Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Tyrosine Kinase Inhibitors (TKIs) in Lung Cancer Treatment: A Comprehensive Analysis

Author(s): Sivakumar Murugesan, Jayakumar Murugesan, Seedevi Palaniappan , Sivasankar Palaniappan, Tamilselvi Murugan, Shahid S. Siddiqui and Sivakumar Loganathan*

Volume 21, Issue 1, 2021

Published on: 09 October, 2020

Page: [55 - 69] Pages: 15

DOI: 10.2174/1568009620666201009130008

Price: $65

Abstract

Lung cancer is the leading type of cancer worldwide today. Kinases play a crucial role in mediating the signaling pathways, and it directs to control several necessary cellular processes. Conversely, the deregulation of tyrosine kinases leads to oncogenic conversion, uncontrolled cell proliferation and tumorigenesis. Tyrosine kinases are largely deregulated in lung cancer and specifically in non-small cell lung cancer (NSCLC). Therefore, the inhibition of pathogenic kinases is a breakthrough development in cancer research, treatment and care, which clinically improve the quality of life. In the last decades, various single or combination inhibitors are approved by U.S Food and Drug Administration (FDA) and commercially available in clinics, and currently, several preclinical studies are ongoing and examining the kinase inhibitors. However, many gaps remain in understanding the mechanisms of kinase inhibitors and their selectivity. In this analysis, we focus on a class of receptor and non-receptor tyrosine kinase inhibitors and their novel role in lung cancer.

Keywords: Receptor tyrosine kinases, non-small cell lung cancer, FDA approved drugs, tyrosine kinases inhibitors, tumorigenesis, immunotherapy.

Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Munoz, L. Non-kinase targets of protein kinase inhibitors. Nat. Rev. Drug Discov., 2017, 16(6), 424-440.
[http://dx.doi.org/10.1038/nrd.2016.266] [PMID: 28280261]
[3]
Sawyers, C.L. Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev., 2003, 17(24), 2998-3010.
[http://dx.doi.org/10.1101/gad.1152403] [PMID: 14701871]
[4]
Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.; Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C.L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med., 2001, 344(14), 1031-1037.
[http://dx.doi.org/10.1056/NEJM200104053441401] [PMID: 11287972]
[5]
Slamon, D.J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; Baselga, J.; Norton, L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med., 2001, 344(11), 783-792.
[http://dx.doi.org/10.1056/NEJM200103153441101] [PMID: 11248153]
[6]
Demetri, G.D.; von Mehren, M.; Blanke, C.D.; Van den Abbeele, A.D.; Eisenberg, B.; Roberts, P.J.; Heinrich, M.C.; Tuveson, D.A.; Singer, S.; Janicek, M.; Fletcher, J.A.; Silverman, S.G.; Silberman, S.L.; Capdeville, R.; Kiese, B.; Peng, B.; Dimitrijevic, S.; Druker, B.J.; Corless, C.; Fletcher, C.D.; Joensuu, H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med., 2002, 347(7), 472-480.
[http://dx.doi.org/10.1056/NEJMoa020461] [PMID: 12181401]
[7]
Schiffer, C.A. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N. Engl. J. Med., 2007, 357(3), 258-265.
[http://dx.doi.org/10.1056/NEJMct071828] [PMID: 17634461]
[8]
Cohen, P. Protein kinases-the major drug targets of the twenty- first century? Nat. Rev. Drug Discov., 2002, 1(4), 309-315.
[http://dx.doi.org/10.1038/nrd773] [PMID: 12120282]
[9]
Morgensztern, D.; Campo, M.J.; Dahlberg, S.E.; Doebele, R.C.; Garon, E.; Gerber, D.E.; Goldberg, S.B.; Hammerman, P.S.; Heist, R.S.; Hensing, T.; Horn, L.; Ramalingam, S.S.; Rudin, C.M.; Salgia, R.; Sequist, L.V.; Shaw, A.T.; Simon, G.R.; Somaiah, N.; Spigel, D.R.; Wrangle, J.; Johnson, D.; Herbst, R.S.; Bunn, P.; Govindan, R. Molecularly targeted therapies in non-small-cell lung cancer annual update 2014. J. Thorac. Oncol., 2015, 10(1)(Suppl. 1), S1-S63.
[http://dx.doi.org/10.1097/JTO.0000000000000405] [PMID: 25535693]
[10]
Sequist, L.V.; Yang, J.C-H.; Yamamoto, N.; O’Byrne, K.; Hirsh, V.; Mok, T.; Geater, S.L.; Orlov, S.; Tsai, C-M.; Boyer, M.; Su, W.C.; Bennouna, J.; Kato, T.; Gorbunova, V.; Lee, K.H.; Shah, R.; Massey, D.; Zazulina, V.; Shahidi, M.; Schuler, M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol., 2013, 31(27), 3327-3334.
[http://dx.doi.org/10.1200/JCO.2012.44.2806] [PMID: 23816960]
[11]
Vanneman, M.; Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer, 2012, 12(4), 237-251.
[http://dx.doi.org/10.1038/nrc3237] [PMID: 22437869]
[12]
Cunningham, D.; Humblet, Y.; Siena, S.; Khayat, D.; Bleiberg, H.; Santoro, A.; Bets, D.; Mueser, M.; Harstrick, A.; Verslype, C.; Chau, I.; Van Cutsem, E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med., 2004, 351(4), 337-345.
[http://dx.doi.org/10.1056/NEJMoa033025] [PMID: 15269313]
[13]
Hubbard, S.R.; Till, J.H. Protein tyrosine kinase structure and function. Annu. Rev. Biochem., 2000, 69(1), 373-398.
[http://dx.doi.org/10.1146/annurev.biochem.69.1.373] [PMID: 10966463]
[14]
Blume-Jensen, P.; Hunter, T. Oncogenic kinase signalling. Nature, 2001, 411(6835), 355-365.
[http://dx.doi.org/10.1038/35077225] [PMID: 11357143]
[15]
Neet, K.; Hunter, T. Vertebrate non-receptor protein-tyrosine kinase families. Genes Cells, 1996, 1(2), 147-169.
[http://dx.doi.org/10.1046/j.1365-2443.1996.d01-234.x] [PMID: 9140060]
[16]
Kuriyan, J.; Cowburn, D. Modular peptide recognition domains in eukaryotic signaling. Annu. Rev. Biophys. Biomol. Struct., 1997, 26(1), 259-288.
[http://dx.doi.org/10.1146/annurev.biophys.26.1.259] [PMID: 9241420]
[17]
Hanks, S.K.; Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification. FASEB J., 1995, 9(8), 576-596.
[http://dx.doi.org/10.1096/fasebj.9.8.7768349] [PMID: 7768349]
[18]
Pearce, L.R.; Komander, D.; Alessi, D.R. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol., 2010, 11(1), 9-22.
[http://dx.doi.org/10.1038/nrm2822] [PMID: 20027184]
[19]
Zhu, G.; Fujii, K.; Liu, Y.; Codrea, V.; Herrero, J.; Shaw, S. A single pair of acidic residues in the kinase major groove mediates strong substrate preference for P-2 or P-5 arginine in the AGC, CAMK, and STE kinase families. J. Biol. Chem., 2005, 280(43), 36372-36379.
[http://dx.doi.org/10.1074/jbc.M505031200] [PMID: 16131491]
[20]
Kannan, N.; Neuwald, A.F. Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2α. Protein Sci., 2004, 13(8), 2059-2077.
[http://dx.doi.org/10.1110/ps.04637904] [PMID: 15273306]
[21]
Adams, J.A. Activation loop phosphorylation and catalysis in protein kinases: is there functional evidence for the autoinhibitor model? Biochemistry, 2003, 42(3), 601-607.
[http://dx.doi.org/10.1021/bi020617o] [PMID: 12534271]
[22]
Tridente, G. Adverse events and oncotargeted kinase inhibitors. Academic Press; , 2017.
[23]
Stroehlein, A.J.; Young, N.D.; Korhonen, P.K.; Chang, B.C.H.; Nejsum, P.; Pozio, E.; La Rosa, G.; Sternberg, P.W.; Gasser, R.B. Whipworm kinomes reflect a unique biology and adaptation to the host animal. Int. J. Parasitol., 2017, 47(13), 857-866.
[http://dx.doi.org/10.1016/j.ijpara.2017.04.005] [PMID: 28606697]
[24]
Pawson, T. Regulation and targets of receptor tyrosine kinases. Eur. J. Cancer, 2002, 38(Suppl. 5), S3-S10.
[http://dx.doi.org/10.1016/S0959-8049(02)80597-4] [PMID: 12528767]
[25]
Molina-Arcas, M.; Moore, C.; Rana, S.; van Maldegem, F.; Mugarza, E.; Romero-Clavijo, P.; Herbert, E.; Horswell, S.; Li, L.S.; Janes, M.R.; Hancock, D.C.; Downward, J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci. Transl. Med., 2019, 11(510), eaaw7999.
[http://dx.doi.org/10.1126/scitranslmed.aaw7999] [PMID: 31534020]
[26]
Jiang, W.; Cai, G.; Hu, P.C.; Wang, Y. Personalized medicine in non-small cell lung cancer: A review from a pharmacogenomics perspective. Acta Pharm. Sin. B, 2018, 8(4), 530-538.
[http://dx.doi.org/10.1016/j.apsb.2018.04.005] [PMID: 30109178]
[27]
Johnson, G.L.; Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 2002, 298(5600), 1911-1912.
[http://dx.doi.org/10.1126/science.1072682] [PMID: 12471242]
[28]
Gerthoffer, W.T.; Singer, C.A. MAPK regulation of gene expression in airway smooth muscle. Respir. Physiol. Neurobiol., 2003, 137(2-3), 237-250.
[http://dx.doi.org/10.1016/S1569-9048(03)00150-2] [PMID: 14516729]
[29]
Welch, P.J.; Wang, J.Y. A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell, 1993, 75(4), 779-790.
[http://dx.doi.org/10.1016/0092-8674(93)90497-E] [PMID: 8242749]
[30]
Edelman, A.M.; Blumenthal, D.K.; Krebs, E.G. Protein serine/threonine kinases. Annu. Rev. Biochem., 1987, 56(1), 567-613.
[http://dx.doi.org/10.1146/annurev.bi.56.070187.003031] [PMID: 2956925]
[31]
Capra, M.; Nuciforo, P.G.; Confalonieri, S.; Quarto, M.; Bianchi, M.; Nebuloni, M.; Boldorini, R.; Pallotti, F.; Viale, G.; Gishizky, M.L.; Draetta, G.F.; Di Fiore, P.P. Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res., 2006, 66(16), 8147-8154.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3489] [PMID: 16912193]
[32]
Młynarski, W.; McDermott, J.H. Learning midlevel auditory codes from natural sound statistics. Neural Comput., 2018, 30(3), 631-669.
[http://dx.doi.org/10.1162/neco_a_01048] [PMID: 29220308]
[33]
Guicciardi, M.E.; Gores, G.J. AIP1: a new player in TNF signaling. J. Clin. Invest., 2003, 111(12), 1813-1815.
[http://dx.doi.org/10.1172/JCI200318911] [PMID: 12813014]
[34]
Davies, H.; Hunter, C.; Smith, R.; Stephens, P.; Greenman, C.; Bignell, G.; Teague, J.; Butler, A.; Edkins, S.; Stevens, C.; Parker, A.; O’Meara, S.; Avis, T.; Barthorpe, S.; Brackenbury, L.; Buck, G.; Clements, J.; Cole, J.; Dicks, E.; Edwards, K.; Forbes, S.; Gorton, M.; Gray, K.; Halliday, K.; Harrison, R.; Hills, K.; Hinton, J.; Jones, D.; Kosmidou, V.; Laman, R.; Lugg, R.; Menzies, A.; Perry, J.; Petty, R.; Raine, K.; Shepherd, R.; Small, A.; Solomon, H.; Stephens, Y.; Tofts, C.; Varian, J.; Webb, A.; West, S.; Widaa, S.; Yates, A.; Brasseur, F.; Cooper, C.S.; Flanagan, A.M.; Green, A.; Knowles, M.; Leung, S.Y.; Looijenga, L.H.; Malkowicz, B.; Pierotti, M.A.; Teh, B.T.; Yuen, S.T.; Lakhani, S.R.; Easton, D.F.; Weber, B.L.; Goldstraw, P.; Nicholson, A.G.; Wooster, R.; Stratton, M.R.; Futreal, P.A. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res., 2005, 65(17), 7591-7595.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1855] [PMID: 16140923]
[35]
Knight, Z.A.; Lin, H.; Shokat, K.M. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer, 2010, 10(2), 130-137.
[http://dx.doi.org/10.1038/nrc2787] [PMID: 20094047]
[36]
Romano, G.; Giordano, A. Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. Cell Cycle, 2008, 7(23), 3664-3668.
[37]
Frisch, S.M.; Screaton, R.A. Anoikis mechanisms. Curr. Opin. Cell Biol., 2001, 13(5), 555-562.
[http://dx.doi.org/10.1016/S0955-0674(00)00251-9] [PMID: 11544023]
[38]
Lim, T.K. Quercus infectoria. Edible Medicinal And Non-Medicinal Plants; , 2012, pp. pp. 16-26.
[http://dx.doi.org/10.1007/978-94-007-4053-2_3]
[39]
Wei, L.; Yang, Y.; Yu, Q. Tyrosine kinase-dependent, phosphatidylinositol 3′-kinase, and mitogen-activated protein kinase-independent signaling pathways prevent lung adenocarcinoma cells from anoikis. Cancer Res., 2001, 61(6), 2439-2444.
[PMID: 11289112]
[40]
Meredith, J.E., Jr; Fazeli, B.; Schwartz, M.A. The extracellular matrix as a cell survival factor. Mol. Biol. Cell, 1993, 4(9), 953-961.
[http://dx.doi.org/10.1091/mbc.4.9.953] [PMID: 8257797]
[41]
Scagliotti, G.; Govindan, R. Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. Oncologist, 2010, 15(5), 436-446.
[http://dx.doi.org/10.1634/theoncologist.2009-0225] [PMID: 20427383]
[42]
Santoro, M.M. Fashioning blood vessels by ROS signalling and metabolism. Semin. Cell Dev. Biol., 2018, 80, 35-42.
[http://dx.doi.org/10.1016/j.semcdb.2017.08.002] [PMID: 28800930]
[43]
Knelson, E.H.; Nee, J.C.; Blobe, G.C. Heparan sulfate signaling in cancer. Trends Biochem. Sci., 2014, 39(6), 277-288.
[http://dx.doi.org/10.1016/j.tibs.2014.03.001] [PMID: 24755488]
[44]
Ferguson, F.M.; Gray, N.S. Kinase inhibitors: the road ahead. Nat. Rev. Drug Discov., 2018, 17(5), 353.
[http://dx.doi.org/10.1038/nrd.2018.21]
[45]
Roskoski, R., Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. Pharmacol. Res., 2020, 152, 104609.
[http://dx.doi.org/10.1016/j.phrs.2019.104609] [PMID: 31862477]
[46]
Zhang, J.; Yang, P.L.; Gray, N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer, 2009, 9(1), 28-39.
[http://dx.doi.org/10.1038/nrc2559] [PMID: 19104514]
[47]
Patterson, H.; Nibbs, R.; McInnes, I.; Siebert, S. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin. Exp. Immunol., 2014, 176(1), 1-10.
[http://dx.doi.org/10.1111/cei.12248] [PMID: 24313320]
[48]
Klaeger, S.; Heinzlmeir, S.; Wilhelm, M.; Polzer, H.; Vick, B.; Koenig, P.A.; Reinecke, M.; Ruprecht, B.; Petzoldt, S.; Meng, C.; Zecha, J.; Reiter, K.; Qiao, H.; Helm, D.; Koch, H.; Schoof, M.; Canevari, G.; Casale, E.; Depaolini, S.R.; Feuchtinger, A.; Wu, Z.; Schmidt, T.; Rueckert, L.; Becker, W.; Huenges, J.; Garz, A.K.; Gohlke, B.O.; Zolg, D.P.; Kayser, G.; Vooder, T.; Preissner, R.; Hahne, H.; Tõnisson, N.; Kramer, K.; Götze, K.; Bassermann, F.; Schlegl, J.; Ehrlich, H.C.; Aiche, S.; Walch, A.; Greif, P.A.; Schneider, S.; Felder, E.R.; Ruland, J.; Médard, G.; Jeremias, I.; Spiekermann, K.; Kuster, B. The target landscape of clinical kinase drugs. Science, 2017, 358(6367), 4368.
[http://dx.doi.org/10.1126/science.aan4368] [PMID: 29191878]
[49]
Dar, A.C.; Shokat, K.M. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu. Rev. Biochem., 2011, 80, 769-795.
[http://dx.doi.org/10.1146/annurev-biochem-090308-173656] [PMID: 21548788]
[50]
Shaw, A.T.; Felip, E.; Bauer, T.M.; Besse, B.; Navarro, A.; Postel-Vinay, S.; Gainor, J.F.; Johnson, M.; Dietrich, J.; James, L.P.; Clancy, J.S.; Chen, J.; Martini, J.F.; Abbattista, A.; Solomon, B.J. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol., 2017, 18(12), 1590-1599.
[http://dx.doi.org/10.1016/S1470-2045(17)30680-0] [PMID: 29074098]
[51]
Krishnaswamy, S.; Kanteti, R.; Duke-Cohan, J.S.; Loganathan, S.; Liu, W.; Ma, P.C.; Sattler, M.; Singleton, P.A.; Ramnath, N.; Innocenti, F.; Nicolae, D.L.; Ouyang, Z.; Liang, J.; Minna, J.; Kozloff, M.F.; Ferguson, M.K.; Natarajan, V.; Wang, Y.C.; Garcia, J.G.; Vokes, E.E.; Salgia, R. Ethnic differences and functional analysis of MET mutations in lung cancer. Clin. Cancer Res., 2009, 15(18), 5714-5723.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0070] [PMID: 19723643]
[52]
Zhang, G.; Scarborough, H.; Kim, J.; Rozhok, A.I.; Chen, Y.A.; Zhang, X.; Song, L.; Bai, Y.; Fang, B.; Liu, R.Z.; Koomen, J.; Tan, A.C.; Degregori, J.; Haura, E.B. Coupling an EML4-ALK- centric interactome with RNA interference identifies sensitizers to ALK inhibitors. Sci. Signal., 2016, 9(450), rs12-rs12.
[http://dx.doi.org/10.1126/scisignal.aaf5011] [PMID: 27811184]
[53]
Chan, B.A.; Hughes, B.G. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl. Lung Cancer Res., 2015, 4(1), 36-54.
[PMID: 25806345]
[54]
Cohen, M.S.; Zhang, C.; Shokat, K.M.; Taunton, J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science, 2005, 308(5726), 1318-1321.
[http://dx.doi.org/10.1126/science1108367] [PMID: 15919995]
[55]
Kwak, E.L.; Sordella, R.; Bell, D.W.; Godin-Heymann, N.; Okimoto, R.A.; Brannigan, B.W.; Harris, P.L.; Driscoll, D.R.; Fidias, P.; Lynch, T.J.; Rabindran, S.K.; McGinnis, J.P.; Wissner, A.; Sharma, S.V.; Isselbacher, K.J.; Settleman, J.; Haber, D.A. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl. Acad. Sci. USA, 2005, 102(21), 7665-7670.
[http://dx.doi.org/10.1073/pnas.0502860102] [PMID: 15897464]
[56]
Rabindran, S.K.; Discafani, C.M.; Rosfjord, E.C.; Baxter, M.; Floyd, M.B.; Golas, J.; Hallett, W.A.; Johnson, B.D.; Nilakantan, R.; Overbeek, E.; Reich, M.F.; Shen, R.; Shi, X.; Tsou, H.R.; Wang, Y.F.; Wissner, A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res., 2004, 64(11), 3958-3965.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-2868] [PMID: 15173008]
[57]
Kobayashi, S.; Ji, H.; Yuza, Y.; Meyerson, M.; Wong, K.K.; Tenen, D.G.; Halmos, B. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res., 2005, 65(16), 7096-7101.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1346] [PMID: 16103058]
[58]
Fry, D.W.; Kraker, A.J.; McMichael, A.; Ambroso, L.A.; Nelson, J.M.; Leopold, W.R.; Connors, R.W.; Bridges, A.J. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science, 1994, 265(5175), 1093-1095.
[http://dx.doi.org/10.1126/science.8066447] [PMID: 8066447]
[59]
Heymach, J.V.; Nilsson, M.; Blumenschein, G.; Papadimitrakopoulou, V.; Herbst, R. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin. Cancer Res., 2006, 12(14 Pt 2), 4441s-4445s.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0286] [PMID: 16857825]
[60]
Felip, E.; Santarpia, M.; Rosell, R. Emerging drugs for non-small- cell lung cancer. Expert Opin. Emerg. Drugs, 2007, 12(3), 449-460.
[http://dx.doi.org/10.1517/14728214.12.3.449] [PMID: 17874972]
[61]
Kwak, E.L.; Bang, Y.J.; Camidge, D.R.; Shaw, A.T.; Solomon, B.; Maki, R.G.; Ou, S.H.I.; Dezube, B.J.; Jänne, P.A.; Costa, D.B.; Varella-Garcia, M.; Kim, W.H.; Lynch, T.J.; Fidias, P.; Stubbs, H.; Engelman, J.A.; Sequist, L.V.; Tan, W.; Gandhi, L.; Mino-Kenudson, M.; Wei, G.C.; Shreeve, S.M.; Ratain, M.J.; Settleman, J.; Christensen, J.G.; Haber, D.A.; Wilner, K.; Salgia, R.; Shapiro, G.I.; Clark, J.W.; Iafrate, A.J. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med., 2010, 363(18), 1693-1703.
[http://dx.doi.org/10.1056/NEJMoa1006448] [PMID: 20979469]
[62]
Ou, S.H.I.; Kwak, E.L.; Siwak-Tapp, C.; Dy, J.; Bergethon, K.; Clark, J.W.; Camidge, D.R.; Solomon, B.J.; Maki, R.G.; Bang, Y.J.; Kim, D.W.; Christensen, J.; Tan, W.; Wilner, K.D.; Salgia, R.; Iafrate, A.J. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J. Thorac. Oncol., 2011, 6(5), 942-946.
[http://dx.doi.org/10.1097/JTO.0b013e31821528d3] [PMID: 21623265]
[63]
Solomon, B.J.; Kim, D.W.; Wu, Y.L.; Nakagawa, K.; Mekhail, T.; Felip, E.; Cappuzzo, F.; Paolini, J.; Usari, T.; Tang, Y.; Wilner, K.D.; Blackhall, F.; Mok, T.S. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J. Clin. Oncol., 2018, 36(22), 2251-2258.
[http://dx.doi.org/10.1200/JCO.2017.77.4794] [PMID: 29768118]
[64]
Soria, J.C.; Ohe, Y.; Vansteenkiste, J.; Reungwetwattana, T.; Chewaskulyong, B.; Lee, K.H.; Dechaphunkul, A.; Imamura, F.; Nogami, N.; Kurata, T.; Okamoto, I.; Zhou, C.; Cho, B.C.; Cheng, Y.; Cho, E.K.; Voon, P.J.; Planchard, D.; Su, W.C.; Gray, J.E.; Lee, S.M.; Hodge, R.; Marotti, M.; Rukazenkov, Y.; Ramalingam, S.S. FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N. Engl. J. Med., 2018, 378(2), 113-125.
[http://dx.doi.org/10.1056/NEJMoa1713137] [PMID: 29151359]
[65]
Spigel, D.R.; Rubin, M.S.; Gian, V.G.; Shipley, D.L.; Burris, H.A., III; Kosloff, R.A.; Shih, K.C.; Quinn, R.; Greco, F.A.; Hainsworth, J.D. Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI). Lung Cancer, 2017, 113, 79-84.
[http://dx.doi.org/10.1016/j.lungcan.2017.09.007] [PMID: 29110854]
[66]
Paz-Ares, L.; Hirsh, V.; Zhang, L.; de Marinis, F.; Yang, J.C.; Wakelee, H.A.; Seto, T.; Wu, Y.L.; Novello, S.; Juhász, E.; Arén, O.; Sun, Y.; Schmelter, T.; Ong, T.J.; Peña, C.; Smit, E.F.; Mok, T.S. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: a phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small lung cancer after 2 or 3 previous treatment regimens. J. Thorac. Oncol., 2015, 10(12), 1745-1753.
[http://dx.doi.org/10.1097/JTO.0000000000000693] [PMID: 26743856]
[67]
Spector, N.L.; Blackwell, K.L. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol., 2009, 27(34), 5838-5847.
[http://dx.doi.org/10.1200/JCO.2009.22.1507] [PMID: 19884552]
[68]
Huijberts, S.C.F.A.; van Geel, R.M.J.M.; van Brummelen, E.M.J.; Opdam, F.L.; Marchetti, S.; Steeghs, N.; Pulleman, S.; Thijssen, B.; Rosing, H.; Monkhorst, K.; Huitema, A.D.R.; Beijnen, J.H.; Bernards, R.; Schellens, J.H.M. Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer. Cancer Chemother. Pharmacol., 2020, 85(5), 917-930.
[http://dx.doi.org/10.1007/s00280-020-04066-4] [PMID: 32274564]
[69]
Cohen, M.H.; Gootenberg, J.; Keegan, P.; Pazdur, R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist, 2007, 12(6), 713-718.
[http://dx.doi.org/10.1634/theoncologist.12-6-713] [PMID: 17602060]
[70]
Faoro, L.; Loganathan, S.; Husain, A.; Westerhoff, M.; Janamanchi, V.; Vokes, E.; Salgia, R. Expression of protein kinase C beta (PKCß) as a prognostic marker in non-small cell lung cancer (NSCLC) and mesothelioma. ASCO Annual Meeting Proceedings J clin oncol., 2007, 25(18), p. p. 7656.
[71]
Kojima, H.; Shijubo, N.; Yamada, G.; Ichimiya, S.; Abe, S.; Satoh, M.; Sato, N. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer, 2005, 104(8), 1668-1677.
[http://dx.doi.org/10.1002/cncr.21366] [PMID: 16116610]
[72]
Zhao, Y.; Adjei, A.A. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist, 2015, 20(6), 660-673.
[http://dx.doi.org/10.1634/theoncologist.2014-0465] [PMID: 26001391]
[73]
Sandler, A.; Herbst, R. Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin. Cancer Res., 2006, 12(14 Pt 2), 4421s-4425s.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0796] [PMID: 16857821]
[74]
Polier, S.; Samant, R.S.; Clarke, P.A.; Workman, P.; Prodromou, C.; Pearl, L.H. ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat. Chem. Biol., 2013, 9(5), 307-312.
[http://dx.doi.org/10.1038/nchembio.1212] [PMID: 23502424]
[75]
June, C.H.; O’Connor, R.S.; Kawalekar, O.U.; Ghassemi, S.; Milone, M.C. CAR T cell immunotherapy for human cancer. Science, 2018, 359(6382), 1361-1365.
[http://dx.doi.org/10.1126/science.aar6711] [PMID: 29567707]
[76]
Caruso, H.G.; Hurton, L.V.; Najjar, A.; Rushworth, D.; Ang, S.; Olivares, S.; Mi, T.; Switzer, K.; Singh, H.; Huls, H.; Lee, D.A.; Heimberger, A.B.; Champlin, R.E.; Cooper, L.J. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res., 2015, 75(17), 3505-3518.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0139] [PMID: 26330164]
[77]
Reinhard, K.; Rengstl, B.; Oehm, P.; Michel, K.; Billmeier, A.; Hayduk, N.; Klein, O.; Kuna, K.; Ouchan, Y.; Wöll, S.; Christ, E.; Weber, D.; Suchan, M.; Bukur, T.; Birtel, M.; Jahndel, V.; Mroz, K.; Hobohm, K.; Kranz, L.; Diken, M.; Kühlcke, K.; Türeci, Ö.; Sahin, U. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science, 2020, 367(6476), 446-453.
[http://dx.doi.org/10.1126/science.aay5967] [PMID: 31896660]
[78]
Sadelain, M.; Rivière, I.; Riddell, S. Therapeutic T cell engineering. Nature, 2017, 545(7655), 423-431.
[http://dx.doi.org/10.1038/nature22395] [PMID: 28541315]
[79]
Shah, N.N.; Stetler-Stevenson, M.; Yuan, C.M.; Shalabi, H.; Yates, B.; Delbrook, C.; Zhang, L.; Lee, D.W., III; Stroncek, D.; Mackall, C.L.; Fry, T.J. Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood, 2016, 128, 650.
[http://dx.doi.org/10.1182/blood.V128.22.650.650]
[80]
Zeltsman, M.; Dozier, J.; McGee, E.; Ngai, D.; Adusumilli, P.S. CAR T-cell therapy for lung cancer and malignant pleural mesothelioma. Transl. Res., 2017, 187, 1-10.
[http://dx.doi.org/10.1016/j.trsl.2017.04.004] [PMID: 28502785]
[81]
Kiesgen, S.; Chicaybam, L.; Chintala, N.K.; Adusumilli, P.S. Chimeric antigen receptor (CAR) T-cell therapy for thoracic malignancies. J. Thorac. Oncol., 2018, 13(1), 16-26.
[http://dx.doi.org/10.1016/j.jtho.2017.10.001] [PMID: 29107016]
[82]
Ishino, Y.; Shinagawa, H.; Makino, K.; Amemura, M.; Nakata, A. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J. Bacteriol., 1987, 169(12), 5429-5433.
[http://dx.doi.org/10.1128/JB.169.12.5429-5433.1987] [PMID: 3316184]
[83]
Mojica, F.J.M.; Ferrer, C.; Juez, G.; Rodríguez-Valera, F. Long stretches of short tandem repeats are present in the largest replicons of the Archaea Haloferax mediterranei and Haloferax volcanii and could be involved in replicon partitioning. Mol. Microbiol., 1995, 17(1), 85-93.
[http://dx.doi.org/10.1111/j.1365-2958.1995.mmi_17010085.x] [PMID: 7476211]
[84]
Mojica, F.J.; Juez, G.; Rodríguez-Valera, F. Transcription at different salinities of Haloferax mediterranei sequences adjacent to partially modified PstI sites. Mol. Microbiol., 1993, 9(3), 613-621.
[http://dx.doi.org/10.1111/j.1365-2958.1993.tb01721.x] [PMID: 8412707]
[85]
Jansen, R.; Embden, J.D.V.; Gaastra, W.; Schouls, L.M. Identification of genes that are associated with DNA repeats in prokaryotes. Mol. Microbiol., 2002, 43(6), 1565-1575.
[http://dx.doi.org/10.1046/j.1365-2958.2002.02839.x] [PMID: 11952905]
[86]
Mojica, F.J.; Díez-Villaseñor, C.; García-Martínez, J.; Soria, E. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J. Mol. Evol., 2005, 60(2), 174-182.
[http://dx.doi.org/10.1007/s00239-004-0046-3] [PMID: 15791728]
[87]
Becker, K.; Xu, Y. Management of tyrosine kinase inhibitor resistance in lung cancer with EGFR mutation. World J. Clin. Oncol., 2014, 5(4), 560-567.
[http://dx.doi.org/10.5306/wjco.v5.i4.560] [PMID: 25302160]
[88]
Komlodi-Pasztor, E.; Sackett, D.; Wilkerson, J.; Fojo, T. Mitosis is not a key target of microtubule agents in patient tumors. Nat. Rev. Clin. Oncol., 2011, 8(4), 244-250.
[http://dx.doi.org/10.1038/nrclinonc.2010.228] [PMID: 21283127]
[89]
Parker, A.L.; Kavallaris, M.; McCarroll, J.A. Microtubules and their role in cellular stress in cancer. Front. Oncol., 2014, 4, 153.
[http://dx.doi.org/10.3389/fonc.2014.00153] [PMID: 24995158]
[90]
Munshi, N.; Jeay, S.; Li, Y.; Chen, C.R.; France, D.S.; Ashwell, M.A.; Hill, J.; Moussa, M.M.; Leggett, D.S.; Li, C.J. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol. Cancer Ther., 2010, 9(6), 1544-1553.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-1173] [PMID: 20484018]
[91]
Basilico, C.; Pennacchietti, S.; Vigna, E.; Chiriaco, C.; Arena, S.; Bardelli, A.; Valdembri, D.; Serini, G.; Michieli, P. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin. Cancer Res., 2013, 19(9), 2381-2392.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3459] [PMID: 23532890]
[92]
Katayama, R.; Aoyama, A.; Yamori, T.; Qi, J.; Oh-hara, T.; Song, Y.; Engelman, J.A.; Fujita, N. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res., 2013, 73(10), 3087-3096.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3256] [PMID: 23598276]
[93]
Cheong, J.K.; Nguyen, T.H.; Wang, H.; Tan, P.; Voorhoeve, P.M.; Lee, S.H.; Virshup, D.M. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1δ/ɛ and Wnt/β- catenin independent inhibition of mitotic spindle formation. Oncogene, 2011, 30(22), 2558-2569.
[http://dx.doi.org/10.1038/onc.2010.627] [PMID: 21258417]
[94]
Gurgis, F.; Åkerfeldt, M.C.; Heng, B.; Wong, C.; Adams, S.; Guillemin, G.J.; Johns, T.G.; Chircop, M.; Munoz, L. Cytotoxic activity of the MK2 inhibitor CMPD1 in glioblastoma cells is independent of MK2. Cell Death Discov., 2015, 1(1), 15028.
[http://dx.doi.org/10.1038/cddiscovery.2015.28] [PMID: 27551460]
[95]
Mahale, S.; Bharate, S.B.; Manda, S.; Joshi, P.; Jenkins, P.R.; Vishwakarma, R.A.; Chaudhuri, B. Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization. Cell Death Dis., 2015, 6(5), e1743.
[http://dx.doi.org/10.1038/cddis.2015.96] [PMID: 25950473]
[96]
Kawamura, T.; Kawatani, M.; Muroi, M.; Kondoh, Y.; Futamura, Y.; Aono, H.; Tanaka, M.; Honda, K.; Osada, H. Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival. Sci. Rep., 2016, 6, 26521.
[http://dx.doi.org/10.1038/srep26521] [PMID: 27210421]
[97]
Aoyama, A.; Katayama, R.; Oh-Hara, T.; Sato, S.; Okuno, Y.; Fujita, N. Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance. Mol. Cancer Ther., 2014, 13(12), 2978-2990.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0462] [PMID: 25313010]
[98]
Wang, Y.; Zhang, H.; Gigant, B.; Yu, Y.; Wu, Y.; Chen, X.; Lai, Q.; Yang, Z.; Chen, Q.; Yang, J. Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery. FEBS J., 2016, 283(1), 102-111.
[http://dx.doi.org/10.1111/febs.13555] [PMID: 26462166]
[99]
Pao, W.; Miller, V.A.; Politi, K.A.; Riely, G.J.; Somwar, R.; Zakowski, M.F.; Kris, M.G.; Varmus, H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med., 2005, 2(3), e73.
[http://dx.doi.org/10.1371/journal.pmed.0020073] [PMID: 15737014]
[100]
Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; Nishiwaki, Y.; Ohe, Y.; Yang, J.J.; Chewaskulyong, B.; Jiang, H.; Duffield, E.L.; Watkins, C.L.; Armour, A.A.; Fukuoka, M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med., 2009, 361(10), 947-957.
[http://dx.doi.org/10.1056/NEJMoa0810699] [PMID: 19692680]
[101]
Yu, H.A.; Arcila, M.E.; Rekhtman, N.; Sima, C.S.; Zakowski, M.F.; Pao, W.; Kris, M.G.; Miller, V.A.; Ladanyi, M.; Riely, G.J. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res., 2013, 19(8), 2240-2247.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2246] [PMID: 23470965]
[102]
Murillo, M.M.; Rana, S.; Spencer-Dene, B.; Nye, E.; Stamp, G.; Downward, J. Disruption of the interaction of RAS with PI 3-Kinase induces regression of EGFR-Mutant-Driven lung Cancer. Cell Rep., 2018, 25(13), 3545-3553.e2.
[http://dx.doi.org/10.1016/j.celrep.2018.12.003] [PMID: 30590030]
[103]
Romanidou, O.; Landi, L.; Cappuzzo, F.; Califano, R. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer. Ther. Adv. Med. Oncol., 2016, 8(3), 176-187.
[http://dx.doi.org/10.1177/1758834016631531] [PMID: 27239236]
[104]
Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; Asami, K.; Katakami, N.; Takada, M.; Yoshioka, H.; Shibata, K.; Kudoh, S.; Shimizu, E.; Saito, H.; Toyooka, S.; Nakagawa, K.; Fukuoka, M. West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol., 2010, 11(2), 121-128.
[http://dx.doi.org/10.1016/S1470-2045(09)70364-X] [PMID: 20022809]
[105]
Wu, Y.L.; Cheng, Y.; Zhou, X.; Lee, K.H.; Nakagawa, K.; Niho, S.; Tsuji, F.; Linke, R.; Rosell, R.; Corral, J.; Migliorino, M.R.; Pluzanski, A.; Sbar, E.I.; Wang, T.; White, J.L.; Nadanaciva, S.; Sandin, R.; Mok, T.S. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small- cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol., 2017, 18(11), 1454-1466.
[http://dx.doi.org/10.1016/S1470-2045(17)30608-3] [PMID: 28958502]
[106]
Scagliotti, G.; von Pawel, J.; Novello, S.; Ramlau, R.; Favaretto, A.; Barlesi, F.; Akerley, W.; Orlov, S.; Santoro, A.; Spigel, D.; Hirsh, V.; Shepherd, F.A.; Sequist, L.V.; Sandler, A.; Ross, J.S.; Wang, Q.; von Roemeling, R.; Shuster, D.; Schwartz, B. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol., 2015, 33(24), 2667-2674.
[http://dx.doi.org/10.1200/JCO.2014.60.7317] [PMID: 26169611]
[107]
Sequist, L.V.; von Pawel, J.; Garmey, E.G.; Akerley, W.L.; Brugger, W.; Ferrari, D.; Chen, Y.; Costa, D.B.; Gerber, D.E.; Orlov, S.; Ramlau, R.; Arthur, S.; Gorbachevsky, I.; Schwartz, B.; Schiller, J.H. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small- cell lung cancer. J. Clin. Oncol., 2011, 29(24), 3307-3315.
[http://dx.doi.org/10.1200/JCO.2010.34.0570] [PMID: 21768463]
[108]
Shaw, A.T.; Kim, D.W.; Nakagawa, K.; Seto, T.; Crinó, L.; Ahn, M.J.; De Pas, T.; Besse, B.; Solomon, B.J.; Blackhall, F.; Wu, Y.L.; Thomas, M.; O’Byrne, K.J.; Moro-Sibilot, D.; Camidge, D.R.; Mok, T.; Hirsh, V.; Riely, G.J.; Iyer, S.; Tassell, V.; Polli, A.; Wilner, K.D.; Jänne, P.A. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med., 2013, 368(25), 2385-2394.
[http://dx.doi.org/10.1056/NEJMoa1214886] [PMID: 23724913]
[109]
Spigel, D.R.; Ervin, T.J.; Ramlau, R.A.; Daniel, D.B.; Goldschmidt, J.H., Jr; Blumenschein, G.R., Jr; Krzakowski, M.J.; Robinet, G.; Godbert, B.; Barlesi, F.; Govindan, R.; Patel, T.; Orlov, S.V.; Wertheim, M.S.; Yu, W.; Zha, J.; Yauch, R.L.; Patel, P.H.; Phan, S.C.; Peterson, A.C. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small- cell lung cancer. J. Clin. Oncol., 2013, 31(32), 4105-4114.
[http://dx.doi.org/10.1200/JCO.2012.47.4189] [PMID: 24101053]
[110]
Lu, X.; Peled, N.; Greer, J.; Wu, W.; Choi, P.; Berger, A.H.; Wong, S.; Jen, K.Y.; Seo, Y.; Hann, B.; Brooks, A.; Meyerson, M.; Collisson, E.A. MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma. Cancer Res., 2017, 77(16), 4498-4505.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1944] [PMID: 28522754]
[111]
Kang, J.; Chen, H.J.; Wang, Z.; Liu, J.; Li, B.; Zhang, T.; Yang, Z.; Wu, Y.L.; Yang, J.J. Osimertinib and cabozantinib combinatorial therapy in an EGFR-mutant lung adenocarcinoma patient with multiple MET secondary-site mutations after resistance to crizotinib. J. Thorac. Oncol., 2018, 13(4), e49-e53.
[http://dx.doi.org/10.1016/j.jtho.2017.10.028] [PMID: 29128427]
[112]
Wakelee, H.; Zvirbule, Z.; De Braud, F.; Kingsley, C.D.; Mekhail, T.; Lowe, T.; Schütte, W.; Lena, H.; Lawler, W.; Braiteh, F.; Cosgriff, T.; Kaen, D.; Boyer, M.; Hsu, J.; Phan, S.; Novello, S. Efficacy and safety of onartuzumab in combination with first-line bevacizumab- or pemetrexed-based chemotherapy regimens in advanced non-squamous non-small-cell lung cancer. Clin. Lung Cancer, 2017, 18(1), 50-59.
[http://dx.doi.org/10.1016/j.cllc.2016.09.013] [PMID: 27856142]
[113]
Yoshioka, H.; Azuma, K.; Yamamoto, N.; Takahashi, T.; Nishio, M.; Katakami, N.; Ahn, M.J.; Hirashima, T.; Maemondo, M.; Kim, S.W.; Kurosaki, M.; Akinaga, S.; Park, K.; Tsai, C.M.; Tamura, T.; Mitsudomi, T.; Nakagawa, K. A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann. Oncol., 2015, 26(10), 2066-2072.
[http://dx.doi.org/10.1093/annonc/mdv288] [PMID: 26153496]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version331msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[20:07:30] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[20:07:30] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[20:07:30] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[20:07:30] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (111ms)time
  • Application (220ms)time
  • 1 x Application (66.37%)
    220ms
    1 x Booting (33.63%)
    111ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated131ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('309813860','',1,1740514050,1740514050) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740514050
      950μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('309813860','/article/110571',1,1740514050,1740514050)
      180μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 309813860 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309813860) limit 1
      18.88msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 309813860
      • 1: 309813860
      • 2: 309813860
      • 3: 309813860
      • 4: 309813860
      • 5: 309813860
      • 6: 309813860
      • 7: 309813860
      • 8: 309813860
      • 9: 309813860
      • 10: 309813860
      • 11: 309813860
      • 12: 309813860
      • 13: 309813860
      • 14: 309813860
      • 15: 309813860
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=110571
      730μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 7 limit 1
      840μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 7
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and sj.journal_id!=7 group by `j`.`nid`) as `aggregate_table`
      970μsalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and sj.journal_id!=7 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      770μsalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.41msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.21msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '110571'
      710μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 110571
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '110571'
      4.75msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 110571
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '110571' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.79msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 110571
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      300μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      470μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 7 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      25.67msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      8.87msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      6.89msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 110571 limit 1
      670μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 110571
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 110571 and content_type = 'article' order by status desc limit 1
      1.5msalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 16 and cd.sub_disease_id = 487 and content_id!=110571 and cd.content_type = 'article' order by rand() limit 20
      30.19msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 186762 limit 1
      250μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 186762
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      260μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CCDT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      320μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CCDT
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '110571' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      370μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '10370' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      300μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '2970' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      290μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2970) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2970) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2970)
      13.36msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10370) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10370) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10370)
      670μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110571) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110571) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309813860 and j.to_ip >=309813860 )) and ((j.from_date <= 1740514050 and j.to_date >= 1740514050 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110571)
      640μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '55' and is_uploaded = 1 and issue_id = 10370 order by cast(first_page as SIGNED) desc limit 1
      550μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 55
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '69' and is_uploaded = 1 and issue_id = 10370 order by cast(first_page as SIGNED) asc limit 1
      440μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 69
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      200μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      220μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 110571 limit 1
      1.97msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 110571
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 7 and `b`.`banner_from_date` <= 1740514050 and `b`.`banner_to_date` >= 1740514050 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.25msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1740514050
      • 4: 1740514050
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 7 and `b`.`banner_from_date` <= 1740514050 and `b`.`banner_to_date` >= 1740514050 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.56msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1740514050
      • 4: 1740514050
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='8606177341c7977c28dbf055a9f00ada'
      310μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
        _token
        ikvJcD5byJ4r9emMYBbmTPUbBdJ0OsrWJFz947r0
        uc_cart_id
        8606177341c7977c28dbf055a9f00ada
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/110571" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/110571
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 20:07:30 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjdVK0dBYVptRXZJZDB6SkllQTJycEE9PSIsInZhbHVlIjoiaW5zL0w5VGQwTVV1aFIrM0YwQTJxdlRWUVJmZ1BzaTB5SWNPM2NqVEZVMXNtM3hJZFFZcHFjZFhlcjRRbUNNdjFUZWltL2R3OCs5bVhDOTVYdUwxTDd4dEg1RERoNXd4VnlQZURrMHJBRUdTU3pEWXpCdDVSdk0zNUU0RzF4QloiLCJtYWMiOiIyOTZkMTljNWQ0OWE2ODU0MjUwZWQ4NzNhYjA5NGNhNGZiMDAyZjYzZGRlMGVjYTJlNTQ0ZDk1YzA0YWI1OTg3IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 08:07:30 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjdVK0dBYVptRXZJZDB6SkllQTJycEE9PSIsInZhbHVlIjoiaW5zL0w5VGQwTVV1aFIrM0YwQTJxdlRWUVJmZ1BzaTB5SWNPM2NqVEZVMXNtM3hJZFFZcHFjZFhlcjRRbUNNdjFUZWltL" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkxnVUwxUU40ZlhMUld1aFk2OWkxTUE9PSIsInZhbHVlIjoiWXJnSHhoZWNXNndwdXdDSlhPSXpRYXYramJqaFZiRFFRVU1HTHNtNXdvUlhsdkRFamppMFR3MnErRU9manpraFA3WVFPSVV6ZHlubUI1a0oxY1dad3FkSzFMNXQ2VHljMElEUFJCQ2JydDIrYkJHRG82cVFMczlkYzA3VUpOQjEiLCJtYWMiOiJlM2QwMGRkYTdiYzEzNjBiMDIwOTdlOTgzZTcyMGRhN2ZjMDM2NTcxNjkwZTY4MTE1N2MzYWU2ODZiNTZmOGFhIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkxnVUwxUU40ZlhMUld1aFk2OWkxTUE9PSIsInZhbHVlIjoiWXJnSHhoZWNXNndwdXdDSlhPSXpRYXYramJqaFZiRFFRVU1HTHNtNXdvUlhsdkRFamppMFR3MnE" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjdVK0dBYVptRXZJZDB6SkllQTJycEE9PSIsInZhbHVlIjoiaW5zL0w5VGQwTVV1aFIrM0YwQTJxdlRWUVJmZ1BzaTB5SWNPM2NqVEZVMXNtM3hJZFFZcHFjZFhlcjRRbUNNdjFUZWltL2R3OCs5bVhDOTVYdUwxTDd4dEg1RERoNXd4VnlQZURrMHJBRUdTU3pEWXpCdDVSdk0zNUU0RzF4QloiLCJtYWMiOiIyOTZkMTljNWQ0OWE2ODU0MjUwZWQ4NzNhYjA5NGNhNGZiMDAyZjYzZGRlMGVjYTJlNTQ0ZDk1YzA0YWI1OTg3IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 08:07:30 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjdVK0dBYVptRXZJZDB6SkllQTJycEE9PSIsInZhbHVlIjoiaW5zL0w5VGQwTVV1aFIrM0YwQTJxdlRWUVJmZ1BzaTB5SWNPM2NqVEZVMXNtM3hJZFFZcHFjZFhlcjRRbUNNdjFUZWltL" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkxnVUwxUU40ZlhMUld1aFk2OWkxTUE9PSIsInZhbHVlIjoiWXJnSHhoZWNXNndwdXdDSlhPSXpRYXYramJqaFZiRFFRVU1HTHNtNXdvUlhsdkRFamppMFR3MnErRU9manpraFA3WVFPSVV6ZHlubUI1a0oxY1dad3FkSzFMNXQ2VHljMElEUFJCQ2JydDIrYkJHRG82cVFMczlkYzA3VUpOQjEiLCJtYWMiOiJlM2QwMGRkYTdiYzEzNjBiMDIwOTdlOTgzZTcyMGRhN2ZjMDM2NTcxNjkwZTY4MTE1N2MzYWU2ODZiNTZmOGFhIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkxnVUwxUU40ZlhMUld1aFk2OWkxTUE9PSIsInZhbHVlIjoiWXJnSHhoZWNXNndwdXdDSlhPSXpRYXYramJqaFZiRFFRVU1HTHNtNXdvUlhsdkRFamppMFR3MnE" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "ikvJcD5byJ4r9emMYBbmTPUbBdJ0OsrWJFz947r0" "uc_cart_id" => "8606177341c7977c28dbf055a9f00ada" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/110571" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:07:30GET/article/110571414372