{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T17:45:43Z","timestamp":1777398343936,"version":"3.51.4"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T00:00:00Z","timestamp":1590451200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T00:00:00Z","timestamp":1590451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Freiburg"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Graefes Arch Clin Exp Ophthalmol"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>The aim of this study was to investigate HIF-1\u03b1, HIF-2\u03b1, and ProExC expression in conjunctival intraepithelial neoplasia (CIN), to differentiate between metaplasia and dysplasia, and to access their value as diagnostic and prognostic immunohistochemical markers. Recurrence and progression into SCC (squamous cell carcinoma) were defined as endpoints.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Forty-three specimens including CIN I (2), CIN II (9), CIN III (29), with and without metaplasia, and metaplasia alone (3), as well as 21 conjunctival control specimens, were stained with antibodies against HIF-1\u03b1, HIF-2\u03b1, and ProExC. The percentage of positively stained cells were calculated and used for further analysis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The mean percentages of HIF-1\u03b1 and HIF-2\u03b1 were not increased in CIN. In comparison, the expressions of these markers were even significantly elevated in control specimens (<jats:italic>p<\/jats:italic> &lt; 0.001). Upper epithelial cells in CIN were more often ProExC-positive compared with normal conjunctiva or metaplasia (<jats:italic>p<\/jats:italic> = 0.06 and <jats:italic>p<\/jats:italic> = 0.07). Cox proportional-hazards analysis was performed for characterization of factors influencing the combined endpoint and showed a significant elevated hazard ratio for staining with ProExC (<jats:italic>p<\/jats:italic> = 0.04) compared with HIF-1\u03b1 (<jats:italic>p<\/jats:italic> = 0.26) and HIF-2\u03b1 (<jats:italic>p<\/jats:italic> = 0.49).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our study shows that HIF-1\u03b1 and HIF-2\u03b1 do not serve as diagnostic or prognostic markers in CIN. ProExC seems to be a potential indicator for CIN, but not a reliable diagnostic marker. However, control specimens occasionally also display a high percentage of ProExC-positive cells and staining over the entire epithelial layer.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00417-020-04734-4","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T04:02:20Z","timestamp":1590465740000},"page":"2023-2030","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["HIF-1\u03b1, HIF-2\u03b1, and ProExC: diagnostic or prognostic relevance in conjunctival intraepithelial neoplasia?"],"prefix":"10.1007","volume":"258","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4401-8344","authenticated-orcid":false,"given":"Simone","family":"Nuessle","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Soriano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Boehringer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Mittelviefhaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Lange","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Reinhard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Atzrodt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Auw-Haedrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"4734_CR1","first-page":"73","volume":"6","author":"EC Sun","year":"1997","unstructured":"Sun EC, Fears TR, Goedert JJ (1997) Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol Biomark Prev 6:73\u201377","journal-title":"Cancer Epidemiol Biomark Prev"},{"key":"4734_CR2","unstructured":"Curado MP, Edwards B, Shin HR et al (2007) Cancer incidence in five continents, Volume IX. Cancer incidence in five continents, Volume IX"},{"key":"4734_CR3","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/S0039-6257(05)80054-2","volume":"39","author":"GA Lee","year":"1995","unstructured":"Lee GA, Hirst LW (1995) Ocular surface squamous neoplasia. Surv Ophthalmol 39:429\u2013450","journal-title":"Surv Ophthalmol"},{"key":"4734_CR4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.survophthal.2003.10.008","volume":"49","author":"CL Shields","year":"2004","unstructured":"Shields CL, Shields JA (2004) Tumors of the conjunctiva and cornea. Surv Ophthalmol 49:3\u201324","journal-title":"Surv Ophthalmol"},{"key":"4734_CR5","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1111\/j.1749-6632.2009.04891.x","volume":"1171","author":"JH No","year":"2009","unstructured":"No JH, Jo H, Kim S-H et al (2009) Expression of vascular endothelial growth factor and hypoxia inducible factor-1\u03b1 in cervical neoplasia. Ann N Y Acad Sci 1171:105\u2013110. https:\/\/doi.org\/10.1111\/j.1749-6632.2009.04891.x","journal-title":"Ann N Y Acad Sci"},{"key":"4734_CR6","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1309\/AJCP1LLX8QMDXHHO","volume":"135","author":"M Guo","year":"2011","unstructured":"Guo M, Baruch AC, Silva EG et al (2011) Efficacy of p16 and ProExC immunostaining in the detection of high-grade cervical intraepithelial neoplasia and cervical carcinoma. Am J Clin Pathol 135:212\u2013220. https:\/\/doi.org\/10.1309\/AJCP1LLX8QMDXHHO","journal-title":"Am J Clin Pathol"},{"key":"4734_CR7","first-page":"4693","volume":"60","author":"P Birner","year":"2000","unstructured":"Birner P, Schindl M, Obermair A et al (2000) Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60:4693\u20134696","journal-title":"Cancer Res"},{"key":"4734_CR8","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/s0002-9440(10)64554-3","volume":"157","author":"KL Talks","year":"2000","unstructured":"Talks KL, Turley H, Gatter KC et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411\u2013421. https:\/\/doi.org\/10.1016\/s0002-9440(10)64554-3","journal-title":"Am J Pathol"},{"key":"4734_CR9","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/cdd.2008.21","volume":"15","author":"EB Rankin","year":"2008","unstructured":"Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15:678\u2013685. https:\/\/doi.org\/10.1038\/cdd.2008.21","journal-title":"Cell Death Differ"},{"key":"4734_CR10","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/s0092-8674(01)00507-4","volume":"107","author":"AC Epstein","year":"2001","unstructured":"Epstein AC, Gleadle JM, McNeill LA et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43\u201354. https:\/\/doi.org\/10.1016\/s0092-8674(01)00507-4","journal-title":"Cell"},{"key":"4734_CR11","doi-asserted-by":"publisher","first-page":"5197","DOI":"10.1093\/emboj\/20.18.5197","volume":"20","author":"N Masson","year":"2001","unstructured":"Masson N, Willam C, Maxwell PH et al (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197\u20135206. https:\/\/doi.org\/10.1093\/emboj\/20.18.5197","journal-title":"EMBO J"},{"key":"4734_CR12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/20459","volume":"399","author":"PH Maxwell","year":"1999","unstructured":"Maxwell PH, Wiesener MS, Chang GW et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271\u2013275. https:\/\/doi.org\/10.1038\/20459","journal-title":"Nature"},{"key":"4734_CR13","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1159\/000331418","volume":"227","author":"CAK Lange","year":"2012","unstructured":"Lange CAK, Bainbridge JWB (2012) Oxygen sensing in retinal health and disease. Ophthalmologica 227:115\u2013131. https:\/\/doi.org\/10.1159\/000331418","journal-title":"Ophthalmologica"},{"key":"4734_CR14","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/nrm3228","volume":"12","author":"SM Vos","year":"2011","unstructured":"Vos SM, Tretter EM, Schmidt BH, Berger JM (2011) All tangled up: how cells direct, manage and exploit topoisomerase function. Nat Rev Mol Cell Biol 12:827\u2013841. https:\/\/doi.org\/10.1038\/nrm3228","journal-title":"Nat Rev Mol Cell Biol"},{"key":"4734_CR15","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/s0092-8674(00)80459-6","volume":"91","author":"CS Newlon","year":"1997","unstructured":"Newlon CS (1997) Putting it all together: building a prereplicative complex. Cell 91:717\u2013720. https:\/\/doi.org\/10.1016\/s0092-8674(00)80459-6","journal-title":"Cell"},{"key":"4734_CR16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1038\/s41433-018-0172-6","volume":"32","author":"CAK Lange","year":"2018","unstructured":"Lange CAK, Lehnert P, Boneva SK et al (2018) Increased expression of hypoxia-inducible factor-1 alpha and its impact on transcriptional changes and prognosis in malignant tumours of the ocular adnexa. Eye (Lond) 32:1772\u20131782. https:\/\/doi.org\/10.1038\/s41433-018-0172-6","journal-title":"Eye (Lond)"},{"key":"4734_CR17","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1038\/sj.emboj.7600196","volume":"23","author":"M Koshiji","year":"2004","unstructured":"Koshiji M, Kageyama Y, Pete EA et al (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23:1949\u20131956. https:\/\/doi.org\/10.1038\/sj.emboj.7600196","journal-title":"EMBO J"},{"key":"4734_CR18","first-page":"6669","volume":"61","author":"HM Sowter","year":"2001","unstructured":"Sowter HM, Ratcliffe PJ, Watson P et al (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669\u20136673","journal-title":"Cancer Res"},{"key":"4734_CR19","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/35102167","volume":"414","author":"T Reya","year":"2001","unstructured":"Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105\u2013111. https:\/\/doi.org\/10.1038\/35102167","journal-title":"Nature"},{"key":"4734_CR20","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1016\/j.ophtha.2012.03.037","volume":"119","author":"CA Lange","year":"2012","unstructured":"Lange CA, Tisch-Rottensteiner J, B\u00f6hringer D et al (2012) Enhanced TKTL1 expression in malignant tumors of the ocular adnexa predicts clinical outcome. Ophthalmology 119:1924\u20131929. https:\/\/doi.org\/10.1016\/j.ophtha.2012.03.037","journal-title":"Ophthalmology"},{"key":"4734_CR21","doi-asserted-by":"publisher","unstructured":"Heller S, Maurer GD, Wanka C et al (2018) Gene suppression of transketolase-like protein 1 (TKTL1) sensitizes glioma cells to hypoxia and ionizing radiation. Int J Mol Sci 19. https:\/\/doi.org\/10.3390\/ijms19082168","DOI":"10.3390\/ijms19082168"},{"key":"4734_CR22","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.neulet.2009.01.077","volume":"453","author":"JY Ding","year":"2009","unstructured":"Ding JY, Kreipke CW, Speirs SL et al (2009) Hypoxia-inducible factor-1\u03b1 signaling in aquaporin upregulation after traumatic brain injury. Neurosci Lett 453:68\u201372. https:\/\/doi.org\/10.1016\/j.neulet.2009.01.077","journal-title":"Neurosci Lett"}],"container-title":["Graefe's Archive for Clinical and Experimental Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-020-04734-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00417-020-04734-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-020-04734-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T23:32:25Z","timestamp":1621985545000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00417-020-04734-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,26]]},"references-count":22,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2020,9]]}},"alternative-id":["4734"],"URL":"https:\/\/doi.org\/10.1007\/s00417-020-04734-4","relation":{},"ISSN":["0721-832X","1435-702X"],"issn-type":[{"value":"0721-832X","type":"print"},{"value":"1435-702X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,26]]},"assertion":[{"value":"1 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}