{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:13:21Z","timestamp":1785831201196,"version":"3.56.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T00:00:00Z","timestamp":1495756800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T00:00:00Z","timestamp":1495756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous protein phosphatase 2A (PP2A) inhibitor, has been identified as an oncoprotein in promoting cancer initiation and progression of several types of cancer. However, the expression and the role played by CIP2A in the pathogenesis of multiple myeloma (MM) remain unclear. In this study, we showed that CIP2A was overexpressed in human MM cell lines and MM patients\u2019 bone marrow tissues. Clinicopathologic analysis showed that CIP2A expression was significantly correlated with clinical stage and percent of plasma cells in bone marrow. Kaplan\u2013Meier analysis revealed that patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. Moreover, CIP2A knockdown in MM cells resulted in attenuated proliferative abilities. In addition, CIP2A depletion sensitizes dexamethasone (Dex)-resistant cells to Dex. The effect of CIP2A on proliferation and Dex therapy was mediated by the inhibition of PP2A, which in turn activated Akt. <jats:italic>In vivo<\/jats:italic> studies confirmed that CIP2A regulated MM tumorigenesis and the phosphorylation of Akt. Taken together, our results suggest that CIP2A oncoprotein plays an important role in MM progression and could serve as a prognosis marker and a novel therapeutic target for the treatment of patients with MM.<\/jats:p>","DOI":"10.1038\/sigtrans.2017.13","type":"journal-article","created":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T06:23:10Z","timestamp":1495779790000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Overexpression of CIP2A is associated with poor prognosis in multiple myeloma"],"prefix":"10.1038","volume":"2","author":[{"given":"Xuewen","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Te","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junnian","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinghong","family":"Ming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baofu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,26]]},"reference":[{"key":"BFsigtrans201713_CR1","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1038\/leu.2013.293","volume":"28","author":"H Ludwig","year":"2014","unstructured":"Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia SR, Powles R et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia 2014; 28: 981\u2013992.","journal-title":"Leukemia"},{"key":"BFsigtrans201713_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21387","volume":"67","author":"RL Siegel","year":"2017","unstructured":"Siegel RL, Miller KD, Jemal A . Cancer statistics, 2017. CA Cancer J Clin 2017; 67: 7\u201330.","journal-title":"CA Cancer J Clin"},{"key":"BFsigtrans201713_CR3","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1182\/blood-2012-05-432203","volume":"121","author":"PL Bergsagel","year":"2013","unstructured":"Bergsagel PL, Mateos MV, Gutierrez NC, Rajkumar SV, San Miguel JF . Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 2013; 121: 884\u2013892.","journal-title":"Blood"},{"key":"BFsigtrans201713_CR4","doi-asserted-by":"crossref","first-page":"14913","DOI":"10.18632\/oncotarget.3818","volume":"6","author":"H Liu","year":"2015","unstructured":"Liu H, Gu Y, Wang H, Yin J, Zheng G, Zhang Z et al. Overexpression of PP2A inhibitor SET oncoprotein is associated with tumor progression and poor prognosis in human non-small cell lung cancer. Oncotarget 2015; 6: 14913\u201314925.","journal-title":"Oncotarget"},{"key":"BFsigtrans201713_CR5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.cell.2007.04.044","volume":"130","author":"MR Junttila","year":"2007","unstructured":"Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T et al. CIP2A inhibits PP2A in human malignancies. Cell 2007; 130: 51\u201362.","journal-title":"Cell"},{"key":"BFsigtrans201713_CR6","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1093\/jnci\/djp103","volume":"101","author":"A Khanna","year":"2009","unstructured":"Khanna A, Bockelman C, Hemmes A, Junttila MR, Wiksten JP, Lundin M et al. MYC-dependent regulation and prognostic role of CIP2A in gastric cancer. J Natl Cancer Inst 2009; 101: 793\u2013805.","journal-title":"J Natl Cancer Inst"},{"key":"BFsigtrans201713_CR7","doi-asserted-by":"publisher","first-page":"3722","DOI":"10.1158\/1078-0432.CCR-07-4137","volume":"14","author":"W Li","year":"2008","unstructured":"Li W, Ge Z, Liu C, Liu Z, Bjorkholm M, Jia J et al. CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res 2008; 14: 3722\u20133728.","journal-title":"Clin Cancer Res"},{"key":"BFsigtrans201713_CR8","doi-asserted-by":"publisher","first-page":"R68","DOI":"10.1186\/bcr3175","volume":"14","author":"LM Tseng","year":"2012","unstructured":"Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW, Chen KF . CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res 2012; 14: R68.","journal-title":"Breast Cancer Res"},{"key":"BFsigtrans201713_CR9","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1038\/bjc.2011.167","volume":"104","author":"C Bockelman","year":"2011","unstructured":"Bockelman C, Hagstrom J, Makinen LK, Keski-Santti H, Hayry V, Lundin J et al. High CIP2A immunoreactivity is an independent prognostic indicator in early-stage tongue cancer. Br J Cancer 2011; 104: 1890\u20131895.","journal-title":"Br J Cancer"},{"key":"BFsigtrans201713_CR10","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1038\/bjc.2011.346","volume":"105","author":"C Bockelman","year":"2011","unstructured":"Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C et al. Prognostic role of CIP2A expression in serous ovarian cancer. Br J Cancer 2011; 105: 989\u2013995.","journal-title":"Br J Cancer"},{"key":"BFsigtrans201713_CR11","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1093\/carcin\/bgt395","volume":"35","author":"Z Liu","year":"2014","unstructured":"Liu Z, Ma L, Wen ZS, Hu Z, Wu FQ, Li W et al. Cancerous inhibitor of PP2A is targeted by natural compound celastrol for degradation in non-small-cell lung cancer. Carcinogenesis 2014; 35: 905\u2013914.","journal-title":"Carcinogenesis"},{"key":"BFsigtrans201713_CR12","doi-asserted-by":"publisher","first-page":"e183","DOI":"10.3324\/haematol.2014.118117","volume":"100","author":"E Barragan","year":"2015","unstructured":"Barragan E, Chillon MC, Castello-Cros R, Marcotegui N, Prieto MI, Hoyos M et al. CIP2A high expression is a poor prognostic factor in normal karyotype acute myeloid leukemia. Haematologica 2015; 100: e183\u2013e185.","journal-title":"Haematologica"},{"key":"BFsigtrans201713_CR13","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.ccr.2013.10.022","volume":"24","author":"E Piovan","year":"2013","unstructured":"Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 2013; 24: 766\u2013776.","journal-title":"Cancer Cell"},{"key":"BFsigtrans201713_CR14","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1111\/j.1751-553X.2010.01288.x","volume":"33","author":"J Wang","year":"2011","unstructured":"Wang J, Li W, Li L, Yu X, Jia J, Chen C . CIP2A is over-expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation. Int J Lab Hematol 2011; 33: 290\u2013298.","journal-title":"Int J Lab Hematol"},{"key":"BFsigtrans201713_CR15","doi-asserted-by":"publisher","first-page":"144","DOI":"10.18632\/oncotarget.2670","volume":"6","author":"S Ventela","year":"2015","unstructured":"Ventela S, Sittig E, Mannermaa L, Makela JA, Kulmala J, Loyttyniemi E et al. CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance. Oncotarget 2015; 6: 144\u2013158.","journal-title":"Oncotarget"},{"key":"BFsigtrans201713_CR16","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/j.febslet.2011.01.018","volume":"585","author":"YA Choi","year":"2011","unstructured":"Choi YA, Park JS, Park MY, Oh KS, Lee MS, Lim JS et al. Increase in CIP2A expression is associated with doxorubicin resistance. FEBS Lett 2011; 585: 755\u2013760.","journal-title":"FEBS Lett"},{"key":"BFsigtrans201713_CR17","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1007\/s13277-014-2748-5","volume":"36","author":"J Huang","year":"2015","unstructured":"Huang J, Jia J, Tong Q, Liu J, Qiu J, Sun R et al. Knockdown of cancerous inhibitor of protein phosphatase 2A may sensitize metastatic castration-resistant prostate cancer cells to cabazitaxel chemotherapy. Tumour Biol 2015; 36: 1589\u20131594.","journal-title":"Tumour Biol"},{"key":"BFsigtrans201713_CR18","doi-asserted-by":"publisher","first-page":"8477","DOI":"10.1038\/srep08477","volume":"5","author":"W Cao","year":"2015","unstructured":"Cao W, Liu Y, Zhang R, Zhang B, Wang T, Zhu X et al. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6\/JAK1\/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci Rep 2015; 5: 8477.","journal-title":"Sci Rep"},{"key":"BFsigtrans201713_CR19","first-page":"6864135","volume":"2016","author":"X Yang","year":"2016","unstructured":"Yang X, Zhang Y, Liu H, Lin Z . Cancerous inhibitor of PP2A silencing inhibits proliferation and promotes apoptosis in human multiple myeloma cells. Biomed Res Int 2016; 2016: 6864135.","journal-title":"Biomed Res Int"},{"key":"BFsigtrans201713_CR20","doi-asserted-by":"publisher","first-page":"556","DOI":"10.3892\/ol.2013.1370","volume":"6","author":"Y Liu","year":"2013","unstructured":"Liu Y, Dong Y, Zhang B, Cheng YX . Small compound 6\u2013angeloylplenolin induces caspase-dependent apoptosis in human multiple myeloma cells. Oncol Lett 2013; 6: 556\u2013558.","journal-title":"Oncol Lett"},{"key":"BFsigtrans201713_CR21","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1038\/srep03098","volume":"3","author":"Y Liu","year":"2013","unstructured":"Liu Y, Cao W, Zhang B, Liu YQ, Wang ZY, Wu YP et al. The natural compound magnolol inhibits invasion and exhibits potential in human breast cancer therapy. Sci Rep 2013; 3: 3098.","journal-title":"Sci Rep"},{"key":"BFsigtrans201713_CR22","doi-asserted-by":"publisher","first-page":"e21930","DOI":"10.1371\/journal.pone.0021930","volume":"6","author":"Y Liu","year":"2011","unstructured":"Liu Y, Chen XQ, Liang HX, Zhang FX, Zhang B, Jin J et al. Small compound 6-O-angeloylplenolin induces mitotic arrest and exhibits therapeutic potentials in multiple myeloma. PloS One 2011; 6: e21930.","journal-title":"PloS One"},{"key":"BFsigtrans201713_CR23","doi-asserted-by":"publisher","first-page":"2608","DOI":"10.3892\/ijo.2016.3488","volume":"48","author":"X Xiao","year":"2016","unstructured":"Xiao X, He Z, Cao W, Cai F, Zhang L, Huang Q et al. Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR\/ERK\/MMP-12 and CIP2A\/Akt signaling pathways. Int J Oncol 2016; 48: 2608\u20132618.","journal-title":"Int J Oncol"},{"key":"BFsigtrans201713_CR24","doi-asserted-by":"publisher","first-page":"729","DOI":"10.3324\/haematol.2011.050187","volume":"98","author":"CY Liu","year":"2013","unstructured":"Liu CY, Shiau CW, Kuo HY, Huang HP, Chen MH, Tzeng CH et al. Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells. Haematologica 2013; 98: 729\u2013738.","journal-title":"Haematologica"},{"key":"BFsigtrans201713_CR25","doi-asserted-by":"publisher","first-page":"6257","DOI":"10.1038\/onc.2010.357","volume":"29","author":"KF Chen","year":"2010","unstructured":"Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR et al. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 2010; 29: 6257\u20136266.","journal-title":"Oncogene"},{"key":"BFsigtrans201713_CR26","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1007\/s13277-013-1150-z","volume":"35","author":"M Zhai","year":"2014","unstructured":"Zhai M, Cong L, Han Y, Tu G . CIP2A is overexpressed in osteosarcoma and regulates cell proliferation and invasion. Tumour Biol 2014; 35: 1123\u20131128.","journal-title":"Tumour Biol"},{"key":"BFsigtrans201713_CR27","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcp.24176","volume":"228","author":"Z Radisavljevic","year":"2013","unstructured":"Radisavljevic Z . AKT as locus of cancer multidrug resistance and fragility. J Cell Physiol 2013; 228: 671\u2013674.","journal-title":"J Cell Physiol"},{"key":"BFsigtrans201713_CR28","doi-asserted-by":"publisher","first-page":"6660","DOI":"10.1182\/blood-2010-08-304477","volume":"117","author":"CM Lucas","year":"2011","unstructured":"Lucas CM, Harris RJ, Giannoudis A, Copland M, Slupsky JR, Clark RE . Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood 2011; 117: 6660\u20136668.","journal-title":"Blood"},{"key":"BFsigtrans201713_CR29","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s12253-013-9709-y","volume":"20","author":"N Li","year":"2013","unstructured":"Li N, Abe S, Kurata M, be-Suzuki S, Onishi I, Kirimura S et al. Over-expression of cancerous inhibitor of PP2A (CIP2A) in bone marrow cells from patients with a group of high-risk myelodysplastic syndromes. Pathol Oncol Res 2013; 20: 399\u2013407.","journal-title":"Pathol Oncol Res"},{"key":"BFsigtrans201713_CR30","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1111\/his.12162","volume":"63","author":"L Lilja","year":"2013","unstructured":"Lilja L, Haapasaari KM, Bloigu R, Salonen T, Ristimaki A, Turpeenniemi-Hujanen T et al. Increased expression of CIP2A in aggressive subtypes of B-cell lymphoma. Histopathology 2013; 63: 438\u2013439.","journal-title":"Histopathology"},{"key":"BFsigtrans201713_CR31","doi-asserted-by":"publisher","first-page":"6548","DOI":"10.1158\/0008-5472.CAN-13-1994","volume":"73","author":"A Khanna","year":"2013","unstructured":"Khanna A, Pimanda JE, Westermarck J . Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target. Cancer Res 2013; 73: 6548\u20136553.","journal-title":"Cancer Res"},{"key":"BFsigtrans201713_CR32","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1038\/bjc.2011.492","volume":"105","author":"J Ren","year":"2011","unstructured":"Ren J, Li W, Yan L, Jiao W, Tian S, Li D et al. Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients' survival. Br J Cancer 2011; 105: 1905\u20131911.","journal-title":"Br J Cancer"},{"key":"BFsigtrans201713_CR33","doi-asserted-by":"publisher","first-page":"4672","DOI":"10.1128\/MCB.19.7.4672","volume":"19","author":"MK Mateyak","year":"1999","unstructured":"Mateyak MK, Obaya AJ, Sedivy JM . c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol 1999; 19: 4672\u20134683.","journal-title":"Mol Cell Biol"},{"key":"BFsigtrans201713_CR34","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.1182\/blood.V98.9.2853","volume":"98","author":"J Hsu","year":"2001","unstructured":"Hsu J, Shi Y, Krajewski S, Renner S, Fisher M, Reed JC et al. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001; 98: 2853\u20132855.","journal-title":"Blood"},{"key":"BFsigtrans201713_CR35","doi-asserted-by":"publisher","first-page":"4299","DOI":"10.18632\/oncotarget.3012","volume":"6","author":"R Rincon","year":"2015","unstructured":"Rincon R, Cristobal I, Zazo S, Arpi O, Menendez S, Manso R et al. PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects. Oncotarget 2015; 6: 4299\u20134314.","journal-title":"Oncotarget"}],"updated-by":[{"DOI":"10.1038\/s41392-025-02225-8","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000}}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/sigtrans201713.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/sigtrans201713","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/sigtrans201713","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/sigtrans201713.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T05:27:42Z","timestamp":1744435662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/sigtrans201713"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,26]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12,22]]}},"alternative-id":["BFsigtrans201713"],"URL":"https:\/\/doi.org\/10.1038\/sigtrans.2017.13","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41392-025-02225-8","asserted-by":"object"}]},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,26]]},"assertion":[{"value":"22 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2017","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2017","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2017","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2025","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41392-025-02225-8","URL":"https:\/\/doi.org\/10.1038\/s41392-025-02225-8","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17013"}}