with or without intraperitoneal administration of anti-CCL20. Finally, the anti-inflammatory effect of VPC 23019, S1PR1/3 antagonist, in the OVA-induced asthma was examined. RESULTS: S1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells. The knock-down of SIPR3 suppressed the expression of S1P-inducing CCL20. Anti-CCL20 antibody significantly attenuated the eosinophil numbers in the bronchoalveolar lavage fluid (P<0.01). Upon OVA challenge, VPC23019 exhibited substantially attenuated eosinophilic inflammation. CONCLUSIONS: S1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells. Our results suggest that S1P/S1PR3 may be a possible candidate for the treatment of bronchial asthma.2018年09月, PLoS One, 13(9) (9), e0203211, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3. A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors however, these patients did not have HDR syndrome. A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T> C (p.C318R) germline mutation in GATA3. This is the first report describing cancer in a patient with HDR syndrome. Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer.Dove Medical Press Ltd., 2018年03月, OncoTargets and Therapy, 11, 1595 - 1599, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Bronchoscopy Using Virtual Navigation and Endobronchial Ultrasonography with a Guide Sheath (EBUS-GS) with or without Fluoroscopy for Peripheral Pulmonary LesionsOBJECTIVE: Endobronchial ultrasonography and guide sheath (EBUS-GS) technique has high diagnostic yield in lung nodules. Virtual bronchoscopic navigation (VBN) can lead bronchoscope to the target bronchi. The aim of this prospective study was to compare the diagnostic yield of two bronchoscopic procedures: bronchoscopy under EBUS-GS and VBN with or without x-ray fluoroscopy in small peripheral pulmonary lesions (PPLs, ≤30mm) with apparent CT-bronchus sign. METHODS: 31 patients with PPLs which had apparent CT-bronchus sign were randomly assigned to the X-ray or the non-X-ray groups (18 with and 13 without fluoroscopy) between September 1, 2012, and September 30, 2015. A bronchoscope was introduced into the target bronchus using the VBN system. Sites of specimen sampling were verified using EBUS-GS with or without fluoroscopy. RESULTS: The overall diagnostic yield was 83.3% in the X-ray and 69.2% in the non-X-ray group. The diagnostic yield of malignancy was 88.2% and 81.8%, respectively. The duration of the examination and time elapsed until the first EBUS visualization were similar in the X-ray and the non-X-ray group (9.0 (5.8-20.) min vs 11.0 (5.3-17.3) min, and 2.5 (1.3-14.2) min vs 4.1 (1.4-8.1) min, respectively). The fluoroscopy exposure time was 3.7 (2.9-10.56) min. The only adverse event was mild pneumothorax in a patient from the non-X-ray group, who had consequent TBB under fluoroscopy. CONCLUSIONS: There was a possibility that VBN-guided EBUS-transbronchial diagnosis without fluoroscopy might be equivalent to that under fluoroscopy. Further multi-center randomized study may be desired. (UMIN000008592).2018年03月, Kobe J Med Sci, 63(4) (4), E99 - E104, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- Background Nivolumab improves the survival of advanced non-small cell lung cancer (NSCLC), but a significant number of patients still fail to benefit from this treatment. In this study, we evaluated the efficacy of the time-series behavior of neutrophil-to-lymphocyte ratio (NLR) in a complete blood count from advanced NSCLC patients as a predictive marker of the anticancer effect of nivolumab. Methods We performed a retrospective review of medical records and collected data on patients with advanced NSCLC treated with nivolumab as second- and further-line treatments from December 2015 to March 2017. The NLRs were calculated before each treatment cycle for four cycles. These parameters were tested for its association with the overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF). Results Nineteen patients were treated with nivolumab. Stratified by the response to nivolumab, the median OS was 2.8 months in progressive disease (PD) and 14.0 months in non-PD (p = 0.002). Before discontinuation of PD or toxicity, an NLR is rising from baseline in 5 out of 7 patients with PD and all of 4 patients with discontinuation due to toxicity. Patients with an > 30% increase in NLR were associated with a significantly shorter TTF compared with those with stable or decrease in NLR both after first cycle (p = 0.014) and second cycle (p < 0.001). Conclusions The NLR is suggested to be useful not only as a prognostic marker but also as a predictive marker for treatment with nivolumab. Further prospective study is warranted to develop a predictive algorithm to detect PD cases as early as possible by focusing the time-series behavior of NLR.Public Library of Science, 2018年02月, PLoS ONE, 13(2) (2), e0193018, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the Epidermal growth factor receptor (EGFR) was treated with EGFR-tyrosine kinase inhibitors (TKIs) and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone. The patient showed neither disease progression nor a recurrence of ILD at 5 months. In situations in which no alternative treatment is available, osimertinib rechallenge should thus be considered as an alternative treatment.Japanese Society of Internal Medicine, 2018年, Internal Medicine, 57(1) (1), 91 - 95, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2017年12月, 肺癌, 57(7) (7), 884 - 884, 日本語当科の非小細胞肺癌に対するニボルマブの治療成績に関する検討
- (NPO)日本肺癌学会, 2017年09月, 肺癌, 57(5) (5), 460 - 460, 日本語
- 2017年07月, Cancer science, 108(7) (7), 1368 - 1377[査読有り]
- In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor-tyrosine kinase inhibitor-induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR-mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 M gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell-related markers by quantitative RT-PCR and the expression of the cellular senescence-associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem-like cell targeting drug, withaferin A. Drug-tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem-like cells (CSCs) and the other with the properties of therapy-induced senescent (TIS) cells. The CD133(high) cell population had CSC properties and the CD133(low) cell population had TIS properties. The CD133(low) cell population containing TIS cells showed a senescence-associated secretory phenotype that supported the emergence of the CD133(high) cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133(low) cell population. Withaferin A effectively eliminated the CD133(high) cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib-resistant tumor growth.WILEY, 2017年07月, CANCER SCIENCE, 108(7) (7), 1368 - 1377, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2017年06月, 肺癌, 57(3) (3), 240 - 240, 日本語当科でのEGFR遺伝子変異陽性肺癌における再生検についての検討
- (NPO)日本肺癌学会, 2017年06月, 肺癌, 57(3) (3), 243 - 243, 日本語オシメルチニブに起因する薬剤性間質性肺炎発症後にステロイド内服下でのオシメルチニブ再投与が奏効した1例
- (一社)日本睡眠学会, 2017年06月, 日本睡眠学会定期学術集会プログラム・抄録集, 42回, 212 - 212, 日本語閉塞性睡眠時無呼吸症候群(OSA)患者における減量とAHIの改善の関連
- (一社)日本アレルギー学会, 2017年05月, アレルギー, 66(4-5) (4-5), 606 - 606, 日本語
- (一社)日本アレルギー学会, 2017年05月, アレルギー, 66(4-5) (4-5), 624 - 624, 日本語
- Background/Aim: Amrubicin (AMR) has shown promising activity for lung cancer. However, little is known about the mechanism underlying resistance to this agent. The aim of this study was to elucidate the mechanism underlying resistance to AMR. Materials and Methods: We first developed amrubicinol (AMR-OH)-resistant cell lines (H520/R and DMS53/R) by exposing lung cancer cell lines (H520 and DMS53) to increasing concentrations of AMROH and performed functional analysis by using these cell lines. Results: Transcriptome analyses showed that amphiregulin (AREG) was the most highly up-regulated gene in both AMR-OH-resistant cell lines compared to parent cells. Conditioned medium from DMS53/R cells reduced the sensitivity to AMR-OH in DMS53 cells. In contrast, DMS53/R cells transfected with siRNA directed against AREG recovered their sensitivity to AMR-OH. An additional administration of cetuximab with amrubicinol also restored the sensitivity to AMR-OH. Conclusion: Amphiregulin plays an important role in resistance to AMR-OH.INT INST ANTICANCER RESEARCH, 2017年05月, ANTICANCER RESEARCH, 37(5) (5), 2225 - 2231, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本結核・非結核性抗酸菌症学会, 2017年02月, 結核, 92(2) (2), 244 - 244, 日本語
- (NPO)日本肺癌学会, 2016年12月, 肺癌, 56(7) (7), 1077 - 1078, 日本語悪性黒色腫の肺転移と思われた1例[査読有り]
- Background: Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that acts as a signal transducer by binding to S1P receptors (S1PR) 1 to 5. The S1P/S1PRs pathway has been associated with remodeling and allergic inflammation in asthma, but the expression pattern of S1PR and its effects on non-immune cells have not been completely clarified. The aim of this study was to examine the contribution of the signaling of S1P and S1PRs expressed in airway epithelial cells (ECs) to asthma responses in mice. Methods: Bronchial asthma was experimentally induced in BALB/c mice by ovalbumin (OVA) sensitization followed by an OVA inhalation challenge. The effects of S1PR antagonists on the development of asthma were analyzed 24 h after the OVA challenge. Results: Immunohistological analysis revealed S1PR1-3 expression on mouse airway ECs. Quantitative real-time polymerase chain reaction demonstrated that S1P greatly stimulated the induction of CCL3 and TIMP2 mRNA in human airway ECs, i.e., BEAS-2B cells, in a dose-dependent manner. Pretreatment with the S1PR2 antagonist JTE013 inhibited the CCL3 gene expression in BEAS-2B cells. Immunohistological analysis also showed that the expression level of CCL3 was attenuated by JTE013 in asthmatic mice. Furthermore, JTE013 as well as anti-CCL3 antibody attenuated allergic responses. Intratracheal administration of JTE013 also attenuated eosinophilic reactions in bronchoalveolar lavage fluids. S1P induced transcription factor NF kappa B activation, while JTE013 greatly reduced the NF kappa B activation. Conclusions: JTE013 attenuated allergic airway reactions by regulating CCL3 production from bronchial ECs. The intratracheal administration of JTE013 may be a promising therapeutic strategy for bronchial asthma.BIOMED CENTRAL LTD, 2016年11月, RESPIRATORY RESEARCH, 17(1) (1), 146 - 146, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (NPO)日本呼吸器内視鏡学会, 2016年09月, 気管支学, 38(5) (5), 449 - 449, 日本語
- (一社)日本呼吸器学会, 2016年03月, 日本呼吸器学会誌, 5(増刊) (増刊), 223 - 223, 日本語
- (NPO)日本肺癌学会, 2015年08月, 肺癌, 55(4) (4), 317 - 317, 日本語肺癌と鑑別を要した炎症性結節の1例
- (NPO)日本肺癌学会, 2015年02月, 肺癌, 55(1) (1), 78 - 78, 日本語肺癌手術材料で腫瘍との鑑別が求められる粘液化生を認めた2例
- 2014年10月, 肺癌, 54(5号) (5号), 479, 日本語当科における若年者肺癌の検討研究論文（その他学術会議資料等）
- BACKGROUND: Phospholipase Cε (PLCε) is an effector of Ras and Rap small GTPases and expressed in non-immune cells. It is well established that PLCε plays an important role in skin inflammation, such as that elicited by phorbol ester painting or ultraviolet irradiation and contact dermatitis that is mediated by T helper (Th) 1 cells, through upregulating inflammatory cytokine production by keratinocytes and dermal fibroblasts. However, little is known about whether PLCε is involved in regulation of inflammation in the respiratory system, such as Th2-cells-mediated allergic asthma. METHODS: We prepared a mouse model of allergic asthma using PLCε+/+ mice and PLCεΔX/ΔX mutant mice in which PLCε was catalytically-inactive. Mice with different PLCε genotypes were immunized with ovalbumin (OVA) followed by the challenge with an OVA-containing aerosol to induce asthmatic response, which was assessed by analyzing airway hyper-responsiveness, bronchoalveolar lavage fluids, inflammatory cytokine levels, and OVA-specific immunoglobulin (Ig) levels. Effects of PLCε genotype on cytokine production were also examined with primary-cultured bronchial epithelial cells. RESULTS: After OVA challenge, the OVA-immunized PLCεΔX/ΔX mice exhibited substantially attenuated airway hyper-responsiveness and broncial inflammation, which were accompanied by reduced Th2 cytokine content in the bronchoalveolar lavage fluids. In contrast, the serum levels of OVA-specific IgGs and IgE were not affected by the PLCε genotype, suggesting that sensitization was PLCε-independent. In the challenged mice, PLCε deficiency reduced proinflammatory cytokine production in the bronchial epithelial cells. Primary-cultured bronchial epithelial cells prepared from PLCεΔX/ΔX mice showed attenuated pro-inflammatory cytokine production when stimulated with tumor necrosis factor-α, suggesting that reduced cytokine production in PLCεΔX/ΔX mice was due to cell-autonomous effect of PLCε deficiency. CONCLUSIONS: PLCε plays an important role in the pathogenesis of bronchial asthma through upregulating inflammatory cytokine production by the bronchial epithelial cells.2014年09月, PLoS One, 9(9) (9), e108373, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (NPO)日本肺癌学会, 2014年08月, 肺癌, 54(4) (4), 243 - 243, 日本語腸型が疑われた肺腺癌の1例
- The purpose is to examine the synergistic effect of pemetrexed (PEM) and amrubicin (AMR) on the proliferation of lung cancer cell lines. In vitro, dose-dependent synergistic effects of concurrent PEM and AMRol, which is an active metabolite of AMR were observed in A549 and H460 cells. In real-time RT-qPCR analysis and western blotting, expression of the target enzymes of PEM were suppressed in cells treated with amrubicinol alone. In vivo, AMR/PEM treatment also showed synergistic antitumor activity both in A549-bearing and H520-bearing mice. PEM and AMR work synergistically to inhibit the proliferation of several different lung cancer cell lines.2014年02月, Cancer Lett, 343(1) (1), 74 - 9, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2013年03月, 日本呼吸器学会誌, 2(増刊) (増刊), 338, 日本語当院における局所麻酔下胸腔鏡検査症例の検討[査読有り]研究論文（その他学術会議資料等）
- An open-label, prospective clinical study to evaluate the efficacy of prophylactic antibiotics after diagnostic bronchoscopyThe aim of this study was to prospectively examine the effect of prophylactic antibiotic use on the development of respiratory infections and on the worsening of symptoms after diagnostic fiberoptic bronchoscopy procedures. This study was an open-label, multicenter, controlled, clinical trial. Patients were alternately assigned to a group given prophylactic antibiotics after bronchoscopy (prophylaxis(+) group) and a group not given antibiotic prophylaxis after bronchoscopy (prophylaxis(-) group), and they were followed-up for 1 week. 158 patients were assigned to the prophylaxis(-) group and 153 to the prophylaxis(+) group. Therapeutic antibiotic administration was needed in 3 patients (1.90%) in the prophylaxis(-) group and 5 patients (3.27%) in the prophylaxis(+) group (risk ratio 1.014, 95% confidence interval 0.978-1.052; p=0.446). Worsening of symptoms after bronchoscopy occurred in 57.6% of all patients by day 7, but no significant differences were observed between the 2 study groups. Prophylactic antibiotic use after bronchoscopy did not prevent the development of infectious events and worsening of symptoms, suggesting that prophylactic antibiotics might not be necessary for routine diagnostic bronchoscopic procedures.2012年12月, Kobe J Med Sci, 58(4) (4), E110 - 8, 英語, 国内誌[査読有り]研究論文（大学，研究機関等紀要）
- (NPO)日本肺癌学会, 2012年10月, 肺癌, 52(5) (5), 724 - 724, 日本語当科における傍腫瘍性神経症候群合併小細胞肺癌の臨床的検討
- There have been no reports describing acute exacerbations of idiopathic pulmonary fibrosis after particle radiotherapy for non-small cell lung cancer. The present study describes the case of a 76-year-old Japanese man with squamous cell carcinoma of the lung that relapsed in the left upper lobe 1 year after right upper lobectomy. He had been treated with oral prednisolone 20 mg/day every 2 days for idiopathic pulmonary fibrosis, and the relapsed lung cancer was treated by proton beam therapy, which was expected to cause the least adverse effects on the idiopathic pulmonary fibrosis. Fifteen days after the initiation of proton beam therapy, the idiopathic pulmonary fibrosis exacerbated, centered on the left upper lobe, for which intensive steroid therapy was given. About 3 months later, the acute exacerbation of idiopathic pulmonary fibrosis had improved, and the relapsed lung cancer became undetectable. Clinicians should be aware that an acute exacerbation of idiopathic pulmonary fibrosis may occur even in proton beam therapy, although proton beam therapy appears to be an effective treatment option for patients with idiopathic pulmonary fibrosis.2012年10月, Jpn J Clin Oncol, 42(10) (10), 965 - 9, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Graft-versus-host-disease (GVHD) with erythroderma can rarely occur in the context of thymoma and is associated with a poor prognosis due to an increased risk of infection-related death. The present study describes a case of a 50-year-old man with malignant thymoma who developed sepsis in addition to skin manifestations similar to that seen in GVHD. This patient experienced marked improvement in skin lesions in response to steroids and combination chemotherapy with carboplatin and paclitaxel, with subsequent resolution of infection. The present study describes the clinical course of this patient, followed by a review of pertinent reports of thymoma associated with GVHD with particular focus on the efficacy of treatment strategies.2011年05月, BMJ Case Rep, 2011, pii: bcr0320113936, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- A 73-year-old Japanese man was histologically diagnosed with lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor. The patient was treated with gefitinib for 6 weeks until he developed substantially elevated hepatic enzyme levels that resulted in the discontinuation of gefitinib. Gefitinib was reintroduced with an intermittent treatment schedule after the transaminase levels normalized, but the patient's enzyme levels rose again, and the cancer progressed. Gefitinib was eventually replaced with erlotinib. There was stable disease for 7 weeks without any signs of liver toxicity. Thus, erlotinib may be a beneficial and well-tolerated treatment option for patients with gefitinib-related hepatotoxicity.2011年, Case reports in pulmonology, 2011, 812972 - 812972, 英語, 国際誌研究論文（学術雑誌）
- Long-term outcome after multidisciplinary approach for leptomeningeal carcinomatosis in a non-small cell lung cancer patient with poor performance statusThe present study describes a case of a 60-year-old Japanese man who was histologically diagnosed with lung adenocarcinoma harboring L858R mutation of epidermal growth factor receptor. He was successfully treated with gefitinib, but eventually developed leptomeningeal carcinomatosis. He underwent ventriculoperitoneal shunting for hydrocephalus and received erlotinib in place of gefitinib with concurrent whole brain radiotherapy; this resulted in dramatic improvement in his symptoms and performance status from four to one and he survived for as long as 13.6 months after the initiation of erlotinib therapy. This multidisciplinary approach may be particularly useful in terms of increasing survival and improving quality of life.2011年, Internal medicine (Tokyo, Japan), 50(24) (24), 3019 - 22, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC-1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1-treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation.2010年12月, International journal of cancer, 127(11) (11), 2699 - 706, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: It has been demonstrated that NK012, a novel 7-ethyl-10-hydroxycamptothecin (SN-38)-incorporating polymeric micelle, exerts significantly more potent antitumor activity against various human tumor xenografts than irinotecan (CPT-11) (a water-soluble prodrug of SN-38). Combination therapy of anticancer agents with bevacizumab (Bv), an anti-vascualr endothelial growth factor humanized monoclonal antibody, has more potently inhibited tumor growth than either agent alone. In the current study, the authors examined the antitumor effect of NK012 in combination with Bv against human lung cancer. METHODS: Nude mice bearing lung adenocarcinoma (PC-14 or A549 xenografts) were administered NK012 at SN-38-equivalent doses of 5 mg/kg or 30 mg/kg in combination with or without Bv at 5 mg/kg. CPT-11 at a dose of 66.7 mg/kg was administered with or without Bv at a dose of 5 mg/kg in the same experimental model. To evaluate interaction with Bv, the pharmacokinetics and microvessel density in tumors that were treated on each regimen were analyzed. RESULT: In vitro, the growth-inhibitory effect of NK012 was 50-fold more potent than that of CPT-11 and was almost equivalent to that of SN-38. In vivo studies revealed that the combination of NK012 plus Bv had significantly greater antitumor activity against human lung cancer xenografts compared with NK012 alone (PC-14, P=.0261; A549, P<.001). The pharmacokinetic profile of NK012 revealed that coadministration of Bv did not interfere with the accumulation of NK012. CONCLUSIONS: In this study, significant antitumor activity was noted with NK012 in combination with Bv against lung cancer cells. The current results warrant the clinical evaluation of NK012 in lung cancer.2010年10月, Cancer, 116(19) (19), 4597 - 604, 英語, 国際誌研究論文（学術雑誌）
- There has been no report about re-challenge chemotherapy (RC) consisting of the same regimen as first-line chemotherapy in non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy of RC as second-line chemotherapy in patients with relapsed NSCLC. We conducted a retrospective review of 28 consecutive NSCLC patients who were treated with RC and compared their clinical outcomes with those of 38 consecutive NSCLC patients who were treated with docetaxel (DOC) at our hospital between July 1992 and December 2003. The RC group consisted of 21 men and 7 women, with a median age of 62 years (range, 42-76 years). Most first-line regimens were platinum-based and the median administered course was 3 (range, 2-7). All patients had responded to the first-line chemotherapy and had performance status (PS) 1 at relapse. The median interval from the end of first-line chemotherapy to relapse was 5.0 months (range, 1.6-36.1 months). The overall response rate of RC was 29%. The median survival time from the beginning of RC was 17.0 months and the 1-year survival rate was 60%. RC led to a significantly better overall survival rate than DOC (p=0.0342). RC could be an active second-line regimen in patients with relapsed NSCLC who responded to first-line chemotherapy.2010年09月, Lung cancer (Amsterdam, Netherlands), 69(3) (3), 315 - 8, 英語, 国際誌研究論文（学術雑誌）
- (一社)日本呼吸器学会, 2010年03月, 日本呼吸器学会雑誌, 48(増刊) (増刊), 366 - 366, 日本語
- Lung adenocarcinoma with a micropapillary component (MPC) is an aggressive subtype of adenocarcinoma with a papillary component. The aim of this study was to explore the pathobiological properties of a papillary component which generates MPC. We reviewed the 445 cases of resected primary lung adenocarcinoma and confirmed all of the MPC(+) cases (n=150) were found only in the cases of adenocarcinoma with a papillary component (n=228) and no features of the MPC were detected in any of the other histological subtypes without papillary component. Even in the cases of adenocarcinoma with a papillary component, the MPC(+) group (n=150) had significantly poorer outcome than the MPC(-) group (n=78) (P<0.0001). When this MPC(+) cases were divided into grade 0-2 according to the proportion of the tumor occupied by the MPC, the stage I patients with grade 2 MPC had a significantly poorer outcome than the stage I patients with grade 0 or grade 1 MPC. By considering the histological characteristics that MPC has always structural continuity with papillary component, we evaluated the pathobiological profile of (1) MPC, (2) papillary component which generate MPC [PC MPC(+)], and (3) papillary component without MPC [PC MPC(-)]. The mean width of the stalks in the PC MPC(+) was significantly smaller than in the PC MPC(-) (17.64+/-9.53 vs. 26.07+/-10.16mum, P<0.001). Although staining for CD34 and collagen IV showed that MPC lacked both fibrovascular stalks and basement membranes, staining for cleaved caspase 3 showed that apoptotic cells were rare in the MPC (1.0%), and the expression levels of the adhesion molecules E-cadherin, beta-catenin, and CD44 were similar in all three lesions. The immunohistochemical staining scores of hypoxic marker GLUT-1 in the MPC, PC MPC(+), and PC MPC(-) were 69, 26, and 8.6, respectively, and the differences between the MPC and PC MPC(+) and between the PC MPC(+) and PC MPC(-) were significant (P=0.001 and 0.025, respectively). These results indicated that the biological behavior of the papillary component which generates MPC is different from the papillary component without MPC in terms of structural alternation and hypoxic state, and the difference may be related to the aggressive behavior of MPC(+) adenocarcinoma.2010年03月, Lung cancer (Amsterdam, Netherlands), 67(3) (3), 282 - 9, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To investigate the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with cisplatin [cis-dichlorodiammineplatinum (II) (CDDP)] in mice bearing a small cell lung cancer xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity. EXPERIMENTAL DESIGN: Cytotoxic effects were evaluated in human small cell lung cancer cell lines [H69, H82, and vascular endothelial growth factor (VEGF)-secreting cells (SBC-3/VEGF and its mock transfectant SBC-3/Neo)]. In vivo antitumor effects were evaluated in SBC-3/Neo-bearing and SBC-3/VEGF-bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined. RESULTS: The in vitro growth-inhibitory effects of NK012 were 198- to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT-11/CDDP treatments (P = 0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice but were commonly observed in CPT-11-treated mice. Moreover, a large amount of CPT-11 was excreted into the feces and high CPT-11 concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium. CONCLUSIONS: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity and therefore warrants further clinical evaluation.2009年07月, Clinical cancer research : an official journal of the American Association for Cancer Research, 15(13) (13), 4348 - 55, 英語, 国際誌研究論文（学術雑誌）
- The aim of this study was to identify clinicopathological and biological prognostic markers for patients who had undergone complete resection of pathological stage IB squamous cell carcinoma (SqCC) of the lung. A total of 136 consecutive stage IB SqCC patients fulfilled eligibility criteria, and their clinicopathological factors were evaluated. Tissue microarrays were also constracted, and immunohistochemical staining with 24 antibodies was performed. Correlations between clinicopathological factors, antibody immunohistochemical reactions, the patients' overall survival (OS) and relapse-free survival (RFS) were evaluated. The univariate analysis showed that 70-year-old and over elderly group had a shorter OS time and RFS time than the younger group (p=0.0086 and p=0.0091, respectively). The univariate analysis for immunohistochemical staining showed that the podoplanin-negative group had a shorter OS time and RFS time than the podoplanin-positive group (p=0.0106 and p=0.0308, respectively). Multivariate analysis revealed a significant correlation between both the 70-year-old and over elderly group and the podoplanin-negative group and poor outcome (OS, p=0.007 and p=0.008, respectively; RFS, p=0.008 and p=0.024, respectively). The results showed that patient age and a novel biological prognostic marker, podoplanin, are useful for predicting a poor outcome of patients after complete resection of stage IB SqCC of the lung.2009年03月, Lung cancer (Amsterdam, Netherlands), 63(3) (3), 418 - 24, 英語, 国際誌研究論文（学術雑誌）
- Recent studies have reported increased podoplanin expression by cancer cells and stromal cells, but little is known about its expression and biological significance in adenocarcinoma of the lung. We examined podoplanin expression by both cancer cells and stromal cells in 177 consecutive lung adenocarcinoma cases and analyzed relations between podoplanin expression and both clinicopathological factors and outcome. Podoplanin expression was observed on the apical membrane of the cancer cells in only 9 of the 177 (5.1%) cases. By contrast, cancer-associated fibroblasts (CAFs) were found to express podoplanin in 54 cases (30.5%). Podoplanin (+) CAFs were found only in invasive adenocarcinoma and none were found in noninvasive adenocarcinoma. Conventional prognostic factors were significantly correlated with podoplanin expression by CAFs. The univariate analyses and log-rank test showed that podoplanin expression was significantly associated with shorter survival time (p < 0.001 and p < 0.001, respectively). We divided the cases into 3 groups according grade based on the proportion of CAFs expressing podoplanin [a grade 0 group (n = 123), a grade 1 group (n = 36) and a grade 2 group (n = 18)]. The result showed that conventional prognostic factors were significantly correlated with the grade of podoplanin expression by CAFs. Furthermore, the grade 2 group tended to have a shorter survival time than the grade 1 group (p = 0.092). The results of this study highlight the importance of podoplanin expression by CAFs and provide new insights into the biology of the cancer microenvironment in adenocarcinoma of the lung.2008年09月, International journal of cancer, 123(5) (5), 1053 - 9, 英語, 国際誌研究論文（学術雑誌）
- (一社)日本アレルギー学会, 2024年12月, アレルギー, 73(10) (10), 1219 - 1219, 日本語
- (有)科学評論社, 2024年11月, 呼吸器内科, 46(5) (5), 470 - 471, 日本語【睡眠関連呼吸障害の呼吸器的新展開】特発性肺線維症と睡眠関連呼吸障害
- 2024年, 日本呼吸器学会誌(Web), 13睡眠時無呼吸症候群(SAS)における酸素飽和度の波形分類ごとの解析
- 2024年, 日本呼吸器学会誌(Web), 13ウエアラブル呼吸センサの性能評価のための前向き観察試験
- 2023年, 日本睡眠学会定期学術集会プログラム・抄録集, 45thいびき音のディープラーニングによる睡眠時無呼吸症候群のスクリーニング
- Recently, the microbiome has been gaining traction as a major player regulating various functions that correlate with many pathological conditions, including cancer. The central gut microbiota population has the capability to regulate normal inflammatory, immune, and metabolic functions, and disturbance in the balance of the normal microbiota population can subsequently induce pathological responses that closely relate with the mechanistic development and progression of cancer in various forms and sites. As a disease with major socioeconomic burden partly due to its current therapeutic options, modulating the imbalanced gut microbiota represents a novel option not only as an adjuvant therapy to relieve cancer treatment–related symptoms but also to influence cancer progression itself. In this review, we will discuss how the microbiome, specifically the gut microbiota, could affect cancer pathogenesis and what the effect of gut microbiota–targeting treatment options have on the many aspects of cancer pathologies based on the knowledge of recent years.SAGE Publications Inc., 2020年, Integrative Cancer Therapies, 19, 1534735420920721 - 1534735420920721, 英語, 国際誌
- 2020年, 日本呼吸器学会誌(Web), 9IPF患者における夜間低酸素血症の病型分類の確立
- (NPO)日本肺癌学会, 2019年11月, 肺癌, 59(6) (6), 772 - 772, 日本語Pseudo-progressionをきたした非小細胞肺癌4例と好中球・リンパ球比の変化についての検討
- (NPO)日本肺癌学会, 2019年11月, 肺癌, 59(6) (6), 860 - 860, 日本語根治的化学放射線治療後の維持療法としてのデュルバルマブ投与例の検討
- (NPO)日本肺癌学会, 2019年11月, 肺癌, 59(6) (6), 902 - 902, 日本語再発・進行非小細胞肺癌に対する二次治療以降の免疫チェックポイント阻害薬投与例の検討
- (一社)日本アレルギー学会, 2019年09月, アレルギー, 68(8) (8), 970 - 970, 日本語アレルギー用語解説シリーズ エンドタイプ
- (NPO)日本肺癌学会, 2019年08月, 肺癌, 59(4) (4), 416 - 416, 日本語ペムブロリズマブにより腱滑膜炎をきたした1例
- (一社)日本アレルギー学会, 2019年05月, アレルギー, 68(4-5) (4-5), 499 - 499, 日本語アレルゲン・抗原 農業関連喘息の原因物質と考えられる新規野菜抗原の同定
- (一社)日本アレルギー学会, 2019年05月, アレルギー, 68(4-5) (4-5), 499 - 499, 日本語アレルゲン・抗原 農業関連喘息の原因物質と考えられる新規野菜抗原の同定
- (一社)日本結核病学会, 2019年03月, 結核, 94(3) (3), 248 - 248, 日本語
- (一社)日本呼吸器学会, 2019年03月, 日本呼吸器学会誌, 8(増刊) (増刊), 150 - 150, 日本語重症喘息 治療 Xenon肺換気CTで評価した気管支サーモプラスティによる換気改善効果
- (一社)日本呼吸器学会, 2019年03月, 日本呼吸器学会誌, 8(増刊) (増刊), 162 - 162, 日本語肺癌 基礎 アダパレンのヒト表皮細胞における炎症性サイトカイン産生調節と細胞増殖促進によるエルロチニブ誘発皮膚障害の抑制効果
- Smoking causes various diseases and is a major public health threat worldwide. Therefore, promoting smoking cessation is the most important intervention contributing to maintaining the health of smokers and nonsmokers and saving enormous financial expense. We reviewed existing and emerging smoking-cessation pharmacotherapies from the Cochrane Database of Systemic Reviews, PubMed, Ovid, and ClinicalTrials.gov databases. A literature review revealed that bupropion may be appropriate for patients interested in reducing smoking who dislike, or who have failed, nicotine-replacement therapy (NRT). Additionally, varenicline and NRT are efficacious first-line smoking cessation treatments and should be given to all individuals unless contraindicated. The reviews of this paper are available via the supplementary material section.SAGE Publications Ltd, 2019年, Therapeutic Advances in Respiratory Disease, 13, 1753466619875925 - 1753466619875925, 英語, 国際誌
- Lung cancer is the leading cause of cancer death worldwide. Molecular targeted therapy has greatly advanced the field of treatment for non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancers. Indeed, gefitinib, which was the first molecular targeted therapeutic agent, has actually doubled the survival time of NSCLC patients. Vigorous efforts of clinicians and researchers have revealed that lung cancer develops through the activating mutations of many driver genes including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), and rearranged during transfection (RET) genes. Although ALK, ROS1, and RET are rare genetic abnormalities, corresponding tyrosine kinase inhibitors (TKIs) can exert dramatic therapeutic effects. In addition to anticancer drugs targeting driver genes, bevacizumab specifically binds to human vascular endothelial growth factor (VEGF) and blocks the VEGF signaling pathway. The VEGF signal blockade suppresses angiogenesis in tumor tissues and inhibits tumor growth. In this review, we also explore immunotherapy, which is a promising new NSCLC treatment approach. In general, antitumor immune responses are suppressed in cancer patients, and cancer cells escape from the immune surveillance mechanism. Immune checkpoint inhibitors (ICIs) are antibodies that target the primary escape mechanisms, immune checkpoints. Patients who respond to ICIs are reported to experience longlasting therapeutic effects. A wide range of clinical approaches, including combination therapy involving chemotherapy or radiation plus adjuvant therapy, are being developed.2018年12月, Curr Cancer Drug Targets, 19(8) (8), 595 - 630, 英語, 国際誌[査読有り]
- Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib-a third-generation EGFR-TKI-targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial⁻mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.2018年11月, Cells, 7(11) (11), 英語, 国際誌[査読有り]
- (NPO)日本肺癌学会, 2018年10月, 肺癌, 58(6) (6), 457 - 457, 日本語間質性肺炎合併肺癌の治療 間質性肺炎合併肺癌における抗PD-1抗体による間質性肺炎増悪のリスク因子の検討
- (NPO)日本肺癌学会, 2018年10月, 肺癌, 58(6) (6), 545 - 545, 日本語免疫チェックポイント阻害薬で治療したPD-L1陽性肺癌に対する好中球リンパ球比の検討
- (NPO)日本肺癌学会, 2018年10月, 肺癌, 58(6) (6), 641 - 641, 日本語免疫チェックポイント阻害剤投与例における赤血球容積粒度分布幅の有用性
- 日本職業・環境アレルギー学会, 2018年07月, 日本職業・環境アレルギー学会雑誌, 26(1) (1), 90 - 90, 日本語
- (一社)日本呼吸器学会, 2018年03月, 日本呼吸器学会誌, 7(増刊) (増刊), 231 - 231, 日本語ブレオマイシン誘導肺線維症マウスモデルにおけるPLCεの役割
- (一社)日本呼吸器学会, 2018年03月, 日本呼吸器学会誌, 7(増刊) (増刊), 328 - 328, 日本語連続パルスオキシメトリーによる在宅酸素療法患者の夜間低酸素血症の調査
- AME Publishing Company, 2018年02月01日, Translational Cancer Research, 7(Suppl 1) (Suppl 1), S6 - S9, 英語[査読有り]記事・総説・解説・論説等（学術雑誌）
- (NPO)日本肺癌学会, 2015年08月, 肺癌, 55(4) (4), 316 - 316, 日本語ROS1融合遺伝子肺癌の1例
- (NPO)日本肺癌学会, 2015年02月, 肺癌(Web), 55(1) (1), 78(J‐STAGE) - 78, 日本語肺癌手術材料で腫瘍との鑑別が求められる粘液化生を認めた2例
- AMER THORACIC SOC, 2014年, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189, 英語Crucial Role Of Phospholipase C epsilon In T Helper Type 2 Cell Mediated Airway Inflammation In Mice研究発表ペーパー・要旨（国際会議）
- 日本DDS学会, 2008年05月, Drug Delivery System, 23(3) (3), 418 - 418, 日本語卵巣がんにおける核酸治療法の開発
- (NPO)日本肺癌学会, 2006年11月, 肺癌, 46(5) (5), 506 - 506, 日本語
- 分担執筆, 南江堂, 2011年02月, 日本語, ISBN: 9784524263486分子標的治療薬の副作用マネジメント
- 分担執筆, 篠原出版新社, 2008年03月, 日本語, ISBN: 9784884126179MOOK肺癌の臨床 : 『疫学』『病理・分子生物学』『発見・診断』『治療』『診断・治療』
- 分担執筆, 篠原出版新社, 2003年10月, 日本語, ISBN: 4884126130MOOK肺癌の臨床Annual Review : 疫学・発見・診断・治療
- 第58回 日本肺癌学会学術集会, 2018年11月, 日本語, 横浜, 国内会議免疫チェックポイント阻害薬で治療したPD-L1陽性肺癌に対する好中球リンパ球比の検討口頭発表（一般）
- 第59回 日本肺癌学会学術集会, 2018年11月, 日本語, 横浜, 国内会議免疫チェックポイント阻害剤投与例における赤血球容積粒度分布幅の有用性口頭発表（一般）
- 第27回Pneumo Forum, 2018年11月, 日本語, 東京, 国内会議農作業関連喘息の疫学調査とプロテオーム解析による原因抗原の同定口頭発表（招待・特別）
- 第61回 日本肺癌学会学術集会, 2018年11月, 日本語, 横浜, 国内会議間質性陰影合併肺癌における抗PD-1抗体による間質性陰影増悪のリスク因子の検討口頭発表（一般）
- Asian Pacific Society of Respirology 2018, 2018年11月, 英語, Taipei, 国際会議S1P/S1PR3 pathway has the role in eosinophilic airway inflammation via release of CCL20 from bronchial epithelial cellsポスター発表
- Asian Pacific Society of Respirology 2018, 2018年11月, 英語, Taipei, 国際会議Gemcitabine enhances anti-tumor activity of Paclitaxel by Modulating Tubulin Acetylation口頭発表（一般）
- 24th World Asthma Congress 2018, 2018年10月, 英語, INTERASTHMA Globa Asthma Association, Tokyo, 国際会議Xenon Ventilation Computed Tomography and Bronchial Thermoplasty for Asthma口頭発表（一般）
- 24th World Asthma Congress 2018, 2018年10月, 英語, Tokyo, 国際会議Occupational Lettuce-induced Respiratory Allergy口頭発表（一般）
- 19th world conference on lung cancer, 2018年09月, 英語, Toronto, 国際会議Nab-paclitaxel plus gemcitabine in advanced NSCLC after platinum-based chemotherapy: final results and caveolin-1 expression口頭発表（一般）
- 第49回職業・環境アレルギー学会, 2018年07月, 日本語, 横浜, 国内会議香川県中讃地区における農作業関連喘息に関しての検討口頭発表（一般）
- 第16回 日本臨床腫瘍学会学術集会, 2018年07月, 日本語, 神戸, 国内会議プラチナ製剤無効後の既治療非小細胞肺癌患者に対するweekly Nab-paclitaxelとGemcitabine併用療法の第II相試験口頭発表（一般）
- 第91回 日本呼吸器学会, 2018年07月, 日本語, 神戸, 国内会議アレクチニブによる治療中に神経内分泌癌へ形質転換したと考えられたALK融合遺伝子陽性肺腺癌の一例口頭発表（一般）
- 第58回日本呼吸器学会学術講演会, 2018年04月, 日本語, 大阪, 国内会議連続パルスオキシメトリーによる在宅酸素療法患者の夜間低酸素血症の調査ポスター発表
- 第58回日本呼吸器学会学術講演会, 2018年04月, 日本語, 大阪, 国内会議ブレオマイシン誘導肺線維症マウスモデルにおけるPLCεの役割ポスター発表
- European Lung Cancer Congress 2018, 2018年04月, 英語, Geneva, 国際会議A Phase II Trial of Nab-Paclitaxel and Gemcitabine in Patients with Non-Small-Cell Lung Cancer Previously Treated with Platinum Based Chemotherapy口頭発表（一般）
- 第90回日本呼吸器学会近畿地方会, 2017年12月, 日本語, 日本呼吸器学会, 大阪, 国内会議化学療法により症状の改善を認めたLambert-Eaton症候群合併肺小細胞癌の1例ポスター発表
- 第58回日本肺癌学会学術集会, 2017年10月, 日本語, 日本肺癌学会, 横浜, 国内会議Nivolumab投与例における末梢血好中球/リンパ球比(NLR)の変化とその有用性口頭発表（一般）
- 27 th ERS international congress, 2017年09月, 英語, European Respiratory Society, ミラノ, イタリア, 国際会議The clinical survey of lettuce-associated respiratory symptomsポスター発表
- 第216回日本内科学会近畿地方会, 2017年07月, 日本語, 日本内科学会, 大阪, 国内会議HDR症候群に肺扁平上皮癌を発症した1例口頭発表（一般）
- 日本睡眠学会第42回定期学術集会, 2017年06月, 日本語, 日本睡眠学会, 横浜, 国内会議閉塞性睡眠時無呼吸症候群における減量とAHIの改善ポスター発表
- 第106回日本肺癌学会関西支部学術集会, 2017年06月, 日本語, 日本肺癌学会, 大阪, 国内会議当科の非小細胞肺癌に対するニボルマブの治療成績に関する検討ポスター発表
- 第66回日本アレルギー学会学術大会, 2017年06月, 日本語, 日本アレルギー学会, 東京, 国内会議JTE013による気道上皮を介した喘息の抑制作用口頭発表（一般）
- 第66回日本アレルギー学会学術大会, 2017年06月, 日本語, 日本アレルギー学会, 東京, 国内会議2016年度喘息吸入薬の吸入指導に関するアンケート口頭発表（一般）
- 第105回日本肺癌学会関西支部学術集会, 2017年01月, 日本語, 日本肺癌学会, 大阪, 国内会議当科でのEGFR遺伝子変異陽性肺癌における再生検についての検討口頭発表（一般）
- 第105回日本肺癌学会関西支部学術集会, 2017年01月, 日本語, 日本肺癌学会, 大阪, 国内会議オシメルチニブに起因する薬剤性間質性肺炎発症後にステロイド内服下でのオシメルチニブ再投与が奏功した一例ポスター発表
- 第88回日本呼吸器学会近畿地方会, 2016年12月, 日本語, 日本呼吸器学会, 京都, 国内会議病因と考えられる肺炎を確認できたSwyer-James症候群の一例口頭発表（一般）
- 第88回日本呼吸器学会近畿地方会, 2016年12月, 日本語, 日本呼吸器学会, 京都, 国内会議肺移植後の経過でアスペルギルス症による喀血をきたした肺リンパ脈管筋腫症の一例口頭発表（一般）
- 第78回臨床アレルギー研究会（関西）, 2016年11月, 日本語, 臨床アレルギー研究会（関西）, 大阪, 国内会議農作業関連喘息が疑われた10例に関する検討口頭発表（一般）
- 第214回日本内科学会近畿地方会, 2016年11月, 日本語, 日本内科学会, 大阪, 国内会議胸水貯留で発症したIgG4関連肺疾患の1例口頭発表（一般）
- ERS International Congress 2016, 2016年09月, 英語, European Respiratory Society, London, UK, 国際会議A mouse model of acute lung injury implicates phospholipase Ce in neutrophilic inflammation through CXC chemokine productionポスター発表
- 第99回日本呼吸器内視鏡学会近畿支部会, 2016年07月, 日本語, 日本呼吸器内視鏡学会, 大阪, 国内会議気管支鏡により診断しえた炎症性筋線維芽細胞腫の一例口頭発表（一般）
- 第104回日本肺癌学会関西支部会, 2016年07月, 日本語, 日本肺癌学会, 大阪, 国内会議悪性黒色腫の肺転移と思われた1例ポスター発表
- 第14回日本臨床腫瘍学会学術集会, 2016年07月, 日本語, 日本臨床腫瘍学会, 神戸, 国内会議アファチニブ初回治療耐性後に再生検を施行した症例の検討ポスター発表
- 第56回日本呼吸器学会学術講演会, 2016年04月, 日本語, 日本呼吸器学会, 京都, 国内会議肺癌細胞株におけるアムルビシン耐性化機序の検討ポスター発表
- 第113回日本内科学会講演会, 2016年04月, 日本語, 日本内科学会, 東京, 国内会議腎移植後のタクロリムス内服中に反復する肺炎を来たし肺ノカルジア症と診断した1例ポスター発表
- 第56回日本呼吸器学会学術講演会, 2016年04月, 日本語, 日本呼吸器学会, 京都, 国内会議急性呼吸窮迫症候群におけるホスホリパーゼeの役割シンポジウム・ワークショップパネル（公募）
- 第56回日本呼吸器学会学術講演会, 2016年04月, 日本語, 日本呼吸器学会, 京都, 国内会議EGFR-TKI耐性クローンに対する糖代謝阻害剤，癌幹細胞治療薬の有効性についてポスター発表
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2021年04月01日 - 2024年03月31日KIAA1462/JCADを標的としたARDSの革新的治療法の開発急性呼吸窮迫症候群(ARDS)に対する現行の治療法は肺胞内の好中球炎症に対する抗炎症治療が主体であるが、生命予後を改善するまでには至っていない。本研究ではARDSの重要な病態の一つである肺血管内皮細胞の炎症、血管透過性に着目した。一般的に血管新生や血管透過性を制御すると考えられている血管新生分子であるVEGFや当研究科で同定し、機能解析を行ったJCAD/KIAA1462系分子群が、ARDSの病態においても、血管新生や血管透過性亢進による肺水腫の形成、炎症細胞の血管内から肺胞腔内への浸潤に関与していることを証明するとともに、血管内皮細胞と好中球の相互作用に、これらの分子が関与していることを想定して、その関連性を明らかにし、これらの血管新生や血管透過性を制御する分子が、ARDSの治療標的分子となり得るかについて、ARDSモデルマウスを用いて検討する。 まず、KIAA1462遺伝子欠損型（KO）マウスと野生型マウスを使用してLPS0.5㎎/㎏を経気道的に投与することでLPS誘導性ARDSマウスを作成する。試薬投与後24時間後に気管支肺胞洗浄（BAL）を行ったところ、白血球数とその分画に遺伝子型による違いは認めなかった。次に、肺血管透過性亢進をBAL液（BALF）中の蛋白量を測定することで評価したところ、JCAD KOマウスで透過した蛋白量が多い傾向があった。また、BALF中のmyeloperoxidase活性、TNF-α、IL-6、CXCケモカインを測定したが、TNF-αやIL-6はKOで高く、一方でICAM-1やVCAM-1など細胞間接着因子はKOで低かった。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2021年04月01日 - 2024年03月31日肺がん分子標的薬の選択を可能にする分子シミュレーションと数理モデルの解析系の確立本研究の目的は、肺がん分子標的薬であるEGFRチロシンキナーゼ阻害剤（EGFR-TKI）を１、２、３の世代別に分け、申請者らが既に進めている第１世代のゲフィチニブ以外の、エルロチニブ（第１世代）、アファチニブ（第２世代）、オシメルチニブ（第３世代）と各変異型EGFRとの薬物相互作用を、チロシンキナーゼ活性阻害の分子シミュレーション解析とその数理モデル化により解明し、各々の薬効予測法を確立することである。今回、本研究により変異型EGFRごとの最適な肺がん分子標的薬の選択指標を提供可能にする方法論の確立を目指す。 2021年度は、高速の計算機を購入し、解析に必要なプログラムを導入し、３世代全てに感受性を有する変異のうち未解析の5変異の構造を、ドッキング解析や数理モデル導出の実験用として解析した。なお、EGFRは二量体で各サブユニットの機能が異なる（レシーバーとアクティベータ）ため、単独変異と複数変異（cis）では1変異で(1)変異ホモ、(2) レシーバーが変異型のヘテロ、(3)アクティベータが変異型のヘテロの計3分子の解析が必要なため、実際には15種類の分子の解析を行なった。さらに、他の変異型の解析を進める準備も進めた。また、解析したEGFR変異型の構造を用いて、ゲフィチニブとのドッキング解析を進めることで、本研究のドッキング解析に用いる条件設定について検討を進めた。後に述べる理由で解析が少々遅れており、当初解析予定の変異型の半分程度の構造解析を完了した。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2020年04月01日 - 2023年03月31日食物アレルギーの抗原同定と診断・治療法の開発レタスはキク科の植物で職業性喘息、アナフィラキシー、花粉-食物アレルギー症候群等の原因となるが、その診断のための感度・特異度の高い検査は現時点では存在せず、減感作療法も確立していない。申請者はこれまでに質量分析装置を用いて、レタスによる職業性呼吸器アレルギーの原因抗原の同定に成功している。本研究では現在までの研究成果をもとに、アレルギーの診断キットを作成し、治療モデルを確立することが目的である。具体的には、①大腸菌を用いて組換えレタスアレルゲンを精製し、ELISAキットの底面に埋め込んでレタスアレルギー診断ELISAキットを作成する。さらに、②レタスアレルギーモデルマウスを作成し、経口免疫療法を行う。これらの成果はレタスアレルギー患者の診断率の向上や克服につながるのみならず、食物アレルギー全般の特異的診断方法の開発や、減感作療法による食物アレルギーの治療の開発につながることが期待される。 申請者の同定した34 kDaと51 kDaおよび未発表のXX kDaのアレルゲンタンパクをコードする遺伝子をゲノムデータベースの検索により特定し、配列特異的なプライマーを設計する。レタスから抽出したtotal RNAを逆転写して得られるcDNAを鋳型としてPCRにより増幅し、発現用ベクターに組み込み、大腸菌に形質転換する。ベクター内の遺伝子配列はシーケンス解析により確認する。大腸菌内で6xHisやGSTのタグを付けた組換えタンパク質としてアレルゲンを発現誘導し、集菌・抽出後にアフィニティカラムによる大量精製を行う。農学部の宇野雄一教授の協力のもと精製したXX kDaの組換えレタスアレルゲン液を100 μL/Wellずつ96 Well Plateに入れ、4℃で一晩固着させ、レタスアレルギーELISAキットを作成する。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2020年04月01日 - 2023年03月31日がん幹細胞と老化細胞を標的とした分子標的治療薬耐性の克服上皮成長因子受容体（EGFR）などの特定の遺伝子の変異によって生じる肺がんに対して、そのチロシンキナーゼ阻害剤（TKI）は劇的な効果を示すことが証明されたが、がん細胞がTKIに対して薬剤耐性を示すようになるため、根治は依然として不可能なままである。申請者らはEGFR-TKI投与後に残存する薬剤耐性クローン（DTPs；drug-tolerant persisters）ががん幹細胞と細胞老化を起こした細胞の少なくとも2種の異なる細胞群で形成されることを発見した。また、EGFR-TKIと同様、ALK-TKIにおいても、治療数年後に薬剤耐性の獲得が起こることが知られている。その薬剤耐性機序として、神経内分泌腫瘍への形質転換が起こることが双方のTKIで報告されている。本研究は、①薬剤耐性の機序として重要な、非小細胞肺がんから小細胞肺がんへの形質転換におけるがん幹細胞の役割や、②がん幹細胞から小細胞肺がんへ分化する機序を解明し、治療法の開発に結びつけることを主な目的としている。 申請者はALK-TKIにより形質転換が起こった組織で幹細胞のマーカーであるCD133やSOX-2と老化細胞のマーカーであるBCL-2を発現していることを発見した。 ALK-TKIでもDTPsと呼ばれる耐性クローンが誘導されるかをまず確認する。そのために、ALK遺伝子陽性肺がん細胞株H2228にALK-TKIとしてAlectinib（3 μM）を投与し、DTPsを作成する。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2020年04月01日 - 2023年03月31日PLCεを標的とした呼吸器疾患の新たな治療法の構築rasがん遺伝子産物Rasの標的蛋白質の一つであるホスホリパーゼCε (PLCε)は当研究科が発見し、セカンドメッセンジャーの産生を通じてシグナル伝達に関与し、またNF-κBを介する炎症や発がんに関与することを報告してきた。本研究の目的は、K-ras遺伝子変異陽性のNSCLCにおけるPLCεの役割を明らかにし、PLCεが治療標的になりうるかを明らかにすることである。ras誘導性のがんはヒトの悪性腫瘍の約20％と極めて高頻度に認められている。本研究成果は気管支喘息やNSCLCの新規治療法の開発に寄与するだけでなく、多くの炎症性疾患とK-ras遺伝子変異が関与する複数のがん種に応用展開され、生命予後を改善しうるものとして期待される。 まず、申請者の施設で飼育しているPLCεのKOマウスと、三重大学の鈴木昇准教授より提供を受け飼育を開始しているLSL-K-ras（LoxP-STOP-LoxP-K-RasG12V）マウスを交配させ、PLCε遺伝子改変K-ras（LSL-K-rasG12V/PLCεΔx/Δx）マウスモデルを作成した。 また並行して、ルイス肺がん由来細胞株による担がんマウスモデルを作成して、腫瘍増殖能、生存に与えるPLCεの遺伝子型の影響を調べた。これまでにPLCεの野生型16匹、ノックアウトマウス7匹について実験を行い、有意差には至っていないものの、PLCεの遺伝子ノックアウトマウスで腫瘍増殖が遅く、生存率が良い傾向があることが分かった。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2019年04月01日 - 2022年03月31日JCAD/KIAA1462のCOPDにおける役割の解明と治療法の開発近年行われたヒトゲノムワイド関連解析（GWAS）の結果、KIAA1462という遺伝子がCOPDと関連していることが報告された。当研究科では、KIAA1462が血管新生や細胞骨格形成に関係していることを世界に先駆けて明らかにしてきたが、COPDの疾患病態とKIAA1462の関係については詳細が明らかではない。本研究は、KIAA1462の遺伝子ノックアウト（KO）マウスを用いて、COPDにおけるKIAA1462の役割を明らかにするとともに、従来にない肺血管と肺胞壁構造を標的とした新規COPDの分子標的治療薬を開発することを目的としている。 まずは、申請者の施設で既に飼育している10週齢のKIAA1462遺伝子野生型（WT）マウスと、KOマウスにエラスターゼを経気道的に投与し、COPDモデルマウスを作成し、投与21日目の肺組織を摘出し、表現型を確認したところ、肺気腫の程度は差異を認めなかった。しかし、同標本で血管内皮細胞マーカーであるCD31で免疫染色を行ったところ、血管新生の程度はKOマウスで少ない印象であった。また、既述のCOPDモデルマウスに対し、同様に投与21日目に気管支肺胞洗浄（BAL）を施行したところ、BAL回収液の細胞分画はWT、KOマウスとも差異を認めずほとんどが分葉核球であったが、回収液の細胞数はWTで多い傾向であった。さらに、BAL施行後の肺組織でのVEGFの発現をqRT-PCRで確認したところ、WT、KOで差異は認めなかった。 本研究は、COPDの分子生物学的病態のさらなる理解と、それに伴う新しい治療アプローチができることにより、多くのCOPD患者の生命予後の改善に寄与することが期待される。
- 日本学術振興会, 学術研究助成基金助成金／基盤研究(C), 基盤研究(C), 神戸大学, 2018年04月 - 2021年03月粒径が0.1µm以下のナノ粒子（PM0.1）は肺胞まで到達し、その影響は全身へと波及することから、健康への影響が懸念されている。しかし、PM0.1が喘息の増悪や難治化に及ぼす影響は分かっておらず、本研究ではそれを明らかにする。 まず、粒子状物質の分級サンプリングが可能なナノサンプラーⅡ（Kanomax）を用い、2019年2月7日から2月12日の5日間、東京都新宿区において計640.5µgのPM0.1を回収した。次に、マウス喘息モデルの作成およびPM0.1の経鼻投与実験を行った。すなわち、OVA（卵白アルブミン）10µg/匹と水酸化アルミニウム1mg/匹をDay1とDay8に腹腔注射してOVAに感作させたマウスに、PM0.1 10µg/匹とOVA 200µg/匹をDay14,15,16に経鼻投与し、Day17に気管支肺胞洗浄液を採取した（PM0.1群）。OVA群、PBS群では、Day14,15,16にOVAのみ、ないしPBSのみを投与した。気道炎症の評価として気管支肺胞洗浄液の総細胞数、好酸球数の解析をしたところ、PM0.1群およびOVA群ではPBS群に比して有意な上昇を認めたが、PM0.1群とOVA群の間に差を認めなかった。また、上記のPM0.1群とOVA群に対して、Day14, 15, 16の経鼻投与1時間前にステロイド（デキサメタゾン20µg/匹）を腹腔注射する治療実験も行った。ステロイド投与により、PM0.1群、OVA群ともに総細胞数、好酸球数の減少を認めたが、ステロイドへの反応性は2群間で有意な差を認めなかった。 上記の結果、PM0.1と喘息の増悪や難治化には関係性がみられない可能性があるが、粒子径の違いにより気道炎症の程度に差が生じる可能性があり、引き続きPM2.5やPM10といった粒径のより大きな物質との比較検討を行う予定である。競争的資金
- 日本学術振興会, 学術研究助成基金助成金／基盤研究(C), 基盤研究(C), 神戸大学, 2017年04月 - 2020年03月, 研究代表者74名の患者のパラフィン包埋ブロックを用いて、スパイラルアレイブロックを作成した。まず、骨髄細胞に高発現しており、自然免疫で中心的な役割を果たしており、近年、癌における役割が注目されているCaspase recruitment domain-containing protein 9 (CARD9)に着目して、免疫染色を行ったところ、CARD9を高発現している症例は肺腺がん全体の32.4%に見られ、低発現しているものより有意に予後不良であった（P = 0.0402）。また、単変量解析、多変量解析にてCARD9の高発現は肺腺がんの独立した予後不良因子であることが分かった。競争的資金
- 日本学術振興会, 学術研究助成基金助成金／基盤研究(C), 基盤研究(C), 神戸大学, 2017年04月 - 2020年03月気管支サーモプラスティは、重症喘息患者に対して行われる気管支鏡下の治療手技である。しかしながら、直接的な治療機序の解明はされていない。気管支サーモプラスティは3週おきに①右下葉枝、②左下葉枝、③両上葉枝の順に計3回に分けて高周波電流治療を施行するため、気管支サーモプラスティ1回目の前、2回目の前、3回目の前、3回目終了6週間後の計4回、喘息コントロールテスト、Xenon肺換気CT検査、呼気NO検査、呼吸機能検査を施行し、改善程度を評価した。4人の患者で、エアトラッピングの程度は治療を行った上下葉のみならず中葉でも改善が見られた。競争的資金
- 日本学術振興会, 科学研究費助成事業 若手研究(B), 若手研究(B), 神戸大学, 2016年04月01日 - 2019年03月31日本研究の目的は、エルロチニブ誘導性の皮膚障害に対するアダパレンの治療効果および作用メカニズムを明らかにすることである。エルロチニブによる皮膚障害はエルロチニブとTNFα、IL1βおよびHaCaT細胞を使って再現した。まずエルロチニブを投与した時のサイトカインの変化として、CCL2、CCL27およびIL8の有意な発現上昇が見れらた（P<0.05）。次にエルロチニブ誘導性のIκBαとp65のリン酸化はアダパレンにより抑制された。また、NFκBを阻害するRARγの発現がアダパレンにより増加していた。
- 日本学術振興会, 科学研究費助成事業 若手研究(B), 若手研究(B), 神戸大学, 2016年04月01日 - 2019年03月31日スフィンゴシン1リン酸は様々な生体反応を調整している。本研究の目的は、スフィンゴシン1リン酸とその受容体の関係をヒトの気管の初代培養細胞とマウスの実験モデルを用いて明らかにすることであった。まず、BEAS 2B細胞とCalu 3細胞をスフィンゴシン1リン酸で刺激をしてトランスクリプトーム解析を行ったところ、CCL20の発現更新が見られた。続いてスフィンゴシン1リン酸受容体3型をノックダウンすると、CCL20の発現が減少した。喘息のマウスモデルでは、スフィンゴシン1リン酸受容体1型と3型のアンタゴニストであるVPC23019やCCL20抗体で喘息の表現型が抑制された。
- 日本学術振興会, 学術研究助成基金助成金／基盤研究(C), 基盤研究(C), 神戸大学, 2016年04月 - 2019年03月レタス栽培時に生じる呼吸器症状の実態調査と抗原タンパクの同定を行った。1168人のレタス栽培従事者にアンケート調査を行い、呼吸器症状があり、同意の得られた患者を対象に臨床検査を行った。その結果、932人（79.8%）から回答が得られ、6.8%にレタス誘発性の呼吸器症状がみられた。14人の患者の協力が得られ、健常人群に比較して患者群で有意な活性化好中球の増加が見られた（P<0.05）。SDS PAGEと免疫ブロッティングにより、患者血清中のレタス抗原特異的IgEと結合するレタスタンパクとして2種類の抗原タンパクの同定に成功した。競争的資金
- 日本学術振興会, 学術研究助成基金助成金／基盤研究(C), 基盤研究(C), 神戸大学, 2014年04月 - 2017年03月ホスホリパーゼCε（PLCε）は低分子量GTP 蛋白質Ras/Rap の標的タンパク質である。好中球性の気道炎症におけるPLCεの役割を明らかにするため、PLCεのノックアウト（KO）マウスを用いてLPS誘導性の急性肺障害マウスモデルを作成した。PLCεの野生型（WT）のマウスに比較してKOマウスでは肺胞腔内への炎症細胞の浸潤や肺組織のCXCファミリーのケモカインのmRNAの発現が著名に低下していた。以上からPLCεが上皮からのCXCケモカインの産生を介して好中球性の気道炎症に重要な役割を果たしていることが示唆された。PLCεはARDSの重要な分子標的となりうると考えられた。競争的資金
- 日本学術振興会, 科学研究費助成事業 若手研究(B), 若手研究(B), 神戸大学, 2014年04月01日 - 2016年03月31日ホスホリパーゼCε（PLCε）は低分子量GTP 蛋白質Ras/Rap の標的タンパク質である。本研究は、PLCεの遺伝子改変マウスとブレオマイシン誘導性肺線維症モデルを用いて、肺線維症におけるPLCεの役割を明らかにすることを目的としている。病理組織学的に、PLCε欠損マウスでは、炎症細胞の浸潤やコラーゲンの沈着が著明に抑制されていることを明らかにした。また、PLCεの欠損により、気管支肺胞洗浄液中の好中球やリンパ球の増加が抑制されることが明らかとなった。以上より、PLCεは好中球やリンパ球を介する肺線維症の形成に重要な役割を果たしていることが示唆された。
- 日本学術振興会, 学術研究助成基金助成金／基盤研究(C), 基盤研究(C), 神戸大学, 2013年04月 - 2016年03月アムルビシンにより耐性を誘導した肺がん細胞株では、EGFRのリガンドであるアンフィレグリンの遺伝子の発現が亢進していることが明らかとなった。アンフィレグリンはアムルビシンに対する感受性を低下させる一方で、アムルビシン耐性株のアンフィレグリンの発現をsiRNAによりノックダウンすると、アムルビシンに対する感受性が回復した。セツキシマブにもsiRNAと同様の効果を認めた。競争的資金
- 日本学術振興会, 科学研究費助成事業 若手研究(B), 若手研究(B), 神戸大学, 2012年04月01日 - 2014年03月31日ホスホリパーゼCepsilon（PLCepsilon）は低分子量GTP 蛋白質Ras/Rap の標的タンパク質で、非免疫細胞に高発現している。本研究の目的は、PLCepsilonの遺伝子改変マウスと喘息モデルを用いて、呼吸器免疫におけるPLCepsilonの役割を明らかにすることである。PLCepsilon欠損マウスでは、気道過敏性の亢進や気管支血管周囲の炎症細胞の浸潤が著明に抑制され、ヘルパーT細胞2型のサイトカインや、気道上皮細胞からのサイトカインの産生が抑制されることが明らかとなった。PLCepsilonは少なくともTh2を介する呼吸器免疫に重要な役割を果たしていることが示唆された。