{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:22:50Z","timestamp":1787026970593,"version":"build-2736575974"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The intrinsic autofluorescence of biological tissues interferes with the detection of fluorophores administered for fluorescence guidance, an emerging auxiliary technique in oncological surgery. Yet, autofluorescence of the human brain and its neoplasia is sparsely examined. This study aims to assess autofluorescence of the brain and its neoplasia on a microscopic level by stimulated Raman histology (SRH) combined with two-photon fluorescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>With this experimentally established label-free microscopy technique unprocessed tissue can be imaged and analyzed within minutes and the process is easily incorporated in the surgical workflow. In a prospective observational study, we analyzed 397 SRH and corresponding autofluorescence images of 162 samples from 81 consecutive patients that underwent brain tumor surgery. Small tissue samples were squashed on a slide for imaging. SRH and fluorescence images were acquired with a dual wavelength laser (790 nm and 1020 nm) for excitation. In these images tumor and non-tumor regions were identified by a convolutional neural network that reliably differentiates between tumor, healthy brain tissue and low quality SRH images. The identified areas were used to define regions.of- interests (ROIs) and the mean fluorescence intensity was measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In healthy brain tissue, we found an increased mean autofluorescence signal in the gray (11.86,\n                      <jats:italic>SD<\/jats:italic>\n                      2.61,\n                      <jats:italic>n<\/jats:italic>\n                      =29) compared to the white matter (5.99,\n                      <jats:italic>SD<\/jats:italic>\n                      5.14,\n                      <jats:italic>n<\/jats:italic>\n                      =11,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.01) and in the cerebrum (11.83,\n                      <jats:italic>SD<\/jats:italic>\n                      3.29,\n                      <jats:italic>n<\/jats:italic>\n                      =33) versus the cerebellum (2.82,\n                      <jats:italic>SD<\/jats:italic>\n                      0.93,\n                      <jats:italic>n<\/jats:italic>\n                      =7,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), respectively. The signal of carcinoma metastases, meningiomas, gliomas and pituitary adenomas was significantly lower (each\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.05) compared to the autofluorescence in the cerebrum and dura, and significantly higher (each\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.05) compared to the cerebellum. Melanoma metastases were found to have a higher fluorescent signal (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.01) compared to cerebrum and cerebellum.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In conclusion we found that autofluorescence in the brain varies depending on the tissue type and localization and differs significantly among various brain tumors. This needs to be considered for interpreting photon signal during fluorescence-guided brain tumor surgery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2023.1146031","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T17:21:23Z","timestamp":1683739283000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["Intraoperative microscopic autofluorescence detection and characterization in brain tumors using stimulated Raman histology and two-photon fluorescence"],"prefix":"10.3389","volume":"13","author":[{"given":"Gina","family":"F\u00fcrtjes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Reinecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"von Spreckelsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Katharina","family":"Mei\u00dfner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rue\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Timmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Freudiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Ion-Margineanu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Khalid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Watrinet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mawrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Chmyrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Goldbrunner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Bruns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Neuschmelting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s12274-014-0549-1","article-title":"1.3 \u03bcm emitting SrF2:Nd3+ nanoparticles for high contrast in vivo imaging in the second biological window","volume":"8","author":"Villa","year":"2015","journal-title":"Nano Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/smtd.201800075","article-title":"Strategies to overcome autofluorescence in nanoprobe-driven in vivo fluorescence imaging","volume":"2","author":"Del Rosal","year":"2018","journal-title":"Small Methods"},{"key":"B3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-3-030-32036-2_2","article-title":"NIR autofluorescence: molecular origins and emerging clinical applications","volume-title":"Near infrared-emitting nanoparticles for biomedical applications","author":"del Rosal","year":"2020"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75621-X","article-title":"Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein","volume":"82","author":"Huang","year":"2002","journal-title":"Biophys J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/srep03432","article-title":"Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation","volume":"3","author":"Quinn","year":"2013","journal-title":"Sci Rep"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.etp.2010.06.005","article-title":"Evaluation of lipofuscin-like pigments as an index of lead-induced oxidative damage in the brain","volume":"64","author":"Patkov\u00e1","year":"2012","journal-title":"Exp Toxicol Pathol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(92)90767-P","article-title":"Characterization of ultraviolet laser-induced autofluorescence of ceroid deposits and other structures in atherosclerotic plaques as a potential diagnostic for laser angiosurgery","volume":"123","author":"Verbunt","year":"1992","journal-title":"Am Heart J"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3109\/08820538.2012.711415","article-title":"Lipofuscin and the principles of fundus autofluorescence: a review","volume":"27","author":"Nandakumar","year":"2012","journal-title":"Semin Ophthalmol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1146\/annurev.physchem.47.1.555","article-title":"Quantitative optical spectroscopy for tissue diagnosis","volume":"47","author":"Richards-Kortum","year":"1996","journal-title":"Annu Rev Phys Chem"},{"key":"B10","doi-asserted-by":"publisher","first-page":"024017","DOI":"10.1117\/1.3103310","article-title":"Near-infrared autofluorescence imaging of cutaneous melanins and human skin in vivo","volume":"14","author":"Han","year":"2009","journal-title":"J BioMed Opt."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1800075","DOI":"10.1111\/j.1600-0846.2012.00632.x","article-title":"In vivo near-infrared autofluorescence imaging of pigmented skin lesions: methods, technical improvements and preliminary clinical results","volume":"19","author":"Wang","year":"2013","journal-title":"Ski Res Technol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2011.08.040","article-title":"Near-infrared autofluorescence spectroscopy for in vivo identification of hyperplastic and adenomatous polyps in the colon","volume":"30","author":"Shao","year":"2011","journal-title":"Biosens Bioelectron."},{"key":"B13","doi-asserted-by":"publisher","first-page":"067005","DOI":"10.1117\/1.3589099","article-title":"In vivo diagnosis of colonic precancer and cancer using near-infrared autofluorescence spectroscopy and biochemical modeling","volume":"16","author":"Shao","year":"2011","journal-title":"J BioMed Opt."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1364\/OL.40.005498","article-title":"Near-infrared autofluorescence spectroscopy of in vivo soft tissue sarcomas","volume":"40","author":"Nguyen","year":"2015","journal-title":"Opt Lett"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/jbio.202000154","article-title":"The near-infrared autofluorescence fingerprint of the brain","volume":"13","author":"Lifante","year":"2020","journal-title":"J Biophotonics."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-016-0027","article-title":"Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated raman scattering microscopy","volume":"1","author":"Orringer","year":"2017","journal-title":"Nat BioMed Eng"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.1165758","article-title":"Label-free biomedical imaging with high sensitivity by stimulated raman scattering microscopy","volume":"322","author":"Freudiger","year":"2008","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40478-022-01411-x","article-title":"Novel rapid intraoperative qualitative tumor detection by a residual convolutional neural network using label-free stimulated raman scattering microscopy","volume":"10","author":"Reinecke","year":"2022","journal-title":"Acta Neuropathol Commun"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s10143-021-01712-0","article-title":"Stimulated raman histology in the neurosurgical workflow of a major European neurosurgical center {{\/amp]]mdash; part a","volume":"45","author":"Neidert","year":"2022","journal-title":"Neurosurg Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0715-9","article-title":"Near real-time intraoperative brain tumor diagnosis using stimulated raman histology and deep neural networks","volume":"26","author":"Hollon","year":"2020","journal-title":"Nat Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3171\/2019.9.JNS192075","article-title":"Stimulated raman histology for rapid and accurate intraoperative diagnosis of CNS tumors: prospective blinded study","volume":"134","author":"Eichberg","year":"2019","journal-title":"J Neurosurg"},{"key":"B22","doi-asserted-by":"publisher","first-page":"E12","DOI":"10.3171\/2022.9.FOCUS22429","article-title":"Towards digital histopathological assessment in surgery of central nervous system tumors using stimulated raman histology","volume":"53","author":"Wadiura","year":"2022","journal-title":"Neurosurg Focus"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s10143-021-01711-1","article-title":"Neuropathological interpretation of stimulated raman histology images of brain and spine tumors: part b","volume":"45","author":"Straehle","year":"2022","journal-title":"Neurosurg Rev"},{"key":"B24","first-page":"1","article-title":"Microscopy","volume-title":"Nat Biomed Eng","author":"Orringer","year":"2017"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02252-4","article-title":"Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging","volume":"29","author":"Hollon","year":"2023","journal-title":"Nat Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1364\/BOE.6.001219","article-title":"Spectral and lifetime domain measurements of rat brain tumors","volume":"6","author":"Haidar","year":"2015","journal-title":"BioMed Opt Express."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep41724","article-title":"Multimodal optical analysis discriminates freshly extracted human sample of gliomas, metastases and meningiomas from their appropriate controls","volume":"7","author":"Zanello","year":"2017","journal-title":"Sci Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4081\/ejh.2014.2461","article-title":"Autofluorescence spectroscopy and imaging: a tool for biomedical research and diagnosis","volume":"58","author":"Croce","year":"2014","journal-title":"Eur J Histochem"},{"key":"B29","doi-asserted-by":"publisher","first-page":"79060T","DOI":"10.1117\/12.874676","article-title":"Development of a skin phantom of the epidermis and evaluation by using fluorescence techniques","volume":"7906","author":"Bergmann","year":"2011","journal-title":"Proceedings"},{"key":"B30","doi-asserted-by":"publisher","first-page":"047008","DOI":"10.1364\/BOE.6.001219","article-title":"Changes of collagen and nicotinamide adenine dinucleotide in human cancerous and normal prostate tissues studied using native fluorescence spectroscopy with selective excitation wavelength","volume":"15","author":"Pu","year":"2010","journal-title":"J BioMed Opt."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1109\/TBME.2006.883643","article-title":"Comparison of the performance of linear multivariate analysis methods for normal and dyplasia tissues differentiation using autofluorescence spectroscopy","volume":"53","author":"Shou","year":"2006","journal-title":"IEEE Trans BioMed Eng."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27451","article-title":"Real-time detection of breast cancer at the cellular level","volume":"234","author":"Carver","year":"2019","journal-title":"J Cell Physiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3171\/2018.12.JNS182422","article-title":"Dual labeling with 5-aminolevulinic acid and fluorescein in high-grade glioma surgery with a prototype filter system built into a neurosurgical microscope: technical note","volume":"132","author":"Molina","year":"2020","journal-title":"J Neurosurg"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00701-020-04227-7","article-title":"Validating a new generation filter system for visualizing 5-ALA-induced PpIX fluorescence in malignant glioma surgery: a proof of principle study","volume":"162","author":"Suero Molina","year":"2020","journal-title":"Acta Neurochir"},{"key":"B35","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s007010050206","article-title":"Technical principles for protoporphyrin-IX-Fluorescence guided microsurgical resection of malignant glioma tissue","volume":"140","author":"Ehrhardt","year":"1998","journal-title":"Acta Neurochir"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2011.04.005","article-title":"Combining near-infrared-excited autofluorescence and raman spectroscopy improves in vivo diagnosis of gastric cancer","volume":"26","author":"Bergholt","year":"2011","journal-title":"Biosens Bioelectron"},{"key":"B37","article-title":"Lipid pigments (chromolipids): their origin, nature, and significance","volume":"10","author":"Wolman","year":"1980","journal-title":"Pathobiology Annu"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/0047-6374(92)90085-R","article-title":"Chromatography and spectrofluorometry of brain fluorophores in neuronal ceroid lipofuscinosis (NCL)","volume":"64","author":"Armstrong","year":"1992","journal-title":"Mech Ageing Dev"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3038","article-title":"Otto Warburg\u2019s contributions to current concepts of cancer metabolism","volume":"11","author":"Koppenol","year":"2011","journal-title":"Nat Rev Cancer"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/jbio.201900136","article-title":"Quantitative assessment of microenvironment characteristics and metabolic activity in glioma via multiphoton microscopy","volume":"12","author":"Fang","year":"2019","journal-title":"J Biophotonics."},{"key":"B41","doi-asserted-by":"publisher","first-page":"114003","DOI":"10.1117\/1.JBO.21.11.114003","article-title":"Optical redox imaging indices discriminate human breast cancer from normal tissues","volume":"21","author":"Xu","year":"2016","journal-title":"J BioMed Opt."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2008.01.006","article-title":"Mitochondria in cancer cells: what is so special about them","volume":"18","author":"Gogvadze","year":"2008","journal-title":"Trends Cell Biol"},{"key":"B43","doi-asserted-by":"crossref","DOI":"10.1117\/12.382720","article-title":"Characterization of type I, II, III, IV, and V collagens by time-resolved laser-induced fluorescence spectroscopy","volume-title":"Optical biopsy III","author":"Marcu","year":"2000"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1117\/12.382720","article-title":"Photobleaching as a tool to measure the local strain field in fibrous membranes of connective tissues","volume":"10","author":"Jayyosi","year":"2014","journal-title":"Acta Biomater."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/jbio.201200092","article-title":"From molecular structure to tissue architecture: collagen organization probed by SHG microscopy","volume":"6","author":"Cicchi","year":"2013","journal-title":"J Biophotonics."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0832308100","article-title":"Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation","volume":"100","author":"Zipfel","year":"2003","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.1991.tb02013.x","article-title":"Age-related changes in the fluorescence of melanin and lipofuscin granules of the retinal pigment epithelium: a time-resolved fluorescence spectroscopy study","volume":"54","author":"Docchio","year":"1991","journal-title":"Photochem Photobiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.1987.tb04829.x","article-title":"Quantitative analysis of intracellular behaviour of porphyrins","volume":"46","author":"Bottiroli","year":"1987","journal-title":"Photochem Photobiol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2003.08.007","article-title":"In vivo near-infrared fluorescence imaging","volume":"7","author":"Frangioni","year":"2003","journal-title":"Curr Opin Chem Biol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1718917115","article-title":"Shortwave infrared fluorescence imaging with the clinically approved near-infrared dye indocyanine green","volume":"115","author":"Carr","year":"2018","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-017-0056","article-title":"Next-generation in vivo optical imaging with short-wave infrared quantum dots","volume":"1","author":"Bruns","year":"2017","journal-title":"Nat BioMed Eng."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-022-12317-y","article-title":"In vivo imaging with a fast large-area multiphoton exoscope (FLAME) captures the melanin distribution heterogeneity in human skin","volume":"12","author":"Vicente","year":"2022","journal-title":"Sci Rep"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-77268-8","article-title":"Macroscopic fluorescence-lifetime imaging of NADH and protoporphyrin IX improves the detection and grading of 5-aminolevulinic acid-stained brain tumors","volume":"10","author":"Erkkil\u00e4","year":"2020","journal-title":"Sci Rep"},{"key":"B54","article-title":"Two-photon fluorescence microscopy: basic principles, advantages and risks","volume":"2","author":"Mulligan","year":"2007","journal-title":"Mod Res Educ Top Microsc"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1227\/NEU.0b013e318212464e","article-title":"Intraoperative confocal microscopy for brain tumors: a feasibility analysis in humans","volume":"68","author":"Sanai","year":"2011","journal-title":"Neurosurgery"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3171\/2011.12.JNS11696","article-title":"In vivo intraoperative confocal microscopy for real-time histopathological imaging of brain tumors: clinical article","volume":"116","author":"Eschbacher","year":"2012","journal-title":"J Neurosurg"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3171\/2016.1.FOCUS15559","article-title":"Prospective evaluation of the utility of intraoperative confocal laser endomicroscopy in patients with brain neoplasms using fluorescein sodium: experience with 74 cases","volume":"40","author":"Martirosyan","year":"2016","journal-title":"Neurosurg Focus."}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1146031\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T17:21:33Z","timestamp":1683739293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1146031\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,10]]},"references-count":57,"alternative-id":["10.3389\/fonc.2023.1146031"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1146031","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,10]]},"article-number":"1146031"}}