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ICAM-I plays an important role in inflammatory diseases. To assess level of soluble ICAM-I in the circulation and inflamed lesions, we measured levels of soluble ICAM-1 in the circulation and bronchoalvcolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF) and with pulmonary sarcoidosis (PS) and of healthy volunteers (HV), and we also analysed ICAM-I expression of BALF cells in some patients and HV. IPF patients had significantly higher levels of circulating ICAM-I than HV, while PS patients did not. By contrast, significantly increased levels of BALF soluble ICAM-I were found in PS patients compared with those of HV, but not in IPF patients. There were no significant differences in the proportions of ICAM-1+ BALF lymphocytes in IPF patients, PS patients and HV, whereas significantly increased proportions of ICAM-I + pulmonary alveolar macrophages were found in PS patients compared with those of HV, but not in IPF patients. There was a significant positive correlation of BALF soluble ICAM-I levels to BALF lymphocyte proportions in PS patients. Although the source of BALF soluble ICAM-l is unclear, BALF soluble ICAM-1 appears to reflect the grade of local activity of sarcoidosis. An interesting discrepancy between soluble ICAM-1 levels in the circulation and BALF was found in IPF patients, and this might be an important clue to an understanding of this disorder. [ABSTRACT FROM AUTHOR]

Intercellular adhesion molecule-1 (ICAM-1), a member of immunoglobulin supergene family with a five-domain structure, is known to play an important role in inflammatory diseases. An ELISA was developed using two MoAbs against human ICAM-1 in order to detect the soluble shedding ICAM-1 antigen in sera. We measured levels of circulating ICAM-1 antigen in sera of patients with idiopathic pulmonary fibrosis (IPF), pulmonary sarcoidosis, hypersensitive pneumonitis, bacterial and mycoplasmal pneumonia, and inflammatory diseases of other organs. The results clearly demonstrated that IPF had significantly high levels of circulating ICAM-1 in sera as compared with other disorders or normal controls. Moreover, immunohistochemical analysis with MoAb against human ICAM-1 disclosed that in IPF, the expression of ICAM-1 was intensively enhanced on alveolar epithelial cells. These results suggest that ICAM-1 may contribute to the pathogenesis of IPF. [ABSTRACT FROM AUTHOR]

Background: Ciliary beat frequency (CBF) is crucial in mucociliary clearance. High-speed video analysis (HSVA) is commonly used to measure CBF but lacks standardization. We compared visual observation and computer-assisted calculation using fast Fourier transformation (FFT) in freshly collected bronchial ciliary epithelial cells and cultured cells., Methods: Bronchial epithelial cells were obtained from 12 patients who required bronchoscopic examination. Eighty-five videos of ciliary movement of freshly collected and cultured cells were recorded and used to calculate CBF using manual observation, region of interest (ROI) selection, and whole-field analysis., Results: CBF measured by the ROI selection method strongly correlated with that measured using manual observation, especially in freshly collected cells. However, 27.8% of the manual observation method values were doubled in the ROI selection method, probably because a round trip of cilia was calculated as two cycles and needed to be corrected to 1/2 value. Upon increasing the number of ROIs, the results of the ROI selection method came closer to that of WFA., Conclusions: Computer-assisted calculation using FFT can aid in measuring CBF; however, current methods require visual confirmation. Further automated evaluation techniques are needed to establish more standardized and generalized CBF measurement methods using HSVA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Cough is a common and important sign/symptom in patients with idiopathic pulmonary fibrosis (IPF). However, there have been few reports focusing on cough, and the exact mechanisms for cough in patients with IPF have remained unclear. The objective of this study was to investigate the clinical features of IPF patients with refractory cough and to clarify mechanisms for cough in these patients. We retrospectively reviewed the files of patients with the diagnosis of IPF at Kanazawa University Hospital and compared the clinical features of IPF patients with refractory cough with the clinical features of IPF patients without refractory cough. Among a total of 23 patients with IPF, 10 patients (43.5%) had chronic cough. Of the ten patients, seven patients had concomitant conditions that could lead to cough. Of these seven patients, the cough of four patients was resolved after treatment of their concomitant condition. Finally, among the 23 patients there were 6 (26.1%) with refractory cough associated with IPF. Significant differences were seen between the following clinical features of IPF patients with or without refractory cough, respectively, as follows: lower body mass index (BMI; 18.8±2.5 vs. 22.8±2.5 kg/m 2 , P<0.01), lower forced vital capacity (FVC; 77.5%±30.4% predicted vs. 99.9%±0.53% predicted, P=0.046), and presence of traction bronchiectasis and distorted airway architecture on high-resolution computed tomography (HRCT; 83.3% vs. 11.8%, P<0.01). The difference between the proportions of patients with or without refractory cough with capsaicin cough sensitivity was not significant. Mechanical stress on the airways due to traction bronchiectasis and distorted airway architecture is a possible mechanism for cough in IPF patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1443/coif). The series “Cough Section” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is crucial for patients with lung cancer harboring EGFR mutations. However, almost all patients experience disease progression, regardless of their response to the targeted therapy, necessitating the development of additional treatment options. Two patients with lung cancer harboring EGFR-L858R mutations in exon 21 were treated by surgical resection during successful osimertinib treatment. Because the pathological diagnosis was suspected to be pleural metastasis, osimertinib treatment was continued until disease progression. We analyzed the evolution of genomic alterations and the levels of AXL using tumor specimens obtained by repeated biopsies during the course of treatment: initial diagnosis, operation, and disease progression. Genetic alterations detected at the three time points were dramatically changed and showed reductions in numbers, while EGFR-L858R mutations were detected in all samples tested in both patients. Immunohistochemical expression of AXL remained positive from the beginning of analysis to disease progression. Clonal evolution under oncogenesis is related to gradual accumulation of genomic alterations during tumor growth. However, our case series revealed that volume reduction procedures may cause this phenomenon. Therefore, identification of intrinsic drug-resistant cells in tumors may be as important as detection of acquired genetic alterations., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background/aim: Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Although several ICI options are available, the treatment regimen for NSCLC with large size tumors (large NSCLC) is controversial and the efficacy of anti-CTLA-4 antibody is unclear. This study thus investigated potential biomarkers for CTLA-4 blockade., Patients and Methods: The correlation between tumor diameter and treatment duration was examined in patients with advanced NSCLC treated with anti-PD-1 antibody monotherapy in our institution. In addition, the ratio of tumor-infiltrating CD8 + T cells and regulatory T (Treg) cells in small and large size NSCLC was also evaluated using immunohistochemical staining. Finally, the efficacy of treatment with anti-CTLA-4 antibody against large NSCLC was investigated., Results: A negative correlation was found between tumor diameter and treatment duration in patients treated with anti-PD-1 antibody monotherapy. Immuno-histochemical staining revealed that Treg cell infiltration was significantly higher in large NSCLC tumors than in small tumors. Among the patients with large NSCLC, the ICI regimen including anti-CTLA-4 antibody showed significant efficacies., Conclusion: Anti-PD-1 antibody monotherapy might be less effective against large NSCLC due to the infiltration of Treg cells. Therefore, it might be appropriate for large NSCLC to select a treatment including an anti-CTLA-4 antibody, which can target Treg cells., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Glycation products are generated during the Maillard reaction, a non-enzymatic reaction between reducing sugars and the amino groups of proteins, which accumulate in the body with aging and cause many diseases. Herein, we have focused on dihydropyrazines (DHPs), which are glycation products formed by the dimerization of D-glucosamine or 5-aminolevulinic acid, and have reported that DHPs can produce several kinds of radicals and induce cytotoxicity via oxidative stress. To advance our understanding of DHP-mediated cytotoxicity, we selected a DHP, 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), and two major Maillard reaction products, N ε -(carboxymethyl)-L-lysine (CML) and acrylamide, and performed comparative experiments focusing on their cytotoxicity and their ability to induce oxidative stress. The order of increasing cytotoxicity was DHP-3, acrylamide, and CML, and the LC 50 value could be calculated only for DHP-3 (0.53 mM), indicating that DHP-3 is more toxic than the other Maillard reaction products. However, their toxicities were significantly lower than those of common toxic chemicals. Further, the results of their cytotoxicity assay were consistent with the results of intracellular reactive oxygen species production and activation of oxidative stress response signaling. These results indicate that the acute toxicity of Maillard reaction products is closely related to their ability to induce oxidative stress, and that DHP-3 is a particularly strong inducer of oxidative stress and thus exhibits high cytotoxicity among Maillard reaction products. In addition, we have shown that a comprehensive analysis comparing multiple Maillard reaction products is effective for elucidating their complex and diverse toxicities.

Background: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited., Patients and Methods: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases., Results: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS., Conclusions: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Molecular targeted therapy has been developed as an innovative treatment for metastatic cancer. Epidermal growth factor receptor (EGFR) mutation is one of the most important and frequent oncogenic drivers in non-small-cell lung cancer, and EGFR-tyrosine kinase inhibitors are indispensable drugs for mutation-positive patients. Currently, the acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a problem, the mechanism of which has not been elucidated. The histological transformation from original adenocarcinoma to small-cell carcinoma is rare; however, it has been detected in many cases after EGFR-TKI treatment. This study aimed to evaluate mutational status in two different histological types and further elucidate the molecular pathogenesis., Methods: Three patients with EGFR - mutant lung cancer who underwent a histological transformation to small-cell carcinoma after growth factor receptor-TKI treatment were enrolled in this study. Two samples per patient were collected from histologically different lesions, and DNA samples were extracted from formalin-fixed, paraffin-embedded tumor tissues. The paired samples were subjected to next-generation sequencing of 160 cancer-related genes. Based on the sequencing results, the expression levels of related proteins were validated using reverse-transferase polymerase chain reaction and immunohistochemical staining., Results: The following five variants were common among the three cases: MTOR, JAK1, NOTCH2, CSF1R , and MAP2K2 . The former four variants were additive to small-cell carcinoma, and the last variant was lost. Both TP53 and Rb1 alterations were detected in adenocarcinoma. Notch2 expression was negative in small-cell carcinoma in both reverse-transcriptase polymerase chain reaction analysis and immunohistochemical staining. ASCL1 expression increased after histological transformation detected using both methods in one case, only these samples were evaluable., Conclusions: Notch and ASCL1 signaling are the master regulators of neuroendocrine differentiation in small-cell lung carcinoma. Our results suggest that the Notch-ASCL1 axis may also play an essential role in the transformation of small-cell carcinoma under TP53 and RB1 inactivation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-536). HKo reports the relevant financial activities outside the submitted work; personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co., Ltd. and Boehringer Ingelheim GmbH. HKi reports that this work was financially supported by the JSPS KAKENHI Grant-in-Aid for Scientific Research (C) Grant Number: 19K07727 by HKi. KK reports the JSPS KAKENHI Grant-in-Aid for Scientific Research (C) Grant Number: 17K09606, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.)., (Copyright © 2020 Doi et al.)

ATF6α is an endoplasmic reticulum (ER)-embedded transcription factor which is rapidly activated by ER stress, and a major regulator of ER chaperone levels in vertebrates. We previously suggested that ATF6α occurs as a monomer, dimer and oligomer in the unstressed ER of Chinese hamster ovary cells due to the presence of two evolutionarily conserved cysteine residues in its luminal region (C467 and C618), and showed that ATF6α is reduced upon ER stress, such that only reduced monomer ATF6α is translocated to the Golgi apparatus for activation by proteolysis. However, mutagenesis analysis (C467A and C618A) revealed that the C618A mutant behaves in an unexpected manner (monomer and oligomer) during non-reducing SDS-PAGE, for reasons which remained unclear. Here, we used human colorectal carcinoma-derived HCT116 cells deficient in ATF6α and its relevant ATF6β, and found that ATF6α dimer and oligomer are both dimers, which we designated C618-dimer and C467-dimer, respectively. We demonstrated that C467-dimer (previously considered an oligomer) behaved bigger than C618-dimer (previously considered a dimer) during non-reducing SDS-PAGE, based on their disulfide-bonded structures. Furthermore, ATF6α monomer physically associates with another ATF6α monomer in the absence of disulfide bonding, which renders two C467 residues in close proximity so that formation of C467-dimer is much easier than that of C618-dimer. In contrast, C618-dimer is more easily reduced upon ER stress. Thus, our analysis revealed that all forms of ATF6α, namely monomer, C618-dimer and C467-dimer, are activated by single reduction of a disulfide bond in response to ER stress, ensuring the rapidity of ATF6α activation.Key words: disulfide-bonded structure, endoplasmic reticulum, membrane-bound transcription factor, non-reducing SDS-PAGE, unfolded protein response.

A 65-year-old woman presented to a hospital with complaints of dyspnea and lumbar pain. Chest computed tomography (CT) showed left pleural effusion. Thoracentesis showed pleural effusion with elevated levels of amylase. Enhanced CT showed fluid accumulation from the thoracic crus of the diaphragm to the left iliopsoas muscle. Based on the postoperative notes following left nephrectomy performed 29 years ago, we suspected that the internal pancreatic fistula had resulted from the postoperative scar. Conservative management was performed. However, occlusion of the pancreatic fistula failed. Subsequently, she underwent pancreatic body tail spleen merger resection, and the pleural effusion disappeared.

Objective: In Japan, most asthma deaths occur among the elderly. We should improve the control of asthma in elderly patients to reduce the number of deaths due to asthma. This retrospective study aimed to evaluate the efficacy of tiotropium Respimat Ⓡ (Tio-Res) in symptomatic, never-smoking, elderly asthmatics with irreversible airflow limitation despite the use of high-dose inhaled corticosteroids (ICS) plus long-acting β 2 -adrenoceptor agonists (LABA)., Methods: The Asthma Control Test™ (ACT), pulmonary function tests, morning and evening peak flow (mPEF, ePEF, respectively, evaluated with an ASSESS ® peak flow meter), and respiratory impedance (assessed with MostGraph ® ) were measured before and after a minimum of one year of Tio-Res 5 µg/day administration. Sixteen symptomatic, never-smoking asthmatics, aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA, were analyzed., Results: All patients were female (mean age, 81.6 years). Tio-Res led to statistically significant improvements in the total ACT score (19.9 to 23.6), FVC and FEV 1 (1.97 to 2.14 L and 1.13 to 1.23 L, respectively), and mPEF and ePEF (229.9 to 253.8 L/min and 259.8 to 277.4 L/min, respectively). Tio-Res also resulted in statistically significant improvements in respiratory resistance at 5 Hz (R5), respiratory resistance at 20 Hz (R20), R5-R20, low-frequency reactant indices at 5 Hz (X5), resonant frequency (Fres) and low-frequency reactance area (ALX)., Conclusions: Our retrospective study suggests that Tio-Res improves symptoms, pulmonary function, and respiratory impedance in symptomatic asthmatics aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Pulmonary carcinosarcoma is a rare lung malignancy and little analysis has been performed to identify associated genomic alterations. We used next-generation sequencing (NGS) to analyze a pulmonary carcinosarcoma harboring an epidermal growth factor receptor (EGFR) mutation., Materials and Methods: The lung carcinosarcoma used for this study contained components of adenocarcinoma and chondrosarcoma and originated from a 73-year-old female. Both components carried deletion mutations in exon 19 of EGFR and both had equally strong EGFR protein expression. This study analyzed the biological and genetic characteristics of both components, using NGS and immunohistochemical (IHC) staining., Results and Conclusion: IHC staining revealed that both total EGFR and deletion mutation specific EGFR proteins were equally expressed in both components. Intriguingly, identification of genomic alterations with NGS found five identical alterations in four genes (EGFR, CBLB, TP53, and MEN1) that were shared by the two components, and that each component had a large number of individual alterations. Additionally, we focused on an alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation which was only present in the sarcoma component. ATRX protein expression was also only detected in the sarcoma component. This is the first report of the exhaustive genomic alterations in a pulmonary carcinosarcoma harboring an EGFR mutation. The results show that our case had the same EGFR status in both components. The EGFR mutation is the driver mutation in both components. In our case, we found that TP53 may be a common alteration and ATRX may be a specific alteration in the sarcoma component., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, tissues for the genotyping of the EGFR T790M mutation can be difficult to obtain in a clinical setting. The aims of this study were to evaluate a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients using the PointMan™ EGFR DNA enrichment kit, which is a novel method for the selective amplification of specific genotype sequences., Methods: Blood samples were collected from NSCLC patients who had activating EGFR mutations and who were resistant to EGFR-TKI treatment. Using cell-free DNA (cfDNA) from plasma, EGFR T790M mutations were amplified using the PointMan™ enrichment kit, and all the reaction products were confirmed using direct sequencing. The concentrations of plasma DNA were then determined using quantitative real-time PCR., Results: Nineteen patients were enrolled, and 12 patients (63.2%) were found to contain EGFR T790M mutations in their cfDNA, as detected by the kit. T790M mutations were detected in tumor tissues in 12 cases, and 11 of these cases (91.7%) also exhibited the T790M mutation in cfDNA samples. The concentrations of cfDNA were similar between patients with the T790M mutation and those without the mutation., Conclusions: The PointMan™ kit provides a useful method for determining the EGFR T790M mutation status in cfDNA., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch., Methods: Healthy never-smokers (21 men, 20 women; mean 22.3 ± 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects' ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects' tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV 1 ) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined., Results: The number of coughs was 11.1 ± 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity., Conclusions: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects.

Rationale: Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition involving various organs and vessels including the pancreas, bile duct, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, and aorta. Recently, some cases of IgG4-RD have been reported, in which only pulmonary lesions were present. It is not known whether IgG4-RD can be diagnosed on the basis of pulmonary lesions only, because increases in serum IgG4 levels and infiltration of IgG4-positive plasma cells into the lung tissue also occur in other inflammatory conditions. A case of IgG-RD that was followed-up for 7 years after onset is described., Patient Concerns: Initially, only pulmonary lesions were present; however, other lesions in the submandibular glands, pancreas, periarterial region, and other areas occurred over time, with a gradual increase in serum IgG4 levels., Diagnoses, Interventions, and Outcomes: Histopathology results from the patient's submandibular gland confirmed the diagnosis of IgG4-RD. Following diagnosis, the patient was treated with corticosteroids immediately, and his symptoms disappeared rapidly., Lessons: Because other diseases, including malignancies, mimic IgG4-RD in clinical and histopathological features, an absolute diagnosis is necessary to avoid missing the presence of underlying diseases. This case more provides insight into the clinical pathology of IgG4-RD.

We report the case of a 62-year-old man treated with nivolumab as fourth-line therapy for stage IV squamous cell carcinoma of the lung. Because of the onset of nivolumab-induced pneumonitis after 2 doses, nivolumab was discontinued. After discontinuation, the tumor gradually continued to decrease in size without any additional treatment for lung cancer. The patient obtained a long-lasting shrinking of the tumor over 6 subsequent treatment-free months after only 2 administrations of nivolumab. This type of response has not been seen for conventional anticancer drug treatments for NSCLC, and we speculate that a small group of patients with NSCLC will obtain sufficient efficacy from a few doses of nivolumab., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A 50-year-old man presented to our hospital in 1995. Invasive thymoma was diagnosed and extended thymectomy and left upper lobe partial resection were performed. In 2013, he complained of dyspnea. Chest computed tomography showed postoperative recurrence of invasive thymoma. Several chemotherapies were administered. Severe anemia and an increase in the total bilirubin level were observed with chemotherapies. In additional, an examination showed that the direct Coombs test was positive. Cold agglutinin was also high. We herein experienced a rare case of postoperative recurrence of invasive thymoma with cold agglutinin disease and autoimmune hemolytic anemia.

Epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors' (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The aims of this study are to develop a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients, using PointMan™ EGFR DNA Enrichment Kit which is a novel method for selective amplification of genotype specific sequences.Pairs of blood samples and tumor tissues were collected from NSCLC patients with an EGFR activating mutation and who were resistant to EGFR-TKI treatment. EGFR T790M mutation in plasma DNA were detected using the PointMan™ EGFR DNA Enrichment Kit. The concentrations of plasma DNA were determined using quantitative real-time PCR.Of the 52 patients enrolled in this study, 41 of the patients' plasma samples were collected at post EGFR-TKIs. Nineteen (46.3 %) of the 41 patients had an EGFR T790M mutation in their plasma DNA as detected using the PointMan™ EGFR DNA Enrichment Kit after disease progression to EFGR-TKI. Of 11 cases with a detected T790M mutation from tumor tissues, 10 (90.9 %) also had a detectable T790M mutation in the plasma DNA. There was no difference in the progression-free survival between patients with T790M and those without T790M.The PointMan™ proved to be a useful method for determining plasma EGFR T790M mutation status.

Animal bodies are shaped by skeletons, which are built inside the body by biomineralization of condensed mesenchymal cells in vertebrates [1, 2] and echinoderms [3, 4], or outside the body by apical secretion of extracellular matrices by epidermal cell layers in arthropods [5]. In each case, the skeletons' shapes are a direct reflection of the pattern of skeleton-producing cells [6]. Here we report a newly discovered mode of skeleton formation: assembly of sponges' mineralized skeletal elements (spicules) in locations distant from where they were produced. Although it was known that internal skeletons of sponges consist of spicules assembled into large pole-and-beam structures with a variety of morphologies [7-10], the spicule assembly process (i.e., how spicules become held up and connected basically in staggered tandem) and what types of cells act in this process remained unexplored. Here we found that mature spicules are dynamically transported from where they were produced and then pierce through outer epithelia, and their basal ends become fixed to substrate or connected with such fixed spicules. Newly discovered "transport cells" mediate spicule movement and the "pierce" step, and collagen-secreting basal-epithelial cells fix spicules to the substratum, suggesting that the processes of spiculous skeleton construction are mediated separately by specialized cells. Division of labor by manufacturer, transporter, and cementer cells, and iteration of the sequential mechanical reactions of "transport," "pierce," "raise up," and "cementation," allows construction of the spiculous skeleton spicule by spicule as a self-organized biological structure, with the great plasticity in size and shape required for indeterminate growth, and generating the great morphological diversity of individual sponges., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the Vmax for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S50 and Km both which are the substrate concentration giving 0.5 Vmax were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the Vmax of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDP-glucuronic acid (UDP-GlcUA), the Km for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The Km of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoform-specific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.

Proteins misfolded in the endoplasmic reticulum (ER) are cleared by the ubiquitin-dependent proteasome system in the cytosol, a series of events collectively termed ER-associated degradation (ERAD). It was previously shown that SEL1L, a partner protein of the E3 ubiquitin ligase HRD1, is required for degradation of misfolded luminal proteins (ERAD-Ls substrates) but not misfolded transmembrane proteins (ERAD-Lm substrates) in both mammalian and chicken DT40 cells. Here, we analyzed ATF6, a type II transmembrane glycoprotein that serves as a sensor/transducer of the unfolded protein response, as a potential ERAD-Lm substrate in DT40 cells. Unexpectedly, degradation of endogenous ATF6 and exogenously expressed chicken and human ATF6 by the proteasome required SEL1L. Deletion analysis revealed that the luminal region of ATF6 is a determinant for SEL1L-dependent degradation. Chimeric analysis showed that the luminal region of ATF6 confers SEL1L dependence on type I transmembrane protein as well. In contrast, degradation of other known type I ERAD-Lm substrates (BACE457, T-cell receptor-α, CD3-δ, and CD147) did not require SEL1L. Thus, ATF6 represents a novel type of ERAD-Lm substrate requiring SEL1L for degradation despite its transmembrane nature. In addition, endogenous ATF6 was markedly stabilized in wild-type cells treated with kifunensine, an inhibitor of α1,2-mannosidase in the ER, indicating that degradation of ATF6 requires proper mannose trimming. Our further analyses revealed that the five ERAD-Lm substrates examined are classified into three subgroups based on their dependence on mannose trimming and SEL1L. Thus, ERAD-Lm substrates are degraded through much more diversified mechanisms in higher eukaryotes than previously thought.

Introduction: Centrilobular emphysema (CLE) is recognized as low attenuation areas (LAA) with centrilobular pattern on high-resolution computed tomography (CT). However, several shapes of LAA are observed. Our preliminary study showed three types of LAA in CLE by CT-pathologic correlations. This study was performed to investigate whether the morphological features of LAA affect pulmonary functions., Materials and Methods: A total of 73 Japanese patients with stable CLE (63 males, 10 females) were evaluated visually by CT and classified into three subtypes based on the morphology of LAA including shape and sharpness of border; patients with CLE who shows round or oval LAA with well-defined border (Subtype A), polygonal or irregular-shaped LAA with ill-defined border (Subtype B), and irregular-shaped LAA with ill-defined border coalesced with each other (Subtype C). CT score, pulmonary function test and smoking index were compared among three subtypes., Results: Twenty (27%), 45 (62%) and 8 cases (11%) of the patients were grouped into Subtype A, Subtype B and Subtype C, respectively. In CT score and smoking index, both Subtype B and Subtype C were significantly higher than Subtype A. In FEV1%, Subtype C was significantly lower than both Subtype A and Subtype B. In diffusing capacity of lung for carbon monoxide, Subtype B was significantly lower than Subtype A., Conclusion: The morphological differences of LAA may relate with an airflow limitation and alveolar diffusing capacity. To assess morphological features of LAA may be helpful for the expectation of respiratory function.

Introduction: Centrilobular emphysema (CLE) is recognized as low attenuation areas (LAA) with centrilobular distribution on high-resolution computed tomography. The LAA often exhibit a variety of shape or sharpness of border. This study was performed to elucidate the relationship between morphological features of LAA and pathological findings in CLE., Materials and Methods: The inflated-fixed lungs from 50 patients with CLE (42 males, 8 females; 14 operated, 36 autopsied) were examined by a method of CT-pathologic correlations that consisted of three steps. The first, CT images of the sliced lungs of the inflated-fixed lung specimens were examined on the shape and the peripheral border of each LAA. The second, the sliced lungs were radiographed in contact with high magnification. The third, the surface of the sliced lungs was observed by using stereomicroscopy. The views at low magnification of stereomicroscope were compared with the radiographs and the CT images of the same sample., Results: Using CT-pathologic correlations, LAAs of CLE were classified into three types as follows; round or oval shape with well-defined border (Type A), polygonal or irregular shape with ill-defined border and less than 5 mm in diameter (Type B), and irregular shape with ill-defined border and 5 mm or over in diameter (Type C). Type A, Type B and Type C LAA were mainly related to dilatation of bronchioles, destruction of proximal part of alveolar ducts, and destruction of distal part of alveolar ducts, respectively. Type A, Type B and Type C were dominant LAA in 5 (10%), 29 (58%) and 12 (24%) patients, respectively. However, remained 4 patients (8%) did not show dominant LAA type., Conclusion: Morphological features of LAA in CLE may depend on dilatation or destruction of certain parts of the secondary lobule. Type B LAA was the commonest type in CLE.

Introduction: The purpose of this study is to know the influence of coronary artery bypass grafting (CABG) on coronary circulation. In the present study, we evaluated CABG by using a novel flow analyzer that can calculate bypass graft resistance (Ra), resistance of the peripheral bed to which graft connects (Rp), the inertia of blood flow through the graft (L) and vascular wall compliance (C)., Methods: We performed off-pump CABG surgery on fifteen pigs assigned to the following groups (n = 5 each): normal CABG, competitive flow grafts and constrictive grafts., Results: The wave pattern of 3 groups showed a clearly different form. In normal CABG and competitive flow group, we accepted a statistical difference in Rp and flow. In normal CABG and constrictive grafts. We accepted a statistical difference in Ra and flow., Conclusion: We can know the relationship between CABG and coronary circulation by this device in detail. This device will be useful for evaluating graft performance during CABG.

Purpose: The aim of this study was to evaluate a new flow analyze device that can intraoperatively measure compliance and resistance of coronary artery bypass grafting (CABG) by the parameter identification method., Methods: Subjects were 95 patients who underwent CABG. Angiography soon after surgery confirmed patency in 90 grafts and graft failure in 5 grafts. Variables of aortic pressure and the graft flow were entered into this new device that includes a mathematical coronary circulation model to extrapolate other information the data; thus, we can estimate intraoperative flow rate, resistance, and compliance. Flow rate, resistance, and compliance were compared between patent and failed graft groups and among three different type grafts., Results: There were no differences in flow rate, resistance, and compliance among the three grafts types. Between the patent and failed graft groups, there were statistically significant differences in flow rate and resistance, and compliance tended to be lower for the failed graft group., Conclusions: By measuring graft resistance and compliance, this new device is useful for evaluating graft performance during CABG.

Objective: Streptococcus gordonii is a pioneer colonizer of the enamel salivary pellicle that forms biofilm on the tooth surfaces. Recent reports show the surface protein analogue peptide {400 (T) of SspB 390-402 is substituted to K forming SspB (390-T400K-402)} from S. gordonii interacts strongly with salivary receptors to cariogenic bacteria, Streptococcus mutans. To characterize the analogue peptide biological activities, we investigated its binding and inhibiting effects, and the role of its amino acid moities., Methods: We measured binding activity of analogue peptides to salivary components using the BIAcore assay; assayed inhibition activities of peptides for bacterial binding and growth on saliva-coated hydroxyapatite beads (s-HA); and describe the peptides interfering with biofilm formation of S. mutans on polystyrene surfaces., Results: The SspB (390-T400K-402 and -401) peptides significantly bound with salivary components and inhibited the binding of S. mutans and S. gordonii to s-HA without bactericidal activity; but did not inhibit binding of Streptococcus mitis, a beneficial commensal. Further, the lack of D and E-L at position 390 and 401-402 in the peptide, and substituted peptide SspB (D390H- or D390K-T400K-402) did not bind to salivary components or inhibit binding of S. mutans. The SspB (390-T400K-402) peptide inhibited biofilm formation on salivary components-coated polystyrene surfaces in absence of conditioned planktonic cells., Conclusions: We found constructing the peptide to include positions 390(D), 400(K) and 401(E), two surface positive and negative connective charges, and at least 12 amino acids are required to bind salivary components and inhibit the binding of S. mutans and S. gordonii., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A 47-year-old man, who had been diagnosed as myelodysplastic syndrome (MDS), complained of a severe cough and a high-grade fever. Chest CT disclosed scattered small nodules and ground-glass opacities with interlobular septal thickening in both lung fields and a mass lesion in the right lower lobe. Pathological findings of the ground-glass opacities and the mass lesion obtained by video-assisted thoracoscopic surgery revealed the accumulation of eosinophilic amorphous material in the alveoli and confirmed the diagnosis of pulmonary alveolar proteinosis (PAP). Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in sera were below sensitivity, while the GM-CSF level was elevated in bronchoalveolar lavage fluid. He was diagnosed as secondary PAP associated with MDS.

We investigated fluorescence in situ hybridization (FISH) analysis using microwave irradiation in formalin-fixed, paraffin-embedded tissue sections of breast fibroadenoma. Higher percentage of cells with 2 signal copies of chromosome 3 centromere could be obtained in the condition of 5 microns thick sections, when we counted cells of more than 4 microns of nuclei in thickness. This method showed about the same results as FISH using cells separated from the same tissues. Percentage of cells with 2 signal copies of chromosome 17 centromere in 14 cases was 80.6 +/- 4.0% (Mean +/- S.D.). This method is expected in the application of the prognosis estimation of the breast cancer.

A 53-year-old woman was admitted to our hospital complaining of cough, low grade fever, chest pain and sicca symptoms. A chest radiograph showed an abnormal shadow and chest computed tomography revealed a tumor in left S6. She was diagnosed as Sjögren's syndrome by sialography and histological findings of labial biopsy. The surgically resected tumor specimen showed proliferation of lymphoid cells with lymphoepithelial lesions, which were positive for CD20 and kappa light chain. Kappa light chain-positive amyloid was found within the tumor. The tumor showed rearranged kappa light chain genes. The diagnosis was pulmonary mucosa associated lymphoid tissue lymphoma with amyloid production.

A 76-year-old man in whom interstitial pneumonia and diabetes mellitus had been diagnosed complained of bloody sputum in August, 1998. Chest radiography disclosed irregular shadows in the left lower lung field. Chest computed tomography (CT) scans revealed a cyst and a small nodular lesion in the left S6 segment. Although primary lung cancer was suspected, we did not detect any malignant cells in the transbronchial lung biopsy specimen. CT scans in January 2000 showed a ball-like shadow in the thick-walled cyst in the left S6 segment. Cytologic examination of the sputum and the bronchial lavage fluid from the left B6 revealed squamous cell carcinoma. Left lower lobectomy and mediastinal lymph node dissection were performed. Pathological examination revealed that moderately differentiated squamous cell carcinoma had extensively invaded the wall of the cyst in the left S6 and S10 segments, and was accompanied with aspergilloma. Abnormal thickening of a cyst wall may in some cases suggest the presence of lung cancer.

A 61-year-old man was admitted to our hospital with a 6-month history of productive cough. He, along with his wife, had been involved with Shiitake mushroom cultures for a period of 12 years. On admission, chest radiography showed bilateral fine-nodular shadow and CT scans showed reticulonodular opacities and a ground-glass appearance predominantly in the subpleural area in both lungs, and a mass in the left S6. Resected pathological specimens obtained by left lower lobectomy revealed lung adenosquamous carcinoma (stage IB), interstitial changes accompanied with lymphocyte proliferation and fibrosis, and granuloma with giant cells. Serum precipitins for Shiitake mushroom antigens were positive. The productive cough improved after the hospital admission and occurred again when he returned to work with the Shiitake mushroom production. Therefore, chronic hypersensitivity pneumonitis (HP) caused by Shiitake mushroom spores was diagnosed. Moreover, his wife was found to have HP caused by mushrooms at this time. There are only two previous reports of chronic HP caused by Shiitake mushroom in Japan, and this is the first case of chronic HP associated with lung cancer.

We reviewed 33 patients who underwent a limited operation for primary lung cancer between 1980 and 1998. These cases were divided into three groups; a poor risk group consisting of 18 patients who had a high risk such as pulmonary or cardiac dysfunction and who underwent partial resection of a lung, a reduction group consisting of 9 patients who had advanced lung cancer or uncontrolled cancer of an organ other than the lung and who underwent partial resection, and an active limited operation group consisting of 6 patients who underwent segmentectomy with lymphoadenectomy for the treatment of early lung cancer. The 1 and 3-year survival rates in the poor risk group, reduction group and active limited operation group were 73.9, 60.0, 100%, and 63.4, 0.0, 100%, respectively. The results of limited operations performed for poor risk cases were satisfactory in terms of both functional state and prognosis. Limited operations performed to reduce tumor in advanced lung cancer cases did not improve the prognosis. Although an active limited operation for a case of early lung cancer remains controversial with respect to indication, it is thought that this operation is not inferior to a standard radical operation (lobotomy with mediastinal lymphoadenectomy) in selective cases in which the maximum tumor diameter is 2 cm or less. The indication for a limited operation must be further examined from aspects of tumor size, tumor histology and the other factors of the tumor.