Generic placeholder image

Current Enzyme Inhibition

Editor-in-Chief

ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

Review Article

A Brief Review on Dual Target of PARP1 and STAT3 for Cancer Therapy: A Novel Perception

Author(s): Kaviarasan Lakshmanan, Gowramma Byran* and Manal Mohammed

Volume 16, Issue 2, 2020

Page: [115 - 134] Pages: 20

DOI: 10.2174/1573408016666200316114209

Price: $65

Abstract

Background: Cancer is a disease characterized by the uncontrolled growth and spread of abnormal cells. Around the world, over 10 million cancer cases occur annually. Half of all men and one-third of all women will develop some form of cancer during their lifetime. It is one of the most feared diseases, primarily because half of those diagnosed with cancer die from it. There are several treatments available for cancer. Almost all traditional cytotoxic agents suffer from severe toxicities and other undesirable side effects.

Objective: In recent years, the development of targeted medicines has made significant achievements. Unfortunately, though these agents can block key regulators of signaling pathways in cancer, multiple compensatory pathways always attenuate pharmacological effect of single-target drugs. In addition, poor response rates and acquired drug resistance also represent a significant barrier to widespread use of targeted medicines. More recently, a number of combinatorial therapies have expanded treatment options, which can directly block several key signaling pathways and create a synergistic effect.

Conclusion: Therefore, in order to overcome these barriers, the present investigation aims to develop a new strategy for designing a single molecule with inhibition of two receptors (PARP1 and STAT3) simultaneously and producing enhanced anti-cancer activity with less and/or null toxicity.

Keywords: Cancer, cytotoxic agent, dual inhibitor, PARP1, STAT3, side effect.

Graphical Abstract

[1]
Cancer Facts & Figures 2015; American Cancer Society: Atlanta, 2015.
[2]
Ghorbani, M. Hamed Karimi. Role of biotechnology in cancer control. IJSRST, 2015, 5(1), 180-185.
[3]
Aaron, J.S.; John, O. Dino Prato. Immunotherapy in cancer treatment. Open J. Med. Microbiol., 2014, 4, 178-191.
[http://dx.doi.org/10.4236/ojmm.2014.43020]
[4]
Sudhakar, A. History of cancer, ancient and modern treatment methods. J. Cancer Sci. Ther., 2009, 1(2), 1-4.
[http://dx.doi.org/10.4172/1948-5956.100000e2] [PMID: 20740081]
[5]
Hu, Y.; Fu, L. Targeting cancer stem cells: a new therapy to cure cancer patients. Am. J. Cancer Res., 2012, 2(3), 340-356.
[PMID: 22679565]
[6]
Bhatt, A.N.; Mathur, R.; Farooque, A.; Verma, A.; Dwarakanath, B.S. Cancer biomarkers - current perspectives. Indian J. Med. Res., 2010, 132, 129-149.
[PMID: 20716813]
[7]
Jurisevic, M.; Arsenijevic, A.; Pantic, J.; Gajovic, N.; Milovanovic, J.; Milovanovic, M.; Poljarevic, J.; Sabo, T.; Vojvodic, D.; Radosavljevic, G.D.; Arsenijevic, N. The organic ester O,O′-diethyl-(S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoate dihydrochloride attenuates murine breast cancer growth and metastasis. Oncotarget, 2018, 9(46), 28195-28212.
[http://dx.doi.org/10.18632/oncotarget.25610] [PMID: 29963272]
[8]
Darnell, J.E., Jr STATs and gene regulation. Science, 1997, 277(5332), 1630-1635.
[http://dx.doi.org/10.1126/science.277.5332.1630] [PMID: 9287210]
[9]
Levy, D.E.; Darnell, J.E., Jr Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol., 2002, 3(9), 651-662.
[http://dx.doi.org/10.1038/nrm909] [PMID: 12209125]
[10]
Karlberg, T.; Hammarström, M.; Schütz, P.; Svensson, L.; Schüler, H. Crystal structure of the catalytic domain of human PARP2 in complex with PARP inhibitor ABT-888. Biochemistry, 2010, 49(6), 1056-1058.
[http://dx.doi.org/10.1021/bi902079y] [PMID: 20092359]
[11]
Langelier, M.F.; Planck, J.L.; Roy, S.; Pascal, J.M. Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: structural and functional insights into DNA-dependent PARP-1 activity. J. Biol. Chem., 2011, 286(12), 10690-10701.
[http://dx.doi.org/10.1074/jbc.M110.202507] [PMID: 21233213]
[12]
Antolin, A.A.; Carotti, A.; Nuti, R.; Hakkaya, A.; Camaioni, E.; Mestres, J.; Pellicciari, R.; Macchiarulo, A. Exploring the effect of PARP-1 flexibility in docking studies. J. Mol. Graph. Model., 2013, 45, 192-201.
[http://dx.doi.org/10.1016/j.jmgm.2013.08.006] [PMID: 24056306]
[13]
Zaja, R.; Mikoč, A.; Barkauskaite, E.; Ahel, I. Molecular insights into Poly(ADP-ribose) recognition and processing. Biomolecules, 2012, 3(1), 1-17.
[http://dx.doi.org/10.3390/biom3010001] [PMID: 24970154]
[14]
Morales, J.; Li, L.; Fattah, F.J.; Dong, Y.; Bey, E.A.; Patel, M.; Gao, J.; Boothman, D.A. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit. Rev. Eukaryot. Gene Expr., 2014, 24(1), 15-28.
[http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2013006875] [PMID: 24579667]
[15]
Hongyan, L.; Antoinette, R.T. PARP Inhibitors. Curr. Breast Cancer Rep., 2011, 3, 44-54.
[http://dx.doi.org/10.1007/s12609-010-0036-y]
[16]
Telli, M.L.; Ford, J.M. PARP inhibitors in breast cancer. Clin. Adv. Hematol. Oncol., 2010, 8(9), 629-635.
[PMID: 21157412]
[17]
Rouleau, M.; Patel, A.; Hendzel, M.J.; Kaufmann, S.H.; Poirier, G.G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer, 2010, 10(4), 293-301.
[http://dx.doi.org/10.1038/nrc2812] [PMID: 20200537]
[18]
Sodhi, R.K.; Singh, N.; Jaggi, A.S. Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. Vascul. Pharmacol., 2010, 53(3-4), 77-87.
[http://dx.doi.org/10.1016/j.vph.2010.06.003] [PMID: 20633699]
[19]
Schiewer, M.J.; Goodwin, J.F.; Han, S.; Brenner, J.C.; Augello, M.A.; Dean, J.L.; Liu, F.; Planck, J.L.; Ravindranathan, P.; Chinnaiyan, A.M.; McCue, P.; Gomella, L.G.; Raj, G.V.; Dicker, A.P.; Brody, J.R.; Pascal, J.M.; Centenera, M.M.; Butler, L.M.; Tilley, W.D.; Feng, F.Y.; Knudsen, K.E. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov., 2012, 2(12), 1134-1149.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0120] [PMID: 22993403]
[20]
Li, H.; Hu, Y.; Wang, X.; He, G.; Xu, Y.; Zhu, Q. Novel tricyclic poly (ADP-ribose) polymerase-1/2 inhibitors with potent anticancer chemopotentiating activity: Design, synthesis and biological evaluation. Bioorg. Med. Chem., 2016, 24(19), 4731-4740.
[http://dx.doi.org/10.1016/j.bmc.2016.08.016] [PMID: 27561983]
[21]
Ryu, K.W.; Kim, D.S.; Kraus, W.L. New facets in the regulation of gene expression by ADP-ribosylation and poly(ADP-ribose) polymerases. Chem. Rev., 2015, 115(6), 2453-2481.
[http://dx.doi.org/10.1021/cr5004248] [PMID: 25575290]
[22]
Haince, J.F.; Kozlov, S.; Dawson, V.L.; Dawson, T.M.; Hendzel, M.J.; Lavin, M.F.; Poirier, G.G.; Guy, G.P. Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J. Biol. Chem., 2007, 282(22), 16441-16453.
[http://dx.doi.org/10.1074/jbc.M608406200] [PMID: 17428792]
[23]
Hegde, M.L.; Izumi, T.; Mitra, S. Oxidized base damage and single-strand break repair in mammalian genomes: role of disordered regions and posttranslational modifications in early enzymes. Prog. Mol. Biol. Transl. Sci., 2012, 110, 123-153.
[http://dx.doi.org/10.1016/B978-0-12-387665-2.00006-7] [PMID: 22749145]
[24]
Li, M.; Yu, X. The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy. Oncogene, 2015, 34(26), 3349-3356.
[http://dx.doi.org/10.1038/onc.2014.295] [PMID: 25220415]
[25]
Khodyreva, S.N.; Prasad, R.; Ilina, E.S.; Sukhanova, M.V.; Kutuzov, M.M.; Liu, Y.; Hou, E.W.; Wilson, S.H.; Lavrik, O.I. Apurinic/apyrimidinic (AP) site recognition by the 5′-dRP/AP lyase in poly(ADP-ribose) polymerase-1 (PARP-1). Proc. Natl. Acad. Sci. USA, 2010, 107(51), 22090-22095.
[http://dx.doi.org/10.1073/pnas.1009182107] [PMID: 21127267]
[26]
Hegde, M.L.; Hazra, T.K.; Mitra, S. Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res., 2008, 18(1), 27-47.
[http://dx.doi.org/10.1038/cr.2008.8] [PMID: 18166975]
[27]
Pleschke, J.M.; Kleczkowska, H.E.; Strohm, M.; Althaus, F.R. Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. J. Biol. Chem., 2000, 275(52), 40974-40980.
[http://dx.doi.org/10.1074/jbc.M006520200] [PMID: 11016934]
[28]
Gagné, J.P.; Isabelle, M.; Lo, K.S.; Bourassa, S.; Hendzel, M.J.; Dawson, V.L.; Dawson, T.M.; Poirier, G.G. Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res., 2008, 36(22), 6959-6976.
[http://dx.doi.org/10.1093/nar/gkn771] [PMID: 18981049]
[29]
Fu, D.; Calvo, J.A.; Samson, L.D. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat. Rev. Cancer, 2012, 12(2), 104-120.
[http://dx.doi.org/10.1038/nrc3185] [PMID: 22237395]
[30]
Dantzer, F.; de La Rubia, G.; Ménissier-De Murcia, J.; Hostomsky, Z.; de Murcia, G.; Schreiber, V. Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry, 2000, 39(25), 7559-7569.
[http://dx.doi.org/10.1021/bi0003442] [PMID: 10858306]
[31]
Bryant, H.E.; Petermann, E.; Schultz, N.; Jemth, A.S.; Loseva, O.; Issaeva, N.; Johansson, F.; Fernandez, S.; McGlynn, P.; Helleday, T. PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J., 2009, 28(17), 2601-2615.
[http://dx.doi.org/10.1038/emboj.2009.206] [PMID: 19629035]
[32]
Dragony, F.; Jennifer, A. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat. Rev. Cancer, 2012, 12(2), 104-20.
[33]
Boulares, A.H.; Yakovlev, A.G.; Ivanova, V.; Stoica, B.A.; Wang, G.; Iyer, S.; Smulson, M. Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J. Biol. Chem., 1999, 274(33), 22932-22940.
[http://dx.doi.org/10.1074/jbc.274.33.22932] [PMID: 10438458]
[34]
Sulkowski, P.L.; Sundaram, R.K.; Oeck, S.; Corso, C.D.; Liu, Y.; Noorbakhsh, S.; Niger, M.; Boeke, M.; Ueno, D.; Kalathil, A.N.; Bao, X.; Li, J.; Shuch, B.; Bindra, R.S.; Glazer, P.M. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat. Genet., 2018, 50(8), 1086-1092.
[http://dx.doi.org/10.1038/s41588-018-0170-4] [PMID: 30013182]
[35]
D’Amours, D.; Sallmann, F.R.; Dixit, V.M.; Poirier, G.G. Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis. J. Cell Sci., 2001, 114(Pt 20), 3771-3778.
[PMID: 11707529]
[36]
Francuoise, D. Guadelupe de la, R.; Josiane, M. M.; Zdenek, H.; Gilbert de, M.; Valerie, S. Base excision repair is impaired in mammalian cells lacking poly (ADP-ribose) Polymerase-1. Biochemistry, 2000, 39, 7559-7569.
[http://dx.doi.org/10.1021/bi0003442]
[37]
Chaitanya, G.V.; Steven, A.J.; Babu, P.P. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun. Signal., 2010, 8(31), 31.
[http://dx.doi.org/10.1186/1478-811X-8-31] [PMID: 21176168]
[38]
Wang, Y.Q.; Wang, P.Y.; Wang, Y.T.; Yang, G.F.; Zhang, A.; Miao, Z.H. An update on poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and challenges in cancer therapy. J. Med. Chem., 2016, 59(21), 9575-9598.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00055] [PMID: 27416328]
[39]
Shen, Y.; Aoyagi-Scharber, M.; Wang, B. Trapping Poly(ADP-Ribose) Polymerase. J. Pharmacol. Exp. Ther., 2015, 353(3), 446-457.
[http://dx.doi.org/10.1124/jpet.114.222448] [PMID: 25758918]
[40]
Fouquerel, E.; Sobol, R.W. ARTD1 (PARP1) activation and NAD(+) in DNA repair and cell death. DNA Repair (Amst.), 2014, 23, 27-32.
[http://dx.doi.org/10.1016/j.dnarep.2014.09.004] [PMID: 25283336]
[41]
Ko, H.L.; Ren, E.C. Functional aspects of PARP1 in DNA repair and transcription. Biomolecules, 2012, 2(4), 524-548.
[http://dx.doi.org/10.3390/biom2040524] [PMID: 24970148]
[42]
Giannini, G.; Battistuzzi, G.; Vesci, L.; Milazzo, F.M.; De Paolis, F.; Barbarino, M.; Guglielmi, M.B.; Carollo, V.; Gallo, G.; Artali, R.; Dallavalle, S. Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold. Bioorg. Med. Chem. Lett., 2014, 24(2), 462-466.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.048] [PMID: 24388690]
[43]
Eskander, R.N.; Tewari, K.S. PARP inhibition and synthetic lethality in ovarian cancer. Expert Rev. Clin. Pharmacol., 2014, 7(5), 613-622.
[http://dx.doi.org/10.1586/17512433.2014.930662] [PMID: 24984781]
[44]
Salvati, E.; Botta, L.; Amato, J.; Di Leva, F.S.; Zizza, P.; Gioiello, A.; Pagano, B.; Graziani, G.; Tarsounas, M.; Randazzo, A.; Novellino, E.; Biroccio, A.; Cosconati, S. Lead discovery of dual G-Quadruplex stabilizers and Poly(ADP-ribose) polymerases (PARPs) Inhibitors: A new avenue in anticancer treatment. J. Med. Chem., 2017, 60(9), 3626-3635.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01563] [PMID: 28445046]
[45]
Anders, C.K.; Winer, E.P.; Ford, J.M.; Dent, R.; Silver, D.P.; Sledge, G.W.; Carey, L.A. Poly(ADP-Ribose) polymerase inhibition: “targeted” therapy for triple-negative breast cancer. Clin. Cancer Res., 2010, 16(19), 4702-4710.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-0939] [PMID: 20858840]
[46]
James, D.I.; Smith, K.M.; Jordan, A.M.; Fairweather, E.E.; Griffiths, L.A.; Hamilton, N.S.; Hitchin, J.R.; Hutton, C.P.; Jones, S.; Kelly, P.; McGonagle, A.E.; Small, H.; Stowell, A.I.; Tucker, J.; Waddell, I.D.; Waszkowycz, B.; Ogilvie, D.J. First-in-class chemical probes against Poly(ADP-ribose) glycohydrolase (PARG) inhibit DNA repair with differential pharmacology to olaparib. ACS Chem. Biol., 2016, 11(11), 3179-3190.
[http://dx.doi.org/10.1021/acschembio.6b00609] [PMID: 27689388]
[47]
Nguewa, P.A.; Fuertes, M.A.; Cepeda, V.; Alonso, C.; Quevedo, C.; Soto, M.; Pérez, J.M.; Poly, M.P. Poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells. Med. Chem., 2006, 2(1), 47-53.
[http://dx.doi.org/10.2174/157340606775197697] [PMID: 16787355]
[48]
Bing, W.; Danie, C.; Ying, F.; Yuqiao, S.; Mika, A.S.; Leonard, E.P. Discovery and characterization of (8S, 9R)-5-Fluoro-8-(4-fluorophenyl)-9- (1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, talazoparib), a novel, highly potent, and orally efficacious Poly(ADP-ribose) Polymerase-1/2 inhibitor as an anticancer agent. J. Med. Chem., 2016, 59(1), 335-57.
[49]
Weaver, A.N.; Yang, E.S. Beyond DNA repair: Additional functions of PARP-1 in Cancer. Front. Oncol., 2013, 3, 290.
[http://dx.doi.org/10.3389/fonc.2013.00290] [PMID: 24350055]
[50]
Ferraris, D.V. Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic. J. Med. Chem., 2010, 53(12), 4561-4584.
[http://dx.doi.org/10.1021/jm100012m] [PMID: 20364863]
[51]
Cepeda, V.; Fuertes, M.A.; Castilla, J.; Alonso, C.; Quevedo, C.; Soto, M.; Pérez, J.M. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors in cancer chemotherapy. Recent Patents Anticancer Drug Discov., 2006, 1(1), 39-53.
[http://dx.doi.org/10.2174/157489206775246430] [PMID: 18221025]
[52]
Mohd Imran, A.; Chad, J.; Andrew, C. PARP Inhibitors: A breakthrough in cancer chemotherapy. Mod Appro Drug Des., 2018, 1(2), 1-4.
[53]
Sakamoto-Hojo, E.T.; Balajee, A.S. Targeting poly (ADP) ribose polymerase I (PARP-1) and PARP-1 interacting proteins for cancer treatment. Anticancer. Agents Med. Chem., 2008, 8(4), 402-416.
[http://dx.doi.org/10.2174/187152008784220302] [PMID: 18473725]
[54]
Lu, Y.; Liu, Y.; Pang, Y.; Pacak, K.; Yang, C. Double-barreled gun: Combination of PARP inhibitor with conventional chemotherapy. Pharmacol. Ther., 2018, 188, 168-175.
[http://dx.doi.org/10.1016/j.pharmthera.2018.03.006] [PMID: 29621593]
[55]
Antonio, G.M.; Bhavana, P.; Ignace, V.; Rene, D.C. Whitney, Graybill, M.D.; Mansoor, R.; Colleen, M.; Domenica, L.; Paul, H.; Gilles, F.; Klaus, B.; Kris, J. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med., 2019, 381, 2391-2402.
[http://dx.doi.org/10.1056/NEJMoa1910962]
[56]
Litton, J.K.; Scoggins, M.; Ramirez, D.L.; Murthy, R.K.; Whitman, G.J.; Hess, K.R.; Adrada, B.E.; Moulder, S.L.; Barcenas, C.H.; Valero, V.; Gomez, J.S.; Mittendorf, E.A.; Thompson, A.; Helgason, T.; Mills, G.B.; Piwnica-Worms, H.; Arun, B.K. A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. NPJ Breast Cancer, 2017, 3, 49.
[http://dx.doi.org/10.1038/s41523-017-0052-4] [PMID: 29238749]
[57]
Pulliam, N.; Fang, F.; Ozes, A.R.; Tang, J.; Adewuyi, A.; Keer, H.; Lyons, J.; Baylin, S.B.; Matei, D.; Nakshatri, H.; Rassool, F.V.; Miller, K.D.; Nephew, K.P. An Effective epigenetic-PARP inhibitor combination therapy for breast and ovarian cancers independent of BRCA mutations. Clin. Cancer Res., 2018, 24(13), 3163-3175.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0204] [PMID: 29615458]
[58]
Malyuchenko, N.V.; Yu, K.; Kulaeva, O.I.; Kirpichnikov, M.P.; Studitskiy, V.M. PARP1 Inhibitors: antitumor drug design. Acta naturae.,, 2015, 3(7), 27-37.
[59]
Benafif, S.; Hall, M. An update on PARP inhibitors for the treatment of cancer. OncoTargets Ther., 2015, 8, 519-528.
[PMID: 25750544]
[60]
Anthony, R.G.; Jason, B. Ron de, J.; Douglas, R.D.; Charles, E.G.; Mark, H.; Andy, J.; Ruhi, K.; Andre, K.; Shawn, O.C.; Ewan, T.; Phong, V. Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose) polymerase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 4501-4505.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.055]
[61]
Wang, L.; Liang, C.; Li, F.; Guan, D.; Wu, X.; Fu, X.; Lu, A.; Zhang, G. PARP1 in carcinomas and PARP1 inhibitors as antineoplastic drugs. Int. J. Mol. Sci., 2017, 18(10), 2111-2118.
[http://dx.doi.org/10.3390/ijms18102111] [PMID: 28991194]
[62]
Cao, X.; Lu, Y.; Liu, Y.; Zhou, Y.; Song, H.; Zhang, W.; Davis, D.; Cui, J.; Hao, S.; Jung, J.; Wu, Q.; Park, D.M.; Yang, C. Combination of PARP inhibitor and temozolomide to suppress chordoma progression. J. Mol. Med. (Berl.), 2019, 97(8), 1183-1193.
[http://dx.doi.org/10.1007/s00109-019-01802-z] [PMID: 31201471]
[63]
Lok, B.H.; Gardner, E.E.; Schneeberger, V.E.; Ni, A.; Desmeules, P.; Rekhtman, N.; de Stanchina, E.; Teicher, B.A.; Riaz, N.; Powell, S.N.; Poirier, J.T.; Rudin, C.M. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin. Cancer Res., 2017, 23(2), 523-535.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1040] [PMID: 27440269]
[64]
Yuan, Z.; Chen, S.; Chen, C.; Chen, J.; Chen, C.; Dai, Q.; Gao, C.; Jiang, Y. Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy. Eur. J. Med. Chem., 2017, 138, 1135-1146.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.050] [PMID: 28763648]
[65]
Fang, B. Development of synthetic lethality anticancer therapeutics. J. Med. Chem., 2014, 57(19), 7859-7873.
[http://dx.doi.org/10.1021/jm500415t] [PMID: 24893124]
[66]
Kathryn, A.; Sian, F.; Cliff, M. Anna de, F.; Catherine, E.; Joshy, G.; Alexander, D.; Michael, J.B.; Penelope, M.W.; Colin, S.; Michael, F.; Stephen, F.; David, B.; Gillian, M. BRCA mutation frequency and patterns of treatment response in brca mutation-positive women with ovarian cancer: a report from the australian ovarian cancer study group. J. Clin. Oncol., 2012, 30, 1-11.
[67]
Luo, J.; Jin, J.; Yang, F.; Sun, Z.; Zhang, W.; Shi, Y.; Xu, J.; Guan, X. The correlation between PARP1 and BRCA1 in AR positive triple-negative breast cancer. Int. J. Biol. Sci., 2016, 12(12), 1500-1510.
[http://dx.doi.org/10.7150/ijbs.16176] [PMID: 27994514]
[68]
Lord, C.J.; Ashworth, A. PARP inhibitors: Synthetic lethality in the clinic. Science, 2017, 355(6330), 1152-1158.
[http://dx.doi.org/10.1126/science.aam7344] [PMID: 28302823]
[69]
Kruse, V.; Rottey, S.; De Backer, O.; Van Belle, S.; Cocquyt, V.; Denys, H. PARP inhibitors in oncology: a new synthetic lethal approach to cancer therapy. Acta Clin. Belg., 2011, 66(1), 2-9.
[http://dx.doi.org/10.1179/ACB.66.1.2062507] [PMID: 21485757]
[70]
Nijman, S.M. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett., 2011, 585(1), 1-6.
[http://dx.doi.org/10.1016/j.febslet.2010.11.024] [PMID: 21094158]
[71]
Furtek, S.L.; Backos, D.S.; Matheson, C.J.; Reigan, P. strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem. Biol., 2016, 11(2), 308-318.
[http://dx.doi.org/10.1021/acschembio.5b00945] [PMID: 26730496]
[72]
Wang, X.; Crowe, P.J.; Goldstein, D.; Yang, J.L. STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers(review). Int. J. Oncol., 2012, 41(4), 1181-1191.
[http://dx.doi.org/10.3892/ijo.2012.1568] [PMID: 22842992]
[73]
Banerjee, K.; Resat, H. Constitutive activation of STAT3 in breast cancer cells: A review. Int. J. Cancer, 2016, 138(11), 2570-2578.
[http://dx.doi.org/10.1002/ijc.29923] [PMID: 26559373]
[74]
Shin, Y.C.; Yen, H.C; Rong, P.L.; Ta Chung, C.; Jung Chen, S.; Chung Wai, S; Yeu,, S. Two novel SHP-1 agonists, SC-43 and SC-78, are more potent than regorafenib in suppressing the in vitro stemness of human colorectal cancer cells. Cell Death Discov., 2019, 5, 25-36.
[75]
Corvinus, F.M.; Orth, C.; Moriggl, R.; Tsareva, S.A.; Wagner, S.; Pfitzner, E.B.; Baus, D.; Kaufmann, R.; Huber, L.A.; Zatloukal, K.; Beug, H.; Ohlschläger, P.; Schütz, A.; Halbhuber, K.J.; Friedrich, K. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia, 2005, 7(6), 545-555.
[http://dx.doi.org/10.1593/neo.04571] [PMID: 16036105]
[76]
Kamran, M.Z.; Patil, P.; Gude, R.P. Role of STAT3 in cancer metastasis and translational advances. BioMed Res. Int., 2013, 2013421821
[http://dx.doi.org/10.1155/2013/421821] [PMID: 24199193]
[77]
Xiong, A.; Yang, Z.; Shen, Y.; Zhou, J.; Shen, Q. Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers (Basel), 2014, 6(2), 926-957.
[http://dx.doi.org/10.3390/cancers6020926] [PMID: 24743778]
[78]
Blaskovich, M.A.; Sun, J.; Cantor, A.; Turkson, J.; Jove, R.; Sebti, S.M. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res., 2003, 63(6), 1270-1279.
[PMID: 12649187]
[79]
Han, M.; Wang, Y.; Guo, G.; Li, L.; Dou, D.; Ge, X.; Lv, P.; Wang, F.; Gu, Y. microRNA-30d mediated breast cancer invasion, migration, and EMT by targeting KLF11 and activating STAT3 pathway. J. Cell. Biochem., 2018, 119(10), 8138-8145.
[http://dx.doi.org/10.1002/jcb.26767] [PMID: 29923255]
[80]
Ioannis, G.; Nikolaos, N.; John, S. STAT3 Signaling in Cancer. J. Cancer Ther., 2015, 6, 709-726.
[http://dx.doi.org/10.4236/jct.2015.68078]
[81]
von Manstein, V.; Groner, B. Tumor cell resistance against targeted therapeutics: the density of cultured glioma tumor cells enhances Stat3 activity and offers protection against the tyrosine kinase inhibitor canertinib. MedChemComm, 2016, 8(1), 96-102.
[http://dx.doi.org/10.1039/C6MD00463F] [PMID: 30108694]
[82]
Chiba, T. STAT3 Inhibitors for Cancer Therapy -the Rationale and Remained Problems; EC Cancer, 2016, pp. 1-8.
[83]
Zhang, H.F.; Lai, R. STAT3 in cancer-friend or foe? Cancers (Basel), 2014, 6(3), 1408-1440.
[http://dx.doi.org/10.3390/cancers6031408] [PMID: 24995504]
[84]
Zhang, X.; Yue, P.; Page, B.D.; Li, T.; Zhao, W.; Namanja, A.T.; Paladino, D.; Zhao, J.; Chen, Y.; Gunning, P.T.; Turkson, J. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc. Natl. Acad. Sci. USA, 2012, 109(24), 9623-9628.
[http://dx.doi.org/10.1073/pnas.1121606109] [PMID: 22623533]
[85]
Yue, P.; Turkson, J. Targeting STAT3 in cancer: how successful are we? Expert Opin. Investig. Drugs, 2009, 18(1), 45-56.
[http://dx.doi.org/10.1517/13543780802565791] [PMID: 19053881]
[86]
Gao, S.P.; Mark, K.G.; Leslie, K.; Pao, W.; Motoi, N.; Gerald, W.L.; Travis, W.D.; Bornmann, W.; Veach, D.; Clarkson, B.; Bromberg, J.F. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest., 2007, 117(12), 3846-3856.
[http://dx.doi.org/10.1172/JCI31871] [PMID: 18060032]
[87]
Sartor, C.I.; Dziubinski, M.L.; Yu, C.L.; Jove, R.; Ethier, S.P. Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. Cancer Res., 1997, 57(5), 978-987.
[PMID: 9041204]
[88]
Garcia, R.; Bowman, T.L.; Niu, G.; Yu, H.; Minton, S.; Muro-Cacho, C.A.; Cox, C.E.; Falcone, R.; Fairclough, R.; Parsons, S.; Laudano, A.; Gazit, A.; Levitzki, A.; Kraker, A.; Jove, R. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene, 2001, 20(20), 2499-2513.
[http://dx.doi.org/10.1038/sj.onc.1204349] [PMID: 11420660]
[89]
Huang, M.; Page, C.; Reynolds, R.K.; Lin, J. Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells. Gynecol. Oncol., 2000, 79(1), 67-73.
[http://dx.doi.org/10.1006/gyno.2000.5931] [PMID: 11006034]
[90]
Chen, C.L.; Hsieh, F.C.; Lieblein, J.C.; Brown, J.; Chan, C.; Wallace, J.A.; Cheng, G.; Hall, B.M.; Lin, J. Stat3 activation in human endometrial and cervical cancers. Br. J. Cancer, 2007, 96(4), 591-599.
[http://dx.doi.org/10.1038/sj.bjc.6603597] [PMID: 17311011]
[91]
Quintanilla-Martinez, L.; Kremer, M.; Specht, K.; Calzada-Wack, J.; Nathrath, M.; Schaich, R.; Höfler, H.; Fend, F. Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events. Am. J. Pathol., 2003, 162(5), 1449-1461.
[http://dx.doi.org/10.1016/S0002-9440(10)64278-2] [PMID: 12707028]
[92]
DeMiguel, F.; Lee, S.O.; Lou, W.; Xiao, X.; Pflug, B.R.; Nelson, J.B.; Gao, A.C. Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice. Prostate, 2002, 52(2), 123-129.
[http://dx.doi.org/10.1002/pros.10110] [PMID: 12111703]
[93]
Barton, B.E.; Karras, J.G.; Murphy, T.F.; Barton, A.; Huang, H.F. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol. Cancer Ther., 2004, 3(1), 11-20.
[http://dx.doi.org/10.1186/1476-4598-3-11] [PMID: 14749471]
[94]
Wei, D.; Le, X.; Zheng, L.; Wang, L.; Frey, J.A.; Gao, A.C.; Peng, Z.; Huang, S.; Xiong, H.Q.; Abbruzzese, J.L.; Xie, K. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3), 319-329.
[http://dx.doi.org/10.1038/sj.onc.1206122] [PMID: 12545153]
[95]
Segatto, I.; Baldassarre, G.; Belletti, B. STAT3 in Breast Cancer Onset and Progression: A Matter of Time and Context. Int. J. Mol. Sci., 2018, 19(9), 2818-2827.
[http://dx.doi.org/10.3390/ijms19092818] [PMID: 30231553]
[96]
Shen, S.; Niso-Santano, M.; Adjemian, S.; Takehara, T.; Malik, S.A.; Minoux, H.; Souquere, S.; Mariño, G.; Lachkar, S.; Senovilla, L.; Galluzzi, L.; Kepp, O.; Pierron, G.; Maiuri, M.C.; Hikita, H.; Kroemer, R.; Kroemer, G. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol. Cell, 2012, 48(5), 667-680.
[http://dx.doi.org/10.1016/j.molcel.2012.09.013] [PMID: 23084476]
[97]
Gao, Y.; Cimica, V.; Reich, N.C. Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3. J. Biol. Chem., 2012, 287(25), 20904-20912.
[http://dx.doi.org/10.1074/jbc.M111.334144] [PMID: 22547065]
[98]
Wang, T.; Niu, G.; Kortylewski, M.; Burdelya, L.; Shain, K.; Zhang, S.; Bhattacharya, R.; Gabrilovich, D.; Heller, R.; Coppola, D.; Dalton, W.; Jove, R.; Pardoll, D.; Yu, H. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med., 2004, 10(1), 48-54.
[http://dx.doi.org/10.1038/nm976] [PMID: 14702634]
[99]
McCarty, O.J.T.; Mousa, S.A.; Bray, P.F.; Konstantopoulos, K. Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood, 2000, 96(5), 1789-1797.
[http://dx.doi.org/10.1182/blood.V96.5.1789] [PMID: 10961878]
[100]
Grunstein, J.; Roberts, W.G.; Mathieu-Costello, O.; Hanahan, D.; Johnson, R.S. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res., 1999, 59(7), 1592-1598.
[PMID: 10197634]
[101]
Sano, S.; Itami, S.; Takeda, K.; Tarutani, M.; Yamaguchi, Y.; Miura, H.; Yoshikawa, K.; Akira, S.; Takeda, J. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J., 1999, 18(17), 4657-4668.
[http://dx.doi.org/10.1093/emboj/18.17.4657] [PMID: 10469645]
[102]
Silver, D.L.; Naora, H.; Liu, J.; Cheng, W.; Montell, D.J. Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res., 2004, 64(10), 3550-3558.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3959] [PMID: 15150111]
[103]
Bromberg, J.F.; Wrzeszczynska, M.H.; Devgan, G.; Zhao, Y.; Pestell, R.G.; Albanese, C.; Darnell, J.E., Jr Stat3 as an oncogene. Cell, 1999, 98(3), 295-303.
[http://dx.doi.org/10.1016/S0092-8674(00)81959-5] [PMID: 10458605]
[104]
Turkson, J.; Bowman, T.; Garcia, R.; Caldenhoven, E.; De Groot, R.P.; Jove, R. Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol. Cell. Biol., 1998, 18(5), 2545-2552.
[http://dx.doi.org/10.1128/MCB.18.5.2545] [PMID: 9566874]
[105]
Suiqing, C.; Min, Z.; Lirong, C. Overexpression of phosphorylated-STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma. J. Dermatol., 2005, 32(5), 354-360.
[http://dx.doi.org/10.1111/j.1346-8138.2005.tb00906.x] [PMID: 16043897]
[106]
Qiu, Z.; Huang, C.; Sun, J.; Qiu, W.; Zhang, J.; Li, H.; Jiang, T.; Huang, K.; Cao, J. RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci., 2007, 98(7), 1099-1106.
[http://dx.doi.org/10.1111/j.1349-7006.2007.00485.x] [PMID: 17459060]
[107]
Martic, S.; Rains, M.K.; Haftchenary, S.; Shahani, V.M.; Kraskouskaya, D.; Ball, D.P.; Gunning, P.T.; Kraatz, H.B. Electrochemical detection of the Fc-STAT3 phosphorylation and STAT3-Fc-STAT3 dimerization and inhibition. Mol. Biosyst., 2014, 10(3), 576-580.
[http://dx.doi.org/10.1039/c3mb70493a] [PMID: 24402062]
[108]
Schust, J.; Sperl, B.; Hollis, A.; Mayer, T.U.; Berg, T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol., 2006, 13(11), 1235-1242.
[http://dx.doi.org/10.1016/j.chembiol.2006.09.018] [PMID: 17114005]
[109]
Nunez Lopez, O.; Bohanon, F.J.; Wang, X.; Ye, N.; Corsello, T.; Rojas-Khalil, Y.; Chen, H.; Chen, H.; Zhou, J.; Radhakrishnan, R.S. STAT3 inhibition suppresses hepatic stellate cell fibrogenesis: HJC0123, a potential therapeutic agent for liver fibrosis. RSC Advances, 2016, 6(102), 100652-100663.
[http://dx.doi.org/10.1039/C6RA17459K] [PMID: 28546859]
[110]
Cai, N.; Zhou, W.; Ye, L.L.; Chen, J.; Liang, Q.N.; Chang, G.; Chen, J.J. The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression. Am. J. Transl. Res., 2017, 9(8), 3853-3866.
[PMID: 28861175]
[111]
Ji, P.; Xu, X.; Ma, S.; Fan, J.; Zhou, Q.; Mao, X.; Qiao, C. Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway. ACS Med. Chem. Lett., 2015, 6(9), 1010-1014.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00228] [PMID: 26396689]
[112]
Löcken, H.; Clamor, C.; Müller, K. Napabucasin and related heterocycle-fused naphthoquinones as STAT3 inhibitors with antiproliferative activity against cancer cells. J. Nat. Prod., 2018, 81(7), 1636-1644.
[http://dx.doi.org/10.1021/acs.jnatprod.8b00247] [PMID: 30003778]
[113]
Daniela, M.; Stefania, V.; Fiorella, M.; Alessandro, P.; Daniela, B.; Laura, L.; Lucio, T.; Byoung, M.K.; Shintaro, N.; Akira, A.; Arianna, G. Biological and computational evaluation of an oxadiazole derivative (MD77) as a new lead for direct STAT3 inhibitors. MedChemComm, 2012, 3, 592.
[http://dx.doi.org/10.1039/c2md20018j]
[114]
Revanna, C.N. Basappa.; Srinivasa, V.; Feng, L.; Kodappully Sivaraman, S.; Xiaoyun, D.; Shivananju Nanjunda, S.; Bhadregowda, D.G.; Gautam, S.; Mantelingu, K.; Andreas, B.R. Synthesis and biological evaluation of tetrahydropyridinepyrazoles (‘PFPs’) as inhibitors of STAT3 phosphorylation. MedChemComm, 2014, 5, 32.
[115]
Zheng, H.; Hong, H.; Zhang, L.; Cai, X.; Hu, M.; Cai, Y.; Zhou, B.; Lin, J.; Zhao, C.; Hu, W. Nifuratel, a novel STAT3 inhibitor with potent activity against human gastric cancer cells. Cancer Manag. Res., 2017, 9, 565-572.
[http://dx.doi.org/10.2147/CMAR.S146173] [PMID: 29138596]
[116]
Lee, H.J.; Seo, N.J.; Jeong, S.J.; Park, Y.; Jung, D.B.; Koh, W.; Lee, H.J.; Lee, E.O.; Ahn, K.S.; Ahn, K.S.; Lü, J.; Kim, S.H. Oral administration of penta-O-galloyl-β-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition. Carcinogenesis, 2011, 32(6), 804-811.
[http://dx.doi.org/10.1093/carcin/bgr015] [PMID: 21289371]
[117]
Yang, S.F.; Hou, M.F.; Chen, F.M.; Ou-Yang, F.; Wu, Y.C.; Chai, C.Y.; Yeh, Y.T. Prognostic value of protein inhibitor of activated STAT3 in breast cancer patients receiving hormone therapy. BMC Cancer, 2016, 16, 20.
[http://dx.doi.org/10.1186/s12885-016-2063-1] [PMID: 26768588]
[118]
Kleppe, M.; Kwak, M.; Koppikar, P.; Riester, M.; Keller, M.; Bastian, L.; Hricik, T.; Bhagwat, N.; McKenney, A.S.; Papalexi, E.; Abdel-Wahab, O.; Rampal, R.; Marubayashi, S.; Chen, J.J.; Romanet, V.; Fridman, J.S.; Bromberg, J.; Teruya-Feldstein, J.; Murakami, M.; Radimerski, T.; Michor, F.; Fan, R.; Levine, R.L. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov., 2015, 5(3), 316-331.
[http://dx.doi.org/10.1158/2159-8290.CD-14-0736] [PMID: 25572172]
[119]
Kluge, A.; Dabir, S.; Vlassenbroeck, I.; Eisenberg, R.; Dowlati, A. Protein inhibitor of activated STAT3 expression in lung cancer. Mol. Oncol., 2011, 5(3), 256-264.
[http://dx.doi.org/10.1016/j.molonc.2011.03.004] [PMID: 21497567]
[120]
Jia, L.; Bian, M.; Hua, G.G.; Di, W.; Gui, L.B.; Li Jun, Y. Current research on anti-breast cancer synthetic compounds. RSC Advances, 2018, 8, 4386.
[http://dx.doi.org/10.1039/C7RA12912B]
[121]
Debanjana, C.; Chetan Kumar, J.; Arindam, M.; Shekhar, G.; Susanta Roy, C.; Tarun, J.; Hemanta, K.M.; Nirup, B.M. Chenopodium album metabolites act as dual topoisomerase inhibitors and induce apoptosis in the MCF7 cell line. Med. Chem. Commun., 2016, 10.1039-1052.
[122]
Chan, C.T.; Qi, J.; Smith, W.; Paranol, R.; Mazitschek, R.; West, N.; Reeves, R.; Chiosis, G.; Schreiber, S.L.; Bradner, J.E.; Paulmurugan, R.; Gambhir, S.S. Syntheses and discovery of a novel class of cinnamic hydroxamates as histone deacetylase inhibitors by multimodality molecular imaging in living subjects. Cancer Res., 2014, 74(24), 7475-7486.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0197] [PMID: 25320008]
[123]
Yang, E.G.; Mustafa, N.; Tan, E.C.; Poulsen, A.; Ramanujulu, P.M.; Chng, W.J.; Yen, J.J.; Dymock, B.W. Design and synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) bispecific inhibitors based on pacritinib and evidence of dual pathway inhibition in hematological cell lines. J. Med. Chem., 2016, 59(18), 8233-8262.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00157] [PMID: 27541357]
[124]
Ding, L.; Chen, X.; Xu, X.; Qian, Y.; Liang, G.; Yao, F.; Yao, Z.; Wu, H.; Zhang, J.; He, Q.; Yang, B. PARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3. Cancer Immunol. Res., 2019, 7(1), 136-149.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0071] [PMID: 30401677]
[125]
Wang, L.; Li, Z.; Tan, Y.; Li, Q.; Yang, H.; Wang, P.; Lu, J.; Liu, P. PARP1 interacts with STAT3 and retains active phosphorylated-STAT3 in nucleus during pathological myocardial hypertrophy. Mol. Cell. Endocrinol., 2018, 474, 137-150.
[http://dx.doi.org/10.1016/j.mce.2018.02.020] [PMID: 29501586]
[126]
Wang, C.; Wenjing, Xu.; Jie, An.; Minglu, Liang.; Yiqing, Li.; Fengxiao, Zhang.; Qiangsong, Tong.; Kai, Huang. Poly(ADP-ribose) polymerase 1 accelerates vascular calcification by upregulating Runx2. Nat. Commun., 2019, 10(1), :1203.
[127]
Dorsam, B. Nina Seiwerta.; Sebastian Foersch.; Svenja Stroh.; Georg Nagel.; Diana Begaliew.; Erika Diehl.; Alexander Kraus.; Maureen Mc Keague.; Vera Minnekere.; Vassilis Roukos.; Sonja Reibig.; Ari Waisman.; Markus Moehler.; Anna Stier.; Aswin Mangerich.; Françoise Dantzer.; Bernd Kaina.; Jorg Fahr. PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression. Proc. Natl. Acad. Sci. USA, 2017, 115(17), 4061-4070.
[128]
Yuan, Z.; Chen, S.; Sun, Q.; Wang, N.; Li, D.; Miao, S.; Gao, C.; Chen, Y.; Tan, C.; Jiang, Y. Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy. Bioorg. Med. Chem., 2017, 25(15), 4100-4109.
[http://dx.doi.org/10.1016/j.bmc.2017.05.058] [PMID: 28601509]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version400msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[06:25:29] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[06:25:30] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[06:25:30] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (102ms)time
  • Application (298ms)time
  • 1 x Application (74.4%)
    298ms
    1 x Booting (25.59%)
    102ms
    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 duplicated204ms
    • 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 ('59467608','',1,1740551129,1740551129) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740551129
      1.1msalphaeurekaselec_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 ('59467608','/article/105251',1,1740551129,1740551129)
      250μsalphaeurekaselec_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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) limit 1
      12.55msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59467608
      • 1: 59467608
      • 2: 59467608
      • 3: 59467608
      • 4: 59467608
      • 5: 59467608
      • 6: 59467608
      • 7: 59467608
      • 8: 59467608
      • 9: 59467608
      • 10: 59467608
      • 11: 59467608
      • 12: 59467608
      • 13: 59467608
      • 14: 59467608
      • 15: 59467608
      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=105251
      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` = 17 limit 1
      750μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 17
      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=17) and sj.journal_id!=17 group by `j`.`nid`) as `aggregate_table`
      820μsalphaeurekaselec_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=17) and sj.journal_id!=17 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      720μsalphaeurekaselec_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=17) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.44msalphaeurekaselec_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=17) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.1msalphaeurekaselec_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` = '105251'
      1.83msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 105251
      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` = '105251'
      4.53msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 105251
      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` = '105251' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.06msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 105251
      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
      230μsalphaeurekaselec_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
      480μsalphaeurekaselec_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 = 17 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      26.74msalphaeurekaselec_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 = 17 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      3.65msalphaeurekaselec_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 = 17 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      2.4msalphaeurekaselec_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` = 105251 limit 1
      240μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 105251
      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 = 105251 and content_type = 'article' order by status desc limit 1
      760μsalphaeurekaselec_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 = 298 and content_id!=105251 and cd.content_type = 'article' order by rand() limit 20
      119msalphaeurekaselec_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` = 180231 limit 1
      340μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 180231
      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
      250μsalphaeurekaselec_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` = 'CEI' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      300μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CEI
      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 = '105251' 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) )
      390μsalphaeurekaselec_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 = '9895' 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) )
      320μsalphaeurekaselec_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 = '2726' 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2726) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2726) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2726)
      7.34msalphaeurekaselec_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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9895) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9895) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9895)
      650μsalphaeurekaselec_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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 105251) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 105251) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740551130 and j.to_date >= 1740551130 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 105251)
      930μsalphaeurekaselec_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` < '115' and is_uploaded = 1 and issue_id = 9895 order by cast(first_page as SIGNED) desc limit 1
      630μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 115
      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` > '134' and is_uploaded = 1 and issue_id = 9895 order by cast(first_page as SIGNED) asc limit 1
      560μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 134
      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'
      220μsalphaeurekaselec_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
      260μsalphaeurekaselec_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` = 105251 limit 1
      3.87msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 105251
      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` = 17 and `b`.`banner_from_date` <= 1740551130 and `b`.`banner_to_date` >= 1740551130 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.74msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 17
      • 3: 1740551130
      • 4: 1740551130
      • 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` = 17 and `b`.`banner_from_date` <= 1740551130 and `b`.`banner_to_date` >= 1740551130 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.79msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 17
      • 3: 1740551130
      • 4: 1740551130
      • 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='8bec7ffe8091bf556c65fe20f4743d05'
      380μsalphaeurekaselec_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#?
        _token
        XatJmW1mXX3CJDqdg9mCmabtsxDHf7t3BjbsyzDi
        uc_cart_id
        8bec7ffe8091bf556c65fe20f4743d05
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/105251" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/105251
        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 => "Wed, 26 Feb 2025 06:25:30 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpscGpuZFlzaFJWL28reFJlbis5dkE9PSIsInZhbHVlIjoiZGwrdEZiY1p4QkZPZ0FraDV3d3liUFBZUUt4ekhPczRHaERmVWZwZU9NWlQyRGpsZlBRZ3lYY2dRMjUyMkpINE1HMktBNWdVRDJDd2o3d2FNM3ZSZEFYdHBHTzBLcDl1a3ZCVFZXV3N4Q25IMURwc3ZESFBSU3EyR1ZwS2NpMW4iLCJtYWMiOiJiN2ViMjhhMzVhNGQ4YjNkMGJjOTUzYTBhOWIzZDE2ZDg3MGE2Zjk4ODJlNGQyMDBjZWVlNWY2ODliM2E4NDU1IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 18:25:30 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImpscGpuZFlzaFJWL28reFJlbis5dkE9PSIsInZhbHVlIjoiZGwrdEZiY1p4QkZPZ0FraDV3d3liUFBZUUt4ekhPczRHaERmVWZwZU9NWlQyRGpsZlBRZ3lYY2dRMjUyMkpINE1HMktBN" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ilp0OHpzQkRvVVRObzFJaG55TXkrN1E9PSIsInZhbHVlIjoicEpZTVZCTXJOWk5sZ3IwOUdURnJYaFNpV29kMUxwT2RwWlcyeUZqd2VOdDQ3SUNqVzFxZEg1LzdWbzFQQ2loYjdhWGJLU0szcTc0S0JDQjc0bDRrRDkvMDJqR1I3ckk5QTVEMFNjUU05NkJ6VFR3QnJpcC8raTlmc2hRZ0djMFgiLCJtYWMiOiIxNjEyYjE4NTA3N2M0ZjhkZTVhYTNjYjAyOGQwMzcyYjE5MWM2NTdkMTI5ZmExOGRmZmM2OTJiZDU0MGNiNGEzIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Ilp0OHpzQkRvVVRObzFJaG55TXkrN1E9PSIsInZhbHVlIjoicEpZTVZCTXJOWk5sZ3IwOUdURnJYaFNpV29kMUxwT2RwWlcyeUZqd2VOdDQ3SUNqVzFxZEg1Lzd" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpscGpuZFlzaFJWL28reFJlbis5dkE9PSIsInZhbHVlIjoiZGwrdEZiY1p4QkZPZ0FraDV3d3liUFBZUUt4ekhPczRHaERmVWZwZU9NWlQyRGpsZlBRZ3lYY2dRMjUyMkpINE1HMktBNWdVRDJDd2o3d2FNM3ZSZEFYdHBHTzBLcDl1a3ZCVFZXV3N4Q25IMURwc3ZESFBSU3EyR1ZwS2NpMW4iLCJtYWMiOiJiN2ViMjhhMzVhNGQ4YjNkMGJjOTUzYTBhOWIzZDE2ZDg3MGE2Zjk4ODJlNGQyMDBjZWVlNWY2ODliM2E4NDU1IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 18:25:30 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImpscGpuZFlzaFJWL28reFJlbis5dkE9PSIsInZhbHVlIjoiZGwrdEZiY1p4QkZPZ0FraDV3d3liUFBZUUt4ekhPczRHaERmVWZwZU9NWlQyRGpsZlBRZ3lYY2dRMjUyMkpINE1HMktBN" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ilp0OHpzQkRvVVRObzFJaG55TXkrN1E9PSIsInZhbHVlIjoicEpZTVZCTXJOWk5sZ3IwOUdURnJYaFNpV29kMUxwT2RwWlcyeUZqd2VOdDQ3SUNqVzFxZEg1LzdWbzFQQ2loYjdhWGJLU0szcTc0S0JDQjc0bDRrRDkvMDJqR1I3ckk5QTVEMFNjUU05NkJ6VFR3QnJpcC8raTlmc2hRZ0djMFgiLCJtYWMiOiIxNjEyYjE4NTA3N2M0ZjhkZTVhYTNjYjAyOGQwMzcyYjE5MWM2NTdkMTI5ZmExOGRmZmM2OTJiZDU0MGNiNGEzIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Ilp0OHpzQkRvVVRObzFJaG55TXkrN1E9PSIsInZhbHVlIjoicEpZTVZCTXJOWk5sZ3IwOUdURnJYaFNpV29kMUxwT2RwWlcyeUZqd2VOdDQ3SUNqVzFxZEg1Lzd" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "XatJmW1mXX3CJDqdg9mCmabtsxDHf7t3BjbsyzDi" "uc_cart_id" => "8bec7ffe8091bf556c65fe20f4743d05" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/105251" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-26 06:25:30GET/article/105251314371