Search

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Yu Fujita, Hirofumi Utsumi, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata Tel +81-3-3433-1111 (ex 3271)Fax +81-3-3433-1020Email t-numata@jikei.ac.jpBackground: In Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain.Methods: To elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy.Results: Thirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness.Conclusion: Switching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective.Keywords: benralizumab, dupilumab, mepolizumab, omalizumab, switching

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)–induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Background Benralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidate the efficacy of benralizumab by evaluating changes in clinical parameters after benralizumab treatment in patients with SEA. Methods From July 2018 to December 2019, 24 Japanese patients with SEA received benralizumab at Jikei University Hospital. We retrospectively evaluated the patients’ characteristics, parameters, numbers of exacerbations and maintenance OCS doses. Results Among the 24 patients, eleven patients had received mepolizumab treatment and were directly switched to benralizumab. The peripheral blood eosinophil and basophil counts significantly decreased after benralizumab treatment regardless of previous mepolizumab treatment. Pulmonary function, Asthma Control Test scores, the numbers of annual exacerbations and maintenance OCS doses in patients without previous mepolizumab treatment tended to improve without significant differences. Fourteen patients (58%) were responders according to the Global Evaluation of Treatment Effectiveness (GETE) score. The proportion of GETE responders among patients with aspirin-exacerbated respiratory disease (AERD) tended to be lower than that among patients without AERD (p = 0.085). After benralizumab treatment, the change in the forced expiratory volume in 1 s from baseline was 200 ml or greater in eight patients (33%), including three patients who were switched from mepolizumab. Conclusion Benralizumab treatment improved and controlled asthma symptoms based on the GETE score.

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.

Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient’s respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure.

Mepolizumab significantly reduces the number of annual exacerbations (AEs) and the maintenance dose of systemic corticosteroids (CSs) in patients with severe eosinophilic asthma (SEA). However, there are few studies based on real life with a long-term observational period in Japan. Between July 2016 and December 2019, 24 Japanese patients received mepolizumab at Jikei University Hospital for at least 12 months. We retrospectively evaluated these characteristics, AEs and CS doses. To elucidate the predictors of the enhanced responders, we performed multivariate logistic regression analysis. After introduction, asthma symptoms improved and were maintained for over a year. The number of AEs and CS doses significantly decreased. In the subgroup analysis, the younger than 65 years-old, body mass index (BMI) < 25 kg/m2, eosinophilic chronic rhinosinusitis, or eosinophil count ≥ 400/mm3 exhibited effective reductions in either AEs or CS doses with mepolizumab treatment. The percentage change in the AEs (≤ −75%) was significantly decreased in the patients with a BMI < 25 using multivariate logistic regression analysis (odds ratio 31, 95% confidence interval: 1.4–700, P = 0.03). In real-life, BMI < 25 could be a predictor for reductions in AEs with mepolizumab treatment in the patients with SEA. Abbreviations IL, interleukin; CS, corticosteroid; SEA, severe eosinophilic asthma; BMI, body mass index; ECRS, eosinophilic chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps

Background Postoperative pulmonary complications (PPC) in patients with pulmonary diseases remain to be resolved clinical issue. However, most evidence regarding PPC has been established more than 10 years ago. Therefore, it is necessary to evaluate perioperative management using new inhalant drugs in patients with obstructive pulmonary diseases. Methods April 2014 through March 2015, 346 adult patients with pulmonary diseases (257 asthma, 89 chronic obstructive pulmonary disease (COPD)) underwent non-pulmonary surgery except cataract surgery in our university hospital. To analyze the risk factors for PPC, we retrospectively evaluated physiological backgrounds, surgical factors and perioperative specific treatment for asthma and COPD. Results Finally, 29 patients with pulmonary diseases (22 asthma, 7 COPD) had PPC. In patients with asthma, smoking index (≥ 20 pack-years), peripheral blood eosinophil count (≥ 200/mm3) and severity (Global INitiative for Asthma(GINA) STEP ≥ 3) were significantly associated with PPC in the multivariate logistic regression analysis [odds ratio (95% confidence interval) = 5.4(1.4–20.8), 0.31 (0.11–0.84) and 3.2 (1.04–9.9), respectively]. In patients with COPD, age, introducing treatment for COPD, upper abdominal surgery and operation time (≥ 5 h) were significantly associated with PPC [1.18 (1.00–1.40), 0.09 (0.01–0.81), 21.2 (1.3–349) and 9.5 (1.2–77.4), respectively]. Conclusions History of smoking or severe asthma is a risk factor of PPC in patients with asthma, and age, upper abdominal surgery, or long operation time is a risk factor of PPC in patients with COPD. Adequate inhaled corticosteroids treatment in patients with eosinophilic asthma and introducing treatment for COPD in patients with COPD could reduce PPCs.

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

In this phase Ib study, four combination therapies of nivolumab 10 mg/kg and standard chemotherapy (cisplatin/gemcitabine, cisplatin/pemetrexed, carboplatin/paclitaxel/bevacizumab, or docetaxel) showed acceptable toxicity profiles in patients with advanced non-small-cell lung cancer. Furthermore, these combination therapies presented encouraging antitumor activities., Background The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. Results As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. Conclusions Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Clinical trials number Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.

Background This study aimed to determine whether the neutrophil-to-lymphocyte ratio (NLR) reflected poor treatment benefits in patients with tumor proportion score (TPS) ≥50% and who under went first-line pembrolizumab monotherapy. Patients and methods This study retrospectively analyzed patients with untreated stage III/IV or recurrent non-small cell lung cancer (NSCLC) with TPS ≥50% and who received pembrolizumab monotherapy at two hospitals between February 2017 and April 2019. The NLR was calculated from pre-treatment complete blood counts. Results A total of 51 previously untreated patients with NSCLC who had TPS ≥50% and who underwent pembrolizumab monotherapy were evaluated. Multivariate analysis revealed that high NLR, Eastern Cooperative Oncology Group performance status (PS) ≥2, stage IV or recurrent cancer, and TPS=50-74% were significantly and independently associated with poor progression-free survival. Moreover, high NLR and PS ≥2 were significantly associated with short overall survival. Conclusion A high pre-treatment NLR was associated with significantly short progression-free and overall survival in previously untreated patients with NSCLC with high expression of programmed cell-death ligand 1 treated with pembrolizumab monotherapy.

The aim of this paper is to take issue with the opinion that, in sociology, the concept of ‘society’ was equated with the nation-state. Firstly, a diachronic analysis of the term ‘society’, as used by the general public, shall be attempted: ‘society as a whole’ and ‘the social’. Secondly, the article shall illustrate that sociology has developed its own analytical concept of society within the space between the two lay terms. Thirdly, the fact that the process of globalisation yet again problematizes the distinction between ‘society as a whole’ and ‘the social’ shall be shown. The conclusion of the paper is that, by yet again, becoming aware of the three dimensions of the concept of ‘society’, we can provide cues for a theoretical reconstruction of the sociological concept of ‘society’ that will contribute to research on ‘society’ in the age of globalisation.

Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)–induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)–treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain–containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β–mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-β–induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-β–induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-β signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.

Background Several major randomized control studies have demonstrated that mepolizumab, an anti-IL-5 monoclonal antibody, is effective for patients with severe eosinophilic asthma who show exacerbation or require systemic corticosteroid maintenance therapy. However, the predictive factors of the response to mepolizumab other than blood eosinophil count are unclear in clinical practice. Objective To elucidate the predictive factors of the response to mepolizumab for patients with severe eosinophilic asthma. Methods From July 2016 to December 2017, 28 patients with severe asthma received mepolizumab in our hospital. To determine the predictive factors, we retrospectively evaluated patient characteristics, comorbidities, biomarkers, pulmonary function, maintenance dose of systemic corticosteroids and number of exacerbations. Results The response rate to mepolizumab treatment was 70% (19/27; one pregnant woman was excluded from analysis). Compared with 11 patients without eosinophilic chronic rhinosinusitis (ECRS), 16 patients with ECRS showed significantly improved systemic corticosteroid-sparing effects [− 71.3 ± 37.0% vs − 10.7 ± 20.1%, P = 0.006], change from baseline FeNO [− 19 ± 57 (%) vs 30 ± 77 (%), P = 0.023] and symptoms [14 patients (88%) vs five patients (45%), P = 0.033]. ECRS was identified as a predictive factor of the response to mepolizumab in a multivariate logistic regression analysis [odds ratio = 22.5, 95% CI (1.5–336), P = 0.024]. Of the eight patients previously administered omalizumab, five responded to mepolizumab. Staphylococcus aureus enterotoxin B IgE results were negative in 80% of responders (P = 0.14). Conclusion Both groups showed improved symptom scores and a decreased number of exacerbations. Mepolizumab substantially improved the clinical variables of patients with eosinophilic asthma complicated with ECRS.

The purpose of this paper is to show the new directions for reconstruction of the concept of society made possible by another concept – that of hybridity. First we shall argue that in the era of globalisation, the conventional view perceiving society as a self-fulfilling entity is no longer valid. Next, we will critically review the spatial and temporal frameworks, which have served as the basis for the concept of society so far, basing our analysis on the recent theories of space and time. We shall then focus on the concept of hybridity, showing that it can serve as a pivot providing us with the clue for reconstruction of society making the latter valid again. Although ‘hybridity’ is a term predominantly used in cultural research, here we shall try to look at it from a sociological perspective. We shall demonstrate that ‘social hybridity’ presents a new way to see society as a complex entity made of various interactions both within and across borders. Lastly, in order to show how this theory can be applied in empirical research, we shall introduce the concept of ‘zones of interactivity’. We will show that the ‘social hybridity’ approach built around a core of the ‘zone’ concept makes it possible to resurrect ‘society’ helping us to see the present social change from a completely new perspective.

The recommended dose of erlotinib is 150 mg daily either 1 h before a meal (complete fasting) or 2 h after a meal (2 h post-meal), because of the food effect. We conducted a cross-over pharmacokinetic study to compare the fed bioequivalence in the two conditions. Twenty-three patients with non-small cell lung cancer were included in the analysis. AUC0–24 and C max in the 2-h post-meal status were significantly higher than in the complete fasting status (GMR = 1.33, P

Introduction: Downregulation of lamin B1 has been recognized to be a crucial step for development of full senescence. Accelerated cellular senescence linked to dysregulated autophagy and mTOR activation have been implicated in COPD pathogenesis. We have demonstrated reduced lamin B1 was associated with COPD pathogenesis through activating mTOR during cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). Methods: To further elucidate the mechanisms for lamin B1 downregulation related to autophagy, confocal microscopic evaluation and immunoprecipitation were performed in HBEC. DNA microarray and mass spectrometry were examined. C57BL/6J mice were exposed to cigarette smoke over a 6-month period as COPD model. Results: LaminB1 reduction during CSE exposure was recovered by lysosomal protease inhibitors and ATG5 knockdown. Confocal microscopic evaluation detected cytoplasmic colocarization between lamin B1 and LC3, reflecting autophagic degradation. DNA microarray and mass spectrometry demonstrated decrease in DEPTOR expression, an mTOR inhibitor by lamin B1 knockdown, which was responsible for subsequent autophagy impairment and cellular senescence. Lamin B1 knockdown also enhanced histone modification of H4K20me3. Decreased lamin B1 and DEPTOR with concomitantly increased p62 reflecting insufficient autophagic degradation were demonstrated in lung homogenate from cigarette smoke exposed-mice. Conclusion: These findings suggest CSE-induced autophagic degradation is involved in the mechanisms of lamin B1 reduction. Phenotypic alterations linked to cellular senescence can be attributed to epigenetic histone modifications by reduced laminB1.

Background Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. Methods Transforming growth factor-β (TGF-β)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. Results We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-β. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. Conclusions These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.

Background: Prostaglandin E2 (PGE2) is metabolized to prostaglandin E-major urinary metabolite (PGE-MUM). Enhanced cyclooxygenase-2 (COX-2) expression demonstrated in lung adenocarcinoma indicates increased PGE-MUM levels in patients with lung adenocarcinoma. Objectives: We aimed to elucidate the clinical usefulness of measuring PGE-MUM as an indicator of tumor burden in patients with lung adenocarcinoma. Methods: PGE-MUM was measured by a radioimmunoassay in control healthy volunteers (n = 124) and patients with lung adenocarcinoma (n = 54). Associations between PGE-MUM levels and clinical characteristics of the patients (including lung cancer stage and TNM factors (T: Tumor, N: Node, M: Metastasis) were examined. Results: PGE-MUM levels were significantly elevated in patients with lung adenocarcinoma. A PGE-MUM level of 14.9 &mu, g/g∙Cr showed 70.4% sensitivity and 67.7% specificity for the diagnosis of lung adenocarcinoma. PGE-MUM levels tended to be positively correlated with cancer progression as determined by the TNM staging system. Advanced stage (stage III, stage IV, and recurrence) was significantly associated with high PGE-MUM levels by logistic regression analysis. No apparent correlation was demonstrated between PGE-MUM and carcinoma embryonic antigen (CEA) levels. Conclusions: PGE-MUM can be a promising biomarker reflecting the systemic tumor burden of lung adenocarcinoma.

Background Fatigue is an important clinical state and limits physical, mental activities in the patients with chronic lung diseases. However mechanisms and evaluation methods of fatigue are not well established. Recently reactivation of human herpesvirus (HHV)6/7 and HHV6 related molecules, named SITH-1 (Small protein encoded by the Intermediate Stage Transcript of HHV6-1) and its serum antibody (aSITH-1Ab) have been studied as novel biomarkers for fatigue.1),2) Fatigue due to chronic stress can cause increase of HHV6/7 DNAs in saliva, and aSITH-1Ab in blood of patients with mental disturbance. The HHV-related biomarkers could be good candidates to evaluate the pathological fatigue. Method To evaluate fatigue state, patients in stable conditions with COPD, asthma (BA) and BA COPD overlap syndrome (ACOS) were enrolled. The fatigue markers, depression score, and inflammation markers were measured. Result 60 patients were enrolled (mean age=60±14.8y, M/F=45/15, COPD/BA/ACOS=15/32/14). The rates (%) of high HHV DNA in saliva, meaning fatigue state, in COPD/BA/ACOS were 40/36/30, for both viruses equally. aSITH-1Ab positive rates (%) in COPD/BA/ACOS were 15.8/57.9/26.3. The markers for systemic inflammation were higher in COPD/ACOS than BA alone. Conclusion 30∼40% of the patients with COPD/BA/ACOS were estimated as fatigue. The patients with COPD (COPD/ACOS) showed higher systemic inflammation than BA alone, whereas those with BA (BA/ACOS) showed higher prevalence of mental disturbance than COPD alone. 1) Kondo K. et al. Journal of Virology 2002; 76: 4145-4151 2) Kondo K. et al. US Patent Application US 2013/0137088 A1 May 30, 2013.

Background The postoperative pulmonary complication (PPC) is an important surgical risk as common as the cardiac one, containing atelectasis, pneumonia, and respiratory failure. Objective The purpose of this study is to evaluate the risk factors for PPC in the patients with major respiratory underlying diseases such as bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) in our university hospital. Methods Totally 10699 patients were surgically treated in our university hospital from April to December in 2014. Among them, there were 68 COPD patients and 181 BA ones studied here. Eight of 68 COPD patients (11.8%) had PPC with 6 consolidations and 2 consolidations + respiratory failures, whereas 16 of 181 BA patients (8.8%) had PPC with 14 asthma attacks and 2 consolidations. We retrospectively evaluated physiological background, pulmonary function, duration of surgery, and perioperative specific treatment for pulmonary diseases to analyze the risk for PPC in these patients. Results In the BA patients, smoking index> 20 pack-year was significantly associated with PPC [OR (95%CI) = 11.7(2.6-52.1), P= 0.0013]. In the COPD patients, induction of COPD specific treatment and duration of surgery >300minites were significantly associated with PPC [OR (95%CI) = 0.09(0.01-0.63), P= 0.016; OR (95%CI) = 9.5(1.4-65.3), P= 0.022, respectively] Conclusions To prevent PPC, smoking cessation in BA and induction of specific treatment and shortening of surgery time in COPD were critically important.

A 76-year-old man with ulcerative colitis presented with a 1-week history of low-grade fever and progressive dyspnea. He was taking infliximab for the ulcerative colitis. He was known to be negative for human immunodeficiency virus. Computed tomography (CT) of the chest revealed infiltrates in the

Background Biomarkers for predicting the effect of anti–programmed cell death 1 (PD-1) monoclonal antibody against non–small-cell lung cancer (NSCLC) are urgently required. Although it is known that the blood levels of soluble programmed cell death ligand 1 (sPD-L1) are elevated in various malignancies, the nature of sPD-L1 has not been thoroughly elucidated. We investigated the significance of plasma sPD-L1 levels as a biomarker for anti–PD-1 monoclonal antibody, nivolumab therapy. Patients and Methods The present prospective study included 39 NSCLC patients. The patients were treated with nivolumab at the dose of 3 mg/kg every 2 weeks, and the effects of nivolumab on NSCLC were assessed according to the change in tumor size, time to treatment failure (TTF), and overall survival (OS). The baseline plasma sPD-L1 concentration was determined using an enzyme-linked immunosorbent assay. Results The area under the curve of the receiver operating characteristic curve was 0.761. The calculated optimal cutoff point for sPD-L1 in the plasma samples was 3.357 ng/mL. Of the 39 patients, 59% with low plasma sPD-L1 levels achieved a complete response or partial response and 25% of those with high plasma sPD-L1 levels did so. In addition, 22% of the patients with low plasma sPD-L1 levels developed progressive disease compared with 75% of those with high plasma sPD-L1 levels. The TTF and OS were significantly longer for those patients with low plasma sPD-L1 levels compared with the TTF and OS for those with high plasma sPD-L1 levels. Conclusion The clinical benefit from nivolumab therapy was significantly associated with the baseline plasma sPD-L1 levels. Plasma sPD-L1 levels might represent a novel biomarker for the prediction of the efficacy of nivolumab therapy against NSCLC.

Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers).Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h.Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV.NCT01722825.

The present study investigated whether bevacizumab (BV) is associated with postoperative wound complications (PWCs).We retrospectively analyzed patients undergoing surgery for liver metastases of colorectal cancer at our Institution. Patients were divided into 3 groups according to the preoperative treatment: che mo therapy with BV (group A), chemotherapy without BV (group B) and no chemotherapy (group C).Between February 2003 and September 2012, 297 patients underwent 373 surgeries. Groups A, B and C consisted of 23, 62 and 288 patients, respectively. PWCs occurred in 29 patients (7.8%). In multivariate analysis, there were no differences in PWCs among the groups (C vs. B:P=0.739; C vs. A: P=0.110). Conversely, lower serum albumin levels (3.5 g/dl vs. ≥ 3.5 g/dl: p=0.030) and synchronous colorectal resection (no vs. yes; p0.001) remained significant risk factors of developing PWCs.Chemotherapy with or without BV did not influence the risk of PWCs.

Background Several studies have assessed the expression of programmed death-ligand 1 (PD-L1) in resected surgical specimens of non–small-cell lung cancer (NSCLC). However, the expression of PD-L1 in smaller biopsy samples of advanced NSCLC has not been reported. Patients and Methods A total of 79 patients with NSCLC at our institution with available biopsy samples and resected specimens were retrospectively enrolled in the present study. PD-L1 expression was assessed by immunohistochemistry and scored using the hybrid scoring method. The concordance rates for the expression of PD-L1 between the 2 samples were analyzed. Results The pathologic stage of the patients (51 men, 28 women; median age, 68 years) was stage I in 37, stage II in 18, and stage III in 24. The diagnostic procedures included transbronchial biopsy in 59, transbronchial needle aspiration biopsy in 14, and computed tomography (CT)-guided needle biopsy in 6. The positivity rate of PD-L1 in these samples was 38.0% (27 transbronchial biopsies, 6 transbronchial needle aspiration biopsies, 3 CT-guided needle biopsies) versus 35.4% in the resected specimens. The median hybrid score was 0 (range, 0-170), and the mean score was 28.7 ± 43.4. Comparing the biopsy samples and resected specimens with a score of ≥ 1 as positive for PD-L1 staining, 6 tumors were discordant for PD-L1 expression and 73 were concordant, for a concordance rate of 92.4% and κ value of 0.8366. Conclusion PD-L1 status showed good concordance between the biopsy samples and resected specimens. These small samples, even those derived from transbronchial needle aspiration biopsies, appear adequate for the assessment of PD-L1 expression.

The Japanese government conducted the first public-opinion poll on the utilization of nuclear power in 1968. It was significant in two aspects.1 First, by emphasizing the difference between military and nonmilitary uses, it had the plainly propagandistic aim to state the potential and safety of peaceful nuclear technologies. Second, the outcome showed two tendencies. Approximately 70 percent of the respondents associated nuclear power not with “peaceful use” but with fear of “atomic and hydrogen bombs, Hiroshima and Nagasaki, or war”; also, almost 70 percent approved of promotion of “nuclear energy for peaceful use,” even though they distrusted the safety of nuclear power plants and felt some anxiety about radiation. The former tendency indicated that a majority of the Japanese people in the mid-1960s had a negative image of nuclear technology for military use; the latter showed that most had a positive image of peaceful uses, in spite of some doubts and fears. These attitudes persisted until quite recently. In a poll conducted by Nippon Hoso Kyokai (Japan Broadcasting Corporation) in 2010, almost 80 percent of the respondents opposed both the possession and the use of nuclear weapons.2 In another poll taken by the government in 2009, nearly 80 percent expressed their approval of promoting or maintaining production of nuclear electric power.3

[Background] The bioavailability of several oral anticancer drugs changes with food exposure. The recommended dose of erlotinib (E) is 150 mg daily either one hour before a meal (complete fasting) or two hours after a meal (post-meal), because of the food effect. Although the two gastric emptying states have been considered equivalent in clinical practice, no study had in fact demonstrated the fed bioequivalence in the two conditions. [Methods] We conducted a cross-over pharmacokinetic study in Cohort A (post-meal to complete fasting) and Cohort B (complete fasting to post-meal); seven days in each fed condition period. Blood samples were obtained just before administration of E on days 1, 2, 5, 7, 8, 9, 12, and 14, and at 1, 2, 4, 6, 8, 10, and 24 hours after administration on days 7 and 14. Area under the curve from 0 to 24 hours (AUC0-24), mean residence time (MRT) from 0 to 24 hours, peak concentration (Cmax), and time to Cmax (Tmax) were estimated by noncompartment analysis. Statistical analysis in the ln-transformed AUC0-24 and Cmax of E was performed using a two-sample t-test with unequal variance, and the ratios of geometric means (GMR) were calculated for AUC0-24 and Cmax. Time to first skin rash was analyzed with a Kaplan-Meier curve compared with the log-rank test, with P < 0.05 considered significant. [Results] Twenty-five patients were randomly assigned, and 23 patients (12 in Cohort A and 11 in Cohort B) were included in the pharmacokinetic analysis. The geometric mean of AUC0-24 was significantly higher in the post-meal status than in the complete fasting status (41.5 ± 11.2 vs. 31.0 ±13.7 μg*h/mL; P < .001) and GMR was 1.33, and likewise in the geometric mean of Cmax (2.64 ± 0.77 vs. 1.83 ± 0.82 μg/mL; P < .001), and GMR was 1.44. Tmax was also significantly longer in the post-meal status (P = .014) while MRT was significantly longer in the complete fasting status (P < .001). Alteration in AUC0-24, Cmax, Tmax, and MRT on day 7 suggested that the two gastric emptying states might differ in their absorption. However, because the concentration of E did not reach the steady state within seven days in the complete fasting group, we conducted further analyses only on day 14. No significant difference between the complete fasting and post-meal condition was seen in AUC0-24 (P = .815), nor in Cmax (P = .564). GMRs were 1.08 in Cmax, and 1.03 in AUC. In Cohort A, a skin rash appeared in 50% in eight days, and in 83% in 15 days. In Cohort B, a skin rash was seen in 64% in 8 days, and in 82% in 15 days. There was no significant association between time to first skin rash of any grade and the two conditions (P = .974). [Conclusion] Although the AUC0-24 of E increased significantly faster in the post-meal status than in complete fasting status, there was no significant difference in pharmacokinetics in steady state and toxicitiy between the two clinically-used fed conditions of E. Citation Format: Yuki Katsuya, Yutaka Fujiwara, Kuniko Sunami, Hirofumi Utsumi, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Hiroshi Nokihara, Noboru Yamamoto, Yuichiro Ohe, Satoko Osawa, Akinobu Hamada. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and two hours after a meal in non-small cell lung cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4509. doi:10.1158/1538-7445.AM2015-4509

Aim: ONO-4538 (BMS-936558, nivolumab) is a fully human monoclonal antibody targeting PD-1 (programmed cell death 1) and enhances antitumor activity by blocking PD-1 / PD-L1·L2 (programmed cell death 1 ligand 1·2) binding that down-regulates T-cell co-stimulatory signal. This phase I study investigated the tolerability, safety and pharmacokinetics of ONO-4538 in combination with chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). Methods: Patients who have stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. ONO-4538 (10 mg/kg, day 1) and chemotherapy [Arm A: cisplatin (80 mg/m2, day 1) / gemcitabine (1250 mg/m2, day 1 and 8), Arm B: cisplatin (75 mg/m2, day 1) / pemetrexed (500 mg/m2, day 1), Arm C: carboplatin (AUC 6, day 1) / paclitaxel (200 mg/m2, day 1) / bevacizumab (15 mg/kg, day 1), Arm D: docetaxel (75 mg/m2, day 1)] were administered every three weeks. Arm A and B were administrated for four cycles and Arm C was for six cycles as first-line chemotherapy. After that, ONO-4538 in Arm A, ONO-4538 / pemetrexed in Arm B, and ONO-4538 / bevacizumab in Arm C were continued every three weeks as maintenance therapy until disease progression. Arm D were administrated until disease progression as second-line chemotherapy. Dose limiting toxicity was evaluated during the first treatment cycle. Results: As of April 10, 2014, six patients each in Arms A to D, total 24 patients [male / female: 17 / 7, PS 0 / 1: 11 / 13), aged 34-73 (median 63) years] were enrolled. Dose limiting toxicity was observed in one patient in Arm A (ALT increased). Severe adverse events were reported in eight patients. Two patients in Arm A, 3 in Arm B, 5 in Arm C, and 1 in Arm D achieved partial response (evaluated by RECIST version 1.1). Conclusions: ONO-4538 10 mg/kg showed acceptable toxicity profile and encouraging antitumor activity in combination with chemotherapy in Japanese patients with advanced NSCLC. Disclosure: T. Tamura: TT has a commercial research grant from Chugai, BMS, Boehringer Ingelheim, Yakult, Abbott, GSK, Eli Lilly, Ono, Kirin, and Quintiles Transnational Japan; and has a honoraria from Taiho, Chigai, and Eli Lilly. All other authors have declared no conflicts of interest.