Researcher basic information

• 博士（保健科学）, 北海道大学

• https://researchmap.jp/7000027018?lang=en

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201801018767378321
• https://bloodregulregen.wixsite.com/hs-brr

• 60722626

• 201801018767378321

• 巨核球
• 骨髄造血微小環境
• オルガノイド
• 血栓止血学（血小板・出血性・血栓性素因）
• 先天性血液凝固異常症

• Life Science, Biomedical engineering
• Life Science, Medical biochemistry
• Life Science, Hematology and medical oncology

• Bachelor's degree program, Departments of Health Sciences, School of Medicine
• Master's degree program, Graduate School of Health Sciences
• Doctoral (PhD) degree program, Graduate School of Health Sciences

Research activity information

• 02 Jul. 2016, 第十二回麒麟塾, 麒麟児賞
  International society, Japan

• Spatiotemporal dynamics and ossification of podoplanin-positive cells in the developing femur
  Hinako Notoh; Nagaharu Tsukiji; Hiroyuki Takashima; Hiroyuki Sugimori; Rikuto Nara; Ayuka Kamata; Hayuki Hayakawa; Nobuaki Suzuki; Atsuo Suzuki; Shuichi Okamoto; Takeshi Kanematsu; Akira Katsumi; Tetsuhito Kojima; Tadashi Matsushita; Katsue Suzuki-Inoue; Shogo Tamura
  Scientific Reports, Springer Science and Business Media LLC, 19 Apr. 2026, [Peer-reviewed], [Last author, Corresponding author]
  Scientific journal
• An Exploratory Plasma-Based Functional Assay for Phenotypic Characterization of Fibrinolysis in Dysfibrinogenemia
  Atsuo Suzuki; Shuichi Okamoto; Nobuaki Suzuki; Shogo Tamura; Takeshi Kanematsu; Masashi Tomita; Tetsuhito Kojima; Tadashi Matsushita
  Research and Practice in Thrombosis and Haemostasis, 103426, 103426, Elsevier BV, Mar. 2026, [Peer-reviewed]
  Scientific journal
• Antithrombotic Therapy on Antithrombin Resistance in a Mouse Model
  Nobuaki Suzuki; Atsuo Suzuki; Shogo Tamura; Sena Tokumaru; Hinako Notoh; Akira Takagi; Sachiko Suzuki; Ayako Isotani; Naruko Suzuki; Shuichi Okamoto; Takeshi Kanematsu; Masahito Ikawa; Fumihiko Hayakawa; Hitoshi Kiyoi; Tetsuhito Kojima; Tadashi Matsushita
  Arteriosclerosis, Thrombosis, and Vascular Biology, 46, 3, Ovid Technologies (Wolters Kluwer Health), Mar. 2026, [Peer-reviewed]
  Scientific journal, BACKGROUND:
  
  Antithrombin resistance (ATR) is a congenital thrombotic predisposition caused by abnormal prothrombin, FII (Factor II). Abnormal FII with ATR characteristics, when converted to thrombin, FIIa (Factor IIa), shows a reduced affinity of binding to AT (antithrombin), resulting in reduced anti-FIIa and a thrombotic tendency. Data on the efficacy of anticoagulants in ATR are currently insufficient.
  
  METHODS:
  
  Mouse models of ATR were generated to investigate the efficacy of anticoagulants. Because FII R596L, which causes ATR in humans, was considered to correspond to R593L in mice based on gene sequence analysis, knock-in mice that systemically express FII R593L were generated. First, the nature of ATR was confirmed by blood coagulation analysis. We then evaluated thrombotic tendency at the individual level using an inferior vena cava stenosis model, and evaluated the antithrombotic effects of unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, and direct oral anticoagulants.
  
  RESULTS:
  
  In coagulation studies, R593L Homo and Hetero mice (R593L Homo and Hetero, respectively) exhibited lower FII antigen levels and lower FIIa generation potential than wild-type mice, but residual FIIa activity after addition of AT confirmed the presence of ATR properties. In the inferior vena cava stenosis model, significantly higher thrombus formation was maintained in R593L Homo and Hetero compared with wild-type, even 96 hours after inferior vena cava stenosis. In anticoagulant administration experiments, anticoagulants with anti-FIIa effects appeared more effective against FII R593L.
  
  CONCLUSIONS:
  
  Knock-in of FII R593L produced ATR model mice, which showed a strong thrombotic tendency. Evaluation of antithrombotic therapies showed that anticoagulants with anti-FIIa effects were highly effective.
• von Willebrand factor-T441N, a novel missense variant in the von Willebrand factor D2 domain, exhibits impaired multimerization and deformed Weibel-Palade bodies
  Shuichi Okamoto; Shogo Tamura; Atsuo Suzuki; Nobuaki Suzuki; Takeshi Kanematsu; Naruko Suzuki; Masashi Tomita; Fumihiko Hayakawa; Akira Katsumi; Hitoshi Kiyoi; Tetsuhito Kojima; Tadashi Matsushita
  Journal of Thrombosis and Haemostasis, Elsevier BV, Nov. 2025, [Peer-reviewed]
  Scientific journal
• C-type lectin-like receptor 2 in platelets amplifies inflammation in rheumatoid arthritis
  Tomoyuki Sasaki; Ewelina Golebiewska; Toshiaki Shirai; Nagaharu Tsukiji; Kensuke Koyama; Shogo Tamura; Shimon Otake; Makoto Osada; Hirotaka Haro; Yukio Ozaki; Katsue Suzuki-Inoue
  Research and Practice in Thrombosis and Haemostasis, 102866, 102866, Elsevier BV, Apr. 2025, [Peer-reviewed], [International Magazine]
  Scientific journal
• Dysfibrinogenemia With the γSer358Cys Variant, Fibrinogen Milano VII, Escapes From the Clauss‐CWA Classification
  Atsuo Suzuki; Nobuaki Suzuki; Shogo Tamura; Shuichi Okamoto; Takeshi Kanematsu; Tetsuhito Kojima; Tadashi Matsushita
  International Journal of Laboratory Hematology, 47, 3, 559, 562, Wiley, 19 Feb. 2025
  Scientific journal
• A case of primary cutaneous diffuse large B-cell lymphoma, leg type with MYC rearrangement and high BCL2 protein expression due to trisomy 18
  Yosuke Matsui; Akira Katsumi; Ken Tanaka; Fumiya Ohara; Akihiro Abe; Shogo Tamura; Katsuya Yamamoto; Tadashi Matsushita; Miwa Adachi; Yasuyuki Nagata; Masaki Hasegawa
  Nagoya Journal of Medical Science, 2025, [Peer-reviewed]
  Scientific journal
• PDPN/CLEC-2 axis modulates megakaryocyte subtypes in a hematopoietic stem cell-regulating megakaryocyte-dominant manner
  Rikuto Nara; Hinako Notoh; Tomoyuki Sasaki; Nagaharu Tsukiji; Toshiaki Shirai; Ayuka Kamata; Nobuaki Suzuki; Atsuo Suzuki; Shuichi Okamoto; Takeshi Kanematsu; Naruko Suzuki; Akira Katsumi; Tetsuhito Kojima; Katsue Suzuki-Inoue; Tadashi Matsushita; Shogo Tamura
  Thrombosis Research, 109230, 109230, Elsevier BV, Jan. 2025, [Last author, Corresponding author]
  Scientific journal
• Prevalence Estimation of Dysfibrinogenemia Using the Clauss‐CWA Approach
  Atsuo Suzuki; Nobuaki Suzuki; Shuichi Okamoto; Shogo Tamura; Takeshi Kanematsu; Ryosuke Kikuchi; Tetsuhito Kojima; Tadashi Matsushita
  International Journal of Laboratory Hematology, 47, 2, 297, 303, Wiley, 17 Dec. 2024, [Peer-reviewed]
  Scientific journal, ABSTRACT
  
  Introduction
  
  The actual prevalence of the qualitative fibrinogen abnormalities dysfibrinogenemia and hypodysfibrinogenemia is unknown. The major reasons are that patients with dysfibrinogenemia are frequently asymptomatic, and a recommended screening test, the Clauss fibrinogen assay, cannot completely distinguish qualitative from quantitative abnormalities. We previously established a high‐throughput screening test (Clauss‐CWA) to identify dysfibrinogenemia with high specificity and sensitivity by the Clauss fibrinogen assay alone.
  
  Aim and Methods
  
  This was a single‐center, observational study to estimate the prevalence of dysfibrinogenemia using Clauss‐CWA technology. A total of 25 471 patients in Nagoya University Hospital were screened to identify patients with suspected dysfibrinogenemia. The suspected patients were investigated by further confirmatory analyses, such as antigenic fibrinogen determination, reptilase time, fibrin polymerization analysis, and scanning electron microscopy.
  
  Results and Conclusions
  
  Of the 25 471 enrolled patients, five with suspected dysfibrinogenemia were identified. Unfortunately, one patient was not confirmed due to a lack of plasma samples. The ratio of functional to antigenic fibrinogen was decreased, and the reptilase time was prolonged in the four patients. Interestingly, two of them showed normal functional fibrinogen levels due to acute inflammatory responses. Fibrin polymerization was impaired, and structural abnormalities were found in the fibrinogen from the patients. In some cases, functional fibrinogen levels may not be effective for identifying functional fibrinogen abnormalities. Further nationwide studies are needed to more precisely understand the epidemiology of dysfibrinogenemia.
• Novel SERPINC1 Mutation in a Brazilian Patient with Sudden-onset Sagittal Sinus Thrombosis Caused by Congenital Antithrombin Deficiency
  Junji Hiraga; Yasuhiko Harada; Naruko Suzuki; Shogo Tamura; Nobuaki Suzuki
  European Journal of Medical and Health Sciences, 6, 5, 53, 56, European Open Science Publishing, 12 Oct. 2024, [Peer-reviewed]
  Scientific journal, A 19-year-old Brazilian man visited the emergency department of our hospital complaining of nausea and fever. He presented with left hemispatial neglect. Magnetic resonance imaging led to a diagnosis of sagittal sinus thrombosis. Blood tests showed decreased antithrombin (ATIII) activity, and ATIII deficiency was diagnosed. He was treated with heparin sodium and warfarin. Genetic counseling through medical interpreters was recommended, and the patient and his mother consented to genetic testing, which revealed a novel mutation variant of the SERPINC1 gene. Genetic counseling is important to connect patients to genetic testing, even if language barriers are present.
• Misleading Antigenic von Willebrand Factor Levels in Acquired von Willebrand Syndrome Secondary to Monoclonal Gammopathy of Undetermined Significance
  Shuichi Okamoto, Atsuo Suzuki, Shogo Tamura, Nobuaki Suzuki, Takeshi Kanematsu, Naruko Suzuki, Akira Katsumi, Fumihiko Hayakawa, Hitoshi Kiyoi, Tetsuhito Kojima, Tadashi Matsushita
  International Journal of Hematology, Oct. 2024, [Peer-reviewed]
  Scientific journal
• Newly diagnosed multiple myeloma with bleeding and coagulation abnormalities caused by a thrombin-inhibiting substance
  Fumiya Ohara; Atsuo Suzuki; Nobuaki Suzuki; Takeshi Kanematsu; Shuichi Okamoto; Shogo Tamura; Hitoshi Kiyoi; Tadashi Matsushita; Akira Katsumi
  International Journal of Hematology, Springer Science and Business Media LLC, 18 Sep. 2024, [Peer-reviewed]
  Scientific journal
• Variability in combinations of APTT reagent and substrate plasma for a one-stage clotting assay to measure factor VIII products.
  Atsuo Suzuki; Nobuaki Suzuki; Takeshi Kanematsu; Shuichi Okamoto; Naruko Suzuki; Shogo Tamura; Ryosuke Kikuchi; Akira Katsumi; Tetsuhito Kojima; Tadashi Matsushita
  International journal of laboratory hematology, 01 Mar. 2024, [Peer-reviewed], [International Magazine]
  English, Scientific journal, INTRODUCTION: An investigation of the suitability of reagents for measuring FVIII products in a one-stage clotting assay (OSA) showed variations in their FVIII activity (FVIII:C). Most studies have focused on the activated partial thromboplastin time (APTT) reagent rather than FVIII-deficient plasma (F8DP), even though the APTT-based OSA is comprised of APTT reagents and factor-deficient plasma. AIM: A single-centre study was conducted to clarify variations in measurements of FVIII products in an OSA using a total of 12 reagent combinations, including four APTT reagents and three types of F8DP. METHODS: FVIII:C in nine types of FVIII product-spiked plasma was measured using an OSA with four different APTT reagents and three types of F8DP. RESULTS: F8DP-dependent variations were found in addition to differences derived from APTT reagents. Variations in target recovery (TR) were observed for NovoEight®, Eloctate®, and Jivi®. Reduced TR for Jivi was found only for Pathromtin SL in combination with congenital F8DP (F8DP-3). This lower TR was not observed with alternative manufacturing lots of F8DP-3. The reduced TR for Jivi might be related to impaired contact activation due to lower factor XI activity in F8DP-3. CONCLUSION: In addition to APTT reagents, variations in F8DPs used for OSAs can also affect FVIII:C results. F8DPs as well as the APTT reagent used for OSA should be chosen with caution, and laboratories should evaluate reagents for F8DPs as they currently do for APTT reagents, especially when lot changes occur.
• Basement membrane extract potentiates the endochondral ossification phenotype of bone marrow-derived mesenchymal stem cell-based cartilage organoids.
  Hinako Notoh; Satoshi Yamasaki; Nobuaki Suzuki; Atsuo Suzuki; Shuichi Okamoto; Takeshi Kanematsu; Naruko Suzuki; Akira Katsumi; Tetsuhito Kojima; Tadashi Matsushita; Shogo Tamura
  Biochemical and biophysical research communications, 701, 149583, 149583, 30 Jan. 2024, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
  English, Scientific journal, Endochondral ossification is a developmental process in the skeletal system and bone marrow of vertebrates. During endochondral ossification, primitive cartilaginous anlages derived from mesenchymal stem cells (MSCs) undergo vascular invasion and ossification. In vitro regeneration of endochondral ossification is beneficial for research on the skeletal system and bone marrow development as well as their clinical aspects. However, to achieve the regeneration of endochondral ossification, a stem cell-based artificial cartilage (cartilage organoid, Cart-Org) that possesses an endochondral ossification phenotype is required. Here, we modified a conventional 3D culture method to create stem cell-based Cart-Org by mixing it with a basement membrane extract (BME) and further characterized its chondrogenic and ossification properties. BME enlarged and matured the bone marrow MSC-based Cart-Orgs without any shape abnormalities. Histological analysis using Alcian blue staining showed that the production of cartilaginous extracellular matrices was enhanced in Cart-Org treated with BME. Transcriptome analysis using RNA sequencing revealed that BME altered the gene expression pattern of Cart-Org to a dominant chondrogenic state. BME triggered the activation of the SMAD pathway and inhibition of the NK-κB pathway, which resulted in the upregulation of SOX9, COL2A1, and ACAN in Cart-Org. BME also facilitated the upregulation of genes associated with hypertrophic chondrocytes (IHH, PTH1R, and COL10A1) and ossification (SP7, ALPL, and MMP13). Our findings indicate that BME promotes cartilaginous maturation and further ossification of bone marrow MSC-based Cart-Org, suggesting that Cart-Org treated with BME possesses the phenotype of endochondral ossification.
• Congenital antithrombin deficiency
  Shogo TAMURA; Atsuo SUZUKI; Nobuaki SUZUKI
  Japanese Journal of Thrombosis and Hemostasis, 35, 5, 612, 618, Japanese Society on Thrombosis and Hemostasis, 2024, [Peer-reviewed], [Invited], [Lead author]
  Scientific journal
• EBF1-JAK2 inhibits the PAX5 function through physical interaction with PAX5 and kinase activity.
  Yukino Kojima; Fumika Kawashima; Takahiko Yasuda; Koya Odaira; Yuichiro Inagaki; Chiharu Yamada; Ami Muraki; Mina Noura; Shuichi Okamoto; Shogo Tamura; Eisuke Iwamoto; Masashi Sanada; Itaru Matsumura; Yasushi Miyazaki; Tetsuhito Kojima; Hitoshi Kiyoi; Shinobu Tsuzuki; Fumihiko Hayakawa
  International journal of hematology, 07 May 2023, [Peer-reviewed], [Domestic magazines]
  English, Scientific journal, Gene aberrations of B-cell regulators and growth signal components such as the JAK-STAT pathway are frequently found in B-cell acute lymphoblastic leukemia (B-ALL). EBF1 is a B-cell regulator that regulates the expression of PAX5 and co-operates with PAX5 to regulate B-cell differentiation. Here, we analyzed the function of the fusion protein of EBF1 and JAK2, EBF1-JAK2 (E-J). E-J caused constitutive activation of JAK-STAT and MAPK pathways and induced autonomous cell growth in a cytokine-dependent cell line. E-J did not affect the transcriptional activity of EBF1 but inhibited that of PAX5. Both the physical interaction of E-J with PAX5 and kinase activity of E-J were required for E-J to inhibit PAX5 function, although the detailed mechanism of inhibition remains unclear. Importantly, gene set enrichment analysis using the results of our previous RNA-seq data of 323 primary BCR-ABL1-negative ALL samples demonstrated repression of the transcriptional target genes of PAX5 in E-J-positive ALL cells, which suggests that E-J also inhibited PAX5 function in ALL cells. Our results shed new light on the mechanisms of differentiation block by kinase fusion proteins.
• The usefulness of tranexamic acid for bleeding symptoms of chronic consumptive coagulopathy complicated by aortic disease: a single-institute, retrospective study of 14 patients.
  Naruko Suzuki; Nobuaki Suzuki; Yuka Kawaguchi; Shuichi Okamoto; Takeshi Kanematsu; Akira Katsumi; Atsuo Suzuki; Shogo Tamura; Tetsuhito Kojima; Hitoshi Kiyoi; Tadashi Matsushita
  Thrombosis journal, 21, 1, 10, 10, 25 Jan. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that blocks lysine-binding sites on the profibrinolytic enzyme plasminogen. Aortic diseases with chronic consumption coagulopathy may lead to disseminated intravascular coagulation (DIC) and cause fatal bleeding. Although the use of antifibrinolytic agents in DIC is generally not recommended due to enhanced fibrin deposition risking thrombotic symptoms, the efficacy of TXA has been reported in several cases of DIC with aortic diseases. However, the efficacy and safety of TXA for bleeding symptoms of chronic consumption coagulopathy with aortic diseases have not been studied in detail. METHODS: We evaluated the efficacy of TXA in 14 patients with chronic consumptive coagulopathy due to aortic disease complicated by bleeding symptoms. Changes in coagulation and fibrinolysis parameters from baseline were analyzed with Wilcoxon matched-pairs signed-rank tests, excluding missing values. Kaplan-Meier curves were used to analyze overall survival. RESULTS: Median age was 78.5 years (range, 66-89 years) and median observation period was 448 days (range, 0-2282 days). Twelve patients had chronic renal failure and 1 patient had chronic liver failure. Before starting treatment, median Japanese Ministry of Health and Welfare DIC diagnostic criteria score was 8 (range, 4-11) and median platelet count was 64 × 109/L (range, 25-97 × 109/L). Twelve patients underwent evaluation of bleeding symptoms after introduction of TXA, and 10 of those 12 patients showed improved bleeding tendencies within 30 days (median, 5.0 days). One patient with chronic liver failure showed worsening of bleeding symptoms. Although only one patient was initiated TXA in combination with anticoagulants, no significant worsening of thrombotic events was observed within 30 days. CONCLUSIONS: TXA therapy appears effective against chronic consumptive coagulopathy with bleeding due to aortic disease, with few side effects.
• Functional inhibition of MEF2 by C/EBP is a possible mechanism of leukemia development by CEBP-IGH fusion gene.
  Koya Odaira; Takahiko Yasuda; Kentaro Okada; Takuya Shimooka; Yukino Kojima; Mina Noura; Shogo Tamura; Shingo Kurahashi; Eisuke Iwamoto; Masashi Sanada; Itaru Matsumura; Yasushi Miyazaki; Tetsuhito Kojima; Hitoshi Kiyoi; Shinobu Tsuzuki; Fumihiko Hayakawa
  Cancer science, 114, 3, 781, 792, 07 Nov. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, CEBPA-IGH, a fusion gene of the immunoglobulin heavy-chain locus (IGH) and the CCAAT enhancer-binding protein α (C/EBPα) gene, is recurrently found in B-ALL cases and causes aberrant expression of C/EBPα, a master regulator of granulocyte differentiation, in B cells. Forced expression of C/EBPα in B cells was reported to cause loss of B-cell identity due to the inhibition of Pax5, a master regulator of B-cell differentiation; however, it is not known whether the same mechanism is applicable for B-ALL development by CEBPA-IGH. It is known that a full-length isoform of C/EBPα, p42, promotes myeloid differentiation, whereas its N-terminal truncated isoform, p30, inhibits myeloid differentiation through the inhibition of p42; however, the differential role between p42 and p30 in ALL development has not been clarified. In the present study, we examined the effect of the expression of p42 and p30 in B cells by performing RNA-seq of mRNA from LCL stably transfected with p42 or p30. Unexpectedly, suppression of PAX5 target genes was barely observed. Instead, both isoforms suppressed the target genes of MEF2 family members (MEF2s), other regulators of B-cell differentiation. Similarly, MEF2s target genes rather than PAX5 target genes were suppressed in CEBP-IGH-positive ALL (n = 8) compared with other B-ALL (n = 315). Furthermore, binding of both isoforms to MEF2s target genes and the reduction of surrounding histone acetylation were observed in ChIP-qPCR. Our data suggest that the inhibition of MEF2s by C/EBPα plays a role in the development of CEBPA-IGH-positive ALL and that both isoforms work co-operatively to achieve it.
• Clinical conditions and risk factors for inhibitor-development in patients with haemophilia: A decade-long prospective cohort study in Japan, J-HIS2 (Japan Hemophilia Inhibitor Study 2).
  Keiji Nogami; Masashi Taki; Tadashi Matsushita; Tetsuhito Kojima; Toshiaki Oka; Shouichi Ohga; Kiyoshi Kawakami; Michio Sakai; Takashi Suzuki; Satoshi Higasa; Yasuo Horikoshi; Keiko Shinozawa; Shogo Tamura; Koji Yada; Masue Imaizumi; Yoshitoshi Ohtsuka; Fuminori Iwasaki; Masao Kobayashi; Junki Takamatsu; Hideyuki Takedani; Hisaya Nakadate; Yoko Matsuo; Takeshi Matsumoto; Teruhisa Fujii; Katsuyuki Fukutake; Akira Shirahata; Akira Yoshioka; Midori Shima
  Haemophilia : the official journal of the World Federation of Hemophilia, 28, 5, 745, 759, Sep. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: Inhibitor-development is a serious complication in patients with haemophilia (PwH). Previous studies reported that therapeutic and genetic factors could be associated with these alloantibodies. Relevant clinical features such as genetic-background and different treatment regimens in Japan remain unclear, however. AIMS: To analyse a nation-wide Japanese registry for PwH, and to examine risk factors for inhibitor-development. METHODS AND RESULTS: Newly diagnosed patients with haemophilia A (PwHA) or haemophilia B (PwHB) without inhibitors after 2007, and with treatment records traceable from 0 to 75 exposure days (ED), were enrolled in the Japan Hemophilia Inhibitor Study 2 (J-HIS2) initiated in 2008. Of 417 patients (340 PwHA, 77 PwHB) from 46 facilities, 83 (76 PwHA, 7 PwHB) were recorded with inhibitors by July 2020. Inhibitors were observed in 31.0% of severe PwHA, 8.0% moderate and 1.6% mild and in 17.1% of severe PwHB. The majority of inhibitors (89.7% in severe PwHA and 71.4% in severe PwHB) were detected on or before 25ED (median 12ED in PwHA and 19ED in PwHB). Genotyping in these severe patients identified an association between inhibitor-development and null variants of F8 (P < .01) or F9 (P < .05). A lower incidence of inhibitors was recorded in severe PwHA treated with prophylaxis than in those treated on-demand (P < .01). A past-history of intracranial-haemorrhage appeared to be associated with inhibitor-development, while FVIII-concentrates infusion and routine vaccination on the same day was not related to inhibitor-development. CONCLUSION: The J-HIS2 study has identified significant clinical variables associated with inhibitor-development in Japanese PwH, consistent with other global studies.
• VWF-Gly2752Ser, a novel non-cysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering C-terminal dimer formation.
  Shuichi Okamoto; Shogo Tamura; Naomi Sanda; Koya Odaira; Yuri Hayakawa; Masato Mukaide; Atsuo Suzuki; Takeshi Kanematsu; Fumihiko Hayakawa; Akira Katsumi; Hitoshi Kiyoi; Tetsuhito Kojima; Tadashi Matsushita; Nobuaki Suzuki
  Journal of thrombosis and haemostasis : JTH, 20, 8, 1784, 1796, Aug. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: Von Willebrand factor (VWF) is a multimeric glycoprotein that plays important roles in hemostasis and thrombosis. C-terminal interchain-disulfide bonds in the cystine knot (CK) domain are essential for VWF dimerization. Previous studies have reported that missense variants of cysteine in the CK domain disrupt the intrachain-disulfide bond and cause type 3 von Willebrand disease (VWD). However, type 3 VWD-associated noncysteine substitution variants in the CK domain have not been reported. OBJECTIVE: To investigate the molecular mechanism of a novel non-cysteine variant in the CK domain, VWF c.8254 G>A (p.Gly2752Ser), which was identified in a patient with type 3 VWD as homozygous. METHODS: Genetic analysis was performed by whole exome sequencing and Sanger sequencing. VWF multimer analysis was performed using SDS-agarose electrophoresis. VWF production and subcellular localization were analyzed using ex vivo endothelial colony forming cells (ECFCs) and an in vitro recombinant VWF (rVWF) expression system. RESULTS: The patient was homozygous for VWF-Gly2752Ser. Plasma VWF enzyme-linked immunosorbent assay showed that the VWF antigen level of the patient was 1.2% compared with healthy subjects. A tiny amount of VWF was identified in the patient's ECFC. Multimer analysis revealed that the circulating VWF-Gly2752Ser presented only low molecular weight multimers. Subcellular localization analysis of VWF-Gly2752Ser-transfected cell lines showed that rVWF-Gly2752Ser was severely impaired in its ER-to-Golgi trafficking. CONCLUSION: VWF-Gly2752Ser causes severe secretory impairment because of its dimerization failure. This is the first report of a VWF variant with a noncysteine substitution in the CK domain that causes type 3 VWD.
• Medical Management of a Mural Thrombus Inducing Repeated Ischemic Strokes in a Patient with Congenital Afibrinogenemia.
  Masahiro Nishihori; Yoshio Araki; Nobuaki Suzuki; Shogo Tamura; Mayo Hattori; Takashi Izumi; Shunsaku Goto; Kinya Yokoyama; Kenji Uda; Tadashi Matsushita; Ryuta Saito
  Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 31, 7, 106526, 106526, Jul. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, OBJECTIVES: Congenital afibrinogenemia is an autosomal recessive inherited disorder that can cause thrombotic as well as hemorrhagic events. We describe a case of repeated mild ischemic strokes due to a mural thrombus in the carotid artery and our medical treatment. CASE DESCRIPTION: A 49-year-old woman with congenital afibrinogenemia developed two minor ischemic strokes in two months. Clinical images revealed scattered fresh infarcts in the right middle cerebral artery region and mild cervical carotid artery stenosis. The risk for surgical treatment was considered to be extraordinarily high. The patient was treated with 100 mg/day of aspirin and 3 g fibrinogen infusion every two weeks. After the one-year course of medication, the mural thrombus gradually decreased, and there were no bleeding or ischemic stroke events. CONCLUSION: This case report highlights the successful treatment of an ischemic stroke in a patient with a congenital afibrinogenemia with an antiplatelet agent and fibrinogen replacement. There are no guidelines for managing ischemic stroke in patients with congenital afibrinogenemia, and further studies are needed.
• EFFICACY OF DESENSITIZATION THERAPY FOR ALLERGY TO FACTOR IX CONCENTRATES
  Nobuaki Suzuki; Takeshi Kanematsu; Mayuko Kishimoto; Naruko Suzuki; Shuichi Okamoto; Shogo Tamura; Hitoshi Kiyoi; Tadashi Matsushita
  Japanese Journal of Transfusion and Cell Therapy, 68, 3, 422, 427, Japan Society of Transfusion Medicine and Cell Therapy, 24 Jun. 2022, [Peer-reviewed]
  Scientific journal
• Periosteum-derived podoplanin-expressing stromal cells regulate nascent vascularization during epiphyseal marrow development
  Shogo Tamura; Masato Mukaide; Yumi Katsuragi; Wataru Fujii; Koya Odaira; Nobuaki Suzuki; Nagaharu Tsukiji; Shuichi Okamoto; Atsuo Suzuki; Takeshi Kanematsu; Akira Katsumi; Akira Takagi; Katsuhide Ikeda; Jun Ueyama; Masaaki Hirayama; Katsue Suzuki-Inoue; Tadashi Matsushita; Tetsuhito Kojima; Fumihiko Hayakawa
  Journal of Biological Chemistry, 298, 5, 101833, 101833, Elsevier BV, May 2022, [Peer-reviewed], [Lead author, Corresponding author]
  Scientific journal
• F9 mRNA splicing aberration due to a deep Intronic structural variation in a patient with moderate hemophilia B
  Koya Odaira; Fumika Kawashima; Shogo Tamura; Nobuaki Suzuki; Mahiru Tokoro; Yuri Hayakawa; Atsuo Suzuki; Takeshi Kanematsu; Shuichi Okamoto; Akira Takagi; Akira Katsumi; Tadashi Matsushita; Midori Shima; Keiji Nogami; Tetsuhito Kojima; Fumihiko Hayakawa
  Thrombosis Research, 213, 91, 96, Elsevier BV, May 2022, [Peer-reviewed], [Corresponding author]
  Scientific journal
• Protein S-Leu17Pro disrupts the hydrophobicity of its signal peptide causing a proteasome-dependent degradation
  Kentaro Okada; Shogo Tamura; Nobuaki Suzuki; Koya Odaira; Masato Mukaide; Wataru Fujii; Yumi Katsuragi; Atsuo Suzuki; Takeshi Kanematsu; Shuichi Okamoto; Naruko Suzuki; Akira Katsumi; Tadashi Matsushita; Tetsuhito Kojima; Fumihiko Hayakawa
  Thrombosis Research, 210, 26, 32, Elsevier BV, Feb. 2022, [Peer-reviewed], [Lead author, Corresponding author]
  Scientific journal
• Development and validation of a novel qualitative test for plasma fibrinogen utilizing clot waveform analysis
  Atsuo Suzuki; Nobuaki Suzuki; Takeshi Kanematsu; Sho Shinohara; Hiroshi Kurono; Nobuo Arai; Shuichi Okamoto; Naruko Suzuki; Shogo Tamura; Ryosuke Kikuchi; Akira Katsumi; Tetsuhito Kojima; Tadashi Matsushita
  Scientific Reports, 12, 1, Springer Science and Business Media LLC, 21 Jan. 2022
  Scientific journal, Abstract
  
  Plasma fibrinogen is commonly examined by Clauss fibrinogen assay, which cannot distinguish between quantitative and qualitative fibrinogen anomalies. However, our previously reported Clauss fibrinogen assay utilizing clot waveform analysis (Clauss-CWA) provides additional information that contributes to the classification of fibrinogen anomalies. In this study, we adopted the Clauss-CWA method for an autoanalyzer to automatically measure the antigenic estimate (eAg) of fibrinogen in addition to the functional amount (Ac), and to thus provide the Ac/eAg ratio as a qualitative indicator. Performance was validated by receiver operating characteristics (ROC) and precision recall (PR) curve analyses using a patient cohort, consisting of a training cohort (n = 519) and a validation cohort (n = 523), both of which contained cases of congenital (hypo)dysfibrinogenemia as qualitative defects. We obtained an optimal cutoff of 0.65 for Ac/eAg by ROC curve analysis of the training cohort, offering superior sensitivity (> 0.9661) and specificity (1.000). This cutoff was validated in the validation cohort, providing positive predictive value > 0.933 and negative predictive value > 0.998. PR curve analysis also showed that Clauss-CWA provided excellent performance for detecting qualitative fibrinogen anomalies. The Clauss-CWA method may represent a useful approach for detecting qualitative fibrinogen abnormalities in routine laboratory testing.
• Anemia in older adults as a geriatric syndrome: A review.
  Akira Katsumi; Akihiro Abe; Shogo Tamura; Tadashi Matsushita
  Geriatrics & gerontology international, 21, 7, 549, 554, Jul. 2021, [Domestic magazines]
  English, Scientific journal, Anemia, a frequently occurring condition in older patients, has no standard definition; however, in most studies, it is defined as hemoglobin level <12 and <13 g/dL in women and men, respectively. Approximately 10% of older adults living in the community have anemia. The prevalence of anemia is significantly correlated with advanced age and male sex. Anemia is associated with falls, frailty and other negative outcomes, including early mortality. However, there remains little consensus regarding whether anemia treatment favorably affects these adverse outcomes. Therefore, this article reviews the prevalence of anemia, and provides updates on its common causes and treatments in older adults. While excluding well-established hematopoietic diseases, the etiology of anemia in older adults has been grouped into four categories: (i) nutritional deficiency; (ii) inflammation; (iii) clonal hematopoiesis; and (iv) "unexplained anemia," when there is no clear mechanism to account for the anemia. Recently, clonal leukocytes were detected in a considerable number of older individuals. The number of somatic mutations in blood leukocytes increases with age; however, single mutations of DNMT3A, TET2 and ASXL1 are not correlated with the presence of unexplained anemia in older adults. With an increased understanding of anemia etiology and the availability of innovative anti-anemic drugs, future studies that evaluate the causes and benefits of treatment are required. Geriatr Gerontol Int 2021; 21: 549-554.
• CLEC-2 stimulates IGF-1 secretion from podoplanin-positive stromal cells and positively regulates erythropoiesis in mice.
  Shimon Otake; Tomoyuki Sasaki; Toshiaki Shirai; Nagaharu Tsukiji; Shogo Tamura; Katsuhiro Takano; Yukio Ozaki; Katsue Suzuki-Inoue
  Journal of thrombosis and haemostasis : JTH, 19, 6, 1572, 1584, Jun. 2021, [International Magazine]
  English, Scientific journal, BACKGROUND: Erythropoiesis is a complex multistep process by which erythrocytes are produced. C-type lectin-like receptor 2 (CLEC-2) is a podoplanin (PDPN) receptor almost exclusively expressed on the surface of platelets and megakaryocytes. Deletion of megakaryocyte/platelet CLEC-2 was reported to cause anemia along with thrombocytopenia in mice. PDPN-expressing stromal cells in the bone marrow (BM) were also reported to facilitate megakaryocyte expansion and maturation depending on the CLEC-2/PDPN interaction. OBJECTIVES: We investigated how specific deletion of CLEC-2 in megakaryocytes/platelets leads to anemia. METHODS: We used flow cytometry to analyze maturation of erythroblasts, apoptotic cell death, and cell cycle distribution. CLEC-2 stimulated PDPN-expressing stromal cell-conditioned medium was analyzed by cytokine array and ELISA, and co-cultured with immature erythroblasts. Cytokine levels in serum and BM extracellular fluid were quantified by ELISA. RESULTS: We observed increased apoptosis of BM erythroblasts in megakaryocyte/platelet-specific CLEC-2 conditional knockout (Clec1bΔPLT ) mice. Moreover, PDPN-expressing stromal cells in the BM secreted insulin-like growth factor 1 (IGF-1) depending on the CLEC-2/PDPN interaction. Pretreatment with IGF-1 receptor inhibitor increased apoptosis rate and decreased the proliferation of erythroblasts in vitro. Furthermore, in Clec1bΔPLT mice, IGF-1 concentrations in serum and BM extracellular fluid were decreased, and IGF-1 replacement in Clec1bΔPLT mice attenuated anemia. CONCLUSIONS: Our findings suggest that IGF-1 secretion from PDPN-expressing stromal cells by CLEC-2 stimulation positively regulates erythroblasts. This novel mechanism of erythropoiesis regulation indicates that a microenvironment consisting of megakaryocytes and PDPN-expressing stromal cells supports erythropoiesis.
• Essential role of a carboxyl-terminal α-helix motif in the secretion of coagulation factor XI.
  Yuri Hayakawa; Shogo Tamura; Nobuaki Suzuki; Koya Odaira; Mahiru Tokoro; Fumika Kawashima; Fumihiko Hayakawa; Akira Takagi; Akira Katsumi; Atsuo Suzuki; Shuichi Okamoto; Takeshi Kanematsu; Tadashi Matsushita; Tetsuhito Kojima
  Journal of thrombosis and haemostasis : JTH, 19, 4, 920, 930, Apr. 2021, [Peer-reviewed], [Corresponding author], [International Magazine]
  English, Scientific journal, BACKGROUND: Coagulation factor XI (FXI) is a plasma serine protease zymogen that contributes to hemostasis. However, the mechanism of its secretion remains unclear. OBJECTIVE: To determine the molecular mechanism of FXI secretion by characterizing a novel FXI mutant identified in a FXI-deficient Japanese patient. PATIENT/METHODS: The FXI gene (F11) was analyzed by direct sequencing. Mutant recombinant FXI (rFXI) was overexpressed in HEK293 or COS-7 cells. Western blotting and enzyme-linked immunosorbent assay were performed to examine the FXI extracellular secretion profile. Immunofluorescence microscopy was used to investigate the subcellular localization of the rFXI mutant. RESULTS: We identified a novel homozygous frameshift mutation in F11 [c.1788dupC (p.E597Rfs*65)], resulting in a unique and extended carboxyl-terminal (C-terminal) structure in FXI. Although rFXI-E597Rfs*65 was intracellularly synthesized, its extracellular secretion was markedly reduced. Subcellular localization analysis revealed that rFXI-E597Rfs*65 was abnormally retained in the endoplasmic reticulum (ER). We generated a series of C-terminal-truncated rFXI mutants to further investigate the role of the C-terminal region in FXI secretion. Serial rFXI experiments revealed that a threonine at position 622, the fourth residue from the C-terminus, was essential for secretion. Notably, Thr622 engages in the formation of an α-helix motif, indicating the importance of the C-terminal α-helix in FXI intracellular behavior and secretion. CONCLUSION: FXI E597Rfs*65 results in the pathogenesis of a severe secretory defect resulting from aberrant ER-to-Golgi trafficking caused by the lack of a C-terminal α-helix motif. This study demonstrates the impact of the C-terminal structure, especially the α-helix motif, on FXI secretion.
• Myh9 R702C is associated with erythroid abnormality with splenomegaly in mice.
  Takeshi Kanematsu; Nobuaki Suzuki; Shogo Tamura; Atsuo Suzuki; Yuichi Ishikawa; Akira Katsumi; Hitoshi Kiyoi; Hidehiko Saito; Shinji Kunishima; Tetsuhito Kojima; Tadashi Matsushita
  Nagoya journal of medical science, 83, 1, 75, 86, Feb. 2021, [Domestic magazines]
  English, Scientific journal, MYH9 disorders are characterized by giant platelets, thrombocytopenia, and Döhle body-like cytoplasmic inclusion bodies in granulocytes. However, whether these disorders cause any changes in erythroid cells has yet to be determined. This study analyzed the influence of Myh9 R702C, as one of the most commonly detected MYH9 disorders, on erythroid cells in a mouse model. Knock-in mice expressing Myh9 R702C mutation either systemically or specific to hematological cells (R702C and R702C vav1 mice, respectively) were used in this study. Both displayed lower hemoglobin and higher erythropoietin levels than wild-type (WT) mice, along with significant splenomegaly. Flow cytometric analysis revealed erythroblasts present at a higher rate than WT mice in the spleen. However, no obvious abnormalities were seen in erythroid differentiation from megakaryocyte/erythroid progenitor to erythrocyte. Cell culture assay by fetal liver and colony assay also showed normal progression of erythroid differentiation from erythroid burst-forming unit to red blood cell. In conclusion, R702C and R702C vav1 mice displayed erythroid abnormality with splenomegaly. However, erythroid differentiation showed no obvious abnormality. Further research is required to elucidate the underlying mechanisms.
• Impact of variation in reagent combinations for one-stage clotting assay on assay discrepancy in nonsevere haemophilia A
  Suzuki Atsuo; Suzuki Nobuaki; Kanematsu Takeshi; Okamoto Shuichi; Tamura Shogo; Kikuchi Ryosuke; Katsumi Akira; Kiyoi Hitoshi; Kojima Tetsuhito; Matsushita Tadashi
  INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, 43, 1, 131, 138, 11 Sep. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, INTRODUCTION: Factor VIII activity (FVIII:C) is measured by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). Significant differences in FVIII:C between OSA (FVIII:C1st ) and CSA (FVIII:CChr ) are described as assay discrepancy in nonsevere haemophilia A (HA). A large number of reagent combinations (APTT reagent and FVIII-deficient plasma) are used for OSA, but the impact of variations in reagent combinations on assay discrepancy has not been fully characterized. AIM: To clarify the variations in FVIII:C1st /FVIII:CChr ratios according to OSA reagent combination in HA subjects with/without assay discrepancy. METHODS: Thirty-nine patients previously diagnosed with nonsevere HA were enrolled, and their FVIII genes were investigated and FVIII:C levels were assessed by a single CSA reagent and 11 OSA reagent combinations. Receiver operating characteristic (ROC) curve analysis was used to predict possible cut-off values of the FVIII:C1st /FVIII:CChr ratio to define FVIII assay discrepancy for each reagent combination. RESULTS: Patients were categorized into nondiscrepant (n = 25), discrepant (n = 5) and unclassified (n = 9) groups according to their genotypes and information in the database. The FVIII:C1st /FVIII:CChr ratio in nondiscrepant HA varied widely, depending on the APTT reagents and FVIII-deficient plasma used. The ratio in discrepant HA patients differed with respect to their genotype and the reagent combination used. ROC curve analyses revealed that cut-off values to distinguish the assay discrepancy differed depending on the reagents used, but revealed two novel genotype variants, p.Cys573Gly and p.Gly582Arg, associated with FVIII assay discrepancy. CONCLUSION: Our findings showed that the FVIII:C1st /FVIII:CChr ratio is dependent on the reagent combination used for OSA.
• 血小板膜糖蛋白質GPIb変異体を用いたvon Willebrand因子活性測定試薬「INNOVANCE VWF Ac」の基本性能評価
  鈴木 敦夫; 鈴木 伸明; 兼松 毅; 岡本 修一; 田村 彰吾; 篠原 翔; 新井 信夫; 菊地 良介; 安藤 善孝; 小嶋 哲人; 松下 正
  日本血栓止血学会誌, 31, 4, 409, 419, (一社)日本血栓止血学会, Aug. 2020
  Japanese, Scientific journal
• Aberrant X chromosomal rearrangement through multi-step template switching during sister chromatid formation in a patient with severe hemophilia A
  Tokoro Mahiru; Tamura Shogo; Suzuki Nobuaki; Kakihara Misaki; Hattori Yuna; Odaira Koya; Suzuki Sachiko; Takagi Akira; Katsumi Akira; Hayakawa Fumihiko; Okamoto Shuichi; Suzuki Atsuo; Kanematsu Takeshi; Matsushita Tadashi; Kojima Tetsuhito
  MOLECULAR GENETICS & GENOMIC MEDICINE, 8, 9, e1390, 05 Jul. 2020, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
  English, Scientific journal, BACKGROUND: Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by pathogenic variants of the coagulation factor VIII gene (F8). Half of the patients with severe HA have a recurrent inversion in the X chromosome, that is, F8 intron 22 or intron 1 inversion. Here, we characterized an abnormal F8 due to atypical complex X chromosome rearrangements in a Japanese patient with severe HA. METHODS: Recurrent F8 inversions were tested with inverse shifting-PCR. The genomic structure was investigated using PCR-based direct sequencing or quantitative PCR. RESULTS: The proband's X chromosome had a 119.5 kb insertion, a reverse duplex of an extragenic sequence on the F8 telomere region into the F8 intron 1 with two breakpoints. The telomeric breakpoint was a joining from the F8 intron 1 to the inverted FUNDC2 via a two-base microhomology, and the centromeric breakpoint was a recombination between F8 intron 1 homologous sequences. The rearrangement mechanism was suggested as a multi-step rearrangement with template switching such as fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR) and/or homologous sequence-associated recombination during a sister chromatid formation. CONCLUSION: We identified the aberrant X chromosome with a split F8 due to a multi-step rearrangement in a patient with severe HA.
• Higher FVIII:C measured by chromogenic substrate assay than by one-stage assay is associated with silent hemophilic arthropathy.
  Ogawa M; Suzuki N; Takahashi N; Tamura S; Suzuki A; Suzuki S; Hattori Y; Kakihara M; Kanematsu T; Kojima T; Katsumi A; Hayakawa F; Kojima T; Ishiguro N; Kiyoi H; Matsushita T
  Thrombosis research, 188, 103-105, 105, 22 Feb. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal
• 先天性凝固異常症の遺伝子解析 「解析のStrategyとPitfall」
  田村彰吾; 高木明; 早川文彦; 小嶋哲人
  日本検査血液学会雑誌, 21, 71, 80, Feb. 2020, [Peer-reviewed], [Invited], [Lead author, Corresponding author]
  Scientific journal
• Successful Perioperative Combination of High-Dose FVIII Therapy Followed by Emicizumab in a Patient with Hemophilia A with Inhibitors.
  Okamoto S; Suzuki N; Suzuki A; Suzuki S; Tamura S; Suzuki M; Takahashi N; Kojima T; Kanematsu T; Kojima T; Kiyoi H; Ishiguro N; Matsushita T
  TH open : companion journal to thrombosis and haemostasis, 3, 4, e364-e366, Oct. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, We managed perioperative hemostasis for a 72-year-old man with hemophilia A and low inhibitor titers (3 BU/mL), who underwent osteosynthesis for supracondylar fracture of the left humerus. He was treated perioperatively using the combination of high doses of factor VIII (FVIII) with recombinant human Factor VIII Fc fusion protein (rFVIIIFc), followed by emicizumab. On the day of surgery (day 0), he was administered bolus infusion of 150 IU/kg rFVIIIFc, followed by continuous infusion at a dose of 4 IU/kg/h. Emicizumab, 3 mg/kg, was injected subcutaneously once a week, on days 5, 12, 19, and 26. Inhibitors were detected on day 6 at a titer of 4 BU/mL and FVIII:C decreased to below assay sensitivity limits on day 10. The rate of increase in inhibitor titers was high, with inhibitors increasing to 343.4 BU/mL on day 14. The transition of thrombin production by thrombin generation assay (TGA) showed temporary decrease in thrombin production on day 7, although it was restored by day 10, i.e., five days after commencement of emicizumab therapy. Rotational thromboelastometry displayed consistent results with TGA, showing that clotting time was prolonged and the alpha angle decreased to less than measurable levels on day 6, although they were improved by day 10. There were no bleeding-related events or other adverse events throughout the perioperative period. In conclusion, emicizumab was effective for the management of perioperative hemostasis after development of an anamnestic response in a patient with hemophilia A with inhibitors. Combination therapy with high doses of FVIII followed by emicizumab could be a workable alternative for patients with hemophilia A with inhibitors.
• Peri-arteriolar megakaryopoietic microenvironment via reciprocal CLEC-2/PDPN axis in bone marrow
  田村 彰吾; 井上 克枝; 尾崎 由基男; 早川 文彦; 小嶋 哲人
  臨床血液, 60, 7, 834, 842, 06 Aug. 2019, [Peer-reviewed], [Lead author, Corresponding author]
  Japanese, Scientific journal
• Apparent synonymous mutation F9 c.87A>G causes secretion failure by in-frame mutation with aberrant splicing.
  Koya Odaira; Shogo Tamura; Nobuaki Suzuki; Misaki Kakihara; Yuna Hattori; Mahiru Tokoro; Sachiko Suzuki; Akira Takagi; Akira Katsumi; Fumihiko Hayakawa; Shuichi Okamoto; Atsuo Suzuki; Takeshi Kanematsu; Tadashi Matsushita; Tetsuhito Kojima
  Thrombosis research, 179, 95, 103, Jul. 2019, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
  English, Scientific journal, INTRODUCTION: Hemophilia B is an X-linked recessive bleeding disorder caused by coagulation factor IX (FIX) gene (F9) mutations. Several F9 synonymous mutations have been known to cause hemophilia B; however, the deleterious mechanisms underlying the development of hemophilia B have not been completely understood. To elucidate the molecular pathogenesis causing hemophilia B, we investigated the synonymous F9 mutation: c.87A>G, p.(Thr29=). MATERIALS AND METHODS: The influence of F9 c.87A>G on mRNA splicing was analyzed by exon-trap assay and in silico prediction. We prepared FIX expression vectors using mutant F9 cDNA and transfected HepG2 cells to investigate intracellular transport and extracellular secretion of FIX. Intracellular kinetics of the expressed FIX was examined by treatment with the proteasome inhibitor MG132. RESULTS: Exon-trap analysis revealed that F9 c.87A>G resulted in almost (99.1%) aberrant splicing (r.83_88del). In silico analysis predicted that F9 c.87A>G influenced the splicing pattern by generating an available aberrant 5' splice site. The aberrant F9 mRNA (r.83_88del) was translated to a mutant FIX p.Cys28_Val30delinsPhe with an in-frame mutation at the signal peptide cleavage site. Simultaneously, a small amount (0.9%) of mutant F9 r.87A>G translating into WT FIX p.Thr29 = was also observed. The mutant FIX was abnormally retained in the endoplasmic reticulum (ER) and was not extracellularly secreted. It appeared to be intracellularly degraded via proteasome-dependent degradation machinery. CONCLUSION: F9 c.87A>G was found to cause abnormal mRNA splicing, r.83_88del, and produce the mutant FIX p.Cys28_Val30delinsPhe. The mutant FIX is an abnormal protein with extracellular secretory defects and is intracellularly eliminated via proteasome-dependent ER-associated degradation.
• Soluble CLEC-2 is generated independently of ADAM10 and is increased in plasma in acute coronary syndrome: comparison with soluble GPVI
  Osamu Inoue; Makoto Osada; Junya Nakamura; Fuminori Kazama; Toshiaki Shirai; Nagaharu Tsukiji; Tomoyuki Sasaki; Hiroshi Yokomichi; Tomotaka Dohi; Makoto Kaneko; Makoto Kurano; Mitsuru Oosawa; Shogo Tamura; Kaneo Satoh; Katsuhiro Takano; Katsumi Miyauchi; Hiroyuki Daida; Yutaka Yatomi; Yukio Ozaki; Katsue Suzuki-Inoue
  INTERNATIONAL JOURNAL OF HEMATOLOGY, 110, 3, 285, 294, The Japanese Society of Hematology, 05 Jun. 2019, [Peer-reviewed]
  English, Scientific journal
• Molecular basis of SERPINC1 mutations in Japanese patients with antithrombin deficiency.
  Tamura S; Hashimoto E; Suzuki N; Kakihara M; Odaira K; Hattori Y; Tokoro M; Suzuki S; Takagi A; Katsumi A; Hayakawa F; Suzuki A; Okamoto S; Kanematsu T; Matsushita T; Kojima T
  Thrombosis research, 178, 159, 170, Apr. 2019, [Peer-reviewed], [Lead author, Corresponding author]
  Scientific journal
• 特発性血栓症 アンチトロンビン抵抗性の診断 検査法を中心に
  高木 明; 田村 彰吾; 小嶋 哲人
  日本検査血液学会雑誌, 19, 3, 393, 400, (一社)日本検査血液学会, Nov. 2018
  Japanese, Scientific journal
• Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction.
  Nagaharu Tsukiji; Osamu Inoue; Mitsuru Morimoto; Norifumi Tatsumi; Hiroaki Nagatomo; Koji Ueta; Toshiaki Shirai; Tomoyuki Sasaki; Shimon Otake; Shogo Tamura; Toshiaki Tachibana; Masataka Okabe; Masanori Hirashima; Yukio Ozaki; Katsue Suzuki-Inoue
  Blood, 132, 11, 1167, 1179, 13 Sep. 2018, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Platelets participate in not only thrombosis and hemostasis but also other pathophysiological processes, including tumor metastasis and inflammation. However, the putative role of platelets in the development of solid organs has not yet been described. Here, we report that platelets regulate lung development through the interaction between the platelet-activation receptor, C-type lectin-like receptor-2 (Clec-2; encoded by Clec1b), and its ligand, podoplanin, a membrane protein. Clec-2 deletion in mouse platelets led to lung malformation, which caused respiratory failure and neonatal lethality. In these embryos, α-smooth muscle actin-positive alveolar duct myofibroblasts (adMYFs) were almost absent in the primary alveolar septa, which resulted in loss of alveolar elastic fibers and lung malformation. Our data suggest that the lack of adMYFs is caused by abnormal differentiation of lung mesothelial cells (luMCs), the major progenitor of adMYFs. In the developing lung, podoplanin expression is detected in alveolar epithelial cells (AECs), luMCs, and lymphatic endothelial cells (LECs). LEC-specific podoplanin knockout mice showed neonatal lethality and Clec1b-/--like lung developmental abnormalities. Notably, these Clec1b-/--like lung abnormalities were also observed after thrombocytopenia or transforming growth factor-β depletion in fetuses. We propose that the interaction between Clec-2 on platelets and podoplanin on LECs stimulates adMYF differentiation of luMCs through transforming growth factor-β signaling, thus regulating normal lung development.
• Optimisation of antithrombin resistance assay as a practical clinical laboratory test: Development of prothrombin activator using factors Xa/Va and automation of assay
  S. Tamura; Y. Suga; M. Tanamura; M. Murata-Kawakami; Y. Takagi; Y. Hottori; M. Kakihara; S. Suzuki; A. Takagi; T. Kojima
  International Journal of Laboratory Hematology, 40, 3, 312, 319, Wiley, Jun. 2018, [Lead author]
  English, Scientific journal
• Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2/podoplanin-dependent platelet aggregation and lung metastasis
  T. Sasaki; T. Shirai; N. Tsukiji; S. Otake; S. Tamura; J. Ichikawa; M. Osada; K. Satoh; Y. Ozaki; K. Suzuki-Inoue
  Journal of Thrombosis and Haemostasis, 16, 5, 960, 972, Blackwell Publishing Ltd, 01 May 2018
  English, Scientific journal
• Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2
  Shogo TAMURA
  日本血栓止血学会誌, 29, 4, 389-397, 2018, [Peer-reviewed], [Invited], [Lead author, Last author, Corresponding author]
  Japanese, Scientific journal
• Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family
  S. Suzuki; Y. Nakamura; N. Suzuki; T. Yamazaki; Y. Takagi; S. Tamura; A. Takagi; T. Kanematsu; T. Matsushita; T. Kojima
  Haemophilia, 24, 1, e13, e16, Blackwell Publishing Ltd, 01 Jan. 2018
  English, Scientific journal
• ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y(12) in platelets
  Miki Kamiyama; Toshiaki Shirai; Shogo Tamura; Katsue Suzuki-Inoue; Shogo Ehata; Kei Takahashi; Kohei Miyazono; Yoshihiro Hayakawa; Takehiro Sato; Kohsuke Takeda; Isao Naguro; Hidenori Ichijo
  CELL DEATH AND DIFFERENTIATION, 24, 12, 2066, 2076, Dec. 2017, [Peer-reviewed]
  English, Scientific journal
• In vitro exploration of latent prothrombin mutants conveying antithrombin resistance
  Shogo Tamura; Moe Murata-Kawakami; Yuki Takagi; Sachiko Suzuki; Akira Katsumi; Akira Takagi; Tetsuhito Kojima
  THROMBOSIS RESEARCH, 159, 159, 33, 38, Nov. 2017, [Peer-reviewed], [Lead author]
  English, Scientific journal
• C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice
  T. Shirai; O. Inoue; S. Tamura; N. Tsukiji; T. Sasaki; H. Endo; K. Satoh; M. Osada; H. Sato-Uchida; H. Fujii; Y. Ozaki; K. Suzuki-Inoue
  JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 15, 3, 513, 525, Mar. 2017, [Peer-reviewed]
  English, Scientific journal
• The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-kappa B activities
  Fumihiko Furuya; Toshihisa Ishii; Shogo Tamura; Kazuya Takahashi; Hidetoshi Kobayashi; Masashi Ichijo; Soichi Takizawa; Masahiro Kaneshige; Katsue Suzuki-Inoue; Kenichiro Kitamura
  SCIENTIFIC REPORTS, 7, 43960, Mar. 2017, [Peer-reviewed]
  English, Scientific journal
• 巨核球造血の微小環境
  田村彰吾; 井上克枝; 小嶋哲人
  血液フロンティア, 27, 6, 37-46, 820,785, 医薬ジャーナル社, 2017, [Invited], [Lead author, Corresponding author]
  Japanese, Scientific journal
• 血小板・巨核球造血微小環境を構成する骨髄間質細胞
  田村彰吾; 尾崎由基男; 小嶋哲人; 井上克枝
  日本血栓止血学会誌, 28, 1, 59-63, 2017, [Lead author, Corresponding author]
  Japanese, Scientific journal
• Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance.
  Takagi Yuki; Murata Moe; Kozuka Toshihiro; Nakata Yukiko; Hasebe Ryo; Tamura Shogo; Takagi Akira; Matsushita Tadashi; Saito Hidehiko; Kojima Tetsuhito
  Thrombosis and Haemostasis, 116, 6, 1-10, 08 Sep. 2016, [Peer-reviewed]
  English, Scientific journal
• New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2.
  Ozaki Yukio; Tamura Shogo; Suzuki-Inoue Katsue
  Thrombosis journal, 14, 27-36, 06 Sep. 2016, [Peer-reviewed]
  English, Scientific journal
• Progestin isoforms provide different levels of protein S expression in HepG2 cells.
  Kozuka Toshihiro; Tamura Shogo; Kawamura Nami; Nakata Yukiko; Hasebe Ryo; Makiyama, Ayumi; Takagi Yuki; Murata Moe; Mizutani Naoki; Takagi Akira; Kojima Tetsuhito
  Thrombosis Research, 145, 40-45, 16 Jul. 2016, [Peer-reviewed]
  English, Scientific journal
• Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2
  Shogo Tamura; Katsue Suzuki-Inoue; Nagaharu Tsukiji; Toshiaki Shirai; Tomoyuki Sasaki; Makoto Osada; Kaneo Satoh; Yukio Ozaki
  BLOOD, 127, 13, 1701, 1710, Mar. 2016, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Laboratory and clinical features of abnormal macroenzymes found in human sera
  Takanori Moriyama; Shogo Tamura; Keiichi Nakano; Kohei Otsuka; Masahiko Shigemura; Naoyuki Honma
  BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 1854, 6, 658, 667, Jun. 2015, [Peer-reviewed]
  English, Scientific journal
• Diverse CD36 expression among Japanese population: defective CD36 mutations cause platelet and monocyte CD36 reductions in not only deficient but also normal phenotype subjects
  Yuya Masuda; Shogo Tamura; Kazuhiko Matsuno; Ayumi Nagasawa; Koji Hayasaka; Chikara Shimizu; Takanori Moriyama
  THROMBOSIS RESEARCH, 135, 5, 951, 957, May 2015, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Measurement of soluble C-type lectin-like receptor 2 in human plasma
  Fuminori Kazama; Junya Nakamura; Makoto Osada; Osamu Inoue; Mitsuru Oosawa; Shogo Tamura; Nagaharu Tsukiji; Kaoru Aida; Akio Kawaguchi; Soichi Takizawa; Masahiro Kaneshige; Shoichiro Tanaka; Katsue Suzuki-inoue; Yukio Ozaki
  PLATELETS, 26, 8, 711, 719, 2015, [Peer-reviewed]
  English, Scientific journal
• The basis examination of leukocyte-platelet aggregates with CD45 gating as a novel platelet activation marker
  A. Nagasawa; K. Matsuno; S. Tamura; K. Hayasaka; C. Shimizu; T. Moriyama
  INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, 35, 5, 534, 541, Oct. 2013, [Peer-reviewed]
  English, Scientific journal
• Development of a highly sensitive three-dimensional gel electrophoresis method for characterization of monoclonal protein heterogeneity
  Keiichi Nakano; Shogo Tamura; Kohei Otuka; Noriyasu Niizeki; Masahiko Shigemura; Chikara Shimizu; Kazuhiko Matsuno; Seiichi Kobayashi; Takanori Moriyama
  Analytical Biochemistry, 438, 2, 117, 123, 15 Jul. 2013, [Peer-reviewed]
  English, Scientific journal
• A rapid method to isolate soluble royal jelly proteins
  Reo Nozaki; Shogo Tamura; Aimi Ito; Takanori Moriyama; Kikuji Yamaguchi; Toru Kono
  FOOD CHEMISTRY, 134, 4, 2332, 2337, Oct. 2012, [Peer-reviewed]
  English, Scientific journal
• BDNF, produced by a TPO-stimulated megakaryocytic cell line, regulates autocrine proliferation
  Shogo Tamura; Ayumi Nagasawa; Yuya Masuda; Tetsuya Tsunematsu; Koji Hayasaka; Kazuhiko Matsuno; Chikara Shimizu; Yukio Ozaki; Takanori Moriyama
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 427, 3, 542, 546, Oct. 2012, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Release reaction of brain-derived neurotrophic factor (BDNF) through PAR1 activation and its two distinct pools in human platelets
  Shogo Tamura; Hidenori Suzuki; Yuji Hirowatari; Masanao Hatase; Ayumi Nagasawa; Kazuhiko Matsuno; Seiichi Kobayashi; Takanori Moriyama
  THROMBOSIS RESEARCH, 128, 5, E55, E61, Nov. 2011, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Molecular characteristics and physiological functions of major royal jelly protein 1 oligomer
  Shougo Tamura; Shizuka Amano; Toru Kono; Jun Kondoh; Kikuji Yamaguchi; Seiichi Kobayashi; Tokiyoshi Ayabe; Takanori Moriyama
  PROTEOMICS, 9, 24, 5534, 5543, Dec. 2009, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Estimation and characterisation of major royal jelly proteins obtained from the honeybee Apis merifera
  Shougo Tamura; Toru Kono; Chika Harada; Kikuji Yamaguchi; Takanori Moriyama
  FOOD CHEMISTRY, 114, 4, 1491, 1497, Jun. 2009, [Peer-reviewed], [Lead author]
  English, Scientific journal

• 最近の血栓止血異常のとらえかた 検査室や研究室から 先天性凝固異常症の遺伝子解析 解析のStrategyとPitfall
  田村 彰吾; 高木 明; 早川 文彦; 小嶋 哲人, 日本検査血液学会雑誌, 21, 1, 71, 81, Feb. 2020
  (一社)日本検査血液学会, Japanese
• Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction.
  Nagaharu Tsukiji; Osamu Inoue; Mitsuru Morimoto; Norifumi Tatsumi; Hiroaki Nagatomo; Koji Ueta; Toshiaki Shirai; Tomoyuki Sasaki; Shimon Otake; Shogo Tamura; Toshiaki Tachibana; Masataka Okabe; Masanori Hirashima; Yukio Ozaki; Katsue Suzuki-Inoue, Blood, 132, 11, 1167, 1179, 13 Sep. 2018, [International Magazine]
  Platelets participate in not only thrombosis and hemostasis but also other pathophysiological processes, including tumor metastasis and inflammation. However, the putative role of platelets in the development of solid organs has not yet been described. Here, we report that platelets regulate lung development through the interaction between the platelet-activation receptor, C-type lectin-like receptor-2 (Clec-2; encoded by Clec1b), and its ligand, podoplanin, a membrane protein. Clec-2 deletion in mouse platelets led to lung malformation, which caused respiratory failure and neonatal lethality. In these embryos, α-smooth muscle actin-positive alveolar duct myofibroblasts (adMYFs) were almost absent in the primary alveolar septa, which resulted in loss of alveolar elastic fibers and lung malformation. Our data suggest that the lack of adMYFs is caused by abnormal differentiation of lung mesothelial cells (luMCs), the major progenitor of adMYFs. In the developing lung, podoplanin expression is detected in alveolar epithelial cells (AECs), luMCs, and lymphatic endothelial cells (LECs). LEC-specific podoplanin knockout mice showed neonatal lethality and Clec1b-/--like lung developmental abnormalities. Notably, these Clec1b-/--like lung abnormalities were also observed after thrombocytopenia or transforming growth factor-β depletion in fetuses. We propose that the interaction between Clec-2 on platelets and podoplanin on LECs stimulates adMYF differentiation of luMCs through transforming growth factor-β signaling, thus regulating normal lung development., English
• Optimisation of antithrombin resistance assay as a practical clinical laboratory test: Development of prothrombin activator using factors Xa/Va and automation of assay
  S. Tamura; Y. Suga; M. Tanamura; M. Murata-Kawakami; Y. Takagi; Y. Hottori; M. Kakihara; S. Suzuki; A. Takagi; T. Kojima, International Journal of Laboratory Hematology, 40, 3, 312, 319, Jun. 2018
  Wiley, English, Report scientific journal
• Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2/podoplanin-dependent platelet aggregation and lung metastasis
  T. Sasaki; T. Shirai; N. Tsukiji; S. Otake; S. Tamura; J. Ichikawa; M. Osada; K. Satoh; Y. Ozaki; K. Suzuki-Inoue, Journal of Thrombosis and Haemostasis, 16, 5, 960, 972, 01 May 2018
  Blackwell Publishing Ltd, English, Report scientific journal
• Pressure-induced coherent sliding-layer transition in the excitonic insulator Ta2NiSe5
  Akitoshi Nakano; Kento Sugawara; Shinya Tamura; Naoyuki Katayama; Kazuyuki Matsubayashi; Taku Okada; Yoshiya Uwatoko; Kouji Munakata; Akiko Nakao; Hajime Sagayama; Reiji Kumai; Kunihisa Sugimoto; Naoyuki Maejima; Akihiko Machida; Tetsu Watanuki; Hiroshi Sawa, IUCrJ, 5, 158, 165, 01 Mar. 2018
  International Union of Crystallography, English, Report scientific journal
• Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders
  James Slack; on behalf of the; Michael H. Albert; Dmitry Balashov; Bernd H. Belohradsky; Alice Bertaina; Jack Bleesing; Claire Booth; Jochen Buechner; Rebecca H. Buckley; Marie Ouachée-Chardin; Elena Deripapa; Katarzyna Drabko; Mary Eapen; Tobias Feuchtinger; Andrea Finocchi; H. Bobby Gaspar; Sujal Ghosh; Alfred Gillio; Luis I. Gonzalez-Granado; Eyal Grunebaum; Tayfun Güngör; Carsten Heilmann; Merja Helminen; Kohei Higuchi; Kohsuke Imai; Krzysztof Kalwak; Nubuo Kanazawa; Gülsün Karasu; Zeynep Y. Kucuk; Alexandra Laberko; Andrzej Lange; Nizar Mahlaoui; Roland Meisel; D. Moshous; Hideki Muramatsu; Suhag Parikh; Srdjan Pasic; Irene Schmid; Catharina Schuetz; Ansgar Schulz; Kirk R. Schultz; Peter J. Shaw; Mary A. Slatter; Karl-Walter Sykora; Shinobu Tamura; Mervi Taskinen; Angela Wawer; Beata Wolska-Kuśnierz; Morton J. Cowan; Alain Fischer; Andrew R. Gennery, Journal of Allergy and Clinical Immunology, 141, 1, 322, 328.e10, 01 Jan. 2018
  Mosby Inc., English, Report scientific journal
• Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family
  S. Suzuki; Y. Nakamura; N. Suzuki; T. Yamazaki; Y. Takagi; S. Tamura; A. Takagi; T. Kanematsu; T. Matsushita; T. Kojima, Haemophilia, 24, 1, e13, e16, 01 Jan. 2018
  Blackwell Publishing Ltd, English, Report scientific journal
• ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y(12) in platelets
  Miki Kamiyama; Toshiaki Shirai; Shogo Tamura; Katsue Suzuki-Inoue; Shogo Ehata; Kei Takahashi; Kohei Miyazono; Yoshihiro Hayakawa; Takehiro Sato; Kohsuke Takeda; Isao Naguro; Hidenori Ichijo, CELL DEATH AND DIFFERENTIATION, 24, 12, 2066, 2076, Dec. 2017, [Peer-reviewed]
  English, Report scientific journal
• ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y(12) in platelets
  Miki Kamiyama; Toshiaki Shirai; Shogo Tamura; Katsue Suzuki-Inoue; Shogo Ehata; Kei Takahashi; Kohei Miyazono; Yoshihiro Hayakawa; Takehiro Sato; Kohsuke Takeda; Isao Naguro; Hidenori Ichijo, CELL DEATH AND DIFFERENTIATION, 24, 12, 2066, 2076, Dec. 2017
  English, Report scientific journal
• In vitro exploration of latent prothrombin mutants conveying antithrombin resistance
  Shogo Tamura; Moe Murata-Kawakami; Yuki Takagi; Sachiko Suzuki; Akira Katsumi; Akira Takagi; Tetsuhito Kojima, THROMBOSIS RESEARCH, 159, 159, 33, 38, Nov. 2017, [Peer-reviewed]
  English, Report scientific journal
• In vitro exploration of latent prothrombin mutants conveying antithrombin resistance
  Shogo Tamura; Moe Murata-Kawakami; Yuki Takagi; Sachiko Suzuki; Akira Katsumi; Akira Takagi; Tetsuhito Kojima, THROMBOSIS RESEARCH, 159, 33, 38, Nov. 2017
  English, Report scientific journal
• Low-rank and sparse decomposition based shape model and probabilistic atlas for automatic pathological organ segmentation
  Changfa Shi; Yuanzhi Cheng; Jinke Wang; Yadong Wang; Kensaku Mori; Shinichi Tamura, MEDICAL IMAGE ANALYSIS, 38, 30, 49, May 2017
  English, Report scientific journal
• C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice
  T. Shirai; O. Inoue; S. Tamura; N. Tsukiji; T. Sasaki; H. Endo; K. Satoh; M. Osada; H. Sato-Uchida; H. Fujii; Y. Ozaki; K. Suzuki-Inoue, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 15, 3, 513, 525, Mar. 2017, [Peer-reviewed]
  English, Report scientific journal
• The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-kappa B activities
  Fumihiko Furuya; Toshihisa Ishii; Shogo Tamura; Kazuya Takahashi; Hidetoshi Kobayashi; Masashi Ichijo; Soichi Takizawa; Masahiro Kaneshige; Katsue Suzuki-Inoue; Kenichiro Kitamura, SCIENTIFIC REPORTS, 7, 43960, Mar. 2017, [Peer-reviewed]
  English, Report scientific journal
• Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family
  Suzuki; S. Nakamura; Y. Suzuki; N. Yamazaki; T. Takagi; Y. Tamura; S. Takagi; A. Kanematsu; T. Matsushita; T. Kojima, T, Haemophilia, 1-3, 2017, [Peer-reviewed]
  English, Report scientific journal
• Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance.
  Yuki Takagi; Moe Murata; Toshihiro Kozuka; Yukiko Nakata; Ryo Hasebe; Shogo Tamura; Akira Takagi; Tadashi Matsushita; Hidehiko Saito; Tetsuhito Kojima, Thrombosis and haemostasis, 116, 6, 1022, 1031, 30 Nov. 2016, [Peer-reviewed], [International Magazine]
  Antithrombin (AT) and thrombomodulin (TM) play important roles in the process of natural anticoagulation in vivo. Recently, we reported that the prothrombin Yukuhashi mutation (p.Arg596Leu) was associated with AT and TM resistance-related thrombophilia. To assess the AT and TM resistances associated with other missense mutations by single base substitution in the Arg596 codon, we generated recombinant variants (596Gln, 596Trp, 596Gly, and 596Pro) and investigated the effects on AT and TM anticoagulant functions. All variants except 596Pro were secreted in amounts comparable to that of the wild-type but exhibited variable procoagulant activities. After a 30-minute inactivation by AT, the relative residual activity of wild-type thrombin decreased to 15 ± 4.0 %, in contrast to values of all variants were maintained at above 80 %. The thrombin-AT complex formation, as determined by enzyme-linked immunosorbent assay, was reduced with all tested variants in the presence and absence of heparin. In the presence of soluble TM (sTM), the relative fibrinogen clotting activity of wild-type thrombin decreased to 16 ± 0.12 %, whereas that of tested variants was 37 %-56 %. In a surface plasmon resonance assay, missense Arg596 mutations reduced thrombin-TM affinity to an extent similar to the reduction of fibrinogen clotting inhibition. In the presence of sTM or cultured endothelial-like cells, APC generation was enhanced differently by variant thrombins in a thrombin-TM affinity-dependent manner. These data indicate that prothrombin Arg596 missense mutations lead to AT and TM resistance in the variant thrombins and suggest that prothrombin Arg596 is important for AT- and TM-mediated anticoagulation., English, Report scientific journal
• New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2.
  Ozaki Yukio; Tamura Shogo; Suzuki-Inoue Katsue, Thrombosis journal, 14, 27-36, 06 Sep. 2016, [Peer-reviewed]
  English, Report scientific journal
• Progestin isoforms provide different levels of protein S expression in HepG2 cells.
  Kozuka Toshihiro; Tamura Shogo; Kawamura Nami; Nakata Yukiko; Hasebe Ryo; Makiyama, Ayumi; Takagi Yuki; Murata Moe; Mizutani Naoki; Takagi Akira; Kojima Tetsuhito, Thrombosis Research, 145, 40-45, 16 Jul. 2016, [Peer-reviewed]
  English, Report scientific journal
• Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2
  Shogo Tamura; Katsue Suzuki-Inoue; Nagaharu Tsukiji; Toshiaki Shirai; Tomoyuki Sasaki; Makoto Osada; Kaneo Satoh; Yukio Ozaki, BLOOD, 127, 13, 1701, 1710, Mar. 2016, [Peer-reviewed]
  English, Report scientific journal
• Laboratory and clinical features of abnormal macroenzymes found in human sera
  Takanori Moriyama; Shogo Tamura; Keiichi Nakano; Kohei Otsuka; Masahiko Shigemura; Naoyuki Honma, BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 1854, 6, 658, 667, Jun. 2015, [Peer-reviewed]
  English, Book review
• 可溶型CLEC-2は血小板活性化に伴って生成される 可溶性GPVIとの比較検討
  井上 修; 長田 誠; 中村 純也; 風間 文智; 横道 洋司; 土肥 智貴; 金子 誠; 蔵野 信; 大澤 満; 田村 彰吾; 佐藤 金夫; 高野 勝弘; 宮内 克己; 代田 浩之; 矢冨 裕; 井上 克枝; 尾崎 由基男, 日本血栓止血学会誌, 26, 2, 215, 215, Apr. 2015
  (一社)日本血栓止血学会, Japanese
• Measurement of soluble C-type lectin-like receptor 2 in human plasma
  Fuminori Kazama; Junya Nakamura; Makoto Osada; Osamu Inoue; Mitsuru Oosawa; Shogo Tamura; Nagaharu Tsukiji; Kaoru Aida; Akio Kawaguchi; Soichi Takizawa; Masahiro Kaneshige; Shoichiro Tanaka; Katsue Suzuki-inoue; Yukio Ozaki, PLATELETS, 26, 8, 711, 719, 2015, [Peer-reviewed]
  English, Report scientific journal
• The basis examination of leukocyte-platelet aggregates with CD45 gating as a novel platelet activation marker
  A. Nagasawa; K. Matsuno; S. Tamura; K. Hayasaka; C. Shimizu; T. Moriyama, INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, 35, 5, 534, 541, Oct. 2013, [Peer-reviewed]
  English, Report scientific journal
• Development of a highly sensitive three-dimensional gel electrophoresis method for characterization of monoclonal protein heterogeneity
  Keiichi Nakano; Shogo Tamura; Kohei Otuka; Noriyasu Niizeki; Masahiko Shigemura; Chikara Shimizu; Kazuhiko Matsuno; Seiichi Kobayashi; Takanori Moriyama, Analytical Biochemistry, 438, 2, 117, 123, 15 Jul. 2013, [Peer-reviewed]
  English, Report scientific journal
• 【事例で学ぶ 免疫検査異常値への対応】 総論 免疫検査における非特異反応
  森山 隆則; 中野 恵一; 田村 彰吾, Medical Technology, 41, 7, 724, 729, Jul. 2013
  医歯薬出版(株), Japanese
• M蛋白多様性解析に向けた高感度3次元電気泳動法の確立
  中野 恵一; 田村 彰吾; 大塚 浩平; 新関 紀康; 重村 雅彦; 澁谷 斉; 松野 一彦; 清水 力; 小林 清一; 森山 隆則, 臨床化学, 42, Suppl.1, 197, 197, Jul. 2013
  (一社)日本臨床化学会, Japanese
• A rapid method to isolate soluble royal jelly proteins
  Reo Nozaki; Shogo Tamura; Aimi Ito; Takanori Moriyama; Kikuji Yamaguchi; Toru Kono, FOOD CHEMISTRY, 134, 4, 2332, 2337, Oct. 2012, [Peer-reviewed]
  English, Report scientific journal

• 総論 静脈血栓症の遺伝的要因, 動脈・静脈の疾患 2024 (上)
  田村彰吾
  日本臨床社, 2024, [Joint work]
• みんなに役立つ血友病の基礎と臨床
  田村彰吾; 小嶋哲人
  医薬ジャーナル社, 20 Aug. 2016, 55-61, Japanese, Textbook, [Joint work]
• 化学検査:アイソザイム染色, 新染色法のすべて
  森山隆則; 中野恵一; 畑瀬正尚; 田村彰吾
  医歯薬出版株式会社, 25 Mar. 2011, 396-403, Japanese, [Joint work]

• 血液再生制御学演習, 2024年, 修士課程, 保健科学院
• 血液再生制御学特論, 2024年, 修士課程, 保健科学院
• 先端検査医学特論, 2024年, 修士課程, 保健科学院
• 生体情報機能解析学特講, 2024年, 博士後期課程, 保健科学院
• 生体情報機能解析学特講演習, 2024年, 博士後期課程, 保健科学院
• 免疫検査学実習, 2024年, 学士課程, 医学部
• 技能修得到達度評価, 2024年, 学士課程, 医学部
• 臨地実習（検体・病理検査）, 2024年, 学士課程, 医学部
• 臨床生理学Ⅰ, 2024年, 学士課程, 医学部
• 臨床生理学Ⅱ, 2024年, 学士課程, 医学部
• 臨床血液学, 2024年, 学士課程, 医学部
• 臨床血液学Ⅰ, 2024年, 学士課程, 医学部
• 臨床血液学Ⅱ, 2024年, 学士課程, 医学部
• 臨床血液学実習, 2024年, 学士課程, 医学部
• 臨床血液学実習Ⅰ, 2024年, 学士課程, 医学部
• 臨床血液学実習Ⅱ, 2024年, 学士課程, 医学部
• 移植検査学, 2024年, 学士課程, 医学部
• 保健生理学, 2024年, 学士課程, 医学部
• 医療安全管理学演習, 2024年, 学士課程, 医学部
• 輸血・移植検査学, 2024年, 学士課程, 医学部
• 輸血検査学, 2024年, 学士課程, 医学部
• 移植検査学実習, 2024年, 学士課程, 医学部
• 輸血検査学演習, 2024年, 学士課程, 医学部
• 臨床病態学Ⅲ, 2024年, 学士課程, 医学部
• 一般教育演習(ﾌﾚｯｼｭﾏﾝｾﾐﾅｰ), 2024年, 学士課程, 全学教育
• 医療安全管理学Ⅱ, 2024年, 学士課程, 医学部

• 日本再生医療学会
• 日本生化学会
• 日本検査血液学会
• 日本血栓止血学会
• 日本血液学会
• International Society of Thrombosis and Hemostasis

• 骨髄発生の再現により達成する骨髄オルガノイド開発
  創発的研究支援事業
  Apr. 2022 - Mar. 2029
  田村彰吾
  国立研究開発法人科学技術振興機構, Principal investigator, 21467527
• バイオバンクコホートを活用した希少血液凝固異常症の解析
  科学研究費助成事業
  Apr. 2025 - Mar. 2028
  勝見 章, 田村彰吾
  日本学術振興会, 基盤研究(C), 国立研究開発法人国立長寿医療研究センター, Coinvestigator, 25K11680
• 巨核球サブタイプ分化の時空間制御をもたらす骨髄間質環境の解明
  科学研究費助成事業
  Apr. 2025 - Mar. 2028
  田村 彰吾; 谷口浩二; 築地長治; 鈴木伸明
  日本学術振興会, 基盤研究(B), 北海道大学, Principal investigator, 25K02448
• 血友病保因者診断の検査法確立と体制構築に向けて
  科学研究費助成事業
  Apr. 2024 - Mar. 2027
  鈴木 伸明; 鈴木 幸子; 田村 彰吾; 鈴木 敦夫; 岡本 修一
  日本学術振興会, 基盤研究(C), 名古屋大学, 24K11512
• 血小板におけるRhoA-フォルミンを介した新規脂質シグナル調節機構の解明
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
  Apr. 2022 - Mar. 2025
  勝見 章; 田村 彰吾
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), National Center for Geriatrics and Gerontology, Coinvestigator, 22K08518
• ライフステージに伴う血小板・巨核球造血微小環境の時空間的変遷の解明
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
  Apr. 2022 - Mar. 2025
  田村 彰吾; 築地 長治; 鈴木 伸明
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, Principal investigator, 22K06881
• 活性値の乖離に着目した血友病性関節症の病態解明とアンメットニーズの開拓
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
  Apr. 2021 - Mar. 2024
  鈴木 伸明; 高橋 伸典; 田村 彰吾; 鈴木 敦夫
  新たに9症例の血友病A患者の遺伝子解析を実施。研究対象症例は合計57症例の患者群となった。新たに判明したバリアントの中には1例の新規バリアントが含まれた。これらの症例に対し、合成基質法と凝固一段法による血液凝固第VIII因子(FVIII)活性測定を実施した。その結果、13症例が活性測定法の違いにより、活性値が解離する研究対象症例であった。次のステップとして、これらの活性乖離症例がどのようなメカニズムで活性乖離を呈するのかを検討することにしたが、基礎検討として、活性乖離を示すことが判明しているFVIII製剤(アルブトレペノナコグ アルファ)を用いて、活性乖離を示さないFVIII製剤であるルリオクトコグアルファを対照として、FVIII製剤を添加したスパイク検体を作製し、トロンビン生成試験やFVIII活性測定、FVIII抗原量測定、凝固波形解析、モディファイド合成基質法の実験系セットアップを行った。しかし、この検討の過程で、発売されている様々なFVIII製剤は抗原量と活性値の比である比活性(活性値/抗原量)のばらつきが非常に大きく、評価が難しいことが判明した。そのため、患者検体での実験系セットアップに方針転換したが、FVIII以外の検体条件など比較条件を揃えるのが難しく、さらには含まれているFVIII量が絶対的に少ないため、差を評価するのが難しいという課題に直面している。
  今回の研究では、研究対象バリアントを保有する患者さんでは本人が関節内出血と認識していない出血、いわゆる微小出血を繰り返し、サイレントに血友病性関節症を発症するという仮説の検証も行う計画であるが、こちらの方は次年度以降に進めていく予定である。
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Nagoya University, Coinvestigator, 21K08388
• Analysis of the bone marrow microenvironment regulating megakaryo/thrombopoiesis
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)
  Apr. 2017 - Mar. 2021
  Tamura Shogo
  This study suggested that a cellular origin of the bone marrow PDPN-expressing stromal cells discovered by the principal investigator is skeletal stem cells (SSCs). We analyzed the distribution of bone marrow PDPN-expressing stromal cells during bone and bone marrow development, especially in the secondary ossification center marrow formed at the epiphysis. We found that, during the formation of the secondary ossification center at the ends of bones, PDPN-positive cells invaded into the secondary ossification center along with periosteal vasculatures and populated the primary marrow. Furthermore, using an in vitro model, we found that PDPN-positive stromal cells maintained vascular homeostasis as a physiological function.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (A), Nagoya University, Principal investigator, 17H05073
• Development zeno-free/self-feeder culture system for an efficient iPSC derived platelet production
  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)
  Jun. 2018 - Mar. 2020
  Tamura Shogo
  The aim of this study is to establish a high efficient in vitro culture system of megakaryocyte/platelet using a novel bone marrow podoplanin (PDPN) positive stromal cells which we previously identified. PDPN positive stromal cells obviously promoted an expansion of megakaryo-progenitor in vitro. However, in the co-culture system with PDPN positive stromal cells and megakaryocytes, we found that platelet collection rate was significantly reduced because of unexpected platelet adhesion onto stromal cells.
  Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Nagoya University, Principal investigator, 18K19910
• Pathophysiological function of CLEC-2 for megaakryocyte and erythrocyte development
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  Apr. 2014 - Mar. 2017
  Tamura Shogo; Inoue Katsue; Ozaki Yukio; Tsukiji Nagaharu; Shirai Toshiaki
  C-type lectin-like receptor 2 (CLEC-2) is a platelet activating receptor which binds to podoplanin (PDPN). In this study, we investigated a physiological function of CLEC-2 and/or PDPN for meagkaryo/thrombopoiesis. The interaction of CLEC-2 with PDPN directly accelerated expansion of megakaryocyte progenitors. We also newly identified PDPN expressing bone marrow stromal cells adjacent to arterioles in the bone marrow, and termed as BM FRC-like cells. Now, we propose that BM FRC-like cells provide a novel CLEC-2/PDPN dependent megakaryopoietic microenvironment in the vicinity of arterioles in the bone marrow.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Principal investigator, 26860723
• Development of a novel platelet-biogenesis marker, BDNF
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
  Apr. 2014 - Mar. 2017
  OZAKI Yukio
  Previously, we reported that brain-derived neurotrophic factor (BDNF) had a novel function which involved in a megakaryocyte differentiation using human megakaryocyte cell-line model, MEG-01. In this study, we investigated whether BDNF affected normal primary megakaryocyte development in mice. BDNF accelerated clonal expansion of primary megakaryocyte progenitor in vitro. On the other hand, megakaryocyte maturation was not promoted by BDNF. These results suggested that BDNF had a potential as a Meg-CSF for primary megakaryocyte. However, BDNF did not show the physiological function to promote a platelet recovery in transient thrombocytopenic mouse model with anti-platelet antibody. Last year, it was reported that mouse megakaryocytes did not produce BDNF, whereas human megakaryocytes produce BDNF and platelets stored abundant BDNF in alpha-granules. To further investigate a BDFN pathophysiological function for in vivo megakaryopoiesis, an alternative in vivo model should be demanded.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), University of Yamanashi, Coinvestigator, 26460671
• 脳由来神経栄養因子（ＢＤＮＦ）の巨核球分化成熟過程に対する病態生理学的意義の解明
  Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows
  Apr. 2013 - Mar. 2016
  田村 彰吾
  これまでのin vitroの検討から、BDNFはマウス正常巨核球の自己増殖（clonal expansion）を促進することが明らかになった。そこで平成27年度はin vivoにおけるBDNFの巨核球・血小板造血への関与を検討した。血小板減少症モデルマウスにおいてBDNFは血小板数の回復を促進すると考え、本検討では抗マウスGPIb抗体カクテル投与による一過性血小板減少症モデルマウスを用いたBDNF投与実験を実施した。しかしながら、今回のモデルではBDNF投与マウスの有意な血小板数回復は認められなかった。本課題の今後の方針は、骨髄抑制モデルなど他の血小板減少症モデルにおけるBDNFの血小板・巨核球増殖促進作用の検討が挙げられる。
  一方、申請者は本課題以外に血小板活性化受容体CLEC-2の血小板造血における役割に関する研究も手掛けた。CLEC-2の生体内リガンドである膜蛋白、ポドプラニンを発現した新規の間質細胞を同定し、同細胞のポドプラニンと巨核球のCLEC-2が結合して全く新しいニッシェが形成されることを見出した。このニッシェで、ポドプラニン刺激で巨核球の増殖が促進され、CLEC-2の刺激で間質細胞が産生するサイトカインが巨核球のproplatelet形成を促進するという、画期的な機序を解明した。
  Japan Society for the Promotion of Science, Grant-in-Aid for JSPS Fellows, Principal investigator, 13J04623
• 脳由来神経栄養因子(BDNF)の循環血液中における存在様式の解明
  Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows
  Apr. 2010 - Mar. 2013
  田村 彰吾
  脳由来神経栄養因子(Brain-derived neurotrophic factor, BDNF)は循環血液中では大部分が血小板に貯蔵されていることが知られているが、血小板母細胞である巨核球でのBDNFの産生はcell lineを用いたin vitroの系では認められず、巨核球はBDNF産生能力が欠如していると考えられてきた。しかしながら我々のこれまでの検討によって血小板母細胞である巨核球によるBDNFの産生の可能性がが提示された。そこで我々は巨核球系細胞株のMEG-01を用いたBDNF産生能の解析を実施した。その結果、MEG-01はTPO存在下でBDNFを産生する事を明らかにした。また、産生されたBDNFはautocrine様式によって自己利用され、MEG-01の細胞増殖を促進する事が明らかになった。一方、MEG-01の多核化に対してBDNFは促進的作用を示さず、むしろ多核化抑制傾向が認められた。造血幹細胞から巨核球産生に至る分化成熟過程はmegakaryopoiesisと呼ばれ、早期の自己増殖能に特徴づけられる分化過程と、それに続発する多核化・細胞質膨張が起こる成熟過程に分けられる。本検討により得られた知見から、BDNFはMEG-01に対して自己細胞増殖を促進するmegakaryocyte-colony stimulating factor(MEG-CSF)様作用を呈する事が明らかになり、BDNFがmegakaryopoiesisに関与する新しいサイトカインである可能性が示唆された。
  Japan Society for the Promotion of Science, Grant-in-Aid for JSPS Fellows, Hokkaido University, Principal investigator, Competitive research funding, 10J01595