Biologic Drugs: A New Target Therapy in COPD?

References

• Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 [cited 2017 02/10/2017]. Available from: http://goldcopd.org.
   Google Scholar
• Lelieveld J, Evans JS, Fnais M, Giannadaki D, Pozzer A. The contribution of outdoor air pollution sources to premature mortality on a global scale. Nature. 2015;525(7569):367–71. doi:10.1038/nature15371.
   PubMed Web of Science ®Google Scholar
• Goren A, Gupta S, Dong P, Feng Y, Chen C, Liu D. Burden of smoking among adults with COPD, chronic bronchitis, and emphysema in urban China. Int J Clin Pract. 2015;69(9):1015–28. doi:10.1111/ijcp.12680.
   PubMed Web of Science ®Google Scholar
• The global burden of disease [Report]. [cited 2017 12/12/2017]. Available from: http://www.who.int/respiratory/copd/en/.
   Google Scholar
• Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health. 2015;5(2):020415. doi:10.7189/jogh.05-020415.
   PubMed Web of Science ®Google Scholar
• The Burden of Lung Disease: a statistics report from the British Thoracic Society 2006 [updated 2006]. Available from: https://www.brit-thoracic.org.uk/document-library/delivery-of-respiratory-care/burden-of-lung-disease/burden-of-lung-disease-2006/.
   Google Scholar
• Castaldi PJ, Benet M, Petersen H, Rafaels N, Finigan J, Paoletti M, et al. Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts. Thorax. 2017;72(11):998–1006. doi:10.1136/thoraxjnl-2016-209846.
   PubMed Web of Science ®Google Scholar
• Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med. 1998;158(4):1277–85. doi:10.1164/ajrccm.158.4.9802078.
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond). 2017;131(13):1541–58. doi:10.1042/CS20160487.
   PubMed Web of Science ®Google Scholar
• Eapen MS, Myers S, Walters EH, Sohal SS. Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox. Expert Rev Respir Med. 2017;11(10):827–39. doi:10.1080/17476348.2017.1360769.
   PubMed Web of Science ®Google Scholar
• Finney LJ, Ritchie A, Pollard E, Johnston SL, Mallia P. Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae. Int J Chron Obstruct Pulmon Dis. 2014;9:1119–32. doi:10.2147/COPD.S54477.
   PubMed Web of Science ®Google Scholar
• George L, Brightling CE. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther Adv Chronic Dis. 2016;7(1):34–51. doi:10.1177/2040622315609251.
   PubMed Web of Science ®Google Scholar
• Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994;150(6 Pt 1):1646–52. doi:10.1164/ajrccm.150.6.7952628.
   PubMed Web of Science ®Google Scholar
• Papi ABC, Pedersen S, Reddel HK. Asthma. The Lancet. 2017. Epub 19/12/2017.
   Google Scholar
• Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(6):1304–9. doi:10.1164/ajrccm.163.6.2009116.
   PubMed Web of Science ®Google Scholar
• Maestrelli P, Saetta M, Mapp CE, Fabbri LM. Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(10 Pt 2):S76–80. doi:10.1164/ajrccm.164.supplement_2.2106067.
   PubMed Web of Science ®Google Scholar
• Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364(9435):709–21. doi:10.1016/S0140-6736(04)16900-6.
   PubMed Web of Science ®Google Scholar
• Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53. doi:10.1056/NEJMoa032158.
   PubMed Web of Science ®Google Scholar
• McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567–75. doi:10.1056/NEJMoa1106955.
   PubMed Web of Science ®Google Scholar
• Rennard SI, Togo S, Holz O. Cigarette smoke inhibits alveolar repair: a mechanism for the development of emphysema. Proc Am Thorac Soc. 2006;3(8):703–8. doi:10.1513/pats.200605-121SF.
   PubMedGoogle Scholar
• Wang H, Liu X, Umino T, Skold CM, Zhu Y, Kohyama T, et al. Cigarette smoke inhibits human bronchial epithelial cell repair processes. Am J Respir Cell Mol Biol. 2001;25(6):772–9. doi:10.1165/ajrcmb.25.6.4458.
   PubMed Web of Science ®Google Scholar
• Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, et al. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1997;156(2 Pt 1):591–9. doi:10.1164/ajrccm.156.2.9609066.
   PubMed Web of Science ®Google Scholar
• Polosa R, Prosperini G, Leir SH, Holgate ST, Lackie PM, Davies DE. Expression of c-erbB receptors and ligands in human bronchial mucosa. Am J Respir Cell Mol Biol. 1999;20(5):914–23.
   PubMed Web of Science ®Google Scholar
• O'Donnell RA, Richter A, Ward J, Angco G, Mehta A, Rousseau K, et al. Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax. 2004;59(12):1032–40. doi:10.1136/thx.2004.028043.
   PubMed Web of Science ®Google Scholar
• de Boer WI, Hau CM, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am J Clin Pathol. 2006;125(2):184–92. doi:10.1309/W1AX-KGT7-UA37-X257.
   PubMed Web of Science ®Google Scholar
• Kim S, Lewis C, Nadel JA. CCL20/CCR6 feedback exaggerates epidermal growth factor receptor-dependent MUC5AC mucin production in human airway epithelial (NCI-H292) cells. J Immunol. 2011;186(6):3392–400. doi:10.4049/jimmunol.1003377.
   PubMed Web of Science ®Google Scholar
• Bosken CH, Wiggs BR, Pare PD, Hogg JC. Small airway dimensions in smokers with obstruction to airflow. Am Rev Respir Dis. 1990;142(3):563–70. doi:10.1164/ajrccm/142.3.563.
   PubMedGoogle Scholar
• Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157(3 Pt 1):822–6. doi:10.1164/ajrccm.157.3.9709027.
   PubMed Web of Science ®Google Scholar
• Araya J, Cambier S, Markovics JA, Wolters P, Jablons D, Hill A, et al. Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J Clin Invest. 2007;117(11):3551–62. doi:10.1172/JCI32526.
   PubMed Web of Science ®Google Scholar
• de Boer WI, van Schadewijk A, Sont JK, Sharma HS, Stolk J, Hiemstra PS, et al. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;158(6):1951–7. doi:10.1164/ajrccm.158.6.9803053.
   PubMed Web of Science ®Google Scholar
• Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, et al. Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med. 2001;163(6):1476–83. doi:10.1164/ajrccm.163.6.9908135.
   PubMed Web of Science ®Google Scholar
• Kranenburg AR, Willems-Widyastuti A, Moori WJ, Sterk PJ, Alagappan VK, de Boer WI, et al. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am J Clin Pathol. 2006;126(5):725–35.
   PubMed Web of Science ®Google Scholar
• Stockley RA. Neutrophils and the pathogenesis of COPD. Chest. 2002;121(5 Suppl):151S–5S.
   PubMed Web of Science ®Google Scholar
• Turino GM, Seniorrm, Garg BD, Keller S, Levi MM, Mandl I. Serum elastase inhibitor deficiency and alpha 1-antitrypsin deficiency in patients with obstructive emphysema. Science. 1969;165(3894):709–11.
   PubMed Web of Science ®Google Scholar
• Lacoste JY, Bousquet J, Chanez P, Van Vyve T, Simony-Lafontaine J, Lequeu N, et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 1993;92(4):537–48.
   PubMed Web of Science ®Google Scholar
• Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356(9240):1480–5. doi:10.1016/S0140-6736(00)02872-5.
   PubMed Web of Science ®Google Scholar
• Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, et al. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax. 2005;60(3):193–8. doi:10.1136/thx.2004.032516.
   PubMed Web of Science ®Google Scholar
• Pizzichini E, Pizzichini MM, Gibson P, Parameswaran K, Gleich GJ, Berman L, et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1511–7. doi:10.1164/ajrccm.158.5.9804028.
   PubMed Web of Science ®Google Scholar
• Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21. doi:10.1016/S0140-6736(02)11679-5.
   PubMed Web of Science ®Google Scholar
• Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2012;186(1):48–55. doi:10.1164/rccm.201108-1553OC.
   PubMed Web of Science ®Google Scholar
• Bafadhel M, Davies L, Calverley PM, Aaron SD, Brightling CE, Pavord ID. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J. 2014;44(3):789–91. doi:10.1183/09031936.00062614.
   PubMed Web of Science ®Google Scholar
• Aaron SD, Vandemheen KL, Maltais F, Field SK, Sin DD, Bourbeau J, et al. TNFalpha antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial. Thorax. 2013;68(2):142–8. doi:10.1136/thoraxjnl-2012-202432.
   PubMed Web of Science ®Google Scholar
• Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(9):926–34. doi:10.1164/rccm.200607-995OC.
   PubMed Web of Science ®Google Scholar
• Kirsten AM, Forster K, Radeczky E, Linnhoff A, Balint B, Watz H, et al. The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD. Pulm Pharmacol Ther. 2015;31:36–41. doi:10.1016/j.pupt.2015.02.001.
   PubMed Web of Science ®Google Scholar
• Brightling CE, Bleecker ER, Panettieri RA, Jr., Bafadhel M, She D, Ward CK, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891–901. doi:10.1016/S2213-2600(14)70187-0.
   PubMed Web of Science ®Google Scholar
• Pavord ID, Chanez P, Criner GJ, Kerstjens HAM, Korn S, Lugogo N, et al. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017;377(17):1613–29. doi:10.1056/NEJMoa1708208.
   PubMed Web of Science ®Google Scholar
• Mahler DA, Huang S, Tabrizi M, Bell GM. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest. 2004;126(3):926–34. doi:10.1378/chest.126.3.926.
   PubMed Web of Science ®Google Scholar
• Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2008;121(1):5–10; quiz 1–2. doi:10.1016/j.jaci.2007.10.028.
   PubMed Web of Science ®Google Scholar
• Suissa S, Ernst P, Hudson M. TNF-alpha antagonists and the prevention of hospitalisation for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008;21(1):234–8. doi:10.1016/j.pupt.2007.03.003.
   PubMed Web of Science ®Google Scholar
• van der Vaart H, Koeter GH, Postma DS, Kauffman HF, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172(4):465–9. doi:10.1164/rccm.200501-147OC.
   PubMed Web of Science ®Google Scholar
• Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52. doi:10.1038/nrd3800.
   PubMed Web of Science ®Google Scholar
• Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6(4):232–41. doi:10.1038/nrrheum.2010.4.
   PubMed Web of Science ®Google Scholar
• Calverley PMA, Sethi S, Dawson M, Ward CK, Finch DK, Penney M, et al. A randomised, placebo-controlled trial of anti-interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease. Respir Res. 2017;18(1):153. doi:10.1186/s12931-017-0633-7.
   PubMedGoogle Scholar
• Safety and Efficacy of Multiple Doses of Canakinumab (ACZ885) in Chronic Obstructive Pulmonary Disease (COPD) Patients [Internet]. 2017 [cited 12/11/2017]. Available from: https://clinicaltrials.gov/ct2/show/NCT00581945?term=NCT00581945&rank=1.
   Google Scholar
• Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–207. doi:10.1056/NEJMoa1403290.
   PubMed Web of Science ®Google Scholar
• Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97. doi:10.1056/NEJMoa1403291.
   PubMed Web of Science ®Google Scholar
• Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66. doi:10.1016/S2213-2600(15)00042-9.
   PubMed Web of Science ®Google Scholar
• Yancey SW, Ortega HG, Keene ON, Mayer B, Gunsoy NB, Brightling CE, et al. Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J Allergy Clin Immunol. 2017;139(4):1167–75 e2. doi:10.1016/j.jaci.2016.08.008.
   PubMed Web of Science ®Google Scholar
• Bagnasco D, Ferrando M, Varricchi G, Puggioni F, Passalacqua G, Canonica GW. Anti-Interleukin 5 (IL-5) and IL-5Ra biological drugs: efficacy, safety, and future perspectives in severe eosinophilic asthma. Front Med (Lausanne). 2017;4:135. doi:10.3389/fmed.2017.00135.
   PubMed Web of Science ®Google Scholar
• Cabon Y, Molinari N, Marin G, Vachier I, Gamez AS, Chanez P, et al. Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials. Clin Exp Allergy. 2017;47(1):129–38. doi:10.1111/cea.12853.
   PubMed Web of Science ®Google Scholar
• Saco TV, Pepper AN, Lockey RF. Benralizumab for the treatment of asthma. Expert Rev Clin Immunol. 2017;13(5):405–13. doi:10.1080/1744666X.2017.1316194.
   PubMed Web of Science ®Google Scholar
• Dasgupta A, Kjarsgaard M, Capaldi D, Radford K, Aleman F, Boylan C, et al. A pilot randomised clinical trial of mepolizumab in COPD with eosinophilic bronchitis. Eur Respir J. 2017;49(3). doi:10.1183/13993003.02486-2016.
   PubMed Web of Science ®Google Scholar
• Brightling CE, Saha S, Hollins F. Interleukin-13: prospects for new treatments. Clin Exp Allergy. 2010;40(1):42–9. doi:10.1111/j.1365-2222.2009.03383.x.
   PubMed Web of Science ®Google Scholar
• Hanania NAKP, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2016;4:781–96.
   PubMed Web of Science ®Google Scholar
• Brightling CECP, Leight R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. The Lancet. 2015;3(9):629–701.
   Web of Science ®Google Scholar
• Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31–44. doi:10.1016/S0140-6736(16)30307-5.
   PubMed Web of Science ®Google Scholar
• Yadava K, Massacand J, Mosconi I, Nicod LP, Harris NL, Marsland BJ. Thymic stromal lymphopoietin plays divergent roles in murine models of atopic and nonatopic airway inflammation. Allergy. 2014;69(10):1333–42. doi:10.1111/all.12469.
   PubMed Web of Science ®Google Scholar
• Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129–55. doi:10.1016/B978-0-12-404717-4.00004-4.
   PubMedGoogle Scholar
• Lloyd CM, Saglani S. Epithelial cytokines and pulmonary allergic inflammation. Curr Opin Immunol. 2015;34:52–8. doi:10.1016/j.coi.2015.02.001.
   PubMed Web of Science ®Google Scholar
• Redhu NS, Gounni AS. Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clin Exp Allergy. 2012;42(7):994–1005. doi:10.1111/j.1365-2222.2011.03919.x.
   PubMed Web of Science ®Google Scholar
• Ying S, O'Connor B, Ratoff J, Meng Q, Fang C, Cousins D, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008;181(4):2790–8.
   PubMed Web of Science ®Google Scholar
• Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol. 2012;129(1):104–11 e1–9. doi:10.1016/j.jaci.2011.08.031.
   PubMed Web of Science ®Google Scholar
• Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med. 2017;377(10):936–46. doi:10.1056/NEJMoa1704064.
   PubMed Web of Science ®Google Scholar
• Kaur D, Gomez E, Doe C, Berair R, Woodman L, Saunders R, et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. Allergy. 2015;70(5):556–67. doi:10.1111/all.12593.
   PubMed Web of Science ®Google Scholar
• Cayrol C, Girard JP. Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev. 2018;281(1):154–68. doi:10.1111/imr.12619.
   PubMed Web of Science ®Google Scholar
• Cayrol C, Girard JP. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014;31:31–7. doi:10.1016/j.coi.2014.09.004.
   PubMed Web of Science ®Google Scholar
• Jackson DJ, Makrinioti H, Rana BM, Shamji BW, Trujillo-Torralbo MB, Footitt J, et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med. 2014;190(12):1373–82. doi:10.1164/rccm.201406-1039OC.
   PubMed Web of Science ®Google Scholar
• Xia J, Zhao J, Shang J, Li M, Zeng Z, Zhao J, et al. Increased IL-33 expression in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2015;308(7):L619–27. doi:10.1152/ajplung.00305.2014.
   PubMed Web of Science ®Google Scholar