Review Article

肽基前列腺特异性膜抗原(PSMA)抑制剂的进展:一种新的前列腺癌治疗方法

卷 28, 期 19, 2021

发表于: 06 October, 2020

页: [3713 - 3752] 页: 40

弟呕挨: 10.2174/0929867327666201006153847

价格: $65

摘要

背景:前列腺癌是世界上最常见的癌症之一,每年约有110万例确诊病例。分子成像的快速发展促进了对结构的进一步理解,这有助于制定治疗方案和更准确诊断的新组合,避免不必要的前列腺活检。这些累积的知识也对疾病的侵袭性阶段和肿瘤复发的提供了更好理解。最近,在开发拟肽基抑制剂作为有效结合前列腺特异性膜抗原(PSMA)——由前列腺癌细胞表达的——有前景的候选物方面取得了很大进展。目的:本文将广泛综述小分子和肽基PSMA抑制剂的最新进展,为未来PSMA抑制剂的合理设计提供基础。方法:本文回顾了1996年至2020年间研究的有关PSMA抑制剂的文献,强调了最近的合成进展和化学策略,同时强调了每种抑制剂的治疗潜力和缺点。结果:本综述中出现的PSMA合成抑制剂皆阐释了其在体内外的临床应用。结论:这篇综述强调了PSMA抑制剂的临床潜力,分析了所使用的化学合成方法的优点和缺点,为发现新的PSMA抑制剂用于未来的临床应用奠定了基础。

关键词: 前列腺特异性膜抗原抑制剂,肿瘤靶向性,正电子发射断层扫描(PET)成像,前列腺癌症。

[1]
Ghosh, A.; Heston, W.D.W. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J. Cell. Biochem., 2004, 91(3), 528-539.
[http://dx.doi.org/10.1002/jcb.10661] [PMID: 14755683]
[2]
Haffner, M.C.; Laimer, J.; Chaux, A.; Schäfer, G.; Obrist, P.; Brunner, A.; Kronberger, I.E.; Laimer, K.; Gurel, B.; Koller, J.-B.; Seifarth, C.; Zelger, B.; Klocker, H.; Rasse, M.; Doppler, W.; Bander, N.H. High expression of prostate specific membrane antigen in the tumor-associated neo vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity. Mod. Pathol., 2012, 25(8), 1079-1085.
[http://dx.doi.org/10.1038/modpathol.2012.66] [PMID: 22460809]
[3]
Wu, J.; Han, D.; Shi, S.; Zhang, Q.; Zheng, G.; Wei, M.; Han, Y.; Li, G.; Yang, F.; Jiao, D.; Xie, P.; Zhang, L.; Yang, A-G.; Zhao, A.; Qin, W.; Wen, W. A novel fully human antibody targeting extracellular domain of PSMA inhibits tumor growth in prostate cancer. Mol. Cancer Ther., 2019, 18(7), 1289-1301.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-1078] [PMID: 31048359]
[4]
Chang, S.S.; Reuter, V.E.; Heston, W.D.W.; Bander, N.H.; Grauer, L.S.; Gaudin, P.B. Five different anti-prostate specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res., 1999, 59(13), 3192-3198.
[PMID: 10397265]
[5]
Huang, X.; Bennett, M.; Thorpe, P.E. Anti-tumor effects and lack of side effects in mice of an immunotoxin directed against human and mouse prostate-specific membrane antigen. Prostate, 2004, 61(1), 1-11.
[http://dx.doi.org/10.1002/pros.20074] [PMID: 15287089]
[6]
Banerjee, S.R.; Ngen, E.J.; Rotz, M.W.; Kakkad, S.; Lisok, A.; Pracitto, R.; Pullambhatla, M.; Chen, Z.; Shah, T.; Artemov, D.; Meade, T.J.; Bhujwalla, Z.M.; Pomper, M.G. Synthesis and evaluation of Gd(III)-based magnetic resonance contrast agents for molecular imaging of prostate specific membrane antigen. Angew. Chem. Int. Ed. Engl., 2015, 54(37), 10778-10782.
[http://dx.doi.org/10.1002/anie.201503417] [PMID: 26212031]
[7]
Davis, M.I.; Bennett, M.J.; Thomas, L.M.; Bjorkman, P.J. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc. Natl. Acad. Sci., 2017, 102(17), 5981-5986.
[http://dx.doi.org/10.1073/pnas.0502101102] [PMID: 15837926]
[8]
Pang, S.-T.; Lin, F.-W.; Chuang, C.-K.; Yang, H.-W. Co-delivery of docetaxel and P44/42 MAPK SiRNA using PSMA antibody-conjugated BSA-PEI layer-by-layer nanoparticles for prostate cancer target therapy. Macromol. Biosci., 2017, 17(5), 1600421.
[http://dx.doi.org/10.1002/mabi.201600421] [PMID: 28128882]
[9]
Bandekar, A.; Zhu, C.; Jindal, R.; Bruchertseifer, F.; Morgenstern, A.; Sofou, S. Anti-prostate-specific membrane antigen liposomes loaded with 225Ac for potential targeted antivascular α-particle therapy of cancer. J. Nucl. Med., 2014, 55(1), 107-114.
[http://dx.doi.org/10.2967/jnumed.113.125476] [PMID: 24337602]
[10]
Wong, P.; Li, L.; Chea, J.; Delgado, M.K.; Crow, D.; Poku, E.; Szpikowska, B.; Bowles, N.; Channappa, D.; Colcher, D.; Wong, J.Y.C.; Shively, J.E.; Yazaki, P.J. PET imaging of 64Cu-DOTA-scFv-anti-PSMA lipid nanoparticles (LNPs): enhanced tumor targeting over anti-PSMA scFv or untargeted LNPs. Nucl. Med. Biol., 2017, 47, 62-68.
[http://dx.doi.org/10.1016/j.nucmedbio.2017.01.004] [PMID: 28126683]
[11]
Gilboa, E.; McNamara, J., II; Pastor, F. Use of oligonucleotide aptamer ligands to modulate the function of immune receptors. Clin. Cancer Res., 2013, 19(5), 1054-1062.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2067] [PMID: 23460536]
[12]
Wang, X.; Huang, S.S.; Heston, W.D.W.; Guo, H.; Wang, B.-C.; Basilion, J.P. Development of targeted near-infrared imaging agents for prostate cancer. Mol. Cancer Ther., 2014, 13(11), 2595-2606.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0422] [PMID: 25239933]
[13]
Ruggiero, A.; Holland, J.P.; Lewis, J.S.; Grimm, J. Cerenkov luminescence imaging of medical isotopes. J. Nucl. Med., 2010, 51(7), 1123-1130.
[http://dx.doi.org/10.2967/jnumed.110.076521] [PMID: 20554722]
[14]
Jackson, P.F.; Cole, D.C.; Slusher, B.S.; Stetz, S.L.; Ross, L.E.; Donzanti, B.A.; Trainor, D.A. Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated α-linked acidic dipeptidase. J. Med. Chem., 1996, 39(2), 619-622.
[http://dx.doi.org/10.1021/jm950801q] [PMID: 8558536]
[15]
Curatolo, A.; D Arcangelo, P.; Lino, A.; Brancati, A. Distribution of N-acetyl-aspartic and N-acetyl-aspartyl-glutamic acids in nervous tissue. J. Neurochem., 1965, 12(4), 339-342.
[http://dx.doi.org/10.1111/j.1471-4159.1965.tb06771.x] [PMID: 14340686]
[16]
Son, S.-H.; Kwon, H.; Ahn, H.-H.; Nam, H.; Kim, K.; Nam, S.; Choi, D.; Ha, H.; Minn, I.; Byun, Y. Design and synthesis of a novel BODIPY-labeled PSMA inhibitor. Bioorg. Med. Chem. Lett., 2020, 30(3), 126894.
[http://dx.doi.org/10.1016/j.bmcl.2019.126894] [PMID: 31874825]
[17]
Machulkin, A.E.; Ivanenkov, Y.A.; Aladinskaya, A.V.; Veselov, M.S.; Aladinskiy, V.A.; Beloglazkina, E.K.; Koteliansky, V.E.; Shakhbazyan, A.G.; Sandulenko, Y.B.; Majouga, A.G. Small-molecule PSMA ligands. Current state, SAR and perspectives. J. Drug Target., 2016, 24(8), 679-693.
[http://dx.doi.org/10.3109/1061186X.2016.1154564] [PMID: 26887438]
[18]
Vitharana, D.; France, J.E.; Scarpetti, D.; Bonneville, G.W.; Majer, P.; Tsukamoto, T. Synthesis and biological evaluation of (R)- and (S)-2-(phosphonomethyl)pentanedioic acids as inhibitors of glutamate carboxypeptidase II. Tetrahedr. Asymm., 2002, 13(15), 1609-1614.
[http://dx.doi.org/10.1016/S0957-4166(02)00412-3]
[19]
Jackson, P.F.; Tays, K.L.; Maclin, K.M.; Ko, Y.-S.; Li, W.; Vitharana, D.; Tsukamoto, T.; Stoermer, D.; Lu, X.-C.M.; Wozniak, K.; Slusher, B.S. Design and pharmacological activity of phosphinic acid based NAALADase inhibitors. J. Med. Chem., 2001, 44(24), 4170-4175.
[http://dx.doi.org/10.1021/jm0001774] [PMID: 11708918]
[20]
Tsukamoto, T.; Flanary, J.M.; Rojas, C.; Slusher, B.S.; Valiaeva, N.; Coward, J.K. Phosphonate and phosphinate analogues of N-acylated γ-glutamylglutamate. potent inhibitors of glutamate carboxypeptidase II. Bioorg. Med. Chem. Lett., 2002, 12(16), 2189-2192.
[http://dx.doi.org/10.1016/S0960-894X(02)00360-8] [PMID: 12127534]
[21]
Nan, F.; Bzdega, T.; Pshenichkin, S.; Wroblewski, J.T.; Wroblewska, B.; Neale, J.H.; Kozikowski, A.P. Dual function glutamate-related ligands: discovery of a novel, potent inhibitor of glutamate carboxypeptidase II possessing mGluR3 agonist activity. J. Med. Chem., 2000, 43(5), 772-774.
[http://dx.doi.org/10.1021/jm9905559] [PMID: 10715144]
[22]
Tsukamoto, T.; Majer, P.; Vitharana, D.; Ni, C.; Hin, B.; Lu, X-C.M.; Thomas, A.G.; Wozniak, K.M.; Calvin, D.C.; Wu, Y.; Slusher, B.S.; Scarpetti, D.; Bonneville, G.W. Enantiospecificity of glutamate carboxypeptidase II inhibition. J. Med. Chem., 2005, 48(7), 2319-2324.
[http://dx.doi.org/10.1021/jm049258g] [PMID: 15801825]
[23]
Synold, T.W.; Willits, E.M.; Barredo, J.C. Role of folylpolygutamate synthetase (FPGS) in antifolate chemotherapy; a biochemical and clinical update. Leuk. Lymphoma, 1996, 21(1-2), 9-15.
[http://dx.doi.org/10.3109/10428199609067573] [PMID: 8907263]
[24]
Barinka, C.; Hlouchova, K.; Rovenska, M.; Majer, P.; Dauter, M.; Hin, N.; Ko, Y.-S.; Tsukamoto, T.; Slusher, B.S.; Konvalinka, J.; Lubkowski, J. Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs. J. Mol. Biol., 2008, 376(5), 1438-1450.
[http://dx.doi.org/10.1016/j.jmb.2007.12.066] [PMID: 18234225]
[25]
Lu, H.; Ng, R.J.; Shieh, C.C.; Martinez, A.R.; Berkman, C.E. Inhibition of glutamate carboxypeptidase by phosphoryl and thiophosphoryl derivatives of glutamic and 2-hydroxyglutaric acid. Phosphorus Sulfur Silicon Relat. Elem., 2003, 178(1), 17-32.
[http://dx.doi.org/10.1080/10426500307817]
[26]
Maung, J.; Mallari, J.P.; Girtsman, T.A.; Wu, L.Y.; Rowley, J.A.; Santiago, N.M.; Brunelle, A.N.; Berkman, C.E. Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates. Bioorg. Med. Chem., 2004, 12(18), 4969-4979.
[http://dx.doi.org/10.1016/j.bmc.2004.06.031] [PMID: 15336276]
[27]
Ganguly, T.; Dannoon, S.; Hopkins, M.R.; Murphy, S.; Cahaya, H.; Blecha, J.E.; Jivan, S.; Drake, C.R.; Barinka, C.; Jones, E.F.; VanBrocklin, H.F.; Berkman, C.E.A. A high-affinity [(18)F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer. Nucl. Med. Biol., 2015, 42(10), 780-787.
[http://dx.doi.org/10.1016/j.nucmedbio.2015.06.003] [PMID: 26169882]
[28]
Krise, J.P.; Stella, V.J. Prodrugs of phosphates, phosphonates, and phosphinates. Adv. Drug Deliv. Rev., 1996, 19(2), 287-310.
[http://dx.doi.org/10.1016/0169-409X(95)00111-J]
[29]
Gehr, T.W.B.; Sica, D.A.; Grasela, D.M.; Duchin, K.L. The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients. Eur. J. Clin. Pharmacol., 1993, 45(5), 431-436.
[http://dx.doi.org/10.1007/BF00315514] [PMID: 8112372]
[30]
Zhong, C.; Luo, Q.; Jiang, J. Blockade of N-acetylaspar-tylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders. Int. J. Neurosci., 2014, 124(12), 867-873.
[http://dx.doi.org/10.3109/00207454.2014.890935] [PMID: 24494725]
[31]
Majer, P.; Jackson, P.F.; Delahanty, G.; Grella, B.S.; Ko, Y.-S.; Li, W.; Liu, Q.; Maclin, K.M.; Poláková, J.; Shaffer, K.A.; Stoermer, D.; Vitharana, D.; Wang, E.Y.; Zakrzewski, A.; Rojas, C.; Slusher, B.S.; Wozniak, K.M.; Burak, E.; Limsakun, T.; Tsukamoto, T. Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: discovery of an orally active GCP II inhibitor. J. Med. Chem., 2003, 46(10), 1989-1996.
[http://dx.doi.org/10.1021/jm020515w] [PMID: 12723961]
[32]
Dannoon, S.; Ganguly, T.; Cahaya, H.; Geruntho, J.J.; Galliher, M.S.; Beyer, S.K.; Choy, C.J.; Hopkins, M.R.; Regan, M.; Blecha, J.E.; Skultetyova, L.; Drake, C.R.; Jivan, S.; Barinka, C.; Jones, E.F.; Berkman, C.E.; VanBrocklin, H.F. Structure-activity relationship of (18)F-labeled phosphoramidate peptidomimetic prostate-specific membrane antigen (PSMA)-targeted inhibitor analogues for PET imaging of prostate cancer. J. Med. Chem., 2016, 59(12), 5684-5694.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01850] [PMID: 27228467]
[33]
Choy, C.J.; Ling, X.; Geruntho, J.J.; Beyer, S.K.; Latoche, J.D.; Langton-Webster, B.; Anderson, C.J.; Berkman, C.E. 177Lu-labeled phosphoramidate-based PSMA inhibitors: the effect of an albumin binder on biodistribution and therapeutic efficacy in prostate tumor-bearing mice. Theranostics, 2017, 7(7), 1928-1939.
[http://dx.doi.org/10.7150/thno.18719] [PMID: 28638478]
[34]
Majer, P.; Hin, B.; Stoermer, D.; Adams, J.; Xu, W.; Duvall, B.R.; Delahanty, G.; Liu, Q.; Stathis, M.J.; Wozniak, K.M.; Slusher, B.S.; Tsukamoto, T. Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1′ side chain. J. Med. Chem., 2006, 49(10), 2876-2885.
[http://dx.doi.org/10.1021/jm051019l] [PMID: 16686531]
[35]
Kozikowski, A.P.; Nan, F.; Conti, P.; Zhang, J.; Ramadan, E.; Bzdega, T.; Wroblewska, B.; Neale, J.H.; Pshenichkin, S.; Wroblewski, J.T. Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase). J. Med. Chem., 2001, 44(3), 298-301.
[http://dx.doi.org/10.1021/jm000406m] [PMID: 11462970]
[36]
Barinka, C.; Byun, Y.; Dusich, C.L.; Banerjee, S.R.; Chen, Y.; Castanares, M.; Kozikowski, A.P.; Mease, R.C.; Pomper, M.G.; Lubkowski, J. Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization. J. Med. Chem., 2008, 51(24), 7737-7743.
[http://dx.doi.org/10.1021/jm800765e] [PMID: 19053759]
[37]
Mlcochová, P.; Plechanovová, A.; Bařinka, C.; Mahadevan, D.; Saldanha, J.W.; Rulísek, L.; Konvalinka, J. Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesis. FEBS J., 2007, 274(18), 4731-4741.
[http://dx.doi.org/10.1111/j.1742-4658.2007.06021.x] [PMID: 17714508]
[38]
Mesters, J.R.; Barinka, C.; Li, W.; Tsukamoto, T.; Majer, P.; Slusher, B.S.; Konvalinka, J.; Hilgenfeld, R. Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer. EMBO J., 2006, 25(6), 1375-1384.
[http://dx.doi.org/10.1038/sj.emboj.7600969] [PMID: 16467855]
[39]
Klusák, V.; Bařinka, C.; Plechanovová, A.; Mlcochová, P.; Konvalinka, J.; Rulísek, L.; Lubkowski, J. Reaction mechanism of glutamate carboxypeptidase II revealed by mutagenesis, X-ray crystallography, and computational methods. Biochemistry, 2009, 48(19), 4126-4138.
[http://dx.doi.org/10.1021/bi900220s] [PMID: 19301871]
[40]
Bařinka, C.; Rovenská, M.; Mlcochová, P.; Hlouchová, K.; Plechanovová, A.; Majer, P.; Tsukamoto, T.; Slusher, B.S.; Konvalinka, J.; Lubkowski, J. Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II. J. Med. Chem., 2007, 50(14), 3267-3273.
[http://dx.doi.org/10.1021/jm070133w] [PMID: 17567119]
[41]
Plechanovová, A.; Byun, Y.; Alquicer, G.; Skultétyová, L.; Mlčochová, P.; Němcová, A.; Kim, H-J.; Navrátil, M.; Mease, R.; Lubkowski, J.; Pomper, M.; Konvalinka, J.; Rulíšek, L.; Bařinka, C. Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity. J. Med. Chem., 2011, 54(21), 7535-7546.
[http://dx.doi.org/10.1021/jm200807m] [PMID: 21923190]
[42]
Choy, C.J.; Fulton, M.D.; Davis, A.L.; Hopkins, M.; Choi, J.K.; Anderson, M.O.; Berkman, C.E. Rationally designed sulfamides as glutamate carboxypeptidase II inhibitors. Chem. Biol. Drug Des., 2013, 82(5), 612-619.
[http://dx.doi.org/10.1111/cbdd.12174] [PMID: 23773397]
[43]
Park, J.D.; Kim, D.H.; Kim, S.-J.; Woo, J.-R.; Ryu, S.E. Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases. J. Med. Chem., 2002, 45(24), 5295-5302.
[http://dx.doi.org/10.1021/jm020258v] [PMID: 12431056]
[44]
Kozikowski, A.P.; Zhang, J.; Nan, F.; Petukhov, P.A.; Grajkowska, E.; Wroblewski, J.T.; Yamamoto, T.; Bzdega, T.; Wroblewska, B.; Neale, J.H. Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents. J. Med. Chem., 2004, 47(7), 1729-1738.
[http://dx.doi.org/10.1021/jm0306226] [PMID: 15027864]
[45]
Chen, Y.; Foss, C.A.; Byun, Y.; Nimmagadda, S.; Pullambhatla, M.; Fox, J.J.; Castanares, M.; Lupold, S.E.; Babich, J.W.; Mease, R.C.; Pomper, M.G. Radiohalogenated prostate-specific membrane antigen (PSMA)-based ureas as imaging agents for prostate cancer. J. Med. Chem., 2008, 51(24), 7933-7943.
[http://dx.doi.org/10.1021/jm801055h] [PMID: 19053825]
[46]
Kim, K.; Kwon, H.; Barinka, C.; Motlova, L.; Nam, S.; Choi, D.; Ha, H.; Nam, H.; Son, S.-H.; Minn, I.; Pomper, M.G.; Yang, X.; Kutil, Z.; Byun, Y. Novel β- and γ-amino acid-derived inhibitors of prostate-specific membrane antigen. J. Med. Chem., 2020, 63(6), 3261-3273.
[http://dx.doi.org/10.1021/acs.jmedchem.9b02022] [PMID: 32097010]
[47]
Banerjee, S.R.; Foss, C.A.; Castanares, M.; Mease, R.C.; Byun, Y.; Fox, J.J.; Hilton, J.; Lupold, S.E.; Kozikowski, A.P.; Pomper, M.G. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA). J. Med. Chem., 2008, 51(15), 4504-4517.
[http://dx.doi.org/10.1021/jm800111u] [PMID: 18637669]
[48]
Maresca, K.P.; Hillier, S.M.; Femia, F.J.; Keith, D.; Barone, C.; Joyal, J.L.; Zimmerman, C.N.; Kozikowski, A.P.; Barrett, J.A.; Eckelman, W.C.; Babich, J.W. A series of halogenated heterodimeric inhibitors of prostate specific membrane antigen (PSMA) as radiolabeled probes for targeting prostate cancer. J. Med. Chem., 2009, 52(2), 347-357.
[http://dx.doi.org/10.1021/jm800994j] [PMID: 19111054]
[49]
Chandran, S.S.; Banerjee, S.R.; Mease, R.C.; Pomper, M.G.; Denmeade, S.R. Characterization of a targeted nanoparticle functionalized with a urea-based inhibitor of prostate-specific membrane antigen (PSMA). Cancer Biol. Ther., 2008, 7(6), 974-982.
[http://dx.doi.org/10.4161/cbt.7.6.5968] [PMID: 18698158]
[50]
Banerjee, S.R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Green, G.; Fox, J.J.; Horti, A.; Mease, R.C.; Pomper, M.G. 68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer. J. Med. Chem., 2010, 53(14), 5333-5341.
[http://dx.doi.org/10.1021/jm100623e] [PMID: 20568777]
[51]
Fani, M.; André, J.P.; Maecke, H.R. 68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals. Contrast Media Mol. Imaging, 2008, 3(2), 67-77.
[http://dx.doi.org/10.1002/cmmi.232] [PMID: 18383558]
[52]
Kularatne, S.A.; Zhou, Z.; Yang, J.; Post, C.B.; Low, P.S. Design, synthesis, and preclinical evaluation of prostate-specific membrane antigen targeted (99m)Tc-radioimaging agents. Mol. Pharm., 2009, 6(3), 790-800.
[http://dx.doi.org/10.1021/mp9000712] [PMID: 19361232]
[53]
Eder, M.; Schäfer, M.; Bauder-Wüst, U.; Hull, W.E.; Wängler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug. Chem., 2012, 23(4), 688-697.
[http://dx.doi.org/10.1021/bc200279b] [PMID: 22369515]
[54]
Eder, M.; Wängler, B.; Knackmuss, S.; LeGall, F.; Little, M.; Haberkorn, U.; Mier, W.; Eisenhut, M. Tetrafluorophenolate of HBED-CC: a versatile conjugation agent for 68Ga-labeled small recombinant antibodies. Eur. J. Nucl. Med. Mol. Imaging, 2008, 35(10), 1878-1886.
[http://dx.doi.org/10.1007/s00259-008-0816-z] [PMID: 18509635]
[55]
Afshar-Oromieh, A.; Avtzi, E.; Giesel, F.L.; Holland-Letz, T.; Linhart, H.G.; Eder, M.; Eisenhut, M.; Boxler, S.; Hadaschik, B.A.; Kratochwil, C.; Weichert, W.; Kopka, K.; Debus, J.; Haberkorn, U. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur. J. Nucl. Med. Mol. Imaging, 2015, 42(2), 197-209.
[http://dx.doi.org/10.1007/s00259-014-2949-6] [PMID: 25411132]
[56]
Demirci, E.; Ocak, M.; Kabasakal, L.; Decristoforo, C.; Talat, Z.; Halaç, M.; Kanmaz, B. (68)Ga-PSMA PET/CT imaging of metastatic clear cell renal cell carcinoma. Eur. J. Nucl. Med. Mol. Imaging, 2014, 41(7), 1461-1462.
[http://dx.doi.org/10.1007/s00259-014-2766-y] [PMID: 24756358]
[57]
Gourni, E.; Canovas, C.; Goncalves, V.; Denat, F.; Meyer, P.T.; Maecke, H.R. (R)-NODAGA-PSMA: a versatile precursor for radiometal labeling and nuclear imaging of PSMA-positive tumors. PLoS One, 2015, 10(12), e0145755.
[http://dx.doi.org/10.1371/journal.pone.0145755] [PMID: 26700033]
[58]
Hoberück, S.; Wunderlich, G.; Michler, E.; Hölscher, T.; Walther, M.; Seppelt, D.; Platzek, I.; Zöphel, K.; Kotzerke, J. Dual-time-point 64 Cu-PSMA-617-PET/CT in patients suffering from prostate cancer. J. Labelled Comp. Radiopharm., 2019, 62(8), 523-532.
[http://dx.doi.org/10.1002/jlcr.3745] [PMID: 31042811]
[59]
Grubmüller, B.; Baum, R.P.; Capasso, E.; Singh, A.; Ahmadi, Y.; Knoll, P.; Floth, A.; Righi, S.; Zandieh, S.; Meleddu, C.; Shariat, S.F.; Klingler, H.C.; Mirzaei, S. 64Cu-PSMA-617 PET/CT imaging of prostate adenocarcinoma: first in-human studies. Cancer Biother. Radiopharm., 2016, 31(8), 277-286.
[http://dx.doi.org/10.1089/cbr.2015.1964] [PMID: 27715146]
[60]
Kim, K.; Kwon, H.; Choi, D.; Lim, T.; Minn, I.; Son, S.-H.; Byun, Y. Design and synthesis of dye-conjugated hepsin inhibitors. Bioorg. Chem., 2019, 89, 102990.
[http://dx.doi.org/10.1016/j.bioorg.2019.102990] [PMID: 31136899]
[61]
Chen, Y.; Pullambhatla, M.; Banerjee, S.R.; Byun, Y.; Stathis, M.; Rojas, C.; Slusher, B.S.; Mease, R.C.; Pomper, M.G. Synthesis and biological evaluation of low molecular weight fluorescent imaging agents for the prostate-specific membrane antigen. Bioconjug. Chem., 2012, 23(12), 2377-2385.
[http://dx.doi.org/10.1021/bc3003919] [PMID: 23157641]
[62]
Kwon, Y.-D.; Oh, J.-M.; La, M.T.; Chung, H.-J.; Lee, S.J.; Chun, S.; Lee, S.-H.; Jeong, B.-H.; Kim, H.-K. Synthesis and evaluation of multifunctional fluorescent inhibitors with synergistic interaction of prostate-specific membrane antigen and hypoxia for prostate cancer. Bioconjug. Chem., 2019, 30(1), 90-100.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00767] [PMID: 30485073]
[63]
Milosevic, M.; Warde, P.; Ménard, C.; Chung, P.; Toi, A.; Ishkanian, A.; McLean, M.; Pintilie, M.; Sykes, J.; Gospodarowicz, M.; Catton, C.; Hill, R.P.; Bristow, R. Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin. Cancer Res., 2012, 18(7), 2108-2114.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2711] [PMID: 22465832]
[64]
Zha, Z.; Zhu, L.; Liu, Y.; Du, F.; Gan, H.; Qiao, J.; Kung, H.F. Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging. Nucl. Med. Biol., 2011, 38(4), 501-508.
[http://dx.doi.org/10.1016/j.nucmedbio.2010.11.001] [PMID: 21531287]
[65]
Kwon, Y.-D.; Lee, J.Y.; La, M.T.; Lee, S.J.; Lee, S.-H.; Park, J.H.; Kim, H.-K. Novel multifunctional 18F-labelled PET tracer with prostate-specific membrane antigen-targeting and hypoxia-sensitive moieties. Eur. J. Med. Chem., 2020, 189, 112099.
[http://dx.doi.org/10.1016/j.ejmech.2020.112099] [PMID: 32014792]
[66]
Jacobs, M.J.; Schneider, G.; Blank, K.G. Mechanical reversibility of strain-promoted azide-alkyne cycloaddition reactions. Angew. Chem. Int. Ed. Engl., 2016, 55(8), 2899-2902.
[http://dx.doi.org/10.1002/anie.201510299] [PMID: 26806106]
[67]
Jayaprakash, S.; Wang, X.; Heston, W.D.; Kozikowski, A.P. Design and synthesis of a PSMA inhibitor-doxorubicin conjugate for targeted prostate cancer therapy. ChemMedChem, 2006, 1(3), 299-302.
[http://dx.doi.org/10.1002/cmdc.200500044] [PMID: 16892363]
[68]
Subedi, M.; Minn, I.; Chen, J.; Kim, Y.; Ok, K.; Jung, Y.W.; Pomper, M.G.; Byun, Y. Design, synthesis and biological evaluation of PSMA/hepsin-targeted heterobivalent ligands. Eur. J. Med. Chem., 2016, 118, 208-218.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.033] [PMID: 27128184]
[69]
Klezovitch, O.; Chevillet, J.; Mirosevich, J.; Roberts, R.L.; Matusik, R.J.; Vasioukhin, V. Hepsin promotes prostate cancer progression and metastasis. Cancer Cell, 2004, 6(2), 185-195.
[http://dx.doi.org/10.1016/j.ccr.2004.07.008] [PMID: 15324701]
[70]
Katz, B.A.; Luong, C.; Ho, J.D.; Somoza, J.R.; Gjerstad, E.; Tang, J.; Williams, S.R.; Verner, E.; Mackman, R.L.; Young, W.B.; Sprengeler, P.A.; Chan, H.; Mortara, K.; Janc, J.W.; McGrath, M.E. Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA). J. Mol. Biol., 2004, 344(2), 527-547.
[http://dx.doi.org/10.1016/j.jmb.2004.09.032] [PMID: 15522303]
[71]
Olszewski, R.T.; Bukhari, N.; Zhou, J.; Kozikowski, A.P.; Wroblewski, J.T.; Shamimi-Noori, S.; Wroblewska, B.; Bzdega, T.; Vicini, S.; Barton, F.B.; Neale, J.H. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J. Neurochem., 2004, 89(4), 876-885.
[http://dx.doi.org/10.1111/j.1471-4159.2004.02358.x] [PMID: 15140187]
[72]
Yuan, Z.; Nodwell, M.B.; Yang, H.; Malik, N.; Merkens, H.; Bénard, F.; Martin, R.E.; Schaffer, P.; Britton, R. Site-selective, late-stage C-H 18 F-fluorination on unprotected peptides for positron emission tomography imaging. Angew. Chem. Int. Ed. Engl., 2018, 57(39), 12733-12736.
[http://dx.doi.org/10.1002/anie.201806966] [PMID: 30086209]
[73]
Yuan, Z.; Yang, H.; Malik, N.; Čolović, M.; Weber, D.S.; Wilson, D.; Bénard, F.; Martin, R.E.; Warren, J.J.; Schaffer, P.; Britton, R. Electrostatic effects accelerate decatungstate-catalyzed C–H fluorination using [18F]- and [19F]NFSI in small molecules and peptide mimics. ACS Catal., 2019, 9(9), 8276-8284.
[http://dx.doi.org/10.1021/acscatal.9b02220]
[74]
Liu, T.; Liu, C.; Xu, X.; Liu, F.; Guo, X.; Li, N.; Wang, X.; Yang, J.; Yang, X.; Zhu, H.; Yang, Z. Preclinical evaluation and pilot clinical study of Al18F-PSMA-BCH for prostate cancer PET imaging. J. Nucl. Med., 2019, 60(9), 1284-1292.
[http://dx.doi.org/10.2967/jnumed.118.221671] [PMID: 30796170]
[75]
Harada, N.; Kimura, H.; Ono, M.; Saji, H. Preparation of asymmetric urea derivatives that target prostate-specific membrane antigen for SPECT imaging. J. Med. Chem., 2013, 56(20), 7890-7901.
[http://dx.doi.org/10.1021/jm400895s] [PMID: 24063417]
[76]
Banerjee, S.R.; Pullambhatla, M.; Foss, C.A.; Nimmagadda, S.; Ferdani, R.; Anderson, C.J.; Mease, R.C.; Pomper, M.G. 64Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer. J. Med. Chem., 2014, 57(6), 2657-2669.
[http://dx.doi.org/10.1021/jm401921j] [PMID: 24533799]
[77]
Hillier, S.M.; Maresca, K.P.; Lu, G.; Merkin, R.D.; Marquis, J.C.; Zimmerman, C.N.; Eckelman, W.C.; Joyal, J.L.; Babich, J.W. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J. Nucl. Med., 2013, 54(8), 1369-1376.
[http://dx.doi.org/10.2967/jnumed.112.116624] [PMID: 23733925]
[78]
Tykvart, J.; Schimer, J.; Jančařík, A.; Bařinková, J.; Navrátil, V.; Starková, J.; Šrámková, K.; Konvalinka, J.; Majer, P.; Šácha, P. Design of highly potent urea-based, exosite-binding inhibitors selective for glutamate carboxypeptidase II. J. Med. Chem., 2015, 58(10), 4357-4363.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00278] [PMID: 25923815]
[79]
Youn, S.; Kim, K.I.; Ptacek, J.; Ok, K.; Novakova, Z.; Kim, Y.; Koo, J.; Barinka, C.; Byun, Y. Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: synthesis and structural characterization. Bioorg. Med. Chem. Lett., 2015, 25(22), 5232-5236.
[http://dx.doi.org/10.1016/j.bmcl.2015.09.062] [PMID: 26459214]
[80]
Mosayebnia, M.; Hajimahdi, Z.; Beiki, D.; Rezaeianpour, M.; Hajiramezanali, M.; Geramifar, P.; Sabzevari, O.; Amini, M.; Hatamabadi, D.; Shahhosseini, S. Design, synthesis, radiolabeling and biological evaluation of new urea-based peptides targeting prostate specific membrane antigen. Bioorg. Chem., 2020, 99, 103743.
[http://dx.doi.org/10.1016/j.bioorg.2020.103743] [PMID: 32217372]
[81]
Huang, S.S.; Wang, X.; Zhang, Y.; Doke, A.; DiFilippo, F.P.; Heston, W.D. Improving the biodistribution of PSMA-targeting tracers with a highly negatively charged linker. Prostate, 2014, 74(7), 702-713.
[http://dx.doi.org/10.1002/pros.22789] [PMID: 24615708]
[82]
Wurzer, A.; Pollmann, J.; Schmidt, A.; Reich, D.; Wester, H.-J.; Notni, J. Molar activity of Ga-68 labeled PSMA inhibitor conjugates determines PET imaging results. Mol. Pharm., 2018, 15(9), 4296-4302.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00602] [PMID: 30011372]
[83]
Liolios, C.; Schäfer, M.; Haberkorn, U.; Eder, M.; Kopka, K. Novel bispecific PSMA/GRPr targeting radioligands with optimized pharmacokinetics for improved PET imaging of prostate cancer. Bioconjug. Chem., 2016, 27(3), 737-751.
[http://dx.doi.org/10.1021/acs.bioconjchem.5b00687] [PMID: 26726823]
[84]
Stenberg, V.Y.; Juzeniene, A.; Chen, Q.; Yang, X.; Bruland, Ø.S.; Larsen, R.H. Preparation of the alpha-emitting prostate-specific membrane antigen targeted radioligand [212 Pb]Pb-NG001 for prostate cancer. J. Labelled Comp. Radiopharm., 2020, 63(3), 129-143.
[http://dx.doi.org/10.1002/jlcr.3825] [PMID: 31919866]
[85]
Banerjee, S.R.; Pullambhatla, M.; Shallal, H.; Lisok, A.; Mease, R.C.; Pomper, M.G. A modular strategy to prepare multivalent inhibitors of prostate-specific membrane antigen (PSMA). Oncotarget, 2011, 2(12), 1244-1253.
[http://dx.doi.org/10.18632/oncotarget.415] [PMID: 22207391]
[86]
Yang, X.; Mease, R.C.; Pullambhatla, M.; Lisok, A.; Chen, Y.; Foss, C.A.; Wang, Y.; Shallal, H.; Edelman, H.; Hoye, A.T.; Attardo, G.; Nimmagadda, S.; Pomper, M.G. [(18)F]fluorobenzoyllysinepentanedioic acid carbamates: new scaffolds for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA). J. Med. Chem., 2016, 59(1), 206-218.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01268] [PMID: 26629713]
[87]
Merrifield, R.B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc., 1963, 85(14), 2149-2154.
[http://dx.doi.org/10.1021/ja00897a025]
[88]
Cameron, A.J.; Squire, C.J.; Gérenton, A.; Stubbing, L.A.; Harris, P.W.R.; Brimble, M.A. Investigations of the key macrolactamisation step in the synthesis of cyclic tetrapeptide pseudoxylallemycin A. Org. Biomol. Chem., 2019, 17(16), 3902-3913.
[http://dx.doi.org/10.1039/C9OB00227H] [PMID: 30941386]
[89]
Siow, A.; Hung, K.; Harris, P.W.R.; Brimble, M.A. Solid-phase synthesis of the peptaibol alamethicin U-22324 by using a double-linker strategy. Eur. J. Org. Chem., 2017, 2017(2), 350-354.
[http://dx.doi.org/10.1002/ejoc.201601102]
[90]
Carter, R.E.; Feldman, A.R.; Coyle, J.T. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase. Proc. Natl. Acad. Sci. USA, 1996, 93(2), 749-753.
[http://dx.doi.org/10.1073/pnas.93.2.749] [PMID: 8570628]
[91]
Barinka, C.; Rinnová, M.; Sácha, P.; Rojas, C.; Majer, P.; Slusher, B.S.; Konvalinka, J. Substrate specificity, inhibition and enzymological analysis of recombinant human glutamate carboxypeptidase II. J. Neurochem., 2002, 80(3), 477-487.
[http://dx.doi.org/10.1046/j.0022-3042.2001.00715.x] [PMID: 11905994]
[92]
Aggarwal, S.; Singh, P.; Topaloglu, O.; Isaacs, J.T.; Denmeade, S.R. A dimeric peptide that binds selectively to prostate-specific membrane antigen and inhibits its enzymatic activity. Cancer Res., 2006, 66(18), 9171-9177.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1520] [PMID: 16982760]
[93]
Aggarwal, S.; Janssen, S.; Wadkins, R.M.; Harden, J.L.; Denmeade, S.R. A combinatorial approach to the selective capture of circulating malignant epithelial cells by peptide ligands. Biomaterials, 2005, 26(30), 6077-6086.
[http://dx.doi.org/10.1016/j.biomaterials.2005.03.040] [PMID: 15907998]
[94]
Wrighton, N.C.; Balasubramanian, P.; Barbone, F.P.; Kashyap, A.K.; Farrell, F.X.; Jolliffe, L.K.; Barrett, R.W.; Dower, W.J. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat. Biotechnol., 1997, 15(12), 1261-1265.
[http://dx.doi.org/10.1038/nbt1197-1261] [PMID: 9359108]
[95]
Lupold, S.E.; Rodriguez, R. Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen. Mol. Cancer Ther., 2004, 3(5), 597-603.
[PMID: 15141017]
[96]
Shen, D.; Xie, F.; Edwards, W.B. Evaluation of phage display discovered peptides as ligands for prostate-specific membrane antigen (PSMA). PLoS One, 2013, 8(7), e68339.
[http://dx.doi.org/10.1371/journal.pone.0068339] [PMID: 23935860]
[97]
Conway, R.E.; Rojas, C.; Alt, J.; Nováková, Z.; Richardson, S.M.; Rodrick, T.C.; Fuentes, J.L.; Richardson, N.H.; Attalla, J.; Stewart, S.; Fahmy, B.; Barinka, C.; Ghosh, M.; Shapiro, L.H.; Slusher, B.S. Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide. Angiogenesis, 2016, 19(4), 487-500.
[http://dx.doi.org/10.1007/s10456-016-9521-x] [PMID: 27387982]
[98]
Brehmer, B.; Biesterfeld, S.; Jakse, G. Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue. Prostate Cancer Prostatic Dis., 2003, 6(3), 217-222.
[http://dx.doi.org/10.1038/sj.pcan.4500657] [PMID: 12970724]
[99]
Ahn, T.; Roberts, M.J.; Abduljabar, A.; Joshi, A.; Perera, M.; Rhee, H.; Wood, S.; Vela, I. A review of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in renal cell carcinoma (RCC). Mol. Imaging Biol., 2019, 21(5), 799-807.
[http://dx.doi.org/10.1007/s11307-018-01307-0] [PMID: 30617728]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version418msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[05:07:54] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[05:07:54] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[05:07:54] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[05:07:54] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (103ms)time
  • Application (315ms)time
  • 1 x Application (75.41%)
    315ms
    1 x Booting (24.59%)
    103ms
    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
    41 statements were executed, 4 of which were duplicates, 37 unique. Show only duplicated232ms
    • 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 ('51368230','',1,1740460074,1740460074) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740460074
      920μsalphaeurekaselec_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 ('51368230','/article/110494/cn',1,1740460074,1740460074)
      140μsalphaeurekaselec_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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) limit 1
      11.76msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 51368230
      • 1: 51368230
      • 2: 51368230
      • 3: 51368230
      • 4: 51368230
      • 5: 51368230
      • 6: 51368230
      • 7: 51368230
      • 8: 51368230
      • 9: 51368230
      • 10: 51368230
      • 11: 51368230
      • 12: 51368230
      • 13: 51368230
      • 14: 51368230
      • 15: 51368230
      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=110494
      610μsalphaeurekaselec_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` = 25 limit 1
      710μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      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=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      1.31msalphaeurekaselec_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=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.07msalphaeurekaselec_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=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.36msalphaeurekaselec_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=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.76msalphaeurekaselec_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` = '110494'
      870μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 110494
      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` = '110494'
      5.56msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 110494
      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` = '110494' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.24msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 110494
      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
      260μsalphaeurekaselec_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
      580μsalphaeurekaselec_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 = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      34.06msalphaeurekaselec_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 = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      38.74msalphaeurekaselec_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 = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      25.42msalphaeurekaselec_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` = 110494 limit 1
      270μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 110494
      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 = 110494 and content_type = 'article' order by status desc limit 1
      300μsalphaeurekaselec_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 = 483 and content_id!=110494 and cd.content_type = 'article' order by rand() limit 20
      78.07msalphaeurekaselec_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` = 186668 limit 1
      280μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 186668
      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
      330μsalphaeurekaselec_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` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      490μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      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 = '110494' 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) )
      430μsalphaeurekaselec_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 = '10711' 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 = '2916' 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) )
      340μsalphaeurekaselec_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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2916) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2916) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2916)
      1.37msalphaeurekaselec_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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10711) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10711) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10711)
      590μsalphaeurekaselec_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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110494) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110494) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740460074 and j.to_date >= 1740460074 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110494)
      560μsalphaeurekaselec_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` < '3713' and is_uploaded = 1 and issue_id = 10711 order by cast(first_page as SIGNED) desc limit 1
      550μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 3713
      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` > '3752' and is_uploaded = 1 and issue_id = 10711 order by cast(first_page as SIGNED) asc limit 1
      440μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 3752
      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` = 'cn'
      170μsalphaeurekaselec_live_10_06_2022ArticleController.php#2486
      Bindings
      • 0: cn
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2486
      • 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` = 2
      200μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 2
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2487
      • 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 `multilanguage_article` where (`language_id` = 2 and `article_id` = 110494)
      5.69msalphaeurekaselec_live_10_06_2022ArticleController.php#2488
      Bindings
      • 0: 2
      • 1: 110494
      Backtrace
      • 15. app/Http/Controllers/ArticleController.php:2488
      • 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
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `keyword` from `multilanguage_keywords` where (`language_id` = 2 and `article_id` = 110494)
      2.48msalphaeurekaselec_live_10_06_2022ArticleController.php#2489
      Bindings
      • 0: 2
      • 1: 110494
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2489
      • 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 CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT_WS(' ',au.last_name, ', ', ifnull(au.initials,''), ' ', au.first_name) as authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs , `au`.*, (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 `multilanguage_authors` as `au` left join `multilanguage_author_affiliation` as `af` on `au`.`id` = `af`.`author_id` where `au`.`article_id` = 110494 group by `au`.`id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.78msalphaeurekaselec_live_10_06_2022MultiLangAuthor.php#30
      Bindings
      • 0: 110494
      Backtrace
      • 13. app/Models/MultiLangAuthor.php:30
      • 14. app/Http/Controllers/ArticleController.php:2493
      • 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 `multilanguage_journal`.`title` from `multilanguage_journal` where `multilanguage_journal`.`journal_id` = 25 and `language_id` = 2
      250μsalphaeurekaselec_live_10_06_2022ArticleController.php#2495
      Bindings
      • 0: 25
      • 1: 2
      Backtrace
      • 13. app/Http/Controllers/ArticleController.php:2495
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `id` from `multilanguage_article` where `article_id` = 110494 limit 1
      2.11msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 110494
      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` = 25 and `b`.`banner_from_date` <= 1740460074 and `b`.`banner_to_date` >= 1740460074 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.17msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740460074
      • 4: 1740460074
      • 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` = 25 and `b`.`banner_from_date` <= 1740460074 and `b`.`banner_to_date` >= 1740460074 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.46msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740460074
      • 4: 1740460074
      • 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='2e069db5ebe4b98c37751fef7663632a'
      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\MultiLangArticle
    2MultiLangArticle.php#?
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        2s9T8sRxJDTgR5FIsHHqIWu1OYiA9SCwyHRIfaqd
        uc_cart_id
        2e069db5ebe4b98c37751fef7663632a
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/110494/cn" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/110494/cn
        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:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IkhBTmlMQ0FKdllPMVZuM1UrTVdpL2c9PSIsInZhbHVlIjoiR2NOVi84M0QwckF1c090ZW0wczI1UVFaS2ZIeHB1enp4dGR0cVJTR0tlaz0iLCJtYWMiOiIyYTk1Yjk2Y2IwMjY3Y2ZjZjcwYTM1NWE5Zjc2MmU1YzAwNDFkNDkwMmY2NmIyOWI4MWQwMjIxMWQ3NDU1YTgwIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IkhBTmlMQ0FKdllPMVZuM1UrTVdpL2c9PSIsInZhbHVlIjoiR2NOVi84M0QwckF1c090ZW0wczI1UVFaS2ZIeHB1enp4dGR0cVJTR0tlaz0iLCJtYWMiOiIyYTk1Yjk2Y2IwMjY3" ] "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
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        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 05:07:54 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImdlKzBOV0hyY1NVQk1RT1hsdHc4L0E9PSIsInZhbHVlIjoidkVCcThKSFY4ZXlwaWVXOE0wTnhDSXpSYTB0c1VmTndZbnB6NE9laTExa2JzeDRoTlR0ODR6VGZvaWtLK0dyT1JPeEhVT01wMXNCQ2svVTVSaDc2NEVrQkljeERCdTVlVzcxOENoV0ZjWFM4SGg1b1lyeDZSU01CaE9TK1VXcy8iLCJtYWMiOiJkNjc0YTUzZTIxMGFhZjlhYTI4YTE2OGM1NzVkNmEzMTUwZGZkMjE2NWVkNGJiN2RhMzRlNjYyOTM1NmNjMGUxIiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 17:07:54 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImdlKzBOV0hyY1NVQk1RT1hsdHc4L0E9PSIsInZhbHVlIjoidkVCcThKSFY4ZXlwaWVXOE0wTnhDSXpSYTB0c1VmTndZbnB6NE9laTExa2JzeDRoTlR0ODR6VGZvaWtLK0dyT1JPeEhVT" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlYrQjV2bWFwK3poSVl5d2ZIbEtZRUE9PSIsInZhbHVlIjoia2pPbVMrY01CZ09DVHNsbzVCaXpvQ0hicmI0dG00dEhoemQrWStVdXIxQ0dkZFNBcVFDUDc0OU5JMEwxanpYT2lKZThBckExT2ZjejFydUFPUG5PSCtDckIzNHRSM1poQlVWQ1lTaEFCKzRMc1pxNFhyUElZQ2NaVHdVS1JIZzMiLCJtYWMiOiIxYWQyY2Q2ZTYwYTVlOWFlOTc2ODNkMGQzZjZhY2FiMTI0Y2JiNTVkZTAzZjVjNWExNDFiOTBkN2NmZWU5MGE0IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IlYrQjV2bWFwK3poSVl5d2ZIbEtZRUE9PSIsInZhbHVlIjoia2pPbVMrY01CZ09DVHNsbzVCaXpvQ0hicmI0dG00dEhoemQrWStVdXIxQ0dkZFNBcVFDUDc0OU5" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImdlKzBOV0hyY1NVQk1RT1hsdHc4L0E9PSIsInZhbHVlIjoidkVCcThKSFY4ZXlwaWVXOE0wTnhDSXpSYTB0c1VmTndZbnB6NE9laTExa2JzeDRoTlR0ODR6VGZvaWtLK0dyT1JPeEhVT01wMXNCQ2svVTVSaDc2NEVrQkljeERCdTVlVzcxOENoV0ZjWFM4SGg1b1lyeDZSU01CaE9TK1VXcy8iLCJtYWMiOiJkNjc0YTUzZTIxMGFhZjlhYTI4YTE2OGM1NzVkNmEzMTUwZGZkMjE2NWVkNGJiN2RhMzRlNjYyOTM1NmNjMGUxIiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 17:07:54 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImdlKzBOV0hyY1NVQk1RT1hsdHc4L0E9PSIsInZhbHVlIjoidkVCcThKSFY4ZXlwaWVXOE0wTnhDSXpSYTB0c1VmTndZbnB6NE9laTExa2JzeDRoTlR0ODR6VGZvaWtLK0dyT1JPeEhVT" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlYrQjV2bWFwK3poSVl5d2ZIbEtZRUE9PSIsInZhbHVlIjoia2pPbVMrY01CZ09DVHNsbzVCaXpvQ0hicmI0dG00dEhoemQrWStVdXIxQ0dkZFNBcVFDUDc0OU5JMEwxanpYT2lKZThBckExT2ZjejFydUFPUG5PSCtDckIzNHRSM1poQlVWQ1lTaEFCKzRMc1pxNFhyUElZQ2NaVHdVS1JIZzMiLCJtYWMiOiIxYWQyY2Q2ZTYwYTVlOWFlOTc2ODNkMGQzZjZhY2FiMTI0Y2JiNTVkZTAzZjVjNWExNDFiOTBkN2NmZWU5MGE0IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IlYrQjV2bWFwK3poSVl5d2ZIbEtZRUE9PSIsInZhbHVlIjoia2pPbVMrY01CZ09DVHNsbzVCaXpvQ0hicmI0dG00dEhoemQrWStVdXIxQ0dkZFNBcVFDUDc0OU5" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "2s9T8sRxJDTgR5FIsHHqIWu1OYiA9SCwyHRIfaqd" "uc_cart_id" => "2e069db5ebe4b98c37751fef7663632a" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/110494/cn" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 05:07:54GET/article/110494/cn414413