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Current Proteomics

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ISSN (Print): 1570-1646
ISSN (Online): 1875-6247

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Platelet-Derived Growth Factors (PDGFs) are Key Players in the Stimulation of Airway Smooth Muscle Cells (ASMCs) Alteration in Asthma and Chronic Obstructive Pulmonary Disease (COPD) with Multifarious Inhibitors at an Early Stage of Development

Author(s): Xiaodong Shi and Kwaku Appiah-Kubi*

Volume 17, Issue 4, 2020

Page: [324 - 332] Pages: 9

DOI: 10.2174/1570164617666190906151348

Price: $65

Abstract

Background: Alterations in airway smooth muscle cells cause an increase in their mass and result in a significant impact on airway remodeling diseases such as asthma and chronic obstructive pulmonary disease. Several studies have used platelet-derived growth factors to stimulate the alterations of airway smooth muscle cells.

Objective: This review discusses the platelet-derived growth factor-stimulated alterations of airway smooth muscle cells, diversity of inhibitors and inhibitory actions against these alterations and their related mechanisms, and how this diversity presents an avenue for the development of multifarious therapeutic targets for airway remodeling diseases especially asthma and chronic obstructive pulmonary disease.

Methods: A comprehensive search of PubMed and Medscape database for studies that investigated the stimulation of the alterations of airway smooth muscle cells in asthma and chronic obstructive pulmonary disease by platelet-derived growth factors and inhibitions of these alterations.

Results: Marked platelet-derived growth factor-stimulated alterations of airway smooth muscle cells are proliferation, migration and proliferative phenotype with diverse inhibitors and inhibitory actions against these alterations. Inhibitory actions are the result of the activation of protein kinase, overexpression of Tripartite motif protein, human transporter sub-family ABCA1 protein and miRNAs, knockdown of an isoform of reticulon 4 and follistatin protein, exogenous applications of recombinant proteins, supplements and active metabolite of retinoic acid, flavonoid extracts and polysaccharides extract.

Conclusion: The multifarious inhibitors and inhibitory actions with varied mechanisms in platelet-derived growth factors-stimulated alterations of airway smooth muscle cells present a potential for diverse therapeutic targets for the treatment of airway remodeling diseases.

Keywords: PDGFs, ASMCs, proliferation, migration, phenotype, inhibitors.

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[1]
Chou, K-C.; Zhang, C-T. Prediction of protein structural classes. Crit. Rev. Biochem. Mol. Biol., 1995, 30(4), 275-349.
[http://dx.doi.org/10.3109/10409239509083488] [PMID: 7587280]
[2]
Chou, J.J.; Matsuo, H.; Duan, H.; Wagner, G. Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell, 1998, 94(2), 171-180.
[http://dx.doi.org/10.1016/S0092-8674(00)81417-8] [PMID: 9695946]
[3]
Oxenoid, K.; Dong, Y.; Cao, C.; Cui, T.; Sancak, Y.; Markhard, A.L.; Grabarek, Z.; Kong, L.; Liu, Z.; Ouyang, B.; Cong, Y.; Mootha, V.K.; Chou, J.J. Architecture of the mitochondrial calcium uniporter. Nature, 2016, 533(7602), 269-273.
[http://dx.doi.org/10.1038/nature17656] [PMID: 27135929]
[4]
Fu, Q.; Fu, T-M.; Cruz, A.C.; Sengupta, P.; Thomas, S.K.; Wang, S.; Siegel, R.M.; Wu, H.; Chou, J.J. Structural basis and functional role of intramembrane trimerization of the Fas/CD95 death receptor. Mol. Cell, 2016, 61(4), 602-613.
[http://dx.doi.org/10.1016/j.molcel.2016.01.009] [PMID: 26853147]
[5]
Chou, J.J.; Li, H.; Salvesen, G.S.; Yuan, J.; Wagner, G. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell, 1999, 96(5), 615-624.
[http://dx.doi.org/10.1016/S0092-8674(00)80572-3] [PMID: 10089877]
[6]
Oxenoid, K.; Chou, J.J. The structure of phospholamban pentamer reveals a channel-like architecture in membranes. Proc. Natl. Acad. Sci. USA, 2005, 102(31), 10870-10875.
[http://dx.doi.org/10.1073/pnas.0504920102] [PMID: 16043693]
[7]
Chou, K-C.; Jones, D.; Heinrikson, R.L. Prediction of the tertiary structure and substrate binding site of caspase-8. FEBS Lett., 1997, 419(1), 49-54.
[http://dx.doi.org/10.1016/S0014-5793(97)01246-5] [PMID: 9426218]
[8]
Chou, K-C. Insights from modelling the 3D structure of the extracellular domain of α7 nicotinic acetylcholine receptor. Biochem. Biophys. Res. Commun., 2004, 319(2), 433-438.
[http://dx.doi.org/10.1016/j.bbrc.2004.05.016] [PMID: 15178425]
[9]
Chou, K-C. Insights from modeling the tertiary structure of human BACE2. J. Proteome Res., 2004, 3(5), 1069-1072.
[http://dx.doi.org/10.1021/pr049905s] [PMID: 15473697]
[10]
Chou, K-C. Impacts of bioinformatics to medicinal chemistry. Med. Chem., 2015, 11(3), 218-234.
[http://dx.doi.org/10.2174/1573406411666141229162834] [PMID: 25548930]
[11]
Chou, K-C. An unprecedented revolution in medicinal chemistry driven by the progress of biological science. Curr. Top. Med. Chem., 2017, 17(21), 2337-2358.
[http://dx.doi.org/10.2174/1568026617666170414145508] [PMID: 28413951]
[12]
Gunst, S.J. Airway Smooth Muscle and Asthma in Muscle; Hill, J.A; Olson, E.N., Ed.; Academic Press: Boston, Waltham, 2012, pp. 1359-1369.
[13]
Amrani, Y.; Panettieri, R.A. Airway smooth muscle: contraction and beyond. Int. J. Biochem. Cell Biol., 2003, 35(3), 272-276.
[http://dx.doi.org/10.1016/S1357-2725(02)00259-5] [PMID: 12531237]
[14]
Shi, W.; Luo, Y. The Origin of Stem Cells in Developmental Lungs in Reference Module in Biomedical Sciences; Elsevier, 2018.
[15]
Panettieri, R.A., Jr Airway smooth muscle: immunomodulatory cells that modulate airway remodeling? Respir. Physiol. Neurobiol., 2003, 137(2-3), 277-293.
[http://dx.doi.org/10.1016/S1569-9048(03)00153-8] [PMID: 14516732]
[16]
Doeing, D.C.; Solway, J. Airway smooth muscle in the pathophysiology and treatment of asthma. J. Appl. Physiol., 2013, 114(7), 834-843.
[http://dx.doi.org/10.1152/japplphysiol.00950.2012] [PMID: 23305987]
[17]
Wright, D.B.; Trian, T.; Siddiqui, S.; Pascoe, C.D.; Johnson, J.R.; Dekkers, B.G.J.; Dakshinamurti, S.; Bagchi, R.; Burgess, J.K.; Kanabar, V.; Ojo, O.O. Phenotype modulation of airway smooth muscle in asthma. Pulm. Pharmacol. Ther., 2013, 26(1), 42-49.
[http://dx.doi.org/10.1016/j.pupt.2012.08.005] [PMID: 22939888]
[18]
Zuyderduyn, S.; Sukkar, M.B.; Fust, A.; Dhaliwal, S.; Burgess, J.K. Treating asthma means treating airway smooth muscle cells. Eur. Respir. J., 2008, 32(2), 265-274.
[http://dx.doi.org/10.1183/09031936.00051407] [PMID: 18669785]
[19]
Stamatiou, R.; Paraskeva, E.; Gourgoulianis, K.; Molyvdas, P-A.; Hatziefthimiou, A. Cytokines and growth factors promote airway smooth muscle cell proliferation. ISRN Inflamm., 2012, 2012 731472
[http://dx.doi.org/10.5402/2012/731472] [PMID: 24049651]
[20]
McKay, S.; Sharma, H.S. Autocrine regulation of asthmatic airway inflammation: role of airway smooth muscle. Respir. Res., 2002, 3, 11.
[http://dx.doi.org/10.1186/rr160] [PMID: 11806846]
[21]
Shimizu, S.; Gabazza, E.C.; Hayashi, T.; Ido, M.; Adachi, Y.; Suzuki, K. Thrombin stimulates the expression of PDGF in lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol., 2000, 279(3), L503-L510.
[http://dx.doi.org/10.1152/ajplung.2000.279.3.L503] [PMID: 10956625]
[22]
Ito, I.; Fixman, E.D.; Asai, K.; Yoshida, M.; Gounni, A.S.; Martin, J.G.; Hamid, Q. Platelet-derived growth factor and transforming growth factor-β modulate the expression of matrix metalloproteinases and migratory function of human airway smooth muscle cells. Clin. Exp. Allergy, 2009, 39(9), 1370-1380.
[http://dx.doi.org/10.1111/j.1365-2222.2009.03293.x] [PMID: 19522858]
[23]
Rosethorne, E.M.; Charlton, S.J. Airway remodeling disease: primary human structural cells and phenotypic and pathway assays to identify targets with potential to prevent or reverse remodeling. J. Exp. Pharmacol., 2018, 10, 75-85.
[http://dx.doi.org/10.2147/JEP.S159124] [PMID: 30568517]
[24]
Girodet, P-O.; Ozier, A.; Bara, I.; Tunon de Lara, J.M.; Marthan, R.; Berger, P. Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention. Pharmacol. Ther., 2011, 130(3), 325-337.
[http://dx.doi.org/10.1016/j.pharmthera.2011.02.001] [PMID: 21334378]
[25]
Elias, J.A. Airway remodeling in asthma. Unanswered questions. Am. J. Respir. Crit. Care Med., 2000, 161(3 Pt 2), S168-S171.
[http://dx.doi.org/10.1164/ajrccm.161.supplement_2.a1q4-4] [PMID: 10712368]
[26]
Tang, J.; Luo, L. MicroRNA-20b-5p inhibits platelet-derived growth factor-induced proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3. Biomed. Pharmacother., 2018, 102, 34-40.
[http://dx.doi.org/10.1016/j.biopha.2018.03.015] [PMID: 29549727]
[27]
Zeng, X.; Cheng, Y.; Qu, Y.; Xu, J.; Han, Z.; Zhang, T. Curcumin inhibits the proliferation of airway smooth muscle cells in vitro and in vivo. Int. J. Mol. Med., 2013, 32(3), 629-636.
[http://dx.doi.org/10.3892/ijmm.2013.1425] [PMID: 23807697]
[28]
Deng, Y.; Zhang, Y.; Wu, H.; Shi, Z.; Sun, X. Knockdown of FSTL1 inhibits PDGF‑BB‑induced human airway smooth muscle cell proliferation and migration. Mol. Med. Rep., 2017, 15(6), 3859-3864.
[http://dx.doi.org/10.3892/mmr.2017.6439] [PMID: 28393245]
[29]
Dai, Y.; Li, Y.; Cheng, R.; Gao, J.; Li, Y.; Lou, C. TRIM37 inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells. Biomed. Pharmacother., 2018, 101, 24-29.
[http://dx.doi.org/10.1016/j.biopha.2018.02.057] [PMID: 29477054]
[30]
Ji, Y.; Yang, X.; Su, H. Overexpression of microRNA-375 impedes platelet-derived growth factor-induced proliferation and migration of human fetal airway smooth muscle cells by targeting Janus kinase 2. Biomed. Pharmacother., 2018, 98, 69-75.
[http://dx.doi.org/10.1016/j.biopha.2017.12.012] [PMID: 29245068]
[31]
Dai, Y.; Cheng, R.; Gao, J.; Li, Y.; Lou, C.; Li, Y. Casticin inhibits PDGF-induced proliferation and migration of airway smooth muscle cells. Eur. J. Pharmacol., 2018, 830, 39-46.
[http://dx.doi.org/10.1016/j.ejphar.2018.04.016] [PMID: 29665364]
[32]
García-Olivas, R.; Hoebeke, J.; Castel, S.; Reina, M.; Fager, G.; Lustig, F.; Vilaró, S. Differential binding of platelet-derived growth factor isoforms to glycosaminoglycans. Histochem. Cell Biol., 2003, 120(5), 371-382.
[http://dx.doi.org/10.1007/s00418-003-0576-6] [PMID: 14557886]
[33]
Andersson, M.; Ostman, A.; Westermark, B.; Heldin, C-H. Characterization of the retention motif in the C-terminal part of the long splice form of platelet-derived growth factor A-chain. J. Biol. Chem., 1994, 269(2), 926-930.
[PMID: 8288645]
[34]
Chen, P-H.; Chen, X.; He, X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim. Biophys. Acta, 2013, 1834(10), 2176-2186.
[http://dx.doi.org/10.1016/j.bbapap.2012.10.015] [PMID: 23137658]
[35]
Li, E.; Hristova, K. Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies. Biochemistry, 2006, 45(20), 6241-6251.
[http://dx.doi.org/10.1021/bi060609y] [PMID: 16700535]
[36]
Cao, Y. Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis. Trends Mol. Med., 2013, 19(8), 460-473.
[http://dx.doi.org/10.1016/j.molmed.2013.05.002] [PMID: 23773831]
[37]
Jones, R.L.; Noble, P.B.; Elliot, J.G.; James, A.L. Airway remodelling in COPD: It’s not asthma! Respirology, 2016, 21(8), 1347-1356.
[http://dx.doi.org/10.1111/resp.12841] [PMID: 27381663]
[38]
D’Antoni, M.L.; Torregiani, C.; Ferraro, P.; Michoud, M-C.; Mazer, B.; Martin, J.G.; Ludwig, M.S. Effects of decorin and biglycan on human airway smooth muscle cell proliferation and apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol., 2008, 294(4), L764-L771.
[http://dx.doi.org/10.1152/ajplung.00436.2007] [PMID: 18245265]
[39]
Day, R.M.; Lee, Y.H.; Park, A-M.; Suzuki, Y.J. Retinoic acid inhibits airway smooth muscle cell migration. Am. J. Respir. Cell Mol. Biol., 2006, 34(6), 695-703.
[http://dx.doi.org/10.1165/rcmb.2005-0306OC] [PMID: 16456186]
[40]
D’Antoni, M.L.; Risse, P-A.; Ferraro, P.; Martin, J.G.; Ludwig, M.S. Effects of decorin and biglycan on human airway smooth muscle cell adhesion. Matrix Biol., 2012, 31(2), 101-112.
[http://dx.doi.org/10.1016/j.matbio.2011.11.001] [PMID: 22155154]
[41]
Nakajima, M.; Kawaguchi, M.; Ota, K.; Fujita, J.; Matsukura, S.; Huang, S.K.; Morishima, Y.; Ishii, Y.; Satoh, H.; Sakamoto, T.; Hizawa, N. IL-17F induces IL-6 via TAK1-NFκB pathway in airway smooth muscle cells. Immun. Inflamm. Dis., 2017, 5(2), 124-131.
[http://dx.doi.org/10.1002/iid3.149] [PMID: 28474507]
[42]
Dekkers, B.G.; Bos, I.S.T.; Zaagsma, J.; Meurs, H. Functional consequences of human airway smooth muscle phenotype plasticity. Br. J. Pharmacol., 2012, 166(1), 359-367.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01773.x] [PMID: 22053853]
[43]
Liu, W.; Kong, H.; Zeng, X.; Wang, J.; Wang, Z.; Yan, X.; Wang, Y.; Xie, W.; Wang, H. Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration. Exp. Cell Res., 2015, 336(2), 204-210.
[http://dx.doi.org/10.1016/j.yexcr.2015.06.020] [PMID: 26160451]
[44]
Hirota, J.A.; Ask, K.; Farkas, L.; Smith, J.A.; Ellis, R.; Rodriguez-Lecompte, J.C.; Kolb, M.; Inman, M.D. In vivo role of platelet-derived growth factor-BB in airway smooth muscle proliferation in mouse lung. Am. J. Respir. Cell Mol. Biol., 2011, 45(3), 566-572.
[http://dx.doi.org/10.1165/rcmb.2010-0277OC] [PMID: 21216974]
[45]
Wei, Y.; Xu, Y-D.; Yin, L-M.; Wang, Y.; Ran, J.; Liu, Q.; Ma, Z-F.; Liu, Y-Y.; Yang, Y-Q. Recombinant rat CC10 protein inhibits PDGF-induced airway smooth muscle cells proliferation and migration. BioMed Res. Int., 2013, 2013 690937
[http://dx.doi.org/10.1155/2013/690937] [PMID: 24106713]
[46]
Carlin, S.M.; Roth, M.; Black, J.L. Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol., 2003, 284(6), L1020-L1026.
[http://dx.doi.org/10.1152/ajplung.00092.2002] [PMID: 12576295]
[47]
Yang, C-H.; Tsao, C-F.; Ko, W-S.; Chiou, Y-L. The oligo fucoidan inhibits platelet-derived growth factor-stimulated proliferation of airway smooth muscle cells. Mar. Drugs, 2016, 14(1), 15.
[http://dx.doi.org/10.3390/md14010015] [PMID: 26761017]
[48]
Xu, Y-D.; Wei, Y.; Wang, Y.; Yin, L-M.; Park, G-H.; Liu, Y-Y.; Yang, Y-Q. Exogenous S100A8 protein inhibits PDGF-induced migration of airway smooth muscle cells in a RAGE-dependent manner. Biochem. Biophys. Res. Commun., 2016, 472(1), 243-249.
[http://dx.doi.org/10.1016/j.bbrc.2016.02.098] [PMID: 26920052]
[49]
Pera, T.; Sami, R.; Zaagsma, J.; Meurs, H. TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol., 2011, 301(5), L822-L828.
[http://dx.doi.org/10.1152/ajplung.00017.2011] [PMID: 21873447]
[50]
Cheng, W.; Yan, K.; Chen, Y.; Zhang, W.; Ji, Z.; Dang, C. ABCA1 inhibits PDGF-induced proliferation and migration of rat airway smooth muscle cell through blocking TLR2/NF-κB/NFATc1 signaling. J. Cell. Biochem., 2018, 119(9), 7388-7396.
[http://dx.doi.org/10.1002/jcb.27046]
[51]
Yang, G.; Li, J-Q.; Bo, J-P.; Wang, B.; Tian, X-R.; Liu, T-Z.; Liu, Z-L. Baicalin inhibits PDGF-induced proliferation and migration of airway smooth muscle cells. Int. J. Clin. Exp. Med., 2015, 8(11), 20532-20539.
[PMID: 26884970]
[52]
Yao, J.; Zhang, Y.S.; Feng, G.Z.; Du, Q. Chrysin inhibits human airway smooth muscle cells proliferation through the extracellular signal-regulated kinase 1/2 signaling pathway. Mol. Med. Rep., 2015, 12(5), 7693-7698.
[http://dx.doi.org/10.3892/mmr.2015.4401] [PMID: 26502995]
[53]
Wang, T-Y.; Zhou, Q-L.; Li, M.; Shang, Y-X. Shikonin alleviates allergic airway remodeling by inhibiting the ERK-NF-κB signaling pathway. Int. Immunopharmacol., 2017, 48, 169-179.
[http://dx.doi.org/10.1016/j.intimp.2017.05.011] [PMID: 28521243]
[54]
Simeone-Penney, M.C.; Severgnini, M.; Rozo, L.; Takahashi, S.; Cochran, B.H.; Simon, A.R. PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1. Am. J. Physiol. Lung Cell. Mol. Physiol., 2008, 294(4), L698-L704.
[http://dx.doi.org/10.1152/ajplung.00529.2007] [PMID: 18310224]
[55]
Movassagh, H.; Shan, L.; Halayko, A.J.; Roth, M.; Tamm, M.; Chakir, J.; Gounni, A.S. Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration. J. Allergy Clin. Immunol., 2014, 133(2), 560-567.
[http://dx.doi.org/10.1016/j.jaci.2013.06.011] [PMID: 23932461]
[56]
Liu, L.; Pan, Y.; Song, Y.; Su, X.; Ke, R.; Yang, L.; Gao, L.; Li, M. Activation of AMPK α2 inhibits airway smooth muscle cells proliferation. Eur. J. Pharmacol., 2016, 791, 235-243.
[http://dx.doi.org/10.1016/j.ejphar.2016.09.003] [PMID: 27600020]
[57]
Xu, W.; Hong, W.; Shao, Y.; Ning, Y.; Cai, Z.; Li, Q. Nogo-B regulates migration and contraction of airway smooth muscle cells by decreasing ARPC 2/3 and increasing MYL-9 expression. Respir. Res., 2011, 12, 14.
[http://dx.doi.org/10.1186/1465-9921-12-14] [PMID: 21251247]
[58]
Ning, Y.; Sun, Q.; Dong, Y.; Xu, W.; Zhang, W.; Huang, H.; Li, Q. Slit2-N inhibits PDGF-induced migration in rat airway smooth muscle cells: WASP and Arp2/3 involved. Toxicology, 2011, 283(1), 32-40.
[http://dx.doi.org/10.1016/j.tox.2011.01.026] [PMID: 21315131]
[59]
Chiou, Y-L.; Shieh, J-J.; Lin, C-Y. Blocking of Akt/NF-kappaB signaling by pentoxifylline inhibits platelet-derived growth factor-stimulated proliferation in Brown Norway rat airway smooth muscle cells. Pediatr. Res., 2006, 60(6), 657-662.
[http://dx.doi.org/10.1203/01.pdr.0000246105.56278.98] [PMID: 17065572]
[60]
Seidel, P.; Goulet, S.; Hostettler, K.; Tamm, M.; Roth, M. DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1. Respir. Res., 2010, 11, 145.
[http://dx.doi.org/10.1186/1465-9921-11-145] [PMID: 20961405]
[61]
Chiou, Y-L. The supplementation of zinc increased the apoptosis of airway smooth muscle cells by increasing p38 phosphorylation. Environ. Toxicol. Pharmacol., 2012, 33(1), 70-77.
[http://dx.doi.org/10.1016/j.etap.2011.11.002] [PMID: 22134001]
[62]
Liao, G.; Panettieri, R.A.; Tang, D.D. MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells. Physiol. Rep., 2015, 3(9), 3.
[http://dx.doi.org/10.14814/phy2.12541] [PMID: 26400984]
[63]
Salhiyyah, K.; Forster, R.; Senanayake, E.; Abdel-Hadi, M.; Booth, A.; Michaels, J.A. Pentoxifylline for intermittent claudication. Cochrane Database Syst. Rev., 2015. 9CD005262
[http://dx.doi.org/10.1002/14651858.CD005262.pub3]
[64]
Zhu, Z-R.; He, Q.; Wu, W-B.; Chang, G-Q.; Yao, C.; Zhao, Y.; Wang, M.; Wang, S-M. MiR-140-3p is involved in in-stent restenosis by targeting C-Myb and BCL-2 in peripheral artery disease. J. Atheroscler. Thromb., 2018, 25(11), 1168-1181.
[http://dx.doi.org/10.5551/jat.44024] [PMID: 29760303]

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