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Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle. Methods: The pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS\/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing. Results: Pioglitazone was associated with a 16.634% lower average O2 consumption (mL\u2219h\u22121, p = 0.035), 16.309% lower average CO2 production (mL\u2219h\u22121, p = 0.022), and 16.4% lower cumulative energy expenditure (EE) (kcal\u2219h\u22121, p = 0.035), with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. K-means cluster 5 showed enrichment of the PPAR signaling pathway (adj. p &lt; 0.05, Log2FC = 2.58). Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. In particular, the overall abundance of total ceramide levels was significantly lower in the PioTx group (\u221246.327%, p = 0.048). Despite molecular support for pioglitazone\u2019s efficacy, isolated muscle function was not affected by pioglitazone treatment. No significant difference in the area under the fatigue curve (AUC) was found between the pioglitazone and vehicle groups (p = 0.596). Conclusions: BC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens.<\/jats:p>","DOI":"10.3390\/cancers16213640","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T04:51:33Z","timestamp":1730177493000},"page":"3640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2\/neu Overexpressing Breast Cancer Xenografts"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6863-4822","authenticated-orcid":false,"given":"Stuart A.","family":"Clayton","sequence":"first","affiliation":[{"name":"Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6461-7024","authenticated-orcid":false,"given":"Alan D.","family":"Mizener","sequence":"additional","affiliation":[{"name":"Cancer Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella A.","family":"Whetsell","sequence":"additional","affiliation":[{"name":"Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3513-655X","authenticated-orcid":false,"given":"Lauren E.","family":"Rentz","sequence":"additional","affiliation":[{"name":"Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9633-7596","authenticated-orcid":false,"given":"Ethan M.","family":"Meadows","sequence":"additional","affiliation":[{"name":"Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-376X","authenticated-orcid":false,"given":"Werner J.","family":"Geldenhuys","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, West Virginia University School of Pharmacy, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emidio E.","family":"Pistilli","sequence":"additional","affiliation":[{"name":"Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA"},{"name":"Cancer Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA"},{"name":"Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3322\/caac.21754","article-title":"Breast Cancer Statistics, 2022","volume":"72","author":"Giaquinto","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","unstructured":"Ahmad, A. (2019). Breast Cancer: Current Perspectives on the Disease Status. Breast Cancer Metastasis and Drug Resistance: Challenges and Progress, Springer International Publishing. Advances in Experimental Medicine and Biology."},{"key":"ref_4","unstructured":"(2024, October 07). SEER*Explorer Application, Available online: https:\/\/seer.cancer.gov\/statistics-network\/explorer\/application.html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jama.2018.19323","article-title":"Breast Cancer Treatment: A Review","volume":"321","author":"Waks","year":"2019","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1200\/JCO.22.00519","article-title":"Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2\u2013Positive Breast Cancer: ASCO Guideline Update","volume":"40","author":"Giordano","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11864-020-0707-5","article-title":"Cancer-Related Fatigue: Causes and Current Treatment Options","volume":"21","author":"Thong","year":"2020","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.jpainsymman.2007.08.012","article-title":"Fatigue and Depression in Disease-Free Breast Cancer Survivors: Prevalence, Correlates, and Association with Quality of Life","volume":"35","author":"Kim","year":"2008","journal-title":"J. Pain Symptom Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"693458","DOI":"10.1155\/2009\/693458","article-title":"Estimation of Cachexia among Cancer Patients Based on Four Definitions","volume":"2009","author":"Fox","year":"2009","journal-title":"J. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10549-006-9447-x","article-title":"Psychological Distress and Fatigue Predicted Recurrence and Survival in Primary Breast Cancer Patients","volume":"105","author":"Groenvold","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ceb.2014.11.002","article-title":"PPARs and ERRs: Molecular Mediators of Mitochondrial Metabolism","volume":"33","author":"Fan","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15924","DOI":"10.1073\/pnas.0306981100","article-title":"Activation of Peroxisome Proliferator-Activated Receptor \u03b4 Induces Fatty Acid \u03b2-Oxidation in Skeletal Muscle and Attenuates Metabolic Syndrome","volume":"100","author":"Tanaka","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0092-8674(03)00269-1","article-title":"Peroxisome-Proliferator-Activated Receptor \u03b4 Activates Fat Metabolism to Prevent Obesity","volume":"113","author":"Wang","year":"2003","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0163-7827(01)00005-4","article-title":"The Roles of PPARs in Adipocyte Differentiation","volume":"40","author":"Grimaldi","year":"2001","journal-title":"Prog. Lipid Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/0959-437X(95)80025-5","article-title":"Regulation of Adipocyte Gene Expression and Differentiation by Peroxisome Proliferator Activated Receptor \u03b3","volume":"5","author":"Tontonoz","year":"1995","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.2337\/diabetes.53.2007.S60","article-title":"Role of Peroxisome Proliferator-Activated Receptor-\u03b3 in the Glucose-Sensing Apparatus of Liver and \u03b2-Cells","volume":"53","author":"Kim","year":"2004","journal-title":"Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1158\/1078-0432.CCR-18-1565","article-title":"Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator\u2013Activated Receptor Signaling as Driver of Cancer-Induced Muscle Fatigue","volume":"25","author":"Wilson","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/rco2.69","article-title":"Rescue of a Peroxisome Proliferator Activated Receptor Gamma Gene Network in Muscle after Growth of Human Breast Tumour Xenografts","volume":"5","author":"Stanton","year":"2022","journal-title":"JCSM Rapid Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"C577","DOI":"10.1152\/ajpcell.00264.2020","article-title":"Breast Cancer-Associated Skeletal Muscle Mitochondrial Dysfunction and Lipid Accumulation Is Reversed by PPARG","volume":"320","author":"Wilson","year":"2021","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s13539-011-0030-x","article-title":"Intramyocellular Lipid Droplets Increase with Progression of Cachexia in Cancer Patients","volume":"2","author":"Stephens","year":"2011","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/25931","article-title":"Ligand Binding and Co-Activator Assembly of the Peroxisome Proliferator-Activated Receptor-\u03b3","volume":"395","author":"Nolte","year":"1998","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7921","DOI":"10.1073\/pnas.92.17.7921","article-title":"Structural Organization of Mouse Peroxisome Proliferator-Activated Receptor Gamma (mPPAR Gamma) Gene: Alternative Promoter Use and Different Splicing Yield Two mPPAR Gamma Isoforms","volume":"92","author":"Zhu","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18779","DOI":"10.1074\/jbc.272.30.18779","article-title":"The Organization, Promoter Analysis, and Expression of the Human PPAR\u03b3 Gene","volume":"272","author":"Fajas","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.2165\/11538100-000000000-00000","article-title":"Efficacy and Tolerability of Pioglitazone in Patients with Type 2 Diabetes Mellitus","volume":"70","author":"Derosa","year":"2010","journal-title":"Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-Based Genome Alignment and Genotyping with HISAT2 and HISAT-Genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An Efficient General Purpose Program for Assigning Sequence Reads to Genomic Features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ge, S.X., Son, E.W., and Yao, R. (2018). iDEP: An Integrated Web Application for Differential Expression and Pathway Analysis of RNA-Seq Data. BMC Bioinform., 19.","DOI":"10.1186\/s12859-018-2486-6"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Luo, W., Friedman, M.S., Shedden, K., Hankenson, K.D., and Woolf, P.J. (2009). GAGE: Generally Applicable Gene Set Enrichment for Pathway Analysis. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-161"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1093\/bioinformatics\/bty528","article-title":"MetaboAnalystR: An R Package for Flexible and Reproducible Analysis of Metabolomics Data","volume":"34","author":"Chong","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_32","unstructured":"Clayton, S.A., Mizener, A.D., Rentz, L.E., and Pistilli, E. (2024). CLAMS Wrangler: A Python Program for Preprocessing Data Generated by the Comprehensive Laboratory Animal Monitoring System (v1.0.5), Zenodo."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cmet.2018.06.019","article-title":"CalR: A Web-Based Analysis Tool for Indirect Calorimetry Experiments","volume":"28","author":"Mina","year":"2018","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41523-020-0162-2","article-title":"Skeletal Muscle Reprogramming by Breast Cancer Regardless of Treatment History or Tumor Molecular Subtype","volume":"6","author":"Wilson","year":"2020","journal-title":"NPJ Breast Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1172\/JCI44945","article-title":"Loss of IL-15 Receptor \u03b1 Alters the Endurance, Fatigability, and Metabolic Characteristics of Mouse Fast Skeletal Muscles","volume":"121","author":"Pistilli","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00360-014-0857-5","article-title":"Aging Alters Contractile Properties and Fiber Morphology in Pigeon Skeletal Muscle","volume":"184","author":"Pistilli","year":"2014","journal-title":"J. Comp. Physiol. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1113\/jphysiol.1988.sp017279","article-title":"Contractile Properties of Skeletal Muscles from Young, Adult and Aged Mice","volume":"404","author":"Brooks","year":"1988","journal-title":"J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/j.1469-7793.2001.00591.x","article-title":"Force and Power Output of Fast and Slow Skeletal Muscles from Mdx Mice 6-28 Months Old","volume":"535","author":"Lynch","year":"2001","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"C704","DOI":"10.1152\/ajpcell.00122.2021","article-title":"Dystrophin-Negative Slow-Twitch Soleus Muscles Are Not Susceptible to Eccentric Contraction Induced Injury over the Lifespan of the Mdx Mouse","volume":"321","author":"Kiriaev","year":"2021","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.metabol.2004.07.008","article-title":"Effect of Pioglitazone on Body Composition and Energy Expenditure: A Randomized Controlled Trial","volume":"54","author":"Smith","year":"2005","journal-title":"Metab. Clin. Exp."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.2337\/db12-0428","article-title":"Pioglitazone Acutely Reduces Energy Metabolism and Insulin Secretion in Rats","volume":"62","author":"Lamontagne","year":"2013","journal-title":"Diabetes"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.ejphar.2014.06.008","article-title":"Pioglitazone Ameliorates the Lowered Exercise Capacity and Impaired Mitochondrial Function of the Skeletal Muscle in Type 2 Diabetic Mice","volume":"740","author":"Takada","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/jdi.12606","article-title":"Pioglitazone Improves Whole-Body Aerobic Capacity and Skeletal Muscle Energy Metabolism in Patients with Metabolic Syndrome","volume":"8","author":"Yokota","year":"2017","journal-title":"J. Diabetes Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"154416","DOI":"10.1016\/j.metabol.2020.154416","article-title":"Pioglitazone Corrects Dysregulation of Skeletal Muscle Mitochondrial Proteins Involved in ATP Synthesis in Type 2 Diabetes","volume":"114","author":"Fiorentino","year":"2021","journal-title":"Metabolism"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1074\/mcp.M112.021162","article-title":"Metabolic Labeling Reveals Proteome Dynamics of Mouse Mitochondria","volume":"11","author":"Kim","year":"2012","journal-title":"Mol. Cell. Proteom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1002\/jcsm.12626","article-title":"High Levels of Modified Ceramides Are a Defining Feature of Murine and Human Cancer Cachexia","volume":"11","author":"Morigny","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.2337\/diabetes.53.5.1215","article-title":"Relationship between Insulin Sensitivity and Sphingomyelin Signaling Pathway in Human Skeletal Muscle","volume":"53","author":"Straczkowski","year":"2004","journal-title":"Diabetes"},{"key":"ref_48","first-page":"101","article-title":"Effects of Pioglitazone and High-Fat Diet on Ceramide Metabolism in Rat Skeletal Muscles","volume":"57","author":"Baranowski","year":"2006","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.abb.2003.08.020","article-title":"Characterizing the Effects of Saturated Fatty Acids on Insulin Signaling and Ceramide and Diacylglycerol Accumulation in 3T3-L1 Adipocytes and C2C12 Myotubes","volume":"419","author":"Chavez","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1203\/00006450-198901000-00010","article-title":"Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice","volume":"25","author":"Wood","year":"1989","journal-title":"Pediatr. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1113\/jphysiol.1974.sp010540","article-title":"Motor Units in Cat Soleus Muscle: Physiological, Histochemical and Morphological Characteristics","volume":"238","author":"Burke","year":"1974","journal-title":"J. Physiol."},{"key":"ref_52","unstructured":"Whyte, G., Spurway, N., MacLaren, D., and Cracknell, J. (2006). Chapter 5\u2014The Physiology of Anaerobic Endurance Training. The Physiology of Training, Churchill Livingstone."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"905612","DOI":"10.1155\/2010\/905612","article-title":"Interaction among Skeletal Muscle Metabolic Energy Systems during Intense Exercise","volume":"2010","author":"Baker","year":"2010","journal-title":"J. Nutr. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/jcsm.12294","article-title":"Dysregulation of Metabolic-associated Pathways in Muscle of Breast Cancer Patients: Preclinical Evaluation of Interleukin-15 Targeting Fatigue","volume":"9","author":"Bohlen","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A Simple Practice Guide for Dose Conversion between Animals and Human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.mito.2015.10.004","article-title":"IL-15R\u03b1 Deficiency in Skeletal Muscle Alters Respiratory Function and the Proteome of Mitochondrial Subpopulations Independent of Changes to the Mitochondrial Genome","volume":"25","author":"Nichols","year":"2015","journal-title":"Mitochondrion"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e003388","DOI":"10.1136\/jitc-2021-003388","article-title":"Phase I Study of Single Agent NIZ985, a Recombinant Heterodimeric IL-15 Agonist, in Adult Patients with Metastatic or Unresectable Solid Tumors","volume":"9","author":"Conlon","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e007725","DOI":"10.1136\/jitc-2023-007725","article-title":"First-in-Human Phase I\/Ib Study of NIZ985, a Recombinant Heterodimer of IL-15 and IL-15R\u03b1, as a Single Agent and in Combination with Spartalizumab in Patients with Advanced and Metastatic Solid Tumors","volume":"11","author":"Leidner","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Lee, M.A., Tan, L., Yang, H., Im, Y.-G., and Im, Y.J. (2017). Structures of PPAR\u03b3 Complexed with Lobeglitazone and Pioglitazone Reveal Key Determinants for the Recognition of Antidiabetic Drugs. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17082-x"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/21\/3640\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:22:51Z","timestamp":1760113371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/21\/3640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,29]]},"references-count":59,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["cancers16213640"],"URL":"https:\/\/doi.org\/10.3390\/cancers16213640","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.04.15.589557","asserted-by":"object"}]},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,29]]}}}