80 research outputs found

    Integrated functions of membrane-type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase

    Get PDF
    Membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed in different types of invasive and proliferative cells, including cancer cells and stromal cells. MT1-MMP cleaves extracellular matrix proteins, membrane proteins and other pericellular proteins, thereby changing the cellular microenvironment and regulating signal activation. Critical roles of protease activity in cancer cell proliferation, invasion and metastasis have been demonstrated by many groups. MT1-MMP also has a non-protease activity in that it inhibits the oxygen-dependent suppression of hypoxia-inducible factors (HIFs) via Munc18-1-interacting protein 3 (Mint3) and thereby enhances the expression of HIF target genes. Elevated HIF activity in MT1-MMP-expressing cancer cells is a fundamental mechanism underlying the Warburg effect, a well-known phenomenon where malignant cancer cells exhibit a higher rate of glucose metabolism. Because specific intervention of HIF activation by MT1-MMP suppresses tumor formation by cancer cells in mice, both the proteolytic and non-proteolytic activities of MT1-MMP are important for tumor malignancy and function in an integrated manner. In this review, we summarize recent findings relating to how MT1-MMP activates HIF and its effects on cancer cells and stromal cells. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association

    Protocol to visualize the distribution of exogenously administered small molecules in the mouse brain

    Get PDF
    Here, we present fixation-driven chemical crosslinking of exogenous ligands, a protocol to visualize the distribution of exogenously administered small molecules in the mouse brain. We first describe the probe design of the small molecules of interest and the probe microinjection into a live mouse brain in detail. We then detail procedures for paraformaldehyde-perfusion fixation. This approach is especially useful for imaging-based evaluation of the small-molecule ligands distribution in mouse brain tissue relying on their interaction with endogenous proteins

    Revisiting PFA-mediated tissue fixation chemistry: FixEL enables trapping of small molecules in the brain to visualize their distribution changes

    Get PDF
    ホルマリン漬けから着想した小分子可視化法 --医薬品開発効率化につながる新たな戦略--. 京都大学プレスリリース. 2022-12-05.Various small molecules have been used as functional probes for tissue imaging in medical diagnosis and pharmaceutical drugs for disease treatment. The spatial distribution, target selectivity, and diffusion/excretion kinetics of small molecules in structurally complicated specimens are critical for function. However, robust methods for precisely evaluating these parameters in the brain have been limited. Herein, we report a new method termed “fixation-driven chemical cross-linking of exogenous ligands (FixEL), ” which traps and images exogenously administered molecules of interest (MOIs) in complex tissues. This method relies on protein-MOI interactions and chemical cross-linking of amine-tethered MOI with paraformaldehyde used for perfusion fixation. FixEL is used to obtain images of the distribution of the small molecules, which addresses selective/nonselective binding to proteins, time-dependent localization changes, and diffusion/retention kinetics of MOIs such as the scaffold of PET tracer derivatives or drug-like small molecules

    TGF-β-dependent reprogramming of amino acid metabolism induces epithelial–mesenchymal transition in non-small cell lung cancers

    Get PDF
    Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer

    Central nervous system post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience

    Get PDF
    A 17-year-old male received allogeneic transplantation for acute lymphoblastic leukemia, and presented with generalized seizures due to a solitary brain lesion with massive necrosis on day +621. Epstein?Barr virus (EBV) DNA copies were below the cut-off value in plasma. Stereotactic biopsy of the cerebral lesion confirmed the diagnosis of post-transplant lymphoproliferative disorder (PTLD) with large atypical cells positive for CD20 and EBER.In order to diagnose primary central nervous system PTLD, the biopsy should be applied as early as possible when brain lesion with necrosis develops in post-transplant patients regardless of EBV-DNA in plasma

    Genetic Screening of New Genes Responsible for Cellular Adaptation to Hypoxia Using a Genome-Wide shRNA Library

    Get PDF
    Oxygen is a vital requirement for multi-cellular organisms to generate energy and cells have developed multiple compensatory mechanisms to adapt to stressful hypoxic conditions. Such adaptive mechanisms are intricately interconnected with other signaling pathways that regulate cellular functions such as cell growth. However, our understanding of the overall system governing the cellular response to the availability of oxygen remains limited. To identify new genes involved in the response to hypoxic stress, we have performed a genome-wide gene knockdown analysis in human lung carcinoma PC8 cells using an shRNA library carried by a lentiviral vector. The knockdown analysis was performed under both normoxic and hypoxic conditions to identify shRNA sequences enriched or lost in the resulting selected cell populations. Consequently, we identified 56 candidate genes that might contribute to the cellular response to hypoxia. Subsequent individual knockdown of each gene demonstrated that 13 of these have a significant effect upon oxygen-sensitive cell growth. The identification of BCL2L1, which encodes a Bcl-2 family protein that plays a role in cell survival by preventing apoptosis, validates the successful design of our screen. The other selected genes have not previously been directly implicated in the cellular response to hypoxia. Interestingly, hypoxia did not directly enhance the expression of any of the identified genes, suggesting that we have identified a new class of genes that have been missed by conventional gene expression analyses to identify hypoxia response genes. Thus, our genetic screening method using a genome-wide shRNA library and the newly-identified genes represent useful tools to analyze the cellular systems that respond to hypoxic stress

    Successful outcome of second allogeneic bone marrow transplantation for blastic plasmacytoid dendritic cell neoplasm with MYC locus rearrangement

    Get PDF
    A 62-year-old male was diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN) with a MYC rearrangement. Four months after the first unrelated bone marrow transplantation (BMT), he developed the relapsed BPDCN. After the achievement of partial remission following re-induction therapy, he underwent a second BMT from another unrelated donor, and experienced complete remission with grade II acute graft-versus-host disease and moderate chronic graft-versus-host disease. He remains alive in complete remission more than 71 months after the second BMT. These results suggested that donor change at the second transplantation may represent a considerable therapeutic option for patients with relapsed BPDCN

    Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

    Get PDF
    Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients

    Nonmagnetic framboid and associated iron nanoparticles with a space-weathered feature from asteroid Ryugu

    Get PDF
    リュウグウ試料に初期太陽系の新しい磁気記録媒体を発見~太陽系磁場の新たな研究手法の確立に期待~.京都大学プレスリリース. 2024-04-30.Extraterrestrial minerals on the surface of airless Solar System bodies undergo gradual alteration processes known as space weathering over long periods of time. The signatures of space weathering help us understand the phenomena occurring in the Solar System. However, meteorites rarely retain the signatures, making it impossible to study the space weathering processes precisely. Here, we examine samples retrieved from the asteroid Ryugu by the Hayabusa2 spacecraft and discover the presence of nonmagnetic framboids through electron holography measurements that can visualize magnetic flux. Magnetite particles, which normally provide a record of the nebular magnetic field, have lost their magnetic properties by reduction via a high-velocity (>5 km s⁻¹) impact of a micrometeoroid with a diameter ranging from 2 to 20 μm after destruction of the parent body of Ryugu. Around these particles, thousands of metallic-iron nanoparticles with a vortex magnetic domain structure, which could have recorded a magnetic field in the impact event, are found. Through measuring the remanent magnetization of the iron nanoparticles, future studies are expected to elucidate the nature of the nebular/interplanetary magnetic fields after the termination of aqueous alteration in an asteroid

    2017~2019年度 関西大学研究拠点形成支援経費研究成果報告書

    Get PDF
    目次・研究成果の概要・2-1 工藤 宏人・宮前 翼・上田 正人・村山 憲弘・林 順一 "ノーリア骨格をテンプレートとした空孔内に水酸基を有する架橋化合物の合成とそれらの金属イオン包接性能" ネットワークポリマー論文集 vol.41, No.2, 65 - 71 (2020).・2-2 Mitsuaki Matsuoka, Kaho Yokoyama, Kohei Okura, Norihiro Murayama, Masato Ueda, Makio Naito " Synthesis of Geopolymers from Mechanically Activated Coal Fly Ash and Improvement of Their Mechanical Properties" Minerals 9, 791- 801 (2019).・2-3 Daisuke Shimoyama, Ryo Sekiya, Hiroto Kudo, Takeharu Haino, "Feet-to-Feet Connected Trisresorcinarenes" Organic Letters 22, 352 - 356 (2019).・2-4 Masato Ueda, Masahiko Ikeda, Shigeo Mori, Kenji Doi, Hisashi Kitagaki, Shuntaro Terauchi "Mechanical Properties of Additively Manufactured Porous Titanium with Sub-Millimetre Structural Units" Materials Transactions Vol.60, No.9, 1792 - 1798 (2019).・2-5 五十井 浩平・白杉 文香・松岡 光昭・林 順一・村山 憲弘 "種々のMg-Fe系複合酸化物を用いた希薄水溶液中のホウ素およびヒ素の除去" 環境資源工学 66, 29 - 35 (2019).・2-6 Toru Maruyama, Mitsuyoshi Tamaki, Keisuke Nakamura, Gou Nakamura "EFFECT OF MOLTEN METAL TEMPERATURE ON MOLD FILLING IN EVAPORATIVE PATTERN CASTING" International Journal of Metalcasting 13, 611–617 (2019).・2-7 Ryuta Saito, Toru Maruyama, Toshiki Nakamura, Hitoshi Yanagitani, Takahiro Sakai, Kouji Nakamoto "Influence of Tellurium Addition to Spheroidal Graphite Cast Iron on the Number of Graphite Particles" International Journal of Metalcasting Vol.13, 3, 571-577 (2018).・2-8 Masato Ueda, Rika Yamaguchi, Chika Fujita, Masahiko Ikeda "Control of Cell Adhesion on Titanium Dioxide by Light Irradiation" Materials Science Forum Vol.941, 2507 - 2512 (2018).・2-9 Hiroto Kudo, Mari Fukunaga, Kohei Shiotsuki, Hiroya Takeda, Hiroki Yamamoto, Takahiro Kozawa, Takeo Watanabe "Synthesis of hyperbranched polyacetals containing C-(4-t-butylbenz)calix[4]resorcinarene: Resist properties for extreme ultraviolet (EUV) lithography" Reactive and Functional Polymers 131, 361 - 367 (2018).・2-10 大隈 修・前 一廣・林 順一 "直接液化による豪州ビクトリア褐炭の高度利用 : 改新BCLプロセスによる化学原料の生産" Journal of the Japan Institute of Energy 98, 17 - 26 (2019).・2-11 Issei Suzuki, Ayako Kakinuma, Masato Ueda, Takahisa Omata "Flux growth of β-NaGaO₂ single crystals" Journal of Crystal Growth 504, 26 -30 (2018).・2-12 上田 正人、坂本 貴則、池田 勝彦 "電気抵抗率の精密測定による純チタンの組織評価" 環境資源工学 65, 74 -76 (2018).・2-13 Satoshi Imasaka, Hiroyasu Ishii, Jun\u27ichi Hayashi, Sadao Araki, Hideki Yamamoto "Synthesis of CHA-type titanosilicate zeolites using titanium oxide as Ti source and evaluation of their physicochemical properties" Microporous and Mesoporous Materials 273, 243-248 (2019).・2-14 Hiroto Kudo, Shizuya Ohori, Hiroya Takeda, Hiroki Ogawa, Takeo Watanbe, Hiroki Yamamoto, Takahiro Kozawa "Synthesis and Property of Tannic Acid Derivatives and Their Application for Extreme Ultraviolet Laser Lithography System" Journal of Photopolymer Science and Technology Vol.31, 221 - 225 (2018).・2-15 Hiroto Kudo, Tsubasa Miyamae, Kouta Kitagawa, Kohei Isoi, Norihiro Murayama, Jun\u27ichi Hayashi " Synthesis and Metal-Complexation Ability of Cross-Linking Materials Containing Noria-Templated Cavities with Pendant Carboxylic Acid Groups" Chemistry Select 3, 2223 - 2228 (2018).・2-16 上田 正人、池田 勝彦、土井 研児、 森 重雄、北垣 壽、寺内 俊太郎、関 あずさ "骨部分置換用ポーラスチタン : ポリグリコール酸 : 炭酸カルシウム複合体の開発" 高分子論文集 Vol.75, No.1, 69 - 74 (2018).・2-17 Alexandru C Sonoc, Jacob Jeswiet, Norihiro Murayama, Junji Shibata "A study of the application of Donnan dialysis to the recycling of lithium ion batteries" Hydrometallurgy 175, 133 - 143 (2018).2-3は、著作権の関係により非公開としております。2-8は、著作権の関係により非公開としております。2-9は、著作権の関係により非公開としております。2-10は、著作権の関係により非公開としております。2-11は、著作権の関係により非公開としております。2-16は、著作権の関係により非公開としております
    corecore