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Background: Toothbrushing is important for maintaining oral health and preventing periodontal disease. However, the association between toothbrushing and systemic diseases remains unclear in adolescence. In this study, the association between dental self-care (frequency and duration of toothbrushing) and systemic diseases/disorders in adolescents was examined. Methods: We conducted a retrospective review of mandatory medical questionnaires administered during legally mandated freshman medical checkups between 2017 and 2019 at the University of Tokyo, Japan. Out of 9376 total responses, 9098 cases involving individuals under the age of 20 were included in the analysis. Respondents were classified into three groups based on their daily toothbrushing frequency: "1 time or less", "twice", and "3 times or more". For the duration of each toothbrushing session, they were classified into three groups: "1 min or less", "2–3 min", and "4 min or more". A statistical analysis was performed by Pearson's χ2 test and multinomial logistic regression analysis. Results: Regarding frequency of daily toothbrushing: The χ2 test showed no significant relationship between frequency of toothbrushing and 17 systemic diseases/disorders. A multivariate analysis found that gingival bleeding and sex were independent factors. The risk of gingival bleeding decreased dramatically with increased frequency of toothbrushing (odds ratio (OR): 0.428; 95% confidence interval (CI), 0.366–0.501; p < 0.001). Regarding the amount of time spent on toothbrushing: The χ2 test showed atopic dermatitis and arrhythmia were significantly associated with the duration of toothbrushing (p = 0.032 and p = 0.016, respectively). In the multivariate analysis, atopic dermatitis, gingival bleeding, and sex were independent factors regarding the duration of toothbrushing; longer brushing time was associated with a lower risk of atopic dermatitis (OR: 0.731, 95% CI: 0.578–0.924, p = 0.009) and a lower risk of gingival bleeding (OR: 0.643, 95% CI: 0.567–0.729, p < 0.001). Conclusions: Dental self-care was most strongly associated with gingival bleeding, while the risk of atopic dermatitis was found to increase with shorter toothbrushing times. The results suggest that dental self-care during adolescence is important not only for oral health but also for general health. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Although intrapleural administration of fibrinolytics is an important treatment option for the management of empyema, the addition of fibrinolytics failed to reduce the need for surgery and mortality in previous randomized controlled trials. This study aimed to investigate the effects of administrating fibrinolytics in the early phase (within 3 days of chest tube insertion) of empyema compared with late administration or no administration. METHODS We used the Japanese Diagnosis Procedure Combination Inpatient Database to identify patients aged ≥16 years who were hospitalized and underwent chest tube drainage for empyema. A 1:2 propensity score matching and stabilized inverse probability of treatment weighting were conducted. RESULTS Among the 16 265 eligible patients, 3082 and 13 183 patients were categorized into the early and control group, respectively. The proportion of patients who underwent surgery was significantly lower in the early fibrinolytics group than in the control group; the odds ratio (95% confidence interval) was 0.69 (0.54–0.88) in the propensity score matching (P  =   0.003) and 0.64 (0.50–0.80) in the stabilized inverse probability of treatment weighting analysis (P  <   0.001). All-cause 30-day in-hospital mortality, length of hospital stay, duration of chest tube drainage, and total hospitalization costs were also more favourable in the early fibrinolytics group. CONCLUSIONS The early administration of fibrinolytics may reduce the need for surgery and death in adult patients with empyema. [ABSTRACT FROM AUTHOR]

Introduction: The traditional Japanese herbal medicine hochuekkito (TJ-41) has been reported to ameliorate systemic inflammation and malnutrition in patients with chronic obstructive pulmonary disease (COPD). TJ-41 has also been known to have preventive effects against influenza virus infection. However, its role in the acute exacerbation of COPD (AECOPD) remains to be elucidated. Our previous study established a murine model of viral infection-associated AECOPD that was induced by intratracheal administration of porcine pancreatic elastase (PPE) and polyinosinic-polycytidylic acid [poly(I:C)]. Here, we used this model and investigated the effects of TJ-41 in AECOPD. Methods: Specific pathogen-free C57BL/6J mice were used. A COPD model was induced by treating mice intratracheally with PPE on day 0. To generate the murine model of AECOPD, poly(I:C) was administered intratracheally following PPE treatment on days 22–24. Mice were sacrificed and analyzed on day 25. Mice were fed a diet containing 2% TJ-41 or a control diet. Results: Daily oral intake of TJ-41 significantly decreased the numbers of neutrophils and lymphocytes in the bronchoalveolar lavage fluid (BALF), which was accompanied by decreased transcripts of CXC chemokines involved in neutrophil migration, viz., Cxcl1 and Cxcl2, in whole lung homogenates and reduced Cxcl2 concentration in BALF. Conclusion: This study demonstrates the anti-inflammatory effects of TJ-41 in a mouse model of AECOPD, suggesting the effectiveness of TJ-41 for the management of COPD. Clinical investigations evaluating the therapeutic efficacy of TJ-41 in AECOPD would be meaningful. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that the effects of poor oral hygiene extend beyond the oral cavity and are associated with a variety of systemic diseases, including asthma. Asthma, which results in symptoms of cough, wheezing, and dyspnoea, and is characterized by airflow limitation with variability and (partial or complete) reversibility, is amongst the most prevalent respiratory diseases with approximately 262 million patients worldwide, and its prevalence and disease burden is on the increase. While asthma can occur at a young age, it can also develop later in life and affects a variety of age groups. Both of these diseases have a chronic course, and various researchers have suggested a link between the two. In this article, we aim to provide a literature review focusing on the association between the two diseases. The results demonstrate that medications (primarily, inhaler medicine), hypoxia induced by asthma, and the breathing behaviour of patients potentially trigger periodontal disease. In contrast, oral periodontopathogenic microorganisms and the inflammatory mediators produced by them may be involved in the onset and/or exacerbation of asthma. Common contributing factors, such as smoking, gastro-oesophageal reflux, and type-2 inflammation, should also be considered when evaluating the relationship between the two diseases. [ABSTRACT FROM AUTHOR]

The prevalence of chronic obstructive pulmonary disease (COPD) is increasing worldwide and is currently the third leading cause of death globally. The long-term inhalation of toxic substances, mainly cigarette smoke, deteriorates pulmonary function over time, resulting in the development of COPD in adulthood. Periodontal disease is an inflammatory condition that affects most adults and is caused by the bacteria within dental plaque. These bacteria dissolve the gums around the teeth and the bone that supports them, ultimately leading to tooth loss. Periodontal disease and COPD share common risk factors, such as aging and smoking. Other similarities include local chronic inflammation and links with the onset and progression of systemic diseases such as ischemic heart disease and diabetes mellitus. Understanding whether interventions for periodontal disease improve the disease trajectory of COPD (and vice versa) is important, given our rapidly aging society. This review focuses on the putative relationship between COPD and periodontal disease while exploring current evidence and future research directions. [ABSTRACT FROM AUTHOR]

A man in his late 40s was diagnosed with clinical stage 4B lung adenocarcinoma with a PD-L1 tumor proportion score of 100% and high tumor mutational burden. A partial response was achieved after administration of pembrolizumab. The patient received two doses of a SARS-CoV-2 vaccine (BNT162b2) after 59 courses, and a chest computed tomography revealed consolidation in the peri-tumoral area, which subsequently disappeared, and the tumor continued to shrink in the next 4 months. This case provides indirect evidence for the persistence of cancer immunity during long-term treatment with immune checkpoint inhibitors and the potential for further activation. [ABSTRACT FROM AUTHOR]

Simple Summary: Mutation of the RB1 tumor suppressor gene is fundamental in retinoblastoma initiation and progression although its downstream mechanism has not been well elucidated. Here, we found that expression of proline/arginine-rich end leucine-rich repeat protein (PRELP) is strongly downregulated in human retinoblastoma and highly expressed in Müller glial cells in normal retina. Deletion of PRELP in mice resulted in retinal dysplasia associated with enhanced proliferation. mRNA expression profiling revealed that cancer pathways were strongly activated in PRELP−/− retina. Additionally, cell–cell adhesion was inhibited while epithelial mesenchymal transition (EMT) and inflammation were activated. On the other hand, application of PRELP protein to retinoblastoma cell lines enhances cell–cell and cell–substrate adhesion and inhibits anchorage independent growth by reversing EMT. These observations indicate that PRELP downregulation in human retinoblastoma can contribute cancer progression through regulation of cell adhesion and EMT suggested that PRELP application might be a novel strategy for retinoblastoma treatment. Retinoblastoma (RB) is the most common intraocular pediatric cancer. Nearly all cases of RB are associated with mutations compromising the function of the RB1 tumor suppressor gene. We previously demonstrated that PRELP is widely downregulated in various cancers and our in vivo and in vitro analysis revealed PRELP as a novel tumor suppressor and regulator of EMT. In addition, PRELP is located at chromosome 1q31.1, around a region hypothesized to be associated with the initiation of malignancy in RB. Therefore, in this study, we investigated the role of PRELP in RB through in vitro analysis and next-generation sequencing. Immunostaining revealed that PRELP is expressed in Müller glial cells in the retina. mRNA expression profiling of PRELP−/− mouse retina and PRELP-treated RB cells found that PRELP contributes to RB progression via regulation of the cancer microenvironment, in which loss of PRELP reduces cell–cell adhesion and facilitates EMT. Our observations suggest that PRELP may have potential as a new strategy for RB treatment. [ABSTRACT FROM AUTHOR]

TAZ (transcriptional coactivator with PDZ-binding motif), also called WWTRI (WW domain containing transcription regulator 1). is a 14-3-3-binding molecule homologous to Yes-associated protein. TAZ acts as a coactivator for several transcription factors as well as a modulator of membrane-associated PDZ domain-containing proteins, but its (patho)physiological roles remain unknown. Here we show that gene inactivation of TAZ in mice resulted in pathological changes in the kidney and lung that resemble the common human diseases polycystic kidney disease and pulmonary emphysema. Taz.-null/lacZ knockin mutant homozygotes demonstrated renal cyst formation as early as embryonic day 15.5 with dilatation of Bowman's capsules and proximal tubules, followed by pelvic dilatation and hydronephrosis. After birth, only one-fifth of TAZ-deficient homozygotes grew to adulthood and demonstrated multicystic kidneys with severe urinary concentrating dejects and polyuria. Furthermore, adult TAZ-deficient homozygotes exhibited diffuse emphysematous changes in the lung. Thus TAZ is essential for developmental mechanisms involved in kidney and lung organogenesis, whose disturbance may lead to the pathogenesis of common human diseases. renal disease: knockout mice; transcription factor

A mouse model of asthma-chronic obstructive pulmonary disease overlap induced by intratracheal papain Keywords: animal models; asthma; COPD EN animal models asthma COPD 390 394 5 01/09/21 20210101 NES 210101 Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is recognized as a distinct clinical disorder that can be differentiated from asthma or COPD alone, owing to the rapid disease progression, frequent exacerbations and increased comorbidities.1 A major impediment to the elucidation of mechanisms underlying ACO pathogenesis has been the lack of development and detailed evaluation of appropriate animal models. Both PPE- and papain-treated groups showed increased inspiratory capacity/weight and dynamic compliance (Figure 1B); representative lung histology revealed PPE- and papain-induced emphysema (Figure 1C). [Extracted from the article]

Naftopidil, an α‐1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α‐1 adrenoceptor inhibitor. We examined the incorporation of 5‐bromo‐2ʹ‐deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme‐linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound‐healing assay, and mRNA expressions of type IV collagen and α‐smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin‐induced lung fibrosis in mice were evaluated using histology, micro‐computed tomography, and surfactant protein‐D levels in serum. Naftopidil, dose‐dependently but independently of phenoxybenzamine, inhibited 5‐bromo‐2ʹ‐deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α‐smooth muscle actin in one normal lung fibroblast line. Histological and micro‐computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein‐D levels in bleomycin‐induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy with vinorelbine plus cisplatin (VNR/CDDP) is a standard regimen for treatment of postoperative stage II‐IIIA non‐small cell lung cancer (NSCLC). However, oral fluorouracil offers a feasible alternative adjuvant chemotherapeutic regimen. We compared the prognoses of patients with NSCLC treated with adjuvant chemotherapy with either VNR/CDDP or oral fluorouracil. Methods: We identified patients with stage II‐IIIA NSCLC who underwent lung surgery followed by adjuvant chemotherapy with VNR/CDDP (n = 384) or oral fluorouracil (n = 268) between July 2010 and March 2015, using the national Japanese inpatient and outpatient Diagnosis Procedure Combination database. We compared recurrence‐free survival between the groups by multivariable Cox regression analysis for one‐to‐one propensity score‐matched patients and by instrumental variable analysis. Results: Younger patients and patients with positive N2 nodes were more likely to receive VNR/CDDP, while older patients and those with T3N0 classification were more likely to receive oral fluorouracil. Among 172 pairs of propensity‐matched patients, time to adjuvant chemotherapy was shorter for oral fluorouracil compared with VNR/CDDP. Oral fluorouracil was also significantly associated with improved recurrence‐free survival compared with VNR/CDDP, according to multivariable Cox regression analysis (hazard ratio, 0.41; 95% confidence interval, 0.26‐0.64). Instrumental variable analysis showed a similar relationship (hazard ratio, 0.19; 95% confidence interval, 0.038‐0.92). Conclusions: On a large nationwide cohort, adjuvant chemotherapy with oral fluorouracil prolonged recurrence‐free survival in patients with postoperative stage II‐IIIA NSCLC, compared with VNR/CDDP. Oral fluorouracil may thus be a useful alternative to VNR/CDDP for the adjuvant treatment of these patients. We analyzed data on patients with postoperative stage II‐IIIA non‐small cell lung cancer from a nationwide inpatient database using two pseudorandomization approaches, propensity score‐matching, and instrumental variable analysis. We demonstrated that oral fluorouracil significantly improved recurrence‐free survival compared with vinorelbine plus cisplatin. [ABSTRACT FROM AUTHOR]

Background: Patients with primary spontaneous pneumothorax (PSP) usually complain of sudden-onset dyspnea and pleuritic chest pain. However, asymptomatic PSP has been incidentally detected on chest X-rays. In this study, we analyzed the incidence, characteristics, risk factors, and prognosis of asymptomatic PSP detected during regular medical check-ups in university students.Methods: In this study, 101,709 chest X-rays were performed during medical check-ups for students at the University of Tokyo between April 2011 and March 2016. Among them, 43 cases of asymptomatic PSP (0.042%) were detected. We calculated the lung collapse rate of pneumothorax using Kircher's method. We also analyzed risk factors associated with asymptomatic PSP using characteristics inspected in medical check-ups.Results: The incidence of asymptomatic PSP was significantly higher in men than in women (0.050% vs 0.018%). Multivariate analysis revealed an association of younger age, greater height, lower body mass index, and greater height growth per year with an increased risk of asymptomatic PSP in male students. Mild lung collapse (<10%) was present in 22 of 43 students with asymptomatic PSP; among these, eight students eventually underwent an invasive therapy.Conclusions: The prevalence of asymptomatic PSP among university students was as high as 0.042%. In addition to known risk factors for conventional PSP, greater height growth was a risk factor for asymptomatic PSP. Careful follow-up is very important because a considerable number of patients with mild lung collapse eventually require an invasive medical procedure. [ABSTRACT FROM AUTHOR]

Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress from cigarette smoke and chronic inflammation is likely to induce this corticosteroid insensitivity. Quercetin is a polyphenol that has been reported to be an active oxygen scavenger as well as a functional adenosine monophosphate-activated protein kinase (AMPK) activator. The aim of this study was to investigate the effect of quercetin on corticosteroid responsiveness in COPD cells. Corticosteroid sensitivity was examined in human monocytic U937 cells exposed to cigarette smoke extract (CSE) and peripheral blood mononuclear cells (PBMC) collected from patients with COPD. Corticosteroid sensitivity was determined as the dexamethasone concentration causing 40% inhibition of tumor necrosis factor alpha-induced CXCL8 production (Dex-IC40) in the presence or absence of quercetin. In U937 cells, treatment with quercetin activated AMPK and induced expression of nuclear factor erythroid 2-related factor 2, and consequently reversed CSE-induced corticosteroid insensitivity. PBMC from patients with COPD showed corticosteroid insensitivity compared with those from healthy volunteers, and treatment with quercetin restored corticosteroid sensitivity. In conclusion, quercetin restores corticosteroid sensitivity, and has the potential to be a novel treatment in combination with corticosteroids in COPD. [ABSTRACT FROM PUBLISHER]

Background: The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy.Methods: We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis.Results: Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885-1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464-1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91-1.84).Conclusions: There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue. [ABSTRACT FROM AUTHOR]

Encouraging toothbrushing in younger generations may not only prevent severe periodontitis but also improve systemic health status which would be affected by periodontal diseases. Periodontal diseases are the most common oral diseases affecting the supporting structures of the teeth.1 They are not only responsible for tooth loss but also associated with various systemic diseases including noncommunicable diseases (NCDs) such as cardiovascular diseases, diabetes, and respiratory diseases.2 Most of the extant studies of the relationship between periodontal diseases and systemic diseases have targeted middle-aged and elderly people. [Extracted from the article]

Background: Oral diseases are associated with various systemic disorders. Our previous research revealed new insights into the close relationship between occlusal disorder (functional disorder) and systemic disorders (allergic rhinitis, asthma, and arrhythmia) in late adolescence. Here, we investigated whether there was an association between the awareness of teeth-alignment disorder (morphological disorder) and common systemic disorders. Subjects and Methods: We retrospectively reviewed the data of the mandatory medical questionnaire that is required for the freshman medical checkup in Japan. We collected the data of all students who completed the questionnaire between April 2017 and April 2019. The data were analyzed using the χ2 test, and a multivariate analysis was performed with a binomial logistic regression model. Results: The subjects were 8903 students aged 17–19 who had no awareness of occlusal disorder. The rate of awareness of teeth-alignment disorder was 20.43% (1819 of 8903 eligible subjects), and the aware students had significantly greater rates of gum bleeding (p < 0.001), pollinosis (n = 0.007), and atopic dermatitis (n = 0.042). The multivariate analysis revealed significant rates of gum bleeding (odds ratio (OR) 1.540, 95% confidence interval (CI): 1.386–1.711, p < 0.001), pollinosis (OR 1.197, 95% CI: 1.040–1.378, p = 0.012), and female gender (OR 1.141, 95% CI: 1.002–1.299, p = 0.046) among the students with awareness of teeth-alignment disorder. Conclusion: We identified close associations between the awareness of teeth-alignment disorder and both gum bleeding and pollinosis in a late-adolescent population. The systemic disorders that are targeted by teeth-alignment disorder were found to be different from those targeted by occlusal disorder. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial–mesenchymal transition (EMT) is associated with cancer progression. Here, we found that two secreted proteins of osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) were selectively expressed in bladder umbrella epithelial cells, and they were suppressed in bladder cancer. We revealed that OMD−/− or PRELP−/− knockout mice caused a breakdown of the umbrella cell layer through weakening cell–cell integrity and the activation of partial EMT, which resulted in the formation of early bladder cancer-like structures, while OMD or PRELP application to bladder cancer cells inhibited cancer progression through reversing EMT, which was mediated by the inhibition of TGF-β and EGF. Our result indicates that OMD and PRELP function as tumor-suppressing proteins through inhibiting EMT. OMD and PRELP may be potential therapeutic targets in bladder cancer. Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer. [ABSTRACT FROM AUTHOR]

Background: Oral infectious diseases are typified by dental caries and periodontal diseases and are known to be associated with various systemic diseases. However, clear associations between occlusal disorders and systemic diseases have not yet been established. We investigated the association between an awareness of malocclusion and common diseases in late adolescence. Methods: We retrospectively reviewed the data of mandatory medical questionnaires that are a legal requirement of the freshman medical checkup. We collected the data of all the students who completed the questionnaires between April 2017 and 2019. The data were analyzed using the χ2 test and multivariate analysis was performed with a binomial logistic regression model. Results: The subjects were 9098 students aged 17–19 (mean age 18.3 years). The rate of awareness of malocclusion was 2.14% (195 out of 9098 eligible subjects; 160 males and 35 females). These students had significantly greater rates of allergic rhinitis, asthma, and arrhythmia (p < 0.001). Multivariate analysis revealed significant rates of allergic rhinitis (odds ratio [OR] 2.184, 95% confidence interval [CI]: 1.468–3.250, p < 0.001), asthma (OR 1.843, 95%CI: 1.153–2.945, p = 0.011), and arrhythmia (OR 2.809, 95%CI: 1.083–7.288, p = 0.034) among students with an awareness of malocclusion. Conclusion: We identified close associations between an awareness of malocclusion and systemic diseases including allergic rhinitis, asthma, and arrhythmia in the late adolescent population. These results reinforce the associations between malocclusion and allergic rhinitis and asthma, as well as providing novel insight into the association of malocclusion and arrhythmia. However, further research is necessary to confirm the associations and explore the mechanisms underlying these associations. [ABSTRACT FROM AUTHOR]

Irinotecan hydrochloride (CPT-11) is used to treat a wide spectrum of malignant tumors. Hangeshashin-to (Japanese herbal medicine TJ-14) is reportedly effective in preventing and controlling diarrhea associated with CPT-11. However, the effect of TJ-14 on tolerability of chemotherapy with CPT-11 has not been fully investigated. We used the Japanese Diagnosis Procedure Combination inpatient database to retrospectively identify patients who had received CPT-11 on their first admission with and without TJ-14. Patients who did receive TJ-14 (N = 7092) received CPT-11 more often and in larger doses than those who did not receive TJ-14 (N = 82,019). The incidence rate ratio of CPT-11 administration was 1.34 for frequency (95% confidence interval [CI], 1.31–1.38; p < 0.001), and 1.16 for total dose (95% CI, 1.14–1.19; p < 0.001) according to stabilized inverse probability treatment weighting using propensity scores. Instrumental variable analysis showed similar trends. In-hospital mortality was significantly lower in patients who received TJ-14 than in those who did not. Odds ratios of in-hospital death in patients receiving TJ-14 was 0.81 (95% CI, 0.71–0.93; p = 0.002) according to stabilized inverse probability treatment weighting using propensity scores and 0.42 (95% CI, 0.22–0.81; p = 0.009) according to instrumental variable analysis. Our findings indicate that TJ-14 improve the tolerability of CPT-11. [ABSTRACT FROM AUTHOR]

Transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes. Nuclear translocation and activation of TAZ are regulated by multiple mechanisms, including actin cytoskeleton and mechanical forces. TAZ is involved in lung alveolarization during lung development and Taz-heterozygous mice are resistant to bleomycin-induced lung fibrosis. In this study, we explored the roles of TAZ in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through histological analyses of human lung tissues and cell culture experiments. TAZ was highly expressed in the fibroblastic foci of lungs from patients with IPF. TAZ controlled myofibroblast marker expression, proliferation, migration, and matrix contraction in cultured lung fibroblasts. Importantly, actin stress fibers and nuclear accumulation of TAZ were more evident when cultured on a stiff matrix, suggesting a feedback mechanism to accelerate fibrotic responses. Gene expression profiling revealed TAZ-mediated regulation of connective tissue growth factor (CTGF) and type I collagen. Clinical relevance of TAZ-regulated gene signature was further assessed using publicly available transcriptome data. These findings suggest that TAZ is involved in the pathogenesis of IPF through multifaceted effects on lung fibroblasts. [ABSTRACT FROM AUTHOR]

Inhaler devices play an important role in the management of obstructive lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap. Some of these patients show suboptimal inhaler techniques; however, time for inhaler instruction by pharmacists is limited in daily clinical practice. Therefore, sufficient education regarding inhaler device handling should be provided within a limited time frame. The current study aimed to investigate the instruction methods provided by community pharmacists and their influence on inhaler device handling techniques in outpatient clinical care settings. We retrospectively collected the data of outpatients with obstructive lung diseases who were referred to our hospital and who underwent inhalation technique assessments conducted by community pharmacists. The prevalence of handling errors, clinical characteristics of patients, and instruction methods were analyzed. In total, 138 patients (170 devices) were included in this study. Approximately 70.0% of patients received verbal explanations combined with leaflets about inhaler instructions. In a device-based analysis, 63 (37.1%) of 170 devices had at least one technical error and 18 (10.6%) of the devices had critical errors. Patients without critical errors received practical demonstration instructions from pharmacists combined with leaflets and verbal explanations more frequently than those with critical errors (22.8 vs. 0%, p < 0.01). This study revealed that patients with obstructive lung diseases commonly present with inhaler device handling errors and critical errors were observed with non-negligible frequency in daily practice in Japan. Combined instruction with leaflet, verbal explanation, and pharmacist demonstration may be effective in improving proper inhaler treatment.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder. It often causes weight loss, which is considered a poor prognostic factor. A Japanese herbal Kampo medicine, Hochuekkito (TJ-41), has been reported to prevent systemic inflammation and weight loss in COPD patients, but the underlying biological mechanisms remain unknown. In the present study, we investigated the role of TJ-41 in vivo using a mouse model of lung emphysema. We used lung epithelium-specific Taz conditional knockout mice (Taz CKO mice) as the lung emphysema model mimicking the chronic pulmonary inflammation in COPD. Acute inflammation was induced by intratracheal lipopolysaccharide administration, simulating COPD exacerbation. Mice were fed a diet containing 2% TJ-41 or a control diet. Taz CKO mice showed increased numbers of inflammatory cells in the bronchoalveolar lavage fluid compared to control mice. This effect was reduced by TJ-41 treatment. In the acute exacerbation model, TJ-41 mitigated the increased numbers of inflammatory cells in the bronchoalveolar lavage fluid and attenuated lung inflammation in histopathological studies. Additional in vitro experiments using the human macrophage cell line U-937 demonstrated that lipopolysaccharide-induced tumor necrosis factor-alpha expression was significantly downregulated by TJ-41. These results suggest that TJ-41 has anti-inflammatory effects in lung emphysema both in the chronic phase and during an acute exacerbation. In conclusion, our study sheds light on the anti-inflammatory effects of TJ-41 in lung emphysema. This establishes its potential as a new anti-inflammatory therapy and a preventive medicine for exacerbations during the long-time maintenance of COPD patients.

The mTOR pathway is one of the key signal cascades in the pathogenesis of idiopathic pulmonary fibrosis. Previous studies have mainly focused on this pathway in the fibroblasts and/or myofibroblasts, but not in the epithelial cells. In this study, we sought to investigate the role of the mTOR pathway in lung epithelial cells in lung fibrosis. Using Sftpc-mTOR SL1+IT transgenic mice, in which active mTOR is conditionally expressed in lung epithelial cells, we assessed the effects of chronically activated mTOR in lung epithelial cells on lung phenotypes as well as bleomycin-induced lung fibrosis. Furthermore, we isolated alveolar epithelial cell type 2 from mice and performed RNA sequencing. Sftpc-mTOR SL1+IT transgenic mice had no obvious abnormal findings, but, after bleomycin administration, showed more severe fibrotic changes and lower lung compliance than control mice. RNA sequencing revealed Angptl4 (angiopoietin-like protein 4) as a candidate downstream gene of the mTOR pathway. In vitro studies revealed that ANGPTL4, as well as mTOR, promoted tight junction vulnerability and epithelial-mesenchymal transition. mTOR activation in lung epithelial cells promoted lung fibrosis and the expression of ANGPTL4, a novel downstream target of the mTOR pathway, which could be related to the etiology of fibrosis.

Background: Inhaled corticosteroids (ICSs) are used for advanced-stage chronic obstructive pulmonary disease (COPD). The application and safety of ICS withdrawal remain controversial.This study aimed to evaluate the association between ICS withdrawal and outcomes in elderly patients with COPD with or without comorbid bronchial asthma, who were hospitalised for exacerbation., Patients and Methods: We conducted a retrospective cohort study using the Japanese Diagnosis Procedure Combination database from July 2010 to March 2016 . We identified patients aged ≥65 years who were hospitalised for COPD exacerbation. Re-hospitalisation for COPD exacerbation or death, frequency of antimicrobial medicine prescriptions and frequency of oral corticosteroid prescriptions after discharge were compared between patients with withdrawal and continuation of ICSs using propensity score analyses, namely 1-2 propensity score matching and stabilised inverse probability of treatment weighting., Results: Among 3735 eligible patients, 971 and 2764 patients had ICS withdrawal and continuation, respectively. The hazard ratios (95% confidence intervals) of re-hospitalisation for COPD exacerbation or death for ICS withdrawal compared to continuation were 0.65 (0.52-0.80) in the propensity score matching and 0.71 (0.56-0.90) in the inverse probability of treatment weighting. The frequency of antimicrobial prescriptions but not corticosteroid prescriptions within 1 year was significantly less in the ICS withdrawal group. Among patients with comorbid bronchial asthma, ICS withdrawal was significantly associated with reduced re-hospitalisation for COPD exacerbation or death only in the propensity score matching analysis., Conclusion: ICS withdrawal after COPD exacerbation was significantly associated with reduced incidences of re-hospitalisation or death among elderly patients, including those with comorbid bronchial asthma., Competing Interests: Conflict of interest: T. Jo has nothing to disclose. Conflict of interest: H. Yasunaga reports grants from Ministry of Health, Labour, and Welfare, Japan, during the conduct of the study. Conflict of interest: Y. Yamauchi has nothing to disclose. Conflict of interest: A. Mitani has nothing to disclose. Conflict of interest: Y. Hiraishi has nothing to disclose. Conflict of interest: W. Hasegawa has nothing to disclose. Conflict of interest: Y. Sakamoto has nothing to disclose. Conflict of interest: H. Matsui has nothing to disclose. Conflict of interest: K. Fushimi has nothing to disclose. Conflict of interest: T. Nagase has nothing to disclose., (Copyright ©ERS 2020.)

TAZ (transcriptional coactivator with PDZ-binding motif) and YAP (Yes-associated protein) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their roles during lung development remain unknown. We aimed to investigate YAP and TAZ functions using lung epithelium-specific Taz and Yap conditional knockout mice. We generated lung epithelium-specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Shh (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-β (transforming growth factor-β) stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. Our results provide a novel insight into the molecular mechanisms underlying lung development and contribute to a better understanding of the characteristics of TAZ and YAP.

Purpose: Patients with symptomatic COPD are recommended to use inhaled bronchodilators containing long-acting muscarinic receptor antagonists (LAMAs). However, bronchodilators may cause gastrointestinal adverse effects due to anticholinergic reactions, especially in advanced-age patients with COPD. Dai-kenchu-to (TU-100, Da Jian Zhong Tang in Chinese) is the most frequently prescribed Japanese herbal Kampo medicine and is often prescribed to control abdominal bloating and constipation. The purpose of this study was to evaluate the role of Dai-kenchu-to as a supportive therapy in advanced-age patients with COPD., Patients and Methods: We used the Japanese Diagnosis Procedure Combination inpatient database and identified patients aged ≥75 years who were hospitalized for COPD exacerbation. We then compared the risk of re-hospitalization for COPD exacerbation or death between patients with and without Dai-kenchu-to using 1-to-4 propensity score matching. A Cox proportional hazards model was used to compare the two groups. We performed subgroup analyses for patients with and without LAMA therapy., Results: Patients treated with Dai-kenchu-to had a significantly lower risk of re-hospitalization or death after discharge; the HR was 0.82 (95% CI, 0.67-0.99) in 1-to-4 propensity score matching. Subgroup analysis of LAMA users showed a significant difference in re-hospitalization or death, while subgroup analysis of LAMA non-users showed no significant difference., Conclusion: Our findings indicate that Dai-kenchu-to may have improved the tolerability of LAMA in advanced-age patients with COPD and, therefore, reduced the risk of re-hospitalization or death from COPD exacerbation. Dai-kenchu-to may be recommended as a useful supportive therapy for advanced-age patients with COPD., Competing Interests: Disclosure TJ (corresponding author), NM, and HY have received financial contributions from Tsumura & Company (Tokyo, Japan) because they have academic affiliations with the Department of Health Services Research, Graduate School of Medicine, The University of Tokyo supported by Tsumura & Company. Tsumura & Company played no role in this study. The corresponding author also receives research funding from Tsumura & Company for research not related to this study. The authors report no other conflicts of interest in this work.

Background/aim: Cytological analysis for diagnosing malignant pleural effusion associated with lung adenocarcinoma (Ad-MPE) shows limited sensitivity and novel diagnostic biomarkers are needed. The aim of this study was to evaluate the profile of four microRNAs (miRNAs) in exosomes in Ad-MPE and benign (non-neoplastic) pleural effusion (BPE)., Materials and Methods: A total of 56 pleural effusion samples from patients with lung adenocarcinoma and benign diseases were collected. Exosomal miRNA expressions were evaluated using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR)., Results: The expression levels of miR-182 and miR-210 were significantly higher in the Ad-MPE than in the BPE samples. The receiver operating characteristics curve analyses of miR-182 and miR-210 for diagnosis of Ad-MPE yielded areas under the receiver operating characteristic curves of 0.87 and 0.81, respectively., Conclusion: These miRNA signatures may have a diagnostic potential for differentiating Ad-MPE from BPE., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

An association between chemotherapy and venous thromboembolic events (VTEs) in patients with cancer is well established, with cisplatin (CDDP) being one of the most well-studied risk factors. However, whether CDDP is more strongly associated with occurrence of VTEs than carboplatin (CBDCA) or nedaplatin (CDGP) is controversial. Our purposes were to characterize patients with lung cancer and in-hospital VTEs, identify risk factors associated with VTEs, and compare the risks associated with CDDP-based versus CBDCA/CDGP-based chemotherapy. We retrospectively identified patients with lung cancer who underwent platinum-based chemotherapy from April 2012 to March 2015 from a national inpatient database in Japan. We used multivariable logistic regression analysis to analyze associations between various factors, including chemotherapy regimens and VTE. Of 235 104 eligible patients, 675 (0.29%) had VTEs after receiving platinum-based chemotherapy while hospitalized. Multivariable analysis showed that age, activity of daily living index, and invasive medical procedures were significant risk factors for the occurrence of VTE. Furthermore, CDDP-based chemotherapy was associated with a higher rate of VTE than CBDCA/CDGP-based chemotherapy (adjusted odds ratio: 1.35; 95% confidence interval: 1.08-1.68; P<0.01). In conclusion, CDDP-based chemotherapy is a stronger risk factor for VTEs than CBDCA/CDGP-based chemotherapy in patients with lung cancer.

A malignant tumor can cause hypercoagulation and it also often coexists with thrombosis. Cisplatin-based chemotherapy can also induce adverse vascular effects, including arterial thrombosis. We herein report a case of acute arterial thrombosis in a patient undergoing postoperative adjuvant cisplatin-based chemotherapy for completely resected lung cancer. The patient complained of acute leg pain after chemotherapy, and computed tomography revealed multiple thrombi from the thoracic to popliteal arteries. Arterial thrombosis during adjuvant chemotherapy is extremely rare; however, careful clinical observation of patients receiving cisplatin-based chemotherapy is important, because arterial thrombosis, even in the absence of the primary malignant tumor, is possible.

Background: Patients with primary spontaneous pneumothorax (PSP) usually complain of sudden-onset dyspnea and pleuritic chest pain. However, asymptomatic PSP has been incidentally detected on chest X-rays. In this study, we analyzed the incidence, characteristics, risk factors, and prognosis of asymptomatic PSP detected during regular medical check-ups in university students., Methods: In this study, 101,709 chest X-rays were performed during medical check-ups for students at the University of Tokyo between April 2011 and March 2016. Among them, 43 cases of asymptomatic PSP (0.042%) were detected. We calculated the lung collapse rate of pneumothorax using Kircher's method. We also analyzed risk factors associated with asymptomatic PSP using characteristics inspected in medical check-ups., Results: The incidence of asymptomatic PSP was significantly higher in men than in women (0.050% vs 0.018%). Multivariate analysis revealed an association of younger age, greater height, lower body mass index, and greater height growth per year with an increased risk of asymptomatic PSP in male students. Mild lung collapse (<10%) was present in 22 of 43 students with asymptomatic PSP; among these, eight students eventually underwent an invasive therapy., Conclusions: The prevalence of asymptomatic PSP among university students was as high as 0.042%. In addition to known risk factors for conventional PSP, greater height growth was a risk factor for asymptomatic PSP. Careful follow-up is very important because a considerable number of patients with mild lung collapse eventually require an invasive medical procedure.

Background: The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy., Methods: We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis., Results: Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885-1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464-1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91-1.84)., Conclusions: There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue.