Language：Japanese   Publisher：(NPO)日本肺癌学会  

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A 59-year-old woman presented with a rash on the top part of her hands and pain in the wrist joint and was diagnosed with dermatomyositis complicated by interstitial pneumonia positive for anti-melanoma differentiation-associated gene 5 (MDA-5) antibody. However, the patient reported a severe headache following treatment with oral prednisolone and tacrolimus. Posterior reversible encephalopathy syndrome (PRES) was diagnosed based on the brain magnetic resonance imaging findings. Tacrolimus was discontinued, and mycophenolate mofetil was instead administered with a favorable outcome. Mycophenolate mofetil should therefore be considered as an alternative treatment for anti-MDA-5-positive interstitial lung disease in cases where calcineurin inhibitors cannot be used.

DOI： 10.2169/internalmedicine.3533-24

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

症例は,X-7年から再発性多発軟骨炎に対して,ブレドニゾロン(PSL),メトトレキサート,トシリズマブで加療されていた64歳男性。X年2月に鼻中隔穿孔,皮疹の増悪を認め,PSL増量の後,X年3月,当院に入院。PSLをさらに増量し加療されたが,その後,発熱,左足趾潰瘍,左膝関節炎を認め,左足MR1では骨髄炎の合併を認めた。血液培養,左足趾擦過培養,左膝関節穿刺培養からMycobacterium chelonaeが発育。免疫抑刷薬の投与を背景に,M.chelonaeによる皮膚感染を侵入門戸とした骨髄炎,血流感染,敗血症性化膿性左膝関節炎と診断,複数の抗菌薬で加療を開始した。重症薬疹を発症し薬剤を変更するも,最終的には抗菌菌2剤での治療で軽快し,その後,再燃は認めていない。M.chelonaeは迅速発育抗酸菌,環境常在菌である。確立した治療法はなく,過去の報告,感受牲を参考に,複数の抗菌薬での冶療が推奨される。皮膚軟部組織感染症の報告は多数認める一方で,血流感染の報告は少なく死亡率も高い。本症例は抗菌化学療法で指趾温存および救命できた重要な症例と思われ報告する。(著者抄録)

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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

The primary objective of this study was to identify the predominant organisms associated with ventilator-associated pneumonia (VAP) in Japan. Studies on VAP conducted in Japan were systematically reviewed, and seven studies with a total of 374 cases were included. The detection rate of each bacterium and multidrug-resistant (MDR) pathogen was analyzed using the inverse variance method. Pseudomonas aeruginosa was identified as the predominant pathogen in 29.2 % of cases, followed by methicillin-resistant Staphylococcus aureus (MRSA) (12.0 %), and Klebsiella spp. (9.5 %). An integrated analysis revealed a detection rate of 57.8 % (95 % confidence interval: 48.7%-66.8 %) for MDR pathogens. This review highlights P. aeruginosa and MRSA as the predominant VAP-associated organisms in Japan, with a significant prevalence of MDR pathogens. This analysis provides valuable insights based on the regional distribution of bacteria detected in VAP, which is critical for selecting appropriate empirical therapy.

DOI： 10.1016/j.resinv.2024.01.012

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Aspergillus-specific antibodies are diagnostic indicators of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Tests for detecting Aspergillus-specific antibodies were not used clinically in Japan, and the production of the Aspergillus precipitin test was discontinued. Thus, alternative tests for diagnosing aspergillosis are urgently needed. We retrospectively evaluated 64 patients with suspected ABPA and CPA who underwent precipitin antibody testing. Serum Aspergillus IgG levels were measured and compared using the Bordier Aspergillus fumigatus ELISA and the Platelia Aspergillus IgG (Bio-Rad) kits. Of the participants, 18 were diagnosed with CPA, and 8 were diagnosed with ABPA. Both the Bordier and Bio-Rad kits showed high sensitivity and specificity for CPA and ABPA. The area under the receiver operating characteristic curves for the Bordier and Bio-Rad kits were 0.97 and 0.95, respectively, for CPA, and 0.89 and 0.91, respectively, for ABPA. In contrast to the Bordier kit, the Bio-Rad kit showed relatively low anti-Aspergillus IgG levels and lower sensitivity to non-fumigatus Aspergillus infections. The Aspergillus-specific IgG ELISA tests showed sufficient diagnostic accuracy. Therefore, these assays are recommended as alternatives to the precipitin kit for diagnosing aspergillosis in clinical settings in Japan.

DOI： 10.3314/mmj.24.00004

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INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.

DOI： 10.1016/j.ejca.2023.113469

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

The close relationship between infectious diseases and iron metabolism is well known, but a more detailed understanding based on current knowledge may provide new insights into the diagnosis and treatment of infectious diseases, considering the growing threat of antibiotic-resistant bacteria. This study investigated adult patients with bloodstream infections, temporal changes, and relationships between blood levels of iron and related markers, including hepcidin and lipocalin-2 (LCN2). We included 144 samples from 48 patients (mean age 72 years, 50% male), with 30 diagnosed with sepsis. During the acute phase of infection, blood levels of hepcidin and LCN2 increased rapidly, whereas iron levels decreased, with values in 95.8% of cases below the normal range (40–188 μg/dL). Later, hepcidin and LCN2 decreased significantly during the recovery phase, and the decreased iron concentrations were restored. In the case of persistent inflammation, iron remained decreased. Acute LCN2 levels were significantly higher in patients with sepsis (p < 0.01). Hypoferremia induced by increased hepcidin would reduce iron in the environment of extracellular pathogens, and the increased LCN2 would inhibit siderophores, resulting in the prevention of the pathogen’s iron acquisition in each manner during the acute phase of bloodstream infection.

DOI： 10.1038/s41598-023-46383-7

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Other Link： https://www.nature.com/articles/s41598-023-46383-7

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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INTRODUCTION: A study is eagerly awaited that will reveal the unknown mechanisms of multiple system atrophy (MSA), in which the risk of sudden death is the greatest during sleep. The blunted pulse response to nocturnal respiratory events suggests an abnormal cardiac response to a sleep-related breathing disorder. Patients with MSA have a lower pulse event index (PEI), despite a greater hypoxic burden and a similar frequency of respiratory events. However, the evidence is speculative and not directly proven, and many limitations require further study. METHODS: We conducted a retrospective analysis of 26 patients with MSA who had undergone overnight oximetry between April 2016 and December 2022. RESULTS: The median 4% oxyhemoglobin desaturation index (ODI) was 11.6/h, the 6-bpm PEI was 8.9/h, and the PEI/ODI ratio was as low as 0.91. There were three patients with suspected sudden death; all had low PEI/ODI ratios. The PEI/ODI ratio was followed over time in seven patients, all of whom had a decrease in the ratio. However, the PEI was higher than the ODI in 12/26 (46%) of the patients. CONCLUSION: A low PEI/ODI ratio, reflecting a blunted pulse response to nocturnal respiratory events in patients with MSA, may indicate a worse prognosis. This finding and the significance of the longitudinal decrease in the PEI/ODI ratio will require a prospective study.

DOI： 10.1016/j.parkreldis.2023.105817

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Publisher：株式会社 医学書院  

DOI： 10.11477/mf.1437200659

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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BACKGROUND: Lung transplant (LTx) recipients are at higher risk of infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). There is an increasing demand for additional analysis regarding the efficacy and safety of after the initial series of mRNA SARS-CoV-2 vaccines in Japanese transplant recipients. METHOD: In this open-label, nonrandomized prospective study carried out at Tohoku University Hospital, Sendai, Japan, LTx recipients and controls received third doses of either the BNT162b2 or the mRNA-1273 vaccine, and the cellular and humoral immune responses were analyzed. RESULTS: A cohort of 39 LTx recipients and 38 controls participated in the study. The third dose of SARS-CoV-2 vaccine promoted much greater humoral responses at 53.9 % of LTx recipients than after the initial series at 28.2 % of patients without increasing the risk of adverse events. However, still fewer LTx recipients responded to the SARS-CoV-2 spike protein with the median IgG titer of 129.8 AU/mL and with the median IFN-γ level of 0.01 IU/mL when compared to controls with those of 7394 AU/mL and 0.70 IU/mL, respectively. CONCLUSION: Although the third dose of mRNA vaccine in LTx recipients was effective and safe, impaired cellular and humoral responses to SARS-CoV-2 spike protein were noted. Given lower antibody production and establishing vaccine safety, repeating the administration of mRNA vaccine will lead to robust protection in such a high-risk population (jRCT1021210009).

DOI： 10.1016/j.vaccine.2023.06.011

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BACKGROUND: Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. METHODS: We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-β-d-glucosaminidase (NAG). RESULTS: In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). CONCLUSIONS: Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

DOI： 10.1016/j.sleep.2023.03.028

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BACKGROUND: This multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus pemetrexed 500 mg/m2 for four cycles and maintenance therapy of osimertinib 80 mg QD with pemetrexed 500 mg/m2 every 3 weeks. The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS). RESULTS: In total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. At the data cutoff (28th February 2022), 35 (52.2%) patients had discontinued the protocol treatment, including 10 (14.9%) due to adverse events. No treatment-related deaths occurred. In the full analysis set, the ORR, CRR, and DCR were 90.9% (95% confidence interval [CI], 84.0-97.8), 3.0% (0.0-7.2), and 97.0% (92.8-100.0), respectively. Based on updated survival data (data cutoff on August 31, 2022, median follow-up time: 33.4 months), the median PFS was 31.0 months (95% CI, 26.8 months-not reached) and median overall survival was not reached. CONCLUSIONS: This is the first study to show that OPP has excellent efficacy with acceptable toxicity in previously untreated EGFR-mutated advanced non-squamous NSCLC patients.

DOI： 10.1016/j.ejca.2023.02.023

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Nasal breathing disorders are associated with obstructive sleep apnea (OSA) syndrome and influence the availability of continuous positive airway pressure (CPAP) therapy. However, information is scarce about the impact of nasal resistance assessed by rhinomanometry on CPAP therapy. This study aimed to examine the relationship between CPAP adherence and nasal resistance evaluated by rhinomanometry, and to identify clinical findings that can affect adherence to CPAP therapy for patients with OSA. This study included 260 patients (199 men, 61 women; age 58 [interquartile ranges (IQR) 50-66] years) with a new diagnosis of OSA who underwent rhinomanometry (before, and 1 and 3 months after CPAP introduction) between January 2011 and December 2018. CPAP use was recorded, and the good and poor CPAP adherence groups at the time of patient registration were compared. Furthermore, those with improved and unimproved pre-CPAP high rhinomanometry values were also compared. Their apnea-hypopnea index (AHI) by polysomnography at diagnosis was 45.6 (IQR 33.7-61.6)/hour, but the residual respiratory event (estimated AHI) at enrollment was 2.5 (IQR 1.4-3.9)/hour and the usage time was 318 (IQR 226-397) minutes, indicating that CPAP was effective and adherence was good. CPAP adherence was negatively correlated with nasal resistance (r = -0.188, p = 0.002). The participants were divided into good (n = 153) and poor (n = 107) CPAP adherence groups. In the poor adherence group, rhinomanometry values before CPAP introduction were worse (inspiration, p = 0.003; expiration, p = 0.006). There was no significant difference in patient background when comparing those with improved (n = 16) and unimproved (n = 12) pre-CPAP high rhinomanometry values. However, CPAP usage time was significantly longer in the improved group 1 month (p = 0.002) and 3 months (p = 0.026) after CPAP introduction. The results suggest that nasal resistance evaluated by rhinomanometry is a useful predictor of CPAP adherence, and that improved rhinomanometry values may contribute to extending the duration of CPAP use.

DOI： 10.1371/journal.pone.0283070

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DOI： 10.3389/fonc.2023.1240926

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Small-cell lung cancer (SCLC) is characterized by aggressive disease progression and tendency to metastasize. Although chemotherapy for extensive-stage SCLC (ES-SCLC) has remained unchanged for decades, immune checkpoint inhibitors have become the primary therapy for ES-SCLC. However, the number of patients benefiting from immunotherapy is limited, and the treatment outcomes remain unsatisfactory. In addition, predictive biomarkers for immunotherapy have not yet been identified. Recent reports have shed light on the genomics of SCLC and defined four distinct molecular subtypes based on transcription factor expression. This may increase our understanding of the biology of SCLC and identify novel therapeutic targets and drugs. In this article, we review the current standard management of ES-SCLC and present the most recent reports to further our understanding of molecular classification, predictive biomarkers, and prospective therapies, including immunotherapy, chemotherapy, and targeted therapy.

DOI： 10.2147/OTT.S272552

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INTRODUCTION: Benralizumab, an anti-interleukin-5 receptor chain monoclonal antibody, is used to treat severe asthma and control asthma symptoms or exacerbations. The aim of this study was to examine the changes in airway morphology using computed tomography (CT) images in accordance with clinical efficacy following the administration of benralizumab. METHODS: The clinical efficacy of benralizumab was evaluated in 11 patients with severe asthma by analyzing the changes in parameters, such as the asthma control test, asthma quality of life questionnaire, pulmonary function, and exacerbation count. We also investigated the airway wall thickness of the right bronchus (B1) and the total airway count (TAC) using CT images. RESULTS: Most patients treated with benralizumab showed improvements in asthma symptoms and exacerbations. CT imaging analyses showed a decrease in the right B1 airway wall thickness and an increase in the TAC. Correlations between blood eosinophil count and changes in CT imaging were observed. DISCUSSION/CONCLUSION: The data suggested that benralizumab has the potential to improve airway wall thickening and ventilation by alleviating the obstruction and clearing an obstructed airway.

DOI： 10.1159/000525846

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INTRODUCTION: Mucus plugs are associated with airway obstruction in severe asthma and are involved in the formation of activated eosinophils. Benralizumab, an anti-interleukin-5 receptor antibody, markedly reduces not only peripheral blood eosinophils but also airway eosinophils; however, its effects on mucus plugs have not been clarified. In this study, we examined the efficacy of benralizumab on mucus plugs using computed tomography (CT) imaging. METHODS: Twelve patients who were administered benralizumab and underwent CT before and approximately 4 months after the introduction of benralizumab were included in this study, and the number of mucus plugs before and after benralizumab administration was compared. The correlation between the clinical background and treatment effect was also examined. RESULTS: The number of mucus plugs significantly decreased after the introduction of benralizumab. The number of mucus plugs was correlated with sputum eosinophil percentage and eosinophil cationic protein in the sputum supernatants and inversely correlated with forced expiratory volume in 1 s (FEV1). Benralizumab induction resulted in a marked decrease in blood and sputum eosinophil levels and a significant improvement in asthma symptoms, quality of life scores, FEV1, and exacerbation frequency. Furthermore, there was a significant correlation between the reduction in mucus plugs and changes in the symptom score or FEV1. DISCUSSION/CONCLUSION: These data suggest that benralizumab may have the potential to improve symptoms and respiratory function in patients with severe eosinophilic asthma by reducing mucus plugs.

DOI： 10.1159/000530392

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BACKGROUND: Previous phase III study has demonstrated that osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI), exhibits superior antitumor effects compared to first-generation EGFR-TKIs and successfully prolonged overall survival (OS) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Although first- and second-generation EGFR-TKIs are risk factors for venous thromboembolism (VTE), whether osimertinib increases the VTE risk remains unclear. In addition, no treatment strategy exists for patients with VTE during osimertinib. Here we present the clinical course of three patients with suspected osimertinib-induced VTE who were successfully treated with direct oral anticoagulation without recurrence VTE during osimertinib therapy. CASE DESCRIPTION: Three male patients, aged 66-74 years, with NSCLC harboring EGFR mutations had been treated with osimertinib as the first- and second-line treatments, and developed VTE. All patients responded to osimertinib, and none showed disease progression at VTE onset. All patients were treated with direct oral anticoagulation and could resume osimertinib treatment. The progression-free survival (PFS) from VTE onset in each of the three cases was 11.4+, 7.7, and 6.1 months, respectively. The OS from VTE onset was 11.4+, 26.0, and 25.9+ months, respectively. CONCLUSIONS: We report the cases of three NSCLC patients who developed VTE during osimertinib. Osimertinib may cause VTE and should be used cautiously. In such cases, osimertinib treatment may be continued with direct oral anticoagulation therapy.

DOI： 10.21037/tlcr-22-419

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Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

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Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

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BACKGROUND: Although the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined. We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs. METHODS: We retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021. RESULTS: This analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 (95% CI: 2.7-4.2) and 10 (95% CI: 7.4-14.8) months, respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 (95% CI: 1.1-4.0) vs. 4.2 (95% CI: 2.3-4.8) months, P=0.1142, OS; 10.0 (95% CI: 5.2-14.8) vs. 10.4 (95% CI: 3.8-NE) months, P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events. CONCLUSIONS: AMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.

DOI： 10.21037/tlcr-22-225

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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INTRODUCTION: This study aimed to examine the factors associated with cytomegalovirus (CMV) antigenemia and the time of onset of CMV antigenemia among patients with rheumatic diseases. METHODS: A single-center, retrospective, observational study was conducted in our institution from January 2009 to December 2017. This study included patients with rheumatic diseases who had at least one CMV antigen measurement. Multivariate analysis and receiver operating characteristic analysis was performed. RESULTS: A total of 249 patients underwent CMV antigenemia assay, and 84 (33.7%) patients tested positive. When the association between CMV antigenemia and possible associated factors was investigated, multivariate analysis showed that daily steroid dose increased the odds of having CMV [odds ratio 16.25, 95% confidence interval (CI), 5.360-49.253]. In this study, the cutoff value of daily steroid dose found in this study (0.45 mg/kg/day) was reasonable in clinical practice, and the area under the curve of the steroid dose was 0.838 [95% CI 0.781-0.882], which was the largest of the known indicators. Moreover, the median time from the start of immunosuppressive therapy to the onset of CMV antigenemia was 30 (interquartile range, 21-44) days, and most of the daily steroid users (85.7%) developed CMV antigenemia within 60 days. CONCLUSIONS: The daily steroid dose is the most important factor associated with CMV antigenemia. Therefore, monitoring and treatment strategies based on the steroid dose, especially in the initial 2 months, are important.

DOI： 10.1016/j.jiac.2022.07.004

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BACKGROUND: This multicenter, open-label, single-arm phase II study [Niigata Lung Cancer Treatment Group (NLCTG) 1302] was conducted to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy for previously treated patients with advanced non-small cell lung cancer (NSCLC). We also investigated chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the quality of life (QOL). METHODS: Sixty-five patients with advanced NSCLC from 14 participating institutions who had previously undergone one or two cytotoxic chemotherapy regimens were enrolled in this study. The patients received 100 mg/m2 nab-paclitaxel intravenously on days 1, 8, and 15, every 4 weeks. The primary endpoint was overall objective response rate. CIPN symptoms were prospectively assessed using the Patient Neurotoxicity Questionnaire (PNQ) and Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: The overall response rate (ORR) was 18.5% [95% confidence interval (CI): 10.9-29.6%], and the median progression-free survival (PFS) was 3.4 (95% CI: 2.5-4.3) months. Median overall survival (OS) was 8.6 (95% CI: 7.1-10.2) months. The most common non-hematologic grade ≥3 adverse events were infection (7.7%) and hyponatremia (4.6%). Neutropenia was the most common grade 3 or 4 adverse event (30.8%), and febrile neutropenia developed in 6.2% patients. The PNQ and CTCAE scores for motor peripheral neuropathy were low (kappa =0.10). CONCLUSIONS: The primary endpoint was achieved. Nab-paclitaxel was well tolerated and showed anti-tumor activity in patients with previously treated NSCLC. This study demonstrates a low degree of concordance in CIPN grading between physicians and patients. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000012343).

DOI： 10.21037/tlcr-22-89

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We herein report a 45-year-old-man with multiple foreign body granulomas in the lungs caused by polytetrafluoroethylene (PTFE). A mass in the right lower lobe of the lung and bilateral centrilobular lung nodules were found unexpectedly during the patient's visit to a hospital for a respiratory infection. The patient's occupation for 26 years involved spraying PTFE. A lung biopsy using bronchoscopy revealed granulomatous lesions and giant cells. The presence of fluorine in the granulomatous lesions was confirmed using an electron probe microanalyzer with wavelength dispersive spectrometer. Fluorine is a component of PTFE and is not found in normal lung tissue.

DOI： 10.2169/internalmedicine.9008-21

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INTRODUCTION: Influenza remains a clinically heavy burden worldwide. It is well known that some populations are at high risk of complications from influenza, whereas, even previously healthy people might suffer from severe influenza. The objective of this study was to clarify clinical manifestations of hospitalized patients without risk factors infected with influenza. METHODS: The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2020 (6 influenza seasons) using an internet-surveillance system. Among them, the patients who had no risk factors of complications from influenza were extracted. RESULTS: Finally, a total of 91 patients (9.0% of all influenza-related hospitalizations) without risk factors were analyzed. The no risk group was younger than the risk group, though other significant differences of clinical characteristics were not recognized between the groups. Pneumonia was the most common cause of hospitalization in the no risk group, and primary influenza viral pneumonia was the most common pneumonia. Antiviral drugs were administered in 96.7% of the no-risk group, and artificial ventilation was performed in 18.7%. In-hospital death was recorded for 3 patients without risk factors. CONCLUSIONS: Severe complications of influenza which required hospitalization may occur in a certain degree of patients with no risk factors. Efforts are needed to diagnose and treat influenza appropriately even in previously healthy younger patients. Continuous nationwide surveillance will be required to clarify risk factors for severe influenza even in previously healthy younger patients. (UMIN000015989).

DOI： 10.1016/j.jiac.2022.02.001

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DOI： 10.1016/j.alit.2022.03.005

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The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).

DOI： 10.1038/s41598-022-10288-8

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Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.

DOI： 10.1038/s41698-022-00254-y

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Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows great clinical activity in non-small cell lung cancer (NSCLC) patients with EGFR mutations regardless of T790M mutation at first-line chemotherapy. Previous studies demonstrated that there are few patients with initial resistance to osimertinib. Here, we describe a case to report the efficacy of afatinib in an EGFR-mutated NSCLC patient with early progression to first-line osimertinib treatment. A 68-year-old Japanese male was diagnosed with stage IVB lung adenocarcinoma with the EGFR L858R mutation in exon 21. Two months after the start of osimertinib, his tumor progressed at the initial response evaluation. Because he refused to receive cytotoxic chemotherapy, afatinib treatment was initiated. He was administered afatinib, and the tumor shrank. After five months of afatinib treatment, nevertheless the primary tumor was not enlarged, he experienced disease progression with leptomeningeal metastasis and passed away. To elucidate the resistance mechanisms of osimertinib in this patient, we performed next-generation sequencing (NGS) on tumor samples from pleural effusions after osimertinib failure. NGS revealed no specific gene mutations causing resistance to osimertinib except for the EGFR L858R mutation; however, his tumor had a relatively high tumor mutational burden. Afatinib is considered an option for EGFR-mutated patients with early progression to osimertinib.

DOI： 10.21037/tcr-21-1850

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BACKGROUND: Procalcitonin (PCT) is a serological marker whose utility has been established in infectious disease areas. Although serum calcitonin is a prognostic predictor in patients with medullary thyroid carcinoma, the clinical usefulness of PCT remains unclear in lung cancer patients. METHODS: As a discovery cohort, we retrospectively analyzed consecutive patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) who received first-line chemotherapy at our institution, and PCT blood levels were measured. As the validation cohort, PCT blood levels were prospectively evaluated in SCLC patients before first-line chemotherapy. The correlation between a PCT increase and prognosis was examined in the discovery and validation cohorts. RESULTS: Twenty-three SCLC patients and 26 NSCLC patients were enrolled as the discovery cohort, and 30 SCLC patients were enrolled as the validation cohort. The PCT level in SCLC patients was significantly higher than that in NSCLC patients. The PCT level was not associated with WBC count and weakly associated with the CRP level. In both the discovery and validation cohorts, the median survival time was significantly shorter in SCLC patients with PCT-high than in SCLC patients with PCT-normal (discovery; 11.7 vs. 89.7 months, P<0.005, validation; 9.6 vs. 22.6 months, P<0.005). CONCLUSIONS: It may be difficult to differentiate bacterial infections in SCLC patients by PCT, as PCT is elevated even in SCLC patients without infectious diseases. This is the first study to prospectively verify that pretreatment PCT levels have a significant negative correlation with prognosis in SCLC patients.

DOI： 10.21037/tlcr-21-838

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Pleural disease in silicosis remains an underrecognized entity. Herein, we describe the case of an 85-year-old man with a 20-year history of silica exposure between the ages of 9-28 years. He presented with bilateral exudative pleural effusions, and chest computed tomography revealed typical silicosis findings. Thoracentesis was performed thrice, but did not reveal the cause of effusion. However, pleural fluid cell-block elemental analysis revealed a silicon compound, suggesting that silicosis-related pleural effusion had developed after a long latency period. Therefore, elemental analysis of the pleural fluid cell block may help diagnose occupational lung diseases with pleural effusion.

DOI： 10.1016/j.rmcr.2022.101665

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

There has been a long-standing controversy regarding the physiological role of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) in sleep/wake architecture. Some studies have reported that 5-HT acts as a sleep-promoting agent, but several studies have suggested that DRN 5-HT neurons function predominantly to promote wakefulness and inhibit rapid eye movement (REM) sleep. Furthermore, recent studies have reported that there is a clear neurobiological difference between a waking state that includes alertness and active exploration (i.e., active wakefulness) and a waking state that is devoid of locomotion (i.e., quiet wakefulness). These states have also been shown to differ clinically in terms of memory consolidation. However, the effects of 5-HT neurons on the regulation of these two different waking states have not been fully elucidated. In the present study, we attempted to examine the physiological role of DRN 5-HT neurons in various sleep/wake states using optogenetic methods that allowed manipulation of cell-type specific neuronal activation with high temporal and anatomical precision. We crossed TPH2-tTA and TetO-ChR2(C128S) mice to obtain mice with channelrhodopsin-2 (ChR2) [C128S]-expressing central 5-HT neurons, and we activated DRN-5HT neurons or medullary 5-HT neurons. Optogenetic activation of DRN 5-HT neurons caused rapid transition from non-REM sleep to active wakefulness, not quiet wakefulness, whereas activation of medullary 5-HT neurons did not appear to affect sleep/wake states or locomotor activity. Our results may shed light on the physiological role of DRN 5-HT neurons in sleep/wake architecture and encourage further investigations of the cortical functional connectivity involved in sleep/wake state regulation.

DOI： 10.1016/j.brainresbull.2021.09.019

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Authorship：Last author   Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

背景.気管支静脈瘤は稀な疾患であり,その治療法は確立されていない.症例.78歳,女性.小児期より気管支拡張症を罹患し,膿胸の既往があった.6年前から喀血を繰り返し,計3回の気管支動脈塞栓術が行われていた.今回,喀血を契機に入院し,止血薬投与を受けたが大量喀血を来したため,気管挿管の上で人工呼吸管理となった.左下横隔動脈と左気管支動脈をゼラチンスポンジで塞栓し,止血を得た.その際の選択的動脈造影で左下横隔動脈と肺静脈との動静脈シャントを認めた.気管支鏡で観察すると,左上下葉支分岐部に気管支静脈瘤がみられ,出血源と考えられた.動脈塞栓術の2週後の気管支鏡では同部位の瘤は退縮していた.その後,再喀血なく自宅退院した.結論.気管支静脈瘤は気管支拡張症や動脈塞栓に関連して発症する可能性があり,喀血時は気管支鏡による確認が必要である.治療として異常シャントの塞栓術が有効と考えられた.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00298&link_issn=&doc_id=20211216270004&doc_link_id=%2Fcf0brond%2F2021%2F004306%2F005%2F0589-0594%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2021%2F004306%2F005%2F0589-0594%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

DOI： 10.1007/s00262-021-03078-0

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Psychological disorders, such as depression, are markedly prevalent in patients with airway diseases. In this study, we assessed the effect of treatment with dupilumab, an IL-4 receptor α chain antibody, on depressive symptoms in a cohort of patients with asthma with eosinophilic chronic rhinosinusitis (ECRS). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; The study participants, diagnosed with asthma and ECRS, were assessed for symptoms and quality of life (QOL) scores for asthma and ECRS and medications. The Patient Health Questionnaire-9 (PHQ-9) scores were used to evaluate the depressive state. The depressive symptoms were compared with asthma and ECRS symptoms both at the time of initiation and after 4 months of dupilumab treatment. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Ultimately, 31 patients were included in the study. Most patients demonstrated a depressive state that was correlated with the nasal symptom score. In the evaluation 4 months after dupilumab treatment, the PHQ-9 score was significantly reduced, and the decrease was remarkable in patients whose nasal symptom score was reduced by 50% or more. Additionally, the PHQ-9 scores in patients with improved nasal and asthma symptoms were significantly reduced. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; Dupilumab may improve QOL in patients with bronchial asthma with ECRS by reducing depressive symptoms through the improvement of clinical symptoms.

DOI： 10.1159/000519296

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

<sec><title>Objectives</title>Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.

</sec><sec><title>Methods</title>We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.

</sec><sec><title>Results</title>Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) <italic>vs</italic>. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) <italic>vs</italic>. not reached (95% CI: 8.4–NE); p = 0.031].

</sec><sec><title>Conclusion</title>The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

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DOI： 10.3389/fonc.2021.704475

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本エイズ学会  

2012〜2018年に新潟県内のエイズ治療拠点病院以外の病院を対象にHIV/エイズ出張研修会を行い、研修会前後のアンケート結果を分析した。事前アンケート回答者6791名、事後アンケート回答者4529名で、職種は事前・事後とも看護師が最も多く、次いで事務職・クラークであった。回答は、研修会は実践に非常に役立った4452名(98.3%)、HIV患者や診療に対する気持ちや考え方に変化があった3365名(74.3%)、利用者の受入れ可能3827名(84.5%)で、HIV感染者受入れ促進の取組みとしての研修会の有効性が示唆された。しかし、HIV感染者と関わることへの不安は研修会前後で変化がなく、感染への不安がHIV診療の受入れを妨げていることが示唆された。

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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An outbreak of serotype 19A Streptococcus pneumoniae occurred among the residents of a relief facility. Pneumonia developed in 5 of 99 residents (attack rate, 5.1%). We obtained pharyngeal specimens from non-onset residents, and S. pneumoniae was isolated from 6 individuals (6.4%), 5 of whom had serotype 19A.

DOI： 10.1017/ice.2021.328

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Background: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. Methods: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. Results: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. Conclusions: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

DOI： 10.21037/tlcr-21-198

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A 31-year-old woman who was clinically diagnosed with Silver-Russell syndrome (SRS) in childhood was admitted with complaints of dyspnea. She had hypercapnic respiratory failure accompanied by nocturnal hypoventilation. Computed tomography revealed systemic muscle atrophy and superior mesenteric artery syndrome; however, the bilateral lung fields were normal. She was treated with nocturnal noninvasive positive pressure ventilation and showed improvement of respiratory failure. In this case, loss of methylation on chromosome 11p15 and maternal uniparental disomy of chromosome 7, which are the common causes of SRS, were not detected. This is a rare case of adult SRS manifesting as chronic hypercapnic respiratory failure.

DOI： 10.2169/internalmedicine.5479-20

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We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.

DOI： 10.1016/j.resinv.2020.12.003

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

[目的]全ゲノム解析を用いて,早期発症者と長期潜伏後発症者から分離した結核菌北京株のゲノム変異を解析した。[方法]1999年に中学校で発生した結核集団感染の接触者と二次感染者のうち2009年までに結核を発症した患者より分離した結核菌北京株6株と,別の事例で初発時と再発時の患者より分離した結核菌北京株2株の計8株の全ゲノム解析を行った。結核菌の突然変異率は,初発から1年以内に発症した早期発症者と1年以上の潜伏期を経てから発症または再燃した長期潜伏後発症者の2群間で比較した。[結果]結核菌北京株の突然変異率は,Lineage 4に属する結核菌よりも高く,結核菌北京株の高い病原性や薬剤耐性の要因である可能性が示唆された。遺伝子多型解析では,酸化的損傷に起因すると推定されている突然変異が長期潜伏後発症群のほうに多く,潜伏期間中にも薬剤耐性変異が起こる可能性が示唆された。[結論]結核菌北京株の高頻度の薬剤耐性化を防ぐためには,感染した結核菌の系統により治療法を検討する必要性も考えられた。今後,結核菌系統の特性を理解し,治療法を工夫することで結核の薬剤耐性化や重篤化を防ぐ有効な対策の構築につながることが期待される。(著者抄録)

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BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is now a standard treatment of previously untreated EGFR-mutated advanced non-small-cell lung cancer (NSCLC). However, disease progression occurs within 19 months of treatment. In the NEJ009 study, gefitinib plus carboplatin plus pemetrexed demonstrated significantly better progression-free and overall survival compared with gefitinib monotherapy. Furthermore, the Lung Oncology Group in Kyushu and North East Japan Study Group, major clinical trial groups in Japan, conducted a randomized phase II study to evaluate the efficacy and safety of second-line osimertinib plus carboplatin plus pemetrexed versus osimertinib monotherapy for patients with disease progression during first-line EGFR tyrosine kinase inhibitor therapy and the EGFR T790M resistance mutation (TAKUMI trial; trial registration no., jRCTs071180062). In the first treatment course for the initial 24 patients, no safety issues were reported in the combination arm. Thus, we have planned this phase II study to evaluate the safety and preliminary efficacy of osimertinib plus cisplatin/carboplatin plus pemetrexed therapy for patients with previously untreated EGFR-mutated NSCLC. PATIENTS AND METHODS: A total of 66 patients will be enrolled, because this sample size will be adequate for assessing treatment safety and efficacy. The co-primary endpoints include safety and the objective response rate, and the secondary endpoints include the complete response rate, disease control rate, and progression-free survival. CONCLUSIONS: This is the first study to explore the efficacy and safety of osimertinib combined with platinum-based chemotherapy in previously untreated NSCLC patients with EGFR-sensitizing mutations. Our findings could provide valuable information for phase III studies such as FLAURA2 and for developing treatment strategies for EGFR-mutated NSCLC.

DOI： 10.1016/j.cllc.2020.09.023

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本内科学会  

症例1は67歳男性で、Behcet病に伴う皮疹と診断され、8ヵ月前より、皮膚科からプレドニゾロン(PSL)およびジアフェニルスルホン(DDS)が処方されていた。数日前からの頭痛を訴え、室内気でSpO2 89%と低下していた。Hb 7.5g/dlと貧血あり、白血球10950/μl、CRP 20.05mg/dlと高度の炎症所見を認めた。室内気での動脈血液ガス分析(BGA)でSaO2 95.6%であり、SpO2とSaO2の乖離(saturation gap)を認め、メトヘモグロビン(MetHb)3.3%と上昇していた。症例2は69歳男性で、骨髄異形成症候群に伴うSweet病のため、3ヵ月前より皮膚科からPSLおよびDDSが処方されていた。肝機能障害のために入院となり、無症状であったが入院時よりSpO2 90%以下が持続したため、酸素吸入を開始された。その後もSpO2低値が遷延した。酸素吸入下のBGAでSaO2 90.8%と軽度のsaturation gapを認め、MetHb 7.4%と上昇していた。症例3は40歳男性で、潰瘍性大腸炎に伴う壊疽性膿皮症のため、4ヵ月前より皮膚科からDDSが処方されていた。潰瘍性大腸炎の通院治療のために来院した際、無症状であったがSpO2低下を認めたため入院した。室内気でSpO2 92%と低下していた。軽度の炎症反応上昇が認められた。BGAでSaO2 97.7%とSaturation gapを認め、MetHb 3.2%と上昇を認めた。いずれの症例も、皮膚科より処方されていたDDSによる薬剤性MetHb血症を疑い、DDS内服を中止した。その結果、1週後にはMetHb分画の低下と共にSpO2の上昇が認められた。

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Authorship：Lead author,　Last author,　Corresponding author   Language：English  

DOI： 10.31662/jmaj.2020-0095

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DOI： 10.1017/ice.2020.1400

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Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

DOI： 10.1038/s41598-020-80853-6

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Background: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity. Methods: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire. Results: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively. Conclusions: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).

DOI： 10.21037/tlcr-20-649

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

Nontuberculous mycobacterial (NTM) infections are an emerging problem. Common organisms include Mycobacterium avium, M. intracellulare, and M. kansasii, along with the M. avium intracellulare complex (MAC), which includes both M. avium and M. intracellulare. Typically, NTM infections affect the lungs and subsequently demonstrate a chronic course. Therefore, persistent respiratory symptoms generally indicate of the presence of pulmonary NTM diseases, and chest radiography, along with a sputum examination, are essential for its diagnosis. Because NTM are ubiquitous environmental organisms, a positive culture from a minimum of two separate expectorated sputum samples are required to make a diagnosis. The repertoire of effective drugs for treatment is considerably limited, indicating the need for long-term management with multiple drugs. Establishing a treatment regimen with high therapeutic efficacy and safety is an important issue for the future.

DOI： 10.2169/internalmedicine.4361-19

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

Viral pneumonia caused by varicella-zoster virus (VZV) infection is a rare but important complication, especially regarding varicella infections. Although disseminated cutaneous herpes zoster (DCHZ) is often associated with visceral diseases, there have been few reports of DCHZ-related pneumonia. We herein report a rare case of a lethal disseminated VZV infection that caused severe pneumonia in a Japanese patient who had chronic interstitial pneumonia. Physicians should consider the possibility of VZV-related pneumonia, especially in patients with a medical history of hematopoietic stem cell transplantation and immunosuppressive therapy.

DOI： 10.2169/internalmedicine.5396-20

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A 70-year-old man, treated for asthma for 2 years and chronic sinusitis for several months, presented with fever, numbness in the lower limbs, heaviness in the head, gross hematuria, and black stools. He also had eosinophilia, elevated serum IgG4 levels, high levels of myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and pulmonary infiltrative shadows. Bronchoscopy revealed multiple white flattened lesions (white moss) on the airway mucosa, suggesting mycobacterial infection or malignancy. A biopsy from tracheal mucosa revealed airway inflammation with marked eosinophil infiltration. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with steroids, and all findings improved. However, a year and a half after the initiation of treatment, eosinophils and IgE gradually increased; subjective symptoms, such as asthma symptoms and numbness in the lower limbs, worsened; and ANCA, which had been negative, turned positive. Therefore, we suspected disease relapse and anti-IL-5 antibody (mepolizumab) treatment was initiated. Thereafter, ANCA turned negative again, eosinophils and IgE normalized, and subjective symptoms decreased. The presence of airway mucosal lesions in EGPA is relatively rare, and we report this case as a valuable case owing to the interesting bronchoscopic findings that are worth comprehending as a respiratory physician.

DOI： 10.1016/j.rmcr.2021.101451

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BACKGROUND: Each of the currently available (1→3)-β-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits. METHODS: The plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the β-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared. RESULTS: Of the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results. CONCLUSIONS: The newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.

DOI： 10.1371/journal.pone.0255172

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
<italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original <italic>Mtb</italic> isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent <italic>Mtb</italic> are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of <italic>Mtb</italic> Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.

DOI： 10.1038/s41598-020-75028-2

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Other Link： http://www.nature.com/articles/s41598-020-75028-2

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called “ribosomopathies,” including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions −248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p &lt; 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

DOI： 10.3390/cells9112409

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は74歳男性。発熱と咳嗽を契機に胸部異常影を指摘された。胸部CTで両側多発結節影、すりガラス影を認め、外科的肺生検を施行したが、確定診断に至らなかった。ステロイドパルス療法によりすりガラス影と結節影は改善したが、ステロイドの漸減に伴い呼吸不全が進行し死亡した。剖検で両下葉に多発腫瘤とEpstein-Barr virus(EBV)陽性の異型細胞を認め、EBV陽性びまん性大細胞型B細胞リンパ腫と診断した。ステロイドの漸減に伴い多発腫瘤影を呈する際は、リンパ増殖性疾患の可能性に注意する必要がある。(著者抄録)

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DOI： 10.1016/j.alit.2020.03.009

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Academy of Allergy, Asthma and Immunology  

Exercise-induced bronchoconstriction (EIB) is a phenomenon observed in asthma but is also seen in healthy individuals and frequently in athletes. High prevalence rates are observed in athletes engaged in endurance sports, winter sports, and swimming. The pathophysiology of EIB is thought to be related to hyperventilation, cold air, and epithelial damage caused by chlorine and fine particles in inspired air. Several diagnostic procedures can be used
however, the diagnosis of EIB based on self-reported symptoms is not reliable and requires an objective examination. The hyperosmolar inhalation test and eucapnic voluntary hyperpnea test, which involve indirect stimulation of the airway, are useful for the diagnosis of EIB. A short-acting β-agonist is the first choice for prevention of EIB, and an inhaled corticosteroid is essential for patients with asthma. Furthermore, treatment should accommodate antidoping requirements in elite athletes. Tailoring of the therapeutic strategy to the individual case and the prognosis after cessation of athletic activity are issues that should be clarified in the future.

DOI： 10.1016/j.jaip.2020.03.011

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INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points• To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.• Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.• Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.• These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.

DOI： 10.1007/s10067-020-04984-x

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It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.

DOI： 10.1165/rcmb.2019-0325OC

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Authorship：Lead author,　Last author,　Corresponding author   Language：English  

A novel coronavirus, officially termed as severe acute respiratory syndrome (SARS)-CoV-2, emerged in Wuhan, China, toward the end of 2019. Just four months later, more than 100,000 people were diagnosed with COVID-19, the resulting disease. The genetic analysis of SARS-CoV-2 revealed that this virus is a new Betacoronavirus, closely related to bat-derived SARS-like coronaviruses. Clinical data from hospitals in China have revealed that approximately 10% of the infected patients have severe disease requiring intensive care. Since containment of the outbreak may have partially failed due to asymptomatic transmission, it is imperative to accelerate the development of rapid point-of-care diagnostic tests, vaccines, and therapeutics for the COVID-19 epidemic.

DOI： 10.1016/j.resinv.2020.03.006

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DOI： 10.21037/tlcr.2020.03.31

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Authorship：Last author   Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞▼実臨床において,運動に関連する喘息症状または患者の対応で問題になるのは,(1)運動誘発性喘息の診断,治療およびその予防,(2)運動選手(アスリート)に対するドーピングを含めた対応,である.▼診断には発症機転を含めた詳細な問診が必要である.▼運動前および症状出現時の吸入短時間作用性β2刺激薬は有効であるが,頻回な運動誘発性喘息症状は治療強化の目安であることを認識することも大切である.▼アスリートに対しては,禁止薬物に当たる薬剤も存在するため,注意が必要である.

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00974&link_issn=&doc_id=20200605150018&doc_link_id=issn%3D0022-1961%26volume%3D125%26issue%3D6%26spage%3D1371&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D125%26issue%3D6%26spage%3D1371&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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BACKGROUND: As indices of asthma control, exacerbations are equally important with symptoms and respiratory function. Thus, it is critical to recognize the risk factors of exacerbation. OBJECTIVE: We conducted a questionnaire survey of asthma patients in Niigata Prefecture to clarify the factors involved in asthma exacerbation. METHODS: The questionnaire survey was carried out in patients and their physicians from September to October 2014. In 2015, the same sample population also received a questionnaire about current asthma control and exacerbation. RESULTS: One hundred patients experienced asthma exacerbation during the 1-year period. There were significant differences in age, sex, history of hospitalization due to asthma, smoking history, Asthma Control Test, treatment step, and transient steroid treatment history in the previous year between the exacerbation group and non-exacerbation group. On multivariate analysis, there was a significant difference in history of transient steroid therapy, history of hospitalization associated with asthma attacks, and nonsmoking history. Cluster analysis of cases with exacerbation was classified into three clusters. Cluster 1 comprised slightly older cases with smoking history, Cluster 2 had more females, non-smoking and nonatopic cases with uncontrolled symptoms, and Cluster 3 had more females, non-smoking and mild atopic cases. CONCLUSIONS: Our findings suggest that patients with asthma exacerbation in the previous year and nonsmoking females are important targets for the study of asthma exacerbation. The adequate treatment of women patients might be important for the prevention of asthma exacerbation.

DOI： 10.12932/AP-080918-0404

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PURPOSE: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. EXPERIMENTAL DESIGN: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. RESULTS: ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. CONCLUSIONS: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

DOI： 10.1158/1078-0432.CCR-19-2321

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Authorship：Last author   Language：Japanese   Publisher：(有)科学評論社  

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BACKGROUND: Interstitial lung disease (ILD) induced by anti-programmed-cell death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) is potentially life-threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune-related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti-PD-1/PD-L1 therapies, the association between radiologic features and clinical outcomes remains unclear. METHODS: Patients with advanced non-small-cell lung cancer who were treated with 1st to 3rd line anti-PD-1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. RESULTS: A total of 231 patients who received anti-PD-1 therapy were enrolled. Thirty-one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2-NE) versus not reached (95% CI: 13.2-NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. CONCLUSIONS: This study demonstrated that patients who developed GGO exhibited worse outcomes among non-small-cell lung cancer patients receiving anti-PD-1 therapies.

DOI： 10.1002/cam4.2974

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

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Legionella species are consistently identified as some of the most common causative agents of severe community-acquired pneumonia (CAP) or nosocomial pneumonia. Although the number of reported Legionella infection cases is gradually increasing in Japan, most cases are diagnosed by a urinary antigen test, which identifies only L. pneumophila serogroup 1. Therefore, assessment of pneumonia-causing Legionella species and serogroups would be important. The Japan Society for Chemotherapy Legionella committee has collected the isolates and clinical information on cases of sporadic community-acquired Legionella pneumonia throughout Japan. Between December 2006 and March 2019, totally 140 sporadic cases were identified, in which L. pneumophila was the most frequently isolated species (90.7%) followed by L. bozemanae (3.6%), L. dumofii (3.6%), L. micdadei (1.4%), and L. longbeachae (0.7%). Among 127 isolates of L. pneumophila, 111 isolates were of serogroup 1, two of serogroup 2, four of serogroup 3, one of serogroup 4, one of serogroup 5, seven of serogroup 6, and one was of serogroup 10. We also assessed in vitro activity of antibiotics against these isolates and showed that quinolones and macrolides have potent anti-Legionella activity. Our study showed that pneumonia-causing Legionella species and serogroup distribution was comparable to that reported in former surveillances. L. pneumophila was the most common etiologic agent in patients with community-acquired Legionella pneumonia, and L. pneumophila serogroup 1 was the predominant serogroup.

DOI： 10.1016/j.jiac.2019.12.016

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本呼吸器学会  

オラパリブ(olaparib)は、進行卵巣癌・乳癌に対する新規の分子標的薬(poly ADP-ribose polymerase阻害薬)である。オラパリブによる薬剤性肺障害の発症頻度は低いとされているが、当院ではオラパリブによる薬剤性肺障害と思われる症例を2例経験した。発症時期、症状、経過、検査所見など多くの共通点がみられた一方、画像パターンには一定の傾向はみられなかった。原疾患が悪性腫瘍の場合、再投与の可否が問題となるが、本例では2例とも再燃を認めずに再投与し得た。今後オラパリブは適応が広まっていくことが予想されており、薬剤性肺障害にも留意する必要がある。(著者抄録)

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PURPOSE: In the past decade, the relationship between naturally occurring interferon-γ-neutralizing autoantibodies (IFNγ-Ab) and disseminated non-tuberculous mycobacteria (NTM) infection has been established. Furthermore, immune suppressive therapy aimed at the suppression of antibody production has shown efficacy as a supportive treatment. However, the nature of antibody behavior and antibody titer during the course of this disease, as well as the pathophysiological significance of IFNγ-Ab, has not yet been fully elucidated. METHODS: Thirteen Japanese subjects suffering from disseminated NTM (dNTM) infection with IFNγ-Ab were evaluated. The fluctuation of IFNγ-Ab titer and the neutralizing capacity against IFN-γ during the course of the disease were retrospectively analyzed. IFNγ-Ab titers in the sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. RESULTS: Serum antibody titers were not constant during the treatment period and varied over the course of the disease. The antibody titer decreased when the disease was improved by anti-mycobacterial treatment (p < 0.01) and increased as the disease progressed (p < 0.05). Even after the antibody titer decreased, the neutralizing capacity against IFN-γ was maintained by individual sera. CONCLUSIONS: Despite the improvement in the pathological condition via treatment, the patients' sera maintained neutralizing capacity against IFN-γ. Antibody titer fluctuated over the course of the disease and exhibited potential as a biomarker for judgment of the disease state.

DOI： 10.1007/s10875-020-00762-1

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Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1.

DOI： 10.1002/1878-0261.12608

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DOI： 10.1016/j.lungcan.2019.11.012

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Postoperative pulmonary complications (PPCs) are considered as a leading cause of poor surgical outcomes, and occur frequently even in non-cardiothoracic surgery. Several multifactorial risk indices show potential effectiveness in identification of patients at high risk of developing PPCs. In preoperative consultation from surgeons, pulmonologists often act as gatekeepers for indication of surgery. With regard to preventive strategy for PPCs, recent reports have suggested the usefulness of preoperative interventions, such as smoking cessation, inhalation therapy, medications, pulmonary rehabilitation, and sleep study followed by continuous positive airway pressure therapy. Now, pulmonologists have an important role as supporters for preoperative patient care.

DOI： 10.1016/j.resinv.2019.09.001

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Background: The anti-immunoglobulin E monoclonal antibody, omalizumab, is used to treat severe asthma and has the potential to ameliorate airway inflammation. However, the effect of omalizumab in ameliorating upper airway inflammation has not been fully elucidated. Objective: We investigated the association of upper and lower airway inflammation with the response to omalizumab treatment. Methods: We used the Global Evaluation of Treatment Effectiveness to assess the efficacy of omalizumab in treating 16 patients with severe asthma. We also investigated the symptom score, short-acting β-agonist inhaler use, pulmonary function, biomarkers, computed tomography scans, and nasal mucosa pathology at omalizumab initiation and after four months of treatment. Results: When the fraction of exhaled nitric oxide (FeNO) and the percentage of sputum eosinophil were used as indicators of lower airway inflammation, positive correlations were found between CD20 B-cell, mast cell, and eosinophil counts in the nasal mucosa. Improved asthma symptoms were observed in 12 of the 16 severe asthma cases. The FeNO and eosinophil levels in the nasal tissue, prior to the administration of omalizumab were predictors of the response to asthma treatment. Conclusions: These findings suggest heterogeneity among people with severe asthma. In addition, the phenotype associated with response to omalizumab, leading to improvement in asthma symptoms, comprises upper airway eosinophilia and high FeNO levels.

DOI： 10.1080/02770903.2018.1541357

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BACKGROUND: Adherence Starts with Knowledge-12 (ASK-12) is a useful indicator of drug adherence. In this study, we analyzed patient background including social and psychological factors in a low-adherence group of patients with asthma defined using ASK-12. METHODS: From a questionnaire survey for patients with asthma from the Niigata Prefecture, Japan, conducted in the fall of 2016, we enrolled patients who answered all ASK-12 items and underwent a measured respiratory function test within 1 year. The low-adherence group (ASK-12 ≥ 28) was compared with the control group (ASK-12 < 28), and we conducted a cluster analysis of the low-adherence group. RESULTS: There were 170 patients in the low-adherence group and 402 patients in the control group. There was a significant difference between age, gender, working status, smoking history, the percentage of forced expiratory volume in one second (%FEV1), asthma control test (ACT), and Patient Health Questionnaire-9 (PHQ-9) score between the two groups. Logistic analysis revealed that working status (working), % FEV1 (<90%), and PHQ-9 score (>5) were independent factors for the low-adherence group. The cluster analysis identified three clusters in the low-adherence group. Among these, one cluster was characterized by elderly males with chronic obstructive pulmonary disease and another by middle-aged nonsmoking females with a depression tendency, had problems with asthma control. CONCLUSIONS: Several factors were considered to be attributed to low drug-adherence. There were several phenotypes in the low-adherence population correlated with incomplete asthma control. Intervention with drug adherence should be a future goal for asthma treatment.

DOI： 10.1016/j.alit.2019.07.006

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© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Introduction: Influenza remains a clinically heavy burden worldwide. The objective of this study was to clarify clinical manifestations of severely ill patients infected with influenza. Methods: The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2019 (5 influenza seasons) using an internet-surveillance system. Results: A total of 924 patients were enrolled and analyzed. The median age was 78 years (IQR, 67–84), and the patients in the 2015–2016 season were significantly younger than those in other seasons. Pneumonia was the most common disease indicated as a cause for hospitalization, followed by a poor general condition and exacerbation of underlying respiratory diseases. Antiviral drugs were administered in 97.0% of the patients with peramivir being the most-frequently use antiviral. In-hospital death was recorded for 44 patients (4.8%). Multivariate analysis indicated that nursing home resident (OR: 6.554) and obesity (OR: 24.343) were independent predictors of in-hospital mortality. Conclusions: Complications of influenza infection remain a heavy burden especially among the elderly. Continuous nationwide surveillance will be required to grasp the actual situation of influenza epidemics. (UMIN000015989).

DOI： 10.1016/j.jiac.2020.10.021

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BACKGROUND: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer. METHODS: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α1-microglobulin, β2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment. RESULTS: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline. CONCLUSIONS: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.

DOI： 10.1186/s12885-019-6398-2

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BACKGROUND: Although fluoroquinolones are considered as alternative therapies of pulmonary Mycobacterium avium complex (MAC) disease, the association between fluoroquinolone resistance and MAC genotypes in clinical isolates from individuals not previously treated for MAC infection is not fully clear. METHODS: Totals of 154 M. avium isolates and 35 Mycobacterium intracellulare isolates were obtained from treatment-naïve patients with pulmonary MAC disease at the diagnosis of MAC infection at 8 hospitals in Japan. Their susceptibilities of moxifloxacin were determined by broth microdilution methods. Moxifloxacin-resistant isolates were examined for mutations of gyrA and gyrB. Variable numbers of tandem repeats (VNTR) assay was performed using 15 M. avium VNTR loci and 16 M. intracellulare VNTR loci. RESULTS: Moxifloxacin susceptibility was categorized as resistant and intermediate for 6.5% and 16.9%, respectively, of M. avium isolates and 8.6% and 17.1% of M. intracellulare isolates. Although the isolates of both species had amino acid substitutions of Thr 96 and Thr 522 at the sites corresponding to Ser 95 in the M. tuberculosis GyrA and Gly 520 in the M. tuberculosis GyrB, respectively, these substitutions were observed irrespective of susceptibility and did not confer resistance. The VNTR assays showed revealed three clusters among M. avium isolates and two clusters among M. intracellulare isolates. No significant differences in moxifloxacin resistance were observed among these clusters. CONCLUSIONS: Although resistance or intermediate resistance to moxifloxacin was observed in approximately one-fourth of M. avium and M. intracellulare isolates, this resistance was not associated with mutations in gyrA and gyrB or with VNTR genotypes.

DOI： 10.1016/j.jiac.2019.05.028

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BACKGROUND: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases. METHODS: We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy. RESULTS: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. CONCLUSION: EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.

DOI： 10.1111/1759-7714.13189

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本感染症学会  

[目的]国内3種の(1→3)-β-D-グルカン(以下β-D-グルカン)測定試薬における測定結果と患者の臨床背景を比較し,深在性真菌症の診断における有用性および試薬間での測定結果の乖離,偽陽性の要因について評価する.[方法]新潟大学医歯学総合病院において2017年8月から2017年11月にかけてβ-D-グルカン検査が提出された患者を対象とし,測定残余血漿を用いて以下の3試薬について測定した.(1)ファンギテックGテストMKII「ニッスイ」(以下MKII法),(2)ファンギテックGテストES「ニッスイ」(以下ES法),(3)β-グルカンテストワコー(以下ワコー法).[成績]171患者,245検体が対象となった.深在性真菌症患者は疑診を含め7例であった.β-D-グルカン測定値は,同一検体間の比較でMKII法が最も高く,次いでES法,ワコー法の順であったが,互いに有意に相関していた.感度,特異度,陽性的中率,陰性的中率などの診断特性は各試薬によって異なっていた.MKII法で偽陽性を比較的多く認めたものの,深在性真菌症(疑診含む)診断におけるROC曲線下面積には有意差はなかった.いずれかの試薬による偽陽性を呈した14例について,階層型クラスター分析を用いて分類したところ,偽陽性のパターンに一定の傾向が認められた.[結論]各測定試薬によるβ-D-グルカン測定の結果は概ね相関しているが,測定値は大きく異なっており,異なる試薬同士の比較は困難である.深在性真菌症診断における差は小さいが,それぞれの試薬の診断特性を理解し使用するべきである.また試薬によって偽陽性の原因が異なる可能性が示唆された.(著者抄録)

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© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Background: Community-acquired pneumonia (CAP) due to Legionella has a high mortality rate in patients who do not receive adequate antibiotic therapy. In a previous study, we developed a simple Legionella Score to distinguish patients with Legionella and non-Legionella pneumonia based on clinical information at diagnosis. In the present study, we validated this Legionella Score for the presumptive diagnosis of Legionella CAP. Methods: This validation cohort included 109 patients with Legionella CAP and 683 patients with non-Legionella CAP. The Legionella Score includes six parameters by assigning one point for each of the following items: being male, absence of cough, dyspnea, C-reactive protein (CRP) ≥ 18 mg/dL, lactate dehydrogenase (LDH) ≥ 260 U/L, and sodium < 134 mmol/L. Results: When the Legionella CAP and non-Legionella CAP were compared by univariate analysis, most of the evaluated symptoms and laboratory test results differed substantially. The six parameters that were used for the Legionella Score also indicated clear differences between the Legionella and non-Legionella CAP. All Legionella patients had a score of 2 points or higher. The median Legionella Scores were 4 in the Legionella CAP cases and 2 in the non-Legionella CAP cases. A receiver operating characteristics curve showed that the area under the curve was 0.93. The proposed best cutoff, total score ≥3, had sensitivity of 93% and specificity of 75%. Conclusion: Our Legionella Score was shown to have good diagnostic ability with a positive likelihood of 3.7 and a negative likelihood of 0.10.

DOI： 10.1016/j.jiac.2019.03.009

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Authorship：Last author   Language：Japanese   Publisher：医歯薬出版(株)  

気管支鏡検査は、気管支、肺疾患の診断や治療において必須の検査であり、呼吸器内科医にとっては基本的かつ重要なスキルのひとつである。一般的に安全性の高い検査ではあるものの、被検者に苦痛と侵襲をもたらす検査でもあり、その教育と訓練の重要性はいうまでもない。近年、気管支鏡シミュレータを利用した教育は、患者の安全を保ちながら、反復して同じ手技をトレーニングできるといった多くの点でその有用性が指摘されている。当院では医学生・レジデント教育の一環として、気管支内視鏡シミュレータを用いた実習を取り入れている。気管支鏡シミュレータは、基本的な検査手技スキルの習得や解剖学的知識の向上などの教育的意義だけでなく、気管支鏡に対する興味・関心を持つきっかけとしても有用である。その有用性に関するエビデンスが集積しつつあり、今後、医学生・レジデントに対する気管支鏡シミュレータ教育は、より一般的なものとなっていくと考えられる。(著者抄録)

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Pneumocystis pneumonia (PCP) is an opportunistic disease that mainly affects patients with a deficiency of cell-mediated immunity, especially acquired immunodeficiency syndrome (AIDS). The incidence of PCP in these patients has declined substantially owing to the widespread use of antiretroviral therapy and PCP prophylaxis. However, PCP is still a major AIDS-related opportunistic infection, particularly in patients with advanced immunosuppression in whom human immunodeficiency virus type 1 (HIV-1) infection remains undiagnosed or untreated. The clinical manifestations, diagnosis, treatment, and prevention of PCP in patients with HIV-1 infection are addressed in this review.

DOI： 10.1016/j.resinv.2019.01.009

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BACKGROUND: Treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR-mutated non-small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. PATIENTS AND METHODS: We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR-TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. RESULTS: We enrolled 27 patients who harbored EGFR-activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P < 0.01, respectively). Patients with uncommon EGFR mutations or without T790M mutations exhibited a significantly longer median progression-free survival than those with common EGFR mutations or with T790M mutations (P = 0.003 and P = 0.03, respectively). CONCLUSION: Patients with uncommon EGFR mutations and without T790M mutations are associated with the best outcomes for treatment with immunotherapy among those with EGFR-mutated NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders with EGFR mutations.

DOI： 10.1002/cam4.2037

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BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) can deteriorate rapidly to become fatal. Reported poor prognostic factors include radiographic findings, undernutrition, anemia and high inflammation test values. However, the association of these prognostic factors with the pathophysiology of the disease remains unknown. We aimed to clarify the pathophysiology of MAC-LD and develop a new biomarker that reflects the immune response to the disease. METHODS: We performed the cytokine panel analyses of serum from patients with MAC-LD and compared each cytokine level with clinically negative prognostic factors (radiographic disease type, body mass index, albumin, C-reactive protein and hemoglobin) and high-resolution CT scores. RESULTS: We analyzed 27 patients with MAC-LD, 6 with the fibrocavitary form and 21 with the nodular bronchiectatic form on high-resolution CT. Serum CXC motif ligand 10 (CXCL10) concentration was significantly elevated in patients with the fibrocavitary form (p = 0.008). CXCL10 levels correlated with body mass index (r = - 0.60, p = 0.0008), serum albumin concentration (r = - 0.45, p = 0.016) and high-resolution CT scores (r = 0.61, p = 0.0006). Among 14 patients initially untreated, antibiotic therapy was initiated for five during the study period. CXCL10 concentration was significantly higher in these patients (p = 0.046), and receiver operating characteristic analysis for CXCL10 concentration on treatment initiation produced an area under the curve of 0.844, with a sensitivity of 100%, specificity of 66.7%, and cut-off value of 366.5 pg/mL. CONCLUSION: We revealed cytokine profiles in patients with MAC-LD. Serum CXCL10 levels probably reflect the severity of MAC-LD. Our findings suggest that CXCL10 concentration may be a promising biomarker for managing treatment for patients with MAC disease of the lung.

DOI： 10.1186/s12879-019-3888-4

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A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

DOI： 10.1038/s41467-018-08074-0

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Pseudomonas aeruginosa is one of the most common causes of nosocomial infections, and its multi-drug resistance has been a serious problem worldwide. The aim of this study was to evaluate whether exposure to piperacillin and reactive oxygen species (ROS) could lead to multi-drug resistance for clinical isolates of P. aeruginosa. The inhibition of this acquired resistance by the anti-ROS agent was also examined. In vitro inducement of multi-drug resistance was performed against 20 clinical isolates. These strains were incubated for 24 h and transferred 5 times after being exposed to 1 mM H2O2 (ROS) in addition to a sub-MIC of piperacillin by the agar dilution method. Each MIC of piperacillin and levofloxacin was determined. As the mechanism of levofloxacin resistance, mutation of QRDR was investigated. The expression level of genes encoding efflux pumps; mexA, mexY, mexC, and D2 porin; oprD were determined by real-time PCR. Multi-resistance to both piperacillin and levofloxacin was induced with 4 of 20 strains (20%). No amino acid change was confirmed in QRDR. These strains showed overexpression of mexA, mexY, mexC, and another one showed decrease of oprD expression. Resistance development in 4 strains was inhibited by the same method including the anti-ROS agent, sodium zinc histidine dithiooctanamide (DHL-His-Zn). In conclusion, stimulation by ROS promoted acquisition of multi-drug resistance in 20% of isolates of P. aeruginosa, and DHL-His-Zn completely inhibited this acquisition of resistance. Therefore, this anti-ROS agent may be useful to assist antimicrobial chemotherapy by preventing multi-drug resistance.

DOI： 10.1016/j.jiac.2018.10.003

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Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.

DOI： 10.1371/journal.pone.0215292

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Language：Japanese   Publisher：(一社)日本エイズ学会  

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Baloxavir marboxil is an orally available prodrug of baloxavir acid. Japan was the first country to approve baloxavir marboxil as a treatment for influenza. The antiviral mechanism of action of baloxavir is unique; the drug blocks initiation of viral mRNA synthesis, thus preventing proliferation of the influenza virus. A single oral dose of baloxavir is usually well tolerated; it hastens alleviation of influenza symptoms and shortens the duration of viral shedding. However, novel influenza variants exhibiting over 10-fold reductions in baloxavir susceptibility emerged in baloxavir-treated patients. Although further clinical investigation is required to explore this issue, baloxavir may revolutionize our understanding of influenza virus biology.

DOI： 10.1016/j.resinv.2018.10.002

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DOI： 10.1111/bjd.17007

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BACKGROUND: Anti-MDA-5 antibody is closely associated with interstitial lung disease (ILD) in amyopathic dermatomyositis (ADM). Patients with ADM with anti-MDA-5 antibody sometimes develop fatal ILD in spite of intensive immunosuppressive therapy. However, an initial decrease after treatment in anti-MDA-5 antibody titers may not be predictive of subsequent better survival of the disease. METHODS: To clarify immunoregulatory features of deadly ILD in ADM with the anti-MDA-5 antibody, we retrospectively examined clinical records of consecutive patients with anti-MDA-5 antibody positive ADM-ILD with preserved serum since 2000. Serum cytokine/growth factor (GF) protein concentration was measured using a cytokine panel analysis. We compared concentrations of each cytokine/GF between survivors and non-survivors and further examined changes in cytokines/GF levels during treatment in some patients. RESULTS: Twenty-six patients were enrolled in the study. Nine out of 26 patients did not respond to intensive immunosuppressive therapy and died due to respiratory failure. We compared cytokine/GF concentrations and found that serum IL-15 before treatment was significantly elevated in non-survivors than in survivors (p < 0.05). 11 out of 17 responders and 6 of 9 dead patients had preserved serum taken more than one time. We then calculated rates of change per day (slopes) in each cytokine/GF concentration. Comparison of slopes of cytokine/GF protein over the treatment duration showed that the slopes in non-survivors were significantly increased in IL-10 and IL-15 (p < 0.01). CONCLUSIONS: IL-15, as well as IL-10, may play a key role in the progression of the patients with ADM-ILD with anti-MDA-5 antibody positive.

DOI： 10.1016/j.rmed.2018.06.012

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BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

DOI： 10.21873/anticanres.12776.

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Objective Whether or not depression affects the control or severity of asthma is unclear. We performed a cluster analysis of asthma patients with depressive symptoms to clarify their characteristics. Methods Multiple medical institutions in Niigata Prefecture, Japan, were surveyed in 2014. We recorded the age, disease duration, body mass index (BMI), medications, and surveyed asthma control status and severity, as well as depressive symptoms and adherence to treatment using questionnaires. A hierarchical cluster analysis was performed on the group of patients assessed as having depression. Results Of 2,273 patients, 128 were assessed as being positive for depressive symptoms [DS(+)]. Thirty-three were excluded because of missing data, and the remaining 95 DS[+] patients were classified into 3 clusters (A, B, and C). The patients in cluster A (n=19) were elderly, had severe, poorly controlled asthma, and demonstrated possible adherence barriers; those in cluster B (n=26) were elderly with a low BMI and had no significant adherence barriers but had severe, poorly controlled asthma; and those in cluster C (n=50) were younger, with a high BMI, no significant adherence barriers, well-controlled asthma, and few were severely affected. The scores for depressive symptoms were not significantly different between clusters. Conclusion About half of the patients in the DS[+] group had severe, poorly controlled asthma, and these clusters were able to be distinguished by their Adherence Starts with Knowledge (ASK)-12 score, which reflects adherence barriers. The control status and severity of asthma may also be related to the age, disease duration, and BMI in the DS[+] group.

DOI： 10.2169/internalmedicine.9073-17

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

Background: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. Methods: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. Results: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B
35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB
p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). Conclusions: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.

DOI： 10.1245/s10434-018-6401-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

The activities of various antibiotics against 58 clinical isolates of Legionella species were evaluated using two methods, extracellular activity (minimum inhibitory concentration [MIC]) and intracellular activity. Susceptibility testing was performed using BSYEα agar. The minimum extracellular concentration inhibiting intracellular multiplication (MIEC) was determined using a human monocyte-derived cell line, THP-1. The most potent drugs in terms of MICs against clinical isolates were levofloxacin, garenoxacin, and rifampicin with MIC90 values of 0.015 μg/ml. The activities of ciprofloxacin, pazufloxacin, moxifloxacin, clarithromycin, and azithromycin were slightly higher than those of levofloxacin, garenoxacin, and rifampicin with an MIC90 of 0.03–0.06 μg/ml. Minocycline showed the highest activity, with an MIC90 of 1 μg/ml. No resistance against the antibiotics tested was detected. No difference was detected in the MIC distributions of the antibiotics tested between L. pneumophila serogroup 1 and L. pneumophila non-serogroup 1. The MIECs of ciprofloxacin, pazufloxacin, levofloxacin, moxifloxacin, garenoxacin, clarithromycin, and azithromycin were almost the same as their MICs, with MIEC90 values of 0.015–0.06 μg/ml, although the MIEC of minocycline was relatively lower and that of rifampicin was higher than their respective MICs. No difference was detected in the MIEC distributions of the antibiotics tested between L. pneumophila serogroup 1 and L. pneumophila non-serogroup 1. The ratios of MIEC:MIC for rifampicin (8) and pazufloxacin (2) were higher than those for levofloxacin (1), ciprofloxacin (1), moxifloxacin (1), garenoxacin (1), clarithromycin (1), and azithromycin (1). Our study showed that quinolones and macrolides had potent antimicrobial activity against both extracellular and intracellular Legionella species. The present data suggested the possible efficacy of these drugs in treatment of Legionella infections.

DOI： 10.1016/j.jiac.2018.01.018

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

A 52-year-old man with chronic myelogenous leukemia (CML) received dasatinib after the failure of imatinib and nilotinib therapy. Two years after the initiation of dasatinib, he developed shortness of breath that gradually worsened. Chest X-ray and computed tomography scan showed pulmonary infiltrative shadows and bilateral pleural effusion. We performed a transbronchial lung biopsy and diagnosed organizing pneumonia caused by dasatinib treatment. Corticosteroid therapy was initiated after the discontinuation of dasatinib and all his symptoms were significantly improved. Because of the exacerbation of CML, the patient was treated with imatinib and then nilotinib; however, these drugs failed to decrease the leukemic cells. Re - administration of dasatinib in combination with corticosteroid therapy successfully controlled CML without recurrence of organizing pneumonia.

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

DOI： 10.1093/cid/cix996

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier USA  

We report a very rare case of pulmonary chromomycosis caused by Scedosporium prolificans that developed after lung transplantation and was successfully treated with endobronchial topical amphotericin B instillation. The subject was a woman in her 50s with a history of bilateral lobar lung transplantation from living donors for idiopathic pulmonary hypertension. Eight years after the lung transplantation, chest radiography X-ray and computed tomography showed an abnormal shadow in the right lung. Bronchoscopic findings showed obstruction by a fungal component at the laterobasal bronchus B9. She was diagnosed with pulmonary chromomycosis after S. prolificans was detected in the bronchial aspirate. Systemic antifungal treatment with itraconazole was ineffective. Therefore, we administered topical amphotericin B weekly via endobronchial instillation and replaced oral itraconazole with voriconazole. The endobronchial procedure was safe and tolerable. Bronchial obstruction improved after three 3 instillations. We continued topical amphotericin B instillation once every 3 months for 2 years, and the abnormal shadow nearly disappeared. This case report describes infection by S. prolificans, which rarely becomes an etiologic agent in lung transplant patients, and shows that endobronchial topical amphotericin B instillation is a therapeutic option when systemic antifungal treatment is ineffective.

DOI： 10.1016/j.transproceed.2017.12.028

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Language：Japanese  

目的. サルコイドーシスやサルコイド反応は肺門・縦隔リンパ節腫大を呈し、これらを合併した肺癌症例には、リンパ節病変の評価が治療方針決定上で問題となる。本研究では、これらサルコイド反応合併肺癌症例の病期診断におけるEBUS-TBNAの有用性を検討した。対象と方法. 2009年1月から2016年12月に気管支鏡検査を実施され、サルコイドーシス/サルコイド反応と肺癌の合併と診断された症例におけるEBUS-TBNAの有効性について検討した。結果. EBUS-TBNAにより、サルコイドーシス/サルコイド反応と肺癌との合併と診断された症例は4例であった。造影CT、FDG-PET/CTでは癌のリンパ節転移とサルコイドーシス/サルコイド反応の鑑別は困難であった。4例中3例はI期の非小細胞肺癌と診断され、2例は手術が施行された。術後検体でも転移はなく、granulomaが認められたことから、サルコイド反応と診断された。4例中1例は全身性サルコイドーシスに合併したIII期の肺癌症例であった。結論. サルコイドーシス/サルコイド反応合併肺癌症例におけるN因子の評価に、EBUS-TBNAは有用であると考えられる。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01244&link_issn=&doc_id=20180515270004&doc_link_id=%2Fec7jaluc%2F2018%2F005802%2F004%2F0088-0092%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2018%2F005802%2F004%2F0088-0092%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Part of collection (book)   Publisher：Springer Singapore  

Biological agents have had a tremendous effect in the management of rheumatoid arthritis (RA). However, subsequent infection is regarded as an emerging problem owing to the suppression of host immunity by these agents. Cellular immunity with T lymphocytes plays a crucial role in host defense against mycobacterial infections
hence, immunosuppression due to these biological agents may lead to tuberculosis (TB) and nontuberculous mycobacteria (NTM) infections. Therefore, pretreatment screening for TB and NTM infection and appropriate management are crucial. In general, the lungs are the major site of infection caused by mycobacteria, and the disease may typically have a chronic course. Thus, persistent respiratory symptoms and signs trigger suspicion of pulmonary TB or NTM infection, and chest radiography as well as sputum examination plays a major role in the diagnosis. In addition, promising diagnostic tools such as interferon-gamma release assay (IGRA), anti-MAC antibody measurement, and Xpert MTB/rifampin (RIF) assay are newly available. Further research is needed to verify these assays. As a rule, to avoid development of drug-resistant strains, treatment with multiple drugs for a relatively extensive duration is required for therapy.

DOI： 10.1007/978-981-10-6750-1_11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

DOI： 10.1016/j.jiac.2017.12.009

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Nitric oxide and alveolar macrophage inflammation http://ow.ly/czCx30i12n8.

DOI： 10.1183/23120541.00071-2017

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OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

DOI： 10.1159/000486622.

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Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease.

DOI： 10.1038/s41598-017-18560-y.

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Systemic sclerosis (SSc) is an intractable disease that causes fibrosis in all organs. Approximately 40% of patients with SSc have some degree of interstitial lung disease (ILD). One third of patients with SSc and ILD, approximately 15% of all patients, have pulmonary lesions, which slowly progress to respiratory failure resistant to corticosteroid and other treatments. A randomized controlled trial conducted in the United States indicated that one year of treatment with oral cyclophosphamide in patients with SSc-ILD had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and health-related quality of life. However, all the effects, except for a sustained impact on dyspnea, disappeared approximately one year after stopping oral administration of cyclophosphamide. A randomized controlled trial using cyclophosphamide and mycophenolate mofetil (MMF) was then held in the United States for 142 patients with SSc-ILD. Treatment of SSc-ILD with MMF for two years or cyclophosphamide for one year both resulted in significant improvements in lung function over the 2-year course of the study. Leukopenia and thrombocytopenia occurred less often in patients administered MMF than in those administered cyclophosphamide. MMF is currently not approved for the treatment of SSc-ILD in Japan. Both MMF and cyclophosphamide were effective against ILD associated with SSc and, in particular, MMF was useful in terms of tolerability. When MMF is approved, it should be positioned as one of the first treatment options for SSc-ILD, which will further enhance the treatment of this disease in Japan.

DOI： 10.1016/j.resinv.2017.11.004

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Objective High adherence to medications and accurate handling of inhaler devices are important for asthma management. However, few reports to date have simultaneously evaluated adherence and handling errors. We therefore investigated the adherence to inhaled corticosteroid (ICS) and inhaler handling errors in the same patients in cooperation with pharmacists. Methods Data were derived from a survey of physicians and pharmacists treating asthma patients who visited participating hospitals and pharmacies from July 2012 to January 2013. The patients were evaluated for asthma control using the Asthma Control Test (ACT) and for inhaler handling errors using checklists. ICS adherence was evaluated based on pharmaceutical records. Results Adherence among participants (n=290) was 33.3% (mean), and the percentage of inhaler handling errors was 20.0% (mean). Total inhalation times in the high-adherence group were fewer than those in the low-adherence group. In a comparison by device, adherence to pressurized metered dose inhalers was significantly lower than that to Diskus® inhalers, presumably attributable to the total number of inhalations per day. Adherence, handling errors, and total number of inhalations per day were significantly different between the asthma-controlled group and the uncontrolled group. A multivariate analysis showed that adherence and handling errors were independent factors contributing to asthma control. Conclusion Our data indicated that both adherence to ICS and device handling errors contributed to asthma control in this population.

DOI： 10.2169/internalmedicine.0986-18.

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BACKGROUND: Presepsin is a widely recognized biomarker for sepsis. However, little is known about the usefulness of presepsin in invasive fungal infection. The aim of this study was to determine the plasma levels of presepsin in fungal bloodstream infections and to investigate whether it reflects the disease severity, similar to its utility in bacterial infections. METHODS: We prospectively measured presepsin in plasma samples from participants with fungemia from April 2016 to December 2017. The associations of C-reactive protein, procalcitonin, and presepsin concentrations with the severity of fungemia were statistically analyzed. In vitro assay was performed by incubating Escherichia coli, Candida albicans, and lipopolysaccharide to whole blood cells collected from healthy subjects; after 3 h, the presepsin concentration was measured in the supernatant and was compared among the bacteria, fungi, and LPS groups. RESULTS: Presepsin was increased in 11 patients with fungal bloodstream infections. Serial measurement of presepsin levels demonstrated a prompt decrease in 7 patients in whom treatment was effective, but no decrease or further increase in the patients with poor improvement. Additionally, presepsin concentrations were significantly correlated with the Sequential Organ Failure Assessment score (r = 0.89, p < 0.001). In vitro assay with co-incubation of C. albicans and human whole blood cells indicated that the viable cells of C. albicans caused an increase in presepsin, as seen with E. coli. CONCLUSIONS: Plasma presepsin levels increased in patients with fungal bloodstream infection, with positive association with the disease severity. Presepsin could be a useful biomarker of sepsis secondary to fungal infections.

DOI： 10.1371/journal.pone.0206089

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Lung Cancer Society  

Objective. Sarcoidosis is a systemic disease that causes the formation of noncaseating epithelioid granuloma in various organs and which often exhibits hilar and mediastinal lymphadenopathy. Among lung cancer patients with sarcoidosis or sarcoid reactions, it is difficult to evaluate the lymph node status and stage by CT and FDG-PET/CT scans. In this study, we examined the usefulness of EBUS-TBNA in the staging of the lung cancer in patients with sarcoidosis or sarcoid reactions. Materials and Methods. We evaluated the effectiveness of EBUS-TBNA in lung cancer patients with sarcoidosis or sarcoid reactions from January 2009 to December 2016. Results. We found 4 patients who were diagnosed with lung cancer accompanied by sarcoidosis and sarcoid reactions by EBUS-TBNA. All of these patients had hilar and mediastinal lymphadenopathy. EBUS-TBNA was useful for the differential diagnosis of lymph-node metastasis of lung cancer. Three of the 4 patients were diagnosed with stage I non-small cell lung cancer and surgery was performed in 2 cases. The histopathological examination of the surgical specimens confirmed that these patients had sarcoid reactions with no lymph-node metastasis. One of the 4 patients was diagnosed with stage III non-small cell lung cancer with systemic sarcoidosis. Conclusion. EBUS-TBNA seems to be useful for the evaluation of the lymph-node status of lung cancer patients with sarcoidosis and sarcoid reactions.

DOI： 10.2482/haigan.58.88

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To evaluate scoring systems to predict Legionella pneumonia and therapeutic efficacy against Legionella pneumonia, the Japanese Society of Chemotherapy Legionella committee has collected data on cases of Legionella pneumonia from throughout Japan. We analyzed 176 patients with Legionella pneumonia and compared them with 217 patients with Streptococcus pneumoniae pneumonia and 202 patients with Mycoplasma pneumoniae pneumonia. We evaluated four scoring systems, the Winthrop-University Hospital score, Community-Based Pneumonia Incidence Study Group score, and Japan Respiratory Society score, but they demonstrated limited sensitivity and specificity for predicting Legionella pneumonia. Using six clinical and laboratory parameters (high fever, high C-reactive protein, high lactate dehydrogenase, thrombocytopenia, hyponatremia, and unproductive cough) reported by Fiumefreddo and colleagues, only 6% had Legionnella pneumonia when less than 2 parameters were present. The efficacy rates of antibiotics at the time of termination were 94.6% for intravenous antibiotics, including ciprofloxacin and pazufloxacin, and 95.5% for oral antibiotics, including ciprofloxacin, levofloxacin, garenoxacin, moxifloxacin, and clarithromycin. Our results suggested that the previously reported clinical scoring systems to predict Legionnella pneumonia are not useful, but 6 simple diagnostic score accurately ruled out Legionnella pneumonia, which may help to optimize initial empiric therapy. Quinolones and clarithromycin still showed good clinical efficacy against Legionella pneumonia. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2017.09.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

Mast cells, basophils, and eosinophils are central effectors in allergic inflammatory disorders. These cells secrete abundant serine proteases as well as chemical mediators and cytokines; however, the expression profiles and functions of their endogenous inhibitors remain elusive. We found that murine secretory leukoprotease inhibitor (SLPI) is expressed in basophils and eosinophils but in not in mast cells. SLPI-deficient (Slpi(-/-)) basophils produce more cytokines than wild-type mice after IgE stimulation. Although the deletion of SLPI in basophils did not affect the release of chemical mediators upon IgE stimulation, the enzymatic activity of the serine protease tryptase was increased in Slpi-/-basophils. Mice transferred with Slpi(-/-) basophils were highly sensitive to IgE-mediated chronic allergic inflammation. Eosinophils lacking SLPI showed greater interleukin-6 secretion and invasive activity upon lipopolysaccharide stimulation, and the expression of matrix metalloproteinase-9 by these eosinophils was increased without stimulation. The absence of SLPI increases JNK1 phosphorylation at the steady state, and augments the serine phosphorylation of JNK1-downstream ETS transcriptional factor Elk-1 in eosinophils upon stimulation. Of note, SLPI interacts with a scaffold protein, JNK-interacting protein 3 (JIP3), that constitutively binds to the cytoplasmic domain of toll-like receptor (TLR) 4, suggesting that SLPI controls Elk-1 activation via binding to JIP3 in eosinophils. Mice transferred with Slpi(-/-) eosinophils showed the exacerbation of chitin-induced allergic inflammation. These findings showed that SLPI is a negative regulator in allergic effector cells and suggested a novel inhibitory role of SLPI in the TLR4 signaling pathways.

DOI： 10.3389/fimmu.2017.01538

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

Background: Asthma in athlete populations such as Olympic athletes has various pathogeneses. However, few reports are available on the features of asthma in the athlete population in clinical practice. In this study, we focused on classifying asthma in Japanese athlete population.
Methods: We performed a cluster analysis of data from pulmonary function tests and clinical biomarkers before administering inhaled corticosteroids (ICS) therapy in athlete population of individuals diagnosed with asthma (n = 104; male, 76.9%; median age, 16.0 years), based on respiratory symptoms and positive data on methacholine provocation tests. We also compared backgrounds, sports types, and treatments between clusters.
Results: Three clusters were identified. Cluster 1 (32%) comprised athletes with a less atopic phenotype and normal pulmonary function. Cluster 2 (44%) comprised athletes with a less atopic phenotype and lower percent predicted forced expiratory volume in 1 s (%FEV1) values, despite less symptomatic state. Cluster 3 (24%) comprised athletes with a strong atopic phenotype such as high eosinophil count in the blood and total serum immunoglobulin E level. After treatment with ICS or ICS plus long-acting beta-adrenergic receptor agonist for 6-12 months, %FEV1 values were significantly improved in Cluster 2 athletes, whereas Cluster 3 athletes had a significant decrease in the fraction of exhaled nitric oxide compared to pretreatment values.
Conclusions: These data suggest three clusters exist in Japanese athlete population with asthma. Between the clusters, the characteristics differed with regard to symptoms, atopic features, and lower %FEV1 values. The pathogeneses between clusters may vary depending on the inflammation type and airway hyperresponsiveness. Copyright (C) 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

DOI： 10.1016/j.alit.2017.02.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Nursing and healthcare-associated pneumonia (NHCAP) is a category of healthcare-associated pneumonia that was modified for the healthcare system of Japan. The NHCAP guidelines stated the difficulty in assessing the severity classifications, for instance, A-DROP. We compared the usefulness of different severity classifications (A-DROP, CURB-65, PSI, and I-ROAD) in predicting the prognosis of nursing and healthcare-associated pneumonia.
We conducted a retrospective analysis on 303 adult patients hospitalized for nursing healthcare-associated pneumonia and community-acquired pneumonia, which were diagnosed at the Department of Respiratory Medicine of Niigata General City Hospital between January 2012 and December 2014.
We evaluated 159 patients with community-acquired pneumonia and 144 with nursing and healthcare-associated pneumonia. In the nursing and healthcare-associated pneumonia group, 30-days mortality and in-hospital mortality rates were 6.5% and 8.7%, respectively, in severe cases and 16.1% and 25.0%, respectively, in the most severe cases, based on A-DROP. With I-ROAD, these rates were 11.1% and 11.1%, respectively, in group B and 14.9% and 20.7%, respectively, in group C. With PSI, the rates were 2.3% and 6.8%, respectively, in class IV and 14.3% and 19.8%, respectively, in class V. Despite some variability due to the small sample size, both the 30-days and in-hospital mortality rates increased as the severity increased.
In this study, both the 30-days mortality and in-hospital mortality rates in the nursing and healthcare-associated pneumonia group tended to increase in severity with the A-DROP. We found that A-DROP was useful in predicting the prognosis of nursing and healthcare-associated pneumonia. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2017.04.013

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The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naive T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naive T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naive T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-D expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo D expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo D expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.

DOI： 10.1371/journal.pone.0183976

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A 59-year-old Japanese man diagnosed with interstitial lung disease associated with amyopathic dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA-5) antibodies was treated with intravenous methyl prednisolone (PSL) 1000 mg, oral PSL 1 mg/kg, and oral cyclosporin 200 mg daily. His respiratory condition worsened after treatment with two times of intravenous cyclophosphamide and another steroid pulse therapy as well as PSL and cyclosporin. Addition of mycophenolate mofetil (MMF), 1.5 g daily improved PaO2/FiO2 (PF) ratio of the patient from 294 to 360 at 4 weeks and 416 at 15 weeks after addition of MMF. We measured cytokine concentration in preserved serum taken at 11 and 7 weeks before addition of MMF and at 4, 11, and 15 weeks after MMF administration. Of the 28 cytokines evaluated, the concentrations of fibroblast growth factors-2 (FGF-2), chemokine (C-X3-C motif) ligand 1 (CX3CL1), interleukin (IL)-1ra, IL-17A, inducible protein 10 (IP-10), and monocyte chemotactic protein-1 (MCP-1) decreased after addition of MMF. These results suggest that MMF may be beneficial to patients with interstitial lung disease by modification of the cytokine/growth factor protein expression.

DOI： 10.1002/rcr2.235

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEPHROLOGY  

Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant Staphylococcus aureus, and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin in vitro, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated via megalin in the clinical setting.

DOI： 10.1681/ASN.2016060606

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Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral-blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR-mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto-oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR-mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3-mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR-mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR-mutant lung cancer by underscoring MET-related signaling molecules.

DOI： 10.1111/cas.13233

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objective/background: Multiple system atrophy (MSA) frequently results in the development of sleep disordered breathing (SDB). Few reports have described the natural course of this phenomenon. The aim of the present study was to determine the natural course of SDB and prognostic factors associated with such conditions in MSA.
Patients/methods: Twenty-four consecutive patients were recruited with probable MSA, who had not been treated with continuous positive airway pressure (CPAP) and had undergone overnight poly-somnography (PSG) more than once following the development of snoring or stridor. Based on changes in the apnea-hypopnea index (AHI) over the course of the disease, patients were divided into two groups (AHI-maintained and AHI-deteriorated) and the clinical findings were compared.
Results: Mean duration between the first and last PSG was 2.4 +/- 1.5 years, and patients underwent PSG assessment an average of 2.5 +/- 0.6 times during this period. During this interval, AHI increased from 19.4 +/- 22.8/hour to 34.4 +/- 30.1/hour (p = 0.006), although spontaneous improvement was observed in 29% of patients. Following the first PSG, all patients were diagnosed with obstructive sleep apnea; however, the SDB type changed from obstructive sleep apnea to central sleep apnea in 3 of the 24 (13%) patients during the period between the first and last PSG.
Conclusions: Although SDB associated with MSA exacerbates with disease progression, spontaneous improvement in AHI may occur in some patients. Earlier development of snoring or stridor may predict rapid progression of SDB in MSA. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.sleep.2017.01.020

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Language：Japanese  

[目的]静注用ヒト免疫グロブリン製剤(以下,IVIG製剤)が,(1→3)-β-Dグルカン(以下,β-D-グルカン)の測定結果に及ぼす影響を明らかにする.[方法]国内で使用可能なIVIG製剤7種に含有されるβ-D-グルカン濃度を,各製剤3ロットずつ(ファンギテックGテストMKII,以下MKII法),βグルカンテストワコー(以下ワコー法)を用い測定した.また,新潟大学医歯学総合病院で2012年1月から2013年12月にかけてIVIG製剤が使用され,その前後でβ-D-グルカンが測定されている成人例を対象に,β-D-グルカン値の挙動を検討した.[成績]IVIG製剤ごとにβ-D-グルカン含有量は大きく異っていた(MKII法:7.3〜300以上pg/mL,ワコー法:3.5以下-288.8pg/mL)が,ロット間での違いは限定的であり,製造工程での混入が推定された.2種類の測定キットによるβ-D-グルカン測定結果間の相関係数rは0.90と一定の相関が見られた.調査の対象となった臨床検体51例(年齢中央値64歳,男性60.1%)中,他の要因を除外し,IVIG製剤投与によるβ-D-グルカン偽陽性と考えられた症例は5例(9.8%)で,β-D-グルカンの最高値は57.1pg/mL,使用前後の変動幅は最大で44.5pg/mLであった.[結論]IVIG製剤の種類によりβ-D-グルカン含有量は大きく異なっていた.IVIG製剤の投与によると推定される血清β-D-グルカン値の偽陽性率は9.8%であった.またIVIG製剤投与後の陽性予測値は37.5%と低値であり,IVIG製剤使用後のβ-D-グルカン測定結果の解釈には注意が必要と思われた.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

Background: Sublingual immunotherapy (SLIT) has received attention as a method for allergen immunotherapy. However, the mechanism of SLIT has not yet been fully investigated. Therefore, we evaluated the effects of SLIT in a murine asthma model, sensitized by intranasal administration of house dust mite (HDM) extracts.
Methods: Female BALB/c mice were intranasally exposed to HDM for either 3 or 5 weeks (5 consecutive days per week). Mice were administered either low-dose (0.5 mg/day) or high-dose (5 mg/day) sublingual HDM extracts for 2 weeks, followed by an additional week of intranasal exposure. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, cytokine levels in the BALF and lymph node cell culture supernatants, and allergen-specific antibodies were measured. Lung histology was also investigated.
Results: In mice sensitized for 5 weeks, high-dose SLIT ameliorated AHR, airway eosinophilia and goblet cell metaplasia. In mice sensitized for 3 weeks, even low dose SLIT ameliorated AHR and airway eosinophilia. Th2 cytokine levels in culture supernatants of submandibular lymph node cells in high dose SLIT mice decreased, whereas IL-10 levels increased. Total IgA in BALF increased in mice sensitized for 3 or 5 weeks, and high-dose SLIT also increased allergen-specific IgG2a in mice sensitized for 5 weeks.
Conclusions: These data suggest that earlier induction of SLIT in HDM-sensitized mice provides superior suppression of AHR and goblet cell metaplasia. The modulation of allergen specific IgG2a and local IgA might play a role in the amelioration of AHR and airway inflammation. Copyright (C) 2016, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

DOI： 10.1016/j.alit.2016.05.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER LONDON LTD  

DOI： 10.1007/s10067-016-3443-2

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DOI： 10.4172/2327-5073.1000264

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Pseudo-achalasia with lung cancer is a rare complication. We present 2 cases of pseudo-achalasia with lung cancer and summarize previous reports. The previous reports suggested that lung cancer can be complicated with pseudo-achalasia caused by paraneoplastic neurological syndromes rather than direct invasion of the tumor cells to the lower esophageal sphincter, irrespective of the histology of the lung cancer
this can strongly influence the performance status. Treatment for pseudo-achalasia improves not only the symptoms, but also the performance status. Therefore, pseudo-achalasia should be considered when lung cancer patients present with dysphagia without other known causes.

DOI： 10.1016/j.resinv.2016.04.006

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症例1は75歳、男性。症例2は64歳、男性。いずれも、術後再発非小細胞肺癌に対する胸部照射後に出現した浸潤影を放射線肺炎と診断し、ステロイド治療を行った。陰影は急速に増大したために抗菌薬治療を行ったが不応性であった。喀痰または肺洗浄検体よりアスペルギルス属を検出し、その後長期にわたる抗真菌薬治療を必要とした。呼吸器内科医として日常遭遇する可能性が高く、鑑別診断に慎重を要する2症例と考えられ報告する。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J05953&link_issn=&doc_id=20161205180012&doc_link_id=%2Fci6respo%2F2016%2F000506%2F012%2F0341-0345%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fci6respo%2F2016%2F000506%2F012%2F0341-0345%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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© 2016 The Author(s). Background: In response to tissue damage or inflammation, adenosine-5'-triphosphate (ATP) is released into the extracellular compartment and has been demonstrated to augment inflammation via purinergic P2 receptors (P2Rs). Recently, ATP has been shown to be increased in the airways of COPD patients. In the present study, we examined the possible involvement of extracellular ATP in airway mucus hypersecretion during viral-induced COPD exacerbations. Methods: The involvement of extracellular ATP in the release of a major airway mucin, MUC5AC, and its signal pathway was examined after stimulation with polyinosine-polycytidylic acid [poly(I:C)], a synthetic analog of dsRNA to mimic viral infection, and rhinovirus (RV) infection in NCI-H292 cells and differentiated airway epithelial cells from COPD patients. Results: Treatment with poly(I:C) significantly increased the amount of extracellular ATP and induced MUC5AC release in NCI-H292 cells. Pre-treatment with a pannexin channel inhibitor, carbenoxolone (CBX), reduced the amount of extracellular ATP and suppressed MUC5AC release from poly(I:C)-treated cells. Pre-treatment with the P2R antagonist suramin significantly reduced the expression and release of MUC5AC. The inhibitory effects of CBX and suramin on the release of ATP and/or MUC5AC were replicated with RV infection. Pre-treatment with suramin also significantly reduced the expression and amount of extracellular EGFR ligands and the phosphorylation of EGFR and ERK in poly(I:C)-treated cells. In addition, pre-treatment with a P2Y2 receptor siRNA significantly suppressed the poly(I:C)-potentiated EGFR ligands and MUC5AC release. After poly(I:C) stimulation, the expression of MUC5AC in the differentiated cells from COPD patients was significantly higher than those from healthy subjects and the values of MUC5AC expression were inversely related with forced expiratory volume in 1 s (FEV1) % predicted. The inhibitory effects of CBX and suramin on poly(I:C)-potentiated MUC5AC expression were confirmed in differentiated airway epithelium from COPD patients. Conclusions: These results demonstrate that dsRNA induces the release of ATP via pannexin channel and that the extracellular ATP is involved in the expression and release of MUC5AC, mainly via P2Y2R, in an autocrine manner. Modulation of this pathway could be a therapeutic target for viral-induced mucus hypersecretion in COPD exacerbations.

DOI： 10.1186/s12931-016-0438-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Cellular senescence is reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously showed that 27-hydroxy-cholesterol (27-OHC) is elevated in the airways of COPD patients compared with those in healthy subjects. The aim of this study was to investigate whether lung fibroblasts of COPD patients are senescent and to determine the effects of 27-OHC on senescence of lung resident cells, including fibroblasts and airway epithelial cells. Localization of senescence-associated proteins and sterol 27-hydroxylase was investigated in the lungs of COPD patients by immunohistochemical staining. To evaluate whether 27-OHC accelerates cellular senescence, lung resident cells were exposed to 27-OHC. Senescence markers and fibroblast-mediated tissue repair were investigated in the 27-OHC-treated cells. Expression of senescence-associated proteins was significantly enhanced in lung fibroblasts of COPD patients. Similarly, expression of sterol 27-hydroxylase was significantly up-regulated in lung fibroblasts and alveolar macrophages in these patients. Treatment with the concentration of 27-OHC detected in COPD airways significantly augmented expression of senescence-associated proteins and senescence-associated beta-galactosidase activity, and delayed cell growth through the prostaglandin E2-reactive nitrogen species pathway. The 27-OHC-treated fibroblasts impaired tissue repair function. Fibroblasts from lungs of COPD patients showed accelerated senescence and were more susceptible to 27-OHC-induced cellular senescence compared with those of healthy subjects. In conclusion, 27-OHC accelerates cellular senescence in lung resident cells and may play a pivotal role in cellular senescence in COPD.

DOI： 10.1152/ajplung.00351.2015

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© 2016 The Japanese Respiratory Society. Endobronchial aspergilloma is a rare and unusual presentation of lung aspergilloma; the natural history for such rare diseases is poorly understood. This report presents two cases of endobronchial aspergilloma complicated by primary and metastatic lung cancer, and summarizes previous reports that suggest that an endobronchial lung cancer lesion may promote the colonialization and growth of Aspergillus species in the bronchus. Therefore, if endobronchial aspergilloma is found, the complication of primary or metastatic endobronchial lung cancer should be carefully considered.

DOI： 10.1016/j.resinv.2015.12.005

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

Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40-OX40 ligand (OX40L) interactions has been explored in the non-infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza-damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense-like host responses lead to more extensive infection owing to the induced OX40L with -2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L-mediated susceptibility to influenza. Our data illustrate that the influenza-induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza.

DOI： 10.15252/emmm.201506154

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Paradoxical inflammations during anti-TNF-alpha therapy are defined as adverse effects such as psoriasiform skin lesions, uveitis and sarcoidosis-like granulomas induced by immune reactions, not by infectious agents. Here, we report a very rare case of the simultaneous development of sarcoidosis and cutaneous vasculitis in a patient with refractory Crohn's disease during infliximab therapy and both of which resolved spontaneously without the cessation of infliximab.
Case presentation: In September 2000, 23-year old Japanese male was diagnosed with Crohn's disease. Prednisolone in combination with mesalazine was introduced at first and succeeded for almost one year. In June 2002, since his gastrointestinal symptoms relapsed and were refractory, infliximab (IFX) therapy 5 mg/kg was introduced. In February 2011, because he had repeated arthralgia almost every intravenous IFX administration, IFX was increased to 10 mg/kg under the diagnosis of a secondary failure of IFX. In December 2012, he complained of slight dry cough and an itchy eruption on both lower limbs, and he was referred to our hospital due to the appearance of bilateral hilar lymphadenopathy on chest X-ray examination. Chest computed tomogram revealed bilateral hilar lymphadenopathy and fine reticulonodular shadows on the bilateral upper lungs. Serum calcium, angiotensin-converting enzyme and soluble interleukin 2 receptor levels were not elevated, but the titer of antinuclear antibody was considerably elevated. Mycobacterium infection was carefully excluded. Trans-bronchial lung biopsy showed non-caseating epithelioid cell granulomas compatible with sarcoidosis. The skin biopsy of the right limb was diagnosed as leukocytoclastic vasculitis. The patient was diagnosed as having a series of paradoxical inflammations during anti-TNF-alpha therapy. Since his paradoxical inflammations were not severe and opportunistic infections were excluded, IFX was cautiously continued for refractory Crohn's disease. Nine months later, not only his intrathoracic lesions but also his cutaneous lesions had spontaneously resolved.
Conclusion: Physicians caring for patients with anti-TNF-alpha therapy should know that, based on a careful exclusion of infectious agents and thoughtful assessment of the patient's possible risks and benefits, paradoxical inflammations can be resolved without the cessation of anti-TNF-alpha therapy.

DOI： 10.1186/s12890-016-0193-5

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© 2016 Abe et al. Background: Small airway remodeling is an important cause of the airflow limitation in chronic obstructive pulmonary disease (COPD). A large population of patients with COPD also have pulmonary hypertension. Krüppel-like factor 5 (KLF5) is a zinc-finger transcription factor that contributes to tissue remodeling in cardiovascular diseases. Here, we evaluate the possible involvement of KLF5 in the remodeling of small airways and pulmonary vessels in COPD. Methods: Lung tissues were obtained from 23 control never-smokers, 17 control ex-smokers and 24 ex-smokers with COPD. The expression of KLF5 in the lung tissues was investigated by immunohistochemistry. We investigated whether oxidative/nitrosative stress, which is a major cause of the pathogenesis in COPD, could augment the production of KLF5. We examined the role of KLF5 in the stress-mediated tissue remodeling responses. We also investigated the susceptibility of KLF5 expression to nitrosative stress using bronchial fibroblasts isolated from the lung tissues. Results: The expression of KLF5 was up-regulated in the small airways and pulmonary vessels of the COPD patients and it was mainly expressed in bronchial fibroblasts and cells of the pulmonary vessels. The extent of the KLF5 expression in the small airway of the COPD group had a significant correlation with the severity of the airflow limitation. Oxidative/nitrosative stress augmented the production of KLF5 in lung fibroblasts as well as the translocation of KLF5 into the nuclei. Silencing of KLF5 suppressed the stress-augmented differentiation into myofibroblasts, the release of collagens and metalloproteinases. Bronchial fibroblasts from the patients with COPD highly expressed KLF5 compared to those from the control subjects under basal condition and were more susceptible to the induction of KLF5 expression by nitrosative stress compared to those from the control subjects. Conclusion: We provide the first evidence that the expression of KLF5 is up-regulated in small airways and pulmonary vessels of patients with COPD and may be involved in the tissue remodeling of COPD.

DOI： 10.1186/s12931-016-0322-y

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公益社団法人日本化学療法学会では、厚生労働省医薬食品局審査管理課より、レジオネラ属の適応を取得した抗菌薬を製造・販売する製薬企業が実施する製造販売後調査への協力依頼を受け、2006年よりレジオネラ治療薬評価事業を行っている。本委員会では、これまで各製薬企業が製造販売後調査で収集した症例を中心に調査を行ってきたが、今回、実地医療におけるレジオネラの診断方法や治療の実態について、より多くの情報を収集することを目的に日本化学療法学会員を対象にアンケート調査を実施した。本アンケートは日本化学療法学会員3,867名に発送し、322名(回答率:8.3%)の医師から回答を得た。その結果、温泉や循環式浴槽等の入浴歴がある患者や肺炎の病態が急激に悪化した患者、β-ラクタム系薬の効果が不十分(または無効)の患者に対しては、7〜8割の医師がレジオネラ検査を実施し、約2割の医師では、高齢者や肺炎の患者には全例でレジオネラ検査が実施されていた。また、レジオネラ検査の種類は、ほとんどの医師が尿中抗原検査を実施し、培養検査、血清抗体価検査、PCR検査は補足的に実施されていた。治療抗菌薬は、注射用キノロン系薬やマクロライド系薬が選択されており、レジオネラに効果が期待される抗菌薬が適切に選択されていると考えられた。さらに、レジオネラ検査の結果が陽性の場合だけでなく、陰性であった場合でも、レジオネラ肺炎が疑われる患者には、これらの抗菌薬で治療されていることが明らかになった。再燃予防には、キノロン系薬やマクロライド系薬の経口剤が処方され、治療効果判定には、臨床症状、胸部X線・CT検査、臨床検査結果を指標とし、補足的に尿中抗原検査等のレジオネラ検査の結果が用いられていた。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The use of lung progenitors for regenerative medicine appears promising, but their biology is not fully understood. Here, we found anti-inflammatory attributes in bronchiolar progenitors that were sorted as a multipotent subset of mouse club cells and found to express secretory leukocyte protease inhibitor (SLPI). Notably, the impaired expression of SLPI in mice increased the number of bronchiolar progenitors and decreased the lung inflammation. We determined a transcriptional profile for the bronchiolar progenitors of Slpi-deficient mice and identified syndecan 4, whose expression was markedly elevated as compared to that of wild-type mice. Systemic administration of recombinant syndecan 4 protein caused a substantial increase in the number of bronchiolar progenitors with concomitant attenuation of both airway and alveolar inflammation. The syndecan 4 administration also resulted in activation of the Keap1-Nrf2 antioxidant pathway in lung cells, which is critically involved in the therapeutic responses to the syndecan 4 treatment. Moreover, in 3D culture, the presence of syndecan 4 induced differentiated club cells to undergo Nrf2-dependent transition into bronchiolar progenitors. Our observations reveal that differentiative switches between bronchiolar progenitors and club cells are under the Nrf2-mediated control of SLPI and syndecan 4, suggesting the possibility of new therapeutic approaches in inflammatory lung diseases.

DOI： 10.1038/mt.2015.153

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

Background: Small airway remodeling is an important cause of the airflow limitation in chronic obstructive pulmonary disease (COPD). A large population of patients with COPD also have pulmonary hypertension. Kruppel-like factor 5 (KLF5) is a zinc-finger transcription factor that contributes to tissue remodeling in cardiovascular diseases. Here, we evaluate the possible involvement of KLF5 in the remodeling of small airways and pulmonary vessels in COPD.Methods: Lung tissues were obtained from 23 control never-smokers, 17 control ex-smokers and 24 ex-smokers with COPD. The expression of KLF5 in the lung tissues was investigated by immunohistochemistry. We investigated whether oxidative/nitrosative stress, which is a major cause of the pathogenesis in COPD, could augment the production of KLF5. We examined the role of KLF5 in the stress-mediated tissue remodeling responses. We also investigated the susceptibility of KLF5 expression to nitrosative stress using bronchial fibroblasts isolated from the lung tissues.Results: The expression of KLF5 was up-regulated in the small airways and pulmonary vessels of the COPD patients and it was mainly expressed in bronchial fibroblasts and cells of the pulmonary vessels. The extent of the KLF5 expression in the small airway of the COPD group had a significant correlation with the severity of the airflow limitation. Oxidative/nitrosative stress augmented the production of KLF5 in lung fibroblasts as well as the translocation of KLF5 into the nuclei. Silencing of KLF5 suppressed the stress-augmented differentiation into myofibroblasts, the release of collagens and metalloproteinases. Bronchial fibroblasts from the patients with COPD highly expressed KLF5 compared to those from the control subjects under basal condition and were more susceptible to the induction of KLF5 expression by nitrosative stress compared to those from the control subjects.Conclusion: We provide the first evidence that the expression of KLF5 is up-regulated in small airways and pulmonary vessels of patients with COPD and may be involved in the tissue remodeling of COPD.

DOI： 10.1186/s12931-016-0322-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

The prognosis of glioblastoma (GBM) remains poor; therefore, effective therapeutic strategies need to be developed. CD40 is a costimulatory molecule whose agonistic antibody has been shown to activate antitumor effects. Recently, CD40 has been extensively targeted for immunotherapeutic purposes.
Expressions of CD40/CD40L mRNAs were examined in 86 cases of World Health Organization grade IV GBM and 36 cases of grade III gliomas and correlated with outcomes. CD40 signaling was employed to augment the efficacy of immunotherapy against gliomas. The efficacy of FGK45, an agonistic antibody for CD40, was examined by adding it to a tumor lysate-based subcutaneous vaccination against a GL261 glioma model and an NSCL61 glioma-initiating cell-like cell tumor model.
We demonstrated for the first time using quantitative PCR that grade III gliomas express higher levels of CD40/CD40L than does grade IV GBM. The higher expression of CD40/CD40L was associated with good prognoses in patients with GBM. Addition of FGK45 to the subcutaneous tumor cell lysate-based vaccination significantly prolonged survival in both tumor models. However, the efficacy was modest in NSCL61-model mice. Therefore, we established combination immunotherapeutic strategies using FGK45 and OX86, an agonistic antibody for OX40. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis increased and proliferation decreased in tumors treated with combination immunotherapy.
The high expression of CD40/CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells.

DOI： 10.1093/neuonc/nov090

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Pseudomonas aeruginosa is the main causative bacteria of contact lens (CL)-associated microbial keratitis. Generally, multi-purpose solutions (MPSs) are widely used for washing, disinfection, and storage of CLs. However, the sterilization effect of an MPS against biofilm-producing P. aeruginosa is insufficient. The aim of the present study is to evaluate the bactericidal effect against biofilm-producing P. aeruginosa on CLs using plasma discharge. The standard strain of P. aeruginosa, PAO1, was used to make a biofilm-formed contamination model. The bactericidal effect of five MPSs and plasma discharge against biofilm-producing P. aeruginosa was observed using the culture method, scanning electron microscopy, and fluorescence microscopy. Plasma discharge was produced for 3, 5, or 10 min. Temperature, pH, and the concentrations of ozone (O-3), hydrogen peroxide (H2O2), and nitrogen dioxide (NO2) in the discharged water were monitored. None of the tested MPSs showed a bactericidal effect after 4 h. In contrast, biofilm-producing P. aeruginosa strains were sterilized within 10 min using plasma discharge. Moreover, it was confirmed using fluorescence microscopy that there was no viable bacterium on the surface of the contamination model irradiated for 10 min. Although the concentration of O-3 was 5 ppm after 3 min of discharge, it gradually decreased subsequently. Both NO2 and H2O2 concentrations gradually increased. Water temperature rose from 18 to 45 A degrees C, and pH changed from 6 to 2. The results show that plasma discharge may be effective for the sterilization of biofilm-producing P. aeruginosa on CLs.

DOI： 10.1007/s40846-015-0080-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The prevalence and severity of bronchial asthma are higher in females than in males after puberty. Although antigen-specific CD8(+) T cells play an important role in the development of asthma through their suppressive effect on cytokine production, the contribution of CD8(+) T cells to sex differences in asthmatic responses remains unclear. In the present study, we investigated the sex-specific effect of CD8(+) T cells in the suppression of asthma using an ovalbumin mouse model of asthma. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, lung type 2 T-helper cytokine levels, and interleukin-4 (IL-4) production by bronchial lymph node cells were significantly higher in female wild-type (WT) mice compared with male mice, whereas no such sex differences were observed between male and female cd8a-disrupted mice. The adaptive transfer of male, but not female, CD8(+) T cells reduced the number of inflammatory cells in the recovered BAL fluid of male recipient mice, while no such sex difference in the suppressive activity of CD8(+) T cells was observed in female recipient mice. Male CD8(+) T cells produced higher levels of IFN-gamma than female CD8(+) T cells did, and this trend was associated with reduced IL-4 production by male, but not female, CD4(+) T cells. Interestingly, IFN-gamma receptor expression on CD4(+) T cells was significantly lower in female mice than in male mice. These results suggest that female-dominant asthmatic responses are orchestrated by the reduced production of IFN-gamma by CD8(+) T cells and the lower expression of IFN-gamma receptor on CD4(+) T cells in females compared with males.

DOI： 10.1371/journal.pone.0140808

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
The current guidelines recommend 21-day adjunctive corticosteroid therapy for HIV-1-infected pneumocystis pneumonia patients (HIV-PCP) with moderate-to-severe disease. Whether shorter adjunctive corticosteroid therapy is feasible in such patients is unknown.
Methods
We conducted a retrospective study to elucidate the proportion of patients with moderate and severe HIV-PCP who required adjunctive corticosteroid therapy for 21 days. The enrollment criteria included HIV-PCP that fulfilled the current criteria for 21-day corticosteroid therapy; PaO2 on room air of &lt;70mmHg or A-aDO(2) &gt;= 35 mmHg.
Results
The median duration of corticosteroid therapy in the 73 study patients was 13 days (IQR 9-21). Adjunctive corticosteroid therapy was effective and discontinued within 10 and 14 days in 30% and 60% of the patients, respectively. Only 9% of the patients with moderate HIV-PCP (n = 22, A-aDO(2) 35-45 mmHg) received steroids for &gt; 14 days, whereas 35% of the patients with severe HIV-PCP (n = 51, A-aDO(2) &gt;= 45 mmHg) required corticosteroid therapy for &gt;= 21 days. Four (13%) of the severe cases died, whereas no patient with moderate disease died. Among patients with severe HIV-PCP, discontinuation of corticosteroid therapy within 14 days correlated significantly with higher baseline CD4 (p = 0.049).
Conclusion
Shorter adjunctive corticosteroid therapy was clinically effective and adjunctive corticosteroid could be discontinued within 14 days in 60% of moderate-to-severe HIV-PCP and 90% of moderate cases.

DOI： 10.1371/journal.pone.0138926

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Chronic inflammation induces lymphangiogenesis and blood vessel remodelling. Since aged pneumonia patients often have repeated episodes of aspiration pneumonia, the pathogenesis may involve chronic inflammation. For lymphangiogenesis, VEGFR-3 and its ligand VEGF-C are key factors. No previous studies have examined chronic inflammation or vascular changes in aspiration pneumonia or its mouse models. In lung inflammation, little is known about the effect of blocking VEGFR-3 on lung lymphangiogenesis and, moreover, its effect on the disease condition. This study aimed to establish a mouse model of aspiration pneumonia, examine the presence of chronic inflammation and vascular changes in the model and in patients, and evaluate the effect of inhibiting VEGFR-3 on the lymphangiogenesis and disease condition in this model. To induce aspiration pneumonia, we repeated inoculation of pepsin at low pH and LPS into mice for 21-28 days, durations in which bronchioalveolar lavage and plasma leakage in the lung suggested the presence of exaggerated inflammation. Conventional and immunohistochemical analysis of tracheal whole mounts suggested the presence of chronic inflammation, lymphangiogenesis, and blood vessel remodelling in the model. Quantitative RT-PCR of the trachea and lung suggested the involvement of lymphangiogenic factor VEGF-C, VEGFR-3, and pro-inflammatory cytokines. In the lung, the aspiration model showed the presence of chronic inflammation and exaggerated lymphangiogenesis. Treatment with the VEGFR inhibitor axitinib or the VEGFR-3 specific inhibitor SAR131675 impaired lymphangiogenesis in the lung and improved oxygen saturation in the aspiration model. Since the lung is the main site of aspiration pneumonia, the changes were intensive in the lung and mild in the trachea. Human lung samples also showed the presence of chronic inflammation and exaggerated lymphangiogenesis, suggesting the relevance of the model to the disease. These results suggest lymphatics in the lung as a new target of analysis and therapy in aspiration pneumonia. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.4473

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-beta 1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-beta 1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-beta 1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial mesenchymal relationships and that STC1 plasnnid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.

DOI： 10.1038/mt.2014.217

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Glioblastoma is the most malignant human brain tumor and has a dismal prognosis; however, some patients show long-term survival. The interaction between the costimulatory molecule OX40 and its ligand OX40L generates key signals for T-cell activation. The augmentation of this interaction enhances antitumor immunity. In this present study, we explored whether OX40 signaling is responsible for antitumor adaptive immunity against glioblastoma and also established therapeutic antiglioma vaccination therapy.
Methods: Tumor specimens were obtained from patients with primary glioblastoma (n = 110) and grade III glioma (n = 34). Quantitative polymerase chain reaction (PCR), flow cytometry, and immunohistochemistry were used to analyze OX40L expression in human glioblastoma specimens. Functional consequences of OX40 signaling were studied using glioblastoma cell lines, mouse models of glioma, and T cells isolated from human subjects and mice. Cytokine production assay with mouse regulatory T cells was conducted under hypoxic conditions (1.5% O-2).
Results: OX40L mRNA was expressed in glioblastoma specimens and higher levels were associated with prolonged progression-free survival of patients with glioblastoma, who had undergone gross total resection. In this regard, OX40L protein was expressed in A172 human glioblastoma cells and its expression was induced under hypoxia, which mimics the microenvironment of glioblastoma. Notably, human CD4 T cells were activated when cocultured in anti-CD3-coated plates with A172 cells expressing OX40L, as judged by the increased production of interferon-y. To confirm the survival advantage of OX40L expression, we then used mouse glioma models. Mice bearing glioma cells forced to express OX40L did not die during the observed period after intracranial transplantation, whereas all mice bearing glioma cells lacking OX40L died. Such a survival benefit of OX40L was not detected in nude mice with an impaired immune system. Moreover, compared with systemic intraperitoneal injection, the subcutaneous injection of the OX40 agonist antibody together with glioma cell lysates elicited stronger antitumor immunity and prolonged the survival of mice bearing glioma or glioma-initiating cell-like cells. Finally, OX40 triggering activated regulatory T cells cultured under hypoxia led to the induction of the immunosuppressive cytokine IL10.
Conclusion: Glioblastoma directs immunostimulation or immunosuppression through OX40 signaling, depending on its microenvironment.

DOI： 10.1186/s12943-015-0307-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) was proposed by the science committees of both Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD). However, the definition of ACOS has remained unclear all over the world, and the prevalence rate of ACOS is basically dependent on the patient's symptoms or the physician's opinion, based on questionnaire testing. In the current case report, we investigated the prevalence rate of COPD patients with high levels of fractional exhaled nitric oxide (FENO) or immunoglobulin E (IgE) as candidate markers of ACOS in COPD, as a multicenter, cross-sectional study. Outpatients with COPD were enrolled from Tohoku University Hospital, Sendai, Japan, and five hospitals (Tohoku University Hospital, Sendai, Japan; NTT East Tohoku Hospital, Sendai, Japan; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to February 28, 2014. When they were estimated using 35 ppb as the cutoff value of FENO, the prevalence rate of ACOS was 16.3% in COPD. When estimated by both FENO and IgE, the high-FENO/highIgE group was 7.8% in COPD. To the best of our knowledge, this study is the first to detect the prevalence rate of ACOS in COPD populations by using objective biomarkers. The results from the current study should be useful to identify the subgroup requiring early intervention by inhaled corticosteroids/long-acting beta agonist combination in COPD in order to improve the long-term management for ACOS.

DOI： 10.2147/COPD.S88274

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

The functional interplay between cancer cells and marrow stromal cells (MSCs) has attracted a great deal of interest due to the MSC tropism for tumors but remains to be fully elucidated. In this study, we investigated human MSC-secreted paracrine factors that appear to have critical functions in cancer stem cell subpopulations. We show that MSC-conditioned medium reduced the cancer stem cell-enriched subpopulation, which was detected as a side population and quiescent (G(0)) cell cycle fraction in human lung cancer cells by virtue of fibroblast growth factor 10 (FGF10). This reduction of the stem cell-enriched fraction was also observed in lung cancer cells supplemented with recombinant human FGF10 protein. Moreover, supplementary FGF10 attenuated the expression of stemness genes encoding transcription factors, such as OCT3/4 and SOX2, and crippled the self-renewal capacity of lung cancer cells, as evidenced by the impaired formation of floating spheres in the suspension culture. We finally confirmed the therapeutic potential of the FGF10 treatment, which rendered lung cancer cells prone to a chemotherapeutic agent, probably due to the reduced cancer stem cell subpopulation. Collectively, these results add further clarification to the molecular mechanisms underlying MSC-mediated cancer cell kinetics, facilitating the development of future therapies.

DOI： 10.1128/MCB.00871-13

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Secretory leukocyte protease inhibitor (SLPI), 11.7 kDa serine protease inhibitor, is produced primarily in the respiratory tract, but it is often elevated in lung, head/neck and ovarian cancers. SLPI expression in relation to cancer progression, metastasis and invasion has been studied extensively in non-small cell lung cancer. However, the role of SLPI during the early stages of carcinogenesis remains unknown. We hypothesized that SLPI is required from the initiation and promotion to the progression of lung carcinogenesis. A skin allograft model using SLPI-knockout (SLPI-KO) mice and short hairpin RNA-treated cells was used to demonstrate that SLPI expression in tumor cells is crucial for tumor formation. Moreover, lung tumorigenesis induced by urethane, a chemical lung carcinogen, was significantly suppressed in SLPI-KO mice in association with decreased nuclear factor-kappaB (NF-B) activity. SLPI deficiency also resulted in decreased cell numbers and decreased production of inflammatory cytokines in bronchoalveolar lavage fluids. The suppression of NF-B activation in SLPI-KO mice was associated with lower expression of NF-B-related survival genes and DNA repair genes. Our findings demonstrate that SLPI plays an important role from the initial stages of lung carcinogenesis to the progression of lung cancer in an NF-B-dependent manner.We showed that lung tumorigenesis induced by urethane, was suppressed in SLPI-KO mice in association with decreased NF-B activity. SLPI is important from the initial stages of lung carcinogenesis to the progression of lung cancer in an NF-B-dependent manner.

DOI： 10.1093/carcin/bgt382

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Factors that can interfere with the successful treatment of Mycobacterium avium lung infection have been inadequately studied. To identify a potent predictor of therapeutic responses of M.avium lung infection, we analyzed variable number tandem repeats (VNTR) at 16 minisatellite loci of M.avium clinical isolates. Associations between the VNTR profiling data and a therapeutic response were evaluated in 59 subjects with M.avium lung infection. M.avium lung infection of 30 subjects in whom clarithromycin-containing regimens produced microbiological and radiographic improvement was defined as responsive disease, while that of the remaining 29 subjects was defined as refractory disease. In phylogenetic analysis using the genotypic distance aggregated from 16-dimensional VNTR data, 59M.avium isolates were divided into three clusters, which showed a nearly significant association with therapeutic responses (p 0.06). We then subjected the raw 16-dimensional VNTR data directly to principal component analysis, and identified the genetic features that were significantly associated with the therapeutic response (p&lt;0.05). By further analysis of logistic regression with a stepwise variable-selection, we constructed the highest likelihood multivariate model, adjusted for age, to predict a therapeutic response, using VNTR data from only four minisatellite loci. In conclusion, we identified four mycobacterial minisatellite loci that together were associated with the therapeutic response of M.avium lung infections.

DOI： 10.1111/1469-0691.12285

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

Background: Psychological stress is associated with the aggravation of asthma symptoms. Glucocorticoids (GC), which are stress hormones released upon exposure to stress, have the potential to shift immune responses towards a predominant Th2 response by priming antigen-presenting cells to produce lower levels of IL-12 as well as reducing the development of regulatory T cells. However, the involvement of GC in psychological stress-induced exacerbations of allergic asthma has not yet been clarified. Methods: Sensitized mice were exposed to restraint stress followed by forced swimming stress, during which a GC receptor antagonist or a GC synthesis inhibitor was administered, and then antigen was inhaled. Corticosterone levels in the blood were measured in stressed and nonstressed mice. After antigen inhalation, the airway responses to aerosolized methacholine, epithelial mucus secretion and airway inflammation were evaluated, and the IL-13 contents in bronchoalveolar lavage fluid were measured. Results: The exposure to stress significantly increased corticosterone levels. Allergic airway responses and the increase of IL-13 contents evoked by antigen inhalation were significantly higher in stressed mice than in non-stressed mice. The administration of a GC receptor antagonist and a GC synthesis inhibitor during stress exposure significantly reduced the exacerbation of the airway responses and the increase of IL-13 contents in stressed mice challenged with antigen. Conclusions: These results indicate that the increased release of GC upon exposure to stress has a priming effect on the aggravation of allergic airway responses following the exposure, suggesting a pathophysiological role for the neuroendocrine axis in linking psychological stress to asthma exacerbations. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000360577

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Muramatsu S, Tamada T, Nara M, Murakami K, Kikuchi T, Kanehira M, Maruyama Y, Ebina M, Nukiwa T, Ichinose M. Flagellin/TLR5 signaling potentiates airway serous secretion from swine tracheal submucosal glands. Am J Physiol Lung Cell Mol Physiol 305: L819-L830, 2013. First published October 4, 2013; doi:10.1152/ajplung.00053.2013.-Airway serous secretion is essential for the maintenance of mucociliary transport in airway mucosa, which is responsible for the upregulation of mucosal immunity. Although there are many articles concerning the importance of Toll-like receptors (TLRs) in airway immune systems, the direct relationship between TLRs and airway serous secretion has not been well investigated. Here, we focused on whether TLR5 ligand flagellin, which is one of the components of Pseudomonas aeruginosa, is involved in the upregulation of airway serous secretion. Freshly isolated swine tracheal submucosal gland cells were prepared, and the standard patch-clamp technique was applied for measurements of the whole cell ionic responses of these cells. Flagellin showed potentiating effects on these oscillatory currents induced by physiologically relevant low doses of acetylcholine (ACh) in a dose-dependent manner. These potentiating effects were TLR5 dependent but TLR4 independent. Both nitric oxide (NO) synthase inhibitors and cGMP-dependent protein kinase (cGK) inhibitors abolished these flagellin-induced potentiating effects. Furthermore, TLR5 was abundantly expressed on tracheal submucosal glands. Flagellin/TLR5 signaling further accelerated the intracellular NO synthesis induced by ACh. These findings suggest that TLR5 takes part in the airway mucosal defense systems as a unique endogenous potentiator of airway serous secretions and that NO/cGMP/cGK signaling is involved in this rapid potentiation by TLR5 signaling.

DOI： 10.1152/ajplung.00053.2013

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Nosocomial infections caused by metallo-beta-lactamase (MBL)-producing multidrug-resistant (MDR) Pseudomonas aeruginosa have become a worldwide problem. Pyocyanin, a representative pigment produced by P. aeruginosa, is the major virulence factor of this organismThe aim of this study was to investigate the pyocyanin-producing ability of MBL-producing MDR P. aeruginosa. A total of 50 clinical isolates of P. aeruginosa, including 20 MDR strains, were collected at 18 general hospitals in Japan. The chromaticity and luminosity produced by pyocyanin in each isolate were measured. The quantity of pyocyanin and the expression of the phzM and phzS genes coding a pyocyanin synthesis enzyme were measured. MDR strains showed a bright yellow-green, while non-MDR strains tended to show a dark blue-green. The quantities of pyocyanin in MBL-producing strains and non-producing strains were 0.015 +/- A 0.002 and 0.41 +/- A 0.10 mu g, respectively. The expression of the phzM and phzS genes in the MDR strains was 11 and 14 %, respectively, of the expression in the non-MDR strains. When the MBL gene was transduced into P. aeruginosa and it acquired multidrug resistance, it was shown that the pyocyanin-producing ability decreased. The pathogenicity of MBL-producing MDR P. aeruginosa may be lower than that of non-MDR strains. These MBL-producing MDR strains may be less pathogenic than non-MDR strains. This may explain why MDR-P. aeruginosa is unlikely to cause infection but, rather, causes subclinical colonization only.

DOI： 10.1007/s10156-012-0457-9

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

Background: After puberty, asthma severity is higher in women than in men. The underlying mechanisms of this gender difference are not fully understood. In murine models of allergic asthma, more severe airway inflammation in female mice is associated with higher levels of T helper type 2 (Th2) cytokines. The aim of this study was to investigate the contributions of CD4(+) T cells and dendritic cells (DCs) to the differences in Th2 cytokine production between sexes. Methods: Bronchial lymph node (BLN) cells from ovalbumin (OVA)-sensitized male and female C57BL/6 mice were stimulated with OVA and anti-CD3/CD28 antibodies. The CD4(+) T cells and DCs purified from BLN cells were cocultured with OVA in a sex-matched or mismatched fashion. The CD4(+) T cells were also stimulated with anti-CD3/CD28 antibodies. The concentrations of interleukin (IL)-5, IL-4, IL-13 and interferon (IFN)-gamma in the culture supernatants were measured. Results: The concentrations of IL-5, IL-4 and IL-13, but not IFN-gamma, were significantly higher in female BLN cells stimulated with OVA than in male BLN cells. Sex differences were also observed in the CD4(+) T cells stimulated with anti-CD3/CD28 antibodies, whereas only IL-4 was significantly different in the BLN cells stimulated with antibodies. IL-5 production by OVA-stimulated male and female CD4 + T cells, but not IL-4 or IL-13 production, was significantly increased in the coculture with female DCs when compared to the male DCs. Conclusions: The differences in Th2 cytokine production between sexes by the BLN cells may be attributable, at least in part, to the differing functions of CD4(+) T cells and DCs between sexes. Copyright (C) 2013 S. Karger AG, Basel

DOI： 10.1159/000350426

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.102.2902

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Language：English   Publisher：AMER THORACIC SOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTERS DISEASE CONTROL  

DOI： 10.3201/eid1811.111660

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Language：English   Publisher：OXFORD UNIV PRESS INC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

The Runx1 transcription factor is abundantly expressed in naive T cells but rapidly downregulated in activated T cells, suggesting that it plays an important role in a naive stage. In the current study, Runx1(-/-) Bcl2(tg) mice harboring Runx1-deleted CD4(+) T cells developed a fatal autoimmune lung disease. CD4(+) T cells from these mice were spontaneously activated, preferentially homed to the lung, and expressed various cytokines, including IL-17 and IL-21. Among these, the deregulation of IL-21 transcription was likely to be associated with Runx binding sites located in an IL-21 intron. IL-17 produced in Runx1-deleted cells mobilized innate immune responses, such as those promoted by neutrophils and monocytes, whereas IL-21 triggered humoral responses, such as plasma cells. Thus, at an initial stage, peribronchovascular regions in the lung were infiltrated by CD4(+) lymphocytes, whereas at a terminal stage, interstitial regions were massively occupied by immune cells, and alveolar spaces were filled with granular exudates that resembled pulmonary alveolar proteinosis in humans. Mice suffered from respiratory failure, as well as systemic inflammatory responses. Our data indicate that Runx1 plays an essential role in repressing the transcription of cytokine genes in naive CD4(+) T cells and, thereby, maintains cell quiescence. The Journal of Immunology, 2012, 188: 5408-5420.

DOI： 10.4049/jimmunol.1102991

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Clinical results for linezolid (LZD) treatment of hospital-acquired pneumonia (HAP) caused by methicillin-resistant Staphylococcus aureus (MRSA), particularly microbiologically evaluable or severe cases, are limited in Japan. A prospective observational study was conducted in order to assess the usefulness of LZD in Japanese patients with MRSA pneumonia. The study tracked fifteen participants treated with LZD for pneumonia who met the criteria of the HAP guidelines and were confirmed to have pneumonia caused by MRSA. Of these, six were severe and 13 had received antibiotic treatment before treatment with LZD. Of the 13 participants assessed for their clinical responses, seven were rated as cures, three were rated as failures, and three were indeterminate. The overall cure rate (cure/cure + failure) was 70.0% (7/10), and the cure rate by severity was 33.3% (1/3) for severe cases and 85.5% (6/7) for moderate cases. The one severe case with a clinical response rating of cure had failed to respond to vancomycin. Among the seven participants with a clinical response rating of cure, the microbiological response was eradication in three, presumed eradication in three, and indeterminate in one. Three serious adverse events occurred in two of the 15 participants, but none were considered to be causally related to LZD. The results suggest that LZD has high potential for severe and multidrug-resistant cases. A higher cure rate was achieved in moderate cases. In cases of pneumonia that are most likely MRSA infections with poor prognosis, it was suggested to be important for patient outcome to implement the most effective therapy before the patient's condition becomes serious.

DOI： 10.1007/s10156-011-0309-z

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Previous studies have demonstrated that mesenchymal stromal cells (MSCs) enhance cell survival through upregulation and secretion of stanniocalcin-1 (STC1). This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation, reducing intracellular reactive oxygen species (ROS), and shifting metabolism towards a more glycolytic metabolic profile. MSC-derived STC1 upregulated uncoupling protein 2 (UCP2) in injured A549 cells in an STC1-dependent manner. Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 (rSTC1) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS, mitochondrial membrane potential (MMP), and increased lactate production, all of which were dependent on the upregulation of UCP2. Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1.

DOI： 10.1038/mt.2011.259

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Marrow stromal cells (MSCs) isolated from mesenchymal tissues can propagate in vitro to some extent and differentiate into various tissue lineages to be used for cell-based therapies. Cellular senescence, which occurs readily in continual MSC culture, leads to loss of these characteristic properties, representing one of the major limitations to achieving the potential of MSCs. In this study, we investigated the effect of lysophosphatidic acid (LPA), a ubiquitous metabolite in membrane phospholipid synthesis, on the senescence program of human MSCs. We show that MSCs preferentially express the LPA receptor subtype 1, and an abrogation of the receptor engagement with the antagonistic compound Ki16425 attenuates senescence induction in continually propagated human MSCs. This anti-aging effect of Ki16425 results in extended rounds of cellular proliferation, increased clonogenic potential, and retained plasticity for osteogenic and adipogenic differentiation. Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling. Disruption of this signaling pathway was accompanied by morphological changes such as cell thinning and elongation as well as actin filament deformation through decreased phosphorylation of focal adhesion kinase. Prevention of LPA receptor engagement also promoted ubiquitination-mediated c-Myc elimination in MSCs, and consequently the entry into a quiescent state, G(0) phase, of the cell cycle. Collectively, these results highlight the potential of pharmacological intervention against LPA signaling for blunting senescence-associated loss of function characteristic of human MSCs.

DOI： 10.1371/journal.pone.0032185

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

Background: Asthma prevalence and severity are higher in females than in males after puberty. The underlying mechanisms of this gender difference are not fully understood. More severe airway inflammation in female mice has been reported to be associated with higher levels of T helper type 2 (Th2) cytokines in asthma models. The aim of this study was to investigate sex differences in CD4+ and CD8+ T cell functions in Th2 cytokine production. Methods: Splenocytes from naive mice were stimulated with anti-CD3/CD28 antibodies and the proportions of CD4+ and CD8+ T cells were analyzed. CD4+ T cells were stimulated in the presence of CD8+ T cells. The concentrations of interleukin (IL)-5, IL-10 and interferon (IFN)-gamma in the cultures were measured. Results: The concentration of IL-5, but not IFN-gamma, was significantly higher in female splenocytes than in male splenocytes. There were no sex differences in the proportions of CD4+ and CD8+ T cells in the splenocytes. Although the IL-5 production levels in male and female CD4+ T cells were similar, IL-5 production in male CD4+ T cells, but not female CD4+ T cells, was suppressed by both male and female CD8+ T cells. While IL-5 and IL-10 were not detected in the cultures from both male and female CD8+ T cells, IFN-gamma concentration in female CD8+ T cells was significantly higher than in male CD8+ T cells. Conclusions: The sex difference in the sensitivity of CD4+ T cells to CD8+ T cell suppression might contribute to the sex difference in IL-5 production by splenocytes. Copyright (C) 2012 S. Karger AG, Basel

DOI： 10.1159/000337759

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

Airway surface fluids are mainly secreted from submucosal glands, and play important roles in the defense of airways via the up-regulation of mucociliary transport, resulting in an exclusion of many microbes or foreign substances. Although there are many articles concerning the importance of Toll-like receptors (TLRs) in airway immune systems, whether TLRs directly cooperate with tracheal submucosal glands to increase secretion remains unknown. We investigated the effects of ligands of the three TLR subtypes (TLR2, TLR3, and TLR4) on the physiologic secretion of electrolytes by using a patch-clamp technique. Among these TLRs, only the TLR4 ligand, LPS, showed potentiating effects on acetylcholine (ACh)-induced ionic currents in a dose-dependent manner. These potentiating effects were completely abolished by pretreatment with a specific TLR4 antagonist or the anti-TLR4 antibody. LPS per se exerted no appreciable effect on baseline currents. Next, we demonstrated the abundant expression of TLR4 in submucosal gland acinar cells by using immunofluorescent staining and RT-PCR. Furthermore, we revealed that both nitric oxide synthase inhibitors and cyclic guanosine monophosphate (cGMP)-dependent protein kinase (cGK) inhibitors abolished the LPS-induced potentiating effects completely. Analyses of fluorescence intensities, using an intracellular nitric oxide (NO) indicator, demonstrated that LPS could further increase the ACh-induced synthesis of NO. These findings suggest that TLR4 takes part in airway mucosal defense systems as a unique exogenous potentiator of electrolyte-water secretion from submucosal gland acinar cells, and that NO/cGMP/cGK signaling is involved in this rapid TLR4 signaling pathway.

DOI： 10.1165/rcmb.2011-0020OC

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

The aim of the present study was to determine whether the intensity of bronchiolar epithelial cell injury is ameliorated by transbronchial human IL-10 (hIL-10) gene transfer in a rat model of lung allograft rejection. The left lung was extracted from a donor Brown Norway rat and transbronchially instilled with encoding hIL-10 (IL-10 group) or beta-galactosidase (control group). The lung graft was then transplanted into a Lewis rat and harvested on day 6 after transplantation. The allografts were histologically examined and all bronchioles in the slides were assigned one of three grades according to the intensity of epithelial cell loss. The distribution of the grades was significantly different between the two groups, and the epithelial cell injury was significantly improved in the IL-10 group. The present study demonstrated the effect of transbronchial hIL-10 gene transfer on ameliorating bronchiolar epithelial cell injury in a rat model of lung allograft rejection.

DOI： 10.1007/s00595-010-4472-0

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00009&link_issn=&doc_id=20111019170452&doc_link_id=%2Fcw4aller%2F2011%2F006009%2F498%2F1381-1381%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw4aller%2F2011%2F006009%2F498%2F1381-1381%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

Mycobacteria are among the most common causes of hypersensitivity pneumonitis (HP), but controversy persists with regard to the involvement of the infectious potency of the organism in mycobacterial HP (hot tub lung). This study aimed to establish a mouse model of hot tub lung to clarify its pathophysiology.
Mice were exposed intranasally to formalin-killed Mycobacterium avium from a patient with hot tub lung (HP strain) or chronic pulmonary infection (non-HP strain), and bronchoalveolar lavage fluids and lung tissues were evaluated for allergic inflammation.
Dead M. avium HP strain, but not non-HP strain, elicited marked HP-like pulmonary inflammation in wild-type mice. Although the inflammation was induced in mice lacking CD4 or CD8, the induction of HP-like responses was prevented in mice lacking myeloid differentiation factor (MyD)88 or Toll-like receptor (TLR)9. Cultured lung CD11c+ cells responded to M. avium in a TLR9-dependent manner, and reconstitution of TLR9-/- mice with lung CD11c+ cells from wildtype mice restored the inflammatory responses. Further investigation revealed that pulmonary exposure to M. avium HP strain increased the number of lung CD11b+ CD11c+ cells (dendritic cells) through TLR9 signalling.
Our results provide evidence that hot tub lung develops via the mycobacterial engagement of TLR9-MyD88 signalling in lung CD11b+ dendritic cells independent of the mycobacterial infectious capacity.

DOI： 10.1183/09031936.00177110

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

As the increasing prevalence of resistant strains of respiratory bacterial pathogens has recently been reported, continuous monitoring of the susceptibility of clinical isolates to antibacterial agents is important. We performed a surveillance study focusing on the susceptibility of major respiratory bacterial pathogens in the northeastern region of Japan to carbapenems and control drugs. A total of 168 bacterial strains isolated from patients with respiratory tract infections in 2007 were collected and the minimum inhibitory concentration (MIC) determined. MIC data were subjected to pharmacokinetic/pharmacodynamic analysis with Monte Carlo simulation to calculate the probability of achieving the target of time above MIC with each carbapenem. All Moraxella catarrhalis, Streptococcus pneumoniae, and methicillin-sensitive Staphylococcus aureus isolates were susceptible to carbapenems. Despite the increasing prevalence of beta-lactamase-nonproducing ampicillin-resistant strains, all Haemophilus influenzae isolates were susceptible to meropenem. For Pseudomonas aeruginosa, the susceptibility rates for meropenem and biapenem were 76.7%, and the highest probability of achieving pharmacodynamic target (40% of the time above MIC) was obtained with meropenem 0.5 g three times daily as a 4-h infusion (89.4%), followed by meropenem 0.5 g four times daily as a 1-h infusion (88.4%). Carbapenems have retained their position as key drugs for severe respiratory tract infections.

DOI： 10.1007/s10156-010-0112-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

DOI： 10.1016/j.ajic.2010.06.020

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Glycopeptide antibiotics, such as vancomycin and teicoplanin, have been used worldwide to treat infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Generic teicoplanin products were manufactured by many companies in 2009. We investigated the susceptibility of 147 MRSA strains to brand-name teicoplanin (TEIC-1) and seven generic products (TEIC-2 to TEIC-8). The MIC(90) of generic TEIC-5 and TEIC-7 was 8 mu g/ml whereas that of TEIC-1 and other generic products was 4 mu g/ml. The potency equivalent of generic TEIC-5 and TEIC-7 was lower than that of TEIC-1, and TEIC content (%) per potency equivalent (200 mg) in a vial of these two generic products varied greatly compared with the other products. Although the potency equivalent of the TEIC used in this study was within the range stipulated in the Japanese Pharmacopeia, these results showed that the potency equivalent and susceptibility of two of the seven generic products differed from that of TEIC-1. The predicted AUC(0-72) value of those two generic products was 84-85% in comparison with that of TEIC-1. Among generic drugs, there may be products whose antimicrobial effect is not equal to that of the brand teicoplanin.

DOI： 10.1007/s10156-010-0094-0

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

Background: Before puberty, the prevalence and severity of asthma are higher in boys than in girls, but this pattern is reversed after puberty. The underlying mechanisms of these gender differences in asthma are not fully understood. Using murine models of allergic asthma, a sex difference in Th2 cytokine production has been suggested to contribute to the gender differences in asthma. Therefore, we determined which subsets of T cells are involved in the sex difference in Th2 cytokine production. Methods: Splenocytes from wildtype mice and CD4+ T cell-, CD8+ T cell-, and iNKT cell-deficient mice were stimulated with anti-CD3/CD28 antibodies for 3 days, and the concentrations of IL-4, IL-5, IL-13, and IFN-gamma in the cultures were measured by ELISA. Results: IL-5, but not IL-4 and IL-13, concentrations in culture derived from female wild-type mice were significantly higher than those in male wild-type mice. The sex difference in IL-5 concentrations was not observed in the cultures of splenocytes from CD4+ and CD8+ T cell-deficient mice. The disappearance of the sex differences in CD4+ and CD8+ T cell-deficient mice was attributable to a decrease in IL-5 concentration in female mice and an increase in IL-5 concentration in male mice. In iNKT cell-deficient mice, the sex difference was still observed. There was no significant difference between the sexes in any type of mice with respect to IFN-gamma production. Conclusions: There was a sex difference in IL-5 production by splenocytes stimulated by TCR activation. The difference might be attributable to sex differences in CD4+ and CD8+ T cell functions. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000327261

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

Rationale: OX40-OX40 ligand (OX40L) interactions have been proposed to support induction of allergic airway inflammation, which may be attributable to OX40 signaling in CD4(+) helper T cells for adaptive immune responses. However, a possible involvement of natural killer T (NKT) cells in the pathogenesis suggests that the underlying mechanisms are not yet fully elucidated.
Objectives: We aimed to characterize the OX40-modulated cellular contribution to allergic airway inflammation in a mouse model of house dust mite (HDM) allergen exposure.
Methods: Mice were sensitized to HDM and, 3 weeks later, challenged with HDM on three consecutive days through the airways. Two days after the last exposure, bronchoalveolar lavage fluids and blood samples and lung tissues were evaluated for the airway inflammation.
Measurements and Main Results: The development of HDM-induced eosinophilic airway inflammation was dependent on OX40 of both CD4(+) T cells and NKT cells; OX40 engagement on CD4(+) T cells in the sensitization led to pulmonary OX40L augmentation after the allergen challenge, which stimulated pulmonary NKT cells through OX40 to provide the pathogenic cytokine milieu. This was ablated by OX40L blockade by inhalation of the neutralizing antibody during the challenge, suggesting the therapeutic potential of targeting pulmonary OX40-OX40L interactions. Moreover, OX40 expression in CD4(+) T cells, but not in NKT cells, was reciprocally regulated by the helper T cell type 1-skewing transcription factor Runx3.
Conclusions: OX40 on not only CD4(+) T cells but also NKT cells is involved in allergic airway inflammation. Notably, pulmonary blockade of OX40 ligation on NKT cells has therapeutic implications.

DOI： 10.1164/rccm.200910-1598OC

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

BACKGROUND: The ability to express genes with potential immunoregulatory capacity could reduce allograft rejection (AR). This study examined the effect of ex vivo lipid-mediated transbronchial human interleukin-10 (hIL-10) gene transfer on AR and the intragraft cytokine profile in a rat model of lung transplantation.
METHODS: Left single lung transplants were performed between a highly histoincompatible combination of inbred rats. The donor left lung was extracted and intrabronchially instilled with a plasmid encoding hIL-10 (IL-10 group) or Escherichia coli beta-galactosidase (control group), mixed with a cationic lipid. At 3 and 6 days after transplantation, the degree of AR was graded histologically (stage 1-4) and several pathologic categories of inflammation were scored on a scale of 0 to 4 according to the percentage of involvement. Intragraft cytokine profile was examined by real-time reverse transcription polymerase chain reaction.
RESULTS: The stage of AR (3.1 +/- 0.4 vs 3.8 +/- 0.4) and the pathologic scores for edema (2.3 +/- 0.8 vs 3.2 +/- 0.4), intraalveolar hemorrhage (0.3 +/- 0.5 vs 2.2 +/- 0.8), and necrosis (0.3 +/- 0.5 vs 1.2 +/- 0.4) in the IL-10 group were significantly decreased compared with the control group at Day 6. IL-2 and tumor necrosis factor-alpha messenger RNA expression levels on Day 3 were significantly decreased in the IL-10 group.
CONCLUSIONS: Ex vivo lipid-mediated transbronchial hIL-10 gene transfer attenuated acute inflammation associated with AR, which was related to decreased levels of proinflammatory cytokine gene expression in a rat model of lung transplantation. J Heart Lung Transplant 2010;29:360-7 (C) 2010 International Society for Heart and Lung Transplantation. All rights reserved.

DOI： 10.1016/j.healun.2009.10.002

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

Ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii in intensive care units has become a problem worldwide. In Japan, few reports of antimicrobial susceptibility or nosocomial infection have involved A. baumannii. We confirmed A. baumannii nosocomial infection in a neonatal intensive care unit (NICU) of general hospital A in the Tohoku region from May 2008 to February 2009, so spreading of infection and environmental contamination were examined. Antimicrobial susceptibilities of 51 clinical isolates in NICU and 2 environmental isolates, thermometer and knob, in March 2009 were determined by the micro-dilution method. Furthermore, the genotype of these strains was determined using the AP-PCR and ERIC-PCR methods. During this period, three nosocomial infections (June, September, February) caused by A. baumannii were confirmed. In this study, there was no isolation of multidrug-resistant strains. The genotype of each A. baumannii strain in these nosocomial infections was different. The genotype of the A. baumannii strain isolated from the thermometer which only patient A had used was identified with that of the nosocomial infection in February. These results showed the possibility that several A. baumannii strains were transmitted through staff of the NICU. A. baumannii surveillance may be important to prevent nosocomial infection in the NICU. © 2010, Japanese Society for Infection Prevention and Control. All rights reserved.

DOI： 10.4058/jsei.25.242

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：B M J PUBLISHING GROUP  

Background: Non-tuberculous mycobacterial lung disease, most commonly caused by Mycobacterium avium infection, tends to show variable disease progression, and significant disease predictors have not been adequately established.
Methods: Variable numbers of tandem repeats (VNTR) were evaluated in 16 mycobacterial interspersed repetitive unit (MIRU) loci from M avium isolates cultured from respiratory specimens obtained from 2005 to 2007. Specifically, the association between VNTR profiles and disease progression was assessed.
Results: Among the 37 subjects who provided positive respiratory cultures for M avium during the 2005-6 period, 15 subjects were treated within 10 months following a microbiological diagnosis of progressive M avium lung disease. Nine subjects underwent long-term follow-up (&gt;24 months) without treatment for stable M avium lung disease. Based on a neighbour-joining cluster analysis used to classify M avium-positive subjects according to the VNTR profile, subjects with progressive versus stable lung disease were found to be grouped together in distinct clusters. Further analysis using logistic regression modelling showed that disease progression was significantly associated with the genetic distance of the M avium isolate from an appropriately selected reference (age-adjusted odds ratio 1.95; 95% confidence interval 1.16 to 3.30; p = 0.01 for the most significant model). A best-fit model could be used to predict the progression of M avium lung disease when subjects from the 2005-6 period were combined with those from 2007 (p = 0.003).
Conclusion: Progressive lung disease due to M avium infection is associated with specific VNTR genotypes of M avium.

DOI： 10.1136/thx.2009.114603

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Background. Staphylococcal biofilms pose an important problem, especially after orthopedic surgery using foreign implants. Clarithromycin (CAM) eliminates the biofilms formed by a wide variety of aerobic and anaerobic bacteria. In a previous in vitro study, we showed that treatment with CAM and vancomycin (VCM) eradicated staphylococcal biofilms from surgical implants. To investigate the efficacy of this eradication therapy, we assessed its effects against Staphylococcus aureus on titanium plates implanted in mice.
Methods. A titanium washer covered with S. aureus biofilms was implanted in the muscular tissue around the femoral bone. Mice were given intravenous injections of CAM and intraperitoneal injections of VCM twice daily beginning 72 h after implantation. To confirm eradication of biofilms and S. aureus strains, the resected washer was examined by scanning electron microscopy.
Results. Dense colonization and biofilms were seen on the washer implanted in the control mice that received saline, saline plus CAM, or saline plus VCM. Treatment with CAM plus VCM eliminated the biofilms, indicating an S. aureus eradication effect.
Conclusions. Staphylococcal biofilms have demonstrated resistance to most antibiotics, including VCM. Our in vivo data support the hypothesis that combined treatment using CAM plus VCM may effectively eradicate staphylococcal biofilms in patients with implant-related infection.

DOI： 10.1007/s00776-009-1366-3

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Language：Japanese  

59歳男性。患者は発熱と咳嗽を主訴に受診となり、肺炎の診断にて入院となった。所見では左下腿の腫脹と発赤、左上腕と左右前胸部に潰瘍、多発リンパ節腫大が認められ、胸部CTでは多発結節陰影、ARDS様の陰影がみられた。重症肺炎を疑い、抗生物質投与とステロイドパルス療法を開始したものの、呼吸不全が急速に進行し、第1病日中に人工呼吸器管理となった。一方、皮膚の浸出液と喀痰からは抗酸菌塗抹1+が検出され、PCRで結核菌は陰性であったが、粟粒結核を否定できず、抗結核薬投与が開始された。その結果、抗結核薬を開始後、胸部X線およびCT上の陰影は次第に改善し、呼吸不全も改善し、第64病日目に退院となった。尚、抗酸菌培養では皮膚浸出液、喀痰、気管支洗浄液、いずれからもM. szulgaiが検出され、M. szulgaiによる全身感染症と診断された。

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Publishing type：Research paper (scientific journal)  

We surveyed the susceptibility to ceftazidime, arbekacin(ABK), gentamycin(GM), and amikacin(AMK) of 1,348 strains of Pseudomonas aeruginosa isolated between 2003 and 2007 from patients hospitalized in the Tohoku area, Japan. Susceptibility was tested by the broth microdilution method using frozen plates. Metallo-β-lactamase (MBL) -producing P. aeruginosa was detected by the sodium mercaptoacetate(SMA) disc method, and PCR was used to detect the MBL type. Results of yearly susceptibility testing showed that the MIC50 and MIC90 of aminoglycoside antibiotics against 1.266 P. aeruginosa strains except for 64 MBL-producers and 18 non-MBL multidrug-resistant P. aeruginosa(MDRP) strains, between 2003 and 2007 were 2-4 μg/mL in ABK and GM, and 4 μg/mL, respectively. On the other hand, the range of MIC90 of ABK and GM were 8 to 16 μg/mL and those of AMK were 8 to 32 μg/mL. ABK was more effective than AMK, but MBL-producers and non-MBL MDRP were resistant to these 3 aminoglycoside antibiotics. P. aeruginosa and methicillin-resistant Staphylococcus aureus(MRSA) are frequently isolated as the cause of nosocomial pneumonia and wound infection. Mixed infection by these strains is also frequently encountered. ABK, which is an anti-MRSA drug, may prove effective against nosocomial infection by P. aeruginosa.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We examined the effects of extracellular adenosine 5'-triphosphate (ATP) on single airway smooth muscle (ASM) cells from porcine trachea using a patch-clamp technique. ATP induced a sustained inward current. Phospholipase C inhibitor U-73122 failed to inhibit the current, suggesting the involvement of P2X receptor. A specific effecter of P2X(4), ivermectin, augmented the current indicating the existence of P2X(4) receptors. Immunohistochemistry and reverse transcription/polymerase chain reaction analysis and Western blot analysis also showed the distribution of the P2X(4) receptors. The inward current was reduced by SKF-96365, an inhibitor of both voltage-dependent Ca2+ channels (VDCCs) and voltage-independent Ca2+ channels, although a VDCC antagonist, verapamil, did not affect the current. SKF-96365 caused complete suppression of both the increase in the intracellular Ca2+ concentration and the contraction of ASM cells induced by ATP. Our results demonstrate that P2X(4) receptors exist on ASM and that the receptors are responsible for Ca2+ influx. These findings suggest that the Ca2+ influx regulated by P2X(4) receptors plays an important role in ASM contraction by a pathway distinct from VDCC. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.resp.2009.02.002

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Language：Japanese  

抗緑膿菌活性を有するアミカシン(AMK)と同様の化学構造を示し、抗MRSA薬でもあるアルベカシン(ABK)の臨床分離P.aeruginosa株に対する抗菌力をAMKと比較検討した。一般市中病院20施設より臨床分離した緑膿菌1348株を対象とし、ABK、AMK、ゲンタマイシン(GM)を用いた。各薬剤の03〜07年のMIC50はABKとGMが2〜4μg/mLで、AMKは各年ともに4μg/mLを示した。MIC90も同様にABKおよびGMは8〜16μg/mLを示し、AMKの8〜32μg/mLよりいずれも1管程度優れていた。メタロ-β-ラクタマーゼ(MBL)産生株は64株およびMBL非産生MDRP株は18株分離し、MBL産生株ではABKとGMがAMKより優れていた。ABKのMBL産生株を含む緑膿菌に対する抗菌力はGMとほぼ同等で、AMKより1〜2管程度優れていた。

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

DOI： 10.2169/naika.98.1984

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

In this study, we investigated the in vitro efficacy of clarithromycin (CLA) combined with cefazolin (CFZ) or vancomycin ( VCM) against Staphylococcus aureus biofilms formed on titanium devices in order to confirm the efficacy of eradication therapies against device-related infection. The distribution of CLA in muscle tissue surrounding bone was also investigated by liquid chromatography/tandem mass spectrometry in 10 orthopaedic patients. Biofilm formation and eradication of S. aureus were monitored by scanning electron microscopy and using double-staining dyes, respectively. Although S. aureus biofilms were not eradicated by CLA, CFZ or VCM alone, CLA combined with CFZ or VCM destroyed biofilms, and S. aureus eradication was clearly observed 72 h later. This in vitro study showed that treatment with CLA plus CFZ or VCM destroyed staphylococcal biofilms formed on medical devices and eradicated S. aureus. (C) 2008 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.

DOI： 10.1016/j.ijantimicag.2008.06.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Invariant natural killer T (iNKT) cells are a special subset of tip T cells with invariant TCR, which recognize a-galactosylceramide (a-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with (x-GalCer, costimulatory signals, such as signals through CD28 and OX40, are indispensable for full activation of iNKT cells. In this study, we investigated the functions of a well-known costimulatory molecule, glucocorticoid-induced TNF receptor (GITR), on Ag-induced iNKT cell activation. Unexpectedly, engagement of GITR by agonistic mAb DTA-1 suppressed proliferation and cytokine production of iNKT cells upon (x-GalCer stimulation. in addition, GITR signals in iNKT cells during only the Ag-priming phase was sufficient to inhibit the iNKT cell activation. Consistent with these results, the GITR-deficient iNKT cells showed enhanced proliferation and increased cytokine production upon alpha-GalCer stimulation both in vitro and in vivo. Furthermore, the in vivo administration of alpha-GalCer suppressed tumor metastasis more efficiently in GITR-deficient mice than in wild-type mice. Collectively, GITR plays a co-inhibitory role in Ag-induced iNKT cell activation.

DOI： 10.1002/eji.200838167

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Interstitial lung disease (ILD) is reported as a serious adverse event in lung cancer patients treated with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the mechanisms of ILD associated with gefitinib remain unknown. To address the molecular mechanisms of ILD-associated gefitinib, we determined the effect of gefitinib treatment on surfactant protein expression in vitro and in vivo. Gefitinib treatment suppressed surfactant protein (SP)-A expression in H441 human lung adenocarcinoma cells expressing SP-A, -B, -C and -D by inhibiting epidermal growth factor signal. Next, gefitinib (200 mg/kg) was given p.o. to the mice daily for 1 week. Daily administration of gefitinib gradually reduced SP-A level in the bronchoalveolar lavage fluid. When lipopolysaccharide (LPS) was instilled intratracheally to the mice pretreated with gefitinib for 1 week, lung inflammation by LPS was exacerbated and prolonged. This exacerbation of lung inflammation was rescued by intranasal administration of SP-A. These results demonstrated that pretreatment with gefitinib exacerbated LPS-induced lung inflammation by reducing SP-A expression in the lung. This study suggests that epidermal growth factor receptor tyrosine kinase inhibitor may reduce SP-A expression in the lungs of lung cancer patients and thus patients treated with epidermal growth factor receptor tyrosine kinase inhibitor may be susceptible to pathogens. (Cancer Sci 2008; 99: 1679-1684)

DOI： 10.1111/j.1349-7006.2008.00857.x

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Language：English   Publisher：BLACKWELL PUBLISHING  

Secretory leukocyte peptidase inhibitor (SLPI) belongs to the whey acidic protein four-disulfide core family of proteins, and has antimicrobial and antiprotease functions. SLPI is produced by the epithelial cells lining the respiratory, digestive, and reproductive tracts. Gene-targeting experiments in mice indicated that one function of SLPI is to protect proepithelin from elastase cleavage in wound healing. In addition to its antiprotease function, SLPI has an anti-inflammatory function through the modulation of nuclear factor-kappa B acting intracellularly, especially in macrophages. SLPI is also produced in cancer tissues, but its role in cancer is not well understood. SLPI genes are often upregulated under tumorigenic conditions. We found a negligible number of tumors in the lungs of SLPI knockout mice 20 or 40 weeks after administration of urethane, an interesting experimental model for investigating the function of SLPI in cancer. This review discusses the normal function of SLPI and its possible roles in cancer tissues.

DOI： 10.1111/j.1349-7006.2008.00772.x

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PubMed

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

DOI： 10.1016/j.ijantimicag.2008.01.002

CiNii Article

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-alpha-stimulated DC maturation was accompanied by increased expression of OX40 ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4(+) T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-gamma production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-gamma. production and CD69 expression, indicated that NKT cell activation by DCs presenting cc-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4(+) T cells, in the induction of antitumor immunity in tumor-bearing mice.

DOI： 10.1172/JCI32693

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ALPHAMED PRESS  

MSCs are nonhematopoietic stem cells capable of differentiating into various mesoderm-type cells. MSCs have been considered to be a potential vehicle for cell-based gene therapy because MSCs are relatively easily expanded in vitro and have the propensity to migrate to and proliferate in the tumor tissue after systemic administration. Here, we demonstrated the tropism of mouse MSCs to tumor cells in vitro and multiple tumor tissues in the lung after i.v. injection of green fluorescent protein-positive MSCs in vivo. We transduced CX3CL1 (fractalkine), an immunostimulatory chemokine, to the mouse MSCs ex vivo using an adenoviral vector with the Arg-Gly-Asp-4C peptide in the fiber knob. Intravenous injection of CX3CL1-expressing MSCs to the mice bearing lung metastases of C26 and B16F10 cells strongly inhibited the development of lung metastases and thus prolonged the survival of these tumor-bearing mice. This antitumor effect depended on both innate and adaptive immunity. These results suggest that MSCs can be used as a vehicle for introducing biological agents into multiple lung tumor tissues.

DOI： 10.1634/stemcells.2006-0461

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The current status of the susceptibility of the main respiratory bacterial pathogens was evaluated by analysing the antibacterial activity of 21 drugs, including four carbapenems, against five species of the pathogens isolated between January 2005 and January 2006. A total of 157 strains were studied.
Carbapenems inhibited the growth of all of the tested strains of Moraxella catarrhalis, Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus strains at concentrations that were below the breakpoints set by the Japanese Society of Chemotherapy (2 and 1 mu g/mL for pneumonia and chronic respiratory tract infection, respectively). However, the majority of methicillin-resistant Staphylococcus aureus strains were resistant to carbapenems.
Meropenem, but not the other carbapenems, inhibited the growth of all of the tested strains of Haemophilus influenzae isolates, including beta-lactamase-non-producing ampicillin-resistant strains, at concentrations of &lt;= 1 mu g/mL. The MIC50 and MIC90 of meropenem, 0.25 and 4 mu g/mL, against Pseudomonas aeruginosa were the lowest of the carbapenems.
By comparing these results with our previous data, it was found that there was no increase in resistance to carbapenems in any of the species tested. Thus, it can be stated that carbapenems have retained their position as key drugs for severe respiratory tract infections. (C) 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

DOI： 10.1016/j.ijantimicag.2006.11.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background. Transferring genes with immunoregulatory capacity to transplanted organs has the potential to modify allograft rejection (AR). We examined the effect of ex vivo lipid-mediated transbronchial human interieukin-10 (hIL-10) gene transfer on acute AR in a rat model of lung transplantation.
Methods. Left single lung transplantations were performed between a highly histoincompatible rat combination: Brown Norway to Lewis. The extracted donor left lung was intrabronchially instilled with a plasmid encoding hIL-10 or Escherichia coli P-galactosidase (control), mixed with a cationic lipid. On day 6 posttransplantation, the degree of AR was graded histologically (stages 1-4) based upon pathological categories of inflammation: perivascular, peribronchial, and peribronchiolar lymphocytic infiltrates, edema, intraalveolar hemorrhage, and necrosis.
Results. The stage of AR in the IL-10 group (3.1 +/- 0.4) was significantly lower than the control group (3.8 +/- 0.4). Pathological scores for ederna, intraalveolar hemorrhage, and necrosis in the IL-10 group (2.3 +/- 0.8, 0.3 +/- 0.5, and 0.3 +/- 0.5, respectively) were also significantly decreased compared with those in the control group (3.2 +/- 0.4, 2.2 +/- 0.8, and 1.2 +/- 0.4, respectively).
Conclusion. Ex vivo lipid-mediated transbronchial hIL-10 gene transfer attenuated acute inflammation associated with AR in a rat model of lung transplantation.

DOI： 10.1016/j.transproceed.2006.10.207

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Japan  

Using the Monte Carlo simulation method, the influence of various doses and dosing frequencies of carbapenems on the antimicrobial activities against Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, which are the main causative organisms of respiratory infections, was studied with the aim of identifying optimized effectiveness. Based on pharmacokinetic (PK) parameters of individual carbapenems in healthy adults, data on changes in the respective blood concentrations in 2000 cases were simulated by applying a lognormal distribution to probability distributions of their volume of distributions and half-life periods. Based on minimum inhibitory concentration (MIC) distribution data of the individual carbapenems against these strains, MICs in the 2000 cases were also simulated. Using these data in blood concentrations and MICs, the probabilities of attaining various percentages of the dosing interval during which drug concentrations remain above MIC (T &gt
MIC) were calculated at several dosing regimens. Considering the probabilities of attaining the bactericidal effect (50% T&gt
MIC) and daily drug costs, imipenem (IPM) at 500 mg i.v. BID, panipenem (PAPM) at 500 mg i.v. BID, and biapenem (BIPM) at 300 mg i.v. BID against Streptococcus pneumoniae
meropenem (MEPM) at 500 mg i.v. BID or TID against Haemophilus influenzae infections
and MEPM at 500 or 1000 mg i.v. TID against Pseudomonas aeruginosa, each over 30 min, were determined as appropriate empirical treatments. Selecting carbapenems with superior antimicrobial activities and optimizing their dose regimens are important to improve the efficacy. Application of Monte Carlo simulation to MIC distributions allows determination of appropriate empiric therapy even if drug susceptibility of a causative organism in individual patients is unknown. © 2007 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

DOI： 10.1007/s10156-007-0562-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Chromobacterium violaceum produces autoinducers, including homoserine lactones (HSLs), for genetic regulation. Among the seven HSLs derived from C violaceum we evaluated, only C-12-HSL stimulated the production of inflammatory cytokines in mammalian monocytic cell lines through the activation of the NF-kappa B signaling pathway besides their quorum-sensing role, like 3-oxo-C-12-HSL from Pseudomonas aeruginosa.

DOI： 10.1128/IAI.00038-06

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

症例は42歳女性。喫煙指数420。CT検診で両側上肺野に最大7mmの空洞性病変を多数認めた。気管支肺胞洗浄液中のCD1a陽性細胞数が高値であり、病理組織学的に気道周囲の線維化包巣内にS-100陽性細胞を認め、Pulmonary Langerhans Cell Histiocytosis(以下PLCH)と診断した。禁煙を励行し、3ヵ月後には瘢痕を残し空洞性病変は消失した。禁煙による画像所見の改善に伴い、気管支肺胞洗浄液中のCD1a陽性細胞数は減少し(4.9%→1.8%)、CD4/CD8比は上昇した(1.66→6.16)。PLCHの禁煙後のBAL経過の報告はなく、病態理解上、興味深い所見であった。(著者抄録)

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は42歳女性。喫煙指数420。CT検診で両側上肺野に最大7mmの空洞性病変を多数認めた。気管支肺胞洗浄液中のCD1a陽性細胞数が高値であり、病理組織学的に気道周囲の線維化包巣内にS-100陽性細胞を認め、Pulmonary Langerhans Cell Histiocytosis(以下PLCH)と診断した。禁煙を励行し、3ヵ月後には瘢痕を残し空洞性病変は消失した。禁煙による画像所見の改善に伴い、気管支肺胞洗浄液中のCD1a陽性細胞数は減少し(4.9%→1.8%)、CD4/CD8比は上昇した(1.66→6.16)。PLCHの禁煙後のBAL経過の報告はなく、病態理解上、興味深い所見であった。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J03150&link_issn=&doc_id=20061120300016&doc_link_id=10018400949&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F10018400949&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Fractalkine (CX3CL1) is a unique membrane-bound CX3C chemokine that serves as a potent chemoattractant for lymphocytes. The hypothesis of this study is that dendritic cells (DC) genetically modified ex vivo to overexpress fractalkine would enhance the T cell-mediated cellular immune response with a consequent induction of anti-tumor immunity to suppress tumor growth. To prove this hypothesis, established tumors of different mouse cancer cells (B16-F10 melanoma, H-2(b), and Colon-26 colon adenocarcinoma, H-2(d)) were treated with intratumoral injection of bone marrow-derived DC that had been modified in vitro with an RGD fiber-mutant adenovirus vector expressing mouse fractalkine (Ad-FKN). In both tumor models tested, treatment of tumor-bearing mice with Ad-FKN-transduced DC gave rise to a significant suppression of tumor growth along with survival advantages in the treated mice. Immunohistochemical analysis of tumors treated with direct injection of Ad-FKN-transduced DC demonstrated that the treatment prompted CD8(+) T cells and CD4(+) T cells to accumulate in the tumor milieu, leading to activation of immune-relevant processes. Consistent with the finding, the intratumoral administration of Ad-FKN-transduced DC evoked tumor-specific cytotoxic T lymphocytes, which ensued from in vivo priming of Th1 immune responses in the treated host. In addition, the anti-tumor effect provided by intratumoral injection of Ad-FKN-transduced DC was completely abrogated in CD4+ T cell-deficient mice as well as in CD8(+) T cell-deficient mice. These results support the concept that genetic modification of DC with a recombinant fractalkine adenovirus vector may be a useful strategy for cancer immunotherapy protocols.

DOI： 10.1002/eji.200535549

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Lofgren's syndrome is an acute form of sarcoidosis that is characterized by erythema nodosum (EN), bilateral hilar lymphadenopathy (BHL), and polyarthralgia or polyarthritis. This syndrome is common among white people, but is considered rare among Japanese people. We present the case of a 26-year-old Japanese woman with Lofgren's syndrome. The patient complained of polyarthritis and EN of the lower extremities that lasted for 3 months. A chest radiograph revealed BHL and nodular shadows. The angiotensin-converting enzyme (ACE) level was within the normal range. Transbronchial lung biopsy revealed a noncaseating granuloma with giant cells. Six Japanese cases of Lofgren's syndrome have been reported previously. Five of the seven Japanese patients with Lofgren's syndrome had normal ACE levels; all of them exhibited BHL. Lofgren's syndrome should be considered as a possibility when examining a patient with EN and articular symptoms, even if the patient is Japanese.

DOI： 10.2169/internalmedicine.45.1452

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Dendritic cells are professional antigen presenting cells, which show an extraordinary capacity to initiate primary immune responses by stimulating T cells. This established function of dendritic cells has attracted much attention in efforts to develop useful vaccines for the treatment of cancer and infectious diseases. Designing effective strategies to generate clinical dendritic cell-based vaccine protocols remains a challenging field of research. The successful realization of immunotherapy utilizing dendritic cells will depend on modifications of these protocols to optimize the natural stimulatory properties of dendritic cells, such as genetic modification of dendritic cells. This review focuses on dendritic cell gene modifications for enhancing the multiple effector functions of dendritic cells, including viral and non-viral gene transfer into dendritic cells, and a variety of transferred genes, such as those encoding antigens, co-stimulatory molecules, cytokines, and chemokines. © 2006 Tohoku University Medical Press.

DOI： 10.1620/tjem.208.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.ijantimicag.2005.08.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Legionnaires' disease is clinically manifested as severe pneumonia caused by Legionella pneumophila. However, the dendritic cell (DC)-centered immunological framework of the host defense against L. pneumophila has not been fully delineated. For this study, we focused on a potent chemoattractant for lymphocytes, fractalkine/CX3CL1, and observed that the fractalkine expression of DCs was somewhat up-regulated when they encountered L. pneumophila. We therefore hypothesized that fractalkine expressed by Legionella-capturing DCs is involved in the induction of T-cell-mediated immune responses against Legionella, which would be enhanced by a genetic modulation of DCs to overexpress fractalkine. In vivo immunization-challenge experiments demonstrated that DCs modified with a recombinant adenovirus vector to overexpress fractalkine (AdFKN) and pulsed with heat-killed Legionella protected immunized mice from a lethal Legionella infection and that the generation of in vivo protective immunity depended on the host lymphocyte subsets, including CD4(+) T cells, CD8(+) T cells, and B cells. Consistent with this, immunization with AdFKN/Legionella/DC induced significantly higher levels of serum anti-Legionella antibodies of several isotypes than those induced by control immunizations. Further analysis of spleen cells from the immunized mice indicated that the AdFKN/Legionella/DC immunization elicited Th1-dominated immune responses to L. pneumophila. These observations suggest that fractalkine may play an important role in the DC-mediated host defense against intracellular pathogens such as L. pneumophila.

DOI： 10.1128/IAI.73.9.5350-5357.2005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

The CX3C chemokine fractalkine (CX3CL1) exists as both a membrane-bound form promoting firm cell-cell adhesion and a soluble form chemoattracting leukocytes expressing its receptor CX3CR1. When adenoviral vector expressing mouse fractalkine (AdFKN) was transduced to the tumor cells, fractalkine was expressed as both membrane-bound form on the tumor cells and soluble form in the supernatant in vitro. Intratumoral injection of AdFKN (1x10(9)PFU/tumor) into C26 and B16F10 tumors resulted in marked reduction of tumor growth compared to control (C26: 86.5%, p&LT; 0.001; B16F10: 85.5%,p&LT; 0.001). Histological examination of tumor tissues revealed abundant infiltration of NK cells, dendritic cells, and CD8(+) T lymphocytes 3 and/or 6 days after treatment with AdFKN. Splenocytes from mice treated by AdFKN developed tumor-specific cytotoxic T cells, and thereby protected from rechallenging with parental tumor cells. Antitumor effects by AdFKN were completely abrogated in both NK cell-depleted mice and CD8(-/-) mice, and partially blocked in CD4(-/-) mice. These data indicated that fractalkine mediates antitumor effects by both NK cell-dependent and T cell-dependent mechanisms. This study suggests that fractalkine can be a suitable candidate for immunogene therapy of cancer because fractalkine induces both innate and adaptive immunity.

DOI： 10.1002/eji.200526042

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

The Runx family of transcription factors is thought to regulate the differentiation of thymocytes. Runx3 protein is detected mainly in the CD4(-)8(+) subset of T lymphocytes. In the thymus of Runx3-deficient mice, CD4 expression is de-repressed and CD4(-)8(+) thymocytes do not develop. This clearly implicates Runx3 in CD4 silencing, but does not necessarily prove its role in the differentiation of CD4(-)8(+) thymocytes per se. In the present study, we created transgenic mice that overexpress Runx3 and analyzed the development of thymocytes in these animals. In the Runx3-transgenic thymus, the number of CD4(-)8(+) cells was greatly increased, whereas the numbers of CD4(+)8(+) and CD4(+)8(-) cells were reduced. The CD4(-)8(+) transgenic thymocytes contained mature cells with a TCR(high)HSA(low) phenotype. These cells were released from the thymus and contributed to the elevated level of CD4(-)8(+) cells relative to CD4(+)8(-) cells in the spleen. Runx3 overexpression also increased the number of mature CD4(-)8(+) thymocytes in mice with class II-restricted, transgenic TCR and in mice with a class I-deficient background, both of which are favorable for CD4(+)8(-) lineage selection. Thus, Runx3 can drive thymocytes to select the CD4(-)8(+) lineage. This activity is likely to be due to more than a simple silencing of CD4 gene expression.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC  

DOI： 10.1089/thy.2005.15.176

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-p resenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.

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77歳男.労作時呼吸困難で受診し,慢性肺気腫と診断され,抗コリン薬吸入等で治療を受けていた.発熱で受診した.胸部エックス線写真で肺炎と診断されたが起因菌は決定できなかった.piperacillinとclindamycin(CLDM)で改善は得られずに重症化し,転入院となった.起因菌は不明のままであったが,meropenemとminocycline,ciprofloxacinとCLDMをそれぞれ併用投与した.肺炎は改善の方向に向かったが,下痢が出現し,便培養でMRSAが多量に検出されてMRSA腸炎と診断した.vancomycin内服により改善したが,続いてMRSA敗血症を発症し,急性腎不全併発のため,透析導入となった.linezolid(LZD)投与で臨床症状は速やかに改善した.血液中のMRSAも消失したためLZD投与を中止したところ再びMRSA敗血症を併発した.再度LZDを投与し,速やかなに改善した.腎,肝機能障害の悪化は認めなかった

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Secretory leukoprotease inhibitor (SLPI) is highly expressed in almost all non-small cell lung cancers (NSCLCs), but not in the majority of other tumor types. In an attempt to create a specific gene therapy for NSCLC, we constructed AdSLPI.E1AdB, an adenovirus vector with a double expression cassette consisting of E1A driven by the SLPI promoter gene followed by E1B-19K under the control of the cytomegalovirus (CMV) promoter that can selectively replicate only in NSCLC cells. Infection with AdSLPI.E1AdB yielded E1A protein expression and adenovirus replication resulting in a &gt;100-fold increase of the virus titers only in SLPI-producing NSCLC cells (A549, H358, and HS24 cells). In contrast, neither E1A protein nor replication was detected in non-SLPI-producing HepG2 cells. Treatment with AdSLPI.E1AdB significantly inhibited the proliferation of NSCLC cells in vitro in a dose-dependent manner, whereas the cell growth of HepG2 or normal human bronchial epithelial cells was not affected by AdSLPI.E1AdB infection. Direct injection of AdSLPI.E1AdB into A549 and H358 tumors in nude mice resulted in a marked reduction in tumor growth compared with controls (A549, 57%, P &lt; 0.02; H358, 67%, P &lt; 0.03). Histological examination revealed the replication of AdSLPI.E1AdB and strong induction of necrosis and apoptosis. In addition, we evaluated the combination of AdSLPI.E1AdB and AdCMV.NK4 encoding NK4 protein, which has strong antiangiogenic activity. E1A expressed by AdSLPI.E1AdB trans-acts on the replication of AdCMV.NK4 and thus increases the expression of NK4. Injection of these two vectors into H358 tumors resulted in a more striking reduction of tumor growth compared with single injection of each vector. These results suggest that AdSLPI.E1AdB could provide a selective therapeutic modality for NSCLC and that the combination of AdSLPI.E1AdB and AdCMV.NK4 may be a more effective gene therapy for NSCLC.

DOI： 10.1158/0008-5472.CAN-03-2549

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

OX40 ligand (OX40L), the ligand for OX40 on activated CD4(+) T cells, has adjuvant properties for establishing effective T-cell immunity, a potent effector arm of the immune system against cancer. The hypothesis of this study is that in vivo genetic engineering of tumor cells to express OX40L will stimulate tumor-specific T cells by the OX40L-OX40 engagement, leading to an induction of systemic antitumor immunity. To investigate this hypothesis, s.c. established tumors of three different mouse cancer cells (B16 melanoma, H-2(b); Lewis lung carcinoma, H-2(b); and Colon-26 colon adenocarcinoma, H-2(d)) were treated with intratumoral injection of a recombinant adenovirus vector expressing mouse OX40L (AdOX40L). In all tumor models tested, treatment of tumor-bearing mice with AdOX40L induced a significant suppression of tumor growth along with survival advantages in the treated mice. The in vivo AdOX40L modification of tumors evoked tumor-specific cytotoxic T lymphocytes in the treated host correlated with in vivo priming of T helper 1 immune responses in a tumor-specific manner. Consistent with the finding, the antitumor effect provided by intratumoral injection of AdOX40L was completely abrogated in a CD4(+) T cell-deficient or CD8(+) T cell-deficient condition. In addition, ex vivo AdOX40L-transduced B16 cells also elicited B16-specific cytotoxic T lymphocyte responses, and significantly suppressed the B16 tumor growth in the immunization-challenge experiment. All of these results support the concept that genetic modification of tumor cells with a recombinant OX40L adenovirus vector may be of benefit in cancer immunotherapy protocols.

DOI： 10.1158/0008-5472.CAN-03-3911

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Legionella pneumophila is the causative pathogen of Legionnaires' disease, which is characterized by severe pneumonia. In regard to the pathophysiology of Legionella infection, the role of inflammatory phagocytes such as macrophages has been well documented, but the involvement of dendritic cells (DCs) has not been clarified. In this study, we have investigated the immune responses that DCs generate in vitro and in vivo after contact with L. pneumophila. Heat- and formalin-killed L. pneumophila, but not live L. pneumophilia, induced immature DCs to undergo similar phenotypic maturation, but the secreted proinflammatory cytokines showed different patterns. The mechanisms of the DC maturation by beat- or formalin-killed L. pneumophila depended, at least in part, on Toll-like receptor 4 signaling or on Legionella LPS, respectively. After transfer to naive mice, DCs pulsed with dead Legionella produced serum Ig isotype responses specific for Legionella, leading to protective immunity against an otherwise lethal respiratory challenge with L. pneumophila. The in vivo immune responses required the Ag presentation of DCs, especially that on MHC class II molecules, and the immunity yielded cross-protection between clinical and environmental strains of L. pneumophila. Although the DC maturation was impaired by live Legionella, macrophages were activated toy live as well as dead L. pneumophila, as evidenced by the up-regulation of MHC class II. Finally, DCs, but not macrophages, exhibited a proliferative response to live L. pneumophila that was consistent with their cell cycle progression. These findings provide 2 better understanding of the role of DCs in adaptive immunity to Legionella infection.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background: The aim of this study was to use pharmacokinetic analysis to investigate the efficacy and toxicity of combined chemotherapy with carboplatin (CBDCA) and etoposide (ETP) in small-cell lung cancer (SCLC) patients with chronic renal failure undergoing hemodialysis (HD).
Patients and methods: Three SCLC patients with chronic renal failure undergoing HD were treated with CBDCA (300 mg/m(2)) on day 1 and ETP (50 mg/m(2)) on days 1 and 3, followed by HD 1 h after completing the administration of anticancer agents on each day. The pharmacokinetic analysis of CBDCA and ETP was planned for at least the first two courses of the chemotherapy in each patient.
Results: Two complete responses and one partial response were achieved in the three patients. Two patients experienced grade 3/4 neutropenia and required blood transfusion due to thrombocytopenia and anemia. Non-hematological toxicities were moderate. The pharmacokinetic analysis revealed that the platinum and the ETP concentrations in the plasma were similar to those in patients with normal renal function during the first 24 h, while the platinum still remained in the plasma for over 90 h.
Conclusions: Chemotherapy with CBDCA (300 mg/m(2) on day 1) and ETP (50 mg/m(2) on day 1, 3) as used in the present study may be a suitable regimen for SCLC patients undergoing HD, although careful attention should be given to hematological toxicities.

DOI： 10.1093/annonc/mdh008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to be a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (DeltaN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-x(L) owing to the lack of the BH3 domain needed to interact with the antiapoptotic Bcl-2 family molecules. In this study, we used the Cre-loxP system that allowed us to propagate adenoviruses expressing DeltaN Bax, and investigated the effects of the DeltaN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell tines. DeltaN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the DeltaN Bax-induced cell death was not inhibited by the pan-caspase inhibitor z-VAD-fmk, suggesting that DeltaN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing AN Bax into A549 tumors in Balb/c nude mice showed a significantly stronger suppression of tumor growth (74%) than full-length Bax (25%) compared to the control. Our results suggest that DeltaN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.

DOI： 10.1038/sj.onc.1206331

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Decorin, a small leucin-rich proteoglycan, is a negative regulator of transforming growth factor-beta, but the antifibrotic effect of decorin gene transfer has not been examined in a mouse model of usual interstitial pneumonia (UIP). We constructed a replication-defective recombinant adenovirus harboring human decorin gene (AdCMV.DC) and administered 1x10(9) plaque-forming units of AdCMV.DC intratracheally or intravenously to C57BL/6 mice with intraperitoneal injection of bleomycin, which induces a subpleural fibroproliferation, mimicking UIP, by day 28. Only intratracheal administration of AdCMV.DC increased decorin mRNA expression in the lung and decreased the hydroxyproline content augmented in bleomycin-induced pulmonary fibrosis (1.13+/-0.02 to 0.96+/-0.02, P=0.006). In contrast, intravenous administration of AdCMV.DC increased the decorin expression only in the liver, but not in the lung, and without reducing lung fibrosis. These results indicate that adenoviral decorin gene transfer is effective only by direct administration to fibrosing lungs.

DOI： 10.1152/ajplung.00131.2002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI-/- mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI-/- mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI-/- macrophages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor kappaB activities after LPS treatment than do SLPI+/+ macrophages. SLPI also affects B cell function. SLPI-/- B cells show more proliferation and IgM production after LPS treatment than SLPI+/+ B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.

DOI： 10.1084/jem.20021824

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Macrophage-derived chemokine is chemotactic for a variety of leukocytes, and has been shown to be involved in T(H)2-mediated cellular immunity. To evaluate the role of this chemokine in tumor immunity in vivo, an adenovirus vector encoding the human macrophage-derived chemokine cDNA (AdMDC) was administered to established murine tumors. Gene transfer with AdMDC significantly inhibited tumor growth and prolonged animal survival. AdMDC was not directly cytotoxic to tumor cells, but splenocytes from animals that received intratumoral AdMDC were able to lyse syngeneic tumor cells, and purified splenic CD8(+) cells secreted interferon-gamma in a tumor-specific manner. The antitumor activity of AdMDC was lost in mice lacking CD8(+) T lymphocytes, but surprisingly, it was preserved in animals lacking CD4(+) cells, as was the systemic cytotoxic T lymphocyte response. Systemic NK cells did not play a role in the antitumor immune response induced by AdMDC. Experiments using knockout mice demonstrated that host expression of MHC Class 1, but not Class 11, IL-4, or IL-12, was necessary for AdMDC to exert its antitumor effect, and immunohistochemistry demonstrated infiltrates of CD8(+) and CD86(+) cells, but not CD4(+) cells in treated tumors. These studies highlight a new function for macrophage-derived chemokine by demonstrating that it possesses in vivo antitumor activity with CD8(+) T cells as the effector cells, and interestingly, that the CD4(+) cell/MHC 11 pathway of CD8(+) cell activation is not required for the antitumor effects of this chemokine.

DOI： 10.1097/00002371-200303000-00004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LANCET LTD  

Gefitinib is an oral selective inhibitor of the epidermal growth factor receptor tyrosine kinase that is an effective treatment for patients with advanced non-small cell lung cancer who do not respond to platinum-based chemotherapy. We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities In chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.

DOI： 10.1016/S0140-6736(03)12190-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

NK4, a 4-kringle antagonist of hepatocyte growth factor (HGF), is a potent inhibitor of tumor angiogenesis and functions independently of its HGF-antagonistic activity. We have shown previously that in vivo genetic modification of tumors with an adenovirus vector that expresses NK4 (AdNK4) restrains tumor angiogenesis and slows the rate of tumor growth, in vivo. In the present study, we investigated the hypothesis that this can be made more efficient by also administering bone marrow-generated dendritic cells (Ms) to the tumor. The data show that the growth of mouse subcutaneous tumors is significantly suppressed by direct administration of DCs into established tumors that had been pretreated with AdNK4 3 days previously. The synergistic antitumor effect produced by the combination therapy of AdNK4 With DCs correlated with the in vivo priming of tumor-specific cytotoxic T lymphocytes. Analysis of mice treated with fluorescence-labeled DCs suggested that DCs injected into the flank tumor could migrate to lymphoid organs in vivo for activation of immune-relevant processes. Knockout mice experiments demonstrated that the tumor regression produced by this combination therapy depends on both major histocompatibility complex (MHC) class I antigen presentation of DCs injected into the tumors and CD8(+) T cells of the treated host. Finally, a mechanism for this synergism was suggested by the histological observation that tumor necrosis and apoptosis were induced by genetic engineering of the tumors to express NK4. These findings should be useful in designing novel strategies that use a combination of 2 monotherapies directed against the vascular and immune systems for cancer therapy. (C) 2002 by The American Society of Hematology.

DOI： 10.1182/blood-2002-04-1096

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

We determined beta-lactamase activity and antimicrobial susceptibility of 556 strains consisting of 10 species isolated in four medical institutions and one microbiological laboratory of Miyagi Prefecture in Japan between December in 1999 and February in 2000. beta-Lactamase determined by nitrocefin method was positive in 68% of S. aureus, in 15% of H. influenzae and in 100% of M. catarrhalis. Penicillinase/cephalosporinase determined by acidometry was positive in 9%/10% of E. coli, in 17%/2% of K. pneumoniae, in 16%/58% of E. cloacae, in 43%/78% of S. marcescens, and in 4%/32% of P. aeruginosa, respectively. Of a total of 298 strains of Enterobacteriaceae and P. aeruginosa, 25 strains (14 strains of E. coli, 10 strains of K. pneumoniae and one strain of S. marcescens) produced class A beta-lactamase, two strains of E. cloacae produced class B beta-lactamase, and 12 strains (one strain of E. coli, four strains of E. cloacae, six strains of S. marcescens and one strain of P. aeruginosa) produced class C beta-lactamase. According to NCCLS standard, three strains (one strain of E. coli and two strains of K. pneumoniae) of ESBL-positive microbes were detected. beta-Lactamase-negative ampicillin-resistant (BLNAR) strains of H. influenzae were found in 10/40 (25.0%) of the strains tested.

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240 %, day 18, vs null-vector control LLC/neo; p &lt; 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p &lt; 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and &gt; 10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a &gt;4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

尿中の抗原の検出から確定診断に至った肺炎患者2名(症例1:63歳男,症例2:67歳男)について検討した.2例とも尿中抗原の検出が最初の診断手段となった.症例2では下痢,肝機能障害等のレジオネラに比較的多いとされる所見がみられた.一方,症例1においてレジオネラ肺炎は治癒後に線維化や器質化肺炎様の変化を残す場合や気管支肺胞洗浄液中のリンパ球増多がみられた.又,症例2では胸水からも抗原が検出された

DOI： 10.2169/naika.91.1861

CiNii Article

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Other Link： https://jlc.jst.go.jp/DN/JALC/00159471126?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

Although tumor necrosis factor alpha (TNF-alpha) is a potent cytokine with a myriad of innate immune antitumor properties, systemic administration of TNF-alpha is associated with significant toxicity, limiting the use of the TNF-alpha protein as an antitumor therapeutic. On the basis of the knowledge that dendritic cells (DCs) play a central role in initiating antitumor adaptive immune responses, we hypothesized that intratumoral administration of low doses of an adenovirus encoding TNF-alpha (AdTNF-alpha) together with syngeneic DCs would act synergistically to suppress preexisting tumors. As a model, four different tumor cell lines, all resistant in vitro to the TNF-alpha protein, were implanted in syngeneic mice, and established tumors received intratumor AdTNF-alpha alone or in combination with DCs. At high doses (10(9) PFU), AdTNF-alpha alone suppressed tumor growth, but was associated with systemic toxicity. A 100-fold lower AdTNF-alpha concentration (10(7) PFU) or high doses of the control vector AdNull had no systemic toxicity, but also minimal suppression of tumor growth. In contrast, local administration of the low dose (10(7) PFU) of AdTNF-alpha in combination with syngeneic DCs (AdTNF-alpha + DCs) elicited marked tumor suppression without toxicity. Administration of AdTNF-alpha + DCs into tumors elicited tumor-specific cytotoxic T cells and protected animals against subsequent challenge with the same tumor, suggesting that AdTN-F-alpha + DC therapy induced tumor-specific adaptive immune host responses. Consistent with this concept, studies with syngeneic knockout mice showed that MHC class I molecules on DCs as well as CD8(+) T cells were necessary for the antitumor effect of intratumor AdTNF-alpha + DCs. These data demonstrate that the combination of intratumoral. administration of the TNF-alpha cDNA together with naive DCs can evoke tumor suppression without systemic toxicity, providing a new paradigm for the use of TNF-alpha as antitumor therapy.

DOI： 10.1089/10430340152677395

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Macrophage-derived chemokine (MDC) is a potent chemoattractant for antigen-specific T lymphocytes. We hypothesized that Adenovirus- (Ad-) transduced dendritic cells (DCs) overexpressing MDC would enhance the T cell-mediated humoral immune response specific for antigens presented by the DC. We challenged two strains of mice with lethal Pseudomonas aeruginosa infection 3 weeks after immunization with AdMDC-modified DCs pulsed with heat-killed P. aeruginosa. MDC-expressing DCs specifically attracted T lymphocytes and preserved typical DC surface phenotypes without growth factors in vitro. Mice immunized with AdMDC/Pseudomonas/DCs developed high levels of serum anti-Pseudomonas Ab's and were protected from a lethal respiratory challenge with Pseudomonas. The in vivo protective immunity required CD4(+) T cells, B cells, and IL-4, but not CD8(+) T cells and IL-12. AdMDC/DCs pulsed with Pseudomonas yielded significant but not absolute cross-protection against different strains of P. aeruginosa. Pseudomonas-pulsed AdMDC/DCs protected mice from Pseudomonas but not Escherichia coli and vice versa; this microbe-specific protection correlated with microbe-specific induction of CD4(+) T cell proliferation and IL-4 secretion. Based on these observations, AdMDC-modified DCs pulsed with a killed bacteria maybe a useful approach to vaccination against infectious disorders.

DOI： 10.1172/JCI200111564

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

We have shown that dendritic cells (DCs) genetically engineered with a recombinant adenovirus vector (Ad) to express CD40 ligand (CD40L) elicit specific humoral immunity against the Pseudomonas aeruginosa laboratory strain PAO1, without CD4(+) T cell help. In the present study, using several different strains of P. aeruginosa, we examine whether this strategy is generally applicable to enhancing clinically relevant pathogen-specific immunity. Mice immunized with DCs modified with CD40L and pulsed with heat-killed P. aeruginosa clinical strain PA514, originally isolated from the sputum of an individual with cystic fibrosis, survived lethal respiratory challenge with PA514-impregnated agar beads. Consistent with this effective in vivo protection, the immunized mice generated high levels of serum isotype-switched antibodies directed against PA514 without concomitant nonspecific elevations of total serum immunoglobulin levels. The CD40L genetically engineered DCs pulsed with seven of eight different strains of P. aeruginosa afforded significant, albeit variable, cross-protection against lethal respiratory challenge with a clinical (PA514) or laboratory (PAO1) strain of P. aeruginosa. CD40L genetically modified DCs pulsed with a clinical (PA514) or laboratory (PAO1) strain of P. aeruginosa initiated cross-reacting antibody responses against each other, but not against Escherichia coli and vice versa. These observations may be useful in developing vaccines for infectious diseases, including P. aeruginosa infection.

DOI： 10.1089/104303401750270913

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

To develop a Pseudomonas aeruginosa vaccine that allows the host immune system to select the antigens, we hypothesized that dendritic cells (DC) pulsed with P, aeruginosa would induce protective immunity against pulmonary infections with P, aeruginosa, Incubation of murine bone marrow-derived DC with P. aeruginosa in vitro led to uptake of P. aeruginosa and activation of the DC. Spleen-derived CD4(+) cells from mice immunized with P. aeruginosa-pulsed DC showed increased proliferation, demonstrating that DC pulsed with P. aeruginosa were capable of eliciting a P. aeruginosa-specific immune response. To evaluate if P. aeruginosa-pulsed DC can induce protective immunity against P, aeruginosa pulmonary infection, DC incubated with P, aeruginosa in vitro were administered systemically to syngeneic mice, and the mice were then challenged by intrapulmonary infection with P, aeruginosa (5 x 10(4) CFU/mouse) 13 days later, Unimmunized control mice and mice who had previously received naive DC or DC stimulated with lipopolysaccharide or Escherichia coli died within 72 h, In contrast, 45% of mice receiving P, aeruginosa-pulsed DC demonstrated prolonged survival (&gt; 14 days). Finally, DC-pulsed with heat-inactivated P. aeruginosa protected CD8(-/-) but not CD4(-/-) mice, demonstrating that CD4(+) T cells were required for the DC pulsed with P, aeruginosa to induce protective immunity.

DOI： 10.1128/IAI.69.7.4521-4527.2001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

We have previously shown that in vivo genetic modification of tumors with an adenovirus (Ad) vector engineered to express CD40 ligand (AdmCD40L) induces tumor-specific CTLs and suppresses tumor growth in vivo. In the present study, we investigate the hypothesis that this treatment can be made more efficient with 10(2)-fold less Ad vector by also administering bone marrow-generated dendritic cells (DCs) to the tumor. Using AdmCD40L and the number of DCs that alone had no effect on tumor growth, the data show that the growth of CT26 (colon adenocarcinoma; H-2(d)) and B16 (melanoma; H-2(b)) murine s,c, tumors is significantly suppressed by direct administration of DCs into s,c, established tumors that had been pretreated with AdmCD40L 2 days previously. The antitumor effect produced by the combination therapy of AdmCD40L + DCs correlated with in vivo priming of tumor-specific CTLs, The antitumor cell-mediated immunity was transferable to naive mice by spleen cells from AdmCD40L + DC-treated animals. The interactions between CD40L and CD40 within treated tumors were critical because tumor suppression was abrogated by coadministration to the tumors of neutralizing monoclonal antibody against CD40L along with the DCs. Finally, in vivo depletion and knockout mice experiments demonstrated that tumor regression produced by this combination therapy depends on CD8+ T cells, but not on CD4+ T cells. These findings should be useful in designing strategies for use of DCs and AdmCD40L in cancer immunotherapy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE AMERICA INC  

We have investigated whether dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can trigger B cells to produce antigen-specific antibodies without CD4(+) T-cell help. Dendritic cells modified with a recombinant adenovirus vector to express CD40 ligand and pulsed with heat-killed Pseudomonas induced naive B cells to produce antibodies against Pseudomonas in the absence of CD4(+) T cells in vitro, initiated Pseudomonas-specific humoral immune responses in vivo in wild-type and CD4(-/-) mice, and protected immunized wild-type and CD4(-/-), but not B-cell(-/-) mice, from lethal intrapulmonary challenge with Pseudomonas. Thus, genetic modification of dendritic cells with CD40 ligand enables them to present a complex mixture of microbial antigens and establish CD4(+) T cell-independent, B cell-mediated protective immunity against a specific microbe.

DOI： 10.1038/80498

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

Secretory leukoprotease inhibitor (SLPI), an 11.7-kD nonglycosylated serine protease inhibitor, is produced and released into the fluids of mucosal surfaces including human lung. It comprises two domains with homologous amino acid sequences: the N-terminal domain possessing antibacterial activity, and the C-terminal domain with antiprotease activity. Here we report the positive regulation of hepatocyte growth factor (HGF) production in human lung fibroblasts exerted by SLPI or its C-terminal domain under physiologic concentrations (1 to 10 mu M). This HGF production by SLPI was unaffected by the addition of interleukin (IL)-1 receptor antagonist. In contrast, human skin fibroblasts exerted no SLP1-stimulated increase in HGF production, despite the fact that IL-1 beta increased HGF production with an intensity similar to that of human lung fibroblasts. Both the time-course and dose-response studies in human lung fibroblasts revealed that the induction of HGF messenger RNA (mRNA) and protein occurred in parallel, indicating that the mechanism existed at the steady-state mRNA level. A synthetic elastase inhibitor failed to induce HGF, but alpha(1)-antitrypsin also stimulated HGF production in lung fibroblasts. inactivation of the antiprotease activity of SLPI or its C-terminal domain by an oxidizing agent (N-chlorosuccinimide abolished their stimulatory effect on HGF production. These findings demonstrate that SLPI exerts a novel HGF induction and functions as an anti-inflammatory and regenerative factor in addition to its role in protease inhibition.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

CD40 ligand (CD40L) is essential for the Initiation of antigen-specific T-cell responses. This study is based on the hypothesis that dendritic cells (DCs) genetically modified ex vivo to express CD40L will enhance in vivo presentation of tumor antigen to the cellular immune system with consequent induction of antitumor immunity to suppress tumor growth. To examine this concept, subcutaneous murine tumors were injected with bone marrow-derived DCs that had been modified in vitro with an adenovirus (Ad) vector expressing murine CD40L (AdmCD40L). In B16 (H-2(b), melanoma) and CT26 (H-2(d), colon cancer) murine models, intratumoral injection of 2 x 10(6) AdmCD40L-modified DCs (CD40L-DCs) to established (day 8) subcutaneous tumors resulted in sustained tumor regression and survival advantage. This antitumor effect was sustained when the number of CD40L-DCs were reduced 10-fold to 2 x 10(5). Analysis of spleens from CD40L-DC-treated animals demonstrated that CD40L-DCs injected into the subcutaneous CT26 flank tumors migrated to the spleen, resulting in activation of immune-relevant processes. Consistent with this concept, intratumoral administration of CD40L-DCs elicited tumor-specific cytotoxic T-lymphocyte responses, and the transfer of spleen cells from CD40L-DC-treated mice efficiently protected naive mice against a subsequent tumor challenge. In a distant 2-tumor model of metastatic disease, an untreated B16 tumor in the right flank regressed in parallel with a left B16 tumor treated with direct injection of CD40L-DCs, These results support the concept that genetic modification of DCs with a recombinant CD40L adenovirus vector may be a useful strategy for directly activating DCs for cancer immunotherapy. (Blood. 2000;95:91-99) (C) 2000 by The American Society of Hematology.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Expression of the 37-kDa laminin binding protein (37LBP/p40), a precursor of the 67-kDa laminin receptor, is well-correlated with the biological aggressiveness of cancer cells. To elucidate the direct role played by 37LBP/p40 in cancer cells, a murine lung cancer cell line T11, the 37LBP/p40 expression of which was remarkably diminished, was established by the introduction of the antisense 37LBP/p40-RNA using a retroviral vector. As a result, the population doubling time of T11 was prolonged (60 h) compared with that of P29, the non-transfected parental cell line (42 h), and TN2, a transfectant with vehicle only (40 h). In-vitro studies also showed that T11 cells adhered to immobilized laminin less firmly than P29 cells did. When 5 x 10(5) cells were subcutaneously inoculated into syngenic mice, the mean survival time of T11-recipients (77.0 +/- 14.8 days) was also significantly prolonged compared with that for P29 (34.8 +/- 5.5 days) and TN2 (36.7 +/- 6.1 days) recipients (P &lt; 0.001). The electron-microscopic view of the tumour tissue revealed that T11 cells were loosely apposed and their intercellular space was markedly widened. Some of the T11 cells sporadically degenerated with the infiltration of lymphocytes and neutrophils. These results suggest that the suppressed expression of 37LBP/p40 reduces the capability of lung cancer cell proliferation in vitro and tumour formation in vivo.

DOI： 10.1038/sj.bjc.6690474

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

CD40 ligand (CD40L), the ligand for CD40 on antigen-presenting cells, is essential for the initiation of antigen-specific T cell responses, an important component of the immune response to tumors. This study is based on the hypothesis that in vivo genetic modification of tumor cells to express CD40L will trigger CD40 on local antigen-presenting cells to present tumor antigen to the cellular immune systems, thus eliciting anti-tumor immunity to suppress growth of the tumor, To examine this concept, subcutaneous tumors of three different murine tumor models in two strains of mice were infected with a recombinant adenovirus (Ad) vector expressing murine CD40L (AdmCD40L), In the B16 (H-2(b), melanoma) and CT26 (H-2(d), colon cancer) murine models, injection of AdmCD40L into established subcutaneous tumors resulted in sustained tumor regression and tumor-free status in &gt;60% of animals. Intratumoral injection of AdmCD40L also significantly suppressed the growth of established, weakly immunogenic Lewis lung carcinoma (H-2b) tumors, but to a lesser extent. Ex vivo AdmCD40L-transduced tumor cells implanted in syngeneic hosts induced significant antitumor response against preexisting identical tumors at a distant site. Both in vivo and in vitro AdmCD40L modification of tumors to express CD40L elicited tumor-specific cytolytic T lymphocytes responses, and the transfer of spleen cells from treated mice efficiently protected naive mice against a subsequent tumor challenge. These results support the concept that transduction of tumors with a recombinant CD40L adenovirus vector may be a useful strategy for cancer immunotherapy.

DOI： 10.1089/10430349950018049

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER LUNG ASSOC  

Secretory leukoprotease inhibitor (SLPI) is a serine protease inhibitor involved in antineutrophil elastase protection at inflammatory sites. To elucidate both the function and regulation of SLPI in vivo, We isolated and characterized the mouse Slpi gene. An entire 3-kb mouse Slpi gene fragment was sequenced, including an 0.8-kb 5'-flanking region, the 2.2-kb Slpi gene, and a 0.1-kb 3'-flanking region. The mouse Slpi gene spans 2,222 base pairs containing four exons and three introns. All splicing borders between exons and introns are conserved as predicted by GT-AG rules. Using primer extension analysis, the transcription start site was located 20 nucleotides upstream from the methionine (ATG) initiation codon. At the defined transcription start site, the sequence TCA(+1)GAGC is present. These results indicate that both mouse and human genomic structure are highly conserved. Using fluorescence in situ hybridization, we confirmed that, consistent with the genomic similarity, the human SLPI gene is localized on chromosome 20q12-13.2 and the mouse homologue on chromosome 2H, which are syntenic with each other.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER LUNG ASSOC  

The cDNA of murine secretory leukoprotease inhibitor (SLPI) was cloned from a mouse lung cDNA library. The amino acid sequence deduced from the cDNA showed 58 and 51% homology with those of human and porcine SLPI, respectively. A two-domain structure with similar amino acid sequences, four intradomain disulfide bonds, and high proline content, which are characteristics common to human and porcine SLPI, was also found in the mouse protein. The amino acid residues for the signal sequence and active site are also conserved in mouse SLPI. RNase protection assay showed the expression of the SLPI gene in liver, intestine, spleen, and epididymis, suggesting the distribution of SLPI in tissues other than lung and seminal vesicles. In the lung infected with Streptococcus pneumoniae strain FP1284, 10 h after inoculation of bacteria the number of SLPI mRNA transcripts was three times higher than baseline. The increased level of expression remained constant for at least 48 h. This result clearly contrasts to that obtained for spleen, in which the SLPI mRNA transcript level was mostly unchanged during the course of pneumonia. These facts suggested the local regulation of the SLPI gene expression in vivo in response to inflammatory stimuli at the site of inflammation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER LUNG ASSOC  

Secretory leukoprotease inhibitor (SLPI) is a serine protease inhibitor, produced locally in respiratory and genital glands, but not in the liver. In the present study the promoter region of this gene was analyzed to better understand the molecular mechanisms involved in transcriptional regulation. DNase-I hypersensitive sites were detected within 1 kbp upstream of exon I in chromatin structures of type II pneumocyte cell line A549 and utero-cervical cell line HeLa, both of which express SLPI mRNA transcripts. The function of the SLPI promoter encompassing these DNase-I hypersensitive sites has been studied by deletion analysis with the luciferase gene as a transient expression vector. In this analysis, we found three transcription control regions that function in A549 cells but not in nonlung cell lines, such as HeLa and hepatoma Hep G2. Among three cis-regulatory regions, a proximal 41-bp region (-132 to -92 bp relative to the transcription start site) is responsible for the most striking magnitude of transcriptional activity. This region corresponds to the transcriptional activating sequence detected in another lung cell line, HS-24, indicating that this 41-bp sequence is required for lung cell-specific expression. An electrophoretic mobility shift assay demonstrated that this 41-bp promoter region contains an 1 l-bp recognition sequence for two nuclear binding proteins, one of which is abundant in lung cell lines, and the other in nonlung cell lines. These results suggest that the ratio of these two nuclear binding proteins confers the cell type specificity on the expression pattern of the SLPI gene.

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Language：Japanese   Publisher：The Japanese Respiratory Society  

DOI： 10.11389/jjrs1963.35.5supplement_249

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SLPI遺伝子の転写活性を有するA549細胞(II型肺胞上皮細胞由来)とHeLa細胞(子宮頸癌由来)では,SLPI遺伝子の上流1kb以内にDNase I高感受性領域が認められた.そこで,SLPI遺伝子上流1.2kbまでの領域に転写調節機能があるかを,培養細胞を用いたリポーター遺伝子法により解析した.転写開始時点の上流1228kbから上流91bpまで順次欠失させた所,A549細胞で3ヶ所に有意なプロモータ活性の変動が認められたが,HeLa細胞やHepG2細胞(肝細胞癌由来)では変動は認められなかった.このことからSLPI遺伝子の上流132bpから上流91bpまでの領域が,気道上皮細胞で特異的に転写を調節していることが示唆された

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

The in vitro antimicrobial activity of DU-6859a developed in Japan against a total of 201 isolates of respiratory pathogens including Mycobacteriaceae was determined. The minimum inhibitory concentrations (MIC's) of DU-6859a, ofloxacin, sparfloxacin, ciprofloxacin and rifampicin for 20 strains each of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA). Escherichia coli. Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa, 7 strains of Haemophilus influenzae, 19 strains each of Klebsiella pneumoniae and Mycobacterium avium, 21 strains of RFP-susceptible Mycobacterium tuberculosis and 15 strains of RFP-resistant M. tuberculosis were determined by the micro- broth dilution method using the Dynatech MIC 2000 system. The MIC90's of DU-6859a for the above species were ≤0.06, 1, ≤0.06, 0.12, 0.25, 0.5, ≤0.06, 0.12, 8, 0.25 and 4 μg/ml respectively. DU-6859a was 2 to 16 times as active as the other agents against the species other than H. influenzae, E. coli, K. pneumoniae and E. cloacae. DU-6859a was as active as ofloxacin and ciprofloxacin against the latter four species. DU-6859a was as active as RFP and 4 to 8 times as active as ofloxacin and ciprofloxacin against RFP- susceptible M. tuberculosis. DU-6859a was 4 to 64 times as active as other agents against M. avium and RFP-resistant M. tuberculosis. We conclude from the above results that DU-6859a is one of the most useful quinolone agents for oral use as a drug of first choice in the treatment of respiratory infections.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT JOURNAL ONCOLOGY  

In the present study, we investigated the expression of laminin in three murine neoplastic cell lines; 3LL-SA (Lewis lung carcinoma), NA (neuroblastoma) and F9 (teratocarcinoma). Both Western and Northern blot analyses demonstrated that parietal endoderm-like F9 expressed three laminin chains A, B1 and B2. On the other hand, 3LL-SA cells synthesized two laminin chains B1 and B2, and NA cells only B2 chain. The analyses of the restriction fragment length polymorphism indicated that the genes for coding regions of all chains were present and grossly intact both in 3LL-SA and in NA just as in F9. These findings suggest that expression of laminin seems to be transcriptionally regulated in each neoplastic cell line specifically. Since these cell lines produce different forms of laminin, they can be used for investigation of the multifunctions of laminin molecule.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC CELL BIOLOGY  

We investigated the expression of laminin in two cell lines with different metastatic potentials established from murine Lewis lung carcinoma. Immunostaining of the cells with anti-laminin antibody and Northern blot analysis of laminin mRNA demonstrated that the high metastatic clone expressed less laminin than the low metastatic one. In contrast, expressions of 67 kDa-laminin receptor were at similar levels between these two lines. These findings show the possibility that endogenous laminin may contribute to the difference in metastatic properties in the murine Lewis lung carcinoma cell lines examined.

DOI： 10.1247/csf.18.183

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Cell-adhesive protein laminin and its specific receptor play an important role in the processes of cancer proliferation, invasion and metastasis. In the present study, we cloned the cDNAs of the 67-kDa laminin receptor both from a human lung cell line (IMR90) and from a human lung cancer cell line (SBC3), and determined the nucleotide sequences. In comparison with both cDNA sequences of the protein-coding region, three nucleotide differences were found. These differences in the secondary structure of the protein, however, were caused by nucleotide substitutions. It was also demonstrated that the level of 67-kDa-laminin receptor mRNA was higher in SBC3 than in IMR90.

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Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

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Language：Japanese   Publisher：日本医事新報社  

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Other Link： https://search.jamas.or.jp/link/ui/2019316603

Language：Japanese   Publisher：(一社)日本睡眠学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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J-GLOBAL

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J-GLOBAL

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＜文献概要＞Point ・肺外非結核性抗酸菌(NTM)症は,限局型と播種型(全身型)から成り,好発部位は皮膚やリンパ節,骨などである.・限局型は,宿主要因に関係なく発症し,外科的切除などの局所治療で治癒することがある.・播種型は,宿主要因を背景に発症し,抗菌薬治療だけでは不十分なこともある.

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は73歳、男性。初診時の精査で特発性間質性肺炎と診断された。副腎皮質ステロイドの開始から20ヵ月後にすりガラス影が出現し、病理学的所見、血清抗GM-CSF抗体陽性から自己免疫性肺胞蛋白症(aPAP)と診断した。初診時の保存血清でも抗GM-CSF抗体陽性であり、気管支肺胞洗浄液にPAS陽性物質が存在していることを確認した。潜在的なaPAPがステロイド治療を経て顕在化した経過が考えられた。典型的な臨床所見を呈さない潜在的なaPAPが存在することに留意する必要性が示唆された。(著者抄録)

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Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2018-2717

Web of Science

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese  

症例は52歳、男性。慢性骨髄性白血病(CML)に対してX-4年からメシル酸イマチニブ(imatinib mesylate、以下イマチニブ)、X-2年からニロチニブ、X-1年からダサチニブを開始された。X年11月ごろより息切れが出現し、胸部X線、胸部CTで浸潤影、両側胸水を認めた。抗菌薬と利尿剤を開始されたが改善を認めず、当科を紹介受診した。経気管支肺生検で得られた生検組織で肺胞腔内にポリープ状線維化巣を認め、器質化肺炎と診断した。ダサチニブを中止してステロイド治療を行い、臨床症状、画像所見の改善を認めた。その後CMLに対して、イマチニブ、ニロチニブを投与したが治療効果を認めなかった。ステロイド併用下でダサチニブを再投与し、器質化肺炎の再燃なくCMLをコントロールすることができた。ダサチニブによる器質化肺炎はまれであり、これまで報告はない。ステロイド治療によりダサチニブの再投与が可能であった器質化肺炎の症例を経験したので、文献的考察を含め報告する。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本感染症学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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肺Mycobacterium avium症は、肺非結核性抗酸菌症の主要な病態である。これまで我々は、肺M.avium症患者から分離培養された原因菌を遺伝子解析し、その患者の治療反応性や予後を予測することを目指してきた。その結果、多型縦列反復配列法による菌遺伝子型は、その菌株が由来する肺M.avium症患者の病態と関連していることが示唆された。同様の報告は、肺Mycobacterium abscessus症でも報告されている。原因菌の遺伝子解析から、肺非結核性抗酸菌症の治療反応性や予後を予測できるようになることが今後期待される。(著者抄録)

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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