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Volumn 5, Issue 4, 2004, Pages 353-364

The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-κB activation in anaplastic large cell lymphoma

Author keywords

[No Author keywords available]

Indexed keywords

ANAPLASTIC LYMPHOMA KINASE; CD30 ANTIGEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; NUCLEOPLASMIN; ONCOPROTEIN; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 2;

EID: 1842785805     PISSN: 15356108     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1535-6108(04)00084-4     Document Type: Article
Times cited : (65)

References (55)
  • 2
    • 0025730640 scopus 로고
    • A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells
    • Andrews N.C., Faller D.V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 19:1991;2499.
    • (1991) Nucleic Acids Res. , vol.19 , pp. 2499
    • Andrews, N.C.1    Faller, D.V.2
  • 3
    • 0031755958 scopus 로고    scopus 로고
    • Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-γ to mediate its mitogenicity
    • Bai R.Y., Dieter P., Peschel C., Morris S.W., Duyster J. Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-γ to mediate its mitogenicity. Mol. Cell. Biol. 18:1998;6951-6961.
    • (1998) Mol. Cell. Biol. , vol.18 , pp. 6951-6961
    • Bai, R.Y.1    Dieter, P.2    Peschel, C.3    Morris, S.W.4    Duyster, J.5
  • 5
    • 0033563101 scopus 로고    scopus 로고
    • Signaling by proinflammatory cytokines: Oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain
    • Baud V., Liu Z.G., Bennett B., Suzuki N., Xia Y., Karin M. Signaling by proinflammatory cytokines. Oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain Genes Dev. 13:1999;1297-1308.
    • (1999) Genes Dev. , vol.13 , pp. 1297-1308
    • Baud, V.1    Liu, Z.G.2    Bennett, B.3    Suzuki, N.4    Xia, Y.5    Karin, M.6
  • 6
    • 0029976817 scopus 로고    scopus 로고
    • An essential role for NF-κB in preventing TNF-alpha-induced cell death
    • Beg A.A., Baltimore D. An essential role for NF-κB in preventing TNF-alpha-induced cell death. Science. 274:1996;782-784.
    • (1996) Science , vol.274 , pp. 782-784
    • Beg, A.A.1    Baltimore, D.2
  • 7
    • 0030934862 scopus 로고    scopus 로고
    • Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis
    • Bischof D., Pulford K., Mason D.Y., Morris S.W. Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol. Cell. Biol. 17:1997;2312-2325.
    • (1997) Mol. Cell. Biol. , vol.17 , pp. 2312-2325
    • Bischof, D.1    Pulford, K.2    Mason, D.Y.3    Morris, S.W.4
  • 8
    • 0024966024 scopus 로고
    • Major nucleolar proteins shuttle between nucleus and cytoplasm
    • Borer R.A., Lehner C.F., Eppenberger H.M., Nigg E.A. Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell. 56:1989;379-390.
    • (1989) Cell , vol.56 , pp. 379-390
    • Borer, R.A.1    Lehner, C.F.2    Eppenberger, H.M.3    Nigg, E.A.4
  • 11
    • 0034655650 scopus 로고    scopus 로고
    • MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets
    • Dyomin V.G., Palanisamy N., Lloyd K.O., Dyomina K., Jhanwar S.C., Houldsworth J., Chaganti R.S. MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood. 95:2000;2666-2671.
    • (2000) Blood , vol.95 , pp. 2666-2671
    • Dyomin, V.G.1    Palanisamy, N.2    Lloyd, K.O.3    Dyomina, K.4    Jhanwar, S.C.5    Houldsworth, J.6    Chaganti, R.S.7
  • 12
    • 0030003813 scopus 로고    scopus 로고
    • Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5)
    • Fujimoto J., Shiota M., Iwahara T., Seki N., Satoh H., Mori S., Yamamoto T. Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc. Natl. Acad. Sci. USA. 93:1996;4181-4186.
    • (1996) Proc. Natl. Acad. Sci. USA , vol.93 , pp. 4181-4186
    • Fujimoto, J.1    Shiota, M.2    Iwahara, T.3    Seki, N.4    Satoh, H.5    Mori, S.6    Yamamoto, T.7
  • 14
    • 0344850198 scopus 로고    scopus 로고
    • TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations
    • Hernandez L., Pinyol M., Hernandez S., Bea S., Pulford K., Rosenwald A., Lamant L., Falini B., Ott G., Mason D.Y.et al. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood. 94:1999;3265-3268.
    • (1999) Blood , vol.94 , pp. 3265-3268
    • Hernandez, L.1    Pinyol, M.2    Hernandez, S.3    Bea, S.4    Pulford, K.5    Rosenwald, A.6    Lamant, L.7    Falini, B.8    Ott, G.9    Mason, D.Y.10
  • 15
    • 0034637578 scopus 로고    scopus 로고
    • Mapping the functional domains of nucleolar protein B23
    • Hingorani K., Szebeni A., Olson M.O. Mapping the functional domains of nucleolar protein B23. J. Biol. Chem. 275:2000;24451-24457.
    • (2000) J. Biol. Chem. , vol.275 , pp. 24451-24457
    • Hingorani, K.1    Szebeni, A.2    Olson, M.O.3
  • 16
    • 0032387839 scopus 로고    scopus 로고
    • CD30: Expression and function in health and disease
    • Horie R., Watanabe T. CD30. Expression and function in health and disease Semin. Immunol. 10:1998;457-470.
    • (1998) Semin. Immunol. , vol.10 , pp. 457-470
    • Horie, R.1    Watanabe, T.2
  • 17
    • 10144248976 scopus 로고    scopus 로고
    • A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate and is expressed in alveolar macrophages
    • Horie R., Ito K., Tatewaki M., Nagai M., Aizawa S., Higashihara M., Ishida T., Inoue J., Takizawa H., Watanabe T. A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate and is expressed in alveolar macrophages. Blood. 88:1996;2422-2432.
    • (1996) Blood , vol.88 , pp. 2422-2432
    • Horie, R.1    Ito, K.2    Tatewaki, M.3    Nagai, M.4    Aizawa, S.5    Higashihara, M.6    Ishida, T.7    Inoue, J.8    Takizawa, H.9    Watanabe, T.10
  • 21
  • 22
    • 0035252939 scopus 로고    scopus 로고
    • CD30-mediated cell cycle arrest associated with induced expression of p21(CIP1/WAF1) in the anaplastic large cell lymphoma cell line Karpas 299
    • Hubinger G., Muller E., Scheffrahn I., Schneider C., Hildt E., Singer B.B., Sigg I., Graf J., Bergmann L. CD30-mediated cell cycle arrest associated with induced expression of p21(CIP1/WAF1) in the anaplastic large cell lymphoma cell line Karpas 299. Oncogene. 20:2001;590-598.
    • (2001) Oncogene , vol.20 , pp. 590-598
    • Hubinger, G.1    Muller, E.2    Scheffrahn, I.3    Schneider, C.4    Hildt, E.5    Singer, B.B.6    Sigg, I.7    Graf, J.8    Bergmann, L.9
  • 23
    • 0034627798 scopus 로고    scopus 로고
    • Tumor necrosis factor receptor-associated factor (TRAF) family: Adapter proteins that mediate cytokine signaling
    • Inoue J., Ishida T., Tsukamoto N., Kobayashi N., Naito A., Azuma S., Yamamoto T. Tumor necrosis factor receptor-associated factor (TRAF) family. Adapter proteins that mediate cytokine signaling Exp. Cell Res. 254:2000;14-24.
    • (2000) Exp. Cell Res. , vol.254 , pp. 14-24
    • Inoue, J.1    Ishida, T.2    Tsukamoto, N.3    Kobayashi, N.4    Naito, A.5    Azuma, S.6    Yamamoto, T.7
  • 25
    • 0035082616 scopus 로고    scopus 로고
    • Anaplastic large cell lymphoma: The shifting sands of diagnostic hematopathology
    • Jaffe E.S. Anaplastic large cell lymphoma. The shifting sands of diagnostic hematopathology Mod. Pathol. 14:2001;219-228.
    • (2001) Mod. Pathol. , vol.14 , pp. 219-228
    • Jaffe, E.S.1
  • 26
    • 0028205778 scopus 로고
    • Ki-1/CD30+ (anaplastic) large-cell lymphoma: Maturation of a clinicopathologic entity with prospects of effective therapy
    • Kadin M.E. Ki-1/CD30+ (anaplastic) large-cell lymphoma. maturation of a clinicopathologic entity with prospects of effective therapy J. Clin. Oncol. 12:1994;884-887.
    • (1994) J. Clin. Oncol. , vol.12 , pp. 884-887
    • Kadin, M.E.1
  • 27
    • 0035180858 scopus 로고    scopus 로고
    • Hodgkin's lymphoma of T-cell type: Clonal association with a CD30+ cutaneous lymphoma
    • Kadin M.E., Drews R., Samel A., Gilchrist A., Kocher O. Hodgkin's lymphoma of T-cell type. Clonal association with a CD30+ cutaneous lymphoma Hum. Pathol. 32:2001;1269-1272.
    • (2001) Hum. Pathol. , vol.32 , pp. 1269-1272
    • Kadin, M.E.1    Drews, R.2    Samel, A.3    Gilchrist, A.4    Kocher, O.5
  • 28
    • 2642699794 scopus 로고
    • Rapid and efficient site-specific mutagenesis without phenotypic selection
    • Kunkel T.A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc. Natl. Acad. Sci. USA. 82:1985;488-492.
    • (1985) Proc. Natl. Acad. Sci. USA , vol.82 , pp. 488-492
    • Kunkel, T.A.1
  • 29
    • 0036834540 scopus 로고    scopus 로고
    • Clusterin is widely expressed in systemic anaplastic large cell lymphoma but fails to differentiate primary from secondary cutaneous anaplastic large cell lymphoma
    • Lae M.E., Ahmed I., Macon W.R. Clusterin is widely expressed in systemic anaplastic large cell lymphoma but fails to differentiate primary from secondary cutaneous anaplastic large cell lymphoma. Am. J. Clin. Pathol. 118:2002;773-779.
    • (2002) Am. J. Clin. Pathol. , vol.118 , pp. 773-779
    • Lae, M.E.1    Ahmed, I.2    MacOn, W.R.3
  • 30
    • 0033134786 scopus 로고    scopus 로고
    • A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation
    • Lamant L., Dastugue N., Pulford K., Delsol G., Mariame B. A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Blood. 93:1999;3088-3095.
    • (1999) Blood , vol.93 , pp. 3088-3095
    • Lamant, L.1    Dastugue, N.2    Pulford, K.3    Delsol, G.4    Mariame, B.5
  • 31
    • 0025202643 scopus 로고
    • Hodgkin's disease and CD30-positive anaplastic large cell lymphomas-a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study
    • Leoncini L., Del Vecchio M.T., Kraft R., Megha T., Barbini P., Cevenini G., Poggi S., Pileri S., Tosi P., Cottier H. Hodgkin's disease and CD30-positive anaplastic large cell lymphomas-a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study. Am. J. Pathol. 137:1990;1047-1057.
    • (1990) Am. J. Pathol. , vol.137 , pp. 1047-1057
    • Leoncini, L.1    Del Vecchio, M.T.2    Kraft, R.3    Megha, T.4    Barbini, P.5    Cevenini, G.6    Poggi, S.7    Pileri, S.8    Tosi, P.9    Cottier, H.10
  • 32
    • 0035469831 scopus 로고    scopus 로고
    • CD30-activation-mediated growth inhibition of anaplastic large-cell lymphoma cell lines: Apoptosis or cell-cycle arrest?
    • Levi E., Pfeifer W.M., Kadin M.E. CD30-activation-mediated growth inhibition of anaplastic large-cell lymphoma cell lines. Apoptosis or cell-cycle arrest? Blood. 98:2001;1630-1632.
    • (2001) Blood , vol.98 , pp. 1630-1632
    • Levi, E.1    Pfeifer, W.M.2    Kadin, M.E.3
  • 33
    • 0031017618 scopus 로고    scopus 로고
    • MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1
    • Malinin N.L., Boldin M.P., Kovalenko A.V., Wallach D. MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature. 385:1997;540-544.
    • (1997) Nature , vol.385 , pp. 540-544
    • Malinin, N.L.1    Boldin, M.P.2    Kovalenko, A.V.3    Wallach, D.4
  • 34
    • 0030703604 scopus 로고    scopus 로고
    • Regulation and function of the JNK subgroup of MAP kinases
    • Minden A., Karin M. Regulation and function of the JNK subgroup of MAP kinases. Biochim. Biophys. Acta. 1333:1997;F85-104.
    • (1997) Biochim. Biophys. Acta , vol.1333 , pp. 85-104
    • Minden, A.1    Karin, M.2
  • 35
    • 0034672237 scopus 로고    scopus 로고
    • Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells
    • Mir S.S., Richter B.W., Duckett C.S. Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells. Blood. 96:2000;4307-4312.
    • (2000) Blood , vol.96 , pp. 4307-4312
    • Mir, S.S.1    Richter, B.W.2    Duckett, C.S.3
  • 40
    • 0022510230 scopus 로고
    • Preribosomal ribonucleoprotein particles are a major component of a nucleolar matrix fraction
    • Olson M.O., Wallace M.O., Herrera A.H., Marshall-Carlson L., Hunt R.C. Preribosomal ribonucleoprotein particles are a major component of a nucleolar matrix fraction. Biochemistry. 25:1986;484-491.
    • (1986) Biochemistry , vol.25 , pp. 484-491
    • Olson, M.O.1    Wallace, M.O.2    Herrera, A.H.3    Marshall-Carlson, L.4    Hunt, R.C.5
  • 41
    • 0036861376 scopus 로고    scopus 로고
    • Clusterin expression in malignant lymphomas: A survey of 266 cases
    • Saffer H., Wahed A., Rassidakis G.Z., Medeiros L.J. Clusterin expression in malignant lymphomas. A survey of 266 cases Mod. Pathol. 15:2002;1221-1226.
    • (2002) Mod. Pathol. , vol.15 , pp. 1221-1226
    • Saffer, H.1    Wahed, A.2    Rassidakis, G.Z.3    Medeiros, L.J.4
  • 42
    • 0036302480 scopus 로고    scopus 로고
    • Pleiotropic signal transduction mediated by human CD30: A member of the tumor necrosis factor receptor (TNFR) family
    • Schneider C., Hubinger G. Pleiotropic signal transduction mediated by human CD30. A member of the tumor necrosis factor receptor (TNFR) family Leuk. Lymphoma. 43:2002;1355-1366.
    • (2002) Leuk. Lymphoma , vol.43 , pp. 1355-1366
    • Schneider, C.1    Hubinger, G.2
  • 44
    • 0034658050 scopus 로고    scopus 로고
    • Detection of clonal T-cell receptor gamma-chain gene rearrangements in Reed-Sternberg cells of classic Hodgkin disease
    • Seitz V., Hummel M., Marafioti T., Anagnostopoulos I., Assaf C., Stein H. Detection of clonal T-cell receptor gamma-chain gene rearrangements in Reed-Sternberg cells of classic Hodgkin disease. Blood. 95:2000;3020-3024.
    • (2000) Blood , vol.95 , pp. 3020-3024
    • Seitz, V.1    Hummel, M.2    Marafioti, T.3    Anagnostopoulos, I.4    Assaf, C.5    Stein, H.6
  • 45
    • 0034554843 scopus 로고    scopus 로고
    • CD30(+) anaplastic large cell lymphoma: A review of its histopathologic, genetic, and clinical features
    • Stein H., Foss H.D., Durkop H., Marafioti T., Delsol G., Pulford K., Pileri S., Falini B. CD30(+) anaplastic large cell lymphoma. A review of its histopathologic, genetic, and clinical features Blood. 96:2000;3681-3695.
    • (2000) Blood , vol.96 , pp. 3681-3695
    • Stein, H.1    Foss, H.D.2    Durkop, H.3    Marafioti, T.4    Delsol, G.5    Pulford, K.6    Pileri, S.7    Falini, B.8
  • 46
    • 0032917157 scopus 로고    scopus 로고
    • Nucleolar protein B23 has molecular chaperone activities
    • Szebeni A., Olson M.O. Nucleolar protein B23 has molecular chaperone activities. Protein Sci. 8:1999;905-912.
    • (1999) Protein Sci. , vol.8 , pp. 905-912
    • Szebeni, A.1    Olson, M.O.2
  • 47
    • 0037646535 scopus 로고    scopus 로고
    • Role of protein kinase CK2 phosphorylation in the molecular chaperone activity of nucleolar protein b23
    • Szebeni A., Hingorani K., Negi S., Olson M.O. Role of protein kinase CK2 phosphorylation in the molecular chaperone activity of nucleolar protein b23. J. Biol. Chem. 278:2003;9107-9115.
    • (2003) J. Biol. Chem. , vol.278 , pp. 9107-9115
    • Szebeni, A.1    Hingorani, K.2    Negi, S.3    Olson, M.O.4
  • 49
    • 0034982801 scopus 로고    scopus 로고
    • The TNF-receptor-associated factor family: Scaffold molecules for cytokine receptors, kinases and their regulators
    • Wajant H., Henkler F., Scheurich P. The TNF-receptor-associated factor family. Scaffold molecules for cytokine receptors, kinases and their regulators Cell. Signal. 13:2001;389-400.
    • (2001) Cell. Signal. , vol.13 , pp. 389-400
    • Wajant, H.1    Henkler, F.2    Scheurich, P.3
  • 50
    • 0030997964 scopus 로고    scopus 로고
    • Efficient retrovirus-mediated cytokine-gene transduction of primary-cultured human glioma cells for tumor vaccination therapy
    • Wakimoto H., Yoshida Y., Aoyagi M., Hirakawa K., Hamada H. Efficient retrovirus-mediated cytokine-gene transduction of primary-cultured human glioma cells for tumor vaccination therapy. Jpn. J. Cancer Res. 88:1997;296-305.
    • (1997) Jpn. J. Cancer Res. , vol.88 , pp. 296-305
    • Wakimoto, H.1    Yoshida, Y.2    Aoyagi, M.3    Hirakawa, K.4    Hamada, H.5
  • 51
    • 0042345055 scopus 로고    scopus 로고
    • AP-1 mediated relief of repressive activity of the CD30 promoter microsatellite in Hodgkin and Reed-Sternberg cells
    • Watanabe M., Ogawa Y., Ito K., Higashihara M., Kadin M.E., Abraham L.J., Watanabe T., Horie R. AP-1 mediated relief of repressive activity of the CD30 promoter microsatellite in Hodgkin and Reed-Sternberg cells. Am. J. Pathol. 163:2003;633-641.
    • (2003) Am. J. Pathol. , vol.163 , pp. 633-641
    • Watanabe, M.1    Ogawa, Y.2    Ito, K.3    Higashihara, M.4    Kadin, M.E.5    Abraham, L.J.6    Watanabe, T.7    Horie, R.8
  • 52
    • 0030754799 scopus 로고    scopus 로고
    • The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up-regulation in rat 1a fibroblasts
    • Wellmann A., Doseeva V., Butscher W., Raffeld M., Fukushima P., Stetler-Stevenson M., Gardner K. The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up-regulation in rat 1a fibroblasts. FASEB J. 11:1997;965-972.
    • (1997) FASEB J. , vol.11 , pp. 965-972
    • Wellmann, A.1    Doseeva, V.2    Butscher, W.3    Raffeld, M.4    Fukushima, P.5    Stetler-Stevenson, M.6    Gardner, K.7
  • 53
    • 0034661519 scopus 로고    scopus 로고
    • Detection of differentially expressed genes in lymphomas using cDNA arrays: Identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas
    • Wellmann A., Thieblemont C., Pittaluga S., Sakai A., Jaffe E.S., Siebert P., Raffeld M. Detection of differentially expressed genes in lymphomas using cDNA arrays. identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas Blood. 96:2000;398-404.
    • (2000) Blood , vol.96 , pp. 398-404
    • Wellmann, A.1    Thieblemont, C.2    Pittaluga, S.3    Sakai, A.4    Jaffe, E.S.5    Siebert, P.6    Raffeld, M.7
  • 54
    • 0038492856 scopus 로고    scopus 로고
    • Proliferation of CD30+ T-helper 2 lymphoma cells can be inhibited by CD30 receptor cross-linking with recombinant CD30 ligand
    • Willers J., Dummer R., Kempf W., Kundig T., Burg G., Kadin M.E. Proliferation of CD30+ T-helper 2 lymphoma cells can be inhibited by CD30 receptor cross-linking with recombinant CD30 ligand. Clin. Cancer Res. 9:2003;2744-2754.
    • (2003) Clin. Cancer Res. , vol.9 , pp. 2744-2754
    • Willers, J.1    Dummer, R.2    Kempf, W.3    Kundig, T.4    Burg, G.5    Kadin, M.E.6
  • 55
    • 0033197872 scopus 로고    scopus 로고
    • The structural basis for the recognition of diverse receptor sequences by TRAF2
    • Ye H., Park Y.C., Kreishman M., Kieff E., Wu H. The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol. Cell. 4:1999;321-330.
    • (1999) Mol. Cell , vol.4 , pp. 321-330
    • Ye, H.1    Park, Y.C.2    Kreishman, M.3    Kieff, E.4    Wu, H.5


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