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

The clinical spectrum of COVID-19 includes a wide range of manifestations, from mild symptoms to severe pneumonia. HLA system plays a pivotal role in immune responses to infectious diseases. The purpose of our study was to investigate the association between HLA and COVID-19 severity in a Japanese population. The study included 209 Japanese COVID-19 patients aged ≥20 years. Saliva samples were collected and used to determine the HLA genotype by HLA imputation through genome-wide association analyses. The association between HLA genotype and COVID-19 severity was then evaluated. The allele frequency was compared between patients with respiratory failure (severe group: 91 cases) and those without respiratory failure (non-severe group: 118 cases), categorising the data into three time periods: pre-Omicron epidemic period, Omicron epidemic period, and total period of this study (from January 2021 to May 2023). In comparing the severe and non-severe groups, the frequencies of the HLA-DQA1*01:03 (35.1% vs. 10.5%, odds ratio [OR] = 4.57, corrected p [pc] = 0.041) and -DQB1*06:01 (32.4% vs. 7.9%, OR = 5.54, pc = 0.030) alleles were significantly higher in the severe group during the pre-Omicron epidemic period. During the Omicron epidemic period, HLA-DQB1*06 (32.4% vs. 7.9%, OR = 5.54, pc = 0.030) was significantly higher in the severe group. During total period of this study, HLA-DQA1*01:03 (30.2% vs. 14.4%, OR = 2.57, corrected pc = 0.0013) and -DQB1*06:01 (44.5% vs. 26.7%, OR = 2.20, pc = 0.013) alleles were significantly higher in the severe group. HLA-DQB1*06:01 and -DQA1*01:03 were in strong linkage disequilibrium with each other (r2 = 0.91) during total period of this study, indicating that these two alleles form a haplotype. The frequency of the HLA-DQA1*01:03-DQB1*06:01 in the severe group was significantly higher than in the non-severe group during pre-Omicron epidemic period (32.4% vs. 7.9%, OR = 5.59, pc = 0.00072), and total period of this study (28.6% vs. 13.1%, OR = 2.63, pc = 0.0013). During Omicron epidemic period, the haplotype did not demonstrate statistical significance, although the odds ratio indicated a value greater 1. Frequencies of the HLA-DQA1*01:03 and -DQB1*06:01 alleles were significantly higher in severe COVID-19 patients, suggesting that these alleles are risk factors for severe COVID-19 pneumonia in the Japanese population.

DOI： 10.1111/tan.15609

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DOI： 10.1016/j.resinv.2024.02.009

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

DOI： 10.1016/j.chest.2024.05.015

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

BACKGROUND: For advanced non-small cell lung cancer (NSCLC), combination therapies including a PD-1 inhibitor plus chemotherapy or a PD-1 inhibitor, CTLA-4 inhibitor, and chemotherapy are standard first-line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real-world setting. METHODS: In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first-line therapies in 182 patients with stage IIIB-IV NSCLC. Primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan-Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD-L1 expression. RESULTS: In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3-4 adverse events occurred comparably, but immune-related adverse events were numerically more frequent in the CNI group. CONCLUSIONS: In real-world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC.

DOI： 10.1111/1759-7714.15304

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

Abstract

Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7–7.5%; I², 36%), disease control rate (DCR) was 32.5% (95% CI 27.2–37.7%; I², 73%), median progression-free survival was 2.8 months (95% CI 2.7–2.9 months; I², 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6–13.2 months; I², 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8–5.1]; dual-agent: 12.4% [95% CI 8.0–16.9]; P < 0.001), DCR (single-agent: 29.3%, [95% CI 23.4–35.2]; dual-agent: 44.3% [95% CI 31.7–56.8]; P = 0.03), and OS (single-agent: 9.8 months [95% CI 8.0–12.2]; dual-agent: 16.3 months [95% CI 13.5–19.7]; P < 0.001). Our analysis provided treatment outcomes as described above. Dual-ICIs appear better than single-agent ICIs for the treatment of metastatic uveal melanoma.

DOI： 10.1038/s41598-024-55675-5

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Other Link： https://www.nature.com/articles/s41598-024-55675-5

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BACKGROUND: Combining multiple tumor markers increases sensitivity for lung cancer diagnosis in the cost of false positive. However, some would like to check as many as tumor markers in the fear of missing cancer. We though to propose a panel of fewer tumor markers for lung cancer diagnosis. METHODS: Patients with suspected lung cancer who simultaneously underwent all six tests [carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA), squamous cell carcinoma-associated antigen (SCC), neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), and sialyl Lewis-X antigen (SLX)] were included. Tumor markers with significant impact on the lung cancer in a logistic regression model were included in our panel. Area under the curve (AUC) was compared between our panel and the panel of all six. RESULTS: We included 1,733 [median 72 years, 1,128 men, 605 women, 779 (45%) confirmed lung cancer]. Logistic regression analysis suggested CEA, CYFRA, and NSE were independently associated with the lung cancer diagnosis. The panel of these three tumor markers [AUC =0.656, 95% confidence interval (CI): 0.630-0.682, sensitivity 0.650, specificity 0.662] had better (P<0.001) diagnostic performance than six tumor markers (AUC =0.575, 95% CI: 0.548-0.602, sensitivity 0.829, specificity 0.321). CONCLUSIONS: Compared to applying all six markers (at least one marker above the upper limit of normal), the panel with three markers (at least one marker above the upper limit of normal) led to a better predictive value by lowering the risk of false positives.

DOI： 10.21037/tlcr-23-855

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BACKGROUND: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan. METHODS: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan. RESULTS: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%). CONCLUSIONS: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account.

DOI： 10.1016/j.resinv.2024.02.003

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BACKGROUND: The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine the efficacy and safety of macrolide therapy for adult asthma. METHODS: We searched randomized controlled trials from MEDLINE via the PubMed, CENTRAL, and Ichushi Web databases. The primary outcome was asthma exacerbation. The secondary outcomes were serious adverse events (including mortality), asthma-related quality of life (symptom scales, Asthma Control Questionnaire, and Asthma Quality of Life Questionnaire), rescue medication (puffs/day), respiratory function (morning peak expiratory flow, evening peak flow, and forced expiratory volume in 1 s), bronchial hyperresponsiveness, and minimum oral corticosteroid dose. Of the 805 studies, we selected seven studies for the meta-analysis, which was conducted using a random-effects model. SYSTEMATIC REVIEW REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN000050824). RESULTS: No significant difference between macrolide and placebo for asthma exacerbations was observed (risk ratio 0.71, 95 % confidence interval [CI] 0.46-1.09; p = 0.12). Macrolide therapy for adult asthma showed a significant improvement in rescue medication with short-acting beta-agonists (mean difference -0.41, 95 % CI -0.78 to -0.04; p = 0.03). Macrolide therapy did not show more serious adverse events (odd ratio 0.61, 95 % CI 0.34-1.10; p = 0.10) than those with placebo. The other secondary outcomes were not significantly different between the macrolide and placebo groups. CONCLUSIONS: Macrolide therapy for adult asthma may be more effective than placebo and could be a treatment option.

DOI： 10.1016/j.resinv.2023.12.015

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BACKGROUND: The ILD-GAP scoring system is known to be useful in predicting prognosis in patients with interstitial lung disease (ILD). An elevated monocyte count was associated with increased risks of IPF poor prognosis. We examined whether the ILD-GAP scoring system combined with the monocyte ratio (ILD-GAPM) is superior to the conventional ILD-GAP model in predicting ILD prognosis. METHODS: In patients with ILD treated between April 2013 and April 2017, we were retrospectively assessed the relationships between baseline clinical parameters, including age, sex, Charlson Comorbidity Index score (CCIS), ILD diagnosis, blood biomarkers, pulmonary function test results, and disease outcomes. In ILD patients were included idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD). We also assessed the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPM models. RESULTS: A total of 179 patients (mean age, 73 years) were assessed. All of them were taken pulmonary function test, including percentage predicted diffusion capacity for carbon monoxide. ILD patients included 56 IPF cases, 112 iNSIP and CVD-IP cases, 6 CHP cases and 5 UC-ILD cases. ILD-GAPM provided a greater area under the receiver-operating characteristic curve (0.747) than ILD-GAP (0.710) for predicting 3-year ILD-related events. Furthermore, the log-rank test showed that the Kaplan-Meier curves in ILD-GAPM were significantly different by stage (P = 0.015), but not by stage in ILD-GAP (P = 0.074). CONCLUSIONS: The ILD-GAPM model may be a more accurate predictor of prognosis for ILD patients than the ILD-GAP model.

DOI： 10.1186/s12890-023-02833-6

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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BACKGROUND: Biologics are the important drugs for severe asthma, but clinical trials included few elderly patients. Data on the safety and efficacy of benralizumab in elderly asthma patients are limited. METHODS: This clinical study was a multicentre, retrospective, observational study at two hospitals. Patients aged ≥18 years diagnosed with severe asthma treated with benralizumab were included. Elderly patients were defined as those aged 70 years or older. Efficacy and safety were then analyzed in elderly and non-elderly patients. The primary endpoints were the annual number of asthma exacerbations for efficacy and the discontinuation rate due to adverse events for safety. RESULTS: Between August 2016 and October 2022, 61 patients were enrolled; 10 patients were excluded, and 51 (22 elderly, 29 non-elderly) patients were analyzed. In elderly patients, the annual number of asthma exacerbations before treatment with benralizumab (pre-benralizumab) was 3.78, and the number during treatment with benralizumab was 1.26, a decrease of 2.52 (95% confidence interval [CI], 1.3 to 3.74, p < 0.001). In non-elderly patients, the annual number of asthma exacerbation in the pre-benralizumab period was 3.24, and during treatment with benralizumab it was 0.68, a decrease of 2.56 (95% CI, 1.3 to 3.82, p < 0.001). There was no significant difference in discontinuation due to treatment-related adverse events (elderly vs non-elderly, 2 (9%) vs 0 (0%), p = 0.18). CONCLUSION: Benralizumab reduced the annual number of asthma exacerbations and was well tolerated in elderly patients.

DOI： 10.1080/20018525.2024.2384173

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BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes in cancer treatment but are also associated with adverse events and financial burdens. Identifying accurate biomarkers is crucial for determining which patients are likely to benefit from ICIs. Current markers, such as PD-L1 expression and tumor mutation burden, exhibit limited predictive accuracy. This study utilizes a Clinical Data Warehouse (CDW) to explore the prognostic significance of novel blood-based factors, such as the neutrophil-to-lymphocyte ratio and red cell distribution width (RDW), to enhance the prediction of ICI therapy benefit. METHODS: This retrospective study utilized an exploratory cohort from the CDW that included a variety of cancers to explore factors associated with pembrolizumab treatment duration, validated in a non-small cell lung cancer (NSCLC) patient cohort from electronic medical records (EMR) and CDW. The CDW contained anonymized data on demographics, diagnoses, medications, and tests for cancer patients treated with ICIs between 2017-2022. Logistic regression identified factors predicting ≤2 or ≥5 pembrolizumab doses as proxies for progression-free survival (PFS), and Receiver Operating Characteristic analysis was used to examine their predictive ability. These factors were validated by correlating doses with PFS in the EMR cohort and re-testing their significance in the CDW cohort with other ICIs. This dual approach utilized the CDW for discovery and EMR/CDW cohorts for validating prognostic biomarkers before ICI treatment. RESULTS: A total of 609 cases (428 in the exploratory cohort and 181 in the validation cohort) from CDW and 44 cases from EMR were selected for study. CDW analysis revealed that elevated red cell distribution width (RDW) correlated with receiving ≤2 pembrolizumab doses (p = 0.0008), with an AUC of 0.60 for predicting treatment duration. RDW's correlation with PFS (r = 0.80, p<0.0001) and its weak association with RDW (r = -0.30, p = 0.049) were confirmed in the EMR cohort. RDW also remained significant in predicting short treatment duration across various ICIs (p = 0.0081). This dual methodology verified pretreatment RDW elevation as a prognostic biomarker for shortened ICI therapy. CONCLUSION: This study suggests the utility of CDWs in identifying prognostic biomarkers for ICI therapy in cancer treatment. Elevated RDW before treatment initiation emerged as a potential biomarker of shorter therapy duration.

DOI： 10.1371/journal.pone.0299760

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INTRODUCTION: Total baseline tumor size (BTS) is a prognostic factor for programmed death 1 and programmed death-ligand 1 (PD-L1) inhibitor treatments. However, the prognostic value of total BTS for patients with small-cell lung cancer (SCLC) who receive chemotherapy plus PD-L1 inhibitor remains unknown. Thus, in this study, we aimed to determine whether total BTS is associated with prognosis in patients with SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy. METHODS: This study included patients with extensive-stage SCLC or post-chemoradiotherapy recurrence of limited-stage SCLC who received chemotherapy plus PD-L1 inhibitor as first-line therapy from August 2019 to December 2022. The two lesions with the largest diameter among the measurable lesions in each organ were selected from up to five organs (maximum of 10 lesions), and the sum of all diameters was defined as total BTS. The patients were divided into two groups, large or small, with total BTS using X-tile software. Median survival was analyzed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Univariate and multivariate analyses examined the association between total BTS and prognosis. RESULTS: Fifty patients were included; 14% had large total BTS (>183.2 mm) and 86% had small total BTS (≤183.2 mm). The median observation period was 10.5 months. The large total BTS group showed significantly worse overall survival than the small total BTS group (median: 26.8 months vs. 5.7 months, P = 0.0003). The multivariate analysis indicated that large total BTS was an independent negative predictor of overall survival (hazard ratio: 7.14, 95% confidence interval: 1.89-26.96). DISCUSSION: Total BTS is a potentially useful prognostic factor for patients with advanced SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.

DOI： 10.3389/fonc.2024.1400277

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Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.

DOI： 10.1038/s41598-023-49342-4

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Language：Japanese   Publisher：(株)Gakken  

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BACKGROUND: For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple anti-tuberculosis drugs, the whole genome sequencing (WGS) data can be analyzed using either catalogue-based approach, wherein one causative mutation suggests resistance, (e.g., WHO catalog) or non-catalogue-based approach using complicated algorithm (e.g., TB-profiler, machine learning). The aim was to estimate the predictive ability of WGS-based tests with pDST as the reference, and to compare the two approaches. METHODS: Following the systematic literature search, the diagnostic test accuracies for 14 drugs were pooled using a random-effect bivariate model. RESULTS: Out of 779 articles, 44 articles with 16,821 specimens for meta-analysis and 13 articles not for meta-analysis were adopted. The areas under summary receiver operating characteristic curve suggested "excellent" (0.97-1.00) for 2 drugs (isoniazid 0.975, rifampicin 0.975), "very good" (0.93-0.97) for 8 drugs (pyrazinamide 0.946, streptomycin 0.952, amikacin 0.968, kanamycin 0.963, capreomycin 0.965, para-aminosalicylic acid 0.959, levofloxacin 0.960, ofloxacin 0.958), and "good" (0.75-0.93) for 4 drugs (ethambutol 0.926, moxifloxacin 0.896, ethionamide 0.878, prothionamide 0.908). The non-catalogue-based and catalogue-based approaches had similar ability for all drugs. CONCLUSION: WGS accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results reliably predict pDST positive. The two approaches had similar ability.

DOI： 10.1093/infdis/jiad480

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DOI： 10.3390/cancers15225346

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BACKGROUND: This study aims to assess the real-world impact of advancements in first-line systemic therapies for non-small-cell lung cancer (NSCLC), focusing on the role of driver gene mutations and programmed death-ligand 1 (PD-L1) expression levels. METHODS: Conducted across eight medical facilities in Japan, this multicenter, retrospective observational research included 863 patients diagnosed with NSCLC and treated between January 2015 and December 2022. The patients were categorized based on the type of systemic therapy received: cytotoxic agents, molecular targeting agents, immune checkpoint inhibitors, and combination therapies. Comprehensive molecular and immunohistochemical analyses were conducted, and statistical evaluations were performed. RESULTS: The median overall survival (OS) shows significant variations among treatment groups, with targeted therapies demonstrating the longest OS. This study also revealed that high PD-L1 expression was common in the group treated with immune checkpoint inhibitors. Multivariate analysis was used to identify the type of anticancer drug and the expression of PD-L1 at diagnosis as the impactful variables affecting 5-year OS. CONCLUSIONS: This study underscores the efficacy of targeted therapies and the critical role of comprehensive molecular diagnostics and PD-L1 expression in affecting OS in NSCLC patients, advocating for their integration into routine clinical practice.

DOI： 10.3390/cancers15215248

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Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition with fewer treatments available as the severity increases. Previous systematic reviews have demonstrated the benefits of long-term macrolide use. However, the therapeutic differences between different macrolides and the optimal duration of use remain unclear. Methods: A systematic review and meta-analysis were conducted to assess the effectiveness of long-term macrolide use in reducing COPD exacerbations, compare the therapeutic differences among macrolides, and determine the appropriate treatment duration. Four databases (PubMed, Cochrane Library, Web of Science, and ICHU-SHI) were searched until 20 March 2023, and a random-effects model was used to calculate the pooled effect. Results: The meta-analysis included nine randomized controlled trials involving 1965 patients. The analysis revealed an odds ratio (OR) of 0.34 (95% confidence interval [CI] 0.19, 0.59, p < 0.001) for the reduction in exacerbation frequency. Notably, only azithromycin or erythromycin showed suppression of COPD exacerbations. The ORs for reducing exacerbation frequency per year and preventing hospitalizations were -0.50 (95% CI: -0.81, -0.19; p = 0.001) and 0.60 (95% CI: 0.3, 0.97; p = 0.04), respectively. Statistical analyses showed no significant differences between three- and six-month macrolide prescriptions. However, studies involving a twelve-month prescription showed an OR of 0.27 (95% CI: 0.11, 0.68; p = 0.005; I2 = 81%). Although a significant improvement in St George's Respiratory Questionnaire (SGRQ) total scores was observed with a mean difference of -4.42 (95% CI: -9.0, 0.16; p = 0.06; I2 = 94%), the minimal clinically important difference was not reached. While no adverse effects were observed between the two groups, several studies have reported an increase in bacterial resistance. Conclusions: Long-term use of azithromycin or erythromycin suppresses COPD exacerbations, and previous studies have supported the advantages of a 12-month macrolide prescription over a placebo.

DOI： 10.3390/diseases11040152

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BACKGROUND: The efficacy of adding atezolizumab to the platinum doublet regimen for extensive disease small cell lung cancer (ED-SCLC) remains marginally limited. METHODS: We retrospectively assessed the real-world efficacy and safety of atezolizumab in addition to carboplatin and etoposide (EP + A), versus carboplatin and etoposide (EP) alone in previously untreated ED-SCLC patients. RESULTS: From a total of 99 patients, 46 were assigned to the EP + A group, and 53 to the EP group. No significant difference was observed in progression-free survival between the groups. However, the overall survival (OS) was significantly longer in the EP + A group (20.8 vs 12.1 months; HR: 0.52; p = 0.0127). Patients older than 70 years, male, with performance status 0-1, without liver metastasis, and low levels of C-reactive protein and neutrophil-lymphocyte ratio, experienced longer OS in the EP + A group compared to the EP group. CONCLUSION: The addition of atezolizumab to the platinum doublet regimen significantly extended OS in ED-SCLC patients, particularly among certain subgroups, suggesting its potential value in personalized treatment strategies. Further investigation is warranted to validate these findings.

DOI： 10.1007/s00432-023-05457-9

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BACKGROUND: Personalized treatment for non-small cell lung cancer (NSCLC) has advanced rapidly, and elucidating the genetic changes that trigger this disease is crucial for appropriate treatment selection. Both slow-pull and aspiration methods of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are accepted methods for collecting samples suitable for next-generation sequencing (NGS) to examine driver gene mutations and translocations in NSCLC. Here, we aimed to determine which of these two methods is superior for obtaining higher-quality samples from patients with NSCLC. METHODS: Seventy-one patients diagnosed with NSCLC via EBUS-TBNA using the slow-pull or aspiration (20-mL negative pressure) methods between July 2019 and September 2022 were included. A total of 203 tissue samples from the 71 patients were fixed in formalin, embedded in paraffin, and mounted on slides. The presence of tissue cores, degree of blood contamination, and number of tumor cells were compared between the groups. The success rate of NGS, using Oncomine Dx Target Test Multi-CDx, was also compared between the groups. RESULTS: The slow-pull method was associated with a higher yield of tissue cores, lower degree of blood contamination, and higher number of tumor cells than the aspiration method. The success rate of the NGS was also significantly higher for the slow-pull group (95%) than for the aspiration group (68%). CONCLUSION: Overall, these findings suggest that the slow-pull method is a superior technique for EBUS-TBNA to obtain high-quality tissue samples for NGS. The slow-pull method may contribute to the identification of driver gene mutations and translocations and facilitate personalized treatment of NSCLC.

DOI： 10.1002/cam4.6561

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INTRODUCTION: Tuberculosis (TB) remains a leading cause of death globally. Identifying the factors associated with mortality during hospitalization for TB is crucial for improving patient outcomes. This study aimed to investigate the potential risk factors, including T-SPOT.TB test results and routine laboratory markers of inflammation, associated with death during hospitalization due to TB. METHODS: A retrospective analysis was conducted on 244 hospitalized TB patients. Demographic data, clinical characteristics, T-SPOT.TB results, and laboratory parameters were collected. Univariate and multivariate analyses were performed to identify independent risk factors for in-hospital mortality. RESULTS: Among the patients, 206 survived and 38 died during hospitalization. Multivariate analysis revealed that age (HR: 1.08, 95% CI: 1.02-1.15, p = 0.001), a negative T-SPOT.TB test result (HR: 4.01, 95% CI: 1.78-9.01, p < 0.001), elevated C-reactive protein (CRP) levels (HR: 1.04, 95% CI: 1.01-1.08, p = 0.007), and increased neutrophil-to-lymphocyte ratio (NLR) (HR: 1.04, 95% CI: 1.00-1.07, p = 0.025) were independent risk factors for mortality. CONCLUSIONS: This study identified age, a negative T-SPOT.TB result, elevated CRP levels, and a high NLR as significant independent risk factors for death in hospitalized TB patients. These findings underscore the importance of these parameters in the risk stratification and management of hospitalized TB patients. Further research is warranted to elucidate the mechanisms behind these associations and to validate these results in different populations.

DOI： 10.1016/j.jiac.2023.09.011

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DOI： 10.21037/tlcr-23-271

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Background

Small cell lung cancer (SCLC) is a neuroendocrine tumor with poor prognosis. Neuroendocrine tumors possess characteristics of both nerve cells and hormone‐secreting cells; therefore, targeting the neuronal properties of these tumors may lead to the development of new therapeutic options. Among the endogenous signaling pathways in the nervous system, targeting the glutamate pathway may be a useful strategy for glioblastoma treatment. Perampanel, an antagonist of the synaptic glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR), has been reported to be effective in patients with glioblastoma. In this study, we aimed to investigate the antitumor effects of AMPAR antagonists in human SCLC cell lines.

Methods

We performed to examine the expression of AMPAR using Western blot and immunohistochemical analysis. The antitumor effects of AMPAR antagonists on human SCLC cell lines were investigated in vitro and in vivo. We also analyzed the signaling pathway of AMPAR antagonists in SCLC cell lines. Statistical analysis was performed by the GraphPad Prism 6 software.

Results

We first examined the expression of endogenous AMPAR in six human SCLC cell lines, detecting AMPAR proteins in all of them. Next, we tested the anti−proliferative effect of two AMPAR antagonists, talampanel and cyanquixaline, using SCLC cells in vitro and in vivo. Both AMPAR antagonists inhibited cell proliferation and mitogen‐activated protein kinase (MAPK) phosphorylation in SCLC cells in vitro. Further, we observed reduced proliferation of implanted cell lines in an in vivo setting, assessed by Ki‐67 immunohistochemistry. Additionally, using immunohistochemical analysis we confirmed AMPAR protein expression in human SCLC samples.

Conclusion

AMPAR may be a potential therapeutic target for SCLC.

DOI： 10.1111/1759-7714.15075

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BACKGROUND: Based on the results of the PACIFIC trial, maintenance with durvalumab has emerged as the standard treatment following concurrent chemoradiotherapy in patients with unresectable locally advanced non-small cell lung carcinoma (NSCLC). However, adverse events attributed to durvalumab, especially lung injuries, including immune-related adverse events, and radiation pneumonitis, are concerning. This study retrospectively investigated the factors related to lung injury in patients receiving the PACIFIC regimen. METHODS: Patients with unresectable locally advanced NSCLC who received durvalumab maintenance therapy following concurrent chemoradiotherapy at Yokohama City University Medical Centre between July 2018 and March 2022 were included. Clinical data, volume of normal lung receiving 20 or 5 Gy or more (V20 or V5), planning target volume (PTV), and relative lung parenchyma volume in emphysematous lung receiving 20 or 5 Gy or more (RLPV20 or 5; V20 or V5/100-percentage of low-attenuation volume) were evaluated. RESULTS: Performance status (PS), V20, V5, PTV, RLPV20, and RLPV5 were significantly higher in the lung injury group in the univariate analysis. Furthermore, RLPV20 was the most significant factor in the lung injury group in the multivariate analysis comprising PS, PTV, V20, and RLPV20. CONCLUSION: RLPV20 and RLPV5 are useful in estimating lung inflammation. RLPV20 could be considered the most reliable risk factor for maintenance therapy with durvalumab following concurrent chemoradiotherapy in patients with unresectable locally advanced NSCLC.

DOI： 10.1111/1759-7714.15042

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DOI： 10.1002/cam4.6405

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Acute exacerbation (AE) of interstitial pneumonia (IP) shows poor prognosis, due to the typical histological pattern of diffuse alveolar damage superimposed upon lung fibrosis. The previous reports comparing clinical features between AE of idiopathic interstitial pneumonias (IIPs) and those of IPs with known etiology are limited. We retrospectively compared clinical parameters including age, sex, Charlson Comorbidity Index score (CCIS), blood biomarkers at diagnosis of AE, treatment, and 3-month mortality between patients with AE of IIPs and collagen vascular disease-associated interstitial pneumonia (CVD-IP). We assessed 85 patients, comprising 66 patients with AE of IIPs (78%) and 19 patients with AE of CVD-IP (22%). The least absolute shrinkage and selection operator regression selected CCIS (hazard ratio, 1.281; 95% confidence interval, 1.055-1.556; P = 0.012) and log serum lactate dehydrogenase (LDH) (hazard ratio, 6.267; 95% confidence interval, 2.172-18.085; P < 0.001) as significant predictors of 3-month mortality among these patients. Also, the adjusted survival curves using sex, CCIS, and serum LDH showed no significant differences between these two groups. In conclusion, among AE patients, CCIS and serum LDH level may be more important prognostic factors for 3-month mortality rather than two classification of IP subtypes: IIPs and CVD-IP.

DOI： 10.18999/nagjms.85.3.602

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(有)科学評論社  

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BACKGROUND: Long-acting beta-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and inhaled corticosteroids (ICSs) are inhaled medications used to manage chronic obstructive pulmonary disease (COPD). When two classes of medications are required, a LAMA plus an ICS (LABA+ICS) were previously recommended within a single inhaler as the first-line treatment for managing stable COPD in people in high-risk categories. However, updated international guidance recommends a LAMA plus a LABA (LAMA+LABA). This systematic review is an update of a Cochrane Review first published in 2017. OBJECTIVES: To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD. SEARCH METHODS: We performed an electronic search of the Cochrane Airways Group Specialised Register, ClinicalTrials.gov, and the World Health Organization Clinical Trials Search Portal, followed by handsearches. Two review authors screened the selected articles. The most recent search was run on 10 September 2022. SELECTION CRITERIA: We included parallel or cross-over randomised controlled trials of at least one month's duration, comparing LAMA+LABA and LABA+ICS for stable COPD. We included studies conducted in an outpatient setting and irrespective of blinding. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and evaluated risk of bias. We resolved any discrepancies through discussion. We analysed dichotomous data as odds ratios (ORs), and continuous data as mean differences (MDs), with 95% confidence intervals (CIs) using Review Manager 5. Primary outcomes were: participants with one or more exacerbations of COPD; serious adverse events; quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score change from baseline; and trough forced expiratory volume in one second (FEV1). We used the GRADE framework to rate our certainty of the evidence in each meta-analysis as high, moderate, low or very low.  MAIN RESULTS: This review updates the first version of the review, published in 2017, and increases the number of included studies from 11 to 19 (22,354 participants). The median number of participants per study was 700. In each study, between 54% and 91% (median 70%) of participants were males. Study participants had an average age of 64 years and percentage predicted FEV1 of 51.5% (medians of study means). Included studies had a generally low risk of selection, performance, detection, attrition, and reporting biases. All but two studies were sponsored by pharmaceutical companies, which had varying levels of involvement in study design, conduct, and data analysis. Primary outcomes The odds of having an exacerbation were similar for LAMA+LABA compared with LABA+ICS (OR 0.91, 95% CI 0.78 to 1.06; I2 = 61%; 13 studies, 20,960 participants; moderate-certainty evidence). The odds of having a serious adverse event were also similar (OR 1.02, 95% CI 0.91 to 1.15; I2 = 20%; 18 studies, 23,183 participants; high-certainty evidence). Participants receiving LAMA+LABA had a similar improvement in quality of life, as measured by the SGRQ, to those receiving LABA+ICS (MD -0.57, 95% CI -1.36 to 0.21; I2 = 78%; 9 studies, 14,437 participants; moderate-certainty evidence) but showed a greater improvement in trough FEV1 (MD 0.07, 95% CI 0.05 to 0.08; I2 = 73%; 12 studies, 14,681 participants; moderate-certainty evidence).  Secondary outcomes LAMA+LABA decreased the odds of pneumonia compared with LABA+ICS from 5% to 3% (OR 0.61, 95% CI 0.52 to 0.72; I2 = 0%; 14 studies, 21,829 participants; high-certainty evidence) but increased the odds of all-cause death from 1% to 1.4% (OR 1.35, 95% CI 1.05 to 1.75; I2 = 0%; 15 studies, 21,510 participants; moderate-certainty evidence). The odds of achieving a minimal clinically important difference of four or more points on the SGRQ were similar between LAMA+LABA and LABA+ICS (OR 1.06, 95% CI 0.90 to 1.25; I2 = 77%; 4 studies, 13,614 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Combination LAMA+LABA therapy probably holds similar benefits to LABA+ICS for exacerbations and quality of life, as measured by the St George's Respiratory Questionnaire, for people with moderate to severe COPD, but offers a larger improvement in FEV1 and a slightly lower risk of pneumonia. There is little to no difference between LAMA+LABA and LAMA+ICS in the odds of having a serious adverse event. Whilst all-cause death may be lower with LABA+ICS, there was a very small number of events in the analysis, translating to a low absolute risk. Findings are based on moderate- to high-certainty evidence from heterogeneous trials with an observation period of less than one year. This review should be updated again in a few years.

DOI： 10.1002/14651858.CD012066.pub3

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BACKGROUND: The clinical features of asthma with connective tissue diseases (CTDs) are not well-known. This study therefore aimed to investigate the clinical characteristics of asthma with CTDs. METHODS: We retrospectively examined the records of adults (≥18 years old) with asthma followed up between January 2010 and December 2019. We then compared the clinical features of asthma with and without CTDs. RESULTS: Among 568 subjects with asthma, 42 subjects (7.4%) had CTDs. The most frequent concomitant CTD was rheumatoid arthritis (n = 23, 54.8%), followed by systemic lupus erythematosus (n = 6, 14.3%). The proportion of women (with vs. without CTDs, 85.7% vs. 56.5%, p < 0.001) and Global Initiative for Asthma step were higher (Step 4 or 5, with vs. without CTDs, 81.0% vs. 62.0%, p = 0.01) in asthma with CTDs, whereas frequency of allergic rhinitis was higher in asthma without CTDs (with vs. without CTDs, 7.1% vs. 26.1%, p = 0.005). Eosinophil ratio (with vs. without CTDs, 2.1% vs. 3.5%, p = 0.009) and total immunoglobulin E level (with vs. without CTDs, 43 IU/mL vs. 237 IU/mL, p = 0.002) were lower in asthma with CTDs. In terms of lung function, percentage predicted forced vital capacity (with vs. without CTDs, 86.7% vs. 99.7%, p = 0.008) and percentage predicted forced expiratory volume in 1 s (%FEV1) (with vs. without CTDs, 77.2% vs. 88.4%, p = 0.02) were all lower in asthma with CTDs. With multivariable analysis, CTDs (odds ratio [OR] 2.8, 95%CI 1.3-6.0; p = 0.008), chronic obstructive pulmonary disease (OR 3.8, 95%CI 2.1-6.7; p < 0.001) and asthma onset at <20 years old (OR 1.8, 95%CI 1.1-3.2; p = 0.03) were associated with low FEV1 (defined as %FEV1 < 80%) in asthma. CONCLUSIONS: Asthma with CTDs was related to lower lung function and low-T2 inflammation asthma.

DOI： 10.1111/crj.13595

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

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are extensively used in the treatment of non-small cell lung cancer (NSCLC); hence, equal access to them is important. Therefore, this study aimed to identify regional differences in the prescription of EGFR-TKIs and the factors contributing to these differences. In this ecological study, we collected data using the National Database Open Data and the National Cancer Registry. The standardized claim ratio (SCR) was used as an indicator of the number of EGFR-TKI prescriptions. Additionally, we examined the association between SCR and various factors to identify the factors associated with this difference. The average SCR for the top three provinces was 153.4, while the average for the bottom three provinces was 61.6. Multivariate analysis used for evaluating the association of SCR with variables revealed that the number of designated cancer hospitals and radiation therapies were independent factors associated with the SCR of EGFR-TKIs. There were significant regional differences in the prescriptions of EGFR-TKIs in Japan based on the number of coordinated designated cancer hospitals and the number of patients receiving radiotherapy alone. These findings emphasize the need to implement policies to increase the number of hospitals to reduce regional differences.

DOI： 10.1038/s41598-023-31856-6

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Other Link： https://www.nature.com/articles/s41598-023-31856-6

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Primary tracheal small-cell carcinoma is rare, and is often treated using small-cell lung cancer guidelines given that no standard treatment has been established for it. We report a patient in whom nodules appeared in the trachea and left main bronchus 11 months after surgery for pulmonary large-cell neuroendocrine carcinoma; a biopsy revealed small-cell carcinoma. Given the absence of malignant lesions elsewhere in the body, the lesions were diagnosed as primary tracheal small-cell carcinoma. Respiratory failure progressed rapidly owing to airway stenosis caused by the growing lesion, and the patient required nasal high-flow therapy. However, the lesions shrank a few days after commencing first-line chemotherapy, and his respiratory failure resolved. Accelerated hyperfractionated radiotherapy was administered in conjunction with the third course of chemotherapy, and the patient ultimately achieved a complete response. Although the lesions were initially suspected of being postoperative recurrence of pulmonary large-cell neuroendocrine carcinoma, the fact that the biopsy revealed them to be primary tracheal small-cell carcinoma indicates that intra-airway nodules that appear after lung cancer surgery may possibly be primary tracheal tumors.

DOI： 10.1111/1759-7714.14860

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Language：Japanese   Publisher：(同)クリニコ出版  

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BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown remarkable therapeutic outcomes among cancer patients. Durvalumab plus tremelimumab (DT) is under investigation as a new ICI combination therapy, and its efficacy has been reported in various types of cancer. However, the safety profile of DT remains unclear, especially considering rare adverse events (AEs). OBJECTIVE: We aimed to assess the frequency of AEs associated with DT. DESIGN: This study type is a systematic review and meta-analysis. DATA SOURCES AND METHODS: Four databases were searched for articles. Randomized trials, single-arm trials, and prospective and retrospective observational studies were included. The type of cancer, previous treatment, and performance status were not questioned. Major AE indicators such as any AE and the pooled frequency of each specific AE were used as outcomes. As a subgroup analysis, we also compared cases in which DT was performed as first-line treatment with those in which it was performed as second-line or later treatment. The protocol for this systematic review was registered on the University Hospital Medical Information Network (UMIN) Center website (ID: UMIN000046751). RESULTS: Forty-one populations including 3099 patients were selected from 30 articles. Pooled frequencies of key AE indicators are shown below: any AEs, 77.8% [95% confidence interval (CI): 67.9-87.6]; grade ⩾ 3 AEs, 29.3% (95% CI: 24.2-34.4); serious AEs, 34.9% (95% CI: 28.1-41.7); AE leading to discontinuation, 13.3% (95% CI: 9.3-17.4); treatment-related deaths, 0.98% (95% CI: 0.5-1.5). AEs with a frequency exceeding 15% are shown below: fatigue, 30.1% (95% CI: 23.8-36.3); diarrhea, 21.7% (95% CI: 17.8-25.6); pruritus 17.9% (95% CI: 14.4-21.3); decreased appetite, 17.7% (95% CI: 13.7-22.0); nausea, 15.6% (95% CI: 12.1-19.6). There were no significant differences in these pooled frequencies between subgroups. CONCLUSIONS: The incidence of any AE in DT therapy was approximately 78%, and the incidence of grade 3 or higher AEs was approximately 30%, which was independent of prior therapy.

DOI： 10.1177/17588359231198453

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BACKGROUND: Among patients with idiopathic pulmonary fibrosis (IPF), few studies have investigated the clinical impact of anti-fibrotic treatment (AFT) with and without comorbidities. The aim of the study was to determine whether Charlson Comorbidity Index score (CCIS) can predict the efficacy of AFT in patients with IPF. METHODS: We retrospectively assessed data extracted from the medical records of IPF patients who received anti-fibrotic agents between 2009 and 2019. The collected data included age, sex, CCIS, pulmonary function test, high-resolution computed tomography (HRCT) pattern, gender/age/physiology (GAP) score, and 3-year IPF-related events defined as the first acute exacerbation or death within 3 years after starting AFT. RESULTS: We assessed 130 patients (median age, 74 years) who received nintedanib (n = 70) or pirfenidone (n = 60). Median duration of AFT was 425 days. Patients were categorized into high (≥ 3 points) and low (≤ 2 points) CCIS groups. There was no significant difference between the groups in terms of age, sex, duration of AFT, GAP score, or incidence of usual interstitial pneumonia pattern on HRCT except percentage predicted diffusion capacity of lung for carbon monoxide. Also, significant difference was not seen between the groups for 3-year IPF-related events (P = 0.75). Especially, in the low CCIS group but not the high CCIS group, the longer duration of AFT had better disease outcome. CONCLUSION: In the present study, we could not show any relation between CCIS and IPF disease outcomes in patients undergoing AFT, though the longer duration of AFT might be beneficial for IPF outcomes among patients with low CCIS.

DOI： 10.1371/journal.pone.0291489

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BACKGROUND: The ILD-GAP scoring system has been widely used to predict the prognosis of patients with interstitial lung disease (ILD). The ability of the ILD-GAP scoring system combined with the Charlson Comorbidity Index score (CCIS) (ILD-GAPC) to predict ILD prognosis was investigated. METHODS: In ILD patients, including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD), treated between April 2013 and April 2017, the relationships between baseline clinical parameters, including age, sex, CCIS, ILD diagnosis, pulmonary function test results, and disease outcomes, were retrospectively assessed, and the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPC models, respectively. RESULTS: A total of 185 patients (mean age, 71.9 years), all of whom underwent pulmonary function testing, including percentage predicted diffusion capacity for carbon monoxide, were assessed. ILD diagnosis consisted of IPF in 57 cases, iNSIP and CVD-IP in 117 cases, CHP in 6 cases, and UC-ILD in 5 cases. The ILD-GAPC provided a greater area under the receiver operating characteristic curve (0.758) for predicting 3-year ILD-related events than the ILD-GAP (0.721). In addition, log-rank tests showed that the Kaplan-Meier curves differed significantly among low, middle, and high ILD-GAPC scores (P < 0.001), unlike ILD-GAP scores (P = 0.083). CONCLUSIONS: The ILD-GAPC model could provide more accurate information for predicting prognosis in patients with ILD than the ILD-GAP model.

DOI： 10.1155/2023/5088207

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

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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

The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.

DOI： 10.1038/s41598-021-98253-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Respiratory Society  

DOI： 10.1183/20734735.0288-2020

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DOI： 10.1016/S1470-2045(21)00008-5

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DOI： 10.21203/rs.3.rs-36714/v1

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OBJECTIVES: The interferon-gamma release assay (IGRA) is useful for diagnosing Mycobacterium tuberculosis infections, especially in countries where Bacille Calmette-Guérin vaccinations are performed. However, reproducibility of the IGRA is unclear, as recent data suggest high IGRA conversion and reversion rates in serial tests among healthcare workers. This longitudinal study aimed to evaluate reproducibility of T-SPOT.TB for screening M. tuberculosis infections in Japan. METHODS: Results of T-SPOT.TB tests performed between April 2014 and March 2016 at two hospitals in Yokohama, Japan, where the incidence of tuberculosis was 18.0 per 100,000 population in 2014, were analyzed. RESULTS: In total, 3890 T-SPOT.TB tests were included. Overall, positive and negative test rates were 8.4% and 87.6%, respectively. Among 373 serial tests within two years, conversion and reversion rates were only 1.1% and 12.5%, respectively. Almost all patients who were initially negative (98.9%) remained so. There was no statistically significant difference between the outcomes observed at the two hospitals. CONCLUSIONS: The conversion rate of T-SPOT.TB in Japan is as low as that recently reported in other countries where the incidence of tuberculosis is low. These data indicate that T-SPOT.TB is a reproducible tuberculosis screening tool at local hospitals in areas with a moderate incidence of tuberculosis.

DOI： 10.1016/j.jiac.2019.08.006

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An 82-year-old man with chronic tuberculous empyema visited our hospital for an annual computed tomography (CT) scan. No differences were noted between the CT scan at presentation and a scan performed a year previously in August 2017. He began experiencing right chest, epigastrium, and back pain since the end of October 2017. A CT scan taken in November of 2017 to evaluate the pain in his right chest, epigastrium, and back showed an irregular thickening of the pleura adjacent to the empyema and an abnormal right seventh costal mass infiltrating the vertebral body. CT-guided needle biopsy of the mass showed angiosarcoma. Positron emission tomography/CT revealed multiple metastases in his bones and liver. Chemotherapy was not recommended owing to his poor performance status, which was related to angiosarcoma. Therefore, he was offered palliative radiotherapy for the metastasis to the vertebral body.

DOI： 10.1002/rcr2.479

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

DOI： 10.4103/ijmy.ijmy_134_19

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We report the case of an 85-year-old man who was surgically diagnosed with lung adenocarcinoma (pT2aN1M0 stage IIA). He was administered platinum combination chemotherapy as first-line treatment for lung cancer recurrence. The patient's pleural fluid sample was obtained and analysed using a next-generation sequencer, which demonstrated the presence of mesenchymal-epithelial transition gene (MET) exon 14 skipping mutations. As the patient developed progressive disease after receiving first-line chemotherapy, crizotinib was administered as the second-line treatment. The treatment was effective, and the patient had a stable disease for 7 months. This case suggests that crizotinib is effective against non-small cell lung cancer with MET exon 14 alterations.

DOI： 10.1002/rcr2.453

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

OBJECTIVES: A major regulatory peptide in iron metabolism, hepcidin, has been shown to predict mortality in HIV-infected tuberculosis patients. The aim of this study was to evaluate whether plasma hepcidin levels on admission can be used to predict the treatment outcome of patients with smear-positive pulmonary tuberculosis (PTB) without HIV co-infection. METHODS: In this prospective observational study, a total of 35 PTB patients with Mycobacterium tuberculosis-positive sputum smears were enrolled. The relationship between plasma hepcidin levels on admission and the time period to sputum culture-negative was explored. RESULTS: Plasma hepcidin levels of PTB patients were significantly higher than those of healthy subjects (p<0.001). A positive correlation between hepcidin level on admission and the period until culture-negative was also observed (r=0.46, p=0.006). Furthermore, the hepcidin level showed a negative correlation with spot numbers in the positive control wells of the T-SPOT.TB assay; thus the effect of the peptide on interferon-gamma production in T cells was explored. Hepcidin reduced interferon-gamma gene transcription and interferon-gamma production in a dose-dependent manner in Jurkat cells stimulated with phytohaemagglutinin, an antigen non-specific stimulation. CONCLUSIONS: These findings indicate that hepcidin alters immunological reactions against M. tuberculosis infection and has an influence on the outcomes of PTB patients without HIV co-infection.

DOI： 10.1016/j.ijid.2019.06.023

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Objectives: To scrutinize the influence of HLA-B51 to each clinical manifestation of patients with Behçet's disease (BD) using a database of the Ministry of Health, Labour and Welfare of Japan. Methods: The database of newly registered patients with BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met International Criteria for Behçet's Disease (ICBD) and had data for HLA-B51 were selected and analyzed. Results: Among the 3044 analyzable cases, 1334 (43.8%) were men and 1710 (56.2%) were women; the median age was 38 years (IQR 29-48). HLA-B51 was positive for 1334 (44.5%). Prevalence of selected manifestations was 98.5% for oral ulceration, 85.5% for skin lesion, 42.1% for ocular lesion, 69.1% for genital ulceration, and 29.0% for gastrointestinal symptom. HLA-B51-positive patients had higher risk for ocular lesion (OR 1.59, 95%CI: 1.37-1.84; p < .001) and lower risk for genital ulceration (OR 0.72, 95%CI: 0.62-0.84; p < .001) and gastrointestinal symptom (OR 0.65, 95%CI: 0.55-0.77; p < .001). No significant difference was observed for other organ involvement; oral ulceration, skin lesion, positive pathergy test, arthritis, epididymitis, vascular lesion, or neurological manifestation. Subgroup analyses revealed that HLA-B51 was not related to genital ulceration in the cases with an ICBD score of 6 or higher and that HLA-B51 tended to more largely affect the risk of three manifestations for men compared to that for women. Conclusion: HLA-B51 positive is a risk factor for ocular lesion and vice versa for genital ulceration and gastrointestinal symptoms in patients with Japanese BD.

DOI： 10.1080/14397595.2019.1649103

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Background: Clinical data of patients with entro-, vasculo-, and neuro-variant possible Behçet's disease (BD) based on Japanese criteria has not yet comprehensively reported. Methods: This ongoing nation-wide registration has been carried out by the Japanese Ministry of Health, Labour and Welfare. The Ministry asked physicians who diagnosed a patient with confirmed or possible BD to register the patient data by filling out a registration form. The Ministry provided us with the dataset after unlinkable anonymization. We analyzed 2003-2014 database generated from the early stage new cases. Results: Among the 7950 analyzable cases, 694 (8.7%) had variant-type possible BD without satisfying complete/incomplete criteria. Of the 694 patients, 479, 46, and 169 had entero-, vasculo-, and neuro-variant possible BD, respectively. Out of these 694 patients, 35 (5.0%) and 154 (22.2%) satisfied the International Study Group criteria and the International Criteria of BD, respectively. Entero-variant possible patients rarely (1.8%) had ocular lesions. Patients with vasculo-variant possible BD were featured by low genital ulceration risk (6.8%) and frequent positive HLA-B51 (60.0%). Neuro-variant possible BD was featured by high median age at registration (48 year). Vasculo- (69.6%) and neuro-variant (68.6%) BD patients showed clear male dominance. Epididymitis was very rare among variant-type possible BD men. Conclusion: We analyzed 694 early-stage variant-type possible BD cases. We believe the data from our study will contribute to further international discussion regarding BD diagnostic criteria and clarification of the clinical presentations of the Japanese variant-type possible BD patients.

DOI： 10.1080/14397595.2018.1494501

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Chemoprevention began to be considered as a potential strategy for lowering the incidence of cancer and cancer-related deaths in the 1970s. For clinical chemoprevention trials against cancer, including colorectal cancer (CRC), well-established biomarkers are necessary for use as reliable endpoints. Difficulty in establishing validated biomarkers has delayed the start of CRC chemoprevention development. Chemoprevention trials for CRC have only recently been initiated thanks to the identification of reliable biomarkers, such as colorectal adenomas and aberrant crypt foci. Some promising agents have been developed for the prevention of CRC. The chemopreventive effect of selective cyclooxygenase 2 inhibitors has been shown, although these inhibitors are associated with cardiovascular toxicity as a crucial adverse effect. Aspirin, which is a unique agent among non-steroidal anti-inflammatory drugs (NSAIDs) showing minimal gastrointestinal toxicity and no cardiovascular risk, has prevented adenoma recurrence in some randomized controlled trials. More recently, metformin, which is a first-line oral medicine for type 2 diabetes, has been shown to be safe and to prevent adenoma recurrence. A recommendation of the United States Preventive Services Task Force published in 2016 provides a Grade B recommendation for the use of aspirin for chronic prophylaxis against diseases, including CRC, in certain select populations. However, the roles of other agents have yet to be determined, and investigations to identify novel "post-aspirin" agents are also needed. The combined use of multiple drugs, such as aspirin and metformin, is another option that may lead not only to stronger CRC prevention, but also to improvement of other obesity-related diseases.

DOI： 10.1111/cas.14149

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The evidence for stereotactic body radiotherapy (SBRT) is meagre for patients with clinical T3-4N0M0 non-small cell lung cancer (8th Edition of the Union for International Cancer Control (UICC)). This study retrospectively investigated clinical outcomes following SBRT for such patients. Among consecutive patients treated with SBRT, patients staged as cT3-4N0M0 by all criteria were examined, most of whom were unsuitable to chemoradiotherapy due to their fragile characters. Clinical outcomes were evaluated and factors associated with outcomes were investigated. Between 2005 and 2017, 70 eligible patients (T3: 58, T4: 12; median age 81 (63-93) years) were identified. Median follow-up duration was 28.6 (1.0-142.5) months. No adjuvant chemotherapy was administered. The 3-year local recurrence rates were 15.8% and 16.7% in T3 and T4 patients, respectively, and they were significantly lower in the high-dose group (3.1% vs 28.6%, P < 0.01). Multivariate analyses showed that the dose-volumetric factor was the significant factor for local recurrence. The 3-year regional and distant metastasis rates, cancer-specific mortality, and overall survival in T3 and T4 patients were 22.7% and 25.0%, 26.5% and 33.3%, 32.2% and 41.7%, and 39.5% and 41.7%, respectively. Only age was correlated with overall survival. Radiation pneumonitis ≥grade 3 and fatal hemoptysis occurred in 3 and 1 patients, respectively. SBRT for cT3-4N0M0 lung cancer patients achieved good local control. Survival was rather good considering that patients were usually frail, staged with clinical staging, and were not given adjuvant chemotherapy, and it may be comparable to surgery. To validate these outcomes following SBRT, a prospective study is warranted.

DOI： 10.1093/jrr/rrz044

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Background: Currently, there is some controversy regarding indications for stereotactic body radiotherapy (SBRT) for lung cancer patients. We investigated the treatment preferences of patients with experience of both surgery and SBRT using a questionnaire survey. Methods: Of lung cancer patients treated with SBRT between 2005 and 2017, we identified those who also previously underwent surgery for lung cancer. These patients were asked about their experiences of surgery and SBRT including perceived condition, distress, stress, convenience, adverse effects, and satisfaction during and after treatment. Participants were also asked about treatment decision-making for hypothetical scenarios. Results: Of 653 lung cancer patients treated with SBRT, 149 also underwent surgery for lung cancer, 52 of whom participated in this questionnaire. The median age at the time of this survey was 76 years (range, 59-91 years). Significantly more participants had a favorable impression of SBRT during and after treatment (all question items; P<0.01). In terms of overall satisfaction, 27 patients preferred SBRT and three patients preferred surgery. In a hypothetical scenario (equivalent treatment outcomes) aged 70 years and faced with decision-making for first-time lung cancer treatment, significantly more patients selected SBRT (P<0.01): 38 patients selected SBRT. In a scenario with 20% better survivals for surgical resection, 14 patients selected SBRT, 12 selected surgery, and 26 were indecisive (P=0.47). In a scenario at age 80 years, significantly more patients selected SBRT (P<0.01). Conclusions: Most patients with experience of both surgery and SBRT for lung cancer prefer SBRT. This information would be helpful at treatment decision-making.

DOI： 10.21037/jtd.2019.05.76

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Background: A prognostic factor for patients with acute or subacute idiopathic interstitial pneumonias (IIPs) or acute exacerbation (AE) of collagen vascular diseases-related interstitial pneumonia (CVD-IP) has not been established. We aimed to determine whether the Charlson comorbidity index (CCI) could serve as a prognostic factor for patients with these patients. Methods: We assessed baseline prognostic factors among patients with acute or subacute IIPs and AE of CVD-IP who were admitted to hospital between January 2014 and December 2017. We classified them as survivors and non-survivors at 3 months and compared their age, sex, CCI, blood parameters [lactate dehydrogenase (LDH), surfactant protein (SP)-D, Krebs von den Lungen-6, and partial pressure of oxygen in arterial blood/fraction of the inspiratory oxygen], high resolution CT (HRCT) scores and treatment. Results: Sixty eight patients with (mean age, 75 years), were assessed. All patients received steroid pulse therapy. We found that 45 of acute or subacute IIPs and 16 of AE of CVD-IP were included. Stepwise multivariate analysis selected CCI (OR, 1.306; 95% CI, 1.090-1.573; P=0.004), serum LDH (OR, 1.003; 95% CI, 1.001-1.005; P=0.002), and sex (OR, 8.555; 95% CI, 1.729-154.978; P=0.038) as significant predictors of 3-month mortality among these patients. Three-month mortality was significantly worse among patients with high (≥4) than low (<4) CCI (mortality rates: 63.2% vs. 16.3%, P<0.001). Moreover, the composite scoring system including CCI, serum LDH, and sex was acceptable (Bootstrap AUC, 0.859; Bootstrap C-index, 0.747). Conclusions: The composite scoring system including CCI, sex, and serum LDH could be a useful mortality prediction tool for patients with acute or subacute IIPs and AE of CVD-IP requiring steroid pulse therapy.

DOI： 10.21037/jtd.2019.05.46

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BACKGROUND: Clinical staging, as used for patients treated with stereotactic body radiotherapy (SBRT) for early-stage lung cancer, inadequately accounts for pleural invasion, which is a pathologic criteria. Considering the current situation, we analyzed effects of relationships between tumors and the pleura on treatment outcomes of SBRT for early-stage lung cancer. MATERIALS AND METHODS: Among consecutive patients treated with SBRT between 2006 and 2017, we retrospectively identified non-small cell lung cancer patients with primary tumor diameters ≤4 cm and N0M0. The relationships between tumors and the pleura were investigated. The effects of these findings on treatment outcomes were analyzed. RESULTS: We identified 386 patients which met the inclusion criteria. Among these patients, 323 patients were with tumors of 0.1-3.0 cm (T1-size), and 63 patients were with tumors of 3.1-4.0 cm (T2a-size). Among patients with T1-size tumors, 120, 134, and 23 had findings of pleural contact, pleural indentation, and pleural thickening, respectively. When we divided T1-size patients into 2 groups based on pleural contact (contact- or contact+), the 3-year cause-specific mortality and overall survival in patients with T1-size & contact+ were significantly worse than those in patients with T1-size & contact- (17.6% (95% confidence interval (CI), 10.7-25.9%) vs. 6.6% (95% CI, 3.5-11.1%), p < 0.01), and 58.2% (95% CI, 47.6-67.5%) vs. 77.6% (95% CI, 70.5-83.2%), p < 0.01). Local recurrence, regional recurrence, pleural cavity recurrence, and distant metastasis were associated with worse cause-specific mortality and overall survival. On multivariate analysis, pleural contact was associated with cause-specific mortality (hazard ratio (HR), 1.96; 95% CI, 1.09-3.52; p = 0.03) and overall survival (HR, 1.59; 95% CI, 1.08-2.34; p = 0.02). CONCLUSION: Pleural contact in clinical T1N0M0 lung cancer patients was associated with significantly worse survivals.

DOI： 10.1016/j.radonc.2019.02.005

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DOI： 10.4103/ijc.IJC_512_18

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OBJECTIVES: This study aimed to identify patients with high-probability of ocular involvement of Behçet's disease (BD). METHODS: The Japanese Ministry of Health, Labour and Welfare provided dataset of ongoing nationwide BD registration project. A patient who had confirmed BD and who was suspected to have BD was registered. We mainly analyzed newly registered patients who had the data for all demographic and diagnostic parameters regardless of fulfilment of any diagnostic criteria. RESULTS: Among 3213 patients with confirmed or possible BD, 1382 (43.0%) were men and 1831 (57.0%) were women with a median age of 38 years (interquartile range (IQR) 30-49 years). The median duration between onset and registration was 0 year (IQR 0-3). A binomial multivariable logistic regression analysis revealed that being female (odds ratio (OR) 0.63, 95% confidence interval (CI) 0.53-0.75, p < .001), duration since onset (OR 1.33 per 10 years, 95% CI 1.18-1.51, p < .001), genital ulceration (OR 0.28, 95% CI 0.23-0.34, p < .001), and gastrointestinal symptoms (OR 0.36, 95% CI 0.30-0.44, p < .001) were related to the ocular lesion. Analyses based on data of 2800 patients who satisfied International criteria of BD, age-, sex-, duration-based subgroup analyses, analyses targeting iridocyclitis and retino-uveitis, and analysis including patients with missing data confirmed that the four factors were associated with the probability of eye involvement. CONCLUSION: The ocular involvement did not accompany with genital ulcer or gastrointestinal symptoms at the early stage of BD.

DOI： 10.1080/14397595.2018.1457424

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DOI： 10.1111/cea.13209

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BACKGROUND: Silicosis, a progressive inflammatory lung disease attributed mainly to occupational exposure to silica dust, shows loss of lung function even after cessation of exposure. In addition to conventional evaluation methods such as chest X-ray, computed tomography, and spirometry, we identified heme oxygenase (HO)-1, an inducible antioxidant, as a potential biomarker to identify at-risk patients. We found that HO-1 was critical in attenuating the disease progression of silicosis; however, the key signaling pathway has not yet been elucidated. Here, we report the critical pathway after silica exposure, focusing on the role of silica-derived reactive oxygen species (ROS) signaling and its attenuation, which is mediated by HO-1 induction, in vivo and in vitro. METHODS: Normal bronchial epithelial cells and a macrophage cell line, as well as a murine silicosis model generated by intratracheal administration of 2.5 mg of crystalline silica, were used in this study. The pathways activated in response to silica exposure, including the mitogen-activated protein kinase (MAPK) signaling pathway, were examined and compared with or without super-induction of HO-1. RESULTS: The murine silicosis model was first assessed for the evaluation of activated pathways after silica exposure, focusing on ROS-MAPK activation. In the murine model, increased expression of HO-1 in the lungs was observed after silica-instillation. Moreover, silica-medicated activation of extracellular signal-regulated kinase (ERK) in the lungs was attenuated in response to silica-induced HO-1 upregulation. Activation of other MAPKs, such as p38 and c-Jun N-terminal kinase pathways, after silica exposure was not significantly different irrespective of HO-1 induction. Further in vitro studies showed that 1) silica-induced HO-1 was significantly attenuated by inhibiting ERK activation, and 2) carbon monoxide and bilirubin as final byproducts of HO-1 could inhibit ERK activation. Taken together, silica-induced HO-1 upregulation was mediated by ERK activation, and HO-1 further regulates ERK activation via its final byproducts, carbon monoxide and bilirubin. CONCLUSIONS: This is the first study to demonstrate the regulatory role of HO-1 in silicosis. This finding could contribute to the development of a treatment strategy of monitoring HO-1 levels as a marker of therapeutic intervention.

DOI： 10.1186/s12931-018-0852-6

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DOI： 10.1016/j.jtho.2018.03.029

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BACKGROUND: In this study, we conducted a questionnaire survey to clarify and improve problems related to oxygen concentrators. METHODS: Using a questionnaire survey of 30 patients receiving long-term oxygen therapy for chronic respiratory failure, we investigated the necessity of using a remote controller, portability, fire prevention system, built-in battery type and so on. Patients were divided into two groups according to age, sex, underlying conditions and amount of oxygen prescribed, then analyzed accordingly. RESULTS: Mean age was 72.3 ± 8.09 years. The mean flow rate for prescribed oxygen was 1.10 L/min at rest and 2.96 L/min under exertion. Median duration of use was 17.5 months. Built-in battery type, environmentally friendly system and voice guidance system received the most attention according to four-grade evaluations of each function. Significant differences were seen in design features in patients less than 72 years old (P = .03), in voice guidance system in patients who only used the equipment during exertion (P = .01), and in brand imaging in those using the equipment under exertion at a flow ≥3 L/min (P = .04). In questionnaire results for the three most desired features, built-in battery type was of primary concern, followed by portability and use of a remote control. CONCLUSIONS: Overall, built-in battery type, portability, use of a remote control and an environmentally friendly system were desired features for oxygen concentrators. Desired features could vary according to age and the amount of oxygen prescribed.

DOI： 10.1111/crj.12761

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

DOI： 10.4103/ijmy.ijmy_38_18

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Massive corticothalamic afferents originating from layer 6a of primary sensory cortical areas modulate sensory responsiveness of thalamocortical neurons and are pivotal for shifting neuronal firing between burst and tonic modes. The influence of the corticothalamic pathways on the firing mode and sensory gain of thalamic neurons has only been extensively examined in anesthetized animals, but has yet to be established in the awake state. We made lesions of the rat barrel cortex and on the following day recorded responses of single thalamocortical and thalamic reticular neurons to a single vibrissal deflection in the somatosensory system during wakefulness. Our results showed that the cortical lesions shifted the response of thalamic neurons towards bursting, elevated the response probability and the gain of thalamocortical neurons, predominantly of recurring responses. In addition, after the lesions, the spontaneous activities of the vibrissa-responsive thalamic neurons, but not those of vibrissa-unresponsive cells, were typified by waxing-and-waning spindle-like rhythmic spiking with frequent bursting. In awake rats with intact cortex, identified layer 6a corticothalamic neurons responded to a single vibrissal deflection with short latencies that matched those of layer 4 neurons, strongly suggesting the existence of an immediate corticothalamic feedback. The present results show the importance of corticothalamic neurons in shaping thalamic activities during wakefulness.

DOI： 10.1007/s00429-017-1522-z

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DOI： 10.1016/j.ijid.2017.11.018

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Objective: To evaluate diagnostic test accuracy of US compared with MRI for the detection of synovitis in RA patients. Methods: A systematic literature search was performed in the PubMed, EMBASE, Cochrane Library and Web of Science Core Collection databases. Studies evaluating the diagnostic test accuracy of US for synovitis detected by MRI as the reference standard for wrist, MCP, PIP and knee joints were included. To assess the overall accuracy, we calculated the diagnostic odds ratio using a DerSimonian-Laird random effects model and the area under the curve (AUC) for the hierarchical summary receiver operating characteristics using Holling's proportional hazards models. The summary estimate of the sensitivity and specificity were obtained using the bivariate model. Results: Fourteen of 601 identified articles were included in the review. The diagnostic odds ratio was 11.6 (95% CI 5.6, 24; I2 = 0%), 28 (95% CI 12, 66; I2 = 11%), 23 (95% CI 6.5, 84; I2 = 19%) and 5.3 (95% CI 0.60, 48; I2 = 0%) and the AUC was 0.81, 0.91, 0.91 and 0.61 for wrist, MCP, PIP and knee joints, respectively. The summary estimates of sensitivity and specificity were 0.73 (95% CI 0.51, 0.87)/0.78 (95% CI 0.46, 0.94), 0.64 (95% CI 0.43, 0.81)/0.93 (95% CI 0.88, 0.97), 0.71 (95% CI 0.33, 0.93)/0.94 (95% CI 0.89, 0.97) and 0.91 (95% CI 0.56, 0.99)/0.60 (95% CI 0.20, 0.90) for wrist, MCP, PIP and knee joints, respectively. Conclusion: US is a valid and reproducible technique for detecting synovitis in the wrist and finger joints. It may be considered for routine use as part of the standard diagnostic tools in RA.

DOI： 10.1093/rheumatology/kex036

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DOI： 10.1111/ajco.12837

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Background: Serum hemeoxygenase-1 (HO-1) has been proposed to be a biomarker of lung disease activity and prognosis. The present study aimed at evaluating whether HO-1 could be a useful marker for evaluating disease activity and predicting prognosis in patients with interstitial pneumonia (IP). Materials and Methods: Serum HO-1 levels of newly diagnosed or untreated patients with IP were measured at hospitalization. We evaluated the relationships between serum HO-1 and other serum biomarkers, high resolution CT (HRCT) findings, and hospital mortality. Results: Twenty-eight patients with IP, including 14 having an acute exacerbation (AE) and 14 not having an AE, were evaluated. The patients having an AE had significantly higher HO-1 levels than those not having an AE (53.5 ng/mL vs. 24.1 ng/mL; p < 0.001), and the best cut-off level to discriminate between having an AE or not having an AE was 41.6 ng/mL. Serum HO-1 levels were positively correlated with serum levels of surfactant protein-D (r=0.66, p < 0.001) and the ground glass opacity score (calculated from HRCT; r=0.40, p=0.036). Patients who subsequently died in hospital had presented with significantly higher HO-1 levels than those who did not die in hospital (64.8 ng/mL vs. 32.0 ng/mL; p=0.009). Conclusion: Serum HO-1 may serve as a useful biomarker for detecting AE or predicting hospital mortality in patients with IP.

DOI： 10.1155/2018/7260178

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

DOI： 10.2169/internalmedicine.0138-17

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Background: Hemeoxygenase-1 (HO-1) is an essential enzyme in heme catabolism and has been proposed as a biomarker of lung disease prognosis. We modified a commercial HO-1 enzyme-linked immunosorbent assay (ELISA) kit to achieve higher sensitivity and evaluated if serum HO-1 could be a biomarker to predict the prognosis of acute respiratory distress syndrome (ARDS) patients. Methods: Serum samples were collected from 15 healthy volunteers to validate the modified ELISA. In the 22 patients with ARDS who were enrolled, serum HO-1 was measured upon diagnosis (D0) and at 7 days after diagnosis (D7). Results: The serum HO-1 concentration could be measured in all healthy volunteers. The intra- and interassay tests and the percentage recovery test were acceptable. Compared with normal control subjects, patients with ARDS had significantly higher D0 HO-1 concentrations (75.4 ng/mL versus 31.7 ng/mL, P < 0.001). The 28-day survival was significantly better in patients with low D0 HO-1 (<75.8 ng/mL) than in those with high D0 HO-1 (≥75.8 ng/mL) (mortality rate: 18% versus 73%, P=0.016). Nonsurvivors had significantly higher D0 and D7 HO-1 concentrations than survivors (P < 0.05). Conclusion: Serum HO-1 may be a useful biomarker to predict the prognosis of patients with ARDS.

DOI： 10.1155/2018/9627420

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BACKGROUND: T790M is a major cause of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance, but the clinical significance of T790M disappearance is unknown. CASE REPORT: We report 3 cases of pulmonary adenocarcinoma which did not respond to EGFR-TKI retreatment even with T790M disappearance. T790M mutations were detected in the pleural effusions after the tumors had acquired EGFR-TKI resistance. T790M mutations disappeared from cancer cells in the pleural effusion after a break from the treatment drug and cytotoxic agent administration. However, no therapeutic effect was obtained despite EGFR-TKI reinitiation. CONCLUSIONS: Responsiveness to EGFR-TKI might not be restored in some cases, although the disappearance of T790M mutations is confirmed.

DOI： 10.1159/000491937

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DOI： 10.3389/fncel.2018.00113

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DOI： 10.1016/j.cmi.2017.05.009

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DOI： 10.1016/j.radonc.2017.08.026

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DOI： 10.1093/rheumatology/kex285

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DOI： 10.1001/jama.2017.11903

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DOI： 10.1038/s41598-017-13724-2

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DOI： 10.1016/j.cmi.2017.03.024

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DOI： 10.1111/crj.12358

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DOI： 10.1038/srep46488

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DOI： 10.2169/internalmedicine.56.7418

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DOI： 10.1038/srep39090

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DOI： 10.1111/resp.12835

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DOI： 10.1038/srep29325

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DOI： 10.1038/srep29754

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DOI： 10.1016/j.tube.2016.04.004

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Diagnostic test accuracy of D-dimer for acute aortic dissection (AAD) has not been evaluated by meta-analysis with the bivariate model methodology. Four databases were electrically searched. We included both case-control and cohort studies that could provide sufficient data concerning both sensitivity and specificity of D-dimer for AAD. Non-English language articles and conference abstract were allowed. Intramural hematoma and penetrating aortic ulcer were regarded as AAD. Based on 22 eligible articles consisting of 1140 AAD subjects and 3860 non-AAD subjects, the diagnostic odds ratio was 28.5 (95% CI 17.6-46.3, I(2) = 17.4%) and the area under curve was 0.946 (95% CI 0.903-0.994). Based on 833 AAD subjects and 1994 non-AAD subjects constituting 12 studies that used the cutoff value of 500 ng/ml, the sensitivity was 0.952 (95% CI 0.901-0.978), the specificity was 0.604 (95% CI 0.485-0.712), positive likelihood ratio was 2.4 (95% CI 1.8-3.3), and negative likelihood ratio was 0.079 (95% CI 0.036-0.172). Sensitivity analysis using data of three high-quality studies almost replicated these results. In conclusion, D-dimer has very good overall accuracy. D-dimer <500 ng/ml largely decreases the possibility of AAD. D-dimer >500 ng/ml moderately increases the possibility of AAD.

DOI： 10.1038/srep26893

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DOI： 10.1111/crj.12228

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DOI： 10.1016/j.arbres.2015.02.021

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DOI： 10.1016/j.chest.2015.11.018

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DOI： 10.1016/j.resinv.2015.09.006

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DOI： 10.5507/bp.2016.030

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Since 2010, studies on the diagnostic accuracy of COBAS TaqMan MTB (CTM) have been frequently reported with an unignorable discrepancy. The key inclusion criterion for this systematic review was original studies that could provide sufficient data for calculating the sensitivity and the specificity of CTM for M tuberculosis (TB) or M tuberculosis complex. The reference test was Mycobacterium culture. We used bivariate model for meta-analyses. Of the 201 candidate articles, we finally identified 17 eligible articles.Concerning the respiratory specimens, 1900 culture positive specimens and 20983 culture negative specimens from 15 studies were assessed. This provided the summary estimate sensitivity of 0.808 (95% CI 0.758-0.850) and the summary estimate specificity of 0.990 (95% CI 0.981-0.994). The area under curve was 0.956. The diagnostic odds ratio was 459 (95% CI 261-805, I(2) 26%). For the smear positive respiratory specimens, the sensitivity was 0.952 (95% CI 0.926-0.969) and the specificity was 0.916 (95% CI 0.797-0.968). For the smear negative respiratory specimens, the sensitivity and the specificity were 0.600 (95% CI 0.459-0.726) and 0.989 (95% CI 0.981-0.993), respectively. The diagnostic accuracy was poorer for the non-respiratory specimens, than for the respiratory specimens, but was acceptable. We believe that the information obtained from this study will aid physicians' decision making.

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DOI： 10.1016/j.intimp.2015.10.016

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DOI： 10.1111/resp.12603

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DOI： 10.1038/srep15437

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DOI： 10.1016/j.mgene.2015.04.003

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DOI： 10.1038/srep14061

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DOI： 10.1016/j.resinv.2015.01.006

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DOI： 10.2147/COPD.S56067

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DOI： 10.3109/15412555.2014.898051

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DOI： 10.1111/resp.12448

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DOI： 10.3978/j.issn.2218-6751.2014.07.03

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Purpose. The predictive factor of response to antituberculous therapy has not been fully elucidated. Airway acidity has been thought to be a potential indicator of the bactericidal activity. Therefore, we hypothesized that monitoring airway acidity by measuring sputum pH could predict response to therapy. Methods. A total of 47 patients having newly diagnosed, smear-positive, active pulmonary tuberculosis were enrolled between October 2011 and March 2014. Sputum samples were serially analyzed before and after treatment. Eligible patients who initiated a standard 6-month treatment were monitored for the length of time to sputum smear and culture conversion. Results. There were 39 patients who completed a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide, and ethambutol therapy followed by a 4-month continuation phase of isoniazid and rifampicin. Although factors including age, cavitation, sputum grade, and use of an acid-suppressant were associated with initial low sputum pH in univariate analysis, multivariate analysis revealed that only age ≥61 years was a statistically important factor predicting low pH value (p = 0.005). Further outcome analysis showed that initial low sputum pH before treatment was the only factor significantly associated with shorter length of time to both sputum smear and culture conversion (p = 0.034 and 0.019, respectively) independent of the effects of age, sputum bacterial load, extent of lung lesion, and cavitation. Thus, initial low sputum pH indicated favorable response to anti-tuberculosis therapy. Conclusions. Measuring sputum pH is an easy and inexpensive way of predicting response to standard combination therapy in patients with pulmonary tuberculosis.

DOI： 10.7717/peerj.1448

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Acute fibrinous and organizing pneumonia (AFOP) is a very rare pathological entity of lung injury characterized by intra-alveolar fibrin balls. Hemeoxygenase (HO) -1 is a cytoprotective enzyme against oxidative stress and inflammation. It is known to be expressed in the alveolar macrophages in the healthy adults and overexpressed in other various lung cells of the lung injury patients. We experienced two cases of subacute form AFOP for these 10 years and reviewed clinico-pathological characteristics. The average age was 62 years old and both were male. The etiology of both cases was idiopathic. The average PaO2/FIO2 ratio was 274.5 ± 84.1. The average levels of C-reactive protein and surfactant protein - A of the serum were elevated to 19.8 ± 6.3 mg/dL and 67.6 ± 15.8 ng/mL, respectively. Serum sialylated carbohydrate antigen levels were normal in both cases. The characteristic radiographic findings were bilateral consolidations and ground glass opacities. Lung biopsy specimens revealed fibrin balls and alveolitis with abundant cellular HO-1 expression. Steroid response was excellent and the pulmonary involvements absolutely disappeared for about 3 months.

DOI： 10.1016/j.rmcr.2015.01.003

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DOI： 10.2169/internalmedicine.54.5533

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DOI： 10.2169/internalmedicine.54.4940

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DOI： 10.2169/internalmedicine.54.4015

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DOI： 10.1016/j.arbres.2013.11.013

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DOI： 10.1016/j.resp.2014.07.008

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DOI： 10.1093/jrr/rru037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

DOI： 10.1186/1465-9921-15-80

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

DOI： 10.1186/1465-9921-15-37

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

DOI： 10.1111/crj.12062

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DOI： 10.3109/15412555.2013.808615

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Yokohama City University  

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DOI： 10.1097/JTO.0b013e3182a47524

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DOI： 10.1111/resp.12163

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

DOI： 10.1016/j.athoracsur.2013.06.014

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DOI： 10.1371/journal.pone.0073794

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DOI： 10.1016/j.cllc.2013.03.006

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BACKGROUND: Some investigations have revealed an association between depression and physical measurements of COPD patients in North America and Europe, but few related studies have been performed in Asia. METHODS: In this cross-sectional study, 84 consecutive, stable out-patients with COPD (mean ± SD age 72.0 ± 9.0 y, percent-of-predicted FEV1 46 ± 15%, 15 [17.9%] female) in a Japanese community hospital were recruited. "Probable depression" was defined as a score of ≥ 6 on the short-form Geriatric Depression Scale (SF-GDS). Relationships among commonly used physical measurements, SF-GDS raw score, and probable depression were evaluated with the Spearman rank correlation test, multiple linear regression analysis, logistic regression analysis, and receiver operating characteristic curves. RESULTS: Thirty-two subjects (38.1%) had probable depression. Body mass index, obstruction, dyspnea, exercise capacity index, percent-of-predicted FEV1, Modified Medical Research Council dyspnea score, 6-min walk distance, and SpO2 had: simple correlations (r 0.42-0.60, P < .001 for all) with the SF-GDS raw score; partial correlations (r 0.25-0.51, P < .05 for all) with the SF-GDS raw score after adjusting for demographic and social factors; association with probable depression in the logistic regression analysis after adjusting for demographic and social factors (P < .05 for all); and areas under the receiver operating characteristic curve of 0.72-0.84 (P < .001 for any) for probable depression. CONCLUSIONS: Physical parameters were associated with depression in our Japanese COPD out-patients.

DOI： 10.4187/respcare.02065

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DOI： 10.1093/trstmh/trt037

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DOI： 10.1700/1361.15119

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DOI： 10.1186/1465-9921-14-62

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DOI： 10.1016/j.ijrobp.2013.01.006

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

DOI： 10.1111/resp.12008

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DOI： 10.3892/ijo.2012.1755

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DOI： 10.5588/ijtld.12.0476

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

DOI： 10.2169/internalmedicine.52.1116

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DOI： 10.2169/internalmedicine.52.0701

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DOI： 10.1097/JOM.0b013e3182636e93

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DOI： 10.1111/j.1758-5910.2011.00125.x

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

DOI： 10.3892/etm.2012.493

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DOI： 10.2169/internalmedicine.51.8284

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DOI： 10.2169/internalmedicine.51.8585

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

DOI： 10.1186/1752-1947-6-281

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DOI： 10.1186/1752-1947-6-266

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DOI： 10.1007/s10156-011-0253-y

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

A 71-year-old man underwent pleural biopsy due to left pleural effusion and pleural thickening in August, 2001. An inflammatory pseudotumor (IPT) was diagnosed, and therefore systemic oral steroid therapy (prednisolone [PSL] 30 mg/day) was initiated. However, after tapering PSL to 7.5 mg/day, a complication of secondary central diabetes insipidus due to hypophysitis developed in 2008. As his pulmonary condition deteriorated over time and he began to experience exertional dyspnea, he was admitted to our hospital for re-evaluation of the disease in October, 2010. High-resolution CT (HRCT) revealed pulmonary involvements distributed in the interstitium and a high serum IgG4 level (240 mg/dl). Upon re-evaluating the pleural biopsy specimens of the first visit, we found lymphoplasmacytic-type IPT with approximately 10% IgG4-positive plasma cells in the affected areas. After increasing the PSL dose up to 0.6 mg/kg/day, his serum IgG4 levels decreased, his dyspnea improved, and the radiological findings of his pulmonary and pituitary involvements improved. This case was diagnosed as lymphoplasmacytic type IPT which appeared to be highly homologous with IgG4-related disease due to high serum levels of IgG4, pituitary involvements and the observed efficacy of PSL.

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

DOI： 10.1507/endocrj.K10E-255

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DOI： 10.1136/bmjopen-2011-000105

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DOI： 10.3892/ol_00000088

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DOI： 10.1007/s00705-010-0624-1

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DOI： 10.1007/s10156-009-0020-5

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Recently, we reported that a complex with an essential role in the degradation of Fructose-1,6-bisphosphatase in yeast is well conserved in mammalian cells; we named this mammalian complex C-terminal to the Lissencephaly type-1-like homology (CTLH) complex. Although the function of the CTLH complex remains unclear, here we used yeast two-hybrid screening to isolate Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) as a protein binding to a key component of CTLH complex, Armadillo repeat containing 8 (ARMc8) alpha. The association was confirmed by a yeast two-hybrid assay and a co-immunoprecipitation assay. The proline-rich domain of HRS was essential for the association. As demonstrated through immunofluorescence microscopy, ARMc8alpha co-localized with HRS. ARMc8alpha promoted the interaction of HRS with various ubiquitinated proteins through the ubiquitin-interacting motif. These findings suggest that HRS mediates protein endosomal trafficking partly through its interaction with ARMc8alpha.

DOI： 10.2174/1874091X01004010001

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DOI： 10.1016/j.lungcan.2009.03.015

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DOI： 10.1099/mic.0.028993-0

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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DOI： 10.1007/s00296-008-0795-1

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BACKGROUND: Using the ELISPOT assay, a promising immunological tool for detecting Mycobacterium tuberculosis (MTB) antigen-specific response, we monitored the clinical course of patients with tuberculosis (TB). METHODS: Blood samples were obtained from 35 patients with TB and healthy controls, numbering 52 age-matched control subjects and 43 university students. Nine of those with TB were examined twice before and after anti-tuberculosis treatment. The frequency of IFN-gamma secreting cells was determined using the ELISPOT assay in peripheral mononuclear cells (PBMC) stimulated with purified protein derivative (PPD), early secretory antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP-10). RESULTS: The frequency of PPD secreting cells correlated significantly with tuberculin skin test (TST) magnitude in BCG-vaccinated individuals. Significant responses to either ESAT-6 or CFP-10 were found in 94% of those with TB. The frequency of IFN-gamma secreting cells decreased when negative sputum tests were confirmed by successful tuberculosis treatment. CONCLUSIONS: The ELISPOT assay detecting MTB-specific immune response is promising both in diagnosing MTB and monitoring responsiveness to tuberculosis therapy.

DOI： 10.11150/kansenshogakuzasshi.83.229

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DOI： 10.1007/s10156-009-0672-1

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DOI： 10.1016/j.tube.2008.12.004

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DOI： 10.1007/s10156-008-0655-7

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DOI： 10.1378/chest.07-2904

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DOI： 10.2169/internalmedicine.47.1006

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DOI： 10.1111/j.1440-1827.2007.02155.x

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DOI： 10.3816/CLC.2007.n.029

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DOI： 10.1164/rccm.200508-1237OC

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DOI： 10.2169/internalmedicine.44.1120

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DOI： 10.1007/s00011-005-1348-7

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DOI： 10.1089/hum.2005.16.318

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DOI： 10.1016/j.ejphar.2004.11.032

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DOI： 10.2169/internalmedicine.43.1105

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DOI： 10.1089/104303404322886129

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DOI： 10.1111/j.1365-2443.2004.00717.x

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DOI： 10.2169/internalmedicine.43.69

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DOI： 10.1183/09031936.03.00303503

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DOI： 10.2169/internalmedicine.41.915

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DOI： 10.1038/sj.bjp.0704572

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DOI： 10.1165/ajrcmb.20.2.3305

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DOI： 10.1007/s000110050322

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DOI： 10.1016/S0196-9781(97)00017-X

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DOI： 10.1164/ajrccm.153.1.8542106

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DOI： 10.1165/ajrcmb.13.5.7576693

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DOI： 10.1016/0898-6568(95)00023-I

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DOI： 10.1164/ajrccm.150.3.8087343

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DOI： 10.1152/ajplung.1994.267.3.L250

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Language：English   Publishing type：Research paper, summary (international conference)  

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