메뉴 건너뛰기




Volumn 36, Issue 11, 2017, Pages 2073-2083

Mucosa-associated microbiota signature in colorectal cancer

Author keywords

[No Author keywords available]

Indexed keywords

DNA 16S; LIPOPOLYSACCHARIDE; RNA 16S; KRAS PROTEIN, HUMAN; PROTEIN P21;

EID: 85020691345     PISSN: 09349723     EISSN: 14354373     Source Type: Journal    
DOI: 10.1007/s10096-017-3026-4     Document Type: Article
Times cited : (100)

References (74)
  • 3
    • 84863922124 scopus 로고    scopus 로고
    • Comprehensive molecular characterization of human colon and rectal cancer
    • Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337
    • (2012) Nature , vol.487 , Issue.7407 , pp. 330-337
  • 5
    • 85032144708 scopus 로고    scopus 로고
    • Associations between diet, gut microbiota and markers of CRC risk
    • Culpepper T, Ukhanova M, Wang X, Sun Y, Mai V (2014) Associations between diet, gut microbiota and markers of CRC risk. Cancer Metab 2(Suppl 1):P45
    • (2014) Cancer Metab , vol.2 , pp. P45
    • Culpepper, T.1    Ukhanova, M.2    Wang, X.3    Sun, Y.4    Mai, V.5
  • 6
    • 84941364888 scopus 로고    scopus 로고
    • Genetic architecture of colorectal cancer
    • COI: 1:CAS:528:DC%2BC28Xlt12iu70%3D, PID: 26187503
    • Peters U, Bien S, Zubair N (2015) Genetic architecture of colorectal cancer. Gut 64(10):1623–1636
    • (2015) Gut , vol.64 , Issue.10 , pp. 1623-1636
    • Peters, U.1    Bien, S.2    Zubair, N.3
  • 7
    • 84920148330 scopus 로고    scopus 로고
    • Cellular metabolism in colorectal carcinogenesis: influence of lifestyle, gut microbiome and metabolic pathways
    • COI: 1:CAS:528:DC%2BC2cXks1WnsLc%3D, PID: 24614287
    • Hagland HR, Søreide K (2015) Cellular metabolism in colorectal carcinogenesis: influence of lifestyle, gut microbiome and metabolic pathways. Cancer Lett 356(2 Pt A):273–280
    • (2015) Cancer Lett , vol.356 , Issue.2 , pp. 273-280
    • Hagland, H.R.1    Søreide, K.2
  • 8
    • 84878699293 scopus 로고    scopus 로고
    • The role of gut microbiota in the pathogenesis of colorectal cancer
    • PID: 23397545
    • Zhu Q, Gao R, Wu W, Qin H (2013) The role of gut microbiota in the pathogenesis of colorectal cancer. Tumour Biol 34(3):1285–1300
    • (2013) Tumour Biol , vol.34 , Issue.3 , pp. 1285-1300
    • Zhu, Q.1    Gao, R.2    Wu, W.3    Qin, H.4
  • 9
    • 85044695622 scopus 로고    scopus 로고
    • Cancer and the microbiota
    • COI: 1:CAS:528:DC%2BC2MXls1Wmu78%3D, PID: 25838377
    • Garrett WS (2015) Cancer and the microbiota. Science 348(6230):80–86
    • (2015) Science , vol.348 , Issue.6230 , pp. 80-86
    • Garrett, W.S.1
  • 14
    • 80052473669 scopus 로고    scopus 로고
    • The intestinal microbiota and chronic disorders of the gut
    • PID: 21844910
    • DuPont AW, DuPont HL (2011) The intestinal microbiota and chronic disorders of the gut. Nat Rev Gastroenterol Hepatol 8(9):523–531
    • (2011) Nat Rev Gastroenterol Hepatol , vol.8 , Issue.9 , pp. 523-531
    • DuPont, A.W.1    DuPont, H.L.2
  • 16
    • 84933073666 scopus 로고    scopus 로고
    • The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota
    • PID: 26695747
    • Engen PA, Green SJ, Voigt RM, Forsyth CB, Keshavarzian A (2015) The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota. Alcohol Res 37(2):223–236
    • (2015) Alcohol Res , vol.37 , Issue.2 , pp. 223-236
    • Engen, P.A.1    Green, S.J.2    Voigt, R.M.3    Forsyth, C.B.4    Keshavarzian, A.5
  • 17
    • 84866146940 scopus 로고    scopus 로고
    • Diversity, stability and resilience of the human gut microbiota
    • COI: 1:CAS:528:DC%2BC38Xhtleru7jO, PID: 22972295
    • Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R (2012) Diversity, stability and resilience of the human gut microbiota. Nature 489(7415):220–230
    • (2012) Nature , vol.489 , Issue.7415 , pp. 220-230
    • Lozupone, C.A.1    Stombaugh, J.I.2    Gordon, J.I.3    Jansson, J.K.4    Knight, R.5
  • 18
    • 84919768380 scopus 로고    scopus 로고
    • Diets that differ in their FODMAP content alter the colonic luminal microenvironment
    • COI: 1:CAS:528:DC%2BC2MXitlOhu7g%3D, PID: 25016597
    • Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG (2015) Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 64(1):93–100
    • (2015) Gut , vol.64 , Issue.1 , pp. 93-100
    • Halmos, E.P.1    Christophersen, C.T.2    Bird, A.R.3    Shepherd, S.J.4    Gibson, P.R.5    Muir, J.G.6
  • 19
    • 84977622019 scopus 로고    scopus 로고
    • Diet–microbiota interactions as moderators of human metabolism
    • COI: 1:CAS:528:DC%2BC28XhtFensLzI, PID: 27383980
    • Sonnenburg JL, Bäckhed F (2016) Diet–microbiota interactions as moderators of human metabolism. Nature 535(7610):56–64
    • (2016) Nature , vol.535 , Issue.7610 , pp. 56-64
    • Sonnenburg, J.L.1    Bäckhed, F.2
  • 20
    • 84954099831 scopus 로고    scopus 로고
    • Diet-induced extinctions in the gut microbiota compound over generations
    • COI: 1:CAS:528:DC%2BC28Xns1KgtA%3D%3D, PID: 26762459
    • Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL (2016) Diet-induced extinctions in the gut microbiota compound over generations. Nature 529(7585):212–215
    • (2016) Nature , vol.529 , Issue.7585 , pp. 212-215
    • Sonnenburg, E.D.1    Smits, S.A.2    Tikhonov, M.3    Higginbottom, S.K.4    Wingreen, N.S.5    Sonnenburg, J.L.6
  • 24
    • 84925534569 scopus 로고    scopus 로고
    • The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity
    • COI: 1:CAS:528:DC%2BC2MXitVCns7k%3D, PID: 25619480
    • Tai N, Wong FS, Wen L (2015) The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord 16(1):55–65
    • (2015) Rev Endocr Metab Disord , vol.16 , Issue.1 , pp. 55-65
    • Tai, N.1    Wong, F.S.2    Wen, L.3
  • 25
    • 84905586295 scopus 로고    scopus 로고
    • Microbiota and diabetes: an evolving relationship
    • COI: 1:CAS:528:DC%2BC2cXhvVyitr7P, PID: 24833634
    • Tilg H, Moschen AR (2014) Microbiota and diabetes: an evolving relationship. Gut 63(9):1513–1521
    • (2014) Gut , vol.63 , Issue.9 , pp. 1513-1521
    • Tilg, H.1    Moschen, A.R.2
  • 26
    • 79960501919 scopus 로고    scopus 로고
    • Interaction between obesity and the gut microbiota: relevance in nutrition
    • COI: 1:CAS:528:DC%2BC3MXhtFais7zK, PID: 21568707
    • Delzenne NM, Cani PD (2011) Interaction between obesity and the gut microbiota: relevance in nutrition. Annu Rev Nutr 31:15–31
    • (2011) Annu Rev Nutr , vol.31 , pp. 15-31
    • Delzenne, N.M.1    Cani, P.D.2
  • 27
    • 84977669212 scopus 로고    scopus 로고
    • Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden
    • COI: 1:CAS:528:DC%2BC28XptVWks7c%3D, PID: 27256833
    • Senthong V, Li XS, Hudec T, Coughlin J, Wu Y, Levison B, Wang Z, Hazen SL, Tang WH (2016) Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol 67(22):2620–2628
    • (2016) J Am Coll Cardiol , vol.67 , Issue.22 , pp. 2620-2628
    • Senthong, V.1    Li, X.S.2    Hudec, T.3    Coughlin, J.4    Wu, Y.5    Levison, B.6    Wang, Z.7    Hazen, S.L.8    Tang, W.H.9
  • 28
    • 84995414949 scopus 로고    scopus 로고
    • Diet, microorganisms and their metabolites, and colon cancer
    • PID: 27848961
    • O’Keefe SJ (2016) Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol 13(12):691–706
    • (2016) Nat Rev Gastroenterol Hepatol , vol.13 , Issue.12 , pp. 691-706
    • O’Keefe, S.J.1
  • 30
    • 84926436561 scopus 로고    scopus 로고
    • Microbiota disbiosis is associated with colorectal cancer
    • PID: 25699023
    • Gao Z, Guo B, Gao R, Zhu Q, Qin H (2015) Microbiota disbiosis is associated with colorectal cancer. Front Microbiol 6:20
    • (2015) Front Microbiol , vol.6 , pp. 20
    • Gao, Z.1    Guo, B.2    Gao, R.3    Zhu, Q.4    Qin, H.5
  • 31
    • 79955466291 scopus 로고    scopus 로고
    • Microbial and viral pathogens in colorectal cancer
    • COI: 1:CAS:528:DC%2BC3MXlsVGnt7c%3D, PID: 21067973
    • Collins D, Hogan AM, Winter DC (2011) Microbial and viral pathogens in colorectal cancer. Lancet Oncol 12(5):504–512
    • (2011) Lancet Oncol , vol.12 , Issue.5 , pp. 504-512
    • Collins, D.1    Hogan, A.M.2    Winter, D.C.3
  • 32
    • 84896078883 scopus 로고    scopus 로고
    • Microbes, microbiota, and colon cancer
    • COI: 1:CAS:528:DC%2BC2cXks1Olu7w%3D, PID: 24629338
    • Sears CL, Garrett WS (2014) Microbes, microbiota, and colon cancer. Cell Host Microbe 15(3):317–328
    • (2014) Cell Host Microbe , vol.15 , Issue.3 , pp. 317-328
    • Sears, C.L.1    Garrett, W.S.2
  • 33
    • 55849096955 scopus 로고    scopus 로고
    • Infectious agents and colorectal cancer: a review of Helicobacter pylori, Streptococcus bovis, JC virus, and human papillomavirus
    • PID: 18990738
    • Burnett-Hartman AN, Newcomb PA, Potter JD (2008) Infectious agents and colorectal cancer: a review of Helicobacter pylori, Streptococcus bovis, JC virus, and human papillomavirus. Cancer Epidemiol Biomarkers Prev 17(11):2970–2979
    • (2008) Cancer Epidemiol Biomarkers Prev , vol.17 , Issue.11 , pp. 2970-2979
    • Burnett-Hartman, A.N.1    Newcomb, P.A.2    Potter, J.D.3
  • 34
    • 84910116215 scopus 로고    scopus 로고
    • The human gut microbiome as a screening tool for colorectal cancer
    • COI: 1:CAS:528:DC%2BC2cXhvVyjur3J
    • Zackular JP, Rogers MA, Ruffin MT 4th, Schloss PD (2014) The human gut microbiome as a screening tool for colorectal cancer. Cancer Prev Res (Phila) 7(11):1112–1121
    • (2014) Cancer Prev Res (Phila) , vol.7 , Issue.11 , pp. 1112-1121
    • Zackular, J.P.1    Rogers, M.A.2    Ruffin, M.T.3    Schloss, P.D.4
  • 39
    • 78650160489 scopus 로고    scopus 로고
    • PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541
    • PID: 20378689
    • Hägerstrand D, Lindh MB, Peña C, Garcia-Echeverria C, Nistér M, Hofmann F, Ostman A (2010) PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541. Neuro Oncol 12(9):967–975
    • (2010) Neuro Oncol , vol.12 , Issue.9 , pp. 967-975
    • Hägerstrand, D.1    Lindh, M.B.2    Peña, C.3    Garcia-Echeverria, C.4    Nistér, M.5    Hofmann, F.6    Ostman, A.7
  • 44
    • 77956534324 scopus 로고    scopus 로고
    • ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
    • PID: 20601685
    • Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164
    • (2010) Nucleic Acids Res , vol.38 , Issue.16
    • Wang, K.1    Li, M.2    Hakonarson, H.3
  • 49
    • 78651430230 scopus 로고    scopus 로고
    • Control-free calling of copy number alterations in deep-sequencing data using GC-content normalization
    • COI: 1:CAS:528:DC%2BC3MXnsFansw%3D%3D, PID: 21081509
    • Boeva V, Zinovyev A, Bleakley K, Vert JP, Janoueix-Lerosey I, Delattre O, Barillot E (2011) Control-free calling of copy number alterations in deep-sequencing data using GC-content normalization. Bioinformatics 27(2):268–269
    • (2011) Bioinformatics , vol.27 , Issue.2 , pp. 268-269
    • Boeva, V.1    Zinovyev, A.2    Bleakley, K.3    Vert, J.P.4    Janoueix-Lerosey, I.5    Delattre, O.6    Barillot, E.7
  • 52
    • 84940758687 scopus 로고    scopus 로고
    • phylogeo: an R package for geographic analysis and visualization of microbiome data
    • COI: 1:CAS:528:DC%2BC28Xhs1Git7jK, PID: 25913208
    • Charlop-Powers Z, Brady SF (2015) phylogeo: an R package for geographic analysis and visualization of microbiome data. Bioinformatics 31(17):2909–2911
    • (2015) Bioinformatics , vol.31 , Issue.17 , pp. 2909-2911
    • Charlop-Powers, Z.1    Brady, S.F.2
  • 53
    • 85012191633 scopus 로고    scopus 로고
    • Advances in gut microbiome research, opening new strategies to cope with a western lifestyle
    • PID: 28119734
    • Rodriguez-Castaño GP, Caro-Quintero A, Reyes A, Lizcano F (2017) Advances in gut microbiome research, opening new strategies to cope with a western lifestyle. Front Genet 7:224
    • (2017) Front Genet , vol.7 , pp. 224
    • Rodriguez-Castaño, G.P.1    Caro-Quintero, A.2    Reyes, A.3    Lizcano, F.4
  • 55
    • 85007367207 scopus 로고    scopus 로고
    • Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle
    • PID: 27902422
    • García-Castillo V, Sanhueza E, McNerney E, Onate SA, García A (2016) Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle. J Med Microbiol 65(12):1347–1362
    • (2016) J Med Microbiol , vol.65 , Issue.12 , pp. 1347-1362
    • García-Castillo, V.1    Sanhueza, E.2    McNerney, E.3    Onate, S.A.4    García, A.5
  • 56
    • 85018493034 scopus 로고    scopus 로고
    • Microbiome-driven carcinogenesis in colorectal cancer: models and mechanisms
    • Wang X, Yang Y, Huycke MM (2016) Microbiome-driven carcinogenesis in colorectal cancer: models and mechanisms. Free Radic Biol Med 105:3–15
    • (2016) Free Radic Biol Med , vol.105 , pp. 3-15
    • Wang, X.1    Yang, Y.2    Huycke, M.M.3
  • 57
    • 84862997111 scopus 로고    scopus 로고
    • Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer
    • COI: 1:CAS:528:DC%2BC38XpvVWrtr4%3D, PID: 22761885
    • Chen W, Liu F, Ling Z, Tong X, Xiang C (2012) Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One 7(6):e39743
    • (2012) PLoS One , vol.7 , Issue.6
    • Chen, W.1    Liu, F.2    Ling, Z.3    Tong, X.4    Xiang, C.5
  • 60
    • 21744456543 scopus 로고    scopus 로고
    • Fluorescence based measurements of Fusobacterium nucleatum coaggregation and of fusobacterial attachment to mammalian cells
    • COI: 1:CAS:528:DC%2BD2MXlvFKmsrg%3D, PID: 15993010
    • Bachrach G, Ianculovici C, Naor R, Weiss EI (2005) Fluorescence based measurements of Fusobacterium nucleatum coaggregation and of fusobacterial attachment to mammalian cells. FEMS Microbiol Lett 248(2):235–240
    • (2005) FEMS Microbiol Lett , vol.248 , Issue.2 , pp. 235-240
    • Bachrach, G.1    Ianculovici, C.2    Naor, R.3    Weiss, E.I.4
  • 61
    • 0034079238 scopus 로고    scopus 로고
    • Interactions between periodontal bacteria and human oral epithelial cells: Fusobacterium nucleatum adheres to and invades epithelial cells
    • COI: 1:CAS:528:DC%2BD3cXjsFyqtbo%3D, PID: 10816455
    • Han YW, Shi W, Huang GT, Kinder Haake S, Park NH, Kuramitsu H, Genco RJ (2000) Interactions between periodontal bacteria and human oral epithelial cells: Fusobacterium nucleatum adheres to and invades epithelial cells. Infect Immun 68(6):3140–3146
    • (2000) Infect Immun , vol.68 , Issue.6 , pp. 3140-3146
    • Han, Y.W.1    Shi, W.2    Huang, G.T.3    Kinder Haake, S.4    Park, N.H.5    Kuramitsu, H.6    Genco, R.J.7
  • 62
    • 79959438740 scopus 로고    scopus 로고
    • Fusobacterium nucleatum infection of colonic cells stimulates MUC2 mucin and tumor necrosis factor alpha
    • COI: 1:CAS:528:DC%2BC3MXot1Kjtbs%3D, PID: 21536792
    • Dharmani P, Strauss J, Ambrose C, Allen-Vercoe E, Chadee K (2011) Fusobacterium nucleatum infection of colonic cells stimulates MUC2 mucin and tumor necrosis factor alpha. Infect Immun 79(7):2597–2607
    • (2011) Infect Immun , vol.79 , Issue.7 , pp. 2597-2607
    • Dharmani, P.1    Strauss, J.2    Ambrose, C.3    Allen-Vercoe, E.4    Chadee, K.5
  • 64
    • 84882334105 scopus 로고    scopus 로고
    • Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin
    • COI: 1:CAS:528:DC%2BC3sXht1yhsr3N, PID: 23954158
    • Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW (2013) Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe 14(2):195–206
    • (2013) Cell Host Microbe , vol.14 , Issue.2 , pp. 195-206
    • Rubinstein, M.R.1    Wang, X.2    Liu, W.3    Hao, Y.4    Cai, G.5    Han, Y.W.6
  • 65
    • 85014373123 scopus 로고    scopus 로고
    • Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-kappaB, and up-regulating expression of microRNA-21
    • COI: 1:CAS:528:DC%2BC2sXjs1WgsLc%3D, PID: 27876571
    • Yang Y, Weng W, Peng J, Hong L, Yang L, Toiyama Y, Gao R, Liu M, Yin M, Pan C, Li H, Guo B, Zhu Q, Wei Q, Moyer MP, Wang P, Cai S, Goel A, Qin H, Ma Y (2017) Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-kappaB, and up-regulating expression of microRNA-21. Gastroenterology 152(4):851–866.e24
    • (2017) Gastroenterology , vol.152 , Issue.4 , pp. 851-866.e24
    • Yang, Y.1    Weng, W.2    Peng, J.3    Hong, L.4    Yang, L.5    Toiyama, Y.6    Gao, R.7    Liu, M.8    Yin, M.9    Pan, C.10    Li, H.11    Guo, B.12    Zhu, Q.13    Wei, Q.14    Moyer, M.P.15    Wang, P.16    Cai, S.17    Goel, A.18    Qin, H.19    Ma, Y.20    more..
  • 70
    • 0018966776 scopus 로고
    • Peptococcus magnus: a significant human pathogen
    • COI: 1:STN:280:DyaL3c3mtlyjsA%3D%3D, PID: 7406374
    • Bourgault AM, Rosenblatt JE, Fitzgerald RH (1980) Peptococcus magnus: a significant human pathogen. Ann Intern Med 93(2):244–248
    • (1980) Ann Intern Med , vol.93 , Issue.2 , pp. 244-248
    • Bourgault, A.M.1    Rosenblatt, J.E.2    Fitzgerald, R.H.3
  • 71
    • 0028077003 scopus 로고
    • Peptostreptococcal infection in children
    • COI: 1:STN:280:DyaK2M7lvVyhtg%3D%3D, PID: 7855547
    • Brook I (1994) Peptostreptococcal infection in children. Scand J Infect Dis 26(5):503–510
    • (1994) Scand J Infect Dis , vol.26 , Issue.5 , pp. 503-510
    • Brook, I.1
  • 72
    • 85018829135 scopus 로고    scopus 로고
    • Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice
    • PID: 28126350
    • Tsoi H, Chu ESH, Zhang X, Sheng J, Nakatsu G, Ng SC, Chan AWH, Chan FKL, Sung JJY, Yu J (2017) Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice. Gastroenterology 152(6):1419–1433.e5
    • (2017) Gastroenterology , vol.152 , Issue.6 , pp. 1419-1433.e5
    • Tsoi, H.1    Chu, E.S.H.2    Zhang, X.3    Sheng, J.4    Nakatsu, G.5    Ng, S.C.6    Chan, A.W.H.7    Chan, F.K.L.8    Sung, J.J.Y.9    Yu, J.10
  • 73
    • 85016217153 scopus 로고    scopus 로고
    • Right versus left colon cancer biology: integrating the consensus molecular subtypes
    • PID: 28275039
    • Lee MS, Menter DG, Kopetz S (2017) Right versus left colon cancer biology: integrating the consensus molecular subtypes. J Natl Compr Canc Netw 15(3):411–419
    • (2017) J Natl Compr Canc Netw , vol.15 , Issue.3 , pp. 411-419
    • Lee, M.S.1    Menter, D.G.2    Kopetz, S.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.