Overexpression of Synoviolin and miR-125a-5p, miR-19b-3p in peripheral blood of rheumatoid arthritis patients after treatment with conventional DMARDs and methylprednisolone.

DMARDs Rheumatoid arthritis SYVN1 ncRNAs

Journal

Clinical rheumatology
ISSN: 1434-9949
Titre abrégé: Clin Rheumatol
Pays: Germany
ID NLM: 8211469

Informations de publication

Date de publication:
04 Dec 2023
Historique:
received: 11 04 2023
accepted: 31 10 2023
revised: 02 10 2023
medline: 5 12 2023
pubmed: 5 12 2023
entrez: 4 12 2023
Statut: aheadofprint

Résumé

SYVN1 is an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase that has an essential function along with SEL1L in rheumatoid arthritis (RA) pathogenesis. This study aimed to investigate the changes in the expression of peripheral blood ncRNAs and SYVN1-SEL1L affected by DMARDs treatment. Twenty-five newly diagnosed RA patients were randomly assigned to receive conventional DMARDs (csDMARDs) and methylprednisolone for six months. The peripheral blood gene expression of SYVN1 and SEL1L and possible regulatory axes, NEAT1, miR-125a-5p, and miR-19b-3p, were evaluated before and after qRT-PCR. We also compared differences between the patients and healthy controls (HCs), and statistical analyses were performed to determine the correlation between ncRNAs with SYVN1-SEL1L and the clinical parameters of RA. Expression of NEAT1 (P = 0.0001), miR-19b-3p (P = 0.007), miR-125a-5p (P = 0.005), and SYVN1 (P = 0.036) was significantly increased in newly diagnosed patients compared to HCs; also, miR-125a-5p, miR-19b-3p, and SYVN1 were significantly overexpressed after treatment (P = 0.001, P = 0.001, and P = 0.005, respectively). NEAT1 was positively correlated with SYVN1, and miR-125a-5p had a negative correlation with anti-cyclic citrullinated peptides. The ROC curve analysis showed the potential role of selected ncRNAs in RA pathogenesis. The results indicate the ineffectiveness of the csDMARDs in reducing SYVN1 expression. The difference in expression of ncRNAs might be useful markers for monitoring disease activity and determining therapeutic responses in RA patients. Key Points • The expression of NEAT1 is significantly upregulated in RA patients compared to HC subjects. • miR-19b-3p, miR-125a-5p, and SYVN1 are significantly upregulated in RA patients compared to HC subjects. • The expression of miR-19b-3p and miR-125a-5p is significantly increased in RA patients after treatment with DMARDs and methylprednisolone. • NEAT1 is positively correlated with SYVN1.

Identifiants

pubmed: 38049563
doi: 10.1007/s10067-023-06808-0
pii: 10.1007/s10067-023-06808-0
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Kermanshah University of Medical Sciences
ID : 4000650

Informations de copyright

© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).

Références

Anca C, Akilan K, Bence R (2021) Current view on the pathogenic role of anti-citrullinated protein antibodies in rheumatoid arthritis. RMD Open 7:e001228
doi: 10.1136/rmdopen-2020-001228
Pitzalis C, Kelly S, Humby F (2013) New learnings on the pathophysiology of RA from synovial biopsies. Curr Opin Rheumatol 25:334–344
pubmed: 23492740 doi: 10.1097/BOR.0b013e32835fd8eb
Mahmoudi Z, Karamali N, Roghani SA, Assar S, Pournazari M, Soufivand P, Salari F, Rezaiemanesh A (2022) Efficacy of DMARDs and methylprednisolone treatment on the gene expression levels of HSPA5, MMD, and non-coding RNAs MALAT1, H19, miR-199a-5p, and miR-1-3p, in patients with rheumatoid arthritis. Int Immunol 108:108878
Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poór G, Richez C, van Riel P, Rubbert-Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 76:960–977
pubmed: 28264816 doi: 10.1136/annrheumdis-2016-210715
Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, van Vollenhoven RF, de Wit M, Aletaha D, Aringer M, Askling J, Balsa A, Boers M, den Broeder AA, Buch MH, Buttgereit F, Caporali R, Cardiel MH, De Cock D, Codreanu C, Cutolo M, Edwards CJ, van Eijk-Hustings Y, Emery P, Finckh A, Gossec L, Gottenberg JE, Hetland ML, Huizinga TWJ, Koloumas M, Li Z, Mariette X, Müller-Ladner U, Mysler EF, da Silva JAP, Poór G, Pope JE, Rubbert-Roth A, Ruyssen-Witrand A, Saag KG, Strangfeld A, Takeuchi T, Voshaar M, Westhovens R, van der Heijde D (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79:685–699
pubmed: 31969328 doi: 10.1136/annrheumdis-2019-216655
Cronstein BN, Aune TM (2020) Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 16:145–154
pubmed: 32066940 doi: 10.1038/s41584-020-0373-9
Schrezenmeier E, Dörner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:155–166
pubmed: 32034323 doi: 10.1038/s41584-020-0372-x
Benjamin O, Goyal A, Lappin SL (2023) Disease modifying anti-rheumatic drugs (DMARD). StatPearls Publishing, Treasure Island (FL)
Tanaka Y (2020) Rheumatoid arthritis. Inflamm Regener 40:20
doi: 10.1186/s41232-020-00133-8
Sun S, Shi G, Sha H, Ji Y, Han X, Shu X, Ma H, Inoue T, Gao B, Kim H, Bu P, Guber RD, Shen X, Lee AH, Iwawaki T, Paton AW, Paton JC, Fang D, Tsai B, Yates JR 3rd, Wu H, Kersten S, Long Q, Duhamel GE, Simpson KW, Qi L (2015) IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat Cell Biol 17:1546–1555
pubmed: 26551274 pmcid: 4670240 doi: 10.1038/ncb3266
Omura T, Matsuda H, Nomura L, Imai S, Denda M, Nakagawa S, Yonezawa A, Nakagawa T, Yano I, Matsubara K (2018) Ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) prevents cell death in a cellular model of Parkinson’s disease. Biochem Biophys Res Commun 506:516–521
pubmed: 30361093 doi: 10.1016/j.bbrc.2018.10.094
Shrestha N, Liu T, Ji Y, Reinert RB, Torres M, Li X, Zhang M, Tang CA, Hu CA, Liu C, Naji A, Liu M, Lin JD, Kersten S, Arvan P, Qi L (2020) Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling. J Clin Investig 130:3499–3510
pubmed: 32182217 pmcid: 7324191 doi: 10.1172/JCI134874
Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci USA 97:12625–12630
pubmed: 11035797 pmcid: 18814 doi: 10.1073/pnas.220247197
Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258
pubmed: 10847680 doi: 10.1016/S0092-8674(00)80835-1
Yamasaki S, Yagishita N, Tsuchimochi K, Nishioka K, Nakajima T (2005) Rheumatoid arthritis as a hyper-endoplasmic-reticulum-associated degradation disease. Arthritis Res Ther 7:181–186
pubmed: 16207344 pmcid: 1257448 doi: 10.1186/ar1808
Yamasaki S, Yagishita N, Sasaki T, Nakazawa M, Kato Y, Yamadera T, Bae E, Toriyama S, Ikeda R, Zhang L, Fujitani K, Yoo E, Tsuchimochi K, Ohta T, Araya N, Fujita H, Aratani S, Eguchi K, Komiya S, Maruyama I, Higashi N, Sato M, Senoo H, Ochi T, Yokoyama S, Amano T, Kim J, Gay S, Fukamizu A, Nishioka K, Tanaka K, Nakajima T (2007) Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase “Synoviolin.” EMBO J 26:113–122
pubmed: 17170702 doi: 10.1038/sj.emboj.7601490
Gao B, Lee SM, Chen A, Zhang J, Zhang DD, Kannan K, Ortmann RA, Fang D (2008) Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Rep 9:480–485
pubmed: 18369366 pmcid: 2373369 doi: 10.1038/embor.2008.37
Kong S, Yang Y, Xu Y, Wang Y, Zhang Y, Melo-Cardenas J, Xu X, Gao B, Thorp EB, Zhang DD, Zhang B, Song J, Zhang K, Zhang J, Zhang J, Li H, Fang D (2016) Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proc Natl Acad Sci USA 113:10394–10399
pubmed: 27573825 pmcid: 5027446 doi: 10.1073/pnas.1606742113
Xu Y, Zhao F, Qiu Q, Chen K, Wei J, Kong Q, Gao B, Melo-Cardenas J, Zhang B, Zhang J, Song J, Zhang DD, Zhang J, Fan Y, Li H, Fang D (2016) The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nat Commun 7:12073
pubmed: 27417417 pmcid: 4947160 doi: 10.1038/ncomms12073
Yang Y, Kong S, Zhang Y, Melo-Cardenas J, Gao B, Zhang Y, Zhang DD, Zhang B, Song J, Thorp E, Zhang K, Zhang J, Fang D (2018) The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. J Biol Chem 293:12934–12944
pubmed: 29907570 pmcid: 6102136 doi: 10.1074/jbc.RA117.001267
Xu Y, Melo-Cardenas J, Zhang Y, Gau I, Wei J, Montauti E, Zhang Y, Gao B, Jin H, Sun Z, Lee SM, Fang D (2019) The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine-induced ER stress response. JCI Insight 4(5). https://doi.org/10.1172/jci.insight.121887
Mueller B, Lilley BN, Ploegh HL (2006) SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J Cell Biol 175:261–270
pubmed: 17043138 pmcid: 2064567 doi: 10.1083/jcb.200605196
Christianson JC, Olzmann JA, Shaler TA, Sowa ME, Bennett EJ, Richter CM, Tyler RE, Greenblatt EJ, Harper JW, Kopito RR (2011) Defining human ERAD networks through an integrative mapping strategy. Nat Cell Biol 14:93–105
pubmed: 22119785 pmcid: 3250479 doi: 10.1038/ncb2383
Sun S, Shi G, Han X, Francisco AB, Ji Y, Mendonça N, Liu X, Locasale JW, Simpson KW, Duhamel GE, Kersten S, Yates JR 3rd, Long Q, Qi L (2014) Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival. Proc Natl Acad Sci USA 111:E582-591
pubmed: 24453213 pmcid: 3918815 doi: 10.1073/pnas.1318114111
Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159
pubmed: 19188922 doi: 10.1038/nrg2521
Lao MX, Xu HS (2020) Involvement of long non-coding RNAs in the pathogenesis of rheumatoid arthritis. Chin Med J 133:941–950
pubmed: 32187055 pmcid: 7176443 doi: 10.1097/CM9.0000000000000755
Xiao J, Lin L, Luo D, Shi L, Chen W, Fan H, Li Z, Ma X, Ni P, Yang L, Xu Z (2020) Long noncoding RNA TRPM2-AS acts as a microRNA sponge of miR-612 to promote gastric cancer progression and radioresistance. Oncogenesis 9:29
pubmed: 32123162 pmcid: 7052141 doi: 10.1038/s41389-020-0215-2
Chatterjee S, Bhattcharjee D, Misra S, Saha A, Bhattacharyya NP, Ghosh A (2020) Increase in MEG3, MALAT1, NEAT1 significantly predicts the clinical parameters in patients with rheumatoid arthritis. Pers Med 17:445–457
doi: 10.2217/pme-2020-0009
Xiao J, Wang R, Zhou W, Cai X, Ye Z (2021) LncRNA NEAT1 regulates the proliferation and production of the inflammatory cytokines in rheumatoid arthritis fibroblast-like synoviocytes by targeting miR-204-5p. Hum Cell 34:372–382
pubmed: 33394349 doi: 10.1007/s13577-020-00461-4
Chakravarty D, Sboner A, Nair SS, Giannopoulou E, Li R, Hennig S, Mosquera JM, Pauwels J, Park K, Kossai M, MacDonald TY, Fontugne J, Erho N, Vergara IA, Ghadessi M, Davicioni E, Jenkins RB, Palanisamy N, Chen Z, Nakagawa S, Hirose T, Bander NH, Beltran H, Fox AH, Elemento O, Rubin MA (2014) The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat Commun 5:5383
pubmed: 25415230 doi: 10.1038/ncomms6383
Ahmed ASI, Dong K, Liu J, Wen T, Yu L, Xu F, Kang X, Osman I, Hu G, Bunting KM, Crethers D, Gao H, Zhang W, Liu Y, Wen K, Agarwal G, Hirose T, Nakagawa S, Vazdarjanova A, Zhou J (2018) Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells. Proc Natl Acad Sci USA 115:E8660-e8667
pubmed: 30139920 pmcid: 6140535 doi: 10.1073/pnas.1803725115
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581
pubmed: 20872595 doi: 10.1002/art.27584
Toh ML, Marotte H, Blond JL, Jhumka U, Eljaafari A, Mougin B, Miossec P (2006) Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatment. Arthritis Rheum 54:2109–2118
pubmed: 16802346 doi: 10.1002/art.21926
Wang J, Yan S, Yang J, Lu H, Xu D, Wang Z (2019) Non-coding RNAs in Rheumatoid Arthritis: From Bench to Bedside. Front Immunol 10:3129
pubmed: 32047497 doi: 10.3389/fimmu.2019.03129
Taheri M, Eghtedarian R, Dinger ME, Ghafouri-Fard S (2020) Dysregulation of non-coding RNAs in Rheumatoid arthritis. Biomed & Pharmacother Biomedecine & pharmacotherapie 130:110617
doi: 10.1016/j.biopha.2020.110617
Shui X, Chen S, Lin J, Kong J, Zhou C, Wu J (2019) Knockdown of lncRNA NEAT1 inhibits Th17/CD4(+) T cell differentiation through reducing the STAT3 protein level. J Cell Physiol 234:22477–22484
pubmed: 31119756 doi: 10.1002/jcp.28811
Murata K, Furu M, Yoshitomi H, Ishikawa M, Shibuya H, Hashimoto M, Imura Y, Fujii T, Ito H, Mimori T, Matsuda S (2013) Comprehensive microRNA analysis identifies miR-24 and miR-125a-5p as plasma biomarkers for rheumatoid arthritis. PLoS ONE 8:e69118
pubmed: 23874885 pmcid: 3715465 doi: 10.1371/journal.pone.0069118
Rezaeepoor M, Pourjafar M, Tahamoli-Roudsari A, Basiri Z, Hajilooi M, Solgi G (2020) Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients. Int Immunopharmacol 83:106404
pubmed: 32197230 doi: 10.1016/j.intimp.2020.106404
Safari F, Damavandi E, Rostamian AR, Movassaghi S, Imani-Saber Z, Saffari M, Kabuli M, Ghadami M (2021) Plasma Levels of MicroRNA-146a-5p, MicroRNA-24-3p, and MicroRNA-125a-5p as Potential Diagnostic Biomarkers for Rheumatoid Arthris. Iran J Allergy Asthma Immunol 20:326–337
pubmed: 34134454
Xiaoling G, Shuaibin L, Kailu L (2020) MicroRNA-19b-3p promotes cell proliferation and osteogenic differentiation of BMSCs by interacting with lncRNA H19. BMC Med Genet 21:11
pubmed: 31918667 pmcid: 6953218 doi: 10.1186/s12881-020-0948-y
Jiang L, Wang M, Sun R, Lin Z, Liu R, Cai H, Tang Z, Zhang R (2021) Methylation of miR-19b-3p promoter exacerbates inflammatory responses in sepsis-induced ALI via targeting KLF7. Cell Biol Int 45:1666–1675
pubmed: 33760339 doi: 10.1002/cbin.11601
Xu M, Zhan J, Xie J, Zhu L, Chen L, Luo X, Sheng X, Liu T, Zhang S, Lu Z (2021) MiR-125a-5p inhibits cell proliferation, cell cycle progression, and migration while promoting apoptosis in head and neck cancers by targeting ERBB3. Auris Nasus Larynx 48:477–486
pubmed: 33077307 doi: 10.1016/j.anl.2020.10.001
Duan L, Duan D, Wei W, Sun Z, Xu H, Guo L, Wu X (2019) MiR-19b-3p attenuates IL-1β induced extracellular matrix degradation and inflammatory injury in chondrocytes by targeting GRK6. Mol Cell Biochem 459:205–214
pubmed: 31227976 doi: 10.1007/s11010-019-03563-2
Li Y, Yuan F, Song Y, Guan X (2020) miR-17-5p and miR-19b-3p prevent osteoarthritis progression by targeting EZH2. Exp Ther Med 20:1653–1663
pubmed: 32765678 pmcid: 7388554 doi: 10.3892/etm.2020.8887
Xia Q, Wang Q, Lin F, Wang J (2021) miR-125a-5p-abundant exosomes derived from mesenchymal stem cells suppress chondrocyte degeneration via targeting E2F2 in traumatic osteoarthritis. Bioengineered 12:11225–11238
pubmed: 34709978 pmcid: 8809923 doi: 10.1080/21655979.2021.1995580
Connor AM, Mahomed N, Gandhi R, Keystone EC, Berger SA (2012) TNFα modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts. Arthritis Res Ther 14:R62
pubmed: 22417670 pmcid: 3446430 doi: 10.1186/ar3778
Savic S, Ouboussad L, Dickie LJ, Geiler J, Wong C, Doody GM, Churchman SM, Ponchel F, Emery P, Cook GP, Buch MH, Tooze RM, McDermott MF (2014) TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes. J Autoimmun 50:59–66
pubmed: 24387801 pmcid: 4012140 doi: 10.1016/j.jaut.2013.11.002
Qiu Q, Zheng Z, Chang L, Zhao YS, Tan C, Dandekar A, Zhang Z, Lin Z, Gui M, Li X, Zhang T, Kong Q, Li H, Chen S, Chen A, Kaufman RJ, Yang WL, Lin HK, Zhang D, Perlman H, Thorp E, Zhang K, Fang D (2013) Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J 32:2477–2490
pubmed: 23942232 pmcid: 3770952 doi: 10.1038/emboj.2013.183
Izumi NTS, Miyaki S, Ochi M (2015) Stf-083010, the inhibitor of ER stress transducer Ire1, suppresses rheumatoid synovitis. Arthritis Rheumatol 67:3280–3281
Yagishita N, Aratani S, Leach C, Amano T, Yamano Y, Nakatani K, Nishioka K, Nakajima T (2012) RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis. Int J Mol Med 30:1281–1286
pubmed: 22992760 pmcid: 4042867 doi: 10.3892/ijmm.2012.1129
Liu Y, Han Y, Qu H, Fang J, Ye M, Yin W (2019) Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: A prospective cohort study. J Clin Lab Anal 33:e22953
pubmed: 31245894 pmcid: 6757134 doi: 10.1002/jcla.22953

Auteurs

Negin Karamali (N)

Student Research Committee, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Zahra Mahmoudi (Z)

Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Seyed Askar Roghani (SA)

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Shirin Assar (S)

Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Mehran Pournazari (M)

Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Parviz Soufivand (P)

Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Ali Gorgin Karaji (AG)

Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, Kermanshah, 6714869914, Iran.

Alireza Rezaiemanesh (A)

Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, Kermanshah, 6714869914, Iran. alireza.rezaiemanesh@kums.ac.ir.

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