{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T23:12:49Z","timestamp":1777417969285,"version":"3.51.4"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fluorescence lifetime imaging microscopy of a fluorescence probe, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (<jats:italic>o<\/jats:italic>-BMVC), provides an objective method for preoperative diagnosis of fine-needle aspiration (FNA) of thyroid nodules. The key of this <jats:italic>o<\/jats:italic>-BMVC test of FNA smears is the measurement of the digital number of <jats:italic>o<\/jats:italic>-BMVC foci in the nucleus. Thus, there are three categories classified in the <jats:italic>o<\/jats:italic>-BMVC test, which are nondiagnostic for unsatisfactory samples, benign for less numbers of <jats:italic>o<\/jats:italic>-BMVC foci, and malignant for more numbers of <jats:italic>o<\/jats:italic>-BMVC foci. The discrimination of indeterminate (including atypia, follicular neoplasm, suspicious) cytology into benign or malignant cases can reduce diagnostic uncertainty and benefit clinical decision making. This pilot study strongly suggests that the <jats:italic>o<\/jats:italic>-BMVC test is an invaluable method for diagnosing FNA samples. Particularly, the combination of FNA cytology and the <jats:italic>o<\/jats:italic>-BMVC test holds great promise to improve the efficacy of diagnosis and reduce the healthcare costs.<\/jats:p>","DOI":"10.1038\/s41598-021-02887-8","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T11:06:05Z","timestamp":1638788765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pilot imaging study of o-BMVC foci for discrimination of indeterminate cytology in diagnosing fine-needle aspiration of thyroid nodules"],"prefix":"10.1038","volume":"11","author":[{"given":"Ting-Yuan","family":"Tseng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyang-Rong","family":"Shih","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Ping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shang-Jyun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.-Shiow","family":"Jan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiung-Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin-Ya","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Chung","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Jen","family":"Lou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ta-Chau","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"2887_CR1","first-page":"16670","volume":"368","author":"NS Ospina","year":"2020","unstructured":"Ospina, N. S., I\u00f1iguez-Ariza, N. M. & Castro, M. R. Thyroid nodules: diagnostic evaluation based on thyroid cancer risk assessment. BMJ 368, 16670 (2020).","journal-title":"BMJ"},{"key":"2887_CR2","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1111\/j.1365-2362.2009.02162.x","volume":"39","author":"S Guth","year":"2009","unstructured":"Guth, S., Theune, U., Aberle, J., Galach, A. & Bamberger, C. M. Very hiogh prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur. J. Clin. Invest. 39, 699\u2013706 (2009).","journal-title":"Eur. J. Clin. Invest."},{"key":"2887_CR3","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1056\/NEJM199302253280807","volume":"328","author":"EL Mazzaferri","year":"1993","unstructured":"Mazzaferri, E. L. Management of a solitary thyroid nodule. N. Engl. J. Med. 328, 553\u2013559 (1993).","journal-title":"N. Engl. J. Med."},{"key":"2887_CR4","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1056\/NEJMcp031436","volume":"351","author":"L Hegedus","year":"2004","unstructured":"Hegedus, L. Clinical practice: the thyroid nodule. N. Engl. J. Med. 351, 1764\u20131771 (2004).","journal-title":"N. Engl. J. Med."},{"key":"2887_CR5","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1089\/thy.2016.0555","volume":"27","author":"AL Tang","year":"2017","unstructured":"Tang, A. L. et al. Validation of American thyroid association ultrasound risk assessment of thyroid nodules selected for ultrasound fine-needle aspiration. Thyroid 27, 1077\u20131082 (2017).","journal-title":"Thyroid"},{"key":"2887_CR6","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1309\/AJCPPHLWMI3JV4LA","volume":"132","author":"ES Cibas","year":"2009","unstructured":"Cibas, E. S. & Ali, S. Z. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol. 132, 658\u2013665 (2009).","journal-title":"Am J Clin Pathol."},{"key":"2887_CR7","doi-asserted-by":"crossref","unstructured":"Baloch Z. W., Cooper D. S., Gharib, H. et al. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes. Chap. 1. (Springer, 2017.)","DOI":"10.1007\/978-3-319-60570-8_1"},{"key":"2887_CR8","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1001\/jamaoncol.2018.4616","volume":"5","author":"DL Steward","year":"2019","unstructured":"Steward, D. L. et al. Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology: a prospective blinded multicenter study. JAMA Oncol. 5, 204\u2013212 (2019).","journal-title":"JAMA Oncol."},{"key":"2887_CR9","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1001\/jamaoncol.2020.5935","volume":"7","author":"MJ Livhits","year":"2021","unstructured":"Livhits, M. J. et al. Effectiveness of molecular testing techniques for diagnosis of indeterminate thyroid nodules. JAMA Oncol. 7, 70\u201377 (2021).","journal-title":"JAMA Oncol."},{"key":"2887_CR10","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1056\/NEJMoa1203208","volume":"367","author":"EK Alexander","year":"2012","unstructured":"Alexander, E. K. et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N. Engl. J. Med. 367, 705\u2013715 (2012).","journal-title":"N. Engl. J. Med."},{"key":"2887_CR11","doi-asserted-by":"publisher","first-page":"21401","DOI":"10.1073\/pnas.1911333116","volume":"116","author":"RJ DeHoog","year":"2019","unstructured":"DeHoog, R. J. et al. Preoperative metabolic classification of thyroid nodules using mass spectroscopy imaging of fine-needle aspiration biopsies. Proc. Natl. Acad. Sci. USA 116, 21401\u201321408 (2019).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2887_CR12","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1001\/jamasurg.2018.1153","volume":"153","author":"KN Patel","year":"2018","unstructured":"Patel, K. N. et al. Performance of a genomic sequencing classifier for the preoperative diagnosis of cytologically indeterminate thyroid nodules. JAMA Surg. 153, 817\u2013824 (2018).","journal-title":"JAMA Surg."},{"key":"2887_CR13","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1001\/jama.2018.0898","volume":"319","author":"C Durante","year":"2018","unstructured":"Durante, C. et al. The diagnosis and management of thyroid nodules: A review. JAMA 319, 914\u2013924 (2018).","journal-title":"JAMA"},{"key":"2887_CR14","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","volume":"100","author":"D Hanahan","year":"2000","unstructured":"Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57\u201370 (2000).","journal-title":"Cell"},{"key":"2887_CR15","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1038\/nsmb.2089","volume":"18","author":"S De","year":"2011","unstructured":"De, S. & Michor, F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat. Struct. Mol. Biol. 18, 950\u2013955 (2011).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2887_CR16","doi-asserted-by":"publisher","first-page":"8627","DOI":"10.1093\/nar\/gkv862","volume":"43","author":"D Rhodes","year":"2015","unstructured":"Rhodes, D. & Lipps, H. J. G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res. 43, 8627\u20138637 (2015).","journal-title":"Nucleic Acids Res."},{"key":"2887_CR17","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nrm.2017.3","volume":"18","author":"R H\u00e4nsel-Hertsch","year":"2017","unstructured":"H\u00e4nsel-Hertsch, R., Di Antonio, M. & Balasubramanian, S. DNA G-quadruplexes in the human genome: Detection, functions and therapeutic potential. Nat. Rev. Mol. Cell Biol. 18, 279\u2013284 (2017).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2887_CR18","doi-asserted-by":"publisher","first-page":"0041","DOI":"10.1038\/s41570-017-0041","volume":"1","author":"S Neidle","year":"2017","unstructured":"Neidle, S. Quadruplex nucleic acids as targets for anticancer therapeutics. Nat. Rev. Chem. 1, 0041 (2017).","journal-title":"Nat. Rev. Chem."},{"key":"2887_CR19","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1146\/annurev.bb.23.060194.003415","volume":"23","author":"JR Williamson","year":"1994","unstructured":"Williamson, J. R. G-quartet structures in telomeric DNA. Annu. Rev. Biophys. Biomol. Struct. 23, 703\u2013730 (1994).","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"2887_CR20","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1002\/anie.200300589","volume":"43","author":"JT Davis","year":"2004","unstructured":"Davis, J. T. G-Quartets 40 years later: From 5\u2032-GMP to molecular biology and supramolecular chemistry. Angew. Chem. 43, 668\u2013698 (2004).","journal-title":"Angew. Chem."},{"key":"2887_CR21","doi-asserted-by":"publisher","first-page":"11593","DOI":"10.1073\/pnas.182256799","volume":"99","author":"A Siddiqui-Jain","year":"2002","unstructured":"Siddiqui-Jain, A. et al. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc. Natl. Acad. Sci. USA 99, 11593\u201311598 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2887_CR22","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1038\/ng.3662","volume":"48","author":"R H\u00e4nsel-Hertsch","year":"2016","unstructured":"H\u00e4nsel-Hertsch, R. et al. G-quadruplex structures mark human regulatory chromatin. Nat. Genet. 48, 1267\u20131272 (2016).","journal-title":"Nat. Genet."},{"key":"2887_CR23","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/s41580-020-0236-x","volume":"21","author":"D Varshney","year":"2020","unstructured":"Varshney, D. et al. The regulation and functions of DNA and RNA G-quadruplexes. Nat. Rev. Mol. Cell Biol. 21, 459\u2013474 (2020).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2887_CR24","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nchem.1548","volume":"5","author":"G Biffi","year":"2013","unstructured":"Biffi, G. et al. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat. Chem. 5, 182\u2013186 (2013).","journal-title":"Nat. Chem."},{"key":"2887_CR25","doi-asserted-by":"crossref","unstructured":"Tseng T. Y., Chien C. H., Chu J. F. et al. Fluorescent probe for visualizing guanine-quadruplex DNA by fluorescence lifetime imaging microscopy. J. Biomed. Opt. 18, 101309 (2013).","DOI":"10.1117\/1.JBO.18.10.101309"},{"key":"2887_CR26","first-page":"10102","volume":"43","author":"WC Huang","year":"2015","unstructured":"Huang, W. C. et al. Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents. Nucleic Acids Res. 43, 10102\u201310113 (2015).","journal-title":"Nucleic Acids Res."},{"key":"2887_CR27","doi-asserted-by":"publisher","first-page":"8521","DOI":"10.1021\/jacs.5b03413","volume":"137","author":"A Laguerre","year":"2015","unstructured":"Laguerre, A. et al. Visualization of RNA-quadruplexes in live cells. J Am Chem Soc. 137, 8521\u20138525 (2015).","journal-title":"J Am Chem Soc."},{"key":"2887_CR28","doi-asserted-by":"publisher","first-page":"e1027111","DOI":"10.1371\/journal.pone.0102711","volume":"9","author":"G Biffi","year":"2014","unstructured":"Biffi, G. et al. Elevated levels of G-quadruplex formation in human stomach and liver cancer tissues. PLoS ONE 9, e1027111 (2014).","journal-title":"PLoS ONE"},{"key":"2887_CR29","doi-asserted-by":"publisher","first-page":"16082","DOI":"10.1038\/s41598-018-34378-8","volume":"8","author":"TY Tseng","year":"2018","unstructured":"Tseng, T. Y. et al. The G-quadruplex fluorescent probe 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide as a biosensor for human cancers. Sci. Rep. 8, 16082 (2018).","journal-title":"Sci. Rep."},{"key":"2887_CR30","doi-asserted-by":"publisher","first-page":"9719","DOI":"10.1002\/anie.202002422","volume":"59","author":"LY Liu","year":"2020","unstructured":"Liu, L. Y. et al. Quantitative detection of G-quadruplex DNA in live cells based on photon counts and complex structure discrimination. Angew. Chem. 59, 9719\u20139726 (2020).","journal-title":"Angew. Chem."},{"key":"2887_CR31","doi-asserted-by":"publisher","first-page":"6517","DOI":"10.1093\/nar\/gkm706","volume":"35","author":"AT Phan","year":"2007","unstructured":"Phan, A. T., Kuryavyi, V., Luu, K. N. & Patel, D. J. Structure of two intramolecular G-quadruplexes formed by natural human telomere sequences in K+ solution. Nucleic Acids Res. 35, 6517\u20136525 (2007).","journal-title":"Nucleic Acids Res."},{"key":"2887_CR32","doi-asserted-by":"publisher","first-page":"2048","DOI":"10.1021\/bi048242p","volume":"44","author":"A Ambrus","year":"2005","unstructured":"Ambrus, A., Chen, D., Dai, J., Jones, R. A. & Yang, D. Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Biochemistry 44, 2048\u20132058 (2005).","journal-title":"Biochemistry"},{"key":"2887_CR33","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1109\/TSMC.1979.4310076","volume":"9","author":"N Otsu","year":"1979","unstructured":"Otsu, N. A threshold selection method from gray-level histograms. IEEE Trans. Syst. Man Cybern. 9, 62\u201366 (1979).","journal-title":"IEEE Trans. Syst. Man Cybern."},{"key":"2887_CR34","unstructured":"Eng, J. ROC Analysis: Web-Based Calculator for ROC Curves. http:\/\/www.jrocfit.org. Accessed 18 Feb 2021."},{"key":"2887_CR35","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/nchembio.780","volume":"8","author":"R Rodriguez","year":"2012","unstructured":"Rodriguez, R. et al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat. Chem. Biol. 8, 301\u2013310 (2012).","journal-title":"Nat. Chem. Biol."},{"key":"2887_CR36","doi-asserted-by":"publisher","first-page":"4083","DOI":"10.3390\/molecules25184083","volume":"25","author":"TY Tseng","year":"2020","unstructured":"Tseng, T. Y., Liu, S. Y., Wang, C. L. & Chang, T. C. Antisense oligonucleotides used to identify telomeric G-quadruplexes in metaphase chromosomes and fixed cells by fluorescence lifetime imaging microscopy of o-BMVC foci. Molecules 25, 4083 (2020).","journal-title":"Molecules"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02887-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02887-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02887-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T17:53:05Z","timestamp":1670089985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02887-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["2887"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-02887-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,6]]},"assertion":[{"value":"16 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23475"}}