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Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Mini-Review Article

Potential Alternatives to Conventional Cancer Therapeutic Approaches: The Way Forward

Author(s): Muddasarul Hoda*

Volume 22, Issue 9, 2021

Published on: 16 October, 2020

Page: [1141 - 1148] Pages: 8

DOI: 10.2174/1389201021666201016142408

Price: $65

Abstract

Conventional cancer therapeutic approaches broadly include chemotherapy, radiation therapy and surgery. These established approaches have evolved over several decades of clinical experience. For a complex disease like cancer, satisfactory treatment remains an enigma for the simple fact that the causal factors for cancer are extremely diverse. In order to overcome existing therapeutic limitations, consistent scientific endeavors have evolved several potential therapeutic approaches, majority of which focuses essentially on targeted drug delivery, minimal concomitant ramification, and selective high cytotoxicity. The current review focuses on highlighting some of these potential alternatives that are currently in various stages of in vitro, in vivo, and clinical trials. These include physical, chemical and biological entities that are avidly being explored for therapeutic alternatives. Some of these entities include suicide gene, micro RNA, modulatory peptides, ultrasonic waves, free radicals, nanoparticles, phytochemicals, and gene knockout, and stem cells. Each of these techniques may be exploited exclusively and in combination with conventional therapeutic approaches thereby enhancing the therapeutic efficacy of the treatment. The review intends to briefly discuss the mechanism of action, pros, and cons of potential alternatives to conventional therapeutic approaches.

Keywords: Cancer therapeutic technique, transcriptional modulation, oncolytic viruses, photodynamic therapy, nanomedicine, suicide gene.

Graphical Abstract

[1]
Deurloo, E.E.; Smets, A.M.J.B. Complications of therapy. Imag. Pediatr. Oncol., 2019, 197-221.
[http://dx.doi.org/10.1007/978-3-030-03777-2_11]
[2]
Baumann, B.C.; Sargos, P.; Eapen, L.J.; Efstathiou, J.A.; Choudhury, A.; Bahl, A.; Murthy, V.; Ballas, L.K.; Fonteyne, V.; Richaud, P.M.; Zaghloul, M.S.; Christodouleas, J.P. The rationale for post-operative radiation in localized bladder cancer. Bl. Cancer, 2017, 3(1), 19-30.
[http://dx.doi.org/10.3233/BLC-160081] [PMID: 28149931]
[3]
Bae, Y.H.; Mrsny, R.J.; Park, K. Cancer Targeted Drug Delivery; Springer New York: New York, NY, 2013.
[http://dx.doi.org/10.1007/978-1-4614-7876-8]
[4]
Duarte, S.; Carle, G.; Faneca, H.; de Lima, M.C.P.; Pierrefite-Carle, V. Suicide gene therapy in cancer: Where do we stand now? Cancer Lett., 2012, 324(2), 160-170.
[http://dx.doi.org/10.1016/j.canlet.2012.05.023] [PMID: 22634584]
[5]
Dai, M.; Liu, J.; Chen, D-E.; Rao, Y.; Tang, Z-J.; Ho, W-Z.; Dong, C-Y. Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice. Cancer Gene Ther., 2012, 19(2), 77-83.
[http://dx.doi.org/10.1038/cgt.2011.65] [PMID: 21959967]
[6]
Xu, Y.; Liu, Z.; Kong, H.; Sun, W.; Liao, Z.; Zhou, F.; Xie, C.; Zhou, Y. Co-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse model. Biochem. Biophys. Res. Commun., 2011, 412(4), 763-768.
[http://dx.doi.org/10.1016/j.bbrc.2011.08.077] [PMID: 21875574]
[7]
Philip, B.; Kokalaki, E.; Mekkaoui, L.; Thomas, S.; Straathof, K.; Flutter, B.; Marin, V.; Marafioti, T.; Chakraverty, R.; Linch, D.; Quezada, S.A.; Peggs, K.S.; Pule, M. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood, 2014, 124(8), 1277-1287.
[http://dx.doi.org/10.1182/blood-2014-01-545020] [PMID: 24970931]
[8]
Glybochko, P.V.; Amosov, A.V.; Krupinov, G.E.; Petrovskii, N.V.; Lumpov, I.S. Hemiablation of localized prostate cancer by high-intensity focused ultrasound: A series of 35 cases. Oncology, 2019, 97(1), 44-48.
[http://dx.doi.org/10.1159/000499739] [PMID: 31071712]
[9]
Wood, A.K.W.; Sehgal, C.M. A review of low-intensity ultrasound for cancer therapy. Ultrasound Med. Biol., 2015, 41(4), 905-928.
[http://dx.doi.org/10.1016/j.ultrasmedbio.2014.11.019] [PMID: 25728459]
[10]
Ziglioli, F.; Baciarello, M.; Maspero, G.; Bellini, V.; Bocchialini, T.; Cavalieri, D.; Bignami, E.G.; Maestroni, U. Oncologic outcome, side effects and comorbidity of High-Intensity Focused Ultrasound (HIFU) for localized prostate cancer. A review. Ann. Med. Surg. (Lond.), 2020, 56, 110-115.
[http://dx.doi.org/10.1016/j.amsu.2020.05.029] [PMID: 32637083]
[11]
Vaezy, S.; Andrew, M.; Kaczkowski, P.; Crum, L. Image-guided acoustic therapy. Annu. Rev. Biomed. Eng., 2001, 3, 375-390.
[http://dx.doi.org/10.1146/annurev.bioeng.3.1.375] [PMID: 11447068]
[12]
Laughlin-Tommaso, S.; Barnard, E.P. AbdElmagied, A.M.; Vaughan, L.E.; Weaver, A.L.; Hesley, G.K.; Woodrum, D.A.; Jacoby, V.L.; Kohi, M.P.; Price, T.M.; Nieves, A.; Miller, M.J.; Borah, B.J.; Moriarty, J.P.; Gorny, K.R.; Leppert, P.C.; Severson, A.L.; Lemens, M.A.; Stewart, E.A. FIRSTT study: Randomized controlled trial of uterine artery embolization vs. focused ultrasound surgery. Am. J. Obstet. Gynecol., 2019, 220(2), 174.e1-174.e13.
[http://dx.doi.org/10.1016/j.ajog.2018.10.032] [PMID: 30696556]
[13]
Zhong, X.; Zhang, M.; Tian, Z.; Wang, Q.; Wang, Z. The study of enhanced high-intensity focused ultrasound therapy by sonodynamic N2O microbubbles. Nanoscale Res. Lett., 2019, 14(1), 381.
[http://dx.doi.org/10.1186/s11671-019-3219-0] [PMID: 31845016]
[14]
Izadifar, Z.; Babyn, P.; Chapman, D. Mechanical and biological effects of ultrasound: A review of present knowledge. Ultrasound Med. Biol., 2017, 43(6), 1085-1104.
[http://dx.doi.org/10.1016/j.ultrasmedbio.2017.01.023] [PMID: 28342566]
[15]
Lejbkowicz, F.; Salzberg, S. Distinct sensitivity of normal and malignant cells to ultrasound in vitro. Environ. Health Perspect., 1997, 105(Suppl. 6), 1575-1578.
[http://dx.doi.org/10.1289/ehp.97105s61575] [PMID: 9467085]
[16]
Wang, T.; Zhang, F-S.; Ye, H-Y.; An, L-Z.; Xiong, L-L.; Huang, X-B.; Xu, Q-Q. Targeting silencing androgen receptor gene by shRNA with low-intensity focused ultrasonic irradiation inhibits growth of prostate cancer xenografts in nude mice. Int. J. Clin. Exp. Pathol., 2019, 12(4), 1295-1304.
[PMID: 31933943]
[17]
Lentacker, I.; Geers, B.; Demeester, J.; De Smedt, S.C.; Sanders, N.N. Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: Cytotoxicity and mechanisms involved. Mol. Ther., 2010, 18(1), 101-108.
[http://dx.doi.org/10.1038/mt.2009.160] [PMID: 19623162]
[18]
Devulapally, R.; Lee, T.; Barghava-Shah, A.; Sekar, T.V.; Foygel, K.; Bachawal, S.V.; Willmann, J.K.; Paulmurugan, R. Ultrasound-guided delivery of thymidine kinase-nitroreductase dual therapeutic genes by PEGylated-PLGA/PIE nanoparticles for enhanced triple negative breast cancer therapy. Nanomedicine (Lond.), 2018, 13(9), 1051-1066.
[http://dx.doi.org/10.2217/nnm-2017-0328] [PMID: 29790803]
[19]
Carr, K.R.; Ioffe, Y.J.; Filippova, M.; Duerksen-Hughes, P.; Chan, P.J. Combined ultrasound-curcumin treatment of human cervical cancer cells. Eur. J. Obstet. Gynecol. Reprod. Biol., 2015, 193, 96-101.
[http://dx.doi.org/10.1016/j.ejogrb.2015.07.011] [PMID: 26262768]
[20]
Rkein, A.M.; Ozog, D.M. Photodynamic therapy. Dermatol. Clin., 2014, 32(3), 415-425.
[http://dx.doi.org/10.1016/j.det.2014.03.009] [PMID: 24891062]
[21]
Dawson, W.R.; Ebbell, B. The Papyrus Ebers; The Greatest Egyptian Medical Document. J. Egypt. Archaeol., 1938, 24(2), 250.
[http://dx.doi.org/10.2307/3854804]
[22]
Rkein, A.M.; Ozog, D.M. The photodynamic phenomenon (sensitization by fluorescent substances). Results Physiol., 1909, 8(1), 698-741.
[http://dx.doi.org/10.1016/j.det.2014.03.009]
[23]
Ozog, D.M.; Rkein, A.M.; Fabi, S.G.; Gold, M.H.; Goldman, M.P.; Lowe, N.J.; Martin, G.M.; Munavalli, G.S. Photodynamic therapy. Dermatol. Surg., 2016, 42(7), 804-827.
[http://dx.doi.org/10.1097/DSS.0000000000000800] [PMID: 27336945]
[24]
Simone, C.B., II; Cengel, K.A. Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin. Oncol., 2014, 41(6), 820-830.
[http://dx.doi.org/10.1053/j.seminoncol.2014.09.017] [PMID: 25499640]
[25]
Keyal, U.; Bhatta, A.K.; Zhang, G.; Wang, X.L. Present and future perspectives of photodynamic therapy for cutaneous squamous cell carcinoma. J. Am. Acad. Dermatol., 2019, 80(3), 765-773.
[http://dx.doi.org/10.1016/j.jaad.2018.10.042] [PMID: 30393093]
[26]
Korbelik, M. PDT-associated host response and its role in the therapy outcome. Lasers Surg. Med., 2006, 38(5), 500-508.
[http://dx.doi.org/10.1002/lsm.20337] [PMID: 16634073]
[27]
Ferrario, A.; Fisher, A.M.; Rucker, N.; Gomer, C.J. Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors. Cancer Res., 2005, 65(20), 9473-9478.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1659] [PMID: 16230411]
[28]
Lambert, M.; Jambon, S.; Depauw, S.; David-Cordonnier, M-H. Targeting transcription factors for cancer treatment. Molecules, 2018, 23(6), 1479.
[http://dx.doi.org/10.3390/molecules23061479] [PMID: 29921764]
[29]
Bishop, T.R.; Zhang, Y.; Erb, M.A. Pharmacological modulation of transcriptional coregulators in cancer. Trends Pharmacol. Sci., 2019, 40(6), 388-402.
[http://dx.doi.org/10.1016/j.tips.2019.04.004] [PMID: 31078321]
[30]
Papavassiliou, A.G. Transcription-factor-modulating agents: Precision and selectivity in drug design. Mol. Med. Today, 1998, 4(8), 358-366.
[http://dx.doi.org/10.1016/S1357-4310(98)01303-3] [PMID: 9755455]
[31]
Ren, L.; Li, Z.; Dai, C.; Zhao, D.; Wang, Y.; Ma, C.; Liu, C. Chrysophanol inhibits proliferation and induces apoptosis through NF-κB/cyclin D1 and NF-κB/Bcl-2 signaling cascade in breast cancer cell lines. Mol. Med. Rep., 2018, 17(3), 4376-4382.
[http://dx.doi.org/10.3892/mmr.2018.8443] [PMID: 29344652]
[32]
Sato, T.; Cesaroni, M.; Chung, W.; Panjarian, S.; Tran, A.; Madzo, J.; Okamoto, Y.; Zhang, H.; Chen, X.; Jelinek, J.; Issa, J.J. Transcriptional selectivity of epigenetic therapy in cancer. Cancer Res., 2017, 77(2), 470-481.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0834] [PMID: 27879268]
[33]
Garzon, R.; Marcucci, G.; Croce, C.M. Targeting microRNAs in cancer: Rationale, strategies and challenges. Nat. Rev. Drug Discov., 2010, 9(10), 775-789.
[http://dx.doi.org/10.1038/nrd3179] [PMID: 20885409]
[34]
Sanz, G.; Singh, M.; Peuget, S.; Selivanova, G. Inhibition of p53 inhibitors: Progress, challenges and perspectives. J. Mol. Cell Biol., 2019, 11(7), 586-599.
[http://dx.doi.org/10.1093/jmcb/mjz075] [PMID: 31310659]
[35]
Rocha, M.; Arcanjo, R.; Lopes, C.; Carneiro, M.; Souza, A.; Báo, S. Modulation of fibronectin and laminin expression by Rhodium (II) citrate-coated maghemite nanoparticles in mice bearing breast tumor. Sci. Rep., 2017, 7(1), 17904.
[http://dx.doi.org/10.1038/s41598-017-18204-1] [PMID: 29263369]
[36]
Tao, F.; Zhang, Y.; Zhang, Z. The role of herbal bioactive components in mitochondria function and cancer therapy. Evid. Based Complement. Alternat. Med., 2019, 2019, 3868354.
[http://dx.doi.org/10.1155/2019/3868354] [PMID: 31308852]
[37]
Pratheeshkumar, P.; Son, Y-O.; Korangath, P.; Manu, K.A.; Siveen, K.S. Phytochemicals in cancer prevention and therapy. BioMed Res. Int., 2015, 2015324021.
[http://dx.doi.org/10.1155/2015/324021] [PMID: 26783517]
[38]
Cheuk, W.; Chan, J.K.C.; Nuovo, G.; Chan, M.K.M.; Fok, M. Regression of gastric large B-Cell lymphoma accompanied by a florid lymphoma-like T-cell reaction: Immunomodulatory effect of Ganoderma lucidum (Lingzhi)? Int. J. Surg. Pathol., 2007, 15(2), 180-186.
[http://dx.doi.org/10.1177/1066896906295890] [PMID: 17478779]
[39]
Bange, E.; Timlin, C.; Kabel, C.; Svoboda, J.; Roeker, L.; Mato, A.R. Evidence for and against green tea and turmeric in the management of chronic lymphocytic leukemia. Clin. Lymphoma Myeloma Leuk., 2018, 18(10), e421-e426.
[http://dx.doi.org/10.1016/j.clml.2018.06.021] [PMID: 30007569]
[40]
Olaku, O.; White, J.D. Herbal therapy use by cancer patients: A literature review on case reports. Eur. J. Cancer, 2011, 47(4), 508-514.
[http://dx.doi.org/10.1016/j.ejca.2010.11.018] [PMID: 21185719]
[41]
Williamson, E.M. Synergy and other interactions in phytomedicines. Phytomedicine, 2001, 8(5), 401-409.
[http://dx.doi.org/10.1078/0944-7113-00060] [PMID: 11695885]
[42]
Liu, C.; Guo, D.A.; Liu, L. Quality transitivity and traceability system of herbal medicine products based on quality markers. Phytomedicine, 2018, 44, 247-257.
[http://dx.doi.org/10.1016/j.phymed.2018.03.006] [PMID: 29631807]
[43]
Mena, P.; Calani, L.; Dall’Asta, C.; Galaverna, G.; García-Viguera, C.; Bruni, R.; Crozier, A.; Del Rio, D. Rapid and comprehensive evaluation of (poly)phenolic compounds in pomegranate (Punica granatum L.) juice by UHPLC-MSN. Molecules, 2012, 17(12), 14821-14840.
[http://dx.doi.org/10.3390/molecules171214821] [PMID: 23519255]
[44]
Bhattaram, V.A.; Graefe, U.; Kohlert, C.; Veit, M.; Derendorf, H. Pharmacokinetics and bioavailability of herbal medicinal products. Phytomedicine, 2002, 9(Suppl. 3), 1-33.
[http://dx.doi.org/10.1078/1433-187X-00210] [PMID: 12222652]
[45]
Bhagyashree, H.A.P. Phytosome as a novel biomedicine: A microencapsulated drug delivery system. J. Bioanal. Biomed., 2015, 07(01)
[http://dx.doi.org/10.4172/1948-593X.1000116]
[46]
Wang, S.; Su, R.; Nie, S.; Sun, M.; Zhang, J.; Wu, D.; Moustaid-Moussa, N. Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. J. Nutr. Biochem., 2014, 25(4), 363-376.
[http://dx.doi.org/10.1016/j.jnutbio.2013.10.002] [PMID: 24406273]
[47]
Tsung, K.; Norton, J.A. Lessons from Coley’s toxin. Surg. Oncol., 2006, 15(1), 25-28.
[http://dx.doi.org/10.1016/j.suronc.2006.05.002] [PMID: 16814541]
[48]
Kimoto, T. Pathological observations during treatment with the biological response modifier Maruyama vaccine in cancer: Implications for collagen production in the prevention of cancer invasion and metastasis. Cancer Detect. Prev., 1998, 22(4), 340-349.
[http://dx.doi.org/10.1046/j.1525-1500.1998.CDOA33.x] [PMID: 9674877]
[49]
Liu, R.; Luo, F.; Liu, X.; Wang, L.; Yang, J.; Deng, Y.; Huang, E.; Qian, J.; Lu, Z.; Jiang, X. Biological response modifier in cancer immunotherapy; Prog. Cancer Immunother, 2016, pp. 69-138.
[http://dx.doi.org/10.1007/978-94-017-7555-7_2]
[50]
Garcia, P.V.; Seiva, F.R.F.; Carniato, A.P.; de Mello Júnior, W.; Duran, N.; Macedo, A.M.; de Oliveira, A.G.; Romih, R. Nunes, Ida.S.; Nunes, Oda, S.; Fávaro, W.J. Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: Mechanism of action of P-MAPA biological response modifier. BMC Cancer, 2016, 16(1), 422.
[http://dx.doi.org/10.1186/s12885-016-2474-z] [PMID: 27389279]
[51]
Sato, Y.; Goto, Y.; Narita, N.; Hoon, D.S.B. Cancer cells expressing toll-like receptors and the tumor microenvironment. Cancer Microenviron., 2009, 2(S1 Suppl. 1), 205-214.
[http://dx.doi.org/10.1007/s12307-009-0022-y] [PMID: 19685283]
[52]
Kopp, T.I.; Vogel, U.; Tjonneland, A.; Andersen, V. Meat and fiber intake and interaction with pattern recognition receptors (TLR1, TLR2, TLR4, and TLR10) in relation to colorectal cancer in a Danish prospective, case-cohort study. Am. J. Clin. Nutr., 2018, 107(3), 465-479.
[http://dx.doi.org/10.1093/ajcn/nqx011] [PMID: 29566186]
[53]
Sato-Kaneko, F.; Yao, S.; Ahmadi, A.; Zhang, S.S.; Hosoya, T.; Kaneda, M.M.; Varner, J.A.; Pu, M.; Messer, K.S.; Guiducci, C.; Coffman, R.L.; Kitaura, K.; Matsutani, T.; Suzuki, R.; Carson, D.A.; Hayashi, T.; Cohen, E.E. Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer. JCI Insight, 2017, 2(18), 93397.
[http://dx.doi.org/10.1172/jci.insight.93397] [PMID: 28931759]
[54]
Feng, Y.; Zou, L.; Yan, D.; Chen, H.; Xu, G.; Jian, W.; Cui, P.; Chao, W. Extracellular microRNAs induce potent innate immune responses via TLR7/MyD88-dependent mechanisms. J. Immunol., 2017, 199(6), 2106-2117.
[http://dx.doi.org/10.4049/jimmunol.1700730] [PMID: 28768728]
[55]
Yu, D.; Wang, D.; Zhu, F-G.; Bhagat, L.; Dai, M.; Kandimalla, E.R.; Agrawal, S. Modifications incorporated in CpG motifs of oligodeoxynucleotides lead to antagonist activity of toll-like receptors 7 and 9. J. Med. Chem., 2009, 52(16), 5108-5114.
[http://dx.doi.org/10.1021/jm900730r] [PMID: 19650625]
[56]
van Holstein, Y.; Kapiteijn, E.; Bastiaannet, E.; van den Bos, F.; Portielje, J.; de Glas, N.A. Efficacy and adverse events of immunotherapy with checkpoint inhibitors in older patients with cancer. Drugs Aging, 2019, 36(10), 927-938.
[http://dx.doi.org/10.1007/s40266-019-00697-2] [PMID: 31317421]
[57]
Sebastian, M.; Schröder, A.; Scheel, B.; Hong, H.S.; Muth, A.; von Boehmer, L.; Zippelius, A.; Mayer, F.; Reck, M.; Atanackovic, D.; Thomas, M.; Schneller, F.; Stöhlmacher, J.; Bernhard, H.; Gröschel, A.; Lander, T.; Probst, J.; Strack, T.; Wiegand, V.; Gnad-Vogt, U.; Kallen, K.J.; Hoerr, I.; von der Muelbe, F.; Fotin-Mleczek, M.; Knuth, A.; Koch, S.D. A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer. Cancer Immunol. Immunother., 2019, 68(5), 799-812.
[http://dx.doi.org/10.1007/s00262-019-02315-x] [PMID: 30770959]
[58]
Zeichner, J.A.; Patel, R.V.; Birge, M.B. Treatment of basal cell carcinoma with curettage followed by imiquimod 3.75% cream. J. Clin. Aesthet. Dermatol., 2011, 4(5), 39-43.
[PMID: 21607193]
[59]
Lobo, N.A.; Shimono, Y.; Qian, D.; Clarke, M.F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol., 2007, 23, 675-699.
[http://dx.doi.org/10.1146/annurev.cellbio.22.010305.104154] [PMID: 17645413]
[60]
Trounson, A.; DeWitt, N.D. Pluripotent stem cells progressing to the clinic. Nat. Rev. Mol. Cell Biol., 2016, 17(3), 194-200.
[http://dx.doi.org/10.1038/nrm.2016.10] [PMID: 26908143]
[61]
Orkin, S.H.; Zon, L.I. Hematopoiesis: An evolving paradigm for stem cell biology. Cell, 2008, 132(4), 631-644.
[http://dx.doi.org/10.1016/j.cell.2008.01.025] [PMID: 18295580]
[62]
Yin, H.; Price, F.; Rudnicki, M.A. Satellite cells and the muscle stem cell niche. Physiol. Rev., 2013, 93(1), 23-67.
[http://dx.doi.org/10.1152/physrev.00043.2011] [PMID: 23303905]
[63]
Serakinci, N.; Tulay, P.; Kalkan, R. Role of mesenchymal stem cells in cancer development and their use in cancer therapy. Adv. Exp. Med. Biol., 2018, 1083, 45-62.
[http://dx.doi.org/10.1007/5584_2017_64] [PMID: 28730382]
[64]
Shafren, D.R.; Dorahy, D.J.; Ingham, R.A.; Burns, G.F.; Barry, R.D. Coxsackie virus A21 binds to decay-accelerating factor but requires intercellular adhesion molecule 1 for cell entry. J. Virol., 1997, 71(6), 4736-4743.
[http://dx.doi.org/10.1128/JVI.71.6.4736-4743.1997] [PMID: 9151867]
[65]
O’Shea, C.C.; Soria, C.; Bagus, B.; McCormick, F. Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell, 2005, 8(1), 61-74.
[http://dx.doi.org/10.1016/j.ccr.2005.06.009] [PMID: 16023599]
[66]
Thorne, S.H.; Brooks, G.; Lee, Y-L.; Au, T.; Eng, L.F.; Reid, T. Effects of febrile temperature on adenoviral infection and replication: Implications for viral therapy of cancer. J. Virol., 2005, 79(1), 581-591.
[http://dx.doi.org/10.1128/JVI.79.1.581-591.2005] [PMID: 15596850]
[67]
de Graaf, J.F.; de Vor, L.; Fouchier, R.A.M.; van den Hoogen, B.G. Armed oncolytic viruses: A kick-start for anti-tumor immunity. Cytokine Growth Factor Rev., 2018, 41, 28-39.
[http://dx.doi.org/10.1016/j.cytogfr.2018.03.006] [PMID: 29576283]
[68]
Asad, A.S.; Moreno Ayala, M.A.; Gottardo, M.F.; Zuccato, C.; Nicola Candia, A.J.; Zanetti, F.A.; Seilicovich, A.; Candolfi, M. Viral gene therapy for breast cancer: Progress and challenges. Expert Opin. Biol. Ther., 2017, 17(8), 945-959.
[http://dx.doi.org/10.1080/14712598.2017.1338684] [PMID: 28604109]
[69]
Cordaro, T.A.; de Visser, K.E.; Tirion, F.H.; Graus, Y.M.F.; Haanen, J.B.A.G.; Kioussis, D.; Kruisbeek, A.M. Tumor size at the time of adoptive transfer determines whether tumor rejection occurs. Eur. J. Immunol., 2000, 30(5), 1297-1307.
[http://dx.doi.org/10.1002/(SICI)1521-4141(200005)30:5<1297:AID-IMMU1297>3.0.CO;2-C] [PMID: 10820375]
[70]
Ricca, J.M.; Oseledchyk, A.; Walther, T.; Liu, C.; Mangarin, L.; Merghoub, T.; Wolchok, J.D.; Zamarin, D. Pre-existing immunity to oncolytic virus potentiates its immunotherapeutic efficacy. Mol. Ther., 2018, 26(4), 1008-1019.
[http://dx.doi.org/10.1016/j.ymthe.2018.01.019] [PMID: 29478729]
[71]
Kim, J-H.; Lee, Y-S.; Kim, H.; Huang, J-H.; Yoon, A-R.; Yun, C-O. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J. Natl. Cancer Inst., 2006, 98(20), 1482-1493.
[http://dx.doi.org/10.1093/jnci/djj397] [PMID: 17047197]
[72]
Draganov, D.D.; Santidrian, A.F.; Minev, I.; Nguyen, D.; Kilinc, M.O.; Petrov, I.; Vyalkova, A.; Lander, E.; Berman, M.; Minev, B.; Szalay, A.A. Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers. J. Transl. Med., 2019, 17(1), 100.
[http://dx.doi.org/10.1186/s12967-019-1829-z] [PMID: 30917829]
[73]
Takahashi, R.U.; Prieto-Vila, M.; Kohama, I.; Ochiya, T. Development of miRNA-based therapeutic approaches for cancer patients. Cancer Sci., 2019, 110(4), 1140-1147.
[http://dx.doi.org/10.1111/cas.13965] [PMID: 30729639]
[74]
Subramaniam, S.; Jeet, V.; Clements, J.A.; Gunter, J.H.; Batra, J. Emergence of MicroRNAs as key players in cancer cell metabolism. Clin. Chem., 2019, 65(9), 299651.
[http://dx.doi.org/10.1373/clinchem.2018.299651]
[75]
Johannes, L.; Lucchino, M. Current challenges in delivery and cytosolic translocation of therapeutic RNAs. Nucleic Acid Ther., 2018, 28(3), 178-193.
[http://dx.doi.org/10.1089/nat.2017.0716] [PMID: 29883296]
[76]
Leucuta, S. Withdrawn: Cytosolic mRNA target and bioavailability of nanoparticulate siRNA delivery systems for gene silencing. Curr. Drug Targets, 2017, 18(999), 1-1.
[http://dx.doi.org/10.2174/1389450118666170322150337] [PMID: 27333902]
[77]
Frieden, M.; Ørum, H. Locked nucleic acid holds promise in the treatment of cancer. Curr. Pharm. Des., 2008, 14(11), 1138-1142.
[http://dx.doi.org/10.2174/138161208784246234] [PMID: 18473860]
[78]
Grimm, D.; Büning, H. Small but increasingly mighty: Latest advances in AAV vector research, design, and evolution. Hum. Gene Ther., 2017, 28(11), 1075-1086.
[http://dx.doi.org/10.1089/hum.2017.172] [PMID: 28835125]
[79]
Zhang, M.; Viennois, E.; Xu, C.; Merlin, D. Plant derived edible nanoparticles as a new therapeutic approach against diseases. Tissue Barriers, 2016, 4(2), e1134415.
[http://dx.doi.org/10.1080/21688370.2015.1134415] [PMID: 27358751]
[80]
Pugazhendhi, A.; Edison, T.N.J.I.; Karuppusamy, I.; Kathirvel, B. Inorganic nanoparticles: A potential cancer therapy for human welfare. Int. J. Pharm., 2018, 539(1-2), 104-111.
[http://dx.doi.org/10.1016/j.ijpharm.2018.01.034] [PMID: 29366941]
[81]
Kumari, P.; Ghosh, B.; Biswas, S. Nanocarriers for cancer-targeted drug delivery. J. Drug Target., 2016, 24(3), 179-191.
[http://dx.doi.org/10.3109/1061186X.2015.1051049] [PMID: 26061298]
[82]
Lee, W-H.; Loo, C-Y.; Leong, C-R.; Young, P.M.; Traini, D.; Rohanizadeh, R. The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer. Expert Opin. Drug Deliv., 2017, 14(8), 937-957.
[http://dx.doi.org/10.1080/17425247.2017.1247804] [PMID: 27759437]
[83]
Teleanu, D.M.; Chircov, C.; Grumezescu, A.M.; Volceanov, A.; Teleanu, R.I. Blood-brain delivery methods using nanotechnology. Pharmaceutics, 2018, 10(4), 269.
[http://dx.doi.org/10.3390/pharmaceutics10040269] [PMID: 30544966]
[84]
Salatin, S.; Maleki Dizaj, S.; Yari, K.A. Effect of the surface modification, size, and shape on cellular uptake of nanoparticles. Cell Biol. Int., 2015, 39(8), 881-890.
[http://dx.doi.org/10.1002/cbin.10459] [PMID: 25790433]
[85]
Wang, T.; Zhang, J.; Hou, T.; Yin, X.; Zhang, N. Selective targeting of tumor cells and tumor associated macrophages separately by twin-like core-shell nanoparticles for enhanced tumor-localized chemoimmunotherapy. Nanoscale, 2019, 11(29), 13934-13946.
[http://dx.doi.org/10.1039/C9NR03374B] [PMID: 31305839]
[86]
Karlsson, J.; Vaughan, H.J.; Green, J.J. Biodegradable polymeric nanoparticles for therapeutic cancer treatments. Annu. Rev. Chem. Biomol. Eng., 2018, 9(1), 105-127.
[http://dx.doi.org/10.1146/annurev-chembioeng-060817-084055] [PMID: 29579402]
[87]
Yang, B.; Han, X.; Ji, B.; Lu, R. Competition between tumor and mononuclear phagocyte system causing the low tumor distribution of nanoparticles and strategies to improve tumor accumulation. Curr. Drug Deliv., 2016, 13(8), 1261-1274.
[http://dx.doi.org/10.2174/1567201813666160418105703] [PMID: 27086698]
[88]
Poon, W.; Zhang, Y-N.; Ouyang, B.; Kingston, B.R.; Wu, J.L.Y.; Wilhelm, S.; Chan, W.C.W. Elimination pathways of nanoparticles. ACS Nano, 2019, 13(5), 5785-5798.
[http://dx.doi.org/10.1021/acsnano.9b01383] [PMID: 30990673]
[89]
Jain, K.K. Nanotechnology in clinical laboratory diagnostics. Clin. Chim. Acta, 2005, 358(1-2), 37-54.
[http://dx.doi.org/10.1016/j.cccn.2005.03.014] [PMID: 15890325]
[90]
Guo, Y.; Li, S.; Wang, Y.; Zhang, S. Diagnosis-therapy integrative systems based on magnetic RNA nanoflowers for co-drug delivery and targeted therapy. Anal. Chem., 2017, 89(4), 2267-2274.
[http://dx.doi.org/10.1021/acs.analchem.6b03346] [PMID: 28192920]
[91]
Hodos, R.A.; Kidd, B.A.; Shameer, K.; Readhead, B.P.; Dudley, J.T. In silico methods for drug repurposing and pharmacology. Wiley Interdiscip. Rev. Syst. Biol. Med., 2016, 8(3), 186-210.
[http://dx.doi.org/10.1002/wsbm.1337] [PMID: 27080087]
[92]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[93]
Grosdidier, A.; Zoete, V.; Michielin, O. SwissDock, a proteinsmall molecule docking web service based on EADock DSS. Nucleic Acids Res., 2011, 39(Web Server issue), W270-7.
[http://dx.doi.org/10.1093/nar/gkr366] [PMID: 21624888]
[94]
Daina, A.; Michielin, O.; Zoete, V. Swiss target prediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res., 2019, 47(W1), W357-W364.
[http://dx.doi.org/10.1093/nar/gkz382] [PMID: 31106366]

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Request history8.2.27PHP Version299msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
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    • 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
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      1.05msalphaeurekaselec_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
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      160μsalphaeurekaselec_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 >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) 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 >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) 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 >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) 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 >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) 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 >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) 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 >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 51833477 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51833477) limit 1
      11.49msalphaeurekaselec_live_10_06_2022UserAccess.php#784
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      • 1: 51833477
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      • 3: 51833477
      • 4: 51833477
      • 5: 51833477
      • 6: 51833477
      • 7: 51833477
      • 8: 51833477
      • 9: 51833477
      • 10: 51833477
      • 11: 51833477
      • 12: 51833477
      • 13: 51833477
      • 14: 51833477
      • 15: 51833477
      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=110711
      2.33msalphaeurekaselec_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` = 30 limit 1
      970μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 30
      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=30) and sj.journal_id!=30 group by `j`.`nid`) as `aggregate_table`
      1.12msalphaeurekaselec_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=30) and sj.journal_id!=30 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      920μsalphaeurekaselec_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=30) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      41.98msalphaeurekaselec_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=30) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.85msalphaeurekaselec_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` = '110711'
      290μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 110711
      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` = '110711'
      3.89msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 110711
      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` = '110711' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      830μsalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 110711
      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
      310μsalphaeurekaselec_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
      520μsalphaeurekaselec_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 = 30 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      21.73msalphaeurekaselec_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 = 30 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      14.55msalphaeurekaselec_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 = 30 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      11.92msalphaeurekaselec_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` = 110711 limit 1
      230μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 110711
      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 = 110711 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 * from `node_meta` where `nid` = 186929 limit 1
      210μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 186929
      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
      220μsalphaeurekaselec_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` = 'CPB' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      290μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CPB
      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 = '110711' 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) )
      340μsalphaeurekaselec_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 = '10661' 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) )
      280μsalphaeurekaselec_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 = '2947' 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) )
      260μsalphaeurekaselec_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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2947) 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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2947) 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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2947)
      1.3msalphaeurekaselec_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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10661) 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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10661) 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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10661)
      540μsalphaeurekaselec_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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110711) 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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110711) 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 <= 51833477 and j.to_ip >=51833477 )) and ((j.from_date <= 1740515452 and j.to_date >= 1740515452 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110711)
      550μsalphaeurekaselec_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` < '1141' and is_uploaded = 1 and issue_id = 10661 order by cast(first_page as SIGNED) desc limit 1
      460μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1141
      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` > '1148' and is_uploaded = 1 and issue_id = 10661 order by cast(first_page as SIGNED) asc limit 1
      520μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1148
      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'
      180μsalphaeurekaselec_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
      180μsalphaeurekaselec_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` = 110711 limit 1
      3.57msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 110711
      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` = 30 and `b`.`banner_from_date` <= 1740515452 and `b`.`banner_to_date` >= 1740515452 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.28msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 30
      • 3: 1740515452
      • 4: 1740515452
      • 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` = 30 and `b`.`banner_from_date` <= 1740515452 and `b`.`banner_to_date` >= 1740515452 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.72msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 30
      • 3: 1740515452
      • 4: 1740515452
      • 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='189d912fbbcc9e4e2159c66ec2d796f4'
      270μsalphaeurekaselec_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#?
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        _flash
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        PHPDEBUGBAR_STACK_DATA
        []
        path_info
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        status_code
        200
        
        status_text
        OK
        format
        html
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        request_query
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        request_request
        []
        
        request_headers
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:30:52GET/article/110711414361