Details of a Researcher - Asakura, Takanori

Papers - Asakura, Takanori

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A novel DNA chromatography method to discriminate Mycobacterium abscessus subspecies and macrolide susceptibility.

Mitsunori Yoshida, Sotaro Sano, Jung-Yien Chien, Hanako Fukano, Masato Suzuki, Takanori Asakura, Kozo Morimoto, Yoshiro Murase, Shigehiko Miyamoto, Atsuyuki Kurashima, Naoki Hasegawa, Po-Ren Hsueh, Satoshi Mitarai, Manabu Ato, Yoshihiko Hoshino

EBioMedicine 64 103187 - 103187 2021.02

BACKGROUND: The clinical impact of infection with Mycobacterium (M.) abscessus complex (MABC), a group of emerging non-tuberculosis mycobacteria (NTM), is increasing. M. abscessus subsp. abscessus/bolletii frequently shows natural resistance to macrolide antibiotics, whereas M. abscessus subsp. massiliense is generally susceptible. Therefore, rapid and accurate discrimination of macrolide-susceptible MABC subgroups is required for effective clinical decisions about macrolide treatments for MABC infection. We aimed to develop a simple and rapid diagnostic that can identify MABC isolates showing macrolide susceptibility. METHODS: Whole genome sequencing (WGS) was performed for 148 clinical or environmental MABC isolates from Japan to identify genetic markers that can discriminate three MABC subspecies and the macrolide-susceptible erm(41) T28C sequevar. Using the identified genetic markers, we established PCR based- or DNA chromatography-based assays. Validation testing was performed using MABC isolates from Taiwan. FINDING: We identified unique sequence regions that could be used to differentiate the three subspecies. Our WGS-based phylogenetic analysis indicated that M. abscessus carrying the macrolide-susceptible erm(41) T28C sequevar were tightly clustered, and identified 11 genes that were significantly associated with the lineage for use as genetic markers. To detect these genetic markers and the erm(41) locus, we developed a DNA chromatography method that identified three subspecies, the erm(41) T28C sequevar and intact erm(41) for MABC in a single assay within one hour. The agreement rate between the DNA chromatography-based and WGS-based identification was 99·7%. INTERPRETATION: We developed a novel, rapid and simple DNA chromatography method for identification of MABC macrolide susceptibility with high accuracy. FUNDING: AMED, JSPS KAKENHI.

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Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease.

Takanori Asakura, Yoshifumi Kimizuka, Tomoyasu Nishimura, Shoji Suzuki, Ho Namkoong, Yohei Masugi, Yasunori Sato, Makoto Ishii, Naoki Hasegawa

Respirology (Carlton, Vic.) 26 ( 1 ) 112 - 119 2021.01

Accepted, ISSN 13237799

BACKGROUND AND OBJECTIVE: The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. METHODS: Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). RESULTS: The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. CONCLUSION: Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

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Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.

Hiroaki Katsura, Vishwaraj Sontake, Aleksandra Tata, Yoshihiko Kobayashi, Caitlin E Edwards, Brook E Heaton, Arvind Konkimalla, Takanori Asakura, Yu Mikami, Ethan J Fritch, Patty J Lee, Nicholas S Heaton, Richard C Boucher, Scott H Randell, Ralph S Baric, Purushothama Rao Tata

Cell stem cell 27 ( 6 ) 890 - 904 2020.10

Accepted

Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report a feeder-free, scalable, chemically defined, and modular alveolosphere culture system for the propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor type-2 (ACE2) and can be infected with virus. Transcriptome and histological analysis of infected alveolospheres mirror features of COVID-19 lungs, including emergence of interferon (IFN)-mediated inflammatory responses, loss of surfactant proteins, and apoptosis. Treatment of alveolospheres with IFNs recapitulates features of virus infection, including cell death. In contrast, alveolospheres pretreated with low-dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres, thus, provide novel insights into COVID-19 pathogenesis and can serve as a model for understanding human respiratory diseases.

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Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a claims-data analysis.

Shunsuke Uno, Takanori Asakura, Kozo Morimoto, Kimio Yoshimura, Yoshifumi Uwamino, Tomoyasu Nishimura, Yoshihiko Hoshino, Naoki Hasegawa

BMC pulmonary medicine 20 ( 1 ) 262 - 262 2020.10

Accepted

BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

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Clinical significance of anti-glycopeptidolipid-core IgA antibodies in patients newly diagnosed with Mycobacterium avium complex lung disease.

Shuichi Matsuda, Takanori Asakura, Kozo Morimoto, Shoji Suzuki, Keiji Fujiwara, Koji Furuuchi, Takeshi Osawa, Ho Namkoong, Makoto Ishii, Atsuyuki Kurashima, Koichiro Tatsumi, Ken Ohta, Naoki Hasegawa, Yuka Sasaki

Respiratory medicine 171 106086 - 106086 2020.09

Accepted

BACKGROUND: Although recent studies have identified anti-glycopeptidolipid (GPL)-core IgA antibodies as a serodiagnostic test for Mycobacterium avium complex lung disease (MAC-LD), this test shows insufficient sensitivity. This study aimed to determine the clinical utility of these antibodies in assessing disease progression and the clinical characteristics of MAC-LD patients with negative antibody results. METHODS: We retrospectively reviewed the medical records of consecutive newly diagnosed, untreated MAC-LD patients in two referral hospitals. We evaluated the association of anti-GPL-core IgA antibody results with disease progression requiring treatment and the factors associated with negative antibody results. RESULTS: In total, 229 patients (161 females; median age, 71 years; 185 with nodular/bronchiectatic disease phenotype; 69 with cavitary lesions) were enrolled; 146 patients (64%) were anti-GPL-core IgA antibody-positive. Radiological severity scores were associated with anti-GPL-core IgA antibody titers. During the median 364-day follow-up, 114 patients (49.8%) required treatment. Multivariate Cox proportional hazards analysis showed that positive anti-GPL-core IgA antibody results, a younger age, the absence of malignancy, and the presence of cavitary lesions were associated with disease progression requiring treatment. Multivariate logistic analysis revealed that significant factors related to the negative antibody results included underlying pulmonary disease, lower radiological scores, chronic sinusitis, and macrolide monotherapy. CONCLUSION: In addition to cavitary lesions, anti-GPL-core IgA antibody positivity was associated with disease progression requiring treatment. Physicians should carefully use anti-GPL-core IgA antibody results for the diagnosis of patients with underlying pulmonary disease, chronic sinusitis, macrolide monotherapy, and lower radiological severity.

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SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.

Yixuan J Hou, Kenichi Okuda, Caitlin E Edwards, David R Martinez, Takanori Asakura, Kenneth H Dinnon 3rd, Takafumi Kato, Rhianna E Lee, Boyd L Yount, Teresa M Mascenik, Gang Chen, Kenneth N Olivier, Andrew Ghio, Longping V Tse, Sarah R Leist, Lisa E Gralinski, Alexandra Schäfer, Hong Dang, Rodney Gilmore, Satoko Nakano, Ling Sun, M Leslie Fulcher, Alessandra Livraghi-Butrico, Nathan I Nicely, Mark Cameron, Cheryl Cameron, David J Kelvin, Aravinda de Silva, David M Margolis, Alena Markmann, Luther Bartelt, Ross Zumwalt, Fernando J Martinez, Steven P Salvatore, Alain Borczuk, Purushothama R Tata, Vishwaraj Sontake, Adam Kimple, Ilona Jaspers, Wanda K O'Neal, Scott H Randell, Richard C Boucher, Ralph S Baric

Cell 182 ( 2 ) 429 - 446 2020.07

Accepted

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.

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ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice.

Shoji Suzuki, Makoto Ishii, Takanori Asakura, Ho Namkoong, Satoshi Okamori, Kazuma Yagi, Hirofumi Kamata, Tatsuya Kusumoto, Shizuko Kagawa, Ahmed E Hegab, Masaki Yoda, Keisuke Horiuchi, Naoki Hasegawa, Tomoko Betsuyaku

American journal of physiology. Lung cellular and molecular physiology 318 ( 6 ) L1172-L1182 2020.06

Accepted

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre (Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.

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Complete Genome Sequence of Mycobacterium xenopi JCM15661T, Obtained Using Nanopore and Illumina Sequencing Technologies.

Mitsunori Yoshida, Hanako Fukano, Takanori Asakura, Junzo Hisatsune, Yoshihiko Hoshino

Microbiology resource announcements 9 ( 10 ) 2020.03

Accepted

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Placental transmogrification of the lung masquerading as difficult-to-treat pneumonia.

K Horiuchi, T Asakura, S Sakaguchi, F Saito, J Yamamoto

QJM : monthly journal of the Association of Physicians 113 ( 3 ) 213 - 214 2020.03

Accepted, ISSN 1460-2725

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Correction to: Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.

Yoshifumi Uwamino, Tomoyasu Nishimura, Yasunori Sato, Eiko Tamizu, Takanori Asakura, Shunsuke Uno, Masaaki Mori, Hiroshi Fujiwara, Makoto Ishii, Hiroshi Kawabe, Mitsuru Murata, Naoki Hasegawa

BMC infectious diseases 20 ( 1 ) 131 - 131 2020.02

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Long-Lasting Response to Nivolumab for a Patient With Lynch Syndrome-Associated Lung Adenocarcinoma.

Keita Masuzawa, Takanori Asakura, Shinnosuke Ikemura, Hiroyuki Yasuda, Ichiro Kawada, Sosuke Takaoka, Yuichiro Hayashi, Takeshi Nakajima, Masami Arai, Koichi Fukunaga, Kenzo Soejima

JCO precision oncology 4 2020

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Pneumothorax associated with giant bullous emphysema and mediastinum deviation.

Kohei Horiuchi, Takanori Asakura, Junichi Ochi, Fumitake Saito

BMJ case reports 12 ( 12 ) 2019.12

Accepted

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Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.

Yoshifumi Uwamino, Tomoyasu Nishimura, Yasunori Sato, Eiko Tamizu, Takanori Asakura, Shunsuke Uno, Masaaki Mori, Hiroshi Fujiwara, Makoto Ishii, Hiroshi Kawabe, Mitsuru Murata, Naoki Hasegawa

BMC infectious diseases 19 ( 1 ) 1055 - 1055 2019.12

Accepted

BACKGROUND: The risk factors for Mycobacterium avium complex lung disease (MAC-LD) are not well known. We hypothesized that low serum estradiol (E2) levels are related to MAC-LD as most patients with MAC-LD are postmenopausal women. METHODS: This cross-sectional study compared patients with MAC-LD and healthy controls. Study subjects were postmenopausal women aged 65 years or younger. Serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and E2 levels were measured and categorized as high or low based on median levels. We performed multivariate analysis, receiver operating characteristic (ROC) curve analysis, and age- and body mass index (BMI)-matched subgroup analysis to evaluate the association between low serum E2 levels and MAC-LD. Additionally, using blood samples obtained for other clinical studies, the levels of sex steroid hormones were compared between age- and BMI-matched MAC-LD and bronchiectasis female patients without non-tuberculosis mycobacterial infections (non-NTM BE). RESULTS: Forty-two patients with MAC-LD and 91 healthy controls were included. The median E2 (2.20 pg/mL vs. 15.0 pg/mL, p < 0.001), testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005), and DHEA-S (82.5 μg/dL vs. 114.0 μg/dL, p < 0.001) levels were lower in the MAC-LD group than in the control group. Multivariate analysis revealed that low serum E2 (adjusted odds ratio = 34.62, 95% confidence interval = 6.02-199.14) was independently related to MAC-LD, whereas low DHEA-S and testosterone were not. ROC analysis illustrated a strong relationship between low serum E2 levels and MAC-LD (area under the curve = 0.947, 95% confidence interval = 0.899-0.995). Even the age- and BMI-matched subgroup analysis of 17 MAC-LD patients and 17 healthy controls showed lower serum E2 in MAC-LD patients than in healthy controls. Additionally, serum E2 levels of 20 MAC-LD patients were lower than plasma E2 levels of 11 matched non-NTM BE patients (1.79 pg/mL vs. 11.0 pg/mL, p < 0.001). CONCLUSIONS: Low serum E2 levels were strongly related to MAC-LD in postmenopausal women.

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Superior vena cava syndrome.

K Horiuchi, T Asakura, F Saito, T Asakura

QJM : monthly journal of the Association of Physicians 112 ( 9 ) 703 - 704 2019.09

Accepted

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Rhabdomyolysis diagnosed in an older woman with dementia on examination after a wandering episode.

Kohei Horiuchi, Takanori Asakura, Nobuhiro Ikeda

Geriatrics & gerontology international 19 ( 9 ) 956 - 957 2019.09

Accepted, ISSN 1444-1586

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Successful osimertinib treatment in a patient who exhibited intramedullary spinal cord metastases of lung adenocarcinoma with an acquired EGFR T790M mutation.

Kohei Horiuchi, Takanori Asakura, Shinji Sakaguchi, Fumitake Saito

BMJ case reports 12 ( 6 ) 2019.06

Accepted

Intramedullary spinal cord metastases (ISCMs) of non-small cell lung cancer (NSCLC) constitute a serious if infrequent complication, characterised by rapid progression of neurological deficits, with poor prognosis. We describe a 52-year-old man with ISCMs secondary to lung adenocarcinoma who acquired the T790M mutation of the epidermal growth factor receptor (EGFR) after previous use of a first-generation EGFR tyrosine kinase inhibitor (TKI); he was successfully treated with osimertinib. This is the first report of the use of osimertinib in ISCMs: due to its high central nervous system activity, osimertinib could be useful for treating ISCMs secondary to NSCLC in patients who exhibit the T790M mutation.

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The eggs of Paragonimiasis westermani in bronchial lavage fluid.

K Masaki, T Asakura, I Nakachi

QJM : monthly journal of the Association of Physicians 112 ( 6 ) 463 - 464 2019.06

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Adenovirus type 5 community-acquired pneumonia in an immunocompetent patient.

Katsunori Masaki, Takanori Asakura, Kaori Sakurai, Kiyofumi Ohkusu

BMJ case reports 12 ( 4 ) 2019.04

Accepted

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Bilateral chylothorax associated with osteophytes in an elderly patient.

Kohei Horiuchi, Takanori Asakura, Shinji Sakaguchi, Fumitake Saito

BMJ case reports 12 ( 4 ) 2019.04

Accepted

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Disseminated histoplasmosis from a calcified lung nodule after long-term corticosteroid therapy in an elderly Japanese patient: A case report.

Keigo Kobayashi, Takanori Asakura, Ichiro Kawada, Hanako Hasegawa, Shotaro Chubachi, Kentaro Ohara, Junko Kuramoto, Hiroaki Sugiura, Seitaro Fujishima, Satoshi Iwata, Takashi Umeyama, Harutaka Katano, Yoshifumi Uwamino, Yoshitsugu Miyazaki, Katsuhiko Kamei, Naoki Hasegawa, Tomoko Betsuyaku

Medicine 98 ( 17 ) e15264 2019.04

Accepted

RATIONALE: Histoplasmosis occurs most commonly in Northern and Central America and Southeast Asia. Increased international travel in Japan has led to a few annual reports of imported histoplasmosis. Healed sites of histoplasmosis lung infection may remain as nodules and are often accompanied by calcification. Previous studies in endemic areas supported the hypothesis that new infection/reinfection, rather than reactivation, is the main etiology of symptomatic histoplasmosis. No previous reports have presented clinical evidence of reactivation. PATIENT CONCERNS: An 83-year-old Japanese man was hospitalized with general fatigue and high fever. He had been treated with prednisolone at 13 mg/d for 7 years because of an eczematous skin disease. He had a history of travel to Los Angeles, Egypt, and Malaysia 10 to 15 years prior to admission. Five years earlier, computed tomography (CT) identified a solitary calcified nodule in the left lingual lung segment. The nodule size remained unchanged throughout a 5-year observation period. Upon admission, his respiratory condition remained stable while breathing room air. CT revealed small, randomly distributed nodular shadows in the bilateral lungs, in addition to the solitary nodule. DIAGNOSIS: Disseminated histoplasmosis, based on fungal staining and cultures of autopsy specimens. INTERVENTIONS: The patient's fever continued despite several days of treatment with meropenem, minocycline, and micafungin. Although he refused bone marrow aspiration, isoniazid, rifampicin, ethambutol, and prednisolone were administered for a tentative diagnosis of miliary tuberculosis. OUTCOMES: His fever persisted, and a laboratory examination indicated severe thrombocytopenia with disseminated intravascular coagulation. He died on day 43 postadmission. During autopsy, the fungal burden was noted to be higher in the calcified nodule than in the disseminated nodules of the lung, suggesting a pathogenesis involving endogenous reactivation of the nodule and subsequent hematogenous and lymphatic spread. LESSONS: Physicians should consider histoplasmosis in patients with calcified nodules because the infection may reactivate during long-term corticosteroid therapy.

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