{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:36:22Z","timestamp":1788381382271,"version":"build-2803163510"},"reference-count":127,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T00:00:00Z","timestamp":1541721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called \u2018master modulators\u2019 of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning \u2018communication\u2019 in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control\u2014in contrast to an immediate, \u2018poisoning\u2019 with maximal tolerable doses of targeted\/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.<\/jats:p>","DOI":"10.3390\/ijms19113540","type":"journal-article","created":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T03:27:31Z","timestamp":1542079651000},"page":"3540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Peroxisome Proliferator-Activated Receptors (PPAR)\u03b3 Agonists as Master Modulators of Tumor Tissue"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8790-4584","authenticated-orcid":false,"given":"Daniel","family":"Heudobler","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rechenmacher","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"L\u00fcke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Vogelhuber","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Pukrop","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Herr","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Ghibelli","sequence":"additional","affiliation":[{"name":"Department Biology, Universita\u2019 di Roma Tor Vergata, 00173 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4964-0642","authenticated-orcid":false,"given":"Christopher","family":"Gerner","sequence":"additional","affiliation":[{"name":"Institut for Analytical Chemistry, Faculty Chemistry, University Vienna, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1821-7887","authenticated-orcid":false,"given":"Albrecht","family":"Reichle","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60704","DOI":"10.18632\/oncotarget.19610","article-title":"Peroxisome proliferator-activated receptors (PPARs) are potential drug targets for cancer therapy","volume":"8","author":"Gou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/S0140-6736(05)67528-9","article-title":"Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial","volume":"366","author":"Dormandy","year":"2005","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1056\/NEJMoa072761","article-title":"Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes","volume":"356","author":"Nissen","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12032-017-1040-0","article-title":"Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-\u03b3 agonist: A phase II trial","volume":"34","author":"Walter","year":"2017","journal-title":"Med. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s12032-011-9982-0","article-title":"Pioglitazone, etoricoxib, interferon-\u03b1, and metronomic capecitabine for metastatic renal cell carcinoma: Final results of a prospective phase II trial","volume":"29","author":"Walter","year":"2012","journal-title":"Med. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nrg.2017.102","article-title":"Nuclear receptors in cancer\u2014Uncovering new and evolving roles through genomic analysis","volume":"19","author":"Dhiman","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s12672-016-0259-0","article-title":"The metabolism, analysis, and targeting of steroid hormones in breast and prostate cancer","volume":"7","author":"Capper","year":"2016","journal-title":"Horm. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00262-013-1477-8","article-title":"Non-genomic events determining the sensitivity of hemopoietic malignancies to glucocorticoid-induced apoptosis","volume":"63","author":"Yefenof","year":"2014","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0065-230X(08)00406-5","article-title":"Mechanisms regulating the susceptibility of hematopoietic malignancies to glucocorticoid-induced apoptosis","volume":"101","author":"Sionov","year":"2008","journal-title":"Adv. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s11912-018-0678-x","article-title":"Systemic treatment options for advanced-stage mycosis fungoides and s\u00e9zary syndrome","volume":"20","author":"Photiou","year":"2018","journal-title":"Curr. Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1200\/JCO.2016.67.1982","article-title":"Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial","volume":"35","author":"Platzbecker","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s12307-015-0170-1","article-title":"Anakoinosis: Communicative Reprogramming of Tumor Systems\u2014for Rescuing from Chemorefractory Neoplasia","volume":"8","author":"Hart","year":"2015","journal-title":"Cancer Microenviron."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s12307-009-0023-x","article-title":"Principles of modular tumor therapy","volume":"2","author":"Reichle","year":"2009","journal-title":"Cancer Microenviron."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cell.2016.12.013","article-title":"Transcriptional Addiction in Cancer","volume":"168","author":"Bradner","year":"2017","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"745","DOI":"10.3389\/fimmu.2018.00745","article-title":"Crosstalk Between Peroxisome Proliferator-Activated Receptor \u03b3 and the Canonical WNT\/\u03b2-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis","volume":"9","author":"Lecarpentier","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nrc1254","article-title":"Peroxisome-proliferator-activated receptors and cancers: Complex stories","volume":"4","author":"Michalik","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/35013000","article-title":"Roles of PPARs in health and disease","volume":"405","author":"Kersten","year":"2000","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Reichle, A. (2010). From Molecular to Modular Tumor Therapy, Springer.","DOI":"10.1007\/978-90-481-9531-2"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1080\/14728222.2017.1280467","article-title":"Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome","volume":"21","author":"Tan","year":"2017","journal-title":"Exp. Opin. Ther. Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jsbmb.2010.02.027","article-title":"Selective Glucocorticoid Receptor modulators","volume":"120","author":"Bosscher","year":"2010","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1146\/annurev-med-051812-145316","article-title":"Nuclear receptor coactivators: Master regulators of human health and disease","volume":"65","author":"Dasgupta","year":"2014","journal-title":"Ann. Rev. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1182\/blood-2004-03-0926","article-title":"Human bone marrow megakaryocytes and platelets express PPAR\u03b3, and PPAR\u03b3 agonists blunt platelet release of CD40 ligand and thromboxanes","volume":"104","author":"Akbiyik","year":"2004","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/j.cell.2009.11.030","article-title":"Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer","volume":"139","author":"Lin","year":"2009","journal-title":"Cell"},{"key":"ref_24","first-page":"1","article-title":"Peroxisome proliferator-activated receptor \u03b3 and cancers","volume":"9","author":"Koeffler","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1002\/j.1460-2075.1992.tb05141.x","article-title":"Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors","volume":"11","author":"Danielian","year":"1992","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14073","DOI":"10.1038\/ncomms14073","article-title":"Glucocorticoid receptor signalling activates YAP in breast cancer","volume":"8","author":"Sorrentino","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1158\/1078-0432.CCR-06-2316","article-title":"WNT signaling pathway and stem cell signaling network","volume":"13","author":"Katoh","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_28","first-page":"733","article-title":"Inhibition of cyclooxygenase-2 and activation of peroxisome proliferator-activated receptor-\u03b3 synergistically induces apoptosis and inhibits growth of human breast cancer cells","volume":"11","author":"Michael","year":"2003","journal-title":"Int. J. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1074\/jbc.272.6.3406","article-title":"Peroxisome proliferator-activated receptors \u03b1 and \u03b3 are activated by indomethacin and other non-steroidal anti-inflammatory drugs","volume":"272","author":"Lehmann","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1007\/s000180050345","article-title":"An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer","volume":"55","author":"Gelman","year":"1999","journal-title":"Cell. Mol. life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12440","DOI":"10.1074\/jbc.M007237200","article-title":"Peroxisome proliferator-activated receptor \u03b3 ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein\/p300","volume":"276","author":"Subbaramaiah","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/ijc.10770","article-title":"Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-\u03b3 and levels of prostaglandin E2 and 15-deoxy-delta12,14-prostaglandin J2 in human breast cancer and metastasis","volume":"103","author":"Badawi","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s10495-006-4003-z","article-title":"Pioglitazone, a synthetic ligand for PPAR\u03b3, induces apoptosis in RB-deficient human colorectal cancer cells","volume":"11","author":"Lee","year":"2006","journal-title":"Apoptosis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1093\/carcin\/20.10.1905","article-title":"Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells","volume":"20","author":"Clay","year":"1999","journal-title":"Carcinogenesis"},{"key":"ref_35","first-page":"1281","article-title":"Mechanisms of anti-proliferative effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on human liver cancer cells","volume":"18","author":"Nagahara","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_36","first-page":"848645","article-title":"Cyclooxygenase 2 (COX2) and peroxisome proliferator-activated receptor \u03b3 (PPARG) are stage-dependent prognostic markers of malignant melanoma","volume":"2009","author":"Meyer","year":"2009","journal-title":"PPAR Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"816","DOI":"10.2174\/187152009789056912","article-title":"Targeting the tumor stroma with peroxisome proliferator activated receptor (PPAR) agonists","volume":"9","author":"Bundscherer","year":"2009","journal-title":"ACAMC"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10549-013-2716-6","article-title":"Distinct nuclear receptor expression in stroma adjacent to breast tumors","volume":"142","author":"Knower","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"60954","DOI":"10.18632\/oncotarget.11273","article-title":"PPAR\u03b3 agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity","volume":"7","author":"Han","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1210\/er.2003-0034","article-title":"Interaction of nuclear receptors with the Wnt\/\u03b2-catenin\/Tcf signaling axis: Wnt you like to know?","volume":"26","author":"Mulholland","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s12264-018-0219-5","article-title":"Opposite Interplay Between the Canonical WNT\/\u03b2-Catenin Pathway and PPAR\u03b3: A Potential Therapeutic Target in Gliomas","volume":"34","author":"Lecarpentier","year":"2018","journal-title":"Neurosci. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4685","DOI":"10.1172\/JCI45797","article-title":"Crosstalk between the canonical NF-\u03baB and Notch signaling pathways inhibits Ppar\u03b3 expression and promotes pancreatic cancer progression in mice","volume":"121","author":"Maniati","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"28","DOI":"10.4048\/jbc.2018.21.1.28","article-title":"Troglitazone inhibits matrix metalloproteinase-9 expression and invasion of breast cancer cell through a peroxisome proliferator-activated receptor \u03b3-dependent mechanism","volume":"21","author":"Hong","year":"2018","journal-title":"J. Breast Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00262-011-1106-3","article-title":"Metronomic cyclophosphamide treatment in metastasized breast cancer patients: Immunological effects and clinical outcome","volume":"61","author":"Ge","year":"2012","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1073\/pnas.94.1.237","article-title":"Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor \u03b3 and the retinoid X receptor","volume":"94","author":"Tontonoz","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3951","DOI":"10.1073\/pnas.96.7.3951","article-title":"Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-\u03b3 ligand troglitazone in patients with liposarcoma","volume":"96","author":"Demetri","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1038\/sj.bjc.6601306","article-title":"A phase II trial with rosiglitazone in liposarcoma patients","volume":"89","author":"Debrock","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1001\/archderm.140.12.1504","article-title":"Antiangiogenic therapy with pioglitazone, rofecoxib, and trofosfamide in a patient with endemic kaposi sarcoma","volume":"140","author":"Coras","year":"2004","journal-title":"Arch. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1002\/cncr.11775","article-title":"Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors","volume":"98","author":"Vogt","year":"2003","journal-title":"Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1023\/A:1024038127156","article-title":"Use of the peroxisome proliferator-activated receptor (PPAR) \u03b3 ligand troglitazone as treatment for refractory breast cancer: A phase II study","volume":"79","author":"Burstein","year":"2003","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1111\/jdv.13391","article-title":"Biomodulatory metronomic therapy in stage IV melanoma is well-tolerated and may induce prolonged progression-free survival, a phase I trial","volume":"30","author":"Hart","year":"2016","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/CMR.0b013e3282f1d2c8","article-title":"Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: A randomized phase II trial","volume":"17","author":"Reichle","year":"2007","journal-title":"Melanoma Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/00130404-200209000-00010","article-title":"A phase II study of troglitazone, an activator of the PPAR\u03b3 receptor, in patients with chemotherapy-resistant metastatic colorectal cancer","volume":"8","author":"Kulke","year":"2002","journal-title":"Cancer J."},{"key":"ref_54","first-page":"87","article-title":"C-reactive protein in patients with metastatic clear cell renal carcinoma: An important biomarker for tumor-associated inflammation","volume":"1","author":"Reichle","year":"2007","journal-title":"Biomark. Insights"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10990","DOI":"10.1073\/pnas.180329197","article-title":"Effects of ligand activation of peroxisome proliferator-activated receptor \u03b3 in human prostate cancer","volume":"97","author":"Mueller","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s12307-014-0161-7","article-title":"Biomodulatory treatment of patients with castration-resistant prostate cancer: A phase II study of imatinib with pioglitazone, etoricoxib, dexamethasone and low-dose treosulfan","volume":"8","author":"Vogelhuber","year":"2015","journal-title":"Cancer Microenviron."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1007\/s00345-010-0567-x","article-title":"Modular therapy approach in metastatic castration-refractory prostate cancer","volume":"28","author":"Walter","year":"2010","journal-title":"World J. Urol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S1470-2045(06)70798-7","article-title":"Antiangiogenic therapy in metastatic prostate carcinoma complicated by cutaneous lupus erythematodes","volume":"7","author":"Vogt","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1002\/cncr.20493","article-title":"Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and\/or radiation therapy","volume":"101","author":"Smith","year":"2004","journal-title":"Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e15584","DOI":"10.1200\/jco.2009.27.15_suppl.e15584","article-title":"Control of cancer-associated inflammation and survival: Results from a prospective randomized phase II trial in gastric cancer","volume":"27","author":"Reichle","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1159\/000120028","article-title":"Low-dose chemotherapy in combination with COX-2 inhibitors and PPAR-\u03b3 agonists in recurrent high-grade gliomas\u2014A phase II study","volume":"73","author":"Hau","year":"2007","journal-title":"Oncology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1182\/blood.V120.21.5029.5029","article-title":"Anti-inflammatory, immuno-modulatory and angiostatic treatment as third-line therapy for multiple myeloma (MM)\u2014A combined treatment setting of lenalidomide with pioglitazone, dexamethasone and low-dose treosulfan (phase I\/II)","volume":"120","author":"Reichle","year":"2012","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.1182\/blood.V128.22.4254.4254","article-title":"Biomodulatory metronomic therapy shows remarkable activity in chemorefractory multi-system langerhans cell histiocytosis","volume":"128","author":"Heudobler","year":"2016","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/j.1365-2141.2004.05359.x","article-title":"Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans\u2019 cell histiocytosis of adults","volume":"128","author":"Reichle","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/bjh.13480","article-title":"Biomodulatory metronomic therapy induces PET-negative remission in chemo- and brentuximab-refractory Hodgkin lymphoma","volume":"172","author":"Ugocsai","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature15248","article-title":"Erosion of the chronic myeloid leukaemia stem cell pool by PPAR\u03b3 agonists","volume":"525","author":"Prost","year":"2015","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3324\/haematol.2014.115055","article-title":"Biomodulatory therapy induces complete molecular remission in chemorefractory acute myeloid leukemia","volume":"100","author":"Thomas","year":"2015","journal-title":"Haematologica"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Heudobler, D., Klobuch, S., Thomas, S., Hahn, J., Herr, W., and Reichle, A. (2018). Cutaneous leukemic infiltrates successfully treated with biomodulatory therapy in a rare case of therapy-related high risk MDS\/AML. Front. Pharmacol.","DOI":"10.3389\/fphar.2018.01279"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/S0140-6736(14)62004-3","article-title":"Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): A phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group","volume":"385","author":"Simkens","year":"2015","journal-title":"Lancet"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1001\/jamaoncol.2017.0324","article-title":"Metronomic Chemotherapy vs Best Supportive Care in Progressive Pediatric Solid Malignant Tumors: A Randomized Clinical Trial","volume":"3","author":"Pramanik","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rochlitz, C., Bigler, M., Moos, R., Bernhard, J., Matter-Walstra, K., Wicki, A., Zaman, K., Anchisi, S., K\u00fcng, M., and Na, K.-J. (2016). SAKK 24\/09: Safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer\u2014A multicenter, randomized phase III trial. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2823-y"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10637-016-0335-x","article-title":"Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer","volume":"34","author":"Kummar","year":"2016","journal-title":"Investig. New Drugs"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1200\/JCO.2005.04.5773","article-title":"Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients","volume":"24","author":"Bottini","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1200\/JCO.2008.20.7944","article-title":"Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma","volume":"27","author":"Clarke","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/cncr.30411","article-title":"Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment","volume":"123","author":"Senerchia","year":"2017","journal-title":"Cancer"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1097\/00062752-200207000-00006","article-title":"Role of peroxisome proliferator-activated receptor-\u03b3 in hematologic malignancies","volume":"9","author":"Konopleva","year":"2002","journal-title":"Curr. Opin. Hematol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"704165","DOI":"10.1155\/2008\/704165","article-title":"PPAR\u03b3 and Apoptosis in Cancer","volume":"2008","author":"Elrod","year":"2008","journal-title":"PPAR Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/j.ejca.2005.08.015","article-title":"Role of nuclear receptors in lung tumourigenesis","volume":"41","author":"Nemenoff","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"ref_79","first-page":"465","article-title":"Can PPAR\u03b3 ligands be used in cancer therapy?","volume":"4","author":"Rumi","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1100\/tsw.2010.213","article-title":"The nuclear hormone receptor PPAR\u03b3 as a therapeutic target in major diseases","volume":"10","author":"Schmidt","year":"2010","journal-title":"Sci. World J."},{"key":"ref_81","first-page":"68","article-title":"Peroxisome proliferator-activated receptors and cancer: Challenges and opportunities","volume":"164","author":"Youssef","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_82","first-page":"946943","article-title":"The Key to Unlocking the Chemotherapeutic Potential of PPAR\u03b3 Ligands: Having the Right Combination","volume":"2012","author":"Nicol","year":"2012","journal-title":"PPAR Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.3748\/wjg.v22.i8.2441","article-title":"Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer","volume":"22","author":"Polvani","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3389\/fendo.2017.00031","article-title":"PPAR-\u03b3 Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis","volume":"8","author":"Vella","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1517\/14656566.7.7.907","article-title":"Bexarotene in the treatment of cutaneous T-cell lymphoma","volume":"7","author":"Querfeld","year":"2006","journal-title":"Exp. Opin. Pharmacother."},{"key":"ref_86","first-page":"845340","article-title":"Chemotherapy and chemoprevention by thiazolidinediones","volume":"2015","author":"Wahl","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S1470-2045(15)00565-3","article-title":"Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial","volume":"17","author":"Higurashi","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1093\/annonc\/mdw410","article-title":"Metformin as an adjuvant treatment for cancer: A systematic review and meta-analysis","volume":"27","author":"Coyle","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41586-018-0350-5","article-title":"Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer","volume":"559","author":"Di","year":"2018","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mam.2014.12.003","article-title":"Retinoic acid receptors: From molecular mechanisms to cancer therapy","volume":"41","author":"Leboffe","year":"2015","journal-title":"Mol. Aspects Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1111\/j.1365-2141.2005.05509.x","article-title":"Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: Results of the UK Medical Research Council ALL97 randomized trial","volume":"129","author":"Mitchell","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1200\/JCO.2005.03.206","article-title":"Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma","volume":"23","author":"McDermott","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/nature23304","article-title":"Correction of aberrant growth preserves tissue homeostasis","volume":"548","author":"Brown","year":"2017","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1593\/neo.10804","article-title":"Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy","volume":"12","author":"Tang","year":"2010","journal-title":"Neoplasia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/aps.2009.119","article-title":"Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPAR\u03b3 signaling pathway","volume":"30","author":"Cao","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1111\/j.1745-7254.2007.00571.x","article-title":"Upregulation of PTEN involved in rosiglitazone-induced apoptosis in human hepatocellular carcinoma cells","volume":"28","author":"Cao","year":"2007","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6678","DOI":"10.1158\/1078-0432.CCR-05-0621","article-title":"Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: A complementation antiangiogenic strategy","volume":"11","author":"Yap","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1097\/CAD.0000000000000319","article-title":"Cellular and molecular effects of metronomic vinorelbine and 4-O-deacetylvinorelbine on human umbilical vein endothelial cells","volume":"27","author":"Biziota","year":"2016","journal-title":"Anti-Cancer Drugs"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2005.06.029","article-title":"Molecular determinants of crosstalk between nuclear receptors and toll-like receptors","volume":"122","author":"Ogawa","year":"2005","journal-title":"Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1053\/sonc.2003.50065","article-title":"Novel biologically based therapies for Waldenstrom\u2019s macroglobulinemia","volume":"30","author":"Mitsiades","year":"2003","journal-title":"Semin. Oncol."},{"key":"ref_101","first-page":"5494","article-title":"Down-Regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor \u03b3 in human prostate cancer","volume":"60","author":"Hisatake","year":"2000","journal-title":"Cancer Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrurol.2015.254","article-title":"Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy","volume":"13","author":"Narayanan","year":"2016","journal-title":"Nat. Rev. Urol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"537","DOI":"10.3892\/ijo.2010.877","article-title":"Thiazolidinediones\/PPAR\u03b3 agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer","volume":"38","author":"Mansour","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/cdd.2011.207","article-title":"Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells","volume":"19","author":"Papi","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.canlet.2010.04.026","article-title":"RXR\u03b3 and PPAR\u03b3 ligands in combination to inhibit proliferation and invasiveness in colon cancer cells","volume":"297","author":"Papi","year":"2010","journal-title":"Cancer Lett."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Papi, A., Storci, G., Guarnieri, T., Carolis, S., Bertoni, S., Avenia, N., Sanguinetti, A., Sidoni, A., Santini, D., and Ceccarelli, C. (2013). Peroxisome proliferator activated receptor-\u03b1\/hypoxia inducible factor-1\u03b1 interplay sustains carbonic anhydrase IX and apoliprotein E expression in breast cancer stem cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054968"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1111\/j.1471-4159.2009.06111.x","article-title":"PPAR\u03b3 and RXR\u03b3 ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models","volume":"109","author":"Papi","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1158\/1535-7163.1249.3.10","article-title":"Peroxisome proliferator-activated receptor \u03b3 and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias","volume":"3","author":"Konopleva","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0165-2478(97)00036-9","article-title":"IL-6 is a survival prognostic factor in renal cell carcinoma","volume":"58","author":"Thiounn","year":"1997","journal-title":"Immunol. Lett."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1182\/blood.V85.2.433.433","article-title":"Interferon-\u03b1 induces circulating tumor necrosis factor receptor p55 in humans","volume":"85","author":"Tilg","year":"1995","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1111\/j.1523-1755.2005.00666.x","article-title":"Expression of C-reactive protein by renal cell carcinomas and unaffected surrounding renal tissue","volume":"68","author":"Jabs","year":"2005","journal-title":"Kidney Int."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1200\/JCO.1995.13.10.2679","article-title":"Response to 13-cis-retinoic acid plus interferon alfa-2a in two patients with therapy-refractory advanced renal cell carcinoma","volume":"13","author":"Buer","year":"1995","journal-title":"J. Clin. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1179\/1607845415Y.0000000002","article-title":"Interferon and low doses of methotrexate versus interferon and retinoids in the treatment of refractory\/relapsed cutaneous T-cell lymphoma","volume":"20","author":"Aviles","year":"2015","journal-title":"Hematology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1182\/blood-2016-08-736405","article-title":"Activation of PPAR\u03b3 by endogenous prostaglandin J2 mediates the antileukemic effect of selenium in murine leukemia","volume":"129","author":"Finch","year":"2017","journal-title":"Blood"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.18632\/oncotarget.1745","article-title":"Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN","volume":"5","author":"Chu","year":"2014","journal-title":"Oncotarget"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"11859","DOI":"10.1158\/0008-5472.CAN-06-1445","article-title":"Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)\u03b1\/cyclooxygenase-2\/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells","volume":"66","author":"Xu","year":"2006","journal-title":"Cancer Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"653","DOI":"10.7150\/ijms.6050","article-title":"Prognostic role of C-reactive protein in hepatocellular carcinoma: A systematic review and meta-analysis","volume":"10","author":"Zheng","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1158\/1078-0432.CCR-08-0958","article-title":"Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor \u03b3 agonist in an in vivo mouse model of spontaneous breast cancer","volume":"14","author":"Mustafa","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ygcen.2015.12.027","article-title":"Tumour necrosis factor-\u03b1 inhibits hepatic lipid deposition through GSK-3\u03b2\/\u03b2-catenin signaling in juvenile turbot (Scophthalmus maximus L.)","volume":"228","author":"Liu","year":"2015","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1093\/carcin\/bgh210","article-title":"The effect of thalidomide on non-small cell lung cancer (NSCLC) cell lines: Possible involvement in the PPAR\u03b3 pathway","volume":"25","author":"DeCicco","year":"2004","journal-title":"Carcinogenesis"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1002\/cncr.30490","article-title":"Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study","volume":"123","author":"Rousselot","year":"2017","journal-title":"Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1158\/1535-7163.MCT-05-0347","article-title":"Rosiglitazone suppresses human lung carcinoma cell growth through PPAR\u03b3-dependent and PPAR\u03b3-independent signal pathways","volume":"5","author":"Han","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2174\/1568009054863591","article-title":"New indications for established drugs: Combined tumor-stroma-targeted cancer therapy with PPAR\u03b3 agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy","volume":"5","author":"Hafner","year":"2005","journal-title":"CCDT"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Reichle, A. (2013). Evolution-adjusted Tumor Pathophysiology, Springer.","DOI":"10.1007\/978-94-007-6866-6"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1074\/mcp.M116.063313","article-title":"Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma","volume":"16","author":"Muqaku","year":"2017","journal-title":"Mol. Cell. Proteom."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nature06916","article-title":"Mining the plasma proteome for cancer biomarkers","volume":"452","author":"Hanash","year":"2008","journal-title":"Nature"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Reichle, A. (2010). Tumor Systems Need to be Rendered Usable for a New Action-Theoretical Abstraction: The Starting Point for Novel Therapeutic Options. From Molecular to Modular Tumor Therapy, Springer Netherlands.","DOI":"10.1007\/978-90-481-9531-2_2"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3540\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:28:57Z","timestamp":1760196537000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,9]]},"references-count":127,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["ijms19113540"],"URL":"https:\/\/doi.org\/10.3390\/ijms19113540","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,9]]}}}