270 results on '"Tohru Sakamoto"'
Search Results
2. A solitary rod‐shaped intertrabecular metastasis in the femur
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Mako Yokoyama, Toshihide Inui, Tomohiro Namiki, Hiroaki Ishikawa, Hiroko Watanabe, Yuichi Dai, and Tohru Sakamoto
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adenocarcinoma ,femur ,intertrabecular metastasis ,lung cancer ,Diseases of the respiratory system ,RC705-779 - Abstract
Key message Intertrabecular metastasis (ITM) is a type of bone metastasis characterized by tumour growth without significant trabecular changes. ITM is most commonly found in vertebral bodies, and rarely in long bones. We report a solitary rod‐shaped ITM of lung adenocarcinoma in the femur.
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- 2024
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3. Expression quantitative trait loci for ETV4 and MEOX1 are associated with adult asthma in Japanese populations
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Yohei Yatagai, Hisayuki Oshima, Tohru Sakamoto, Rie Shigemasa, Haruna Kitazawa, Kentaro Hyodo, Hironori Masuko, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Tomomitsu Hirota, Mayumi Tamari, and Nobuyuki Hizawa
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Medicine ,Science - Abstract
Abstract ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E−5 and 2.77E−5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E−7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6.
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- 2021
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4. The Macklin effect in tension pneumomediastinum in a patient with interstitial pneumonia
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Hiroko Watanabe, Hiroaki Ishikawa, Toshihide Inui, Kai Kawashima, Tomohiro Namiki, and Tohru Sakamoto
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interstitial pneumonia ,Macklin effect ,pneumomediastinum ,Diseases of the respiratory system ,RC705-779 - Abstract
Key message Tension pneumomediastinum is a rare complication of interstitial pneumonia. This case shows computed tomography findings of the Macklin effect, in which air dissection along the bronchovascular interstitium caused by alveolar rupture leads to pneumomediastinum.
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- 2022
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5. ORMDL3/GSDMB genotype is associated with distinct phenotypes of adult asthma
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Haruna Kitazawa, Hironori Masuko, Jun Kanazawa, Rie Shigemasa, Kentaro Hyodo, Hideyasu Yamada, Yohei Yatagai, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Tomomitsu Hirota, Mayumi Tamari, Tohru Sakamoto, and Nobuyuki Hizawa
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2021
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6. ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization
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Haruna Kitazawa, Hironori Masuko, Jun Kanazawa, Rie Shigemasa, Kentaro Hyodo, Hideyasu Yamada, Yohei Yatagai, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Tomomitsu Hirota, Mayumi Tamari, Tohru Sakamoto, and Nobuyuki Hizawa
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Asthma phenotype ,Early-onset asthma ,Genetics ,Immunoglobulin E (IgE) ,ORMDL3/GSDMB ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. Methods: We conducted a case–control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. Results: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p 0.1). Conclusions: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.
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- 2021
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7. A longitudinal comparison of college student mental health under the COVID-19 self-restraint policy in Japan
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Yuki Shiratori, Takafumi Ogawa, Miho Ota, Noriko Sodeyama, Tohru Sakamoto, Tetsuaki Arai, and Hirokazu Tachikawa
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COVID-19 ,Depression ,University students ,Sleep disturbances ,Morphological analysis ,Mental healing ,RZ400-408 - Abstract
Background: The coronavirus-19 (COVID-19) pandemic has resulted in substantial mental health problems. In addition to the fear of infection, prevention policies that result in isolation such as lockdowns or, in Japan, “self-restraint,” are associated with psychological symptoms. University students are vulnerable to emotional disorders because of the psychological challenges associated with the transition to adulthood. Therefore, we investigated changes in the mental health of university students before and during the COVID-19 pandemic. Methods: We used data from depression screening conducted by the University of Tsukuba, Japan, during student health examinations. Students completed the Patient Health Questionnaire-9 (PHQ-9) and an open-ended question on stress self-coping. Results: In 2020, 9.6% of students were depressed, approximately twice as many as in previous years. The paired samples Wilcoxon test showed that PHQ-9 scores were significantly higher in 2020 than in 2019; the largest effect size was for sleep difficulties. Analysis of the open-ended responses for stress coping strategies showed that physical activity and online communication were most frequently used. Limitations: The 2020 survey was web-based, whereas the surveys in previous years were completed in person. Only approximately one-sixth of participants answered the open-ended question. Conclusions: The percentage of students with mental health problems has doubled, and more attention to student mental health is needed. However, many students seem to be using appropriate coping measures. Education about best practices and raising awareness about establishing and maintaining sleep–wake rhythms may be useful.
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- 2022
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8. Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD).
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Kentaro Hyodo, Hironori Masuko, Hisayuki Oshima, Rie Shigemasa, Haruna Kitazawa, Jun Kanazawa, Hiroaki Iijima, Hiroichi Ishikawa, Takahide Kodama, Akihiro Nomura, Katsunori Kagohashi, Hiroaki Satoh, Takefumi Saito, Tohru Sakamoto, and Nobuyuki Hizawa
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Medicine ,Science - Abstract
Background and objectivesChronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and to specifically investigate the role of the IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes.MethodsThe study population comprised patients with asthma (n = 117), asthma-COPD overlap (ACO; n = 37) or COPD (n = 48) and a history of exacerbation within the previous year. Cluster analyses were performed using factors associated with both asthma and COPD exacerbation. The association of the IL4RA gene polymorphism rs8832 with each exacerbation-prone phenotype was evaluated by multinomial logistic analyses using non-asthma non-COPD healthy adults as controls (n = 1,529). In addition, the genetic influence of rs8832 was also examined in asthma patients with allergic rhinitis and no history of exacerbation (n = 130).ResultsTwo-step cluster analyses identified five clusters that did not necessarily correspond to the diagnostic disease labels. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total immunoglobulin E levels. A significant association with rs8832 was observed for cluster 5 (odds ratio, 3.88 (1.34-11.26), p = 0.013) and also for the type 2 exacerbation-prone phenotypes (clusters 1 and 5: odds ratio, 2.73 (1.45-5.15), p = 1.9 × 10-3).DiscussionOur results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases.
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- 2022
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9. A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts
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Jun Kanazawa, Haruna Kitazawa, Hironori Masuko, Yohei Yatagai, Tohru Sakamoto, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Masaharu Nishimura, Tomomitsu Hirota, Mayumi Tamari, and Nobuyuki Hizawa
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Chitinase 3-like 1 (CHI3L1) ,YKL-40 ,Expression quantitative trait loci (eQTLs) ,Asthma ,Genetics ,Late-onset adult asthma ,Internal medicine ,RC31-1245 ,QH426-470 - Abstract
Abstract Background The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. Methods This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. Results In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07–1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03–1.61; P = 0.027). Conclusions The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.
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- 2019
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10. Association analyses of eQTLs of the TYRO3 gene and allergic diseases in Japanese populations
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Jun Kanazawa, Hironori Masuko, Yohei Yatagai, Tohru Sakamoto, Hideyasu Yamada, Haruna Kitazawa, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Tomomitsu Hirota, Mayumi Tamari, and Nobuyuki Hizawa
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. Methods: We performed a candidate gene case–control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. Results: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene–gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. Conclusions: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese. Keywords: Allergic rhinitis, Asthma, Atopy, eQTL, TYRO3
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- 2019
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11. Dust mite-dominant sensitization pattern as a causal factor for adult-onset asthma
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Rie Shigemasa, Hironori Masuko, Hisayuki Oshima, Kentaro Hyodo, Haruna Kitazawa, Jun Kanazawa, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Tohru Sakamoto, and Nobuyuki Hizawa
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2021
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12. Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations
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Jun Kanazawa, Hironori Masuko, Yohei Yatagai, Tohru Sakamoto, Hideyasu Yamada, Yoshiko Kaneko, Haruna Kitazawa, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Masaharu Nishimura, Tomomitsu Hirota, Mayumi Tamari, and Nobuyuki Hizawa
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Asthma phenotype ,Cadherin-related family member 3 (CDHR3) ,Early-onset asthma ,Genetics ,Human rhinovirus C ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Recent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma. Methods: We performed a candidate gene case–control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined. Results: The A allele was associated with asthma (OR = 1.56; Mantel–Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function. Conclusions: Our study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma.
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- 2017
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13. Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung
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Aoi Kuroda, Ahmed E. Hegab, Gao Jingtao, Shuji Yamashita, Nobuyuki Hizawa, Tohru Sakamoto, Hideyasu Yamada, Satoshi Suzuki, Makoto Ishii, Ho Namkoong, Takanori Asakura, Mari Ozaki, Hiroyuki Yasuda, Junko Hamamoto, Shizuko Kagawa, Kenzo Soejima, and Tomoko Betsuyaku
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ALDH2 ,Aldehyde ,Epithelial cell ,Basal cell ,Club cell ,Trachea ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer’s diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. Methods We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 −/− mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 −/− mice. Results In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 −/− and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 −/− mice. Aldh2 −/− tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 −/− mice than in WT mice. Conclusions ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a “premature lung aging” effect.
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- 2017
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14. How important is allergic sensitization as a cause of atopic asthma?
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Jun Kanazawa, Hironori Masuko, Hideyasu Yamada, Yohei Yatagai, Tohru Sakamoto, Haruna Kitazawa, Hiroaki Iijima, Takashi Naito, Tomomitsu Hirota, Mayumi Tamari, and Nobuyuki Hizawa
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2018
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15. A Distinct Sensitization Pattern Associated with Asthma and the Thymic Stromal Lymphopoietin (TSLP) Genotype
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Hiroaki Iijima, Yoshiko Kaneko, Hideyasu Yamada, Yohei Yatagai, Hironori Masuko, Tohru Sakamoto, Takashi Naito, Tomomitsu Hirota, Mayumi Tamari, Satoshi Konno, Masaharu Nishimura, Emiko Noguchi, and Nobuyuki Hizawa
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cluster analysis ,immunoglobulin E (IgE) ,sensitization pattern ,smoking habit ,TSLP ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Atopy is a phenotypically heterogeneous condition, and the extent to which atopy accounts for asthma is controversial. In this study, we aimed to identify the presence of distinct sensitization patterns to common inhaled allergens and their association with asthma, allergic rhinitis and TSLP genotypes. Methods: We studied 1683 adults from Tsukuba, a city in central Japan and 297 adults from Kamishihoro, a cedar-free, birch-dominant town in northern Japan. Levels of total serum IgE and specific IgE antibodies towards 14 major inhaled allergens were measured. With the use of these measures, cluster analysis was applied to classify the subjects' sensitization patterns. We also examined the genetic effects of 2 TSLP functional SNPs on the development of each sensitization pattern. Results: In the Tsukuba study, cluster analysis identified four clusters, including "Dust mite dominant", "Multiple pollen", "Cedar dominant", and "Low reactivity". In the Kamishihoro study, "Dust mite dominant", "Multiple pollen" and "Low reactivity" clusters were also identified, but a "Cedar dominant" cluster was not formed. The association with asthma was strongest for the "Dust mite dominant" cluster in both the Tsukuba and the Kamishihoro studies. In never smokers, both SNPs were associated with the "Dust mite dominant" cluster (OR > 1.2). In contrast, in current or past smokers, these alleles were inversely associated with the "Multiple pollen" cluster (OR
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- 2013
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16. Asthma Phenotypes in Japanese Adults - Their Associations with the CCL5 ADRB2 Genotypes
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Yoshiko Kaneko, Hironori Masuko, Tohru Sakamoto, Hiroaki Iijima, Takashi Naito, Yohei Yatagai, Hideyasu Yamada, Satoshi Konno, Masaharu Nishimura, Emiko Noguchi, and Nobuyuki Hizawa
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ADRB2 ,age at onset ,asthma phenotype ,CCL5 ,lung function ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Cluster analyses were previously performed to identify asthma phenotypes underlying asthma syndrome. Although a large number of patients with asthma develop the disease later in life, these previous cluster analyses focused mainly patients with younger-onset asthma. Methods: Cluster analysis examined the existence of distinct phenotypes of late-onset asthma in Japanese patients with adult asthma. We then associated genotypes at the CCL5, TSLP, IL4, and ADRB2 genes with the clusters of asthma identified. Results: Using the 8 variables of age, sex, age at onset of the disease, smoking status, total serum IgE, %FEV1, FEV1/FVC, and specific IgE responsiveness to common inhaled allergens, two-step cluster analysis of 880 Japanese adult asthma patients identified 6 phenotypes: cluster A (n = 155): older age at onset, no airflow obstruction; cluster B (n = 170): childhood onset, normal-to-mild airflow obstruction; cluster C (n = 119): childhood onset, the longest disease duration, and moderate-to-severe airflow obstruction; cluster D (n = 108): older age at onset, severe airflow obstruction; cluster E (n = 130): middle-age at onset, no airflow obstruction; and cluster F (n = 198): older age at onset, mild-to-moderate airflow obstruction. The CCL5-28C>G genotype was significantly associated with clusters A, B and D (OR 1.65, p = 0.0021; 1.67, 0.018; and 1.74, 0.011, respectively). The ADRB2 Arg16Gly genotype was also associated with clusters B and D (OR 0.47, p = 0.0004; and 0.63, 0.034, respectively). Conclusions: The current cluster analysis identified meaningful adult asthma phenotypes linked to the functional CCL5 and ADRB2 genotypes. Genetic and phenotypic data have the potential to elucidate the pheno- typic heterogeneity and pathophysiology of asthma.
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- 2013
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17. Role of Lung Function Genes in the Development of Asthma.
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Hideyasu Yamada, Hironori Masuko, Yohei Yatagai, Tohru Sakamoto, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Emiko Noguchi, Satoshi Konno, Masaharu Nishimura, Tomomitsu Hirota, Mayumi Tamari, and Nobuyuki Hizawa
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Medicine ,Science - Abstract
Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 × 10(-4)) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.
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- 2016
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18. Lower FEV1 in non-COPD, nonasthmatic subjects: association with smoking, annual decline in FEV1, total IgE levels, and TSLP genotypes
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Hironori Masuko, Tohru Sakamoto, Shiko Kaneko, and et al
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Diseases of the respiratory system ,RC705-779 - Abstract
Hironori Masuko1, Tohru Sakamoto1, Yoshiko Kaneko1, Hiroaki Iijima2, Takashi Naito2, Emiko Noguchi3, Tomomitsu Hirota4, Mayumi Tamari4, Nobuyuki Hizawa11Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan; 2Tsukuba Medical Center, Ibaraki, Japan; 3Department of Medical Genetics, Majors of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; 4Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, JapanAbstract: Few studies have investigated the significance of decreased FEV1 in non-COPD, nonasthmatic healthy subjects. We hypothesized that a lower FEV1 in these subjects is a potential marker of an increased susceptibility to obstructive lung disease such as asthma and COPD. This was a cross-sectional analysis of 1505 Japanese adults. We divided the population of healthy adults with no respiratory diseases whose FEV1/FVC ratio was ≥70% (n = 1369) into 2 groups according to their prebronchodilator FEV1 (% predicted) measurements:
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- 2011
19. Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population.
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Yohei Yatagai, Tohru Sakamoto, Hironori Masuko, Yoshiko Kaneko, Hideyasu Yamada, Hiroaki Iijima, Takashi Naito, Emiko Noguchi, Tomomitsu Hirota, Mayumi Tamari, Yoshimasa Imoto, Takahiro Tokunaga, Shigeharu Fujieda, Satoshi Konno, Masaharu Nishimura, and Nobuyuki Hizawa
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Medicine ,Science - Abstract
Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10(-10)). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.
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- 2013
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20. Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis: case-control studies.
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Tomomitsu Hirota, Hidehisa Saeki, Kaori Tomita, Shota Tanaka, Kouji Ebe, Masafumi Sakashita, Takechiyo Yamada, Shigeharu Fujieda, Akihiko Miyatake, Satoru Doi, Tadao Enomoto, Nobuyuki Hizawa, Tohru Sakamoto, Hironori Masuko, Takashi Sasaki, Tamotsu Ebihara, Masayuki Amagai, Hitokazu Esaki, Satoshi Takeuchi, Masutaka Furue, Emiko Noguchi, Naoyuki Kamatani, Yusuke Nakamura, Michiaki Kubo, and Mayumi Tamari
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Medicine ,Science - Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1(st) population, 916 cases and 1,032 controls; 2(nd) population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10⁻⁶; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.
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- 2011
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21. The Opposite Effect of the CCL5 Gene on Asthma and Baseline FEV1 in Nonasthmatic Healthy Adults
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Yoshiko Kaneko, Hironori Masuko, Tohru Sakamoto, Hiroaki Iijima, Takashi Naito, and Nobuyuki Hizawa
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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22. Investigation of age and smoking in NSCLC patients with uncommon EGFR mutations.
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Yosuke MAEZAWA, Manato TAGUCHI, Takeshi KAWAKAMI, Toshihide INUI, Shinichiro OKAUCHI, Takeshi NUMATA, Toshihiro SHIOZAWA, Kunihiko MIYAZAKI, Ryota NAKAMURA, Kesato IGUCHI, Takeo ENDO, Tohru SAKAMOTO, Hiroaki SATOH, and Nobuyuki HIZAWA
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- 2024
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23. Data from Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer
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Masayuki Yamamoto, Ken Itoh, Nobuyuki Hizawa, Tohru Sakamoto, Hiroaki Satoh, Norihiro Kikuchi, Norihiro Haraguchi, Yosuke Matsuno, Tadahiro Yamadori, Yuko Morishima, Yukio Ishii, and Shinsuke Homma
- Abstract
Purpose: NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated.Experimental Design: We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions.Result: A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G1 phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells.Conclusion: These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs.
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- 2023
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24. Supplementary Table 1 from Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer
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Masayuki Yamamoto, Ken Itoh, Nobuyuki Hizawa, Tohru Sakamoto, Hiroaki Satoh, Norihiro Kikuchi, Norihiro Haraguchi, Yosuke Matsuno, Tadahiro Yamadori, Yuko Morishima, Yukio Ishii, and Shinsuke Homma
- Abstract
PDF file, 23K, Primers used in RT-PCR.
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- 2023
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25. Early chronic obstructive pulmonary disease: Associations of two spirometry criteria with clinical features
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Fumi Mochizuki, Naoya Tanabe, Hiroaki Iijima, Takafumi Shimada, Yusuke Shiraishi, Tomoki Maetani, Hajime Yamazaki, Kaoruko Shimizu, Masaru Suzuki, Shotaro Chubachi, Hiroichi Ishikawa, Takashi Naito, Hironori Masuko, Tohru Sakamoto, Izuru Masuda, Susumu Sato, Nobuyuki Hizawa, and Toyohiro Hirai
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Pulmonary and Respiratory Medicine ,Pulmonary Disease, Chronic Obstructive ,Spirometry ,Forced Expiratory Volume ,Vital Capacity ,Humans ,Retrospective Studies - Abstract
Two spirometry criteria have been proposed for early chronic obstructive pulmonary disease (COPD) in young smokers: 1) forced expiratory volume in 1 s (FEVThis retrospective study analysed medical check-up data from 13,010 consecutive subjects aged50 years who underwent current and 3 previous spirometry tests in Japan. Current ≥10 pack-year smokers were the main focus of analysis; those meeting one or more spirometry criteria were diagnosed with early COPD. Early COPD was categorized into three subtypes: FEVOf the 1579 current ≥ 10 pack-year smokers, 488 (30.9%) met the early COPD criteria. Multivariate multinomial logistic models adjusted for age, sex, height, body mass index (BMI) and smoking history indicated that past BMI increase and low exercise were associated with higher type 2 early COPD incidence (odds ratio (OR) [95% confidence interval (CI)] = 4.30 [3.10, 6.04], and 0.80 [0.69, 0.93], respectively) but not with higher type 1 incidence. A history of asthma was associated with higher type 3 incidence (OR [95% CI] = 1.98 [1.18, 3.07]).The 3 types of spirometry-based early COPD have different clinical factors. Their trajectories should be explored in longitudinal studies.
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- 2022
26. ORMDL3/GSDMB genotype is associated with distinct phenotypes of adult asthma
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Takashi Naito, Takefumi Saito, Yoshiko Kaneko, Hiroaki Iijima, Hironori Masuko, Kentaro Hyodo, Mayumi Tamari, Emiko Noguchi, Tomomitsu Hirota, Rie Shigemasa, Nobuyuki Hizawa, Haruna Kitazawa, Hideyasu Yamada, Jun Kanazawa, Tohru Sakamoto, Yohei Yatagai, and Satoshi Konno
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Pore Forming Cytotoxic Proteins ,Genetics ,Genotype ,business.industry ,MEDLINE ,Membrane Proteins ,General Medicine ,RC581-607 ,medicine.disease ,Polymorphism, Single Nucleotide ,Phenotype ,Asthma ,Text mining ,Humans ,Immunology and Allergy ,Medicine ,Genetic Predisposition to Disease ,Immunologic diseases. Allergy ,business ,Alleles ,Genetic Association Studies - Published
- 2021
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27. Effects of Lung Function-Related Genes and TSLP on COPD Phenotypes
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Tohru Sakamoto, Nobuyuki Hizawa, Norihito Hida, Hironori Masuko, and Hideyasu Yamada
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Pulmonary and Respiratory Medicine ,COPD ,business.industry ,fungi ,Single-nucleotide polymorphism ,Eosinophil ,respiratory system ,medicine.disease ,Phenotype ,respiratory tract diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Immunology ,Medicine ,030212 general & internal medicine ,Genetic risk ,business ,Gene ,Lung function ,Asthma - Abstract
A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (N = 270) underwent lung function testing followed by genotyping with allele-specific arrays for 16 SNPs as well as expression quantitative trait loci at TSLP (rs2289276, rs3806933). Lung function GRS scoring and two-step cluster analyses grouped patients into different COPD phenotypes based on gender, age, smoking index, %FEV1 and lung function GRS. The genetic effect of TSLP on COPD phenotypes was also examined for interactions with the lung function GRS. A total of 270 participants were grouped into 5 clusters. The cluster with the highest levels of lung function GRS was characterized by moderate to severe airflow obstruction and the highest blood eosinophil counts. Regarding TSLP, an increased number of T alleles at both SNPs was found in the cluster characterized by moderate to severe airflow obstruction and heavy smoking (rs2289276, p value = 0.035; rs3806933, p value = 0.047) independent of the lung function GRS. A genetic susceptibility to impaired lung function carries an increased risk of developing COPD characterized by increased eosinophil counts and severe airflow obstruction while individuals with increased TSLP responses to external stimuli have an independent risk of developing severe airflow obstruction in the presence of heavy smoking.
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- 2020
28. A longitudinal comparison of college student mental health under the COVID-19 self-restraint policy in Japan
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Yuki Shiratori, Takafumi Ogawa, Miho Ota, Noriko Sodeyama, Tohru Sakamoto, Tetsuaki Arai, and Hirokazu Tachikawa
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Morphological analysis ,Depression ,COVID-19 ,Sleep disturbances ,RZ400-408 ,Mental healing ,University students - Abstract
Background: The coronavirus-19 (COVID-19) pandemic has resulted in substantial mental health problems. In addition to the fear of infection, prevention policies that result in isolation such as lockdowns or, in Japan, “self-restraint,” are associated with psychological symptoms. University students are vulnerable to emotional disorders because of the psychological challenges associated with the transition to adulthood. Therefore, we investigated changes in the mental health of university students before and during the COVID-19 pandemic. Methods: We used data from depression screening conducted by the University of Tsukuba, Japan, during student health examinations. Students completed the Patient Health Questionnaire-9 (PHQ-9) and an open-ended question on stress self-coping. Results: In 2020, 9.6% of students were depressed, approximately twice as many as in previous years. The paired samples Wilcoxon test showed that PHQ-9 scores were significantly higher in 2020 than in 2019; the largest effect size was for sleep difficulties. Analysis of the open-ended responses for stress coping strategies showed that physical activity and online communication were most frequently used. Limitations: The 2020 survey was web-based, whereas the surveys in previous years were completed in person. Only approximately one-sixth of participants answered the open-ended question. Conclusions: The percentage of students with mental health problems has doubled, and more attention to student mental health is needed. However, many students seem to be using appropriate coping measures. Education about best practices and raising awareness about establishing and maintaining sleep–wake rhythms may be useful.
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- 2021
29. Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD)
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Kentaro Hyodo, Hironori Masuko, Hisayuki Oshima, Rie Shigemasa, Haruna Kitazawa, Jun Kanazawa, Hiroaki Iijima, Hiroichi Ishikawa, Takahide Kodama, Akihiro Nomura, Katsunori Kagohashi, Hiroaki Satoh, Takefumi Saito, Tohru Sakamoto, and Nobuyuki Hizawa
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Pulmonary Disease, Chronic Obstructive ,Multidisciplinary ,Phenotype ,Chronic Disease ,Humans ,Female ,Rhinitis, Allergic ,Asthma - Abstract
Background and objectives Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and to specifically investigate the role of the IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes. Methods The study population comprised patients with asthma (n = 117), asthma-COPD overlap (ACO; n = 37) or COPD (n = 48) and a history of exacerbation within the previous year. Cluster analyses were performed using factors associated with both asthma and COPD exacerbation. The association of the IL4RA gene polymorphism rs8832 with each exacerbation-prone phenotype was evaluated by multinomial logistic analyses using non-asthma non-COPD healthy adults as controls (n = 1,529). In addition, the genetic influence of rs8832 was also examined in asthma patients with allergic rhinitis and no history of exacerbation (n = 130). Results Two-step cluster analyses identified five clusters that did not necessarily correspond to the diagnostic disease labels. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total immunoglobulin E levels. A significant association with rs8832 was observed for cluster 5 (odds ratio, 3.88 (1.34–11.26), p = 0.013) and also for the type 2 exacerbation-prone phenotypes (clusters 1 and 5: odds ratio, 2.73 (1.45–5.15), p = 1.9 × 10−3). Discussion Our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases.
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- 2021
30. The Concavity of the Maximal Expiratory Flow–Volume Curve Reflects the Extent of Emphysema in Obstructive Lung Diseases
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Shigeo Muro, Susumu Sato, Hiroaki Iijima, Nobuyuki Hizawa, Hironori Masuko, Naoya Tanabe, Keiji Fujiwara, Masanari Shiigai, Hiroichi Ishikawa, Azusa Watanabe, Tohru Sakamoto, Yohei Yatagai, Jun Kanazawa, Fumi Mochizuki, and Takafumi Shimada
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Spirometry ,Male ,medicine.medical_specialty ,Vital capacity ,lcsh:Medicine ,Sensitivity and Specificity ,Severity of Illness Index ,Article ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Internal medicine ,Severity of illness ,medicine ,Humans ,030212 general & internal medicine ,lcsh:Science ,Lung ,Asthma ,Aged ,Maximal Expiratory Flow-Volume Curves ,COPD ,Multidisciplinary ,medicine.diagnostic_test ,business.industry ,Chronic obstructive pulmonary disease ,lcsh:R ,Volume Curve ,Middle Aged ,medicine.disease ,MEFV ,Respiratory Function Tests ,respiratory tract diseases ,medicine.anatomical_structure ,030228 respiratory system ,Pulmonary Emphysema ,Cardiology ,Female ,lcsh:Q ,business ,Tomography, X-Ray Computed - Abstract
A concave-shaped maximal expiratory flow-volume (MEFV) curve is a spirometric feature in chronic obstructive pulmonary disease (COPD). The MEFV curve is characterized by an increase in the Obstructive Index, which is defined as a ratio of forced vital capacity to the volume-difference between two points of half of the peak expiratory flow on the MEFV curve. We hypothesized that the Obstructive Index would reflect the severity of emphysema in patients with COPD and asthma-COPD overlap (ACO). Thus, the aim of this retrospective study was to evaluate whether the Obstructive Index on spirometry is associated with the extent of emphysema on computed tomography (CT) in patients with COPD, ACO, and asthma (N = 65, 15, and 53, respectively). The percentage of low-attenuation volume (LAV%) and wall area (WA%) were measured on CT. The Obstructive Index was higher in patients with COPD and ACO than in those with asthma. Spearman correlation showed that a greater Obstructive Index was associated with a higher LAV%, but not WA%. Multivariate analysis showed that Obstructive Index was associated with LAV% (standardized β = 0.43, P
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- 2019
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31. Small-Cell Lung Cancer Treatment of Newly Diagnosed Patients with Poor Performance Status
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Tohru Sakamoto, Yuka Aida, Kensuke Nakazawa, Yuko Morishima, Nobuyuki Hizawa, Takumi Kiwamoto, Ikuo Sekine, Ryoko Ogawa, and Toshihiro Shiozawa
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Case Report ,Neutropenia ,Gastroenterology ,lcsh:RC254-282 ,Small-cell lung cancer ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Chemotherapy ,Poor performance status ,Lung cancer ,Survival rate ,Platinum ,Response rate (survey) ,business.industry ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,business ,Febrile neutropenia ,Supportive care - Abstract
Small-cell lung cancer (SCLC) is highly sensitive to platinum-based chemotherapy. However, its indication in patients with a poor performance status (PS) at initial diagnosis is controversial. We retrospectively reviewed all clinical courses of pathologically diagnosed SCLC patients with poor PS, Eastern Cooperative Oncology Group PS 3 and 4. Among 18 patients, 12 were treated with chemotherapy and 6 with supportive care alone. During the chemotherapy courses, PS improved in 7 (58.3%, including the PS 4 cases), remained stable in 2 (16.7%), and deteriorated in 3 (25%) patients. Moreover, 5 patients showed partial responses to chemotherapy (response rate of 41.7%). Grade 3-4 neutropenia developed in 10 (83.3%) patients and grade 3 febrile neutropenia occurred in 5 (41.7%) patients, but no grade 4 non-hematological toxicity was noted. Mortality associated with lung toxicity (grade 5) due to treatment occurred in a 77-year-old-male patient with PS 3. No substantial difference in survival was observed between patients with PS 3 and 4, even when including those treated with supportive care alone. Treatment had a positive effect on survival: after chemotherapy, the 6-month survival rate of PS 3 and 4 patients was 66.7%. In contrast, all patients treated with supportive care alone died within 5 months. These findings suggest that chemotherapy is indicated in selected SCLC patients not only with PS 3, but also with PS 4. (C) 2019 The Author(s) Published by S. Karger AG, Basel
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- 2019
32. Expression quantitative trait loci for ETV4 and MEOX1 are associated with adult asthma in Japanese populations
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Hisayuki Oshima, Mayumi Tamari, Haruna Kitazawa, Rie Shigemasa, Hironori Masuko, Takefumi Saito, Kentaro Hyodo, Tomomitsu Hirota, Takashi Naito, Hiroaki Iijima, Nobuyuki Hizawa, Tohru Sakamoto, and Yohei Yatagai
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Adult ,Male ,Science ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Pathogenesis ,Young Adult ,Japan ,immune system diseases ,Gene expression ,medicine ,Humans ,Genetic Predisposition to Disease ,Transcription factor ,Asthma ,Genetic association ,Aged ,Aged, 80 and over ,Homeodomain Proteins ,Multidisciplinary ,Proto-Oncogene Proteins c-ets ,Haplotype ,Middle Aged ,medicine.disease ,respiratory tract diseases ,Case-Control Studies ,Immunology ,Expression quantitative trait loci ,Medicine ,Female ,Transcription Factors - Abstract
ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E−5 and 2.77E−5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E−7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6.
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- 2021
33. Dust mite-dominant sensitization pattern as a causal factor for adult-onset asthma
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Hisayuki Oshima, Tohru Sakamoto, Rie Shigemasa, Hironori Masuko, Kentaro Hyodo, Nobuyuki Hizawa, Haruna Kitazawa, Takashi Naito, Takefumi Saito, Jun Kanazawa, and Hiroaki Iijima
- Subjects
Adult ,biology ,business.industry ,Pyroglyphidae ,General Medicine ,RC581-607 ,Allergens ,biology.organism_classification ,Asthma ,medicine.anatomical_structure ,Adult onset asthma ,Immunology ,Mite ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Immunization ,Disease Susceptibility ,Immunologic diseases. Allergy ,business ,Sensitization - Published
- 2020
34. ORMDL3/GSDMB Genotype as a Risk Factor for Early-Onset Adult Asthma Is Linked to Total Serum IgE Levels but Not to Atopy
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Jun Kanazawa, Tohru Sakamoto, Rie Shigemasa, Yohei Yatagai, T. Saito, Hironori Masuko, Kentaro Hyodo, Satoshi Konno, Hiroaki Iijima, Nobuyuki Hizawa, Hideyasu Yamada, Takashi Naito, Tomomitsu Hirota, Haruna Kitazawa, and Mayumi Tamari
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Atopy ,business.industry ,Genotype ,Immunology ,Medicine ,Risk factor ,business ,medicine.disease ,Serum ige ,Early onset ,Asthma - Published
- 2020
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35. Exacerbation Clusters Demonstrate Asthma and Chronic Obstructive Pulmonary Disease Overlap with Distinct Phenotypes
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Jun Kanazawa, Hisayuki Oshima, Tohru Sakamoto, A. Nomura, H. Sato, Rie Shigemasa, Katsunori Kagohashi, T. Kodama, T. Saito, Hiroaki Iijima, Haruna Kitazawa, Nobuyuki Hizawa, Hironori Masuko, and Kentaro Hyodo
- Subjects
Exacerbation ,business.industry ,Immunology ,medicine ,Pulmonary disease ,medicine.disease ,business ,Phenotype ,Asthma - Published
- 2020
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36. Genetic impact of CDHR3 on the adult onset of asthma and COPD
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Takashi Naito, Nobuyuki Hizawa, Takefumi Saito, Rie Shigemasa, Mayumi Tamari, Hiroaki Iijima, Jun Kanazawa, Tohru Sakamoto, Tomomitsu Hirota, Hironori Masuko, Kentaro Hyodo, Yohei Yatagai, and Haruna Kitazawa
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Vital capacity ,Immunology ,Cadherin Related Proteins ,Polymorphism, Single Nucleotide ,Risk Assessment ,Atopy ,03 medical and health sciences ,FEV1/FVC ratio ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Japan ,Risk Factors ,Internal medicine ,medicine ,Enterovirus Infections ,Immunology and Allergy ,Humans ,Genetic Predisposition to Disease ,Longitudinal Studies ,Risk factor ,Age of Onset ,Genetic Association Studies ,Asthma ,Aged ,Enterovirus ,Retrospective Studies ,Aged, 80 and over ,COPD ,business.industry ,Membrane Proteins ,Middle Aged ,medicine.disease ,Cadherins ,respiratory tract diseases ,030104 developmental biology ,Phenotype ,030228 respiratory system ,Female ,business ,Body mass index ,Cohort study - Abstract
Background Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases caused by complex gene-environment interactions. A functional single nucleotide polymorphism of cadherin-related family member 3 (CDHR3), known as a receptor of rhinovirus-C, is associated with childhood-onset asthma especially in atopic individuals. Objective Here, we identified risk factors for adult-onset asthma and COPD, focusing on the impact of the CDHR3 variant in atopic individuals. Methods We conducted a longitudinal, retrospective, observational cohort study of 1523 healthy adults with baseline examinations at Tsukuba Medical Center Hospital in 2008 and retrospectively identified new-onset, physician-diagnosed asthma or COPD from 2009 to 2018. We assessed risk factors by the Cox regression analysis. The impact of CDHR3 variant rs6967330 was also examined in individuals with pre-existing atopy. Results Over 10 study years, 103 people developed airway diseases (79 asthma and 24 COPD; 52 females, average onset-age 55 years old, range 38-80). Higher body mass index (BMI) and lower forced expiratory volume in one second/forced vital capacity (FEV1 /FVC) ratio were significant risk factors (BMI: HR 1.072 [95% CI 1.005-1.14], P = .034; FEV1 /FVC ratio: HR 1.091 [1.044-1.14], P = .00011). Restriction to atopic individuals saw the A allele at rs6967330 and lower FEV1 /FVC ratio to associate with adult-onset disease (A allele: HR 2.89 [1.57-5.20], P = .00062; FEV1 /FVC ratio: HR 1.10 [1.04-1.17], P = .0010). Conclusion and clinical relevance Genetic susceptibility to rhinovirus-C infection in atopic individuals is a risk factor for chronic airway diseases even in later life.
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- 2020
37. ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization
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Hiroaki Iijima, Hideyasu Yamada, Tomomitsu Hirota, Mayumi Tamari, Yoshiko Kaneko, Rie Shigemasa, Takefumi Saito, Takashi Naito, Jun Kanazawa, Emiko Noguchi, Tohru Sakamoto, Nobuyuki Hizawa, Yohei Yatagai, Hironori Masuko, Kentaro Hyodo, Satoshi Konno, and Haruna Kitazawa
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Asthma phenotype ,lcsh:Immunologic diseases. Allergy ,Adult ,Genotype ,Locus (genetics) ,Immunoglobulin E ,Serum ige ,Allergic sensitization ,Genetics ,medicine ,Immunology and Allergy ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Child ,Alleles ,Early-onset asthma ,Asthma ,Early onset ,biology ,business.industry ,Membrane Proteins ,General Medicine ,Allergens ,ORMDL3/GSDMB ,medicine.disease ,Neoplasm Proteins ,Case-Control Studies ,Child, Preschool ,Expression quantitative trait loci ,Immunology ,biology.protein ,Immunization ,Immunoglobulin E (IgE) ,lcsh:RC581-607 ,business - Abstract
Background: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. Methods: We conducted a case–control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. Results: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p 0.1). Conclusions: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.
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- 2020
38. Effects of Lung Function-Related Genes and
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Hideyasu, Yamada, Norihito, Hida, Hironori, Masuko, Tohru, Sakamoto, and Nobuyuki, Hizawa
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Aged, 80 and over ,Male ,Genotype ,Vital Capacity ,Middle Aged ,Polymorphism, Single Nucleotide ,Severity of Illness Index ,Eosinophils ,Leukocyte Count ,Pulmonary Disease, Chronic Obstructive ,Phenotype ,Risk Factors ,Case-Control Studies ,Forced Expiratory Volume ,Cluster Analysis ,Cytokines ,Humans ,Female ,Genetic Predisposition to Disease ,Aged - Abstract
A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (
- Published
- 2020
39. A cis-eQTL Allele Lowering Gene Expression of CHL3L1 Is Associated with Late-Onset Adult Asthma in Japanese
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Jun Kanazawa, Takashi Naito, Emiko Noguchi, Tohru Sakamoto, Hironori Masuko, Rie Shigemasa, Kentaro Hyodo, Yohei Yatagai, Masaharu Nishimura, T. Saito, Yoshiko Kaneko, Nobuyuki Hizawa, Hiroaki Iijima, Mayumi Tamari, Haruna Kitazawa, Tomomitsu Hirota, and Satoshi Konno
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Expression quantitative trait loci ,Immunology ,Gene expression ,medicine ,Late onset ,Biology ,Allele ,medicine.disease ,Asthma - Published
- 2019
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40. Genetic Effects of ORMDL3/GSDMB on Asthma Are Modified by the GSDMC Genotype at Chromosome 8
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Takashi Naito, Hironori Masuko, Kentaro Hyodo, Mayumi Tamari, Haruna Kitazawa, Tomomitsu Hirota, Jun Kanazawa, T. Saito, Tohru Sakamoto, Hiroaki Iijima, Yohei Yatagai, Rie Shigemasa, and Nobuyuki Hizawa
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Genetics ,Chromosome (genetic algorithm) ,Genotype ,medicine ,Biology ,medicine.disease ,Asthma - Published
- 2019
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41. A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts
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Mayumi Tamari, Satoshi Konno, Emiko Noguchi, Yoshiko Kaneko, Haruna Kitazawa, Takashi Naito, Hiroaki Iijima, Jun Kanazawa, Hironori Masuko, Tohru Sakamoto, Yohei Yatagai, Tomomitsu Hirota, Takefumi Saito, Masaharu Nishimura, and Nobuyuki Hizawa
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Adult ,0301 basic medicine ,lcsh:Internal medicine ,Endotype ,YKL-40 ,lcsh:QH426-470 ,Quantitative Trait Loci ,Genome-wide association study ,Late onset ,030105 genetics & heredity ,Chitinase 3-like 1 (CHI3L1) ,CHI3L1 ,Cohort Studies ,Atopy ,03 medical and health sciences ,Japan ,Genetics ,Humans ,Medicine ,Chitinase-3-Like Protein 1 ,Age of Onset ,lcsh:RC31-1245 ,Expression quantitative trait loci (eQTLs) ,Alleles ,Genetics (clinical) ,Asthma ,business.industry ,Late-onset adult asthma ,Odds ratio ,medicine.disease ,respiratory tract diseases ,lcsh:Genetics ,Phenotype ,030104 developmental biology ,Case-Control Studies ,Immunology ,Cohort ,business ,Research Article ,Genome-Wide Association Study - Abstract
Background The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. Methods This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. Results In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07–1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03–1.61; P = 0.027). Conclusions The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.
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- 2019
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42. Genetics in Asthma
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Nobuyuki Hizawa and Tohru Sakamoto
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Genetics ,Candidate gene ,Genetic heterogeneity ,medicine ,Epistasis ,Epigenetics ,Heritability ,Gene–environment interaction ,Biology ,medicine.disease ,respiratory tract diseases ,Asthma ,Genetic association - Abstract
Asthma is a complex disease determined by the interaction between genetic and environmental factors. The heritability of asthma is estimated to be more than 50%. The search for genes with genomic variants associated with asthma has been greatly advanced by hypothesis-driven candidate gene association studies and hypothesis-free genome-wide association studies (GWASs). The genes identified by the hypothesis-driven approach are roughly classified into four types of functional group: (1) innate immunity and immunoregulation, (2) differentiation and regulation of T-helper 2 cells, (3) airway epithelial mucosal immunity, and (4) airway remodeling and lung function. Although the majority of the variants have been identified by the hypothesis-driven approach, novel genes and pathways associated with asthma have been successively clarified by GWASs. Nonetheless, these genomic variants explain only a small proportion of asthma heritability. This is partly due to the phenotypic heterogeneity of asthma, epistatic gene-gene interactions, gene-environment interactions, and epigenetic effects. Further elucidation of the causal variants can be achieved by GWASs that limit participants to those with distinct asthma phenotypes and by integrative applications of genome-wide epistatic and epigenetic approaches. Understanding of the genetic profiles of asthma pathogenesis contributes to individualized disease prevention as well as to development of new therapies.
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- 2018
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43. Basic Study on Automated Extraction of Symptom Related Words from Patient Complaints (Preprint)
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Misa Usui, Eiji Aramaki, Tomohide Iwao, Shoko Wakamiya, Tohru Sakamoto, and Mayumi Mochizuki
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BACKGROUND Although methods of obtaining knowledge from texts written by healthcare professionals such as electronic medical records and discharge summaries have been studied, there are few reports analyzing free-text data on patients’ complaints in Japanese. OBJECTIVE This study aimed to establish a new method for extracting keywords from patients’ free descriptions accumulated in Japanese medical institutions. METHODS We developed a system that automatically annotates free-text data with the codes of the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD10) using electronic medication history data (target period: September 1, 2015 to August 31, 2016). The performance of the system was evaluated through comparisons with data manually annotated by healthcare workers. RESULTS The number of ICD10 codes extracted from 5,000 patient statements by healthcare workers was 2,348, while the system extracted 2,236 codes. Of those cases, 1,480 matched. Compared with manual extraction, the performance of the system was 0.66 in terms of precision, 0.63 in recall, and 0.65 for the F-measure. CONCLUSIONS Our results suggested that the system was helpful for extracting and standardizing patient’s words related to symptoms from massive amounts of free-text data instead of manual work. After improving the extraction accuracy, we expect to utilize this system to detect the signals of adverse drug reactions from patients’ statements in the future.
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- 2018
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44. Association analyses of eQTLs of the TYRO3 gene and allergic diseases in Japanese populations
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Tohru Sakamoto, Yohei Yatagai, Haruna Kitazawa, Takefumi Saito, Tomomitsu Hirota, Hiroaki Iijima, Mayumi Tamari, Hideyasu Yamada, Hironori Masuko, Nobuyuki Hizawa, Jun Kanazawa, Emiko Noguchi, and Takashi Naito
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lcsh:Immunologic diseases. Allergy ,Adult ,Male ,Candidate gene ,Adolescent ,Genotype ,Quantitative Trait Loci ,Genome-wide association study ,Polymorphism, Single Nucleotide ,Allergic sensitization ,Atopy ,Young Adult ,Asian People ,Genetic variation ,Hypersensitivity ,Odds Ratio ,Immunology and Allergy ,Medicine ,Humans ,Genetic Predisposition to Disease ,Lung ,Asthma ,Aged ,Aged, 80 and over ,business.industry ,Receptor Protein-Tyrosine Kinases ,General Medicine ,Middle Aged ,medicine.disease ,Case-Control Studies ,Immunology ,Expression quantitative trait loci ,Female ,business ,lcsh:RC581-607 ,Genome-Wide Association Study - Abstract
Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. Methods: We performed a candidate gene case–control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. Results: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene–gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. Conclusions: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese. Keywords: Allergic rhinitis, Asthma, Atopy, eQTL, TYRO3
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- 2018
45. Transcription Elongation Factor P-TEFb Is Involved in IL-17F Signaling in Airway Smooth Muscle Cells
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Tohru Sakamoto, Satoshi Matsukura, Kyoko Ota, Yukio Ishii, Mio Kawaguchi, Nobuyuki Hizawa, Yuko Morishima, Hiroaki Satoh, Masayuki Nakajima, Shau Ku Huang, Masashi Matsuyama, and Junichi Fujita
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0301 basic medicine ,Small interfering RNA ,Cyclin T1 ,Immunology ,Myocytes, Smooth Muscle ,Bronchi ,03 medical and health sciences ,Gene expression ,Immunology and Allergy ,Humans ,Positive Transcriptional Elongation Factor B ,Interleukin 8 ,Phosphorylation ,P-TEFb ,Budesonide ,Cells, Cultured ,Chemistry ,Kinase ,Cyclin T ,Interleukin-17 ,Interleukin-8 ,NF-kappa B ,General Medicine ,Transfection ,Cyclin-Dependent Kinase 9 ,Cell biology ,030104 developmental biology ,Signal Transduction - Abstract
Background: IL-17F is involved in the pathogenesis of several inflammatory diseases, including asthma and COPD. However, the effects of steroids on the function of IL-17F signaling mechanisms are largely unknown. One of the transcription elongation factors, positive transcription elongation factor b (P-TEFb) composed of cyclin T1 and cyclin-dependent kinase 9 (CDK9), is known as a novel checkpoint regulator of gene expression via bromodomain-containing protein 4 (Brd4). Methods: Human airway smooth muscle cells were stimulated with IL-17F and the expression of IL-8 was evaluated by real-time PCR and ELISA. Next, the phosphorylation of CDK9 was determined by Western blotting. The CDK9 inhibitor and short interfering RNAs (siRNAs) targeting Brd4, cyclin T1, and CDK9 were used to identify the effect on IL-17F-induced IL-8 expression. Finally, the effect of steroids and its signaling were evaluated. Results: IL-17F markedly induced the transcription of the IL-8 gene and the expression of the protein. Pretreatment of CDK9 inhibitor and transfection of siRNAs targeting CDK9 markedly abrogated IL-17F-induced IL-8 production. Transfection of siRNAs targeting Brd4 and cyclin T1 diminished IL-17F-induced phosphorylation of CDK9 and IL-8 production. Moreover, budesonide decreased CDK9 phosphorylation and markedly inhibited IL-17F-induced IL-8 production. Conclusions: This is the first report that P-TEFb is involved in IL-17F-induced IL-8 expression and that steroids diminish it via the inhibition of CDK9 phosphorylation. IL-17F and P-TEFb might be novel therapeutic targets for airway inflammatory diseases.
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- 2018
46. Synthetic double-stranded RNA induces interleukin-32 in bronchial epithelial cells
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Kyoko Ota, Mio Kawaguchi, Yukio Ishii, Shau Ku Huang, Yuko Morishima, Satoshi Matsukura, Tohru Sakamoto, Junichi Fujita, Hiroaki Satoh, Masatsugu Kurokawa, Fumio Kokubu, and Nobuyuki Hizawa
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Pulmonary and Respiratory Medicine ,medicine.medical_treatment ,Clinical Biochemistry ,Bronchi ,Biology ,Lactones ,chemistry.chemical_compound ,Western blot ,Nitriles ,medicine ,Humans ,Sulfones ,Phosphorylation ,Molecular Biology ,Cells, Cultured ,RNA, Double-Stranded ,medicine.diagnostic_test ,Interleukins ,NF-kappa B ,Transcription Factor RelA ,RNA ,Interleukin ,Epithelial Cells ,NF-κB ,Pneumonia ,Resorcinols ,MAP Kinase Kinase Kinases ,Molecular biology ,RNA silencing ,Interleukin 32 ,Cytokine ,chemistry ,I-kappa B Proteins ,Signal Transduction ,Transforming growth factor - Abstract
Interleukin (IL)-32 is a novel cytokine and is involved in the pathogenesis of various inflammatory diseases, including asthma and COPD. However, the regulatory mechanisms of IL-32 expression and its precise pathogenic role remain to be defined. Given that viral infections are known to potentially cause and exacerbate airway inflammation, in this study, we investigated the expression of IL-32 induced by synthetic double-stranded (ds) RNA, and its signaling mechanisms involved.Bronchial epithelial cells were stimulated with synthetic dsRNA poly I:C. The levels of IL-32 expression were analyzed using real-time PCR and ELISA. The involvement of transforming growth factor β-activated kinase 1 (TAK1) and a subunit of nuclear factor-κB (NF-κB), p65 was determined by western blot analyses. TAK1 inhibitor, 5Z-7-Oxozeaenol and NF-κB inhibitor, BAY 11-7082 were added to the culture to identify key signaling events leading to the expression of IL-32. Finally, the effect of short interfering RNAs (siRNAs) targeting TAK1 and p65 was investigated.dsRNA significantly induced IL-32 gene and protein expression, concomitant with activation of TAK1 and p65. Pretreatment of 5Z-7-Oxozeaenol diminished dsRNA-induced phosphorylation of NF-κB. Both 5Z-7-Oxozeaenol and BAY 11-7082 significantly abrogated dsRNA-induced IL-32 production. Moreover, transfection of the cells with siRNAs targeting TAK1 and p65 inhibited the expression of IL-32.The expression of IL-32 is induced by dsRNA via the TAK1-NF-κB signaling pathway in bronchial epithelial cells. IL-32 is involved in the pathogenesis of airway inflammation, and may be a novel therapeutic target for airway inflammatory diseases.
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- 2015
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47. How important is allergic sensitization as a cause of atopic asthma?
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Hiroaki Iijima, Nobuyuki Hizawa, Hideyasu Yamada, Tomomitsu Hirota, Takashi Naito, Haruna Kitazawa, Hironori Masuko, Mayumi Tamari, Jun Kanazawa, Tohru Sakamoto, and Yohei Yatagai
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Adult ,Genotype ,business.industry ,MEDLINE ,Genome-wide association study ,General Medicine ,Polymorphism, Single Nucleotide ,Allergic sensitization ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Immunology ,Hypersensitivity ,Immunology and Allergy ,Medicine ,Humans ,Atopic asthma ,business ,lcsh:RC581-607 ,Genome-Wide Association Study - Published
- 2017
48. Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung
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Junko Hamamoto, Shizuko Kagawa, Hideyasu Yamada, Kenzo Soejima, Mari Ozaki, Takanori Asakura, Tomoko Betsuyaku, Gao Jingtao, Makoto Ishii, Satoshi Suzuki, Tohru Sakamoto, Hiroyuki Yasuda, Aoi Kuroda, Ahmed E. Hegab, Shuji Yamashita, Ho Namkoong, and Nobuyuki Hizawa
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Male ,0301 basic medicine ,Aging ,Pathology ,Club cell ,Aldehyde dehydrogenase ,Mice ,Japan ,Risk Factors ,Lung ,Mice, Knockout ,education.field_of_study ,Stem cell ,Aldehyde Dehydrogenase, Mitochondrial ,Middle Aged ,respiratory system ,Mitochondria ,Trachea ,medicine.anatomical_structure ,Female ,Genetic Markers ,medicine.medical_specialty ,Aldehyde ,Population ,Biology ,Polymorphism, Single Nucleotide ,Sensitivity and Specificity ,03 medical and health sciences ,FEV1/FVC ratio ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,education ,Genetic Association Studies ,ALDH2 ,lcsh:RC705-779 ,Research ,Wild type ,Reproducibility of Results ,lcsh:Diseases of the respiratory system ,Molecular biology ,respiratory tract diseases ,Epithelial cell ,030104 developmental biology ,Basal cell ,biology.protein - Abstract
Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer’s diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 −/− mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 −/− mice. In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 −/− and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 −/− mice. Aldh2 −/− tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 −/− mice than in WT mice. ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a “premature lung aging” effect.
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- 2017
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49. Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations
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Tohru Sakamoto, Yohei Yatagai, Yoshiko Kaneko, Hiroaki Iijima, Hironori Masuko, Tomomitsu Hirota, Emiko Noguchi, Haruna Kitazawa, Jun Kanazawa, Hideyasu Yamada, Masaharu Nishimura, Nobuyuki Hizawa, Satoshi Konno, Takashi Naito, Takefumi Saito, and Mayumi Tamari
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Asthma phenotype ,0301 basic medicine ,Male ,Candidate gene ,Genome-wide association study ,Atopy ,Cadherin-related family member 3 (CDHR3) ,0302 clinical medicine ,Gene Frequency ,Japan ,Risk Factors ,Genotype ,Odds Ratio ,Medicine ,Immunology and Allergy ,Age of Onset ,Child ,Human rhinovirus C ,Aged, 80 and over ,General Medicine ,Middle Aged ,Cadherins ,Respiratory Function Tests ,Phenotype ,Child, Preschool ,Population Surveillance ,Female ,lcsh:Immunologic diseases. Allergy ,Adult ,Adolescent ,Cadherin Related Proteins ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,Genetics ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Genetic Association Studies ,Early-onset asthma ,Genetic association ,Asthma ,Aged ,business.industry ,Infant, Newborn ,Genetic Variation ,Infant ,Membrane Proteins ,Odds ratio ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,030228 respiratory system ,Case-Control Studies ,Immunology ,lcsh:RC581-607 ,business - Abstract
Background Recent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 ( CDHR3 ), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma. Methods We performed a candidate gene case–control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined. Results The A allele was associated with asthma (OR = 1.56; Mantel–Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function. Conclusions Our study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma.
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- 2017
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50. Genomewide association study identifiesHAS2as a novel susceptibility gene for adult asthma in a Japanese population
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Tomomitsu Hirota, Emiko Noguchi, Masaharu Nishimura, Nobuyuki Hizawa, Mayumi Tamari, Tohru Sakamoto, Hiroaki Iijima, Yoshiko Kaneko, Yohei Yatagai, Takashi Naito, Satoshi Konno, Hideyasu Yamada, and Hironori Masuko
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Adult ,Male ,Linkage disequilibrium ,Candidate gene ,Deception ,Genotype ,Quantitative Trait Loci ,Immunology ,Gene Expression ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Asian People ,Japan ,Risk Factors ,medicine ,Humans ,Immunology and Allergy ,SNP ,Genetic Predisposition to Disease ,RNA, Messenger ,Glucuronosyltransferase ,Aged ,Asthma ,Genetics ,Case-control study ,Middle Aged ,medicine.disease ,Case-Control Studies ,Expression quantitative trait loci ,Female ,Hyaluronan Synthases ,Chromosomes, Human, Pair 8 ,Genome-Wide Association Study - Abstract
SummaryBackground It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. Objective To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. Methods We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP–gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. Results In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10−7). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10−9). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. Conclusions Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.
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- 2014
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