研究者総覧

大森 司 (オオモリ ツカサ)

  • 生化学講座(病態生化学部門) 教授
Last Updated :2021/11/23

研究者情報

ホームページURL

J-Global ID

研究キーワード

  • ST2   血友病   第VIII因子   遺伝子治療   第IX因子   血小板   スフィンゴシン1-リン酸   

研究分野

  • ライフサイエンス / 血液、腫瘍内科学
  • ライフサイエンス / 整形外科学

経歴

  • 2017年04月 - 現在  自治医科大学医学部生化学講座病態生化学部門教授

所属学協会

  • 日本内科学会   日本臨床検査医学会   日本検査血液学会   日本生化学会   日本血栓止血学会   日本血液学会   

研究活動情報

論文

  • Morisada Hayakawa, Asuka Sakata, Hiroko Hayakawa, Hikari Matsumoto, Takafumi Hiramoto, Yuji Kashiwakura, Nemekhbayar Baatartsogt, Noriyoshi Fukushima, Yoichi Sakata, Katsue Suzuki-Inoue, Tsukasa Ohmori
    Scientific Reports 11 1 2021年12月 [査読有り]
     
    AbstractCoagulation factors are produced from hepatocytes, whereas production of coagulation factor VIII (FVIII) from primary tissues and cell species is still controversial. Here, we tried to characterize primary FVIII-producing organ and cell species using genetically engineered mice, in which enhanced green fluorescent protein (EGFP) was expressed instead of the F8 gene. EGFP-positive FVIII-producing cells existed only in thin sinusoidal layer of the liver and characterized as CD31high, CD146high, and lymphatic vascular endothelial hyaluronan receptor 1 (Lyve1)+. EGFP-positive cells can be clearly distinguished from lymphatic endothelial cells in the expression profile of the podoplanin and C-type lectin-like receptor-2 (CLEC-2)+. In embryogenesis, EGFP-positive cells began to emerge at E14.5 and subsequently increased according to liver maturation. Furthermore, plasma FVIII could be abolished by crossing F8 conditional deficient mice with Lyve1-Cre mice. In conclusion, in mice, FVIII is only produced from endothelial cells exhibiting CD31high, CD146high, Lyve1+, CLEC-2+, and podoplanin in liver sinusoidal endothelial cells.
  • Development of a sensitive and reproducible cell-based assay via secNanoLuc to detect neutralizing antibody against adeno-associated virus vector capsid
    Baatartsogt N, Kashiwakura Y, Hayakawa M, Kamoshita N, Hiramoto T, Mizukami H, Ohmori T
    Mol Ther Method and Clin Dev 22 162 - 172 2021年09月 [査読有り]
  • プロテインC完全欠損症に対するアデノ随伴ウイルスベクターを用いた遺伝子治療法の開発
    冨樫 朋貴, 早川 盛禎, 鴨下 信彦, 柏倉 裕志, 平本 貴史, 長尾 恭光, 森下 英理子, 大森 司
    日本血栓止血学会誌 32 2 206 - 206 (一社)日本血栓止血学会 2021年05月
  • Suvd Byambaa, Hideki Uosaki, Tsukasa Ohmori, Hiromasa Hara, Hitoshi Endo, Osamu Nureki, Yutaka Hanazono
    Molecular therapy. Methods & clinical development 20 451 - 462 2021年03月 
    We conducted two lines of genome-editing experiments of mouse hematopoietic stem cells (HSCs) with the clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein 9 (Cas9). First, to evaluate the genome-editing efficiency in mouse bona fide HSCs, we knocked out integrin alpha 2b (Itga2b) with Cas9 ribonucleoprotein (Cas9/RNP) and performed serial transplantation in mice. The knockout efficiency was estimated at approximately 15%. Second, giving an example of X-linked severe combined immunodeficiency (X-SCID) as a target genetic disease, we showed a proof-of-concept of universal gene correction, allowing rescue of most of X-SCID mutations, in a completely non-viral setting. We inserted partial cDNA of interleukin-2 receptor gamma chain (Il2rg) into intron 1 of Il2rg via non-homologous end-joining (NHEJ) with Cas9/RNP and a homology-independent targeted integration (HITI)-based construct. Repaired HSCs reconstituted T lymphocytes and thymuses in SCID mice. Our results show that a non-viral genome-editing of HSCs with CRISPR/Cas9 will help cure genetic diseases.
  • Suvd Byambaa, Hideki Uosaki, Tsukasa Ohmori, Hiromasa Hara, Hitoshi Endo, Osamu Nureki, Yutaka Hanazono
    Molecular Therapy - Methods & Clinical Development 20 451 - 462 2021年03月 [査読有り]
  • Ulrike M Reiss, Lei Zhang, Tsukasa Ohmori
    Haemophilia : the official journal of the World Federation of Hemophilia Suppl 3 132 - 141 2021年02月 [査読有り][通常論文]
     
    Gene therapy is an opportunity for haemophilia patients to receive a one-time treatment and have lasting factor levels for years or decades instead of dependence on repeated administration within short intervals and on sustained supply of drug. Great strides have been made in the development of gene therapy for haemophilia in the last decade. Adeno-associated virus (AAV) vector-mediated gene transfer in haemophilia A and B has entered the phase III trial stage. Gene transfer by lentiviral vector or gene editing technologies using factor VIII (FVIII) or IX (FIX) genes are now entering clinical evaluation. It is expected that the first FVIII and FIX gene therapy products will soon be approved and distributed in major markets. Global access to gene therapy is a critical goal. This review presents new and ongoing efforts towards this goal in countries other than North America and Europe. In Japan, researchers, regulators and funders have established a promising gene therapy development platform for multiple diseases including haemophilia. Decades of scientific and clinical research in haemophilia gene therapy in China have led to a recently registered clinical trial of AAV-mediated gene therapy for haemophilia B. Other countries are in earlier phases of building gene therapy programmes or participate in international trials. A phase 2 feasibility trial of AAV-mediated FIX gene therapy in low- and middle-income countries aims to demonstrate that gene therapy could become available in resource-constrained socio-economic settings. The different strategies for establishing gene therapy provide opportunities for closing the global gap in haemophilia care.
  • Sachiko Watanabe, Fumitake Usui-Kawanishi, Takanori Komada, Tadayoshi Karasawa, Ryo Kamata, Naoya Yamada, Hiroaki Kimura, Katsuya Dezaki, Tsukasa Ohmori, Masafumi Takahashi
    Biochemical and biophysical research communications 531 2 125 - 132 2020年10月 [査読有り][通常論文]
     
    BACKGROUND: Platelets are critical mediators of vascular homeostasis and thrombosis, and also contribute to the development of inflammation. NLRP3 inflammasome is a cytosolic multi-protein complex that consists of NLRP3, ASC and caspase-1, and regulates IL-1β-mediated inflammation. METHOD AND RESULTS: Using two mouse models of thrombosis (i.e., occlusion of the middle cerebral artery and inferior vena cava), we found that thrombus formation was significantly enhanced in ASC-deficient (ASC-/-) mice, compared to that in wild-type (WT) and IL-1β-/- mice. ASC deficiency had no effects on blood coagulation parameters (i.e., prothrombin time [PT] and activated partial thromboplastin time [APTT]). Platelets from WT mice express ASC, but neither NLRP3 nor caspase-1. ASC deficiency significantly enhanced the expression of P-selectin and GPIIb/IIIa in response to a GPVI agonist (collagen-related peptide [CRP]), but not to thrombin, in platelets. CRP induced ASC speck formation in WT platelets. ASC deficiency also enhanced cytosolic Ca2+ elevation and phosphorylation of ERK1/2 and Akt in platelets. CONCLUSION: Our results demonstrate that ASC negatively regulates GPVI signaling in platelets and enhances thrombus formation, independent of NLRP3 inflammasome and IL-1β, and provide novel insights into the link between inflammation and thrombosis.
  • Rie Goka, Naoki Morimoto, Kouichi Miura, Shunji Watanabe, Yoshinari Takaoka, Hiroaki Nomoto, Mamiko Tsukui, Takeshi Fujieda, Hiroshi Maeda, Naoto Sato, Tsukasa Ohmori, Norio Isoda, Hironori Yamamoto
    Clinical journal of gastroenterology 13 5 907 - 913 2020年10月 [査読有り][通常論文]
     
    Percutaneous radiofrequency ablation (RFA) is a good indication for hepatocellular carcinoma (HCC) in cases involving ≦ 3 tumors of ≦ 30 mm in size, many hepatologists are hesitant to perform the procedure for patients with hemorrhagic disorders. We herein report the successful treatment of HCC by laparoscopic RFA in a patient with hemophilia A. A 48-year-old man with moderate form of hemophilia A had a single HCC at segment 8. To perform laparoscopic RFA safely, recombinant factor VIII (rFVIII) was administered to maintain factor VIII activity (FVIII:C) > 80% on the operation day and > 40% for 6 days after the operation in accordance with the guidelines. A total of 23,000 units of rFVIII was used. Laparoscopic RFA was completed with an operation time of 105 min and < 10 mL of blood loss. As a result, blood transfusion was not required. At 2 years after the initial treatment, HCC recurred at segment 7. Under rFVIII supplementation, we performed a second laparoscopic RFA without any events. Although partial hepatectomy is the main procedure used to treat HCC in patients with hemophilia, we could reduce in total use of rFVIII, blood and operation time by laparoscopic RFA compared with those in partial hepatectomy.
  • Ryota Watano, Tsukasa Ohmori, Shuji Hishikawa, Asuka Sakata, Hiroaki Mizukami
    Gene therapy 27 9 427 - 434 2020年09月 [査読有り][通常論文]
     
    Adeno-associated virus (AAV) vectors can transduce hepatocytes efficiently in vivo in various animal species, including humans. Few reports, however, have examined the utility of pigs in gene therapy. Pigs are potentially useful in preclinical studies because of their anatomical and physiological similarity to humans. Here, we evaluated the utility of microminipigs for liver-targeted gene therapy. These pigs were intravenously inoculated with an AAV8 vector encoding the luciferase gene, and gene expression was assessed by an in vivo imaging system. Robust transgene expression was observed almost exclusively in the liver, even though the pig showed a low-titer of neutralizing antibody (NAb) against the AAV8 capsid. We assessed the action of NAbs against AAV, which interfere with AAV vector-mediated gene transfer by intravascular delivery. When a standard dose of vector was administered intravenously, transgene expression was observed in both NAb-negative and low-titer (14×)-positive subjects, whereas gene expression was not observed in animals with higher titers (56×). These results are compatible with our previous observations using nonhuman primates, indicating that pigs are useful in gene therapy experiments, and that the role of low-titer NAb in intravenous administration of the AAV vector shows similarities across species.
  • Koji Kawamura, Yukie Tanaka, Hideki Nakasone, Yuko Ishihara, Shinichi Kako, Seiichiro Kobayashi, Yuetsu Tanaka, Tsukasa Ohmori, Kaoru Uchimaru, Sachiko Okamoto, Junichi Mineno, Hiroshi Shiku, Satoshi Nishimura, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 8 1377 - 1385 2020年08月 [査読有り][通常論文]
     
    Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm caused by infection with human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains extremely poor. Tax, the most important regulatory protein for HTLV-1, is associated with the aggressive proliferation of host cells and is also a major target antigen for CD8+ cytotoxic T cells (CTLs). Based on our previous findings that Tax-specific CTLs with a T cell receptor (TCR) containing a unique amino-acid sequence motif exhibit strong HLA-A*24:02-restricted, Tax301-309-specific activity against HTLV-1, we aimed to develop a Tax-redirected T cell immunotherapy for ATL. TCR-ɑ/β genes were cloned from a previously established CTL clone and transduced into peripheral blood mononuclear cells (PBMCs) of healthy volunteers using a retroviral siTCR vector. Then the cytotoxic efficacy against HTLV-1-infected T cells or primary ATL cells was assessed both in vitro and in vivo. The redirected CTLs (Tax-siCTLs) produced a large amount of cytokines and showed strong killing activity against ATL/HTLV-1-infected T cells in vitro, although they did not have universal activity against ATL cells. Next, in a xenograft mouse model using an HTLV-1-infected T cell line (MT-2), in all mice treated with Tax-siCTLs, the tumor rapidly diminished and finally disappeared without normal tissue damage, although all mice that were untreated or treated with non-gene-modified PBMCs died because of tumor progression. Our findings confirm that Tax-siCTLs can exert strong anti-ATL/HTLV-1 effects without a significant reaction against normal cells and have the potential to be a novel immunotherapy for ATL patients.
  • Hiroshi Saito, Morisada Hayakawa, Nobuhiko Kamoshita, Atsushi Yasumoto, Katsue Suzuki-Inoue, Yutaka Yatomi, Tsukasa Ohmori
    International journal of hematology 111 6 786 - 794 2020年06月 [査読有り][通常論文]
     
    Platelet function tests utilizing agonists or patient serum are generally performed to assess platelet activation ex vivo. However, inter-individual differences in platelet reactivity and donor requirements make it difficult to standardize these tests. Here, we established a megakaryoblastic cell line for the conventional assessment of platelet activation. We first compared intracellular signaling pathways using CD32 crosslinking in several megakaryoblastic cell lines, including CMK, UT-7/TPO, and MEG-01 cells. We confirmed that CD32 was abundantly expressed on the cell surface, and that intracellular calcium mobilization and tyrosine phosphorylation occurred after CD32 crosslinking. We next employed GCaMP6s, a highly sensitive calcium indicator, to facilitate the detection of calcium mobilization by transducing CMK and MEG-01 cells with a plasmid harboring GCaMP6s under the control of the human elongation factor-1α promoter. Cells that stably expressed GCaMP6s emitted enhanced green fluorescent protein fluorescence in response to intracellular calcium mobilization following agonist stimulation in the absence of pretreatment. In summary, we have established megakaryoblastic cell lines that mimic platelets by mobilizing intracellular calcium in response to several agonists. These cell lines can potentially be utilized in high-throughput screening assays for the discovery of new antiplatelet drugs or diagnosis of disorders caused by platelet-activating substances.
  • Tomoyuki Kabutoya, Tsukasa Ohmori, Takeshi Fujiwara, Kazuomi Kario
    Clinical and experimental hypertension (New York, N.Y. : 1993) 42 4 365 - 370 2020年05月 [査読有り][通常論文]
     
    Background: Anticoagulant activity and blood pressure increase in the morning. The aim of this study was to evaluate changes of anticoagulant activity, blood pressure and target organ damage in patients with nonvalvular atrial fibrillation (AF) given combination treatment with Xa inhibitor and antihypertensive agent.Methods: We enrolled 72 patients with nonvalvular AF. Rivaroxaban (10-15 mg) was continuously administered once daily over 8 weeks (study period I). For subjects (n = 50) who exhibited uncontrolled morning hypertension (home systolic blood pressure [SBP]≥125 mmHg) at the end of study period I (at 8 weeks), nifedipine CR (20-40 mg) was added at bedtime, and rivaroxaban administration was continued an additional 8 weeks. We assessed prothrombin fragment 1 + 2 (optimal range: 69-229 pmol/L) and D-dimer (negative D-dimer measurement: <1.0 μg/mL).Results: The percentage of patients with optimal-range prothrombin fragment 1 + 2 was significantly increased at 4 weeks compared to baseline (70.8% vs. 86.1%, p = .033). In period II, office and home morning SBP were reduced at 12 compared to 8 weeks (office SBP: 135.2 ± 15.7 vs. 125.6 ± 18.4mmHg, p < .001; home morning SBP: 133.5 ± 10.5 vs. 119.9 ± 12.1mmHg, p<.001).The percentage of patients with negative D-dimer  was increased at 8 weeks compared to baseline (92% vs. 100%, p = .044), and remained at 100% at 16 weeks.Conclusions: Xa inhibitor therapy improved anticoagulant activity, and additional antihypertensive therapy maintained the anticoagulant activity in patients with nonvalvular AF.
  • Motoshi Kikuchi, Kenkichi Takase, Morisada Hayakawa, Hiroko Hayakawa, Shin-Ichi Tominaga, Tsukasa Ohmori
    Molecular brain 13 1 74 - 74 2020年05月 [査読有り][通常論文]
     
    Psychoneuroimmunological studies have clearly demonstrated that both cellular and humoral immunity are related to major depression. Soluble ST2 is regarded as a key molecule regulating immune system as well as cell proliferation. Indeed, soluble ST2 is reported to reduce IL-33-induced IL-6 and TNF-α production in macrophages and IL-33-induced IL-5 and IL-13 production in type 2 innate lymphoid cells. Elevated serum concentrations of soluble ST2 have been reported in patients with neuropsychiatric disorders, suggesting pathophysiological roles of soluble ST2 in behavioral phenotypes. Nevertheless, the relation between soluble ST2 and depressive behavior remain to be uncovered. To complement this point, we performed broad behavioral phenotyping, utilizing transgenic mice with a high concentration of serum ST2 in the present study. Soluble ST2 overexpression mice (ST2 Tg mice) were generated on a C3H/HeJ background. ST2 Tg mice crossed onto the BALB/c genetic background were used. Before starting tests, each mouse was observed in a clean cage for a general health check and neurological screening tests. In Experiment I, comprehensive behavioral phenotyping was performed to reveal the role of soluble ST2 on sensorimotor functions, anxiety-like behaviors, depression-like behaviors, social behaviors, and learning and memory functions. In Experiment II, to confirm the role of soluble ST2 on depression-like behaviors, a depression test battery (two bottle choice test, forced swimming test, and tail suspension test) was applied. The general health check indicated good general health and normal gross appearance for ST2 Tg mice. Further, the neurological reflexes of all the mice were normal. We found that soluble ST2 overexpression resulted in decreased social interaction. Moreover, depression-like behaviors of ST2 Tg mice were observed in two well-established behavioral paradigms, the forced swimming test and the tail suspension test. Nevertheless, hedonic reaction to sucrose was observed in ST2 Tg mice similar to WT mice. These results suggest the depression in the ST2 Tg mice. In conclusion, through a series of experiments, we established the animal model for assessing role of soluble ST2 in neuropsychiatric disorders, and revealed the possible involvement of soluble ST2 in depressive behavior.
  • Yasuyuki Shiraishi, Atsushi Kimura, Hiroaki Kimura, Tsukasa Ohmori, Masafumi Takahashi, Katsushi Takeshita
    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 2020年05月 [査読有り][通常論文]
     
    BACKGROUND: Research has revealed the crucial roles of inflammasomes in various central nervous system disorders. However, the role of inflammasomes in secondary damage following spinal cord injury (SCI) remains incompletely understood. METHODS: Here, we investigated the role of apoptosis-associated speck-like protein (ASC), an adaptor protein for inflammasome formation, after contusion SCI in ASC homozygous knockout (ASC-/-) mice. Contusion SCI was induced using a force of 60 kdyn, and recovery of open-field locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS). Bone marrow transplantation (BMT) was performed to create mice chimeric for ASC expression in bone marrow cells. RESULTS: Western blot analysis revealed that protein expression of NLRP3, ASC, Caspase-1, and IL-β were increased in injured spinal cords compared with sham-control spinal cords at 1 day post injury (dpi). Double immunostaining showed that ASC expression was co-localized to cellular constituents of the spinal cord, including NeuN+ neurons, CD11b+ microglia/macrophages, GFAP+ astrocytes, and MOG+ oligodendrocytes. ASC-/- mice had significantly better locomotor function assessed by BMS than wild-type (WT) mice. ASC-/- mice also had significantly reduced levels of Nlrp3, Casp1, IL1b, Il-6, Tnfa, Cxcl1, and Ly6g mRNA compared with WT mice. BMT (WT→ASC-/-) mice had significantly better BMS scores than BMT (WT→WT) mice. BMT (ASC-/-→WT) mice also had significantly better BMS scores than BMT (WT→WT) mice. However, the statistical significance was limited to time points between 7 and 21 dpi. CONCLUSIONS: These results suggest that ASC-dependent inflammasome formation, especially in resident cells of the spinal cord, plays a pivotal role in the progression of secondary damage following SCI.
  • 塩基編集による血友病B患者由来iPSCの遺伝子修復
    平本 貴史, 阿部 朋行, 早川 盛禎, 鴨下 信彦, 稲葉 浩, 柏倉 裕志, 冨樫 朋貴, 西増 弘志, 花園 豊, 濡木 理, 大森 司
    日本血栓止血学会誌 31 2 220 - 220 (一社)日本血栓止血学会 2020年05月
  • Hiromi Ohto-Ozaki, Morisada Hayakawa, Nobuhiko Kamoshita, Takashi Maruyama, Shin-Ichi Tominaga, Tsukasa Ohmori
    Journal of immunology (Baltimore, Md. : 1950) 204 8 2033 - 2042 2020年04月 [査読有り][通常論文]
     
    IκBζ (encoded by the Nfkbiz) is a member of the nuclear IκB family, which is involved in the expression of secondary response genes based on signals from TLR or IL-1R. ST2L, an IL-33R, is a member of the IL-1R family and abundantly expressed in tissue-resident immune cells, such as mast cells and innate lymphoid cells; however, its downstream signaling pathway remains unelucidated. In this study, we examined the role of IκBζ in ST2L-mediated cytokine and chemokine production in mast cells. Murine bone marrow cells were differentiated ex vivo into bone marrow-derived mast cells (BMMCs). The treatment of BMMCs with IL-33 transiently induced robust IκBζ expression. Of the 40 cytokines and chemokines examined using a cytokine and chemokine array, the concentrations of IL-6, IL-13, CCL2, CCL3, and TNF-α in the supernatant were augmented by IL-33. The deletion of IκBζ in BMMCs resulted in a significant reduction of the production of these mediators and the expression of their mRNA. NF-κB p50 but not p65 translocated to the nucleus by IL-33 and was not affected by the deletion of IκBζ. However, induction of IκBζ and the resultant cytokine and chemokine productions were significantly inhibited by pretreatment with an NF-κB inhibitor. The deletion of IκBζ did not affect the phosphorylation of ERK, p38 MAPK, or JNK by IL-33, and the treatment with inhibitors of these mitogen-activated kinases failed to abolish the expression of Nfkbiz Our findings suggest that IκBζ augments IL-33-dependent cytokine and chemokine production in BMMCs through the action of NF-κB.
  • Suvd Byambaa, Hideki Uosaki, Hiromasa Hara, Yasumitsu Nagao, Tomoyuki Abe, Hiroaki Shibata, Osamu Nureki, Tsukasa Ohmori, Yutaka Hanazono
    Experimental Animals 69 2 189 - 198 2020年 [査読有り]
     
    X-linked severe combined immunodeficiency (X-SCID) is an inherited genetic disorder. A majority of X-SCID subjects carries point mutations in the Interleukin-2 receptor gamma chain (IL2RG) gene. In contrast, Il2rg-knockout mice recapitulating X-SCID phenotype lack a large part of Il2rg instead of point mutations. In this study, we generated novel X-SCID mouse strains with small insertion and deletion (InDel) mutations in Il2rg by using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. To this end, we injected Streptococcus pyogenes Cas9 (SpCas9) mRNA and single guide RNA targeting the exon 2, 3 or 4 of Il2rg into mouse zygotes. In the F0 generation, we obtained 35 pups and 25 out of them were positive for Surveyor assay, and most of mutants displayed dramatic reductions of T and B lymphocytes in the peripheral blood. By amplicon sequencing, 15 out of 31 founder mice were determined as monoallelic mutants with possible minor mosaicisms while 10 mice were mosaic. Finally, we established new strains with 7-nucleotide deletion and 1-nucleotide insertions in the exon 2 and the exons 3 and 4, respectively. Although no IL2RG protein was detected on T cells of exons 3 and 4 mutants, IL2RG protein was unexpectedly detected in the exon 2 mutants. These data indicated that CRISPR/Cas9 targeting Il2rg causes InDel mutations effectively and generates genetically X-SCID mice. Genetic mutations, however, did not necessarily grant phenotypical alteration, which requires an intensive analysis after establishing a strain to confirm their phenotypes.
  • Tsukasa Ohmori
    International journal of hematology 111 1 31 - 41 2020年01月 [査読有り][通常論文]
     
    Hemophilia is a congenital hemorrhagic disease caused by genetic abnormalities in coagulation factor VIII or factor IX. Current conventional therapy to prevent bleeding requires frequent intravenous injections of coagulation factor concentrates from early childhood. Accordingly, gene therapy for hemophilia remains an exciting future prospect for patients and their families, due to its potential to cure the disease through a one-time treatment. After a series of successes in basic research, recent clinical trials have demonstrated clear efficacy of gene therapy for hemophilia using adeno-associated virus (AAV) vectors. Although this is likely to alter the paradigm of hemophilia care in the near future, it will be important to overcome immune responses against AAV. Gene therapy for hemophilia cannot be given to patients with anti-AAV capsid-neutralizing antibodies, and cellular immunity with CD8+ T cells should be controlled for sustained expression. Furthermore, long-term therapeutic effects should be closely observed because of the failure of the AAV vector genome to replicate during cell division. This review focuses on the basis of gene therapy, current successes of clinical trials, and the future direction of hemophilia gene therapy.
  • Daisuke Minakata, Shin-Ichiro Fujiwara, Jin Hayakawa, Hideki Nakasone, Takashi Ikeda, Shin-Ichiro Kawaguchi, Yumiko Toda, Shoko Ito, Shin-Ichi Ochi, Takashi Nagayama, Kiyomi Mashima, Kento Umino, Hirofumi Nakano, Ryoko Yamasaki, Kaoru Morita, Yasufumi Kawasaki, Miyuki Sugimoto, Yuko Ishihara, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Tsukasa Ohmori, Yoshinobu Kanda
    Acta haematologica 143 3 250 - 259 2020年 [査読有り][通常論文]
     
    BACKGROUND: Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan. OBJECTIVES: To compare the clinical results of the treatment of DIC with danaparoid or SPIs. METHODS: We retrospectively examined 188 patients with hematological malignancy-related DIC. RESULTS: DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21-4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15-13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278). CONCLUSIONS: Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.
  • Yasuyuki Shiraishi, Atsushi Kimura, Osamu Matsuo, Yoichi Sakata, Katsushi Takeshita, Tsukasa Ohmori
    Scientific reports 9 1 16024 - 16024 2019年11月 [査読有り][通常論文]
     
    Spinal cord injury (SCI) is caused by an initial mechanical insult followed by a series of deleterious events that promote the progressive damage of affected tissues. Fibrinolysis, the process by which plasmin degrades cross-linked fibrin clots, has numerous functions in the central nervous system. However, the roles of the fibrinolytic system in SCI pathophysiology remain unknown. We investigated the roles of fibrinolysis in SCI, and explored therapeutic applications targeting fibrinolysis. Plasminogen-deficient (Plg-/-) mice exhibited significantly improved locomotor function in the early phase of SCI (the first 7 days post injury), with significant inhibition of bleeding and vascular permeability, but failed to demonstrate conclusive functional recovery. Consistent with these findings, the short-term administration of tranexamic acid (TXA) in wild-type mice over the first 3 days post injury significantly improved locomotor function after SCI, whereas prolonged TXA administration did not. Prolonged TXA administration resulted in significantly lower levels of matrix metalloproteinase activities in the spinal cord, suggesting that inhibition of the fibrinolytic system impaired tissue remodeling. Our results indicate that the fibrinolytic system has time-dependent biphasic actions following SCI. The temporally optimised modulation of fibrinolytic activity may thus be a novel therapeutic strategy to improve functional outcomes after SCI.
  • Yasufumi Kawasaki, Kazuya Sato, Hirofumi Nakano, Hiroko Hayakawa, Junko Izawa, Norihito Takayama, Kiyomi Mashima, Iekuni Oh, Daisuke Minakata, Ryoko Yamasaki, Kaoru Morita, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Shin-Ichiro Fujiwara, Ken Ohmine, Kazuo Muroi, Ryoji Ito, Morisada Hayakawa, Tsukasa Ohmori, Yoshinobu Kanda
    Transplantation 103 9 1834 - 1843 2019年09月 [査読有り][通常論文]
     
    BACKGROUND: Chemokines and chemokine receptors are potential targets for the prevention and treatment of graft-versus-host disease (GVHD). The objective of the current study is to determine the clinical relevance of xenogeneic transplantation models in terms of host and donor chemokine profiles and, if this is the case, to assess the clinical efficacy of C-C chemokine receptor (CCR) 5 antagonist maraviroc for the prevention of GVHD using this model. METHODS: Xenogeneic GVHD was induced by intravenous injection of 5 × 10 human pan T cells into NOD/Shi-scid-IL2rγ (NOG) mice or MHC class I/II-deficient NOG mice in the presence or absence of total body irradiation before transplantation. RESULTS: Extensive tissue destruction with human T-cell infiltration was observed throughout the body, particularly in lungs and liver, but relatively mild in gut. Consistent with this finding, quantitative polymerase chain reaction confirmed the upregulation of mouse CXC chemokine ligand (CXCL) 9 and CXCL10 in lungs and CCL4 in lungs and liver but not in gut. The addition of total body irradiation (1) led to the early release of mouse CCL4 and CXCL10, (2) upregulated a number of chemokine-related genes in human T cells, (3) induced higher expression of CCR5 on human CD4 and CD8 T cells and CXCR3 on human CD4 T cells, and (4) promoted their migration and proliferation in organs, resulting in more severe tissue damage. In this context, pharmacological CCR5 blockade neither ameliorated GVHD nor prolonged survival in NOG mice. CONCLUSIONS: Our experimental data do not demonstrate clinical benefit of CCR5 antagonist for the prevention of GVHD in a myeloablative setting.
  • Daisuke Minakata, Shin-Ichiro Fujiwara, Takashi Ikeda, Shin-Ichiro Kawaguchi, Yumiko Toda, Shoko Ito, Shin-Ichi Ochi, Takashi Nagayama, Kiyomi Mashima, Kento Umino, Hirofumi Nakano, Ryoko Yamasaki, Kaoru Morita, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Tsukasa Ohmori, Yoshinobu Kanda
    International journal of hematology 109 2 141 - 146 2019年02月 [査読有り][通常論文]
     
    We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients [acute myeloid leukemia (n = 48), acute lymphoblastic leukemia (n = 25), and non-Hodgkin lymphoma (n = 54)] with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs [FOY (n = 55) and FUT (n = 72)] at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups [40.3% vs. 45.5% (day 7), P = 0.586; 56.3% vs. 69.8% (day 14), P = 0.179, respectively]. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P = 0.007; ORR 2.51, 95% CI 1.12-5.65, P = 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs.
  • Ritsuko Sasaki, Yoshiya Horimoto, Ju Mizuno, Yoko Edahiro, Tsukasa Ohmori, Norio Komatsu, Mitsue Saito
    Surgical case reports 4 1 118 - 118 2018年09月 [査読有り][通常論文]
     
    BACKGROUND: Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those of congenital von Willebrand disease (VWD). Patients with aVWS may require prophylactic treatment to prevent excessive bleeding following surgery. To our knowledge, to date, there have been no reports on perioperative management for breast cancer patients with aVWS. CASE PRESENTATION: A 60-year-old woman with breast cancer was diagnosed with aVWS due to polycythemia vera. Pre-operative laboratory testing showed a high platelet count and low von Willebrand factor (VWF) activity. The VWF activity did not improve despite an attempt to suppress platelet count with hydroxyurea. Therefore, we decided to perioperatively supplement with plasma-derived factor VIII (FVIII) containing von Willebrand factor (FVIII/VWF concentrates) to perform curative surgery for breast cancer safely. Consequently, the patient did not develop hemorrhage during/after surgery and was discharged on postoperative day 7, as planned, without problems. CONCLUSIONS: For a patient with aVWS, which carries a high risk of hemorrhage during the perioperative period, initiation of appropriate management like supplementation of FVIII/VWF concentrates might enable safe curative surgery for breast cancer, and collaboration with the hematology department is critical.
  • Tsukasa Ohmori, Hiroaki Mizukami, Yuko Katakai, Sho Kawai, Hitoyasu Nakamura, Makoto Inoue, Tsugumine Shu, Hideharu Sugimoto, Yoichi Sakata
    International journal of hematology 108 3 239 - 245 2018年09月 [査読有り][通常論文]
     
    Joint bleeding and resultant arthropathy are major determinants of quality of life in haemophilia patients. We previously developed a mesenchymal stromal cell (MSC)-based treatment approach for haemophilic arthropathy in a mouse model of haemophilia A. Here, we evaluated the long-term safety of intra-articular injection of lentivirally transduced autologous MSCs in non-human primates. Autologous bone-marrow-derived MSCs transduced with a lentiviral vector expressing coagulation factor VIII (FVIII) were injected into the left knee joint of cynomolgus monkeys. We first conducted codon optimization to increase FVIII production in the cells. Lentiviral transduction of autologous MSCs resulted in a significant increase of FVIII in the culture supernatant before transplantation. We did not find any tumour generation around the knee structure at 11-16 months after injection by magnetic resonance imaging. The proviral sequence of the simian immunodeficiency virus lentiviral vector was not detected in the heart, lungs, spleen, liver, testis, or bone marrow by real-time quantitative PCR. We confirmed the long-term safety of intra-articular injection of transduced MSCs in a non-human primate. The procedure may be an attractive therapeutic approach for joint diseases in haemophilia patients.
  • Kosuke Ichida, Koichi Suzuki, Taro Fukui, Yuji Takayama, Nao Kakizawa, Fumiaki Watanabe, Hideki Ishikawa, Yuta Muto, Takaharu Kato, Masaaki Saito, Kazushige Futsuhara, Yasuyuki Miyakura, Hiroshi Noda, Tsukasa Ohmori, Fumio Konishi, Toshiki Rikiyama
    International journal of oncology 52 5 1685 - 1693 2018年05月 [査読有り][通常論文]
     
    The impairment of the stability of the chromosomal structure facilitates the abnormal segregation of chromosomes, thus increasing the risk of carcinogenesis. Chromosomal stability during segregation is managed by appropriate methylation at the centromere of chromosomes. Insufficient methylation, or hypomethylation, results in chromosomal instability. The centromere consists of satellite alpha repetitive sequences, which are ideal targets for DNA hypomethylation, resulting in the overexpression of satellite alpha transcript (SAT). The overexpression of SAT has been reported to induce the abnormal segregation of chromosomes. In this study, we verified the oncogenic pathway via chromosomal instability involving DNA hypomethylation and the overexpression of SAT. For this purpose, we constructed lentiviral vectors expressing SAT and control viruses and then infected human mammary epithelial cells with these vectors. The copy number alterations and segregation errors of chromosomes were evaluated by microarray-based comparative genomic hybridization (array CGH) and immunocytochemistry, respectively. The levels of hypomethylation of satellite alpha sequences were determined by MethyLight polymerase chain reaction. Clinical specimens from 45 patients with breast cancer were recruited to verify the data in vitro. The results of immunocytochemistry revealed that the incidence of segregation errors was significantly higher in the cells overexpressing SAT than in the controls. An array CGH identified the specific chromosomes of 8q and 20q as frequent sites of copy number alterations in cells with SAT overexpression, although no such sites were noted in the controls, which was consistent with the data from clinical specimens. A regression analysis revealed that the expression of SAT was significantly associated with the levels of hypomethylation of satellite alpha sequences. On the whole, the overexpression of SAT led to chromosomal instability via segregation errors at specific chromosomes in connection with DNA hypomethylation, which was also recognized in clinical specimens of patients with breast cancer. Thus, this oncogenic pathway may be involved in the development of breast cancer.
  • Satoshi Niijima, Tsukasa Ohmori, Kazuomi Kario
    Thrombosis journal 16 5 - 5 2018年 [査読有り][通常論文]
     
    Background: Although prasugrel exerts stronger antiplatelet effects compared with clopidogrel, the factors affecting platelet reactivity under prasugrel have not been fully determined. This study aimed to find the novel mechanistic differences between two thienopyridines and identify the factor that influence platelet reactivity to each drug. Methods: Forty patients with stable angina who underwent elective percutaneous coronary intervention were randomly assigned to receive either prasugrel (20 mg) or clopidogrel (300 mg) as a loading dose. Platelet function (light transmission, laser light scattering, and vasodilator-stimulated phosphoprotein phosphorylation) and plasma active metabolite levels were measured after the loading dose. Results: Prasugrel consistently inhibited adenosine diphosphate receptor P2Y12 signalling to abolish amplification of platelet aggregation. Prasugrel abolished even small platelet aggregates composed of less than 100 platelets. On the other hand, clopidogrel inhibited large aggregates but increased small and medium platelet aggregates. Diabetes was the only independent variable for determining antiplatelet effects and active metabolite concentration of prasugrel, but not clopidogrel. Sleep-disordered breathing was significantly correlated with platelet reactivity in patients who had clopidogrel. Conclusions: Prasugrel efficiently abolishes residual P2Y12 signalling that causes small platelet aggregates, but these small aggregates are not inhibited by clopidogrel. Considering the differential effect of diabetes on antiplatelet effects between these two drugs, the pharmacokinetics of prasugrel, other than cytochrome P450 metabolism, might be affected by diabetes. Trial registration: UMIN-CTR UMIN000017624, retrospectively registered 21 May 2015.
  • Tsukasa Ohmori, Yasumitsu Nagao, Hiroaki Mizukami, Asuka Sakata, Shin-Ichi Muramatsu, Keiya Ozawa, Shin-Ichi Tominaga, Yutaka Hanazono, Satoshi Nishimura, Osamu Nureki, Yoichi Sakata
    Scientific reports 7 1 4159 - 4159 2017年06月 [査読有り][通常論文]
     
    Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B. Mutation-specific gene editing by simultaneous induction of homology-directed repair (HDR) sufficiently increased FIX levels to correct the disease phenotype. Insertion of F9 cDNA into the intron more efficiently restored haemostasis via both processes of non-homologous end-joining (NHEJ) and HDR following DSB. Notably, these therapies also cured neonate mice with haemophilia, which cannot be achieved with conventional gene therapy with AAV vector. Ongoing haemophilia therapy targeting the antithrombin gene with antisense oligonucleotide could be replaced by SaCas9/sgRNA-expressing AAV8 vector. Our results suggest that CRISPR/Cas9-mediated genome editing using an AAV8 vector provides a flexible approach to induce DSB at target genes in hepatocytes and could be a good strategy for haemophilia gene therapy.
  • Atsushi Kimura, Tsukasa Ohmori, Asuka Sakata, Teruaki Endo, Hirokazu Inoue, Satoshi Nishimura, Katsushi Takeshita
    PloS one 12 6 e0179829  2017年 [査読有り][通常論文]
     
    Although bleeding is a common complication of surgery, routine laboratory tests have been demonstrated to have a low ability to predict perioperative bleeding. Better understanding of hemostatic function during surgery would lead to identification of high-risk patients for bleeding. Here, we aimed to elucidate hemostatic mechanisms to determine perioperative bleeding. We prospectively enrolled 104 patients undergoing cervical spinal surgery without bleeding diathesis. Blood sampling was performed just before the operation. Volumes of perioperative blood loss were compared with the results of detailed laboratory tests assessing primary hemostasis, secondary hemostasis, and fibrinolysis. Platelet aggregations induced by several agonists correlated with each other, and only two latent factors determined inter-individual difference. Platelet aggregability independently determined perioperative bleeding. We also identified low levels of plasminogen-activator inhibitor-1 (PAI-1) and α2-plasmin inhibitor to be independent risk factors for intraoperative and postoperative bleeding, respectively. Most important independent factor to determine postoperative bleeding was body weight. Of note, obese patients with low levels of PAI-1 became high-risk patients for bleeding during surgery. Our data suggest that bleeding after surgical procedure may be influenced by inter-individual differences of hemostatic function including platelet function and fibrinolysis, even in the patients without bleeding diathesis.
  • 消化器外科における凝固線溶異常 静脈血栓塞栓症(VTE)に関する術前スクリーニング(Coagulation Abnormalities in Gastroenterological Surgery Pre-operative screening for venous thromboembolism(VTE))
    清水 徹一郎, 堀江 久永, 窓岩 清治, 大森 司, 三室 淳, 西村 智, 坂田 洋一, 細谷 好則, 佐田 尚宏, 安田 是和
    日本消化器外科学会総会 70回 WS - 3 2015年07月
  • Satoshi Nishimura, Mika Nagasaki, Shinji Kunishima, Akira Sawaguchi, Asuka Sakata, Hiroyasu Sakaguchi, Tsukasa Ohmori, Ichiro Manabe, Joseph E Italiano Jr, Tomiko Ryu, Naoya Takayama, Issei Komuro, Takashi Kadowaki, Koji Eto, Ryozo Nagai
    The Journal of cell biology 209 3 453 - 66 2015年05月 [査読有り][通常論文]
     
    Intravital visualization of thrombopoiesis revealed that formation of proplatelets, which are cytoplasmic protrusions in bone marrow megakaryocytes (MKs), is dominant in the steady state. However, it was unclear whether this is the only path to platelet biogenesis. We have identified an alternative MK rupture, which entails rapid cytoplasmic fragmentation and release of much larger numbers of platelets, primarily into blood vessels, which is morphologically and temporally different than typical FasL-induced apoptosis. Serum levels of the inflammatory cytokine IL-1α were acutely elevated after platelet loss or administration of an inflammatory stimulus to mice, whereas the MK-regulator thrombopoietin (TPO) was not elevated. Moreover, IL-1α administration rapidly induced MK rupture-dependent thrombopoiesis and increased platelet counts. IL-1α-IL-1R1 signaling activated caspase-3, which reduced plasma membrane stability and appeared to inhibit regulated tubulin expression and proplatelet formation, and ultimately led to MK rupture. Collectively, it appears the balance between TPO and IL-1α determines the MK cellular programming for thrombopoiesis in response to acute and chronic platelet needs.
  • 救急・外傷 当科における術後静脈血栓塞栓症(VTE)予防の現状
    清水 徹一郎, 窓岩 清治, 大森 司, 三室 淳, 西村 智, 堀江 久永, 細谷 好則, 佐田 尚宏, 安田 是和
    日本外科学会定期学術集会抄録集 115回 OP - 2 (一社)日本外科学会 2015年04月
  • Satoshi Nishimura, Mika Nagasaki, Shinichi Okudaira, Junken Aoki, Tsukasa Ohmori, Ryunosuke Ohkawa, Kazuhiro Nakamura, Koji Igarashi, Hiroshi Yamashita, Koji Eto, Kansei Uno, Naoto Hayashi, Takashi Kadowaki, Issei Komuro, Yutaka Yatomi, Ryozo Nagai
    Diabetes 63 12 4154 - 64 2014年12月 [査読有り][通常論文]
     
    Body weight is tightly regulated by food intake and energy dissipation, and obesity is related to decreased energy expenditure (EE). Herein, we show that nucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2, autotaxin) is an adipose-derived, secreted enzyme that controls adipose expansion, brown adipose tissue (BAT) function, and EE. In mice, Enpp2 was highly expressed in visceral white adipose tissue and BAT and is downregulated in hypertrophied adipocytes/adipose tissue. Enpp2(+/-) mice and adipocyte-specific Enpp2 knockout mice fed a high-fat diet showed smaller body weight gains and less insulin resistance than control mice fed the same diet. BAT was functionally more active and EE was increased in Enpp2-deficient mice. In humans, ENPP2 expression in subcutaneous fat and ENPP2 levels in serum were reduced in obese subjects. Taken together, our results establish ENPP2 as an adipose-derived, secreted enzyme that regulates adipose obesity and systemic metabolism. They also suggest ENPP2 could be a useful therapeutic target for the treatment of metabolic disease.
  • Jun Mimuro, Hiroaki Mizukami, Midori Shima, Tadashi Matsushita, Masashi Taki, Shinji Muto, Satoshi Higasa, Michio Sakai, Tsukasa Ohmori, Seiji Madoiwa, Keiya Ozawa, Yoichi Sakata
    Journal of medical virology 86 11 1990 - 7 2014年11月 [査読有り][通常論文]
     
    Pre-existing antibodies against adeno-associated virus (AAV), caused by natural AAV infections, interfere with recombinant AAV vector-mediated gene transfer. We studied the prevalence of neutralizing antibodies against AAV serotypes 1, 2, 5, 8, and 9 in healthy subjects (n = 85) and hemophilia patients (n = 59) in a Japanese population. For healthy subjects, the prevalence of neutralizing antibodies against AAV serotypes 1, 2, 5, 8, and 9 was 36.5%, 35.3%, 37.6%, 32.9%, and 36.5%, respectively, while that in hemophilia patients was 39.7%, 28.8%, 35.6%, 32.9%, and 27.4%, respectively. There was no difference in the prevalence of neutralizing antibody against each AAV serotype between the healthy subjects and the hemophilia patients. The prevalence of neutralizing antibodies against all AAV serotypes increased with age in both healthy subjects and hemophilia patients. High titers of neutralizing antibodies against AAV2 (≥1:224) and AAV8 (≥1:224) were more evident in older individuals (≥42 years old). Approximately 50% of all screened individuals were seronegative for neutralizing antibodies against each AAV tested, while approximately 25% of individuals were seropositive for each AAV serotype tested. The prevalence of seronegativity for all AAV serotypes was 67.0% (healthy subjects, 68.6%; hemophilia patients, 65.0%) and 18.6% (healthy subjects, 20.5%; hemophilia patients, 15.7%) in young (<42 years old) and older subjects (≥42 years old), respectively. The findings from this study suggested that young subjects are more likely to be eligible for gene therapy based on AAV vectors delivered via an intravascular route because of the low prevalence of antibodies to AAV capsids.
  • Tsukasa Ohmori, Hiroaki Mizukami, Seiji Madoiwa, Keiya Ozawa, Yoichi Sakata
    [Rinsho ketsueki] The Japanese journal of clinical hematology 55 8 899 - 907 2014年08月 [査読有り][通常論文]
  • 当科における術後静脈血栓塞栓症(VTE)予防の現状
    清水 徹一郎, 窓岩 清治, 大森 司, 三室 淳, 西村 智, 坂田 洋一, 堀江 久永, 細谷 好則, 佐田 尚宏, 安田 是和
    日本血栓止血学会誌 25 2 267 - 267 (一社)日本血栓止血学会 2014年04月
  • Kansuke Koyama, Seiji Madoiwa, Shin Nunomiya, Toshitaka Koinuma, Masahiko Wada, Asuka Sakata, Tsukasa Ohmori, Jun Mimuro, Yoichi Sakata
    Critical care (London, England) 18 1 R13  2014年01月 [査読有り][通常論文]
     
    INTRODUCTION: Current criteria for early diagnosis of coagulopathy in sepsis are limited. We postulated that coagulopathy is already complicated with sepsis in the initial phase, and severe coagulopathy or disseminated intravascular coagulation (DIC) becomes overt after progressive consumption of platelet and coagulation factors. To determine early diagnostic markers for severe coagulopathy, we evaluated plasma biomarkers for association with subsequent development of overt DIC in patients with sepsis. METHODS: A single-center, prospective observational study was conducted in an adult ICU at a university hospital. Plasma samples were obtained from patients with sepsis at ICU admission. Fourteen biomarkers including global markers (platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen and fibrin degradation product (FDP)); markers of thrombin generation (thrombin-antithrombin complex (TAT) and soluble fibrin); markers of anticoagulants (protein C (PC) and antithrombin); markers of fibrinolysis (plasminogen, α2-plasmin inhibitor (PI), plasmin-α2-PI complex, and plasminogen activator inhibitor (PAI)-1); and a marker of endothelial activation (soluble E-selectin) were assayed. Patients who had overt DIC at baseline were excluded, and the remaining patients were followed for development of overt DIC in 5 days, and for mortality in 28 days. RESULTS: A total of 77 patients were enrolled, and 37 developed overt DIC within the following 5 days. Most patients demonstrated hemostatic abnormalities at baseline with 98.7% TAT, 97.4% FDP and 88.3% PC. Most hemostatic biomarkers at baseline were significantly associated with subsequent development of overt DIC. Notably, TAT, PAI-1 and PC discriminated well between patients with and without developing overt DIC (area under the receiver operating characteristic curve (AUROC), 0.77 (95% confidence interval, 0.64 to 0.86); 0.87 (0.78 to 0.92); 0.85 (0.76 to 0.91), respectively), and using the three together, significantly improved the AUROC up to 0.95 (vs. TAT, PAI-1, and PC). Among the significant diagnostic markers for overt DIC, TAT and PAI-1 were also good predictors of 28-day mortality (AUROC, 0.77 and 0.81, respectively). CONCLUSIONS: Severe coagulation and fibrinolytic abnormalities on ICU admission were associated with subsequent development of overt DIC. A single measurement of TAT, PAI-1, and PC activity could identify patients with ongoing severe coagulopathy, early in the course of sepsis.
  • Asuka Sakata, Tsukasa Ohmori, Satoshi Nishimura, Hidenori Suzuki, Seiji Madoiwa, Jun Mimuro, Kazuomi Kario, Yoichi Sakata
    Thrombosis journal 12 1 1 - 1 2014年01月 [査読有り][通常論文]
     
    BACKGROUND: Paxillin is a LIM domain protein localized at integrin-mediated focal adhesions. Although paxillin is thought to modulate the functions of integrins, little is known about the contribution of paxillin to signaling pathways in platelets. Here, we studied the role of paxillin in platelet activation in vitro and in vivo. METHODS AND RESULTS: We generated paxillin knockdown (Pxn-KD) platelets in mice by transplanting bone marrow cells transduced with a lentiviral vector carrying a short hairpin RNA sequence, and confirmed that paxillin expression was significantly reduced in platelets derived from the transduced cells. Pxn-KD platelets showed a slight increased in size and augmented integrin αIIbβ3 activation following stimulation of multiple receptors including glycoprotein VI and G protein-coupled receptors. Thromboxane A2 biosynthesis and the release of α-granules and dense granules in response to agonist stimulation were also enhanced in Pxn-KD platelets. However, Pxn-KD did not increase tyrosine phosphorylation or intracellular calcium mobilization. Intravital imaging confirmed that Pxn-KD enhanced thrombus formation in vivo. CONCLUSIONS: Our findings suggest that paxillin negatively regulates several common platelet signaling pathways, resulting in the activation of integrin αIIbβ3 and release reactions.
  • Y. Kashiwakura, T. Ohmori, J. Mimuro, S. Madoiwa, M. Inoue, M. Hasegawa, K. Ozawa, Y. Sakata
    HAEMOPHILIA 20 1 E40 - E44 2014年01月 [査読有り][通常論文]
     
    The use of induced pluripotent stem cells (iPSCs) as an autologous cell source has shed new light on cell replacement therapy with respect to the treatment of numerous hereditary disorders. We focused on the use of iPSCs for cell-based therapy of haemophilia. We generated iPSCs from mesenchymal stem cells that had been isolated from C57BL/6 mice. The mouse iPSCs were generated through the induction of four transcription factor genes Oct3/4, Klf-4, Sox-2 and c-Myc. The derived iPSCs released functional coagulation factor VIII (FVIII) following transduction with a simian immunodeficiency virus vector. The subcutaneous transplantation of iPSCs expressing FVIII into nude mice resulted in teratoma formation, and significantly increased plasma levels of FVIII. The plasma concentration of FVIII was at levels appropriate for human therapy at 2-4weeks post transplantation. Our data suggest that iPSCs could be an attractive and prospective autologous cell source for the production of coagulation factor, and that engineered iPSCs expressing coagulation factor might provide a cell-based therapeutic strategy appropriate for haemophilia.
  • Kansuke Koyama, Seiji Madoiwa, Shinichiro Tanaka, Toshitaka Koinuma, Masahiko Wada, Asuka Sakata, Tsukasa Ohmori, Jun Mimuro, Shin Nunomiya, Yoichi Sakata
    Journal of critical care 28 5 556 - 63 2013年10月 [査読有り][通常論文]
     
    PURPOSE: The hemostatic biomarkers for early diagnosis of sepsis-associated coagulopathy have not been identified. The purpose of this study was to evaluate hemostatic biomarker abnormalities preceding a decrease in platelet count, which is a surrogate indicator of overt coagulopathy in sepsis. MATERIALS AND METHODS: Seventy-five septic patients with a platelet count more than 80×10(3)/μL were retrospectively analyzed. Hemostatic biomarkers at intensive care unit admission were compared between patients with and patients without a subsequent decrease in platelet count (≥30% within 5 days), and the ability of biomarkers to predict a decrease in platelet count was evaluated. RESULTS: Forty-two patients (56.0%) developed a subsequent decrease in platelet count. Severity of illness, incidence of organ dysfunction, and 28-day mortality rate were higher in patients with a subsequent decrease in platelet count. There were significant differences between patients with and patients without a subsequent decrease in platelet count in prothrombin time-international normalized ratio, fibrinogen, thrombin-antithrombin complex, antithrombin, protein C (PC), plasminogen, and α2-plasmin inhibitor (α2-PI). Receiver operating characteristic curve analysis showed that PC (area under the curve, 0.869; 95% confidence interval, 0.699-0.951) and α2-PI (area under the curve, 0.885; 95% confidence interval, 0.714-0.959) were strong predictors of a subsequent decrease in platelet count. CONCLUSIONS: Decreased PC and α2-PI activity preceded a decrease in platelet count in intensive care unit patients with sepsis.
  • Seiji Madoiwa, Isao Kitajima, Tsukasa Ohmori, Yoichi Sakata, Jun Mimuro
    Thrombosis research 132 4 457 - 64 2013年10月 [査読有り][通常論文]
     
    Fibrin degradation products (FDP) are an important marker of coagulopathy. We assessed the reactivity of the monoclonal antibodies used in clinical laboratory testing (6 D-dimer reagents, D-dimer-1-6; 4 plasma FDP reagents, plasma FDP-1-4) to quantify FDP using in vitro-generated FDP as well as FDP in clinical samples. The monoclonal antibodies used in D-dimer-1, -2, -5, and -6 reacted poorly to the low molecular weight forms of in vitro-generated FDP. The monoclonal antibodies used in D-dimer-3 and -4 had better reactivity to the low molecular weight forms of in vitro-generated FDP. The monoclonal antibodies used in plasma FDP-2, -3, and -4 reacted well to the high and low molecular weight FDP forms, while the monoclonal antibody in plasma FDP-1 reacted poorly to the low molecular weight FDP forms. Analysis of clinical samples revealed deviations in FDP molecular weight forms in DIC samples. The reactivity of the monoclonal antibodies of laboratory FDP testing to FDP variants in clinical samples was similar to that of in vitro-generated FDP. In conclusion, the monoclonal antibodies used in clinical laboratories to detect FDP have distinct reactivity to the molecular variants of FDP generated in vitro as well as those present in clinical samples. Our findings support the consensus for the standardization of D-dimer and plasma FDP testing.
  • Tsukasa Ohmori
    [Rinsho ketsueki] The Japanese journal of clinical hematology 54 10 1888 - 96 2013年10月 [査読有り][通常論文]
  • 当科における術後静脈血栓塞栓症予防の現状
    清水 徹一郎, 窓岩 清治, 大森 司, 三室 淳, 堀江 久永, 細谷 好則, 佐田 尚宏, 安田 是和
    日本臨床外科学会雑誌 74 増刊 490 - 490 日本臨床外科学会 2013年10月
  • Masahiro Ashizawa, Shun-ichi Kimura, Hidenori Wada, Kana Sakamoto, Miki Sato, Kiriko Terasako, Misato Kikuchi, Hideki Nakasone, Shinya Okuda, Shinichi Kako, Rie Yamazaki, Kumi Oshima, Katsuhiko Matsuura, Tsukasa Ohmori, Seiji Madoiwa, Junji Nishida, Jun Mimuro, Kaoru Tabei, Yoichi Sakata, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 18 5 300 - 4 2013年09月 [査読有り][通常論文]
     
    A mixing test is useful for distinguishing between coagulation factor deficiency and the presence of inhibitor as the cause of coagulopathy. However, we experienced a patient with acquired factor V (FV) inhibitor whose mixing test showed a coagulation factor deficiency pattern. A 65-year-old man with a tendency for bleeding was referred to our center. The laboratory data showed remarkable prolongation of prothrombin time and activated partial thromboplastin time (APTT). FV activity was less than 3%. A mixing test showed a coagulation factor deficiency pattern. However, neither the tendency for bleeding nor the coagulation tests were corrected by transfusion of fresh frozen plasma. A few days later, a positive test for FV inhibitor of 3 Bethesda units was obtained. Therefore, we started prednisolone and plasma exchange, and the coagulation test results normalized after 6 weeks. Although an incubation period is generally not considered necessary in a mixing test for FV inhibitor, we repeated mixing tests with various incubation periods and confirmed an incubation period-dependent prolongation of the APTT. Therefore, a mixing test with an incubation period is recommended for the detection of FV inhibitor, since a mixing test without an incubation period may show a coagulation factor deficiency pattern when the titer of FV inhibitor is low.
  • Nobuko Makino, Seiji Madoiwa, Tsukasa Ohmori, Kazuo Katoh, Shigeo Ookawara, Takeharu Kanazawa, Osamu Matsuo, Masumi Ichikawa, Jun Mimuro, Keiichi Ichimura, Yoichi Sakata
    International forum of allergy & rhinology 3 6 458 - 67 2013年06月 [査読有り][通常論文]
     
    BACKGROUND: Tissue type plasminogen activator (tPA) functions as a fibrinolytic factor in the blood and has unique roles in the nervous system. However, the role of tPA in the olfactory epithelium (OE) is still unclear. Generally, surgical ablation of the olfactory bulb (bulbectomy) triggers degeneration followed by regeneration of OE. In this experimental study, we investigated the role of tPA in OE regeneration. METHODS: Wild-type (WT) mice and tPA-knockout (tPA(-/-) ) mice were subjected to bulbectomy. Reverse-transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemical examination was done to detect tPA expression in the olfactory bulb and OE. Cellular proliferation and apoptosis was also monitored in the OE. RESULTS: Before bulbectomy, tPA was found to be expressed in the olfactory bulb and OE. OE degenerated to a similar extent in both strains between 0 and 3 days after bulbectomy. However, OE was thicker and contained more cells in tPA(-/-) mice than in WT mice at 7 days after bulbectomy. Moreover, the number of apoptotic bodies was reduced and the number of proliferating cells was increased in the OE of tPA(-/-) mice compared to WT mice, after bulbectomy. Transmission electron microscopy revealed continuous degeneration of the OE for up to 7 days after bulbectomy in WT mice. In contrast, we observed some intact olfactory vesicles and almost normal supporting cells in the OE of tPA(-/-) mice, at 7 days after bulbectomy. CONCLUSION: The current findings show that the tPA-plasmin system plays an inhibitory role in the regulation of regeneration in the OE.
  • Atsushi Yasumoto, Seiji Madoiwa, Yuji Kashiwakura, Akira Ishiwata, Tsukasa Ohmori, Hiroaki Mizukami, Keiya Ozawa, Yoichi Sakata, Jun Mimuro
    Thrombosis research 131 5 444 - 9 2013年05月 [査読有り][通常論文]
     
    INTRODUCTION: Factor VIII (FVIII) treatment for hemophilia A has difficulties in correcting bleeding diathesis in the presence of inhibitors. MATERIALS AND METHODS: An adeno-associated virus type 8 (AAV8) vector containing the factor VII (FVII) gene or the activated factor VII (FVIIa) gene was used to investigate the therapeutic effect of FVII or FVIIa overexpression in FVIII-deficient mice with inhibitors. RESULTS: Following repeated human FVIII injection, FVIII-deficient mice developed anti-human FVIII antibodies that cross-reacted with mouse FVIII. High transgene expression of murine FVII or murine FVIIa was achieved using the AAV8 vector and resulted in increased blood FVII activity greater than 800% of normal murine FVII levels in vector-injected FVIII-deficient mice. Thromboelastography analysis showed significant improvements in clotting time, clot formation time, α angle, and mean clot firmness in AAV8 vector-injected FVIII-deficient mice with inhibitors. Overexpression of FVIIa ameliorated the bleeding phenotype of FVIII-deficient mice with inhibitors and significantly increased the survival rate after tail clipping. In addition, overexpression of FVII increased the survival rate of FVIII-deficient mice with inhibitors after tail clipping though it was not as efficient as FVIIa overexpression. CONCLUSIONS: These data suggest that FVII overexpression is an alternative strategy for the treatment of hemophilia A with inhibitors.
  • Natsumi Watanabe, Kazuo Ohashi, Kohei Tatsumi, Rie Utoh, In Kyong Shim, Kazuko Kanegae, Yuji Kashiwakura, Tsukasa Ohmori, Yoichi Sakata, Makoto Inoue, Mamoru Hasegawa, Teruo Okano
    Human gene therapy 24 3 283 - 94 2013年03月 [査読有り][通常論文]
     
    Hemophilia is an X-linked bleeding disorder, and patients with hemophilia are deficient in a biologically active coagulation factor. This study was designed to combine the efficiency of lentiviral vector transduction techniques with murine adipose tissue-derived stem/stromal cells (mADSCs) as a new method to produce secreted human coagulation factor IX (hFIX) and to treat hemophilia B. mADSCs were transduced with simian immunodeficiency virus (SIV)-hFIX lentiviral vector at multiplicities of infection (MOIs) from 1 to 60, and the most effective dose was at an MOI of 10, as determined by hFIX production. hFIX protein secretion persisted over the 28-day experimental period. Cell sheets composed of lentiviral vector-transduced mADSCs were engineered to further enhance the usefulness of these cells for future therapeutic applications in transplantation modalities. These experiments demonstrated that genetically transduced ADSCs may become a valuable cell source for establishing cell-based gene therapies for plasma protein deficiencies, such as hemophilia.
  • Jun Mimuro, Hiroaki Mizukami, Shuji Hishikawa, Tomokazu Ikemoto, Akira Ishiwata, Asuka Sakata, Tsukasa Ohmori, Seiji Madoiwa, Fumiko Ono, Keiya Ozawa, Yoichi Sakata
    Molecular therapy : the journal of the American Society of Gene Therapy 21 2 318 - 23 2013年02月 [査読有り][通常論文]
     
    Neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) are known to interfere with AAV vector-mediated gene transfer by intravascular delivery. Evading the inhibitory effects of antibodies against AAV vectors is necessary for efficient transfer of therapeutic genes clinically. For this purpose, we tested the efficacy of saline flushing in order to avoid contact of vectors with NAbs present in blood. Direct injection of the AAV8 vector carrying the factor IX (FIX) gene into the portal vein of macaques using saline flushing achieved transgene-derived FIX expression (4.7 ± 2.10-10.1 ± 5.45% of normal human FIX concentration) in the presence of NAbs. Expression was as efficient as that (5.43 ± 2.59-12.68 ± 4.83%) in macaques lacking NAbs. We next tested the efficacy of saline flushing using less invasive balloon catheter-guided injection. This approach also resulted in efficient expression of transgene-derived FIX (2.5 ± 1.06-9.0 ± 2.37%) in the presence of NAbs (14-56× dilutions). NAbs at this range of titers reduced the efficiency of transduction in the macaque liver by 100-fold when the same vector was injected into mesenteric veins without balloon catheters. Our results suggest that portal vein-directed vector delivery strategies with flushing to remove blood are efficacious for minimizing the inhibitory effect of anti-AAV antibodies.
  • Yuichiro Yano, Tsukasa Ohmori, Kazuyuki Shimada, Yoichi Sakata, Kazuomi Kario
    Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 23 7 590 - 6 2012年10月 [査読有り][通常論文]
     
    Our aim was to examine the pathophysiology of sleep onset of acute coronary syndrome (ACS); in particular, we focused on the association of sleep onset of ACS, sleep-apnea syndrome (SAS), and diurnal variation of hemostasis and adipokine levels. Seventy-four patients (mean 60.0 years; 84% men) with ACS were cross-sectionally examined. They were examined by circulatory levels of hemostasis [plasminogen activator inhibitor-1 (PAI-1), D-dimer, soluble fibrin] and adipokines (adiponectin, visfatin) before and after sleep, and cardiorespiratory function. The severity of SAS was defined as mild to no SAS [apnea-hypopnea index (AHI) <15/h, n = 30], moderate SAS (AHI 15-30/h, n = 26), and severe SAS (AHI >30/h, n = 18). Nineteen patients (26%) were diagnosed with sleep onset of ACS, and these patients had a greater extent of morning increase from the night-time levels of PAI-1 (median PAI-1 increase: +37.1 vs. +27.3 ng/ml; P = 0.01) and visfatin (median visfatin increase: +0.40 vs. +0.00 ng/ml; P = 0.08) than those who had daytime onset of ACS. Among patients who had sleep onset of ACS, 89% were diagnosed with moderate to severe SAS. According to the severity of SAS, the morning increase from the night-time levels of PAI-1 and visfatin became greater (median PAI-1 increase: +23.7 vs. +29.2 vs. +39.3 ng/ml; median visfatin increase: 0.00 vs. 0.00 vs. +0.45 ng/ml; both P < 0.05), and these differences remained unchanged even after adjustment for significant covariates (both P < 0.05). Patients who have sleep onset of ACS are likely to have high prevalence of SAS and abnormal diurnal variations of PAI-1 and visfatin levels.
  • Kashiwakura Y, Ohmori T, Mimuro J, Yasumoto A, Ishiwata A, Sakata A, Madoiwa S, Inoue M, Hasegawa M, Ozawa K, Sakata Y
    Journal of thrombosis and haemostasis : JTH 10 9 1802 - 1813 2012年09月 [査読有り][通常論文]
  • Tsukasa Ohmori, Yuichiro Yano, Asuka Sakata, Tomokazu Ikemoto, Masahisa Shimpo, Seiji Madoiwa, Takaaki Katsuki, Jun Mimuro, Kazuyuki Shimada, Kazuomi Kario, Yoichi Sakata
    Thrombosis research 129 4 e36-40 - E40 2012年04月 [査読有り][通常論文]
     
    High residual platelet aggregability during thienopyridine treatment occurs because of low levels of the active drug metabolite, and is associated with an increased rate of major adverse cardiovascular events. Recent findings suggest that paraoxonase-1 (PON1) is a major determinant for clopidogrel efficacy. The aim of this study was to assess the impact of serum PON1 activity on platelet aggregability in thienopyridine-treated patients. In 72 patients receiving treatment with aspirin and ticlopidine after acute coronary syndrome, various laboratory data including the formation of platelet aggregations induced by agonists were compared with serum PON1 activities, measured as paraoxonase and homocysteine thiolactone hydrolase (HTLase). Serum paraoxonase activity was significantly associated with HTLase activity (R=0.4487, P<0.0001). These PON1 activities were not correlated with any parameters for platelet aggregation, hypertension, sleep apnea, and diabetes mellitus. In contrast, serum PON1 activities seemed to be involved in cardiac function, with brain natriuretic peptide and ejection fraction being significantly correlated with serum HTLase activity (R=-0.2767, P=0.0214) and paraoxonase activity (R=0.2558, P=0.0339), respectively. Paraoxonase activity also demonstrated a significant association with increased levels of ankle-brachial index (R=0.267, P=0.0255). Serum PON1 activities did not influence platelet aggregability during treatment with thienopyridine. However, they might modulate cardiac function after acute coronary syndrome and progression of atherosclerosis.
  • Yusuke Norimatsu, Tsukasa Ohmori, Atsushi Kimura, Seiji Madoiwa, Jun Mimuro, Atsushi Seichi, Yutaka Yatomi, Yuichi Hoshino, Yoichi Sakata
    The American journal of pathology 180 4 1625 - 35 2012年04月 [査読有り][通常論文]
     
    Spinal cord injury (SCI) is an incapacitating injury that can result in limited functional recovery. We have previously shown increases in the lysophospholipid mediator, sphingosine-1-phosphate (S1P), in the spinal cord after contusion injury. To apply S1P receptor modulation to the treatment of SCI, we examined the therapeutic effects of FTY720, an S1P receptor agonist, on locomotor recovery after SCI in mice. Oral administration of FTY720 shortly after contusion SCI significantly improved motor function recovery, as assessed by both Basso Mouse Scale scores and Rotarod Performance test results. FTY720 induced lymphopenia and reduced T-cell infiltration in the spinal cord after SCI but did not affect the early infiltration of neutrophils and the activation of microglia. In addition, plasma levels and mRNA expression of inflammatory cytokines in the spinal cord after SCI were not attenuated by FTY720. Vascular permeability and astrocyte accumulation were both decreased by FTY720 in the injured spinal cord. The therapeutic effects of FTY720 were not solely dependent on immune modulation, as confirmed by the demonstration that FTY720 also ameliorated motor function after SCI in mice with severe combined immunodeficiency. Finally, the S1P(1) receptor agonist, SEW2871, partly mimicked the therapeutic effect of FTY720. Our data highlight the importance of immune-independent functions of FTY720 in decreasing vascular permeability and astrogliosis in the injured spinal cord and promoting locomotor function recovery after SCI.
  • Yuji Kashiwakura, Jun Mimuro, Akira Onishi, Masaki Iwamoto, Seiji Madoiwa, Daiichiro Fuchimoto, Shunichi Suzuki, Misae Suzuki, Shoichiro Sembon, Akira Ishiwata, Atsushi Yasumoto, Asuka Sakata, Tsukasa Ohmori, Michiko Hashimoto, Satoko Yazaki, Yoichi Sakata
    PloS one 7 11 e49450  2012年 [査読有り][通常論文]
     
    Hemophilia A is a common X chromosome-linked genetic bleeding disorder caused by abnormalities in the coagulation factor VIII gene (F8). Hemophilia A patients suffer from a bleeding diathesis, such as life-threatening bleeding in the brain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal models have been sought. Current mouse hemophilia A models generated by gene targeting of the F8 have difficulties to extrapolate human disease due to differences in the coagulation and immune systems between mice and humans. Here, we generated a porcine model of hemophilia A by nuclear transfer cloning from F8-targeted fibroblasts. The hemophilia A pigs showed a severe bleeding tendency upon birth, similar to human severe hemophiliacs, but in contrast to hemophilia A mice which rarely bleed under standard breed conditions. Infusion of human factor VIII was effective in stopping bleeding and reducing the bleeding frequency of a hemophilia A piglet but was blocked by the inhibitor against human factor VIII. These data suggest that the hemophilia A pig is a severe hemophilia A animal model for studying not only hemophilia A gene therapy but also the next generation recombinant coagulation factors, such as recombinant factor VIII variants with a slower clearance rate.
  • Hideaki Watanabe, Seiji Madoiwa, Hitoshi Sekiya, Yutaka Nagahama, Shirou Matsuura, Yusei Kariya, Tsukasa Ohmori, Jun Mimuro, Yuichi Hoshino, Shinya Hayasaka, Yoichi Sakata
    THROMBOSIS RESEARCH 128 6 E137 - E143 2011年12月 [査読有り][通常論文]
     
    Pulmonary embolism development may be prevented if asymptomatic venous thromboembolism (VTE) can be predicted and treated preoperatively or soon after total knee arthroplasty (TKA). The purpose of this study was to evaluate whether asymptomatic VTE can be predicted by blood coagulation markers preoperatively or early after TKA. This prospective single-centre study enrolled 68 patients (6 men, 62 women; mean age: 71 years) who underwent TKA between September 2004 and August 2009. Sixteen-row multidetector computed tomography was performed 4 days before and after surgery for diagnosis of asymptomatic VTE. Blood samples were taken to measure the plasma levels of soluble fibrin monomer complex (SFMC), D-dimer and cross-linked fibrin degradation products by leukocyte elastase (e-XDP) at 4 days preoperatively, and at 1 hour, 1 day and 4 days postoperatively. The preoperative SFMC, D-dimer and e-XDP levels did not differ significantly between the thrombus (n=36) and no-thrombus (n=32) groups. D-dimer and e-XDP levels showed the most significant increases at days 4 and 1, respectively, after surgery in the thrombus group. With cut-off points of 7.5 mu g/ml for D-dimer and 8.2 U/ml for e-XDP, the sensitivities were 75% and 75%, and the specificities were 63% and 59%, respectively. By multiple logistic regression analysis, D-dimer at day 4 and e-XDP at day 1 postoperatively were independent markers for early diagnosis of VTE (odds ratio=1.61 and 1.19, P=0.01 and 0.04, respectively). The postoperative occurrence of new asymptomatic VTE may be predicted by D-dimer at day 4 and e-XDP at day 1 after TKA. (C) 2011 Elsevier Ltd. All rights reserved.
  • Dokai M, Madoiwa S, Yasumoto A, Kashiwakura Y, Ishiwata A, Sakata A, Makino N, Ohmori T, Mimuro J, Sakata Y
    Thrombosis research 128 3 283 - 92 3 2011年09月 [査読有り][通常論文]
     
    Neutrophil elastase released from activated neutrophils contributes in combating bacterial infection. While chronic inflammation results in anemia and decreased bone marrow activities, little is known about the effect of neutrophil elastase on hematological cell growth in severe inflammatory states. Here, we demonstrated that α1-antitrypsin, a physiological inhibitor of neutrophil elastase, functions as a regulator for cell growth by neutralizing neutrophil elastase activity in lipopolysaccharide-primed hematological cells. HL-60 cells were resistant to neutrophil elastase, as they also expressed α1-antitrypsin. The growth of HL-60 cells transduced with a LentiLox-short hairpin α1-antitrypsin vector was significantly suppressed by neutrophil elastase or lipopolysaccharide. When CD34(+) progenitor cells were differentiated towards a granulocytic lineage, they concomitantly expressed neutrophil elastase and α1-antitrypsin and prevented neutrophil elastase-induced growth inhibition. These results suggest that granulocytes might protect themselves from neutrophil elastase-induced cellular damage by efficiently neutralizing its activity through the simultaneous secretion of endogenous α1-antitrypsin.
  • Seiji Madoiwa, Hideyuki Tanaka, Yutaka Nagahama, Momoko Dokai, Yuji Kashiwakura, Akira Ishiwata, Asuka Sakata, Atsushi Yasumoto, Tsukasa Ohmori, Jun Mimuro, Yoichi Sakata
    Thrombosis research 127 4 349 - 55 2011年04月 [査読有り][通常論文]
     
    An alternative pathway for fibrinolysis that comprises leukocyte elastase and its interaction with the plasminogen activator-plasmin system has been suggested. Plasma levels of cross-linked fibrin degradation product by leukocyte elastase (e-XDP) were significantly increased in patients with sepsis induced disseminated intravascular coagulation (DIC) compared with healthy subjects (18.6±19.9 vs 0.58±0.47U/mL, p<0.001). Twenty seven unique spots were identified from e-XDP dominant patients by immune-purification and two-dimensional difference gel electrophoresis, and they contained fibrinogen Bβ-chain derived fragments Bβ Asp-164, Ser-200, Gln-301, Ala-354, Ile-484 and γ-chain derivatives γ Val-274 at their amino-termini by acquired and processed tandem mass spectrometer. The Sequential Organ Failure Assessment Scores in patients with e-XDPs levels 3-10U/mL were significantly lower than those with e-XDPs levels -3U/mL, 10-30U/mL, and 30- U/mL. The adjusted odds for 28-day mortality rate in patients with e-XDP levels less than 3U/mL (hazard ratio, 4.432; 95% CI, 1.557-12.615 [p=0.005]) were significantly higher than those in patients with e-XDP levels of 3-10U/mL. These data suggest that leukocyte elastase might contribute to the degradation of cross-linked fibrin in sepsis-induced DIC.
  • Tsukasa Ohmori, Yuji Kashiwakura, Akira Ishiwata, Seiji Madoiwa, Jun Mimuro, Yusuke Furukawa, Yoichi Sakata
    The Journal of biological chemistry 285 41 31763 - 73 2010年10月 [査読有り][通常論文]
     
    Vinculin is a highly conserved actin-binding protein that is localized in integrin-mediated focal adhesion complexes. Although critical roles have been proposed for integrins in hematopoietic stem cell (HSC) function, little is known about the involvement of intracellular focal adhesion proteins in HSC functions. This study showed that the ability of c-Kit(+)Sca1(+)Lin(-) HSCs to support reconstitution of hematopoiesis after competitive transplantation was severely impaired by lentiviral transduction with short hairpin RNA sequences for vinculin. The potential of these HSCs to differentiate into granulocytic and monocytic lineages, to migrate toward stromal cell-derived factor 1α, and to home to the bone marrow in vivo were not inhibited by the loss of vinculin. However, the capacities to form long term culture-initiating cells and cobblestone-like areas were abolished in vinculin-silenced c-Kit(+)Sca1(+)Lin(-) HSCs. In contrast, adhesion to the extracellular matrix was inhibited by silencing of talin-1, but not of vinculin. Whole body in vivo luminescence analyses to detect transduced HSCs confirmed the role of vinculin in long term HSC reconstitution. Our results suggest that vinculin is an indispensable factor determining HSC repopulation capacity, independent of integrin functions.
  • Ohmori T, Kashiwakura Y, Ishiwata A, Madoiwa S, Mimuro J, Honda S, Miyata T, Sakata Y
    Biochemical and biophysical research communications 400 3 323 - 8 3 2010年09月 [査読有り][通常論文]
     
    Although vinculin is used frequently as a marker for integrin-mediated focal adhesion complexes, how it regulates the activation of integrin is mostly unknown. In this study, we examined whether vinculin would activate integrin in Chinese hamster ovary (CHO) cells expressing human integrin αIIbβ3. Silencing of vinculin by lentiviral transduction with a short hairpin RNA sequence affected the binding of PAC-1 (an antibody recognizing activated human αIIbβ3) to a constitutively active form of αIIbβ3 (α6Bβ3) expressed on CHO cells, while its inhibitory effects were much weaker than those of talin-1. Overexpression of an active form of vinculin without intramolecular interactions, but not the full length one, induced PAC-1 binding to native αIIbβ3 expressed on CHO cells in a manner dependent on talin-1. On the other hand, silencing of talin-1, but not vinculin, failed to induce cell spreading of α6Bβ3-CHO cells on fibrinogen, even in the presence of PT 25-2, a monoclonal antibody that activates αIIbβ3. Thus, an active form of vinculin could induce αIIbβ3 inside-out signaling through the actions of talin-1, while vinculin was dispensable for outside-in signaling.
  • Tsukasa Ohmori, Seiji Madoiwa, Jun Mimuro, Yoichi Sakata
    [Rinsho ketsueki] The Japanese journal of clinical hematology 51 8 625 - 31 2010年08月 [査読有り][通常論文]
  • Akira Ishiwata, Jun Mimuro, Hiroaki Mizukami, Yuji Kashiwakura, Atsushi Yasumoto, Asuka Sakata, Tsukasa Ohmori, Seiji Madoiwa, Fumiko Ono, Midori Shima, Akira Yoshioka, Keiya Ozawa, Yoichi Sakata
    Thrombosis research 125 6 533 - 7 2010年06月 [査読有り][通常論文]
     
    INTRODUCTION: Gene therapy is expected to be the next generation therapy for hemophilia, and a good animal model is required for hemophilia gene therapy preclinical studies. METHODS: Taking advantage of the human factor IX (FIX) specificity of monoclonal antibody 3A6, the epitope of which resides in the amino acid polypeptide segment including Ala 262 of human FIX, mutant macaque FIX with an amino acid substitution of Thr 262 to Ala (macaque FIX T262A) was generated and its reactivity to monoclonal antibody 3A6, biological activity and expression in vivo were studied. RESULTS: Enzyme-linked immunosorbent assays (ELISAs) and Western blot analyses showed that monoclonal antibody 3A6 bound to human FIX and macaque FIX T262A but not to wild-type macaque FIX. Recombinant macaque FIX T262A exhibited a comparable coagulation activity to wild-type macaque FIX and human FIX. High expression of macaque FIX T262A was achieved in mice by injection of AAV8 vectors carrying the macaque FIX T262A gene and reached levels of up to 31.5microg/mL (1050% of the normal human FIX concentration). Macaque FIX T262A expressed in the liver of mice was as biologically active as that expressed in vitro. In addition, the macaque FIX T262A concentrations determined by a 3A6-based ELISA were not influenced by the presence of normal macaque plasma. CONCLUSIONS: The results of the present study suggest that macaque FIX T262A may be processed appropriately in vivo and that the macaque FIX T262A concentration in the macaque circulation can be quantified precisely by a monoclonal antibody 3A6-based ELISA.
  • Jun Mimuro, Koichi Mizuta, Yoichi Kawano, Shuji Hishikawa, Akiei Hamano, Yuji Kashiwakura, Akira Ishiwata, Tsukasa Ohmori, Seiji Madoiwa, Hideo Kawarasaki, Yoichi Sakata
    Pediatric transplantation 14 3 369 - 76 2010年05月 [査読有り][通常論文]
     
    We studied restoration of the coagulation and fibrinolysis system in pediatric patients following liver transplantation and biomarkers of blood coagulation and fibrinolysis for suspecting the occurrence of acute cellular rejection. Coagulation activity recovered rapidly within two days following transplantation, but it took approximately 21-28 days for full recovery of the coagulation and fibrinolysis factors synthesized in the liver. PAI-1 levels were significantly higher in patients at the time of acute cellular rejection compared with levels after control of AR, and levels on days 14 and 28 in patients without AR. Plasma protein C and plasminogen levels at the time of rejection were significantly lower than those on day 14 in patients without AR. Statistical analysis suggested that an increase in plasma PAI-1 at a single time point in the post-operative period is a reliable marker among the coagulation and fibrinolysis factors for suspecting the occurrence of acute cellular rejection. These data suggested that appropriate anticoagulation may be required for 14 days after liver transplantation in order to avoid vascular complications and measurement of plasma PAI-1 levels may be useful for suspecting the occurrence of acute cellular rejection in pediatric patients following liver transplantation.
  • Akira Ishiwata, Jun Mimuro, Hiroaki Mizukami, Yuji Kashiwakura, Katsuhiro Takano, Tsukasa Ohmori, Seiji Madoiwa, Keiya Ozawa, Yoichi Sakata
    The journal of gene medicine 11 11 1020 - 9 2009年11月 [査読有り][通常論文]
     
    BACKGROUND: Gene therapy for hemophilia A with adeno-associated virus (AAV) vectors involves difficulties in the efficient expression of factor VIII (FVIII) and in antibody formation against transgene-derived FVIII. METHODS: AAV8 vectors carrying the canine B domain deleted FVIII (cFVIII) gene under the control of the ubiquitous beta-actin promoter, the liver-specific human alpha1 anti-trypsin promoter (HAAT) and the liver-specific hepatic control region (HCR) enhancer/human alpha1 anti-trypsin promoter complex (HCRHAAT) were used for the expression of cFVIII in FVIII deficient (fviii(-/-)) mice. RESULTS: Addition of the hepatic control region enhancer element to the HAAT promoter successfully augmented HAAT promoter activity without loss of liver-specificity in vivo. Using this enhancer/promoter complex, a high cFVIII transgene expression was achieved, resulting in increased blood cFVIII activities to more than 100% of the normal canine FVIII levels in fviii(-/-) mice at a 1 : 10 lower dose of the AAV8 vector carrying the cFVIII gene driven by the HAAT promoter. Under short-term immunosuppression, neutralizing antibodies against cFVIII developed in only one out of six mice when the HAAT promoter was used for cFVIII expression, whereas all the mice developed neutralizing antibodies against cFVIII when the beta-actin promoter was used for cFVIII expression. No neutralizing antibodies against cFVIII developed in fviii(-/-) mice that received the AAV8 vector carrying the cFVIII gene driven by the HCRHAAT enhancer/promoter complex without immunosuppression. CONCLUSIONS: These data suggest that AAV8 vector-mediated liver-restricted cFVIII gene expression is sufficient for immune hypo-responsiveness to transgene-derived cFVIII in fviii(-/-) mice.
  • Kimura A, Ohmori T, Kashiwakura Y, Ohkawa R, Madoiwa S, Mimuro J, Shimazaki K, Hoshino Y, Yatomi Y, Sakata Y
    Stroke; a journal of cerebral circulation 39 3411 - 3417 12 2008年12月 [査読有り][通常論文]
  • Tsukasa Ohmori, Akira Ishiwata, Yuji Kashiwakura, Seiji Madoiwa, Katsuyuki Mitomo, Hidenori Suzuki, Mamoru Hasegawa, Jun Mimuro, Yoichi Sakata
    Molecular therapy : the journal of the American Society of Gene Therapy 16 8 1359 - 65 2008年08月 [査読有り][通常論文]
     
    Platelets are receiving much attention as novel target cells to secrete a coagulation factor for hemophilia gene therapy. In order to extend the application of platelet-directed gene therapy, we examined whether ectopic expression of activated factor VII (FVIIa) in platelets would result in an efficient bypass therapy to induce sufficient thrombin generation on platelet surfaces in mice with hemophilia A. Transduction of bone marrow cells with a simian immunodeficiency virus (SIV)-based lentiviral vector harboring the platelet-specific GPIb alpha promoter resulted in efficient transgene expression in platelets. FVIIa antigen was expressed in platelets by this SIV system; FVII transgene products were found to localize in the cytoplasm and translocate toward the sub-membrane zone and cell surface after activation. Although FVII antigen levels in platelets did not reach the therapeutic levels seen with FVIIa infusion therapy, whole-blood coagulation, as assessed by thromboelastography, was significantly improved in mice with hemophilia A. Further, we observed correction of the bleeding phenotype in mice with hemophilia A after transplantation, even in the presence of FVIII-neutralizing antibodies. Our results demonstrate that FVIIa-expressing platelets can strengthen hemostatic function and may be useful in treating hemophilia and other inherited bleeding disorders. These findings are comparable to the proven therapeutic effects of FVIIa infusion.
  • Yuichiro Yano, Tsukasa Ohmori, Satoshi Hoshide, Seiji Madoiwa, Keiji Yamamoto, Takaaki Katsuki, Takeshi Mitsuhashi, Jun Mimuro, Kazuyuki Shimada, Kazuomi Kario, Yoichi Sakata
    European heart journal 29 14 1729 - 38 2008年07月 [査読有り][通常論文]
     
    AIMS: The aim of the study was to assess mechanisms and clinical backgrounds in order to determine residual platelet aggregability in dual antiplatelet therapy and to ascertain whether platelet aggregability is involved in systemic thrombogenicity. METHODS AND RESULTS: A cross-sectional study was conducted in 85 consecutive patients who underwent dual antiplatelet therapy (aspirin and thienopyridine/cilostazol) after percutaneous coronary intervention (PCI). Although serum thromboxane B(2) and dephosphorylation of vasodilator-stimulated phosphoprotein were significantly abolished, the platelet aggregation tests showed inter-individual differences that could be partly explained by plasma glucose levels. Platelet aggregability was not related to other factors involved in thrombogenicity. Thrombin generation assessed by soluble fibrin was independently associated with total cholesterol (beta = 0.349, P < 0.001), brain natriuretic peptide (beta = 0.222, P = 0.018), and ankle-brachial index (beta = -0.330, P = 0.001). Plasminogen activator inhibitor-1 was associated with the apnea-hypopnea index (beta = 0.300, P = 0.006). E-selectin was correlated with diabetes mellitus (beta = 0.279, P = 0.008) and body mass index (beta = 0.323, P = 0.002). CONCLUSION: Although dual antiplatelet therapy effectively inhibited its pharmacological targets, thrombin generation, inhibition of fibrinolytic activity, and endothelial dysfunction were determined by other clinical backgrounds. Our data suggested that some patients remain at risk of thrombotic complications after PCI and that these may benefit from anticoagulant treatment despite adequate dual antiplatelet therapy.
  • Miyuki Yamaguchi, Tsukasa Ohmori, Yoichi Sakata, Masaaki Ueki
    Bioorganic & medicinal chemistry 16 6 3342 - 51 2008年03月 [査読有り][通常論文]
     
    Since the discovery of anti-HIV activity in oligo(tyrosine sulfate)s in our laboratory, we have been interested in their potential as heparin pentasaccharide mimics. In this study, we investigated their interactions with synthetic heparin-binding peptides, derived from human antithrombin III (hAT III) and heparin-interacting protein (HIP), using surface noncovalent affinity mass spectrometry. We compared binding affinities to those heparin-binding peptides between oligo(tyrosine sulfate)s and several known sulfated compounds and found that oligo(tyrosine sulfate)s bind to hAT III (123-139) more strongly than a heparin-derived hexasaccharide dp6. Moreover, we found longer oligo(tyrosine sulfate) has higher binding affinity to hAT III (123-139).
  • Kazuki Niwa, Jun Mimuro, Masaaki Miyata, Teruko Sugo, Tsukasa Ohmori, Seiji Madoiwa, Chuwa Tei, Yoichi Sakata
    Thrombosis research 121 6 773 - 80 2008年 [査読有り][通常論文]
     
    INTRODUCTION: Emerging lines of evidence have suggested that certain dysfibrinogens present a significant risk of thrombosis. PATIENT/METHODS: The thrombophilic nature of a new-type of dysfibrinogen Kagoshima identified in a 36-year-old female with deep vein thrombosis during the postpartum period was studied. RESULTS/DISCUSSION: Based on the analyses of the patient fibrinogen and the fibrinogen genes, fibrinogen Kagoshima was shown to have the amino acid substitution of gammaThr-314 to Ile that resulted in impaired function and hypofibrinogenemia. Polymerization of fibrin monomers derived from patient fibrinogen was severely impaired with a partial correction in the presence of calcium ions, causing very low clottability and delayed cross-linking of patient fibrin catalyzed by activated factor XIII. Because of the low clottability, a large amount of soluble fibrin was formed upon thrombin treatment, resulting in an increase of thrombin in the soluble fraction. Additionally, tPA-mediated plasmin generation on fibrin was impaired and calcium-ion-dependent integrity of the gamma-chain D domain of Kagoshima fibrinogen was perturbed. The presence of many tapered-fiber ends inside the tangled fibrin networks, observed by scanning electron microscopy, suggested early termination of fibrin polymerization and the structural alteration. CONCLUSION: These data suggest that fibrinogen Kagoshima is dysfunctional, giving rise to formation of fibrinolysis-resistant soluble fibrin polymers and entrance of soluble fibrin associating with thrombin to the circulation, partly accounting for the thrombophilic nature of the affected fibrinogen and fibrin molecules.
  • Jun Mimuro, Masanori Niimura, Yuji Kashiwakura, Akira Ishiwata, Tomoko Ono, Tsukasa Ohmori, Seiji Madoiwa, Kiyotaka Okada, Osamu Matsuo, Yoichi Sakata
    Thrombosis research 122 1 91 - 7 2008年 [査読有り][通常論文]
     
    INTRODUCTION: Secondary ADAMTS13 deficiency may occur in septic patients. The expression of ADAMTS13 in mouse endotoxinemia was studied. METHODS: The blood and mRNA expression levels of ADAMTS13 and von Willebrand factor were measured in lipopolysaccharide-injected mice. RESULTS: The plasma ADAMTS13 activity in wild-type mice was significantly decreased at 2 h after lipopolysaccharide injection, and this decrease in ADAMTS13 activity preceded the decrease in ADAMTS13 mRNA expression in the liver and continued for 24 h. However, no decreases in the plasma ADAMTS13 activity after lipopolysaccharide injection were observed in mice pretreated with a neutrophil elastase inhibitor or in plasminogen-deficient mice, suggesting that the decrease in ADAMTS13 activity was processed efficiently by the coordinated actions of plasmin and neutrophil elastase. von Willebrand factor mRNA was abundantly expressed in the lung and moderately in the kidney, but showed relatively low expression in the liver without lipopolysaccharide injection. However, von Willebrand factor mRNA expression in the liver was significantly increased after lipopolysaccharide injection and this high expression level continued for 24 h after the injection. The von Willebrand factor and ADAMTS13 mRNA expression levels in these organs changed in the opposite manners following lipopolysaccharide administration. Furthermore, the blood von Willebrand factor level increased after lipopolysaccharide administration, in contrast to the decrease in the blood ADMTS13 level after lipopolysaccharide administration. CONCLUSION: These data suggest that imbalance between the blood von Willebrand factor and ADAMTS13 levels may occur in endotoxinemia, and that this may partly contribute to the thrombotic state associated with endotoxinemia.
  • Tsukasa Ohmori, Yuji Kashiwakura, Akira Ishiwata, Seiji Madoiwa, Jun Mimuro, Yoichi Sakata
    Arteriosclerosis, thrombosis, and vascular biology 27 10 2266 - 72 2007年10月 [査読有り][通常論文]
     
    OBJECTIVE: Because platelets are anucleate cells having a limited life span, direct gene manipulation cannot in principle be used to investigate the involvement of a specific signal transduction pathway in platelet activation. In this study, we examined whether the expression of a short hairpin RNA (shRNA) sequence in hematopoietic stem cells is maintained during megakaryocyte differentiation, thus resulting in inhibition of targeted protein in platelets. METHODS AND RESULTS: To identify platelets derived from transduced stem cells, we generated a lentiviral vector that simultaneously expresses the shRNA sequence driven by the U6 promoter and GFP under the control of the glycoprotein (GP) Ib alpha promoter. Transplantation of mouse bone marrow cells transduced with the vector facilitated specifically mark platelets derived from the transduced cells. Transplantation of cells transduced with shRNA sequence targeting integrin alphaIIb caused a significant reduction of integrin alphaIIb beta3 (alphaIIb beta3) expression in GFP-positive platelets. It also inhibited alphaIIb beta3 activation assessed by the binding of JON/A, an antibody that recognizes activated alphaIIb beta3. Talin-1 silencing by the same method resulted in normal alphaIIb beta3 expression but deficient inside-out alphaIIb beta3 signaling. CONCLUSIONS: shRNA expression driven by the U6 promoter is preserved during megakaryopoiesis. This method facilitates functional analysis of targeted protein in platelet activation.
  • Makoto Osada, Yutaka Yatomi, Tsukasa Ohmori, Shinya Aoki, Shigemi Hosogaya, Yukio Ozaki
    Journal of biochemistry 142 3 351 - 5 2007年09月 [査読有り][通常論文]
     
    Platelet-derived mediators may play an important role in the development of renal diseases through interaction with glomerular mesangial cells (MCs), and we, in this study, examined the effect of sphingosine 1-phosphate (Sph-1-P), a bioactive lipid released from activated platelets, on the contraction of MCs. Sph-1-P was found to induce MC contraction through mediation of Rho kinase both in cell shape change and collagen gel contraction assays. The specific antagonist of the Sph-1-P receptor S1P(2) inhibited the response. Similar results were obtained when the supernatant from activated platelet suspensions were used instead of Sph-1-P. Our findings suggest that platelet-derived Sph-1-P may be involved in MC contraction via S1P(2) and that regulation of this receptor might be useful therapeutically.
  • Seiji Madoiwa, Tsutomu Someya, Mitsugu Hironaka, Hiroshi Kobayashi, Tsukasa Ohmori, Jun Mimuro, Yukihiko Sugiyama, Tatsuo Morita, Yoshioki Nishimura, Takahisa Tarumoto, Keiya Ozawa, Ken Saito, Yoichi Sakata
    Thrombosis research 119 2 229 - 40 2007年 [査読有り][通常論文]
     
    Vascular intimal carcinomatosis refers to a characteristic tumor proliferation on vascular intima that replaces normal endothelium. This pathological event of unknown cause is quite different from tumor thrombotic microangiopathy due to the absence of thrombi on the tumor cell surfaces. We analyzed renal transitional cell carcinoma cases with metastasis to the main pulmonary arteries and marked hyperfibrino(geno)lysis. The fibrinogen-derived products from patients' plasma were identified as D1A/gamma, D1/gamma, and D1/beta by immunoblotting with the NH2-terminus of the fragment D specific antibody JIF-23. In all cases, the neoplastic cells with vascular intimal carcinomatosis were stained positive for anti-human annexin 2, which is a unique cell surface co-receptor for plasminogen and tissue-type plasminogen activator. In contrast, normal renal pelvic mucosa or renal transitional cell carcinoma without vascular intimal carcinomatosis did not express any annexin 2. The isolated transitional cell carcinoma cells contained annexin 2 mRNA and expressed its protein. Anti-annexin 2 antibody and transfection of annexin 2 small interfering RNA into these carcinoma cells significantly inhibited tissue-type plasminogen activator dependent plasmin generation. These findings suggest that annexin 2 mediated fibrinolysis on the transitional cell carcinoma cells may play a role in inducing hemorrhagic disorder in vascular intimal carcinomatosis.
  • Atsushi Kimura, Tsukasa Ohmori, Ryunosuke Ohkawa, Seiji Madoiwa, Jun Mimuro, Takashi Murakami, Eiji Kobayashi, Yuichi Hoshino, Yutaka Yatomi, Yoichi Sakata
    Stem cells (Dayton, Ohio) 25 1 115 - 24 2007年01月 [査読有り][通常論文]
     
    Neural stem/progenitor cells (NSPCs) migrate toward a damaged area of the central nervous system (CNS) for the purpose of limiting and/or repairing the damage. Although this migratory property of NSPCs could theoretically be exploited for cell-based therapeutics of CNS diseases, little is known of the mechanisms responsible for migratory responses of NSPCs. Here, we found that sphingosine 1-phosphate (Sph-1-P), a physiological lysophospholipid mediator, had a potent chemoattractant activity for NSPCs, in which, of Sph-1-P receptors, S1P(1) was abundantly expressed. Sph-1-P-induced NSPC migration was inhibited by the pretreatment with pertussis toxin, Y-27632 (a Rho kinase inhibitor), and VPC23019 (a competitive inhibitor of S1P(1) and S1P(3)). Sph-1-P does not act as intracellular mediator or in an autocrine manner, because [(3)H]sphingosine, incorporated into NSPCs, was mainly converted to ceramide and sphingomyeline intracellularly, and the stimulation-dependent formation and extracellular release of Sph-1-P were not observed. Further, Sph-1-P concentration in the spinal cord was significantly increased at 7 days after a contusion injury, due to accumulation of microglia and reactive astrocytes in the injured area. This locally increased Sph-1-P concentration contributed to the migration of in vivo transplanted NSPCs through its receptor S1P(1), given that lentiviral transduction of NSPCs with a short hairpin RNA interference for S1P(1) abolished in vivo NSPC migration toward the injured area. This is the first report to identify a physiological role for a lipid mediator in NSPC migration toward a pathological area of the CNS and further indicates that the Sph-1-P/S1P(1) pathway may have therapeutic potential for CNS injuries.
  • Seiji Madoiwa, Shin Nunomiya, Tomoko Ono, Yuichi Shintani, Tsukasa Ohmori, Jun Mimuro, Yoichi Sakata
    International journal of hematology 84 5 398 - 405 2006年12月 [査読有り][通常論文]
     
    Sepsis-induced disseminated intravascular coagulation (DIC) is a serious condition because it is closely linked to the development of multiple organ dysfunctions. We compared molecular fibrinolysis markers for 117 patients with sepsis-induced DIC and 1627 patients with nonseptic DIC. Levels of fibrinogen and fibrin degradation products and D-dimer were significantly lower in sepsis-induced DIC cases than in nonseptic DIC cases. In septic DIC cases, plasma plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in nonseptic DIC cases. D-dimer levels were negatively correlated with plasma PAI-1 levels in septic DIC cases. Multiple Organ Dysfunction Scores were significantly higher in septic DIC patients with PAI-1 levels >90 ng/mL than in the group with PAI-1 levels <30 ng/mL. The Kaplan-Meier survival functions until 28 days after DIC diagnosis were significantly lower in the group with PAI-1 levels >90 ng/mL than in the other groups. In a multivariate analysis, plasma PAI-1 levels at DIC diagnosis were an independent risk factor for mortality in sepsis-induced DIC (hazard ratio, 1.012; P = .008). These data suggest that plasma PAI-1 plays an important role in sustaining DIC in septic DIC cases and contributes to multiple organ failure and decreased survival in such patients.
  • Tsukasa Ohmori, Jun Mimuro, Katsuhiro Takano, Seiji Madoiwa, Yuji Kashiwakura, Akira Ishiwata, Masanori Niimura, Katsuyuki Mitomo, Toshiaki Tabata, Mamoru Hasegawa, Keiya Ozawa, Yoichi Sakata
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 9 1522 - 4 2006年07月 [査読有り][通常論文]
     
    Platelets release several mediators that modify vascular integrity and hemostasis. In the present study, we developed a technique for efficient transgene expression in platelets in vivo and examined whether this targeted-gene-product delivery system using a platelet release reaction could be exploited for clinical applications. Analysis of luciferase reporter gene constructs driven by platelet-specific promoters (the GPIIb, GPIbalpha, and GPVI) revealed that the GPIbalpha promoter was the most potent in the megakaryoblastic cell line UT-7/TPO and human CD34+-derived megakaryocytes. Transduction of UT-7/TPO; CD34+-derived megakaryocytes; and c-Kit+, ScaI+, and Lineage- (KSL) murine hematopoietic stem cells with a simian immunodeficiency virus (SIV)-based lentiviral vector carrying eGFP resulted in efficient, dose-dependent expression of eGFP, and the GPIbalpha promoter seemed to bestow megakaryocytic-specific expression. Transplantation of KSL cells transduced with SIV vector containing eGFP into mice showed that there was preferable expression of eGFP in platelets driven by the GPIbalpha promoter [7-11% for the cytomeglovirus (CMV) promoter, 16-27% for the GPIbalpha promoter]. Furthermore, transplantation of ex vivo-transduced KSL cells by SIV vector carrying human factorVIII (hFVIII) driven by the GPIbalpha promoter induced the production of detectable transcripts of the hFVIII gene and the hFVIII antigen in bone marrow and spleen for at least 90 days and partially corrected the hemophilia A phenotype. Platelet-targeting gene therapy using SIV vectors appears to be promising for gene therapy approaches toward not only inherited platelet diseases but also other hemorrhagic disorders such as hemophilia A.
  • Tomoko Ono, Jun Mimuro, Seiji Madoiwa, Kenji Soejima, Yuji Kashiwakura, Akira Ishiwata, Katsuhiro Takano, Tsukasa Ohmori, Yoichi Sakata
    Blood 107 2 528 - 34 2006年01月 [査読有り][通常論文]
     
    Deficiency of ADAMTS13 is found in patients with thrombotic thrombocytopenic purpura (TTP), and the genetic defects in the ADAMTS13 gene or the autoantibody against ADAMTS13 is thought to be responsible for the development of TTP. The clinical correlation and mechanisms of secondary ADAMTS13 deficiency in other disease states were investigated. In addition to TTP, ADAMTS13 levels were severely decreased in patients with sepsis-induced disseminated intravascular coagulation (DIC). The incidence of acute renal failure and serum creatinine levels in patients with ADAMTS13 activity levels lower than 20% (incidence, 41.2%; creatinine, 160 +/- 150 microM [1.81 +/- 1.70 mg/dL]) (P < .05) were significantly higher than they were in patients with ADAMTS13 activity levels higher than 20% (incidence, 15.4%; creatinine, 84 +/- 67 microM [0.95 +/- 0.76 mg/dL]) (P < .01). Additionally, unusually large von Willebrand factor multimers were detected in 26 (51.0%) of 51 patients with ADAMTS13 activity levels lower than 20%. Lower molecular weight forms of ADAMTS13 were found in the plasma of patients with sepsis-induced DIC, suggesting that the deficiency of ADAMTS13 was partially caused by its cleavage by proteases in addition to decreased synthesis in the liver. These data suggested that severe secondary ADAMTS13 deficiency can be associated with sepsis-induced DIC and may contribute to the development of renal failure.
  • Akira Ishiwata, Jun Mimuro, Yuji Kashiwakura, Masanori Niimura, Katsuhiro Takano, Tsukasa Ohmori, Seiji Madoiwa, Hiroaki Mizukami, Takashi Okada, Hiroyuki Naka, Akira Yoshioka, Keiya Ozawa, Yoichi Sakata
    Thrombosis research 118 5 627 - 35 2006年 [査読有り][通常論文]
     
    Adeno-associated virus (AAV) vectors carrying the B domain-deleted canine FVIII (BDD cFVIII) gene utilizing the beta-actin minimum promoter (167b) pseudotyped with serotype 1 (AAV1-beta-actin-cFVIII) and serotype 8 (AAV8-beta-actin-cFVIII) were developed to express cFVIII in hemophilia A mice. FVIII clotting activities measured by the APTT method increased in hemophilia A mice with intramuscular injection of AAV1-beta-actin-cFVIII in a dose-dependent manner. Therapeutic FVIII levels (2.9+/-1.0%) in hemophilia A mice with the AAV1-beta-actin-cFVIII dose of 1 x 10(12) gc/body were achieved, suggesting partial correction of the phenotype with AAV1-beta-actin-cFVIII vectors. FVIII clotting activity levels in hemophilia A mice with intravenous injection of AAV8-beta-actin-cFVIII also were increased dose-dependently, achieving therapeutic FVIII levels (5-90%) in hemophilia A mice with the AAV8-beta-actin-cFVIII doses of 1-3 x 10(11) gc/body and supernormal FVIII levels (180-670%) in hemophilia A mice with the AAV8-beta-actin-cFVIII dose of 1 x 10(12) gc/body. Transduction of the liver with AAV8-beta-actin-cFVIII is superior to transduction of skeletal muscles with AAV1cFVIII regarding the FVIII production and antibody formation. These data suggested that both AAV1 and AAV8 vectors carrying the FVIII gene utilizing a minimum promoter have a potential for hemophilia A gene therapy.
  • T Yuminamochi, Y Yatomi, M Osada, T Ohmori, Y Ishii, K Nakazawa, S Hosogaya, Y Ozaki
    JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY 51 4 513 - 521 2003年04月 [査読有り][通常論文]
     
    The LIM domain is a protein-protein interaction motif critically involved in a variety of fundamental biological processes, including cytoskeletal organization, cell lineage specification, and organ development. In this study we examined the expression of the LIM proteins paxillin and Hic-5 in adult human tissues by immunohistochemistry and immunoblotting. Paxillin expression was widespread and observed both in non-muscle and muscle tissues. Of the latter, paxillin was mainly expressed in multinuclear striated muscle. In contrast, Hic-5 showed restricted expression and was expressed in muscle tissues, mainly in mononuclear smooth muscle. Taken together with previous findings, it appears likely that the counterbalance between paxillin and Hic-5 may be deeply involved in muscle differentiation.
  • T Ohmori, Y Yatomi, M Osada, F Kazama, T Takafuta, H Ikeda, Y Ozaki
    CARDIOVASCULAR RESEARCH 58 1 170 - 177 2003年04月 [査読有り][通常論文]
     
    Objectives: Sphingosine 1-phosphate (Sph-1-P), a bioactive lipid derived from activated platelets, may play an important role in coronary artery spasm and hence the pathogenesis of ischemic heart diseases, since we reported that a decrease in coronary blood flow was induced by this lysophospholipid in an in vivo canine heart model [Cardiovasc. Res. 46 (2000) 1191]. In this study, metabolism related to and cellular responses elicited by Sph-1-P were examined in human coronary artery smooth muscle cells (CASMCs). Methods and results: [H-3]Sphingosine (Sph), incorporated into CASMCs, was converted to [H-3]Sph-1-P intracellularly, but its stimulation-dependent formation and extracellular release were not observed. Furthermore, the cell surface Sph-1-P receptors of SIP family (previously called EDG) were found to be expressed in CASMCs. Accordingly, Sph-1-P seems to act as an extracellular mediator in CASMCs. Consistent with Sph-1-P-elicited coronary vasoconstriction in vivo, Sph-1-P strongly induced CASMC contraction, which was inhibited by JTE-013, a newly-developed specific antagonist of SIP2 (EDG-5). Furthermore, C3 exoenzyme or Y-27632 inhibited the CASMC contraction induced by Sph-1-P, indicating Rho involvement. Finally, exogenously-added [3H]Sph-1-P underwent a rapid degradation. Since lipid phosphate phosphatases, ectoenzymes capable of dephosphorylating Sph-1-P, were expressed in CASMCs, Sph-1-P may be dephosphorylated by the ectophosphatases. Conclusions: Sph-1-P, derived from platelets and dephosphorylated on the cell surface, may induce the contraction of coronary artery smooth muscle cells through the S1P(2)/RHO signaling. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.
  • M Osada, Y Yatomi, T Ohmori, H Ikeda, Y Ozaki
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 299 3 483 - 487 2002年12月 [査読有り][通常論文]
     
    Sphingosine 1-phosphate (Sph-1-P), a bioactive lysophospholipid capable of inducing a wide spectrum of biological responses, acts as an intercellular mediator, through interaction with the endothelial differentiation gene (EDG)/S1P family of G protein-coupled receptors. In this study, the effects of JTE-013, a specific antagonist of the migration-inhibitory receptor EDG-5, on Sph-1-P-elicited responses were examined in human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs), which expressed EDG-5 protein weakly and abundantly, respectively. This pyrazolopyridine compound reversed the inhibitory effect of Sph-1-P on SMC migration and further enhanced Sph-1-P-stimulated HUVEC migration. In contrast, its effect on Sph-1-P-induced intracellular Ca2+ mobilization was marginal. Our results indicate that specific regulation of Sph-1-P-modulated migration responses in vascular cells can be achieved by EDG-5 antagonists and that manipulation of Sph-1-P biological activities by each EDG antagonist may lead to a therapeutical application to control vascular diseases. (C) 2002 Elsevier Science (USA). All rights reserved.
  • M Osada, Y Yatomi, T Ohmori, S Hosogaya, Y Ozaki
    THROMBOSIS RESEARCH 108 2-3 169 - 174 2002年11月 [査読有り][通常論文]
  • Ohmori T, Yatomi Y
    Rinsho byori. The Japanese journal of clinical pathology Suppl 123 112 - 119 2002年11月 [査読有り][通常論文]
  • Yutaka Yatomi, Tsukasa Ohmori, Makoto Osada, Yukio Ozaki
    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 47 4 Suppl 488 - 95 2002年03月 [査読有り][通常論文]

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    Frontiers in Haemophilia 2021年
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    新臨床内科学 医学書院 2020年
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    血液疾患最新の治療 2020-2022 南江堂 2020年
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    今日の疾患辞典〜検査処方例つき〜 カイ書林 2020年
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    今日の診断指針 第8版 医学書院 2020年
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    血液内科 2020年
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    内科 2020 2020年
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    羊土社 2020年
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    血液内科 2020年
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    内科学書 中山書店 2019年
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    未来型 血液治療学 中外医学社 2019年
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    今日の治療指針 2018 医学書院 2018年
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    日常診療に活かす診療ガイドラインUP-TO-DATE2018-2019 メディカルビュー社 2018年
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    臨床血液(教育講演号) 2018年
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    臨床に直結する血栓止血学 中外医学社 2018年
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    臨床に直結する血栓止血学 中外医学社 2018年
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    【特集 ゲノム編集技術の基礎と応用】 血液フロンティア 2018年
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    EBM血液疾患の治療2019-2020 中外医学社 2018年
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    内科学 第11版 朝倉書店 2017年
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    血液疾患最新の治療 2017-2019 南江堂 2017年
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    今日の治療指針 2016 医学書院 2016年
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    血液内科ゴールデンハンドブック 第2版 南江堂 2016年
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    血液内科ゴールデンハンドブック 第2版 南江堂 2016年
  • 特発性血小板減少性紫斑病
    大森 司 ()
    血液内科ゴールデンハンドブック 第2版 南江堂 2016年
  • 血小板機能異常症
    大森 司 ()
    血液内科ゴールデンハンドブック 第2版 南江堂 2016年
  • 血友病に対する止血療法
    大森 司 ()
    血液内科ゴールデンハンドブック 第2版 南江堂 2016年
  • 血友病
    大森 司 ()
    血液内科ゴールデンハンドブック 第2版 南江堂 2016年
  • DIC
    大森 司 ()
    日常診療に活かす診療ガイドラインUP-TO-DATE2016-2017 メディカルビュー社 2016年
  • Ashwell-Morell受容体を介した血小板数調節メカニズム
    大森 司 ()
    Annual Review血液2016 中外医学社 2016年
  • 出血・血栓傾向のみかた
    大森 司 ()
    血液科研修ノート2016 診断と治療社 2016年
  • 出血傾向
    大森 司 ()
    内科診断の道しるべーその症候,どう診る どう考える? 2016年
  • 【Hot topics】血小板
    大森 司, 羽藤高明, 横山健次 ()
    日本血栓止血学会誌 2016年
  • 遺伝子修復
    大森 司 ()
    Frontiers in Haemophilia 2016年
  • 播種性血管内凝固症候群(DIC)
    大森 司 ()
    今日の診断指針 第7版 医学書院 2015年
  • 先天性血小板減少症・機能異常症
    大森 司 ()
    血液専門医テキスト 南江堂 2015年
  • 抗血栓薬
    大森 司 ()
    血液専門医テキスト 南江堂 2015年
  • 血友病治療の進歩-遺伝子治療と薬物療法
    大森 司 ()
    Annual Review血液2015 中外医学社 2015年
  • 出血時間・毛細血管抵抗試験
    大森 司 ()
    臨床検査ガイド2015-2016 文光堂 2015年
  • 血小板活性化マーカー
    大森 司 ()
    【これだけはしっておきたい検査のポイント】medicina 52 臨時増刊号 2015年
  • 凝固因子,インヒビター
    ()
    【これだけはしっておきたい検査のポイント】medicina 52 臨時増刊号 2015年
  • 先天性出血病の遺伝子・細胞治療
    大森 司 ()
    新・血栓止血血管学 金芳堂 2015年
  • 血栓性血小板減少性紫斑病
    大森 司 ()
    【内科疾患の診断基準・病型分類・重症度】 臨床雑誌「内科」 2015年
  • 播種性血管内凝固症候群
    大森 司 ()
    【内科疾患の診断基準・病型分類・重症度】臨床雑誌「内科」 2015年
  • 抗血栓療法と血小板機能検査:臨床効果を反映する検査指標はあり得るか
    大森 司 ()
    Pharma Medica 2015年
  • 播種性血管内凝固症候群(DIC)の診断と治療【血液疾患〜基本知識と診断の実際】
    大森 司 ()
    レジデント 2015年
  • 凝固異常へのアプローチ【特集 血液疾患】
    大森 司 ()
    Hospitalist 2015年
  • ゲノム編集技術の概要とその可能性
    大森 司 ()
    日本血栓止血学会誌 2015年
  • 特発性血小板減少性紫斑病
    大森 司 ()
    今日の治療指針 2014 医学書院 2014年
  • 血小板機能異常症
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 血栓性血小板減少性紫斑病
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 薬剤性血小板減少症
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 特発性血小板減少性紫斑病
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 血管壁・毛細血管の異常
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 血液凝固の異常による出血
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 血管壁・血小板の異常による出血
    大森 司 ()
    出血性疾患の実践診療マニュアル 南江堂 2014年
  • 静脈血栓症に果たす血小板の役割
    大森 司 ()
    Annual Review血液2014 中外医学社 2014年
  • 血小板減少症-発症機序に基づく鑑別診断と治療戦略-【止血異常とDICの実地診療】
    大森 司 ()
    Medical Practice 2014 2014年
  • RASによる凝固制御と血液機能検査【血液凝固とRAS】
    大森 司 ()
    Angiotensin Research 2014年
  • 抗血小板薬
    大森 司 ()
    プリンシプル血液疾患の臨床 中山書店 2014年
  • 血小板減少の誤診【もう見逃さない!迷わない!非血液専門医のための血液診療】
    大森 司 ()
    Medicina 2014年
  • DIC【マイナーエマージェンシー-実地医家に必要な救急対処法のすべて-】
    大森 司 ()
    Medical Practice 2014 臨時増刊号 2014年
  • 先天性血栓性素因
    大森 司 ()
    内科外来基本処方ナビ 中外医学社 2014年
  • 抗血小板薬:米国胸部専門医学会 エビデンスに基づく臨床方針ガイドライン
    大森 司 ()
    【特集 血栓症治療ガイドラインup-to-date】血栓と循環2014 2014年
  • 血友病
    大森 司 ()
    【内科疾患 最新の治療】臨床雑誌「内科」 2014年
  • 血管性紫斑病
    大森 司 ()
    【内科疾患 最新の治療】臨床雑誌「内科」 2014年
  • 医原性血小板減少症
    大森 司 ()
    【一般内科外来でみる出血傾向】臨床雑誌「内科」 2014年
  • 血友病に対する治療の進歩 2.遺伝子細胞治療の面から
    大森 司, 水上 浩明, 窓岩 清治, 小澤 敬也, 坂田 洋一 ()
    臨床血液 2014年
  • 血液凝固第IX因子
    大森 司 ()
    日本血栓止血学会誌 2014年
  • von Willebrand病に対する治療
    大森 司 ()
    EBM血液疾患の治療 中外医学社 2014年
  • 止血機構と動脈硬化
    大森 司 ()
    日本血栓止血学会誌 2013年
  • 【Hot topics】血小板
    大森 司, 堀内 久徳, 松原 由美子 ()
    日本血栓止血学会誌 2013年
  • 抗凝固療法・抗血小板療法とはなにか?
    大森 司 ()
    フジメディカル出版 2013年
  • 血小板機能検査【検査値を読む2013】
    大森 司 ()
    内科 2013年
  • β-トロンボグロブリン・血小板第4因子【検査値を読む2013】
    大森 司 ()
    内科 2013年
  • 出血時間・毛細血管抵抗試験【検査値を読む2013】
    大森 司 ()
    内科 2013年
  • 血小板【血栓症に対する臨床検査】
    大森 司 ()
    血栓と循環 2013年
  • 後天性血小板機能異常症
    大森 司 ()
    臨床に直結する血栓止血学 中外医学社 2013年
  • 抗血小板療法によるアンチエイジングー抗血小板薬剤間のアンチエイジング効果の違い【抗凝固・抗血小板とアンチエイジング】
    大森 司 ()
    Anti-aging Science 2013年
  • 出血性疾患の診断アプローチ【教育講演特集号】
    大森 司 ()
    臨床血液2013 2013年
  • 【診療の秘訣】原因不明の血小板減少症
    大森 司 ()
    モダンフィジシャン2013 2013年
  • 動脈硬化,血栓性疾患発症予防におけるアスピリンと抗血小板薬の有効性と問題点【特集 動脈硬化性疾患と抗血栓療法】
    大森 司 ()
    動脈硬化予防 Prevention of Artersclerosis Vol.12 2013年
  • DIC
    大森 司 ()
    今日の治療指針 2012 医学書院 2012年
  • 古典的抗血小板薬アスピリン【臨床医のための抗凝固薬・抗血小板薬の使い方】
    大森 司 ()
    Modern Physician 2012年
  • パラオキソナーゼ-1とクロピドグレル抵抗性
    大森 司 ()
    日本血栓止血学会誌 2012年
  • 新規経口抗凝固薬の薬効マーカーは考えられるか【新規経口抗凝固薬の光と影】
    大森 司 ()
    Medicina 2012年
  • 血小板と蛋白質合成
    大森 司 ()
    Pharma Medica 2012年
  • 血小板・凝固検査異常の外来対応における留意点
    大森 司 ()
    血液内科 2012年
  • ワルファリンとアセトアミノフェンの相互作用
    大森 司 ()
    血液内科 2012年
  • 抵抗性を越えて 基本薬アスピリン【抗血栓療法 最近の進歩】
    大森 司 ()
    循環器内科 2011年
  • 抗血小板薬抵抗性【抗血栓療法の新潮流-作用機序に基づく治療戦略】
    大森 司 ()
    カレントテラピー 2011年
  • 出血傾向・血小板減少症の鑑別診断【一般内科医がみる血液疾患】
    大森 司 ()
    Medicina 2011年
  • 先天性血小板減少症・機能異常症
    大森 司 ()
    血液専門医テキスト 南江堂 2011年
  • 抗血栓薬
    大森 司 ()
    血液専門医テキスト 南江堂 2011年
  • 抗凝固薬・抗血小板薬
    大森 司 ()
    血液内科ゴールデンハンドブック 南江堂 2011年
  • ヘパリン起因性血小板減少症
    大森 司 ()
    血液内科ゴールデンハンドブック 南江堂 2011年
  • 血栓性血小板減少性紫斑病・溶血性尿毒症症候群
    大森 司 ()
    血液内科ゴールデンハンドブック 南江堂 2011年
  • VON WILLEBRAD病
    大森 司 ()
    血液内科ゴールデンハンドブック 南江堂 2011年
  • 特発性血小板減少性紫斑病
    大森 司 ()
    血液内科ゴールデンハンドブック 南江堂 2011年
  • 血小板機能異常症
    大森 司 ()
    血液内科ゴールデンハンドブック 南江堂 2011年
  • クロピドグレル抵抗性とは何か? 【臨床医からの質問に答える】
    大森 司 ()
    検査と技術 2010年
  • アスピリンレジスタンスの発症機構【抗血小板薬の反応性】
    大森 司 ()
    血栓と循環 2010年
  • 抗血小板療法における血小板機能モニタリングの意義【血小板機能検査による抗血小板療法の個別化】
    大森 司 ()
    医学のあゆみ 2010年
  • レンチウイルスベクターを用いた血小板標的遺伝子導入法の開発
    大森 司, 窓岩 清治, 三室 淳, 坂田 洋一 ()
    臨床血液 2010年
  • 組織因子と血液細胞
    大森 司 ()
    Review血液2009 中外医学社 2009年
  • 抗血小板薬の諸問題 抗血小板薬抵抗性の概念とその実態【抗凝固・抗血小板療法Update】
    大森 司 ()
    医学のあゆみ 2009年
  • 臨床講座 抗凝固・抗血小板療法【病気について知りたい! 】
    大森 司, 坂田 洋一 ()
    PharmaTribune 2009年
  • 有害事象と対策 癌と血栓症【大腸癌治療UPDATE】
    大森 司, 坂田 洋一 ()
    医学のあゆみ 2008年
  • アスピリン,抗血小板薬【やさしく学べる血小板・血栓止血の管理】
    大森 司 ()
    救急・集中治療 2008年
  • 血小板と臨床検査【血栓止血の臨床 臨床医のために】
    ()
    日本血栓止血学会誌 2008年
  • 我が国の急性冠症候群に対する抗血小板療法
    大森 司 ()
    日本血栓止血学会誌 2008年
  • 動脈系血栓に関わる血小板の機能【INTERFACE 基礎 循環器領域の血栓症】
    大森 司 ()
    International Review of Thrombosis 2008年
  • 出血傾向とQOL【血液病とQOL】
    大森 司 ()
    血液フロンティア 2008年
  • ウイルスベクターを用いた遺伝子改変血小板の作成【血小板を作ろう】
    大森 司 ()
    日本血栓止血学会誌 2008年
  • Von Willebrand病
    大森 司 ()
    血液内科診療マニュアル 日本医学館 2008年
  • 血小板機能異常症
    大森 司 ()
    血液内科診療マニュアル 日本医学館 2008年
  • スフィンゴシン1-リン酸と心血管疾患【脂質メディエータ研究の新展開と心血管疾患】
    大森 司, 矢冨 裕 ()
    分子心血管病 2008年
  • 抗血小板療法【血栓・塞栓症の病態・検査・治療】
    大森 司 ()
    Medical Technology臨時増刊 2007年
  • 血小板活性化マーカー【血栓・塞栓症の病態・検査・治療】
    大森 司 ()
    Medical Technology臨時増刊 2007年
  • 血友病遺伝子治療を目指した遺伝子改変マウス
    大森 司 ()
    血栓と循環 2007年
  • 出血傾向【臨床症状からわかる血液疾患】
    大森 司 ()
    Modern Physician 2007年
  • アスピリン抵抗性(不応症)
    大森 司 ()
    Annual Review血液2007 中外医学社 2007年
  • 出血性疾患の実地診療の実際 血小板機能検査の進歩【出血性疾患の実地診療 最新の知見を踏まえた日常臨床】
    大森 司 ()
    Medical Practice 2007年
  • 抗血小板療法
    大森 司, 苅尾 七臣 ()
    日本血栓止血学会誌 2006年
  • アスピリン抵抗性の定義と問題点
    大森 司 ()
    Heart View 2006年
  • データ解説「 女性の心血管系イベントに対する,低用量アスピリン投与の一次予防効果(WHS):無作為化二重盲検試験」
    大森 司, 苅尾 七臣 ()
    International Review of Thrombosis 2006年
  • アスピリンは全ての症例に効くわけではない-アスピリン抵抗性の問題,評価,いかに克服するか?
    大森 司 ()
    臨床現場におけるアスピリン使用の実際 南江堂 2006年
  • 血液凝固・線溶系へ及ぼすアスピリンの影響【アスピリンのpleiotropic action】
    大森 司, 坂田 洋一 ()
    炎症と免疫 2006年
  • 線溶分子マーカー
    大森 司, 坂田 洋一 ()
    血栓症ナビゲーター メディカルレビュー社 2005年
  • プラスミン/プラスミノゲンアクチベーター
    大森 司,坂田 洋一 ()
    メディカルレビュー社 2005年
  • 血管内皮傷害のマーカーとして何を測定すべきか? 【アテローム血栓症の病態と対策を探る】
    大森 司, 苅尾 七臣 ()
    Vascular Medicine 2005年
  • アスピリン抵抗性【血液疾患-state of arts Ver.3】
    大森 司 ()
    医学のあゆみ 2005年
  • ADP受容体
    大森 司, 矢冨 裕, 尾崎由基男 ()
    血小板生物学 メディカルレビュー社 2004年
  • 血小板と血管新生
    大森 司, 矢冨 裕 ()
    分子心血管病 2004年
  • 白血球エラスターゼによるフィブリノーゲン-フィブリン分解産物 (E-FDP) 【血栓症検査ガイドブック】
    大森 司, 坂田 洋一 ()
    血栓と循環 2004年
  • フォンヴィレブランド因子【血栓症検査ガイドブック】
    大森 司, 苅尾 七臣 ()
    血栓と循環 2004年
  • 血小板系疾患
    大森 司, 矢冨 裕 ()
    臨床に有用な遺伝子検査 臨床病理レビュー 2002年
  • 血小板における接着斑関連蛋白質の動態
    大森 司 ()
    日本血栓止血学会誌 2001年
  • FAK
    大森 司, 矢冨 裕, 尾崎由基男 ()
    Vascular Biologyナビゲーター メディカルレビュー社 2001年
  • 血管炎症候群
    大森 司, 西岡雄一 ()
    内科 1996年
  • プレドニン
    大森 司, 西岡雄一 ()
    Medicina 1996年
  • 慢性関節リウマチの経過中に大量の消化管出血を来たした続発性アミロイドーシスの一例
    大森 司, 川合耕治, 川口章夫, 稲田俊秀, 土家 清, 石川 るみ, 三枝 修, 平賀寛孝, 高相和彦, 加賀美年秀, 小山敏雄 ()
    山梨県立中央病院年報 1995年
  • その他の先天性凝固異常症・線溶異常症
    大森 司 ()
    血液疾患最新の治療 2014-2016 南江堂
  • 血小板機能検査・凝固線溶系検査
    大森 司 ()
    カラーテキスト血液病学 中外医学社
  • 止血機構
    大森 司 ()
    カラーテキスト血液病学 中外医学社

講演・口頭発表等

  • あたらしい血友病治療.
    大森 司
    第69回日本輸血細胞治療学会学術総会(WEBとのハイブリット開催) 2021年06月
  • アデノ随伴ウイルスベクターをも用いた血友病に対する遺伝子治療
    第20回日本再生医療学会総会(Web開催) 2021年03月
  • 血友病に対する遺伝子治療の現状
    大森 司
    第15回日本血栓止血学会学術標準化委員会シンポジウム(Web開催) 2021年02月
  • 血友病治療のいまとこれから
    大森 司
    北関東ヘモフィリア研究会(Web開催) 2021年02月
  • 血友病に対する遺伝子治療の現状と展望
    大森 司
    EMPOWER2020(Web開催) 2020年11月
  • いちから学ぶ出血傾向
    大森 司
    第82回日本血液学会学術集会(Web開催) 2020年10月
  • 世界と日本における血友病遺伝子治療の現状
    大森 司
    バーチャルヘモフィリアシンポジウム2020(Web開催) 2020年09月
  • 血友病に対する新規治療
    大森 司
    バイエル薬品WEBカンファ(Web開催) 2020年08月
  • 血友病に対する凝固因子補充療法と遺伝子治療
    大森 司
    血友病WEB講演会 2020年07月
  • Increase in the treatment efficacy of genome editing for hemphilia b by codon-optimization of SaCas9 in mice
    Hiramoto T, Hayakawa M, Kamoshita N, Kashiwakura Y, Nhishimasu H, Nureki O, Ohmori T
    Congress The International Society on Thrombosis and Haemostasis 2020年07月 口頭発表(一般)
  • 難治性疾患に対する遺伝子治療の現状と展望
    大森 司
    第44回日本遺伝カウンセリング学会学術集会(Web開催) 2020年07月
  • 血友病の病態解明と治療への応用
    大森 司
    第42回日本血栓止血学会学術集会(Web開催) 2020年07月
  • 血友病に対する遺伝子治療の現状
    大森 司
    第14回日本血栓止血学会学術標準化委員会シンポジウム(紙面発表) 2020年02月
  • 血友病に対する遺伝子治療とゲノム編集治療の進歩
    大森 司
    第61回日本小児血液・がん学会学術集会 2019年11月
  • 血友病治療の進歩から凝固因子カスケードを理解する
    大森 司
    第84回山梨血液研究会 2019年11月
  • 血栓形成機序から学ぶ血栓止血検査
    大森 司
    Sysmex血栓止血セミナー2019 in 新潟 2019年10月
  • 血友病に対する遺伝子治療とゲノム編集治療
    大森 司
    BioJapan2019 2019年10月
  • ついに現実となった遺伝子治療とは
    大森 司
    バイエルヘモフィリアセミナー 2019年10月
  • 血友病の最新治療(分科会)
    大森 司
    ヘモフィリア友の会 全国ネットワーク 2019年09月
  • 血友病治療の“いま”と“これから”
    大森 司
    第25回熊本血友病研究会 2019年09月
  • 血友病治療の遺伝子治療
    大森 司
    栃木血友病懇話会 2019年08月
  • 血友病治療のこれから
    大森 司
    第16回四国血友病治療セミナー 2019年08月
  • Adeno-associated virus vector based on serotype 3 represents an alternative serotype for hemophilia gene therapy.
    Ohmori, T, Mizukami, H, Hishikawa, S, Nakamura, H, Katakai, Y, Muramatsu, S, Ozawa, K, Sakata, Y
    Congress The International Society on Thrombosis and Haemostasis 2019年07月 口頭発表(一般)
  • 血友病治療のこれから
    大森 司
    第19回東海ヘモフィリアワークショップ 2019年06月
  • カニクイザルを用いた血友病性関節症に対する凝固因子発現間葉系幹細胞の安全性評価
    大森 司, 水上 浩明, 片貝 祐子, 川合 創, 中村 仁康, 井上 誠, 朱 亜峰, 杉本 英治, 坂田 洋一
    第41回 日本血栓止血学会学術集会 2019年06月 口頭発表(一般)
  • 血友病治療の“いま”と“これから”
    大森 司
    第14回東北ヘモフィリアセミナー 2019年06月
  • 明日から活かせる血栓止血検査の基礎知識
    大森 司
    シスメックスライブセミナー 2019年05月
  • 血友病治療の“いま”と“これから”
    大森 司
    第19回九州血友病治療懇話会 2019年03月
  • 血友病に対する遺伝子治療・ゲノム編集治療
    大森 司
    自治医科大学GCTR設立記念シンポジウム 2019年02月
  • 血友病のアンメットメディカルニーズに応える未来の治療選択肢
    大森 司
    第13回日本血栓止血学会学術標準化委員会シンポジウム 2019年02月
  • 血友病に対する遺伝子治療の現状と展望
    大森 司
    関東甲信越ブロック医療等相談会 2019年01月
  • 血液はなぜ固まるの?〜出血しやすい病気の最新治療〜
    大森 司
    宇都宮高校学外講義 2018年12月
  • 血友病診療から止血メカニズムを理解する
    大森 司
    中外さいたまオープンカンファレンス 2018年12月
  • みんなで考える未来の血友病診療
    大森 司
    市民公開講座 2018年12月
  • やさしく学ぶ血栓形成のメカニズム
    大森 司
    呼吸器で見る血栓症セミナー 2018年11月
  • 血液凝固反応の理解から血栓症診療の闇を斬る
    大森 司
    さいたまDICフォーラム 2018年11月
  • 血友病遺伝子治療の現状と展望
    大森 司
    第80回日本血液学会学術集会 教育講演 2018年10月
  • 血友病診療から血液凝固の闇を斬る
    大森 司
    第80回日本血液学会学術集会 コーポレートセミナー 2018年10月
  • ゲノム編集による血友病治療の試み
    大森 司
    創薬薬理フォーラム第26回シンポジウム 2018年10月
  • 血友病に対する遺伝子治療の展望
    大森 司
    第91回日本生化学会大会 シンポジウム 2018年09月
  • 血友病遺伝子治療の可能性
    大森 司
    第13回さいたま血友病地域連携ネットワーク 2018年09月
  • 血友病遺伝子治療の可能性
    大森 司
    東北ヘマトロジーネットワーク 2018年09月
  • 臨床医の視点でみる凝固検査
    大森 司
    シスメックスセミナー in さいたま 2018年08月
  • 血友病に対する遺伝子治療の現状と展望
    大森 司
    第7回止血異常懇話会 2018年07月
  • Development of Genome editing treatment for Hemophilia.
    Ohmori T
    The 24th Annual Meeting of Japan Society of Gene and Cell Therapy (Symposium) 2018年07月
  • 血友病に対する遺伝子治療の可能性
    大森 司
    第15回三重県血友病ネットワーク 2018年07月
  • CRISPR/Cas9-mediated Genome Editing for Hemophilia B by AAV vector.
    Ohmori T
    The 10th Congress of Asia Pacific Society on Thrombosis and Hemostasis (Symposium) 2018年06月
  • 血友病に対するin vivoゲノム編集治療
    大森 司
    第3回日本ゲノム編集学会学術集会 2018年06月
  • 血友病のアンメットメディカルニーズを満たす近未来の治療選択肢
    大森 司
    Hemophilia Total Care Seminar in Tokyo 2018年06月
  • ゲノム編集技術による疾患治療戦略
    大森 司
    日本小児神経学会 2018年05月
  • 血友病治療をサイエンスから考える
    大森 司
    第8回血友病東京学術講演会 2018年05月
  • 血液凝固反応から血栓症治療を理解する
    大森 司
    静岡県東部血栓症研究会 2018年03月
  • 血友病Bマウスのゲノム編集による治療法の開発
    大森 司
    第20回ヒューマンサイエンス総合研究ワークショップ 2018年03月
  • 血友病に対する遺伝子治療の可能性
    大森 司
    第12回日本血栓止血学会学術標準化委員会シンポジウム 2018年02月
  • Development of genome editing treatment for haemophilia B by CRISPR/Cas9.
    Ohmori, T, Nagao, Y, Mizukami, H, Sakata, A, Muramatsu, S, Ozawa, K, Tominaga, S, Hanazono, Y, Nishimura, S, Nureki, O, Sakata, Y
    The 9th Takeda Science Foundation Symposium on PharmaSciences 2018年02月 口頭発表(一般)
  • CRISPR/Cas9-mediated Genome Editing for Hemophilia B by AAV vector.
    Ohmori T
    The 5th IMSUT-GGCT Symposium 2018 2018年01月
  • 近未来の血友病治療〜遺伝子治療
    大森 司
    埼玉西部Hemophilia Conference 2017年11月
  • 血友病治療の“いま”と“これから”
    大森 司
    ACC血友病患者会勉強会 2017年09月
  • 血友病遺伝子治療の現状と未来
    大森 司
    関西血友病治療研究会 2017年09月
  • CRISPR/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B in mice.
    Ohmori, T, Nagao, Y, Mizukami, H, Sakata, A, Muramatsu, S, Ozawa, K, Tominaga, S, Hanazono, Y, Nishimura, S, Nureki, O, Sakata, Y
    Congress The International Society on Thrombosis and Haemostasis 2017年07月 口頭発表(一般)
  • 血友病Bに対するin vivoゲノム編集技術の開発
    大森 司
    第8回ゲノム創薬・医療フォーラム談話会 2017年07月
  • 血友病治療をサイエンスから考える
    大森 司
    千葉県凝固研究会 2017年07月
  • 血栓止血学から見た抗血栓療法
    大森 司
    Network Meeting in 峡東 2017年06月
  • The cure for hemophilia B by CRISPR/Cas9-mediated gene editing.
    Ohmori T
    The 23rd Annual Meeting of Japan Society of Gene and Cell Therapy 2017年06月
  • in vivoゲノム編集
    大森 司
    第39回日本血栓止血学会学術集会 2017年06月
  • CRISPR/Cas9-mediated genome editing using AAV vector improves hemostasis in a mouse model of haemophilia B.
    Ohmori, T
    The 8th Japanese Society of Hematology International Symposium 2017. 2017年05月 口頭発表(一般)
  • CRISPR/Cas9-Mediated Genome Editing using an AAV8 Vector Improves Hemostasis in a Mouse Model of Hemophilia B in vivo
    Ohmori T
    The 25thUS-Japan Cellular and Gene Therapy Conference 2017年05月
  • 静脈血栓症診断のための臨床検査のポイント
    大森 司
    静岡県東部血栓症研究会 2017年02月
  • 血友病治療をサイエンスから考える
    大森 司
    山形血液グループ研修会 2016年12月
  • 血友病治療をサイエンスから考える
    大森 司
    日本血栓止血学会教育セミナー 2016年10月
  • DOACs Update 2016
    大森 司
    Werfen血液凝固セミナー in Tokyo 2016 2016年10月
  • 血友病遺伝子治療の可能性
    大森 司
    バクスアルタWeb講演会 2016年10月
  • 血友病遺伝子治療の現状と展望
    大森 司
    第38回 日本血栓止血学会学術集会 教育講演 2016年06月
  • 血友病遺伝子治療の現状と展望
    大森 司
    平成28年度日本生化学会関東支部例会 ミニシンポジウム 遺伝子治療UP TO DATE 2016年06月
  • Forkhead box転写因子Foxf1aは血小板インテグリンの発現・機能に関与しない
    大森 司, 西村 智, 富永 眞一
    平成28年度 日本生化学会関東支部例会 2016年06月 口頭発表(一般)
  • 血友病遺伝子治療の可能性
    大森 司
    奈良県立医科大学小児科学教室主催 特別講演 2016年05月
  • ひとめでわかる血栓症のいろは
    大森 司
    第94回地域学術研究会(黒須病院・バイエル薬品株式会社・塩谷郡市医師会) 2016年05月
  • ひとめみておぼえて帰ろう止血機構〜抗血栓薬を理解して使用するために〜
    大森 司
    静岡県東部血栓症研究会 2016年02月
  • ひとめでわかる凝固カスケードの仕組み〜日常診療で抗血栓薬を理解して使用するために〜
    大森 司
    第237回日本循環器学会関東甲信越地方会 2015年09月
  • 血友病の遺伝子治療と今後の展望
    大森 司
    第6回新潟ヘモフィリアセミナー 2015年07月
  • ひと目で分かる凝固カスケードの機序
    大森 司
    エリキュース発売2周年セミナー 2015年07月
  • 抗血栓療法の功罪
    大森 司
    第35回甲信血液血管セミナー 2015年07月
  • 血小板機能異常症の病態と診断へのアプローチ
    大森 司
    第16回日本検査血液学会学術集会 2015年07月
  • New approaches to gene and cell therapy for hemophilia
    Ohmori T
    The 25th Congress of the International Society on Thrombosis and Haemostasis 2015年06月
  • 日常診療に役立つ血栓止血検査の見方と考え方
    大森 司
    第9回SIRS−DIC研究会 2015年06月
  • 血友病Aに対するアデノ随伴ウイルスベクターを用いた遺伝子治療法の開発
    大森 司, 水上 浩明, 片貝 祐子, 坂田 飛鳥, 小澤 敬也, 坂田 洋一, 西村 智
    第37回 日本血栓止血学会学術集会 2015年05月 口頭発表(一般)
  • ACSと抗血小板薬
    大森 司
    Alliance for Revolution and International Cardiology Advancement 2014年11月
  • 抗血栓薬の功罪〜治療効果と出血リスクのエビデンス
    大森 司
    東山梨プライマリーケア学術講演会 2014年10月
  • 出血性疾患の診断と治療
    大森 司
    御茶ノ水血液セミナー 2014年09月
  • 血友病遺伝子治療の最先端と展望
    大森 司
    第5回岐阜血友病治療ネットワーク 2014年09月
  • 新規抗凝固薬の基礎と臨床
    大森 司
    峡東Expert Meeting 2014年08月
  • 新規経口抗凝固薬の基礎と臨床
    大森 司
    第4回栃木総合診療研究会 2014年06月
  • ITPの病態とITP治療におけるTPO受容体作動薬の役割
    大森 司
    第36回日本血栓止血学会学術集会 2014年05月
  • 実地医家のための出血性疾患の診断と治療
    大森 司
    第529回甲府市内科医会 2014年04月
  • 新規抗凝固薬の基礎と臨床
    大森 司
    南巨摩プラザキサ講演会 2014年04月
  • 出血性疾患の診断と治療へのアプローチ
    大森 司
    第4回長崎血液疾患エキスパートミーティング 2013年11月
  • 血友病研究の魅力
    大森 司
    第1回日本血栓止血学会教育セミナー 2013年10月
  • 出血性疾患の診断アプローチ
    大森 司
    第75回日本血液学会学術集会(教育講演) 2013年10月
  • 遺伝子改変血小板の作製とその応用
    大森 司
    第4回血小板巨核球学術講演会 2013年09月
  • 血友病の次世代治療研究の最前線—遺伝子治療の最前線
    大森 司
    コージネイト発売20周年記念ウェブセミナー企画 2013年07月
  • Development of a cell-based therapy for treating hemophoilic arthropathy by local injection of transduced MSCs.
    Ohmori T
    第35回日本血栓止血学会学術集会 SPCシンポジウム 2013年05月
  • 血清パラオキソナーゼ活性は抗血小板薬投与下の凝集能と関連しない
    大森 司, 矢野 裕一郎, 坂田 飛鳥, 池本 智一, 新保 昌久, 窓岩 清治, 勝木 孝明, 三室 淳, 島田 和幸, 苅尾 七臣, 坂田 洋一
    第34回日本血栓止血学会学術集会 2012年06月 口頭発表(一般)
  • Application of lentiviral vectors to therapies for inherited bleeding disorders and research into blood cell signal transduction.
    Ohmori T
    Aso International Meeting 2011年07月
  • Platelet-directed gene therapy for hemophilia by lentiviral vector
    Ohmori T
    The 6th Congress of Asia Pacific Society on Thrombosis and Haemostasis 2010年10月
  • Vinculin is indispensable factor for repopulation by hematopoietic stem cells.
    大森 司, 柏倉 祐志, 石渡 彰, 窓岩 清治, 三室 淳, 古川 祐介, 坂田 洋一
    第72回日本血液学会総会 2010年09月 口頭発表(一般)
  • Silencing of a targeted protein in platelets using a lentiviral vector delivering short hairpin RNA sequence.
    Ohmori T, Kashiwakura Y, Ishiwata A, Madoiwa S, Mimuro J, Sakata Y
    The 16th annual meeting Japan Society of Gene Therapy 2010年07月 口頭発表(一般)
  • The chicken hypersensitive site-4 chromatin insulator sequence protects clonal dominance of hematopoietic stem cells transduced with a self-inactivating SIV vector in platelet-directed gene therapy.
    Ohmori T, Kashiwakura Y, Ishiwata A, Madoiwa S, Akiba E, Hasegawa M, Mimuro J, Ozawa K, Sakata Y
    The 16th annual meeting Japan Society of Gene Therapy 2010年07月 口頭発表(一般)
  • 抗血小板薬抵抗性の臨床
    大森 司
    栃木県臨床循環器懇話会 2010年05月
  • 中数神経損傷とスフィンゴシン1-リン酸
    大森 司
    東京脂質懇話会 2010年04月
  • Vinculinha巨核球分化とインテグリンαIIbβ3の活性化に関与する
    大森 司, 柏倉 裕志, 石渡 彰, 窓岩 清治, 三室 淳, 坂田 洋一
    第33回日本血栓止血学会学術集会 2010年04月 口頭発表(一般)
  • レンチウイルスベクターを用いた遺伝子改変血小板の作製
    大森 司
    近畿血栓症研究会 2009年10月
  • Platelet-directed Gene Modification by Lentiviral Vector: Application to Therapies for Inherited Bleeding Disorders and Research into Platelet Signal Transduction
    大森 司, 窓岩 清治, 三室 淳, 坂田 洋一
    第71回日本血液学会総会 2009年10月
  • 抗血小板薬抵抗性の臨床.新潟血栓止血研究会
    大森 司
    新潟血栓止血研究会 2009年06月
  • GPIbα近傍のクロマチンインスレーター配列の同定
    大森 司, 柏倉 裕志, 石渡 彰, 窓岩 清治, 三室 淳, 秋葉, 英治, 長谷川 護, 坂田 洋一
    第32回日本血栓止血学会学術集会 2009年06月 口頭発表(一般)
  • クロマチンインスレーター挿入による安全性を高めた血小板への遺伝子導入法
    大森 司, 柏倉 裕志, 石渡 彰, 窓岩 清治, 三室 淳, 秋葉, 英治, 長谷川 護, 坂田 洋一
    第31回日本血栓止血学会学術集会 2008年11月 口頭発表(一般)
  • 血小板への活性型血液凝固第VII因子の発現による血友病遺伝子治療
    大森 司, 窓岩 清治, 柏倉 裕志, 石渡 彰, 秋葉 英治, 長谷川 護, 三室 淳, 坂田 洋一
    第69回日本血液学会総会 2008年10月 口頭発表(一般)
  • 抗血小板薬抵抗性の機序
    大森 司
    Japan Thrombosis Forum 2008年02月
  • レンチウイルスベクターを用いた血小板蛋白のノックダウン
    大森 司, 柏倉 裕志, 石渡 彰, 窓岩 清治, 三室 淳, 坂田 洋一
    第30回日本血栓止血学会学術集会 2007年11月 口頭発表(一般)
  • レンチウイルスベクターを用いた血小板蛋白の発現調節
    大森 司
    血液科学セミナー 2007年11月
  • 抗血小板薬抵抗性の基礎と臨床
    大森 司
    神奈川カルディアックセミナー 2006年12月
  • アスピリンレジスタンス
    大森 司
    第29回日本血栓止血学会学術集会(動脈硬化学会合同シンポジウム) 2006年11月
  • 血液凝固第VII因子の発現による止血反応を強化した血小板の作成
    大森 司, 高野 勝弘, 見供 克之, 窓岩 清治, 柏倉 裕志, 石渡 彰, 新村 真則, 諏合 輝子, 長谷川 護, 三室 淳, 坂田 洋一
    第29回日本血栓止血学会学術集会 2006年11月 口頭発表(一般)
  • 日本人におけるアスピリン感受性の差異:臨床予後との関連
    大森 司, 矢冨 裕, 窓岩 清治, 諏合 輝子, 三室 淳, 浅妻 直樹, 尾崎 由基男, 坂田 洋一
    第28回日本血栓止血学会学術集会 2005年11月 口頭発表(一般)
  • SIVベクターとGPIbaプロモータを用いた血小板特異的なin vivo遺伝子導入:血小板を標的とした血友病遺伝子治療への応用
    大森 司, 高野 勝弘, 見供 克之, 窓岩 清治, 柏倉 裕志, 石渡 彰, 新村 真則, 諏合 輝子, 長谷川 護, 三室 淳, 坂田 洋一
    第28回日本血栓止血学会学術集会 2005年11月 口頭発表(一般)
  • 市販漢方薬“寿位”による血小板減少症
    大森 司, 西井 清行, 萩原 淳, 関戸 清貴, 窓岩 清治, 諏合 輝子, 三室 淳, 坂田 洋一
    第27回日本血栓止血学会学術集会 2004年11月 口頭発表(一般)
  • スフィンゴシン 1-リン酸による血管内皮細胞Casのチロシンリン酸化:細胞運動への関与
    大森 司, 矢冨 裕, 長田 誠, 尾崎 由基男
    第24回日本血栓止血学会学術集会 2001年11月 口頭発表(一般)
  • Wheat germ agglutinin-induced platelet activation via platelet endothelial cell adhesion molecule-1: involvement of rapid phospholipase Cg2 activation by Src family kinases .
    Ohmori T, Yatomi Y, Ozaki Y
    XVIII Congress The International Society on Thrombosis and Haemostasis 2001年07月 口頭発表(一般)
  • リゾリン脂質による細胞骨格再編成:ヒト臍帯静脈内皮細胞を用いた検討
    大森 司, 矢冨 裕, 長田 誠, 尾崎由基男
    第73回日本生化学学会大会 2000年10月 口頭発表(一般)
  • WGAとコラーゲンによるチロシンリン酸化反応の差異
    大森 司, 矢冨 裕, 佐藤金夫, 尾崎由基男
    第62回日本血液学会総会 2000年03月 口頭発表(一般)
  • レクチンWGAによる血小板活性化に伴うチロシンリン酸化反応
    大森 司, 矢冨 裕, 井上 克枝, 佐藤 金夫, 尾崎 由基男
    第22回日本血栓止血学会学術集会 1999年12月 口頭発表(一般)
  • 血小板におけるCasのチロシンリン酸化
    大森 司, 矢冨 裕, 井上 克枝, 佐藤 金夫, 尾崎 由基男
    第72回日本生化学学会大会 1999年10月 口頭発表(一般)
  • Tyrosine dephosphorylation, but not phosphorylation, of p130Cas is dependent on integrin IIb3-mediated aggregation in platelets: implication of p130 Cas involvement in pathways unrelated to cytoskeletal reorganization.
    Ohmori, T, Yatomi, Y, Inoue, K, Satoh, K, Ozaki, Y
    XVII Congress The International Society on Thrombosis and Haemostasis 1999年08月 口頭発表(一般)
  • 血小板におけるCasのチロシンリン酸化
    大森 司, 矢冨 裕, 佐藤金夫, 尾崎由基男
    第61回日本血液学会総会 1999年04月 口頭発表(一般)
  • 血小板におけるPYK2, FAKの動態の比較
    大森 司, 矢冨 裕, 佐藤 金夫, 浅妻 直樹, 尾崎 由基男
    第21回日本血栓止血学会学術集会 1998年09月 口頭発表(一般)
  • 血小板PYK2のリン酸化と凝集との関係
    大森 司, 矢富 裕, 佐藤 金夫, 浅妻 直樹, 尾崎 由基男
    第60回日本血液学会総会 1998年03月 口頭発表(一般)

MISC

  • HAYAKAWA Morisada, SAKATA Asuka, FUKUSHIMA Noriyoshi, NISHIMURA Satoshi, SAKATA Yoichi, OHMORI Tsukasa 臨床血液 58 (9) 1456 2017年09月 [査読無し][通常論文]
  • 血友病遺伝子治療の現状と展望
    大森 司, 水上 浩明, 三室 淳, 菱川 修司, 坂田 飛鳥, 柏倉 裕志, 石渡 彰, 安本 篤史, 窓岩 清治, 小澤 敬也, 坂田 洋一, 西村 智 日本血栓止血学会誌 27 (2) 133 -133 2016年05月 [査読無し][通常論文]
  • 複数の生体モデルを使用した抗血栓薬の多面的評価系の構築
    坂田 飛鳥, 大森 司, 永野 達哉, 瀬尾 欣也, 西村 智 日本血栓止血学会誌 26 (2) 186 -186 2015年04月 [査読無し][通常論文]
  • 血友病Aインヒビターの制御を目的した人工多能性幹細胞による遺伝子細胞療法の開発
    窓岩 清治, 坂田 飛鳥, 大森 司, 伊藤 恒敏, 谷口 伸行, 坂田 洋一 日本血栓止血学会誌 26 (2) 192 -192 2015年04月 [査読無し][通常論文]
  • 血友病Aに対するアデノ随伴ウイルスベクターを用いた遺伝子治療法の開発
    大森 司, 水上 浩明, 片貝 裕子, 坂田 飛鳥, 小澤 敬也, 坂田 洋一, 西村 智 日本血栓止血学会誌 26 (2) 201 -201 2015年04月 [査読無し][通常論文]
  • 【血液凝固の制御機構と臨床応用への展望】 Tissue factor pathway inhibitor(TFPI)の基礎
    坂田 飛鳥, 大森 司 日本血栓止血学会誌 25 (1) 5 -10 2014年02月 [査読無し][通常論文]
     
    TFPIは外因系凝固反応を抑制する生理的なセリンプロテアーゼインヒビターである.TFPIは主に血管内皮上で作用し,TFPI・FXa複合体がTF・FVIIa複合体に結合することで外因系凝固反応開始を抑制する.3つのKunitz型ドメインを有し,K1とK2がそれぞれFVIIa,FXaと結合し活性を阻害する.TFPIの抗凝固能の完全な発揮にFXaを必要とすることは,生じた血栓に応じた凝固制御反応に重要と考えられる.また,TFPIによる凝固制御が個体発生に重要な役割を持つこと,ならびにTFPIが直接的に血管構成細胞の増殖制御を引き起こすこと等が示唆されている.(著者抄録)
  • PaxillinはRap1bの修飾を介して血小板活性化を負に制御する
    坂田 飛鳥, 大森 司, 西村 智, 鈴木 英紀, 窓岩 清治, 三室 淳, 苅尾 七臣, 坂田 洋一 日本血栓止血学会誌 24 (2) 181 -181 2013年04月 [査読無し][通常論文]
  • 血友病Aクローンブタ
    柏倉 裕志, 三室 淳, 大西 彰, 岩元 正樹, 窓岩 清治, 淵本 大一郎, 鈴木 俊一, 鈴木 美佐枝, 千本 昭一郎, 石渡 彰, 安本 篤史, 坂田 飛鳥, 大森 司, 橋本 径子, 矢崎 智子, 坂田 洋一 日本血栓止血学会誌 24 (2) 227 -227 2013年04月 [査読無し][通常論文]
  • 清水 徹一郎, 堀江 久永, 細谷 好則, 佐田 尚宏, 安田 是和, 窓岩 清治, 大森 司, 三室 淳, 篠原 貴子, 丹羽 康則 日本外科学会雑誌 114 (2) 882 -882 2013年03月
  • 清水 徹一郎, 堀江 久永, 細谷 好則, 佐田 尚宏, 安田 是和, 窓岩 清治, 大森 司, 三室 淳, 篠原 貴子, 丹羽 康則 日本外科学会雑誌 114 (2) 2013年03月 [査読無し][通常論文]
  • 大橋一夫, 辰巳公平, 沈仁卿, 渡辺夏巳, 柏倉裕志, 大森司, 坂田洋一, 井上誠, 岡野光夫 再生医療 12 174 2013年02月 [査読無し][通常論文]
  • 重症患者の凝固線溶系異常とその対策 エキスパートの管理 血液凝固線溶系と敗血症
    窓岩 清治, 小山 寛介, 坂田 飛鳥, 大森 司, 三室 淳, 坂田 洋一 日本集中治療医学会雑誌 20 (Suppl.) 266 -266 2013年01月 [査読無し][通常論文]
  • 大森 司 日本血栓止血学会誌 24 (1) 17 -29 2013年 [査読無し][通常論文]
  • 窓岩 清治, 牧野 伸子, 大森 司, 三室 淳, 坂田 洋一 日本血栓止血学会誌 24 (5) 485 -490 2013年 [査読無し][通常論文]
  • 清水徹一郎, 窓岩清治, 大森司, 三室淳, 堀江久永, 細谷好則, 佐田尚宏, 安田是和 日本臨床外科学会雑誌 73 589 2012年10月 [査読無し][通常論文]
  • 人工多能性幹細胞を用いた新規血友病治療法に対する基礎的検討
    柏倉 裕志, 大森 司, 坂田 飛鳥, 窓岩 清治, 井上 誠, 長谷川 護, 三室 淳, 坂田 洋一 臨床血液 53 (9) 1406 -1406 2012年09月 [査読無し][通常論文]
  • 渡辺夏巳, 大橋一夫, 辰巳公平, 鵜頭理恵, 沈仁卿, 鐘ケ江佳寿子, 柏倉裕志, 大森司, 坂田洋一, 井上誠, 岡野光夫 再生医療 11 161 2012年05月 [査読無し][通常論文]
  • 敗血症性DICにおける血小板減少の予測因子としての凝固・線溶系マーカーの評価
    小山 寛介, 窓岩 清治, 坂田 飛鳥, 大森 司, 三室 淳, 坂田 洋一 日本血栓止血学会誌 23 (2) 194 -194 2012年04月 [査読無し][通常論文]
  • 第VIII因子感作血友病Aマウスにおけるマイクロポートを用いた連続的抗原投与モデルの構築
    窓岩 清治, 小林 英司, 坂田 飛鳥, 柏倉 裕志, 大森 司, 三室 淳, 坂田 洋一 日本血栓止血学会誌 23 (2) 197 -197 2012年04月 [査読無し][通常論文]
  • FVIII遺伝子導入MSCの関節内移植は血友病Aマウスの血友病性関節症を改善する
    柏倉 裕志, 大森 司, 三室 淳, 安本 篤志, 石渡 彰, 坂田 飛鳥, 窓岩 清治, 井上 誠, 長谷川 護, 小澤 敬也, 坂田 洋一 日本血栓止血学会誌 23 (2) 198 -198 2012年04月 [査読無し][通常論文]
  • 血清パラオキソナーゼ活性は抗血小板薬投与下の凝集能と関連しない
    大森 司, 矢野 裕一郎, 坂田 飛鳥, 池本 智一, 新保 昌久, 窓岩 清治, 勝木 孝明, 三室 淳, 島田 和幸, 苅尾 七臣, 坂田 洋一 日本血栓止血学会誌 23 (2) 200 -200 2012年04月 [査読無し][通常論文]
  • 敗血症性DIC 下部消化管穿孔における凝固障害の特徴
    小山 寛介, 窓岩 清治, 坂田 飛鳥, 大森 司, 三室 淳, 坂田 洋一 日本血栓止血学会誌 23 (2) 227 -227 2012年04月 [査読無し][通常論文]
  • 大森 司 日本血栓止血学会誌 23 (1) 51 -54 2012年 [査読無し][通常論文]
  • 渡辺夏巳, 大橋一夫, 辰巳公平, 鵜頭理恵, 柏倉裕志, 大森司, 坂田洋一, 井上誠, 長谷川護, 岡野光夫 再生医療 10 218 2011年02月 [査読無し][通常論文]
  • 大森 司, 窓岩 清治, 三室 淳, 坂田 洋一 臨床血液 51 (8) 625 -631 2010年08月 [査読無し][通常論文]
  • Vinculinは巨核球分化とintegrin αIIbβ3の活性化に関与する
    大森 司, 柏倉 祐志, 石渡 彰, 坂田 飛鳥, 安本 篤史, 窓岩 清治, 三室 淳, 本田 繁則, 宮田 敏行, 坂田 洋一 日本血栓止血学会誌 21 (2) 191 -191 2010年04月 [査読無し][通常論文]
  • 肝移植におけるバイオマーカーに与える急性細胞性拒絶反応の影響(Impact of acute cellular rejection on biomarkers in liver transplantation)
    三室 淳, 水田 耕一, 川野 陽一, 菱川 修司, 浜野 明栄, 柏倉 裕志, 石渡 彰, 坂田 飛鳥, 安本 篤史, 大森 司, 窓岩 清治, 河原崎 秀雄, 坂田 洋一 日本血栓止血学会誌 21 (2) 199 -199 2010年04月 [査読無し][通常論文]
  • 非ヒト霊長類を用いた血友病B遺伝子治療研究 末梢静脈投与AAV8ベクターによる第IX因子遺伝子導入
    石渡 彰, 三室 淳, 水上 浩明, 小野 文子, 安本 篤史, 坂田 飛鳥, 柏倉 裕志, 大森 司, 窓岩 清治, 久米 晃啓, 保富 康宏, 小澤 敬也, 坂田 洋一 日本血栓止血学会誌 21 (2) 204 -204 2010年04月 [査読無し][通常論文]
  • 非ヒト霊長類を用いた血友病A遺伝子治療研究に向けたヒトBDDFVIII特異的検出法の確立
    柏倉 裕志, 三室 淳, 石渡 彰, 安本 篤史, 坂田 飛鳥, 大森 司, 窓岩 清治, 水上 浩明, 小野 文子, 小澤 敬也, 坂田 洋一 日本血栓止血学会誌 21 (2) 204 -204 2010年04月 [査読無し][通常論文]
  • 大森 司 日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 20 (6) 569 -570 2009年12月 [査読無し][通常論文]
  • 岡部 寛, 鈴木 隆浩, 大森 司, 森 政樹, 上原 英輔, 畑野 かおる, 上田 真寿, 松山 智洋, 外島 正樹, 尾崎 勝俊, 永井 正, 室井 一男, 小澤 敬也 臨床血液 50 (11) 1626 -1629 2009年11月 [査読無し][通常論文]
  • 大森 司 日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 19 (6) 767 -773 2008年12月 [査読無し][通常論文]
  • 大森 司 日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 19 (4) 456 -458 2008年08月 [査読無し][通常論文]
     
    Point(1)血小板の初期粘着には血小板上の糖タンパクGPIb/IX/V,凝集にはGPIIb/IIIaが重要である.(2)血小板数に疑問が生じた際にはスメアで確認する.(3)出血時間は血小板の数や機能の異常だけでなく,VWFの異常や血管の脆弱性にも左右される.(4)血小板機能検査のゴールドスタンダードは透過度法である.
  • 大森 司 日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 19 (4) 504 -509 2008年08月 [査読無し][通常論文]
  • 大森 司, 苅尾 七臣 日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 17 (6) 649 -663 2006年12月 [査読無し][通常論文]
  • 大森 司 日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 17 (5) 2006年10月 [査読無し][通常論文]

受賞

  • 2018年 自治医科大学優秀論文賞
  • 2018年 武田医学振興財団薬科学シンポジウム褒賞金受賞
  • 2017年 日本血液学会国際シンポジウムOral Presentation Award Platinum
  • 2012年 自治医科大学優秀論文賞
  • 2010年 自治医科大学優秀論文賞
  • 2008年 自治医科大学優秀論文賞
  • 2007年 自治医科大学優秀論文賞
  • 2007年 血液血管オルビス優秀賞
  • 2006年 血液血管オルビス最優秀賞
  • 2000年 日本血栓止血学会学術奨励賞受賞

委員歴

  • 2020年06月 - 現在   日本血栓止血学会   理事
  • - 現在   日本血栓止血学会   代議員
  • - 現在   臨床血液   編集委員
  • - 現在   日本血液学会   代議員
  • 日本血液学会   教育委員
  • 日本血液学会   診療委員
  • 日本血液学会   プログラム委員

担当経験のある科目

  • 血液学 BSL クルズス
  • 血液学 系統講義
  • 病態生化学(2年生)
  • 生化学実習(1年生)


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