Updated on 2023/02/05

写真a

 
TANAKA Takahiro
 
Organization
University Medical and Dental Hospital Clinical and Translational Research Center Assistant Professor
Title
Assistant Professor
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Degree

  • 博士(農学) ( 2010.3   東北大学 )

  • 修士(農学) ( 2004.3   東北大学 )

Research Interests

  • 臨床研究支援

  • 生物統計

Research Areas

  • Life Science / Clinical pharmacy  / 臨床試験

  • Life Science / Respiratory medicine  / 肺胞蛋白症

Research History (researchmap)

  • Niigata University   Medical and Dental Hospital Clinical and Translational Research Center   Assistant Professor

    2017.4

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    Country:Japan

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  • Niigata University   Medical and Dental Hospital   Specially Appointed Assistant Professor

    2015.4 - 2017.3

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    Country:Japan

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  • Niigata University   Medical and Dental Hospital Bioscience Medical Research Center   Specially Appointed Assistant Professor

    2013.1 - 2015.3

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    Country:Japan

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  • National Center for Global Health and Medicine

    2006.12 - 2012.12

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    Country:Japan

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Research History

  • Niigata University   University Medical and Dental Hospital Clinical and Translational Research Center   Assistant Professor

    2018.3

  • Niigata University   University Medical and Dental Hospital Protocol Data Center   Specially Appointed Assistant Professor

    2017.4 - 2018.2

  • Niigata University   University Medical and Dental Hospital Protocol Data Center   Specially Appointed Assistant Professor

    2015.4 - 2017.3

  • Niigata University   University Medical and Dental Hospital Bioscience Medical Research Center   Specially Appointed Assistant Professor

    2013.1 - 2015.3

Education

  • Tohoku University   Graduate School of Agricultural Science   Division of Life Science

    2004.4 - 2010.3

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    Country: Japan

    Notes: 博士課程後期3年

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  • Tohoku University   Graduate School of Agricultural Science   Division of Life Science

    2002.4 - 2004.3

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    Country: Japan

    Notes: 博士課程前期2年

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  • Tokyo University of Science   Faculty of Science, Division 1   Applied Chemistry

    1998.4 - 2002.3

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    Country: Japan

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Qualification acquired

  • 実務試験統計家

 

Papers

  • Quantitative Evaluation of Changes in Three-Dimensional CT Density Distributions in Pulmonary Alveolar Proteinosis after GM-CSF Inhalation. International journal

    Miku Oda, Kentaro Yamaura, Haruyuki Ishii, Nobutaka Kitamura, Ryushi Tazawa, Mitsuhiro Abe, Koichiro Tatsumi, Ryosuke Eda, Shotaro Kondoh, Konosuke Morimoto, Takeshi Tanaka, Etsuro Yamaguchi, Ayumu Takahashi, Shinyu Izumi, Haruhito Sugiyama, Atsushi Nakagawa, Keisuke Tomii, Masaru Suzuki, Satoshi Konno, Shinya Ohkouchi, Naoki Tode, Tomohiro Handa, Toyohiro Hirai, Yoshikazu Inoue, Toru Arai, Katsuaki Asakawa, Takahiro Tanaka, Toshinori Takada, Hirofumi Nonaka, Koh Nakata

    Respiration; international review of thoracic diseases   1 - 9   2022.12

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    BACKGROUND: A previous clinical trial for autoimmune pulmonary alveolar proteinosis (APAP) demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation reduced the mean density of the lung field on computed tomography (CT) across 18 axial slice planes at a two-dimensional level. In contrast, in this study, we challenged three-dimensional analysis for changes in CT density distribution using the same datasets. METHODS: As a sub-study of the trial, CT data of 31 and 27 patients who received GM-CSF and placebo, respectively, were analyzed. To overcome the difference between various shooting conditions, a newly developed automatic lung field segmentation algorithm was applied to CT data to extract the whole lung volume, and the accuracy of the segmentation was evaluated by five pulmonary physicians independently. For normalization, the percent pixel (PP) in a certain density range was calculated as a percentage of the total number of pixels from -1,000 to 0 HU. RESULTS: The automatically segmented images revealed that the lung field was accurately extracted except for 7 patients with minor deletion or addition. Using the change in PP from baseline to week 25 (ΔPP) as the vertical axis, we created a histogram with 143 HU bins set for each patient. The most significant difference in ΔPP between GM-CSF and placebo groups was observed in two ranges: from -1,000 to -857 and -143 to 0 HU. CONCLUSION: Whole lung extraction followed by density histogram analysis of ΔPP may be an appropriate evaluation method for assessing CT improvement in APAP.

    DOI: 10.1159/000528038

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  • Urinary A- and C-megalin predict progression of diabetic kidney disease: an exploratory retrospective cohort study. International journal

    Tomomichi Iida, Michihiro Hosojima, Hideyuki Kabasawa, Keiko Yamamoto-Kabasawa, Sawako Goto, Takahiro Tanaka, Nobutaka Kitamura, Mitsutaka Nakada, Shino Itoh, Shinya Ogasawara, Ryohei Kaseda, Yoshiki Suzuki, Ichiei Narita, Akihiko Saito

    Journal of diabetes and its complications   36 ( 11 )   108312 - 108312   2022.9

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    AIMS: Megalin, a proximal tubular endocytosis receptor, is excreted in urine in two forms: ectodomain (A-megalin) and full-length (C-megalin). We explored whether urinary megalin levels can be used as independent prognostic biomarkers in the progression of diabetic kidney disease (DKD). METHODS: The associations between baseline urinary A-megalin/creatinine (Cr) and/or C-megalin/Cr levels and the subsequent estimated glomerular filtration rate (eGFR) slope were analyzed using a generalized estimating equation. Patients were categorized into higher or lower groups based on the optimal cutoff values, obtained from a receiver operating characteristic curve, of the two forms of urinary megalin. RESULTS: We retrospectively analyzed 188 patients with type 2 diabetes. The eGFR slopes of the higher A-megalin/Cr and higher C-megalin/Cr groups were - 0.904 and -0.749 ml/min/1.73 m2/year steeper than those of the lower groups, respectively. Moreover, the eGFR slope was -1.888 ml/min/1.73 m2/year steeper in the group with both higher A- and higher C-megalin/Cr than in the other group. These results remained significant when adjusted for known urinary biomarkers (albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-d-glucosaminidase). CONCLUSIONS: Urinary A- and C-megalin/Cr levels are likely to be prognostic biomarkers in the progression of DKD independent of other urinary biomarkers.

    DOI: 10.1016/j.jdiacomp.2022.108312

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  • Incidence and Risk Factors of Future Need for Long-Term Care Insurance in Japanese Elderly Patients With Left Ventricular Systolic Dysfunction.

    Shinya Fujiki, Takeshi Kashimura, Yuji Okura, Kunio Kodera, Hiroshi Watanabe, Komei Tanaka, Shogo Bannai, Taturo Hatano, Takahiro Tanaka, Nobutaka Kitamura, Tohru Minamino, Takayuki Inomata

    Circulation journal : official journal of the Japanese Circulation Society   86 ( 1 )   158 - 165   2021.11

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    BACKGROUND: Heart failure in elderly people causes physical and cognitive dysfunction and often requires long-term care insurance (LTCI); however, among patients with left ventricular (LV) systolic dysfunction, the incidence and risk factors of future LTCI requirements need to be elucidated.Methods and Results:The study included 1,852 patients aged ≥65 years with an echocardiographic LV ejection fraction (LVEF) ≤50%; we referred to their LTCI data and those of 113,038 community-dwelling elderly people. During a mean 1.7-year period, 332 patients newly required LTCI (incidence 10.7 per 100 person-years); the incidence was significantly higher than that for the community-dwelling people (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.32-1.64). On multivariate analysis, the risk factors at the time of echocardiography leading to future LTCI requirement were atrial fibrillation (HR, 1.588; 95% CI, 1.279-1.971), history of stroke (HR, 2.02; 95% CI, 1.583-2.576), osteoporosis (HR, 1.738; 95% CI, 1.253-2.41), dementia (HR, 2.804; 95% CI, 2.075-3.789), hypnotics (HR, 1.461; 95% CI, 1.148-1.859), and diuretics (HR, 1.417; 95% CI, 1.132-1.773); however, the LVEF was not a risk factor (HR, 0.997; 95% CI, 0.983-1.011). CONCLUSIONS: In elderly patients with LV systolic dysfunction, the incidence of LTCI requirement was more common than that for community-dwelling people; its risk factors did not include LVEF, but included many other non-cardiac comorbidities and therapies, suggesting the need for interdisciplinary cooperation to prevent disabilities.

    DOI: 10.1253/circj.CJ-21-0580

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  • Risk factors of medication-related osteonecrosis of the jaw in preventive tooth extraction before bone resorption inhibitor administration: A multicenter nested case–control study

    Taro Saito, Atsushi Nishikawa, Yuko Hara‐Saito, Andrea Rei Estacio Salazar, Akira Kurokawa, Akihiko Iida, Masahiro Yamaga, Hiroyuki Kano, Yusuke Kato, Yoshiyuki Takata, Hideyoshi Nishiyama, Nobutaka Kitamura, Takahiro Tanaka, Ritsuo Takagi

    Oral Science International   19 ( 2 )   79 - 87   2021.9

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    DOI: 10.1002/osi2.1122

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/osi2.1122

  • Low-dose Droperidol Reduces the Amplitude of Transcranial Electrical Motor-evoked Potential: A Randomized, Double-blind, Placebo-controlled Trial. International journal

    Yusuke Mitsuma, Kenta Furutani, Hiroyuki Deguchi, Yoshinori Kamiya, Takahiro Tanaka, Nobutaka Kitamura, Hiroshi Baba

    Journal of neurosurgical anesthesiology   2021.8

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    BACKGROUND: Low-dose droperidol has been reported to suppress the amplitude of transcranial electrical motor-evoked potentials (TCE-MEPs), but no randomized controlled trials have been conducted to assess this. This randomized, double-blinded, placebo-controlled trial aimed to test the hypothesis that low-dose droperidol reduced TCE-MEP amplitudes. METHODS: Twenty female patients with adolescent idiopathic scoliosis, aged between 12 and 20 years, and scheduled to undergo corrective surgery were randomly allocated to receive droperidol (20 µg/kg) or 0.9% saline. After recording baseline TCE-MEPs, the test drug was administered, following which TCE-MEP recordings were carried out every 2 minutes for up to 10 minutes. The primary outcome was the minimum relative TCE-MEP amplitude (peak-to-peak amplitude, percentage of baseline value) recorded in the left tibialis anterior muscle. Secondary outcomes included minimum relative MEP amplitudes recorded from all other muscle groups monitored in the study. Data are expressed as medians (interquartile range). RESULTS: The TCE-MEP amplitude of the left tibialis anterior muscle was significantly reduced following droperidol administration compared with saline (37% [30% to 55%] vs. 76% [58% to 93%], respectively, P<0.01). In the other muscles, the amplitudes were reduced in the droperidol group, except for the bilateral abductor pollicis brevis and the left quadriceps femoris muscles. The relative amplitude of the bilateral F waves recorded from the gastrocnemius was decreased in the droperidol group. CONCLUSIONS: Low-dose droperidol (20 µg/kg) reduced TCE-MEP amplitudes. Anesthesiologists should pay attention to the timing of droperidol administration during intraoperative TCE-MEP recordings, even if used in a low dose.

    DOI: 10.1097/ANA.0000000000000784

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  • Effects of DPP-4 Inhibitors on Blood Glucose Variability in Japanese Patients with Type 2 Diabetes on Maintenance Hemodialysis: A Prospective Observational Exploratory Study. International journal

    Tomomi Ishikawa-Tanaka, Michihiro Hosojima, Hideyuki Kabasawa, Ryohei Kaseda, Ryota Yasukawa, Yusuke Yata, Shoji Kuwahara, Emiko Kono, Takuma Takata, Noriaki Iino, Takahiro Tanaka, Nobutaka Kitamura, Yoshiki Suzuki, Akihiko Saito, Ichiei Narita

    Diabetes therapy : research, treatment and education of diabetes and related disorders   11 ( 12 )   2845 - 2861   2020.12

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    INTRODUCTION: The precise blood glucose (BG) profile of hemodialysis patients is unclear, as is the effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors in hemodialysis patients with type 2 diabetes. Here, we used continuous glucose monitoring (CGM) to evaluate BG variability in these patients and to assess the efficacy of DPP-4 inhibitors, particularly during hemodialysis sessions and at nighttime (UMIN000012638). METHODS: We examined BG profiles using CGM in 31 maintenance hemodialysis patients with type 2 diabetes. Differences between patients with and without DPP-4 inhibitors (n = 15 and 16, respectively) were analyzed using a linear mixed-effects model to assess changes in glucose levels in 5-min intervals. RESULTS: The model revealed that DPP-4 inhibitor use was significantly associated with suppression of a rapid drop in glucose levels, both with and without adjustment for BG levels at the start of hemodialysis. Moreover, the model revealed that the two groups differed significantly in the pattern of changes in BG levels from 0:00 to 6:55 am. DPP-4 inhibitors suppressed the tendency for subsequent nocturnal hypoglycemia. CONCLUSIONS: This prospective observational exploratory study showed that DPP-4 inhibitors could suppress BG variability during hemodialysis sessions as well as subsequent nocturnal changes in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, UMIN000012638.

    DOI: 10.1007/s13300-020-00928-5

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  • Placebo-Controlled, Double-Blind Study of Empagliflozin (EMPA) and Implantable Cardioverter-Defibrillator (EMPA-ICD) in Patients with Type 2 Diabetes (T2DM): Rationale and Design. International journal

    Shinya Fujiki, Kenichi Iijima, Masaaki Okabe, Shinichi Niwano, Kenichi Tsujita, Shigeto Naito, Kenji Ando, Kengo Kusano, Ritsushi Kato, Junichi Nitta, Tetsuji Miura, Takeshi Mitsuhashi, Kazuomi Kario, Yusuke Kondo, Masaki Ieda, Nobuhisa Hagiwara, Toyoaki Murohara, Kazuyoshi Takahashi, Hirofumi Tomita, Yasuchika Takeishi, Toshihisa Anzai, Wataru Shimizu, Masafumi Watanabe, Yoshihiro Morino, Takeshi Kato, Hiroshi Tada, Yoshihisa Nakagawa, Masafumi Yano, Koji Maemura, Takeshi Kimura, Hisako Yoshida, Keiko Ota, Takahiro Tanaka, Nobutaka Kitamura, Koichi Node, Yoshifusa Aizawa, Ippei Shimizu, Daisuke Izumi, Kazuyuki Ozaki, Tohru Minamino

    Diabetes therapy : research, treatment and education of diabetes and related disorders   11 ( 11 )   2739 - 2755   2020.11

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    INTRODUCTION: Type 2 diabetes (T2DM) is associated with cardiovascular death, including sudden cardiac death due to arrhythmias. Patients with an implantable cardioverter-defibrillator (ICD) are also at high risk of developing a clinically significant ventricular arrhythmia. It has been reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce cardiovascular deaths; however, the physiological mechanisms of this remain unclear. It is, however, well known that SGLT2 inhibitors increase blood ketone bodies, which have been suggested to have sympatho-suppressive effects. Empagliflozin (EMPA) is an SGLT2 inhibitor. The current clinical trial titled "Placebo-controlled, double-blind study of empagliflozin (EMPA) and implantable cardioverter-defibrillator (EMPA-ICD) in patients with type 2 diabetes (T2DM)" was designed to investigate the antiarrhythmic effects of EMPA. METHODS: The EMPA-ICD study is a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial currently in progress. A total of 210 patients with T2DM (hemoglobin A1c 6.5-10.0%) will be randomized (1:1) to receive once-daily placebo or EMPA, 10 mg, for 24 weeks. The primary endpoint is the number of clinically significant ventricular arrhythmias for 24 weeks before and 24 weeks after study drug administration, as documented by the ICD. The secondary endpoints of the study are the change from baseline concentrations in blood ketone and catecholamine 24 weeks after drug treatment. CONCLUSION: The EMPA-ICD study is the first clinical trial to assess the effect of an SGLT2 inhibitor on clinically significant ventricular arrhythmias in patients with T2DM and an ICD. TRIAL REGISTRATION: Unique trial number, jRCTs031180120 ( https://jrct.niph.go.jp/latest-detail/jRCTs031180120 ).

    DOI: 10.1007/s13300-020-00924-9

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  • Higher genome mutation rates of Beijing lineage of Mycobacterium tuberculosis during human infection. International journal

    Mariko Hakamata, Hayato Takihara, Tomotada Iwamoto, Aki Tamaru, Atsushi Hashimoto, Takahiro Tanaka, Shaban A Kaboso, Gebremichal Gebretsadik, Aleksandr Ilinov, Akira Yokoyama, Yuriko Ozeki, Akihito Nishiyama, Yoshitaka Tateishi, Hiroshi Moro, Toshiaki Kikuchi, Shujiro Okuda, Sohkichi Matsumoto

    Scientific reports   10 ( 1 )   17997 - 17997   2020.10

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    Mycobacterium tuberculosis (Mtb) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original Mtb isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent Mtb are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of Mtb Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.

    DOI: 10.1038/s41598-020-75028-2

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  • Comparison of cytokine profiles between anti-ARS antibody-positive interstitial lung diseases and those with anti-MDA-5 antibodies. International journal

    Katsuaki Asakawa, Kazutaka Yoshizawa, Ami Aoki, Yosuke Kimura, Takahiro Tanaka, Kazumasa Ohashi, Masachika Hayashi, Toshiaki Kikuchi, Shinji Sato, Toshinori Takada

    Clinical rheumatology   39 ( 7 )   2171 - 2178   2020.7

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    INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points• To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.• Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.• Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.• These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.

    DOI: 10.1007/s10067-020-04984-x

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  • Proteogenomic analysis of granulocyte macrophage colony- stimulating factor autoantibodies in the blood of a patient with autoimmune pulmonary alveolar proteinosis. International journal

    Atsushi Hashimoto, Shiho Takeuchi, Ryo Kajita, Akira Yamagata, Ryota Kakui, Takahiro Tanaka, Koh Nakata

    Scientific reports   10 ( 1 )   4923 - 4923   2020.3

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    Recently, attempts to reveal the structures of autoantibodies comprehensively using improved proteogenomics technology, have become popular. This technology identifies peptides in highly purified antibodies by using an Orbitrap device to compare spectra from liquid chromatography-tandem mass spectrometry against a cDNA database obtained through next-generation sequencing. In this study, we first analyzed granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in a patient with autoimmune pulmonary alveolar proteinosis, using the trapped ion mobility spectrometry coupled with quadrupole time-of-flight (TIMS-TOF) instrument. The TIMS-TOF instrument identified peptides that partially matched sequences in up to 156 out of 162 cDNA clones. Complementarity-determining region 3 (CDR3) was fully and partially detected in nine and 132 clones, respectively. Moreover, we confirmed one unique framework region 4 (FR4) and at least three unique across CDR3 to FR4 peptides via de novo peptide sequencing. This new technology may thus permit the comprehensive identification of autoantibody structure.

    DOI: 10.1038/s41598-020-61934-y

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  • Validation of a new serum granulocyte-macrophage colony-stimulating factor autoantibody testing kit. International journal

    Koh Nakata, Tatsuki Sugi, Keiko Kuroda, Kazutaka Yoshizawa, Toshinori Takada, Ryushi Tazawa, Takahiro Ueda, Ami Aoki, Mitsuhiro Abe, Koichiro Tatsumi, Ryosuke Eda, Shotaro Kondoh, Konosuke Morimoto, Takeshi Tanaka, Etsuro Yamaguchi, Ayumu Takahashi, Miku Oda, Haruyuki Ishii, Shinyu Izumi, Haruhito Sugiyama, Atsushi Nakagawa, Keisuke Tomii, Masaru Suzuki, Satoshi Konno, Shinya Ohkouchi, Taizou Hirano, Tomohiro Handa, Toyohiro Hirai, Yoshikazu Inoue, Toru Arai, Katsuaki Asakawa, Takuro Sakagami, Takahiro Tanaka, Ayako Mikami, Nobutaka Kitamura

    ERJ open research   6 ( 1 )   2020.1

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    Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

    DOI: 10.1183/23120541.00259-2019

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  • Rice Endosperm Protein Administration to Juvenile Mice Regulates Gut Microbiota and Suppresses the Development of High-Fat Diet-Induced Obesity and Related Disorders in Adulthood. International journal

    Yuki Higuchi, Michihiro Hosojima, Hideyuki Kabasawa, Shoji Kuwahara, Sawako Goto, Koji Toba, Ryohei Kaseda, Takahiro Tanaka, Nobutaka Kitamura, Hayato Takihara, Shujiro Okuda, Masayuki Taniguchi, Hitoshi Arao, Ichiei Narita, Akihiko Saito

    Nutrients   11 ( 12 )   2019.12

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    Obesity and related disorders, which are increasing in adults worldwide, are closely linked to childhood diet and are associated with chronic inflammation. Rice endosperm protein (REP) intake during adulthood has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. However, the effects of REP intake during childhood on adulthood health are unclear. Therefore, we used a mouse model to experimentally investigate the preconditioning effects of REP intake during childhood on the development of obesity and related disorders in adulthood. Male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP during the juvenile period and then a high-fat diet (HFD) containing casein or REP during adulthood. Mice fed REP during the juvenile period showed better body weight, blood pressure, serum lipid profiles, lipopolysaccharide (LPS)-binding protein levels, and glucose tolerance in adulthood than those fed casein during the juvenile period. HFD-induced renal tubulo-glomerular alterations and hepatic microvesicular steatosis were less evident in REP-fed mice than in casein-fed ones. REP intake during the juvenile period improved HFD-induced dysbiosis (i.e., Escherichia genus proliferation and reduced gut microbiota diversity), thereby suppressing endotoxin-related chronic inflammation. Indeed, REP-derived peptides showed antibacterial activity against Escherichia coli, a major producer of LPS. In conclusion, REP supplementation during the juvenile period may regulate the gut microbiota and thus suppress the development of obesity and related disorders in adulthood in mice.

    DOI: 10.3390/nu11122919

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  • Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. International journal

    Ryushi Tazawa, Takahiro Ueda, Mitsuhiro Abe, Koichiro Tatsumi, Ryosuke Eda, Shotaro Kondoh, Konosuke Morimoto, Takeshi Tanaka, Etsuro Yamaguchi, Ayumu Takahashi, Miku Oda, Haruyuki Ishii, Shinyu Izumi, Haruhito Sugiyama, Atsushi Nakagawa, Keisuke Tomii, Masaru Suzuki, Satoshi Konno, Shinya Ohkouchi, Naoki Tode, Tomohiro Handa, Toyohiro Hirai, Yoshikazu Inoue, Toru Arai, Katsuaki Asakawa, Takuro Sakagami, Atsushi Hashimoto, Takahiro Tanaka, Toshinori Takada, Ayako Mikami, Nobutaka Kitamura, Koh Nakata

    The New England journal of medicine   381 ( 10 )   923 - 932   2019.9

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    BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

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  • Memory B cell pool of autoimmune pulmonary alveolar proteinosis patients contains higher frequency of GM-CSF autoreactive B cells than healthy subjects. International journal

    Takahito Nei, Shinya Urano, Natsuki Motoi, Atsushi Hashimoto, Nobutaka Kitamura, Takahiro Tanaka, Kazuhide Nakagaki, Jun Takizawa, Chinatsu Kaneko, Ryushi Tazawa, Koh Nakata

    Immunology letters   212   22 - 29   2019.8

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    The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects.

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  • Incidence of autoimmune pulmonary alveolar proteinosis estimated using Poisson distribution. International journal

    Nobutaka Kitamura, Shinya Ohkouchi, Ryushi Tazawa, Haruyuki Ishii, Toshinori Takada, Takuro Sakagami, Takahiro Tanaka, Koh Nakata

    ERJ open research   5 ( 1 )   2019.2

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    The incidence and prevalence of autoimmune pulmonary alveolar proteinosis in Japan were previously estimated to be 0.49 and 6.2 per million, respectively. Thereafter, an increase in serological diagnosis forced a re-estimation of the incidence based on more contemporaneous data using more robust methods. Sera of 702 patients were positive for granulocyte-macrophage colony-stimulating factor autoantibody during the 2006-2016 period (group A). Of these patients, 43 were actively surveyed in Niigata prefecture (group B) for estimation of the incidence. To estimate the survival period, 103 patients (group C) were investigated retrospectively for the 1999-2017 period using restricted mean survival time. In group A, the number of patients diagnosed in each prefecture was closely correlated with the corresponding population, indicating no regional integration of onset. In group B, a total of 43 patients were diagnosed, the annual number followed a Poisson distribution and the incidence was thus estimated to be 1.65 per million. In group C, the retrospective cohort study revealed the mean survival period to be 16.1 years. Taken together, the prevalence was estimated to be 26.6 per million, indicating that the previous data for incidence and prevalence was an underestimation.

    DOI: 10.1183/23120541.00190-2018

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  • Assay system development to measure the concentration of sargramostim with high specificity in patients with autoimmune pulmonary alveolar proteinosis after single-dose inhalation. International journal

    Ryu Nakano, Kazuhide Nakagaki, Yuko Itoh, Utako Seino, Takahiro Ueda, Ryushi Tazawa, Nobutaka Kitamura, Takahiro Tanaka, Koh Nakata

    Journal of immunological methods   460   1 - 9   2018.9

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    During a clinical trial of a Saccharomyces cerviciae-derived recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), sargramostim, in patients with autoimmune pulmonary alveolar proteinosis (aPAP), we conducted a pharmacokinetic study of single-dose sargramostim inhalation. Several problems were encountered whereby sargramostim formed an immune-complex with GM-CSF autoantibodies (GMAbs) immediately after entering the body; thus, we could not measure the concentration of sargramostim using a commercial high sensitivity enzyme-linked immunosorbent assay (ELISA). Moreover, the ELISA could not discriminate inhaled sargramostim from intrinsic GM-CSF. To solve these problems, we developed a novel ELISA system with a capture antibody that is specific for sargramostim and a detection antibody capable of binding with GM-CSF. This system quantified the serum sargramostim concentration, but not E. coli-, CHO-, or HEK293T-derived human recombinant GM-CSF. Using this system, serum pharmacokinetics were estimated in five patients after inhalation of 250 μg sargramostim, with a mean Cmax of 9.7 ± 2.85 pg/ml at a Tmax of 2 ± 1.22 h.

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  • Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study. International journal

    Nobutaka Kitamura, Kuniaki Seyama, Yoshikazu Inoue, Katsura Nagai, Masaru Suzuki, Hiroshi Moriyama, Toshinori Takada, Ryushi Tazawa, Toyohiro Hirai, Michiaki Mishima, Mie Hayashida, Masaki Hirose, Toru Arai, Chikatoshi Sugimoto, Noboru Hattori, Kentaro Watanabe, Tsutomu Tamada, Kohei Akazawa, Takahiro Tanaka, Koh Nakata

    Pharmacoepidemiology and drug safety   26 ( 10 )   1182 - 1189   2017.10

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    PURPOSE: Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial. METHODS: Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses. RESULTS: The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study. CONCLUSIONS: Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

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  • Intraoperative Detection of Persistent Endoleak by Detecting Residual Spontaneous Echocardiographic Contrast in the Aneurysmal Sac During Thoracic Endovascular Aortic Repair. International journal

    Hidekazu Imai, Nobuko Ohashi, Takayuki Yoshida, Takeshi Okamoto, Nobutaka Kitamura, Takahiro Tanaka, Hiroshi Baba

    Anesthesia and analgesia   125 ( 2 )   417 - 420   2017.8

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    Persistent endoleaks may lead to adverse events after endovascular aortic repair. We prospectively examined the relationship between intraoperative residual spontaneous echocardiographic contrast (SEC) within the aneurysmal sac and the incidence of postoperative endoleaks in 60 patients undergoing thoracic endovascular aortic repair. Patients with SEC had a higher incidence of postoperative endoleaks than did patients without SEC within a few days postoperatively (60.0% vs 12.5%, respectively; P < .001) and at 6 months postoperatively (40.0% vs 2.5%, respectively; P < .001). Intraoperative confirmation of the absence of SEC may identify patients at low risk for persistent endoleaks after thoracic endovascular aortic repair.

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  • Efficacy and Safety of Long-Term Sirolimus Therapy for Asian Patients with Lymphangioleiomyomatosis. International journal

    Toshinori Takada, Ayako Mikami, Nobutaka Kitamura, Kuniaki Seyama, Yoshikazu Inoue, Katsura Nagai, Masaru Suzuki, Hiroshi Moriyama, Keiichi Akasaka, Ryushi Tazawa, Toyohiro Hirai, Michiaki Mishima, Mie Hayashida, Masaki Hirose, Chikatoshi Sugimoto, Toru Arai, Noboru Hattori, Kentaro Watanabe, Tsutomu Tamada, Hirohisa Yoshizawa, Kohei Akazawa, Takahiro Tanaka, Keita Yagi, Lisa R Young, Francis X McCormack, Koh Nakata

    Annals of the American Thoracic Society   13 ( 11 )   1912 - 1922   2016.11

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    RATIONALE: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. OBJECTIVES: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. METHODS: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. MEASUREMENTS AND MAIN RESULTS: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. CONCLUSIONS: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

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  • Establishment of the consecutive registration system for pulmonary alveolar proteinosis in Japan: Updated incidence, prevalence and surveillance for intractable cases Reviewed

    Yoshikazu Inoue, Koh Nakata, Etsuro Yamaguchi, Toru Arai, Chikatoshi Sugimoto, Yasuhiro Setoguchi, Toshio Ichiwata, Masahito Ebina, Kazutoshi Cho, Ryushi Tazawa, Haruyuki Ishii, Takahiro Kasai, Masanori Akira, Kanji Uchida, Hiroshi Kida, Sakae Homma, Koichiro Tatsumi, Arata Azuma, Koichi Hagiwara, Keisuke Tomii, Masanori Kitaichi, Masaru Suzuki, Kohnosuke Morimoto, Toshinori Takada, Hideaki Nakayama, Shinya Ohkouchi, Takahiro Tanaka, Masaki Hirose, Akiko Matsumuro

    EUROPEAN RESPIRATORY JOURNAL   48   2016.9

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    DOI: 10.1183/13993003.congress-2016.PA3873

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  • Inhalation of granulocyte/macrophage-colony stimulating factor (GM-CSF) and GM-CSF antibody

    R. Tazawa, K. Nakagaki, Y. Ito, A. Hashimoto, T. Tanaka, K. Akasaka, K. Nakata

    EUROPEAN JOURNAL OF IMMUNOLOGY   46   865 - 865   2016.8

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  • Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease. International journal

    Shoji Kuwahara, Michihiro Hosojima, Reika Kaneko, Hiroyuki Aoki, Daisuke Nakano, Taiji Sasagawa, Hideyuki Kabasawa, Ryohei Kaseda, Ryota Yasukawa, Tomomi Ishikawa, Akiyo Suzuki, Hiroyoshi Sato, Shun Kageyama, Takahiro Tanaka, Nobutaka Kitamura, Ichiei Narita, Masaaki Komatsu, Akira Nishiyama, Akihiko Saito

    Journal of the American Society of Nephrology : JASN   27 ( 7 )   1996 - 2008   2016.7

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    Obesity, an important risk factor for metabolic syndrome (MetS) and cardiovascular disease, is often complicated by CKD, which further increases cardiovascular risk and causes ESRD. To elucidate the mechanism underlying this relationship, we investigated the role of the endocytic receptor megalin in proximal tubule epithelial cells (PTECs). We studied a high-fat diet (HFD)-induced obesity/MetS model using kidney-specific mosaic megalin knockout (KO) mice. Compared with control littermates fed a normal-fat diet, control littermates fed an HFD for 12 weeks showed autolysosomal dysfunction with autophagy impairment and increased expression of hypertrophy, lipid peroxidation, and senescence markers in PTECs of the S2 segment, peritubular capillary rarefaction with localized interstitial fibrosis, and glomerular hypertrophy with mesangial expansion. These were ameliorated in HFD-fed megalin KO mice, even though these mice had the same levels of obesity, dyslipidemia, and hyperglycemia as HFD-fed control mice. Intravital renal imaging of HFD-fed wild-type mice also demonstrated the accumulation of autofluorescent lipofuscin-like substances in PTECs of the S2 segment, accompanied by focal narrowing of tubular lumens and peritubular capillaries. In cultured PTECs, fatty acid-rich albumin induced the increased expression of genes encoding PDGF-B and monocyte chemoattractant protein-1 via megalin, with large (auto)lysosome formation, compared with fatty acid-depleted albumin. Collectively, the megalin-mediated endocytic handling of glomerular-filtered (lipo)toxic substances appears to be involved primarily in hypertrophic and senescent PTEC injury with autophagy impairment, causing peritubular capillary damage and retrograde glomerular alterations in HFD-induced kidney disease. Megalin could be a therapeutic target for obesity/MetS-related CKD, independently of weight, dyslipidemia, and hyperglycemia modification.

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  • Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study. International journal

    Keiichi Akasaka, Takahiro Tanaka, Nobutaka Kitamura, Shinya Ohkouchi, Ryushi Tazawa, Toshinori Takada, Toshio Ichiwata, Etsuro Yamaguchi, Masaki Hirose, Toru Arai, Kentaro Nakano, Takahito Nei, Haruyuki Ishii, Tomohiro Handa, Yoshikazu Inoue, Koh Nakata

    BMC pulmonary medicine   15   88 - 88   2015.8

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    BACKGROUND: Although no report has demonstrated the efficacy of corticosteroid therapy for autoimmune pulmonary alveolar proteinosis (aPAP), we sometimes encounter patients who have received this therapy for various reasons. However, as corticosteroids can suppress alveolar macrophage function, corticosteroid therapy might worsen disease severity and increase the risk of infections. METHODS: For this retrospective cohort study, we sent a screening form to 165 institutions asking for information on aPAP patients treated with corticosteroids. Of the resulting 45 patients screened, 31 were enrolled in this study. We collected demographic data and information about corticosteroid treatment period, dose, disease severity score (DSS) over the treatment period, and complications. RESULTS: DSS deteriorated during corticosteroid therapy in 23 cases (74.1 %) and the estimated overall cumulative worsening rate was 80.8 % for the total observation period. The worsening rate was significantly higher in patients treated with high-dose prednisolone (>18.9 mg/day, n = 16) than treated with low-dose prednisolone (≤18.9 mg/day, n = 15) divided by median daily dose (p < 0.02). Of patients with worsening, one died of disseminated aspergillosis and another of respiratory failure. Infections newly emerged in 6 cases during corticosteroid therapy (p < 0.05). Median serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody levels were similar to previously reported data in a large cohort study. CONCLUSION: The results demonstrate that corticosteroid therapy may worsen DSS of aPAP, increasing the risk for infections.

    DOI: 10.1186/s12890-015-0085-0

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  • A mathematical model to predict protein wash out kinetics during whole-lung lavage in autoimmune pulmonary alveolar proteinosis. International journal

    Keiichi Akasaka, Takahiro Tanaka, Takashi Maruyama, Nobutaka Kitamura, Atsushi Hashimoto, Yuko Ito, Hiroyoshi Watanabe, Tomoshige Wakayama, Takero Arai, Masachika Hayashi, Hiroshi Moriyama, Kanji Uchida, Shinya Ohkouchi, Ryushi Tazawa, Toshinori Takada, Etsuro Yamaguchi, Toshio Ichiwata, Masaki Hirose, Toru Arai, Yoshikazu Inoue, Hirosuke Kobayashi, Koh Nakata

    American journal of physiology. Lung cellular and molecular physiology   308 ( 2 )   L105-17   2015.1

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    Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10-30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and β2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of β2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

    DOI: 10.1152/ajplung.00239.2014

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  • A PRE-CLINICAL STUDY FOR DEVELOPMENT OF A NEW GM-CSF INHALATION DRUG AS A TREATMENT OF PULMONARY ALVEOLAR PROTEINOSIS

    R. Tazawa, K. Nakagaki, Y. Ito, A. Hashimoto, T. Tanaka, K- Akasaka, K. Nakata

    RESPIROLOGY   19   29 - 29   2014.11

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  • A mechanism for acceleration of GM-CSF autoantibody (GMAb) production in autoimmune pulmonary alveolar proteinosis (aPAP)

    Koh Nakata, Takahiro Tanaka, Ryushi Tazawa

    EUROPEAN RESPIRATORY JOURNAL   44   2014.9

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  • Low concentrations of recombinant granulocyte macrophage-colony stimulating factor derived from Chinese hamster ovary cells augments long-term bioactivity with delayed clearance in vitro. International journal

    Atsushi Hashimoto, Takahiro Tanaka, Yuko Itoh, Akira Yamagata, Nobutaka Kitamura, Ryushi Tazawa, Kazuhide Nakagaki, Koh Nakata

    Cytokine   68 ( 2 )   118 - 26   2014.8

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    To date, the biological activity of granulocyte macrophage-colony stimulating factor (GM-CSF) has been investigated by using mostly Escherichia coli- or yeast cell-derived recombinant human GM-CSF (erhGM-CSF and yrhGM-CSF, respectively). However, Chinese hamster ovary cell-derived recombinant human GM-CSF (crhGM-CSF), as well as natural human GM-CSF, is a distinct molecule that includes modifications by complicated oligosaccharide moieties. In the present study, we reevaluated the bioactivity of crhGM-CSF by comparing it with those of erhGM-CSF and yrhGM-CSF. The effect of short-term stimulation (0.5h) on the activation of neutrophils/monocytes or peripheral blood mononuclear cells (PBMCs) by crhGM-CSF was lower than those with erhGM-CSF or yrhGM-CSF at low concentrations (under 60pM). Intermediate-term stimulation (24h) among the different rhGM-CSFs with respect to its effect on the activation of TF-1 cells, a GM-CSF-dependent cell line, or PBMCs was not significantly different. In contrast, the proliferation/survival of TF-1 cells or PBMCs after long-term stimulation (72-168h) was higher at low concentrations of crhGM-CSF (15-30pM) than that of cells treated with other GM-CSFs. The proportion of apoptotic TF-1 cells after incubation with crhGM-CSF for 72h was lower than that of cells incubated with other rhGM-CSFs. These effects were attenuated by desialylation of crhGM-CSF. Clearance of crhGM-CSF but not desialylated-crhGM-CSF by both TF-1 cells and PBMCs was delayed compared with that of erhGM-CSF or yrhGM-CSF. These results suggest that sialylation of oligosaccharide moieties delayed the clearance of GM-CSF, thus eliciting increased long-term bioactivity in vitro.

    DOI: 10.1016/j.cyto.2014.03.009

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  • Light chain (κ/λ) ratio of GM-CSF autoantibodies is associated with disease severity in autoimmune pulmonary alveolar proteinosis. International journal

    Takahito Nei, Shinya Urano, Yuko Itoh, Nobutaka Kitamura, Atsushi Hashimoto, Takahiro Tanaka, Natsuki Motoi, Chinatsu Kaneko, Ryushi Tazawa, Kazuhide Nakagaki, Toru Arai, Yoshikazu Inoue, Koh Nakata

    Clinical immunology (Orlando, Fla.)   149 ( 3 )   357 - 64   2013.12

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    Previous studies demonstrated that antigranulocyte colony-stimulating factor autoantibody (GMAb) was consistently present in patients with autoimmune pulmonary alveolar proteinosis (aPAP), and, thus, represented candidature as a reliable diagnostic marker. However, our large cohort study suggested that the concentration of this antibody was not correlated with disease severity in patients. We found that the κ/λ ratio of GMAb was significantly correlated with the degree of hypoxemia. The proportion of λ-type GMAb per total λ-type IgG was significantly higher in severely affected patients than those in mildly affected patients, but the proportion of κ-type was unchanged. The κ/λ ratio was significantly correlated with both KL-6 and SP-D, which have been previously reported as disease severity markers. Thus, the light chain isotype usage of GMAb may not only be associated with the severity of aPAP, but may also represent a useful disease severity marker.

    DOI: 10.1016/j.clim.2013.10.002

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  • Circulating levels of adiponectin, leptin, fetuin-A and retinol-binding protein in patients with tuberculosis: markers of metabolism and inflammation. International journal

    Naoto Keicho, Ikumi Matsushita, Takahiro Tanaka, Takuro Shimbo, Nguyen Thi Le Hang, Shinsaku Sakurada, Nobuyuki Kobayashi, Minako Hijikata, Pham Huu Thuong, Luu Thi Lien

    PloS one   7 ( 6 )   e38703   2012

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    BACKGROUND: Wasting is known as a prominent feature of tuberculosis (TB). To monitor the disease state, markers of metabolism and inflammation are potentially useful. We thus analyzed two major adipokines, adiponectin and leptin, and two other metabolic markers, fetuin-A and retinol-binding protein 4 (RBP4). METHODS: The plasma levels of these markers were measured using enzyme-linked immunosorbent assays in 84 apparently healthy individuals (=no-symptom group) and 46 patients with active pulmonary TB around the time of treatment, including at the midpoint evaluation (=active-disease group) and compared them with body mass index (BMI), C-reactive protein (CRP), chest radiographs and TB-antigen specific response by interferon-γ release assay (IGRA). RESULTS: In the no-symptom group, adiponectin and leptin showed negative and positive correlation with BMI respectively. In the active-disease group, at the time of diagnosis, leptin, fetuin-A and RBP4 levels were lower than in the no-symptom group [adjusted means 2.01 versus 4.50 ng/ml, P<0.0001; 185.58 versus 252.27 µg/ml, P<0.0001; 23.88 versus 43.79 µg/ml, P<0.0001, respectively]. High adiponectin and low leptin levels were associated with large infiltrates on chest radiographs even after adjustment for BMI and other covariates (P=0.0033 and P=0.0020). During treatment, adiponectin levels increased further and then decreased. Leptin levels remained low. Initial low levels of fetuin-A and RBP4 almost returned to the normal reference range in concert with reduced CRP. CONCLUSIONS: Our data and recent literature suggest that low fat store and underlying inflammation may regulate these metabolic markers in TB in a different way. Decreased leptin, increased adiponectin, or this ratio may be a promising marker for severity of the disease independent of BMI. We should further investigate pathological roles of the balance between these adipokines.

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  • Identification of tuberculosis-associated proteins in whole blood supernatant. International journal

    Takahiro Tanaka, Shinsaku Sakurada, Keiko Kano, Eri Takahashi, Kazuki Yasuda, Hisashi Hirano, Yasushi Kaburagi, Nobuyuki Kobayashi, Nguyen Thi Le Hang, Luu Thi Lien, Ikumi Matsushita, Minako Hijikata, Takafumi Uchida, Naoto Keicho

    BMC infectious diseases   11   71 - 71   2011.3

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    BACKGROUND: Biological parameters are useful tools for understanding and monitoring complicated disease processes. In this study, we attempted to identify proteins associated with active pulmonary tuberculosis (TB) using a proteomic approach. METHODS: To assess TB-associated changes in the composition of human proteins, whole blood supernatants were collected from patients with active TB and healthy control subjects. Two-dimensional difference gel electrophoresis (2D-DIGE) was performed to analyze proteins with high molecular weights (approximately >20 kDa). Baseline protein levels were initially compared between patients with active TB and control subjects. Possible changes of protein patterns in active TB were also compared ex vivo between whole blood samples incubated with Mycobacterium tuberculosis (Mtb)-specific antigens (stimulated condition) and under unstimulated conditions. Immunoblot and enzyme-linked immunosorbent assays (ELISA) were performed to confirm differences in identified proteins. RESULTS: Under the baseline condition, we found that the levels of retinol-binding protein 4 (RBP4), fetuin-A (also called α-HS-glycoprotein), and vitamin D-binding protein differed between patients with active TB and control subjects on 2D gels. Immunoblotting results confirmed differential expression of RBP4 and fetuin-A. ELISA results further confirmed significantly lower levels of these two proteins in samples from patients with active TB than in control subjects (P < 0.0001). Mtb-specific antigen stimulation ex vivo altered clusterin expression in whole blood samples collected from patients with active TB. CONCLUSIONS: We identified TB-associated proteins in whole blood supernatants. The dynamics of protein expression during disease progression may improve our understanding of the pathogenesis of TB.

    DOI: 10.1186/1471-2334-11-71

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  • 肺胞蛋白症診療ガイドライン2022

    日本呼吸器学会肺胞蛋白症診療ガイドライ, 作成委員会( Role: Joint author ,  肺胞蛋白症(PAP)の疫学)

    一般社団法人 日本呼吸器学会  2022.6 

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  • 肺胞蛋白症に対する吸入療法開発の現状—Inhaled protein drugs currently in clinical development for pulmonary alveolar proteinosis

    田中 崇裕, 田澤 立之

    呼吸器内科 = Respiratory medicine / 呼吸器内科編集委員会 編   41 ( 5 )   483 - 487   2022.5

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  • 肺胞蛋白症をめぐって 自己免疫性肺胞蛋白症におけるCT値測定による定量的評価の解析

    小田 未来, 石井 晴之, 北村 信隆, 鈴木 雅, 大河内 眞也, 高田 俊範, 巽 浩一郎, 泉 信有, 三上 礼子, 山口 悦郎, 井上 義一, 新井 徹, 半田 知宏, 富井 啓介, 江田 良輔, 森本 浩之輔, 田中 健之, 赤坂 圭一, 坂上 拓郎, 田中 崇裕, 田澤 立之, 中田 光, 肺胞蛋白症GMCSF吸入製剤多施設共同二重盲検比較試験(PAGE)PAGE研究班

    日本呼吸器学会誌   9 ( 増刊 )   142 - 142   2020.8

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  • SGLT2阻害薬による腎保護作用機序と尿中コンパニオン診断法の検討

    忰田 亮平, 飯田 倫理, 細島 康宏, 蒲澤 秀門, 後藤 佐和子, 桑原 頌治, 宇賀村 大亮, 吉澤 優太, 田中 崇裕, 成田 一衛, 斎藤 亮彦

    臨床薬理の進歩   ( 41 )   148 - 153   2020.6

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    軽度〜中等度腎機能障害を有する成人2型糖尿病患者(残存機能ネフロンに過剰代謝負荷がかかっていることが推測される)を対象に、エンパグリフロジンによる腎機能保護作用を検証するとともに尿中メガリン(およびメガリンリガンド分子)の動態を調べ、腎機能保護作用がメガリン機能に関連したものであるか検討した。さらに、尿中メガリンなどの検査がコンパニオン診断として有用であるか、探索的な検討を行った。また、SGLT2阻害薬がメガリンの発現・機能に及ぼす影響についても検討を継続した。臨床試験の被験者51名で、平均年齢は62歳であり、男性が32名であった。2名が有害反応のため脱落したが、6ヵ月後、HbA1cとBMIが減少した。現在、メガリンを含む尿中バイオマーカーの推移について解析を行っている。ダパグリフロジン、エンパグリフロジンを投与されたマウスでは尿中の糖排泄増加を認めたが血糖値に差は認められなかった。免疫組織化学染色では近位尿細管におけるメガリンの染色性が低下していることが確認された。またウエスタンブロット法において、メガリンの蛋白がvehicle群と比較して低下していることが認められた。リアルタイムRT-PCRにおいてもメガリンmRNAがvehicle群と比較して低下していることが確認された。ダパグリフロジンを添加されたIRPTCではメガリン蛋白の低下が認められ、mRNAの低下も認められた。

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  • 自記式食事歴質問票(DHQ)を用いたSGLT2阻害薬の効果と食事摂取状況の検討

    村山 稔子, 細島 康宏, 蒲澤 秀門, 桑原 頌治, 田中 崇裕, 鈴木 芳樹, 成田 一衛, 斎藤 亮彦

    糖尿病   62 ( Suppl.1 )   S - 263   2019.4

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  • 自記式食事歴質問票(DHQ)を用いたSGLT2阻害薬の効果と食事摂取状況の検討

    村山 稔子, 細島 康宏, 蒲澤 秀門, 桑原 頌治, 田中 崇裕, 鈴木 芳樹, 成田 一衛, 斎藤 亮彦

    糖尿病   62 ( Suppl.1 )   S - 263   2019.4

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  • 肺胞蛋白症の20年史 自己免疫性肺胞蛋白症の最新疫学

    北村 信隆, 大河内 眞也, 田澤 立之, 石井 晴之, 高田 俊範, 坂上 拓郎, 田中 崇裕, 中田 光

    日本呼吸器学会誌   8 ( 増刊 )   22 - 22   2019.3

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  • 肺胞蛋白症の20年史 自己免疫性肺胞蛋白症に対するGM-CSF吸入療法

    田澤 立之, 鈴木 雅, 大河内 眞也, 朝川 勝明, 巽 浩一郎, 石井 晴之, 泉 信有, 山口 悦郎, 井上 義一, 半田 知宏, 富井 啓介, 江田 良輔, 森本 浩之輔, 三上 礼子, 田中 崇裕, 北村 信隆, 高田 俊範, 上田 隆宏, 中垣 和英, 中田 光

    日本呼吸器学会誌   8 ( 増刊 )   23 - 23   2019.3

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  • 肺胞蛋白症の20年史 自己免疫性肺胞蛋白症に対するGM-CSF吸入療法

    田澤 立之, 鈴木 雅, 大河内 眞也, 朝川 勝明, 巽 浩一郎, 石井 晴之, 泉 信有, 山口 悦郎, 井上 義一, 半田 知宏, 富井 啓介, 江田 良輔, 森本 浩之輔, 三上 礼子, 田中 崇裕, 北村 信隆, 高田 俊範, 上田 隆宏, 中垣 和英, 中田 光

    日本呼吸器学会誌   8 ( 増刊 )   23 - 23   2019.3

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  • 自記式食事歴質問票(DHQ)を用いたSGLT2阻害薬使用時の食事内容の検討

    村山 稔子, 細島 康宏, 蒲澤 秀門, 桑原 頌治, 田中 崇裕, 鈴木 芳樹, 成田 一衛, 斎藤 亮彦

    日本病態栄養学会誌   22 ( Suppl. )   S - 60   2019.1

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  • 自記式食事歴質問票(DHQ)を用いたSGLT2阻害薬使用時の食事内容の検討

    村山 稔子, 細島 康宏, 蒲澤 秀門, 桑原 頌治, 田中 崇裕, 鈴木 芳樹, 成田 一衛, 斎藤 亮彦

    日本病態栄養学会誌   22 ( Suppl. )   S - 60   2019.1

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  • 次世代シークエンサーによる自己免疫性肺胞蛋白症のGM-CSF自己抗体軽鎖配列の解析 (第15回肺サーファクタント分子病態研究会)

    橋本 淳史, 竹内 志穂, 中垣 和英, 伊藤 祐子, 高田 俊範, 赤坂 圭一, 田澤 立之, 根井 貴仁, 田中 崇裕, 中田 光

    分子呼吸器病   21 ( 1 )   98 - 102,図巻頭13   2017.3

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    Other Link: http://search.jamas.or.jp/link/ui/2017202282

  • ステロイドは自己免疫性肺胞蛋白症に対して有効か無効か?

    赤坂 圭一, 田中 崇裕, 有福 一, 仲野 堅太郎, 時田 心悟, 石井 晴之, 大河内 眞也, 田澤 立之, 北村 信隆, 中田 光

    日本呼吸器学会誌   4 ( 増刊 )   259 - 259   2015.3

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  • Exploration of anti-mycobacterial factors in the culture supernatant of monocytes-derived macrophages differentiated with M-CSF

    Tanaka Takahiro, Sakurada Shinsaku, Takii Takemasa, Akagawa Kiyoko, Satou Megumi, Kaburagi Yasushi, Keicho Naoto

    Abstracts for Annual Meeting of Japanese Proteomics Society   2012   124 - 124   2012

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    DOI: 10.14889/jhupo.2012.0.124.0

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  • 活動性結核患者血漿タンパク質の2D-DIGEとLC-MS/MSによる解析

    田中 崇裕, 櫻田 紳策, 高橋 枝里, 鏑木 康志, 平野 久, 小林 信之, 原田 登之, 慶長 直人

    日本プロテオーム学会大会要旨集   2010   110 - 110   2010

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    Language:Japanese   Publisher:日本プロテオーム学会(日本ヒトプロテオーム機構)  

    DOI: 10.14889/jhupo.2010.0.110.1

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Presentations

  • 栄養状態による心不全患者の長期ケアの予測(Nutritional Status Predicts Long-term Care in Patients with Heart Failure)

    藤木 伸也, 藤木 伸也, 大倉 裕二, 古寺 邦夫, 渡部 裕, 田中 孔明, 坂内 省五, 田中 崇裕, 北村 信隆, 南野 徹

    日本循環器学会学術集会抄録集  2021.3  (一社)日本循環器学会

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    Event date: 2021.3

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  • Chronic Inhalation Of Recombinant Human Granulocyte/ macrophage Colony Stimulating Factor (gm-Csf) And Gm-Csf Antibody In Nonhuman Primates

    R. Tazawa, K. Nakagaki, Y. Ito, M. Iizuka, A. Hashimoto, R. Nakano, T. Tanaka, K. Akasaka, S. Takeuchi, K. Nakata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2017  AMER THORACIC SOC

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    Event date: 2017

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  • Light Chain Genotype Analysis Of Gm-Csf Autoantibody In Autoimmune Pulmonary Alveolar ProteINOSis By Next Generation Sequencing

    A. Hashimoto, T. Tanaka, A. Hayakawa, Y. Itoh, T. Nei, K. Shiiya, M. Higuchi, K. Nakagaki, T. Takada, K. Akasaka, R. Tazawa, K. Nakata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2016  AMER THORACIC SOC

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    Event date: 2016

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  • Early And Late Onset Adverse Events In Lam Patients Treated With Sirolimus For Two Years

    K. Nakata, Y. Inoue, K. Seyama, R. Tazawa, T. Tamada, A. Mikami, H. Nakayama, M. Suzuki, M. Ebina, M. Hanaoka, N. Hattori, T. Hirai, T. Arai, C. Sugimoto, N. Kitamura, T. Tanaka, K. Akazawa, M. Mishima

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2016  AMER THORACIC SOC

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    Event date: 2016

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  • Early Intervention With Sirolimus Benefits Mild Lymphangioleiomyomatosis-Related Lung Disease

    T. Takada, K. Seyama, Y. Inoue, K. Nagai, M. Suzuki, H. Moriyama, K. Akasaka, R. Tazawa, T. Hirai, M. Mishima, M. Hayashida, M. Hirose, C. Sugimoto, T. Arai, N. Hattori, K. Watanabe, A. Mikami, T. Tamada, H. Yoshizawa, K. Akazawa, T. Tanaka, N. Kitamura, K. Nakata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2016  AMER THORACIC SOC

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    Event date: 2016

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  • Inhalation Of Recombinant Human Granulocyte/macrophage-Colony Stimulating Factor And Induction Of The Gm-Csf Antibody In Pulmonary Alveolar ProteINOSis

    R. Tazawa, K. Nakagaki, Y. Ito, A. Hashimoto, T. Tanaka, K. Akasaka, K. Nakata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2015  AMER THORACIC SOC

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    Event date: 2015

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  • A Novel Method For Measuring Low Concentration Of Gm-Csf Autoantibody In The Sera Of Healthy Subjects

    K. Shiiya, A. Hashimoto, T. Tanaka, K. Akasaka, Y. Itoh, R. Tazawa, K. Nakata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2015  AMER THORACIC SOC

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    Event date: 2015

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  • A Differential Equation For Permeation Of Antibody From Blood To The Lung

    K. Nakata, K. Akasaka, T. Tanaka, T. Maruyama, R. Tazawa, E. Yamaguchi, T. Ichiwata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2014  AMER THORACIC SOC

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    Event date: 2014

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  • 活動性結核患者血漿タンパク質の2D-DIGEとLC-MS/MSによる解析

    田中 崇裕, 櫻田 紳策, 高橋 枝里, 鏑木 康志, 平野 久, 小林 信之, 原田 登之, 慶長 直人

    日本プロテオーム学会大会要旨集  2010  日本プロテオーム学会(日本ヒトプロテオーム機構)

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    Event date: 2010

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Research Projects

  • 抗体を利用する、新しい結核の診断法と制御法の開発を目指した、国際共同研究

    Grant number:21KK0136  2021.10 - 2025.3

    日本学術振興会  科学研究費助成事業 国際共同研究加速基金(国際共同研究強化(B))  国際共同研究加速基金(国際共同研究強化(B))

    松本 壮吉

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    Grant amount:\19240000 ( Direct Cost: \14800000 、 Indirect Cost:\4440000 )

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  • 新規リン代謝マーカー:ポリリン酸と腎臓病で増悪する感染症の関連

    Grant number:20K08628  2020.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山本 卓, 成田 一衛, 後藤 祐児, 田中 崇裕, 北村 信隆, 山口 圭一

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

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  • Novel protocols of inhaled GM-CSF therapy for smoker patients with pulmonary alveolar proteinosis

    Grant number:20H03686  2020.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

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  • 血球吸着モデルを用いたLAM患者におけるシロリムス最適薬用量決定法の提案

    Grant number:20K08537  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    田中 崇裕, 中田 光, 北村 信隆, 高田 俊範

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

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