메뉴 건너뛰기




Volumn 237, Issue 2, 2005, Pages 117-132

A mathematical model of hematopoiesis - I. Periodic chronic myelogenous leukemia

Author keywords

Leukemia; Mathematical model

Indexed keywords

NUMERICAL MODEL;

EID: 26044443571     PISSN: 00225193     EISSN: 10958541     Source Type: Journal    
DOI: 10.1016/j.jtbi.2005.03.033     Document Type: Article
Times cited : (243)

References (60)
  • 1
    • 0034669933 scopus 로고    scopus 로고
    • The in vivo kinetics of murine hemopoietic stem cells
    • J. Abkowitz, D. Golinelli, D. Harrison, and P. Guttorp The in vivo kinetics of murine hemopoietic stem cells Blood 96 2000 3399 3405
    • (2000) Blood , vol.96 , pp. 3399-3405
    • Abkowitz, J.1    Golinelli, D.2    Harrison, D.3    Guttorp, P.4
  • 2
    • 0024240969 scopus 로고
    • Cyclic hematopoiesis in dogs: Studies of erythroid burst forming cells confirm an early stem cell defect
    • J.L. Abkowitz, R.D. Holly, and W.P. Hammond Cyclic hematopoiesis in dogs: studies of erythroid burst forming cells confirm an early stem cell defect Exp. Hematol. 16 1988 941 945
    • (1988) Exp. Hematol. , vol.16 , pp. 941-945
    • Abkowitz, J.L.1    Holly, R.D.2    Hammond, W.P.3
  • 3
    • 0028358438 scopus 로고
    • The relationship of erythropoietin and iron metabolism to red blood cell production in humans
    • J. Adamson The relationship of erythropoietin and iron metabolism to red blood cell production in humans Semin. Oncol. 21 1974 9 15
    • (1974) Semin. Oncol. , vol.21 , pp. 9-15
    • Adamson, J.1
  • 4
    • 0036464648 scopus 로고    scopus 로고
    • Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells
    • S. Akbarzadeh, D. Golinelli, D. harrison, and P. Guttorp Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells Blood 99 2002 879 887
    • (2002) Blood , vol.99 , pp. 879-887
    • Akbarzadeh, S.1    Golinelli, D.2    Harrison, D.3    Guttorp, P.4
  • 5
    • 0000268882 scopus 로고
    • A model for the regulation of mammalian platelet
    • J. Bélair, and M. Mackey A model for the regulation of mammalian platelet Ann. NY Acad. Sci. 504 1987 280 282
    • (1987) Ann. NY Acad. Sci. , vol.504 , pp. 280-282
    • Bélair, J.1    MacKey, M.2
  • 6
    • 0029025412 scopus 로고
    • Age-structured and two-delay models for erythropoiesis
    • J. Bélair, M. Mackey, and J. Mahaffy Age-structured and two-delay models for erythropoiesis Math. Biosci. 128 1995 317 346
    • (1995) Math. Biosci. , vol.128 , pp. 317-346
    • Bélair, J.1    MacKey, M.2    Mahaffy, J.3
  • 7
    • 0037678721 scopus 로고    scopus 로고
    • Oscillations in cyclical neutropenia: New evidence based on mathematical modeling
    • S. Bernard, J. Belair, and M. Mackey Oscillations in cyclical neutropenia: new evidence based on mathematical modeling J. Theor. Biol. 223 2003
    • (2003) J. Theor. Biol. , vol.223
    • Bernard, S.1    Belair, J.2    MacKey, M.3
  • 9
    • 0019954603 scopus 로고
    • Hematopoietic stem cells with high proliferative potential: Assay of their concentration in marrow by the frequency and duration of cure of W/Wv mice
    • D. Boggs, S. Boggs, D. Saxe, L. Gress, and D. Canfield Hematopoietic stem cells with high proliferative potential: assay of their concentration in marrow by the frequency and duration of cure of W/Wv mice J. Clin. Invest. 70 1982 242 253
    • (1982) J. Clin. Invest. , vol.70 , pp. 242-253
    • Boggs, D.1    Boggs, S.2    Saxe, D.3    Gress, L.4    Canfield, D.5
  • 10
    • 0032980506 scopus 로고    scopus 로고
    • In vivo proliferation and cell cycle kinetics of long term self-renewing haematopoietic stem cells
    • S. Cheshier, S. Morrison, X. Liao, and I. Weissman In vivo proliferation and cell cycle kinetics of long term self-renewing haematopoietic stem cells Proc. Natl Acad. Sci. USA 96 1999 3120 3125
    • (1999) Proc. Natl Acad. Sci. USA , vol.96 , pp. 3120-3125
    • Cheshier, S.1    Morrison, S.2    Liao, X.3    Weissman, I.4
  • 11
    • 0017185632 scopus 로고
    • Periodic oscillation of blood leukocytes, platelets, and reticulocytes in a patient with chronic myelocytic leukemia
    • G. Chikkappa, A.H.B. Borner, A.D. Chanana, E.P. Cronkite, S. Ohl, M. Pavelec, and J.S. Robertso Periodic oscillation of blood leukocytes, platelets, and reticulocytes in a patient with chronic myelocytic leukemia Blood 47 1976 1023 1030
    • (1976) Blood , vol.47 , pp. 1023-1030
    • Chikkappa, G.1    Borner, A.H.B.2    Chanana, A.D.3    Cronkite, E.P.4    Ohl, S.5    Pavelec, M.6    Robertso, J.S.7
  • 12
    • 0015795079 scopus 로고
    • Evolution cyclique spontanée de la leucocytose dans un cas de leucémie myéloide chronique
    • J. Delobel, P. Charbord, P. Passa, and J. Bernard Evolution cyclique spontanée de la leucocytose dans un cas de leucémie myéloide chronique Nouv. Rev. franc Hémat. 13 1973 221 228
    • (1973) Nouv. Rev. Franc Hémat. , vol.13 , pp. 221-228
    • Delobel, J.1    Charbord, P.2    Passa, P.3    Bernard, J.4
  • 14
    • 0025884718 scopus 로고
    • Erythropoietin titers in health and disease
    • Erslev, A., 1991. Erythropoietin titers in health and disease. Semin. Hematol., 779-791.
    • (1991) Semin. Hematol. , pp. 779-791
    • Erslev, A.1
  • 15
    • 0032956844 scopus 로고    scopus 로고
    • Periodic chronic myelogenous leukemia: Spectral analysis of blood cell counts and etiological implications
    • P. Fortin, and M. Mackey Periodic chronic myelogenous leukemia: Spectral analysis of blood cell counts and etiological implications Br. J. Haematol. 104 1999 245 336
    • (1999) Br. J. Haematol. , vol.104 , pp. 245-336
    • Fortin, P.1    MacKey, M.2
  • 16
    • 0036706324 scopus 로고    scopus 로고
    • Relaxation oscillations in a class of delay differential equations
    • A. Fowler, and M. Mackey Relaxation oscillations in a class of delay differential equations SIAM J. Appl. Math. 63 2002 299 323
    • (2002) SIAM J. Appl. Math. , vol.63 , pp. 299-323
    • Fowler, A.1    MacKey, M.2
  • 19
    • 0034697629 scopus 로고    scopus 로고
    • Modeling complex neutrophil dynamics in the grey collie
    • C. Haurie, and M. Mackey Modeling complex neutrophil dynamics in the grey collie J. Theor. Biol. 204 2000 504 519
    • (2000) J. Theor. Biol. , vol.204 , pp. 504-519
    • Haurie, C.1    MacKey, M.2
  • 20
    • 0032532631 scopus 로고    scopus 로고
    • Cyclical neutropenia and other periodic hematological diseases: A review of mechanisms and mathematical models
    • C. Haurie, M.C. Mackey, and D.C. Dale Cyclical neutropenia and other periodic hematological diseases: a review of mechanisms and mathematical models Blood 92 1998 2629 2640
    • (1998) Blood , vol.92 , pp. 2629-2640
    • Haurie, C.1    MacKey, M.C.2    Dale, D.C.3
  • 21
    • 0032554934 scopus 로고    scopus 로고
    • Cyclical neutropenia and the peripherial control of white blood cell production
    • T. Hearn, C. Haurie, and M. Mackey Cyclical neutropenia and the peripherial control of white blood cell production J. Theor. Biol 192 1998 167 181
    • (1998) J. Theor. Biol , vol.192 , pp. 167-181
    • Hearn, T.1    Haurie, C.2    MacKey, M.3
  • 23
    • 0021267140 scopus 로고
    • Periodic fluctuation of leukocytes, platelets and reticulocytes in a case of chronic myelocytic leukemia: The relation between leukocyte counts, cfu-c colony formation, csa and cia
    • Y. Iizuka, A. Horikoshi, S. Sekiya, U. Sawada, T. Ohshima, and I. Amaki Periodic fluctuation of leukocytes, platelets and reticulocytes in a case of chronic myelocytic leukemia: The relation between leukocyte counts, cfu-c colony formation, csa and cia Acta Haematol. Japan 47 1984 71 79
    • (1984) Acta Haematol. Japan , vol.47 , pp. 71-79
    • Iizuka, Y.1    Horikoshi, A.2    Sekiya, S.3    Sawada, U.4    Ohshima, T.5    Amaki, I.6
  • 24
    • 0014802284 scopus 로고
    • Cyclic leukocyte oscillations in chronic myelogenous leukemia during hydroxyurea therapy
    • B.J. Kennedy Cyclic leukocyte oscillations in chronic myelogenous leukemia during hydroxyurea therapy Blood 35 1970 751 760
    • (1970) Blood , vol.35 , pp. 751-760
    • Kennedy, B.J.1
  • 25
    • 0030307622 scopus 로고    scopus 로고
    • The physiology of platelet production
    • D. Kuter The physiology of platelet production Stem Cells 14 1996 88 101
    • (1996) Stem Cells , vol.14 , pp. 88-101
    • Kuter, D.1
  • 26
    • 0014499229 scopus 로고
    • Grain count distributions in labeled cell populations
    • J. Lebowitz, and S. Rubinow Grain count distributions in labeled cell populations J. Theor. Biol. 23 1969 99 123
    • (1969) J. Theor. Biol. , vol.23 , pp. 99-123
    • Lebowitz, J.1    Rubinow, S.2
  • 27
    • 0022474392 scopus 로고
    • Developmental potential and dynamic behavior of hemopoietic stem cells
    • I.R. Lemishka, D.H. Raulet, and R.C. Mulligan Developmental potential and dynamic behavior of hemopoietic stem cells Cell 45 1986 917
    • (1986) Cell , vol.45 , pp. 917
    • Lemishka, I.R.1    Raulet, D.H.2    Mulligan, R.C.3
  • 28
    • 33748319101 scopus 로고
    • Least-squares frequency analysis of unequally spaced data
    • N.R. Lomb Least-squares frequency analysis of unequally spaced data Astrophys. Space Sci. 39 1976 447 462
    • (1976) Astrophys. Space Sci. , vol.39 , pp. 447-462
    • Lomb, N.R.1
  • 29
    • 0023853242 scopus 로고    scopus 로고
    • In vivo control of differentiation of myeloid leukemic cells by recombinant granulocyte-macrophage colony-stimulating factor and interleukin 3
    • J. Lotem, and L. Sachs In vivo control of differentiation of myeloid leukemic cells by recombinant granulocyte-macrophage colony-stimulating factor and interleukin 3 Blood 71 1998 375 382
    • (1998) Blood , vol.71 , pp. 375-382
    • Lotem, J.1    Sachs, L.2
  • 30
    • 0032712575 scopus 로고    scopus 로고
    • Divided we stand: Tracing cell proliferation with carboxy uorescein diacetate syccinimidyl ester
    • A.B. Lyons Divided we stand: tracing cell proliferation with carboxy uorescein diacetate syccinimidyl ester Immunol. Cell Biol. 77 1999
    • (1999) Immunol. Cell Biol. , vol.77
    • Lyons, A.B.1
  • 31
    • 0018138249 scopus 로고
    • A unified hypothesis for the origin of aplastic anemia and periodic haematopoiesis
    • M.C. Mackey A unified hypothesis for the origin of aplastic anemia and periodic haematopoiesis Blood 51 1978 941 956
    • (1978) Blood , vol.51 , pp. 941-956
    • MacKey, M.C.1
  • 32
    • 0003117329 scopus 로고
    • Dynamic haematological disorders of stem cell origin
    • J.G. Vassileva-Popova E.V. Jensen Plenum Publishing Corp New York
    • M.C. Mackey Dynamic haematological disorders of stem cell origin J.G. Vassileva-Popova E.V. Jensen Biophysical and Biochemical Information Transfer in Recognition 1979 Plenum Publishing Corp New York 373 409
    • (1979) Biophysical and Biochemical Information Transfer in Recognition , pp. 373-409
    • MacKey, M.C.1
  • 33
    • 0018570535 scopus 로고
    • Periodic auto-immune hemolytic anemia: An induced dynamical disease
    • M.C. Mackey Periodic auto-immune hemolytic anemia: an induced dynamical disease Bull. Math. Biol. 41 1979 829 834
    • (1979) Bull. Math. Biol. , vol.41 , pp. 829-834
    • MacKey, M.C.1
  • 34
    • 0001413222 scopus 로고    scopus 로고
    • Mathematical models of hematopoietic cell replication and control
    • H. Othmer F. Adler M. Lewis J. Dallon Prentice-Hall New York
    • M.C. Mackey Mathematical models of hematopoietic cell replication and control H. Othmer F. Adler M. Lewis J. Dallon The Art of Mathematical Modeling: Case Studies in Ecology, Physiology and Biofluids 1996 Prentice-Hall New York 149 178
    • (1996) The Art of Mathematical Modeling: Case Studies in Ecology, Physiology and Biofluids , pp. 149-178
    • MacKey, M.C.1
  • 35
    • 0035030264 scopus 로고    scopus 로고
    • Cell kinetic status of haematopoietic stem cells
    • M.C. Mackey Cell kinetic status of haematopoietic stem cells Cell Prolif. 34 2000 71 83
    • (2000) Cell Prolif. , vol.34 , pp. 71-83
    • MacKey, M.C.1
  • 36
    • 0032554028 scopus 로고    scopus 로고
    • Hematopoietic model with moving boundary condition and state dependent delay: Applications in erythropoiesis
    • J. Mahaffy, J. Belair, and M. Mackey Hematopoietic model with moving boundary condition and state dependent delay: applications in erythropoiesis J. Theor. Biol. 190 1998 135 146
    • (1998) J. Theor. Biol. , vol.190 , pp. 135-146
    • Mahaffy, J.1    Belair, J.2    MacKey, M.3
  • 37
    • 0032554028 scopus 로고    scopus 로고
    • Hematopoietic model with moving boundary condition and state dependent delay
    • J.M. Mahaffy, J. Bélair, and M. Mackey Hematopoietic model with moving boundary condition and state dependent delay J. Theor. Biol. 190 1998 135 146
    • (1998) J. Theor. Biol. , vol.190 , pp. 135-146
    • Mahaffy, J.M.1    Bélair, J.2    MacKey, M.3
  • 38
    • 0029816460 scopus 로고    scopus 로고
    • The diversity of bcr-abl fusion proteins and their relationship to leukemia phenotype
    • J. Melo The diversity of bcr-abl fusion proteins and their relationship to leukemia phenotype Blood 88 1996 2375
    • (1996) Blood , vol.88 , pp. 2375
    • Melo, J.1
  • 40
    • 0023245271 scopus 로고
    • Numbers and dispersion of repopulating hematopoietic cell clones in radiation chimeras as functions of injected cell dose
    • Micklem, H., Lennon, J., Ansell, J., Gray., R.A., 1987. Numbers and dispersion of repopulating hematopoietic cell clones in radiation chimeras as functions of injected cell dose. Exp. Hematol. 15(3), 251-257.
    • (1987) Exp. Hematol. , vol.15 , Issue.3 , pp. 251-257
    • Micklem, H.1    Lennon, J.2    Ansell, J.3    Gray, R.A.4
  • 41
    • 0014215158 scopus 로고
    • Cyclic leukocytosis as evidence for retention of normal homeostatic control in chronic granulocytic leukaemia
    • Morley, A.A., Baikie, A., Galton, D., 1967. Cyclic leukocytosis as evidence for retention of normal homeostatic control in chronic granulocytic leukaemia. Lancet, 1320-1322.
    • (1967) Lancet , pp. 1320-1322
    • Morley, A.A.1    Baikie, A.2    Galton, D.3
  • 42
    • 0027978362 scopus 로고
    • Proliferation differentiation pathways of murine haematopoiesis: Correlation of lineage fluxes
    • J.P. Novak, and E. Necas Proliferation differentiation pathways of murine haematopoiesis: correlation of lineage fluxes Cell. Prolif. 27 1994 597 633
    • (1994) Cell. Prolif. , vol.27 , pp. 597-633
    • Novak, J.P.1    Necas, E.2
  • 44
    • 0027325195 scopus 로고
    • Differentiation and proliferation of hematopoietic stem cells
    • M. Ogawa Differentiation and proliferation of hematopoietic stem cells Blood 81 1993 2844 2853
    • (1993) Blood , vol.81 , pp. 2844-2853
    • Ogawa, M.1
  • 45
    • 0034141522 scopus 로고
    • High-resolution tracking of cell division suggests similar cell cycle kinetics of hematopoietic stem cells stimulated in vitro and in vivo
    • Oostendorp, R.A., Audet, J., Eaves, C.J., 1995. High-resolution tracking of cell division suggests similar cell cycle kinetics of hematopoietic stem cells stimulated in vitro and in vivo. Blood, 855-862.
    • (1995) Blood , pp. 855-862
    • Oostendorp, R.A.1    Audet, J.2    Eaves, C.J.3
  • 46
    • 0004574725 scopus 로고    scopus 로고
    • Large scale-invariant fluctuations in normal blood cell counts: A sign of criticality?
    • C. Perazzo, E. Fernandez, and P. Chialvo Large scale-invariant fluctuations in normal blood cell counts: a sign of criticality? Fractals 8 2000 279 283
    • (2000) Fractals , vol.8 , pp. 279-283
    • Perazzo, C.1    Fernandez, E.2    Chialvo, P.3
  • 48
    • 0030003411 scopus 로고    scopus 로고
    • Effect of recombinant granulocyte colony stimulating factor on neutrophil kinetics in normal young and elderly humans
    • T.H. Price, G.S. Chatta, and D.C. Dale Effect of recombinant granulocyte colony stimulating factor on neutrophil kinetics in normal young and elderly humans Blood 88 1996 335 340
    • (1996) Blood , vol.88 , pp. 335-340
    • Price, T.H.1    Chatta, G.S.2    Dale, D.C.3
  • 49
    • 26044470795 scopus 로고    scopus 로고
    • Long period oscillations in a g 0 model of hematopoietic stem cells
    • L. Pujo-Menjouet, S. Bernard, and M. Mackey Long period oscillations in a g 0 model of hematopoietic stem cells J. Theor. Biol. 209 2001
    • (2001) J. Theor. Biol. , vol.209
    • Pujo-Menjouet, L.1    Bernard, S.2    MacKey, M.3
  • 51
    • 0017120863 scopus 로고
    • Marked cyclic leukocytosis leukopenia in chronic myelogenous leukemia
    • A.R. Rodriguez, and C.L. Lutcher Marked cyclic leukocytosis leukopenia in chronic myelogenous leukemia Am. J. Med. 60 1976 1041 1047
    • (1976) Am. J. Med. , vol.60 , pp. 1041-1047
    • Rodriguez, A.R.1    Lutcher, C.L.2
  • 52
    • 0027953852 scopus 로고
    • The network of hematopoietic cytokines
    • L. Sachs, and J. Lotem The network of hematopoietic cytokines Proc. Soc. Exp. Biol. Med. 206 1994 170 175
    • (1994) Proc. Soc. Exp. Biol. Med. , vol.206 , pp. 170-175
    • Sachs, L.1    Lotem, J.2
  • 54
    • 0034699773 scopus 로고    scopus 로고
    • Regulation of platelet production: The normal response to perturbation and cyclical platelet disease
    • M. Santillan, J. Mahaffy, J. Belair, and M. Mackey Regulation of platelet production: the normal response to perturbation and cyclical platelet disease J. Theor. Biol. 206 2000 585 603
    • (2000) J. Theor. Biol. , vol.206 , pp. 585-603
    • Santillan, M.1    Mahaffy, J.2    Belair, J.3    MacKey, M.4
  • 55
    • 0029794641 scopus 로고    scopus 로고
    • Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through bcl-1 and bcl-2
    • M. Silva, D. Grillot, A. Benito, C. Richard, G. Nunez, and J. Fernandez-Luna Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through bcl-1 and bcl-2 Blood 88 1996 1576 1582
    • (1996) Blood , vol.88 , pp. 1576-1582
    • Silva, M.1    Grillot, D.2    Benito, A.3    Richard, C.4    Nunez, G.5    Fernandez-Luna, J.6
  • 56
    • 0030884466 scopus 로고    scopus 로고
    • Recombinant human c-Mpl ligand (thrombopoietin) not only acts on megakaryocyte progenitors, but also on erythroid and multipotential progenitors in vitro
    • S. Tanimukai, T. Kimura, H. Sakabe, Y. Ohmizono, T. Kato, H. Miyazaki, H. Yamagishi, and Y. Sonoda Recombinant human c-Mpl ligand (thrombopoietin) not only acts on megakaryocyte progenitors, but also on erythroid and multipotential progenitors in vitro Exp. Hematol. 25 1997 1025 1033
    • (1997) Exp. Hematol. , vol.25 , pp. 1025-1033
    • Tanimukai, S.1    Kimura, T.2    Sakabe, H.3    Ohmizono, Y.4    Kato, T.5    Miyazaki, H.6    Yamagishi, H.7    Sonoda, Y.8
  • 57
    • 0022924199 scopus 로고
    • Periodical appearance of erythropoietin-independent erythropoiesis in chronic myelogenous leukemia with cyclic oscillation
    • T. Umemura, J. Hirata, S. Kaneko, J. Nishimura, S. Motomura, M. Kozuru, and H. Ibayashi Periodical appearance of erythropoietin-independent erythropoiesis in chronic myelogenous leukemia with cyclic oscillation Acta Haematol. 76 1986 230 234
    • (1986) Acta Haematol. , vol.76 , pp. 230-234
    • Umemura, T.1    Hirata, J.2    Kaneko, S.3    Nishimura, J.4    Motomura, S.5    Kozuru, M.6    Ibayashi, H.7
  • 58
    • 0015500407 scopus 로고
    • Spontaneous cyclic leukocytosis and thrombocytosis in chronic granulocytic leukemia
    • H. Vodopick, E.M. Rupp, C.L. Edwards, G.A. Goswitt, and J. Beauchamp Spontaneous cyclic leukocytosis and thrombocytosis in chronic granulocytic leukemia New Eng. J. Med. 286 1972 284 290
    • (1972) New Eng. J. Med. , vol.286 , pp. 284-290
    • Vodopick, H.1    Rupp, E.M.2    Edwards, C.L.3    Goswitt, G.A.4    Beauchamp, J.5
  • 59
    • 0033575794 scopus 로고    scopus 로고
    • Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor and in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment
    • A.C. Ward, Y.M. van Aesch, J. Gits, A.M. Schelen, J.P. de Koning, D. van Leeuwen, M.H. Freedman, and I.P. Touw Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor and in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment J. Exp. Med. 190 1999 497 508
    • (1999) J. Exp. Med. , vol.190 , pp. 497-508
    • Ward, A.C.1    Van Aesch, Y.M.2    Gits, J.3    Schelen, A.M.4    De Koning, J.P.5    Van Leeuwen, D.6    Freedman, M.H.7    Touw, I.P.8
  • 60
    • 0027093606 scopus 로고
    • Spontaneous remission with cyclic leukocytosis in chronic myelogenous leukemia
    • K. Yamauchi, and A. Ide Spontaneous remission with cyclic leukocytosis in chronic myelogenous leukemia Acta Haematol. 88 1992 136 138
    • (1992) Acta Haematol. , vol.88 , pp. 136-138
    • Yamauchi, K.1    Ide, A.2


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.