Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Progress in Research on Tumor Metastasis Inhibitors

Author(s): Weiqi Xia and Chunqi Hu*

Volume 27, Issue 34, 2020

Page: [5758 - 5772] Pages: 15

DOI: 10.2174/0929867326666190927120847

Price: $65

Abstract

Tumor metastasis is a significant cause of malignant cancer-related death. Therefore, inhibiting tumor metastasis is an effective means of treating malignant tumors. Increasing our understanding of the molecular mechanisms that govern tumor metastasis can reveal new anti-cancer targets. This article will discuss the breakthroughs in this area and the corresponding recent developments in anti-cancer drug discovery.

Keywords: Metastasis, anti-cancer, drug discovery, tumor, malignant, molecular mechanism.

[1]
Mekhdjian, A.H.; Kai, F.; Rubashkin, M.G.; Prahl, L.S.; Przybyla, L.M.; McGregor, A.L.; Bell, E.S.; Barnes, J.M.; DuFort, C.C.; Ou, G.; Chang, A.C.; Cassereau, L.; Tan, S.J.; Pickup, M.W.; Lakins, J.N.; Ye, X.; Davidson, M.W.; Lammerding, J.; Odde, D.J.; Dunn, A.R.; Weaver, V.M. Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix. Mol. Biol. Cell, 2017, 28(11), 1467-1488.
[http://dx.doi.org/10.1091/mbc.e16-09-0654 ] [PMID: 28381423]
[2]
Ji, Y.; Li, J.; Li, P.; Wang, L.; Yang, H.; Jiang, G. C/EBPβ promotion of MMP3-dependent tumor cell invasion and association with metastasis in colorectal cancer. Genet. Test. Mol. Biomarkers, 2018, 22(1), 5-10.
[http://dx.doi.org/10.1089/gtmb.2017.0113 ] [PMID: 29172775]
[3]
Ma, Qixiang.Z.X.; Kaiwen, Hb. New thoughts upon seed and soil hypothesis of tumor metastasis. Dept. Oncol., 2015, 42(10), 1049-1053.
[4]
Vaupel, P. Metabolic microenvironment of tumor cells: a key factor in malignant progression. Exp. Oncol., 2010, 32(3), 125-127.
[PMID: 21403604]
[5]
Weber, C.E.; Kuo, P.C. The tumor microenvironment. Surg. Oncol., 2012, 21(3), 172-177.
[http://dx.doi.org/10.1016/j.suronc.2011.09.001 ] [PMID: 21963199]
[6]
Quail, D.F.; Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med., 2013, 19(11), 1423-1437.
[http://dx.doi.org/10.1038/nm.3394 ] [PMID: 24202395]
[7]
Zhang, Baihong.Y.H. Theories of cancer metastasis. Mod. Oncol. Med., 2015, 23(01), 128-130.
[8]
de la Mare, J.A.; Jurgens, T.; Edkins, A.L. Extracellular Hsp90 and TGFβ regulate adhesion, migration and anchorage independent growth in a paired colon cancer cell line model. BMC Cancer, 2017, 17(1), 202.
[http://dx.doi.org/10.1186/s12885-017-3190-z ] [PMID: 28302086]
[9]
Song, D.W.Y.; Wei, S.; Zhang, Y. Research progress in cancer stem cell theory and isolation and identification of cancer stem cells. Zhongguo Yaolixue Yu Dulixue Zazhi, 2012, 26(05), 674-679.
[10]
Kreso, A.; Dick, J.E. Evolution of the cancer stem cell model. Cell Stem Cell, 2014, 14(3), 275-291.
[http://dx.doi.org/10.1016/j.stem.2014.02.006 ] [PMID: 24607403]
[11]
Aceto, N.; Toner, M.; Maheswaran, S.; Haber, D.A. En route to metastasis: circulating tumor cell clusters and epithelial-to-mesenchymal transition. Trends Cancer, 2015, 1(1), 44-52.
[http://dx.doi.org/10.1016/j.trecan.2015.07.006 ] [PMID: 28741562]
[12]
Micalizzi, D.S.; Maheswaran, S.; Haber, D.A. A conduit to metastasis: circulating tumor cell biology. Genes Dev., 2017, 31(18), 1827-1840.
[http://dx.doi.org/10.1101/gad.305805.117 ] [PMID: 29051388]
[13]
Yan, Z.; Zhang, C.; Qu, L.; Shou, C. Progress in mechanism of tumor metastatic colonization. Cancer, 2013, 33(02), 202-206.
[http://dx.doi.org/10.3781/j.issn.1000-7431.2013.02.016 ]
[14]
Shibue, T.; Weinberg, R.A. Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin. Cancer Biol., 2011, 21(2), 99-106.
[http://dx.doi.org/10.1016/j.semcancer.2010.12.003 ] [PMID: 21145969]
[15]
Qi, Fei-Fei He, F-C.; Jiang, Y. Status and development trend on tumor metastasis. Progress in biochemistry and biophysics 2009, 36(10), 1244-1251.
[http://dx.doi.org/10.3724/SP.J.1206.2009.00157]
[16]
Chen, H.; Qu, J.L.; Gong, J.N. [Research progress on mechanisms of modern medicine in cancer metastasis Zhongguo Zhongyao Zazhi, 2014, 39(15), 2823-2828.
[PMID: 25423816]
[17]
Su, S.C.; Hsieh, M.J.; Yang, W.E.; Chung, W.H.; Reiter, R.J.; Yang, S.F. Cancer metastasis: Mechanisms of inhibition by melatonin. J. Pineal Res., 2017, 62(1)
[http://dx.doi.org/10.1111/jpi.12370 ] [PMID: 27706852]
[18]
Kim, K.J.; Kwon, S.H.; Yun, J.H.; Jeong, H.S.; Kim, H.R.; Lee, E.H.; Ye, S.K.; Cho, C.H. STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression. Oncogene, 2017, 36(39), 5445-5459.
[http://dx.doi.org/10.1038/onc.2017.148 ] [PMID: 28534515]
[19]
Jixiao, N. The role of cell adhesion molecules in tumor metastasis. J. China-Japan Frien. Hosp., 2006, (02), 110-112.
[20]
Notni, J.; Steiger, K.; Hoffmann, F.; Reich, D.; Kapp, T.G.; Rechenmacher, F.; Neubauer, S.; Kessler, H.; Wester, H.J. Complementary, selective PET imaging of integrin subtypes α5β1 and αvβ3 using 68Ga-aquibeprin and 68Ga-avebetrin. J. Nucl. Med., 2016, 57(3), 460-466.
[http://dx.doi.org/10.2967/jnumed.115.165720 ] [PMID: 26635338]
[21]
Li, Z.; Biswas, S.; Liang, B.; Zou, X.; Shan, L.; Li, Y.; Fang, R.; Niu, J. Integrin β6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma. Sci. Rep., 2016, 6, 30081.
[http://dx.doi.org/10.1038/srep30081 ] [PMID: 27440504]
[22]
Ruan, J.Y.L.; Lei, Z.; Li, T.; Yin, L. Drugs development in anti-tumor metastasis by targeting of integrins. World. Clin. Med. (Northfield Ill.), 2011, 32(10), 614-618.
[23]
Xu, H.; Tian, Y.; Yuan, X.; Wu, H.; Liu, Q.; Pestell, R.G.; Wu, K. The role of CD44 in epithelial-mesenchymal transition and cancer development. OncoTargets Ther., 2015, 8, 3783-3792.
[PMID: 26719706]
[24]
Neto, J.X.L. Energetic description of cilengitide bound to integrin. New J. Chem., 2017, 41(19), 11405-11412.
[http://dx.doi.org/10.1039/C7NJ02166F]
[25]
Zabala-Uncilla, N.; Miranda, J.I.; Laso, A.; Fernández, X.; Ganboa, J.I.; Palomo, C. Linear and cyclic depsipeptidomimetics with β-lactam cores: a class of new αv β3 integrin receptor inhibitors. ChemBioChem, 2017, 18(7), 654-665.
[http://dx.doi.org/10.1002/cbic.201600642 ] [PMID: 28140512]
[26]
Yang, Y.X.H.; Hu, J. Research progress of anti-tumor drugs targeting integrins. Pharm. Biotechnol., 2012, 19(03), 256-260.
[27]
Zou, Caiyan W.F. Integrins and targeted therapy of cancer therapy. Medical Review, 2008, (01), 60-62.
[28]
Chen, X.Y.C.; Xin, Z. Research progress in epithelial-mesenchymal transition and tumor metastasis. Chin. J. Otor.-laryn.-skull Base Surg, 2015, 21(04), 346-350.
[29]
Bruner, H.C.; Derksen, P.W.B. Loss of E-cadherin-dependent cell-cell adhesion and the development and progression of cancer. Cold Spring Harb. Perspect. Biol., 2018, 10(3), a029330.
[http://dx.doi.org/10.1101/cshperspect.a029330 ] [PMID: 28507022]
[30]
Tian, L.W.Y.; Ren, H. Regulation of E-cadherin in tumor metastasis. Chin. J. Lab. Anim., 2012, 20(03), 81-85.
[31]
Zeimet, A.G.; Reimer, D.; Huszar, M.; Winterhoff, B.; Puistola, U.; Azim, S.A.; Müller-Holzner, E.; Ben-Arie, A.; van Kempen, L.C.; Petru, E.; Jahn, S.; Geels, Y.P.; Massuger, L.F.; Amant, F.; Polterauer, S.; Lappi-Blanco, E.; Bulten, J.; Meuter, A.; Tanouye, S.; Oppelt, P.; Stroh-Weigert, M.; Reinthaller, A.; Mariani, A.; Hackl, W.; Netzer, M.; Schirmer, U.; Vergote, I.; Altevogt, P.; Marth, C.; Fogel, M. L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. J. Natl. Cancer Inst., 2013, 105(15), 1142-1150.
[http://dx.doi.org/10.1093/jnci/djt144 ] [PMID: 23781004]
[32]
Yu, X.; Yang, F.; Fu, D.L.; Jin, C. L1 cell adhesion molecule as a therapeutic target in cancer. Expert Rev. Anticancer Ther., 2016, 16(3), 359-371.
[http://dx.doi.org/10.1586/14737140.2016.1143363 ] [PMID: 26781307]
[33]
Doberstein, K.; Harter, P.N.; Haberkorn, U.; Bretz, N.P.; Arnold, B.; Carretero, R.; Moldenhauer, G.; Mittelbronn, M.; Altevogt, P. Antibody therapy to human L1CAM in a transgenic mouse model blocks local tumor growth but induces EMT. Int. J. Cancer, 2015, 136(5), E326-E339.
[http://dx.doi.org/10.1002/ijc.29222 ] [PMID: 25230579]
[34]
Binmadi, N.; Elsissi, A.; Elsissi, N. Expression of cell adhesion molecule CD44 in mucoepidermoid carcinoma and its association with the tumor behavior. Head Face Med., 2016, 12(1), 8.
[http://dx.doi.org/10.1186/s13005-016-0102-4 ] [PMID: 26821610]
[35]
Günthertand, U.; Hofmann, M.; Rudy, W.; Reber, S.; Zöller, M.; Haussmann, I.; Matzku, S.; Wenzel, A.; Ponta, H.; Herrlich, P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell, 1991, 65(1), 13-24.
[http://dx.doi.org/10.1016/0092-8674(91)90403-L ] [PMID: 1707342]
[36]
Jang, M.H.; Kang, H.J.; Jang, K.S.; Paik, S.S.; Kim, W.S. Clinicopathological analysis of CD44 and CD24 expression in invasive breast cancer. Oncol. Lett., 2016, 12(4), 2728-2733.
[http://dx.doi.org/10.3892/ol.2016.4987 ] [PMID: 27698848]
[37]
Mattheolabakis, G.; Milane, L.; Singh, A.; Amiji, M.M. Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine. J. Drug Target., 2015, 23(7-8), 605-618.
[http://dx.doi.org/10.3109/1061186X.2015.1052072 ] [PMID: 26453158]
[38]
Qiu, L.L.M.; Chen, D. Research progress of targeted delivery system for hyaluronic acid tumors. Yao Xue Xue Bao, 2013, 48(09), 1376-1382.
[PMID: 24358769]
[39]
Li, Z.; Takino, T.; Endo, Y.; Sato, H. Activation of MMP-9 by membrane type-1 MMP/MMP-2 axis stimulates tumor metastasis. Cancer Sci., 2017, 108(3), 347-353.
[http://dx.doi.org/10.1111/cas.13134 ] [PMID: 27987367]
[40]
Liming, D.L.Z. Relationship between matrix metalloproteinases and tumor metastasis. Sich. J. Physiol. Sci., 2014, 36(02), 80-82.
[41]
Zhang, X.; Yuan, Q.; Gao, X. Assessment of the MT1-MMP expression level of different cell lines by the naked eye. Sci. China Life Sci., 2018, 61(4), 492-500.
[http://dx.doi.org/10.1007/s11427-017-9261-9 ] [PMID: 29556904]
[42]
Wang, X.; Hu, Y.; Cui, J.; Zhou, Y.; Chen, L. Coordinated targeting of MMP-2/MMP-9 by miR-296-3p/FOXCUT exerts tumor-suppressing effects in choroidal malignant melanoma. Mol. Cell. Biochem., 2018, 445(1-2), 25-33.
[http://dx.doi.org/10.1007/s11010-017-3248-x ] [PMID: 29260433]
[43]
Blanco, M.J.; Rodríguez-Martín, I.; Learte, A.I.R.; Clemente, C.; Montalvo, M.G.; Seiki, M.; Arroyo, A.G.; Sánchez-Camacho, C. Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/Mmp17) in the mouse embryo. PLoS One, 2017, 12(9), e0184767.
[http://dx.doi.org/10.1371/journal.pone.0184767 ] [PMID: 28926609]
[44]
Gershtein, E.S.; Mushtenko, S.V.; Ermilova, V.D.; Levchenko, N.E.; Kushlinskii, N.E. Matrix metalloproteinases and their tissue inhibitors in blood serum of patients with endometrial cancer: clinical and morphological correlations. Bull. Exp. Biol. Med., 2018, 165(1), 75-79.
[http://dx.doi.org/10.1007/s10517-018-4103-0 ] [PMID: 29796809]
[45]
Zhong, Y.; Lu, Y.T.; Sun, Y.; Shi, Z.H.; Li, N.G.; Tang, Y.P.; Duan, J.A. Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer. Expert Opin. Drug Discov., 2018, 13(1), 75-87.
[http://dx.doi.org/10.1080/17460441.2018.1398732 ] [PMID: 29088927]
[46]
Mohan, V. Matrix metalloproteinase protein inhibitors: highlighting a new beginning for metalloproteinases in medicine. Metalloproteinases Med., 2016, 3, 31-47.
[http://dx.doi.org/10.2147/MNM.S65143]
[47]
Han, Y.X.J.; Hu, J.; Xu, H. Advances in clinical research of matrix metalloproteinase inhibitors as anticancer agents. Prog. Pharm., 2018, 42(02), 129-137.
[48]
Ragab, H. M. Expression of vascular endothelial growth factor protein in both serum samples and excised tumor tissues of breast carcinoma patients. Int. J. Can. Res., 2000, 12(3), 152-161.
[http://dx.doi.org/10.3923/ijcr.2016.152.161]
[49]
Frezzetti, D.; Gallo, M.; Maiello, M.R.; D’Alessio, A.; Esposito, C.; Chicchinelli, N.; Normanno, N.; De Luca, A. VEGF as a potential target in lung cancer. Expert Opin. Ther. Targets, 2017, 21(10), 959-966.
[http://dx.doi.org/10.1080/14728222.2017.1371137 ] [PMID: 28831824]
[50]
Mir, O.; Boudou-Rouquette, P.; Giroux, J.; Chapron, J.; Alexandre, J.; Gibault, L.; Ropert, S.; Coriat, R.; Durand, J.P.; Burgel, P.R.; Dusser, D.; Goldwasser, F. Pemetrexed, oxaliplatin and bevacizumab as first-line treatment in patients with stage IV non-small cell lung cancer. Lung Cancer, 2012, 77(1), 104-109.
[http://dx.doi.org/10.1016/j.lungcan.2012.01.014 ] [PMID: 22364783]
[51]
Koch, S.; Tugues, S.; Li, X.; Gualandi, L.; Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Biochem. J., 2011, 437(2), 169-183.
[http://dx.doi.org/10.1042/BJ20110301 ] [PMID: 21711246]
[52]
Goel, H.L.; Mercurio, A.M. VEGF targets the tumour cell. Nat. Rev. Cancer, 2013, 13(12), 871-882.
[http://dx.doi.org/10.1038/nrc3627 ] [PMID: 24263190]
[53]
Osaadon, P.; Fagan, X.J.; Lifshitz, T.; Levy, J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond.), 2014, 28(5), 510-520.
[http://dx.doi.org/10.1038/eye.2014.13 ] [PMID: 24525867]
[54]
Pożarowska, D.; Pożarowski, P. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy. Cent. Eur. J. Immunol., 2016, 41(3), 311-316.
[http://dx.doi.org/10.5114/ceji.2016.63132 ] [PMID: 27833450]
[55]
Chuan, Q.Z.C. Bevacizumab as the first-line chemotherapy in the treatment for non-small cell lung cancer. J. Oncol., 2011, 17(04), 294-297.
[56]
Tabernero, J.; Yoshino, T.; Cohn, A.L.; Obermannova, R.; Bodoky, G.; Garcia-Carbonero, R.; Ciuleanu, T.E.; Portnoy, D.C.; Van Cutsem, E.; Grothey, A.; Prausová, J.; Garcia-Alfonso, P.; Yamazaki, K.; Clingan, P.R.; Lonardi, S.; Kim, T.W.; Simms, L.; Chang, S.C.; Nasroulah, F.; Investigators, R.S. RAISE study investigators Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol., 2015, 16(5), 499-508.
[http://dx.doi.org/10.1016/S1470-2045(15)70127-0 ] [PMID: 25877855]
[57]
Lin, G.; Sun, X.J.; Han, Q.B.; Wang, Z.; Xu, Y.P.; Gu, J.L.; Wu, W.; Zhang, G.U.; Hu, J.L.; Sun, W.Y.; Mao, W.M. Epidermal growth factor receptor protein overexpression and gene amplification are associated with aggressive biological behaviors of esophageal squamous cell carcinoma. Oncol. Lett., 2015, 10(2), 901-906.
[http://dx.doi.org/10.3892/ol.2015.3277 ] [PMID: 26622592]
[58]
Jing, Y.Z.X.; Xiang, Z. New research progresses of small molecule epidermal growth factor receptor inhibitors. Zhon. Xin Yao Zazhi, 2017, 26(17), 2026-2033.
[59]
Tsigelny, I.F.; Wheler, J.J.; Greenberg, J.P.; Kouznetsova, V.L.; Stewart, D.J.; Bazhenova, L.; Kurzrock, R. Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer. Oncotarget, 2015, 6(8), 6029-6039.
[http://dx.doi.org/10.18632/oncotarget.3472 ] [PMID: 25760241]
[60]
Keedy, V.L.; Temin, S.; Somerfield, M.R.; Beasley, M.B.; Johnson, D.H.; McShane, L.M.; Milton, D.T.; Strawn, J.R.; Wakelee, H.A.; Giaccone, G. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J. Clin. Oncol., 2011, 29(15), 2121-2127.
[http://dx.doi.org/10.1200/JCO.2010.31.8923 ] [PMID: 21482992]
[61]
Kim, Y.; Ko, J.; Cui, Z.; Abolhoda, A.; Ahn, J.S.; Ou, S.H.; Ahn, M.J.; Park, K. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol. Cancer Ther., 2012, 11(3), 784-791.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0750 ] [PMID: 22228822]
[62]
Miller, V.A.; Hirsh, V.; Cadranel, J.; Chen, Y.M.; Park, K.; Kim, S.W.; Zhou, C.; Su, W.C.; Wang, M.; Sun, Y.; Heo, D.S.; Crino, L.; Tan, E.H.; Chao, T.Y.; Shahidi, M.; Cong, X.J.; Lorence, R.M.; Yang, J.C. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol., 2012, 13(5), 528-538.
[http://dx.doi.org/10.1016/S1470-2045(12)70087-6 ] [PMID: 22452896]
[63]
Hu, C.; Dong, X. Cysteine-targeted irreversible inhibitors of tyrosine kinases and key interactions. Curr. Med. Chem., 2019, 26(31), 5811-5824.
[http://dx.doi.org/10.2174/0929867325666180713124223 ] [PMID: 30009703]
[64]
Wu, Y.L.; Zhou, C.; Hu, C.P.; Feng, J.; Lu, S.; Huang, Y.; Li, W.; Hou, M.; Shi, J.H.; Lee, K.Y.; Xu, C.R.; Massey, D.; Kim, M.; Shi, Y.; Geater, S.L. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol., 2014, 15(2), 213-222.
[http://dx.doi.org/10.1016/S1470-2045(13)70604-1 ] [PMID: 24439929]
[65]
Bang, Y.J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; Aprile, G.; Kulikov, E.; Hill, J.; Lehle, M.; Rüschoff, J.; Kang, Y.K. ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742), 687-697.
[http://dx.doi.org/10.1016/S0140-6736(10)61121-X ] [PMID: 20728210]
[66]
Xu, X.; Zheng, L.; Yuan, Q.; Zhen, G.; Crane, J.L.; Zhou, X.; Cao, X. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res., 2018, 6, 2.
[http://dx.doi.org/10.1038/s41413-017-0005-4 ] [PMID: 29423331]
[67]
Shi, Q.; Chen, Y.G. Interplay between TGF-β signaling and receptor tyrosine kinases in tumor development. Sci. China Life Sci., 2017, 60(10), 1133-1141.
[http://dx.doi.org/10.1007/s11427-017-9173-5 ] [PMID: 29067649]
[68]
Wendt, M.K.; Tian, M.; Schiemann, W.P. Deconstructing the mechanisms and consequences of TGF-β-induced EMT during cancer progression. Cell Tissue Res., 2012, 347(1), 85-101.
[http://dx.doi.org/10.1007/s00441-011-1199-1 ] [PMID: 21691718]
[69]
Yang, X.G.F.; Ren, L.; Yi, Z.; Xin, W. Expression and clinical significance of TGF-β2 and TGFβRII in the vulvar squamous cell carcinoma. Advances in Modern Biomedicine, 2016, 16(19), 3751-3754.
[70]
Ding, M.J.; Su, K.E.; Cui, G.Z.; Yang, W.H.; Chen, L.; Yang, M.; Liu, Y.Q.; Dai, D.L. Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer. Oncol. Lett., 2016, 11(6), 4040-4044.
[http://dx.doi.org/10.3892/ol.2016.4497 ] [PMID: 27313737]
[71]
Guo, B.Q. TGF β1 upregulates the expression of MACC1 to promote invasion and metastasis of ovarian cancer. Int. J. Clin. Exp. Med., 2016, 9, 12629-12638.
[72]
Watanabe-Takano, H.; Takano, K.; Hatano, M.; Tokuhisa, T.; Endo, T. DA-raf-mediated suppression of the Ras--ERK pathway is essential for TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial type 2 cells. PLoS One, 2015, 10(5), e0127888.
[http://dx.doi.org/10.1371/journal.pone.0127888 ] [PMID: 25996975]
[73]
Li, X.Z.J.; Zhang, K. a TGF-β receptor (TβR)-I inhibitor, suppresses growth and invasion of an anaplastic thyroid cancer 8505C cell in vitro and in vivo. Int. J. Clin. Exp. Pathol., 2016, 9(7), 7050-7059.
[74]
Van De Water, L.; Varney, S.; Tomasek, J.J. Mechanoregulation of the myofibroblast in wound contraction, scarring, and fibrosis: opportunities for new therapeutic intervention. Adv. Wound Care (New Rochelle), 2013, 2(4), 122-141.
[http://dx.doi.org/10.1089/wound.2012.0393 ] [PMID: 24527336]
[75]
Neuzillet, C.; Tijeras-Raballand, A.; Cohen, R.; Cros, J.; Faivre, S.; Raymond, E.; de Gramont, A. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther., 2015, 147, 22-31.
[http://dx.doi.org/10.1016/j.pharmthera.2014.11.001 ] [PMID: 25444759]
[76]
Pedoeem, A.; Azoulay-Alfaguter, I.; Strazza, M.; Silverman, G.J.; Mor, A. Programmed death-1 pathway in cancer and autoimmunity. Clin. Immunol., 2014, 153(1), 145-152.
[http://dx.doi.org/10.1016/j.clim.2014.04.010 ] [PMID: 24780173]
[77]
D’Incecco, A.; Andreozzi, M.; Ludovini, V.; Rossi, E.; Capodanno, A.; Landi, L.; Tibaldi, C.; Minuti, G.; Salvini, J.; Coppi, E.; Chella, A.; Fontanini, G.; Filice, M.E.; Tornillo, L.; Incensati, R.M.; Sani, S.; Crinò, L.; Terracciano, L.; Cappuzzo, F. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br. J. Cancer, 2015, 112(1), 95-102.
[http://dx.doi.org/10.1038/bjc.2014.555 ] [PMID: 25349974]
[78]
Kamamoto, D.; Ohara, K.; Kitamura, Y.; Yoshida, K.; Kawakami, Y.; Sasaki, H. Association between programmed cell death ligand-1 expression and extracranial metastasis in intracranial solitary fibrous tumor/hemangiopericytoma. J. Neurooncol., 2018, 139(2), 251-259.
[http://dx.doi.org/10.1007/s11060-018-2876-7 ] [PMID: 29675794]
[79]
Goldberg, S.B.; Gettinger, S.N.; Mahajan, A.; Chiang, A.C.; Herbst, R.S.; Sznol, M.; Tsiouris, A.J.; Cohen, J.; Vortmeyer, A.; Jilaveanu, L.; Yu, J.; Hegde, U.; Speaker, S.; Madura, M.; Ralabate, A.; Rivera, A.; Rowen, E.; Gerrish, H.; Yao, X.; Chiang, V.; Kluger, H.M. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol., 2016, 17(7), 976-983.
[http://dx.doi.org/10.1016/S1470-2045(16)30053-5 ] [PMID: 27267608]
[80]
de Greef, R.; Elassaiss-Schaap, J.; Chatterjee, M.; Turner, D.C.; Ahamadi, M.; Forman, M.; Cutler, D.; de Alwis, D.P.; Kondic, A.; Stone, J. Pembrolizumab: role of modeling and simulation in bringing a novel immunotherapy to patients with melanoma. CPT Pharmacometrics Syst. Pharmacol., 2017, 6(1), 5-7.
[http://dx.doi.org/10.1002/psp4.12131 ] [PMID: 27653180]
[81]
Longoria, T.C.; Tewari, K.S. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin. Drug Metab. Toxicol., 2016, 12(10), 1247-1253.
[http://dx.doi.org/10.1080/17425255.2016.1216976 ] [PMID: 27485741]
[82]
Specenier, P. Nivolumab in melanoma. Expert Rev. Anticancer Ther., 2016, 16(12), 1247-1261.
[http://dx.doi.org/10.1080/14737140.2016.1249856 ] [PMID: 27776441]
[83]
Tan, S.; Zhang, H.; Chai, Y.; Song, H.; Tong, Z.; Wang, Q.; Qi, J.; Wong, G.; Zhu, X.; Liu, W.J.; Gao, S.; Wang, Z.; Shi, Y.; Yang, F.; Gao, G.F.; Yan, J. An unexpected N-terminal loop in PD-1 dominates binding by nivolumab. Nat. Commun., 2017, 8, 14369.
[http://dx.doi.org/10.1038/ncomms14369 ] [PMID: 28165004]
[84]
Kahle, M.P.C.B.D. MEKK2: A potential target for cancer cell migration and metastasis. Cancer Cell Microenviron., 2014, 1, 114-119.
[85]
Koul, H.K.; Pal, M.; Koul, S.; Koul, S. Role of p38 MAP kinase signal transduction in solid tumors. Genes Cancer, 2013, 4(9-10), 342-359.
[http://dx.doi.org/10.1177/1947601913507951 ] [PMID: 24349632]
[86]
Grilley-Olson, J.E.; Bedard, P.L.; Fasolo, A.; Cornfeld, M.; Cartee, L.; Razak, A.R.; Stayner, L.A.; Wu, Y.; Greenwood, R.; Singh, R.; Lee, C.B.; Bendell, J.; Burris, H.A.; Del Conte, G.; Sessa, C.; Infante, J.R. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. Invest. New Drugs, 2016, 34(6), 740-749.
[http://dx.doi.org/10.1007/s10637-016-0377-0 ] [PMID: 27450049]
[87]
Long, G.V.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; de Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; Grob, J.J.; Chiarion-Sileni, V.; Lebbe, C.; Mandalà, M.; Millward, M.; Arance, A.; Bondarenko, I.; Haanen, J.B.; Hansson, J.; Utikal, J.; Ferraresi, V.; Kovalenko, N.; Mohr, P.; Probachai, V.; Schadendorf, D.; Nathan, P.; Robert, C.; Ribas, A.; DeMarini, D.J.; Irani, J.G.; Swann, S.; Legos, J.J.; Jin, F.; Mookerjee, B.; Flaherty, K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet, 2015, 386(9992), 444-451.
[http://dx.doi.org/10.1016/S0140-6736(15)60898-4 ] [PMID: 26037941]
[88]
Goubran, H.A.; Kotb, R.R.; Stakiw, J.; Emara, M.E.; Burnouf, T. Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis, 2014, 7, 9-18.
[http://dx.doi.org/10.4137/CGM.S11285 ] [PMID: 24926201]
[89]
Wood, S.L.; Pernemalm, M.; Crosbie, P.A.; Whetton, A.D. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat. Rev., 2014, 40(4), 558-566.
[http://dx.doi.org/10.1016/j.ctrv.2013.10.001 ] [PMID: 24176790]
[90]
Guan, X. Cancer metastases: challenges and opportunities. Acta Pharm. Sin. B, 2015, 5(5), 402-418.
[http://dx.doi.org/10.1016/j.apsb.2015.07.005 ] [PMID: 26579471]
[91]
Fang, H.; Declerck, Y.A. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res., 2013, 73(16), 4965-4977.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0661 ] [PMID: 23913938]
[92]
Profumo, V.; Gandellini, P. MicroRNAs: Cobblestones on the road to cancer metastasis. Crit. Rev. Oncog., 2013, 18(4), 341-355.
[http://dx.doi.org/10.1615/critrevoncog.2013007182 ] [PMID: 23614620]
[93]
Calin, G.A.; Dumitru, C.D.; Shimizu, M.; Bichi, R.; Zupo, S.; Noch, E.; Aldler, H.; Rattan, S.; Keating, M.; Rai, K.; Rassenti, L.; Kipps, T.; Negrini, M.; Bullrich, F.; Croce, C.M. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15524-15529.
[http://dx.doi.org/10.1073/pnas.242606799 ] [PMID: 12434020]
[94]
Han, C.; Yu, Z.; Duan, Z.; Kan, Q. Role of microRNA-1 in human cancer and its therapeutic potentials. BioMed Res. Int., 2014, 2014, 428371.
[http://dx.doi.org/10.1155/2014/428371 ] [PMID: 24949449]
[95]
Burk, U.; Schubert, J.; Wellner, U.; Schmalhofer, O.; Vincan, E.; Spaderna, S.; Brabletz, T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep., 2008, 9(6), 582-589.
[http://dx.doi.org/10.1038/embor.2008.74 ] [PMID: 18483486]
[96]
Fujii, T.; Reuben, J.M.; Huo, L.; Espinosa Fernandez, J.R.; Gong, Y.; Krupa, R.; Suraneni, M.V.; Graf, R.P.; Lee, J.; Greene, S.; Rodriguez, A.; Dugan, L.; Louw, J.; Lim, B.; Barcenas, C.H.; Marx, A.N.; Tripathy, D.; Wang, Y.; Landers, M.; Dittamore, R.; Ueno, N.T. Androgen receptor expression on circulating tumor cells in metastatic breast cancer. PLoS One, 2017, 12(9), e0185231.
[http://dx.doi.org/10.1371/journal.pone.0185231 ] [PMID: 28957377]
[97]
Kim, C.; Lee, J.; Lee, W.; Kim, A. Changes in intrinsic subtype of breast cancer during tumor progression in the same patient. Int. J. Clin. Exp. Pathol., 2015, 8(11), 15184-15190.
[PMID: 26823864]
[98]
Feng, L.W.H.; Li, C.; Hui, L.; Ting, W.; Peng, N.; Qian, H.; Zhan, Q. Effects of esophageal cancer cell-derived exosomes on cancer cell migration and invasion and its mechanism research. Med. J. Chin. P. Lib. Army, 2017, 42(4), 307-313.
[http://dx.doi.org/10.11855/j.issn.0577-7402.2017.04.07 ]
[99]
Franzen, C.A.; Blackwell, R.H.; Todorovic, V.; Greco, K.A.; Foreman, K.E.; Flanigan, R.C.; Kuo, P.C.; Gupta, G.N. Urothelial cells undergo epithelial-to-mesenchymal transition after exposure to muscle invasive bladder cancer exosomes. Oncogenesis, 2015, 4(8), e163.
[http://dx.doi.org/10.1038/oncsis.2015.21 ] [PMID: 26280654]
[100]
Chen, L.; Guo, P.; He, Y.; Chen, Z.; Chen, L.; Luo, Y.; Qi, L.; Liu, Y.; Wu, Q.; Cui, Y.; Fang, F.; Zhang, X.; Song, T.; Guo, H. HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway. Cell Death Dis., 2018, 9(5), 513.
[http://dx.doi.org/10.1038/s41419-018-0534-9 ] [PMID: 29725020]
[101]
Wang, C.Y.M.; Wang, H.; Li, X.; Yang, C.; Shi, F.; Zhan, X.; Zhang, W. Lü, Y.; Wang, W. Exploration of the 20-year medication rule of traditional Chinese medicine applied to tumor metastasis Global. Zhong Yi Xue, 2014, 7(02), 113-116.
[102]
Chen, Y.W.J. Advances in molecular mechanisms of anti-tumor metastasis of traditional Chinese medicine. Shaanxi. Zhong Yi Xue, 2010, 31(06), 762-764.
[103]
Liu, X.; Rui-qin, L. Traditional Chinese medicine combination resistant to tumor metastasis. CN 105012845A 2015.
[104]
Wang, Y. Drug for preventing and treating tumors and preparation method thereof. CN 107375841A 2017.
[105]
Wan, L.; Pantel, K.; Kang, Y. Tumor metastasis: moving new biological insights into the clinic. Nat. Med., 2013, 19(11), 1450-1464.
[http://dx.doi.org/10.1038/nm.3391 ] [PMID: 24202397]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version610msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[13:37:57] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[13:37:58] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[13:37:58] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (124ms)time
  • Application (486ms)time
  • 1 x Application (79.65%)
    486ms
    1 x Booting (20.35%)
    124ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated400ms
    • 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 ('309679543','',1,1739972277,1739972277) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739972277
      990μsalphaeurekaselec_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 ('309679543','/article/101062',1,1739972277,1739972277)
      190μsalphaeurekaselec_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 >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) 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 >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) 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 >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) 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 >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) 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 >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) 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 >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 309679543 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309679543) limit 1
      19.05msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 309679543
      • 1: 309679543
      • 2: 309679543
      • 3: 309679543
      • 4: 309679543
      • 5: 309679543
      • 6: 309679543
      • 7: 309679543
      • 8: 309679543
      • 9: 309679543
      • 10: 309679543
      • 11: 309679543
      • 12: 309679543
      • 13: 309679543
      • 14: 309679543
      • 15: 309679543
      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=101062
      1.05msalphaeurekaselec_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
      1.2msalphaeurekaselec_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`
      2.24msalphaeurekaselec_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
      1.92msalphaeurekaselec_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`
      76.73msalphaeurekaselec_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
      3.19msalphaeurekaselec_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` = '101062'
      340μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 101062
      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` = '101062'
      3.39msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 101062
      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` = '101062' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.73msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 101062
      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
      210μsalphaeurekaselec_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
      460μsalphaeurekaselec_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
      32.67msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      37.23msalphaeurekaselec_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
      30.34msalphaeurekaselec_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` = 101062 limit 1
      220μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 101062
      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 = 101062 and content_type = 'article' order by status desc limit 1
      250μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 16 and cd.sub_disease_id = 298 and content_id!=101062 and cd.content_type = 'article' order by rand() limit 20
      167msalphaeurekaselec_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` = 175180 limit 1
      330μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 175180
      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
      320μsalphaeurekaselec_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
      580μsalphaeurekaselec_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 = '101062' 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) )
      520μsalphaeurekaselec_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 = '10041' 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 = '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) )
      340μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 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)
      8msalphaeurekaselec_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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10041) 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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10041) 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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10041)
      880μsalphaeurekaselec_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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 101062) 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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 101062) 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 <= 309679543 and j.to_ip >=309679543 )) and ((j.from_date <= 1739972278 and j.to_date >= 1739972278 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 101062)
      840μsalphaeurekaselec_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` < '5758' and is_uploaded = 1 and issue_id = 10041 order by cast(first_page as SIGNED) desc limit 1
      670μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 5758
      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` > '5772' and is_uploaded = 1 and issue_id = 10041 order by cast(first_page as SIGNED) asc limit 1
      650μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 5772
      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'
      240μsalphaeurekaselec_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
      300μsalphaeurekaselec_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` = 101062 limit 1
      2.44msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 101062
      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` <= 1739972278 and `b`.`banner_to_date` >= 1739972278 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.14msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1739972278
      • 4: 1739972278
      • 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` <= 1739972278 and `b`.`banner_to_date` >= 1739972278 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.59msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1739972278
      • 4: 1739972278
      • 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='49d3387b373e4400141e07d7fde0c8ed'
      260μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
        _token
        8f2Zbc2bum7f3oblMyrzRUO1KWsclf4MuT2u36Xc
        uc_cart_id
        49d3387b373e4400141e07d7fde0c8ed
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/101062" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/101062
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IkRIY1FMUVhMYUxLekRjNUc5V3pTcUE9PSIsInZhbHVlIjoiKzh5QUdONWcvQWN4aFYwbUV4OEV3WE9CeUc0VkVOdmFjbm9Yc0FtYVYvOD0iLCJtYWMiOiIxZjdhYTZlOWYxNDhiMzM3ZDcxMDZkNjAyMWY5ZmUzN2RjYzEzZmM1MWMyY2Y5ZGJiMDE0MDRlZjcxZGUzY2RmIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IkRIY1FMUVhMYUxLekRjNUc5V3pTcUE9PSIsInZhbHVlIjoiKzh5QUdONWcvQWN4aFYwbUV4OEV3WE9CeUc0VkVOdmFjbm9Yc0FtYVYvOD0iLCJtYWMiOiIxZjdhYTZlOWYxNDhi" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Wed, 19 Feb 2025 13:37:58 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlNlT0t4Y1p6NjBhWkJucTVIL3dxeFE9PSIsInZhbHVlIjoiZnRXV1Q5MHZXcjhFcyttK1krUGtQSnFWdGdhRDB0RXZ0M25ETENsRmVKbXlOMDgwSk9Jc1JQOTEwdi91NkZSNDF5cFNMT0V5aHNKcWp1cjNxODIxTjgvNUtJY1U2TW9sSnB3S1N6TllvWjJPYkdLdzdsTmVaNUw2S1ZSZXZ0K0EiLCJtYWMiOiI3NTJiNDQ4YjIxOGNhNGNlZWNhMWU3Y2U4MDYxZmNjZTgzMzA5NTNkNmYyMTlhZTNiMmViNzRiZjM0ZDFhMDJiIiwidGFnIjoiIn0%3D; expires=Sat, 22 Feb 2025 01:37:58 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IlNlT0t4Y1p6NjBhWkJucTVIL3dxeFE9PSIsInZhbHVlIjoiZnRXV1Q5MHZXcjhFcyttK1krUGtQSnFWdGdhRDB0RXZ0M25ETENsRmVKbXlOMDgwSk9Jc1JQOTEwdi91NkZSNDF5cFNMT" 1 => "alphaeurekaselectnet_session=eyJpdiI6InhWM1p6NlR6S0pFWWdWTlBQTGtWckE9PSIsInZhbHVlIjoiWUdIcmJRTG5TVUx2VXNDZFd1VEd4Q09FcGFvdHBySy9WVUdLOTM4SklvUGZ2dFFXVUFoOS8rcVNkU2E3OVYwSnovYmpnbm5rT3NQb1ljUDhLUXRMVUJSWUU2Q0p4ZEhYYWFDSy9OQTJQRXp3Q2M3TmhkTjk0cDZQSlUvbE9FUzAiLCJtYWMiOiI3N2VkZTZlMTg2MWJkNGY2MDEwMTI4YWYwNjQzMjIzZjk4ODg0Yzc3NmMzZTMyNDViM2QyYWI2ZmQ1OGFjZDk1IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InhWM1p6NlR6S0pFWWdWTlBQTGtWckE9PSIsInZhbHVlIjoiWUdIcmJRTG5TVUx2VXNDZFd1VEd4Q09FcGFvdHBySy9WVUdLOTM4SklvUGZ2dFFXVUFoOS8rcVN" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlNlT0t4Y1p6NjBhWkJucTVIL3dxeFE9PSIsInZhbHVlIjoiZnRXV1Q5MHZXcjhFcyttK1krUGtQSnFWdGdhRDB0RXZ0M25ETENsRmVKbXlOMDgwSk9Jc1JQOTEwdi91NkZSNDF5cFNMT0V5aHNKcWp1cjNxODIxTjgvNUtJY1U2TW9sSnB3S1N6TllvWjJPYkdLdzdsTmVaNUw2S1ZSZXZ0K0EiLCJtYWMiOiI3NTJiNDQ4YjIxOGNhNGNlZWNhMWU3Y2U4MDYxZmNjZTgzMzA5NTNkNmYyMTlhZTNiMmViNzRiZjM0ZDFhMDJiIiwidGFnIjoiIn0%3D; expires=Sat, 22-Feb-2025 01:37:58 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IlNlT0t4Y1p6NjBhWkJucTVIL3dxeFE9PSIsInZhbHVlIjoiZnRXV1Q5MHZXcjhFcyttK1krUGtQSnFWdGdhRDB0RXZ0M25ETENsRmVKbXlOMDgwSk9Jc1JQOTEwdi91NkZSNDF5cFNMT" 1 => "alphaeurekaselectnet_session=eyJpdiI6InhWM1p6NlR6S0pFWWdWTlBQTGtWckE9PSIsInZhbHVlIjoiWUdIcmJRTG5TVUx2VXNDZFd1VEd4Q09FcGFvdHBySy9WVUdLOTM4SklvUGZ2dFFXVUFoOS8rcVNkU2E3OVYwSnovYmpnbm5rT3NQb1ljUDhLUXRMVUJSWUU2Q0p4ZEhYYWFDSy9OQTJQRXp3Q2M3TmhkTjk0cDZQSlUvbE9FUzAiLCJtYWMiOiI3N2VkZTZlMTg2MWJkNGY2MDEwMTI4YWYwNjQzMjIzZjk4ODg0Yzc3NmMzZTMyNDViM2QyYWI2ZmQ1OGFjZDk1IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InhWM1p6NlR6S0pFWWdWTlBQTGtWckE9PSIsInZhbHVlIjoiWUdIcmJRTG5TVUx2VXNDZFd1VEd4Q09FcGFvdHBySy9WVUdLOTM4SklvUGZ2dFFXVUFoOS8rcVN" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "8f2Zbc2bum7f3oblMyrzRUO1KWsclf4MuT2u36Xc" "uc_cart_id" => "49d3387b373e4400141e07d7fde0c8ed" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/101062" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-19 13:37:58GET/article/101062314372