메뉴 건너뛰기




Volumn 30, Issue 3, 2015, Pages e301-e314

Expression of ERCC1 and TUBB3 in locally advanced cervical squamous cell cancer and its correlation with different therapeutic regimens

Author keywords

Cervical cancer; ERCC1; Predictive factors; Prognostic factors; TUBB3

Indexed keywords

BETA TUBULIN; CISPLATIN; DOCETAXEL; EXCISION REPAIR CROSS COMPLEMENTING PROTEIN 1; IFOSFAMIDE; MESNA; MONOCLONAL ANTIBODY; NAVELBINE; ALKYLATING AGENT; ANTINEOPLASTIC AGENT; DNA BINDING PROTEIN; ENDONUCLEASE; ERCC1 PROTEIN, HUMAN; TUBB3 PROTEIN, HUMAN; TUBULIN; TUMOR PROTEIN; VINBLASTINE;

EID: 84937875286     PISSN: 03936155     EISSN: 17246008     Source Type: Journal    
DOI: 10.5301/jbm.5000161     Document Type: Article
Times cited : (11)

References (40)
  • 2
    • 77950877038 scopus 로고    scopus 로고
    • Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev, CD008285
    • Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev. 2010;(1):CD008285.
    • (2010) , Issue.1
  • 3
    • 0031034329 scopus 로고    scopus 로고
    • Vinorelbine as neoadjuvant chemotherapy in advanced cervical carcinoma
    • Lacava JA, Leone BA, Machiavelli M, et al. Vinorelbine as neoadjuvant chemotherapy in advanced cervical carcinoma. J Clin Oncol. 1997;15(2):604-609.
    • (1997) J Clin Oncol , vol.15 , Issue.2 , pp. 604-609
    • Lacava, J.A.1    Leone, B.A.2    Machiavelli, M.3
  • 4
    • 10744232829 scopus 로고    scopus 로고
    • Docetaxel as neoadjuvant chemotherapy in patients with advanced cervical carcinoma
    • Vallejo CT, Machiavelli MR, Pérez JE, et al. Docetaxel as neoadjuvant chemotherapy in patients with advanced cervical carcinoma. Am J Clin Oncol. 2003;26(5):477-482.
    • (2003) Am J Clin Oncol , vol.26 , Issue.5 , pp. 477-482
    • Vallejo, C.T.1    Machiavelli, M.R.2    Pérez, J.E.3
  • 5
    • 0034442749 scopus 로고    scopus 로고
    • Neoadjuvant chemotherapy with ifosfamide, cisplatin, and vinorelbine in advanced squamous cell carcinoma of the cervix
    • Vallejo CT, Pérez JE, Domínguez ME, et al. Neoadjuvant chemotherapy with ifosfamide, cisplatin, and vinorelbine in advanced squamous cell carcinoma of the cervix. Am J Clin Oncol. 2000;23(5):481-486.
    • (2000) Am J Clin Oncol , vol.23 , Issue.5 , pp. 481-486
    • Vallejo, C.T.1    Pérez, J.E.2    Domínguez, M.E.3
  • 6
    • 23044498699 scopus 로고    scopus 로고
    • Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study
    • Buda A, Fossati R, Colombo N, et al. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol. 2005;23(18):4137-4145.
    • (2005) J Clin Oncol , vol.23 , Issue.18 , pp. 4137-4145
    • Buda, A.1    Fossati, R.2    Colombo, N.3
  • 7
    • 63549142273 scopus 로고    scopus 로고
    • A phase II, randomized trial of neo-adjuvant chemotherapy comparing a threedrug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: The Snap-02 Italian Collaborative Study
    • Lissoni AA, Colombo N, Pellegrino A, et al. A phase II, randomized trial of neo-adjuvant chemotherapy comparing a threedrug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study. Ann Oncol. 2009;20(4):660-665.
    • (2009) Ann Oncol , vol.20 , Issue.4 , pp. 660-665
    • Lissoni, A.A.1    Colombo, N.2    Pellegrino, A.3
  • 8
    • 1342321829 scopus 로고    scopus 로고
    • Trial of concomitant vinorelbine, cisplatin, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies
    • Mundt AJ, Rotmensch J, Waggoner SE, Yamada SD, Fleming GF. Phase I trial of concomitant vinorelbine, cisplatin, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies. Gynecol Oncol. 2004;92(3):801-805.
    • (2004) Gynecol Oncol , vol.92 , Issue.3 , pp. 801-805
    • Mundt, A.J.1    Rotmensch, J.2    Waggoner, S.E.3    Yamada, S.D.4    Fleming, G.F.5    Phase, I.6
  • 9
    • 63749107733 scopus 로고    scopus 로고
    • A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer
    • Alvarez EA, Wolfson AH, Pearson JM, et al. A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer. Gynecol Oncol. 2009;113(2):195-199.
    • (2009) Gynecol Oncol , vol.113 , Issue.2 , pp. 195-199
    • Alvarez, E.A.1    Wolfson, A.H.2    Pearson, J.M.3
  • 10
    • 33750183131 scopus 로고    scopus 로고
    • Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy for women with locally advanced carcinoma of the uterine cervix: Final results of a prospective phase II-study
    • Vrdoljak E, Omrcen T, Novaković ZS, et al. Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy for women with locally advanced carcinoma of the uterine cervix: final results of a prospective phase II-study. Gynecol Oncol. 2006;103(2): 494-499.
    • (2006) Gynecol Oncol , vol.103 , Issue.2 , pp. 494-499
    • Vrdoljak, E.1    Omrcen, T.2    Novaković, Z.S.3
  • 11
    • 34447643259 scopus 로고    scopus 로고
    • Treatment of (“bulky”) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para- aortic lymphadenectomy: A phase III trial of the gynecologic oncology group
    • Eddy GL, Bundy BN, Creasman WT, et al. Treatment of (“bulky”) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para- aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Gynecol Oncol. 2007;106(2):362-369.
    • (2007) Gynecol Oncol , vol.106 , Issue.2 , pp. 362-369
    • Eddy, G.L.1    Bundy, B.N.2    Creasman, W.T.3
  • 12
    • 1542408478 scopus 로고    scopus 로고
    • Tumour hypoxia: Impact on biology, prognosis and treatment of solid malignant tumours
    • Weinmann M, Belka C, Plasswilm L. Tumour hypoxia: impact on biology, prognosis and treatment of solid malignant tumours. Onkologie. 2004;27(1):83-90.
    • (2004) Onkologie , vol.27 , Issue.1 , pp. 83-90
    • Weinmann, M.1    Belka, C.2    Plasswilm, L.3
  • 13
    • 34548398070 scopus 로고    scopus 로고
    • Current status of excision repair cross complementing-group 1 (ERCC1) in cancer
    • Gossage L, Madhusudan S. Current status of excision repair cross complementing-group 1 (ERCC1) in cancer. Cancer Treat Rev. 2007;33(6):565-577.
    • (2007) Cancer Treat Rev , vol.33 , Issue.6 , pp. 565-577
    • Gossage, L.1    Madhusudan, S.2
  • 14
    • 49449084673 scopus 로고    scopus 로고
    • ERCC1-XPF endonuclease facilitates DNA double-strand break repair
    • Ahmad A, Robinson AR, Duensing A, et al. ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol. 2008;28(16):5082-5092.
    • (2008) Mol Cell Biol , vol.28 , Issue.16 , pp. 5082-5092
    • Ahmad, A.1    Robinson, A.R.2    Duensing, A.3
  • 15
    • 46349110628 scopus 로고    scopus 로고
    • ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation
    • Jun HJ, Ahn MJ, Kim HS, et al. ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation. Br J Cancer. 2008;99(1):167-172.
    • (2008) Br J Cancer , vol.99 , Issue.1 , pp. 167-172
    • Jun, H.J.1    Ahn, M.J.2    Kim, H.S.3
  • 16
    • 37149046306 scopus 로고    scopus 로고
    • ERCC1 predicting chemoradiation resistance and poor outcome in oesophageal cancer
    • Kim MK, Cho KJ, Kwon GY, et al. ERCC1 predicting chemoradiation resistance and poor outcome in oesophageal cancer. Eur J Cancer. 2008;44(1):54-60.
    • (2008) Eur J Cancer , vol.44 , Issue.1 , pp. 54-60
    • Kim, M.K.1    Cho, K.J.2    Kwon, G.Y.3
  • 17
    • 79251596430 scopus 로고    scopus 로고
    • ERCC1 (Excision repair crosscomplementation group 1) expression as a predictor for response of neoadjuvant chemotherapy for FIGO stage 2B uterine cervix cancer
    • Park JS, Jeon EK, Chun SH, et al. ERCC1 (excision repair crosscomplementation group 1) expression as a predictor for response of neoadjuvant chemotherapy for FIGO stage 2B uterine cervix cancer. Gynecol Oncol. 2011;120(2):275-279.
    • (2011) Gynecol Oncol , vol.120 , Issue.2 , pp. 275-279
    • Park, J.S.1    Jeon, E.K.2    Chun, S.H.3
  • 18
    • 84873315587 scopus 로고    scopus 로고
    • The significance of tumoral ERCC1 status in patients with locally advanced cervical cancer treated with chemoradiation therapy: A multicenter clinicopathologic analysis
    • Doll CM, Aquino-Parsons C, Pintilie M, et al. The significance of tumoral ERCC1 status in patients with locally advanced cervical cancer treated with chemoradiation therapy: a multicenter clinicopathologic analysis. Int J Radiat Oncol Biol Phys. 2013;85(3):721-727.
    • (2013) Int J Radiat Oncol Biol Phys , vol.85 , Issue.3 , pp. 721-727
    • Doll, C.M.1    Aquino-Parsons, C.2    Pintilie, M.3
  • 19
    • 19944430079 scopus 로고    scopus 로고
    • Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients
    • Mozzetti S, Ferlini C, Concolino P, et al. Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res. 2005; 11(1):298-305.
    • (2005) Clin Cancer Res , vol.11 , Issue.1 , pp. 298-305
    • Mozzetti, S.1    Ferlini, C.2    Concolino, P.3
  • 20
    • 14544302690 scopus 로고    scopus 로고
    • Expression of class III beta tubulin in non-small cell lung cancer is correlated with resistance to taxane chemotherapy
    • Dumontet C, Isaac S, Souquet PJ, et al. Expression of class III beta tubulin in non-small cell lung cancer is correlated with resistance to taxane chemotherapy. Bull Cancer. 2005;92(2):E25-E30.
    • (2005) Bull Cancer , vol.92 , Issue.2 , pp. E25-E30
    • Dumontet, C.1    Isaac, S.2    Souquet, P.J.3
  • 21
    • 38349049063 scopus 로고    scopus 로고
    • Hypoxia induces class III beta-tubulin gene expression by HIF-1alpha binding to its 3′ flanking region
    • Raspaglio G, Filippetti F, Prislei S, et al. Hypoxia induces class III beta-tubulin gene expression by HIF-1alpha binding to its 3′ flanking region. Gene. 2008;409(1-2):100-108.
    • (2008) Gene , vol.409 , Issue.1-2 , pp. 100-108
    • Raspaglio, G.1    Filippetti, F.2    Prislei, S.3
  • 22
    • 77953750777 scopus 로고    scopus 로고
    • Kavallaris M. BetaIII-tubulin is a multifunctional protein involved in drug sensitivity and tumorigenesis in non-small cell lung cancer
    • McCarroll JA, Gan PP, Liu M, Kavallaris M. betaIII-tubulin is a multifunctional protein involved in drug sensitivity and tumorigenesis in non-small cell lung cancer. Cancer Res. 2010; 70(12):4995-5003.
    • (2010) Cancer Res , vol.70 , Issue.12 , pp. 4995-5003
    • McCarroll, J.A.1    Gan, P.P.2    Liu, M.3
  • 23
    • 23844534811 scopus 로고    scopus 로고
    • Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. Reporting recommendations for tumor marker prognostic studies (REMARK)
    • McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM; Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97(16):1180-1184.
    • (2005) J Natl Cancer Inst , vol.97 , Issue.16 , pp. 1180-1184
    • McShane, L.M.1    Altman, D.G.2    Sauerbrei, W.3    Taube, S.E.4    Gion, M.5    Clark, G.M.6
  • 24
    • 84655170221 scopus 로고    scopus 로고
    • Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival
    • Zimling ZG, Sørensen JB, Gerds TA, Bech C, Andersen CB, Santoni-Rugiu E. Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival. J Thorac Oncol. 2012; 7(1):249-256.
    • (2012) J Thorac Oncol , vol.7 , Issue.1 , pp. 249-256
    • Zimling, Z.G.1    Sørensen, J.B.2    Gerds, T.A.3    Bech, C.4    Ersen, C.B.5    Santoni-Rugiu, E.6
  • 25
    • 84884362776 scopus 로고    scopus 로고
    • Class III β-tubulin is a predictive marker for taxane-based chemotherapy in recurrent and metastatic gastric cancer
    • Hwang JE, Hong JY, Kim K, et al. Class III β-tubulin is a predictive marker for taxane-based chemotherapy in recurrent and metastatic gastric cancer. BMC Cancer. 2013;13(1):431.
    • (2013) BMC Cancer , vol.13 , Issue.1 , pp. 431
    • Hwang, J.E.1    Hong, J.Y.2    Kim, K.3
  • 26
    • 0035828388 scopus 로고    scopus 로고
    • Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis
    • Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet. 2001;358(9284):781-786.
    • (2001) Lancet , vol.358 , Issue.9284 , pp. 781-786
    • Green, J.A.1    Kirwan, J.M.2    Tierney, J.F.3
  • 27
    • 84857563152 scopus 로고    scopus 로고
    • Biological predictors of cervical cancer response to radiation therapy
    • Klopp AH, Eifel PJ. Biological predictors of cervical cancer response to radiation therapy. Semin Radiat Oncol. 2012;22(2): 143-150.
    • (2012) Semin Radiat Oncol , vol.22 , Issue.2 , pp. 143-150
    • Klopp, A.H.1    Eifel, P.J.2
  • 28
    • 84857490668 scopus 로고    scopus 로고
    • The relationship between ERCC1 expression and clinical outcome in patients with FIGO stage I to stage II uterine cervical adenocarcinoma
    • Hasegawa K, Kato R, Torii Y, Ichikawa R, Oe S, Udagawa Y. The relationship between ERCC1 expression and clinical outcome in patients with FIGO stage I to stage II uterine cervical adenocarcinoma. Int J Gynecol Cancer. 2011;21(8): 1479-1485.
    • (2011) Int J Gynecol Cancer , vol.21 , Issue.8 , pp. 1479-1485
    • Hasegawa, K.1    Kato, R.2    Torii, Y.3    Ichikawa, R.4    Oe, S.5    Udagawa, Y.6
  • 29
    • 80053326668 scopus 로고    scopus 로고
    • Excision repair crosscomplementation group 1 expression predicts response and survival in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy
    • Liang ZL, Song EK, Ko YB, et al. Excision repair crosscomplementation group 1 expression predicts response and survival in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy. Histopathology. 2011; 59(3):564-567.
    • (2011) Histopathology , vol.59 , Issue.3 , pp. 564-567
    • Liang, Z.L.1    Song, E.K.2    Ko, Y.B.3
  • 30
    • 84871909217 scopus 로고    scopus 로고
    • ERCC1 mRNA levels can predict the response to cisplatin-based concurrent chemoradiotherapy of locally advanced cervical squamous cell carcinoma
    • Bai ZL, Wang YY, Zhe H, He JL, Hai P. ERCC1 mRNA levels can predict the response to cisplatin-based concurrent chemoradiotherapy of locally advanced cervical squamous cell carcinoma. Radiat Oncol. 2012;7(1):221.
    • (2012) Radiat Oncol , vol.7 , Issue.1 , pp. 221
    • Bai, Z.L.1    Wang, Y.Y.2    Zhe, H.3    He, J.L.4    Hai, P.5
  • 31
    • 34447109660 scopus 로고    scopus 로고
    • Nuclear excision repairbased personalized therapy for non-small cell lung cancer: From hypothesis to reality
    • Simon GR, Ismail-Khan R, Bepler G. Nuclear excision repairbased personalized therapy for non-small cell lung cancer: from hypothesis to reality. Int J Biochem Cell Biol. 2007;39(7-8): 1318-1328.
    • (2007) Int J Biochem Cell Biol , vol.39 , Issue.7-8 , pp. 1318-1328
    • Simon, G.R.1    Ismail-Khan, R.2    Bepler, G.3
  • 32
    • 33750324135 scopus 로고    scopus 로고
    • Single-nucleotide polymorphisms in base excision repair, nucleotide excision repair, and double strand break genes as markers for response to radiotherapy in patients with Stage I to II head-and-neck cancer
    • Carles J, Monzo M, Amat M, et al. Single-nucleotide polymorphisms in base excision repair, nucleotide excision repair, and double strand break genes as markers for response to radiotherapy in patients with Stage I to II head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006;66(4):1022-1030.
    • (2006) Int J Radiat Oncol Biol Phys , vol.66 , Issue.4 , pp. 1022-1030
    • Carles, J.1    Monzo, M.2    Amat, M.3
  • 33
    • 34548400719 scopus 로고    scopus 로고
    • Adaptive response to gamma radiation in mammalian cells proficient and deficient in components of nucleotide excision repair
    • Hafer K, Iwamoto KS, Scuric Z, Schiestl RH. Adaptive response to gamma radiation in mammalian cells proficient and deficient in components of nucleotide excision repair. Radiat Res. 2007;168(2):168-174.
    • (2007) Radiat Res , vol.168 , Issue.2 , pp. 168-174
    • Hafer, K.1    Iwamoto, K.S.2    Scuric, Z.3    Schiestl, R.H.4
  • 34
    • 0030566883 scopus 로고    scopus 로고
    • The importance of the ERCC1/ ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway
    • Murray D, Rosenberg E. The importance of the ERCC1/ ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway. Mutat Res. 1996;364(3):217-226.
    • (1996) Mutat Res , vol.364 , Issue.3 , pp. 217-226
    • Murray, D.1    Rosenberg, E.2
  • 36
    • 84890297022 scopus 로고    scopus 로고
    • Quantification of excision repair cross-complementing group 1 and survival in p16-negative squamous cell head and neck cancers
    • Mehra R, Zhu F, Yang DH, et al. Quantification of excision repair cross-complementing group 1 and survival in p16-negative squamous cell head and neck cancers. Clin Cancer Res. 2013; 19(23):6633-6643.
    • (2013) Clin Cancer Res , vol.19 , Issue.23 , pp. 6633-6643
    • Mehra, R.1    Zhu, F.2    Yang, D.H.3
  • 37
    • 84897023394 scopus 로고    scopus 로고
    • ERCC1 expression as a predictive marker of cervical cancer treated with cisplatin-based chemoradiation
    • Muallem MZ, Marnitz S, Richter R, Köhler C, Sehouli J, Arsenic R. ERCC1 expression as a predictive marker of cervical cancer treated with cisplatin-based chemoradiation. Anticancer Res. 2014;34(1):401-406.
    • (2014) Anticancer Res , vol.34 , Issue.1 , pp. 401-406
    • Muallem, M.Z.1    Marnitz, S.2    Richter, R.3    Köhler, C.4    Sehouli, J.5    Arsenic, R.6
  • 38
    • 35148854099 scopus 로고    scopus 로고
    • Beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer
    • Gan PP, Pasquier E, Kavallaris M. Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer. Cancer Res. 2007;67(19):9356-9363.
    • (2007) Cancer Res , vol.67 , Issue.19 , pp. 9356-9363
    • Gan, P.P.1    Pasquier, E.2    Kavallaris, M.3    Class, I.4
  • 39
    • 33846366042 scopus 로고    scopus 로고
    • Expression of class III beta tubulin in cervical cancer patients administered preoperative radiochemotherapy: Correlation with response to treatment and clinical outcome
    • Ferrandina G, Martinelli E, Zannoni GF, et al. Expression of class III beta tubulin in cervical cancer patients administered preoperative radiochemotherapy: correlation with response to treatment and clinical outcome. Gynecol Oncol. 2007;104(2):326-330.
    • (2007) Gynecol Oncol , vol.104 , Issue.2 , pp. 326-330
    • Ferrandina, G.1    Martinelli, E.2    Zannoni, G.F.3
  • 40
    • 64249086885 scopus 로고    scopus 로고
    • Acute and chronic in vivo therapeutic resistance
    • Teicher BA. Acute and chronic in vivo therapeutic resistance. Biochem Pharmacol. 2009;77(11):1665-1673.
    • (2009) Biochem Pharmacol , vol.77 , Issue.11 , pp. 1665-1673
    • Teicher, B.A.1


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.