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Kardiyopulmoner Baypasta Gelişebilen Böbrek Hasarında miRNA’ların Biyobelirteç Olma Rolü/ The Role of miRNAs as a Biomarker in Kidney Damage Developing in Cardiopulmonary Bypass

Yıl 2022, , 21 - 28, 31.01.2022
https://doi.org/10.47565/ndthdt.2022.50

Öz

Son yıllarda, vücut dışı dolaşıma bağlı olarak gelişebilen akut böbrek hasarının tanı ve tedavisindeki gecikmelerden dolayı geriye dönüşümü olmayan böbrek hasarları meydana gelebilmektedir. Bu tanı ve tedavideki gecikmelerin ortadan kaldırılabilmesi için tanıya yardımcı olacak yeni biyobelirteçlerin bilinmesi gerekmektedir. Bu bağlamda özellikle mikro ribo nükleik asitler birçok uyaranın hücre tepkilerinin anahtar düzenleyicisidir ve hücre dışı ortama salgılanabilirler. Bu nedenle, mikro ribo nükleik asitler vücut sıvılarında tespit edilebilmelerinden dolayı, akut böbrek hasarı gelişebilecek olan hastalarda erken teşhis amacıyla biyobelirteç olarak kullanılabilecektir. Bu derlemede mikro ribo nükleik asitlerin vücut dışı dolaşıma bağlı olarak meydana gelebilecek olan akut böbrek hasarını erken dönemde belirlemedeki rolü tartışılmıştır.


Anahtar kelimeler: Kardiyopulmoner baypas; mikroRNA; Kardiyak Cerrahi; Akut Böbrek Hasarı.

Kaynakça

  • 1. Lee RC, Feinbaum RL, Ambros V. The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-54. doi: 10.1016/0092-8674(93)90529-Y.
  • 2. Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science. 2001; 294(5543):797-9. doi:10.1126/science.1066315.
  • 3. Ke XS, Liu CM, Liu DP, Liang CC. MicroRNAs: Key participants in gene regulatory networks. Curr Opin Chem Biol. 2003;7(4):516-23. doi: 10.1016/s1367-5931(03)00075-9.
  • 4. Kenyon CJ. The genetics of ageing, Nature. 2010;464(7288):504-12. doi: 10.1038.
  • 5. Gems D, and Guardia Y. Alternative perspectives on aging in caenorhabditis elegans: reactive oxygen species or hyperfunction? Antioxidants and Redox Signaling. 2013; 19(3): 321–329. doi: 10.1089/ars.2012.4840
  • 6. Latronico MV, Catalucci D and Condorelli G. Emerging role of miRNAs in cardiovascular biology. Circulation Research. 2007;101(12):1225-36. doi: 10.1161.
  • 7. Ikeda S, Kong SW, Lu J, and et al. Altered miRNA expression in human heart disease. Physiological Genomics, 2007;31(3):367-73. doi: 10.1152.
  • 8. Garzon R, Croce CM. MiRNAs in normal and malignant hematopoiesis. Current Opinion in Hematology. 2008;15(4):352-8. doi: 10.1097/MOH.0b013e328303e15d.
  • 9. Huang XA and Lin H. The miRNA regulation of stem cells. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 2012;1(1):83-95. doi: 10.1002.
  • 10. Kwak P. Iwasaki B, S. & Tomari Y. The miRNA pathway and cancer. In Cancer Science, 2010;101(11): 2309-15. PMID: 20726859 doi: 10.1111.
  • 11. Lee Y. Kim, M Han, J Yeom, K H, Lee S, Baek et al. MiRNA genes are transcribed by RNA polymerase II. EMBO Journal. 2004;13(20):4051-60. doi: 10.1038/sj.emboj.7600385.
  • 12. Yang JS, Lai EC. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular Cell. 2011; 43(6): 892–903. doi: 10.1016.
  • 13. Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Günther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, Young RA. Linking of microRNA genes to nuclear transcriptional regulatory circuits of embryonic stem cells. Cell. 2008; 134 :521-533.
  • 14. Hobert O. Gene regulation by transcription factors and microRNAs. Science. 2008;319:1785–1786.
  • 15. Lee EJ, Baek M, Gusev Y, Brackett DJ, Nuovo GJ, Schmittgen TD. Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors. RNA. 2008; 14: 35–42.
  • 16. Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006; 20: 2202–2207.
  • 17. Kawahara Y, Zinshteyn B, Chendrimada TP, Shiekhattar R, Nishikura K. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep. 2007; 8: 763–769.
  • 18. Kim YK, Heo I, Kim VN. Modifications of small RNAs and their associated proteins. Cell. 2010;143:703–709.
  • 19. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–1934.
  • 20. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008; 455: 64–71.
  • 21. Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008; 455: 58–63.
  • 22. Shirdel EA, Xie W, Mak TW, Jurisica I. NAViGaTing the micronome–using multiple microRNA prediction databases to identify signalling pathway-associated microRNAs. PLoS One. 2011;6:e17429.
  • 23. Dikme R, Padak M, Korkmaz Ersöz E, Hacanlı Y. miRNA’lar ve koroner arter hastalıklarıyla ilişkileri. İnönü Üniversitesi Sağlık Hizmetleri Meslek Yüksek Okulu Dergisi. 2020; 8; 162-74. doi.org/10.33715/inonusaglik.700995
  • 24. Baltimore W, Wilkins S. Medical dictionary. In: Spraycar M (ed). 26th ed., 1995: 869. ISBN 10: 0683079220 / ISBN 13: 9780683079227
  • 25. Blinder JJ, Goldstein SL, Lee VV, et al. Congenital heart surgery in infants: effects of acute kidney injury on outcomes. J Thorac Cardiovasc Surg 2012; 143: 368–374.
  • 26. Ottonello G, Dessì A, Neroni P, et al. Acute kidney injury in neonatal age. J Pediatr Neonatal Individ Med 2014; 3: e030246.
  • 27. Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics 2015; 136: e463–e473.
  • 28. Huen SC, Parikh CR. Molecular phenotyping of clinical AKI with novel urinary biomarkers. Am J Physiol Renal Physiol 2015; 309: F406–13. PMID: doi: 10.1152/ajprenal.00682.2014.
  • 29. Meersch M, Schmidt C, Van Aken H, Martens S, Rossaint J, Singbartl K, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS One. 2014;9:e93460. doi: 10.1371/journal.pone.0093460.
  • 30. Weber JA, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56:1733–1741. doi: 10.1373/clinchem.2010.147405.
  • 31. Jackson DB. Serum-based microRNAs: are we blinded by potential? Proc Natl Acad Sci U S A. 2009;106:E5. doi: 10.1073/pnas.0809999106.
  • 32. Ajit SK. Circulating microRNAs as biomarkers, therapeutic targets, and signaling molecules. Sensors. 2012;12:3359–3369. doi: 10.3390/s120303359.
  • 33. Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutation research. 2011;717:85–90. doi: 10.1016/j.mrfmmm.2011.03.004.
  • 34. de Planell-Saguer M, Rodicio MC. Analytical aspects of microRNA in diagnostics: a review. Analytica chimica acta. 2011;699:134–152. doi: 10.1016/j.aca.2011.05.025.
  • 35. Khalyfa A, Gozal D. Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. J Transl Med 2014;12:162. doi: 10.1186/1479-5876-12-162.
  • 36. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, et al. A mammalian miRNA expression atlas based on small RNA library sequencing. Cell 2007; 129(7):1401–14. PMID: 17604727. PMCID: PMC2681231 doi: 10.1016/j.cell.2007.04.040.
  • 37. Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M, et al. An oligonucleotide microchip for genome-wide miRNA profiling in human and mouse tissues. Proc Natl Acad Sci U S A 2004; 101 (26):9740–4. PMID: 15210942. PMCID: PMC470744 doi: 10.1073/pnas.0403293101.
  • 38. Aguado-Fraile E, Ramos E, Sáenz-Morales D, Conde E, Blanco-Sánchez I, Stamatakis K, et al. miR- 127 protects proximal tubule cells against ischemia/reperfusion: identification of kinesin family member 3B as miR-127 target. PLoS One 2012; 7(9):e44305. doi: 10.1371/journal.pone.0044305
  • 39. Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kümpers P, Faulhaber-Walter R, et al. Circulating miR- 210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2011; 6 (7):1540–6. doi: 10.2215/CJN.00430111
  • 40. Soto K, Coelho S, Rodrigues B, Martins H, Frade F, Lopes S, et al. Cystatin C as a marker of acute kidney injury in the emergency department. Clin J Am Soc Nephrol 2010; 5(10):1745–54. doi: 10.2215/ CJN.00690110
  • 41. Mariscalco G, Lorusso R, Dominici C, Renzulli A, Sala A. Acute kidney injury: a relevant complication after cardiac surgery. Ann Thorac Surg 2011; 92(4):1539–47. doi: 10.1016/j.athoracsur.2011.04.123
  • 42. Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kumpers P, Faulhaber-Walter R, Haller H, Fliser D, Thum T. Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2011; 6:1540–6
  • 43. Siew ED, Ware LB, Ikizler TA. Biological markers of acute kidney injury. J Am Soc Nephrol 2011; 22 (5):810–20. doi: 10.1681/ASN.2010080796
  • 43. Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, et all. Identification of a miRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci U S A 2010;107(32):14339-44. doi: 10.1073/ pnas.0912701107.
  • 44. Chan JA, Krichevsky AM, and Kosik K S. MiRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029-33. doi: 10.1158/0008-5472.CAN-05-0137.
  • 45. Chau BN, Xin C, Hartner J, Ren S, Castano AP, et al. MiRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med. 2012;4(121):121ra18. doi: 10.1126/scitranslmed.3003205.

The Role of miRNAs as a Biomarker in Kidney Damage Developing in Cardiopulmonary Bypass

Yıl 2022, , 21 - 28, 31.01.2022
https://doi.org/10.47565/ndthdt.2022.50

Öz

In recent years, irreversible kidney damage may occur due to delays in diagnosis and treatment of acute kidney injury which may develop due to extracorporeal circulation. In order to eliminate the delays in the diagnosis and treatment, it is necessary to know the new biomarkers that will help the diagnosis. In this context, especially micro-ribonucleic acids are key regulators of cell responses of many stimuli and can be secreted into the extracellular environment. Therefore, since micro-ribonucleic acids can be detected in body fluids, they can be used as a biomarker for early diagnosis in patients who may develop acute kidney injury. In this review, the role of micro-ribonucleic acids in the early detection of acute kidney injury which may occur due to extracorporeal circulation has been discussed.


Keywords: Cardiopulmonary Bypass; microRNA; Cardiac Surgery; Acute Kidney Injury.

Kaynakça

  • 1. Lee RC, Feinbaum RL, Ambros V. The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-54. doi: 10.1016/0092-8674(93)90529-Y.
  • 2. Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science. 2001; 294(5543):797-9. doi:10.1126/science.1066315.
  • 3. Ke XS, Liu CM, Liu DP, Liang CC. MicroRNAs: Key participants in gene regulatory networks. Curr Opin Chem Biol. 2003;7(4):516-23. doi: 10.1016/s1367-5931(03)00075-9.
  • 4. Kenyon CJ. The genetics of ageing, Nature. 2010;464(7288):504-12. doi: 10.1038.
  • 5. Gems D, and Guardia Y. Alternative perspectives on aging in caenorhabditis elegans: reactive oxygen species or hyperfunction? Antioxidants and Redox Signaling. 2013; 19(3): 321–329. doi: 10.1089/ars.2012.4840
  • 6. Latronico MV, Catalucci D and Condorelli G. Emerging role of miRNAs in cardiovascular biology. Circulation Research. 2007;101(12):1225-36. doi: 10.1161.
  • 7. Ikeda S, Kong SW, Lu J, and et al. Altered miRNA expression in human heart disease. Physiological Genomics, 2007;31(3):367-73. doi: 10.1152.
  • 8. Garzon R, Croce CM. MiRNAs in normal and malignant hematopoiesis. Current Opinion in Hematology. 2008;15(4):352-8. doi: 10.1097/MOH.0b013e328303e15d.
  • 9. Huang XA and Lin H. The miRNA regulation of stem cells. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 2012;1(1):83-95. doi: 10.1002.
  • 10. Kwak P. Iwasaki B, S. & Tomari Y. The miRNA pathway and cancer. In Cancer Science, 2010;101(11): 2309-15. PMID: 20726859 doi: 10.1111.
  • 11. Lee Y. Kim, M Han, J Yeom, K H, Lee S, Baek et al. MiRNA genes are transcribed by RNA polymerase II. EMBO Journal. 2004;13(20):4051-60. doi: 10.1038/sj.emboj.7600385.
  • 12. Yang JS, Lai EC. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular Cell. 2011; 43(6): 892–903. doi: 10.1016.
  • 13. Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Günther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, Young RA. Linking of microRNA genes to nuclear transcriptional regulatory circuits of embryonic stem cells. Cell. 2008; 134 :521-533.
  • 14. Hobert O. Gene regulation by transcription factors and microRNAs. Science. 2008;319:1785–1786.
  • 15. Lee EJ, Baek M, Gusev Y, Brackett DJ, Nuovo GJ, Schmittgen TD. Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors. RNA. 2008; 14: 35–42.
  • 16. Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006; 20: 2202–2207.
  • 17. Kawahara Y, Zinshteyn B, Chendrimada TP, Shiekhattar R, Nishikura K. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep. 2007; 8: 763–769.
  • 18. Kim YK, Heo I, Kim VN. Modifications of small RNAs and their associated proteins. Cell. 2010;143:703–709.
  • 19. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–1934.
  • 20. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008; 455: 64–71.
  • 21. Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008; 455: 58–63.
  • 22. Shirdel EA, Xie W, Mak TW, Jurisica I. NAViGaTing the micronome–using multiple microRNA prediction databases to identify signalling pathway-associated microRNAs. PLoS One. 2011;6:e17429.
  • 23. Dikme R, Padak M, Korkmaz Ersöz E, Hacanlı Y. miRNA’lar ve koroner arter hastalıklarıyla ilişkileri. İnönü Üniversitesi Sağlık Hizmetleri Meslek Yüksek Okulu Dergisi. 2020; 8; 162-74. doi.org/10.33715/inonusaglik.700995
  • 24. Baltimore W, Wilkins S. Medical dictionary. In: Spraycar M (ed). 26th ed., 1995: 869. ISBN 10: 0683079220 / ISBN 13: 9780683079227
  • 25. Blinder JJ, Goldstein SL, Lee VV, et al. Congenital heart surgery in infants: effects of acute kidney injury on outcomes. J Thorac Cardiovasc Surg 2012; 143: 368–374.
  • 26. Ottonello G, Dessì A, Neroni P, et al. Acute kidney injury in neonatal age. J Pediatr Neonatal Individ Med 2014; 3: e030246.
  • 27. Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics 2015; 136: e463–e473.
  • 28. Huen SC, Parikh CR. Molecular phenotyping of clinical AKI with novel urinary biomarkers. Am J Physiol Renal Physiol 2015; 309: F406–13. PMID: doi: 10.1152/ajprenal.00682.2014.
  • 29. Meersch M, Schmidt C, Van Aken H, Martens S, Rossaint J, Singbartl K, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS One. 2014;9:e93460. doi: 10.1371/journal.pone.0093460.
  • 30. Weber JA, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56:1733–1741. doi: 10.1373/clinchem.2010.147405.
  • 31. Jackson DB. Serum-based microRNAs: are we blinded by potential? Proc Natl Acad Sci U S A. 2009;106:E5. doi: 10.1073/pnas.0809999106.
  • 32. Ajit SK. Circulating microRNAs as biomarkers, therapeutic targets, and signaling molecules. Sensors. 2012;12:3359–3369. doi: 10.3390/s120303359.
  • 33. Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutation research. 2011;717:85–90. doi: 10.1016/j.mrfmmm.2011.03.004.
  • 34. de Planell-Saguer M, Rodicio MC. Analytical aspects of microRNA in diagnostics: a review. Analytica chimica acta. 2011;699:134–152. doi: 10.1016/j.aca.2011.05.025.
  • 35. Khalyfa A, Gozal D. Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. J Transl Med 2014;12:162. doi: 10.1186/1479-5876-12-162.
  • 36. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, et al. A mammalian miRNA expression atlas based on small RNA library sequencing. Cell 2007; 129(7):1401–14. PMID: 17604727. PMCID: PMC2681231 doi: 10.1016/j.cell.2007.04.040.
  • 37. Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M, et al. An oligonucleotide microchip for genome-wide miRNA profiling in human and mouse tissues. Proc Natl Acad Sci U S A 2004; 101 (26):9740–4. PMID: 15210942. PMCID: PMC470744 doi: 10.1073/pnas.0403293101.
  • 38. Aguado-Fraile E, Ramos E, Sáenz-Morales D, Conde E, Blanco-Sánchez I, Stamatakis K, et al. miR- 127 protects proximal tubule cells against ischemia/reperfusion: identification of kinesin family member 3B as miR-127 target. PLoS One 2012; 7(9):e44305. doi: 10.1371/journal.pone.0044305
  • 39. Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kümpers P, Faulhaber-Walter R, et al. Circulating miR- 210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2011; 6 (7):1540–6. doi: 10.2215/CJN.00430111
  • 40. Soto K, Coelho S, Rodrigues B, Martins H, Frade F, Lopes S, et al. Cystatin C as a marker of acute kidney injury in the emergency department. Clin J Am Soc Nephrol 2010; 5(10):1745–54. doi: 10.2215/ CJN.00690110
  • 41. Mariscalco G, Lorusso R, Dominici C, Renzulli A, Sala A. Acute kidney injury: a relevant complication after cardiac surgery. Ann Thorac Surg 2011; 92(4):1539–47. doi: 10.1016/j.athoracsur.2011.04.123
  • 42. Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kumpers P, Faulhaber-Walter R, Haller H, Fliser D, Thum T. Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2011; 6:1540–6
  • 43. Siew ED, Ware LB, Ikizler TA. Biological markers of acute kidney injury. J Am Soc Nephrol 2011; 22 (5):810–20. doi: 10.1681/ASN.2010080796
  • 43. Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, et all. Identification of a miRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci U S A 2010;107(32):14339-44. doi: 10.1073/ pnas.0912701107.
  • 44. Chan JA, Krichevsky AM, and Kosik K S. MiRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029-33. doi: 10.1158/0008-5472.CAN-05-0137.
  • 45. Chau BN, Xin C, Hartner J, Ren S, Castano AP, et al. MiRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med. 2012;4(121):121ra18. doi: 10.1126/scitranslmed.3003205.
Toplam 46 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Hemşirelik
Bölüm Makale
Yazarlar

Mahmut Padak 0000-0001-6863-1907

Reşat Dikme 0000-0001-9157-7830

Yayımlanma Tarihi 31 Ocak 2022
Yayımlandığı Sayı Yıl 2022

Kaynak Göster

Vancouver Padak M, Dikme R. Kardiyopulmoner Baypasta Gelişebilen Böbrek Hasarında miRNA’ların Biyobelirteç Olma Rolü/ The Role of miRNAs as a Biomarker in Kidney Damage Developing in Cardiopulmonary Bypass. NefroHemDergi. 2022;17(1):21-8.

Nefroloji Hemşireliği Dergisi/ Journal of Nephrology Nursing Creative Commons Lisansı Creative Commons Atıf-GayriTicari-Türetilemez 4.0 Uluslararası Lisansı ile lisanslanmıştır.