FUJITA Mitsugu

    Department of Medicine Associate Professor
Last Updated :2024/03/24

Researcher Information

Degree

  • Ph.D.(2005/03 Nagoya University)
  • M.D.(1997/03 Nagoya University)

Researcher ID

  • A-6690-2009

J-Global ID

Profile

  • Mitsugu Fujita received his medical degree in 1997 from Nagoya University School of Medicine, where he became interested in the central nervous system and brain diseases. He completed his internship in 1999 and neurosurgical residency in 2001 at Nagoya Daini Red Cross Hospital, Nagoya, Japan and has been certified by the Board of Neurosurgery in Japan in 2003. He has also received his Ph.D. degree in Neurosurgery from Nagoya University Graduate School of Medicine in 2004, where he began to dedicate himself to brain tumor research. Fujita held the position of Neurosurgeon-in-Chief at Konan Kosei Hospital, Aichi, Japan until he joined the Department of Neurological Surgery at the University of Pittsburgh, PA as a Visiting Research Associate in 2006. He was promoted to Research Instructor in 2008 and Assistant Professor in 2009. When he came back to Japan, he was appointed Section Head of Immunology and Neurosurgery at Aichi Cancer Center, Nagoya, Japan in 2011. Since 2012, he has worked as Associate Professor of Microbiology at Kindai University Faculty of Medicine, Osaka, Japan. Fujita currently conducts basic and translational research and focuses on brain tumor immunology and immunotherapy. He has investigated the therapeutic significance of T lymphocytes and dendritic cells as therapeutic targets in brain tumors in humans and animal models. His work has recently extended into the field of immune-mediated neurological disorders.

Research Interests

  • Tumor immunology   Brain tumors   

Research Areas

  • Life sciences / Neurosurgery
  • Life sciences / Immunology

Academic & Professional Experience

  • 2021/04 - Today  Kindai University Faculty of MedicineCenter for Medical Education and Clinical TrainingAssociate Professor
  • 2012/04 - 2021/03  Kindai University Faculty of MedicineDepartment of MicrobiologyAssociate Professor
  • 2011/04 - 2012/03  Aichi Cancer CenterDivision of Cancer ImmunologySection Head
  • 2011/02 - 2011/03  Nagoya Daini Red Cross HospitalDepartment of NeurosurgerySenior Neurosurgeon
  • 2009/11 - 2011/01  University of Pittsburgh School of MedicineDepartment of Neurological SurgeryAssistant Professor
  • 2008/11 - 2009/10  University of Pittsuburgh School of MedicineDepartment of Neurological SurgeryResearch Instructor
  • 2006/01 - 2008/10  University of Pittsuburgh School of MedicineDepartment of Neurological SurgeryVisiting Research Associate
  • 1999/04 - 2001/03  Nagoya Daini Red Cross HospitalDepartment of NeurosurgeryNeurosurgeon
  • 1997/04 - 1999/03  Nagoya Daini Red Cross HospitalResident

Education

  • 2001/04 - 2005/03  Nagoya Universty Graduate School of Medicine (Ph.D.)
  • 1991/04 - 1997/03  Nagoya University School of Medicine (M.D.)

Published Papers

  • KEIICHI ISHIHARA; RYUTO SAKODA; MASAKO MIZOGUCHI; MITSUGU FUJITA; CHIAMI MOYAMA; YURI OKUTANI; KAZUYUKI TAKATA; MIWA TANAKA; TAKASHI MINAMI; HARUHIKO SAGO; KAZUHIRO YAMAKAWA; TAKURO NAKAMURA; ERI KAWASHITA; SATOSHI AKIBA; SUSUMU NAKATA
    Anticancer Research Anticancer Research USA Inc. 44 (2) 489 - 495 0250-7005 2024/02
  • Kotaro Tatebayashi; Manabu Shirakawa; Soichiro Abe; Mitsugu Fujita; Shinichi Yoshimura
    Acta neurochirurgica 165 (12) 3799 - 3804 2023/12 
    This report describes a unique case of vascular Ehlers-Danlos syndrome (vEDS) characterized by multiple spontaneous direct carotid-cavernous sinus fistulas (CCF). The patient initially presented with ocular symptoms and was effectively treated with transarterial coil embolization. Five years later, the patient developed recurrent contralateral CCF that required complex endovascular techniques. Genetic testing identified a novel mutation in the COL3A1 gene, confirming the diagnosis of vEDS. This case report provides a near-term perspective on the identification of structural abnormalities in the COL3A1 protein to ensure the safety of endovascular therapy for patients with vEDS.
  • Tomoki Abe; Kimihiro Yamashita; Toru Nagasaka; Mitsugu Fujita; Kyousuke Agawa; Masayuki Ando; Tomosuke Mukoyama; Kota Yamada; Souichiro Miyake; Masafumi Saito; Ryuichiro Sawada; Hiroshi Hasegawa; Takeru Matsuda; Takashi Kato; Hitoshi Harada; Naoki Urakawa; Hironobu Goto; Shingo Kanaji; Hiroaki Yanagimoto; Taro Oshikiri; Tetsuo Ajiki; Takumi Fukumoto; Yoshihiro Kakeji
    Anticancer research 43 (8) 3755 - 3761 2023/08 [Refereed]
     
    BACKGROUND/AIM: In pathology, the digitization of tissue slide images and the development of image analysis by deep learning have dramatically increased the amount of information obtainable from tissue slides. This advancement is anticipated to not only aid in pathological diagnosis, but also to enhance patient management. Deep learning-based image cytometry (DL-IC) is a technique that plays a pivotal role in this process, enabling cell identification and counting with precision. Accurate cell determination is essential when using this technique. Herein, we aimed to evaluate the performance of our DL-IC in cell identification. MATERIALS AND METHODS: Cu-Cyto, a DL-IC with a bit-pattern kernel-filtering algorithm designed to help avoid multi-counted cell determination, was developed and evaluated for performance using tumor tissue slide images with immunohistochemical staining (IHC). RESULTS: The performances of three versions of Cu-Cyto were evaluated according to their learning stages. In the early stage of learning, the F1 score for immunostained CD8+ T cells (0.343) was higher than the scores for non-immunostained cells [adenocarcinoma cells (0.040) and lymphocytes (0.002)]. As training and validation progressed, the F1 scores for all cells improved. In the latest stage of learning, the F1 scores for adenocarcinoma cells, lymphocytes, and CD8+ T cells were 0.589, 0.889, and 0.911, respectively. CONCLUSION: Cu-Cyto demonstrated good performance in cell determination. IHC can boost learning efficiencies in the early stages of learning. Its performance is expected to improve even further with continuous learning, and the DL-IC can contribute to the implementation of precision oncology.
  • Kotaro Tatebayashi; Noriyuki Nakayama; Daisuke Sakamoto; Tomoko Iida; Shun Ono; Ikuo Matsuda; Yukiko Enomoto; Michihiro Tanaka; Mitsugu Fujita; Seiichi Hirota; Shinichi Yoshimura
    Cancers 15 (15) 3800  2023/07 [Refereed]
     
    Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between 1 April 2013 and 31 March 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of the 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angiography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, p = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.
  • Katsuya Okuhata; Mitsugu Fujita; Kenji Nakamura; Yuya Yanagi; Yusuke Sakai; Kazuki Kubo; Hiroyuki Kosaka; Hajime Monzen
    Cureus 15 (1) e34287  2023/01 [Refereed]
     
    Background Coronavirus disease 2019 and other viruses are transmissible by aerosols and droplets from infected persons. This study aimed to develop a portable device that can trap droplets and deactivate viruses, and verify whether the device in an enclosed room can suction droplets and sanitize them using a filter and an ultraviolet-C (UVC) light-emitting diode. Materials and methods The portable device was evaluated by placing it 50 cm away from the droplet initiation point. A particle image velocimetry laser dispersed into a sheet form was used to visualize the droplets splashed on the irradiated sagittal plane and captured using a charge-coupled device camera at 60 frames per second. The images were overlaid and calculated to determine the percentage of the droplets beyond the portable device. Droplets with a particle size larger than 50 µm that dispersed and were deposited more than 100 cm away were measured using a water-sensitive paper. The effect of UVC sanitization on viruses captured by a high-efficiency particulate air (HEPA) filter was determined using a plaque assay. Results The percentage of droplets was 13.4% and 1.1% with the portable device OFF and ON, respectively, indicating a 91.8% reduction. The deposited droplets were 86 pixels and 26 pixels with the portable device OFF and ON, respectively, indicating a 68.7% reduction. The UVC deactivated more than 99% of the viruses on the HEPA filter surface in 5 minutes. Conclusions Our novel portable device can suck and fall the dispersed droplets, and an active virus was not observed on the exhaust side.
  • Tadaaki Morotomi; Hitoshi Nishiwaki; Tomomi Iuchi; Yasuhiro Sanada; Hitomi Nakao; Mitsugu Fujita; Koji Niwa
    Eplasty 23 QA3  1937-5719 2023 [Refereed]
     
    How often do intracranial epidermoid cysts occur?Is a coronary incision necessary?What are the steps of the procedure, difficulties encountered, and process for circumventing those difficulties?What is the follow-up protocol and outcome?
  • Chiami Moyama; Mitsugu Fujita; Hitoshi Okamoto; Hiromi Li; Susumu Nakata
    Cancer genomics & proteomics 20 (2) 195 - 202 2023 [Refereed]
     
    BACKGROUND/AIM: Glioblastoma is the most common and aggressive malignant brain tumor in adults, and glioblastoma stem cells (GSCs) contribute to treatment resistance and recurrence. Inhibition of Stat5b in GSCs suppresses cell proliferation and induces apoptosis. Herein, we investigated the mechanisms of growth inhibition by Stat5b knockdown (KD) in GSCs. MATERIALS AND METHODS: GSCs were established from a murine glioblastoma model in which shRNA-p53 and EGFR/Ras mutants were induced in vivo using a Sleeping Beauty transposon system. Microarray analyses were performed on Stat5b-KD GSCs to identify genes that are differentially expressed downstream of Stat5b. RT-qPCR and western blot analyses were used to determine Myb levels in GSCs. Myb-overexpressing GSCs were induced by electroporation. Proliferation and apoptosis were evaluated by a trypan blue dye exclusion test and annexin-V staining, respectively. RESULTS: MYB, which is involved in the Wnt pathway, was identified as a novel gene whose expression was down-regulated by Stat5b-KD in GSCs. Both MYB mRNA and protein levels were down-regulated by Stat5b-KD. Overexpression of Myb rescued cell proliferation that was suppressed by Stat5b-KD. Furthermore, Stat5b-KD-induced apoptosis in GSCs was significantly inhibited by Myb overexpression. CONCLUSION: Down-regulation of Myb mediates Stat5b-KD-induced inhibition of proliferation and induction of apoptosis in GSCs. This may represent a promising novel therapeutic strategy against glioblastoma.
  • Kota Yamada; Masafumi Saito; Masayuki Ando; Tomoki Abe; Tomosuke Mukoyama; Kyosuke Agawa; Akihiro Watanabe; Shiki Takamura; Mitsugu Fujita; Naoki Urakawa; Hiroshi Hasegawa; Shingo Kanaji; Takeru Matsuda; Taro Oshikiri; Yoshihiro Kakeji; Kimihiro Yamashita
    Cells MDPI AG 12 (1) 86 - 86 2022/12 
    Obesity, a known risk factor for various types of cancer, reduces the number and function of cytotoxic immune cells in the tumor immune microenvironment (TIME). However, the impact of obesity on CD4+ T cells remains unclear. Therefore, this study aimed to clarify the impact of obesity on CD4+ T cells in the TIME. A tumor-bearing obese mouse model was established by feeding with 45% high-fat diet (HFD), followed by inoculation with a colon cancer cell line MC38. Tumor growth was significantly accelerated compared to that in mice fed a control diet. Tumor CD4+ T cells showed a significant reduction in number and an increased expression of programmed death-1 (PD-1), and decreased CD107a expression and cytokine such as IFN-γ and TNF-α production, indicating dysfunction. We further established CD4+ T cell-depleted HFD-fed model mice, which showed reduced tumor infiltration, increased PD-1 expression in CD8+ T cells, and obesity-induced acceleration of tumor growth in a CD4+ T cell-dependent manner. These findings suggest that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells to ultimately accelerate the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity.
  • Masaharu Miyauchi; Mitsugu Fujita; Naohiro Tsuyuguchi; Naoki Nakano; Takayuki Nakao; Amami Kato; Jun C. Takahashi
    Neurosurgery Open 3 (4) e00024  2022/12 [Refereed]
  • Hiromasa Yoshioka; Takeshi Okuda; Takayuki Nakao; Mitsugu Fujita; Jun C Takahashi
    Anticancer research 42 (8) 4173 - 4178 2022/08 [Refereed]
     
    BACKGROUND/AIM: Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based drug therapy and whole-brain radiation therapy. However, there are many cases in which these standard treatment options are not tolerated for various reasons. In the present study, five cases of refractory/relapsed PCNSL that are difficult to treat with standard treatment were successfully treated by tirabrutinib. PATIENTS AND METHODS: A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The reasons why standard treatment cannot be given to these patients are the low KPS, renal dysfunction, and resistance to HD-MTX. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube. RESULTS: Imaging findings showed that the patients achieved a 100% response rate to tirabrutinib, with a median survival of 8 months. As symptoms improved, 2 of the 3 patients who were initially administered tirabrutinib via a nasogastric tube were able to receive the drug via the oral route. Three patients developed adverse reactions; however, treatment was not interrupted because they were manageable. CONCLUSION: Tirabrutinib was effective in the treatment of patients who were unable to receive standard treatment options. Tirabrutinib may be considered one of the novel treatment strategies that could improve the prognosis of PCNSL patients in the future.
  • Ah-Mee Park; Sundar Khadka; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Kazuki Hashiwaki; Ikuo Tsunoda
    Scientific reports 12 (1) 11361  2022/07 [Refereed]
     
    The COVID-19 pandemic has led people to wear face masks daily in public. Although the effectiveness of face masks against viral transmission has been extensively studied, there have been few reports on potential hygiene issues due to bacteria and fungi attached to the face masks. We aimed to (1) quantify and identify the bacteria and fungi attaching to the masks, and (2) investigate whether the mask-attached microbes could be associated with the types and usage of the masks and individual lifestyles. We surveyed 109 volunteers on their mask usage and lifestyles, and cultured bacteria and fungi from either the face-side or outer-side of their masks. The bacterial colony numbers were greater on the face-side than the outer-side; the fungal colony numbers were fewer on the face-side than the outer-side. A longer mask usage significantly increased the fungal colony numbers but not the bacterial colony numbers. Although most identified microbes were non-pathogenic in humans; Staphylococcus epidermidis, Staphylococcus aureus, and Cladosporium, we found several pathogenic microbes; Bacillus cereus, Staphylococcus saprophyticus, Aspergillus, and Microsporum. We also found no associations of mask-attached microbes with the transportation methods or gargling. We propose that immunocompromised people should avoid repeated use of masks to prevent microbial infection.
  • Tadaaki Morotomi; Tomomi Iuchi; Narihiko Hirano; Mitsugu Fujita; Koji Niwa
    International journal of surgery case reports 96 107324  2022/06 [Refereed]
     
    INTRODUCTION AND IMPORTANCE: In our department, we have been performing bone reconstructions on a case-by-case basis using vascularized free tissue transfers and custom-made artificial bones (HA). While these procedures have specific advantages, they are also limited in terms of the invasiveness as well as the stability and strength of implants. In the present study, we describe the use of a CTP to achieve minimally invasive midface plastic surgery with the superior moldability of a 3D structure and reliable stability compared to the use of autologous tissue. CASE PRESENTATION: A total of three patients were included in the study. The patients (all female, ages: 66, 18, and 35 years) had bone malformation or hemifacial microsomia following surgery for maxillary cancer or multiple facial fractures. Based on DICOM data from preoperative CT, 3D models were created on a computer using CAD/CAM techniques. The models were compared in simulations to determine the optimal structure. These 3D models were used in additive manufacturing systems to create custom-made titanium alloy plates for facial reconstruction. CLINICAL DISCUSSION: Although the amount of soft tissue was insufficient in some cases, all patients were able to maintain the desired morphology without developing any complications such as infections, significant soft tissue atrophy, or implant failure. CONCLUSION: Our CTP model created by CAD/CAM was effective in contouring surgery of the midface as it had the superior stability and biocompatibility of titanium. Changes to the soft tissue should also be considered in order to further improve the procedure.
  • Shota Ando; Naoto Kojima; Chiami Moyama; Mitsugu Fujita; Kaito Ohta; Hiromi Ii; Susumu Nakata
    Molecular Medicine Reports Spandidos Publications 26 (1) 238  1791-2997 2022/05
  • Tadaaki Morotomi; Narihiko Hirano; Yasuhiro Sanada; Mitsugu Fujita; Koji Niwa
    Mathews Journal of Ophthalmology 6 (1) 1 - 8 2022/05 [Refereed]
  • Yoji Kuramoto; Mitsugu Fujita; Toshinori Takagi; Yuki Takeda; Nobutaka Doe; Kenichi Yamahara; Shinichi Yoshimura
    Journal of neuroinflammation 19 (1) 48  2022/02 [Refereed]
     
    BACKGROUND: Intracerebral hemorrhage (ICH) is a significant cause of death and disabilities. Recently, cell therapies using mesenchymal stem cells have been shown to improve ICH-induced neurobehavioral deficits. Based on these findings, we designed this study to evaluate the therapeutic efficacy and underlying mechanisms by which human amnion-derived stem cells (hAMSCs) would ameliorate neurobehavioral deficits of ICH-bearing hosts. METHODS: hAMSCs were induced from amnia obtained by cesarean section and administered intravenously to ICH-bearing mice during the acute phase. The mice were then subject to multitask neurobehavioral tests at the subacute phase. We attempted to optimize the dosage and timing of the hAMSC administrations. In parallel with the hAMSCs, a tenfold higher dose of human adipose-derived stem cells (ADSCs) were used as an experimental control. Specimens were obtained from the ICH lesions to conduct immunostaining, flow cytometry, and Western blotting to elucidate the underlying mechanisms of the hAMSC treatment. RESULTS: The intravenous administration of hAMSCs to the ICH-bearing mice effectively improved their neurobehavioral deficits, particularly when the treatment was initiated at Day 1 after the ICH induction. Of note, the hAMSCs promoted clinical efficacy equivalent to or better than that of hADSCs at 1/10 the cell number. The systemically administered hAMSCs were found in the ICH lesions along with the local accumulation of macrophages/microglia. In detail, the hAMSC treatment decreased the number of CD11b+CD45+ and Ly6G+ cells in the ICH lesions, while splenocytes were not affected. Moreover, the hAMSC treatment decreased the number of apoptotic cells in the ICH lesions. These results were associated with suppression of the protein expression levels of macrophage-related factors iNOS and TNFα. CONCLUSIONS: Intravenous hAMSC administration during the acute phase would improve ICH-induced neurobehavioral disorders. The underlying mechanism was suggested to be the suppression of subacute inflammation and apoptosis by suppressing macrophage/microglia cell numbers and macrophage functions (such as TNFα and iNOS). From a clinical point of view, hAMSC-based treatment may be a novel strategy for the treatment of ICH.
  • Shota Ando; Chiami Moyama; Naoto Kojima; Mitsugu Fujita; Kaito Ohta; Yukina Kohno; Hiromi Ii; Susumu Nakata
    Biochemical and biophysical research communications 591 62 - 67 2022/02 [Refereed]
     
    Glioblastoma, a type of brain cancer, is one of the most aggressive and lethal types of malignancy. The present study shows that JCI-20679, an originally synthesized mitochondrial complex I inhibitor, enhances the anti-proliferative effects of suboptimal concentrations of the clinically used chemotherapeutic drug temozolomide in glioblastoma cells. Analysis of the effects of temozolomide combined with JCI-20679 using isobologram and combination index methods demonstrated that the combination had synergistic effects in murine and human glioblastoma cells. We found that JCI-20679 inhibited the temozolomide-mediated induction of autophagy that facilitates cellular survival. The autophagy induced by temozolomide increased ATP production, which confers temozolomide resistance in glioblastoma cells. JCI-20679 blocked temozolomide-mediated increases in ATP levels and increased the AMP/ATP ratio. Furthermore, JCI-20679 enhanced the therapeutic effects of temozolomide in an orthotopic transplantation model of glioblastoma. These results indicate that JCI-20679 may be promising as a novel agent for enhancing the efficacy of temozolomide against glioblastoma.
  • 高齢発症てんかんに対する調査票を用いたスクリーニング効果の検証
    吉岡 宏真; 奥田 武司; 中岡 良介; 藤田 貢; 高橋 淳
    Geriatric Neurosurgery 日本老年脳神経外科学会 35 59 - 63 1343-4233 2022 [Refereed]
  • Chiami Moyama; Mitsugu Fujita; Shota Ando; Keiko Taniguchi; Hiromi Ii; Seisuke Tanigawa; Naoya Hashimoto; Susumu Nakata
    American journal of cancer research 12 (3) 1129 - 1142 2156-6976 2022 [Refereed]
     
    Glioblastoma (GBM) is the most common and malignant type of brain cancer in adults with poor prognosis. GBM stem cells (GSCs) reside within niches in GBM tissues and contribute to recurrence and therapy resistance. Previous studies have shown that expression of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a Wnt pathway-related stem cell marker, correlates with a poor prognosis in GBM, and its knockdown in GSCs induces apoptosis accompanied with downregulation of signal transducer and activator of transcription 5b (Stat5b). Here, we show that Stat5b co-localizes with Lgr5 in hypoxia-inducible factor 2α (Hif2α)-positive regions in GBM tissues. Functional analyses using GSCs derived from a murine de novo GBM model induced by oncogenic genes transduction using the Sleeping-Beauty transposon system revealed that expression of Stat5b was induced by culturing under hypoxia together with Lgr5, repressed by Hif2α knockdown, and reduced by Lgr5 knockdown or a Wnt/β-catenin signaling inhibitor ICG-001 treatment. Stat5b inhibition in the GSCs induced apoptosis and caused downregulation of Cyclin E2 resulted in blockade of entry into S-phase in the cell cycle. Disruption of Stat5b in an orthotopic transplantation model significantly prolongs event-free survival. These results suggest that Stat5b, regulated by hypoxia and the Wnt pathway, plays an important role in the maintenance and tumorigenicity of GSCs and may be a promising therapeutic molecular target to attack GSCs.
  • Akihiro Watanabe; Kimihiro Yamashita; Mitsugu Fujita; Akira Arimoto; Masayasu Nishi; Shiki Takamura; Masafumi Saito; Kota Yamada; Kyosuke Agawa; Tomosuke Mukoyama; Masayuki Ando; Shingo Kanaji; Takeru Matsuda; Taro Oshikiri; Yoshihiro Kakeji
    Cancers 14 (1) 2021/12 [Refereed]
     
    (1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.
  • Hiromasa Yoshioka; Takeshi Okuda; Takayuki Nakao; Mitsugu Fujita; Jun C Takahashi
    International cancer conference journal 10 (4) 290 - 293 2021/10 [Refereed]
     
    We report that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient's level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia.
  • Kyosuke Agawa; Kimihiro Yamashita; Akio Nakagawa; Kouta Yamada; Akihiro Watanabe; Junko Mukohyama; Masafumi Saito; Mitsugu Fujita; Gosuke Takiguchi; Naoki Urakawa; Hiroshi Hasegawa; Shingo Kanaji; Takeru Matsuda; Taro Oshikiri; Tetsu Nakamura; Satoshi Suzuki; Yoshihiro Kakeji
    Anticancer research 41 (8) 4117 - 4126 2021/08 [Refereed]
     
    BACKGROUND/AIM: Cancer stem cells (CSCs) contribute to resistance against neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC). We conducted a retrospective observational study for the relationship between the expression levels of CSC markers in biopsy specimens prior to 5-fluorouracil plus cisplatin (FP)-NAC and the pathological responses. PATIENTS AND METHODS: We included 171 patients with ESCC who underwent the FP-NAC followed by radical resection. Biopsy specimens prior to the FP-NAC were obtained and immunochemically stained for CD44, CD133, and CD24. RESULTS: The biopsy specimens of the non-responders had the CD44high/CD24low expression at high levels, which was found as an independent predictor of not only FP-NAC resistance but also poor overall survival by multivariate analyses. CONCLUSION: CD44high/CD24low expression in the biopsy specimens prior to FP-NAC may be a predictor of FP-NAC resistance and poor prognosis of ESCC patients.
  • Hiromasa Yoshioka; Takeshi Okuda; Takayuki Nakao; Mitsugu Fujita; Jun C Takahashi
    Anticancer research 41 (8) 4169 - 4172 2021/08 [Refereed]
     
    BACKGROUND/AIM: Leptomeningeal carcinomatosis (LMC) with hydrocephalus is particularly difficult to treat, and its prognosis is extremely poor. The therapeutic outcomes of 14 patients with LMC-associated hydrocephalus who were treated with cerebrospinal fluid shunting are reported. PATIENTS AND METHODS: The study subjects were 14 LMC patients with solid primary cancer who had developed hydrocephalus. RESULTS: Postoperatively, both symptoms and Karnofsky performance status improved in 100% of patients. Postoperative therapy consisted of whole-brain radiotherapy in 4 cases and molecular targeted therapy in 4, with 6 patients not receiving any postoperative treatment. Median overall survival was 3.7 months, with no significant difference between those who underwent postoperative therapy and those who did not. However, two of those who received molecular targeted therapy survived for more than one year. CONCLUSION: Cerebrospinal fluid shunting for LMC-associated hydrocephalus is an effective therapeutic procedure from the palliative viewpoint. Patients for whom molecular targeted therapy is indicated may have better long-term survival.
  • Yutaka Sugita; Kimihiro Yamashita; Mitsugu Fujita; Masafumi Saito; Kota Yamada; Kyosuke Agawa; Akihiro Watanabe; Eiji Fukuoka; Hiroshi Hasegawa; Shingo Kanaji; Taro Oshikiri; Takeru Matsuda; Tetsu Nakamura; Satoshi Suzuki; Yoshihiro Kakeji
    Oncology reports 45 (6) 2021/06 [Refereed]
     
    Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloid‑derived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (M‑MDSCs) and polymorphonuclear MDSCs (PMN‑MDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PD‑relevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PD‑relevant TIME. As a result, intraperitoneal PMN‑MDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMN‑MDSCs. In addition, the concentrations of interleukin (IL)‑6 and granulocyte‑colony stimulating factor (G‑CSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMN‑MDSCs. In vivo depletion of the PMN‑MDSCs by anti‑Ly6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4+ and CD8+ T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMN‑MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T‑cell‑based immunotherapy for CRC‑derived PD.
  • Seisuke Tanigawa; Mitsugu Fujita; Chiami Moyama; Shota Ando; Hiromi Ii; Yasushi Kojima; Teruaki Fujishita; Masahiro Aoki; Hayato Takeuchi; Takumi Yamanaka; Yoshinobu Takahashi; Naoya Hashimoto; Susumu Nakata
    Cancer gene therapy 28 (12) 1339 - 1352 2021/01 [Refereed]
     
    The prognosis of glioblastoma remains poor despite intensive research efforts. Glioblastoma stem cells (GSCs) contribute to tumorigenesis, invasive capacity, and therapy resistance. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a stem cell marker, is involved in the maintenance of GSCs, although the properties of Lgr5-positive GSCs remain unclear. Here, the Sleeping-Beauty transposon-induced glioblastoma model was used in Lgr5-GFP knock-in mice identify GFP-positive cells in neurosphere cultures from mouse glioblastoma tissues. Global gene expression analysis showed that Gli2 was highly expressed in GFP-positive GSCs. Gli2 knockdown using lentiviral-mediated shRNA downregulated Hedgehog-related and Wnt signaling pathway-related genes, including Lgr5; suppressed tumor cell proliferation and invasion capacity; and induced apoptosis. Pharmacological Gli inhibition with GANT61 suppressed tumor cell proliferation. Silencing Gli2 suppressed the tumorigenicity of GSCs in an orthotopic transplantation model in vivo. These findings suggest that Gli2 affects the Hedgehog and Wnt pathways and plays an important role in GSC maintenance, suggesting Gli2 as a therapeutic target for glioblastoma treatment.
  • Sundar Khadka; Roshan Pandit; Subhash Dhital; Jagat Bahadur Baniya; Surendra Tiwari; Bimal Shrestha; Sanjeet Pandit; Fumitaka Sato; Mitsugu Fujita; Mukunda Sharma; Ikuo Tsunoda; Shravan Kumar Mishra
    Pathophysiology : the official journal of the International Society for Pathophysiology 27 (1) 3 - 13 2020/12 [Refereed]
     
    Hepatitis B virus (HBV) infects the liver, causing cirrhosis and cancer. In developed countries, five international guidelines have been used to make a decision for the management of patients with chronic HBV infection. In this review, since the guidelines were established by clinical and epidemiological data of developed countries, we aimed to evaluate whether (1) HBV patient profiles of developing countries are similar to developed countries, and (2) which guideline can be applicable to resource-limited developing countries. First, as an example of the most recent data of HBV infections among developing countries, we evaluated the national HBV viral load study in Nepal, which were compared with the data from other developing countries. In Nepal, the highest number of patients had viral loads of 20-2000 IU/mL (36.7%) and belonged to the age group of 21-30 years; HBV epidemiology in Nepal, based on the viral loads, gender, and age groups was similar to those of not only other developing countries but also developed countries. Next, we reviewed five international HBV treatment guidelines of the World Health Organization (WHO), American Association for the Study of Liver Diseases (AASLD), National Institute for Health and Care Excellence (NICE), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). All guidelines require the viral load and alanine aminotransferase (ALT) levels for decision making. Although four guidelines recommend elastography to assess liver cirrhosis, the WHO guideline alternatively recommends using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), which is inexpensive and conducted routinely in most hospitals. Therefore, in resource-limited developing countries like Nepal, we recommend the WHO guideline for HBV treatment based on the viral load, ALT, and APRI information.
  • Takayuki Nakao; Takeshi Okuda; Hiromasa Yoshioka; Mitsugu Fujita
    Anticancer research 40 (8) 4801 - 4804 2020/08 [Refereed]
     
    BACKGROUND/AIM: Recent advances in systemic chemotherapy, including molecularly targeted therapy, have dramatically improved survival for patients with advanced non-small cell lung cancer. We retrospectively analyzed the clinical outcomes of surgical resection for brain metastases of non-small cell lung cancer cases performed at the Department of Neurosurgery of Kindai University Hospital, Osaka, Japan. PATIENTS AND METHODS: Craniotomy and tumor resection were performed for 56 patients with brain metastases of non-small cell lung cancer. Adenocarcinoma was the most common histological type, appearing in 40 cases, of which 18 were positive for driver gene mutations. RESULTS: Median survival for all 56 patients was 14.5 months, and single brain metastasis and adenocarcinoma were identified as favorable prognostic factors. Analysis limited to the 40 cases of adenocarcinoma identified single brain metastasis as a favorable prognostic factor. Although no significant difference was found for systemic chemotherapy, patients who received molecularly targeted therapy showed a better prognosis than those who received cytotoxic chemotherapy. Analyses of both the entire group and of adenocarcinoma patients alone found that whole-brain radiotherapy showed no significant association with survival. CONCLUSION: Single brain metastasis and adenocarcinoma were identified as favorable prognostic factors, but did not confirm any benefit from whole-brain radiotherapy. These results suggest that multimodal treatment strategies utilizing various methods of treatment, including systemic chemotherapy, may help prolong patient survival in the future.
  • Megumi Kubota; Kazuya Ito; Kazuhiko Tomimoto; Mitsuharu Kanazaki; Kei Tsukiyama; Akio Kubota; Haruo Kuroki; Mitsugu Fujita; Yvan Vandenplas
    Nutrients 12 (1) 2020/01 [Refereed]
     
    OBJECTIVE: Chronic functional constipation is a frequent condition. The aim of the study was to evaluate the efficacy of the probiotic Lactobacillus (L.) reuteri DSM 17938 and magnesium oxide (MgO) for relieving chronic functional constipation in children. STUDY DESIGN: A prospective, double-blind, placebo-controlled, randomized, and parallel-group trial was conducted in five pediatric outpatient clinics in Japan. Sixty patients who were more than six months old and under six years of age with a diagnosis of functional constipation according to Rome IV criteria were randomly divided into three groups: group A (n = 20) received L. reuteri DSM 17938 and lactose hydrate as a placebo of MgO; group B (n = 19) received L. reuteri DSM 17938 and MgO; and group C (n = 21) received a placebo of L. reuteri DSM 17938 and MgO. RESULTS: All three groups exhibited significant improvement in defecation frequency in the fourth week compared with the baseline condition (group A: p < 0.05; group B: p < 0.05; group C: p < 0.05). The MgO group and combination group showed a significant decrease in stool consistency, but the L. reuteri DSM 17938 group did not (group A: p = 0.079; group B: p < 0.05; group C: p < 0.05). MgO significantly suppressed the presence of the genus Dialister. Defecation frequency negatively correlated with the frequency of Clostridiales-belonging bacteria among the gut microbiome. CONCLUSIONS: L. rueteri DSM 17938 and MgO were both effective in the management of functional constipation in young children. MgO caused an imbalance in the gastrointestinal microbiome, which was not the case in the probiotic group.
  • Ah-Mee Park; Sundar Khadka; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Daniel K Hsu; Fu-Tong Liu; Ikuo Tsunoda
    Frontiers in immunology 11 550366 - 550366 2020 [Refereed]
     
    Non-steroidal anti-inflammatory drugs (NSAIDs) induce ulcers in the gastrointestinal tract, including the stomach and small intestine. NSAID-induced gastric ulcers can be prevented by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. In contrast, there are no medicines to control NSAID-induced small intestinal ulcers, which are accompanied by a mucosal invasion of bacteria and subsequent activation of immune cells. Galectin-3 (Gal3), an endogenous lectin, has anti-microbial and pro-inflammatory functions. In the small intestine, since Gal3 is highly expressed in epithelial cells constitutively and macrophages inducibly, the Gal3 level can affect microbiota composition and macrophage activation. We hypothesized that the modulation of Gal3 expression could be beneficial in NSAID-induced intestinal ulcers. Using Gal3 knockout (Gal3KO) mice, we determined whether Gal3 could be a therapeutic target in NSAID-induced intestinal ulcers. Following the administration of indomethacin, an NSAID, we found that small intestinal ulcers were less severe in Gal3KO mice than in wild-type (WT) mice. We also found that the composition of intestinal microbiota was different between WT and Gal3KO mice and that bactericidal antibiotic polymyxin B treatment significantly suppressed NSAID-induced ulcers. Furthermore, clodronate, a macrophage modulator, attenuated NSAID-induced ulcers. Therefore, Gal3 could be an exacerbating factor in NSAID-induced intestinal ulcers by affecting the intestinal microbiota population and macrophage activity. Inhibition of Gal3 may be a therapeutic strategy in NSAID-induced intestinal ulcers. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03832946.
  • Seiichi Omura; Fumitaka Sato; Ah-Mee Park; Mitsugu Fujita; Sundar Khadka; Yumina Nakamura; Aoshi Katsuki; Kazuto Nishio; Felicity N E Gavins; Ikuo Tsunoda
    Frontiers in immunology Frontiers Media SA 11 1138 - 1138 2020 [Refereed]
     
    Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.
  • Susumu Nakata; Mitsugu Fujita; Hayao Nakanishi
    Anticancer research 39 (11) 5927 - 5932 0250-7005 2019/11 [Refereed]
     
    BACKGROUND/AIM: Trastuzumab is the only clinically approved targeted therapy for HER2 gene-amplified gastric cancer at present. However, the clinical significance of multi-targeting tyrosine kinase inhibitors (TKIs) in HER2-positive gastric cancer remains unclear. MATERIALS AND METHODS: We examined the anti-tumor activity of lapatinib and afatinib, that are reversible and irreversible TKIs, in HER2 gene-amplified trastuzumab-sensitive and - resistant gastric cancer cells (GLM-1 and GLM-1HerR2) in vitro and in vivo. RESULTS: Afatinib inhibited the growth of GLM-1 and GLM-1HerR2 cells in vitro more efficiently than lapatinib by inducing G1 cell-cycle arrest and apoptosis. Preclinical studies in mice revealed that afatinib inhibited growth of intraperitoneal GLM-1 and subcutaneous GLM-1HerR2 tumor more strongly than lapatinib. Afatinib was more effective than lapatinib in blocking PI3K/Akt and MAPK signaling in both GLM-1 and GLM-1HerR2 cells. CONCLUSION: Afatinib could be a potential new molecular-targeted therapy for trastuzumab-sensitive and trastuzumab-resistant HER2 gene-amplified gastric cancers.
  • Sho Hanakawa; Akihiko Kitoh; Rintaro Shibuya; Teruki Dainichi; Takashi Nomura; Tetsuya Honda; Gyohei Egawa; Atsushi Otsuka; Saeko Nakajima; Mitsugu Fujita; Kenji Kabashima
    The Journal of allergy and clinical immunology 144 (5) 1343 - 1353 0091-6749 2019/11 [Refereed]
     
    BACKGROUND: Percutaneous sensitization is associated with various allergic diseases, including asthma and food allergies. However, the immunologic mechanisms underlying how the skin regulates percutaneous sensitization are still unclear. OBJECTIVE: We aimed to investigate whether and how CD4+Foxp3+ regulatory T (Treg) cells residing in the skin regulate percutaneous sensitization in the skin. METHODS: Selective reduction of numbers of cutaneous Treg cells was achieved by means of intradermal injection of diphtheria toxin into the ear skin of Foxp3DTR mice, in which Treg cells specifically express the diphtheria toxin receptor fused with green fluorescent protein. RESULTS: Thirty percent to 40% of cutaneous Treg cells were capable of IL-10 production in both mice and human subjects. Selective reduction of cutaneous Treg cells at the sensitization site promoted migration of antigen-bearing dendritic cells (DCs) to the draining lymph nodes (dLNs). Accordingly, sensitization through the skin with reduced numbers of Treg cells led to enhanced antigen-specific immune responses in the dLNs, including both effector T-cell differentiation and T cell-dependent B-cell responses, such as the development of germinal center B cells expressing IgG1 and IgE. Furthermore, antigen-bearing cutaneous DC migration was enhanced in mice with IL-10 deficiency restricted to the cutaneous Treg cell compartment, suggesting an important role of cutaneous IL-10+ Treg cells in limiting percutaneous sensitization. Treg cells with a skin-homing phenotype in skin dLNs expressed high levels of IL-10, suggesting that they contribute to renewal and maintenance of the cutaneous IL-10+ Treg cell population. CONCLUSION: Skin-resident Treg cells limit percutaneous sensitization by suppressing antigen-bearing DC migration through in situ IL-10 production.
  • Takeshi Okuda; Mitsugu Fujita; Amami Kato
    Anticancer research 39 (8) 4491 - 4494 0250-7005 2019/08 [Refereed]
     
    BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation. PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens. RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478). CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.
  • Eiji Fukuoka; Kimihiro Yamashita; Tomoko Tanaka; Ryuichiro Sawada; Yutaka Sugita; Akira Arimoto; Mitsugu Fujita; Gosuke Takiguchi; Takeru Matsuda; Taro Oshikiri; Tetsu Nakamura; Satoshi Suzuki; Yoshihiro Kakeji
    Anticancer research 39 (8) 4539 - 4548 0250-7005 2019/08 [Refereed]
     
    BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.
  • Kotaro Tatebayashi; Toshinori Takagi; Mitsugu Fujita; Nobutaka Doe; Takayuki Nakagomi; Tomohiro Matsuyama; Shinichi Yoshimura
    Brain research 1712 139 - 150 0006-8993 2019/06 [Refereed]
     
    INTRODUCTION: We previously established a method to isolate and culture human adipose-derived stem cells (hADSCs) using fetal bovine serum and showed the therapeutic impact on cerebral infarction. Recently, we modified the culture method with the use of serum-free media for future clinical applications. This study aims to evaluate whether intravenous administration of hADSCs induced by the serum-free culture method would improve neurobehavioral deficits in mice with cerebral infarction. RESULTS: Induced hADSCs possessed the characteristics of mesenchymal stem cells and withstood a freeze-thaw process. hADSC administration improved neurobehavioral deficits in MCAO-treated mice and suppressed brain atrophy at the chronic phase. Although hADSC administration did not affect serum cytokine profiles, it decreased the number of CD11b+ monocytes in the spleen. Concomitantly, hADSC administration increased the local accumulation of CD11b+CD163+ M2 macrophages into the border zone of the cerebral infarction at 4 days post-MCAO (the acute phase). DISCUSSION: Our data indicate that the systemic administration of hADSCs can improve the neurobehavioral deficits that occur after cerebral infarction by modulating the acute immune response mediated by CD11b+CD163+ M2 macrophages in infarcted lesions.
  • Yoji Kuramoto; Toshinori Takagi; Kotaro Tatebayashi; Mikiya Beppu; Nobutaka Doe; Mitsugu Fujita; Shinichi Yoshimura
    Brain research 1711 58 - 67 0006-8993 2019/05 [Refereed]
     
    Even today, intracerebral hemorrhage (ICH) is a major cause of death and disabilities. Rehabilitation is preferentially applied for functional recovery although its effect is limited. Recent studies have suggested that intravenous administration of mesenchymal stem cells would improve the post-ICH neurological deficits. Human adipose-derived stem cells (hADSCs) have been established in our laboratory. We aimed to evaluate the therapeutic efficacy of the hADSCs on the post-ICH neurological deficits using a clinical-relevant ICH mouse model. We also evaluated immune responses to clarify the underlying mechanisms. The hADSCs expressed MSC markers at high levels. The hADSCs administration into the ICH-bearing mice improved the neurological deficits during the subacute phases, which was shown by neurobehavioral experiments. Besides, the hADSC administration decreased the number of CD11+CD45+ cells and increased the proportion of CD86+ and Ly6C+ cells in the ICH lesions. In summary, intravenous administration of hADSCs during the acute phase improved ICH-induced neurological deficits during the subacute phase because of the suppression of acute inflammation mediated by CD11+CD45+ subpopulations. Our data suggest that hADSCs can be served as a novel strategy for ICH treatment.
  • Daisuke Sakamoto; Toshinori Takagi; Mitsugu Fujita; Seiichi Omura; Yasunori Yoshida; Tomoko Iida; Shinichi Yoshimura
    Anticancer research 39 (2) 597 - 607 0250-7005 2019/02 [Refereed]
     
    BACKGROUND: Glioma stem cells (GSCs) play important roles in the tumorigenesis of glioblastoma multiforme (GBM). Using a novel cellular bioinformatics pipeline, we aimed to characterize the differences in gene-expression profiles among GSCs, U251 (glioma cell line), and a human GBM tissue sample. MATERIALS AND METHODS: Total RNA was extracted from GSCs, U251 and GBM and microarray analysis was performed; the data were then applied to the bioinformatics pipeline consisting of a principal component analysis (PCA) with factor loadings, an intracellular pathway analysis, and an immunopathway analysis. RESULTS: The PCA clearly distinguished the three groups. The factor loadings of the PCA suggested that v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), dipeptidyl-peptidase 4 (DPP4), and macrophage migration-inhibitory factor (MIF) contribute to the stemness of GSCs. The intracellular pathway and immunopathway analyses provided relevant information about the functions of representative genes in GSCs. CONCLUSION: The newly-developed cellular bioinformatics pipeline was a useful method to clarify the similarities and differences among samples.
  • Takayuki Nakao; Takeshi Okuda; Mitsugu Fujita; Amami Kato
    Surgical neurology international 10 (131) 131 - 131 2019 [Refereed]
     
    Background: Leptomeningeal metastases (LM) pose the most difficult form of cancer metastasis to treat and portend a poor prognosis. Standard treatment has yet to be established, and intrathecal chemotherapy and whole- brain radiotherapy are administered on an empirical basis. Case Description: We report on a 46-year-old woman with LM from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. She was suffering from intractable headaches, severe nausea and vomiting, and cerebellar ataxia. Contrast-enhanced magnetic resonance imaging (MRI) revealed diffuse enhancement of the meninges, mainly in the posterior cranial fossa, and compression of the cerebellum by the profoundly thickened meninges. The first step in the treatment was decompression of the posterior cranial fossa to relieve intracranial hypertension. After surgery, her symptoms immediately improved. The second step was treatment with lapatinib at 1250 mg and capecitabine 1200 mg, which dramatically improved her symptoms and disappeared diffuse abnormal signal enhancement on MRI. Conclusion: We treated a patient with LM from primary HER2-positive breast cancer who responded well to lapatinib plus capecitabine.
  • Seiichi Omura; Fumitaka Sato; Nicholas E Martinez; Ah-Mee Park; Mitsugu Fujita; Nikki J Kennett; Urška Cvek; Alireza Minagar; J Steven Alexander; Ikuo Tsunoda
    Frontiers in immunology 10 516 - 516 2019 [Refereed]
     
    Previously, we have established two distinct progressive multiple sclerosis (MS) models by induction of experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein (MOG) in two mouse strains. A.SW mice develop ataxia with antibody deposition, but no T cell infiltration, in the central nervous system (CNS), while SJL/J mice develop paralysis with CNS T cell infiltration. In this study, we determined biomarkers contributing to the homogeneity and heterogeneity of two models. Using the CNS and spleen microarray transcriptome and cytokine data, we conducted computational analyses. We identified up-regulation of immune-related genes, including immunoglobulins, in the CNS of both models. Pro-inflammatory cytokines, interferon (IFN)-γ and interleukin (IL)-17, were associated with the disease progression in SJL/J mice, while the expression of both cytokines was detected only at the EAE onset in A.SW mice. Principal component analysis (PCA) of CNS transcriptome data demonstrated that down-regulation of prolactin may reflect disease progression. Pattern matching analysis of spleen transcriptome with CNS PCA identified 333 splenic surrogate markers, including Stfa2l1, which reflected the changes in the CNS. Among them, we found that two genes (PER1/MIR6883 and FKBP5) and one gene (SLC16A1/MCT1) were also significantly up-regulated and down-regulated, respectively, in human MS peripheral blood, using data mining.
  • Takeshi Okuda; Nakamasa Hayashi; Masamichi Takahashi; Takeo Uzuka; Yoshiko Okita; Ryohei Otani; Toshiyuki Fujinaka; Mitsugu Fujita; Amami Kato; Yoshitaka Narita; Yoko Nakasu
    International journal of clinical oncology 23 (6) 1095 - 1100 1341-9625 2018/12 [Refereed]
     
    INTRODUCTION: The introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood. METHODS: We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan. RESULTS: A total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin-bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation. CONCLUSIONS: A multivariate analysis extracted three items-ALBI grade, number of brain metastases, and brain hemorrhage-as prognostic factors for survival of brain metastases from hepatocellular carcinoma.
  • Kimihiro Yamashita; Akira Arimoto; Masayasu Nishi; Tomoko Tanaka; Mitsugu Fujita; Eiji Fukuoka; Yutaka Sugita; Akio Nakagawa; Hiroshi Hasegawa; Satoshi Suzuki; Yoshihiro Kakeji
    Anticancer research 38 (7) 4233 - 4239 0250-7005 2018/07 [Refereed]
     
    In tumor immunity, invariant natural killer T (iNKT) cells play a pivotal role as a link between the innate and adaptive immune systems. With a precisely regulated activation mechanism, iNKT cells have the ability to respond quickly to antigenic stimulation and rapidly produce cytokines and chemokines, and subsequently an effective antitumor immune response. The development of iNKT cell-targeted active immunotherapy enables, not only an antitumor immune response through innate and acquired immunity, but also the conversion of an immunosuppressive into an immunogenic microenvironment. This review is focused on the activation mechanism and the role of iNKT cells after therapeutic active immunization. The therapeutic strategy targeting iNKT cells is expected to be applied to clinical practice in combination with surgery and chemotherapy.
  • Shuichi Izumoto; Masaharu Miyauchi; Takayuki Tasaki; Takeshi Okuda; Nobuhiro Nakagawa; Naoki Nakano; Amami Kato; Mitsugu Fujita
    Anticancer research 38 (7) 4361 - 4366 0250-7005 2018/07 [Refereed]
     
    BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.
  • 次世代シークエンシングを用いた多発性硬化症ウイルスモデルの解析 リンパ管分子発現低下が病気の進行に関連する
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; Alexander J. Steven; Kilgore Phillip C.S.R.; Cvek Urska; 角田 郁生
    NEUROINFECTION 日本神経感染症学会 23 (1) 114 - 120 1348-2718 2018/04 [Refereed]
     
    多発性硬化症(MS)の発症要因はいまだ確定していないが、ウイルス感染がその一つと考えられている。MSの病理学的特徴は中枢神経系(CNS)への免疫細胞浸潤であり、接着分子の発現増加と血液脳関門の破綻が寄与している。一方、侵入した免疫細胞のCNSからの退出機序は不明であったが、近年CNS内リンパ管の存在が報告され、その役割が注目されている。本稿ではMSのウイルス感染モデルであるタイラーウイルス誘導性脱髄疾患マウスを用い、その脊髄トランスクリプトームデータのバイオインフォマティクス解析により、CNS内リンパ管の病態への寄与を検討した。タイラーウイルス感染群と対照群の接着分子、血液脳関門関連分子、リンパ管分子発現データを用いた主成分分析により、リンパ管分子の発現低下がリンパ球のCNSからの退出遅延に寄与することが示唆された。(著者抄録)
  • Computational analyses associate the CNS lymphatic molecules with disease progression of a viral model for multiple sclerosis.
    Omura S; Sato F; Fujita M; Park A.-M; Alexander J.S; Kilgore P.C.S.R; Cvek U; Tsunoda I
    Neuroinfection 23 (1) 114 - 120 1348-2718 2018/04 [Refereed]
  • Kazuhiko Matsuo; Daisuke Nagakubo; Shinya Yamamoto; Akiko Shigeta; Shuta Tomida; Mitsugu Fujita; Takako Hirata; Ikuo Tsunoda; Takashi Nakayama; Osamu Yoshie
    Journal of immunology 200 (2) 800 - 809 0022-1767 2018/01 [Refereed]
     
    CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate-induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.
  • Mitsugu Fujita
    Cancer Science 109 1047  1349-7006 2018/01 [Refereed]
  • F. Sato; S. Omura; A.M. Park; M. Fujita; K. Stokes; I. Tsunoda
    Journal of the Neurological Sciences Elsevier BV 381 1057 - 1058 0022-510X 2017/10
  • Toshiyuki Tsukagawa; Ryu Katsumata; Mitsugu Fujita; Keizo Yasui; Cassim Akhoon; Kenjiro Ono; Kenji Dohi; Toru Aruga
    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association ELSEVIER SCIENCE BV 26 (10) 2404 - 2411 1052-3057 2017/10 [Refereed]
     
    BACKGROUND: In experimental models, inhibition of high-mobility group box-1 (HMGB1) signaling has been reported to protect against the sequelae of ischemic stroke. Here, we determined the clinical significance of serum HMGB1 levels in patients with acute ischemic stroke. METHODS: We enrolled 183 patients (114 men, 69 women; mean age: 72.7 years) over 6 consecutive months. On admission and day 7, we recorded the National Institutes of Health Stroke Scale scores and measured serum high-sensitivity C-reactive protein (hs-CRP) and HMGB1 levels. Stroke volumes were estimated using diffusion-weighted magnetic resonance imaging performed on admission. One year later, clinical outcome was assessed using the modified Rankin Scale (mRS). RESULTS: Serum hs-CRP and HMGB1 levels in patients with ischemic stroke were increased relative to healthy controls (both P < .01). On day 7, hs-CRP, but not HMBG1, levels had increased significantly relative to levels at admission (P < .01 and .54, respectively). Higher HMGB1, but not hs-CRP, levels at day 7 correlated with larger stroke volumes (P < .01 and .28, respectively). HMGB1 levels did not significantly differ between stroke subtypes. Multiple logistic regression analysis indicated that a serum HMGB1 level higher than 7.5 ng/mL was an independent risk factor for poor prognosis, defined as a 1-year mRS score of 3-6 (odds ratio, 2.34; 95% confidence interval, 1.02-5.38). CONCLUSIONS: Acute ischemic stroke is associated with elevated serum HMGB1 levels, and HMGB1 levels at admission independently predict poor outcome at 1 year. These results suggest that HMGB1 quantification provides more accurate prognostic information after ischemic stroke.
  • Ah-Mee Park; Seiichi Omura; Mitsugu Fujita; Fumitaka Sato; Ikuo Tsunoda
    Clinical & experimental neuroimmunology 8 (3) 215 - 232 2017/08 [Refereed]
     
    Alteration of microbiota has been associated with intestinal, inflammatory, and neurological diseases. Abundance of "good bacteria" such as Bifidobacterium, or their products have been generally believed to be beneficial for any diseases, while "bad bacteria" such as pathogenic Helicobacter pylori are assumed to be always detrimental for hosts. However, this is not the case when we compare and contrast the association of the gut microbiota with two neurological diseases, multiple sclerosis (MS) and Alzheimer's disease (AD). Following H. pylori infection, pro-inflammatory T helper (Th)1 and Th17 immune response are initially induced to eradicate bacteria. However, H. pylori evades the host immune response by inducing Th2 cells and regulatory T cells (Tregs) that produce anti-inflammatory interleukin (IL)-10. Suppression of anti-bacterial Th1/Th17 cells by Tregs may enhance gastric H. pylori propagation, followed by a cascade reaction involving vitamin B12 and folic acid malabsorption, plasma homocysteine elevation, and reactive oxygen species induction. This can damage the blood-brain barrier (BBB), leading to accumulation of amyloid-β in the brain, a hallmark of AD. On the other hand, this suppression of pro-inflammatory Th1/Th17 responses to H. pylori has protective effects on the hosts, since it prevents uncontrolled gastritis as well as suppresses the induction of encephalitogenic Th1/Th17 cells, which can mediate neuroinflammation in MS. The above scenario may explain why chronic H. pylori infection is positively associated with AD, while it is negatively associated with MS. Lastly, we list "10 pitfalls of microbiota studies", which will be useful for evaluating and designing clinical and experimental microbiota studies.
  • Okuda T; Kato A; Fujita M
    J Clin Neurol Neurosurg Spine 1 (1) 112  2017/07 [Refereed]
  • Tomoko Tanaka; Mitsugu Fujita; Hiroshi Hasegawa; Akira Arimoto; Masayasu Nishi; Eiji Fukuoka; Yutaka Sugita; Takeru Matsuda; Yasuo Sumi; Satoshi Suzuki; Yoshihiro Kakeji; Kimihiro Yamashita
    Anticancer research INT INST ANTICANCER RESEARCH 37 (7) 3863 - 3869 0250-7005 2017/07 [Refereed]
     
    BACKGROUND: Malignant tumors inhibit antitumor immune responses, which are driven by T-regulatory cells or myeloid-derived suppressor cells (MDSCs). Since MDSCs are involved in invasion, migration, and metastasis of tumor cells, we hypothesized that MDSCs are also involved in tumor recurrence after surgical resection. MATERIALS AND METHODS: C57BL/6 mice were subcutaneously inoculated with B16F10 melanoma cells in the right flank. In some experiments, established tumors were surgically resected. Peripheral blood was drawn over time, and immune cells and cytokines were evaluated using flow cytometry. RESULTS: MDSCs and relevant pro-inflammatory cytokines increased in the peripheral blood of tumor-bearing mice. Moreover, the frequency of MDSCs rapidly increased in mice with tumor recurrence. CONCLUSION: The frequency of MDSCs in the peripheral blood of tumor-bearing mice reflects the status of tumor progression as well as tumor recurrence. Continuous monitoring of MDSCs in the peripheral blood might be a useful indicator of tumor recurrence.
  • Takeshi Okuda; Takayuki Tasaki; Susumu Nakata; Kimihiro Yamashita; Hiromasa Yoshioka; Shuichi Izumoto; Amami Kato; Mitsugu Fujita
    Anticancer research INT INST ANTICANCER RESEARCH 37 (7) 3871 - 3876 0250-7005 2017/07 [Refereed]
     
    BACKGROUND: Glioblastoma multiforme (GBM) is a malignant brain tumor with an extremely poor prognosis. GBM tissues frequently express mesenchymal-epithelial transition factor (MET), which induces cell division, growth and migration. In addition, angiogenesis is a significant feature of GBM, attributable to the overexpression of vascular endothelial growth factor (VEGF). Although the VEGF inhibitor bevacizumab was recently highlighted as the second-line drug for GBM treatment, GBMs often recur even with bevacizumab therapy. Based on these findings, we hypothesized that inhibition of both MET and VEGF would exhibit a synergistic effect on MET-overexpressing GBM. MATERIALS AND METHODS: As we observed MET expression at high levels in some patients with GBM, we designed GL261 murine glioma-based experiments. GL261 cells were transfected with siRNAs specific for MET and VEGF in vitro, and the cell growth ratios were evaluated. Simultaneously, transfected GL261 cells were transplanted into the brain of C57BL/6 mice, and their survival was monitored. RESULTS: GBM tissues frequently overexpressed MET protein at high levels compared with lower-grade gliomas. These GBMs at first responded to bevacizumab, but often eventually recurred. When GL261 cells were co-transfected with both MET-specific siRNA and VEGF-specific siRNA, the in vitro tumor cell growth significantly decelerated compared to single siRNA transfection. Consistently, when mice were transplanted with co-transfected GL261 cells, their survival was significantly prolonged compared to those given cells transfected with single siRNA. CONCLUSION: The current data indicate that the inhibition of both MET and VEGF exhibits efficient therapeutic effects of GBM-bearing hosts.
  • 角田郁生; 尾村誠一; 佐藤文孝; 崎山奈美江; PARK Ah‐Mee; 藤田貢
    Neuroinfection 日本神経感染症学会 22 (1) 28‐35 - 35 1348-2718 2017/04 [Refereed]
     
    多発性硬化症(multiple sclerosis、MS)は中枢神経系の炎症性脱髄と軸索障害を主体とする神経変性疾患であり、全世界では200万人以上、日本では約1万人のMS患者が存在する。MS発症の原因としてはウイルス感染説と自己免疫説が提唱されている。その動物実験モデルとして、前者に対してはタイラーウイルス誘導性脱髄疾患[Theiler's murine encephalomyelitis virus(TMEV)-induced demyelinating disease、TMEV-IDD]が、後者に対しては実験的自己免疫性脳脊髄炎(experimental autoimmune encephalomyelitis、EAE)が、それぞれ頻用されている。両者ともT細胞が病変形成に関与するが、MS様病変である脱髄と軸索変性の進展様式は両者間で異なる。TMEV-IDDでは、病変は神経線維の内側(インサイド)の軸索障害に始まり、外側(アウトサイド)の髄鞘障害(=脱髄)へと進展する(インサイド-アウト・モデル)。一方、EAEでは外側の髄鞘障害が先行し、続いて内側の軸索障害が誘導される(アウトサイド-イン・モデル)。ヒトMSの病理像では、インサイド-アウト・モデルとアウトサイド-イン・モデルそれぞれに合致する病理像が報告されており、前者は"軸索型"MSといえるものであり、後者の古典的"脱髄型"MSとは異なる。また両者の病理像が同一個体でみられるMS症例も存在する。すなわち"インサイド-アウト"と"アウトサイド-イン"の進展様式は相反するものではなく、むしろ共存して悪循環を形成し病態進行に寄与しうると推測される。この悪循環を断つ方法としては、1)炎症抑制、2)軸索保護、3)軸索変性の抑制(ウイルス感染の場合は、ウイルス増殖抑制による)の三つが考えられる。理論的には、この悪循環のいずれかのステップに介入する治療法がMSの進行抑制を可能にする。実際、MS治療に作用点の異なる複数の薬剤が有効であるという臨床データが、MS症例の多くで前述二つの進展様式が共存しうることを示唆する。(著者抄録)
  • Influx and efflux of immune cells in the central nervous system.
    Fujita M; Omura S; Sato F; Park A.-M; Tsunoda I
    Anat. Physiol. 7 274  2017 [Refereed]
  • Hisashi Kubota; Yasuhiro Sanada; Saori Murakami; Masaharu Miyauchi; Michihiro Iwakura; Kazuhiro Nagatsuka; Kentaro Furukawa; Amami Kato; Mitsugu Fujita
    Surgical neurology international 8 204 - 204 2229-5097 2017 [Refereed]
     
    BACKGROUND: The demand of a burr hole surgery for chronic subdural hematoma (CSDH) is increasing in the global aging society. Burr hole-derived autologous bone dusts are not associated with extra costs compared with other commonly used synthetic materials. In addition, postoperative calvarium ossification requires periosteum-mediated blood supply, which is lacking after using avascular synthetic materials. Based on these findings, we hypothesized that the combination of the bone plugs and the preserved periosteum during burr hole surgeries for CSDH would induce efficient calvarium ossification. METHODS: We evaluated the long-term effects of bone plugs on the degree of ossification and cosmetic appearance of the skin covering the burr hole sites. We included 8 patients (9 burr holes) who received the autologous bone dust derived from burr holes. As the control group, 9 burr holes that did not receive any burr hole plugs were retrospectively selected. These burr holes were evaluated by computed tomography (CT) scan for the calvarium defect ratios, CT value-based ossification, and the degree of skin sinking. RESULTS: Ossification was observed in all the bone plugs by the bone density CT scans; they maintained their volume at 12 months after the surgeries. The calvarium defect ratios (volume ratios of the unossified parts in the burr holes) gradually increased during the first 6 months and reached 0.44 at 12 months. The mean CT values also increased from 527 HU to 750 HU for the first 6 months and reached 905 HU at 12 months. The degrees of skin sinking at the burr hole sites with the bone plugs were 1.24 mm whereas those without the bone plugs were 2.69 mm (P = 0.004). CONCLUSION: Application of burr hole-derived autologous bone dust is associated with better ossification and objective cosmetic result following burr hole surgery after CSDH.
  • Hitoshi Nishiwaki; Mitsugu Fujita; Makoto Yamauchi; Noritaka Isogai; Yasuhiko Tabata; Hirohisa Kusuhara
    Cells, tissues, organs 204 (5-6) 251 - 260 1422-6405 2017 [Refereed]
     
    Cartilage tissue is characterized by its poor regenerative properties, and the clinical performance of cartilage grafts to replace cartilage defects has been unsatisfactory. Recently, cartilage regeneration with mature chondrocytes and stem cells has been developed and applied in clinical settings. However, there are challenges with the use of mature chondrocytes and stem cells for tissue regeneration, including the high costs associated with the standard stem cell isolation methods and the decreased cell viability due to cell manipulation. Previous studies demonstrated that cartilage can be regenerated from chondrocyte clusters that contain stem cells. Based upon some of the existing techniques, the goal of this study was to develop a novel and practical method to induce cartilage regeneration. A microslicer device was developed to process cartilage tissues into micron-size cartilage (microcartilage) in a minimally invasive manner. We evaluated microcartilage sizes and demonstrated 100-400 µm as optimal for generating a high cell yield with collagenase digestion. In addition, autologous intrafascial implantation of the composites of microcartilage and an absorbable scaffold with a slow-release system of basic fibroblast growth factor (bFGF) was carried out to induce cartilage regeneration. Our results demonstrated that the extent of bFGF diffusion depends on the size of microcartilage, and that cartilage regeneration was induced most effectively with 100 µm of microcartilage via SOX5 upregulation. These findings suggest that cartilage regeneration is possible with microcartilage as a source of cells without ex vivo cell expansion.
  • Yoshiko Yasuda; Mitsugu Fujita
    Vitamins and Hormones Academic Press Inc. 105 297 - 310 0083-6729 2017 [Refereed]
     
    We have clarified that cancer cells express their own erythropoietin (Epo) and its receptor (EpoR) mRNA levels, and the respective proteins, which are under the control of Epo–EpoR signaling. Then we explored to inhibit the Epo–EpoR signaling with an EpoR antagonist Epo mimetic peptide 9 (EMP9) that is a derivative of an Epo-mimicking peptide EMP1. In the study of the cancer cell lines in vitro, rhEpo accelerated the cancer cell growth, whereas the EMP9 inhibited the cell growth along with the inhibition of STAT5 tyrosine phosphorylation. Moreover, in vitro study of surgically resected histoculture of lung cancers revealed that EMP9 diminishes the expression of myoglobin in the cancer cells and destroys the feeding vessels. Additionally, in the xenografts of lung cancer histoculture, the EMP9 destroyed the xenografts by inducing apoptosis and suppressing proliferation of cancer cells in concomitant with macrophage accumulation. Furthermore, two types of perforations were detected in their cytoplasm: the one is mediated by nNOS in the cancer cells and the other one is by iNOS in the innate immune cells. These findings suggest that the inhibition of the Epo–EpoR signaling by EMP9 induces the cancer cell death that is mediated by the apoptosis and calcification of the cancer cells as well as the oxygen deficiency through the feeding vessels. Taken together, EMP9-based therapy may be a promising strategy to treat cancer patients.
  • Ikuo Tsunoda; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Namie Sakiyama; Ah-Mee Park
    Clinical & experimental neuroimmunology 7 (4) 330 - 345 2016/11 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) infection has been used as a viral model for multiple sclerosis (MS), as TMEV can induce chronic inflammatory demyelinating lesions with viral persistence in the spinal cord of SJL/J mice. In contrast, when C57BL/6 mice are infected with TMEV, the mice can clear the virus from the central nervous system (CNS), without viral persistence or demyelination, but develop seizures and hippocampal sclerosis, which has been used as a viral model for seizures/epilepsy. In the two TMEV-induced CNS disease models, not only viral infection, but also immune responses contribute to the pathogenesis. Interestingly, acquired immunity plays an effector role in the MS model, whereas innate immunity appears to contribute to the development of seizures. Recently, we have established the third TMEV-induced disease model, a mouse model for viral myocarditis, using C3H mice. TMEV-induced myocarditis is a triphasic disease, which mimics human myocarditis; phase I, mediated by viral replication in the heart and innate immunity; phase II, mediated by acquired immunity; and phase III, resulted from cardiac fibrosis. The genetic susceptibility to the aforementioned three models (MS, seizures and myocarditis) differs among mouse strains. We have compared and contrasted the three models induced by one single pathogen, TMEV, particularly in regard to the roles of T helper cells and natural killer T cells, which will give an insight into how interactions between the immune system and the host's genetic background determine the tissue tropism of virus and the development of virus-induced organ-specific immunopathology.
  • Takayuki Tasaki; Mitsugu Fujita; Takeshi Okuda; Azusa Yoneshige; Susumu Nakata; Kimihiro Yamashita; Hiromasa Yoshioka; Shuichi Izumoto; Amami Kato
    Anticancer research INT INST ANTICANCER RESEARCH 36 (7) 3571 - 7 0250-7005 2016/07 [Refereed]
     
    BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the proto-oncogene mesenchymal-epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM. PATIENTS AND METHODS: To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo. RESULTS: Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs. CONCLUSION: Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.
  • Kimihiro Yamashita; Hiroshi Hasegawa; Mitsugu Fujita; Masayasu Nishi; Tomoko Tanaka; Akira Arimoto; Satoshi Suzuki; Takashi Kamigaki; Yoshihiro Kakeji
    Anticancer research INT INST ANTICANCER RESEARCH 36 (7) 3659 - 65 0250-7005 2016/07 [Refereed]
     
    BACKGROUND/AIM: For the application of invariant natural killer T (iNKT) cells in cancer therapy, the CD40-CD40L interaction is indispensable in administering alpha-galactosylceramide (αGalCer). We hypothesized that CD40 plays an important role in dendritic cells (DC) pulsed with αGalCer (DCGs) in the treatment of lung metastases. MATERIALS AND METHODS: Wild-type (WT) and CD40(-/-) mice were treated with DCGs isolated from WT or CD40(-/-) mice in a B16F10 lung metastases model and NK and NKT cell activity in lungs and the spleen were examined. RESULTS: DCG treatment improved WT mice survival but CD40(-/-) hosts received no survival benefit. Conversely, attenuation of a therapeutic effect in mice treated with CD40(-/-) DCGs was not observed. The functional activities of NK and NKT cells in DCG-treated CD40(-/-) mice were partially suppressed. CONCLUSION: Host CD40 is essential for DCG treatment to have a therapeutic effect on B16F10 lung metastases.
  • Endoscopic Biopsy using High-Dose Fluorescein Sodium for Malignant Brain Tumors
    Okuda T; Fujita M; Yoshioka H; Tasaki T; Izumoto S; Kato A
    International Journal of Neurology and Neurotherapy 3 (3) 052  2016/06 [Refereed]
  • 藤田 貢
    近畿大学医学雑誌 近畿大学医学会 41 (1-2) 47 - 54 0385-8367 2016/06 [Refereed][Invited]
  • Takanobu Motoshima; Yoshihiro Komohara; Hasita Horlad; Hirotake Tsukamoto; Mitsugu Fujita; Yoichi Saito; Kenichiro Tanoue; Yutaka Kasejima; Yutaka Sugiyama; Yoshiaki Kawano; Yasuharu Nishimura; Motohiro Takeya; Masatoshi Eto
    ONCOLOGY LETTERS SPANDIDOS PUBL LTD 11 (3) 1911 - 1916 1792-1074 2016/03 [Refereed]
     
    Circulating cluster of differentiation (CD)14+ human leukocyte antigen (HLA)-DRlow/- monocytes, those with a lower HLA-DR expression or are negative for HLA-DR, are considered to be involved in systemic immunosuppression in patients with several malignant tumors. However, few studies have investigated in detail the gene expression profile of CD14+HLA-DRlow/- monocytes. In the present study, the mRNA expression levels of immune-associated molecules in CD14+ monocytes isolated from healthy donors and patients with renal cell carcinoma (RCC) were analyzed. Consistent with previous studies, the percentage of HLA-DRlow/- cells in CD14+ monocytes was significantly increased in patients with RCC compared with healthy donors. In 3 of the 4 patients who underwent surgical resection of the primary tumor, the percentage of CD14+HLA-DRlow/- cells was significantly decreased following surgery. The mRNA expression levels of cyclooxygenase 2, transforming growth factor , interleukin 6R, chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-X-C motif) ligand 10 (CXCL10), oncostatin M, and vascular endothelial growth factor-A in CD14+ monocytes were quantified using reverse transcription-quantitative polymerase chain reaction. The results of the present study revealed that increased expression levels of CCL2 and CXCL10 were inversely correlated with the percentage of CD14+HLA-DRlow/- monocytes. This suggested that monocytes in RCC patients were immunologically suppressed, and that immunosuppression in RCC patients may be due, in part, to the dysfunction of circulating monocytes.
  • Ikuo Tsunoda; Seiichi Omura; Fumitaka Sato; Susumu Kusunoki; Mitsugu Fujita; Ah-Mee Park; Faris Hasanovic; Richard Yanagihara; Satoshi Nagata
    Acta medica Kinki University 41 (2) 37 - 52 0386-6092 2016 [Refereed]
     
    Zika virus (ZIKV) is an enveloped, positive-sense, single-stranded RNA virus that belongs to the genus Flavivirus, family Flaviviridae, which includes many human and animal pathogens, such as dengue virus (DENV), West Nile virus, and Japanese encephalitis virus. In the original as well as subsequent experimental and clinical reports, ZIKV seems to have moderate neurotropism (in animal models) and neurovirulence (in human fetuses), but no neuroinvasiveness (in human adults). Intrauterine ZIKV infection (viral pathology) has been linked to an increased incidence of microcephaly, while increased Guillain-Barré syndrome (GBS) following ZIKV infection is likely immune-mediated (immunopathology). Clinically, in ZIKV infection, antibodies against other flaviviruses, such as DENV, have been detected; these antibodies can cross-react with ZIKV without ZIKV neutralization. In theory, such non-neutralizing antibodies are generated at the expense of decreased production of neutralizing antibodies ("antigenic sin"), leading to poor viral clearance, while the non-neutralizing antibodies can also enhance viral replication in Fc receptor (FcR)-bearing cells via antibody-dependent enhancement (ADE). Here, we propose three potential roles of the antibody-mediated pathogenesis of ZIKV infection: 1) cross-reactive antibodies that recognize ZIKV and neural antigens cause GBS; 2) ZIKV-antibody complex is transported transplacentally via neonatal FcR (FcRn), resulting in fetal infection; and 3) ZIKV-antibody complex is taken up at peripheral nerve endings and transported to neurons in the central nervous system (CNS), by which the virus can enter the CNS without crossing the blood-brain barrier.
  • Kazuhiko Matsuo; Keiichi Koizumi; Mitsugu Fujita; Toshio Morikawa; Michiko Jo; Naotoshi Shibahara; Ikuo Saiki; Osamu Yoshie; Takashi Nakayama
    Frontiers in cell and developmental biology 4 54 - 54 2016 [Refereed]
     
    Chemokine receptors CCR3 and CCR4 are preferentially expressed by TH2 cells, mast cells, and/or eosinophils, all of which are involved in the pathogenesis of allergic diseases. Therefore, CCR3 and CCR4 have long been highlighted as potent therapeutic targets for allergic diseases. Japanese traditional herbal medicine Kampo consists of multiple crude drugs/herbs, which further consist of numerous chemical substances. Recent studies have demonstrated that such chemical substances appear to promising sources in the development of novel therapeutic agents. Based on these findings, we hypothesize that Kampo-related crude drugs/herbs would contain chemical substances that inhibit the cell migration mediated by CCR3 and/or CCR4. To test this hypothesis, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Among those tested, Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4, Cornus Fruit inhibited that mediated by CCR3, and Rhubarb inhibited that mediated by CCR4. Furthermore, Ephedra Herb specifically inhibited the chemotaxis mediated by not only CCR3 and CCR4 but CCR8, all of which are selectively expressed by TH2 cells. This result led us to speculate that ephedrine, a major component of Ephedra Herb, would play a central role in the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. However, ephedrine exhibited little effects on the chemotaxis. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. As the results, ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. In contrast, chloroform-soluble fraction exhibited a weak inhibitory effect on the chemotaxis mediated by CCR8. Furthermore, maoto, one of the Kampo formulations containing Ephedra Herb, exhibited the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. Taken together, our data suggest that these crude drugs/herbs might be useful sources to develop new drugs targeting TH2-mediated allergic diseases.
  • Mitsugu Fujita; Kazunari Shintai; Susumu Nakata; Nagako Maeda; Norikazu Hatano; Yukio Seki
    Journal of vascular and interventional radiology : JVIR ELSEVIER SCIENCE INC 26 (9) 1414 - 6 1051-0443 2015/09 [Refereed]
  • Dai Otsubo; Kimihiro Yamashita; Mitsugu Fujita; Masayasu Nishi; Yutaka Kimura; Hiroshi Hasegawa; Satoshi Suzuki; Yoshihiro Kakeji
    Anticancer research INT INST ANTICANCER RESEARCH 35 (8) 4425 - 31 0250-7005 2015/08 [Refereed]
     
    BACKGROUND/AIM: The outcome of patients with malignant tumors is poor if they suffer from lung metastases. Myeloid-derived suppressor cells (MDSCs), a major player for tumor-induced immunosuppression, can be suppressed by certain chemotherapeutic agents, such as low-dose 5-fluorouracil (5-FU) or surgical treatment. Based on these findings, we hypothesized that early-phase treatment by low-dose 5-FU or surgical resection of primary tumors would prevent lung metastasis formation by inhibiting MDSCs. MATERIALS AND METHODS: B16F10 melanoma-bearing C57BL/5 mice with lung metastases were treated with low-dose 5-FU or surgical resection of primary tumors. RESULTS: Low-dose 5-FU chemotherapy inhibited systemic and lung-accumulating MDSCs in tumor-bearing mice. The therapy inhibited lung metastasis formation and prolonged the survival of the animals. Consistently, early-phase resection of primary tumors improved survival, which was concomitant with a reduction of lung-accumulating MDSCs and lung metastases. CONCLUSION: Early-phase treatment may provide therapeutic values to prevent MDSC-mediated lung metastasis formation in tumor-bearing hosts.
  • 和田裕介; 和田裕介; 樋口智紀; 藤田貢; 頼晋也; 前倉俊治; 浦瀬文明; 松村到; 義江修
    近畿大学医学雑誌 近畿大学医学会 40 (1-2) 23 - 29 0385-8367 2015/06 
    びまん性大細胞型B細胞性リンパ腫(diffuse large B-cell lymphoma/DLBCL)は非ホジキンリンパ腫の中で最頻のサブタイプである。本疾患に対しては、シクロホスファミド、ドキソルビシン、ビンクリスチン、およびプレドニゾロンの併用療法、いわゆるCHOP療法が長きにわたり標準治療法であった。しかし近年、CD20を標的としたキメラIgG1モノクローナル抗体であるリツキシマブがDLBCLに著効することが示され、これを加えたR-CHOPが現在では実質的標準治療となっている。一方SOX4はSOXファミリーに属する転写因子である。これは未熟B/Tリンパ球の分化増殖に関わることが知られ、さらに成人T細胞白血病リンパ腫をはじめとする複数の悪性腫瘍においては癌遺伝子として作用する。しかしながらDLBCLとSOX4との関連については未だ不明である。そこで本研究ではDLBCLにおけるSOX4発現と治療応答性および予後との相関について検証した。我々の集めたDLBCL 70症例の検討から、SOX4のタンパクおよびmRNAレベルでの発現量はともにR-CHOP応答性と負の相関を示した。また予後解析によりSOX4発現量はDLBCL患者の予後不良とも相関を示した。これらの結果よりSOX4がDLBCLの予後予測因子として有用である可能性が示された。(著者抄録)
  • Yoshiko Yasuda; Mitsugu Fujita; Eiji Koike; Koshiro Obata; Mitsuru Shiota; Yasushi Kotani; Terunaga Musha; Sachiyo Tsuji-Kawahara; Takao Satou; Seiji Masuda; Junko Okano; Harufumi Yamasaki; Katsumi Okumoto; Tadao Uesugi; Shinichi Nakao; Hiroshi Hoshiai; Masaki Mandai
    PLOS ONE PUBLIC LIBRARY SCIENCE 10 (4) e0122458  1932-6203 2015/04 [Refereed]
     
    The aim of this study is to explore a cause-oriented therapy for patients with uterine cervical cancer that expresses erythropoietin (Epo) and its receptor (EpoR). Epo, by binding to EpoR, stimulates the proliferation and differentiation of erythroid progenitor cells into hemoglobin-containing red blood cells. In this study, we report that the HeLa cells in the xenografts expressed epsilon,gamma, and a globins as well as myoglobin (Mb) to produce tetrameric alpha 2 epsilon 2 and alpha 2 gamma 2 and monomeric Mb, most of which were significantly suppressed with an EpoR antagonist EMP9. Western blotting revealed that the EMP9 treatment inhibited the AKT-pAKT, MAPKs-pMAPKs, and STAT5-pSTAT5 signaling pathways. Moreover, the treatment induced apoptosis and suppression of the growth and inhibited the survival through disruption of the harmonized hemoprotein syntheses in the tumor cells concomitant with destruction of vascular nets in the xenografts. Furthermore, macrophages and natural killer (NK) cells with intense HIF-1 alpha expression recruited significantly more in the degenerating foci of the xenografts. These findings were associated with the enhanced expressions of nNOS in the tumor cells and iNOS in macrophages and NK cells in the tumor sites. The treated tumor cells exhibited a substantial number of perforations on the cell surface, which indicates that the tumors were damaged by both the nNOS-induced nitric oxide (NO) production in the tumor cells as well as the iNOS-induced NO production in the innate immune cells. Taken together, these data suggest that HeLa cells constitutively acquire e,. and Mb synthetic capacity for their survival. Therefore, EMP9 treatment might be a cause-oriented and effective therapy for patients with squamous cell carcinoma of the uterine cervix.
  • ヘルペス角膜炎発症におけるCCR6陽性Tリンパ球および樹状細胞の役割
    坂本 万寿夫; 藤田 貢; 檜垣 史郎; 福田 昌彦; 義江 修; 下村 嘉一
    日本眼科学会雑誌 (公財)日本眼科学会 119 (臨増) 255 - 255 0029-0203 2015/03
  • 下村嘉一; 松本長太; 福田昌彦; 奥山幸子; 國吉一樹; 杉岡孝二; 板橋幹城; 橋本茂樹; 青松圭一; 七部史; 野本裕貴; 渡邊敬三; 河本庄平; 児玉彩; 坂本万寿夫; 日下俊次; 檜垣史郎; 小池英子; 立花都子; 辻岡大志; 三島弘; 阿部考助; 萱澤朋泰; 萱澤真梨子; 藤田貢; 義江修
    日本眼科学会雑誌 (公財)日本眼科学会 119 (3) 145 - 167 0029-0203 2015/03 [Invited]
     
    単純ヘルペスウイルス1型(herpes simplex virus type 1:HSV-1)はヒト角結膜に初感染後,三叉神経節などに潜伏感染する.精神的ストレス,熱刺激,紫外線,免疫抑制などの誘因によりHSV-1が再活性化され,上皮型ヘルペス性角膜炎,実質型ヘルペス性角膜炎などを発症する.本総説では,HSV-1の潜伏感染,再活性化について最近の研究成果を紹介したい.I.近畿大学眼科におけるヘルペス性角膜炎症例の検討 約13年間に近畿大学(本院,堺病院,奈良病院)の角膜外来を受診し,ヘルペス性角膜炎と診断され,当院で1年以上経過観察した128例129眼を対象とし,受診時病型,再発移行形態につき検討を行った.受診時の病型は,上皮型65眼(50%),実質型30眼(23%),上皮・実質混合型18眼(14%)などで,再発は全体の47%にみられた.上皮型の再発は上皮型が多く,実質型の頻回再発例は上皮型,実質型,混合型などを繰り返した.II.マウス上皮型ヘルペス性角膜炎に対する抗ヘルペス薬の効果 ヒト上皮型ヘルペス性角膜炎症例に対し,アシクロビル(acyclovir:ACV)眼軟膏を2〜3週間投与する場合が一般的に多い.果たして,「これだけの期間の投与が必要なのか?」この疑問を解決するために,マウス上皮型ヘルペス性角膜炎に対する抗ヘルペス薬の効果を経時的に調べた.マウス角膜にHSV-1を感染させ,ACV眼軟膏,バラシクロビル(valaciclovir:VACV)内服,ファムシクロビル(famciclovir:FCV)内服を5日間施行した.結果は,涙液viral culture法で,ACV眼軟膏とVACV内服群では投与開始4日後,FCV内服群では6日後にはウイルスを認めなかった.Real-time polymerase chain reaction(PCR)法による検討では,眼球または三叉神経節において,投与開始4〜6日後に生理食塩水点眼群と比較して,HSV DNAコピー数の有意な減少を認めた.以上により,抗ウイルス薬は5日間の投与で,眼球表面および眼球におけるHSV-1量を十分に減少させることが可能であると考えられた.III.角膜潜伏感染 ウイルス学的手法および分子生物学的手法を用いて,HSV-1角膜潜伏感染を証明するため,ヒト角膜において,(1)HSV DNAが存在する,(2)感染ウイルスは存在しないが,潜伏ウイルスは存在する(negative homogenate,positive explant),(3)角膜にlatency-associated transcript(LAT)のみが検出され,他のウイルス遺伝子(α,β,γ)の転写物が検出されない,の3項目について検討した.結果は,ヘルペス性角膜炎の既往がある症例の摘出角膜3片において,上記の(1),(2),(3)すべてを満たした.以上の結果から,ヒト角膜におけるHSV-1潜伏感染の可能性が示された.IV.Multiplex real-time PCR法を用いた前眼部,前房水からのHSV-1,HHV-6,HHV-7 DNA検出 HSV-1,ヒトヘルペスウイルス6型(human herpes virus 6:HHV-6),ヒトヘルペスウイルス7型(HHV-7)に対するmultiplex real-time PCR法を,眼科学分野において世界で初めて施行した.サンプルは,白内障手術の術前および手術3日後の涙液,全層角膜移植術の術前および手術3日後の涙液,白内障手術中に採取した前房水であった.結果は,multiplex real-time PCR法により,白内障手術および全層角膜移植術前後の涙液において,HSV-1,HHV-6,HHV-7のDNAが存在していることが示された.V.再活性化抑制時の遺伝子発現の検討 近年,HSV-1の再活性化におけるnuclear factor-kappa B(NF-κB)の関与が報告されている.NF-κBの活性を阻害するI kappa B kinase-β(IKK2)阻害薬を用いて,マウスモデルにおいてHSV再活性化抑制時の遺伝子発現を検討した.IKK2阻害薬腹腔内注射(腹注)群では,real-time PCR法で三叉神経節におけるHSV DNAコピー数の有意な減少を認めた.Microarray法では,1,812プローブが2倍以上発現増加していた.パスウェイ解析では,IKK2阻害薬腹注群では免疫抑制効果が緩和されていることが示された.VI.ヘルペス性角膜炎に関わる免疫応答 ヒトヘルペス性角膜炎症例,マウスヘルペス性角膜炎におけるケモカイン発現プロファイルを解析した.Th1型ケモカインであるCxcl9,Cxcl10,Ccl5の上昇,またTh17型ケモカインであるCcl20の上昇がみられた.一方,Th2型ケモカインの上昇はみられなかった.免疫応答は主として三叉神経節内で生じていた.これらの結果から,Th17型免疫応答の積極的誘導によりヘルペス性角膜炎発症を予防しうると考えられた.(著者抄録)
  • Tasaki T; Fujita M; Izumoto S; Nakagawa K; Kato A
    Jpn J Neurosurg 24 (3) 192 - 197 0917-950X 2015/01 [Refereed]
  • Mitsugu Fujita; Takaaki Matsui; Akihiko Ito
    Frontiers in cell and developmental biology 3 55 - 55 2015 [Refereed]
  • Yoneshige A; Hagiyama M; Fujita M; Ito A
    Frontiers in cell and developmental biology 3 75 - 75 2015 [Refereed]
     
    Cell adhesion mediated by adhesion molecules is of central importance in the maintenance of tissue homeostasis. Therefore, altered expression of adhesion molecules leads to the development of various tissue disorders involving cell activation, degeneration, and apoptosis. Nevertheless, it still remains unclear what initiates the altered expression of adhesion molecules and how the subsequent pathological cascades proceed. In this regard, cell adhesion molecule 1 (CADM1) is one of the candidates that is involved in the development of pathological lesions; it is an intercellular adhesion molecule that is expressed in various types of cells such as pulmonary cells, neurons, and mast cells. Recent studies have revealed that alterations in the transcriptional or post-transcriptional expressions of CADM1 correlate with the pathogenesis of pulmonary diseases and allergic diseases. In this review, we specifically focus on how CADM1 is involved in the development of pathological lesions in pulmonary emphysema and atopic dermatitis.
  • Yoshioka H; Okuda T; Fujita M; Inoue T; Tasakai T; Izumoto S; Kato A
    Acta Med Kinki Univ Kinki University Medical Association 39 (2) 105 - 113 0386-6092 2014/12 
    [Abstract] Current evidence indicates that glioma stem cell-like cells (GSC_S) in humans play critical roles in the pathogenesis of carcinogenesis ofglioblastoma (GBM ). The GSC_S are known to overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters to exhibit multidrug resistance. Eradication of the GSC compartment is therefore essential to achieve a stable and long-lasting remission of GBM. To elucidate the characteristics of GSC_S in detail, we generated murine GSC lines from Sleeping Beauty transposon-mediated spontaneous GBM . Using these several cell lines, we evaluated the significance of ABC transporters in the GSC kinetics by cell morphology assays, flow cytometry, and quantitativeRT-PCR for mRNA expressions. As a consequence, we show that siRNA-mediated ABCG2 inhibition enhances the sensitivity of GSC_S to temozolomide (TMZ) and in turn reduces their spheroid-forming capability. Furthermore, we show that GSC_S treated with Abcg2-specific siRNA become sensitive to TMZ and reduce their spheroid-forming capability. In conclusion, our data suggest that targeting of drug transporters in GSC_S is a promising strategy to enhance their chemo-sensitivity for achieving a longlasting remission of GBM .
  • Mitsugu Fujita; Susumu Nakata; Takeshi Okuda; Amami Kato; Osamu Yoshie
    CANCER RESEARCH AMER ASSOC CANCER RESEARCH 74 (19) 0008-5472 2014/10 [Refereed]
  • Susumu Nakata; Harunari Tanaka; Yuichi Ito; Masayasu Hara; Mitsugu Fujita; Eisaku Kondo; Yukihide Kanemitsu; Yasushi Yatabe; Hayao Nakanishi
    International journal of oncology SPANDIDOS PUBL LTD 45 (4) 1583 - 93 1019-6439 2014/10 [Refereed]
     
    Poorly-differentiated colorectal cancers (PD-CRC) show high metastatic potential and poor prognosis. However, molecular characteristics of PD-CRC remain unknown to date, particularly in molecular targeting therapy for patients with PD-CRC. In this study, we examined the expression of EGFR, HER2 and HER3 in PD-CRC by immunohistochemical analysis of archived clinical specimens of primary tumors and investigated the sensitivity of PD-CRC cell lines to gefitinib, a tyrosine kinase inhibitor for EGFR in vitro. We found that HER3 expression of PD-CRC among members of the HER family was significantly lower than that of well to moderately differentiated CRC (WMD-CRC) and 37% of the PD cases showed a EGFR+/HER2+/HER3- expression pattern. COLM-5 cells, a PD-CRC-derived cell line, which exhibits EGFR+/HER2+/HER3- expression pattern and recapitulates the typical histology of PD-CRC in xenografted tumors, showed high gefitinib sensitivity both in vitro and in vivo, compared with WMD-CRC cell line (COLM-2). Treatment with gefitinib resulted in the upregulation of p27Kip1 expression and induction of G1 cell cycle arrest, concomitantly associated with inactivation of PI3K/Akt signaling in COLM-5 cells and marked inhibition of xenografted tumors in nude mice, but not evident in COLM-2 cells. Treatment with sodium butyrate, an HDAC inhibitor that induces differentiation, upregulated the expression of HER3 associated with enhancement of the PI3K/Akt signaling, attenuated gefitinib-mediated p27Kip1 upregulation and reduced gefitinib sensitivity in COLM-5 cells in vitro. Furthermore, enforced expression of HER3 in COLM-5 cells resulted in significant resistance to gefitinib treatment both in vitro and in vivo. These findings suggest that deficient HER3 expression plays an important role in gefitinib sensitivity and that a malignant subset of PD with EGFR+/HER2+/HER3- phenotype is a potential candidate for a target of anti-EGFR molecular therapy such as gefitinib.
  • Takeshi Okuda; Juli Yamashita; Mitsugu Fujita; Hiromasa Yoshioka; Takayuki Tasaki; Amami Kato
    ACTA NEUROCHIRURGICA SPRINGER WIEN 156 (7) 1403 - 1407 0001-6268 2014/07 [Refereed]
     
    We verified the effectiveness of training in endoscopic endonasal transsphenoidal surgery (eETSS) techniques using chicken eggs and a skull model. We verified the area of eggshell removed by drilling when five residents and four experts used the chicken eggs and a skull model. When residents performed drilling on 10 eggs, a mean (+/- standard deviation [SD]) area of 31.2 +/- 17.5 mm2 was removed from the first egg, and 104.8 +/- 3.3 mm2 from the tenth and final egg, representing an increase in area and a decrease in SD. The experts performed the same drilling operation on a single egg, and removed a mean area of 257 +/- 31.7 mm2. These results demonstrated that skills improved as a result of this training, and suggested that this method was also capable of overcoming the initial individual differences in the amount of force applied and ability. An obvious difference between residents and experts was seen in the area removed (p = 0.00011); however, this was attributed to differences in endoscopic manipulation, rather than drilling skill. Our findings suggest that this training method could be adequate for acquiring eETSS techniques. Although experts showed superior endoscopic manipulation, residents may also be able to acquire adequate endoscopic skills through further training, and our training method appears to offer an effective means of improving eETSS techniques.
  • 奥田武司; 藤田貢; 加藤天美
    急性・重症患者ケア (株)総合医学社 3 (2) 301 - 308 2187-2899 2014/05 [Invited]
     
    <ここがPoint!>中枢神経系感染症は特徴的な症状が乏しく、早期発見が難しい疾患である。髄膜炎はまず疑うことが大事であり、確定診断には髄液検査が必要である。髄膜炎に対する抗菌薬は患者背景より選択し、できる限り迅速に投与開始する。脳膿瘍には、原因となりうる患者背景がある。脳膿瘍は感染症だが、感染症状だけではなく腫瘤としての脳圧迫症状もある。脳圧迫により頭蓋内圧亢進が高度の場合や脳室近傍例では、膿瘍ドレナージ術が必要となる。(著者抄録)
  • Mitsugu Fujita
    Journal of Pharmacological Sciences 2014
  • Takeshi Okuda; Hidetoshi Hayashi; Mitsugu Fujita; Hiromasa Yoshioka; Takayuki Tasaki; Kazuhiko Nakagawa; Amami Kato
    Metallography, Microstructure, and Analysis Springer New York LLC 3 (4) 211 - 214 2192-9270 2014 [Refereed]
     
    Meningeal carcinomatosis (MC) is a refractory disease with a dismal prognosis, and no therapeutic strategy has been established to date. Herein we report a case of lung adenocarcinoma-derived MC in which the patient’s performance status was dramatically improved by administration of gefitinib suspension via a nasogastric tube. The patient was a 71-year-old woman who was originally admitted to our hospital for a progressive headache and subsequently presented with severe consciousness disturbance. Cerebrospinal fluid examination and systemic imaging studies revealed MC that was derived from lung adenocarcinoma. Moreover, epidermal growth factor receptor (EGFR) mutations were detected in the tumor cells. Since the patient suffered from hydrocephalus, a ventriculoperitoneal shunt was placed. Nevertheless, her consciousness disturbance persisted. Subsequently, gefitinib suspension was prepared and administered via nasogastric tube, which dramatically improved her consciousness level and enabled her to tolerate oral intake. She died 14 months after the disease onset. The observations in this case report suggest that gefitinib might be a therapeutic option for patients with MC derived from cancers harboring EGFR mutations even though the patient exhibited severe consciousness disturbance.
  • Takeshi Okuda; Mitsugu Fujita; Hiromasa Yoshioka; Takayuki Tasaki; Amami Kato
    Surgical Neurology International Medknow Publications 5 (1) 100  2152-7806 2014 [Refereed]
     
    Background: An outstanding issue regarding the surgical treatment of cyst-type metastatic brain tumors is the incomplete resection of cyst walls. Herein we propose a novel surgical technique that can overcome this issue. During a surgical procedure for cystic tumors, autologous fibrin glue is to be injected into the tumor cysts, which solidifies the cyst lumens and cyst walls en bloc with reducing the tumor size. As a result, tumor masses and cyst walls can be removed completely in an en bloc fashion in all cases. Copyright: Methods: The illustrative case presented in this report is a patient with metastatic brain tumors in the frontal lobe. When we reached the tumor wall surgically, we first suctioned out the cyst content and subsequently injected autologous fibrin glue into the cyst lumen. The autologous fibrin glue solidified the tumor en bloc, and we resected the tumor mass and the cyst walls in an en bloc fashion. Results: We have applied this technique to four cases with cyst-type metastatic brain tumors. This approach made it possible to perform ideal en bloc resection in all cases. There were no adverse events due to the autologous fibrin glue. Conclusion: We developed a novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue, which allows en bloc resection of tumor masses and cyst walls quite safely using inexpensive materials. Given these advantages, it appears a promising surgical strategy for cyst-type metastatic brain tumors.
  • Gary Kohanbash; Kayla McKaveney; Masashi Sakaki; Ryo Ueda; Arlan H. Mintz; Nduka Amankulor; Mitsugu Fujita; John R. Ohlfest; Hideho Okada
    Cancer Research American Association for Cancer Research (AACR) 73 (21) 6413 - 6423 0008-5472 2013/10 
    Abstract Malignant gliomas are lethal cancers in the brain and heavily infiltrated by myeloid cells. Interleukin-4 receptor-α (IL-4Rα) mediates the immunosuppressive functions of myeloid cells, and polymorphisms in the IL-4Rα gene are associated with altered glioma risk and prognosis. In this study, we sought to evaluate a hypothesized causal role for IL-4Rα and myeloid suppressor cells in glioma development. In both mouse de novo gliomas and human glioblastoma cases, IL-4Rα was upregulated on glioma-infiltrating myeloid cells but not in the periphery or in normal brain. Mice genetically deficient for IL-4Rα exhibited a slower growth of glioma associated with reduced production in the glioma microenvironment of arginase, a marker of myeloid suppressor cells, which is critical for their T-cell inhibitory function. Supporting this result, investigations using bone marrow-derived myeloid cells showed that IL-4Rα mediates IL-13–induced production of arginase. Furthermore, glioma-derived myeloid cells suppressed T-cell proliferation in an IL-4Rα–dependent manner, consistent with their identification as myeloid-derived suppressor cells (MDSC). Granulocyte macrophage colony-stimulating factor (GM-CSF) plays a central role for the induction of IL-4Rα expression on myeloid cells, and we found that GM-CSF is upregulated in both human and mouse glioma microenvironments compared with normal brain or peripheral blood samples. Together, our findings establish a GM-CSF–induced mechanism of immunosuppression in the glioma microenvironment via upregulation of IL-4Rα on MDSCs. Cancer Res; 73(21); 6413–23. ©2013 AACR.
  • Shinji Kondo; Ayako Demachi-Okamura; Tomoya Hirosawa; Hiroyuki Maki; Mitsugu Fujita; Yasushi Uemura; Yoshiki Akatsuka; Eiko Yamamoto; Kiyosumi Shibata; Kazuhiko Ino; Fumitaka Kikkawa; Kiyotaka Kuzushima
    Human Immunology Elsevier BV 74 (9) 1103 - 1110 0198-8859 2013/09
  • Mitsugu Fujita
    Journal of Pharmacological Sciences 2013
  • Nobuhiro Nishio; Mitsugu Fujita; Yoshimasa Tanaka; Hiroyuki Maki; Rong Zhang; Tomoya Hirosawa; Ayako Demachi-Okamura; Yasushi Uemura; Osamu Taguchi; Yoshiyuki Takahashi; Seiji Kojima; Kiyotaka Kuzushima
    Journal of Immunotherapy Ovid Technologies (Wolters Kluwer Health) 35 (8) 598 - 606 1524-9557 2012/10
  • Gary Kohanbash; Eiichi Ishikawa; Mitsugu Fujita; Maki Ikeura; Kayla McKaveney; Jianzhong Zhu; Masashi Sakaki; Saumendra N. Sarkar; Hideho Okada
    OncoImmunology Informa UK Limited 1 (4) 487 - 492 2162-4011 2012/07
  • GM-CSF-induced IL-4R alpha Expression on Glioma-infiltrating Monocytes Promotes Immunosuppression and Glioma Growth
    Kohanbash, Gary; McKaveney, Kayla; Sakaki, Masashi; Fujita, Mitsugu; Okada, Hideho
    Journal of Immunotherapy 35 (9) 777 - 777 1524-9557 2012
  • COX-2 BLOCKADE IMMUNOLOGICALLY SUPPRESSES BRAIN METASTASES OF LUNG CANCER
    Fujita, Mitsugu; Zhang, Rong; Nakata, Susumu; Kuzushima, Kiyotaka
    Neuro-Oncology 14 38 - 38 1522-8517 2012
  • Mitsugu Fujita; Gary Kohanbash; Wendy Fellows-Mayle; Ronald L. Hamilton; Yoshihiro Komohara; Stacy A. Decker; John R. Ohlfest; Hideho Okada
    Cancer Research American Association for Cancer Research (AACR) 71 (7) 2664 - 2674 0008-5472 2011/03 
    Abstract Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E2 (PGE2). Because PGE2 induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b+Ly6GhiLy6Clo granulocytic MDSCs in both the bone marrow and the TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration. Cancer Res; 71(7); 2664–74. ©2011 AACR.
  • INTERLEUKIN-4 RECEPTOR ALPHA CHAIN (IL-4R-ALPHA) PROMOTES THE IMMUNOSUPPRESSIVE ACTIVITY OF GLIOMA-INFILTRATING MONOCYTES
    Kohanbash, Gary; McKaveney, Kayla; Sakaki, Masashi; Mintz, Arlan; Ohlfest, John; Bondy, Melissa; Fujita, Mitsugu; Okada, Hideho
    Neuro-Oncology 13 31 - 31 1522-8517 2011
  • ELK-1 REGULATES INTERFERON-ALPHA-8 EXPRESSION VIA A POLYMORPHIC REGION IN INTERFERON-ALPHA-8 PROMOTER ASSOCIATED WITH THE PROGNOSIS OF GLIOMA PATIENTS
    Kohanbash, Gary; Ishikawa, Eiichi; Fujita, Mitsugu; Ohno, Masasuke; Liu, Yan; Sakaki, Masashi; Ikeura, Maki; Scheurer, Michael; Bondy, Melissa; Okada, Hideho
    Neuro-Oncology 13 32 - 32 1522-8517 2011
  • Xinmei Zhu; Mitsugu Fujita; Linda A. Snyder; Hideho Okada
    Journal of Neuro-Oncology Springer Science and Business Media LLC 104 (1) 83 - 92 0167-594X 2010/11
  • Mitsugu Fujita; Michael E. Scheurer; Stacy A. Decker; Heather A. McDonald; Gary Kohanbash; Edward R. Kastenhuber; Hisashi Kato; Melissa L. Bondy; John R. Ohlfest; Hideho Okada
    Clinical Cancer Research American Association for Cancer Research (AACR) 16 (13) 3409 - 3419 1078-0432 2010/06 
    Abstract Purpose: We hypothesized that the type 1 IFNs would play a pivotal role in antiglioma immunosurveillance through promotion of type 1 adaptive immunity and suppression of immunoregulatory cells. Experimental Design: We induced de novo gliomas in Ifnar1−/− (deficient for type 1 IFN receptors) or wild-type mice by intracerebroventricuar transfection of NRas and a short hairpin RNA against P53 using the Sleeping Beauty transposon system. We analyzed the survival of 587 glioma patients for single nucleotide polymorphisms (SNP) in type 1 IFN–related genes. Results: Ifnar1−/− mice exhibited accelerated tumor growth and death. Analyses of brain tumor–infiltrating lymphocytes in Ifnar1−/− mice revealed an increase of cells positive for CD11b+Ly6G+ and CD4+FoxP3+, which represent myeloid-derived suppressor cells and regulatory T cells, respectively, but a decrease of CD8+ cytotoxic T lymphocytes (CTLs) compared with wild-type mice. Ifnar1−/− mouse–derived glioma tissues exhibited a decrease in mRNA for the CTL-attracting chemokine Cxcl10, but an increase of Ccl2 and Ccl22, both of which are known to attract immunoregulatory cell populations. Dendritic cells generated from the bone marrow of Ifnar1−/− mice failed to function as effective antigen-presenting cells. Moreover, depletion of Ly6G+ cells prolonged the survival of mice with developing gliomas. Human epidemiologic studies revealed that SNPs in IFNAR1 and IFNA8 are associated with significantly altered overall survival of patients with WHO grade 2 to 3 gliomas. Conclusions: The novel Sleeping Beauty–induced murine glioma model led us to discover a pivotal role for the type 1 IFN pathway in antiglioma immunosurveillance and relevant human SNPs that may represent novel prognostic markers. Clin Cancer Res; 16(13); 3409–19. ©2010 AACR.
  • Xinmei Zhu; Beth A. Fallert-Junecko; Mitsugu Fujita; Ryo Ueda; Gary Kohanbash; Edward R. Kastenhuber; Heather A. McDonald; Yan Liu; Pawel Kalinski; Todd A. Reinhart; Andres M. Salazar; Hideho Okada
    Cancer Immunology, Immunotherapy Springer Science and Business Media LLC 59 (9) 1401 - 1409 0340-7004 2010/06
  • Kotaro Sasaki; Gary Kohanbash; Aki Hoji; Ryo Ueda; Heather A McDonald; Todd A Reinhart; Jeremy Martinson; Michael T Lotze; Francesco M Marincola; Ena Wang; Mitsugu Fujita; Hideho Okada
    Journal of Translational Medicine Springer Science and Business Media LLC 8 (1) 1479-5876 2010/02 
    Abstract Background Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated. Methods We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells. Results Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD). Conclusion The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.
  • Kohanbash, Gary; Mintz, Arlan H.; McKaveney, Kayla; McDonald, Heather A.; Ohlfest, John R.; Okada, Hideho; Fujita, Mitsugu
    Journal of Immunotherapy 33 (8) 887 - 887 1524-9557 2010
  • Kohanbash, Gary; Mintz, Arlan H.; McKaveney, Kayla; McDonald, Heather A.; Ohlfest, John R.; Okada, Hideho; Fujita, Mitsugu
    Neuro-Oncology 12 1522-8517 2010
  • Roles of Interleukin-4 Receptor alpha-chain on Glioma-Infiltrating Monocytes
    Kohanbash, Gary; Mintz, Arlan H.; McKaveney, Kayla; McDonald, Heather A.; Ohlfest, John R.; Okada, Hideho; Fujita, Mitsugu
    Journal of Immunotherapy 33 (8) 887 - 887 1524-9557 2010
  • ROLES OF INTERLEUKIN-4 RECEPTOR A-CHAIN ON GLIOMA-INFILTRATING MONOCYTES
    Kohanbash, Gary; Mintz, Arlan H.; McKaveney, Kayla; McDonald, Heather A.; Ohlfest, John R.; Okada, Hideho; Fujita, Mitsugu
    Neuro-Oncology 12 1522-8517 2010
  • COX2 Blockade Suppresses Gliomagenesis by Inhibiting CCL2-Mediated Accumulation of Myeloid-derived Suppressor Cells in Glioma Sites
    Fujita, Mitsugu; Kohanbash, Gary; McDonald, Heather A.; Delamarre, Louis; Decker, Stacy A.; Ohlfest, John R.; Okada, Hideho
    Journal of Immunotherapy 33 (8) 897 - 897 1524-9557 2010
  • Ryo Ueda; Mitsugu Fujita; Xinmei Zhu; Kotaro Sasaki; Edward R. Kastenhuber; Gary Kohanbash; Heather A. McDonald; Jay Harper; Scott Lonning; Hideho Okada
    Clinical Cancer Research American Association for Cancer Research (AACR) 15 (21) 6551 - 6559 1078-0432 2009/11 
    Abstract Purpose: A variety of cancers, including malignant gliomas, overexpress transforming growth factor-β (TGF-β), which helps tumors evade effective immune surveillance through a variety of mechanisms, including inhibition of CD8+ CTLs and enhancing the generation of regulatory T (Treg) cells. We hypothesized that inhibition of TGF-β would improve the efficacy of vaccines targeting glioma-associated antigen (GAA)–derived CTL epitopes by reversal of immunosuppression. Experimental Design: Mice bearing orthotopic GL261 gliomas were treated systemically with a TGF-β–neutralizing monoclonal antibody, 1D11, with or without s.c. vaccinations of synthetic peptides for GAA-derived CTL epitopes, GARC-1 (77-85) and EphA2 (671-679), emulsified in incomplete Freund's adjuvant. Results: Mice receiving the combination regimen exhibited significantly prolonged survival compared with mice receiving either 1D11 alone, GAA vaccines alone, or mock treatments alone. TGF-β neutralization enhanced the systemic induction of antigen-specific CTLs in glioma-bearing mice. Flow cytometric analyses of brain-infiltrating lymphocytes revealed that 1D11 treatment suppressed phosphorylation of Smad2, increased GAA-reactive/IFN-γ–producing CD8+ T cells, and reduced CD4+/FoxP3+ Treg cells in the glioma microenvironment. Neutralization of TGF-β also upregulated plasma levels of interleukin-12, macrophage inflammatory protein-1α, and IFN-inducible protein-10, suggesting a systemic promotion of type-1 cytokine/chemokine production. Furthermore, 1D11 treatment upregulated plasma interleukin-15 levels and promoted the persistence of GAA-reactive CD8+ T cells in glioma-bearing mice. Conclusions: These data suggest that systemic inhibition of TGF-β by 1D11 can reverse the suppressive immunologic environment of orthotopic tumor-bearing mice both systemically and locally, thereby enhancing the therapeutic efficacy of GAA vaccines. (Clin Cancer Res 2009;15(21):6551–9)
  • Ryo Ueda; Gary Kohanbash; Kotaro Sasaki; Mitsugu Fujita; Xinmei Zhu; Edward R. Kastenhuber; Heather A. McDonald; Douglas M. Potter; Ronald L. Hamilton; Michael T. Lotze; Saleem A. Khan; Robert W. Sobol; Hideho Okada
    Proceedings of the National Academy of Sciences Proceedings of the National Academy of Sciences 106 (26) 10746 - 10751 0027-8424 2009/06 
    The RNase III endonuclease Dicer plays a key role in generation of microRNAs (miRs). We hypothesized that Dicer regulates cancer cell susceptibility to immune surveillance through miR processing. Indeed, Dicer disruption up-regulated intercellular cell adhesion molecule (ICAM)-1 and enhanced the susceptibility of tumor cells to antigen-specific lysis by cytotoxic T-lymphocytes (CTLs), while expression of other immunoregulatory proteins examined was not affected. Blockade of ICAM-1 inhibited the specific lysis of CTLs against Dicer -disrupted cells, indicating a pivotal role of ICAM-1 in the interaction between tumor cells and CTL. Both miR-222 and -339 are down-regulated in Dicer -disrupted cells and directly interacted with the 3′ untranslated region (UTR) of ICAM-1 mRNA. Modulation of Dicer or these miRs inversely correlated with ICAM-1 protein expression and susceptibility of U87 glioma cells to CTL-mediated cytolysis while ICAM-1 mRNA levels remained stable. Immunohistochemical and in situ hybridization analyses of 30 primary glioblastoma tissues demonstrated that expression of Dicer, miR-222, or miR-339 was inversely associated with ICAM-1 expression. Taken together, Dicer is responsible for the generation of the mature miR-222 and -339, which suppress ICAM-1 expression on tumor cells, thereby down-regulating the susceptibility of tumor cells to CTL-mediated cytolysis. This study suggests development of novel miR-targeted therapy to promote cytolysis of tumor cells.
  • Mitsugu Fujita; Xinmei Zhu; Ryo Ueda; Kotaro Sasaki; Gary Kohanbash; Edward R. Kastenhuber; Heather A. McDonald; Gregory A. Gibson; Simon C. Watkins; Ravikumar Muthuswamy; Pawel Kalinski; Hideho Okada
    Cancer Research American Association for Cancer Research (AACR) 69 (4) 1587 - 1595 0008-5472 2009/02 
    Abstract In an attempt to develop effective vaccines against central nervous system (CNS) tumors, we evaluated the ability of vaccines with standard dendritic cells (DC) versus type 1 polarizing DCs (DC1) to induce glioma-specific type 1 CTLs with CNS tumor-relevant homing properties and the mechanism of their action. C57BL/6 mouse–derived bone marrow cells were cultured with mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) for 6 days, and CD11c+ cells were subsequently cultured with GM-CSF, rmIFN-γ, rmIFN-α, rmIL-4, and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for 24 hours to generate DC1s. In analogy to their human counterparts, mouse DC1s exhibited surface marker profiles of mature DCs and produced high levels of IL-12 and CXCL10. Importantly for their application as cancer vaccines, such DC1s stably retained their type 1 phenotype even when exposed to type 2–promoting or regulatory T cell (Treg)–promoting environments. Consistently, mouse DC1s induced antigen-specific type 1 CTLs more efficiently than nonpolarized DCs in vitro. DC1s given s.c. migrated into draining lymph nodes, induced antigen-specific CTLs, and suppressed Treg accumulation. In addition, s.c. immunization with DC1s loaded with glioma-associated antigen (GAA)–derived CTL epitope peptides prolonged the survival of CNS GL261 glioma-bearing mice, which was associated with efficient CNS glioma homing of antigen-specific CTLs. Intratumoral injections of GAA peptide-loaded DC1s further enhanced the anti-CNS glioma effects of DC1-based s.c. immunization. Interestingly, the antitumor functions were abrogated with CXCL10−/− mouse–derived DC1s. Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines. [Cancer Res 2009;69(4):1587–95]
  • SYSTEMIC INHIBITION OF TRANSFORMING GROWTH FACTOR B IN GLIOMA-BEARING MICE IMPROVED THE THERAPEUTIC EFFICACY OF PEPTIDE VACCINATIONS TARGETING GLIOMA-ASSOCIATED ANTIGENS
    Ueda, Ryo; Fujita, Mitsugu; Zhu, Xinmei; Sasaki, Kotaro; Kastenhuber, Edward R.; Kohanbash, Gary; McDonald, Heather A.; Harper, Jay; Lonning, Scott; Okada, Hideho
    Neuro-Oncology 11 (6) 882 - 882 1522-8517 2009
  • Ueda, Ryo; Fujita, Mitsugu; Zhu, Xinmei; Sasaki, Kotaro; Kastenhuber, Edward R.; Kohanbash, Gary; McDonald, Heather A.; Harper, Jay; Lonning, Scott; Okada, Hideho
    Neuro-Oncology 11 (6) 882 - 882 1522-8517 2009
  • TYPE 1 DENDRITIC CELL VACCINES IN COMBINATION WITH POLY-ICLC-ASSOCIATION BETWEEN POSITIVE TETRAMER RESPONSE AND 6-MONTH PROGRESSION-FREE SURVIVAL
    Okada, Hideho; Lieberman, Frank S.; Ueda, Ryo; Fujita, Mitsugu; Kalinski, Pawel; Mintz, Arlan H.; Park, Deric M.; Bartlett, David L.; Brown, Charles K.; Zeh, Herbert; Whiteside, Theresa L.; Butterfield, Lisa H.; Hamilton, Ronald L.; Salazar, Andres M.; Pollack, Ian P.
    Neuro-Oncology 11 (6) 883 - 883 1522-8517 2009
  • Okada, Hideho; Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu, Xinmei; Lotze, Michael T.; Sobol, Robert W.; Khan, Saleem A.
    Neuro-Oncology 11 (2) 225 - 225 1522-8517 2009
  • INTERFERON-A SIGNALING IN THE BRAIN PLAYS A MAJOR ROLE IN IMMUNE SURVEILLANCE DURING GLIOMA GENESIS IN MICE
    Fujita, Mitsugu; Decker, Stacy A.; Popescu, Flavia; Olhfest, John R.; McDonald, Heather A.; Okada, Hideho
    Neuro-Oncology 11 (6) 882 - 882 1522-8517 2009
  • DICER-REGULATED MICRORNAS 222 AND 339 PROMOTE RESISTANCE OF CANCER CELLS TO CYTOTOXIC T-LYMPHOCYTES BY DOWNREGULATING ICAM-1 EXPRESSION
    Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu, Xinmei; Kastenhuber, Edward R.; McDonald, Hearher A.; Potter, Douglas M.; Lotze, Michael T.; Khan, Saleem A.; Sobol, Robert W.; Okada, Hideho
    Neuro-Oncology 11 (6) 962 - 962 1522-8517 2009
  • DICER-REGULATED MICRORNAS 222 AND 339 PROMOTE IMMUNE ESCAPE OF CANCER CELLS THROUGH DOWNREGULATION OF ICAM-1
    Okada, Hideho; Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu, Xinmei; Lotze, Michael T.; Sobol, Robert W.; Khan, Saleem A.
    Neuro-Oncology 11 (2) 225 - 225 1522-8517 2009
  • Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu, Xinmei; Kastenhuber, Edward R.; McDonald, Hearher A.; Potter, Douglas M.; Lotze, Michael T.; Khan, Saleem A.; Sobol, Robert W.; Okada, Hideho
    Neuro-Oncology 11 (6) 962 - 962 1522-8517 2009
  • Hideho Okada; Gary Kohanbash; Xinmei Zhu; Edward R. Kastenhuber; Aki Hoji; Ryo Ueda; Mitsugu Fujita
    Critical Reviews™ in Immunology Begell House 29 (1) 1 - 42 2162-6472 2009
  • Kotaro Sasaki; Xi Zhao; Angela D. Pardee; Ryo Ueda; Mitsugu Fujita; Sarita Sehra; Mark H. Kaplan; Lawrence P. Kane; Hideho Okada; Walter J. Storkus
    The Journal of Immunology The American Association of Immunologists 181 (1) 104 - 108 0022-1767 2008/07 
    Abstract VLA-4 plays a critical role in T cell trafficking into inflammatory sites. Our recent studies have suggested that VLA-4 expression on CD8+ T cells is negatively controlled by IL-4 and serves as a functionally distinguishing variable for why Type-1, but not Type-2, CD8+ T cells are able to traffic into tumors. In this study, using in vitro culture of murine CD8+ T cells under Type-1 and Type-2 cytokine conditions, we show that IL-4-mediated down-regulation of VLA-4 expression is completely abrogated in Stat6-deficient CD8+ T cells. Conversely, CD8+ T cells expressing a constitutively active mutant form Stat6 (Stat6VT) failed to express VLA-4 even in the absence of IL-4-stimulation. Notably, Type-2 CD8+ T cells developed from Stat6−/− but not wild-type mice were competent to migrate into tumor lesions in vivo. These results suggest that Stat6-signaling is necessary and sufficient to restrict CD8+ T cell expression of VLA-4 (by IL-4), thereby serving as a regulator for CD8+ T cell infiltration into tumors.
  • Mitsugu Fujita; Xinmei Zhu; Kotaro Sasaki; Ryo Ueda; Keri L. Low; Ian F. Pollack; Hideho Okada
    The Journal of Immunology The American Association of Immunologists 180 (4) 2089 - 2098 0022-1767 2008/02 
    Abstract A variety of cancers, including malignant gliomas, show aberrant activation of STAT3, which plays a pivotal role in negative regulation of antitumor immunity. We hypothesized that inhibition of STAT3 signals would improve the efficacy of T cell adoptive transfer therapy by reversal of STAT3-induced immunosuppression in a murine GL261 intracranial glioma model. In vitro treatment of GL261 cells with JSI-124, a STAT3 inhibitor, reversed highly phosphorylated status of STAT3. Systemic i.p. administration of JSI-124 in glioma-bearing immunocompetent mice, but not athymic mice, resulted in prolonged survival, suggesting a role of adaptive immunity in the antitumor effect. Furthermore, JSI-124 promoted maturation of tumor-infiltrating CD11c+ dendritic cells and activation of tumor-conditioned cytotoxic T cells, enhanced dendritic cells and GL261 production of CXCL-10, a critical chemokine for attraction of Tc1 cells. When i.p. JSI-124 administration was combined with i.v. transfer of Pmel-I mouse-derived type-1 CTLs (Tc1), glioma-bearing mice exhibited prolonged survival compared with i.p. JSI-124 or i.v. Tc1 therapy alone. Flow cytometric analyses of brain infiltrating lymphocytes revealed that JSI-124-treatment enhanced the tumor-homing of i.v. transferred Tc1 cells in a CXCL-10-dependent fashion. Systemic JSI-124 administration also up-regulated serum IL-15 levels, and promoted the persistence of transferred Tc1 in the host. These data suggest that systemic inhibition of STAT3 signaling can reverse the suppressive immunological environment of intracranial tumor bearing mice both systemically and locally, thereby promoting the efficacy of adoptive transfer therapy with Tc1.
  • Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu Xinmei; Lotze, Michael; Sobol, Robert; Khan, Saleem; Okada, Hideho
    Neuro-Oncology 10 (5) 807 - 807 1522-8517 2008
  • INDUCTION OF TYPE-1 CTL RESPONSES AGAINST NOVEL GLIOMA-ASSOCIATED ANTIGEN (GAA)-DERIVED EPITOPES EPHA2 (883-891) AND IL-13 ALPHA 2 (345-353) IN PATIENTS WITH RECURRENT MALIGNANT GLIOMA RECEIVING DENDRITIC CELL (DC) VACCINES IN COMBINATION WITH POLY-ICLC
    Okada, Hideho; Lieberman, Frank; Ueda, Ryo; Fujita, Mitsugu; Zhu, Xinmei; Kalinski, Pawel; Lunsford, L.; Kassam, Amin; Mintz, Arlan; Park, Deric; Mabold, Jennifer; Bartlett, David; Brown, Charles; Zeh, Herbert; Whiteside, Theresa; Butterfield, Lisa; Hamilton, Ronald; Salazar, Andres; Pollack, Ian
    Neuro-Oncology 10 (5) 1522-8517 2008
  • DICER-REGULATED MICRORNAS 222 AND 339 PROMOTE IMMUNE-ESCAPE OF GLIOMA CELLS THROUGH DOWN REGULATION OF ICAM-1
    Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu Xinmei; Lotze, Michael; Sobol, Robert; Khan, Saleem; Okada, Hideho
    Neuro-Oncology 10 (5) 807 - 807 1522-8517 2008
  • CPG-ENRICHED PLASMID VACCINATION IN A SPONTANEOUS GLIOMA MOUSE MODEL
    Popescu, Flavia E.; Xiong, Zhengming; Fujita, Mitsugu; Okada, Hideho; Ohlfest, John R.
    Neuro-Oncology 10 (5) 813 - 813 1522-8517 2008
  • ADDRESSING THE ANGIOGENIC SWITCH BY STUDYING TUMOR-HOST INTERACTIONS IN AN ANIMAL MODEL OF GLIOBLASTOMA MULTIFORME
    Ueda, Ryo; Kohanbash, Gary; Sasaki, Kotaro; Fujita, Mitsugu; Zhu Xinmei; Lotze, Michael; Sobol, Robert; Khan, Saleem; Okada, Hideho
    Neuro-Oncology 10 (5) 807 - 807 1522-8517 2008
  • Ryo Ueda; Keri L Low; Xinmei Zhu; Mitsugu Fujita; Kotaro Sasaki; Theresa L Whiteside; Lisa H Butterfield; Hideho Okada
    Journal of Translational Medicine Springer Science and Business Media LLC 5 (1) 68  1479-5876 2007/12 
    Abstract Background In patients with high grade glioma, little is known regarding existence of naturally occurring adaptive T cell reactivity against glioma-associated antigens (GAAs). In this report, we characterized GAA-specific CD8+ T cells and innate immune cells in a patient who has survived with anaplastic astrocytoma (AA) for over 12 years without recurrence. Methods Peripheral blood mononuclear cells (PBMCs) derived from the long term survivor with AA were evaluated for the frequency, cytotoxic T lymphocyte (CTL) activity and differentiation status of CD8+ cells recognizing GAA-derived epitopes as well as relative numbers of other immune cell subsets. This patient's AA tissue was evaluated for expression of two GAAs EphA2 and interleukin-13 receptor α2 subunit (IL-13Rα2) by immunohistochemistry. Results The patient's tumor expressed both EphA2 and IL-13Rα2, and in vitro stimulated PBMC demonstrated superior EphA2883–891 and IL-13Rα2345–353-specific CTL reactivity compared to PBMC samples from two other patients with progressing malignant glioma. Unstimulated EphA2883–891-reactive CD8+ T cells contained high numbers of CD45RA-/CCR7- late effector and CD45RA-/CCR7+ central memory cells. Among other leukocyte subsets, elevated numbers of NK-T cells were found. Conclusion To our knowledge, the current study is one of the first demonstrating the presence of antigen-experienced, GAA-reactive CD8+ T cells in a patient who has survived with AA for over 12 years without recurrence. Further studies are warranted to determine whether the status of GAA-reactive CD8+ T cells dictates survival of patients and/or response to therapeutic vaccines.
  • Fang Tian; Sammy Grimaldo; Mitsugu Fujita; Jonita Cutts; Nikola L Vujanovic; Lu-Yuan Li
    The Journal of Immunology The American Association of Immunologists 179 (9) 6369 - 6369 0022-1767 2007/11
  • Fang Tian; Sammy Grimaldo; Mitsugu Fugita; Jonita Cutts; Nikola L. Vujanovic; Lu-Yuan Li
    The Journal of Immunology The American Association of Immunologists 179 (6) 3742 - 3751 0022-1767 2007/09 
    Abstract Angiogenesis is an essential component of chronic inflammation that is linked to carcinogenesis. In this study, we report that human vascular endothelial growth inhibitor (VEGI, TNF superfamily 15), an endothelial cell-produced antiangiogenic cytokine, induces mouse dendritic cell (DC) maturation, a critical event in inflammation-initiated immunity. VEGI-stimulated bone marrow-derived immature DCs display early activation of maturation signaling molecules NF-κB, STAT3, p38, and JNK, and cytoskeleton reorganization and dendrite formation. The activation signals are partially inhibited by using a neutralizing Ab against death domain-containing receptor-3 (DR3) or a truncated form of DR3 consisting of the extracellular domain, indicating an involvement of DR3 in the transmission of VEGI activity. A VEGI isoform, TL1A, does not induce similar activities under otherwise identical experimental conditions. Additionally, the cells reveal significantly enhanced expression of mature DC-specific marker CD83, secondary lymphoid tissue-directing chemokine receptor CCR7, the MHC class-II protein (MHC-II), and costimulatory molecules CD40, CD80, and CD86. Functionally, the cells exhibit decreased Ag endocytosis, increased cell surface distribution of MHC-II, and increased secretion of IL-12 and TNF. Moreover, VEGI-stimulated DCs are able to facilitate the differentiation of CD4+ naive T cells in cocultures. These findings suggest that the anticancer activity of VEGI arises from coupling the inhibition of endothelial cell growth with the promotion of the adaptive immune mechanisms through the stimulation of DC maturation.
  • Takaya Tsuno; Atsushi Natsume; Shun Katsumata; Masaaki Mizuno; Mitsugu Fujita; Hirokatsu Osawa; Norimoto Nakahara; Toshihiko Wakabayashi; Yu-ichiro Satoh; Masaki Inagaki; Jun Yoshida
    Journal of Neuro-Oncology Springer Science and Business Media LLC 83 (3) 249 - 258 0167-594X 2007/02
  • Xinmei Zhu; Fumihiko Nishimura; Kotaro Sasaki; Mitsugu Fujita; Jill E Dusak; Junichi Eguchi; Wendy Fellows-Mayle; Walter J Storkus; Paul R Walker; Andres M Salazar; Hideho Okada
    Journal of translational medicine BIOMED CENTRAL LTD 5 10 - 10 1479-5876 2007/02 [Refereed]
     
    BACKGROUND: Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations. METHODS: C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes--mEphA2 (671-679), hgp100 (25-33) and mTRP-2 (180-188) for GL261, or ovalbumin (OVA: 257-264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC. RESULTS: The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-gamma by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity. CONCLUSION: These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.
  • Sasaki, Kotaro; Zhu, Xinmei; Vasquez, Cecilia; Nishimura, Fumihiko; Dusak, Jill E.; Huang, Jian; Fujita, Mitsugu; Wesa, Amy; Potter, Douglas M.; Walker, Paul R.; Storkus, Walter J.; Okada, Hideho
    Cancer Research AMER ASSOC CANCER RESEARCH 67 (13) 6451 - 8 0008-5472 2007 [Refereed]
     
    We have previously shown preferential tumor-homing and therapeutic efficacy of adoptively transferred type 1 CTL (Tc1) when compared with type 2 CTL (Tc2) in mice bearing intracranial ovalbumin-transfected melanoma (M05). Further characterizing the expression of a panel of homing receptors on Tc1 and Tc2 cells, we found that very late antigen (VLA)-4 (a heterodimer of CD49d and CD29), but none of other receptors evaluated, was expressed at significantly higher levels on Tc1 cells than on Tc2 cells. Although CD49d (alpha(4) integrin) can form heterodimers with both beta(1) (CD29) and beta(7) integrins, alpha(4)beta(7) complexes were not expressed by either Tc1 or Tc2 cells, suggesting that CD49d is solely expressed in VLA-4 complexes. VLA-4 expression on Tc2 cells was down-regulated in an interleukin (IL)-4 dose-dependent manner but not by other type 2 cytokines, such as IL-10 and IL-13, suggesting that IL-4 uniquely down-regulates VLA-4 expression on these cells. In accordance with the differential expression of VLA-4 on Tc1 versus Tc2 cells, Tc1 cells alone were competent to adhere to plate-bound VCAM-1-Ig fusion protein. Finally, the efficient trafficking of Tc1 cells into intracranial M05 lesions in vivo was efficiently blocked by administration of monoclonal antibodies against CD49d or VCAM-1 or small interfering RNA-mediated silencing of CD49d on Tc1 cells. Collectively, these data support the critical role of VLA-4 in the effective intracranial tumor homing of adoptive-transferred, antigen-specific Tc1 cells and suggest that more effective vaccine and/or ex vivo T-cell activation regimens may be developed by promoting the generation of VLA-4(+) antitumor Tc1 cells.
  • Fujita, Mitsugu; Zhu, Xinmei; Sasaki, Kotaro; Ueda, Ryo; Low, Keri; Pollack, Ian; Okada, Hideho
    Neuro-Oncology 9 (4) 501 - 501 1522-8517 2007
  • Mitsugu Fujita
    Journal of Pharmacological Sciences 2007
  • Vaccine combined with POLY-ICLC treatment promotes the type-1 polarization of the central nervous system glioma environment
    Zhu, Xinmei; Fujita, Mitsugu; Ueda, Ryo; Low, Keri; Salazar, Andres; Okada, Hideho
    Neuro-Oncology 9 (4) 502 - 502 1522-8517 2007
  • Systemic inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 ctls by modulation of the immunological microenvironment in intracranial gliomas
    Fujita, Mitsugu; Zhu, Xinmei; Sasaki, Kotaro; Ueda, Ryo; Low, Keri; Pollack, Ian; Okada, Hideho
    Neuro-Oncology 9 (4) 501 - 501 1522-8517 2007
  • Zhu, Xinmei; Fujita, Mitsugu; Ueda, Ryo; Low, Keri; Salazar, Andres; Okada, Hideho
    Neuro-Oncology 9 (4) 502 - 502 1522-8517 2007
  • Preferential expression of VLA-4 on Tc1 cells plays a critical role in trafficking into central nervous system tumors
    Sasaki, Kotaro; Zhu, Xinmei; Fujita, Mitsugu; Nishimura, Fumihiko; Dusak, Jill E.; Storkus, Walter J.; Okada, Hideho
    Neuro-Oncology 8 (4) 430 - 430 1522-8517 2006
  • Mitsugu Fujita; Miho Sato; Makoto Nakamura; Kazuko Kudo; Tetsuro Nagasaka; Masaaki Mizuno; Emi Amano; Yoko Okamoto; Yoshihiro Hotta; Hisashi Hatano; Norimoto Nakahara; Toshihiko Wakabayashi; Jun Yoshida
    Journal of Neurosurgery: Pediatrics Journal of Neurosurgery Publishing Group (JNSPG) 102 (3) 299 - 302 1933-0707 2005/04
  • Toru Arima; Atsushi Natsume; Hisashi Hatano; Norimoto Nakahara; Mitsugu Fujita; Dai Ishii; Toshihiko Wakabayashi; Manabu Doyu; Tetsuro Nagasaka; Jun Yoshida
    Journal of neurosurgery AMER ASSOC NEUROLOGICAL SURGEONS 102 (4) 733 - 7 0022-3085 2005/04 [Refereed]
     
    A rare case of chordoid meningioma in the lateral ventricle observed in an adult is reported. The first clinical manifestation of the disease was a prolonged fever of unknown origin. Abnormalities in the patient's blood chemistry, principally polyclonal hypergammaglobulinemia (immunoglobulin [Ig]G, IgA, and markedly IgE) and an elevated serum level of C-reactive protein, were associated with the disease. The tumor was histologically confirmed to be a chordoid meningioma, and its surgical removal resulted in complete resolution of the patient's symptoms. By combining reverse transcription-polymerase chain reaction and immunohistochemical analysis, it may be shown that cytokine production, including that of interleukin (IL)-6, IL-1beta, and vascular endothelial growth factor, plays a role in the pathogenesis of chordoid meningioma associated with Castleman syndrome.
  • Mitsugu Fujita; Miho Sato; Makoto Nakamura; Kazuko Kudo; Tetsuro Nagasaka; Masaaki Mizuno; Emi Amano; Yoko Okamoto; Yoshihiro Hotta; Hisashi Hatano; Norimoto Nakahara; Toshihiko Wakabayashi; Jun Yoshida
    Journal of Neurosurgery 102 (3) 299 - 302 0022-3085 2005/04 [Refereed]
     
    Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive malignant tumors found in infants and young children. The tumor is characterized by the presence of a rhabdoid cell component in all cases, but the histological origin is still unclear. Recently, germline mutation of the hSNF5/INI1 gene has been reported in association with AT/RTs. The authors report a rare case of an intraocular AT/RT followed by a fourth ventricular tumor. The results of immunohistochemical studies of the surgical specimens revealed the presence of an AT/RT and from this finding the neural origin was inferred. A novel missense mutation of the hSNF5/INI1 gene was demonstrated by DNA analysis. High-dose chemotherapy with stem cell rescue was effective in treating this patient. The immunohistochemical relationship between rhabdoid cells and the neurogenic zone, which has not been described in AT/RTs, is of great interest in view of the nature of rhabdoid cells.
  • Masato Endou; Masaaki Mizuno; Takuya Nagata; Kazuhiro Tsukada; Norimoto Nakahara; Takaya Tsuno; Hirokatsu Osawa; Tomohiko Kuno; Mitsugu Fujita; Manabu Hatano; Jun Yoshida
    Int J Mol Med PROFESSOR D A SPANDIDOS 15 (2) 277 - 283 1107-3756 2005 [Refereed]
     
    We examined the anti-tumor effect of cationic multilamellar liposome containing human IFN-beta (huIFN-beta) gene against cultured human pancreatic cancer cells. We also evaluated the combined effect of huIFN-beta gene entrapped in liposomes and gemcitabine. Furthermore, we examined the anti-tumor mechanisms of the therapy, with emphasis on the Ras-related signal pathway. Three human pancreatic cancer cell lines (AsPc-1, MIAPaCa-2, and PANC-1) were used in this study. The growth inhibition together with the therapy were evaluated by WST-1 assay; the production of huIFN-beta protein was measured by ELISA; the cell cycle and apoptosis were analyzed using a FACScan flow cytometer; the protein levels of Son of sevenless (SOS-1) and Ras-GAP were measured by Western blotting; and the activation of Ras-GTP was evaluated by the immunoprecipitation method. As a result, we found that huIFN-beta gene entrapped in liposomes demonstrated a strong anti-tumor effect against human pancreatic cancer cells. The treatment that combined huIFN-beta gene entrapped in liposomes and gemcitabine was more effective than each treatment alone. Although gemcitabine remarkably reduced the level of SOS-1, the above combined therapy reduced the level of SOS-1 even more significantly. Both huIFN-beta gene entrapped in liposomes and the com-bination of huIFN-beta gene entrapped in liposomes and gemcitabine increased the level of Ras-GAP, and decreased the activity of Ras-GTP. These results suggest that this combination therapy can induce strong anti-tumor activity against human pancreatic cancer cells through the regulation of the Ras-related signal pathway.
  • Yukio Seki; Masaaki Kimura; Nobuhiko Mizutani; Mitsugu Fujita; Yuri Aimi; Yoshio Suzuki
    Neurochemical Research Springer Science and Business Media LLC 30 (1) 123 - 128 0364-3190 2005/01
  • Mitsugu Fujita; Masaaki Mizuno; Tetsuro Nagasaka; Toshihiko Wakabayashi; Kenkou Maeda; Dai Ishii; Toru Arima; Aie Kawajiri; Masaki Inagaki; Jun Yoshida
    Journal of neurosurgery AMER ASSOC NEUROLOGICAL SURGEONS 101 (6) 1012 - 7 0022-3085 2004/12 [Refereed]
     
    OBJECT: The origin of multinucleated giant cells in glioma has not been made clear. In a previous paper the authors studied multinucleated giant tumor cells by using mitosis-specific phosphorylated antibodies to determine the phosphorylation of intermediate filaments and demonstrated that these cells stay in the early mitotic stage, undergoing neither fusion nor degeneration. In the current study the authors investigated the possible genetic causes of multinucleated giant tumor cells. METHODS: Cultured mono- or multinucleated human glioma cells were immunostained with monoclonal antibodies (mAbs) 4A4, YT33, TM71, HTA28, YG72, and alphaAIM-1. The three former antibodies revealed a particular mitotic cell cycle through site-specific phosphorylation of vimentin; that is, the early phase, mid phase, and late phase, respectively. The three later antibodies demonstrated phosphorylation of H3 at Ser28, phosphorylation of vimentin at Ser72, and aurora-B, respectively, making it possible to identify aurora-B distribution and function during mitosis. In addition, paraffin-embedded tissue sections obtained in three patients with giant cell glioblastoma were also examined. Multinucleated giant tumor cells immunoreacted with the mAb 4A4 and alphaAIM-1 but not with YT33, TM71, HTA28, and YG72 in vitro and in vivo. CONCLUSIONS: Findings in this study indicated that multinucleated giant tumor cells remain in the early mitotic phase because of aurora-B dysfunction, effecting aberrations in cytoplasmic cleavage without affecting nuclear division.
  • Yukio Seki; Mitsugu Fujita; Nobuhiko Mizutani; Masaaki Kimura; Yoshio Suzuki
    Surgical Neurology Elsevier BV 55 (1) 58 - 62 0090-3019 2001/01
  • 木村 雅昭; 藤田 貢; 水谷 信彦; 関 行雄; 鈴木 善男
    Neurosurgical Emergency (NPO)日本脳神経外科救急学会 5 (1) 44 - 50 1342-6214 2000/12 [Refereed]
     
    過去8年間に筆者らの施設に頭部外傷で入院した0〜15歳の患者203例について,頭部単純撮影による骨折の有無とCT所見,入院時の症状,意識レベル,治療経過,転帰等について比較検討した.その結果,頭蓋骨骨折がなくてCT上で頭蓋内出血を認めた症例が21%あり,頭蓋骨骨折があった場合には49%で頭蓋内出血が認められた.入院時意識レベルと頭部単純撮影での骨折の有無を組み合わせると,意識障害も骨折も無い場合にはCT上の頭蓋内病変は12%に,意識障害が無く頭蓋骨骨折がみられた場合には33%に異常を認めた.JCS20以下の意識障害があり骨折が無い場合には16%に,骨折がある場合には57%に異常を認めた.JCS30以上の意識障害があり,骨折が無い場合には39%に,骨折がある場合には100%に頭蓋内病変を伴っていた.以上の結果から頭部単純撮影単独で頭蓋内疾患のスクリーニングをすることは難しいが,意識レベルと組み合わせることでかなり有効なスクリーニングの可能性が示唆された
  • Y Suzuki; M Fujita; N Mizutani; Y Seki; M Kimura; Y Kajita; M Takayasu
    CLINICAL HEMORHEOLOGY AND MICROCIRCULATION IOS PRESS 23 (2-4) 307 - 312 1386-0291 2000 [Refereed]
     
    Effect of nitric oxide (NO) on vasomotor tone of cerebral parenchymal arterioles was studied in rats. Then, the role of NO was clinically investigated in the pathogenesis of progressive cerebral vascular occlusive disease, moyamoya disease. In rat, the cerebral arterioles, about 30-60 mum in diameter, were dilated by L-arginine, a precursor of NO, at concentrations as low as 0.1 mu mol with maximal dilation of 14% at 100 mu mol. The arterioles were constricted by NG-monomethyl-L-arginine (L-NMMA), a NO synthesis inhibitor. Superoxide dismutase, which seems to protect NO from inactivation, increased sensitivity of L-arginine. Compared with control specimens of cerebral spinal fluid (CSF) obtained from 16 patients, concentrations NO metabolites in the CSF of 23 patients with moyamoya disease were significantly higher. NO metabolites concentrations obtained during initial surgery decreased during a second, contralateral procedure. NO plays an important role in the regulation of basal tone of cerebral parenchymal arterioles and contributes to the increase in collateral circulation in cerebral occlusive disease like moyamoya disease. Vascular bypass surgery can reduce NO metabolites together with abnormal collateral circulation.

Books etc

  • Brain Tumors - Current and Emerging Therapeutic Strategies, Immunotherapeutic Strategies for Brain Tumors
    藤田 貢 (Joint work)2013

Conference Activities & Talks

  • 腫瘍免疫微小環境における病理AIイメージサイトメトリーと共局在指標
    長坂 暢; 阿河 杏介; 安藤 正恭; 阿部 智喜; 向山 知佑; 鍵山 大起; 福田 明夏; 藤田 貢; 山下 公大
    日本病理学会会誌  2023/03  (一社)日本病理学会
  • The regulation of GGCT and hedgehog ligands expression in a glioblastoma stem cell model induced by sh-TP53, EGFRvIII and NRasG12V
    山本夏菜; 山向千晶; 松下眞子; 橋本彩花; 野瀬梢; 茂山千愛美; 藤田貢; 飯居宏美; 中田晋
    日本薬学会年会要旨集(Web)  2023
  • γ-glutamylcyclotransferase knockdown inhibits proliferation of glioblastoma stem cells
    野瀬梢; 森昌也; 茂山千愛美; 飯居宏美; 藤田貢; 中田晋
    日本癌学会学術総会抄録集(Web)  2023
  • Antiproliferative mechanisms of γ-glutamylcyclotransferase knockdown in glioblastoma stem cells
    野瀬梢; 茂山千愛美; 飯居宏美; 森昌也; 亀井美保; 椎達哉; 吉田百花; 大草由佳子; 南京香; 安藤翔太; 藤田貢; 中田晋
    日本薬学会年会要旨集(Web)  2023
  • Involvement of Dhh in the inhibition of murine glioblastoma stem cell proliferation by GGCT knockdown
    森昌也; 吉田百花; 茂山千愛美; 安藤翔太; 藤田貢; 飯居宏美; 中田晋
    日本薬学会年会要旨集(Web)  2023
  • Involvement of Desert hedgehog in the Anti-proliferative activity by GGCT knockdown in murine glioblastoma stem cells
    森昌也; 嶋田絢子; 谷口恵香; 茂山千愛美; 藤田貢; 飯居宏美; 中田晋
    日本癌学会学術総会抄録集(Web)  2023
  • 転移性脳腫瘍に対する外科的治療の多様性と役割-自験284例より検証-
    奥田武司; 吉岡宏真; 中尾剛幸; 藤田貢; 高橋淳
    日本脳腫瘍の外科学会プログラム・抄録集  2023
  • ポストコロナへ向けての大学生の意識調査アンケート
    長田 道; 上田 哲也; 岸本 光; 櫻井 興平; 辻阪 英里; 中島 歩; 原 知里; 原田 剛志; 久司 万里子; 矢鋪 百恵; 藤田 貢; 藤本 美香
    全国大学保健管理研究集会プログラム・抄録集  2022/10  (公社)全国大学保健管理協会
  • 膠芽腫幹細胞ではJCI-20679処理によりAMPKの活性化とNFATc2の発現低下が引き起こされる(AMPK activation and decrease of NFATc2 expression levels are caused by JCI-20679 treatment in glioblastoma stem cells)
    安藤 翔太; 小島 直人; 茂山 千愛美; 藤田 貢; 飯居 宏美; 中田 晋
    日本癌学会総会記事  2022/09  (一社)日本癌学会
  • 膠芽腫幹細胞おけるStat5bの阻害はCyclin E2とMybの発現抑制を誘導する(Inhibition of Stat5b in glioblastoma stem cells induced downregulation of Cyclin E2 and Myb expression.)
    茂山 千愛美; 藤田 貢; 安藤 翔太; 飯居 宏美; 中田 晋
    日本癌学会総会記事  2022/09  (一社)日本癌学会
  • 教育形態とその成績評価方法に関する教員自己評価 アンケート調査による現状把握と課題の抽出
    藤田 貢; 池田 行宏; 三井 良之; 赤木 將男
    医学教育  2022/07  (一社)日本医学教育学会
  • 漫画と動画を教材としたオンライン型多職種連携教育の試み
    三井 良之; 池田 行宏; 藤田 貢; 梶 博史; 赤木 將男; 森 文美代
    医学教育  2022/07  (一社)日本医学教育学会
  • コロナ禍の多職種連携教育における仮想空間実施の影響
    池田 行宏; 木村 貴明; 三井 良之; 藤田 貢; 梶 博史; 赤木 將男; 松村 到; 井上 知美; 細見 光一; 大鳥 徹; 小竹 武; 岩城 正宏
    医学教育  2022/07  (一社)日本医学教育学会
  • 西山 理; 藤田 貢; 吉川 和也; 西川 裕作; 大森 隆; 佐野 安希子; 東田 有智; 松本 久子
    日本呼吸器学会誌  2022/04  (一社)日本呼吸器学会
  • マウス膠芽腫モデルにおけるStat5bを標的とした抗腫瘍メカニズムの解明
    茂山 千愛美; 藤田 貢; 安藤 翔太; 飯居 宏美; 中田 晋
    日本薬学会年会要旨集  2022/03  (公社)日本薬学会
  • γ-Glutamylcyclotransferase(GGCT)の発現抑制は膠芽腫幹細胞の増殖を抑制する
    野瀬 梢; 椎 達哉; 吉田 百花; 大草 由佳子; 南 京香; 茂山 千愛美; 安藤 翔太; 藤田 貢; 飯居 宏美; 中田 晋
    日本薬学会年会要旨集  2022/03  (公社)日本薬学会
  • アセトゲニン誘導体JCI-20679はp-AMPKタンパク質の発現上昇とNFATc2の発現低下を介して膠芽腫幹細胞の増殖を抑制する
    安藤 翔太; 小島 直人; 茂山 千愛美; 藤田 貢; 飯居 宏美; 中田 晋
    日本薬学会年会要旨集  2022/03  (公社)日本薬学会
  • 転移性脳腫瘍に対する集学的治療の時代的変遷と治療成績-自験172例の摘出術より検証-
    奥田武司; 吉岡宏真; 中尾剛幸; 藤田貢; 高橋淳
    日本脳腫瘍の外科学会プログラム・抄録集  2022
  • Effectiveness of screening for epilepsy in the elderly using a survey sheet
    吉岡宏真; 奥田武司; 中岡良介; 藤田貢; 高橋淳
    Geriatric Neurosurgery (Web)  2022
  • 髄膜癌腫症に合併した水頭症に対する髄液シャント術の有用性
    中尾 剛幸; 吉岡 宏真; 奥田 武司; 藤田 貢; 高橋 淳
    近畿大学医学雑誌  2021/12  近畿大学医学会
  • Stat5bの阻害はマウスモデル由来膠芽腫幹細胞の腫瘍形成能を抑制する
    茂山 千愛美; 藤田 貢; 安藤 翔太; 飯居 宏美; 中田 晋
    日本癌学会総会記事  2021/09  (一社)日本癌学会
  • JCI-20679はAMPKの活性化とNFAT1の減少を介して膠芽腫幹細胞の増殖を抑制する
    安藤 翔太; 小島 直人; 茂山 千愛美; 藤田 貢; 飯居 宏美; 中田 晋
    日本癌学会総会記事  2021/09  (一社)日本癌学会
  • COVID-19パンデミック下における学生相談形態の変化
    池田 行宏; 藤田 貢; 三井 良之; 梶 博史; 磯貝 典孝; 赤木 將男; 松村 到
    医学教育  2021/07  (一社)日本医学教育学会
  • 西山 理; 藤田 貢; 國田 裕貴; 白波瀬 賢; 御勢 久也; 吉川 和也; 佐伯 翔; 綿谷 奈々瀬; 西川 裕作; 大森 隆; 佐野 安希子; 佐野 博幸; 岩永 賢司; 東田 有智
    日本呼吸器学会誌  2021/04  (一社)日本呼吸器学会
  • マウス由来膠芽腫幹細胞におけるHedgehogシグナル転写因子Gli2抑制による抗腫瘍効果の検討
    谷川成佑; 谷川成佑; 藤田貢; 茂山千愛美; 安藤翔太; 飯居宏美; 武内勇人; 山中巧; 高橋義信; 橋本直哉; 中田晋
    日本分子脳神経外科学会プログラム・抄録集  2021
  • The acetogenin analog JCI-20679 inhibits glioblastoma stem cell proliferation via AMPK activation and NFAT1 suppression.
    安藤翔太; 小島直人; 茂山千愛美; 藤田貢; 飯居宏美; 中田晋
    日本薬学会年会要旨集(Web)  2021
  • In vivo antitumor effects by STAT5b inhibition in a mouse glioblastoma model
    茂山千愛美; 藤田貢; 安藤翔太; 飯居宏美; 中田晋
    日本薬学会年会要旨集(Web)  2021
  • プロドラッグ型クルクミンCMGによる実験的自己免疫性脳脊髄炎の抑制と小腸細菌叢変化
    佐藤 文孝; カドカ・スンダル; 尾村 誠一; 朴 雅美; 藤田 貢; 中村 優美和; 西尾 和人; 掛谷 秀昭; 角田 郁生
    神経免疫学  2020/10  日本神経免疫学会
  • 感染によって誘発される神経免疫病態 タイラーウイルスによる急性灰白脳脊髄炎・多発性硬化症動物モデル 分子相同性から腸内細菌叢まで
    角田 郁生; 尾村 誠一; 佐藤 文孝; 崎山 奈美江; Khadka Sundar; 中村 優美和; 朴 雅美; 藤田 貢
    神経免疫学  2020/10  日本神経免疫学会
  • 朴 雅美; 尾村 誠一; 佐藤 文孝; 藤田 貢; 角田 郁生
    腸内細菌学雑誌  2020/04  (公財)腸内細菌学会
  • The acetogenin analog JCI-20679 inhibits glioblastoma stem cell proliferation through NFAT1 suppression.
    安藤翔太; 小島直人; 茂山千愛美; 藤田貢; 河野雪那; 谷口恵香; 飯居宏美; 中田晋
    日本薬学会年会要旨集(CD-ROM)  2020
  • Stat5b promotes glioblastoma stem cell proliferation and survival derived from a glioblastoma mouse model
    茂山千愛美; 藤田貢; 安藤翔太; 谷口恵香; 飯居宏美; 中田晋
    日本薬学会年会要旨集(CD-ROM)  2020
  • Khadka Sundar; 尾村 誠一; 佐藤 文孝; 朴 雅美; 藤田 貢; 崎山 奈美江; 中村 優美和; 甲木 蒼紫; 角田 郁生
    近畿大学医学雑誌  2019/12  近畿大学医学会
  • 自己免疫性脳炎とてんかん ウイルス誘導性てんかん動物モデルと免疫系(Immune system and Theiler's virus-induced animal model for seizures/epilepsy)
    角田 郁生; 佐藤 文孝; 尾村 誠一; Khadka Sundar; 藤田 貢; 朴 雅美; 甲木 蒼紫; 中村 優美和; 崎山 奈美江; Lindeberg Felicia
    てんかん研究  2019/09  (一社)日本てんかん学会
  • ウイルス性脳脊髄炎モデルにおける中枢神経病態と腸内細菌叢との関連性
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; カドカ・スンダル; 角田 郁生
    NEUROINFECTION  2019/09  日本神経感染症学会
  • MS/NMO1 多発性硬化症ウイルスモデルにおける腸内細菌叢の変化と中枢神経系炎症性脱髄病変との関連
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; カドカ・スンダル; 角田 郁生
    神経免疫学  2019/09  日本神経免疫学会
  • 下垂体卒中とHMGB1
    奥田 武司; 藤田 貢; 加藤 天美
    Brain Tumor Pathology  2019/05  日本脳腫瘍病理学会
  • 尾村 誠一; 佐藤 文孝; 朴 雅美; 藤田 貢; 角田 郁生
    腸内細菌学雑誌  2019/04  (公財)腸内細菌学会
  • Stat5b阻害は発がんマウスモデル由来膠芽腫幹細胞にアポトーシスを誘導する  [Not invited]
    茂山 千愛美; 藤田 貢; 東馬 智未; 安藤 翔太; 河野 雪那; 谷口 恵香; 飯居 宏美; 中田 晋
    日本薬学会年会要旨集  2019/03  (公社)日本薬学会
  • アセトゲニン誘導体JCI-20679は膠芽腫細胞に対するテモゾロミドの効果を増強する  [Not invited]
    河野 雪那; 小島 直人; 茂山 千愛美; 東馬 智未; 藤田 貢; 安藤 翔太; 谷口 恵香; 飯居 宏美; 中田 晋
    日本薬学会年会要旨集  2019/03  (公社)日本薬学会
  • ピコルナウイルス誘導性急性脊髄炎モデルにおける腸内細菌叢と中枢神経遺伝子発現の変化
    佐藤文孝; 尾村誠一; 朴雅美; 藤田貢; SUNDAR Khadka; 西尾和人; 角田郁生
    日本ウイルス学会学術集会プログラム・予稿集(Web)  2019
  • 尾村 誠一; 清水 和秋; 桑原 基; 森川 みゆき; 藤田 貢; 朴 雅美; 佐藤 文孝; Pedio Erika; 楠 進; 角田 郁生
    近畿大学医学雑誌  2018/12  近畿大学医学会
  • 転写因子T-bet過剰発現は神経向性ウイルス感染において致死的となる
    佐藤 文孝; 川合 英一郎; Martinez Nicholas; 尾村 誠一; 藤田 貢; 朴 雅美; 高橋 智; 楊 景堯; 角田 郁生
    NEUROINFECTION  2018/10  日本神経感染症学会
  • 尾村誠一; 清水和秋; 桑原基; 森川みゆき; 藤田貢; 朴雅美; 佐藤文孝; PEDIO Erika; 楠進; 角田郁生
    Neuroimmunology  2018/09  日本神経免疫学会
  • 神経膠腫に合併したてんかん患者におけるペランパネルの発作抑制効果と腫瘍抑制効果(Response to seizure and tumor-progression by perampanel in uncontrollable epilepsy with gliomas)
    藤田 貢; 田崎 貴之; 宮内 正晴; 奥田 武司; 中川 修宏; 中野 直樹; 加藤 天美; 泉本 修一
    日本癌学会総会記事  2018/09  (一社)日本癌学会
  • 次世代シークエンシングを用いた多発性硬化症ウイルスモデルの解析 リンパ管分子発現低下が病気の進行に関連する
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; Alexander J. Steven; Kilgore Phillip C.S.R.; Cvek Urska; 角田 郁生
    NEUROINFECTION  2018/04  日本神経感染症学会
     
    多発性硬化症(MS)の発症要因はいまだ確定していないが、ウイルス感染がその一つと考えられている。MSの病理学的特徴は中枢神経系(CNS)への免疫細胞浸潤であり、接着分子の発現増加と血液脳関門の破綻が寄与している。一方、侵入した免疫細胞のCNSからの退出機序は不明であったが、近年CNS内リンパ管の存在が報告され、その役割が注目されている。本稿ではMSのウイルス感染モデルであるタイラーウイルス誘導性脱髄疾患マウスを用い、その脊髄トランスクリプトームデータのバイオインフォマティクス解析により、CNS内リンパ管の病態への寄与を検討した。タイラーウイルス感染群と対照群の接着分子、血液脳関門関連分子、リンパ管分子発現データを用いた主成分分析により、リンパ管分子の発現低下がリンパ球のCNSからの退出遅延に寄与することが示唆された。(著者抄録)
  • 脳腫瘍幹細胞マウスモデルを用いたアセトゲニン誘導体新規がん治療薬開発  [Not invited]
    東馬 智未; 茂山 千愛美; 小島 直人; 岩崎 仁志; 安藤 翔太; 藤田 貢; 谷口 恵香; 飯居 宏美; 吉貴 達寛; 中田 晋
    日本薬学会年会要旨集  2018/03  (公社)日本薬学会
  • 発がんマウスモデル由来膠芽腫幹細胞の増殖に対するStat5bの寄与  [Not invited]
    茂山 千愛美; 東馬 智未; 藤田 貢; 安藤 翔太; 岩崎 仁志; 谷口 恵香; 飯居 宏美; 吉貴 達寛; 中田 晋
    日本薬学会年会要旨集  2018/03  (公社)日本薬学会
  • 下垂体卒中とHMGB1  [Not invited]
    奥田武司; 藤田貢; 藤田貢; 露口尚弘; 加藤天美
    日本間脳下垂体腫瘍学会プログラム・抄録集  2018/01
  • Stat5b promotes glioblastoma stem-like cells proliferation derived from a glioblastoma mouse model  [Not invited]
    Moyama Chiami; Fujita Mitsugu; Ii Hiromi; Taniguchi Keiko; Yoshiki Tatsuhiro; Nakata Susumu
    CANCER SCIENCE  2018/01
  • 尾村誠一; 佐藤文孝; MARTINEZ Nicholas E; 朴雅美; 藤田貢; KILGORE Phillip; C. S. R; CVEK Urska; TRUTSCHL Marjan; MINAGAR Alireza; ALEXANDER J. Steven; 角田郁生
    近畿大学医学雑誌  2017/12
  • 佐藤文孝; 尾村誠一; 朴雅美; 藤田貢; 角田郁生
    近畿大学医学雑誌  2017/12
  • 尾村 誠一; 佐藤 文孝; Nicholas E.Martinez; 朴 雅美; 藤田 貢; Phillip; C.S.R.Kilgore; Urska Cvek; Marjan Trutschl; Alireza Minagar; J. Steven Alexander; 角田 郁生
    近畿大学医学雑誌 = Medical Journal of Kindai University  2017/12
  • 佐藤 文孝; 尾村 誠一; 朴 雅美; 藤田 貢; 角田 郁生
    近畿大学医学雑誌 = Medical Journal of Kindai University  2017/12
  • 田崎貴之; 泉本修一; 宮内正晴; 奥田武司; 中川修宏; 中野直樹; 加藤天美; 藤田貢
    バイオ治療法研究会学術集会プログラム・抄録集  2017/11
  • MS・NMO2 転写因子T-bet過剰発現は神経向性ウイルス感染を増悪させる  [Not invited]
    佐藤 文孝; 川合 英一郎; マルチネス・ニコラス; 尾村 誠一; 藤田 貢; 朴 雅美; 崎山 奈美江; 高橋 智; 楊 景堯; 角田 郁生
    神経免疫学  2017/10
  • 尾村誠一; 佐藤文孝; 藤田貢; 朴雅美; STEVEN Alexander J; KILGORE Phillip; C. S. R; CVEK Urska; 角田郁生
    Neuroinfection  2017/09
  • 次世代シークエンシングを用いたウイルス性脳脊髄炎モデルの解析 リンパ管分子発現低下が免疫細胞の中枢神経内停滞に関連する
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; Steven Alexander J.; Kilgore Phillip C.S.R.; Cvek Urska; 角田 郁生
    NEUROINFECTION  2017/09  日本神経感染症学会
  • Stat5bは発がんマウスモデル由来膠芽腫幹様細胞の増殖促進に寄与している  [Not invited]
    茂山 千愛美; 藤田 貢; 飯居 宏美; 谷口 恵香; 吉貴 達寛; 中田 晋
    日本癌学会総会記事  2017/09  日本癌学会
  • タイラーウイルス誘導性脳脊髄炎モデルにおける制御性T細胞の役割  [Not invited]
    佐藤 文孝; Martinez Nicholas; Karlsson Fridrik; 尾村 誠一; 朴 雅美; 藤田 貢; Grisham Matthew; 角田 郁生
    Cytometry Research  2017/06
  • グリオーマ幹細胞における薬剤排出分子ABCG2の役割  [Not invited]
    藤田 貢; 田崎 貴之; 奥田 武司; 米重 あずさ; 中田 晋
    Cytometry Research  2017/06
  • 佐藤文孝; 川合英一郎; マルチネス ニコラス; 尾村誠一; 藤田貢; 朴雅美; 崎山奈美江; 高橋智; 楊景堯; 角田郁生
    Neuroimmunology  2017
  • 藤田貢; 田崎貴之; 奥田武司; 吉岡宏真; 泉本修一; 加藤天美
    日本免疫治療学研究会学術集会プログラム・抄録集  2017
  • 奥田武司; 藤田貢; 藤田貢; 田崎貴之; 中田晋; 山下公大; 吉岡宏真; 泉本修一; 加藤天美
    バイオ治療法研究会学術集会プログラム・抄録集  2016/12
  • GENE EXPRESSION LANDSCAPE INCLUDING miRNAs IN DELAYED RADIATION NECROSIS OF BRAIN  [Not invited]
    Miyatake Shin-Ichi; Toho Taichirou; Fujita Mitsugu; Furuse Motomasa; Kawabata Shinji; Kuroiwa Toshihiko; Nonoguchi Naosuke
    NEURO-ONCOLOGY  2016/11
  • 感染因子による神経免疫疾患誘発のメカニズムと治療 ウイルス感染によって誘発される炎症性脱髄と軸索変性のメカニズム  [Not invited]
    角田 郁生; 佐藤 文孝; 尾村 誠一; 崎山 奈美江; 朴 雅美; 藤田 貢
    NEUROINFECTION  2016/09
  • METの膠芽腫幹細胞関連抗原としての可能性  [Not invited]
    藤田 貢; 田崎 貴之; 奥田 武司; 米重 あずさ; 中田 晋; 山下 公大; 加藤 天美
    日本がん免疫学会総会プログラム・抄録集  2016/06
  • 膠芽腫におけるMET遺伝子発現の臨床的意義  [Not invited]
    奥田 武司; 藤田 貢; 田崎 貴之; 中田 晋; 吉岡 宏真; 泉本 修一; 加藤 天美
    Brain Tumor Pathology  2016/05
  • 腸管粘膜免疫におけるケモカインMEC/CCL28の役割  [Not invited]
    山本 真也; 松尾 一彦; 藤田 貢; 義江 修; 中山 隆志
    日本薬学会年会要旨集  2016/03
  • 田崎貴之; 田崎貴之; 藤田貢; 藤田貢; 奥田武司; 吉岡宏真; 加藤天美
    バイオ治療法研究会学術集会プログラム・抄録集  2015/12
  • FUJITA MITSUGU; YOSHIOKA HIROMASA; OKUDA TAKESHI; NAKATA SUSUMU; MIYATAKE SHIN-ICHI; KATO AMAMI; YOSHIE OSAMU
    日本免疫学会総会・学術集会記録  2015/10
  • 腎細胞癌患者における末梢血抑制性ミエロイド細胞の解析  [Not invited]
    元島 崇信; 菰原 義弘; 哈斯塔; 塚本 博丈; 藤田 貢; 西東 洋一; 河野 吉昭; 西村 泰治; 竹屋 元裕; 江藤 正俊
    日本癌学会総会記事  2015/10  日本癌学会
  • 腫瘍内M2マクロファージにおけるB7-H3およびB7-H5発現量は肺癌原発転移性脳腫瘍の発症と相関する  [Not invited]
    藤田 貢; 奥田 武司; 中田 晋; 菰原 義弘; 加藤 天美; 義江 修
    日本癌学会総会記事  2015/10
  • 腎細胞癌患者における末梢血抑制性ミエロイド細胞の解析  [Not invited]
    元島 崇信; 菰原 義弘; 哈斯塔; 塚本 博丈; 藤田 貢; 西東 洋一; 鹿瀬島 裕; 河野 吉昭; 西村 泰治; 竹屋 元裕; 江藤 正俊
    日本泌尿器科学会総会  2015/04  (一社)日本泌尿器科学会総会事務局
  • 田崎 貴之; 奥田 武司; 岡本 邦男; 吉岡 宏真; 藤田 貢; 泉本 修一; 中川 和彦; 加藤 天美
    脳神経外科ジャーナル  2015/03 
    62歳、男性。右側頭葉膠芽腫にて開頭腫瘍摘出術施行。肉眼的全摘出後にテモゾロミドを併用した放射線化学療法を追加した。以後はテモゾロミド単独の維持化学療法を行った。術後17ヵ月で摘出腔内側に再発を認め、その後、大量胸水にて緊急入院となった。胸部CTにて胸膜に多発する腫瘤を認め、生検による病理診断の結果、膠芽腫の胸膜への血行性転移と判明した。(著者抄録)
  • 坂本万寿夫; 藤田貢; 檜垣史郎; 福田昌彦; 義江修; 下村嘉一
    日本眼科学会雑誌  2015/03
  • 松尾 一彦; 北田 卓也; 重田 暁子; 藤田 貢; 義江 修; 中山 隆志
    日本薬学会年会要旨集  2015/03
  • 下垂体卒中とHMGB1  [Not invited]
    奥田武司; 藤田貢; 田崎貴之; 泉本修一; 加藤天美
    日本間脳下垂体腫よう学会プログラム・抄録集  2015/02
  • Fujita Mitsugu; Nakata Susumu; Okuda Takeshi; Kato Amami; Yoshie Osamu
    CANCER RESEARCH  2014/10
  • FUJITA MITSUGU; OKUDA TAKESHI; NAKATA SUSUMU; KOMOHARA YOSHIHIRO; IZUMIMOTO SHUICHI; KATO AMAMI; YOSHIE OSAMU
    日本脳腫瘍学会プログラム・抄録集  2014
  • 葛島清隆; 藤田貢
    がん特異的細胞性免疫の活性化を基盤とする新たな治療の開発 平成22-25年度 総合研究報告書  2014
  • 藤田貢
    がん特異的細胞性免疫の活性化を基盤とする新たな治療の開発 平成25年度 総括・分担研究報告書  2014
  • 奥田武司; 田崎貴之; 藤田貢; 泉本修一; 加藤天美
    日本脳腫瘍の外科学会プログラム・抄録集  2014
  • 北田卓也; 松尾一彦; 重田暁子; 藤田貢; 義江修; 中山隆志
    生体機能と創薬シンポジウム要旨集  2014
  • 吉岡宏真; 藤田貢; 奥田武司; 中田晋; 田崎貴之; 泉本修一
    日本脳腫瘍学会プログラム・抄録集  2014
  • 奥田武司; 藤田貢; 田崎貴之; 吉岡宏真; 泉本修一; 加藤天美
    日本脳腫瘍学会プログラム・抄録集  2014
  • COX-2阻害による肺癌脳転移抑制の免疫学的作用機序(COX-2 Blockade Immunologically Suppresses Brain Metastasis of Lung Cancer)  [Not invited]
    藤田 貢; 中田 晋; 加藤 天美; 義江 修
    日本癌学会総会記事  2013/10
  • 奥田武司; 吉岡宏真; 田崎貴之; 藤田貢; 加藤天美
    日本癌治療学会学術集会(CD-ROM)  2013/09  (一社)日本癌治療学会
  • 奥田 武司; 吉岡 宏真; 田崎 貴之; 藤田 貢; 加藤 天美
    日本癌治療学会誌  2013/09
  • 藤田貢
    がん特異的細胞性免疫の活性化を基盤とする新たな治療の開発 平成24年度 総括・分担研究報告書  2013
  • 藤田貢
    がん特異的細胞性免疫の活性化を基盤とする新たな治療の開発 平成24年度 総括・分担研究報告書  2013
  • 吉岡宏真; 藤田貢; 奥田武司; 田崎貴之; 加藤天美
    日本脳腫瘍学会プログラム・抄録集  2013
  • 田崎貴之; 奥田武司; 吉岡宏真; 藤田貢; 加藤天美
    日本脳腫瘍学会プログラム・抄録集  2013
  • 奥田武司; 吉岡宏真; 田崎貴之; 藤田貢; 加藤天美
    日本脳腫瘍の外科学会プログラム・抄録集  2013
  • 奥田武司; 金田裕靖; 吉岡宏真; 田崎貴之; 藤田貢; 中川和彦; 加藤天美
    日本脳腫瘍学会プログラム・抄録集  2013
  • Kohanbash Gary; McKaveney Kayla; Sakaki Masashi; Fujita Mitsugu; Okada Hideh
    Journal of Immunotherapy  2012/11
  • Fujita Mitsugu; Zhang Rong; Nakata Susumu; Kuzushima Kiyotak
    Neuro-Oncology  2012/10
  • マウス膠芽腫における低酸素領域と幹細胞マーカー発現の解析(Expression of stemness-related genes in hypoxic area of Sleeping Beauty transposon-mediated murine glioblastoma)  [Not invited]
    中田 晋; 藤田 貢; 中西 速夫; 葛島 清隆; 近藤 英作
    日本癌学会総会記事  2012/08
  • 腫瘍抗原特異的TCR遺伝子導入NKT細胞を用いたがん免疫療法の可能性(Tumor-reactive TCR gene-transduced invariant NKT cells as a possible tool for cancer immunotherapy)  [Not invited]
    植村 靖史; 峰野 純一; 池田 裕明; 劉 天懿; 牧 寛之; 近藤 紳司; 張 エイ; 岡村 文子; 藤田 貢; 赤塚 美樹; 薗田 精昭; 珠玖 洋; 葛島 清隆
    日本癌学会総会記事  2012/08
  • COX-2阻害による肺がん脳転移の抑制とその免疫学的メカニズム(COX-2 blockade immunologically suppresses brain metastasis of lung cancer)  [Not invited]
    藤田 貢; 張 エイ; 中田 晋; 葛島 清隆
    日本癌学会総会記事  2012/08
  • Kohanbash Gary; Ishikawa Eiichi; Fujita Mitsugu; Mckaveney Kayla; Sakaki Masashi; Scheurer Michael; Bondy Melissa; Sarkar Saumendra Narayan; Okada Hideho
    CANCER RESEARCH  2012/04
  • 藤田貢
    がん特異的細胞性免疫の活性化を基盤とする新たな治療の開発 平成23年度 総括・分担研究報告書  2012
  • 藤田貢
    がん特異的細胞性免疫の活性化を基盤とする新たな治療の開発 平成23年度 総括・分担研究報告書  2012
  • Kohanbash Gary; Ishikawa Eiichi; Fujita Mitsugu; Ohno Masasuke; Liu Yan; Sakaki Masashi; Ikeura Maki; Scheurer Michael; Bondy Melissa; Okada Hideh
    Neuro-Oncology  2011/11
  • Kohanbash Gary; McKaveney Kayla; Sakaki Masashi; Mintz Arlan; Ohlfest John; Bondy Melissa; Fujita Mitsugu; Okada Hideh
    Neuro-Oncology  2011/11
  • COX-2阻害によるグリオーマ発現抑制メカニズムの免疫学的解析(COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells)  [Not invited]
    藤田 貢; コハンバッシュ・ゲリー; オルフェスト・ジョン; 岡田 秀穂
    日本癌学会総会記事  2011/09
  • 内因性HLAの発現を抑制し目的のHLA-A24を発現する人工抗原提示細胞を用いた卵巣がんを傷害するCTLの誘導(Induction of cancer-specific CTL using aAPCs expressing an extrinsic HLA of interest while silencing intrinsic ones)  [Not invited]
    近藤 紳司; 岡村 文子; 牧 寛之; Zhang Rong; 植村 靖史; 藤田 貢; 山本 英子; 柴田 清住; 吉川 史隆; 葛島 清隆
    日本癌学会総会記事  2011/09
  • 近藤紳司; 岡村文子; 牧寛之; RONG Zhang; 植村靖史; 藤田貢; 山本英子; 柴田清住; 吉川史隆; 葛島清隆
    日本がん免疫学会総会プログラム・抄録集  2011/06
  • Fujita Mitsugu; Kohanash Gary; Fellows-Mayle Wendy; Hamilton Ronald L; Decker Stacy A; Ohlfest John R; Okada Hideho
    CANCER RESEARCH  2011/04
  • COX2 BLOCKADE SUPPRESSES GLIOMAGENESIS BY INHIBITING CCL2-MEDIATED ACCUMULATION OF MYELOID-DERIVED SUPPRESSOR CELLS IN GLIOMA SITES  [Not invited]
    Mitsugu Fujita; Gary Kohanbash; Heather A. McDonald; Louis Delamarre; Stacy A. Decker; John R. Ohlfest; Hideho Okada
    NEURO-ONCOLOGY  2010/11  OXFORD UNIV PRESS INC
  • Kohanbash Gary; Mintz Arlan H; McKaveney Kayla; McDonald Heather A; Ohlfest John R; Okada Hideho; Fujita Mitsug
    Neuro-Oncology  2010/11
  • Fujita Mitsugu; Kohanbash Gary; McDonald Heather A; Delamarre Louis; Decker Stacy A; Ohlfest John R; Okada Hideh
    Journal of Immunotherapy  2010/10
  • Kohanbash Gary; Mintz Arlan H; McKaveney Kayla; McDonald Heather A; Ohlfest John R; Okada Hideho; Fujita Mitsug
    Journal of Immunotherapy  2010/10
  • Fujita Mitsugu; Decker Stacy A; Popescu Flavia; Olhfest John R; McDonald Heather A; Okada Hideh
    Neuro-Oncology  2009/12
  • Okada Hideho; Lieberman Frank S; Ueda Ryo; Fujita Mitsugu; Kalinski Pawel; Mintz Arlan H; Park Deric M; Bartlett David L; Brown Charles K; Zeh Herbert; Whiteside Theresa L; Butterfield Lisa H; Hamilton Ronald L; Salazar Andres M; Pollack Ian P
    Neuro-Oncology  2009/12
  • Ueda Ryo; Fujita Mitsugu; Zhu Xinmei; Sasaki Kotaro; Kastenhuber Edward R; Kohanbash Gary; McDonald Heather A; Harper Jay; Lonning Scott; Okada Hideh
    Neuro-Oncology  2009/12
  • Ueda Ryo; Kohanbash Gary; Sasaki Kotaro; Fujita Mitsugu; Zhu Xinmei; Kastenhuber Edward R; McDonald Hearher A; Potter Douglas M; Lotze Michael T; Khan Saleem A; Sobol Robert W; Okada Hideh
    Neuro-Oncology  2009/12
  • A PIVOTAL ROLE OF TYPE-1 INTERFERON SIGNALING IN IMMUNOSURVEILLANCE AGAINST GLIOMA: MOUSE STUDIES LEADING TO DISCOVERY OF NOVEL PROGNOSTIC MARKERS IN HUMANS  [Not invited]
    Fujita Mitsugu; Scheurer Michael E; Decker Stacy A; Popescu Flavia; McDonald Heather A; Kohanbash Gary; Kato Hisashi; Bondy Melissa L; Ohlfest John R; Okada Hideho
    NEURO-ONCOLOGY  2009/10
  • SYSTEMIC INHIBITION OF TRANSFORMING GROWTH FACTOR-2 IN GLIOMA-BEARING MICE IMPROVES THE THERAPEUTIC EFFICACY OF GLIOMA-ASSOCIATED ANTIGEN PEPTIDE VACCINES  [Not invited]
    Ueda Ryo; Fujita Mitsugu; Zhu Xinmei; Sasaki Kotaro; Kastenhuber Edward R; Kohanbash Gary; McDonald Heather A; Harper Jay; Lonning Scott; Okada Hideho
    NEURO-ONCOLOGY  2009/10
  • Interferon-\#945; signaling in the brain plays a major role in immune surveillance during glioma-genesis in mice  [Not invited]
    Mitsugu Fujita; Decker Stacy; Popescu Flavia; Ohfest John; McDonald Heather; Hideho Okada
    CANCER RESEARCH  2009/05
  • Okada Hideho; Ueda Ryo; Kohanbash Gary; Sasaki Kotaro; Fujita Mitsugu; Zhu Xinmei; Lotze Michael T; Sobol Robert W; Khan Saleem A
    Neuro-Oncology  2009/04
  • Okada Hideho; Lieberman Frank; Ueda Ryo; Fujita Mitsugu; Zhu Xinmei; Kalinski Pawel; Lunsford L; Kassam Amin; Mintz Arlan; Park Deric; Mabold Jennifer; Bartlett David; Brown Charles; Zeh Herbert; Whiteside Theresa; Butterfield Lisa; Hamilton Ronald; Salazar Andres; Pollack Ia
    Neuro-Oncology  2008/10
  • Popescu Flavia E; Xiong Zhengming; Fujita Mitsugu; Okada Hideho; Ohlfest John R
    Neuro-Oncology  2008/10
  • Ueda Ryo; Kohanbash Gary; Sasaki Kotaro; Fujita Mitsugu; Zhu Xinmei; Lotze Michael; Sobol Robert; Khan Saleem; Okada Hideh
    Neuro-Oncology  2008/10
  • Ueda Ryo; Kohanbash Gary; Sasaki Kotaro; Fujita Mitsugu; Zhu Xinmei; Lotze Michael; Sobol Robert; Khan Saleem; Okada Hideh
    Neuro-Oncology  2008
  • Fujita Mitsugu; Zhu Xinmei; Sasaki Kotaro; Ueda Ryo; Low Keri; Pollack Ian; Okada Hideh
    Neuro-Oncology  2007/10
  • Zhu Xinmei; Fujita Mitsugu; Ueda Ryo; Low Keri; Salazar Andres; Okada Hideh
    Neuro-Oncology  2007/10
  • Sasaki Kotaro; Zhu Xinmei; Fujita Mitsugu; Nishimura Fumihiko; Dusak Jill E; Storkus Walter J; Okada Hideh
    Neuro-Oncology  2006/10
  • 悪性神経膠腫で見られる多核巨細胞の性状解析  [Not invited]
    久野 智彦; 藤田 貢; 稲垣 昌樹; 長坂 昌登; 大澤 弘勝; 川面 ひとみ; 水野 正明; 吉田 純
    日本癌学会総会記事  2005/09
  • 久野智彦; 藤田貢; 稲垣昌樹; 長坂昌登; 大沢弘勝; 川面ひとみ; 水野正明; 吉田純
    日本癌学会学術総会記事  2005/08
  • 眼球内に初発し第四脳室に続発したAT/RTの1例  [Not invited]
    藤田 貢; 若林 俊彦; 水野 正明; 中原 紀元; 波多野 寿; 佐藤 美保; 長坂 徹郎; 工藤 寿子; 吉田 純
    Brain Tumor Pathology  2005/04
  • 久野智彦; 藤田貢; 稲垣昌樹; 長坂徹郎; 大沢弘勝; 川面ひとみ; 水野正明; 吉田純
    日本脳神経外科学会総会抄録集(CD-ROM)  2005
  • 波多野寿; 藤田貢; 有馬徹; 若林俊彦; 中原紀元; 浜麻人; 工藤寿子; 小島勢二; 長坂徹郎
    小児がん  2004/12
  • ハイリスクを持つ髄芽種への治療戦略
    波多野 寿; 藤田 貢; 有馬 徹; 岩崎 正重; 吉田 純; 若林 俊彦; 中原 紀元; 濱 麻人; 工藤 寿子; 小島 勢二; 長坂 徹郎
    小児がん  2004/12  (NPO)日本小児がん学会
  • 藤田貢; 水野正明; 若林俊彦; 長坂徹郎; 稲垣昌樹; 吉田純
    日本脳神経外科学会総会抄録集  2004/10
  • 藤田貢; 有馬徹; 若林俊彦; 中原紀元; 佐藤美保; 堀田喜裕; 天野恵美; 工藤寿子; 長坂徹郎
    日本脳神経外科学会総会抄録集  2003/10
  • 岩崎正重; 若林俊彦; 小島勢二; 工藤寿子; 中原紀元; 藤井正純; 国本圭市; 高須俊太郎; 藤田貢
    日本脳神経外科学会総会抄録集  2002/10
  • 藤田貢; 羽多野学; 藤井正純; 中原紀元; 梶田泰一; 水野正明; 若林俊彦; 吉田純
    日本脳神経外科学会総会抄録集  2002/10
  • 若林俊彦; 藤井正純; 岩崎正重; 国本圭市; 高須俊太郎; 藤田貢; 服部新之助; 中原紀元; 梶田泰一
    日本脳神経外科学会総会抄録集  2002/10
  • 藤井正純; 若林俊彦; 高須俊太郎; 岩崎正重; 藤田貢; 梶田泰一; 中原紀元; 国本圭市; 吉田純
    日本脳神経外科学会総会抄録集  2002/10
  • 藤井正純; 若林俊彦; 波太野範和; 中原紀元; 前田憲幸; 国本圭市; 高須俊太郎; 藤田貢; 吉田純
    日本脳神経外科学会総会抄録集  2001/10
  • 国本圭市; 若林俊彦; 藤井正純; 前田憲幸; 波多野寿; 中原紀元; 高須俊太郎; 藤田貢; 吉田純
    日本脳神経外科学会総会抄録集  2001/10
  • 若林俊彦; 藤井正純; 中原紀元; 吉田純; 堀部敬三; 前田憲幸; 高須俊太郎; 国本圭市; 藤田貢
    日本脳神経外科学会総会抄録集  2001/10
  • 関行雄; 鈴木善男; 木村雅昭; 水谷信彦; 藤田貢
    日本脳神経外科学会総会抄録集  2000/10
  • 藤田貢; 木村雅昭; 水谷信彦; 関行雄; 鈴木善男
    日赤医学  2000/10
  • 当院における小児脳死症例についての報告  [Not invited]
    藤田 貢; 田口 弥人; 石本 雅幸; 真野 るみ子; 山田 富雄; 杉浦 建之; 林 和敏; 安田 邦光; 高須 宏江; 石川 清
    日本救急医学会東海地方会誌  1999/09

MISC

Awards & Honors

  • 2012 SGH 財団 SGH がん研究助成
     
    受賞者: 藤田 貢
  • 2011 愛知県がん研究振興会 悪性新生物研究助成金
     
    受賞者: 藤田 貢
  • 2010 Society for Immunotherapy of Cancer Young Investigator Research Award
     
    受賞者: Mitsugu Fujita
  • 2010 Walter L. Copeland Foundation Young Researcher Award
     
    受賞者: Mitsugu Fujita
  • 2008 Walter L. Copeland Foundation Young Researcher Award
     
    受賞者: Mitsugu Fujita
  • 2005 上原記念生命科学財団 ポストドクトラルフェローシップ
     
    受賞者: 藤田 貢

Research Grants & Projects

  • 日本学術振興会:科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 中田 晋; 飯居 宏美; 藤田 貢
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2023/04 -2026/03 
    Author : 西山 理; 藤田 貢; 松本 久子
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2023/04 -2026/03 
    Author : 山下 公大; 藤田 貢; 掛地 吉弘; 齋藤 雅史; 高村 史記
  • 日本学術振興会:科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 奥田 武司; 藤田 貢; 大野 真佐輔; 山下 公大
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2023/06 -2025/03 
    Author : 掛地 吉弘; 中野 秀雄; 大野 真佐輔; 藤田 貢; 船越 洋平; 山下 公大
  • 日本学術振興会:科学研究費助成事業
    Date (from‐to) : 2022/04 -2025/03 
    Author : 中松 清志; 藤田 貢; 李 在俊; 土井 啓至
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2022/04 -2025/03 
    Author : 押切 太郎; 藤田 貢; 掛地 吉弘; 山下 公大; 齋藤 雅史; 高村 史記
  • 日本学術振興会:科学研究費助成事業
    Date (from‐to) : 2022/04 -2025/03 
    Author : 大野 真佐輔; 中野 秀雄; 藤田 貢; 山下 公大
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2022/04 -2025/03 
    Author : 吉村 紳一; 藏本 要二; 藤田 貢; 山原 研一
  • 日本学術振興会:科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 藤田 貢; 山下 公大; 中田 晋; 宮武 伸一
     
    グリオーマに対する治療成績は高線量放射線治療の進歩により向上し、長期生存例が増加している。一方で遅発性脳放射線壊死を生じる症例も増加傾向にある。 本病態は進行性の組織壊死と病変周囲に広範な脳浮腫を来たし、患者は種々の神経脱落症状を呈して QOL が低下し、ひいては患者生命をも脅かす。現在は抗 VEGF 抗体ベバシズマブによる治療が薬事承認されつつあるが、本治療終了後に壊死再発をきたす症例も多く、本病態のすべてが解明され制御されているとは言 い切れない。近年の研究で我々は脳放射線壊死組織内では慢性炎症状態が生じていることが示されている。そこで本研究課題では、脳放射線壊死組織内における 免疫応答の解析を試みた。 我々の先行研究毛により、ヒト脳放射線壊死組織内で集積亢進している M2 マクロファージでは B7-H3 および B7-H5 といっ た免疫抑制性分子の発現亢進が示されていたことから、令和 3 年度からはこれらを深層学習アルゴリズムを用いた病理組織解析システム (Cu-Cyto) を用いた詳細な病理組織解析を試みた。加えて次世代シークエンサーを用いた腸内細菌叢の予備解析により、クロストリジア目が脳放射線壊死に関連する B7 分子発現 M2 マクロファージ集積と相関することが明らかとなった。以上の結果より、脳放射線壊死の悪化には組織中に浸潤する M2 マクロファージの一部が 関与し、それには腸内細菌が産生する代謝産物も関与しうることが示唆された。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2021/04 -2024/03 
    Author : 松田 武; 掛地 吉弘; 山下 公大; 竹内 俊文; 谷野 裕一; 犬伏 祥子; 向山 順子; 中野 秀雄; 藤田 貢
     
    本研究は、Liquid biopsy による原発性大腸癌術後再発の早期検出法の開発を目的とし、患者検体の採取および解析手段として涙液由来エクソソーム検出法 (TearExo 法) を用いる。これまでの成果と併せて述べると、本手法は①症例検体集積が簡便であり、迅速な前向き研究が実施可能、②エクソソームを確保するための抗体は変更可能で、病態・患者特異的に最適化したエクソソーム解析が可能、等の利点がある。転移臓器別抗体および患者個別抗体によるエクソソームを検出することで、個別検出を目指した次世代型精密医療の基盤構築を試みる。 まず、大腸癌細胞株を用いたエクソソーム検出と確認を行う。採取されたexosomeをmiRNA検出で確認する。大腸癌細胞株由来や大腸癌原発巣切除例組織培養液由来のエクソソームの単球系細胞への影響を検討する。この部分は超遠心とELISA 法で検証する。エクソソームと単球系細胞への影響を検討する。超遠心とELISA 法で検証し、RNAシーケンスを行う。さらに、大腸癌原発巣切除例のエクソソーム検出と定量を行うために、術前後でTearExo 法の検証を行う。さらに、同系が確立されれば、大腸癌同時性肝転移症例、同時性肺転移症例に対するエクソソーム検出とエクソソームの解析を行う。術前後でTearExo 法でのエクソソーム検証を行う。さらに、原発性大腸癌切除例に対するエクソソーム検出例の集積と観察研究を行い、大規模前向き臨床研究へと進めたい。 本研究の成果は、大腸癌の再発の早期検出のみならず、臓器指向性転移の検出方法が期待され、臓器別のフォローを重点的に行うことにより、早期発見と早期治療による治療性の向上を目指すものである。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 掛地 吉弘; 山下 公大; 向山 順子; 中野 秀雄; 岡田 誠治; 青井 貴之; 藤田 貢; 高村 史記
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 中田 晋; 飯居 宏美; 藤田 貢
     
    がん細胞およびHEK293細胞において、GGCTの発現上昇はHif1aの発現を増加させ、対照的にGGCTの人為的発現抑制はHif1aの発現を抑制することを発見した。すなわち、GGCTがHif1aの発現を制御することを発見した。メタボローム解析でGGCTの発現の亢進は、好気的解糖系を促進する因子であることを発見し、ワールブルグ効果を制御する全く新しい因子としてGGCTを発見した。また、Sleeping BeautyトランスポゾンシステムでヒトEGFRvIII、NRasG12V、shRNA-p53を新生仔脳室に注入し、脳室周囲の神経幹細胞に導入する技術を用いて独自に樹立した膠芽腫幹細胞モデルにおいて、GGCTの発現低下によるヘッジホッグ経路に対する影響ついて解析を行ったところ、DHHの発現がタンパク質レベルで抑制されることを発見した。さらに、ヘッジホッグ経路のターゲット遺伝子である Gli1の発現もタンパク質レベルで抑制を受けることを確認した。これらの結果は、GGCTが、Hif1aの発現の亢進とそれによるワールブルグ効果を惹起し、ヘッジホッグ経路の活性化の亢進に寄与している可能性を示唆している。すなわち、GGCTはがん代謝を攻撃するために、有用な分子標的である可能性がある。さらに、低酸素により誘導される因子としてStat5bが膠芽腫幹細胞を攻撃するための標的として有望であること、GGCTと結合する因子であるPHB2の阻害剤はp21の誘導を介して膠芽腫細胞を含むがん細胞の増殖を効率よく抑制すること、ミトコンドリア複合体I阻害剤は膠芽腫細胞の進展を制御するNFATの発現を抑制すること、さらに、GGCTを標的としたアンチセンス核酸が生体内腫瘍の進展を抑制すること、新規のGGCT阻害剤としてU83836Eという化合物をみいだし、生体内腫瘍の進展を抑制することをみいだした。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 奥田 武司; 藤田 貢; 山下 公大
     
    2021 年度は肺癌血行性脳転移マウスモデルの脳組織を採取し、フローサイトメトリー法を用いてマクロファージ分画上の B7-H3 および B7-H5 発現レベルを確認した。同時に脳腫瘍組織より M2 マクロファージを単離して mRNA を抽出し、DNA マイクロアレイを用いたトランスクリプトーム解析を行った。さらにマルチプレックスサイトカイン測定も導入し、限定された臨床検体サンプルから相当量のサイトカイン/ケモカインデータの取得を行なっている。 他者の先行研究では肺癌細胞上に B7-H3 が発現することが示され、B7-H3 を標的とした治療薬が治験レベルで用いられるようになった。そこで我々真相学習アルゴリズムを用いた病理組織解析システム Cu-Cyto を用いて、腫瘍組織中の B7-H3 発現を解析した。上記知見と同様、一部の転移性肺癌細胞は B7-H3 を発現しており、かつ腫瘍組織に浸潤するマクロファージ上にも B7-H3 発現がみられた。 近年腫瘍組織近傍に三次リンパ節様構造物 (Tertiary Lymphoid Structures: TLS または Tertiary Lymphoid Organs: TLO) が形成され、腫瘍増殖あるいは腫瘍制御に関わることが示されている。そこで我々は Cu-Cyto システムを用いて上記腫瘍組織中での TLS/TLO を検索し、これらの発現頻度等を調べた。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2019/04 -2022/03 
    Author : NAKAMATSU KIYOSHI
     
    In this study, we conducted a dose-increase test for glioblastoma clinically and were able to collect basic data to establish a safe and appropriate irradiation dose. We experimentally confirmed that radiation brain necrosis is induced in normal mice, and confirmed that MRI can detect that this model is accompanied by tissue destruction, angiogenesis, and peri-edema seen during human radiation brain necrosis.We found that cell migration factor CXCL12 chemokine expression is enhanced in radiation brain necrosis tissues, cell group M2 macrophages that cause chronic inflammation in a CXCL12-dependent manner are infiltrated, and that the expression of novel immune checkpoint molecules B7-H3 and B7-H5 is increased in these cells.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2019/04 -2022/03 
    Author : Yamashita Kimihiro
     
    This study shows the potential of a novel dendritic cell vaccine therapy in antitumor immunity, in which bone marrow-derived dendritic cells are electroporated with an exogenous ovalbumin protein and simultaneously pulsed with α-galactosylceramide. This strategy enhances the induction of cytotoxic CD8+ T cells specific for tumor-associated antigens through the activation of invariant natural killer T cells, natural killer cells, and intrinsic dendritic cells. Moreover, this strategy sustains antigen-specific antitumor T cell responses over time.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2018/04 -2021/03 
    Author : FUJITA Mitsugu
     
    In M2 macrophages accumulating in radioactive necrotic brain tissues, immunosuppressive molecules such as B7-H3 and B7-H5 were found to be upregulated. Likewise, in the mouse model, the expression of these molecules was also enhanced, and they were found to be involved in peripheral edema of radiation brain necrosis. Analysis of intestinal microflora in mice using the next generation sequencer showed that Clostridia correlated with the intensity of the immune response related to cerebral radiation necrosis. M2 removal experiment showed marked prolongation of mouse survival days. These results suggest that M2 macrophages and intestinal bacteria infiltrating into tissues are involved in the deterioration of cerebral radiation necrosis.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : IZUMOTO Shuichi
     
    WT1 based cancer immunotherapy is a therapy, in which HLA class I binding 9-mer WT1 peptide is administered intradermally, to induce WT1-specific cellular immune responses. We investigated the safety and immune response of vaccine therapy of WT1 against grade 2/3 glioma. Glioma cells in the animal model showed expressions of WT1, and immune cells were accumulated focally, but the response of WT1 vaccination was poor. In patients of malignant glioma, accumulation of WT1-specific immune response was detected but WT1-specific killer T cells were poor on the surface of tumor cells. Immunohistochemical analysis of skin specimens, where WT1 peptide was administered intradermally, revealed reactive proliferation of macrophages with giant cell formation and infiltration of CD4+ and CD8+T, and CD20+B lymphocytes in the lower dermis. These findings provide basic information about local immune responses elicited in the vaccination site.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2016/04 -2019/03 
    Author : Nakata Susumu
     
    Stat5b has been identified as a candidate for a novel therapeutic target, which is regulated by both Wnt and hypoxia responsible signaling pathways as a hub-gene in glioblastoma stem cells derived from a transposon-induced mouse model. On the other hand, it has also been clarified that the activity of the Shh pathway, which is maintained by Gli2 expression, forms a feedforward loop that activates Wnt pathway, by the signal crosstalk, in the shTP53/NRasG12V/EGFRvIII-driven glioblastoma stem cells, thereby promotes expansion of the glioblastoma stem cell population. The upregulation of Gli2 is maintained by a novel factor that regulates homeostasis of redox metabolism. These findings would be usuful for a development of a novel strategy targeting Stat5b or Gli2 to improve treatment for patients with glioblastoma.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2016/04 -2019/03 
    Author : Yamashita Kimihiro
     
    We aimed to induce the tumor-reactive T cells using allogeneic reactions. To this end, we planned two projects simultaneously. At first, the mechanisms that allogeneic IgG and tumor cells form an immune complex, which is efficiently phagocytosed by dendritic cells in vitro and exerts a strong antigen presenting ability was reported. Using this system, we tried to establish a therapeutic model for colorectal cancer. Currently, we got the results that T cell activation is not sufficient. Second, we advanced induction of tumor-reactive T cells by NKT cell-activating allogeneic vaccine vectors composed of antigen-introduced allogeneic dendritic cells. We succeeded in establishing a vaccine vector using syngeneic dendritic cells. It is suggested that allogeneic dendritic cells show an effect in a lung metastasis model. We established a vaccine vector using allogeneic dendritic cells. It is suggested that allogeneic vaccine vector system showed an effect in a lung metastasis model.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : OKUDA TAKESHI
     
    It was recognized that the immune system mainly on the M2 macrophage participated in mechanism of the metastasis to brain onset in the lung cancer. Furthermore, I was able to identify the gene cluster which could become the treatment target of this M2 macrophage in microarray analysis. In addition, this immunoresponse proved that the metabolism product which intestinal bacteria produced participated. The possibility that a new treatment strategy to prevent metastasis to brain was provided was suggested in future.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : FUJITA Mitsugu
     
    In M2 macrophages accumulating in radioactive necrotic brain tissues, immunosuppressive molecules such as B7-H3 and B7-H5 were found to be upregulated. Likewise, in the mouse model, the expression of these molecules was also enhanced, and they were found to be involved in peripheral edema of radiation brain necrosis. Analysis of intestinal microflora in mice using the next generation sequencer showed that Clostridia correlated with the intensity of the immune response related to cerebral radiation necrosis. M2 removal experiment showed marked prolongation of mouse survival days. These results suggest that M2 macrophages and intestinal bacteria infiltrating into tissues are involved in the deterioration of cerebral radiation necrosis.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2014/04 -2017/03 
    Author : Miyatake Shin-Ichi
     
    1)Establishment of model rat and mouse of radiation necrosis in the brain:Wister rats were irradiated with 65 Gy X-ray. Five to 6 months after X-ray irradiation brain radiation necrosis was confirmed almost all rats by MRI and autopsy specimen.To establish smaller sized model, mice were irradiated with 70MeV proton with 60Gy-equivalent. The irradiated mice were treated with 2 different kinds of HIF-1 inhibitors (YC-1 and GN44028). Now these mice were observed with periodic MRI. Another couple of months will be mandatory to elucidate some conclusions. 2)Seven recurrent malignant glioma patients were treated with boron neutron capture therapy with the simultaneous use of bevacizumab to prevent the occurrence of symptomatic radiation necrosis. All cases showed favorable prolongation of overall survival without radiation necrosis.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : YOSHIE Osamu; NAKAYAMA Takashi; TSUNODA Ikuo
     
    CCL28 is expressed in the mucosal tissues and to attract IgA-antibody secreting cells (IgA-ASCs) via CCR10. CCL28 has an antimicrobial activity against microbes in vitro. However, in vivo evidence for the role of CCL28 in the mucosal immunity remains scanty. We generated CCL28-deficient mice and demonstrated that CCL28-deficient mice showed reduced numbers and altered distribution of IgA-ASCs in the colon. The IgA contents in the fecal extracts were low. The average amounts of IgA secreted by a single IgA-ASC isolated from the lamina propria of the colon was reduced. Furthermore, the 16S rRNA sequencing analysis of feces revealed an increase of the Class Bacilli. Consistent with the low IgA production and altered microbiota in the colon, CCL28-deficient mice had aggravated colitis upon treatment with dextran sulfate, which was ameliorated by oral antibiotics. Therefore, CCL28 has an role in the mucosal immunity of the colon as a chemoattractant with a direct antimicrobial activity.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : IZUMOTO Shuichi
     
    WT1 based cancer immunotherapy is a therapy, in which HLA class I-binding 9-mer WT1 peptide is administered intradermally, to induce WT1-specific cellular immune responses. We investigated the safety and immune-response of vaccine therapy of WT1 against metastatic brain tumors. Metastatic brain tumor cells in the animal model showed expression of WT1, and immune cells during vaccination were accumulated focally, but the response of WT1 vaccination was poor. In patients of metastatic brain tumors-breast cancer, accumulation of WT1-specific immune response and WT1-specific killer T cells were poor on the surface of tumor cells. Immunohistochemical analysis on skin specimens, where WT1 peptide was administered intradermally, revealed reactive proliferation of macrophages with giant cell formation and infiltration of CD4+ and CD8+ T, and CD20+ B lymphocytes in the lower dermis. These findings provide basic information about local immune responses elicited in the vaccination site.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2013/04 -2016/03 
    Author : Nakata Susumu; FUJITA Mitsugu
     
    The Sleeping Beauty transposon-induced glioblastoma model was successfully introduced in the Lgr5-eGFP transgenic mouse. Precise collections of the mouse glioblastoma tissues were feasible. Several lines of neurosphere culture using a neural stem cell culture system derived from the mouse glioblastoma tissues were established. Higher Lgr5 expression levels in the GFP positive fraction were confirmed. The observations that the Lgr5 positive cells exerted higher tumorigenicity in vivo indicated that the cancer stem cell properties were enriched in the Lgr5 positive glioblastoma cells. Global gene expression analysis was performed, which identified the shh-pathway as a signal activated in the Lgr5 positive population and higher expression of CDKNs in Lgr5 negative population. Furthermore, Gli2 was identified as an indispensible factor for the glioblastoma stem cells.
  • 文部科学省:基盤研究(B)
    Date (from‐to) : 2014 -2016 
    Author : 宮武 伸一
  • 文部科学省:基盤研究(C)
    Date (from‐to) : 2014 -2016 
    Author : 義江 修
  • 文部科学省:基盤研究(C)
    Date (from‐to) : 2014 -2016 
    Author : 泉本 修一
  • 文部科学省:基盤研究(C)
    Date (from‐to) : 2013 -2015 
    Author : 中田 晋
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2012/04 -2014/03 
    Author : FUJITA Mitsugu; YOSHIE Osamu; NAKATA Susumu; OKUDA Takeshi; KATO Amami
     
    Associations between the regular use of NSAIDs and reduced cancer risks in human have been shonw. NSAIDs function as COX-2 inhibitors that prevent the production of PGE2, which induces MDSCs in cancer-bearing hosts. We thus hypothesized that COX-2 blockade would suppress brain metastasis of cancers by inhibiting MDSC development and their chemokine-mediated accumulation in the tumor microenvironment (TME). In both mouse and human brain metastasis cases, the expression levels of COX-2 and CCL2, a chemokine primarily attracting MDSCs, were increased in the tumor tissues compared with the periphery or normal brain. Concomitantly, the infiltration of MDSCs was observed at high levels in the tumor tissues. In the mouse brain tumor models using LL/2 murine lung cancer cell line, treatment with NSAIDs inhibited brain metastasis formation with the suppression of MDSCs. Our findings show that the COX-2 pathway promotes brain metastases of lung cancers by development and accumulation of MDSCs.
  • 文部科学省:若手研究(B)
    Date (from‐to) : 2012 -2013 
    Author : 藤田 貢

Teaching Experience

  • Introduction to Entrepreneurship in Daily LifeIntroduction to Entrepreneurship in Daily Life Kindai University Faculty of Medicine
  • Medico-Pharmaceutical CooperationMedico-Pharmaceutical Cooperation Kindai University
  • Community Comprehensive Care PracticeCommunity Comprehensive Care Practice Kindai University Faculty of Medicine
  • Professionalism PracticeProfessionalism Practice Kindai University Faculty of Medicine
  • Introduction to Data LiteracyIntroduction to Data Literacy Kindai University Faculty of Medicine
  • Clinical General Theory PracticeClinical General Theory Practice Kindai University Faculty of Medicine
  • MicrobiologyMicrobiology Kindai University Faculty of Medicine


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