Review Article

严重肢体缺血的基因治疗:Per Aspera ad Astra

卷 22, 期 3, 2022

发表于: 12 July, 2021

页: [214 - 227] 页: 14

弟呕挨: 10.2174/1566523221666210712185742

价格: $65

摘要

外周动脉疾病仍然是一个严重的公共卫生问题。 尽管有许多使用保守治疗技术和手术进行治疗的传统方法,但基因治疗是一种替代且可能更有效的治疗选择,尤其是对于“无选择”的患者。 本综述将基因治疗多年研究和应用的成果作为治疗严重肢体缺血患者的一个例子。 介绍了使用该技术治疗该疾病的成功和不成功尝试的数据。 注意到改变治疗性血管生成方法范式的趋势:从病毒载体到非病毒载体,从基因转移到整个生物体到靶向转移到细胞和组织,从单基因使用到基因组合; 从 DNA 治疗到 RNA 治疗,从体内治疗到离体治疗。

关键词: 严重肢体缺血,基因治疗,血管生成,载体,治疗基因,问题和观点,外周动脉

图形摘要

[1]
Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA- SCID: Initial trial results after 4 years. Science 1995; 270(5235): 475-80.
[http://dx.doi.org/10.1126/science.270.5235.475] [PMID: 7570001]
[2]
Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: A systematic review and analysis. Lancet 2013; 382(9901): 1329-40.
[http://dx.doi.org/10.1016/S0140-6736(13)61249-0] [PMID: 23915883]
[3]
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007; 45(1)(Suppl. S): S5-S67.
[http://dx.doi.org/10.1016/j.jvs.2006.12.037] [PMID: 17223489]
[4]
Marston WA, Davies SW, Armstrong B, et al. Natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization. J Vasc Surg 2006; 44(1): 108-14.
[http://dx.doi.org/10.1016/j.jvs.2006.03.026] [PMID: 16828434]
[5]
Reinecke H, Unrath M, Freisinger E, et al. Peripheral arterial disease and critical limb ischaemia: Still poor outcomes and lack of guideline adherence. Eur Heart J 2015; 36(15): 932-8.
[http://dx.doi.org/10.1093/eurheartj/ehv006] [PMID: 25650396]
[6]
Sprengers RW, Teraa M, Moll FL, de Wit GA, van der Graaf Y, Verhaar MC. Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment. J Vasc Surg 2010; 52(4): 843-9.
[http://dx.doi.org/10.1016/j.jvs.2010.04.057] [PMID: 20598482]
[7]
Athanasopoulos T, Munye MM, Yáñez-Muñoz RJ. Nonintegrating gene therapy vectors. Hematol Oncol Clin North Am 2017; 31(5): 753-70.
[http://dx.doi.org/10.1016/j.hoc.2017.06.007] [PMID: 28895845]
[8]
Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet 2020; 21(4): 255-72.
[http://dx.doi.org/10.1038/s41576-019-0205-4] [PMID: 32042148]
[9]
Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral gene therapy vectors. Mol Ther 2020; 28(3): 709-22.
[http://dx.doi.org/10.1016/j.ymthe.2020.01.001] [PMID: 31968213]
[10]
Giménez CS, Castillo MG, Simonin JA, et al. Effect of intramuscular baculovirus encoding mutant hypoxia-inducible factor 1-alpha on neovasculogenesis and ischemic muscle protection in rabbits with peripheral arterial disease. Cytotherapy 2020; 22(10): 563-72.
[http://dx.doi.org/10.1016/j.jcyt.2020.06.010] [PMID: 32723595]
[11]
Matsumoto T, Tanaka M, Yoshiya K, et al. Improved quality of life in patients with no-option critical limb ischemia undergoing gene therapy with DVC1-0101. Sci Rep 2016; 6: 30035.
[http://dx.doi.org/10.1038/srep30035] [PMID: 27418463]
[12]
Farrell L-L, Pepin J, Kucharski C, Lin X, Xu Z, Uludag H. A comparison of the effectiveness of cationic polymers poly-L-lysine (PLL) and polyethylenimine (PEI) for non-viral delivery of plasmid DNA to bone marrow stromal cells (BMSC). Eur J Pharm Biopharm 2007; 65(3): 388-97.
[http://dx.doi.org/10.1016/j.ejpb.2006.11.026] [PMID: 17240127]
[13]
Clements BA, Incani V, Kucharski C, Lavasanifar A, Ritchie B, Uludağ H. A comparative evaluation of poly-L-lysine-palmitic acid and Lipofectamine 2000 for plasmid delivery to bone marrow stromal cells. Biomaterials 2007; 28(31): 4693-704.
[http://dx.doi.org/10.1016/j.biomaterials.2007.07.023] [PMID: 17686514]
[14]
Patil ML, Zhang M, Taratula O, Garbuzenko OB, He H, Minko T. Internally cationic polyamidoamine PAMAM-OH dendrimers for siRNA delivery: Effect of the degree of quaternization and cancer targeting. Biomacromolecules 2009; 10(2): 258-66.
[http://dx.doi.org/10.1021/bm8009973] [PMID: 19159248]
[15]
Liu G, Fang Z, Yuan M, et al. Biodegradable carriers for delivery of VEGF plasmid DNA for the treatment of critical limb ischemia. Front Pharmacol 2017; 8: 528-39.
[http://dx.doi.org/10.3389/fphar.2017.00528] [PMID: 28848442]
[16]
Jiang HL, Islam MA, Xing L, et al. Degradable polyethylenimine-based gene carriers for cancer therapy. Top Curr Chem (Cham) 2017; 375(2): 34.
[http://dx.doi.org/10.1007/s41061-017-0124-9] [PMID: 28290156]
[17]
Kuzmich A, Rakitina O, Didych D, et al. Novel histone-based DNA carrier targeting cancer-associated fibroblasts. Polymers (Basel) 2020; 12(8): 1695-711.
[http://dx.doi.org/10.3390/polym12081695] [PMID: 32751200]
[18]
Orefice NS. Development of new strategies using extracellular vesicles loaded with exogenous nucleic acid. Pharmaceutics 2020; 12(8): 705-23.
[http://dx.doi.org/10.3390/pharmaceutics12080705] [PMID: 32722622]
[19]
Jafari D, Shajari S, Jafari R, et al. Designer exosomes: A new platform for biotechnology therapeutics. BioDrugs 2020; 34(5): 567-86.
[http://dx.doi.org/10.1007/s40259-020-00434-x] [PMID: 32754790]
[20]
Hudry E, Martin C, Gandhi S, et al. Exosome-associated AAV vector as a robust and convenient neuroscience tool. Gene Ther 2016; 23(4): 380-92.
[http://dx.doi.org/10.1038/gt.2016.11] [PMID: 26836117]
[21]
Sancho-Albero M, Navascués N, Mendoza G, et al. Exosome origin determines cell targeting and the transfer of therapeutic nanoparticles towards target cells. J Nanobiotechnology 2019; 17(1): 16-29.
[http://dx.doi.org/10.1186/s12951-018-0437-z] [PMID: 30683120]
[22]
Gorenoi V, Brehm MU, Koch A, Hagen A. Growth factors for angiogenesis in peripheral arterial disease. Cochrane Database Syst Rev 2017; 6: 1-81.
[http://dx.doi.org/10.1002/14651858.CD011741.pub2] [PMID: 28594443]
[23]
Järvinen TAH, Pemmari T. Systemically administered, target-specific, multi-functional therapeutic recombinant proteins in regenerative medicine. Nanomaterials (Basel) 2020; 10(2): 226-35.
[http://dx.doi.org/10.3390/nano10020226] [PMID: 32013041]
[24]
Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18(14): 3964-72.
[http://dx.doi.org/10.1093/emboj/18.14.3964] [PMID: 10406801]
[25]
Kalka C, Tehrani H, Laudenberg B, et al. VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg 2000; 70(3): 829-34.
[http://dx.doi.org/10.1016/S0003-4975(00)01633-7] [PMID: 11016318]
[26]
Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 2016; 17(10): 611-25.
[http://dx.doi.org/10.1038/nrm.2016.87] [PMID: 27461391]
[27]
Powell RJ, Simons M, Mendelsohn FO, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 2008; 118(1): 58-65.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.727347] [PMID: 18559703]
[28]
Powell RJ, Goodney P, Mendelsohn FO, Moen EK, Annex BH. Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: Results of the HGF-0205 trial. J Vasc Surg 2010; 52(6): 1525-30.
[http://dx.doi.org/10.1016/j.jvs.2010.07.044] [PMID: 21146749]
[29]
Sanada F, Taniyama Y, Muratsu J, et al. Gene-therapeutic strategies targeting angiogenesis in peripheral artery disease. Medicines (Basel) 2018; 5(2): 31-43.
[http://dx.doi.org/10.3390/medicines5020031] [PMID: 29601487]
[30]
Smith TG, Robbins PA, Ratcliffe PJ. The human side of hypoxia-inducible factor. Br J Haematol 2008; 141(3): 325-34.
[http://dx.doi.org/10.1111/j.1365-2141.2008.07029.x] [PMID: 18410568]
[31]
Semenza GL. Pharmacologic targeting of hypoxia-inducible factors. Annu Rev Pharmacol Toxicol 2019; 59(1): 379-403.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021637] [PMID: 30625281]
[32]
Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005; 16(2): 159-78.
[http://dx.doi.org/10.1016/j.cytogfr.2005.01.004] [PMID: 15863032]
[33]
Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): A randomised trial. Lancet 2002; 359(9323): 2053-8.
[http://dx.doi.org/10.1016/S0140-6736(02)08937-7] [PMID: 12086757]
[34]
Tang J, Wang J, Zheng F, et al. Combination of chemokine and angiogenic factor genes and mesenchymal stem cells could enhance angiogenesis and improve cardiac function after acute myocardial infarction in rats. Mol Cell Biochem 2010; 339(1-2): 107-18.
[http://dx.doi.org/10.1007/s11010-009-0374-0] [PMID: 20058054]
[35]
Shishehbor MH, Rundback J, Bunte M, et al. SDF-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD): Randomized, double-blind, placebo-controlled clinical trial. Vasc Med 2019; 24(3): 200-7.
[http://dx.doi.org/10.1177/1358863X18817610] [PMID: 30786835]
[36]
Kishimoto K, Liu S, Tsuji T, Olson KA, Hu G-F. Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis. Oncogene 2005; 24(3): 445-56.
[http://dx.doi.org/10.1038/sj.onc.1208223] [PMID: 15558023]
[37]
Ucuzian AA, Gassman AA, East AT, Greisler HP. Molecular mediators of angiogenesis. J Burn Care Res 2010; 31(1): 158-75.
[http://dx.doi.org/10.1097/BCR.0b013e3181c7ed82] [PMID: 20061852]
[38]
Meng LB, Zhang YM, Shan MJ, Qiu Y, Zhang TJ, Gong T. Pivotal micro factors associated with endothelial cells. Chin Med J (Engl) 2019; 132(16): 1965-73.
[http://dx.doi.org/10.1097/CM9.0000000000000358] [PMID: 31335473]
[39]
Rashad S, Niizuma K, Tominaga T. tRNA cleavage: A new insight. Neural Regen Res 2020; 15(1): 47-52.
[http://dx.doi.org/10.4103/1673-5374.264447] [PMID: 31535642]
[40]
Buschmann IR, Hoefer IE, van Royen N, et al. GM-CSF: A strong arteriogenic factor acting by amplification of monocyte function. Atherosclerosis 2001; 159(2): 343-56.
[http://dx.doi.org/10.1016/S0021-9150(01)00637-2] [PMID: 11730814]
[41]
Sacramento CB, da Silva FH, Nardi NB, et al. Synergistic effect of vascular endothelial growth factor and granulocyte colony-stimulating factor double gene therapy in mouse limb ischemia. J Gene Med 2010; 12(3): 310-9.
[http://dx.doi.org/10.1002/jgm.1434] [PMID: 20077434]
[42]
Sacramento CB, Cantagalli VD, Grings M, et al. Granulocyte-macrophage colony-stimulating factor gene based therapy for acute limb ischemia in a mouse model. J Gene Med 2009; 11(4): 345-53.
[http://dx.doi.org/10.1002/jgm.1298] [PMID: 19194978]
[43]
Lehtonen A, Matikainen S, Miettinen M, Julkunen I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol 2002; 71(3): 511-9.
[http://dx.doi.org/10.1189/jlb.71.3.511] [PMID: 11867689]
[44]
Huang J, Inoue M, Hasegawa M, et al. Sendai viral vector mediated angiopoietin-1 gene transfer for experimental ischemic limb disease. Angiogenesis 2009; 12(3): 243-9.
[http://dx.doi.org/10.1007/s10456-009-9144-6] [PMID: 19322669]
[45]
Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol 2017; 24(5): 432-8.
[http://dx.doi.org/10.1097/MOH.0000000000000361] [PMID: 28582314]
[46]
Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996; 348(9024): 370-4.
[http://dx.doi.org/10.1016/S0140-6736(96)03361-2] [PMID: 8709735]
[47]
Isner JM, Baumgartner I, Rauh G, et al. Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: Preliminary clinical results. Vasc Surg 1998; 28(6): 964-73.
[http://dx.doi.org/10.1016/s0741-5214(98)70022-9] [PMID: 9845647]
[48]
Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97(12): 1114-23.
[http://dx.doi.org/10.1161/01.CIR.97.12.1114]
[49]
Rajagopalan S, Trachtenberg J, Mohler E, et al. Phase I study of direct administration of a replication deficient adenovirus vector containing the vascular endothelial growth factor cDNA (CI-1023) to patients with claudication. Am J Cardiol 2002; 90(5): 512-6.
[http://dx.doi.org/10.1016/S0002-9149(02)02524-9] [PMID: 12208412]
[50]
Mäkinen K, Manninen H, Hedman M, et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: A randomized, placebo-controlled, double-blinded phase II study. Mol Ther 2002; 6(1): 127-33.
[http://dx.doi.org/10.1006/mthe.2002.0638] [PMID: 12095313]
[51]
Kusumanto YH, van Weel V, Mulder NH, et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: A double-blind randomized trial. Hum Gene Ther 2006; 17(6): 683-91.
[http://dx.doi.org/10.1089/hum.2006.17.683] [PMID: 16776576]
[52]
Guo X, Yuan Z, Xu Y, Zhao X, Fang Z, Yuan WE. A low-molecular-weight polyethylenimine/pDNA-VEGF polyplex system constructed in a one-pot manner for hind-limb ischemia therapy. Pharmaceutics 2019; 11(4): 171.
[http://dx.doi.org/10.3390/pharmaceutics11040171] [PMID: 30965617]
[53]
Yu Z, Witman N, Wang W, et al. Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia. J Control Release 2019; 310: 103-14.
[http://dx.doi.org/10.1016/j.jconrel.2019.08.014] [PMID: 31425721]
[54]
Deev R, Plaksa I, Bozo I, et al. Results of 5-year follow-up study in patients with peripheral artery disease treated with PL-VEGF165 for intermittent claudication. Ther Adv Cardiovasc Dis 2018; 12(9): 237-46.
[http://dx.doi.org/10.1177/1753944718786926] [PMID: 29996720]
[55]
Park JS, Bae SH, Jung S, Lee M, Choi D. Enrichment of vascular endothelial growth factor secreting mesenchymal stromal cells enhances therapeutic angiogenesis in a mouse model of hind limb ischemia. Cytotherapy 2019; 21(4): 433-43.
[http://dx.doi.org/10.1016/j.jcyt.2018.12.007] [PMID: 30879964]
[56]
Morishita R, Aoki M, Hashiya N, et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 2004; 44(2): 203-9.
[http://dx.doi.org/10.1161/01.HYP.0000136394.08900.ed] [PMID: 15238569]
[57]
Morishita R, Makino H, Aoki M, et al. Phase I/IIa clinical trial of therapeutic angiogenesis using hepatocyte growth factor gene transfer to treat critical limb ischemia. Arterioscler Thromb Vasc Biol 2011; 31(3): 713-20.
[http://dx.doi.org/10.1161/ATVBAHA.110.219550] [PMID: 21183732]
[58]
Makino H, Aoki M, Hashiya N, et al. Long-term follow-up evaluation of results from clinical trial using hepatocyte growth factor gene to treat severe peripheral arterial disease. Arterioscler Thromb Vasc Biol 2012; 32(10): 2503-9.
[http://dx.doi.org/10.1161/ATVBAHA.111.244632] [PMID: 22904270]
[59]
Shigematsu H, Yasuda K, Iwai T, et al. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther 2010; 17(9): 1152-61.
[http://dx.doi.org/10.1038/gt.2010.51] [PMID: 20393508]
[60]
Shigematsu H, Yasuda K, Sasajima T, et al. Transfection of human HGF plasmid DNA improves limb salvage in Buerger’s disease patients with critical limb ischemia. Int Angiol 2011; 30(2): 140-9.
[PMID: 21427651]
[61]
Gu Y, Cui S, Wang Q, et al. A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia. Mol Ther 2019; 27(12): 2158-65.
[http://dx.doi.org/10.1016/j.ymthe.2019.10.017] [PMID: 31805256]
[62]
Morishita R, Shimamura M, Takeya Y, et al. Combined analysis of clinical data on HGF gene therapy to treat critical limb ischemia in Japan. Curr Gene Ther 2020; 20(1): 25-35.
[http://dx.doi.org/10.2174/1566523220666200516171447] [PMID: 32416690]
[63]
Boldyreva MA, Shevchenko EK, Molokotina YD, et al. Transplantation of adipose stromal cell sheet producing hepatocyte growth factor induces pleiotropic effect in ischemic skeletal muscle. Int J Mol Sci 2019; 20(12): 3088-95.
[http://dx.doi.org/10.3390/ijms20123088] [PMID: 31238604]
[64]
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 2012; 148(3): 399-408.
[http://dx.doi.org/10.1016/j.cell.2012.01.021] [PMID: 22304911]
[65]
Rajagopalan S, Olin J, Deitcher S, et al. Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: Phase I dose-escalation experience. Circulation 2007; 115(10): 1234-43.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.607994] [PMID: 17309918]
[66]
Creager MA, Olin JW, Belch JJ, et al. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation 2011; 124(16): 1765-73.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.009407] [PMID: 21947297]
[67]
Ouma GO, Rodriguez E, Muthumani K, Weiner DB, Wilensky RL, Mohler ER III. In vivo electroporation of constitutively expressed HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia. J Vasc Surg 2014; 59(3): 786-93.
[http://dx.doi.org/10.1016/j.jvs.2013.04.043] [PMID: 23850058]
[68]
Vincent KA, Shyu K-G, Luo Y, et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation 2000; 102(18): 2255-61.
[http://dx.doi.org/10.1161/01.CIR.102.18.2255] [PMID: 11056102]
[69]
Bosch-Marce M, Okuyama H, Wesley JB, et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res 2007; 101(12): 1310-8.
[http://dx.doi.org/10.1161/CIRCRESAHA.107.153346] [PMID: 17932327]
[70]
Nikol S, Baumgartner I, Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation‐free survival in patients with critical limb ischemia. Mol Ther 2008; 16(5): 972-8.
[http://dx.doi.org/10.1038/mt.2008.33]
[71]
Niebuhr A, Henry T, Goldman J, et al. Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease. Gene Ther 2012; 19(3): 264-70.
[http://dx.doi.org/10.1038/gt.2011.85] [PMID: 21716303]
[72]
Comerota AJ, Throm RC, Miller KA, et al. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: Preliminary results of a phase I trial. J Vasc Surg 2002; 35(5): 930-6.
[http://dx.doi.org/10.1067/mva.2002.123677] [PMID: 12021709]
[73]
Belch J, Hiatt WR, Baumgartner I, et al. Effect of fibroblast growth factor NV1FGF on amputation and death: A randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet 2011; 377(9781): 1929-37.
[http://dx.doi.org/10.1016/S0140-6736(11)60394-2] [PMID: 21621834]
[74]
Yonemitsu Y, Matsumoto T, Itoh H, et al. DVC1-0101 to treat peripheral arterial disease: A Phase I/IIa open-label dose-escalation clinical trial. Mol Ther 2013; 21(3): 707-14.
[http://dx.doi.org/10.1038/mt.2012.279] [PMID: 23319060]
[75]
Hiasa K, Ishibashi M, Ohtani K, et al. Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: Next-generation chemokine therapy for therapeutic neovascularization. Circulation 2004; 109(20): 2454-61.
[http://dx.doi.org/10.1161/01.CIR.0000128213.96779.61] [PMID: 15148275]
[76]
Edwards BB, Fairman AS, Cohen JE, et al. Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb. J Vasc Surg 2016; 64(4): 1093-9.
[http://dx.doi.org/10.1016/j.jvs.2015.06.140] [PMID: 26372192]
[77]
Hammad TA, Rundback J, Bunte M, et al. Stromal cell-derived factor-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD) trial: Six-month results. J Endovasc Ther 2020; 27(4): 669-75.
[http://dx.doi.org/10.1177/1526602820919951] [PMID: 32419594]
[78]
van Royen N, Schirmer SH, Atasever B, et al. START Trial: A pilot study on stimulation of arteriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. Circulation 2005; 112(7): 1040-6.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.529552] [PMID: 16087795]
[79]
McDermott MM, Ferrucci L, Tian L, et al. Effect of granulocyte-macrophage colony-stimulating factor with or without supervised exercise on walking performance in patients with peripheral artery disease: The PROPEL randomized clinical trial. JAMA 2017; 318(21): 2089-98.
[http://dx.doi.org/10.1001/jama.2017.17437] [PMID: 29141087]
[80]
Suri C, McClain J, Thurston G, et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 1998; 282(5388): 468-71.
[http://dx.doi.org/10.1126/science.282.5388.468] [PMID: 9774272]
[81]
Sheng J, Xu Z. Three decades of research on angiogenin: A review and perspective. Acta Biochim Biophys Sin (Shanghai) 2016; 48(5): 399-410.
[http://dx.doi.org/10.1093/abbs/gmv131] [PMID: 26705141]
[82]
Avdeeva SV, Voronov DA, Khaĭdarova NV, et al. The CELO-ANG recombinant avian adenovirus with human angiogenine gene inducing neovascularization in the anterior tibial muscle of rat. Mol Gen Mikrobiol Virusol (Russian) 2004; (4): 38-40.
[PMID: 15597571]
[83]
Zhao XY, Hu SJ, Li J, et al. rAAV-mediated angiogenin gene transfer induces angiogenesis and modifies left ventricular remodeling in rats with myocardial infarction. J Mol Med (Berl) 2006; 84(12): 1033-46.
[http://dx.doi.org/10.1007/s00109-006-0092-y] [PMID: 16955274]
[84]
Bochkov NP, Konstantinov BA, Gavrilenko AV, et al. The technologies of genetic engineering in treatment of chronic lower limb ischemia. Vestn Russ Akad Med Nauk (Russian) 2006; (9-10): 6-11.
[PMID: 17111917]
[85]
Makarevich P, Tsokolaeva Z, Shevelev A, et al. Combined transfer of human VEGF165 and HGF genes renders potent angiogenic effect in ischemic skeletal muscle. PLoS One 2012; 7(6)e38776
[http://dx.doi.org/10.1371/journal.pone.0038776] [PMID: 22719942]
[86]
Barć P, Antkiewicz M, Śliwa B, Baczyńska D, Witkiewicz W, Skóra JP. Treatment of critical limb ischemia by pIRES/VEGF165/HGF administration. Ann Vasc Surg 2019; 60: 346-54.
[http://dx.doi.org/10.1016/j.avsg.2019.03.013] [PMID: 31200059]
[87]
Hu GJ, Feng YG, Lu WP, Li HT, Xie HW, Li SF. Effect of combined VEGF165/SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia. J Neurosurg 2017; 127(3): 670-8.
[http://dx.doi.org/10.3171/2016.9.JNS161234] [PMID: 27982773]
[88]
Chae JK, Kim I, Lim ST, et al. Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol 2000; 20(12): 2573-8.
[http://dx.doi.org/10.1161/01.ATV.20.12.2573] [PMID: 11116055]
[89]
Chen F, Tan Z, Dong CY, Chen X, Guo SF. Adeno-associated virus vectors simultaneously encoding VEGF and angiopoietin-1 enhances neovascularization in ischemic rabbit hind-limbs. Acta Pharmacol Sin 2007; 28(4): 493-502.
[http://dx.doi.org/10.1111/j.1745-7254.2007.00527.x] [PMID: 17376288]
[90]
Barć P, Płonek T, Baczyńska D, et al. Role of vascular endothelial growth factor in inducing production of angiopoetin-1 - in vivo study in Fisher rats. Pol J Pathol 2017; 68(4): 326-9.
[http://dx.doi.org/10.5114/pjp.2017.73549] [PMID: 29517203]
[91]
Flugelman MY, Halak M, Yoffe B, et al. Phase Ib safety, two-dose study of multiGeneAngio in patients with chronic critical limb ischemia. Mol Ther 2017; 25(3): 816-25.
[http://dx.doi.org/10.1016/j.ymthe.2016.12.019] [PMID: 28143739]
[92]
Gavrilenko AV, Voronov DA, Bochkov NP. Complex treatment of patients with chronic lower limb ischemia using gene inducers of angiogenesis: Immediate and long-term results. Genes Cells 2011; 6(3): 84-8.
[93]
Gavrilenko AV, Voronov DA, Bochkov NP. The use of genetic angiogenesis inductors in surgical treatment of chronic lower limb ischemia. Khirurgiia (Russian) 2013; (2): 25-9.
[PMID: 23503379]
[94]
Ieda Y, Fujita J, Ieda M, et al. G-CSF and HGF: Combination of vasculogenesis and angiogenesis synergistically improves recovery in murine hind limb ischemia. J Mol Cell Cardiol 2007; 42(3): 540-8.
[http://dx.doi.org/10.1016/j.yjmcc.2006.11.015] [PMID: 17223129]
[95]
Heuslein JL, Gorick CM, Price RJ. Epigenetic regulators of the revascularization response to chronic arterial occlusion. Cardiovasc Res 2019; 115(4): 701-12.
[http://dx.doi.org/10.1093/cvr/cvz001] [PMID: 30629133]
[96]
Pérez-Cremades D, Cheng HS, Feinberg MW. Noncoding RNAs in critical limb ischemia. Arterioscler Thromb Vasc Biol 2020; 40(3): 523-33.
[http://dx.doi.org/10.1161/ATVBAHA.119.312860] [PMID: 31893949]
[97]
Bonauer A, Carmona G, Iwasaki M, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 2009; 324(5935): 1710-3.
[http://dx.doi.org/10.1126/science.1174381] [PMID: 19460962]
[98]
Caporali A, Meloni M, Völlenkle C, et al. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation 2011; 123(3): 282-91.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.952325] [PMID: 21220732]
[99]
Heuslein JL, McDonnell SP, Song J, Annex BH, Price RJ. MicroRNA-146a regulates perfusion recovery in response to arterial occlusion via arteriogenesis. Front Bioeng Biotechnol 2018; 6: 1-13.
[http://dx.doi.org/10.3389/fbioe.2018.00001] [PMID: 29404323]
[100]
Desjarlais M, Dussault S, Dhahri W, Mathieu R, Rivard A. MicroRNA-150 modulates schemia-induced neovascularization in atherosclerotic conditions. Arterioscler Thromb Vasc Biol 2017; 37(5): 900-8.
[http://dx.doi.org/10.1161/ATVBAHA.117.309189] [PMID: 28254813]
[101]
Hazarika S, Farber CR, Dokun AO, et al. MicroRNA-93 controls perfusion recovery after hindlimb ischemia by modulating expression of multiple genes in the cell cycle pathway. Circulation 2013; 127(17): 1818-28.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000860] [PMID: 23559675]
[102]
Martello A, Mellis D, Meloni M, et al. Phenotypic miRNA screen identifies miR-26b to promote the growth and survival of endothelial cells. Mol Ther Nucleic Acids 2018; 13: 29-43.
[http://dx.doi.org/10.1016/j.omtn.2018.08.006] [PMID: 30227275]
[103]
Uchida S, Dimmeler S. Long noncoding RNAs in cardiovascular diseases. Circ Res 2015; 116(4): 737-50.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.302521] [PMID: 25677520]
[104]
Simion V, Haemmig S, Feinberg MW. LncRNAs in vascular biology and disease. Vascul Pharmacol 2019; 114: 145-56.
[http://dx.doi.org/10.1016/j.vph.2018.01.003]
[105]
Zhao Z, Sun W, Guo Z, Zhang J, Yu H, Liu B. Mechanisms of lncRNA/microRNA interactions in angiogenesis. Life Sci 2020; 254116900
[http://dx.doi.org/10.1016/j.lfs.2019.116900] [PMID: 31786194]
[106]
Ren L, Wei C, Li K, Lu Z. LncRNA MALAT1 up-regulates VEGF-A and ANGPT2 to promote angiogenesis in brain microvascular endothelial cells against oxygen-glucose deprivation via targetting miR-145. Biosci Rep 2019; 39(3)BSR20180226
[http://dx.doi.org/10.1042/BSR20180226] [PMID: 30038058]
[107]
Zhang X, Tang X, Hamblin MH, Yin KJ. Long non-coding RNA Malat1 regulates angiogenesis in hind limb ischemia. Int J Mol Sci 2018; 19(6): 1723-37.
[http://dx.doi.org/10.3390/ijms19061723] [PMID: 29891768]
[108]
Müller R, Weirick T, John D, et al. ANGIOGENES: Knowledge database for protein-coding and noncoding RNA genes in endothelial cells. Sci Rep 2016; 6: 32475.
[http://dx.doi.org/10.1038/srep32475] [PMID: 27582018]
[109]
Deroanne CF, Hajitou A, Calberg-Bacq CM, Nusgens BV, Lapière CM. Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. Cancer Res 1997; 57(24): 5590-7.
[PMID: 9407972]
[110]
Rosell A, Arai K, Lok J, et al. Interleukin-1β augments angiogenic responses of murine endothelial progenitor cells in vitro. J Cereb Blood Flow Metab 2009; 29(5): 933-43.
[http://dx.doi.org/10.1038/jcbfm.2009.17] [PMID: 19240740]
[111]
Song Y, Li X, Wang D, et al. Transcription factor Krüppel-like factor 2 plays a vital role in endothelial colony forming cells differentiation. Cardiovasc Res 2013; 99(3): 514-24.
[http://dx.doi.org/10.1093/cvr/cvt113] [PMID: 23667185]
[112]
Kimáková P, Solár P, Solárová Z, Komel R, Debeljak N. Erythropoietin and its angiogenic activity. Int J Mol Sci 2017; 18(7): 1519-32.
[http://dx.doi.org/10.3390/ijms18071519]
[113]
Moriya J, Wu X, Zavala-Solorio J, Ross J, Liang XH, Ferrara N. Platelet-derived growth factor C promotes revascularization in ischemic limbs of diabetic mice. J Vasc Surg 2014; 59(5): 1402-9.
[http://dx.doi.org/10.1016/j.jvs.2013.04.053] [PMID: 23856609]
[114]
Zhu Y, Gao M, Zhou T, et al. The TRPC5 channel regulates angiogenesis and promotes recovery from ischemic injury in mice. J Biol Chem 2019; 294(1): 28-37.
[http://dx.doi.org/10.1074/jbc.RA118.005392] [PMID: 30413532]
[115]
Neale JPH, Pearson JT, Thomas KN, et al. Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease. Sci Rep 2020; 10(1): 13651.
[http://dx.doi.org/10.1038/s41598-020-70391-6] [PMID: 32788622]
[116]
Guo Z, Mo Z. Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. J Tissue Eng Regen Med 2020; 14(6): 869-83.
[http://dx.doi.org/10.1002/term.3053] [PMID: 32336035]
[117]
Meng S, Gu Q, Yang X, et al. TBX20 regulates angiogenesis through the PROK2-PROKR1 pathway. Circulation 2018; 138(9): 931-28.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033939] [PMID: 29545372]
[118]
Shaikh IA, Rishi MT, Youssef M, et al. Overexpression of Thioredoxin1 enhances functional recovery in a mouse model of hind limb ischemia. J Surg Res 2017; 216: 158-68.
[http://dx.doi.org/10.1016/j.jss.2017.04.019] [PMID: 28807201]
[119]
Wang X, Su B, Gao B, et al. Cascaded bio-responsive delivery of eNOS gene and ZNF580 gene to collaboratively treat hindlimb ischemia via pro-angiogenesis and anti-inflammation. Biomater Sci 2020; 8(23): 6545-60.
[http://dx.doi.org/10.1039/D0BM01573C] [PMID: 33112303]
[120]
Michalik KM, You X, Manavski Y, et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 2014; 114(9): 1389-97.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.303265] [PMID: 24602777]
[121]
Boon RA, Hofmann P, Michalik KM, et al. Long noncoding RNA Meg3 controls endothelial cell aging and function: Implications for regenerative angiogenesis. J Am Coll Cardiol 2016; 68(23): 2589-91.
[http://dx.doi.org/10.1016/j.jacc.2016.09.949] [PMID: 27931619]
[122]
Ma C-C, Wang Z-L, Xu T, He Z-Y, Wei Y-Q. The approved gene therapy drugs worldwide: From 1998 to 2019. Biotechnol Adv 2020; 40107502
[http://dx.doi.org/10.1016/j.biotechadv.2019.107502] [PMID: 31887345]
[123]
Forster R, Liew A, Bhattacharya V, Shaw J, Stansby G. Gene therapy for peripheral arterial disease. Cochrane Database Syst Rev 2018; 10CD012058
[http://dx.doi.org/10.1002/14651858.CD012058.pub2] [PMID: 30380135]
[124]
Conway EM, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth. Cardiovasc Res 2001; 49(3): 507-21.
[http://dx.doi.org/10.1016/S0008-6363(00)00281-9] [PMID: 11166264]
[125]
Klarin D, Lynch J, Aragam K, et al. Genome-wide association study of peripheral artery disease in the Million Veteran Program. Nat Med 2019; 25(8): 1274-9.
[http://dx.doi.org/10.1038/s41591-019-0492-5] [PMID: 31285632]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version296msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[06:44:46] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[06:44:46] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[06:44:46] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[06:44:46] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (98.37ms)time
  • Application (198ms)time
  • 1 x Application (66.77%)
    198ms
    1 x Booting (33.23%)
    98.37ms
    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
    40 statements were executed, 4 of which were duplicates, 36 unique. Show only duplicated119ms
    • 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 ('59699349','',1,1740552286,1740552286) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740552286
      1.16msalphaeurekaselec_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 ('59699349','/article/116654/cn',1,1740552286,1740552286)
      180μsalphaeurekaselec_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 >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) 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 >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) 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 >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) 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 >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) 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 >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) 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 >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59699349 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59699349) limit 1
      18.2msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59699349
      • 1: 59699349
      • 2: 59699349
      • 3: 59699349
      • 4: 59699349
      • 5: 59699349
      • 6: 59699349
      • 7: 59699349
      • 8: 59699349
      • 9: 59699349
      • 10: 59699349
      • 11: 59699349
      • 12: 59699349
      • 13: 59699349
      • 14: 59699349
      • 15: 59699349
      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=116654
      970μsalphaeurekaselec_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` = 28 limit 1
      1.24msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 28
      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=28) and sj.journal_id!=28 group by `j`.`nid`) as `aggregate_table`
      1.2msalphaeurekaselec_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=28) and sj.journal_id!=28 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.03msalphaeurekaselec_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=28) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.05msalphaeurekaselec_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=28) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.26msalphaeurekaselec_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` = '116654'
      1.14msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 116654
      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` = '116654'
      3.34msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 116654
      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` = '116654' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.81msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 116654
      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
      260μsalphaeurekaselec_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
      510μsalphaeurekaselec_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 = 28 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      41.2msalphaeurekaselec_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 = 28 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      7.57msalphaeurekaselec_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 = 28 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      4.08msalphaeurekaselec_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` = 116654 limit 1
      250μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 116654
      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 = 116654 and content_type = 'article' order by status desc limit 1
      270μsalphaeurekaselec_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` = 194718 limit 1
      210μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 194718
      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
      230μsalphaeurekaselec_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` = 'CGT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      310μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CGT
      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 = '116654' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      390μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '11356' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      320μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '3245' 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) )
      280μsalphaeurekaselec_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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3245) 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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3245) 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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3245)
      8.06msalphaeurekaselec_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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11356) 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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11356) 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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11356)
      660μsalphaeurekaselec_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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 116654) 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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 116654) 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 <= 59699349 and j.to_ip >=59699349 )) and ((j.from_date <= 1740552286 and j.to_date >= 1740552286 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 116654)
      650μsalphaeurekaselec_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` < '214' and is_uploaded = 1 and issue_id = 11356 order by cast(first_page as SIGNED) desc limit 1
      510μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 214
      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` > '227' and is_uploaded = 1 and issue_id = 11356 order by cast(first_page as SIGNED) asc limit 1
      470μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 227
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'cn'
      190μsalphaeurekaselec_live_10_06_2022ArticleController.php#2486
      Bindings
      • 0: cn
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2486
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 2
      240μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 2
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2487
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `multilanguage_article` where (`language_id` = 2 and `article_id` = 116654)
      5.66msalphaeurekaselec_live_10_06_2022ArticleController.php#2488
      Bindings
      • 0: 2
      • 1: 116654
      Backtrace
      • 15. app/Http/Controllers/ArticleController.php:2488
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `keyword` from `multilanguage_keywords` where (`language_id` = 2 and `article_id` = 116654)
      2.49msalphaeurekaselec_live_10_06_2022ArticleController.php#2489
      Bindings
      • 0: 2
      • 1: 116654
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2489
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT_WS(' ',au.last_name, ', ', ifnull(au.initials,''), ' ', au.first_name) as authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs , `au`.*, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `multilanguage_authors` as `au` left join `multilanguage_author_affiliation` as `af` on `au`.`id` = `af`.`author_id` where `au`.`article_id` = 116654 group by `au`.`id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.76msalphaeurekaselec_live_10_06_2022MultiLangAuthor.php#30
      Bindings
      • 0: 116654
      Backtrace
      • 13. app/Models/MultiLangAuthor.php:30
      • 14. app/Http/Controllers/ArticleController.php:2493
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `multilanguage_journal`.`title` from `multilanguage_journal` where `multilanguage_journal`.`journal_id` = 28 and `language_id` = 2
      220μsalphaeurekaselec_live_10_06_2022ArticleController.php#2495
      Bindings
      • 0: 28
      • 1: 2
      Backtrace
      • 13. app/Http/Controllers/ArticleController.php:2495
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `id` from `multilanguage_article` where `article_id` = 116654 limit 1
      2.36msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 116654
      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` = 28 and `b`.`banner_from_date` <= 1740552286 and `b`.`banner_to_date` >= 1740552286 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.16msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 28
      • 3: 1740552286
      • 4: 1740552286
      • 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` = 28 and `b`.`banner_from_date` <= 1740552286 and `b`.`banner_to_date` >= 1740552286 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: 28
      • 3: 1740552286
      • 4: 1740552286
      • 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='1908c21d13180dd52eddfdc2e6bc0957'
      230μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLangArticle
    2MultiLangArticle.php#?
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        hoxyQUNmILXe0XxPrqMdKOZzPRXT6Inyje4wBq1g
        uc_cart_id
        1908c21d13180dd52eddfdc2e6bc0957
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/116654/cn" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/116654/cn
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Wed, 26 Feb 2025 06:44:46 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImxINVZZcVYxWTZpbkVtSlU4YVRBQWc9PSIsInZhbHVlIjoiMGVEQ2lDUXQ1VlQyWUp3UllsUGY4WnZhb1QrVTAvR2dFTVIwV3VSR0FsZWE3Wk14R0owbHg4UHV0SnRUbzRzR3NTVFl4dUdyRWE3MkhibE40SWk3TmdwMEMveXpqZ3d3Q0kvVDNsdHVUN2ZjMDkrTDNMLzlXemZzeVErMjFCS0UiLCJtYWMiOiJhZmIwNDllNThiY2UzOTgyNzU3N2M2YzU2NTkxYTk3MTVlYThkNjI5ODJmYjY5OTg3YWE4ODQzYTFiYTk4ZTgyIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 18:44:46 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImxINVZZcVYxWTZpbkVtSlU4YVRBQWc9PSIsInZhbHVlIjoiMGVEQ2lDUXQ1VlQyWUp3UllsUGY4WnZhb1QrVTAvR2dFTVIwV3VSR0FsZWE3Wk14R0owbHg4UHV0SnRUbzRzR3NTVFl4d" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjVsWGlKd3VmWUFqTCtJNU5kZDdJOGc9PSIsInZhbHVlIjoiV3BWaDVWUmlBZVdKR1I2N1FSUXI1VjV1azVEcFZWVWpMNmQzN1dTVExhTnFoZkRIbHRQMzVxRFZyWVFyYmdqa0VvdnVSUXY4b3B1UFZjSmxuUzZHcWptSDhSbWpBejd1N2xYcWYzdXoxTWd3ZVdTNXJOYjBtQWUwZGdIc29TZ0MiLCJtYWMiOiI3Zjk2MmVlMzViNmU0YjE5MDNjODFkYTNlZDgxZDI0YjhjNDM5NjkwMTkwMDc0ZjQ1MzZlYWYwNWZkMzU3ZDdjIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IjVsWGlKd3VmWUFqTCtJNU5kZDdJOGc9PSIsInZhbHVlIjoiV3BWaDVWUmlBZVdKR1I2N1FSUXI1VjV1azVEcFZWVWpMNmQzN1dTVExhTnFoZkRIbHRQMzVxRFZ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImxINVZZcVYxWTZpbkVtSlU4YVRBQWc9PSIsInZhbHVlIjoiMGVEQ2lDUXQ1VlQyWUp3UllsUGY4WnZhb1QrVTAvR2dFTVIwV3VSR0FsZWE3Wk14R0owbHg4UHV0SnRUbzRzR3NTVFl4dUdyRWE3MkhibE40SWk3TmdwMEMveXpqZ3d3Q0kvVDNsdHVUN2ZjMDkrTDNMLzlXemZzeVErMjFCS0UiLCJtYWMiOiJhZmIwNDllNThiY2UzOTgyNzU3N2M2YzU2NTkxYTk3MTVlYThkNjI5ODJmYjY5OTg3YWE4ODQzYTFiYTk4ZTgyIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 18:44:46 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImxINVZZcVYxWTZpbkVtSlU4YVRBQWc9PSIsInZhbHVlIjoiMGVEQ2lDUXQ1VlQyWUp3UllsUGY4WnZhb1QrVTAvR2dFTVIwV3VSR0FsZWE3Wk14R0owbHg4UHV0SnRUbzRzR3NTVFl4d" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjVsWGlKd3VmWUFqTCtJNU5kZDdJOGc9PSIsInZhbHVlIjoiV3BWaDVWUmlBZVdKR1I2N1FSUXI1VjV1azVEcFZWVWpMNmQzN1dTVExhTnFoZkRIbHRQMzVxRFZyWVFyYmdqa0VvdnVSUXY4b3B1UFZjSmxuUzZHcWptSDhSbWpBejd1N2xYcWYzdXoxTWd3ZVdTNXJOYjBtQWUwZGdIc29TZ0MiLCJtYWMiOiI3Zjk2MmVlMzViNmU0YjE5MDNjODFkYTNlZDgxZDI0YjhjNDM5NjkwMTkwMDc0ZjQ1MzZlYWYwNWZkMzU3ZDdjIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IjVsWGlKd3VmWUFqTCtJNU5kZDdJOGc9PSIsInZhbHVlIjoiV3BWaDVWUmlBZVdKR1I2N1FSUXI1VjV1azVEcFZWVWpMNmQzN1dTVExhTnFoZkRIbHRQMzVxRFZ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "hoxyQUNmILXe0XxPrqMdKOZzPRXT6Inyje4wBq1g" "uc_cart_id" => "1908c21d13180dd52eddfdc2e6bc0957" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/116654/cn" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-26 06:44:46GET/article/116654/cn414403