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Sphingolipids: Basic Science and Drug Development pp 197–210Cite as

The Therapeutic Potential of Nanoscale Sphingolipid Technologies

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 215))

Abstract

Nanotechnologies, while small in size, widen the scope of drug delivery options for compounds with problematic pharmacokinetics, such as bioactive sphingolipids. We describe the development of historical sphingolipid nanotechnologies, such as nanoliposomes, and project future uses for a broad repertoire of nanoscale sphingolipid therapy formulations. In particular, we describe sphingo-nanotherapies for treatment of cancer, inflammatory disease, and cardiovascular disease. We conclude with a discussion of the challenges associated with regulatory approval, scale-up, and development of these nanotechnology therapies for clinical applications.

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References

  • Adair JH, Parette MP, Altinoglu EI, Kester M (2010) Nanoparticulate alternatives for drug delivery. ACS Nano 4(9):4967–4970

    Article  PubMed  CAS  Google Scholar 

  • Adrian JE, Wolf A, Steinbach A, Rossler J, Suss R (2011) Targeted delivery to neuroblastoma of novel siRNA-anti-GD2-liposomes prepared by dual asymmetric centrifugation and sterol-based post-insertion method. Pharm Res 28(9):2261–2272

    Article  PubMed  CAS  Google Scholar 

  • Alewijnse AE, Peters SL (2008) Sphingolipid signalling in the cardiovascular system: good, bad or both? Eur J Pharmacol 585(2–3):292–302

    Article  PubMed  CAS  Google Scholar 

  • Allen TM, Chonn A (1987) Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett 223(1):42–46

    Article  PubMed  CAS  Google Scholar 

  • Allen TM, Hansen C, Rutledge J (1989) Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta 981(1):27–35

    Article  PubMed  CAS  Google Scholar 

  • Bangham AD, Standish MM, Watkins JC (1965) Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 13(1):238–252

    Article  PubMed  CAS  Google Scholar 

  • Barbet J, Machy P, Leserman LD (1981) Monoclonal antibody covalently coupled to liposomes: specific targeting to cells. J Supramol Struct Cell Biochem 16(3):243–258

    Article  PubMed  CAS  Google Scholar 

  • Barth BM, Gustafson SJ, Young MM, Fox TE, Shanmugavelandy SS, Kaiser JM, Cabot MC, Kester M, Kuhn TB (2010a) Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance. Cancer Biol Ther 10(11):1126–1136

    Article  PubMed  CAS  Google Scholar 

  • Barth BM, Sharma R, Altinoglu EI, Morgan TT, Shanmugavelandy SS, Kaiser JM, McGovern C, Matters GL, Smith JP, Kester M, Adair JH (2010b) Bioconjugation of calcium phosphosilicate composite nanoparticles for selective targeting of human breast and pancreatic cancers in vivo. ACS Nano 4(3):1279–1287

    Article  PubMed  CAS  Google Scholar 

  • Barth BM, Cabot MC, Kester M (2011) Ceramide-based therapeutics for the treatment of cancer. Anticancer Agents Med Chem 11(9):911–919

    Article  PubMed  CAS  Google Scholar 

  • Bazile D, Prud’homme C, Bassoullet MT, Marlard M, Spenlehauer G, Veillard M (1995) Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system. J Pharm Sci 84(4):493–498

    Article  PubMed  CAS  Google Scholar 

  • Bischoff A, Czyborra P, Meyer Zu Heringdorf D, Jakobs KH, Michel MC (2000) Sphingosine-1-phosphate reduces rat renal and mesenteric blood flow in vivo in a pertussis toxin-sensitive manner. Br J Pharmacol 130(8):1878–1883

    Article  PubMed  CAS  Google Scholar 

  • Boddapati SV, D’Souza GG, Erdogan S, Torchilin VP, Weissig V (2008) Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett 8(8):2559–2563

    Article  PubMed  CAS  Google Scholar 

  • Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277(24):21453–21457

    Article  PubMed  CAS  Google Scholar 

  • Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9(11):883–897

    Article  PubMed  CAS  Google Scholar 

  • Charles R, Sandirasegarane L, Yun J, Bourbon N, Wilson R, Rothstein RP, Levison SW, Kester M (2000) Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in carotid arteries. Circ Res 87(4):282–288

    Article  PubMed  CAS  Google Scholar 

  • Chiba N, Masuda A, Yoshikai Y, Matsuguchi T (2007) Ceramide inhibits LPS-induced production of IL-5, IL-10, and IL-13 from mast cells. J Cell Physiol 213(1):126–136

    Article  PubMed  CAS  Google Scholar 

  • Cho HJ, Yoon HY, Koo H, Ko SH, Shim JS, Lee JH, Kim K, Kwon IC, Kim DD (2011) Self-assembled nanoparticles based on hyaluronic acid-ceramide (HA-CE) and Pluronic(R) for tumor-targeted delivery of docetaxel. Biomaterials 32(29):7181–7190

    Article  PubMed  CAS  Google Scholar 

  • Cho HJ, Yoon IS, Yoon HY, Koo H, Jin YJ, Ko SH, Shim JS, Kim K, Kwon IC, Kim DD (2012) Polyethylene glycol-conjugated hyaluronic acid-ceramide self-assembled nanoparticles for targeted delivery of doxorubicin. Biomaterials 33(4):1190–1200

    Article  PubMed  CAS  Google Scholar 

  • Desai A, Vyas T, Amiji M (2008) Cytotoxicity and apoptosis enhancement in brain tumor cells upon coadministration of paclitaxel and ceramide in nanoemulsion formulations. J Pharm Sci 97(7):2745–2756

    Article  PubMed  CAS  Google Scholar 

  • Devalapally H, Duan Z, Seiden MV, Amiji MM (2007) Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int J Cancer 121(8):1830–1838

    Article  PubMed  CAS  Google Scholar 

  • Devalapally H, Duan Z, Seiden MV, Amiji MM (2008) Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res 14(10):3193–3203

    Article  PubMed  CAS  Google Scholar 

  • Dickson MA, Carvajal RD, Merrill AH Jr, Gonen M, Cane LM, Schwartz GK (2011) A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. Clin Cancer Res 17(8):2484–2492

    Article  PubMed  CAS  Google Scholar 

  • Dobrovolskaia MA, McNeil SE (2007) Immunological properties of engineered nanomaterials. Nat Nanotechnol 2(8):469–478

    Article  PubMed  CAS  Google Scholar 

  • Edmonds Y, Milstien S, Spiegel S (2011) Development of small-molecule inhibitors of sphingosine-1-phosphate signaling. Pharmacol Ther 132(3):352–360

    Article  PubMed  CAS  Google Scholar 

  • Gregoriadis G, Ryman BE (1972) Fate of protein-containing liposomes injected into rats. An approach to the treatment of storage diseases. Eur J Biochem 24(3):485–491

    Article  PubMed  CAS  Google Scholar 

  • Hankins JL, Fox TE, Barth BM, Unrath KA, Kester M (2011) Exogenous ceramide-1-phosphate reduces lipopolysaccharide (LPS)-mediated cytokine expression. J Biol Chem 286(52): 44357–44366

    Article  PubMed  CAS  Google Scholar 

  • Haxby JA, Gotze O, Muller-Eberhard HJ, Kinsky SC (1969) Release of trapped marker from liposomes by the action of purified complement components. Proc Natl Acad Sci U S A 64(1): 290–295

    Article  PubMed  CAS  Google Scholar 

  • Jatoi A, Suman VJ, Schaefer P, Block M, Loprinzi C, Roche P, Garneau S, Morton R, Stella PJ, Alberts SR, Pittelkow M, Sloan J, Pagano R (2003) A phase II study of topical ceramides for cutaneous breast cancer. Breast Cancer Res Treat 80(1):99–104

    Article  PubMed  CAS  Google Scholar 

  • Jiang Y, DiVittore NA, Kaiser JM, Shanmugavelandy SS, Fritz JL, Heakal Y, Tagaram HRS, Cheng H, Cabot MC, Staveley-O’Carroll KF, Tran MA, Fox TE, Barth BM, Kester M (2011) Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther 12(7):574–585

    Article  PubMed  CAS  Google Scholar 

  • Jozefowski S, Czerkies M, Lukasik A, Bielawska A, Bielawski J, Kwiatkowska K, Sobota A (2010) Ceramide and ceramide 1-phosphate are negative regulators of TNF-α production induced by lipopolysaccharide. J Immunol 185(11):6960–6973

    Article  PubMed  CAS  Google Scholar 

  • Kedderis LB, Bozigian HP, Kleeman JM, Hall RL, Palmer TE, Harrison SD Jr, Susick RL Jr (1995) Toxicity of the protein kinase C inhibitor safingol administered alone and in combination with chemotherapeutic agents. Fundam Appl Toxicol 25(2):201–217

    Article  PubMed  CAS  Google Scholar 

  • Kester M, Heakal Y, Fox T, Sharma A, Robertson GP, Morgan TT, Altinoglu EI, Tabakovic A, Parette MR, Rouse SM, Ruiz-Velasco V, Adair JH (2008) Calcium phosphate nanocomposite particles for in vitro imaging and encapsulated chemotherapeutic drug delivery to cancer cells. Nano Lett 8(12):4116–4121

    Article  PubMed  CAS  Google Scholar 

  • Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268(1):235–237

    Article  PubMed  CAS  Google Scholar 

  • Koshkaryev A, Piroyan A, Torchilin VP (2012) Increased apoptosis in cancer cells in vitro and in vivo by ceramides in transferrin-modified liposomes. Cancer Biol Ther 13(1):50–60

    Article  PubMed  CAS  Google Scholar 

  • Kumari A, Yadav SK, Yadav SC (2010) Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 75(1):1–18

    Article  PubMed  CAS  Google Scholar 

  • Lachmann PJ, Munn EA, Weissmanng (1970) Complement-mediated lysis of liposomes produced by the reactive lysis procedure. Immunology 19(6):983–986

    PubMed  CAS  Google Scholar 

  • Lamour NF, Wijesinghe DS, Mietla JA, Ward KE, Stahelin RV, Chalfant CE (2011) Ceramide kinase regulates the production of tumor necrosis factor alpha (TNFalpha) via inhibition of TNFalpha-converting enzyme. J Biol Chem 286(50):42808–42817

    Article  PubMed  CAS  Google Scholar 

  • Larrick JW, Cresswell P (1979) Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J Supramol Struct 11(4):579–586

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Ryland L, Yang J, Liao A, Aliaga C, Watts R, Tan SF, Kaiser J, Shanmugavelandy SS, Rogers A, Loughran K, Petersen B, Yuen J, Meng F, Baab KT, Jarbadan NR, Broeg K, Zhang R, Liao J, Sayers TJ, Kester M, Loughran TP Jr (2010) Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 116(20):4192–4201

    Article  PubMed  CAS  Google Scholar 

  • Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296(5566):346–349

    Article  PubMed  CAS  Google Scholar 

  • Maruyama K, Kennel SJ, Huang L (1990) Lipid composition is important for highly efficient target binding and retention of immunoliposomes. Proc Natl Acad Sci U S A 87(15): 5744–5748

    Article  PubMed  CAS  Google Scholar 

  • Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427(6972):355–360

    Article  PubMed  CAS  Google Scholar 

  • Matsumura Y, Maeda H (1986) A New concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Part 1):6387–6392

    PubMed  CAS  Google Scholar 

  • Morgan TT, Muddana HS, Altinoǧlu EI, Rouse SM, Tabaković A, Tabouillot T, Russin TJ, Shanmugavelandy SS, Butler PJ, Eklund PC, Yun JK, Kester M, Adair JH (2008) Encapsulation of organic molecules in calcium phosphate nanocomposite particles for intracellular imaging and drug delivery. Nano Lett 8(12):4108–4115

    Article  PubMed  CAS  Google Scholar 

  • O’Neill SM, Olympia DK, Fox TE, Brown JT, Stover TC, Houck KL, Wilson R, Waybill P, Kozak M, Levison SW, Weber N, Karavodin LM, Kester M (2008) C(6)-ceramide-coated catheters promote re-endothelialization of stretch-injured arteries. Vasc Dis Prev 5(3):200–210

    Article  PubMed  Google Scholar 

  • Pagnan G, Montaldo PG, Pastorino F, Raffaghello L, Kirchmeier M, Allen TM, Ponzoni M (1999) GD2-mediated melanoma cell targeting and cytotoxicity of liposome-entrapped fenretinide. Int J Cancer 81(2):268–274

    Article  PubMed  CAS  Google Scholar 

  • Pastorino F, Brignole C, Marimpietri D, Pagnan G, Morando A, Ribatti D, Semple SC, Gambini C, Allen TM, Ponzoni M (2003) Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models. Clin Cancer Res 9(12):4595–4605

    PubMed  CAS  Google Scholar 

  • Pastorino F, Brignole C, Di Paolo D, Nico B, Pezzolo A, Marimpietri D, Pagnan G, Piccardi F, Cilli M, Longhi R, Ribatti D, Corti A, Allen TM, Ponzoni M (2006) Targeting liposomal chemotherapy via both tumor cell-specific and tumor vasculature-specific ligands potentiates therapeutic efficacy. Cancer Res 66(20):10073–10082

    Article  PubMed  CAS  Google Scholar 

  • Peters SL, Alewijnse AE (2007) Sphingosine-1-phosphate signaling in the cardiovascular system. Curr Opin Pharmacol 7(2):186–192

    Article  PubMed  CAS  Google Scholar 

  • Product Information Booklet. http://doxil.com/assets/DOXIL_PI_Booklet.pdf Accessed 3 Mar 2012

  • Rahman AM, Yusuf SW, Ewer MS (2007) Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation. Int J Nanomedicine 2(4):567–583

    PubMed  CAS  Google Scholar 

  • Rozenova KA, Deevska GM, Karakashian AA, Nikolova-Karakashian MN (2010) Studies on the role of acid sphingomyelinase and ceramide in the regulation of tumor necrosis factor alpha (TNFalpha)-converting enzyme activity and TNFalpha secretion in macrophages. J Biol Chem 285(27):21103–21113

    Article  PubMed  CAS  Google Scholar 

  • Salli U, Fox TE, Carkaci-Salli N, Sharma A, Robertson GP, Kester M, Vrana KE (2009) Propagation of undifferentiated human embryonic stem cells with nano-liposomal ceramide. Stem Cells Dev 18(1):55–65

    Article  PubMed  CAS  Google Scholar 

  • Shabbits JA, Mayer LD (2003a) High ceramide content liposomes with in vivo antitumor activity. Anticancer Res 23(5A):3663–3669

    PubMed  CAS  Google Scholar 

  • Shabbits JA, Mayer LD (2003b) Intracellular delivery of ceramide lipids via liposomes enhances apoptosis in vitro. Biochim Biophys Acta 1612(1):98–106

    Article  PubMed  CAS  Google Scholar 

  • Siskind LJ, Colombini M (2000) The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J Biol Chem 275(49):38640–38644

    Article  PubMed  CAS  Google Scholar 

  • Stover T, Kester M (2003) Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J Pharmacol Exp Ther 307(2):468–475

    Article  PubMed  CAS  Google Scholar 

  • Stover TC, Sharma A, Robertson GP, Kester M (2005) Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res 11(9):3465–3474

    Article  PubMed  CAS  Google Scholar 

  • Stover TC, Kim YS, Lowe TL, Kester M (2008) Thermoresponsive and biodegradable linear-dendritic nanoparticles for targeted and sustained release of a pro-apoptotic drug. Biomaterials 29(3):359–369

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Fox T, Adhikary G, Kester M, Pearlman E (2008) Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J Leukoc Biol 83(6):1512–1521

    Article  PubMed  CAS  Google Scholar 

  • Tagaram HR, Divittore NA, Barth BM, Kaiser JM, Avella D, Kimchi ET, Jiang Y, Isom HC, Kester M, Staveley-O’Carroll KF (2011) Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut 60(5):695–701

    Article  PubMed  CAS  Google Scholar 

  • Tan KB, Ling LU, Bunte RM, Chng WJ, Chiu GN (2012) In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia. J Control Release 160(2): 290–298

    Article  PubMed  CAS  Google Scholar 

  • Tang YD, Pandey A, Kolmakova A, Wang XT, Venkatraman SS, Chatterjee S, Boey FY (2009) Use of a novel anti-proliferative compound coated on a biopolymer to mitigate platelet-derived growth factor-induced proliferation in human aortic smooth muscle cells: comparison with sirolimus. Glycoconj J 26(6):721–732

    Article  PubMed  CAS  Google Scholar 

  • Tran MA, Smith CD, Kester M, Robertson GP (2008) Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin Cancer Res 14(11):3571–3581

    Article  PubMed  CAS  Google Scholar 

  • van Lummel M, van Blitterswijk WJ, Vink SR, Veldman RJ, van der Valk MA, Schipper D, Dicheva BM, Eggermont AM, ten Hagen TL, Verheij M, Koning GA (2011) Enriching lipid nanovesicles with short-chain glucosylceramide improves doxorubicin delivery and efficacy in solid tumors. FASEB J 25(1):280–289

    Article  PubMed  Google Scholar 

  • van Vlerken LE, Duan Z, Seiden MV, Amiji MM (2007) Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res 67(10): 4843–4850

    Article  PubMed  Google Scholar 

  • Yilmaz E, Borchert HH (2006) Effect of lipid-containing, positively charged nanoemulsions on skin hydration, elasticity and erythema—an in vivo study. Int J Pharm 307(2):232–238

    Article  PubMed  CAS  Google Scholar 

  • Yu B, Tai HC, Xue W, Lee LJ, Lee RJ (2010) Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol 27(7):286–298

    Article  PubMed  CAS  Google Scholar 

  • Zolnik BS, Stern ST, Kaiser JM, Heakal Y, Clogston JD, Kester M, McNeil SE (2008) Rapid distribution of liposomal short-chain ceramide in vitro and in vivo. Drug Metab Dispos 36(8): 1709–1715

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest Statement

Penn State Research Foundation has licensed several nanoscale formulations for sphingolipids to Keystone Nano., Inc. (Boalsburg, PA). Dr. Kester is cofounder and Chief Medical Officer of Keystone Nano.

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Authors and Affiliations

  1. Department of Pharmacology, R130, Penn State University College of Medicine, Hershey, PA, 17033, USA

    Jody L. Hankins, Ushma A. Doshi, Jeremy K. Haakenson, Megan M. Young, Brian M. Barth & Mark Kester

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  1. Jody L. Hankins
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  2. Ushma A. Doshi
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  3. Jeremy K. Haakenson
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  4. Megan M. Young
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  5. Brian M. Barth
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  6. Mark Kester
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Correspondence to Mark Kester .

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Editors and Affiliations

  1. , Department of Molecular Biology, University of Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany

    Erich Gulbins

  2. Division of Pulmonary, Allergy, Critical, Department of Medicine, Indiana University School of Medicine, W. Walnut Street 980, Indianapolis, 46202, Indiana, USA

    Irina Petrache

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Hankins, J.L., Doshi, U.A., Haakenson, J.K., Young, M.M., Barth, B.M., Kester, M. (2013). The Therapeutic Potential of Nanoscale Sphingolipid Technologies. In: Gulbins, E., Petrache, I. (eds) Sphingolipids: Basic Science and Drug Development. Handbook of Experimental Pharmacology, vol 215. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1368-4_11

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