{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T13:10:12Z","timestamp":1761570612731,"version":"build-2065373602"},"posted":{"date-parts":[[2025,10,26]]},"group-title":"In Review","reference-count":72,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T00:00:00Z","timestamp":1761436800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,13]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  We investigated alanine as a magnetic resonance imaging (MRI) biomarker for alanine-serine-cysteine transporter 2 (ASCT2), the primary transporter for glutamine in cancer. Alanine exhibited higher contrast using the chemical exchange saturation transfer (CEST) method than other major ASCT2 substrates. Upon bolus injection of alanine (6 mmole\/kg), CEST MRI enhancement\n                  <italic>in vivo<\/italic>\n                  was higher in\n                  <italic>SLC1A5<\/italic>\n                  -overexpressing Pa20c pancreatic tumors than na\u00efve tumors (p\u2009&lt;\u20090.0001). Enhancement was more pronounced in LNCaP prostate tumors than DU-145 prostate tumors\n                  <italic>in vivo<\/italic>\n                  (p\u2009&lt;\u20090.0001). The temporal dynamics of alanine-weighted CEST (ALAwCEST) signal enhancement depended on the volume of the tumor, which histological analysis revealed to be due to alterations in the expression and distribution of ASCT2 and CD31-positive blood vessels. Mass spectrometric imaging of\n                  <sup>13<\/sup>\n                  C-labeled metabolites confirmed differences in alanine uptake and metabolism in prostate tumors. We demonstrated the feasibility of ALAwCEST imaging for reporting ASCT2-mediated uptake in multiple human cancer models.\n                <\/p>","DOI":"10.21203\/rs.3.rs-7367339\/v1","type":"posted-content","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T11:00:12Z","timestamp":1761562812000},"source":"Crossref","is-referenced-by-count":0,"title":["MRI of ASCT2-mediated amino acid uptake in xenograft tumor models"],"prefix":"10.21203","author":[{"given":"Behnaz","family":"Ghaemi","sequence":"first","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balaji","family":"Krishnamachary","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Dillman","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten N. Bains","family":"Williams","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Hodo","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuguo","family":"Li","sequence":"additional","affiliation":[{"name":"Kennedy Krieger Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-France Penet","family":"Vidaver","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin G.","family":"Pomper","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlin M.","family":"Tressler","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaver M.","family":"Bhujwalla","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T.","family":"McMahon","sequence":"additional","affiliation":[{"name":"Kennedy Krieger Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff W.M.","family":"Bulte","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter C.M.","family":"Zijl","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aline M.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.4062\/biomolther.2017.178","article-title":"Targeting Glutamine Metabolism for Cancer Treatment","volume":"26","author":"Choi YK","year":"2018","unstructured":"Choi, Y. K. & Park, K. G. Targeting Glutamine Metabolism for Cancer Treatment. Biomol Ther (Seoul) 26, 19\u201328 (2018). https:\/\/doi.org:10.4062\/biomolther.2017.178","journal-title":"Biomol Ther (Seoul)"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.molcel.2016.04.033","article-title":"Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53","volume":"62","author":"Riscal R","year":"2016","unstructured":"Riscal, R. et al. Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53. Molecular Cell 62, 890\u2013902 (2016). https:\/\/doi.org:10.1016\/j.molcel.2016.04.033","journal-title":"Molecular Cell"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3819","DOI":"10.1016\/j.celrep.2017.12.002","article-title":"Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis","volume":"21","author":"Yue M","year":"2017","unstructured":"Yue, M., Jiang, J., Gao, P., Liu, H. & Qing, G. Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis. Cell Reports 21, 3819\u20133832 (2017). https:\/\/doi.org:10.1016\/j.celrep.2017.12.002","journal-title":"Cell Reports"},{"key":"ref4","doi-asserted-by":"crossref","DOI":"10.18632\/oncotarget.20545","article-title":"Endogenous glutamine decrease is associated with pancreatic cancer progression","volume":"8","author":"Roux C","year":"2017","unstructured":"Roux, C. et al. Endogenous glutamine decrease is associated with pancreatic cancer progression. Oncotarget 8 (2017).","journal-title":"Oncotarget"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e0168907","DOI":"10.1371\/journal.pone.0168907","article-title":"GLUT1 and ASCT2 as Predictors for Prognosis of Hepatocellular Carcinoma","volume":"11","author":"Sun H-W","year":"2016","unstructured":"Sun, H.-W. et al. GLUT1 and ASCT2 as Predictors for Prognosis of Hepatocellular Carcinoma. PLOS ONE 11, e0168907 (2016). https:\/\/doi.org:10.1371\/journal.pone.0168907","journal-title":"PLOS ONE"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1038\/bjc.2014.88","article-title":"ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer","volume":"110","author":"Shimizu K","year":"2014","unstructured":"Shimizu, K. et al. ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer. British Journal of Cancer 110, 2030\u20132039 (2014). https:\/\/doi.org:10.1038\/bjc.2014.88","journal-title":"British Journal of Cancer"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3489","DOI":"10.1002\/cam4.2965","article-title":"ASCT2 overexpression is associated with poor survival of OSCC patients and ASCT2 knockdown inhibited growth of glutamine-addicted OSCC cells","volume":"9","author":"Luo Y","year":"2020","unstructured":"Luo, Y. et al. ASCT2 overexpression is associated with poor survival of OSCC patients and ASCT2 knockdown inhibited growth of glutamine-addicted OSCC cells. Cancer Medicine 9, 3489\u20133499 (2020). https:\/\/doi.org:doi.org\/10.1002\/cam4.2965","journal-title":"Cancer Medicine"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13058-017-0905-7","article-title":"Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors","volume":"19","author":"Bernhardt S","year":"2017","unstructured":"Bernhardt, S. et al. Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors. Breast Cancer Research 19, 112 (2017). https:\/\/doi.org:10.1186\/s13058-017-0905-7","journal-title":"Breast Cancer Research"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1002\/path.4518","article-title":"Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development","volume":"236","author":"Wang Q","year":"2015","unstructured":"Wang, Q. et al. Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. The Journal of Pathology 236, 278\u2013289 (2015). https:\/\/doi.org:doi.org\/10.1002\/path.4518","journal-title":"The Journal of Pathology"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.cbpa.2021.01.006","article-title":"Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment","volume":"62","author":"Shen Y-A","year":"2021","unstructured":"Shen, Y.-A. et al. Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment. Current Opinion in Chemical Biology 62, 64\u201381 (2021). https:\/\/doi.org:https:\/\/doi.org\/10.1016\/j.cbpa.2021.01.006","journal-title":"Current Opinion in Chemical Biology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"19","DOI":"10.4062\/biomolther.2017.178","article-title":"Targeting Glutamine Metabolism for Cancer Treatment","volume":"26","author":"Choi Y-K","year":"2018","unstructured":"Choi, Y.-K. & Park, K.-G. Targeting Glutamine Metabolism for Cancer Treatment. Biomolecules & Therapeutics 26, 19\u201328 (2018). https:\/\/doi.org:10.4062\/biomolther.2017.178","journal-title":"Biomolecules & Therapeutics"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1158\/1535-7163.Mct-20-0354","article-title":"Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma","volume":"20","author":"Feng Y","year":"2021","unstructured":"Feng, Y. et al. Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma. Molecular Cancer Therapeutics 20, 816\u2013832 (2021). https:\/\/doi.org:10.1158\/1535-7163.Mct-20-0354","journal-title":"Molecular Cancer Therapeutics"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1016\/j.bbamcr.2015.03.017","article-title":"N-linked Glycosylation of human SLC1A5 (ASCT2) transporter is critical for trafficking to membrane","volume":"1853","author":"Console L","year":"2015","unstructured":"Console, L., Scalise, M., Tarmakova, Z., Coe, I. R. & Indiveri, C. N-linked Glycosylation of human SLC1A5 (ASCT2) transporter is critical for trafficking to membrane. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1853, 1636\u20131645 (2015). https:\/\/doi.org:doi.org\/10.1016\/j.bbamcr.2015.03.017","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2019.07.001","author":"Leslie TK","year":"2019","unstructured":"Leslie, T. K. et al. Sodium homeostasis in the tumour microenvironment. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1872, 188304 (2019). https:\/\/doi.org:doi.org\/10.1016\/j.bbcan.2019.07.001"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1002\/mrm.22761","article-title":"Chemical exchange saturation transfer (CEST): What is in a name and what isn't?","volume":"65","author":"Zijl PCM","year":"2011","unstructured":"van Zijl, P. C. M. & Yadav, N. N. Chemical exchange saturation transfer (CEST): What is in a name and what isn't? Magnetic Resonance in Medicine 65, 927\u2013948 (2011). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/mrm.22761","journal-title":"Magnetic Resonance in Medicine"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"14883","DOI":"10.1074\/jbc.271.25.14883","article-title":"Cloning and Functional Characterization of a System ASC-like Na+-dependent Neutral Amino Acid Transporter*","volume":"271","author":"Utsunomiya-Tate N","year":"1996","unstructured":"Utsunomiya-Tate, N., Endou, H. & Kanai, Y. Cloning and Functional Characterization of a System ASC-like Na+-dependent Neutral Amino Acid Transporter*. Journal of Biological Chemistry 271, 14883\u201314890 (1996). https:\/\/doi.org:https:\/\/doi.org\/10.1074\/jbc.271.25.14883","journal-title":"Journal of Biological Chemistry"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/S0005-2736(01)00384-4","article-title":"Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines","volume":"1514","author":"Yanagida O","year":"2001","unstructured":"Yanagida, O. et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochimica et Biophysica Acta (BBA) - Biomembranes 1514, 291\u2013302 (2001). https:\/\/doi.org:https:\/\/doi.org\/10.1016\/S0005-2736(01)00384-4","journal-title":"Biochimica et Biophysica Acta (BBA) - Biomembranes"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/jlcr.3584","article-title":"Synthesis and biological properties of radiohalogenated \u03b1,\u03b1-disubstituted amino acids for PET and SPECT imaging of amino acid transporters (AATs)","volume":"61","author":"Goodman MM","year":"2018","unstructured":"Goodman, M. M., Yu, W. & Jarkas, N. Synthesis and biological properties of radiohalogenated \u03b1,\u03b1-disubstituted amino acids for PET and SPECT imaging of amino acid transporters (AATs). Journal of Labelled Compounds and Radiopharmaceuticals 61, 272\u2013290 (2018). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/jlcr.3584","journal-title":"Journal of Labelled Compounds and Radiopharmaceuticals"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/134.6.1633S","article-title":"The Nature of Human Hazards Associated with Excessive Intake of Amino Acids","volume":"134","author":"Garlick PJ","year":"2004","unstructured":"Garlick, P. J. The Nature of Human Hazards Associated with Excessive Intake of Amino Acids. The Journal of Nutrition 134, 1633S-1639S (2004). https:\/\/doi.org:10.1093\/jn\/134.6.1633S","journal-title":"The Journal of Nutrition"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"21315","DOI":"10.1038\/s41598-020-78353-8","article-title":"Saturation transfer properties of tumour xenografts derived from prostate cancer cell lines 22Rv1 and DU145","volume":"10","author":"Tan Z","year":"2020","unstructured":"Tan, Z. et al. Saturation transfer properties of tumour xenografts derived from prostate cancer cell lines 22Rv1 and DU145. Scientific Reports 10, 21315 (2020). https:\/\/doi.org:10.1038\/s41598-020-78353-8","journal-title":"Scientific Reports"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1186\/s12885-018-4905-5","article-title":"The bone microenvironment promotes tumor growth and tissue perfusion compared with striated muscle in a preclinical model of prostate cancer in vivo","volume":"18","author":"Mussawy H","year":"2018","unstructured":"Mussawy, H. et al. The bone microenvironment promotes tumor growth and tissue perfusion compared with striated muscle in a preclinical model of prostate cancer in vivo. BMC Cancer 18, 979 (2018). https:\/\/doi.org:10.1186\/s12885-018-4905-5","journal-title":"BMC Cancer"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1089\/hum.2005.16.699","article-title":"Long-Term Maspin Expression Efficiently Suppresses Tumor Growth","volume":"16","author":"Adeno-Associated Virus 2-Mediated Intratumoral Prostate Cancer Gene Therapy","year":"2005","unstructured":"Adeno-Associated Virus 2-Mediated Intratumoral Prostate Cancer Gene Therapy: Long-Term Maspin Expression Efficiently Suppresses Tumor Growth. Human Gene Therapy 16, 699\u2013710 (2005). https:\/\/doi.org:10.1089\/hum.2005.16.699","journal-title":"Human Gene Therapy"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s12894-020-00617-2","article-title":"miR-185 inhibits prostate cancer angiogenesis induced by the nodal\/ALK4 pathway","volume":"20","author":"Li Y","year":"2020","unstructured":"Li, Y., Zhong, W., Zhu, M., Li, M. & Yang, Z. miR-185 inhibits prostate cancer angiogenesis induced by the nodal\/ALK4 pathway. BMC Urology 20, 49 (2020). https:\/\/doi.org:10.1186\/s12894-020-00617-2","journal-title":"BMC Urology"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1002\/pros.21240","article-title":"Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1)","volume":"71","author":"Kai L","year":"2011","unstructured":"Kai, L. et al. Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1). The Prostate 71, 268\u2013280 (2011). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/pros.21240","journal-title":"The Prostate"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41467-017-02444-w","article-title":"Structural characterisation reveals insights into substrate recognition by the glutamine transporter ASCT2\/SLC1A5","volume":"9","author":"Scopelliti AJ","year":"2018","unstructured":"Scopelliti, A. J., Font, J., Vandenberg, R. J., Boudker, O. & Ryan, R. M. Structural characterisation reveals insights into substrate recognition by the glutamine transporter ASCT2\/SLC1A5. Nature Communications 9, 38 (2018). https:\/\/doi.org:10.1038\/s41467-017-02444-w","journal-title":"Nature Communications"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"22790","DOI":"10.1074\/jbc.M002965200","article-title":"A Novel System A Isoform Mediating Na\u2009<\u2009sup>+\/Neutral Amino Acid Cotransport *","volume":"275","author":"Yao D","year":"2000","unstructured":"Yao, D. et al. A Novel System A Isoform Mediating Na\u2009<\u2009sup>+\/Neutral Amino Acid Cotransport *. Journal of Biological Chemistry 275, 22790\u201322797 (2000). https:\/\/doi.org:10.1074\/jbc.M002965200","journal-title":"Journal of Biological Chemistry"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e0156551","DOI":"10.1371\/journal.pone.0156551","article-title":"D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1\/SLC1A4 and ASCT2\/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures","volume":"11","author":"Foster AC","year":"2016","unstructured":"Foster, A. C. et al. D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1\/SLC1A4 and ASCT2\/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. PLOS ONE 11, e0156551 (2016). https:\/\/doi.org:10.1371\/journal.pone.0156551","journal-title":"PLOS ONE"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/s41416-019-0620-5","article-title":"New aspects of amino acid metabolism in cancer","volume":"122","author":"Vettore L","year":"2020","unstructured":"Vettore, L., Westbrook, R. L. & Tennant, D. A. New aspects of amino acid metabolism in cancer. British Journal of Cancer 122, 150\u2013156 (2020). https:\/\/doi.org:10.1038\/s41416-019-0620-5","journal-title":"British Journal of Cancer"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1016\/0026-0495(74)90031-6","article-title":"The intravenous L-alanine tolerance test as a means for investigating gluconeogenesis","volume":"23","author":"Fernandes J","year":"1974","unstructured":"Fernandes, J. & Blom, W. The intravenous L-alanine tolerance test as a means for investigating gluconeogenesis. Metabolism - Clinical and Experimental 23, 1149\u20131156 (1974). https:\/\/doi.org:10.1016\/0026-0495(74)90031-6","journal-title":"Metabolism - Clinical and Experimental"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1021\/acs.molpharmaceut.7b00884","article-title":"18F-Alanine Derivative Serves as an ASCT2 Marker for Cancer Imaging","volume":"15","author":"Liu H","year":"2018","unstructured":"Liu, H. et al. 18F-Alanine Derivative Serves as an ASCT2 Marker for Cancer Imaging. Molecular Pharmaceutics 15, 947\u2013954 (2018). https:\/\/doi.org:10.1021\/acs.molpharmaceut.7b00884","journal-title":"Molecular Pharmaceutics"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/S0026-0495(99)90229-9","article-title":"Splanchnic utilization of enteral alanine in humans","volume":"48","author":"Battezzati A","year":"1999","unstructured":"Battezzati, A., Haisch, M., Brillon, D. J. & Matthews, D. E. Splanchnic utilization of enteral alanine in humans. Metabolism - Clinical and Experimental 48, 915\u2013921 (1999). https:\/\/doi.org:10.1016\/S0026-0495(99)90229-9","journal-title":"Metabolism - Clinical and Experimental"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"13975","DOI":"10.1038\/ncomms13975","article-title":"Transportable hyperpolarized metabolites","volume":"8","author":"Ji X","year":"2017","unstructured":"Ji, X. et al. Transportable hyperpolarized metabolites. Nature Communications 8, 13975 (2017). https:\/\/doi.org:10.1038\/ncomms13975","journal-title":"Nature Communications"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.mri.2022.08.015","article-title":"MRI measurement of alanine uptake in a mouse xenograft model of U-87 MG glioblastoma","volume":"93","author":"Yang S-H","year":"2022","unstructured":"Yang, S.-H. et al. MRI measurement of alanine uptake in a mouse xenograft model of U-87 MG glioblastoma. Magnetic Resonance Imaging 93, 189\u2013194 (2022). https:\/\/doi.org:https:\/\/doi.org\/10.1016\/j.mri.2022.08.015","journal-title":"Magnetic Resonance Imaging"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s13402-020-00575-9","article-title":"Glutaminolysis is a metabolic route essential for survival and growth of prostate cancer cells and a target of 5\u03b1-dihydrotestosterone regulation","volume":"44","author":"Cardoso HJ","year":"2021","unstructured":"Cardoso, H. J. et al. Glutaminolysis is a metabolic route essential for survival and growth of prostate cancer cells and a target of 5\u03b1-dihydrotestosterone regulation. Cellular Oncology 44, 385\u2013403 (2021). https:\/\/doi.org:10.1007\/s13402-020-00575-9","journal-title":"Cellular Oncology"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s44303-025-00100-3","article-title":"Imaging the uptake and metabolism of glutamine in prostate tumor models using CEST MRI","volume":"3","author":"Hodo Y","year":"2025","unstructured":"Hodo, Y. et al. Imaging the uptake and metabolism of glutamine in prostate tumor models using CEST MRI. npj Imaging 3, 34 (2025). https:\/\/doi.org:10.1038\/s44303-025-00100-3","journal-title":"npj Imaging"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1007\/s11307-014-0756-x","article-title":"Accumulation of Trans-1-Amino-3-[18F]Fluorocyclobutanecarboxylic Acid in Prostate Cancer due to Androgen-Induced Expression of Amino Acid Transporters","volume":"16","author":"Okudaira H","year":"2014","unstructured":"Okudaira, H. et al. Accumulation of Trans-1-Amino-3-[18F]Fluorocyclobutanecarboxylic Acid in Prostate Cancer due to Androgen-Induced Expression of Amino Acid Transporters. Molecular Imaging and Biology 16, 756\u2013764 (2014). https:\/\/doi.org:10.1007\/s11307-014-0756-x","journal-title":"Molecular Imaging and Biology"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.nucmedbio.2011.06.008","article-title":"Transport mechanisms of trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid in prostate cancer cells","volume":"39","author":"Oka S","year":"2012","unstructured":"Oka, S. et al. Transport mechanisms of trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid in prostate cancer cells. Nuclear Medicine and Biology 39, 109\u2013119 (2012). https:\/\/doi.org:doi.org\/10.1016\/j.nucmedbio.2011.06.008","journal-title":"Nuclear Medicine and Biology"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.ejphar.2018.07.007","article-title":"The role of ASCT2 in cancer: A review","volume":"837","author":"Liu Y","year":"2018","unstructured":"Liu, Y. et al. The role of ASCT2 in cancer: A review. European Journal of Pharmacology 837, 81\u201387 (2018). https:\/\/doi.org:doi.org\/10.1016\/j.ejphar.2018.07.007","journal-title":"European Journal of Pharmacology"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1002\/mrm.26752","article-title":"CEST MRI of 3-O-methyl-D-glucose on different breast cancer models","volume":"79","author":"Rivlin M","year":"2018","unstructured":"Rivlin, M. & Navon, G. CEST MRI of 3-O-methyl-D-glucose on different breast cancer models. Magnetic Resonance in Medicine 79, 1061\u20131069 (2018). https:\/\/doi.org:doi.org\/10.1002\/mrm.26752","journal-title":"Magnetic Resonance in Medicine"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e4602","DOI":"10.1002\/nbm.4602","article-title":"In vitro and in vivo comparison of MRI chemical exchange saturation transfer (CEST) properties between native glucose and 3-O-Methyl-D-glucose in a murine tumor model","volume":"34","author":"Anemone A","year":"2021","unstructured":"Anemone, A. et al. In vitro and in vivo comparison of MRI chemical exchange saturation transfer (CEST) properties between native glucose and 3-O-Methyl-D-glucose in a murine tumor model. NMR in Biomedicine 34, e4602 (2021). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/nbm.4602","journal-title":"NMR in Biomedicine"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.1038\/srep03045","article-title":"Molecular imaging of tumors and metastases using chemical exchange saturation transfer (CEST) MRI","volume":"3","author":"Rivlin M","year":"2013","unstructured":"Rivlin, M., Horev, J., Tsarfaty, I. & Navon, G. Molecular imaging of tumors and metastases using chemical exchange saturation transfer (CEST) MRI. Scientific Reports 3, 3045 (2013). https:\/\/doi.org:10.1038\/srep03045","journal-title":"Scientific Reports"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1038\/nm.3252","article-title":"In vivo imaging of glucose uptake and metabolism in tumors","volume":"19","author":"Walker-Samuel S","year":"2013","unstructured":"Walker-Samuel, S. et al. In vivo imaging of glucose uptake and metabolism in tumors. Nature Medicine 19, 1067\u20131072 (2013). https:\/\/doi.org:10.1038\/nm.3252","journal-title":"Nature Medicine"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1038\/jcbfm.2013.79","article-title":"Imaging Brain Deoxyglucose Uptake and Metabolism by Glucocest MRI","volume":"33","author":"Nasrallah FA","year":"2013","unstructured":"Nasrallah, F. A., Pag\u00e8s, G., Kuchel, P. W., Golay, X. & Chuang, K.-H. Imaging Brain Deoxyglucose Uptake and Metabolism by Glucocest MRI. Journal of Cerebral Blood Flow & Metabolism 33, 1270\u20131278 (2013). https:\/\/doi.org:10.1038\/jcbfm.2013.79","journal-title":"Journal of Cerebral Blood Flow & Metabolism"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e4784","DOI":"10.1002\/nbm.4784","article-title":"Y. Imaging of sugar-based contrast agents using their hydroxyl proton exchange properties","author":"Knutsson L","unstructured":"Knutsson, L., Xu, X., van Zijl, P. C. M. & Chan, K. W. Y. Imaging of sugar-based contrast agents using their hydroxyl proton exchange properties. NMR in Biomedicine n\/a, e4784 https:\/\/doi.org:https:\/\/doi.org\/10.1002\/nbm.4784","journal-title":"NMR in Biomedicine n\/a"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"101736","DOI":"10.1016\/j.nicl.2019.101736","article-title":"pH-weighted molecular MRI in human traumatic brain injury (TBI) using amine proton chemical exchange saturation transfer echoplanar imaging (CEST EPI)","volume":"22","author":"Ellingson BM","year":"2019","unstructured":"Ellingson, B. M. et al. pH-weighted molecular MRI in human traumatic brain injury (TBI) using amine proton chemical exchange saturation transfer echoplanar imaging (CEST EPI). NeuroImage: Clinical 22, 101736 (2019). https:\/\/doi.org:https:\/\/doi.org\/10.1016\/j.nicl.2019.101736","journal-title":"NeuroImage: Clinical"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1093\/neuonc\/nov106","article-title":"pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI","volume":"17","author":"Harris RJ","year":"2015","unstructured":"Harris, R. J. et al. pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI. Neuro-Oncology 17, 1514\u20131524 (2015). https:\/\/doi.org:10.1093\/neuonc\/nov106","journal-title":"Neuro-Oncology"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1002\/nbm.3416","article-title":"Investigating GluCEST and its specificity for pH mapping at low temperatures","volume":"28","author":"Wermter FC","year":"2015","unstructured":"Wermter, F. C., Bock, C. & Dreher, W. Investigating GluCEST and its specificity for pH mapping at low temperatures. NMR in Biomedicine 28, 1507\u20131517 (2015). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/nbm.3416","journal-title":"NMR in Biomedicine"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1002\/mrm.28481","article-title":"Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast","volume":"85","author":"Yao J","year":"2021","unstructured":"Yao, J., Wang, C. & Ellingson, B. M. Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast. Magnetic Resonance in Medicine 85, 1062\u20131078 (2021). https:\/\/doi.org:doi.org\/10.1002\/mrm.28481","journal-title":"Magnetic Resonance in Medicine"},{"key":"ref49","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.4785","author":"Cho NS","year":"2023","unstructured":"Cho, N. S. et al. Amine-weighted chemical exchange saturation transfer magnetic resonance imaging in brain tumors. NMR in Biomedicine 36, e4785 (2023). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/nbm.4785"},{"key":"ref50","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00763","article-title":"Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death","volume":"8","author":"Lee Z-W","year":"2017","unstructured":"Lee, Z.-W. et al. Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death. Frontiers in Pharmacology 8 (2017). https:\/\/doi.org:10.3389\/fphar.2017.00763","journal-title":"Frontiers in Pharmacology"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"5289","DOI":"10.1039\/D0AN00865F","article-title":"A new class of ratiometric small molecule intracellular pH sensors for Raman microscopy","volume":"145","author":"Wilson LT","year":"2020","unstructured":"Wilson, L. T. et al. A new class of ratiometric small molecule intracellular pH sensors for Raman microscopy. Analyst 145, 5289\u20135298 (2020). https:\/\/doi.org:10.1039\/D0AN00865F","journal-title":"Analyst"},{"key":"ref52","first-page":"6167","article-title":"The role of calcium, pH, and cell proliferation in the programmed (apoptotic) death of androgen-independent prostatic cancer cells induced by thapsigargin","volume":"54","author":"Furuya Y","year":"1994","unstructured":"Furuya, Y., Lundmo, P., Short, A. D., Gill, D. L. & Isaacs, J. T. The role of calcium, pH, and cell proliferation in the programmed (apoptotic) death of androgen-independent prostatic cancer cells induced by thapsigargin. Cancer Res 54, 6167\u20136175 (1994).","journal-title":"Cancer Res"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"4510","DOI":"10.1158\/0008-5472.Can-08-3781","article-title":"A Novel Technology for the Imaging of Acidic Prostate Tumors by Positron Emission Tomography","volume":"69","author":"V\u0101vere AL","year":"2009","unstructured":"V\u0101vere, A. L. et al. A Novel Technology for the Imaging of Acidic Prostate Tumors by Positron Emission Tomography. Cancer Research 69, 4510\u20134516 (2009). https:\/\/doi.org:10.1158\/0008-5472.Can-08-3781","journal-title":"Cancer Research"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.juro.2012.03.113","article-title":"Systemic Buffers Inhibit Carcinogenesis in TRAMP Mice","volume":"188","author":"Ibrahim-Hashim A","year":"2012","unstructured":"Ibrahim-Hashim, A. et al. Systemic Buffers Inhibit Carcinogenesis in TRAMP Mice. Journal of Urology 188, 624\u2013631 (2012). https:\/\/doi.org:doi:10.1016\/j.juro.2012.03.113","journal-title":"Journal of Urology"},{"key":"ref55","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27225","article-title":"Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer","volume":"10","author":"Korenchan DE","year":"2019","unstructured":"Korenchan, D. E. et al. Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer. Oncotarget 10 (2019). https:\/\/doi.org:10.18632\/oncotarget.27225","journal-title":"Oncotarget"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1007\/s00066-003-1066-4","article-title":"Tumor Volume and Tumor Hypoxia in Head andNeck Cancers","volume":"179","author":"Dunst J","year":"2003","unstructured":"Dunst, J. et al. Tumor Volume and Tumor Hypoxia in Head andNeck Cancers. Strahlentherapie und Onkologie 179, 521\u2013526 (2003). https:\/\/doi.org:10.1007\/s00066-003-1066-4","journal-title":"Strahlentherapie und Onkologie"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s12967-017-1347-9","article-title":"Vascular abnormalities and development of hypoxia in microscopic melanoma xenografts","volume":"15","author":"Gaustad J-V","year":"2017","unstructured":"Gaustad, J.-V., Simonsen, T. G., Andersen, L. M. K. & Rofstad, E. K. Vascular abnormalities and development of hypoxia in microscopic melanoma xenografts. Journal of Translational Medicine 15, 241 (2017). https:\/\/doi.org:10.1186\/s12967-017-1347-9","journal-title":"Journal of Translational Medicine"},{"key":"ref58","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/4952372","author":"Kis A","year":"2020","unstructured":"Kis, A. et al. <i\u2009>\u2009In Vivo<\/i\u2009>\u2009Imaging of Hypoxia and Neoangiogenesis in Experimental Syngeneic Hepatocellular Carcinoma Tumor Model Using Positron Emission Tomography. BioMed Research International 2020, 4952372 (2020). https:\/\/doi.org:10.1155\/2020\/4952372"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"e0206706","DOI":"10.1371\/journal.pone.0206706","article-title":"Changes in hypoxia level of CT26 tumors during various stages of development and comparing different methods of hypoxia determination","volume":"13","author":"Kiraga \u0141","year":"2018","unstructured":"Kiraga, \u0141. et al. Changes in hypoxia level of CT26 tumors during various stages of development and comparing different methods of hypoxia determination. PLOS ONE 13, e0206706 (2018). https:\/\/doi.org:10.1371\/journal.pone.0206706","journal-title":"PLOS ONE"},{"key":"ref60","first-page":"6449","article-title":"Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review1","volume":"49","author":"Vaupel P","year":"1989","unstructured":"Vaupel, P., Kallinowski, F. & Okunieff, P. Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review1. Cancer Research 49, 6449\u20136465 (1989).","journal-title":"Cancer Research"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.cmet.2019.11.020","article-title":"A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells","volume":"31","author":"Yoo HC","year":"2020","unstructured":"Yoo, H. C. et al. A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. Cell Metabolism 31, 267\u2013283.e212 (2020). https:\/\/doi.org:https:\/\/doi.org\/10.1016\/j.cmet.2019.11.020","journal-title":"Cell Metabolism"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1042\/bj20040487","article-title":"Glutamine availability up-regulates expression of the amino acid transporter protein ASCT2 in HepG2 cells and stimulates the ASCT2 promoter","volume":"382","author":"BUNGARD, Claire I","year":"2004","unstructured":"BUNGARD, Claire I. & McGIVAN, John D. Glutamine availability up-regulates expression of the amino acid transporter protein ASCT2 in HepG2 cells and stimulates the ASCT2 promoter. Biochemical Journal 382, 27\u201332 (2004). https:\/\/doi.org:10.1042\/bj20040487","journal-title":"Biochemical Journal"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"15347354211045349","DOI":"10.1177\/15347354211045349","article-title":"Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer","volume":"20","author":"Ma H","year":"2021","unstructured":"Ma, H. et al. Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer. Integrative Cancer Therapies 20, 15347354211045349 (2021). https:\/\/doi.org:10.1177\/15347354211045349","journal-title":"Integrative Cancer Therapies"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1016\/0026-0495(94)90030-2","article-title":"The effect of dipeptide structure on dipeptide and amino acid clearance in rats","volume":"43","author":"Kee AJ","year":"1994","unstructured":"Kee, A. J., Smith, R. C., Gross, A. S., Madsen, D. C. & Rowe, B. The effect of dipeptide structure on dipeptide and amino acid clearance in rats. Metabolism 43, 1373\u20131378 (1994). https:\/\/doi.org:doi: 10.1016\/0026-0495(94)90030-2","journal-title":"Metabolism"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"F590-F596","DOI":"10.1152\/ajprenal.00324.2003","article-title":"Serial determination of glomerular filtration rate in conscious mice using FITC-inulin clearance","volume":"286","author":"Qi Z","year":"2004","unstructured":"Qi, Z. et al. Serial determination of glomerular filtration rate in conscious mice using FITC-inulin clearance. American Journal of Physiology-Renal Physiology 286, F590-F596 (2004). https:\/\/doi.org:10.1152\/ajprenal.00324.2003","journal-title":"American Journal of Physiology-Renal Physiology"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.neuroscience.2021.01.026","article-title":"Brain pH Imaging and its Applications","volume":"474","author":"Kim H","year":"2021","unstructured":"Kim, H., Krishnamurthy, L. C. & Sun, P. Z. Brain pH Imaging and its Applications. Neuroscience 474, 51\u201362 (2021). https:\/\/doi.org:doi.org\/10.1016\/j.neuroscience.2021.01.026","journal-title":"Neuroscience"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1126\/science.1164368","article-title":"Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses","volume":"321","author":"Jones S","year":"2008","unstructured":"Jones, S. et al. Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses. Science 321, 1801\u20131806 (2008). https:\/\/doi.org:doi:10.1126\/science.1164368","journal-title":"Science"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"4972","DOI":"10.1038\/s41467-018-07411-7","article-title":"Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen\/AR-targeted therapy","volume":"9","author":"Geng H","year":"2018","unstructured":"Geng, H. et al. Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen\/AR-targeted therapy. Nature Communications 9, 4972 (2018). https:\/\/doi.org:10.1038\/s41467-018-07411-7","journal-title":"Nature Communications"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"e96250","DOI":"10.1371\/journal.pone.0096250","article-title":"Distinct Phenotypes of Human Prostate Cancer Cells Associate with Different Adaptation to Hypoxia and Pro-Inflammatory Gene Expression","volume":"9","author":"Ravenna L","year":"2014","unstructured":"Ravenna, L. et al. Distinct Phenotypes of Human Prostate Cancer Cells Associate with Different Adaptation to Hypoxia and Pro-Inflammatory Gene Expression. PLOS ONE 9, e96250 (2014). https:\/\/doi.org:10.1371\/journal.pone.0096250","journal-title":"PLOS ONE"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"e29170","DOI":"10.1371\/journal.pone.0029170","article-title":"Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties","volume":"6","author":"Ma Y","year":"2011","unstructured":"Ma, Y. et al. Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties. PLOS ONE 6, e29170 (2011). https:\/\/doi.org:10.1371\/journal.pone.0029170","journal-title":"PLOS ONE"},{"key":"ref71","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116245","author":"Thomas AM","year":"2020","unstructured":"Thomas, A. M., Xu, J., Calabresi, P. A., van Zijl, P. C. M. & Bulte, J. W. M. Monitoring diffuse injury during disease progression in experimental autoimmune encephalomyelitis with on resonance variable delay multiple pulse (onVDMP) CEST MRI. NeuroImage 204, 116245 (2020). https:\/\/doi.org:doi.org\/10.1016\/j.neuroimage.2019.116245"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1002\/mrm.21873","article-title":"Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments","volume":"61","author":"Kim M","year":"2009","unstructured":"Kim, M., Gillen, J., Landman, B. A., Zhou, J. & van Zijl, P. C. M. Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments. Magnetic Resonance in Medicine 61, 1441\u20131450 (2009). https:\/\/doi.org:https:\/\/doi.org\/10.1002\/mrm.21873","journal-title":"Magnetic Resonance in Medicine"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7367339\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7367339\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T11:59:53Z","timestamp":1761566393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7367339\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,26]]},"references-count":72,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-7367339\/v1","relation":{},"subject":[],"published":{"date-parts":[[2025,10,26]]},"subtype":"preprint"}}