Review Article

3D文化建模:肉瘤转化癌症研究的新兴方法

卷 27, 期 29, 2020

页: [4778 - 4788] 页: 11

弟呕挨: 10.2174/0929867326666191212162102

价格: $65

摘要

肉瘤是间充质起源的肿瘤,可发生在骨骼或软组织中。 它们很少见,但经常具有侵略性,并且效果不佳。 需要新的方法来表征这些肿瘤及其对当前疗法的耐药机制,从而导致肿瘤复发和治疗失败。 这篇综述着重于三维(3D)体外模型的潜力,包括多细胞肿瘤球体(类)和类器官,以及有关它们在研究肿瘤发展的重要特性方面的效用的最新数据。 还讨论了球体在癌症生物学不同领域中作为复合高通量筛选(HTS)的特别有价值的替代方法的使用,这使得能够确定常见耐药性肿瘤的新治疗机会。

关键词: 3D培养,体外模型,肉瘤,多细胞肿瘤球(MCTS),癌症,高通量 筛查(HTS)。

[1]
Taylor, B.S.; Barretina, J.; Maki, R.G.; Antonescu, C.R.; Singer, S.; Ladanyi, M. Advances in sarcoma genomics and new therapeutic targets. Nat. Rev. Cancer, 2011, 11(8), 541-557.
[http://dx.doi.org/10.1038/nrc3087] [PMID: 21753790]
[2]
Doyle, L.A. Sarcoma classification: an update based on the 2013 World Health Organization Classification of tumors of soft tissue and bone. Cancer, 2014, 120(12), 1763-1774.
[http://dx.doi.org/10.1002/cncr.28657] [PMID: 24648013]
[3]
(a)Nielsen, T.O.; West, R.B. Translating gene expression into clinical care: sarcomas as a paradigm. J. Clin. Oncol., 2010, 28(10), 1796-1805.
[http://dx.doi.org/10.1200/JCO.2009.26.1917] [PMID: 20194847]
(b)Bovée, J.V.; Hogendoorn, P.C. Molecular pathology of sarcomas: concepts and clinical implications. Virchows Arch., 2010, 456(2), 193-199.
[http://dx.doi.org/10.1007/s00428-009-0828-5] [PMID: 19787372]
[4]
Fletcher, C.D. The evolving classification of soft tissue tumours - an update based on the new 2013 WHO classification. Histopathology, 2014, 64(1), 2-11.
[http://dx.doi.org/10.1111/his.12267] [PMID: 24164390]
[5]
(a)Sugita, S.; Arai, Y.; Tonooka, A.; Hama, N.; Totoki, Y.; Fujii, T.; Aoyama, T.; Asanuma, H.; Tsukahara, T.; Kaya, M.; Shibata, T.; Hasegawa, T. A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am. J. Surg. Pathol., 2014, 38(11), 1571-1576.
[http://dx.doi.org/10.1097/PAS.0000000000000286] [PMID: 25007147]
(b)Graham, C.; Chilton-MacNeill, S.; Zielenska, M.; Somers, G.R. The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum. Pathol, 2012, 43(2), 180-189.
[http://dx.doi.org/10.1016/j.humpath.2011.04.023] [PMID: 21813156]
[6]
Puls, F.; Niblett, A.; Marland, G.; Gaston, C.L.; Douis, H.; Mangham, D.C.; Sumathi, V.P.; Kindblom, L.G. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am. J. Surg. Pathol., 2014, 38(10), 1307-1318.
[http://dx.doi.org/10.1097/PAS.0000000000000223] [PMID: 24805859]
[7]
Oliner, J.D.; Pietenpol, J.A.; Thiagalingam, S.; Gyuris, J.; Kinzler, K.W.; Vogelstein, B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature, 1993, 362(6423), 857-860.
[http://dx.doi.org/10.1038/362857a0] [PMID: 8479525]
[8]
Crozat, A.; Aman, P.; Mandahl, N.; Ron, D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature, 1993, 363(6430), 640-644.
[http://dx.doi.org/10.1038/363640a0] [PMID: 8510758]
[9]
Recine, F.; Bongiovanni, A.; Riva, N.; Fausti, V.; De Vita, A.; Mercatali, L.; Liverani, C.; Miserocchi, G.; Amadori, D.; Ibrahim, T. Update on the role of trabectedin in the treatment of intractable soft tissue sarcomas. OncoTargets Ther., 2017, 10, 1155-1164.
[http://dx.doi.org/10.2147/OTT.S127955] [PMID: 28260930]
[10]
Nussbaum, D.P.; Rushing, C.N.; Lane, W.O.; Cardona, D.M.; Kirsch, D.G.; Peterson, B.L.; Blazer, D.G., III Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database. Lancet Oncol., 2016, 17(7), 966-975.
[http://dx.doi.org/10.1016/S1470-2045(16)30050-X] [PMID: 27210906]
[11]
Group, E.S.E.S.N.W. ESMO/European Sarcoma Network Working Group. Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2014, 25(Suppl. 3), iii102-iii112.
[http://dx.doi.org/10.1093/annonc/mdu254] [PMID: 25210080]
[12]
Judson, I.; Verweij, J.; Gelderblom, H.; Hartmann, J.T.; Schöffski, P.; Blay, J.Y.; Kerst, J.M.; Sufliarsky, J.; Whelan, J.; Hohenberger, P.; Krarup-Hansen, A.; Alcindor, T.; Marreaud, S.; Litière, S.; Hermans, C.; Fisher, C.; Hogendoorn, P.C. dei Tos, A.P.; van der Graaf, W.T. European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol., 2014, 15(4), 415-423.
[http://dx.doi.org/10.1016/S1470-2045(14)70063-4] [PMID: 24618336]
[13]
(a)Khalifa, J.; Ouali, M.; Chaltiel, L.; Le Guellec, S.; Le Cesne, A.; Blay, J.Y.; Cousin, P.; Chaigneau, L.; Bompas, E.; Piperno-Neumann, S.; Bui-Nguyen, B.; Rios, M.; Delord, J.P.; Penel, N.; Chevreau, C. Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group. BMC Cancer, 2015, 15, 700.
[http://dx.doi.org/10.1186/s12885-015-1697-8] [PMID: 26472661]
(b)Sanfilippo, R.; Dileo, P.; Blay, J.Y.; Constantinidou, A.; Le Cesne, A.; Benson, C.; Vizzini, L.; Contu, M.; Baldi, G.G.; Dei Tos, A.P.; Casali, P.G. Trabectedin in advanced synovial sarcomas: a multicenter retrospective study from four European institutions and the Italian Rare Cancer Network. Anticancer Drugs, 2015, 26(6), 678-681.
[PMID: 25763543]
[14]
Schöffski, P.; Chawla, S.; Maki, R.G.; Italiano, A.; Gelderblom, H.; Choy, E.; Grignani, G.; Camargo, V.; Bauer, S.; Rha, S.Y.; Blay, J.Y.; Hohenberger, P.; D’Adamo, D.; Guo, M.; Chmielowski, B.; Le Cesne, A.; Demetri, G.D.; Patel, S.R. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet, 2016, 387(10028), 1629-1637.
[http://dx.doi.org/10.1016/S0140-6736(15)01283-0] [PMID: 26874885]
[15]
(a)Heinrich, M.C.; Corless, C.L.; Demetri, G.D.; Blanke, C.D.; von Mehren, M.; Joensuu, H.; McGreevey, L.S.; Chen, C.J.; Van den Abbeele, A.D.; Druker, B.J.; Kiese, B.; Eisenberg, B.; Roberts, P.J.; Singer, S.; Fletcher, C.D.; Silberman, S.; Dimitrijevic, S.; Fletcher, J.A. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol, 2003, 21(23), 4342-4349.
[http://dx.doi.org/10.1200/JCO.2003.04.190] [PMID: 14645423]
(b)Poveda, A.; del Muro, X.G.; López-Guerrero, J.A.; Martínez, V.; Romero, I.; Valverde, C.; Cubedo, R.; Martín-Broto, J. GEIS 2013 guidelines for gastrointestinal sarcomas (GIST). Cancer Chemother. Pharmacol, 2014, 74(5), 883-898.
[http://dx.doi.org/10.1007/s00280-014-2547-0] [PMID: 25193432]
[16]
(a)Malhotra, B.; Schuetze, S.M. Dermatofibrosarcoma protruberans treatment with platelet-derived growth factor receptor inhibitor: a review of clinical trial results. Curr. Opin. Oncol., 2012, 24(4), 419-424.
[http://dx.doi.org/10.1097/CCO.0b013e328353d78d] [PMID: 22510939]
(b)McArthur, G.A.; Demetri, G.D.; van Oosterom, A.; Heinrich, M.C.; Debiec-Rychter, M.; Corless, C.L.; Nikolova, Z.; Dimitrijevic, S.; Fletcher, J.A. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J. Clin. Oncol., 2005, 23(4), 866-873.
[http://dx.doi.org/10.1200/JCO.2005.07.088] [PMID: 15681532]
[17]
van der Graaf, W.T.; Blay, J.Y.; Chawla, S.P.; Kim, D.W.; Bui-Nguyen, B.; Casali, P.G.; Schöffski, P.; Aglietta, M.; Staddon, A.P.; Beppu, Y.; Le Cesne, A.; Gelderblom, H.; Judson, I.R.; Araki, N.; Ouali, M.; Marreaud, S.; Hodge, R.; Dewji, M.R.; Coens, C.; Demetri, G.D.; Fletcher, C.D.; Dei Tos, A.P.; Hohenberger, P.; Tissue, E.S.; Bone Sarcoma, G. EORTC Soft Tissue and Bone Sarcoma Group. PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2012, 379(9829), 1879-1886.
[http://dx.doi.org/10.1016/S0140-6736(12)60651-5] [PMID: 22595799]
[18]
van der Graaf, W.T. Olaratumab in soft-tissue sarcomas. Lancet, 2016, 388(10043), 442-444.
[http://dx.doi.org/10.1016/S0140-6736(16)30788-7] [PMID: 27291995]
[19]
(a)Lim, J.; Poulin, N.M.; Nielsen, T.O. New strategies in sarcoma: linking genomic and immunotherapy approaches to molecular subtype. Clin. Cancer Res., 2015, 21(21), 4753-4759.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0831] [PMID: 26330427]
(b)Silveira, S.M.; Villacis, R.A.; Marchi, F.A. Barros Filho, Mde.C.; Drigo, S.A.; Neto, C.S.; Lopes, A.; da Cunha, I.W.; Rogatto, S.R. Genomic signatures predict poor outcome in undifferentiated pleomorphic sarcomas and leiomyosarcomas. PLoS One, 2013, 8(6), e67643.
[http://dx.doi.org/10.1371/journal.pone.0067643] [PMID: 23825657]
[20]
Riegman, P.H.; Dinjens, W.N.; Oosterhuis, J.W. Biobanking for interdisciplinary clinical research. Pathobiology, 2007, 74(4), 239-244.
[http://dx.doi.org/10.1159/000104451] [PMID: 17709966]
[21]
Riegman, P.H.; Morente, M.M.; Betsou, F.; de Blasio, P.; Geary, P. Marble Arch International Working Group on Biobanking for Biomedical Research. Biobanking for better healthcare. Mol. Oncol., 2008, 2(3), 213-222.
[http://dx.doi.org/10.1016/j.molonc.2008.07.004] [PMID: 19383342]
[22]
TCGA’s Study of Adult Soft Tissue Sarcoma. National Cancer Institute (NIH), https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga/studied-cancers/sarcoma [30 October 2019];
[23]
Barretina, J.; Caponigro, G.; Stransky, N.; Venkatesan, K.; Margolin, A.A.; Kim, S.; Wilson, C.J.; Lehár, J.; Kryukov, G.V.; Sonkin, D.; Reddy, A.; Liu, M.; Murray, L.; Berger, M.F.; Monahan, J.E.; Morais, P.; Meltzer, J.; Korejwa, A.; Jané-Valbuena, J.; Mapa, F.A.; Thibault, J.; Bric-Furlong, E.; Raman, P.; Shipway, A.; Engels, I.H.; Cheng, J.; Yu, G.K.; Yu, J.; Aspesi, P., Jr; de Silva, M.; Jagtap, K.; Jones, M.D.; Wang, L.; Hatton, C.; Palescandolo, E.; Gupta, S.; Mahan, S.; Sougnez, C.; Onofrio, R.C.; Liefeld, T.; MacConaill, L.; Winckler, W.; Reich, M.; Li, N.; Mesirov, J.P.; Gabriel, S.B.; Getz, G.; Ardlie, K.; Chan, V.; Myer, V.E.; Weber, B.L.; Porter, J.; Warmuth, M.; Finan, P.; Harris, J.L.; Meyerson, M.; Golub, T.R.; Morrissey, M.P.; Sellers, W.R.; Schlegel, R.; Garraway, L.A. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 2012, 483(7391), 603-607.
[http://dx.doi.org/10.1038/nature11003] [PMID: 22460905]
[24]
Bignell, G.R.; Greenman, C.D.; Davies, H.; Butler, A.P.; Edkins, S.; Andrews, J.M.; Buck, G.; Chen, L.; Beare, D.; Latimer, C.; Widaa, S.; Hinton, J.; Fahey, C.; Fu, B.; Swamy, S.; Dalgliesh, G.L.; Teh, B.T.; Deloukas, P.; Yang, F.; Campbell, P.J.; Futreal, P.A.; Stratton, M.R. Signatures of mutation and selection in the cancer genome. Nature, 2010, 463(7283), 893-898.
[http://dx.doi.org/10.1038/nature08768] [PMID: 20164919]
[25]
Yamada, K.M.; Cukierman, E. Modeling tissue morphogenesis and cancer in 3D. Cell, 2007, 130(4), 601-610.
[http://dx.doi.org/10.1016/j.cell.2007.08.006] [PMID: 17719539]
[26]
(a)Baker, B.M.; Chen, C.S. Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J. Cell Sci, 2012, 125(Pt 13), 3015-3024.
[http://dx.doi.org/10.1242/jcs.079509] [PMID: 22797912]
(b)Minchinton, A.I.; Tannock, I.F. Drug penetration in solid tumours. Nat. Rev. Cancer, 2006, 6(8), 583-592.
[http://dx.doi.org/10.1038/nrc1893] [PMID: 16862189]
[27]
Durand, R.E.; Raleigh, J.A. Identification of nonproliferating but viable hypoxic tumor cells in vivo. Cancer Res., 1998, 58(16), 3547-3550.
[PMID: 9721858]
[28]
Hirschhaeuser, F.; Menne, H.; Dittfeld, C.; West, J.; Mueller-Klieser, W.; Kunz-Schughart, L.A. Multicellular tumor spheroids: an underestimated tool is catching up again. J. Biotechnol., 2010, 148(1), 3-15.
[http://dx.doi.org/10.1016/j.jbiotec.2010.01.012] [PMID: 20097238]
[29]
(a)Sutherland, R.M.; Durand, R.E. Radiation response of multicell spheroids-an in vitro tumour model. Curr. Top. Radiat. Res. Q., 1976, 11(1), 87-139.
[PMID: 128440]
(b)Sutherland, R.M.; Sordat, B.; Bamat, J.; Gabbert, H.; Bourrat, B.; Mueller-Klieser, W. Oxygenation and differentiation in multicellular spheroids of human colon carcinoma. Cancer Res., 1986, 46(10), 5320-5329.
[PMID: 3756881]
[30]
Teicher, B.A.; Polley, E.; Kunkel, M.; Evans, D.; Silvers, T.; Delosh, R.; Laudeman, J.; Ogle, C.; Reinhart, R.; Selby, M.; Connelly, J.; Harris, E.; Monks, A.; Morris, J. Sarcoma cell line screen of oncology drugs and investigational agents identifies patterns associated with gene and microRNA Expression. Mol. Cancer Ther., 2015, 14(11), 2452-2462.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0074] [PMID: 26351324]
[31]
Foty, R. A simple hanging drop cell culture protocol for generation of 3D spheroids. J. Vis. Exp., 2011, (51), e2720.
[http://dx.doi.org/10.3791/2720] [PMID: 21587162]
[32]
Vinci, M.; Gowan, S.; Boxall, F.; Patterson, L.; Zimmermann, M.; Court, W.; Lomas, C.; Mendiola, M.; Hardisson, D.; Eccles, S.A. Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol., 2012, 10, 29.
[http://dx.doi.org/10.1186/1741-7007-10-29] [PMID: 22439642]
[33]
Kessel, S.; Cribbes, S.; Déry, O.; Kuksin, D.; Sincoff, E.; Qiu, J.; Chan, L.L. High-throughput 3D tumor spheroid screening method for cancer drug discovery using celigo image cytometry. SLAS Technol., 2017, 22(4), 454-465.
[http://dx.doi.org/10.1177/2211068216652846] [PMID: 27272155]
[34]
Shelper, T.B.; Lovitt, C.J.; Avery, V.M. Assessing drug efficacy in a miniaturized pancreatic cancer in vitro 3D cell culture model. Assay Drug Dev. Technol., 2016, 14(7), 367-380.
[http://dx.doi.org/10.1089/adt.2016.737] [PMID: 27552143]
[35]
Laporte, A.N.; Barrott, J.J.; Yao, R.J.; Poulin, N.M.; Brodin, B.A.; Jones, K.B.; Underhill, T.M.; Nielsen, T.O. HDAC and proteasome inhibitors synergize to activate pro-apoptotic factors in synovial sarcoma. PLoS One, 2017, 12(1), e0169407.
[http://dx.doi.org/10.1371/journal.pone.0169407] [PMID: 28056055]
[36]
Singh, S.K.; Clarke, I.D.; Terasaki, M.; Bonn, V.E.; Hawkins, C.; Squire, J.; Dirks, P.B. Identification of a cancer stem cell in human brain tumors. Cancer Res., 2003, 63(18), 5821-5828.
[PMID: 14522905]
[37]
(a)Fujii, H.; Honoki, K.; Tsujiuchi, T.; Kido, A.; Yoshitani, K.; Takakura, Y. Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int. J. Oncol., 2009, 34(5), 1381-1386.
[PMID: 19360350]
(b)Gibbs, C.P.; Kukekov, V.G.; Reith, J.D.; Tchigrinova, O.; Suslov, O.N.; Scott, E.W.; Ghivizzani, S.C.; Ignatova, T.N.; Steindler, D.A. Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia, 2005, 7(11), 967-976.
[http://dx.doi.org/10.1593/neo.05394] [PMID: 16331882]
[38]
Wahl, J.; Bogatyreva, L.; Boukamp, P.; Rojewski, M.; van Valen, F.; Fiedler, J.; Hipp, N.; Debatin, K.M.; Beltinger, C. Ewing’s sarcoma cells with CD57-associated increase of tumorigenicity and with neural crest-like differentiation capacity. Int. J. Cancer, 2010, 127(6), 1295-1307.
[http://dx.doi.org/10.1002/ijc.25163] [PMID: 20104521]
[39]
Liu, A.; Feng, B.; Gu, W.; Cheng, X.; Tong, T.; Zhang, H.; Hu, Y. The CD133+ subpopulation of the SW982 human synovial sarcoma cell line exhibits cancer stem-like characteristics. Int. J. Oncol., 2013, 42(4), 1399-1407.
[http://dx.doi.org/10.3892/ijo.2013.1826] [PMID: 23416969]
[40]
Salerno, M.; Avnet, S.; Bonuccelli, G.; Eramo, A.; De Maria, R.; Gambarotti, M.; Gamberi, G.; Baldini, N. Sphere-forming cell subsets with cancer stem cell properties in human musculoskeletal sarcomas. Int. J. Oncol., 2013, 43(1), 95-102.
[http://dx.doi.org/10.3892/ijo.2013.1927] [PMID: 23636271]
[41]
Aydemir, E.; Bayrak, O.F.; Sahin, F.; Atalay, B.; Kose, G.T.; Ozen, M.; Sevli, S.; Dalan, A.B.; Yalvac, M.E.; Dogruluk, T.; Türe, U. Characterization of cancer stem-like cells in chordoma. J. Neurosurg., 2012, 116(4), 810-820.
[http://dx.doi.org/10.3171/2011.12.JNS11430] [PMID: 22283189]
[42]
Bai, C.; Yang, M.; Fan, Z.; Li, S.; Gao, T.; Fang, Z. Associations of chemo- and radio-resistant phenotypes with the gap junction, adhesion and extracellular matrix in a three-dimensional culture model of soft sarcoma. J. Exp. Clin. Cancer Res., 2015, 34, 58.
[http://dx.doi.org/10.1186/s13046-015-0175-0] [PMID: 26055407]
[43]
Edmondson, R.; Broglie, J.J.; Adcock, A.F.; Yang, L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev. Technol., 2014, 12(4), 207-218.
[http://dx.doi.org/10.1089/adt.2014.573] [PMID: 24831787]
[44]
Fong, E.L.; Lamhamedi-Cherradi, S.E.; Burdett, E.; Ramamoorthy, V.; Lazar, A.J.; Kasper, F.K.; Farach-Carson, M.C.; Vishwamitra, D.; Demicco, E.G.; Menegaz, B.A.; Amin, H.M.; Mikos, A.G.; Ludwig, J.A. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. Proc. Natl. Acad. Sci. USA, 2013, 110(16), 6500-6505.
[http://dx.doi.org/10.1073/pnas.1221403110] [PMID: 23576741]
[45]
Monderer, D.; Luseau, A.; Bellec, A.; David, E.; Ponsolle, S.; Saiagh, S.; Bercegeay, S.; Piloquet, P.; Denis, M.G.; Lodé, L.; Rédini, F.; Biger, M.; Heymann, D.; Heymann, M.F.; Le Bot, R.; Gouin, F.; Blanchard, F. New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance. Lab. Invest., 2013, 93(10), 1100-1114.
[http://dx.doi.org/10.1038/labinvest.2013.101] [PMID: 23958880]
[46]
Gemoll, T.; Epping, F.; Heinrich, L.; Fritzsche, B.; Roblick, U.J.; Szymczak, S.; Hartwig, S.; Depping, R.; Bruch, H.P.; Thorns, C.; Lehr, S.; Paech, A.; Habermann, J.K. Increased cathepsin D protein expression is a biomarker for osteosarcomas, pulmonary metastases and other bone malignancies. Oncotarget, 2015, 6(18), 16517-16526.
[http://dx.doi.org/10.18632/oncotarget.4140] [PMID: 26203049]
[47]
Roy, M.; Finley, S.D. Metabolic reprogramming dynamics in tumor spheroids: Insights from a multicellular, multiscale model. PLOS Comput. Biol., 2019, 15(6), e1007053.
[http://dx.doi.org/10.1371/journal.pcbi.1007053] [PMID: 31185009]
[48]
Jimenez Valencia, A.M.; Wu, P.H.; Yogurtcu, O.N.; Rao, P.; DiGiacomo, J.; Godet, I.; He, L.; Lee, M.H.; Gilkes, D.; Sun, S.X.; Wirtz, D. Collective cancer cell invasion induced by coordinated contractile stresses. Oncotarget, 2015, 6(41), 43438-43451.
[http://dx.doi.org/10.18632/oncotarget.5874] [PMID: 26528856]
[49]
Xu, X.; Farach-Carson, M.C.; Jia, X. Three-dimensional in vitro tumor models for cancer research and drug evaluation. Biotechnol. Adv., 2014, 32(7), 1256-1268.
[http://dx.doi.org/10.1016/j.biotechadv.2014.07.009] [PMID: 25116894]
[50]
Lamhamedi-Cherradi, S.E.; Santoro, M.; Ramammoorthy, V.; Menegaz, B.A.; Bartholomeusz, G.; Iles, L.R.; Amin, H.M.; Livingston, J.A.; Mikos, A.G.; Ludwig, J.A. 3D tissue-engineered model of Ewing’s sarcoma. Adv. Drug Deliv. Rev., 2014, 79-80, 155-171.
[http://dx.doi.org/10.1016/j.addr.2014.07.012] [PMID: 25109853]
[51]
Gershovich, J.G.; Dahlin, R.L.; Kasper, F.K.; Mikos, A.G. Enhanced osteogenesis in cocultures with human mesenchymal stem cells and endothelial cells on polymeric microfiber scaffolds. Tissue Eng. Part A, 2013, 19(23-24), 2565-2576.
[http://dx.doi.org/10.1089/ten.tea.2013.0256] [PMID: 23799306]
[52]
Hirt, C.; Papadimitropoulos, A.; Mele, V.; Muraro, M.G.; Mengus, C.; Iezzi, G.; Terracciano, L.; Martin, I.; Spagnoli, G.C. “In vitro” 3D models of tumor-immune system interaction. Adv. Drug Deliv. Rev., 2014, 79-80, 145-154.
[http://dx.doi.org/10.1016/j.addr.2014.05.003] [PMID: 24819215]
[53]
Sutherland, R.M.; McCredie, J.A.; Inch, W.R. Growth of multicell spheroids in tissue culture as a model of nodular carcinomas. J. Natl. Cancer Inst., 1971, 46(1), 113-120.
[PMID: 5101993]
[54]
Lancaster, M.A.; Knoblich, J.A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science, 2014, 345(6194), 1247125.
[http://dx.doi.org/10.1126/science.1247125] [PMID: 25035496]
[55]
Brodin, B.A.; Wennerberg, K.; Lidbrink, E.; Brosjö, O.; Potdar, S.; Wilson, J.N.; Ma, L.; Moens, L.N.; Hesla, A.; Porovic, E.; Bernhardsson, E.; Papakonstantinou, A.; Bauer, H.; Tsagkozis, P.; von Sivers, K.; Wejde, J.; Östling, P.; Kallioniemi, O.; Stragliotto, C.L. Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas. Br. J. Cancer, 2019, 120(4), 435-443.
[http://dx.doi.org/10.1038/s41416-018-0359-4] [PMID: 30745580]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version378msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[18:48:54] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[18:48:55] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[18:48:55] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (95.83ms)time
  • Application (282ms)time
  • 1 x Application (74.64%)
    282ms
    1 x Booting (25.36%)
    95.83ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    41 statements were executed, 4 of which were duplicates, 37 unique. Show only duplicated206ms
    • 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 ('316575447','',1,1740422934,1740422934) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740422934
      940μsalphaeurekaselec_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 ('316575447','/article/102963/cn',1,1740422934,1740422934)
      140μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) 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 >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) 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 >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) 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 >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) 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 >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) 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 >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316575447 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316575447) limit 1
      16.93msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316575447
      • 1: 316575447
      • 2: 316575447
      • 3: 316575447
      • 4: 316575447
      • 5: 316575447
      • 6: 316575447
      • 7: 316575447
      • 8: 316575447
      • 9: 316575447
      • 10: 316575447
      • 11: 316575447
      • 12: 316575447
      • 13: 316575447
      • 14: 316575447
      • 15: 316575447
      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=102963
      790μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 25 limit 1
      800μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      1.46msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.33msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.62msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      3.78msalphaeurekaselec_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` = '102963'
      1.31msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 102963
      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` = '102963'
      2.7msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 102963
      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` = '102963' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.2msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 102963
      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
      240μsalphaeurekaselec_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
      430μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      41.02msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      43.16msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      36.86msalphaeurekaselec_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` = 102963 limit 1
      210μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 102963
      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 = 102963 and content_type = 'article' order by status desc limit 1
      310μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 16 and cd.sub_disease_id = 487 and content_id!=102963 and cd.content_type = 'article' order by rand() limit 20
      22.11msalphaeurekaselec_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` = 177400 limit 1
      250μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 177400
      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
      270μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      390μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '102963' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      430μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '9961' 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) )
      410μsalphaeurekaselec_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 = '2698' 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2698) 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2698) 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2698)
      4.6msalphaeurekaselec_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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9961) 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9961) 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9961)
      560μsalphaeurekaselec_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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 102963) 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 102963) 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 <= 316575447 and j.to_ip >=316575447 )) and ((j.from_date <= 1740422935 and j.to_date >= 1740422935 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 102963)
      540μsalphaeurekaselec_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` < '4778' and is_uploaded = 1 and issue_id = 9961 order by cast(first_page as SIGNED) desc limit 1
      530μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 4778
      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` > '4788' and is_uploaded = 1 and issue_id = 9961 order by cast(first_page as SIGNED) asc limit 1
      400μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 4788
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'cn'
      180μsalphaeurekaselec_live_10_06_2022ArticleController.php#2486
      Bindings
      • 0: cn
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2486
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 2
      170μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 2
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2487
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `multilanguage_article` where (`language_id` = 2 and `article_id` = 102963)
      5.57msalphaeurekaselec_live_10_06_2022ArticleController.php#2488
      Bindings
      • 0: 2
      • 1: 102963
      Backtrace
      • 15. app/Http/Controllers/ArticleController.php:2488
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `keyword` from `multilanguage_keywords` where (`language_id` = 2 and `article_id` = 102963)
      2.38msalphaeurekaselec_live_10_06_2022ArticleController.php#2489
      Bindings
      • 0: 2
      • 1: 102963
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2489
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT_WS(' ',au.last_name, ', ', ifnull(au.initials,''), ' ', au.first_name) as authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs , `au`.*, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `multilanguage_authors` as `au` left join `multilanguage_author_affiliation` as `af` on `au`.`id` = `af`.`author_id` where `au`.`article_id` = 102963 group by `au`.`id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.76msalphaeurekaselec_live_10_06_2022MultiLangAuthor.php#30
      Bindings
      • 0: 102963
      Backtrace
      • 13. app/Models/MultiLangAuthor.php:30
      • 14. app/Http/Controllers/ArticleController.php:2493
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `multilanguage_journal`.`title` from `multilanguage_journal` where `multilanguage_journal`.`journal_id` = 25 and `language_id` = 2
      200μsalphaeurekaselec_live_10_06_2022ArticleController.php#2495
      Bindings
      • 0: 25
      • 1: 2
      Backtrace
      • 13. app/Http/Controllers/ArticleController.php:2495
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `id` from `multilanguage_article` where `article_id` = 102963 limit 1
      2.33msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 102963
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740422935 and `b`.`banner_to_date` >= 1740422935 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.19msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740422935
      • 4: 1740422935
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740422935 and `b`.`banner_to_date` >= 1740422935 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.24msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740422935
      • 4: 1740422935
      • 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='e28da338de9bbaac5845b090f3502e69'
      240μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLangArticle
    2MultiLangArticle.php#?
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        2x0DNloW0x1y9ZyCf8SYMmfKq0dSSvys0otTxz7z
        uc_cart_id
        e28da338de9bbaac5845b090f3502e69
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/102963/cn" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/102963/cn
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array: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 => "Mon, 24 Feb 2025 18:48:55 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjZEYjZmMzVqMnFVcVhvbW84T0JHa2c9PSIsInZhbHVlIjoiYTAxOWNhRStLU1pGak9saGZ6Skk0ZVplOWFVb1FsSkpHaDBiTUx4ZEM1dXZOTURhVHlVNXVlQXNNMFJ4dFdnZnNsbXhsR3cwSUhjaEdtbUUzRHhwd3ZRSDZSY1FTbkVTYXl5YThieFJBRnR5YVdjc1A2UUtJb0l6R2VZOGtEcUQiLCJtYWMiOiJlZDRlNWMzNTBmNDc3MTAxYTdhNjY3MDMzM2I1NmM5MTU0NjkwNDg1ZjJiODA2NGM5ZDFkMjJjNWE3ODc0NDEwIiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 06:48:55 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjZEYjZmMzVqMnFVcVhvbW84T0JHa2c9PSIsInZhbHVlIjoiYTAxOWNhRStLU1pGak9saGZ6Skk0ZVplOWFVb1FsSkpHaDBiTUx4ZEM1dXZOTURhVHlVNXVlQXNNMFJ4dFdnZnNsbXhsR" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjZYdGh1bXFjZDRIV090aFNUa0lheHc9PSIsInZhbHVlIjoiMmEwVm45eEduSGovR3RWRkg4R1JLRDlBMDk1b00xZmxKeE5PRGtrOWJsS2RqOUlOSUZVczgvREVJT1IyeTNHZ2ttT1pDVzBaU1BhMVpSQU9GUnFZdVN1dWduWUZMZEhqYlJLK3JJNmZ2Qkw2MG1oaHpvNTFxVzVUL0p4eFVZSmQiLCJtYWMiOiIxNTE4OWQ5OGIwNmIwYzc1MDMzNGEwNDIxNDNmYzJjYTQzMTA2ODM5YzQwM2FjNzE0NWQ2YjlhZjIwNjExZGI3IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IjZYdGh1bXFjZDRIV090aFNUa0lheHc9PSIsInZhbHVlIjoiMmEwVm45eEduSGovR3RWRkg4R1JLRDlBMDk1b00xZmxKeE5PRGtrOWJsS2RqOUlOSUZVczgvREV" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjZEYjZmMzVqMnFVcVhvbW84T0JHa2c9PSIsInZhbHVlIjoiYTAxOWNhRStLU1pGak9saGZ6Skk0ZVplOWFVb1FsSkpHaDBiTUx4ZEM1dXZOTURhVHlVNXVlQXNNMFJ4dFdnZnNsbXhsR3cwSUhjaEdtbUUzRHhwd3ZRSDZSY1FTbkVTYXl5YThieFJBRnR5YVdjc1A2UUtJb0l6R2VZOGtEcUQiLCJtYWMiOiJlZDRlNWMzNTBmNDc3MTAxYTdhNjY3MDMzM2I1NmM5MTU0NjkwNDg1ZjJiODA2NGM5ZDFkMjJjNWE3ODc0NDEwIiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 06:48:55 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjZEYjZmMzVqMnFVcVhvbW84T0JHa2c9PSIsInZhbHVlIjoiYTAxOWNhRStLU1pGak9saGZ6Skk0ZVplOWFVb1FsSkpHaDBiTUx4ZEM1dXZOTURhVHlVNXVlQXNNMFJ4dFdnZnNsbXhsR" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjZYdGh1bXFjZDRIV090aFNUa0lheHc9PSIsInZhbHVlIjoiMmEwVm45eEduSGovR3RWRkg4R1JLRDlBMDk1b00xZmxKeE5PRGtrOWJsS2RqOUlOSUZVczgvREVJT1IyeTNHZ2ttT1pDVzBaU1BhMVpSQU9GUnFZdVN1dWduWUZMZEhqYlJLK3JJNmZ2Qkw2MG1oaHpvNTFxVzVUL0p4eFVZSmQiLCJtYWMiOiIxNTE4OWQ5OGIwNmIwYzc1MDMzNGEwNDIxNDNmYzJjYTQzMTA2ODM5YzQwM2FjNzE0NWQ2YjlhZjIwNjExZGI3IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IjZYdGh1bXFjZDRIV090aFNUa0lheHc9PSIsInZhbHVlIjoiMmEwVm45eEduSGovR3RWRkg4R1JLRDlBMDk1b00xZmxKeE5PRGtrOWJsS2RqOUlOSUZVczgvREV" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "2x0DNloW0x1y9ZyCf8SYMmfKq0dSSvys0otTxz7z" "uc_cart_id" => "e28da338de9bbaac5845b090f3502e69" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/102963/cn" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-24 18:48:55GET/article/102963/cn314413