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Volumn 79, Issue 11, 2003, Pages 849-861

Cellular origin of ionizing radiation-induced NF-κB activation in vivo and role of NF-κB in ionizing radiation-induced lymphocyte apoptosis

Author keywords

[No Author keywords available]

Indexed keywords

3,3' DIHEXYLOXACARBOCYANINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIPOCORTIN 5; OLIGONUCLEOTIDE; RAG1 PROTEIN;

EID: 0346057817     PISSN: 09553002     EISSN: None     Source Type: Journal    
DOI: 10.1080/09553000310001622814     Document Type: Article
Times cited : (11)

References (57)
  • 1
    • 0034668151 scopus 로고    scopus 로고
    • Apoptosis and nuclear factor-kappa B: A tale of association and dissociation
    • AGGARWAL, B. B., 2000. Apoptosis and nuclear factor-kappa B: a tale of association and dissociation. Biochemical Pharmacology, 60, 1033-1039.
    • (2000) Biochemical Pharmacology , vol.60 , pp. 1033-1039
    • Aggarwal, B.B.1
  • 2
    • 0025730640 scopus 로고
    • A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells
    • ANDREWS, N. C. and FALLER, D. V., 1991, A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Research, 19, 2499.
    • (1991) Nucleic Acids Research , vol.19 , pp. 2499
    • Andrews, N.C.1    Faller, D.V.2
  • 3
    • 0028174061 scopus 로고
    • Function and activation of NF-kappa B in the immune system
    • BAEUERLE, P. A. and HENKEL, T., 1994, Function and activation of NF-kappa B in the immune system. Annual Review of Immunology, 12, 141-179.
    • (1994) Annual Review of Immunology , vol.12 , pp. 141-179
    • Baeuerle, P.A.1    Henkel, T.2
  • 5
    • 0029874138 scopus 로고    scopus 로고
    • The NF-kappa B and 1 kappa B proteins: New discoveries and insights
    • BALDWIN, A. S., JR. 1996, The NF-kappa B and 1 kappa B proteins: new discoveries and insights. Annual Review of Immunology, 14, 649-683.
    • (1996) Annual Review of Immunology , vol.14 , pp. 649-683
    • Baldwin Jr., A.S.1
  • 6
    • 0035137882 scopus 로고    scopus 로고
    • Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB
    • BALDWIN, A. S., 2001, Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. Journal of Clinical Investigation, 107, 241-246.
    • (2001) Journal of Clinical Investigation , vol.107 , pp. 241-246
    • Baldwin, A.S.1
  • 7
    • 0033596127 scopus 로고    scopus 로고
    • Control of apoptosis by Rel/NF-kappaB transcription factors
    • BARKETT, M. and GILMORE, T. D., 1999, Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogenic, 18, 6910-6924.
    • (1999) Oncogenic , vol.18 , pp. 6910-6924
    • Barkett, M.1    Gilmore, T.D.2
  • 8
    • 0030925372 scopus 로고    scopus 로고
    • Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB
    • BOOTHBY, M. R., MORA, A. L., SCHERER, D. C., BROCKMAN, J. A. and BALLARD, D. W., 1997. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB. Journal of Experimental Medicine, 185, 1897-1907.
    • (1997) Journal of Experimental Medicine , vol.185 , pp. 1897-1907
    • Boothby, M.R.1    Mora, A.L.2    Scherer, D.C.3    Brockman, J.A.4    Ballard, D.W.5
  • 10
    • 0033011889 scopus 로고    scopus 로고
    • Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50-p65 recruitment
    • CHAN, H., BARTOS, D. P. and OWEN-SCHAUB, L. B., 1999, Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50-p65 recruitment. Molecular and Cellular Biology, 19, 2098-2108.
    • (1999) Molecular and Cellular Biology , vol.19 , pp. 2098-2108
    • Chan, H.1    Bartos, D.P.2    Owen-Schaub, L.B.3
  • 12
    • 0033910983 scopus 로고    scopus 로고
    • Analysis of apoptotic cells by flow and laser scanning cytometry
    • DARZYNKIEWICZ, Z. and BEDNER, E., 2000, Analysis of apoptotic cells by flow and laser scanning cytometry. Methods in Enzymology, 322, 18-39.
    • (2000) Methods in Enzymology , vol.322 , pp. 18-39
    • Darzynkiewicz, Z.1    Bedner, E.2
  • 14
    • 0345593715 scopus 로고    scopus 로고
    • In vivo inhibition of NF-kappa B in T-lineage cells leads to a dramatic decrease in cell proliferation and cytokine production and to increased cell apoptosis in response to mitogenic stimuli, but not to abnormal thymopoiesis
    • FERREIRA, V., SIDENIUS, N., TARANTINO, N., HUBERT, P., CHATENOUD, L., BLASI, F. and KORNER, M., 1999, In vivo inhibition of NF-kappa B in T-lineage cells leads to a dramatic decrease in cell proliferation and cytokine production and to increased cell apoptosis in response to mitogenic stimuli, but not to abnormal thymopoiesis. Journal of Immunology, 162, 6442-6450.
    • (1999) Journal of Immunology , vol.162 , pp. 6442-6450
    • Ferreira, V.1    Sidenius, N.2    Tarantino, N.3    Hubert, P.4    Chatenoud, L.5    Blasi, F.6    Korner, M.7
  • 15
    • 0031897632 scopus 로고    scopus 로고
    • NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses
    • GHOSH, S., MAY, M. J. and KOPP, E. B., 1998, NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology, 16, 225-260.
    • (1998) Annual Review of Immunology , vol.16 , pp. 225-260
    • Ghosh, S.1    May, M.J.2    Kopp, E.B.3
  • 16
    • 0032473405 scopus 로고    scopus 로고
    • B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells
    • GRUMONT, R. J., ROURKE, I. J., O'REILLY, L. A., STRASSER, A., MIYAKE, K., SHA, W. and GERONDAKIS, S., 1998, B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. Journal of Experimental Medicine, 187, 663-674.
    • (1998) Journal of Experimental Medicine , vol.187 , pp. 663-674
    • Grumont, R.J.1    Rourke, I.J.2    O'Reilly, L.A.3    Strasser, A.4    Miyake, K.5    Sha, W.6    Gerondakis, S.7
  • 18
    • 0033521663 scopus 로고    scopus 로고
    • An essential role for nuclear factor kappaB in promoting double positive thymocyte apoptosis
    • HETTMANN, T., DIDONATO, J., KARIN, M. and LEIDEN, J. M., 1999, An essential role for nuclear factor kappaB in promoting double positive thymocyte apoptosis. Journal of Experimental Medicine, 189, 145-158.
    • (1999) Journal of Experimental Medicine , vol.189 , pp. 145-158
    • Hettmann, T.1    Didonato, J.2    Karin, M.3    Leiden, J.M.4
  • 21
    • 0034788759 scopus 로고    scopus 로고
    • NF-kappa B signaling pathway as a target for human tumor radiosensitization
    • JUNG, M. and DRITSCHILO, A., 2001, NF-kappa B signaling pathway as a target for human tumor radiosensitization. Seminars in Radiation Oncology, 11, 346-351.
    • (2001) Seminars in Radiation Oncology , vol.11 , pp. 346-351
    • Jung, M.1    Dritschilo, A.2
  • 22
    • 0032014073 scopus 로고    scopus 로고
    • DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1
    • KASIBHATLA, S., BRUNNER, T., GENESTIER, L., ECHEVERRI, F., MAHBOUBI, A. and GREEN, D. R., 1998, DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Molecular Cell, 1, 543-551.
    • (1998) Molecular Cell , vol.1 , pp. 543-551
    • Kasibhatla, S.1    Brunner, T.2    Genestier, L.3    Echeverri, F.4    Mahboubi, A.5    Green, D.R.6
  • 23
    • 0033534465 scopus 로고    scopus 로고
    • Regulation of fas-ligand expression during activation-induced cell death in T lymphocytes via nuclear factor kappaB
    • KASIBHATLA, S., GENESTIER, L. and GREEN, D. R., 1999, Regulation of fas-ligand expression during activation-induced cell death in T lymphocytes via nuclear factor kappaB. Journal of Biological Chemistry, 274, 987-992.
    • (1999) Journal of Biological Chemistry , vol.274 , pp. 987-992
    • Kasibhatla, S.1    Genestier, L.2    Green, D.R.3
  • 24
    • 0032005346 scopus 로고    scopus 로고
    • Use of phosphorothioate-modified oligodeoxynucleotides to inhibit NF-kappaB expression and lymphocyte function
    • KHALED, A. R., BUTFILOSKI, E. J., SOBEL, E. S. and SCHIFFENBAUER, J., 1998, Use of phosphorothioate-modified oligodeoxynucleotides to inhibit NF-kappaB expression and lymphocyte function. Clinical Immunology and Immunopathology, 86, 170-179.
    • (1998) Clinical Immunology and Immunopathology , vol.86 , pp. 170-179
    • Khaled, A.R.1    Butfiloski, E.J.2    Sobel, E.S.3    Schiffenbauer, J.4
  • 25
    • 0034663779 scopus 로고    scopus 로고
    • The NF-kappa B cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes
    • KHOSHNAN, A., TINDELL, C., LAUX, I., BAE, D., BENNETT, B. and NEL, A. E., 2000, The NF-kappa B cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. Journal of Immunology, 165, 1743-1754.
    • (2000) Journal of Immunology , vol.165 , pp. 1743-1754
    • Khoshnan, A.1    Tindell, C.2    Laux, I.3    Bae, D.4    Bennett, B.5    Nel, A.E.6
  • 26
    • 0033565406 scopus 로고    scopus 로고
    • Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3
    • KOLENKO, V., BLOOM, T., RAYMAN, P., BUKOWSKI, R., HSI, E. and FINKE, J., 1999, Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3. Journal of Immunology, 163, 590-598.
    • (1999) Journal of Immunology , vol.163 , pp. 590-598
    • Kolenko, V.1    Bloom, T.2    Rayman, P.3    Bukowski, R.4    Hsi, E.5    Finke, J.6
  • 27
    • 0033529416 scopus 로고    scopus 로고
    • NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes
    • LEE, H. H., DADGOSTAR, H., CHENG, Q., SHU, J. and CHENG, G., 1999, NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proceedings of the National Academy of Sciences, USA, 96, 9136-9141.
    • (1999) Proceedings of the National Academy of Sciences, USA , vol.96 , pp. 9136-9141
    • Lee, H.H.1    Dadgostar, H.2    Cheng, Q.3    Shu, J.4    Cheng, G.5
  • 29
    • 0032497587 scopus 로고    scopus 로고
    • A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB
    • LEE, S. J., DIMTCHEV, A., LAVIN, M. F., DRITSCHILO, A. and JUNG, M., 1998, A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB. Oncogene, 17, 1821-1826.
    • (1998) Oncogene , vol.17 , pp. 1821-1826
    • Lee, S.J.1    Dimtchev, A.2    Lavin, M.F.3    Dritschilo, A.4    Jung, M.5
  • 31
    • 0027319521 scopus 로고
    • p53 is required for radiation-induced apoptosis in mouse thymocytes
    • LOWE, S. W., SCHMITT, E. M., SMITH, S. W., OSBORNE, B. A. and JACKS, T., 1993, p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature, 362, 847-849.
    • (1993) Nature , vol.362 , pp. 847-849
    • Lowe, S.W.1    Schmitt, E.M.2    Smith, S.W.3    Osborne, B.A.4    Jacks, T.5
  • 32
    • 0029860159 scopus 로고    scopus 로고
    • DNA-damaging agents induce both p53-dependent and p53-independent apoptosis in immature thymocytes
    • MACFARLANE, M., JONES, N. A., DIVE, C. and COHEN, G. M., 1996, DNA-damaging agents induce both p53-dependent and p53-independent apoptosis in immature thymocytes. Molecular Pharmacology, 50, 900-911.
    • (1996) Molecular Pharmacology , vol.50 , pp. 900-911
    • MacFarlane, M.1    Jones, N.A.2    Dive, C.3    Cohen, G.M.4
  • 33
    • 0028891783 scopus 로고
    • Apoptosis, oncosis, and necrosis. An overview of cell death
    • MAJNO, G. and JORIS, I., 1995, Apoptosis, oncosis, and necrosis. An overview of cell death. American Journal of Pathology, 146, 3-15.
    • (1995) American Journal of Pathology , vol.146 , pp. 3-15
    • Majno, G.1    Joris, I.2
  • 34
    • 0031025384 scopus 로고    scopus 로고
    • Apoptosis induced by gamma-irradiation, but not CD4 ligation, of peripheral T lymphocytes in vivo is p53-dependent
    • MALCOMSON, R. D., CLARKE, A. R., PETER, A., COUTTS, S. B., HOWIE, S. E. and HARRISON, D. J., 1997, Apoptosis induced by gamma-irradiation, but not CD4 ligation, of peripheral T lymphocytes in vivo is p53-dependent. Journal of Pathology, 181, 166-171.
    • (1997) Journal of Pathology , vol.181 , pp. 166-171
    • Malcomson, R.D.1    Clarke, A.R.2    Peter, A.3    Coutts, S.B.4    Howie, S.E.5    Harrison, D.J.6
  • 35
    • 0032194170 scopus 로고    scopus 로고
    • Identification of two NF-kappa B sites in mouse CD95 ligand (Fas ligand) promoter: Functional analysis in T-cell hybridoma
    • MATSUI, K., FINE, A., ZHU, B., MARSHAK-ROTHSTEIN, A. and JU, S. T., 1998, Identification of two NF-kappa B sites in mouse CD95 ligand (Fas ligand) promoter: functional analysis in T-cell hybridoma. Journal of Immunology, 161, 3469-3473.
    • (1998) Journal of Immunology , vol.161 , pp. 3469-3473
    • Matsui, K.1    Fine, A.2    Zhu, B.3    Marshak-Rothstein, A.4    Ju, S.T.5
  • 36
    • 0034719680 scopus 로고    scopus 로고
    • The transcription factor NF-kappaB: Control of oncogenesis and cancer therapy resistance
    • MAYO, M. W. and BALDWIN, A. S., 2000, The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance. Biochimica et Biophysica Acta, 1470, M55-M62.
    • (2000) Biochimica et Biophysica Acta , vol.1470
    • Mayo, M.W.1    Baldwin, A.S.2
  • 37
    • 0027999283 scopus 로고
    • Induction of nuclear factor kappa B after low-dose ionizing radiation involves a reactive oxygen intermediate signaling pathway
    • MOHAN, N. and MELTZ, M. L., 1994, Induction of nuclear factor kappa B after low-dose ionizing radiation involves a reactive oxygen intermediate signaling pathway. Radiation Research, 140, 97-104.
    • (1994) Radiation Research , vol.140 , pp. 97-104
    • Mohan, N.1    Meltz, M.L.2
  • 40
    • 0034283837 scopus 로고    scopus 로고
    • The Rel/NF-kappa B family: Friend and foe
    • PERKINS, N. D., 2000, The Rel/NF-kappa B family: friend and foe. Trends in Biochemical Sciences, 25, 434-440.
    • (2000) Trends in Biochemical Sciences , vol.25 , pp. 434-440
    • Perkins, N.D.1
  • 41
    • 0028271882 scopus 로고
    • Activation of nuclear factor kappa B in human lymphoblastoid cells by low-dose ionizing radiation
    • PRASAD, A. V., MOHAN, N., CHANDRASEKAR, B. and MELTZ, M. L., 1994, Activation of nuclear factor kappa B in human lymphoblastoid cells by low-dose ionizing radiation. Radiation Research, 138, 367-372.
    • (1994) Radiation Research , vol.138 , pp. 367-372
    • Prasad, A.V.1    Mohan, N.2    Chandrasekar, B.3    Meltz, M.L.4
  • 42
    • 0031597406 scopus 로고    scopus 로고
    • IkappaBalpha degradation is not a requirement for the X-ray-induced activation of nuclear factor kappaB in normal rat astrocytes and human brain tumour cells
    • RAJU, U., GUMIN, G. J., NOEL, F. and TOFILON, P. J., 1998, IkappaBalpha degradation is not a requirement for the X-ray-induced activation of nuclear factor kappaB in normal rat astrocytes and human brain tumour cells. International Journal of Radiation Biology, 74, 617-624.
    • (1998) International Journal of Radiation Biology , vol.74 , pp. 617-624
    • Raju, U.1    Gumin, G.J.2    Noel, F.3    Tofilon, P.J.4
  • 44
    • 0034682831 scopus 로고    scopus 로고
    • The NF-kappa B signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death
    • RIVERA-WALSH, I., GVIJIC, M. E., XIAO, G. and SUN, S. C., 2000, The NF-kappa B signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death. Journal of Biological Chemistry, 275, 25222-25230.
    • (2000) Journal of Biological Chemistry , vol.275 , pp. 25222-25230
    • Rivera-Walsh, I.1    Gvijic, M.E.2    Xiao, G.3    Sun, S.C.4
  • 45
    • 0033237348 scopus 로고    scopus 로고
    • The role of NF-kappaB/IkappaB proteins in cancer: Implications for novel treatment strategies
    • SCHWARTZ, S. A., HERNANDEZ, A. and MARK, E. B., 1999, The role of NF-kappaB/IkappaB proteins in cancer: implications for novel treatment strategies. Surgical Oncology, 8, 143-153.
    • (1999) Surgical Oncology , vol.8 , pp. 143-153
    • Schwartz, S.A.1    Hernandez, A.2    Mark, E.B.3
  • 46
  • 48
    • 0028882829 scopus 로고
    • Ionizing radiation activates nuclear factor kappa B but fails to produce an increase in human immunodeficiency virus gene expression in stably transfected human cells
    • VALERIE, K., LASTER, W. S., KIRKHAM, J. C. and KUEMMERLE, N. B., 1995, Ionizing radiation activates nuclear factor kappa B but fails to produce an increase in human immunodeficiency virus gene expression in stably transfected human cells. Biochemistry, 34, 15768-15776.
    • (1995) Biochemistry , vol.34 , pp. 15768-15776
    • Valerie, K.1    Laster, W.S.2    Kirkham, J.C.3    Kuemmerle, N.B.4
  • 50
    • 0032954699 scopus 로고    scopus 로고
    • Innovative treatment programs against cancer: II. Nuclear factor-kappaB (NF-kappaB) as a molecular target
    • WADDICK, K. G. and UCKUN, F. M., 1999, Innovative treatment programs against cancer: II. Nuclear factor-kappaB (NF-kappaB) as a molecular target. Biochemical Pharmacology, 57, 9-17.
    • (1999) Biochemical Pharmacology , vol.57 , pp. 9-17
    • Waddick, K.G.1    Uckun, F.M.2
  • 51
    • 0032905030 scopus 로고    scopus 로고
    • Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB
    • WANG, C. Y., CUSACK, J. C., JR, LIU, R. and BALDWIN, A. S., JR, 1999, Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nature Medicine, 5, 412-417.
    • (1999) Nature Medicine , vol.5 , pp. 412-417
    • Wang, C.Y.1    Cusack Jr., J.C.2    Liu, R.3    Baldwin Jr., A.S.4
  • 52
    • 0032954928 scopus 로고    scopus 로고
    • Transcriptional cross talk between NF-kappaB and pD3
    • WEBSTER, G. A. and PERKINS, N. D., 1999, Transcriptional cross talk between NF-kappaB and pD3. Molecular and Cellular Biology, 19, 3485-3495.
    • (1999) Molecular and Cellular Biology , vol.19 , pp. 3485-3495
    • Webster, G.A.1    Perkins, N.D.2
  • 54
    • 0027494855 scopus 로고
    • Early response gene signalling cascades activated by ionising radiation in primary human B-cells
    • WILSON, R. E., TAYLOR, S. L., ATHERTON, G. T., JOHNSTON, D., WATERS, C. M. and NORTON, J. D., 1993, Early response gene signalling cascades activated by ionising radiation in primary human B-cells. Oncogene, 8, 3229-3237.
    • (1993) Oncogene , vol.8 , pp. 3229-3237
    • Wilson, R.E.1    Taylor, S.L.2    Atherton, G.T.3    Johnston, D.4    Waters, C.M.5    Norton, J.D.6
  • 56
    • 0032977359 scopus 로고    scopus 로고
    • A high dose of ionizing radiation induces tissue-specific activation of nuclear factor-kappaB in vivo
    • ZHOU, D., BROWN, S. A., YU, T., CHEN, G., BARVE, S., KANG, B. C. and THOMPSON, J. S., 1999, A high dose of ionizing radiation induces tissue-specific activation of nuclear factor-kappaB in vivo. Radiation Research, 151, 703-709.
    • (1999) Radiation Research , vol.151 , pp. 703-709
    • Zhou, D.1    Brown, S.A.2    Yu, T.3    Chen, G.4    Barve, S.5    Kang, B.C.6    Thompson, J.S.7
  • 57
    • 0034743275 scopus 로고    scopus 로고
    • Effects of NF-kappaB1 (p50) targeted gene disruption on ionizing radiation-induced NF-kappaB activation and TNFalpha, IL-1alpha, IL-1beta and IL-6 mRNA expression in vivo
    • ZHOU, D., YU, T., CHEN, G., BROWN, S. A., YU, Z., MATTSON, M. P. and THOMPSON, J. S., 2001, Effects of NF-kappaB1 (p50) targeted gene disruption on ionizing radiation-induced NF-kappaB activation and TNFalpha, IL-1alpha, IL-1beta and IL-6 mRNA expression in vivo. International Journal of Radiation Biology, 77, 763-772.
    • (2001) International Journal of Radiation Biology , vol.77 , pp. 763-772
    • Zhou, D.1    Yu, T.2    Chen, G.3    Brown, S.A.4    Yu, Z.5    Mattson, M.P.6    Thompson, J.S.7


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