Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

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

Review Article

Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer

Author(s): Gerhard Hamilton*, Sandra Stickler and Barbara Rath

Volume 24, Issue 9, 2024

Published on: 24 January, 2024

Page: [930 - 940] Pages: 11

DOI: 10.2174/0115680096272757231211113206

Price: $65

Abstract

Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.

Graphical Abstract

[1]
Chen, H.; Liu, H.; Qing, G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct. Target. Ther., 2018, 3(1), 5.
[http://dx.doi.org/10.1038/s41392-018-0008-7] [PMID: 29527331]
[2]
Donati, G.; Amati, B. MYC and therapy resistance in cancer: Risks and opportunities. Mol. Oncol., 2022, 16(21), 3828-3854.
[http://dx.doi.org/10.1002/1878-0261.13319] [PMID: 36214609]
[3]
Duffy, M.J.; O’Grady, S.; Tang, M.; Crown, J. MYC as a target for cancer treatment. Cancer Treat. Rev., 2021, 94, 102154.
[http://dx.doi.org/10.1016/j.ctrv.2021.102154] [PMID: 33524794]
[4]
DePinho, R.; Mitsock, L.; Hatton, K.; Ferrier, P.; Zimmerman, K.; Legouy, E.; Tesfaye, A.; Collum, R.; Yancopoulos, G.; Nisen, P.; Kriz, R.; Alt, F. Myc family of cellular oncogenes. J. Cell. Biochem., 1987, 33(4), 257-266.
[http://dx.doi.org/10.1002/jcb.240330404] [PMID: 3034933]
[5]
Chan, K.I.; Zhang, S.; Li, G.; Xu, Y.; Cui, L.; Wang, Y.; Su, H.; Tan, W.; Zhong, Z. MYC oncogene: A druggable target for treating cancers with natural products. Aging Dis., 2023.
[PMID: 37450923]
[6]
Das, S.K.; Lewis, B.A.; Levens, D. MYC: A complex problem. Trends Cell Biol., 2023, 33(3), 235-246.
[http://dx.doi.org/10.1016/j.tcb.2022.07.006] [PMID: 35963793]
[7]
Nie, Z; Guo, C; Das, SK; Chow, CC; Batchelor, E; Simons, SS, Jnr Dissecting transcriptional amplification by MYC. Elife, 2020, 27(9), e52483.
[http://dx.doi.org/10.7554/eLife.52483]
[8]
Carroll, P.A.; Freie, B.W.; Mathsyaraja, H.; Eisenman, R.N. The MYC transcription factor network: Balancing metabolism, proliferation and oncogenesis. Front. Med., 2018, 12(4), 412-425.
[http://dx.doi.org/10.1007/s11684-018-0650-z] [PMID: 30054853]
[9]
Lin, C.Y.; Lovén, J.; Rahl, P.B.; Paranal, R.M.; Burge, C.B.; Bradner, J.E.; Lee, T.I.; Young, R.A. Transcriptional amplification in tumor cells with elevated c-Myc. Cell, 2012, 151(1), 56-67.
[http://dx.doi.org/10.1016/j.cell.2012.08.026] [PMID: 23021215]
[10]
Scagnoli, F.; Palma, A.; Favia, A.; Scuoppo, C.; Illi, B.; Nasi, S. A new insight into MYC action: Control of RNA polymerase II methylation and transcription termination. Biomedicines, 2023, 11(2), 412.
[http://dx.doi.org/10.3390/biomedicines11020412] [PMID: 36830948]
[11]
Guo, J.; Li, T.; Schipper, J.; Nilson, K.A.; Fordjour, F.K.; Cooper, J.J.; Gordân, R.; Price, D.H. Sequence specificity incompletely defines the genome-wide occupancy of Myc. Genome Biol., 2014, 15(10), 482.
[http://dx.doi.org/10.1186/s13059-014-0482-3] [PMID: 25287278]
[12]
Evan, G.I.; Wyllie, A.H.; Gilbert, C.S.; Littlewood, T.D.; Land, H.; Brooks, M.; Waters, C.M.; Penn, L.Z.; Hancock, D.C. Induction of apoptosis in fibroblasts by c-myc protein. Cell, 1992, 69(1), 119-128.
[http://dx.doi.org/10.1016/0092-8674(92)90123-T] [PMID: 1555236]
[13]
Kumari, A.; Folk, W.; Sakamuro, D. The dual roles of MYC in genomic instability and cancer chemoresistance. Genes, 2017, 8(6), 158.
[http://dx.doi.org/10.3390/genes8060158] [PMID: 28590415]
[14]
Welcker, M.; Orian, A.; Jin, J.; Grim, J.A.; Harper, J.W.; Eisenman, R.N.; Clurman, B.E. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc. Natl. Acad. Sci., 2004, 101(24), 9085-9090.
[http://dx.doi.org/10.1073/pnas.0402770101] [PMID: 15150404]
[15]
Yada, M.; Hatakeyama, S.; Kamura, T.; Nishiyama, M.; Tsunematsu, R.; Imaki, H.; Ishida, N.; Okumura, F.; Nakayama, K.; Nakayama, K.I. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J., 2004, 23(10), 2116-2125.
[http://dx.doi.org/10.1038/sj.emboj.7600217] [PMID: 15103331]
[16]
Brockmann, M.; Poon, E.; Berry, T.; Carstensen, A.; Deubzer, H.E.; Rycak, L.; Jamin, Y.; Thway, K.; Robinson, S.P.; Roels, F.; Witt, O.; Fischer, M.; Chesler, L.; Eilers, M. Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell, 2013, 24(1), 75-89.
[http://dx.doi.org/10.1016/j.ccr.2013.05.005] [PMID: 23792191]
[17]
Macek, P.; Cliff, M.J.; Embrey, K.J.; Holdgate, G.A.; Nissink, J.W.M.; Panova, S.; Waltho, J.P.; Davies, R.A. Myc phosphorylation in its basic helix–loop–helix region destabilizes transient α-helical structures, disrupting Max and DNA binding. J. Biol. Chem., 2018, 293(24), 9301-9310.
[http://dx.doi.org/10.1074/jbc.RA118.002709] [PMID: 29695509]
[18]
Bender, G.; Fahrioglu Yamaci, R.; Taneri, B. CRISPR and KRAS: A match yet to be made. J. Biomed. Sci., 2021, 28(1), 77.
[http://dx.doi.org/10.1186/s12929-021-00772-0] [PMID: 34781949]
[19]
Sears, R.; Nuckolls, F.; Haura, E.; Taya, Y.; Tamai, K.; Nevins, J.R. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev., 2000, 14(19), 2501-2514.
[http://dx.doi.org/10.1101/gad.836800] [PMID: 11018017]
[20]
Duda, P.; Akula, S.M.; Abrams, S.L.; Steelman, L.S.; Martelli, A.M.; Cocco, L.; Ratti, S.; Candido, S.; Libra, M.; Montalto, G.; Cervello, M.; Gizak, A.; Rakus, D.; McCubrey, J.A. Targeting GSK3 and associated signaling pathways involved in cancer. Cells, 2020, 9(5), 1110.
[http://dx.doi.org/10.3390/cells9051110] [PMID: 32365809]
[21]
Gregory, M.A.; Hann, S.R. c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt’s lymphoma cells. Mol. Cell. Biol., 2000, 20(7), 2423-2435.
[http://dx.doi.org/10.1128/MCB.20.7.2423-2435.2000] [PMID: 10713166]
[22]
Sun, X.X.; Li, Y.; Sears, R.C.; Dai, M.S. Targeting the MYC ubiquitination-proteasome degradation pathway for cancer therapy. Front. Oncol., 2021, 11, 679445.
[http://dx.doi.org/10.3389/fonc.2021.679445] [PMID: 34178666]
[23]
Walz, S.; Lorenzin, F.; Morton, J.; Wiese, K.E.; von Eyss, B.; Herold, S.; Rycak, L.; Dumay-Odelot, H.; Karim, S.; Bartkuhn, M.; Roels, F.; Wüstefeld, T.; Fischer, M.; Teichmann, M.; Zender, L.; Wei, C.L.; Sansom, O.; Wolf, E.; Eilers, M. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature, 2014, 511(7510), 483-487.
[http://dx.doi.org/10.1038/nature13473] [PMID: 25043018]
[24]
Sabò, A.; Amati, B. Genome Recognition by MYC. Cold Spring Harb. Perspect. Med., 2014, 4(2), a014191.
[http://dx.doi.org/10.1101/cshperspect.a014191] [PMID: 24492846]
[25]
Nilsson, J.A.; Cleveland, J.L. Myc pathways provoking cell suicide and cancer. Oncogene, 2003, 22(56), 9007-9021.
[http://dx.doi.org/10.1038/sj.onc.1207261] [PMID: 14663479]
[26]
Loosveld, M.; Bonnet, M.; Gon, S.; Montpellier, B.; Quilichini, B.; Navarro, J.M.; Crouzet, T.; Goujart, M.A.; Chasson, L.; Morgado, E.; Picard, C.; Hernandez, L.; Fossat, C.; Gabert, J.; Michel, G.; Nadel, B.; Payet-Bornet, D. MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer, 2014, 53(1), 52-66.
[http://dx.doi.org/10.1002/gcc.22117] [PMID: 24249258]
[27]
Thomas, L.R.; Wang, Q.; Grieb, B.C.; Phan, J.; Foshage, A.M.; Sun, Q.; Olejniczak, E.T.; Clark, T.; Dey, S.; Lorey, S.; Alicie, B.; Howard, G.C.; Cawthon, B.; Ess, K.C.; Eischen, C.M.; Zhao, Z.; Fesik, S.W.; Tansey, W.P. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol. Cell, 2015, 58(3), 440-452.
[http://dx.doi.org/10.1016/j.molcel.2015.02.028] [PMID: 25818646]
[28]
Boi, D.; Rubini, E.; Breccia, S.; Guarguaglini, G.; Paiardini, A. When just one phosphate is one too many: The multifaceted interplay between myc and kinases. Int. J. Mol. Sci., 2023, 24(5), 4746.
[http://dx.doi.org/10.3390/ijms24054746] [PMID: 36902175]
[29]
Struntz, N.B.; Chen, A.; Deutzmann, A.; Wilson, R.M.; Stefan, E.; Evans, H.L.; Ramirez, M.A.; Liang, T.; Caballero, F.; Wildschut, M.H.E.; Neel, D.V.; Freeman, D.B.; Pop, M.S.; McConkey, M.; Muller, S.; Curtin, B.H.; Tseng, H.; Frombach, K.R.; Butty, V.L.; Levine, S.S.; Feau, C.; Elmiligy, S.; Hong, J.A.; Lewis, T.A.; Vetere, A.; Clemons, P.A.; Malstrom, S.E.; Ebert, B.L.; Lin, C.Y.; Felsher, D.W.; Koehler, A.N. Stabilization of the Max homodimer with a small molecule attenuates Myc-driven transcription. Cell Chem. Biol., 2019, 26(5), 711-723.e14.
[http://dx.doi.org/10.1016/j.chembiol.2019.02.009] [PMID: 30880155]
[30]
Dang, C.V.; O’Donnell, K.A.; Zeller, K.I.; Nguyen, T.; Osthus, R.C.; Li, F. The c-Myc target gene network. Semin. Cancer Biol., 2006, 16(4), 253-264.
[http://dx.doi.org/10.1016/j.semcancer.2006.07.014] [PMID: 16904903]
[31]
Poole, C.J.; van Riggelen, J. MYC—master regulator of the cancer epigenome and transcriptome. Genes, 2017, 8(5), 142.
[http://dx.doi.org/10.3390/genes8050142] [PMID: 28505071]
[32]
Vízkeleti, L.; Spisák, S. Rewired metabolism caused by the oncogenic deregulation of MYC as an attractive therapeutic target in cancers. Cells, 2023, 12(13), 1745.
[http://dx.doi.org/10.3390/cells12131745] [PMID: 37443779]
[33]
Karadkhelkar, N.M.; Lin, M.; Eubanks, L.M.; Janda, K.D. Demystifying the druggability of the myc family of oncogenes. J. Am. Chem. Soc., 2023, 145(6), 3259-3269.
[http://dx.doi.org/10.1021/jacs.2c12732] [PMID: 36734615]
[34]
Chen, Y.; McGee, J.; Chen, X.; Doman, T.N.; Gong, X.; Zhang, Y.; Hamm, N.; Ma, X.; Higgs, R.E.; Bhagwat, S.V.; Buchanan, S.; Peng, S.B.; Staschke, K.A.; Yadav, V.; Yue, Y.; Kouros-Mehr, H. Identification of druggable cancer driver genes amplified across TCGA datasets. PLoS One, 2014, 9(5), e98293.
[http://dx.doi.org/10.1371/journal.pone.0098293] [PMID: 24874471]
[35]
Soucek, L.; Whitfield, J.R.; Sodir, N.M.; Massó-Vallés, D.; Serrano, E.; Karnezis, A.N.; Swigart, L.B.; Evan, G.I. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev., 2013, 27(5), 504-513.
[http://dx.doi.org/10.1101/gad.205542.112] [PMID: 23475959]
[36]
Madden, S.K.; de Araujo, A.D.; Gerhardt, M.; Fairlie, D.P.; Mason, J.M. Taking the Myc out of cancer: Toward therapeutic strategies to directly inhibit c-Myc. Mol. Cancer, 2021, 20(1), 3.
[http://dx.doi.org/10.1186/s12943-020-01291-6] [PMID: 33397405]
[37]
Llombart, V.; Mansour, M.R. Therapeutic targeting of “undruggable” MYC. EBioMedicine, 2022, 75, 103756.
[http://dx.doi.org/10.1016/j.ebiom.2021.103756] [PMID: 34942444]
[38]
Kalkat, M.; De Melo, J.; Hickman, K.; Lourenco, C.; Redel, C.; Resetca, D.; Tamachi, A.; Tu, W.; Penn, L. MYC deregulation in primary human cancers. Genes, 2017, 8(6), 151.
[http://dx.doi.org/10.3390/genes8060151] [PMID: 28587062]
[39]
Schaub, F.X.; Dhankani, V.; Berger, A.C.; Trivedi, M.; Richardson, A.B.; Shaw, R.; Zhao, W.; Zhang, X.; Ventura, A.; Liu, Y.; Ayer, D.E.; Hurlin, P.J.; Cherniack, A.D.; Eisenman, R.N.; Bernard, B.; Grandori, C.; Caesar-Johnson, S.J.; Demchok, J.A.; Felau, I.; Kasapi, M.; Ferguson, M.L.; Hutter, C.M.; Sofia, H.J.; Tarnuzzer, R.; Wang, Z.; Yang, L.; Zenklusen, J.C.; Zhang, J.J.; Chudamani, S.; Liu, J.; Lolla, L.; Naresh, R.; Pihl, T.; Sun, Q.; Wan, Y.; Wu, Y.; Cho, J.; DeFreitas, T.; Frazer, S.; Gehlenborg, N.; Getz, G.; Heiman, D.I.; Kim, J.; Lawrence, M.S.; Lin, P.; Meier, S.; Noble, M.S.; Saksena, G.; Voet, D.; Zhang, H.; Bernard, B.; Chambwe, N.; Dhankani, V.; Knijnenburg, T.; Kramer, R.; Leinonen, K.; Liu, Y.; Miller, M.; Reynolds, S.; Shmulevich, I.; Thorsson, V.; Zhang, W.; Akbani, R.; Broom, B.M.; Hegde, A.M.; Ju, Z.; Kanchi, R.S.; Korkut, A.; Li, J.; Liang, H.; Ling, S.; Liu, W.; Lu, Y.; Mills, G.B.; Ng, K-S.; Rao, A.; Ryan, M.; Wang, J.; Weinstein, J.N.; Zhang, J.; Abeshouse, A.; Armenia, J.; Chakravarty, D.; Chatila, W.K.; de Bruijn, I.; Gao, J.; Gross, B.E.; Heins, Z.J.; Kundra, R.; La, K.; Ladanyi, M.; Luna, A.; Nissan, M.G.; Ochoa, A.; Phillips, S.M.; Reznik, E.; Sanchez-Vega, F.; Sander, C.; Schultz, N.; Sheridan, R.; Sumer, S.O.; Sun, Y.; Taylor, B.S.; Wang, J.; Zhang, H.; Anur, P.; Peto, M.; Spellman, P.; Benz, C.; Stuart, J.M.; Wong, C.K.; Yau, C.; Hayes, D.N.; Parker, J.S.; Wilkerson, M.D.; Ally, A.; Balasundaram, M.; Bowlby, R.; Brooks, D.; Carlsen, R.; Chuah, E.; Dhalla, N.; Holt, R.; Jones, S.J.M.; Kasaian, K.; Lee, D.; Ma, Y.; Marra, M.A.; Mayo, M.; Moore, R.A.; Mungall, A.J.; Mungall, K.; Robertson, A.G.; Sadeghi, S.; Schein, J.E.; Sipahimalani, P.; Tam, A.; Thiessen, N.; Tse, K.; Wong, T.; Berger, A.C.; Beroukhim, R.; Cherniack, A.D.; Cibulskis, C.; Gabriel, S.B.; Gao, G.F.; Ha, G.; Meyerson, M.; Schumacher, S.E.; Shih, J.; Kucherlapati, M.H.; Kucherlapati, R.S.; Baylin, S.; Cope, L.; Danilova, L.; Bootwalla, M.S.; Lai, P.H.; Maglinte, D.T.; Van Den Berg, D.J.; Weisenberger, D.J.; Auman, J.T.; Balu, S.; Bodenheimer, T.; Fan, C.; Hoadley, K.A.; Hoyle, A.P.; Jefferys, S.R.; Jones, C.D.; Meng, S.; Mieczkowski, P.A.; Mose, L.E.; Perou, A.H.; Perou, C.M.; Roach, J.; Shi, Y.; Simons, J.V.; Skelly, T.; Soloway, M.G.; Tan, D.; Veluvolu, U.; Fan, H.; Hinoue, T.; Laird, P.W.; Shen, H.; Zhou, W.; Bellair, M.; Chang, K.; Covington, K.; Creighton, C.J.; Dinh, H.; Doddapaneni, H.V.; Donehower, L.A.; Drummond, J.; Gibbs, R.A.; Glenn, R.; Hale, W.; Han, Y.; Hu, J.; Korchina, V.; Lee, S.; Lewis, L.; Li, W.; Liu, X.; Morgan, M.; Morton, D.; Muzny, D.; Santibanez, J.; Sheth, M.; Shinbrot, E.; Wang, L.; Wang, M.; Wheeler, D.A.; Xi, L.; Zhao, F.; Hess, J.; Appelbaum, E.L.; Bailey, M.; Cordes, M.G.; Ding, L.; Fronick, C.C.; Fulton, L.A.; Fulton, R.S.; Kandoth, C.; Mardis, E.R.; McLellan, M.D.; Miller, C.A.; Schmidt, H.K.; Wilson, R.K.; Crain, D.; Curley, E.; Gardner, J.; Lau, K.; Mallery, D.; Morris, S.; Paulauskis, J.; Penny, R.; Shelton, C.; Shelton, T.; Sherman, M.; Thompson, E.; Yena, P.; Bowen, J.; Gastier-Foster, J.M.; Gerken, M.; Leraas, K.M.; Lichtenberg, T.M.; Ramirez, N.C.; Wise, L.; Zmuda, E.; Corcoran, N.; Costello, T.; Hovens, C.; Carvalho, A.L.; de Carvalho, A.C.; Fregnani, J.H.; Longatto-Filho, A.; Reis, R.M.; Scapulatempo-Neto, C.; Silveira, H.C.S.; Vidal, D.O.; Burnette, A.; Eschbacher, J.; Hermes, B.; Noss, A.; Singh, R.; Anderson, M.L.; Castro, P.D.; Ittmann, M.; Huntsman, D.; Kohl, B.; Le, X.; Thorp, R.; Andry, C.; Duffy, E.R.; Lyadov, V.; Paklina, O.; Setdikova, G.; Shabunin, A.; Tavobilov, M.; McPherson, C.; Warnick, R.; Berkowitz, R.; Cramer, D.; Feltmate, C.; Horowitz, N.; Kibel, A.; Muto, M.; Raut, C.P.; Malykh, A.; Barnholtz-Sloan, J.S.; Barrett, W.; Devine, K.; Fulop, J.; Ostrom, Q.T.; Shimmel, K.; Wolinsky, Y.; Sloan, A.E.; De Rose, A.; Giuliante, F.; Goodman, M.; Karlan, B.Y.; Hagedorn, C.H.; Eckman, J.; Harr, J.; Myers, J.; Tucker, K.; Zach, L.A.; Deyarmin, B.; Hu, H.; Kvecher, L.; Larson, C.; Mural, R.J.; Somiari, S.; Vicha, A.; Zelinka, T.; Bennett, J.; Iacocca, M.; Rabeno, B.; Swanson, P.; Latour, M.; Lacombe, L.; Têtu, B.; Bergeron, A.; McGraw, M.; Staugaitis, S.M.; Chabot, J.; Hibshoosh, H.; Sepulveda, A.; Su, T.; Wang, T.; Potapova, O.; Voronina, O.; Desjardins, L.; Mariani, O.; Roman-Roman, S.; Sastre, X.; Stern, M-H.; Cheng, F.; Signoretti, S.; Berchuck, A.; Bigner, D.; Lipp, E.; Marks, J.; McCall, S.; McLendon, R.; Secord, A.; Sharp, A.; Behera, M.; Brat, D.J.; Chen, A.; Delman, K.; Force, S.; Khuri, F.; Magliocca, K.; Maithel, S.; Olson, J.J.; Owonikoko, T.; Pickens, A.; Ramalingam, S.; Shin, D.M.; Sica, G.; Van Meir, E.G.; Zhang, H.; Eijckenboom, W.; Gillis, A.; Korpershoek, E.; Looijenga, L.; Oosterhuis, W.; Stoop, H.; van Kessel, K.E.; Zwarthoff, E.C.; Calatozzolo, C.; Cuppini, L.; Cuzzubbo, S.; DiMeco, F.; Finocchiaro, G.; Mattei, L.; Perin, A.; Pollo, B.; Chen, C.; Houck, J.; Lohavanichbutr, P.; Hartmann, A.; Stoehr, C.; Stoehr, R.; Taubert, H.; Wach, S.; Wullich, B.; Kycler, W.; Murawa, D.; Wiznerowicz, M.; Chung, K.; Edenfield, W.J.; Martin, J.; Baudin, E.; Bubley, G.; Bueno, R.; De Rienzo, A.; Richards, W.G.; Kalkanis, S.; Mikkelsen, T.; Noushmehr, H.; Scarpace, L.; Girard, N.; Aymerich, M.; Campo, E.; Giné, E.; Guillermo, A.L.; Van Bang, N.; Hanh, P.T.; Phu, B.D.; Tang, Y.; Colman, H.; Evason, K.; Dottino, P.R.; Martignetti, J.A.; Gabra, H.; Juhl, H.; Akeredolu, T.; Stepa, S.; Hoon, D.; Ahn, K.; Kang, K.J.; Beuschlein, F.; Breggia, A.; Birrer, M.; Bell, D.; Borad, M.; Bryce, A.H.; Castle, E.; Chandan, V.; Cheville, J.; Copland, J.A.; Farnell, M.; Flotte, T.; Giama, N.; Ho, T.; Kendrick, M.; Kocher, J-P.; Kopp, K.; Moser, C.; Nagorney, D.; O’Brien, D.; O’Neill, B.P.; Patel, T.; Petersen, G.; Que, F.; Rivera, M.; Roberts, L.; Smallridge, R.; Smyrk, T.; Stanton, M.; Thompson, R.H.; Torbenson, M.; Yang, J.D.; Zhang, L.; Brimo, F.; Ajani, J.A.; Angulo Gonzalez, A.M.; Behrens, C.; Bondaruk, J.; Broaddus, R.; Czerniak, B.; Esmaeli, B.; Fujimoto, J.; Gershenwald, J.; Guo, C.; Lazar, A.J.; Logothetis, C.; Meric-Bernstam, F.; Moran, C.; Ramondetta, L.; Rice, D.; Sood, A.; Tamboli, P.; Thompson, T.; Troncoso, P.; Tsao, A.; Wistuba, I.; Carter, C.; Haydu, L.; Hersey, P.; Jakrot, V.; Kakavand, H.; Kefford, R.; Lee, K.; Long, G.; Mann, G.; Quinn, M.; Saw, R.; Scolyer, R.; Shannon, K.; Spillane, A.; Stretch, J.; Synott, M.; Thompson, J.; Wilmott, J.; Al-Ahmadie, H.; Chan, T.A.; Ghossein, R.; Gopalan, A.; Levine, D.A.; Reuter, V.; Singer, S.; Singh, B.; Tien, N.V.; Broudy, T.; Mirsaidi, C.; Nair, P.; Drwiega, P.; Miller, J.; Smith, J.; Zaren, H.; Park, J-W.; Hung, N.P.; Kebebew, E.; Linehan, W.M.; Metwalli, A.R.; Pacak, K.; Pinto, P.A.; Schiffman, M.; Schmidt, L.S.; Vocke, C.D.; Wentzensen, N.; Worrell, R.; Yang, H.; Moncrieff, M.; Goparaju, C.; Melamed, J.; Pass, H.; Botnariuc, N.; Caraman, I.; Cernat, M.; Chemencedji, I.; Clipca, A.; Doruc, S.; Gorincioi, G.; Mura, S.; Pirtac, M.; Stancul, I.; Tcaciuc, D.; Albert, M.; Alexopoulou, I.; Arnaout, A.; Bartlett, J.; Engel, J.; Gilbert, S.; Parfitt, J.; Sekhon, H.; Thomas, G.; Rassl, D.M.; Rintoul, R.C.; Bifulco, C.; Tamakawa, R.; Urba, W.; Hayward, N.; Timmers, H.; Antenucci, A.; Facciolo, F.; Grazi, G.; Marino, M.; Merola, R.; de Krijger, R.; Gimenez-Roqueplo, A-P.; Piché, A.; Chevalier, S.; McKercher, G.; Birsoy, K.; Barnett, G.; Brewer, C.; Farver, C.; Naska, T.; Pennell, N.A.; Raymond, D.; Schilero, C.; Smolenski, K.; Williams, F.; Morrison, C.; Borgia, J.A.; Liptay, M.J.; Pool, M.; Seder, C.W.; Junker, K.; Omberg, L.; Dinkin, M.; Manikhas, G.; Alvaro, D.; Bragazzi, M.C.; Cardinale, V.; Carpino, G.; Gaudio, E.; Chesla, D.; Cottingham, S.; Dubina, M.; Moiseenko, F.; Dhanasekaran, R.; Becker, K-F.; Janssen, K-P.; Slotta-Huspenina, J.; Abdel-Rahman, M.H.; Aziz, D.; Bell, S.; Cebulla, C.M.; Davis, A.; Duell, R.; Elder, J.B.; Hilty, J.; Kumar, B.; Lang, J.; Lehman, N.L.; Mandt, R.; Nguyen, P.; Pilarski, R.; Rai, K.; Schoenfield, L.; Senecal, K.; Wakely, P.; Hansen, P.; Lechan, R.; Powers, J.; Tischler, A.; Grizzle, W.E.; Sexton, K.C.; Kastl, A.; Henderson, J.; Porten, S.; Waldmann, J.; Fassnacht, M.; Asa, S.L.; Schadendorf, D.; Couce, M.; Graefen, M.; Huland, H.; Sauter, G.; Schlomm, T.; Simon, R.; Tennstedt, P.; Olabode, O.; Nelson, M.; Bathe, O.; Carroll, P.R.; Chan, J.M.; Disaia, P.; Glenn, P.; Kelley, R.K.; Landen, C.N.; Phillips, J.; Prados, M.; Simko, J.; Smith-McCune, K.; VandenBerg, S.; Roggin, K.; Fehrenbach, A.; Kendler, A.; Sifri, S.; Steele, R.; Jimeno, A.; Carey, F.; Forgie, I.; Mannelli, M.; Carney, M.; Hernandez, B.; Campos, B.; Herold-Mende, C.; Jungk, C.; Unterberg, A.; von Deimling, A.; Bossler, A.; Galbraith, J.; Jacobus, L.; Knudson, M.; Knutson, T.; Ma, D.; Milhem, M.; Sigmund, R.; Godwin, A.K.; Madan, R.; Rosenthal, H.G.; Adebamowo, C.; Adebamowo, S.N.; Boussioutas, A.; Beer, D.; Giordano, T.; Mes-Masson, A-M.; Saad, F.; Bocklage, T.; Landrum, L.; Mannel, R.; Moore, K.; Moxley, K.; Postier, R.; Walker, J.; Zuna, R.; Feldman, M.; Valdivieso, F.; Dhir, R.; Luketich, J.; Mora Pinero, E.M.; Quintero-Aguilo, M.; Carlotti, C.G., Jr; Dos Santos, J.S.; Kemp, R.; Sankarankuty, A.; Tirapelli, D.; Catto, J.; Agnew, K.; Swisher, E.; Creaney, J.; Robinson, B.; Shelley, C.S.; Godwin, E.M.; Kendall, S.; Shipman, C.; Bradford, C.; Carey, T.; Haddad, A.; Moyer, J.; Peterson, L.; Prince, M.; Rozek, L.; Wolf, G.; Bowman, R.; Fong, K.M.; Yang, I.; Korst, R.; Rathmell, W.K.; Fantacone-Campbell, J.L.; Hooke, J.A.; Kovatich, A.J.; Shriver, C.D.; DiPersio, J.; Drake, B.; Govindan, R.; Heath, S.; Ley, T.; Van Tine, B.; Westervelt, P.; Rubin, M.A.; Lee, J.I.; Aredes, N.D.; Mariamidze, A. Pan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas. Cell Syst., 2018, 6(3), 282-300.e2.
[http://dx.doi.org/10.1016/j.cels.2018.03.003] [PMID: 29596783]
[40]
Amati, B.; Brooks, M.W.; Levy, N.; Littlewood, T.D.; Evan, G.I.; Land, H. Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell, 1993, 72(2), 233-245.
[http://dx.doi.org/10.1016/0092-8674(93)90663-B] [PMID: 8425220]
[41]
Soucek, L.; Whitfield, J.; Martins, C.P.; Finch, A.J.; Murphy, D.J.; Sodir, N.M.; Karnezis, A.N.; Swigart, L.B.; Nasi, S.; Evan, G.I. Modelling Myc inhibition as a cancer therapy. Nature, 2008, 455(7213), 679-683.
[http://dx.doi.org/10.1038/nature07260] [PMID: 18716624]
[42]
Beaulieu, M.E.; Martínez-Martín, S.; Kaur, J.; Castillo, C.V.; Massó-Vallés, D.; Foradada, F.L.; López-Estévez, S.; del Pozo, S.E.; Thabussot, H.; Soucek, L. Pharmacokinetic analysis of omomyc shows lasting structural integrity and long terminal half-life in tumor tissue. Cancers, 2023, 15(3), 826.
[http://dx.doi.org/10.3390/cancers15030826] [PMID: 36765784]
[43]
Rickman, D.S.; Schulte, J.H.; Eilers, M. The expanding world of N-MYC–driven tumors. Cancer Discov., 2018, 8(2), 150-163.
[http://dx.doi.org/10.1158/2159-8290.CD-17-0273] [PMID: 29358508]
[44]
Wistuba, I.; Gazdar, A.F.; Minna, J.D. Molecular genetics of small cell lung carcinoma. Semin. Oncol., 2001, 28(2), 3-13.
[http://dx.doi.org/10.1016/S0093-7754(01)90072-7] [PMID: 11479891]
[45]
Dhanasekaran, R.; Deutzmann, A.; Mahauad-Fernandez, W.D.; Hansen, A.S.; Gouw, A.M.; Felsher, D.W. The MYC oncogene — the grand orchestrator of cancer growth and immune evasion. Nat. Rev. Clin. Oncol., 2022, 19(1), 23-36.
[http://dx.doi.org/10.1038/s41571-021-00549-2] [PMID: 34508258]
[46]
Dhanasekaran, R.; Hansen, A.S.; Park, J.; Lemaitre, L.; Lai, I.; Adeniji, N.; Kuruvilla, S.; Suresh, A.; Zhang, J.; Swamy, V.; Felsher, D.W. MYC overexpression drives immune evasion in hepatocellular carcinoma that is reversible through restoration of proinflammatory macrophages. Cancer Res., 2023, 83(4), 626-640.
[http://dx.doi.org/10.1158/0008-5472.CAN-22-0232] [PMID: 36525476]
[47]
Soucek, L.; Helmer-Citterich, M.; Sacco, A.; Jucker, R.; Cesareni, G.; Nasi, S. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene, 1998, 17(19), 2463-2472.
[http://dx.doi.org/10.1038/sj.onc.1202199] [PMID: 9824157]
[48]
Demma, M.J.; Mapelli, C.; Sun, A.; Bodea, S.; Ruprecht, B.; Javaid, S.; Wiswell, D.; Muise, E.; Chen, S.; Zelina, J.; Orvieto, F.; Santoprete, A.; Altezza, S.; Tucci, F.; Escandon, E.; Hall, B.; Ray, K.; Walji, A.; O’Neil, J. Omomyc reveals new mechanisms to inhibit the MYC oncogene. Mol. Cell. Biol., 2019, 39(22), e00248-19.
[http://dx.doi.org/10.1128/MCB.00248-19] [PMID: 31501275]
[49]
Menssen, A.; Hermeking, H. Characterization of the c-MYC-regulated transcriptome by SAGE: Identification and analysis of c-MYC target genes. Proc. Natl. Acad. Sci., 2002, 99(9), 6274-6279.
[http://dx.doi.org/10.1073/pnas.082005599] [PMID: 11983916]
[50]
Devaiah, B.N.; Case-Borden, C.; Gegonne, A.; Hsu, C.H.; Chen, Q.; Meerzaman, D.; Dey, A.; Ozato, K.; Singer, D.S. BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin. Nat. Struct. Mol. Biol., 2016, 23(6), 540-548.
[http://dx.doi.org/10.1038/nsmb.3228] [PMID: 27159561]
[51]
Kotekar, A.; Singh, A.K.; Devaiah, B.N. BRD4 and MYC: Power couple in transcription and disease. FEBS J., 2022, 290(20), 4820-4842.
[http://dx.doi.org/10.1111/febs.16580] [PMID: 35866356]
[52]
Ali, H.A.; Li, Y.; Bilal, A.H.M.; Qin, T.; Yuan, Z.; Zhao, W. A comprehensive review of BET protein biochemistry, physiology, and pathological roles. Front. Pharmacol., 2022, 13, 818891.
[http://dx.doi.org/10.3389/fphar.2022.818891] [PMID: 35401196]
[53]
Dey, A.; Ellenberg, J.; Farina, A.; Coleman, A.E.; Maruyama, T.; Sciortino, S.; Lippincott-Schwartz, J.; Ozato, K. A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol. Cell. Biol., 2000, 20(17), 6537-6549.
[http://dx.doi.org/10.1128/MCB.20.17.6537-6549.2000] [PMID: 10938129]
[54]
Devaiah, B.N.; Gegonne, A.; Singer, D.S. Bromodomain 4: A cellular Swiss army knife. J. Leukoc. Biol., 2016, 100(4), 679-686.
[http://dx.doi.org/10.1189/jlb.2RI0616-250R] [PMID: 27450555]
[55]
Devaiah, B.N.; Mu, J.; Akman, B.; Uppal, S.; Weissman, J.D.; Cheng, D.; Baranello, L.; Nie, Z.; Levens, D.; Singer, D.S. MYC protein stability is negatively regulated by BRD4. Proc. Natl. Acad. Sci., 2020, 117(24), 13457-13467.
[http://dx.doi.org/10.1073/pnas.1919507117] [PMID: 32482868]
[56]
Weissman, J.D.; Singh, A.K.; Devaiah, B.N.; Schuck, P.; LaRue, R.C.; Singer, D.S. The intrinsic kinase activity of BRD4 spans its BD2-B-BID domains. J. Biol. Chem., 2021, 297(5), 101326.
[http://dx.doi.org/10.1016/j.jbc.2021.101326] [PMID: 34688663]
[57]
Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; Chesi, M.; Schinzel, A.C.; McKeown, M.R.; Heffernan, T.P.; Vakoc, C.R.; Bergsagel, P.L.; Ghobrial, I.M.; Richardson, P.G.; Young, R.A.; Hahn, W.C.; Anderson, K.C.; Kung, A.L.; Bradner, J.E.; Mitsiades, C.S. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 2011, 146(6), 904-917.
[http://dx.doi.org/10.1016/j.cell.2011.08.017] [PMID: 21889194]
[58]
Kazi, A.; Xiang, S.; Yang, H.; Delitto, D.; Trevino, J.; Jiang, R.H.Y.; Ayaz, M.; Lawrence, H.R.; Kennedy, P.; Sebti, S.M. GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors. Nat. Commun., 2018, 9(1), 5154.
[http://dx.doi.org/10.1038/s41467-018-07644-6] [PMID: 30514931]
[59]
Grim, J.E.; Gustafson, M.P.; Hirata, R.K.; Hagar, A.C.; Swanger, J.; Welcker, M.; Hwang, H.C.; Ericsson, J.; Russell, D.W.; Clurman, B.E. Isoform- and cell cycle–dependent substrate degradation by the Fbw7 ubiquitin ligase. J. Cell Biol., 2008, 181(6), 913-920.
[http://dx.doi.org/10.1083/jcb.200802076] [PMID: 18559665]
[60]
Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M.R.; Wang, Y.; Christie, A.L.; West, N.; Cameron, M.J.; Schwartz, B.; Heightman, T.D.; La Thangue, N.; French, C.A.; Wiest, O.; Kung, A.L.; Knapp, S.; Bradner, J.E. Selective inhibition of BET bromodomains. Nature, 2010, 468(7327), 1067-1073.
[http://dx.doi.org/10.1038/nature09504] [PMID: 20871596]
[61]
Mertz, J.A.; Conery, A.R.; Bryant, B.M.; Sandy, P.; Balasubramanian, S.; Mele, D.A.; Bergeron, L.; Sims, R.J., III Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl. Acad. Sci., 2011, 108(40), 16669-16674.
[http://dx.doi.org/10.1073/pnas.1108190108] [PMID: 21949397]
[62]
To, K.K.W.; Xing, E.; Larue, R.C.; Li, P.K. BET bromodomain inhibitors: Novel design strategies and therapeutic applications. Molecules, 2023, 28(7), 3043.
[http://dx.doi.org/10.3390/molecules28073043] [PMID: 37049806]
[63]
Han, X.; Sun, Y. PROTACs: A novel strategy for cancer drug discovery and development. MedComm, 2023, 4(3), e290.
[http://dx.doi.org/10.1002/mco2.290] [PMID: 37261210]
[64]
Raina, K.; Lu, J.; Qian, Y.; Altieri, M.; Gordon, D.; Rossi, A.M.K.; Wang, J.; Chen, X.; Dong, H.; Siu, K.; Winkler, J.D.; Crew, A.P.; Crews, C.M.; Coleman, K.G. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc. Natl. Acad. Sci., 2016, 113(26), 7124-7129.
[http://dx.doi.org/10.1073/pnas.1521738113] [PMID: 27274052]
[65]
Li, Z.; Lim, S.L.; Tao, Y.; Li, X.; Xie, Y.; Yang, C.; Zhang, Z.; Jiang, Y.; Zhang, X.; Cao, X.; Wang, H.; Qian, G.; Wu, Y.; Li, M.; Fang, F.; Liu, Y.; Fu, M.; Ding, X.; Zhu, Z.; Lv, H.; Lu, J.; Xiao, S.; Hu, S.; Pan, J. PROTAC bromodomain inhibitor ARV-825 displays anti-tumor activity in neuroblastoma by repressing expression of MYCN or c-Myc. Front. Oncol., 2020, 10, 574525.
[http://dx.doi.org/10.3389/fonc.2020.574525] [PMID: 33324552]
[66]
Bernabé-Caro, R.; Chen, Y.; Dowlati, A.; Eason, P. Current and emerging treatment options for patients with relapsed small-cell lung carcinoma: A systematic literature review. Clin. Lung Cancer, 2023, 24(3), 185-208.
[http://dx.doi.org/10.1016/j.cllc.2023.01.012] [PMID: 36907793]
[67]
Pietanza, M.C.; Byers, L.A.; Minna, J.D.; Rudin, C.M. Small cell lung cancer: will recent progress lead to improved outcomes? Clin. Cancer Res., 2015, 21(10), 2244-2255.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2958] [PMID: 25979931]
[68]
George, J.; Lim, J.S.; Jang, S.J.; Cun, Y.; Ozretić, L.; Kong, G.; Leenders, F.; Lu, X.; Fernández-Cuesta, L.; Bosco, G.; Müller, C.; Dahmen, I.; Jahchan, N.S.; Park, K.S.; Yang, D.; Karnezis, A.N.; Vaka, D.; Torres, A.; Wang, M.S.; Korbel, J.O.; Menon, R.; Chun, S.M.; Kim, D.; Wilkerson, M.; Hayes, N.; Engelmann, D.; Pützer, B.; Bos, M.; Michels, S.; Vlasic, I.; Seidel, D.; Pinther, B.; Schaub, P.; Becker, C.; Altmüller, J.; Yokota, J.; Kohno, T.; Iwakawa, R.; Tsuta, K.; Noguchi, M.; Muley, T.; Hoffmann, H.; Schnabel, P.A.; Petersen, I.; Chen, Y.; Soltermann, A.; Tischler, V.; Choi, C.; Kim, Y.H.; Massion, P.P.; Zou, Y.; Jovanovic, D.; Kontic, M.; Wright, G.M.; Russell, P.A.; Solomon, B.; Koch, I.; Lindner, M.; Muscarella, L.A.; la Torre, A.; Field, J.K.; Jakopovic, M.; Knezevic, J.; Castaños-Vélez, E.; Roz, L.; Pastorino, U.; Brustugun, O.T.; Lund-Iversen, M.; Thunnissen, E.; Köhler, J.; Schuler, M.; Botling, J.; Sandelin, M.; Sanchez-Cespedes, M.; Salvesen, H.B.; Achter, V.; Lang, U.; Bogus, M.; Schneider, P.M.; Zander, T.; Ansén, S.; Hallek, M.; Wolf, J.; Vingron, M.; Yatabe, Y.; Travis, W.D.; Nürnberg, P.; Reinhardt, C.; Perner, S.; Heukamp, L.; Büttner, R.; Haas, S.A.; Brambilla, E.; Peifer, M.; Sage, J.; Thomas, R.K. Comprehensive genomic profiles of small cell lung cancer. Nature, 2015, 524(7563), 47-53.
[http://dx.doi.org/10.1038/nature14664] [PMID: 26168399]
[69]
Peifer, M.; Fernández-Cuesta, L.; Sos, M.L.; George, J.; Seidel, D.; Kasper, L.H.; Plenker, D.; Leenders, F.; Sun, R.; Zander, T.; Menon, R.; Koker, M.; Dahmen, I.; Müller, C.; Di Cerbo, V.; Schildhaus, H.U.; Altmüller, J.; Baessmann, I.; Becker, C.; de Wilde, B.; Vandesompele, J.; Böhm, D.; Ansén, S.; Gabler, F.; Wilkening, I.; Heynck, S.; Heuckmann, J.M.; Lu, X.; Carter, S.L.; Cibulskis, K.; Banerji, S.; Getz, G.; Park, K.S.; Rauh, D.; Grütter, C.; Fischer, M.; Pasqualucci, L.; Wright, G.; Wainer, Z.; Russell, P.; Petersen, I.; Chen, Y.; Stoelben, E.; Ludwig, C.; Schnabel, P.; Hoffmann, H.; Muley, T.; Brockmann, M.; Engel-Riedel, W.; Muscarella, L.A.; Fazio, V.M.; Groen, H.; Timens, W.; Sietsma, H.; Thunnissen, E.; Smit, E.; Heideman, D.A.M.; Snijders, P.J.F.; Cappuzzo, F.; Ligorio, C.; Damiani, S.; Field, J.; Solberg, S.; Brustugun, O.T.; Lund-Iversen, M.; Sänger, J.; Clement, J.H.; Soltermann, A.; Moch, H.; Weder, W.; Solomon, B.; Soria, J.C.; Validire, P.; Besse, B.; Brambilla, E.; Brambilla, C.; Lantuejoul, S.; Lorimier, P.; Schneider, P.M.; Hallek, M.; Pao, W.; Meyerson, M.; Sage, J.; Shendure, J.; Schneider, R.; Büttner, R.; Wolf, J.; Nürnberg, P.; Perner, S.; Heukamp, L.C.; Brindle, P.K.; Haas, S.; Thomas, R.K. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet., 2012, 44(10), 1104-1110.
[http://dx.doi.org/10.1038/ng.2396] [PMID: 22941188]
[70]
Rudin, C.M.; Poirier, J.T.; Byers, L.A.; Dive, C.; Dowlati, A.; George, J.; Heymach, J.V.; Johnson, J.E.; Lehman, J.M.; MacPherson, D.; Massion, P.P.; Minna, J.D.; Oliver, T.G.; Quaranta, V.; Sage, J.; Thomas, R.K.; Vakoc, C.R.; Gazdar, A.F. Molecular subtypes of small cell lung cancer: A synthesis of human and mouse model data. Nat. Rev. Cancer, 2019, 19(5), 289-297.
[http://dx.doi.org/10.1038/s41568-019-0133-9] [PMID: 30926931]
[71]
Patel, A.S.; Yoo, S.; Kong, R.; Sato, T.; Sinha, A.; Karam, S.; Bao, L.; Fridrikh, M.; Emoto, K.; Nudelman, G.; Powell, C.A.; Beasley, M.B.; Zhu, J.; Watanabe, H. Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer. Sci. Adv., 2021, 7(5), eabc2578.
[http://dx.doi.org/10.1126/sciadv.abc2578] [PMID: 33514539]
[72]
Brägelmann, J.; Böhm, S.; Guthrie, M.R.; Mollaoglu, G.; Oliver, T.G.; Sos, M.L. Family matters: How MYC family oncogenes impact small cell lung cancer. Cell Cycle, 2017, 16(16), 1489-1498.
[http://dx.doi.org/10.1080/15384101.2017.1339849] [PMID: 28737478]
[73]
Kaye, F.; Battey, J.; Nau, M.; Brooks, B.; Seifter, E.; De Greve, J.; Birrer, M.; Sausville, E.; Minna, J. Structure and expression of the human L-myc gene reveal a complex pattern of alternative mRNA processing. Mol. Cell. Biol., 1988, 8(1), 186-195.
[PMID: 2827002]
[74]
Land, H.; Parada, L.F.; Weinberg, R.A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature, 1983, 304(5927), 596-602.
[http://dx.doi.org/10.1038/304596a0] [PMID: 6308472]
[75]
Massó-Vallés, D.; Beaulieu, M.E.; Soucek, L. MYC, MYCL, and MYCN as therapeutic targets in lung cancer. Expert Opin. Ther. Targets, 2020, 24(2), 101-114.
[http://dx.doi.org/10.1080/14728222.2020.1723548] [PMID: 32003251]
[76]
Saida, Y.; Watanabe, S.; Kikuchi, T. Extensive-stage small-cell lung cancer: Current landscape and future prospects. OncoTargets Ther., 2023, 16, 657-671.
[http://dx.doi.org/10.2147/OTT.S272552] [PMID: 37551311]
[77]
Kim, D.W.; Wu, N.; Kim, Y.C.; Cheng, P.F.; Basom, R.; Kim, D.; Dunn, C.T.; Lee, A.Y.; Kim, K.; Lee, C.S.; Singh, A.; Gazdar, A.F.; Harris, C.R.; Eisenman, R.N.; Park, K.S.; MacPherson, D. Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. Genes Dev., 2016, 30(11), 1289-1299.
[http://dx.doi.org/10.1101/gad.279307.116] [PMID: 27298335]
[78]
Augert, A.; Mathsyaraja, H.; Ibrahim, A.H.; Freie, B.; Geuenich, M.J.; Cheng, P.F.; Alibeckoff, S.P.; Wu, N.; Hiatt, J.B.; Basom, R.; Gazdar, A.; Sullivan, L.B.; Eisenman, R.N.; MacPherson, D. MAX functions as a tumor suppressor and rewires metabolism in small cell lung cancer. Cancer Cell, 2020, 38(1), 97-114.e7.
[http://dx.doi.org/10.1016/j.ccell.2020.04.016] [PMID: 32470392]
[79]
Cani, M.; Napoli, V.M.; Garbo, E.; Ferrari, G.; Del Rio, B.; Novello, S.; Passiglia, F. Targeted therapies in small cell lung cancer: From old failures to novel therapeutic strategies. Int. J. Mol. Sci., 2023, 24(10), 8883.
[http://dx.doi.org/10.3390/ijms24108883] [PMID: 37240229]
[80]
Dammert, M.A.; Brägelmann, J.; Olsen, R.R.; Böhm, S.; Monhasery, N.; Whitney, C.P.; Chalishazar, M.D.; Tumbrink, H.L.; Guthrie, M.R.; Klein, S.; Ireland, A.S.; Ryan, J.; Schmitt, A.; Marx, A.; Ozretić, L.; Castiglione, R.; Lorenz, C.; Jachimowicz, R.D.; Wolf, E.; Thomas, R.K.; Poirier, J.T.; Büttner, R.; Sen, T.; Byers, L.A.; Reinhardt, H.C.; Letai, A.; Oliver, T.G.; Sos, M.L. MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat. Commun., 2019, 10(1), 3485.
[http://dx.doi.org/10.1038/s41467-019-11371-x] [PMID: 31375684]
[81]
Ireland, A.S.; Micinski, A.M.; Kastner, D.W.; Guo, B.; Wait, S.J.; Spainhower, K.B.; Conley, C.C.; Chen, O.S.; Guthrie, M.R.; Soltero, D.; Qiao, Y.; Huang, X.; Tarapcsák, S.; Devarakonda, S.; Chalishazar, M.D.; Gertz, J.; Moser, J.C.; Marth, G.; Puri, S.; Witt, B.L.; Spike, B.T.; Oliver, T.G. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell, 2020, 38(1), 60-78.e12.
[http://dx.doi.org/10.1016/j.ccell.2020.05.001] [PMID: 32473656]
[82]
Ito, T.; Kudoh, S.; Fujino, K.; Sanada, M.; Tenjin, Y.; Saito, H.; Nakaishi-Fukuchi, Y.; Kameyama, H.; Ichimura, T.; Udaka, N.; Kudo, N.; Matsuo, A.; Sato, Y. Pulmonary neuroendocrine cells and small cell lung carcinoma: Immunohistochemical study focusing on mechanisms of neuroendocrine differentiation. Acta Histochem. Cytochem., 2022, 55(3), 75-83.
[http://dx.doi.org/10.1267/ahc.22-00031] [PMID: 35821751]
[83]
Borromeo, M.D.; Savage, T.K.; Kollipara, R.K.; He, M.; Augustyn, A.; Osborne, J.K.; Girard, L.; Minna, J.D.; Gazdar, A.F.; Cobb, M.H.; Johnson, J.E. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep., 2016, 16(5), 1259-1272.
[http://dx.doi.org/10.1016/j.celrep.2016.06.081] [PMID: 27452466]
[84]
McFadden, D.G.; Papagiannakopoulos, T.; Taylor-Weiner, A.; Stewart, C.; Carter, S.L.; Cibulskis, K.; Bhutkar, A.; McKenna, A.; Dooley, A.; Vernon, A.; Sougnez, C.; Malstrom, S.; Heimann, M.; Park, J.; Chen, F.; Farago, A.F.; Dayton, T.; Shefler, E.; Gabriel, S.; Getz, G.; Jacks, T. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell, 2014, 156(6), 1298-1311.
[http://dx.doi.org/10.1016/j.cell.2014.02.031] [PMID: 24630729]
[85]
Mollaoglu, G.; Guthrie, M.R.; Böhm, S.; Brägelmann, J.; Can, I.; Ballieu, P.M.; Marx, A.; George, J.; Heinen, C.; Chalishazar, M.D.; Cheng, H.; Ireland, A.S.; Denning, K.E.; Mukhopadhyay, A.; Vahrenkamp, J.M.; Berrett, K.C.; Mosbruger, T.L.; Wang, J.; Kohan, J.L.; Salama, M.E.; Witt, B.L.; Peifer, M.; Thomas, R.K.; Gertz, J.; Johnson, J.E.; Gazdar, A.F.; Wechsler-Reya, R.J.; Sos, M.L.; Oliver, T.G. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Cancer Cell, 2017, 31(2), 270-285.
[http://dx.doi.org/10.1016/j.ccell.2016.12.005] [PMID: 28089889]
[86]
Christensen, C.L.; Kwiatkowski, N.; Abraham, B.J.; Carretero, J.; Al-Shahrour, F.; Zhang, T.; Chipumuro, E.; Herter-Sprie, G.S.; Akbay, E.A.; Altabef, A.; Zhang, J.; Shimamura, T.; Capelletti, M.; Reibel, J.B.; Cavanaugh, J.D.; Gao, P.; Liu, Y.; Michaelsen, S.R.; Poulsen, H.S.; Aref, A.R.; Barbie, D.A.; Bradner, J.E.; George, R.E.; Gray, N.S.; Young, R.A.; Wong, K.K. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell, 2014, 26(6), 909-922.
[http://dx.doi.org/10.1016/j.ccell.2014.10.019] [PMID: 25490451]
[87]
Johnson, B.E.; Battey, J.; Linnoila, I.; Becker, K.L.; Makuch, R.W.; Snider, R.H.; Carney, D.N.; Minna, J.D. Changes in the phenotype of human small cell lung cancer cell lines after transfection and expression of the c-myc proto-oncogene. J. Clin. Invest., 1986, 78(2), 525-532.
[http://dx.doi.org/10.1172/JCI112604] [PMID: 3016030]
[88]
Kenzerki, M.E.; Ahmadi, M.; Mousavi, P.; Ghafouri-Fard, S. MYC and non-small cell lung cancer: A comprehensive review. Hum. Genet., 2023, 37, 201185.
[89]
Chen, J.; Guanizo, A.C.; Jakasekara, W.S.N.; Inampudi, C.; Luong, Q.; Garama, D.J.; Alamgeer, M.; Thakur, N.; DeVeer, M.; Ganju, V.; Watkins, D.N.; Cain, J.E.; Gough, D.J. MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat. J. Exp. Clin. Cancer Res., 2023, 42(1), 100.
[http://dx.doi.org/10.1186/s13046-023-02678-1] [PMID: 37098540]
[90]
Lenhart, R.; Kirov, S.; Desilva, H.; Cao, J.; Lei, M.; Johnston, K.; Peterson, R.; Schweizer, L.; Purandare, A.; Ross-Macdonald, P.; Fairchild, C.; Wong, T.; Wee, S. Sensitivity of small cell lung cancer to BET inhibition is mediated by regulation of ASCL1 gene expression. Mol. Cancer Ther., 2015, 14(10), 2167-2174.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0037] [PMID: 26253517]
[91]
Kumari, A.; Gesumaria, L.; Liu, Y.J.; Hughitt, V.K.; Zhang, X.; Ceribelli, M.; Wilson, K.M.; Klumpp-Thomas, C.; Chen, L.; McKnight, C.; Itkin, Z.; Thomas, C.J.; Mock, B.A.; Schrump, D.S.; Chen, H. mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer. JCI Insight, 2023, 8(5), e156657.
[http://dx.doi.org/10.1172/jci.insight.156657] [PMID: 36883564]
[92]
Chen, H.; Gesumaria, L.; Park, Y.K.; Oliver, T.G.; Singer, D.S.; Ge, K.; Schrump, D.S. BET inhibitors target the SCLC-N subtype of small-cell lung cancer by blocking NEUROD1 transactivation. Mol. Cancer Res., 2023, 21(2), 91-101.
[http://dx.doi.org/10.1158/1541-7786.MCR-22-0594] [PMID: 36378541]
[93]
Cochran, A.G.; Conery, A.R.; Sims, R.J., III Bromodomains: A new target class for drug development. Nat. Rev. Drug Discov., 2019, 18(8), 609-628.
[http://dx.doi.org/10.1038/s41573-019-0030-7] [PMID: 31273347]
[94]
Kato, F.; Fiorentino, F.P.; Alibés, A.; Perucho, M.; Sánchez-Céspedes, M.; Kohno, T.; Yokota, J. MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells. Oncotarget, 2016, 7(47), 77378-77388.
[http://dx.doi.org/10.18632/oncotarget.12671] [PMID: 27764802]
[95]
Nesbit, C.E.; Grove, L.E.; Yin, X.; Prochownik, E.V. Differential apoptotic behaviors of c-myc, N-myc, and L-myc oncoproteins. Cell Growth Differ., 1998, 9(9), 731-741.
[PMID: 9751117]
[96]
Berendsen, H.H.; de Leij, L.; de Vries, E.G.; Mesander, G.; Mulder, N.H.; de Jong, B.; Buys, C.H.; Postmus, P.E.; Poppema, S.; Sluiter, H.J. Characterization of three small cell lung cancer cell lines established from one patient during longitudinal follow-up. Cancer Res., 1988, 48(23), 6891-6899.
[PMID: 2846164]
[97]
Savarese-Brenner, B.; Heugl, M.; Rath, B.; Schweizer, C.; Obermayr, E.; Stickler, S.; Hamilton, G. MUC1 and CD147 are promising markers for the detection of circulating tumor cells in small cell lung cancer. Anticancer Res., 2022, 42(1), 429-439.
[http://dx.doi.org/10.21873/anticanres.15501] [PMID: 34969753]
[98]
Singh, V.V.; Alauddin, S. Review on: BRD4 inhibitors for anticancer research. Hum. Genet., 2023, 37, 201196.
[99]
Wang, Y.W.; Lan, L.; Wang, M.; Zhang, J.Y.; Gao, Y.H.; Shi, L.; Sun, L.P. PROTACS: A technology with a gold rush-like atmosphere. Eur. J. Med. Chem., 2023, 247, 115037.
[http://dx.doi.org/10.1016/j.ejmech.2022.115037] [PMID: 36566716]
[100]
Liu, X.; Wang, A.; Shi, Y.; Dai, M.; Liu, M.; Cai, H.B. PROTACs in epigenetic cancer therapy: Current status and future opportunities. Molecules, 2023, 28(3), 1217.
[http://dx.doi.org/10.3390/molecules28031217] [PMID: 36770884]
[101]
Hamilton, G.; Stickler, S.; Rath, B. Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer. Explor. Target. Anti-tumor Ther., 2023, 1027-1038.
[http://dx.doi.org/10.37349/etat.2023.00178]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version949msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[20:52:08] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[20:52:09] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[20:52:09] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[20:52:09] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (319ms)time
  • Application (631ms)time
  • 1 x Application (66.42%)
    631ms
    1 x Booting (33.58%)
    319ms
    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
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated437ms
    • 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 ('316524867','',1,1740775928,1740775928) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740775928
      4.13msalphaeurekaselec_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 ('316524867','/article/137831',1,1740775928,1740775928)
      280μsalphaeurekaselec_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 >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) 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 >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) 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 >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) 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 >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) 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 >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) 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 >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316524867 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316524867) limit 1
      23.58msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316524867
      • 1: 316524867
      • 2: 316524867
      • 3: 316524867
      • 4: 316524867
      • 5: 316524867
      • 6: 316524867
      • 7: 316524867
      • 8: 316524867
      • 9: 316524867
      • 10: 316524867
      • 11: 316524867
      • 12: 316524867
      • 13: 316524867
      • 14: 316524867
      • 15: 316524867
      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=137831
      1.36msalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 7 limit 1
      24.57msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 7
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and sj.journal_id!=7 group by `j`.`nid`) as `aggregate_table`
      1.64msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and sj.journal_id!=7 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      8.41msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.43msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      7.41msalphaeurekaselec_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` = '137831'
      4.82msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 137831
      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` = '137831'
      8.31msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 137831
      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` = '137831' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      4.26msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 137831
      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
      350μsalphaeurekaselec_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
      740μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 7 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      50.91msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      50.42msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      42.89msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 137831 limit 1
      360μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 137831
      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 = 137831 and content_type = 'article' order by status desc limit 1
      380μsalphaeurekaselec_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 * from `node_meta` where `nid` = 226135 limit 1
      270μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 226135
      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
      310μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CCDT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      4.16msalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CCDT
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '137831' 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) )
      550μsalphaeurekaselec_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 = '13384' 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) )
      450μsalphaeurekaselec_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 = '3459' 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) )
      420μsalphaeurekaselec_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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775928 and j.to_date >= 1740775928 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3459) 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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775928 and j.to_date >= 1740775928 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3459) 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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775928 and j.to_date >= 1740775928 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3459)
      166msalphaeurekaselec_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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775929 and j.to_date >= 1740775929 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13384) 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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775929 and j.to_date >= 1740775929 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13384) 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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775929 and j.to_date >= 1740775929 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13384)
      1.08msalphaeurekaselec_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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775929 and j.to_date >= 1740775929 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 137831) 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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775929 and j.to_date >= 1740775929 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 137831) 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 <= 316524867 and j.to_ip >=316524867 )) and ((j.from_date <= 1740775929 and j.to_date >= 1740775929 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 137831)
      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` < '930' and is_uploaded = 1 and issue_id = 13384 order by cast(first_page as SIGNED) desc limit 1
      830μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 930
      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` > '940' and is_uploaded = 1 and issue_id = 13384 order by cast(first_page as SIGNED) asc limit 1
      670μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 940
      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'
      270μsalphaeurekaselec_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
      310μsalphaeurekaselec_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` = 137831 limit 1
      5.94msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 137831
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 7 and `b`.`banner_from_date` <= 1740775929 and `b`.`banner_to_date` >= 1740775929 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      3.64msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1740775929
      • 4: 1740775929
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 7 and `b`.`banner_from_date` <= 1740775929 and `b`.`banner_to_date` >= 1740775929 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.72msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1740775929
      • 4: 1740775929
      • 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='f3260a5686126bb8c2965bc163e98a7c'
      11.8msalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:291
      • 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
        GWZnJKu0PmV0ti6H0hO8LMsdiji2gW3P4AQWS5Ya
        uc_cart_id
        f3260a5686126bb8c2965bc163e98a7c
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/137831" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/137831
        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 => "Fri, 28 Feb 2025 20:52:09 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ild2ZDkvL2NjV1M0d0oxQittcFZUU3c9PSIsInZhbHVlIjoiSUhTQ2J3Y3RGbFhpZlA3TUZoeXcvcDAva3RKa081UCtKaHhiL1gyVUxqUGhjY3RvK2FncVhDMkVYOXdBOWtGMUpVajdXYWhiTFc1ZVA1cmhGd2ZjcEgwaWxtRGRzaTkvVUZ1WFZBMUZHdTM0M05VUXhnZUlkRno4U29VVkxJUnkiLCJtYWMiOiI0MDNiNzA1MTZlM2NlYmI5YTU4NDUwZDA3ZDYzYzIzM2FlZDY3M2RlMjZmOGQ2MGQxZjg2ODVjYzM3MzJmNGY1IiwidGFnIjoiIn0%3D; expires=Mon, 03 Mar 2025 08:52:09 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Ild2ZDkvL2NjV1M0d0oxQittcFZUU3c9PSIsInZhbHVlIjoiSUhTQ2J3Y3RGbFhpZlA3TUZoeXcvcDAva3RKa081UCtKaHhiL1gyVUxqUGhjY3RvK2FncVhDMkVYOXdBOWtGMUpVajdXY" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkM0UjlIUGtwdWFkTVBGVkR4YUwwU3c9PSIsInZhbHVlIjoiYkFIR0JkUUIvdGRXRDZRM3AyazZtWjRoWGxRbE1TY2hQVGJGc1lJQ3BkTWVnQWQ4ODVxT015dlNaM2gwd21ZbXpBanRyUnY4NTFNa2Z6MyswSXhlQXFXdFNQZ2V5ak9MWEVjSkR5TUQ4OUU0WjMzeS9IWjh0ZzgyMXpRWjZXS3UiLCJtYWMiOiIyMDc2ZTFiMjNmZGQ3NjJjMWUxMTAwNjA5NjkzZDg1NzcyMjMyNDJiM2RjZjM2M2E0NDdiMWQ2NmY0YTFjM2NmIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkM0UjlIUGtwdWFkTVBGVkR4YUwwU3c9PSIsInZhbHVlIjoiYkFIR0JkUUIvdGRXRDZRM3AyazZtWjRoWGxRbE1TY2hQVGJGc1lJQ3BkTWVnQWQ4ODVxT015dlN" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ild2ZDkvL2NjV1M0d0oxQittcFZUU3c9PSIsInZhbHVlIjoiSUhTQ2J3Y3RGbFhpZlA3TUZoeXcvcDAva3RKa081UCtKaHhiL1gyVUxqUGhjY3RvK2FncVhDMkVYOXdBOWtGMUpVajdXYWhiTFc1ZVA1cmhGd2ZjcEgwaWxtRGRzaTkvVUZ1WFZBMUZHdTM0M05VUXhnZUlkRno4U29VVkxJUnkiLCJtYWMiOiI0MDNiNzA1MTZlM2NlYmI5YTU4NDUwZDA3ZDYzYzIzM2FlZDY3M2RlMjZmOGQ2MGQxZjg2ODVjYzM3MzJmNGY1IiwidGFnIjoiIn0%3D; expires=Mon, 03-Mar-2025 08:52:09 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Ild2ZDkvL2NjV1M0d0oxQittcFZUU3c9PSIsInZhbHVlIjoiSUhTQ2J3Y3RGbFhpZlA3TUZoeXcvcDAva3RKa081UCtKaHhiL1gyVUxqUGhjY3RvK2FncVhDMkVYOXdBOWtGMUpVajdXY" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkM0UjlIUGtwdWFkTVBGVkR4YUwwU3c9PSIsInZhbHVlIjoiYkFIR0JkUUIvdGRXRDZRM3AyazZtWjRoWGxRbE1TY2hQVGJGc1lJQ3BkTWVnQWQ4ODVxT015dlNaM2gwd21ZbXpBanRyUnY4NTFNa2Z6MyswSXhlQXFXdFNQZ2V5ak9MWEVjSkR5TUQ4OUU0WjMzeS9IWjh0ZzgyMXpRWjZXS3UiLCJtYWMiOiIyMDc2ZTFiMjNmZGQ3NjJjMWUxMTAwNjA5NjkzZDg1NzcyMjMyNDJiM2RjZjM2M2E0NDdiMWQ2NmY0YTFjM2NmIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkM0UjlIUGtwdWFkTVBGVkR4YUwwU3c9PSIsInZhbHVlIjoiYkFIR0JkUUIvdGRXRDZRM3AyazZtWjRoWGxRbE1TY2hQVGJGc1lJQ3BkTWVnQWQ4ODVxT015dlN" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "GWZnJKu0PmV0ti6H0hO8LMsdiji2gW3P4AQWS5Ya" "uc_cart_id" => "f3260a5686126bb8c2965bc163e98a7c" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/137831" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-28 20:52:09GET/article/137831414361