Suicide Gene Therapy Against Malignant Gliomas by the Local Delivery of Genetically Engineered Umbilical Cord Mesenchymal Stem Cells as Cellular Vehicles

Author(s): Dan Wei, JiaLi Hou, Ke Zheng, Xin Jin, Qi Xie, Lamei Cheng, Xuan Sun*.

Journal Name: Current Gene Therapy

Volume 19 , Issue 5 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Glioblastoma (GBM) is a malignant tumor that is difficult to eliminate, and new therapies are thus strongly desired. Mesenchymal stem cells (MSCs) have the ability to locate to injured tissues, inflammation sites and tumors and are thus good candidates for carrying antitumor genes for the treatment of tumors. Treating GBM with MSCs that have been transduced with the herpes simplex virus thymidine kinase (HSV-TK) gene has brought significant advances because MSCs can exert a bystander effect on tumor cells upon treatment with the prodrug ganciclovir (GCV).

Objective: In this study, we aimed to determine whether HSV-TK-expressing umbilical cord mesenchymal stem cells (MSCTKs) together with prodrug GCV treatment could exert a bystander killing effect on GBM.

Methods and Results: Compared with MSCTK: U87 ratio at 1:10,1:100 and 1:100, GCV concentration at 2.5µM or 250µM, when MSCTKs were cocultured with U87 cells at a ratio of 1:1, 25 µM GCV exerted a more stable killing effect. Higher amounts of MSCTKs cocultured with U87 cells were correlated with a better bystander effect exerted by the MSCTK/GCV system. We built U87-driven subcutaneous tumor models and brain intracranial tumor models to evaluate the efficiency of the MSCTK/GCV system on subcutaneous and intracranial tumors and found that MSCTK/GCV was effective in both models. The ratio of MSCTKs and tumor cells played a critical role in this therapeutic effect, with a higher MSCTK/U87 ratio exerting a better effect.

Conclusion: This research suggested that the MSCTK/GCV system exerts a strong bystander effect on GBM tumor cells, and this system may be a promising assistant method for GBM postoperative therapy.

Keywords: Mesenchymal stem cells, glioblastoma, HSV-TK, bystander effect, local gene therapy, umbilical cord, GCV.

[1]
Shen X, Venero JL, Joseph B, Burguillos MA. Caspases orchestrate microglia instrumental functions. Prog Neurobiol 2018; 171: 50-71.
[http://dx.doi.org/10.1016/j.pneurobio.2018.09.007] [PMID: 30290215]
[2]
Eslaminejad T, Nematollahi-Mahani SN, Ansari M. Glioblastoma targeted gene therapy based on pEGFP/p53-Loaded superparamagnetic iron oxide nanoparticles. Curr Gene Ther 2017; 17(1): 59-69.
[http://dx.doi.org/10.2174/1566523217666170605115829] [PMID: 28578643]
[3]
Balca-Silva J, Matias D, Carmo AD, Sarmento-Ribeiro AB, Lopes MC, Moura-Neto V. Cellular and molecular mechanisms of glioblastoma malignancy: Implications in resistance and therapeutic strategies. Semin Cancer Biol 2018; 58: 130-4.
[http://dx.doi.org/10.1016/j.semcancer.2018.09.007] [PMID: 30266571]
[4]
Akgul S, Patch AM, D’Souza RCJ, et al. Intratumoural heterogeneity underlies distinct therapy responses and treatment resistance in glioblastoma. Cancers (Basel) 2019; 11(2)pii: E190
[http://dx.doi.org/10.3390/cancers11020190]
[5]
Alifieris C, Trafalis DT. Glioblastoma multiforme: Pathogenesis and treatment. Pharmacol Ther 2015; 152: 63-82.
[http://dx.doi.org/10.1016/j.pharmthera.2015.05.005] [PMID: 25944528]
[6]
Castro MG, Candolfi M, Kroeger K, et al. Gene therapy and targeted toxins for glioma. Curr Gene Ther 2011; 11(3): 155-80.
[http://dx.doi.org/10.2174/156652311795684722]
[7]
Pan M, Zhang Y, Deng Z, Yan F, Hong G. Noninvasive and local delivery of adenoviral-mediated herpes simplex virus thymidine kinase to treat glioma through focused ultrasound-induced blood-brain barrier opening in rats. J Biomed Nanotechnol 2018; 14(12): 2031-41.
[http://dx.doi.org/10.1166/jbn.2018.2642] [PMID: 30305211]
[8]
Bai L, Liu Y, Guo K, et al. Ultrasound facilitates naturally equipped exosomes derived from macrophages and blood serum for orthotopic glioma treatment. ACS Appl Mater Interfaces 2019; 11(16): 14576-87.
[http://dx.doi.org/10.1021/acsami.9b00893] [PMID: 30900870]
[9]
Liang Q, Monetti C, Shutova MV, et al. Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 2018; 563(7733): 701-4.
[http://dx.doi.org/10.1038/s41586-018-0733-7] [PMID: 30429614]
[10]
Malik YS, Sheikh MA, Xing Z, et al. Polylysine-modified polyethylenimine polymer can generate genetically engineered mesenchymal stem cells for combinational suicidal gene therapy in glioblastoma. Acta Biomater 2018; 80: 144-53.
[http://dx.doi.org/10.1016/j.actbio.2018.09.015] [PMID: 30223091]
[11]
Han YS, Kim SM, Lee JH, Jung SK, Noh H, Lee SH. Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC -dependent enhancement of the mitochondrial function. J Pineal Res 2019; 66(1)e12535
[http://dx.doi.org/10.1111/jpi.12535] [PMID: 30372554]
[12]
Devarasetty M, Wang E, Soker S, Skardal A. Mesenchymal stem cells support growth and organization of host-liver colorectal-tumor organoids and possibly resistance to chemotherapy. Biofabrication 2017; 9(2)021002
[http://dx.doi.org/10.1088/1758-5090/aa7484] [PMID: 28589925]
[13]
Lu J, Shen X, Sun X, et al. Increased recruitment of endogenous stem cells and chondrogenic differentiation by a composite scaffold containing bone marrow homing peptide for cartilage regeneration. Theranostics 2018; 8(18): 5039-8.
[http://dx.doi.org/10.7150/thno.26981]
[14]
Cao Y, Gang X, Sun C, Wang G. Mesenchymal stem cells improve healing of diabetic foot ulcer. J Diabetes Res 2017; 2017:9328347.
[15]
Oikonomopoulos A, van Deen WK, Manansala AR, et al. Optimization of human mesenchymal stem cell manufacturing: The effects of animal/xeno-free media. Sci Rep 2015; 5: 16570.
[16]
Ragni E, Montemurro T, Montelatici E, et al. Differential microRNA signature of human mesenchymal stem cells from different sources reveals an “environmental-niche memory” for bone marrow stem cells. Exp Cell Res 2013; 319(10): 1562-74.
[http://dx.doi.org/10.1016/j.yexcr.2013.04.002] [PMID: 23578766]
[17]
Venugopal CKS, Rai KS, Pinnelli VB, Kutty BM, Dhanushkodi A. Neuroprotection by human dental pulp mesenchymal stem cells: From billions to nano. Curr Gene Ther 2018; 18(5): 307-23.
[http://dx.doi.org/10.2174/1566523218666180913152615] [PMID: 30209999]
[18]
Niess H, von Einem JC, Thomas MN, et al. Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): Study protocol of a phase I/II clinical trial. BMC Cancer 2015; 15: 237.
[19]
Yang N, Ding Y, Zhang Y, et al. Surface functionalization of polymeric nanoparticles with umbilical cord-derived mesenchymal stem cell membrane for tumor-targeted therapy. ACS Appl Mater Interfaces 2018; 10(27): 22963-73.
[http://dx.doi.org/10.1021/acsami.8b05363] [PMID: 29905067]
[20]
Barrett AN, Fong CY, Subramanian A, et al. Human wharton’s jelly mesenchymal stem cells show unique gene expression compared with bone marrow mesenchymal stem cells using single-cell RNA-Sequencing. Stem Cells Dev 2019; 28(3): 196-211.
[http://dx.doi.org/10.1089/scd.2018.0132] [PMID: 30484393]
[21]
Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Goncalves RM. Mesenchymal stromal cell secretome: Influencing therapeutic potential by cellular pre-conditioning. Front Immunol 2018; 9: 2837.
[22]
Xu H, Chen C, Hu L, Hou J. Gene-modified mesenchymal stem cell-based therapy in renal ischemia- reperfusion injury. Curr Gene Ther 2017; 17(6): 453-60.
[http://dx.doi.org/10.2174/1566523218666180214094253] [PMID: 29446737]
[23]
Tanna T, Sachan V. Mesenchymal stem cells: Potential in treatment of neurodegenerative diseases. Curr Stem Cell Res Ther 2014; 9(6): 513-21.
[http://dx.doi.org/10.2174/1574888X09666140923101110] [PMID: 25248677]
[24]
Liu S, Wang Y, Wang J, et al. A cancellous bone matrix system with specific mineralisation degrees for mesenchymal stem cell differentiation and bone regeneration. Biomater Sci 2019; 7(6): 2452-67.
[http://dx.doi.org/10.1039/C8BM01657G] [PMID: 30942200]
[25]
Rey-Rico A, Cucchiarini M. Smart and controllable rAAV gene delivery carriers in progenitor cells for human musculoskeletal regenerative medicine with a focus on the articular cartilage. Curr Gene Ther 2017; 17(2): 127-38.
[http://dx.doi.org/10.2174/1566523217666170510162459] [PMID: 28494738]
[26]
Abu-El-Rub E, Sequiera GL, Sareen N, et al. Hypoxia-induced 26S proteasome dysfunction increases immunogenicity of mesenchymal stem cells. Cell Death Dis 2019; 10(2): 90.
[27]
Fathi E, Farahzadi R, Sheikhzadeh N. Immunophenotypic characterization, multi-lineage differentiation and aging of zebrafish heart and liver tissue-derived mesenchymal stem cells as a novel approach in stem cell-based therapy. Tissue Cell 2019; 57: 15-21.
[http://dx.doi.org/10.1016/j.tice.2019.01.006] [PMID: 30947959]
[28]
Farahzadi R, Fathi E, Mesbah-Namin SA, Zarghami N. Anti-aging protective effect of L-carnitine as clinical agent in regenerative medicine through increasing telomerase activity and change in the hTERT promoter CpG island methylation status of adipose tissue-derived mesenchymal stem cells. Tissue Cell 2018; 54: 105-13.
[http://dx.doi.org/10.1016/j.tice.2018.08.012] [PMID: 30309499]
[29]
Babrnáková J, Pavliňáková V, Brtníková J, et al. Synergistic effect of bovine platelet lysate and various polysaccharides on the biological properties of collagen-based scaffolds for tissue engineering: Scaffold preparation, chemo-physical characterization, in vitro and ex ovo evaluation. Mater Sci Eng C 2019; 100: 236-46.
[http://dx.doi.org/10.1016/j.msec.2019.02.092] [PMID: 30948058]
[30]
Ji J, Weng Q, Zhang F, et al. Non-small-cell lung cancer: Feasibility of intratumoral radiofrequency hyperthermia-enhanced herpes simplex virus thymidine kinase gene therapy. Radiology 2018; 288(2): 612-20.
[31]
Li L, Ni L, Eugenin EA, Heary RF, Elkabes S. Toll-like receptor 9 antagonism modulates astrocyte function and preserves proximal axons following spinal cord injury. Brain Behav Immun 2019; 80: 328-43.
[http://dx.doi.org/10.1016/j.bbi.2019.04.010] [PMID: 30953770]
[32]
King JG, Hillyer JF. Spatial and temporal in vivo analysis of circulating and sessile immune cells in mosquitoes: Hemocyte mitosis following infection. BMC Biol 2013; 11: 55.
[http://dx.doi.org/10.1186/1741-7007-11-55]
[33]
Abomaray F, Gidlöf S, Bezubik B, Engman M, Götherström C. Mesenchymal stromal cells support endometriotic stromal cells in vitro. Stem Cells Int 2018; 2018: 7318513.
[http://dx.doi.org/10.1155/2018/7318513] [PMID: 29535779]
[34]
Bian Y, Li Y, Shrestha G, et al. ITE, an endogenous aryl hydrocarbon receptor ligand, suppresses endometrial cancer cell proliferation and migration. Toxicology 2019; 421: 1-8.
[http://dx.doi.org/10.1016/j.tox.2019.03.017] [PMID: 30953668]
[35]
Morten BC, Scott RJ, Avery-Kiejda KA. Comparison of Three different methods for determining cell proliferation in breast cancer cell lines. J Vis Exp 2016; 115: e54350.
[36]
Fathi E, Farahzadi R, Valipour B, Sanaat Z. Cytokines secreted from bone marrow derived mesenchymal stem cells promote apoptosis and change cell cycle distribution of K562 cell line as clinical agent in cell transplantation. PLoS One 2019; 14(4): e0215678.
[37]
Philips J, Van den Driessche N, De Paepe K, et al. A novel shewanella isolate enhances corrosion by using metallic iron as the electron donor with fumarate as the electron acceptor. Appl Environ Microbiol 2018; 84(20): 1-18.
[38]
Xiao J, Wang X, Wu Y, et al. Synergistic effect of resveratrol and HSV-TK/GCV therapy on murine hepatoma cells. Cancer Biol Ther 2019; 20(2): 183-91.
[http://dx.doi.org/10.1080/15384047.2018.1523094] [PMID: 30257140]
[39]
Domínguez A, Salazar Z, Betancourt M, et al. Effect of perfluorodecanoic acid on pig oocyte viability, intracellular calcium levels and gap junction intercellular communication during oocyte maturation in vitro. Toxicol In Vitro 2019; 58: 224-9.
[http://dx.doi.org/10.1016/j.tiv.2019.03.041] [PMID: 30946969]
[40]
Tian LL, Yue W, Zhu F, Li S, Li W, Li W. Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol 2011; 226(7): 1860-7.
[http://dx.doi.org/10.1002/jcp.22511] [PMID: 21442622]
[41]
Ma F, Chen D, Chen F, et al. Human umbilical cord mesenchymal stem cells promote breast cancer metastasis by interleukin-8- and interleukin-6-dependent induction of CD44(+)/CD24(-) cells. Cell Transplant 2015; 24(12): 2585-99.
[http://dx.doi.org/10.3727/096368915X687462] [PMID: 25695620]
[42]
Chao KC, Yang HT, Chen MW. Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization. J Cell Mol Med 2012; 16(8): 1803-5.
[43]
Jiao Y, Zhao H, Chen G, et al. Pyroptosis of MCF7 cells induced by the secreted factors of hUCMSCs. Stem Cells Int 2018; 2018: 1-12.
[http://dx.doi.org/10.1155/2018/5912194]
[44]
Akimoto K, Kimura K, Nagano M, et al. Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation. Stem Cells Dev 2013; 22(9): 1370-86.
[http://dx.doi.org/10.1089/scd.2012.0486]
[45]
Tan K, Zheng K, Li D, Lu H, Wang S, Sun X. Impact of adipose tissue or umbilical cord derived mesenchymal stem cells on the immunogenicity of human cord blood derived endothelial progenitor cells. PLoS One 2017; 12(5)e0178624
[46]
Ma S, Liang S, Jiao H, et al. Human umbilical cord mesenchymal stem cells inhibit C6 glioma growth via secretion of dickkopf-1 (DKK1). Mol Cell Biochem 2014; 385(1-2): 277-86.
[http://dx.doi.org/10.1007/s11010-013-1836-y] [PMID: 24104453]
[47]
Yang C, Lei D, Ouyang W, et al. Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. BioMed Res Int 2014; 2014: 1-13.
[http://dx.doi.org/10.1155/2014/109389]
[48]
Jee MH, Johansen JD, Buus TB, et al. Increased production of IL-17A-Producing gammadelta T cells in the thymus of filaggrin-deficient mice. Front Immunol 2018; 9: 988.
[49]
Zong L, Peng H, Sun C, et al. Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice. Nat Commun 2019; 10(1): 221.
[http://dx.doi.org/10.1038/s41467-018-08096-8]
[50]
Rosen SF, Ham B, Haichin M, et al. Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences. Pain 2019; 160(2): 358-66.
[http://dx.doi.org/10.1097/j.pain.0000000000001420] [PMID: 30335680]
[51]
Martin JL, Julovi SM, Lin MZ, de Silva HC, Boyle FM, Baxter RC. Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade. Breast Cancer Res 2017; 19(1): 90.
[http://dx.doi.org/10.1186/s13058-017-0882-x]
[52]
Wang K, Wang H, Lou W, et al. IP-10 promotes blood-brain barrier damage by inducing tumor necrosis factor alpha production in Japanese encephalitis. Front Immunol 2018; 9: 1148.
[53]
Alexander JJ. Blood-brain barrier (BBB) and the complement landscape. Mol Immunol 2018; 102: 26-31.
[http://dx.doi.org/10.1016/j.molimm.2018.06.267] [PMID: 30007547]
[54]
Hoornaert CJ, Le Blon D, Quarta A, et al. Concise review: Innate and adaptive immune recognition of allogeneic and xenogeneic cell transplants in the central nervous system. Stem Cells Transl Med 2017; 6(5): 1434-41.
[55]
Wan Z, Sun J, Xu J, et al. Dual functional immunostimulatory polymeric prodrug carrier with pendent indoximod for enhanced cancer immunochemotherapy. Acta Biomater 2019; 90: 300-13.
[http://dx.doi.org/10.1016/j.actbio.2019.03.048] [PMID: 30930305]
[56]
Moradian Tehrani R, Verdi J, et al. Mesenchymal stem cells: A new platform for targeting suicide genes in cancer. J Cell Physiol 2018; 233(5): 3831-45.
[http://dx.doi.org/10.1002/jcp.26094] [PMID: 28703313]
[57]
Nielsen DA, Deng H, Patriquin MA, et al. Association of TPH1 and serotonin transporter genotypes with treatment response for suicidal ideation: A preliminary study. Eur Arch Psychiatry Clin Neurosci 2019. Epub ahead of print
[http://dx.doi.org/10.1007/s00406-019-01009-w] [PMID: 30923939]
[58]
Touati W, Tran T, Seguin J, et al. A suicide gene therapy combining the improvement of cyclophosphamide tumor cytotoxicity and the development of an anti-tumor immune response. Curr Gene Ther 2014; 14(3): 236-46.
[http://dx.doi.org/10.2174/1566523214666140424152734] [PMID: 24766134]
[59]
Zhang L, Hu XZ, Benedek DM, et al. Genetic predictor of current suicidal ideation in US service members deployed to Iraq and Afghanistan. J Psychiatr Res 2019; 113: 65-71.
[http://dx.doi.org/10.1016/j.jpsychires.2019.03.007] [PMID: 30904785]
[60]
Kimura Y, Shofuda T, Higuchi Y, et al. Human genomic safe harbors and the suicide gene-based safeguard system for iPSC-Based cell therapy. Stem Cells Transl Med 2019; 8(7): 627-38.
[http://dx.doi.org/10.1002/sctm.18-0039] [PMID: 30887735]
[61]
Caceres B, Ramirez A, Carrillo E, et al. Deciphering the mechanism of action involved in enhanced suicide gene colon cancer cell killer effect mediated by gef and apoptin. Cancers (Basel) 2019; 11(2)pii: E264
[http://dx.doi.org/10.3390/cancers11020264]
[62]
Yamasaki T, Wakao S, Kawaji H, et al. Genetically engineered multilineage-differentiating stress-enduring cells as cellular vehicles against malignant gliomas. Mol Ther Oncolytics 2017; 6: 45-56.
[http://dx.doi.org/10.1016/j.omto.2017.06.001]
[63]
Matuskova M, Hlubinova K, Pastorakova A, et al. HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. Cancer Lett 2010; 290(1): 58-67.
[http://dx.doi.org/10.1016/j.canlet.2009.08.028] [PMID: 19765892]
[64]
Niess H, Bao Q, Conrad C, et al. Selective targeting of genetically engineered mesenchymal stem cells to tumor stroma microenvironments using tissue-specific suicide gene expression suppresses growth of hepatocellular carcinoma. Ann Surg 2011; 254(5): 767-74.
[http://dx.doi.org/10.1097/SLA.0b013e3182368c4f] [PMID: 22042469]
[65]
Sulkowski M, Konieczny P, Chlebanowska P, Majka M. Introduction of exogenous HSV-TK suicide gene increases safety of keratinocyte-derived induced pluripotent stem cells by providing genetic “Emergency Exit” switch. Int J Mol Sci 2018; 19(1)pii: E197
[66]
Mohr A, Zwacka R. The future of mesenchymal stem cell-based therapeutic approaches for cancer - From cells to ghosts. Cancer Lett 2018; 414: 239-49.
[http://dx.doi.org/10.1016/j.canlet.2017.11.025] [PMID: 29175461]
[67]
Greco R, Oliveira G, Stanghellini MT, et al. Improving the safety of cell therapy with the TK-suicide gene. Front Pharmacol 2015; 6: 95.
[68]
von Einem JC, Peter S, Gunther C, et al. Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells - TREAT-ME-1 - a phase I, first in human, first in class trial. Oncotarget 2017; 8(46): 80156-66.
[69]
Shi Y, Wang J, Bai Z, et al. Radiofrequency hyperthermia-enhanced herpes simplex virus-thymidine kinase/ganciclovir direct intratumoral gene therapy of esophageal squamous cancers. Am J Cancer Res 2016; 6(9): 2054-63.
[70]
Zhang TY, Huang B, Wu HB, et al. Synergistic effects of co-administration of suicide gene expressing mesenchymal stem cells and prodrug-encapsulated liposome on aggressive lung melanoma metastases in mice. J Control Release 2015; 209: 260-71.
[http://dx.doi.org/10.1016/j.jconrel.2015.05.007] [PMID: 25966361]
[71]
Li S, Gu C, Gao Y, et al. Bystander effect in glioma suicide gene therapy using bone marrow stromal cells. Stem Cell Res (Amst) 2012; 9(3): 270-6.
[http://dx.doi.org/10.1016/j.scr.2012.08.002] [PMID: 23022734]
[72]
de Melo SM, Bittencourt S, Ferrazoli EG, et al. The anti-tumor effects of adipose tissue mesenchymal stem cell transduced with HSV-Tk gene on U-87-Driven brain tumor. PLoS One 2015; 10(6)e0128922
[73]
von Einem JC, Guenther C, Volk HD, et al. Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT-ME-1 trial. Int J Cancer 2019; 145(6): 1538-46.
[http://dx.doi.org/10.1002/ijc.32230] [PMID: 30801698]
[74]
Iwasawa C, Tamura R, Sugiura Y, et al. Increased cytotoxicity of herpes simplex virus thymidine kinase expression in human induced pluripotent stem cells. Int J Mol Sci 2019; 20(4)pii: E810
[http://dx.doi.org/10.3390/ijms20040810]
[75]
Luo J, Zhou J, Xie F, et al. Combined treatment of cholangiocarcinoma with interventional radiofrequency hyperthermia and heat shock protein promoter-mediated HSV-TK gene therapy. Am J Cancer Res 2018; 8(8): 1595-603.
[76]
Locher C, Frey Nascimento A, Kossowsky J, Meyer A, Gaab J. Open-label placebo response - Does optimism matter? A secondary-analysis of a randomized controlled trial. J Psychosom Res 2019; 116: 25-30.
[http://dx.doi.org/10.1016/j.jpsychores.2018.11.009] [PMID: 30654990]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [330 - 341]
Pages: 12
DOI: 10.2174/1566523219666191028103703
Price: $58

Article Metrics

PDF: 30
HTML: 2