2026/05/08 更新

写真a

ハシモト　アツシ
橋本　淳史
HASHIMOTO Atsushi
所属
医歯学総合病院 臨床研究推進センター 特任助教
職名
特任助教
外部リンク

学位

  • 博士（医学） （ 2020年3月   新潟大学 ）

研究キーワード

  • 免疫学

  • 抗体遺伝子

  • バイオインフォマティクス

  • 臨床検査学

  • 生物統計学

研究分野

  • 情報通信 / 統計科学  / 生物統計学

  • ライフサイエンス / 衛生学、公衆衛生学分野：実験系を含む  / 臨床検査学

  • ライフサイエンス / 免疫学  / 抗体、遺伝子、バイオインフォマティクス

  • ライフサイエンス / 免疫学  / 抗体、遺伝子、バイオインフォマティクス

  • 情報通信 / 統計科学  / 生物統計学

  • ライフサイエンス / 衛生学、公衆衛生学分野：実験系を含む  / 臨床検査学

▶ 全件表示

経歴（researchmap）

  • 新潟大学   医歯学総合病院 臨床研究推進センター   特任助教

    2024年10月 - 現在

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  • 新潟大学   医歯学総合病院 臨床研究推進センター   客員研究員

    2024年4月 - 2024年9月

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  • 新潟大学   医歯学総合病院 臨床研究推進センター   特任専門職員

    2018年7月 - 2024年3月

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  • 新潟大学   医歯学総合病院 生命科学医療センター   科学技術振興技術者

    2015年7月 - 2018年6月

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  • 新潟大学   医歯学総合病院 生命科学医療センター   産学連携技術者

    2015年4月 - 2015年6月

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  • 新潟大学   医歯学総合病院 生命科学医療センター   厚生科研費技術者

    2014年5月 - 2015年3月

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▶ 全件表示

経歴

  • 新潟大学   医歯学総合病院 臨床研究推進センター   特任助教

    2024年10月 - 現在

学歴

  • 新潟大学   大学院医歯学総合研究科   生体機能調節医学専攻

    2014年4月 - 2020年3月

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所属学協会

  • 日本計量生物学会

    2019年4月 - 現在

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論文

  • Direct Hemoperfusion with Polymethylmethacrylate for Hemodialysis Patients with Dialysis-Related Amyloidosis. 国際誌

    Shoko Yamazaki, Daisuke Miyauchi, Atsushi Hashimoto, Takahiro Tanaka, Mototsugu Tanaka, Hisaki Shimada, Yuji Ishii, Koji Matsuo, Akio Kasai, Yutaka Koda, Kokichi Saito, Junichi Hoshino, Shinichi Nishi, Suguru Yamamoto

    Blood purification   1 - 10   2025年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    INTRODUCTION: Dialysis-related amyloidosis (DRA) is a serious complication in patients undergoing long-term dialysis that leads to conditions such as carpal tunnel syndrome and destructive spondyloarthropathy. Improved removal of the precursor protein β2-microglobulin (β2-m) is considered an effective treatment strategy for DRA. Polymethylmethacrylate (PMMA) membranes have the capacity to adsorb β2-m in dialysis filters, suggesting that direct hemoperfusion with PMMA in addition to standard dialysis may enhance β2-m removal. METHODS: This prospective cohort study included 10 patients undergoing hemodialysis, who were diagnosed with DRA. The participants were treated with dialysis filter alone during visit 1, both standard dialysis filter and PMMA cartridges (FT-75, volume 75 cm3) during visits 2-4, and FT-145 PMMA cartridges (volume 145 cm3) during visits 5-7. The removal rates and clearances of β2-m were quantified. We also assessed the removal of α1-microglobulin (α1-m), matrix metalloproteinase-3 (MMP-3), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α), which may be associated with DRA symptoms. RESULTS: PMMA cartridge had increased β2-m removal rates compared to dialysis filter alone for treatment duration of 240 min. Similarly, the removal rates of α1-m and MMP-3 were higher with PMMA cartridges than with dialysis filter alone. β2-m, α1-m, and MMP-3 clearance improved with the addition of PMMA cartridges, depending on the cartridge size. The removal rates of IL-6 and TNF-α were higher with PMMA cartridges than with dialysis filter alone at 30 min, but not at 240 min. CONCLUSION: Direct hemoperfusion with PMMA is an effective method for removing β2-m in hemodialysis patients with DRA. Beneficial effects were also observed for the removal of α1-m and MMP-3. Further research is required to evaluate the long-term efficacy of this approach in managing DRA.

    DOI： 10.1159/000546771

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  • Dapagliflozin for peritoneal dialysis patients with chronic heart failure in Japan: study protocol for a multicenter, open-label, randomized controlled trial (the jDAPA-PD study)

    Mototsugu Tanaka, Masahiro Ishizawa, Ryohei Terashima, Atsushi Hashimoto, Takahiro Tanaka, Haruna Miyazawa, Kazuki Watanabe, Akira Iguchi, Hajime Yamazaki, Asa Ogawa, Noriaki Iino, Naoto Hamano, Ken Ataka, Suguru Yamamoto

    Renal Replacement Therapy   11 ( 1 )   2025年6月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    Abstract

    Background

    The effects of dapagliflozin on patients with end-stage kidney disease (ESKD) and chronic heart failure (CHF) who are on peritoneal dialysis (PD) are not well understood. The jDAPA-PD is a proof-of-concept study designed to assess the efficacy and safety of dapagliflozin in such patients in Japan.

    Methods

    This is a multicenter, open-label, randomized controlled trial conducted on 40 patients with ESKD and CHF on maintenance PD, particularly those who have substantial residual kidney function. Patients who were recently on sodium–glucose cotransporter 2 inhibitors, hemodialysis, or treatment for peritonitis or those who have a daily urine volume of < 500 mL will be excluded from the study. Participants will be randomized in a 1:1 allocation to either 10 mg dapagliflozin orally once-daily group or the standard treatment group. The change in extracellular water from baseline to week 24 is the primary endpoint, which will be measured by bioelectrical impedance analysis. The secondary endpoints are all-cause mortality, cardiovascular events, hospitalization, PD discontinuation, and changes in body composition, blood pressure, renal and cardiac function, brain natriuretic peptide, peritoneal function, PD regimen, and weekly fluid removal from baseline to week 24. The safety endpoints are adverse events and adverse drug reactions that occur during the study period.

    Results

    The first participant completed the treatment, and the study is now open for recruitment.

    Conclusions

    This study will determine whether the oral administration of 10 mg of dapagliflozin for 24 weeks is effective in fluid control for patients with CHF on PD. The study will also provide evidence of the safety data and multifaceted effects of dapagliflozin in patients on PD.

    Trial registration jRCT1031230624 (registered on 5 February 2024).

    DOI： 10.1186/s41100-025-00647-2

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    その他リンク： https://link.springer.com/article/10.1186/s41100-025-00647-2/fulltext.html

  • Polyacrylic acid-polyvinylpyrrolidone complex for achieving hemostasis after hemodialysis: study protocol for an open-label crossover randomized controlled trial (PAA-PVP study). 国際誌

    Ryohei Terashima, Mototsugu Tanaka, Atsushi Hashimoto, Daiki Omori, Takahiro Tanaka, Haruna Miyazawa, Masahiro Ishizawa, Yoshihiko Tomita, Tomoko Ito, Yoshiyuki Koyama, Kokichi Saito, Suguru Yamamoto, Shin Goto, Ichiei Narita

    Trials   26 ( 1 )   171 - 171   2025年5月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Achieving rapid and secure hemostasis of the vascular access point is important for patients undergoing maintenance hemodialysis (HD). We developed a polyacrylic acid-polyvinylpyrrolidone (PAA-PVP) complex that absorbs moisture such as blood or sterilizing solution, forms a hydrogel, and adheres to the body's surface, thereby exerting a powerful hemostatic effect. This study aims to compare the effect of PAA-PVP complex versus a conventional non-woven fabric pad on hemostasis at the needle puncture vascular access site in patients on HD. METHODS: This open-label crossover randomized controlled trial will include 50 participants who undergo thrice-weekly HD. Participants in whom hemostasis requires more than 10 min by compression using a conventional pad or who have a severe skin problem at the needle puncture vascular access site will be excluded from the study. Participants will be randomized in a 1:1 ratio to receive either the PAA-PVP complex or conventional pads. Three consecutive weekly hemostatic tests will be performed at 11, 9, 7, 5, 3, and 1 min. The study will employ an individual 3+3 design in which participants in whom hemostasis is achieved in all three sessions in a week will be challenged to a shorter time in the three sessions of the next week. Those in whom hemostasis is achieved in two of three sessions will be tested at the same time point in the three sessions of the next week. The study treatment will be terminated if hemostasis is achieved in only one or none of the sessions, and the minimum time with three consecutive successes will be recorded as the hemostasis time. The primary endpoint, the hemostasis time on the arterial side of the vascular access, will be analyzed using mixed-effect models for repeated measures and include the hemostatic technique and group, period, and individual effects as covariates. DISCUSSION: The study will provide evidence on whether the PAA-PVP complex reduces hemostasis time of the vascular access compared to conventional pad in patients on HD. TRIAL REGISTRATION: jRCTs032220597 (Japan Registry of Clinical Trials; registered on January 30, 2023, https://jrct.niph.go.jp/latest-detail/jRCTs032220597 ).

    DOI： 10.1186/s13063-025-08877-9

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  • Removal of α1-Microglobulin Using Post-Dilution Online Hemodiafiltration with Polymethylmethacrylate Membrane: An Open-Label, Single-Arm Study. 国際誌

    Shiori Yoshida, Suguru Yamamoto, Daisuke Miyauchi, Ryohei Terashima, Atsushi Hashimoto, Haruna Miyazawa, Takahiro Tanaka, Masahiro Ishizawa, Mototsugu Tanaka, Yoshihiko Tomita, Ikuo Aoike, Shin Goto, Ichiei Narita

    Blood purification   53 ( 2 )   123 - 129   2024年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    INTRODUCTION: The removal of low- and medium-molecular-weight proteins has been improved with online hemodiafiltration (OL-HDF) and hemodialysis using high-flux membranes; however, the outcomes of patients with end-stage kidney disease (ESKD) undergoing dialysis treatment are still worse than in the general population. α1-Microglobulin (α1-m), with a molecular weight of 33,000 Da, may contribute to dialysis-related disorders and mortality. However, the removal is insufficient even with current OL-HDF using the polysulfone (PS) membrane, which is common in Japan. Polymethylmethacrylate (PMMA) membranes can remove medium- to high-molecular-weight proteins by adsorption. This study aimed to assess the efficacy of removing medium- to high-molecular-weight proteins, such as α1-m and β2-microglobulin (β2-m), through post-dilution OL-HDF with PMMA (Post-PMMA). The assessment was conducted in comparison to pre-dilution OL-HDF with PS (Pre-PS), using an open-label, single-arm study. METHODS: Seven patients with ESKD on Pre-PS underwent Post-PMMA with replacement volume of 30 mL/min (low flow) and 50 mL/min (high flow). Clearance and removal rates of α1-m, β2-m, small molecules, inflammatory cytokines, and albumin were measured at 60 and 240 min of treatment. RESULTS: Clearance rates of α1-m at 60 min were -2.8 ± 5.2 mL/min with Pre-PS, -0.4 ± 2.6 mL/min with Post-PMMA (low), and 0.6 ± 3.4 mL/min with Post-PMMA (high). The removal rate of α1-m was higher in Post-PMMA than that in Pre-HDF-PS (Post-PMMA [high] 17.7 ± 5.9%, Post-PMMA [low] 15.0 ± 5.6%, and Pre-PS 4.1 ± 5.5%). Adsorption clearance of β2-m was increased with Post-PMMA. Albumin leakage in Post-PMMA was not higher than that in Pre-PS. CONCLUSION: The removal rate of α1-m with Post-PMMA was higher than that with Pre-PS. The PMMA membrane adsorbed β2-m, suggesting the removal effect of medium- to high-molecular-weight proteins by the adsorption method. Since Post-PMMA effectively removes α1-m without excessive albumin leakage, it will be useful for patients with ESKD, especially those with a poor nutritional status.

    DOI： 10.1159/000534459

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  • Misleading Reporting (Spin) in Noninferiority Randomized Clinical Trials in Oncology With Statistically Not Significant Results: A Systematic Review. 国際誌

    Chiyo Ito, Atsushi Hashimoto, Kohei Uemura, Koji Oba

    JAMA network open   4 ( 12 )   e2135765   2021年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    IMPORTANCE: Spin, the inaccurate reporting of randomized clinical trials (RCTs) with results that are not statistically significant for the primary end point, distorts interpretation of results and leads to misinterpretation. However, the prevalence of spin and related factors in noninferiority cancer RCTs remains unclear. OBJECTIVE: To examine misleading reporting, or spin, and the associated factors in noninferiority cancer RCTs through a systematic review. DATA SOURCES: A systematic search of the PubMed database was performed for articles published between January 1, 2010, and December 31, 2019, using the Cochrane Highly Sensitive Search Strategy. STUDY SELECTION: Two investigators independently selected studies using the inclusion criteria of noninferiority parallel-group RCTs aiming to confirm effects to cancer treatments published between January 1, 2010, and December 31, 2019, reporting results that were not statistically significant for the primary end points. DATA EXTRACTION AND SYNTHESIS: Standardized data abstraction was used to extract information concerning the trial characteristics and spin based on a prespecified definition. The main investigator extracted the trial characteristics while both readers independently evaluated the spin. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. MAIN OUTCOMES AND MEASURES: The main outcome was spin prevalence in any section of the report. Spin was defined as use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite no statistically significant difference for the primary outcome, or to distract the reader from results that are not statistically significant. The associations (prevalence difference and odds ratios [ORs]) between spin and trial characteristics were also evaluated. RESULTS: The analysis included 52 of 2752 reports identified in the PubMed search. Spin was identified in 39 reports (75.0%; 95% CI, 61.6%-84.9%), including the abstract (34 reports [65.4%; 95% CI, 51.1%-76.9%]) and the main text (38 reports [73.1%; 95% CI, 59.7%-83.3%]). Univariate analysis found that the spin prevalence was higher in reports with data managers (prevalence difference, 27%; 95% CI, 1.1%-50.3%), reports without funding from for-profit sources (prevalence difference, 31.2%; 95% CI, 4.8%-53.8%), and reports of novel experimental treatments (prevalence difference, 37.5%; 95% CI, 5.8%-64.7%). Multivariable analysis found that novel experimental treatment (OR, 4.64; 95% CI, 0.98-22.02) and funding only from nonprofit sources only (OR, 5.20; 95% CI, 1.21-22.29) were associated with spin. CONCLUSIONS AND RELEVANCE: In this systematic review, most noninferiority RCTs reporting results that were not statistically significant for the primary end points showed distorted interpretation and inaccurate reporting. The novelty of an experimental treatment and funding only from nonprofit sources were associated with spin.

    DOI： 10.1001/jamanetworkopen.2021.35765

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  • Higher genome mutation rates of Beijing lineage of Mycobacterium tuberculosis during human infection. 国際誌

    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年10月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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

    Scientific reports   10 ( 1 )   4923 - 4923   2020年3月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    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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  • Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. 国際誌

    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年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    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.).

    DOI： 10.1056/NEJMoa1816216

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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. 国際誌

    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年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    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.

    DOI： 10.1016/j.imlet.2019.05.013

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  • Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile. 国際誌

    Masayuki Ito, Kazuyuki Nakagome, Hiromitsu Ohta, Keiichi Akasaka, Yoshitaka Uchida, Atsushi Hashimoto, Ayako Shiono, Toshinori Takada, Makoto Nagata, Jun Tohyama, Koichi Hagiwara, Minoru Kanazawa, Koh Nakata, Ryushi Tazawa

    BMC pulmonary medicine   17 ( 1 )   40 - 40   2017年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP. CASE PRESENTATION: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high. CONCLUSIONS: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

    DOI： 10.1186/s12890-017-0382-x

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

    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年1月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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

    Cytokine   68 ( 2 )   118 - 26   2014年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    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. 国際誌

    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年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    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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受賞

  • 若手医学研究賞

    2017年10月   新潟大学  

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  • 若手医学研究賞

    2013年10月   新潟大学  

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担当経験のある授業科目（researchmap）

  • 臨床実習入門 臨床研究学修 （医学科4年生） (新潟大学)

    2024年4月
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    現在

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