{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:29:30Z","timestamp":1790288970894,"version":"4.1.0"},"reference-count":92,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NCI NIH intramural program","doi-asserted-by":"publisher","award":["ZID BC 010990"],"award-info":[{"award-number":["ZID BC 010990"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated survival benefits documented in retrospective and prospective trials, when used in combination with chemo-radiotherapy (CRT). Purpose: The primary goal of this study was to examine if the differential alteration in proteomic expression pre vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA as compared to standard-of-care CRT. The second goal was to explore the associations between the proteomic alterations in response to VPA\/RT\/TMZ correlated to patient outcomes. The third goal was to use the proteomic profile to determine the mechanism of action of VPA in this setting. Materials and Methods: Serum obtained pre- and post-CRT was analyzed using an aptamer-based SOMAScan\u00ae proteomic assay. Twenty-nine patients received CRT plus VPA, and 53 patients received CRT alone. Clinical data were obtained via a database and chart review. Tests for differences in protein expression changes between radiation therapy (RT) with or without VPA were conducted for individual proteins using two-sided t-tests, considering p-values of &lt;0.05 as significant. Adjustment for age, sex, and other clinical covariates and hierarchical clustering of significant differentially expressed proteins was carried out, and Gene Set Enrichment analyses were performed using the Hallmark gene sets. Univariate Cox proportional hazards models were used to test the individual protein expression changes for an association with survival. The lasso Cox regression method and 10-fold cross-validation were employed to test the combinations of expression changes of proteins that could predict survival. Predictiveness curves were plotted for significant proteins for VPA response (p-value &lt; 0.005) to show the survival probability vs. the protein expression percentiles. Results: A total of 124 proteins were identified pre- vs. post-CRT that were differentially expressed between the cohorts who received CRT plus VPA and those who received CRT alone. Clinical factors did not confound the results, and distinct proteomic clustering in the VPA-treated population was identified. Time-dependent ROC curves for OS and PFS for landmark times of 20 months and 6 months, respectively, revealed AUC of 0.531, 0.756, 0.774 for OS and 0.535, 0.723, 0.806 for PFS for protein expression, clinical factors, and the combination of protein expression and clinical factors, respectively, indicating that the proteome can provide additional survival risk discrimination to that already provided by the standard clinical factors with a greater impact on PFS. Several proteins of interest were identified. Alterations in GALNT14 (increased) and CCL17 (decreased) (p = 0.003 and 0.003, respectively, FDR 0.198 for both) were associated with an improvement in both OS and PFS. The pre-CRT protein expression revealed 480 proteins predictive for OS and 212 for PFS (p &lt; 0.05), of which 112 overlapped between OS and PFS. However, FDR-adjusted p values were high, with OS (the smallest p value of 0.586) and PFS (the smallest p value of 0.998). The protein PLCD3 had the lowest p-value (p = 0.002 and 0.0004 for OS and PFS, respectively), and its elevation prior to CRT predicted superior OS and PFS with VPA administration. Cancer hallmark genesets associated with proteomic alteration observed with the administration of VPA aligned with known signal transduction pathways of this agent in malignancy and non-malignancy settings, and GBM signaling, and included epithelial\u2013mesenchymal transition, hedgehog signaling, Il6\/JAK\/STAT3, coagulation, NOTCH, apical junction, xenobiotic metabolism, and complement signaling. Conclusions: Differential alteration in proteomic expression pre- vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA. Using pre- vs. post-data, prognostic proteins emerged in the analysis. Using pre-CRT data, potentially predictive proteins were identified. The protein signals and hallmark gene sets associated with the alteration in the proteome identified between patients who received VPA and those who did not, align with known biological mechanisms of action of VPA and may allow for the identification of novel biomarkers associated with outcomes that can help advance the study of VPA in future prospective trials.<\/jats:p>","DOI":"10.3390\/biom13101499","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T03:24:55Z","timestamp":1696908295000},"page":"1499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma\u2014Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1634-6877","authenticated-orcid":false,"given":"Andra V.","family":"Krauze","sequence":"first","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingdong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Computational and Systems Biology Branch, Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chung","family":"Li","sequence":"additional","affiliation":[{"name":"Computational and Systems Biology Branch, Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Shih","sequence":"additional","affiliation":[{"name":"Computational and Systems Biology Branch, Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Will","family":"Jiang","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6754-2187","authenticated-orcid":false,"given":"Erdal","family":"Tasci","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Cooley Zgela","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Sproull","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Mackey","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Shankavaram","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Tofilon","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Camphausen","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noaa200","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013\u20132017","volume":"22","author":"Ostrom","year":"2020","journal-title":"Neuro-Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/nop\/npz057","article-title":"Radiosensitizers in the temozolomide era for newly diagnosed glioblastoma","volume":"7","author":"Mathen","year":"2020","journal-title":"Neuro-Oncol. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1435","DOI":"10.1038\/cddis.2014.412","article-title":"Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe","volume":"5","author":"Cornago","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3892\/ol.2013.1666","article-title":"Histone deacetylase inhibitor, valproic acid, radiosensitizes the C6 glioma cell line in vitro","volume":"7","author":"Zhou","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"vdz025","DOI":"10.1093\/noajnl\/vdz025","article-title":"Effects of valproic acid on histone deacetylase inhibition in vitro and in glioblastoma patient samples","volume":"1","author":"Berendsen","year":"2019","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1093\/neuonc\/not057","article-title":"Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme","volume":"15","author":"Kerkhof","year":"2013","journal-title":"Neuro-Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"859","DOI":"10.3171\/2012.10.JNS12169","article-title":"Impact of particular antiepileptic drugs on the survival of patients with glioblastoma multiforme","volume":"118","author":"Guthrie","year":"2013","journal-title":"J. Neurosurg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s11060-016-2054-8","article-title":"Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II\/III gliomas treated with temozolomide","volume":"127","author":"Redjal","year":"2016","journal-title":"J. Neuro-Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1212\/WNL.0b013e31822f02e1","article-title":"Prolonged survival with valproic acid use in the EORTC\/NCIC temozolomide trial for glioblastoma","volume":"77","author":"Weller","year":"2011","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.clineuro.2018.09.019","article-title":"The survival effect of valproic acid in glioblastoma and its current trend: A systematic review and meta-analysis","volume":"174","author":"Lu","year":"2018","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e21147","DOI":"10.1097\/MD.0000000000021147","article-title":"Effect of valproic acid on overall survival in patients with high-grade gliomas undergoing temozolomide: A nationwide population-based cohort study in Taiwan","volume":"99","author":"Kuo","year":"2020","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1159\/000526327","article-title":"Administration of Valproic Acid Improves the Survival of Patients with Glioma Treated with Postoperative Radiotherapy","volume":"45","author":"Wang","year":"2022","journal-title":"Oncol. Res. Treat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1192\/pb.27.12.446","article-title":"Sodium valproate or valproate semisodium: Is there a difference in the treatment of bipolar disorder?","volume":"27","author":"Fisher","year":"2003","journal-title":"Psychiatr. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Krauze, A.V., Megan, M., Theresa, C.Z., Peter, M., Shih, J.H., Tofilon, P.J., Rowe, L., Gilbert, M., and Camphausen, K. (2020). The addition of Valproic acid to concurrent radiation therapy and temozolomide improves patient outcome: A Correlative analysis of RTOG 0525, SEER and a Phase II NCI trial. Cancer Stud. Ther., 5.","DOI":"10.31038\/CST.2020511"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1093\/nop\/npy009","article-title":"Late toxicity in long-term survivors from a phase 2 study of concurrent radiation therapy, temozolomide and valproic acid for newly diagnosed glioblastoma","volume":"5","author":"Krauze","year":"2018","journal-title":"Neuro-Oncol. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.ijrobp.2015.04.038","article-title":"A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma","volume":"92","author":"Krauze","year":"2015","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e28283","DOI":"10.1002\/pbc.28283","article-title":"A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma","volume":"67","author":"Su","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.seizure.2014.06.015","article-title":"Survival analysis for valproic acid use in adult glioblastoma multiforme: A meta-analysis of individual patient data and a systematic review","volume":"23","author":"Yuan","year":"2014","journal-title":"Seizure"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"463","DOI":"10.7314\/APJCP.2016.17.2.463","article-title":"Roles of Valproic Acid in Improving Radiation Therapy for Glioblastoma: A Review of Literature Focusing on Clinical Evidence","volume":"17","author":"Ochiai","year":"2016","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"687362","DOI":"10.3389\/fonc.2021.687362","article-title":"Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment","volume":"11","author":"Han","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"186","DOI":"10.2176\/nmc.52.186","article-title":"Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain","volume":"52","author":"Osuka","year":"2012","journal-title":"Neurol. Med.-Chir."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"62989","DOI":"10.18632\/oncotarget.11379","article-title":"Molecular dissection of the valproic acid effects on glioma cells","volume":"7","author":"Hoja","year":"2016","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"963689720981878","DOI":"10.1177\/0963689720981878","article-title":"Valproic Acid Enhanced Apoptosis by Promoting Autophagy Via Akt\/mTOR Signaling in Glioma","volume":"29","author":"Han","year":"2020","journal-title":"Cell Transpl."},{"key":"ref_25","first-page":"4985781","article-title":"Valproic Acid Inhibits Glioma and Its Mechanisms","volume":"2022","author":"Yang","year":"2022","journal-title":"J. Healthc. Eng."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ryu, C.H., Yoon, W.S., Park, K.Y., Kim, S.M., Lim, J.Y., Woo, J.S., Jeong, C.H., Hou, Y., and Jeun, S.S. (2012). Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells. J. Biomed. Biotechnol., 2012.","DOI":"10.1155\/2012\/987495"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"722754","DOI":"10.3389\/fonc.2021.722754","article-title":"Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53-PUMA Apoptosis Pathway","volume":"11","author":"Tsai","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1159\/000447912","article-title":"Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3beta Through ERK\/Akt Signaling","volume":"39","author":"Zhang","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Riva, G., Cilibrasi, C., Bazzoni, R., Cadamuro, M., Negroni, C., Butta, V., Strazzabosco, M., Dalpra, L., Lavitrano, M., and Bentivegna, A. (2018). Valproic Acid Inhibits Proliferation and Reduces Invasiveness in Glioma Stem Cells Through Wnt\/beta Catenin Signalling Activation. Genes, 9.","DOI":"10.3390\/genes9110522"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.3892\/or.2016.4665","article-title":"Epigenetic targeting of glioma stem cells: Short-term and long-term treatments with valproic acid modulate DNA methylation and differentiation behavior, but not temozolomide sensitivity","volume":"35","author":"Riva","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1200\/JCO.2015.63.6563","article-title":"Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma","volume":"34","author":"Happold","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1093\/neuonc\/nov238","article-title":"Prognostic relevance of epilepsy at presentation in glioblastoma patients","volume":"18","author":"Berendsen","year":"2016","journal-title":"Neuro-Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.seizure.2021.03.012","article-title":"Antiseizure medication in patients with Glioblastoma- a collaborative cohort study","volume":"87","author":"Storstein","year":"2021","journal-title":"Seizure"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1127645","DOI":"10.3389\/fonc.2023.1127645","article-title":"Glioblastoma survival is associated with distinct proteomic alteration signatures post chemoirradiation in a large-scale proteomic panel","volume":"13","author":"Krauze","year":"2023","journal-title":"Front. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.nbt.2011.11.016","article-title":"Advances in human proteomics at high scale with the SOMAscan proteomics platform","volume":"29","author":"Gold","year":"2012","journal-title":"New Biotechnol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1126\/science.2200121","article-title":"Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase","volume":"249","author":"Tuerk","year":"1990","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1200\/JCO.2005.04.5963","article-title":"Radiotherapy and temozolomide for newly diagnosed glioblastoma: Recursive partitioning analysis of the EORTC 26981\/22981-NCIC CE3 phase III randomized trial","volume":"24","author":"Mirimanoff","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00066-011-0015-x","article-title":"The ICRU Report 83: Prescribing, recording and reporting photon-beam intensity-modulated radiation therapy (IMRT)","volume":"188","author":"Hodapp","year":"2012","journal-title":"Strahlenther. Onkol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat.Soc. Ser. B (Methodol.)"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1177\/117693510700300022","article-title":"Analysis of gene expression data using BRB-ArrayTools","volume":"3","author":"Simon","year":"2007","journal-title":"Cancer Inform."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/biostatistics\/kxj036","article-title":"Sample size planning for developing classifiers using high-dimensional DNA microarray data","volume":"8","author":"Dobbin","year":"2006","journal-title":"Biostatistics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1158\/1078-0432.CCR-07-0443","article-title":"How large a training set is needed to develop a classifier for microarray data?","volume":"14","author":"Dobbin","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_43","unstructured":"R Core Team (2023) (2023, September 22). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/(SICI)1097-0258(19970228)16:4<385::AID-SIM380>3.0.CO;2-3","article-title":"The lasso method for variable selection in the Cox model","volume":"16","author":"Tibshirani","year":"1997","journal-title":"Stat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v039.i05","article-title":"Regularization Paths for Cox\u2019s Proportional Hazards Model via Coordinate Descent","volume":"39","author":"Simon","year":"2011","journal-title":"J. Stat. Softw."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/bib\/bbr001","article-title":"Using cross-validation to evaluate predictive accuracy of survival risk classifiers based on high-dimensional data","volume":"12","author":"Simon","year":"2011","journal-title":"Brief. Bioinform."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"253","DOI":"10.7326\/0003-4819-154-4-201102150-00006","article-title":"Measuring the performance of markers for guiding treatment decisions","volume":"154","author":"Janes","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1001\/jama.2017.18718","article-title":"Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial","volume":"318","author":"Stupp","year":"2017","journal-title":"JAMA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/S1470-2045(14)70379-1","article-title":"Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomised, open-label, phase 3 trial","volume":"15","author":"Stupp","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/S1470-2045(17)30517-X","article-title":"Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): A randomised, double-blind, international phase 3 trial","volume":"18","author":"Weller","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/tpj.2010.87","article-title":"Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy","volume":"12","author":"Kim","year":"2012","journal-title":"Pharmacogenomics J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/gepi.202","article-title":"Design of studies using DNA microarrays","volume":"23","author":"Simon","year":"2002","journal-title":"Genet. Epidemiol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lin, W.R., and Yeh, C.T. (2020). GALNT14: An Emerging Marker Capable of Predicting Therapeutic Outcomes in Multiple Cancers. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041491"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"54067","DOI":"10.18632\/oncotarget.10042","article-title":"N-acetylgalactosaminyltransferases in cancer","volume":"7","author":"Hussain","year":"2016","journal-title":"Oncotarget"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/nm1627","article-title":"Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L\/TRAIL","volume":"13","author":"Wagner","year":"2007","journal-title":"Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/stem.1120","article-title":"Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity","volume":"30","author":"Jiang","year":"2012","journal-title":"Stem Cells"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ccell.2021.01.006","article-title":"Proteogenomic and metabolomic characterization of human glioblastoma","volume":"39","author":"Wang","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"312","DOI":"10.3389\/fonc.2017.00312","article-title":"The Role of Class IA Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunits in Glioblastoma","volume":"7","author":"Pridham","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Franco, C., Kausar, S., Silva, M.F.B., Guedes, R.C., Falcao, A.O., and Brito, M.A. (2022). Multi-Targeting Approach in Glioblastoma Using Computer-Assisted Drug Discovery Tools to Overcome the Blood-Brain Barrier and Target EGFR\/PI3Kp110\u03b2 Signaling. Cancers, 14.","DOI":"10.3390\/cancers14143506"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.3892\/ol.2017.6533","article-title":"\u03b2-transducin repeat-containing E3 ubiquitin protein ligase inhibits migration, invasion and proliferation of glioma cells","volume":"14","author":"Liang","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1476-4598-14-2","article-title":"NF-\u03baB induces miR-148a to sustain TGF-\u03b2\/Smad signaling activation in glioblastoma","volume":"14","author":"Wang","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Thompson, L.L., Baergen, A.K., Lichtensztejn, Z., and McManus, K.J. (2020). Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover. Cancers, 12.","DOI":"10.3390\/cancers12030531"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"206","DOI":"10.21037\/atm-22-526","article-title":"New prognostic biomarker CMTM3 in low grade glioma and its immune infiltration","volume":"10","author":"Li","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1042\/BST20160191","article-title":"APPL1 is a multifunctional endosomal signaling adaptor protein","volume":"45","author":"Diggins","year":"2017","journal-title":"Biochem. Soc. Trans."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Korbecki, J., Kojder, K., Simi\u0144ska, D., Bohatyrewicz, R., Gutowska, I., Chlubek, D., and Baranowska-Bosiacka, I. (2020). CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218412"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Autelitano, F., Loyaux, D., Roudi\u00e8res, S., D\u00e9on, C., Guette, F., Fabre, P., Ping, Q., Wang, S., Auvergne, R., and Badarinarayana, V. (2014). Identification of novel tumor-associated cell surface sialoglycoproteins in human glioblastoma tumors using quantitative proteomics. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110316"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1002\/ijc.32306","article-title":"Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-1","volume":"145","author":"Kondo","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"35004","DOI":"10.18632\/oncotarget.5253","article-title":"Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells","volume":"6","author":"Thotala","year":"2015","journal-title":"Oncotarget"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1038\/onc.2017.112","article-title":"Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells","volume":"36","author":"Raja","year":"2017","journal-title":"Oncogene"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1002\/term.2219","article-title":"Valproic acid enhances the neural differentiation of human placenta derived-mesenchymal stem cells in vitro","volume":"11","author":"Talwadekar","year":"2017","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Tasci, E., Zhuge, Y., Camphausen, K., and Krauze, A.V. (2022). Bias and Class Imbalance in Oncologic Data-Towards Inclusive and Transferrable AI in Large Scale Oncology Data Sets. Cancers, 14.","DOI":"10.3390\/cancers14122897"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"10180","DOI":"10.1080\/21655979.2022.2061278","article-title":"CTSV (cathepsin V) promotes bladder cancer progression by increasing NF-\u03baB activity","volume":"13","author":"Xia","year":"2022","journal-title":"Bioengineered"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1016\/j.csbj.2022.08.046","article-title":"New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity","volume":"20","author":"Senjor","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Gao, L., Xiong, D.-D., Yang, X., Li, J.-D., He, R.-Q., Huang, Z.-G., Lai, Z.F., Liu, L.-M., Luo, J.-Y., and Du, X.F. (2022). The expression characteristics and clinical significance of ACP6, a potential target of nitidine chloride, in hepatocellular carcinoma. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-10292-1"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.neo.2014.03.006","article-title":"Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation","volume":"16","author":"Berezovsky","year":"2014","journal-title":"Neoplasia"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ehata, S., and Miyazono, K. (2022). Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.883523"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"14569","DOI":"10.1038\/s41598-019-51270-1","article-title":"BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblastoma","volume":"9","author":"Sachdeva","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.redox.2018.09.009","article-title":"Myostatin knockout induces apoptosis in human cervical cancer cells via elevated reactive oxygen species generation","volume":"19","author":"Han","year":"2018","journal-title":"Redox Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.2147\/CMAR.S192095","article-title":"Growth and differentiation factor 15 regulates PD-L1 expression in glioblastoma","volume":"11","author":"Peng","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"147583","DOI":"10.1016\/j.gene.2023.147583","article-title":"Differential expression of SLITRK6 gene as a potential therapeutic target for urothelial carcinoma in particular upper tract cancer","volume":"878","author":"Mir","year":"2023","journal-title":"Gene"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0378-1119(03)00715-7","article-title":"Human SLITRK family genes: Genomic organization and expression profiling in normal brain and brain tumor tissue","volume":"315","author":"Aruga","year":"2003","journal-title":"Gene"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8906","DOI":"10.1158\/0008-5472.CAN-04-1788","article-title":"Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus","volume":"64","author":"Kammerer","year":"2004","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"174216","DOI":"10.1016\/j.ejphar.2021.174216","article-title":"Regulatory effects of IL-1\u03b2 in the interaction of GBM and tumor-associated monocyte through VCAM-1 and ICAM-1","volume":"905","author":"Shen","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.3389\/fimmu.2020.01757","article-title":"The Basic Characteristics of the Pentraxin Family and Their Functions in Tumor Progression","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00702-021-02411-2","article-title":"Neuronal pentraxins as biomarkers of synaptic activity: From physiological functions to pathological changes in neurodegeneration","volume":"129","author":"Massa","year":"2022","journal-title":"J. Neural. Transm."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4611","DOI":"10.1038\/s41467-021-24819-w","article-title":"SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts","volume":"12","author":"Sun","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"458","DOI":"10.55730\/1300-0152.2631","article-title":"VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain","volume":"46","author":"Hiz","year":"2022","journal-title":"Turk. J. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature24023","article-title":"Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN","volume":"549","author":"Arnoult","year":"2017","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/HP.0000000000000852","article-title":"NHEJ Contributes to the Fast Repair of Radiation-induced DNA Double-strand Breaks at Late Prophase I Telomeres","volume":"115","author":"Ahmed","year":"2018","journal-title":"Health Phys."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"791975","DOI":"10.3389\/fimmu.2022.791975","article-title":"Roles of HLA-G\/KIR2DL4 in Breast Cancer Immune Microenvironment","volume":"13","author":"Zheng","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.omto.2021.10.001","article-title":"The emerging role of off-the-shelf engineered natural killer cells in targeted cancer immunotherapy","volume":"23","author":"Fabian","year":"2021","journal-title":"Mol. Ther. Oncolytics"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/10\/1499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:03:52Z","timestamp":1760130232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/10\/1499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,10]]},"references-count":92,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["biom13101499"],"URL":"https:\/\/doi.org\/10.3390\/biom13101499","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,10]]}}}