{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:22:34Z","timestamp":1791555754107,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of Information & communications Technology Planning & Evaluation","award":["IITP-2023-RS-2023-00256629"],"award-info":[{"award-number":["IITP-2023-RS-2023-00256629"]}]},{"DOI":"10.13039\/501100002456","name":"Korea government (MSIT), Chonnam National University","doi-asserted-by":"publisher","award":["2023-0083"],"award-info":[{"award-number":["2023-0083"]}],"id":[{"id":"10.13039\/501100002456","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["BCRI25010"],"award-info":[{"award-number":["BCRI25010"]}]},{"name":"NIH","award":["R01NS126513"],"award-info":[{"award-number":["R01NS126513"]}]},{"name":"NIH","award":["R01NS131474"],"award-info":[{"award-number":["R01NS131474"]}]},{"DOI":"10.13039\/100003287","name":"Rally Foundation for Childhood Cancer Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100003287","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000902","name":"Pediatric Cancer Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000902","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008221","name":"Cure Starts Now Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008221","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Prayers Maria Foundation"},{"name":"Cure Childhood Cancer Foundation"},{"name":"UCSF Brain Tumor SPORE Biorepository","award":["P50 CA097257"],"award-info":[{"award-number":["P50 CA097257"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Despite a specific histone mutation defining the unique genetic makeup, diffuse midline gliomas are heterogeneous tumors with a wide range of morphologic and molecular spectrum. We investigated the feasibility of using hyperpolarized carbon-13(13C) MR metabolic imaging to differentiate distinctive molecular features from two H3K27M-mutant, biopsy-originated diffuse midline glioma xenografts. 13C MR metabolic imaging data were acquired on a 3T scanner from 12 rats that had been implanted with SF8628 or SF7761 diffuse midline glioma cells in brainstem, following injection of hyperpolarized [1-13C]pyruvate. Despite the two tumors\u2019 similar appearance of T2-hyperintensity throughout the cerebellum and pons without contrast enhancement, 13C metabolic imaging data revealed that SF8627 had significantly higher ratios of lactate to pyruvate, lactate to total carbon, and normalized lactate than SF7761. Elevated lactate levels in SF8628 were associated with large amounts of lactate dehydrogenase (LDH)-A and carbonic anhydrase-IX staining in SF8628 compared to SF7761, which implied that the highly hypoxic condition in SF8628 appeared to contribute to the high level of LDH-A enzyme activity, which, in turn, induced the large conversion from hyperpolarized pyruvate to lactate. Our findings suggest that this advanced metabolic imaging technique may be used for the noninvasive characterization of molecular hypoxia and lactate dehydrogenase-A activity in these pediatric brainstem gliomas.<\/jats:p>","DOI":"10.3390\/molecules30214175","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T02:23:28Z","timestamp":1761704608000},"page":"4175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hyperpolarized Carbon-13 Metabolic Imaging Differentiates Distinctive Molecular Phenotypes in Diffuse Midline Gliomas"],"prefix":"10.3390","volume":"30","author":[{"given":"Ilwoo","family":"Park","sequence":"first","affiliation":[{"name":"Department of Radiology, Chonnam National University Medical School and Hospital, Gwangju 61469, Republic of Korea"},{"name":"Department of Artificial Intelligence Convergence, Chonnam National University, Gwangju 61186, Republic of Korea"},{"name":"Department of Data Science, Chonnam National University, Gwangju 61186, Republic of Korea"},{"name":"Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9373-7831","authenticated-orcid":false,"given":"Rintaro","family":"Hashizume","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery and Pathology, University of California, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/bpa.12023","article-title":"Chromatin remodeling defects in pediatric and young adult glioblastoma: A tale of a variant histone 3 tail","volume":"23","author":"Fontebasso","year":"2013","journal-title":"Brain Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature10833","article-title":"Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma","volume":"482","author":"Schwartzentruber","year":"2012","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/bpa.12336","article-title":"Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations","volume":"26","author":"Solomon","year":"2016","journal-title":"Brain Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1093\/neuonc\/noq205","article-title":"Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: A report from the Children\u2019s Oncology Group","volume":"13","author":"Cohen","year":"2011","journal-title":"Neuro-Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1470-2045(06)70615-5","article-title":"Diffuse brainstem glioma in children: Critical review of clinical trials","volume":"7","author":"Hargrave","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/nox158","article-title":"CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010\u20132014","volume":"19","author":"Ostrom","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s11060-012-0973-6","article-title":"Characterization of a diffuse intrinsic pontine glioma cell line: Implications for future investigations and treatment","volume":"110","author":"Hashizume","year":"2012","journal-title":"J. Neurooncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4453","DOI":"10.1073\/pnas.1101657108","article-title":"Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma","volume":"108","author":"Monje","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ng.1102","article-title":"Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas","volume":"44","author":"Wu","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1093\/neuonc\/not144","article-title":"H3F3A K27M mutations in thalamic gliomas from young adult patients","volume":"16","author":"Aihara","year":"2014","journal-title":"Neuro-Oncology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.humpath.2015.07.002","article-title":"The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults","volume":"46","author":"Feng","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s40478-016-0353-0","article-title":"Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma","volume":"4","author":"Ryall","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ejrad.2008.06.033","article-title":"Role of MRI in paediatric neurooncology","volume":"68","author":"Rao","year":"2008","journal-title":"Eur. J. Radiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"795","DOI":"10.3174\/ajnr.A5076","article-title":"Imaging Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3 K27M Mutation","volume":"38","author":"Aboian","year":"2017","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s11060-007-9473-5","article-title":"Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma","volume":"86","author":"Hargrave","year":"2008","journal-title":"J. Neuro-Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1750-3639.2010.00468.x","article-title":"Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model","volume":"21","author":"Caretti","year":"2011","journal-title":"Brain Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/2191-219X-4-8","article-title":"18F-FDG PET standard uptake values of the normal pons in children: Establishing a reference value for diffuse intrinsic pontine glioma","volume":"4","author":"Jansen","year":"2014","journal-title":"EJNMMI Res."},{"key":"ref_19","first-page":"188","article-title":"Evaluation of 18F-FDG PET and MRI associations in pediatric diffuse intrinsic brain stem glioma: A report from the Pediatric Brain Tumor Consortium","volume":"52","author":"Zukotynski","year":"2011","journal-title":"J. Nucl. Med. Off. Publ. Soc. Nucl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10158","DOI":"10.1073\/pnas.1733835100","article-title":"Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR","volume":"100","author":"Fridlund","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8607","DOI":"10.1158\/0008-5472.CAN-08-0749","article-title":"Hyperpolarized 13C lactate, pyruvate, and alanine: Noninvasive biomarkers for prostate cancer detection and grading","volume":"68","author":"Albers","year":"2008","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/nm1650","article-title":"Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy","volume":"13","author":"Day","year":"2007","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1593\/neo.101102","article-title":"Analysis of cancer metabolism by imaging hyperpolarized nuclei: Prospects for translation to clinical research","volume":"13","author":"Kurhanewicz","year":"2011","journal-title":"Neoplasia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.neuroimage.2011.07.034","article-title":"Hyperpolarized 13C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma","volume":"59","author":"Chaumeil","year":"2012","journal-title":"Neuroimage"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1093\/neuonc\/nop043","article-title":"Hyperpolarized 13C magnetic resonance metabolic imaging: Application to brain tumors","volume":"12","author":"Park","year":"2010","journal-title":"Neuro-Oncology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7115","DOI":"10.1158\/0008-5472.CAN-14-0849","article-title":"Changes in pyruvate metabolism detected by magnetic resonance imaging are linked to DNA damage and serve as a sensor of temozolomide response in glioblastoma cells","volume":"74","author":"Park","year":"2014","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/nbm.3509","article-title":"Hyperpolarized 13C-lactate to 13C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment","volume":"29","author":"Park","year":"2016","journal-title":"NMR Biomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e230005","DOI":"10.1148\/rycan.230005","article-title":"Hyperpolarized Carbon 13 MRI: Clinical Applications and Future Directions in Oncology","volume":"5","author":"Deen","year":"2023","journal-title":"Radiol. Imaging Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1002\/mrm.29875","article-title":"Current methods for hyperpolarized [1-13C]pyruvate MRI human studies","volume":"91","author":"Larson","year":"2024","journal-title":"Magn. Reson. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"198ra108","DOI":"10.1126\/scitranslmed.3006070","article-title":"Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate","volume":"5","author":"Nelson","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/mrm.27077","article-title":"Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies","volume":"80","author":"Park","year":"2018","journal-title":"Magn. Reson. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/S0002-9440(10)64038-2","article-title":"Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer","volume":"158","author":"Ivanov","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1101\/gad.12.2.149","article-title":"Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha","volume":"12","author":"Iyer","year":"1998","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1172\/JCI67230","article-title":"HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations","volume":"123","author":"Semenza","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1042\/bj2310537","article-title":"Genomic organization of human lactate dehydrogenase-A gene","volume":"231","author":"Chung","year":"1985","journal-title":"Biochem. J."},{"key":"ref_36","first-page":"7075","article-title":"Hypoxia-inducible expression of tumor-associated carbonic anhydrases","volume":"60","author":"Wykoff","year":"2000","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1158\/0008-5472.CAN-09-2251","article-title":"Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance spectroscopy","volume":"70","author":"Ward","year":"2010","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1161\/CIRCRESAHA.116.309769","article-title":"Hyperpolarized 13C Metabolic MRI of the Human Heart: Initial Experience","volume":"119","author":"Cunningham","year":"2016","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3174\/ajnr.A6937","article-title":"Pilot Study of Hyperpolarized 13C Metabolic Imaging in Pediatric Patients with Diffuse Intrinsic Pontine Glioma and Other CNS Cancers","volume":"42","author":"Autry","year":"2021","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s11060-009-9954-9","article-title":"A human brainstem glioma xenograft model enabled for bioluminescence imaging","volume":"96","author":"Hashizume","year":"2010","journal-title":"J. Neurooncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/mrm.24434","article-title":"Evaluation of heterogeneous metabolic profile in an orthotopic human glioblastoma xenograft model using compressed sensing hyperpolarized 3D 13C magnetic resonance spectroscopic imaging","volume":"70","author":"Park","year":"2013","journal-title":"Magn. Reson. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"125","DOI":"10.13104\/imri.2022.26.2.125","article-title":"Optimization of Scan Parameters for in vivo Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopic Imaging","volume":"26","author":"Nguyen","year":"2022","journal-title":"Investig. Magn. Reson. Imaging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/mrm.1183","article-title":"Analysis of volume MRI and MR spectroscopic imaging data for the evaluation of patients with brain tumors","volume":"46","author":"Nelson","year":"2001","journal-title":"Magn. Reson. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/mrm.21391","article-title":"Sparse MRI: The application of compressed sensing for rapid MR imaging","volume":"58","author":"Lustig","year":"2007","journal-title":"Magn. Reson. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/21\/4175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T05:11:31Z","timestamp":1761714691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/21\/4175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,24]]},"references-count":44,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["molecules30214175"],"URL":"https:\/\/doi.org\/10.3390\/molecules30214175","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,24]]}}}