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4. Uhrf1 governs the proliferation and differentiation of muscle satellite cells

Author

Yuuki Imai, Iori Sakakibara, Tadahiko Kikugawa, Ono Y, Takashi Saika, Yuichiro Sawada, Hiroshi Sakai, So-ichiro Fukada, Nakagawa S, and Tokunaga N

Subjects
Ubiquitin, DNA methylation, Notch signaling pathway, Regulator, biology.protein, Satellite (biology), Epigenetics, Biology, Stem cell, biology.organism_classification, Cell biology, DNA hypomethylation
Abstract

SummaryDNA methylation is an essential form of epigenetic regulation responsible for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are tightly regulated during differentiation. However, it is unclear how these DNA methylation patterns are maintained. We demonstrate that a key epigenetic regulator, ubiquitin like with PHD and RING finger domains 1 (Uhrf1), is activated in proliferating myogenic cells but not expressed in quiescent or differentiated myogenic cells in mice. Ablation of Uhrf1 in mouse satellite cells impairs their proliferation and differentiation, leading to failed muscle regeneration. Loss of Uhrf1 in satellite cells alters transcriptional programs, leading to DNA hypomethylation with activation of Cdkn1a and Notch signaling. Although down-regulation of Cdkn1a rescued proliferation but not differentiation, inhibition of Notch signaling rescued impaired differentiation of Uhrf1-deficient satellite cells. These findings point to Uhrf1 as a regulator of self-renewal and differentiation of satellite cells via genome-wide DNA methylation patterning.

Published
2021

7. Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer

Author

Tsunemitsu, Y., Kagawa, S., Tokunaga, N., Otani, S., Umeoka, T., Roth, J.A., Fang, B., Tanaka, N., and Fujiwara, T.

Subjects
Gene therapy -- Research -- Health aspects, Stomach cancer -- Care and treatment -- Genetic aspects -- Research, Adenovirus diseases -- Care and treatment -- Research -- Genetic aspects, Cancer -- Care and treatment -- Genetic aspects -- Research, Health, Care and treatment, Genetic aspects, Research, Health aspects
Abstract

Gut 2004;53:554-560. doi: 10.1136/gut.2003.021683 Background: Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for [...]

Published
2004

14. Human Monocyte-Derived Dendritic Cells Pulsed with Wild-Type p53 Protein Efficiently Induce CTLs against p53 Overexpressing Human Cancer Cells

Author

Tokunaga, N., Murakami, T., Endo, Y., Nishizaki, M., Shunsuke Kagawa, Tanaka, N., and Fujiwara, T.

Subjects
Cytotoxicity, Immunologic, Cancer Research, Membrane Glycoproteins, Genotype, Immunoglobulins, Cell Differentiation, Dendritic Cells, HLA-DR Antigens, Cytotoxicity Tests, Immunologic, Flow Cytometry, Immunohistochemistry, Monocytes, Cell Line, Oncology, Antigens, CD, Cell Line, Tumor, Mutation, B7-1 Antigen, Humans, B7-2 Antigen, Tumor Suppressor Protein p53, T-Lymphocytes, Cytotoxic
Abstract

Purpose: Dendritic cells are the most potent antigen-presenting cells for initiating cellular immune responses. Dendritic cells are attractive immunoregulatory cells for cancer immunotherapy, and their efficacy has been investigated in clinical trials. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and p53-based immunization is an attractive approach to cancer immunotherapy because of the accumulation of p53 protein in malignant but not in normal cells. It has been shown that dendritic cells transduced with an adenoviral wild-type p53 (wt-p53) construct mediate the antitumor immune responses against p53-overexpressing tumor cells. We examined whether monocyte-derived human dendritic cells pulsed with the purified full-length wt-p53 protein were also capable of inducing the specific antitumor responses against p53-overexpressing tumors in vitro. Experimental Design: Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from monocytes of HLA-A2- or HLA-A24-positive healthy individuals were pulsed with the purified p53 protein. Uptake of p53 protein by human dendritic cells was assessed by Western blotting and immunohistochemical staining using anti-p53 antibody. Induction of p53-specific CTL response was also evaluated by the cytotoxic assay against p53-overexpressing human tumor cells. Results: Both Western blot and immunohistochemical analysis showed the accumulation of p53 protein in human immature dendritic cells. T cells obtained from HLA-A2- or HLA-A24-positive healthy donors were stimulated twice with p53 protein-pulsed dendritic cells and then applied to the cytotoxicity assay against p53-overexpressing target cells. The CTL activity was specific for p53-overexpressing tumor cells and MHC class I restricted. Moreover, the CTL activity generated by p53 protein-pulsed dendritic cells was nearly identical with that induced by adenoviral wt-p53-transduced dendritic cells. Conclusions: Our results indicate that monocyte-derived human dendritic cells pulsed with the wt-p53 protein could induce the specific antitumor effect against p53-overexpressing tumors and that this in vitro model offers a new and more simple approach to the development of p53-based immunotherapy.

Published
2005

42. Anemia in patients with colorectal cancer.

Author

Sadahiro, Sotaro, Suzuki, Toshiyuki, Tokunaga, Nobuhiro, Mukai, Masaya, Tajima, Tomoo, Makuuchi, Hiroyasu, Saito, Toshiaki, Sadahiro, S, Suzuki, T, Tokunaga, N, Mukai, M, Tajima, T, Makuuchi, H, and Saito, T

Subjects
ANEMIA, COLON cancer
Abstract

Although anemia is one of the signs of colorectal cancer, the relationships between histological findings and hematological findings other than hemoglobin level have not been adequately investigated. We investigated the relationship between hematological findings, serum iron, and histological findings in 358 patients (207 men and 157 women) with colorectal cancer. Their mean (+/-SD) ages were 64.3 +/- 12.4 and 63.8 +/- 13.3 years. A hemoglobin level of less than 10 g/dl was the criterion for anemia, and 20.8% of the men and 25.8% of the women met this criterion. Univariate analysis showed that carcinoma of the cecum, ascending colon, and transverse colon; large-size carcinoma, invasion beyond the proper muscle layer; positive lymph node metastasis: and clinical stage (Dukes' B, C, and D) were factors associated with high incidence of anemia. Histological type did not affect the hematological findings. Multivariate analysis showed that age, tumor site, and tumor size were significant factors related to anemia. Depth of invasion, the presence or absence of lymph node metastasis, and Dukes' classification were not significant factors. In the presence of these factors, mean corpuscular volume and mean corpuscular hemoglobin concentration values were low, and red blood cells were microcytic and hypochromic. The incidence of a low serum iron level was about twice the frequency of a hemoglobin level of less than 10 g/dl. The results of the multivariate analysis showed that none of the factors were significantly related to iron deficiency. [ABSTRACT FROM AUTHOR]

Published
1998
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44. Simultaneous Measurements of Thermal, Electrical, and Acoustic Properties of BaTiO3 – New Feature of 403 K Phase Transition

Author

Kojima, A., Sasou, H., Tozaki, K., Okazaki, T., Yoshimura, Y., Tokunaga, N., and Iwasaki, H.

Abstract

In order to obtain useful information on the transient process of phase transitions in ferroelectrics by various methods including calorimetry, the “mK-stabilized cell” of a small size has been developed. It is based on the heat flux differential scanning calorimeter (DSC) and has a temperature stability better than 1 mK. The “cell” can be used to change the temperature under nearly quasi-static conditions by an infinitesimally small rate not only on heating but also on cooling while passing through the transition points. It enables simultaneous measurements of endothermic heat and exothermic heat along with dielectric constants, displacement currents, etc. with a high degree of temperature resolution. X-ray diffraction measurements for sensing thermal anomalies are also possible by a minor modification of the “cell.” Precise and simultaneous measurements of thermal, electrical, and acoustic properties were carried out at the 403 K phase transition in BaTiO3 single crystal grown by the top-seeded solution growth method. It has been clarified that the exothermic heat at the transition on cooling has more useful information than the endothermic heat on heating; in the cooling process two thermal anomalies occur separately at T1 and T2 although the transition is in a narrow temperature range. It is recognized from other methods that the nature of the transition on cooling is not of a single but of multiple steps. Resonant ultrasonic measurements using the “cell” were carried out, after developing a new excitation method. The sample does not have a simple softening approaching the transition point on cooling but has different elastic moduli for the two thermal anomalies at T1 and T2. The dielectric constant also has an intermediate constant value between T1 and T2. The crystal structure in the room temperature phase below the transition point has been determined by X-ray diffraction. In this region, tetragonal and monoclinic structures coordinating with each other exist.

Published
2005
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45. Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids to Coumarins:  Asymmetric Synthesis of (R)-Tolterodine

Author

Chen, G., Tokunaga, N., and Hayashi, T.

Abstract

Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a rhodium catalyst (3 mol %) generated from Rh(acac)(C2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99% ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.

Published
2005

46. C<INF>2</INF>-Symmetric Bicyclo[3.3.1]nonadiene as a Chiral Ligand for Rhodium-Catalyzed Asymmetric Arylation of N-(4-Nitrobenzenesulfonyl)arylimines

Author

Otomaru, Y., Tokunaga, N., Shintani, R., and Hayashi, T.

Abstract

Asymmetric synthesis of diarylmethylamines with high enantioselectivity (95−99% ee) was realized by use of a new C2-symmetric diene ligand, (1R,5R)-2,6-diphenylbicyclo[3.3.1]nona-2,6-diene (Ph-bnd*), for the rhodium-catalyzed asymmetric arylation of N-(4-nitrobenzenesulfonyl)arylimines with arylboroxines.

Published
2005

49. Dehydroepiandrosterone sulphate promotes hyaluronic acid-induced cervical ripening in rabbits.

Author

Belayet, H M, Kanayama, N, Khatun, S, Tokunaga, N, Sugimura, M, Yamashita, M, Kobayashi, T, and Terao, T

Abstract

Hyaluronic acid (HA) stimulates the synthesis of interleukin (IL) 8, while dehydroepiandrosterone sulphate (DHEA-S) induces the expression of IL-8 and its receptor in the human cervical fibroblast. This has led us to investigate the effect of DHEA-S on HA-induced cervical ripening. Experiments were performed in pregnant rabbits using vaginal suppositories containing 1 mg HA, 30 mg DHEA-S, 30 mg DHEA-S + 0.1 mg HA, 30 mg DHEA-S + 1 mg HA, and 500 microl Witepsol-50 base (control). The effects were evaluated by measuring collagenase, gelatinase and elastase activities, water content, neutrophil infiltration, relative collagen concentration and histological assessment. The activities of collagenase, gelatinase and elastase were significantly increased in rabbits treated with DHEA-S + 1 mg HA compared with rabbits treated with DHEA-S + 0.1 mg HA (P < 0.009, P < 0.001, P < 0.009 respectively). Water content was markedly increased in rabbits treated with DHEA-S + 1 mg HA compared with DHEA-S + 0.1 mg HA treatment (P < 0.05). Neutrophil infiltration was markedly increased, while relative collagen concentration was significantly decreased with DHEA-S + 1 mg HA compared with the DHEA-S + 0.1 mg HA approach (P < 0.001, P < 0.002). The histology of cervices treated with DHEA-S + 1 mg HA showed the density of collagen to be markedly decreased, and collagen fibres irregularly separated. Increased vascularity with massive dilatation of blood vessels was also observed in these rabbits. We conclude that DHEA-S upregulates the HA-induced cervical ripening process.

Published
1999
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