{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T22:10:59Z","timestamp":1783030259448,"version":"3.54.6"},"reference-count":59,"publisher":"Impact Journals, LLC","issue":"32","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Oncotarget"],"published-print":{"date-parts":[[2018,4,27]]},"DOI":"10.18632\/oncotarget.24806","type":"journal-article","created":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T21:44:08Z","timestamp":1524865448000},"page":"22316-22331","source":"Crossref","is-referenced-by-count":23,"title":["Tumor targeting with pH-responsive poly(2-oxazoline)-based nanogels for metronomic doxorubicin treatment"],"prefix":"10.18632","volume":"9","author":[{"given":"Doerte","family":"Hoelzer","sequence":"first","affiliation":[{"name":"Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike N.","family":"Leiske","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hartlieb","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Current address: Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht, 14513 Teltow, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Bus","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pretzel","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Hoeppener","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Kempe","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Current address: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Thierbach","sequence":"additional","affiliation":[{"name":"Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich S.","family":"Schubert","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"7892","published-online":{"date-parts":[[2018,4,27]]},"reference":[{"key":"1","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/S0006-2952(98)00307-4","article-title":"A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin","volume":"57","author":"Gewirtz","year":"1999","journal-title":"Biochem Pharmacol"},{"key":"2","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1097\/FPC.0b013e32833ffb56","article-title":"Doxorubicin pathways: pharmacodynamics and adverse effects","volume":"21","author":"Altman","year":"2011","journal-title":"Pharmacogenet Genomics"},{"key":"3","first-page":"84","article-title":"Doxorubicin, DNA torsion, and chromatin dynamics","volume":"1845","author":"Henikoff","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"4","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1016\/S1470-2045(10)70204-7","article-title":"Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial","volume":"11","author":"Samson","year":"2010","journal-title":"Lancet Oncol"},{"key":"5","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.biomaterials.2016.06.002","article-title":"A high capacity polymeric micelle of paclitaxel: implication of high dose drug therapy to safety and in vivo anti-cancer activity","volume":"101","author":"Perou","year":"2016","journal-title":"Biomaterials"},{"key":"6","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1002\/marc.201200354","article-title":"Poly(2-oxazoline)s as polymer therapeutics","volume":"33","author":"Jordan","year":"2012","journal-title":"Macromol Rapid Commun"},{"key":"7","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.addr.2013.11.009","article-title":"Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology","volume":"66","author":"Farokhzad","year":"2014","journal-title":"Adv Drug Deliv Rev"},{"key":"8","doi-asserted-by":"publisher","first-page":"8085","DOI":"10.1039\/C4TB01141D","article-title":"Nanogel carrier design for targeted drug delivery","volume":"2","author":"Muzykantov","year":"2014","journal-title":"J Mater Chem B Mater Biol Med"},{"key":"9","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1158\/1535-7163.MCT-16-0445","article-title":"A prodrug of two approved drugs, cisplatin and chlorambucil, for chemo war against cancer","volume":"16","author":"Dhar","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"10","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.addr.2015.12.024","article-title":"Nanotechnology inspired tools for mitochondrial dysfunction related diseases","volume":"99","author":"Dhar","year":"2016","journal-title":"Adv Drug Deliv Rev"},{"key":"11","doi-asserted-by":"publisher","first-page":"5559","DOI":"10.1039\/C6SC00481D","article-title":"Turn up the cellular power generator with vitamin E analogue formulation","volume":"7","author":"Dhar","year":"2016","journal-title":"Chem Sci (Camb)"},{"key":"12","first-page":"95","article-title":"An Overview of Nanogel Drug Delivery System","volume":"3","author":"Sharmin","year":"2013","journal-title":"J Appl Pharm Sci"},{"key":"13","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1007\/s10856-011-4346-z","article-title":"bio-immunological and cytotoxicity studies of poly(2-oxazolines)","volume":"22","author":"Mendrek","year":"2011","journal-title":"J Mater Sci Mater Med"},{"key":"14","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1002\/mds.25625","article-title":"Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit","volume":"28","author":"Moreadith","year":"2013","journal-title":"Mov Disord"},{"key":"15","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.eurpolymj.2016.09.011","article-title":"Poly(2-oxazoline)-based micro- and nanoparticles: A review","volume":"88","author":"Kempe","year":"2017","journal-title":"Eur Polym J"},{"key":"16","doi-asserted-by":"publisher","first-page":"15763","DOI":"10.1039\/C5NR04612B","article-title":"Tumor pH(e)-triggered charge-reversal and redox-responsive nanoparticles for docetaxel delivery in hepatocellular carcinoma treatment","volume":"7","author":"Chen","year":"2015","journal-title":"Nanoscale"},{"key":"17","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S0022-3565(24)35391-1","article-title":"Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes","volume":"292","author":"Boerman","year":"2000","journal-title":"J Pharmacol Exp Ther"},{"key":"18","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1093\/annonc\/mdg374","article-title":"Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions","volume":"14","author":"Muggia","year":"2003","journal-title":"Ann Oncol"},{"key":"19","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/cncr.22739","article-title":"Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients","volume":"110","author":"Garratty","year":"2007","journal-title":"Cancer"},{"key":"20","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1177\/0192623312474726","article-title":"High molecular weight polyethylene glycol cellular distribution and PEG-associated cytoplasmic vacuolation is molecular weight dependent and does not require conjugation to proteins","volume":"41","author":"Heidel","year":"2013","journal-title":"Toxicol Pathol"},{"key":"21","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1093\/toxsci\/42.2.152","article-title":"Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins","volume":"42","author":"Shopp","year":"1998","journal-title":"Toxicol Sci"},{"key":"22","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1016\/j.drudis.2014.06.002","article-title":"Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis?","volume":"19","author":"Sims","year":"2014","journal-title":"Drug Discov Today"},{"key":"23","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.jconrel.2011.04.010","article-title":"Structure-property relationship in cytotoxicity and cell uptake of poly(2-oxazoline) amphiphiles","volume":"153","author":"Kabanov","year":"2011","journal-title":"J Control Release"},{"key":"24","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1007\/s10856-012-4621-7","article-title":"Immunomodulatory efficiency of poly(2-oxazolines)","volume":"23","author":"Lusto\u0148","year":"2012","journal-title":"J Mater Sci Mater Med"},{"key":"25","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1021\/js9504043","article-title":"Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes","volume":"85","author":"Allen","year":"1996","journal-title":"J Pharm Sci"},{"key":"26","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1021\/bc00030a001","article-title":"New amphipatic polymer-lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes","volume":"5","author":"Zalipsky","year":"1994","journal-title":"Bioconjug Chem"},{"key":"27","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jconrel.2016.05.048","article-title":"\u03bcPET imaging of the pharmacokinetic behavior of medium and high molar mass (89)Zr-labeled poly(2-ethyl-2-oxazoline) in comparison to poly(ethylene glycol)","volume":"235","author":"Staelens","year":"2016","journal-title":"J Control Release"},{"key":"28","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1021\/acs.biomac.6b01392","article-title":"The Label Matters: \u03bcPET Imaging of the Biodistribution of Low Molar Mass 89Zr and 18F-Labeled Poly(2-ethyl-2-oxazoline)","volume":"18","author":"Hoogenboom","year":"2017","journal-title":"Biomacromolecules"},{"key":"29","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1002\/marc.201200266","article-title":"How to modulate the chemical structure of polyoxazolines by appropriate functionalization","volume":"33","author":"Robin","year":"2012","journal-title":"Macromol Rapid Commun"},{"key":"30","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1039\/C4TB01660B","article-title":"Covalently cross-linked poly(2-oxazoline) materials for biomedical applications - from hydrogels to self-assembled and templated structures","volume":"3","author":"Schubert","year":"2015","journal-title":"J Mater Chem B Mater Biol Med"},{"key":"31","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1039\/C4TB02069C","article-title":"Core cross-linked nanogels based on the self-assembly of double hydrophilic poly(2-oxazoline) block copolymers","volume":"3","author":"Schubert","year":"2015","journal-title":"J Mater Chem B Mater Biol Med"},{"key":"32","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1021\/acs.bioconjchem.7b00067","article-title":"Tailoring Cellular Uptake and Fluorescence of Poly(2-oxazoline)-Based Nanogels","volume":"28","author":"Schubert","year":"2017","journal-title":"Bioconjug Chem"},{"key":"33","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.1039\/c2py20290e","article-title":"Schiff's base as a stimuli-responsive linker in polymer chemistry","volume":"3","author":"Yuan","year":"2012","journal-title":"Polym Chem"},{"key":"34","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.canlet.2014.12.039","article-title":"Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance","volume":"358","author":"Lakka Klement","year":"2015","journal-title":"Cancer Lett"},{"key":"35","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s00280-013-2125-x","article-title":"Metronomic chemotherapy for cancer treatment: a decade of clinical studies","volume":"72","author":"Marchetti","year":"2013","journal-title":"Cancer Chemother Pharmacol"},{"key":"36","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/0006-2952(93)90140-R","article-title":"Accumulation of degradation products of doxorubicin and pirarubicin formed in cell culture medium within sensitive and resistant cells","volume":"45","author":"Garnier-Suillerot","year":"1993","journal-title":"Biochem Pharmacol"},{"key":"37","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1021\/mp100269f","article-title":"Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking","volume":"7","author":"Rapoport","year":"2010","journal-title":"Mol Pharm"},{"key":"38","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1039\/b513441m","article-title":"Template-directed synthesis employing reversible imine bond formation","volume":"36","author":"Stoddart","year":"2007","journal-title":"Chem Soc Rev"},{"key":"39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biomaterials.2017.09.003","article-title":"Poly(2-ethyl-2-oxazoline) conjugates with doxorubicin for cancer therapy: in vitro and in vivo evaluation and direct comparison to poly[N-(2-hydroxypropyl)methacrylamide] analogues","volume":"146","author":"Hruby","year":"2017","journal-title":"Biomaterials"},{"key":"40","doi-asserted-by":"publisher","first-page":"10175","DOI":"10.1021\/nn404407g","article-title":"Using fluorescence lifetime imaging microscopy to monitor theranostic nanoparticle uptake and intracellular doxorubicin release","volume":"7","author":"Davis","year":"2013","journal-title":"ACS Nano"},{"key":"41","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.tibs.2014.02.004","article-title":"Serine and glycine metabolism in cancer","volume":"39","author":"Melino","year":"2014","journal-title":"Trends Biochem Sci"},{"key":"42","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1021\/acs.biomac.7b01535","article-title":"How to tune the gene delivery and biocompatibility of poly(2-(4-aminobutyl)-2-oxazoline) by self and co assembly","volume":"19","author":"Schubert","year":"2018","journal-title":"Biomacromolecules"},{"key":"43","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/S0109-5641(01)00056-2","article-title":"Responses of L929 mouse fibroblasts, primary and immortalized bovine dental papilla-derived cell lines to dental resin components","volume":"18","author":"Schweikl","year":"2002","journal-title":"Dent Mater"},{"key":"44","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ejps.2009.11.010","article-title":"Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy","volume":"39","author":"Sahoo","year":"2010","journal-title":"Eur J Pharm Sci"},{"key":"45","doi-asserted-by":"publisher","first-page":"648","DOI":"10.3109\/1061186X.2014.921924","article-title":"Cellular uptake and internalization of hyaluronan-based doxorubicin and cisplatin conjugates","volume":"22","author":"Forrest","year":"2014","journal-title":"J Drug Target"},{"key":"46","doi-asserted-by":"publisher","first-page":"3280","DOI":"10.1021\/acs.biomac.7b00931","article-title":"Polymersomes with Endosomal pH-Induced Vesicle-to-Micelle Morphology Transition and a Potential Application for Controlled Doxorubicin Delivery","volume":"18","author":"Schubert","year":"2017","journal-title":"Biomacromolecules"},{"key":"47","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/BF02967534","article-title":"Resistant mechanisms of anthracyclines\u2014pirarubicin might partly break through the P-glycoprotein-mediated drug-resistance of human breast cancer tissues","volume":"8","author":"Kitajima","year":"2001","journal-title":"Breast Cancer"},{"key":"48","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1038\/sj.bjc.6603985","article-title":"ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein","volume":"97","author":"Lou","year":"2007","journal-title":"Br J Cancer"},{"key":"49","doi-asserted-by":"publisher","first-page":"2882","DOI":"10.1016\/j.biomaterials.2009.12.043","article-title":"The intracellular drug delivery and anti tumor activity of doxorubicin loaded poly(\u03b3-benzyl L-glutamate)-b-hyaluronan polymersomes","volume":"31","author":"Lecommandoux","year":"2010","journal-title":"Biomaterials"},{"key":"50","doi-asserted-by":"publisher","first-page":"2802","DOI":"10.1021\/bm9006419","article-title":"Biomimetic doxorubicin loaded polymersomes from hyaluronan-block-poly(\u03b3-benzyl glutamate) copolymers","volume":"10","author":"Lecommandoux","year":"2009","journal-title":"Biomacromolecules"},{"key":"51","doi-asserted-by":"publisher","first-page":"3856","DOI":"10.1021\/acs.macromol.5b02603","article-title":"Dual Responsive Nanoparticles from a RAFT Copolymer Library for the Controlled Delivery of Doxorubicin","volume":"49","author":"Schubert","year":"2016","journal-title":"Macromolecules"},{"key":"52","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.biomaterials.2005.05.028","article-title":"Self-assembled nanoparticles based on glycol chitosan bearing hydrophobic moieties as carriers for doxorubicin: in vivo biodistribution and anti-tumor activity","volume":"27","author":"Young Jeong","year":"2006","journal-title":"Biomaterials"},{"key":"53","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1039\/C4NR05738D","article-title":"PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking","volume":"7","author":"Liu","year":"2015","journal-title":"Nanoscale"},{"key":"54","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.ijpharm.2013.08.071","article-title":"Folate-modified poly(2-ethyl-2-oxazoline) as hydrophilic corona in polymeric micelles for enhanced intracellular doxorubicin delivery","volume":"456","author":"Zhao","year":"2013","journal-title":"Int J Pharm"},{"key":"55","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/0006-2952(90)90293-T","article-title":"The pharmacokinetics of polymer-bound adriamycin","volume":"39","author":"Duncan","year":"1990","journal-title":"Biochem Pharmacol"},{"key":"56","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1039\/C7BM00271H","article-title":"Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease","volume":"5","author":"Chung","year":"2017","journal-title":"Biomater Sci"},{"key":"57","doi-asserted-by":"publisher","first-page":"4693","DOI":"10.1039\/c3sm00114h","article-title":"Cationic poly(2-oxazoline) hydrogels for reversible DNA binding","volume":"9","author":"Schubert","year":"2013","journal-title":"Soft Matter"},{"key":"58","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.jcis.2006.12.075","article-title":"Measurement and interpretation of electrokinetic phenomena","volume":"309","author":"Lyklema","year":"2007","journal-title":"J Colloid Interface Sci"},{"key":"59","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1006\/jcis.1994.1419","article-title":"A Simple Expression for Henry's Function for the Retardation Effect in Electrophoresis of Spherical Colloidal Particles","volume":"168","author":"Ohshima","year":"1994","journal-title":"J Colloid Interface Sci"}],"container-title":["Oncotarget"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.oncotarget.com\/lookup\/doi\/10.18632\/oncotarget.24806","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:15:09Z","timestamp":1751588109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.oncotarget.com\/lookup\/doi\/10.18632\/oncotarget.24806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,27]]},"references-count":59,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2018,4,27]]}},"alternative-id":["24806","29854280"],"URL":"https:\/\/doi.org\/10.18632\/oncotarget.24806","relation":{},"ISSN":["1949-2553"],"issn-type":[{"value":"1949-2553","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,27]]}}}