nmpЖурнал им. Н.В. Склифосовского «Неотложная медицинская помощь»Russian Sklifosovsky Journal "Emergency Medical Care"2223-90222541-8017“N.V. Sklifosovsky Research Institute for Emergency Medicine”10.23934/2223-9022-2020-9-1-96-107nmp-909Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSВнеклеточная ДНК в медицине неотложных состоянийCell-Free DNA in Emergency Medical Carehttps://orcid.org/0000-0002-5962-0541ФилевА. Д.FilevA. D.

научный сотрудник

Researcher

https://orcid.org/0000-0002-5729-9846ПисаревВ. М.PisarevV. M.

Писарев Владимир Митрофанович, доктор медицинских наук, профессор, заведующий

Vladimir M. Pisarev, Professor, Dr. Med. Sci, Head

vpisarev@gmail.comЛаборатория молекулярных механизмов критических состояний, 1 Научно-исследовательский институт общей реаниматологии им. В.А. Неговского ФГБНУ «Федеральный научно-клинический центр реаниматологии и реабилитологии»; «Медико-генетический научный центр им. академика Н.П. Бочкова»РоссияDepartment of Molecular Biology, V.A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology; N.P. Bochkov Research Centre for Medical GeneticsRussian FederationЛаборатория молекулярных механизмов критических состояний, 1 Научно-исследовательский институт общей реаниматологии им. В.А. Неговского ФГБНУ «Федеральный научно-клинический центр реаниматологии и реабилитологии»РоссияDepartment of Molecular Biology, V.A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and RehabilitologyRussian Federation2020191020209196107Copyright © Филев А.Д., Писарев В.М., 20202020Филев А.Д., Писарев В.М.Filev A.D., Pisarev V.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jnmp.ru/jour/article/view/909

РЕЗЮМЕ. Для медицины неотложных состояний является актуальным поиск молекул с высокой прогностической ценностью для определения течения и исходов жизнеугрожающих состояний — сепсиса, тяжелых травм, сосудистых катастроф. Одним из перспективных биомаркеров-кандидатов (с англ.: candidate biomarkers — кандидатные биомаркеры) с высоким потенциалом применения в медицине неотложных и критических состояний является содержание внеклеточной ДНК (вкДНК) в плазме крови. Цель данного обзора — выявить перспективы внедрения вкДНК в клиническую медицину и трудности, возникающие на этом пути. Уровень и изменения в динамике концентрации фрагментов циркулирующей ДНК, в том числе органоспецифической фракции вкДНК, на сегодняшний день могут иметь значение для оценки степени повреждения интересующего органа, вероятности осложненного течения и прогноза исходов неотложного/критическо- го состояния у пациентов отделений реанимации и интенсивной терапии. Источниками вкДНК, циркулирующих в кровотоке, могут быть ядра погибающих клеток органов и тканей, поврежденные митохондрии, пул которых обновляется в результате митофагии, а также микроорганизмы. Как патоген-ассоциированные молекулы (PAMP), представленные фрагментами бактериальной и вирусной ДНК, молекулы собственной ДНК, ассоциированные с повреждением (DAMP), связываются с толл-подобными рецепторами (TLR9) и внутриклеточными ДНК-сенсорами (cGAS-STING, NLRP3), инициируя запуск воспалительных процессов в тканях и нарушения гемостаза. Эти процессы носят характер и адаптивных реакций, защищающих от микроорганизмов, и дезадаптивных реакций, потенцирующих повреждения клеток органов. Происходящее усиление экспрессии генов провоспалительных сигнальных путей, ассоциированных с транскрипционным NF-kB и интерферон-регулирующими факторами, в свою очередь способствует продукции цитокинов и других факторов, которые усиливают стресс-реакции, нарушающие функциональную активность клеток в разных органах. Имеющиеся литературные данные свидетельствуют о том, что определение количественного содержания в плазме вкДНК, играющей существенную роль в патогенезе критических/неотложных состояний в качестве PAMP и DAMP, может помочь при обосновании прогноза и своевременной персонализации лечения пациентов с жизнеугрожающими состояниями и недавно их перенесших.

ABSTRACT. Defining molecules with high prognostic value for predicting the course and outcomes of life-threatening sepsis, severe injuries, vascular accidents remains an urgent problem in emergency medicine. One of the promising candidate biomarkers of emergency states and critical illness is the content of extracellular DNA (exDNA) in blood plasma. The purpose of this review is to identify the prospects for the introduction of cfDNA in clinical medicine and the severities arose along this way. The levels and altered dynamics of the concentration of circulating DNA fragments, including the organ-specific fraction of exDNA seem informative today for assessing the degree of damage to the organ of interest, the probability of a complicated course and the prognosis of outcomes of emergency/critical illness in Intensive Care Unit (ICU) patients. Sources of exDNA circulating in the bloodstream may include the nuclei of dying cells from organs and tissues, damaged mitochondria, the pool of which should be remodeled with mitophagy, as well as microorganisms. Similarly to pathogen-associated molecules (PAMP) represented by fragments of bacterial and viral DNA, native DNA molecules associated with damage (DAMP) bind to toll-like receptors (TLR9) and intracellular DNA sensors (cGAS-STING, NLRP3), initiating the inflammatory processes in tissues and hemostatic disorders. These processes represent natural adaptive responses protecting against microbes, as well as disadaptation responses potentiating cell damage in organs. The increasing expression of genes encoding proinflammatory signaling pathways associated with NF-kB transcription factor and interferon-regulating factors (IRF), in turn, contribute to production of cytokines and other factors enhancing the stress-responses that alter the functional activity of cells in various organs. The available literature data suggest that the quantitative determining plasma exDNA, which serves as PAMP and DAMP to significantly contribute to pathogenesis of emergency states and critical illness, might aid in predicting the outcome and justifying the in-time personalization of treatment of emergency and post-emergency patients.

внеклеточная ДНКкритические состояниявоспалениенарушение гемостазаcell-free DNAcritical illnessinflammationimpaired hemostasisReferencesКузовлев А.Н., Гречко А.В. Ингаляционные антибиотики в реаниматологии: состояние проблемы и перспективы развития. Общая реаниматология. 2017;13(5):69–84. https://doi.org/10.15360/1813-9779-2017-5-69-84Kuzovlev AN, Grechko AV. Inhaled Antibiotics in Reanimatology: Problem State and Development Prospects (Review). General Reanimatology. 2017;13(5):69–84. (In Russ.) https://doi.org/10.15360/1813-9779-2017-5-69-84Востриков В.А., Кузовлев А.Н. Общедоступная дефибрилляция при внезапной остановке сердца. Общая реаниматология. 2018;14(1):58–67. https://doi.org/10.15360/1813-9779-2018-1-58-67Vostrikov VA, Kuzovlev AN. Public-Access Defibrillation in Sudden Cardiac Arrest (Short Review). General Reanimatology. 2018;14(1):58–67. (In Russ.) https://doi.org/10.15360/1813-9779-2018-1-58-67.Jabaley CS, Blum JM, Groff RF, O’Reilly-Shah VN. Global trends in the awareness of sepsis: insights from search engine data between 2012 and 2017. Crit Care. 2018;22(1):7. PMID: 29343292 https://doi.org/10.1186/s13054-017-1914-8Jabaley CS, Blum JM, Groff RF, O’Reilly-Shah VN: Global trends in the awareness of sepsis: insights from search engine data between 2012 and 2017. Crit Care. 2018;22:7. https://doi.org/10.1186/s13054-017-1914-8 PMID: 29343292Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe Sepsis. JAMA. 2010; 304(16):1787–1794. PMID: 20978258 https://doi.org/ 10.1001/jama.2010.1553Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe Sepsis. JAMA. 2010;304(16): 1787–1794. https://doi.org/10.1001/jama.2010.1553 PMID: 20978258Gaudry S, Messika J, Ricard JD, Guillo S, Pasquet B, Dubief E, et al. Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review. Ann Intensive Care. 2017;7(1):28. PMID: 28271450 https://doi.org/ 10.1186/s13613-017-0243-zGaudry S, Messika J, Ricard JD, Guillo S, Pasquet B, Dubief E, et al. Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review. Ann Intensive Care. 2017;7(1):28. PMID: 28271450. PMCID: PMC5340787. https://doi.org/10.1186/s13613-017-0243-z.Jickling GC, Sharp FR. Blood biomarkers of ischemic stroke. Neurotherapeutics. 2011;8(3):349–360. PMID: 21671123 https://doi.org/10.1007/s13311-011-0050-4Jickling GC, Sharp FR. Blood biomarkers of ischemic stroke. Neurotherapeutics. 2011;8(3):349–360. PMID: 21671123. PMCID: PMC3250275. https://doi.org/10.1007/s13311-011-0050-4.Писарев В.М., Чумаченко А.Г., Филев А.Д., Ершова Е.С., Костюк С.В., Вейко Н.Н., и др. Комбинация молекулярных биомаркеров ДНК в прогнозе исхода критических состояний. Общая реаниматология. 2019;15(3):31–47. https://doi.org/10.15360/1813-9779-2019-3-31-47Pisarev VM, Chumachenko AG, Filev AD, Ershova ES, Kostyuk SV, Veyko NN, et al. Combination of DNA Molecular Biomarkers in the Prediction of Critical Illness Outcome. General Reanimatology. 2019;15(3):31–47. (In Russ.) https://doi.org/10.15360/1813-9779-2019-3-31-47Roca E, Nescolarde L, Lupón J Barallat J, Januzzi JL, Liu P, et al. The Dynamics of Cardiovascular Biomarkers in non-Elite Marathon Runners. J Cardiovasc Transl Res. 2017;10(2):206–208. PMID: 28382580https://doi.org/10.1007/s12265-017-9744-2Roca E, Nescolarde L, Lupón J Barallat J, Januzzi JL, Liu P, et al. The Dynamics of Cardiovascular Biomarkers in non-Elite Marathon Runners. J Cardiovasc Transl Res. 2017;10(2):206–208. PMID: 28382580. https://doi.org/10.1007/s12265-017-9744-2.Дмитриева И.Б., Белобородова Н.В., Черневская Е.А. Биомаркеры прокальцитонин и белок S100β в клинико-лабораторном мониторинге при критических состояниях новорожденных. Общая реаниматология. 2013;9(3):58–65. https://doi.org/10.15360/1813-9779-2013-3-58Dmitriyeva IB, Beloborodova NV, Chernevskaya EA. The Biomarkers Procalcitonin and S100β Ptotein in the Clinical and Laboratory Monitoring of Neonatal Critical Conditions. General Reanimatology. 2013;9(3):58. (In Russ.) https://doi.org/10.15360/1813-9779-2013-3-58.Boyapati RK, Tamborska A, Dorward DA, Ho GT. Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases. F1000Res. 2017;6:169. PMID: 28299196 https://doi.org/10.12688/f1000research.10397.1Boyapati RK, Tamborska A, Dorward DA, Ho GT. Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases. F1000Res. 2017;6:169. PMID: 28299196. PMCID: PMC5321122. https://doi.org/10.12688/f1000research.10397.1.Тамакович С.Н., Власов В.В., Лактионов П.П. Циркулирующие дезоксирибонуклеиновые кислоты крови и их использование в медицинской диагностике. Молекулярная биология. 2008;42(1):12–23.Tamkovich SN, Vlassov VV, Laktionov PP. Circulating DNA in the blood and its application in medical diagnosis. Molecular Biology. 2008;42(1):12–23. PMID: 18389615 (In Russ.)Хубутия М.Ш., Шабанов А.К., Скулачев М.В., Булава Г.В., Савченко И.М., Гребенников О.А. и др. Митохондриальная и ядерная ДНК у пострадавших с тяжелой сочетанной травмой. Общая реаниматология. 2013;9(6):24–35. https://doi.org/10.15360/1813-9779-2013-6-24Khubutiya MSh, Shabanov AK, Skulachev MV, Bulava GV, Savchenko IM, Grebennikov O.A., et al. Mitochondrial and Nuclear DNA in Patients with Severe Polytrauma. General Reanimatology. 2013;9(6):24. (In Russ.) https://doi.org/10.15360/1813-9779-2013-6-24.Мороз В.В., Мягкова Е.А., Жанатаев А.К., Рябов Г.А., Остапченко Д.А., Дурнев А.Д., и др. Повреждения ДНК и процессы клеточной гибели лейкоцитов у пострадавших с тяжелой травмой. Общая реаниматология. 2014;10(4):11–36. https://doi.org/10.15360/1813-9779-2014-4-11-36Moroz VV, Myagkova EA, Zhanataev AK, Ryabov GA, Ostapchenko DA, Durnev AD, et al. DNA Damages and White Blood Cell Death Processes in Victims with Severe Injury. General Reanimatology. 2014;10(4):11–36. (In Russ.) https://doi.org/10.15360/1813-9779-2014-4-11-36.Козлов В.А. Свободная внеклеточная ДНК в норме и при патологии. Медицинская иммунология. 2013;15(5):399–412. https://doi.org/10.15789/1563-0625-2013-5-399-412Kozlov VА. Free Extracellular DNA i Normal State and Under Pathological Conditions. Medical Immunology (Russia). 2013;15(5):399–412. (In Russ.) https://doi.org/10.15789/1563-0625-2013-5-399-412Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38. PMID: 22781841 https://doi.org/10.1038/npp.2012.112Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38. PMID: 22781841 PMCID: PMC3521964 https://doi.org/10.1038/npp.2012.112.Suelves M, Carrió E, Núñez-Álvarez Y, Peinado MA. DNA methylation dynamics in cellular commitment and differentiation. Brief Funct Genomics. 2016;15(6):443–453. PMID: 27416614 https://doi.org/10.1093/bfgp/elw017Suelves M, Carrió E, Núñez-Álvarez Y, Peinado MA. DNA methylation dynamics in cellular commitment and differentiation. Brief Funct Genomics. 2016;15(6):443–453. PMID: 27416614 https://doi.org/10.1093/bfgp/elw017Lehmann-Werman R, Neiman D, Zemmour H. Moss J, Magenheim J, Vaknin-Dembinsky A, et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc Natl Acad Sci USA. 2016;113(13):E1826–34. PMID: 26976580 https://doi.org/10.1073/pnas.1519286113Lehmann-Werman R, Neiman D, Zemmour H. Moss J, Magenheim J, Vaknin-Dembinsky A, et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc Natl Acad Sci U S A. 2016;113(13):E1826–1834. PMID: 26976580. PMCID: PMC4822610. https://doi.org/10.1073/pnas.1519286113.Moss J, Magenheim J, Neiman D Zemmour H, Loyfer N, Korach A, et al. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease. Nat Commun. 2018;9(1):5068. PMID: 30498206 https://doi.org/ 10.1038/s41467-018-07466-6Moss J, Magenheim J, Neiman D Zemmour H, Loyfer N, Korach A, et al. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease. Nat Commun. 2018;9:5068. PMCID: PMC6265251. PMID: 30498206. https://doi.org/10.1038/s41467-018-07466-6.Pisetsky DS. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin Immunol. 2012;144(1):32–40. https://doi.org/10.1016/j.clim.2012.04.006Pisetsky DS. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin Immunol. 2012 Jul;144(1):32–40. https://doi.org/ 10.1016/j.clim.2012.04.006.Peters DL, Pretorius PJ. Origin, translocation and destination of extracellular occurring DNA — a new paradigm in genetic behavior. Clin Chim Acta. 2011;412(11–12):806–11. https://doi.org/10.1016/j.cca.2011.01.026Peters DL, Pretorius PJ. Origin, translocation and destination of extracellular occurring DNA--a new paradigm in genetic behavior. Clin Chim Acta. 2011;412(11–12):806–11. https://doi.org/ 10.1016/j.cca.2011.01.026.Gahan PB, Anker P, Stroun M. Metabolic DNA as the origin of spontaneously released DNA? Ann N Y Acad Sci. 2008;1137:7–17. https://doi.org/10.1196/annals.1448.046Gahan PB, Anker P, Stroun M. Metabolic DNA as the origin of spontaneously released DNA? Ann N Y Acad Sci. 2008 Aug;1137:7–17. https://doi.org/ 10.1196/annals.1448.046.Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–1535. https://doi.org/10.1126/science.1092385Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–1535. https://doi.org/10.1126/science.1092385Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41. https://doi.org/10.1083/jcb.200606027Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–241. https://doi.org/10.1083/jcb.200606027Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–287. PMID: 28267716 https://doi.org/10.1038/nm.4294Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–287. PMID: 28267716 https://doi.org/10.1038/nm.4294Ermakov AV, Kostyuk SV, Konkova MS Egolina NA, Malinovskaya EM, et al. Extracellular DNA fragments. Ann N Y Acad Sci. 2008;1137:41–46. PMID: 18837923 https://doi.org/10.1196/annals.1448.024Ermakov AV, Kostyuk SV, Konkova MS Egolina NA, Malinovskaya EM, et al. Extracellular DNA fragments. Ann N Y Acad Sci. 2008;1137:41–46. PMID: 18837923 https://doi.org/10.1196/annals.1448.024Van der Vaart M, Pretorius PJ. The origin of circulating free DNA. Clin Chem. 2007;53(12):2215. https://doi.org/10.1373/clinchem.2007.092734Van der Vaart M, Pretorius PJ. The origin of circulating free DNA. Clin Chem. 2007;53(12):2215. https://doi.org/10.1373/clinchem.2007.092734Swarup V, Rajeswari MR. Circulating (cell-free) nucleic acids--a promising, non-invasive tool for early detection of several human diseases. FEBS Lett. 2007;581(5):795–799. PMID: 17289032 https://doi.org/ 10.1016/j.febslet.2007.01.051Swarup V, Rajeswari MR. Circulating (cell-free) nucleic acids--a promising, non-invasive tool for early detection of several human diseases. FEBS Lett. 2007;581(5):795–799. PMID: 17289032 https://doi.org/ 10.1016/j.febslet.2007.01.051Zhivotosky B, Orrenius S. Assessment of apoptosis and necrosis by DNA fragmentation and morphological criteria. Curr Protoc Cell Biol. 2001;Ch18:18.3.1–18.3.23. PMID:18228342 https://doi.org/10.1002/0471143030.cb1803s12Zhivotosky B, Orrenius S. Assessment of apoptosis and necrosis by DNA fragmentation and morphological criteria. Curr Protoc Cell Biol. 2001; Ch18:18.3.1–18.3.23. PMID: 18228342 https://doi.org/10.1002/0471143030.cb1803s12Verhoven B, Schlegel RA, Williamson P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J Exp Med. 1995;182(5)1597–1601. PMID: 7595231 https://doi.org/10.1084/jem.182.5.1597Verhoven B, Schlegel RA, Williamson P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J Exp Med. 1995;182(5):1597–1601. PMID: 7595231 https://doi.org/10.1084/jem.182.5.1597Radic M, Marion TN. Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity. Semin Immunopathol. 2013;35(4):465–480. PMID: 23595413 https://doi.org/10.1007/s00281-013-0376-6Radic M, Marion TN. Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity. Semin Immunopathol. 2013;35(4):465–480. PMID: 23595413 https://doi.org/10.1007/s00281-013-0376-6Fernando MR, Jiang C, Krzyzanowski GD, Ryan WL. New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes. PLoS One. 2017; 12(8):e0183915. PMID: 28850588 https://doi.org/10.1371/journal.pone.0183915Fernando MR, Jiang C, Krzyzanowski GD, Ryan WL. New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes. PLoS One. 2017;12(8):e0183915. PMID: 28850588 https://doi.org/10.1371/journal.pone.0183915Anitei M, Wassmer T, Stange C, Hoflack B. Bidirectional transport between the trans-Golgi network and the endosomal system. Mol Membr Biol. 2010;27(8):443–456. PMID: 21054155 https://doi.org/10.3109/09687688.2010.522601Anitei M, Wassmer T, Stange C, Hoflack B. Bidirectional transport between the trans-Golgi network and the endosomal system. Mol Membr Biol. 2010;27(8):443–456. PMID: 21054155 https://doi.org/10.3109/09687688.2010.522601Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–1172. PMID: 8642258 https://doi.org/10.1084/jem.183.3.1161Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–1172. PMID: 8642258 https://doi.org/10.1084/jem.183.3.1161Valadi H, Ekström K, Bossios A Sjöstrand M, Lee JJ, Lötvall JO, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–659. PMID: 17486113 https://doi.org/10.1038/ncb1596Valadi H, Ekström K, Bossios A Sjöstrand M, Lee JJ, Lötvall JO, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–659. PMID: 17486113 https://doi.org/10.1038/ncb1596MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A, et al. Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity. 2001;15(5):825–835. PMID: 11728343 https://doi.org/10.1016/s1074-7613(01)00229-1MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A, et al. Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity. 2001;15(5):825–835. PMID: 11728343 https://doi.org/10.1016/s1074-7613(01)00229-1Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148(6):1145–1159. PMID: 22424226 https://doi.org/10.1016/j.cell.2012.02.035Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148(6):1145–1159. PMID: 22424226 https://doi.org/10.1016/j.cell.2012.02.035Hong EE, Okitsu CY, Smith AD, Hsieh CL. Regionally specific and genome-wide analyses conclusively demonstrate the absence of CpG methylation in human mitochondrial DNA. Mol Cell Biol. 2013;33(14):2683–2690. PMID: 23671186 https://doi.org/10.1128/MCB.00220-13Hong EE, Okitsu CY, Smith AD, Hsieh CL. Regionally specific and genome-wide analyses conclusively demonstrate the absence of CpG methylation in human mitochondrial DNA. Mol Cell Biol. 2013;33(14):2683–2690. PMID: 23671186 https://doi.org/10.1128/MCB.00220-13Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM, et al. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011;108(9):3630–3635. PMID: 21321201 https://doi.org/10.1073/pnas.1012311108Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM, et al. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011;108(9):3630–3635. PMID: 21321201 https://doi.org/10.1073/pnas.1012311108Di Carlo M, Giacomazza D, Picone P Nuzzo D, San Biagio PL. Are oxidative stress and mitochondrial dysfunction the key players in the neurodegenerative diseases? Free Radic Res. 2012;46(11):1327–1338. PMID: 22817279 https://doi.org/10.3109/10715762.2012.714466Di Carlo M, Giacomazza D, Picone P Nuzzo D, San Biagio PL. Are oxidative stress and mitochondrial dysfunction the key players in the neurodegenerative diseases? Free Radic Res. 2012;46(11):1327–1338. PMID: 22817279 https://doi.org/10.3109/10715762.2012.714466Shimada K, Crother TR, Karlin J Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–414. PMID: 22342844 https://doi.org/10.1016/j.immuni.2012.01.009Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–414. PMID: 22342844 https://doi.org/10.1016/j.immuni.2012.01.009Zhong Z, Liang S, Sanchez-Lopez E He F, Shalapour S, Lin XJ, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560(7717):198–203. PMID: 30046112 https://doi.org/10.1038/s41586-018-0372-zZhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560(7717):198–203. PMID: 30046112 https://doi.org/10.1038/s41586-018-0372-zPhaniendra A, Jestadi DB, Periyasamy L. Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J Clin Biochem. 2015;30(1):11–26. https://doi.org/10.1007/s12291-014-0446-0Phaniendra A, Jestadi DB, Periyasamy L. Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J Clin Biochem. 2015;30(1):11–26. https://doi.org/10.1007/s12291-014-0446-0Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–1078. PMID: 19847258 https://doi.org/10.1038/nature08467Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–1078. PMID: 19847258 https://doi.org/10.1038/nature08467Hegde ML, Hazra TK, Mitra S. Early Steps in the DNA Base Excision/ Single-Strand Interruption Repair Pathway in Mammalian Cells. Cell Res. 2008;18(1):27–47. PMID: 18166975 https://doi.org/10.1038/cr.2008.8Hegde ML, Hazra TK, Mitra S. Early Steps in the DNA Base Excision/ Single-Strand Interruption Repair Pathway in Mammalian Cells. Cell Res. 2008;18(1):27–47. PMID: 18166975 https://doi.org/10.1038/cr.2008.8Hegde ML, Izumi T, Mitra S. Oxidized Base Damage and Single-Strand Break Repair in Mammalian Genomes: Role of Disordered Regions and Posttranslational Modifications in Early Enzymes. Prog Mol Biol Transl Sci. 2012;110:123–153. PMID: 22749145 https://doi.org/10.1016/B978-0-12-387665-2.00006-7Hegde ML, Izumi T, Mitra S. Oxidized Base Damage and Single-Strand Break Repair in Mammalian Genomes: Role of Disordered Regions and Posttranslational Modifications in Early Enzymes. Prog Mol Biol Transl Sci. 2012;110:123–153. PMID: 22749145 https://doi.org/10.1016/B978-0-12-387665-2.00006-7Jaruga P, Rozalski R, Jawien A Migdalski A, Olinski R, Dizdaroglu M. DNA damage products (5’R)- and (5’S)-8,5’-cyclo-2’-deoxyadenosines as potential biomarkers in human urine for atherosclerosis. Biochemistry. 2012;51(9):1822–1824. PMID: 22360777 https://doi.org/10.1021/bi201912cJaruga P, Rozalski R, Jawien A, Migdalski A, Olinski R, Dizdaroglu M. DNA damage products (5’R)- and (5’S)-8,5’-cyclo-2’-deoxyadenosines as potential biomarkers in human urine for atherosclerosis. Biochemistry. 2012;51(9):1822–1824. PMID: 22360777 https://doi.org/10.1021/bi201912cFilev AD, Shmarina GV, Ershova E, Veiko NN, Martynov AV, Borzikova MA, et al. Oxidized Cell-Free DNA Role in the Antioxidant Defense Mechanisms under Stress. Hindawi. Oxid Med Cell Longev. 2019(4):1–13. PMID: 31360293 https://doi.org/10.1155/2019/1245749Filev AD, Shmarina GV, Ershova E, Veiko NN, Martynov AV, Borzikova MA, et al. Oxidized Cell-Free DNA Role in the Antioxidant Defense Mechanisms under Stress. Oxid Med Cell Longev. 2019(4):1–13. PMID: 31360293 https://doi.org/10.1155/2019/1245749Zhang L, Deng S, Zhao S , Ai Y, Zhang L, Pan P, et al. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9. Int J Mol Sci. 2016;17(9). pii: E1425. PMID: 27589725 https://doi.org/10.3390/ijms17091425Zhang L, Deng S, Zhao S, Ai Y, Zhang L, Pan P, et al. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9. Int J Mol Sci. 2016;17(9). pii: E1425. PMID: 27589725 https://doi.org/10.3390/ijms17091425Pallen MJ. Time to recognise that mitochondria are bacteria? Trends Microbiol. 2011;19(2):58–64. PMID: 21123072 https://doi.org/10.1016/j.tim.2010.11.001Pallen MJ. Time to recognise that mitochondria are bacteria? Trends Microbiol. 2011;19(2):58–64. PMID: 21123072 https://doi.org/10.1016/j.tim.2010.11.001Gunter TE, Buntinas L, Sparagna GC, Gunter KK. The Ca2+ transport mechanisms of mitochondria and Ca2+ uptake from physiological-type Ca2+ transients. Biochim Biophys Acta. 1998;1366(1–2):5–15. PMID: 9714709 https://doi.org/10.1016/s0005-2728(98)00117-0Gunter TE, Buntinas L, Sparagna GC, Gunter KK. The Ca2+ transport mechanisms of mitochondria and Ca2+ uptake from physiological-type Ca2+ transients. Biochim Biophys Acta. 1998;1366(1–2):5–15. PMID: 9714709 https://doi.org/10.1016/s0005-2728(98)00117-0Hockenbery D, Nuñez G, Milliman C Schreiber RD, Korsmeyer SJ, et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348(6299):334–336. PMID: 2250705 https://doi.org/10.1038/348334a0Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ, et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348(6299):334–336. PMID: 2250705 https://doi.org/10.1038/348334a0Rodríguez-Nuevo A, Zorzano A. The sensing of mitochondrial DAMPs by non-immune cells. Cell Stress. 2019;3(6):195–207. PMID:31225514 https://doi.org/10.15698/cst2019.06.190Rodríguez-Nuevo A, Zorzano A. The sensing of mitochondrial DAMPs by non-immune cells. Cell Stress. 2019;3(6):195–207. PMID: 31225514 https://doi.org/10.15698/cst2019.06.190de Jong SD, Basha G, Wilson KD Kazem M, Cullis P, Jefferies W, et al. The immunostimulatory activity of unmethylated and methylated CpG oligodeoxynucleotide is dependent on their ability to colocalize with TLR9 in late endosomes. J Immunol. 2010;184(11):6092–6102. PMID: 20427776 https://doi.org/10.4049/jimmunol.0802442de Jong SD, Basha G, Wilson KD, Kazem M, Cullis P, Jefferies W, et al. The immunostimulatory activity of unmethylated and methylated CpG oligodeoxynucleotide is dependent on their ability to colocalize with TLR9 in late endosomes. J Immunol. 2010;184(11):6092–6102. PMID: 20427776 https://doi.org/10.4049/jimmunol.0802442Hemmi H, Takeuchi O, Kawai T Kaisho T, Sato S, Sanjo H, et al. A Tolllike receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–745. PMID: 11130078 https://doi.org/10.1038/35047123Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Tolllike receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–745. PMID:11130078 https://doi.org/10.1038/35047123Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A, et al. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003;198(3):513–520. PMID: 12900525 https://doi.org/10.1084/jem.20030162Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A, et al. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003;198(3):513–520. PMID: 12900525 https://doi.org/10.1084/jem.20030162Bird AP, Taggart MH, Nicholls RD, Higgs DR. Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the alpha-globin pseudogene. EMBO J. 1987;6(4):999–1004. PMID: 3595568Bird AP, Taggart MH, Nicholls RD, Higgs DR. Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the alpha-globin pseudogene. EMBO J. 1987;6(4):999-1004. PMID: 3595568Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–420. PMID: 27291964 https://doi.org/10.1038/nri.2016.58Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–420. PMID: 27291964 https://doi.org/10.1038/nri.2016.58Gould TJ, Vu TT, Stafford AR Dwivedi DJ, Kim PY, Fox-Robichaud AE, et al. Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis. Arterioscler Thromb Vasc Biol. 2015;35(12):2544–2553. PMID: 26494232 https://doi.org/10.1161/ATVBAHA.115.306035Gould TJ, Vu TT, Stafford AR Dwivedi DJ, Kim PY, Fox-Robichaud AE, et al. Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis. Arterioscler Thromb Vasc Biol. 2015;35(12):2544–2553. PMID: 26494232 https://doi.org/10.1161/ATVBAHA.115.306035Mai SH, Khan M, Dwivedi DJ, Ross CA, Zhou J, Gould TJ, et al. Canadian Critical Care Translational Biology Group. Delayed but not Early Treatment with DNase Reduces Organ Damage and Improves Outcome in a Murine Model of Sepsis. Shock. 2015;44(2):166–172. PMID: 26009820 https://doi.org/10.1097/SHK.0000000000000396Mai SH, Khan M, Dwivedi DJ, Ross CA, Zhou J, Gould TJ, et al. Delayed but not Early Treatment with DNase Reduces Organ Damage and Improves Outcome in a Murine Model of Sepsis. Shock. 2015;44(2):166–172. PMID: 26009820 https://doi.org/10.1097/SHK.0000000000000396Meng W, Paunel-Görgülü A, Flohé S, Hoffmann A, Witte I, MacKenzie C, et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit Care. 2012;16(4):R137. PMID: 22835277 https://doi.org/10.1186/cc11442Meng W, Paunel-Görgülü A, Flohé S, Hoffmann A, Witte I, MacKenzie C, et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit Care. 2012;16(4):R137. PMID: 22835277 https://doi.org/10.1186/cc11442Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20(11):657–674. PMID: 31358977 https://doi.org/10.1038/s41576-019-0151-1Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20(11):657–674. PMID: 31358977 https://doi.org/10.1038/s41576-019-0151-1Tsai NW, Lin TK, Chen SD, Chang WN, Wang HC, Yang TM, et al. The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke. Clin Chim Acta. 2011;412(5–6):476–479. PMID: 21130757 https://doi.org/10.1016/j.cca.2010.11.036Tsai NW, Lin TK, Chen SD, Chang WN, Wang HC, Yang TM, et al. The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke. Clin Chim Acta. 2011;412(5–6):476–479. PMID: 21130757 https://doi.org/10.1016/j.cca.2010.11.036Конорова И.Л., Максимова М.Ю., Смирнова И.Н., Болотова Т.А., Ершова Е.С., Вейко Н.Н., и др. Циркулирующая в плазме крови внеклеточная ДНК в патогенезе ишемического инсульта: роль транскрибируемой области рибосомного повтора. Патологическая физиология и экспериментальная медицина. 2014;(2):13–23.Konorova IL, Maximova MIu, Smirnova IN, Bolotova TA, Ershova ES, Veiko NN, et al. Circulating in blood plasma cell-free DNA in the pathogenesis of ischemic stroke: the role of the transcribed region of ribosomal repeat. Pathological physiology and experimental therapy. 2014;(2):13–23. (in Russ.)O’Connell GC, Petrone AB, Tennant CS, Lucke-Wold N, Kabbani Y, Tarabishy AR, et al. Circulating extracellular DNA levels are acutely elevated in ischaemic stroke and associated with innate immune system activation. Brain Inj. 2017;31(10):1369–1375. PMID: 28585898 https://doi.org/10.1080/02699052.2017.1312018O’Connell GC, Petrone AB, Tennant CS, Lucke-Wold N, Kabbani Y, Tarabishy AR, et al. Circulating extracellular DNA levels are acutely elevated in ischaemic stroke and associated with innate immune system activation. Brain Inj. 2017;31(10):1369–1375. PMID: 28585898https://doi.org/10.1080/02699052.2017.1312018Glebova KV, Veiko NN, Nikonov AA. Porokhovnik LN, Kostuyk SV, et al. Cell-free DNA as a biomarker in stroke: Current status, problems and perspectives. Crit Rev Clin Lab Sci. 2018;55(1):55–70. PMID: 29303618 https://doi.org/10.1080/10408363.2017.1420032Glebova KV, Veiko NN, Nikonov AA, Porokhovnik LN, Kostuyk SV. Cell-free DNA as a biomarker in stroke: Current status, problems and perspectives. Crit Rev Clin Lab Sci. 2018;55(1):55–70. PMID: 29303618 https://doi.org/10.1080/10408363.2017.1420032Hummel EM, Hessas E, Müller S, Beiter T, Fisch M, Eibl A, et al. Cell-free DNA release under psychosocial and physical stress conditions. Transl Psychiatry. 2018;8(1):236. PMID: 30374018 https://doi.org/10.1038/s41398-018-0264-xHummel EM, Hessas E, Müller S, Beiter T, Fisch M, Eibl A, et al. Cell-free DNA release under psychosocial and physical stress conditions. Transl Psychiatry. 2018;8(1):236. PMID: 30374018 https://doi.org/10.1038/s41398-018-0264-xRannikko J, Seiskari T, Huttunen R, Tarkiainen I, Jylhävä J, Hurme M, et al. Plasma cell-free DNA and qSOFA score predict 7-day mortality in 481 emergency department bacteraemia patients. J Intern Med. 2018;284(4):418–426. PMID: 29687943 https://doi.org/ 0.1111/joim.12766Rannikko J, Seiskari T, Huttunen R, Tarkiainen I, Jylhävä J, Hurme M, et al. Plasma cell-free DNA and qSOFA score predict 7-day mortality in 481 emergency department bacteraemia patients. J Intern Med. 2018;284(4):418–426. PMID: 29687943 https://doi.org/ 0.1111/joim.12766Schneck E, Samara O, Koch C, Hecker A, Padberg W, Lichtenstern C, et al. Plasma DNA and RNA differentially impact coagulation during abdominal sepsis-an explorative study. J Surg Res. 2017;210:231–243. PMID: 28457334 https://doi.org/10.1016/j.jss.2016.11.044Schneck E, Samara O, Koch C, Hecker A, Padberg W, Lichtenstern C, et al. Plasma DNA and RNA differentially impact coagulation during abdominal sepsis-an explorative study. J Surg Res. 2017;210:231–243. PMID: 28457334 https://doi.org/10.1016/j.jss.2016.11.044Jackson Chornenki NL, Coke R, Kwong AC, Dwivedi DJ, Xu MK, McDonald E, et al. Comparison of the source and prognostic utility of cfDNA in trauma and sepsis. Intensive Care Med Exp. 2019;7(1):29. PMID: 31119471 https://doi.org/10.1186/s40635-019-0251-4Jackson Chornenki NL, Coke R, Kwong AC, Dwivedi DJ, Xu MK, McDonald E, et al. Comparison of the source and prognostic utility of cfDNA in trauma and sepsis. Intensive Care Med Exp. 2019;7(1):29. PMID: 31119471 https://doi.org/10.1186/s40635-019-0251-4Базеко Н.П., Алексеенко Ю.В. ; Всемирная Организация Здравоохранения. Инсульт: программа возврата к активной жизни. Москва: Медицинская литература; 2004.Bazeko NP, Alekseenko YuV. Vsemirnaya Organizatsiya Zdravookhraneniya. Insul’t: programma vozvrata k aktivnoy zhizni. Moscow: Meditsinskaya literature Publ.; 2004. (In Russ.)Silva GS, Koroshetz WJ, González RG, Schwamm LH. Causes of Ischemic Stroke. In: González R, Hirsch J, Lev M, Schaefer P, Schwamm L. (eds.) Acute Ischemic Stroke. Imaging and Intervention. Springer, Berlin, Heidelberg; 2011. p.25–42.Silva GS, Koroshetz WJ, González RG, Schwamm LH. Causes of Ischemic Stroke. In: González R, Hirsch J, Lev M, Schaefer P, Schwamm L. (eds.) Acute Ischemic Stroke. Imaging and Intervention. Springer, Berlin, Heidelberg; 2011. pp.25–42.Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular mechanisms of neurovascular damage and repair after stroke. J Child Neurol. 2011; 6(9):1193–1198. PMID: 21628695 https://doi.org/10.1177/0883073811408610Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular mechanisms of neurovascular damage and repair after stroke. J Child Neurol. 2011; 6(9):1193–1198. PMID: 21628695 https://doi.org/10.1177/0883073811408610Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977;1(5):409–17. PMID: 617259 https://doi.org/10.1002/ana.410010502Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977;1(5):409–417. PMID: 617259 https://doi.org/10.1002/ana.410010502Khatri R, McKinney AM, Swenson B, Janardhan V. Blood-brain barrier, reperfusion injury, and haemorrhagic transformation in acute ischemic stroke. Neurology. 2012;79(13 Suppl 1):S52–57. PMID: 23008413 https://doi.org/10.1212/WNL.0b013e3182697e70Khatri R, McKinney AM, Swenson B, Janardhan V. Blood-brain barrier, reperfusion injury, and haemorrhagic transformation in acute ischemic stroke. Neurology. 2012;79(13 Suppl 1):S52–57. PMID: 23008413 https://doi.org/10.1212/WNL.0b013e3182697e70del Zoppo GJ. The neurovascular unit, matrix proteases, and innate inflammation. Ann N Y Acad Sci. 2010;1207:46–49. PMID: 20955425 https://doi.org/10.1111/j.1749-6632.2010.05760.xdel Zoppo GJ. The neurovascular unit, matrix proteases, and innate inflammation. Ann N Y Acad Sci. 2010;1207:46–49. PMID: 20955425 https://doi.org/10.1111/j.1749-6632.2010.05760.xKago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun. 2006;339(4):1197–1203. PMID: 16338221 DOI: 10.1016/j.bbrc.2005.11.133Kago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun. 2006;339(4):1197–1203. PMID: 16338221 https://doi.org/10.1016/j.bbrc.2005.11.133Grossmann J. Molecular mechanisms of «detachment-induced apoptosis – Anoikis». Apoptosis. 2002;7(3):247–260. PMID: 11997669Grossmann J. Molecular mechanisms of «detachment-induced apoptosis--Anoikis». Apoptosis. 2002;7(3):247–260. PMID: 11997669Boyko M, Ohayon S, Goldsmith T, Douvdevani A, Gruenbaum BF, Melamed I, et al. Cell-free DNA-a marker to predict ischemic brain damage in a rat stroke experimental model. J Neurosurg Anesthesiol. 2011;23(3):222–228. PMID: 21593692 https://doi.org/10.1097/ANA.0b013e31821b536aBoyko M, Ohayon S, Goldsmith T, Douvdevani A, Gruenbaum BF, Melamed I, et al. Cell-free DNA-a marker to predict ischemic brain damage in a rat stroke experimental model. J Neurosurg Anesthesiol. 2011;23(3):222–228. PMID: 21593692 https://doi.org/10.1097/ANA.0b013e31821b536aGuidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e440–e441. PMID: 3176529 https://doi.org/10.1161/STR.0000000000000215Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e440–e441. PMID: 3176529 https://doi.org/10.1161/STR.0000000000000215Vajpeyee A, Wijatmiko T, Vajpeyee M, Taywade O. Cell free DNA: A Novel Predictor of Neurological Outcome after Intravenous Thrombolysis and/or Mechanical Thrombectomy in Acute Ischemic Stroke Patients. Neurointervention. 2018;13(1):13–19. PMID: 29535894 https://doi.org/10.5469/neuroint.2018.13.1.13Vajpeyee A, Wijatmiko T, Vajpeyee M, Taywade O. Cell free DNA: A Novel Predictor of Neurological Outcome after Intravenous Thrombolysis and/or Mechanical Thrombectomy in Acute Ischemic Stroke Patients. Neurointervention. 2018;13(1):13–19. PMID: 29535894 https://doi.org/10.5469/neuroint.2018.13.1.13Bhaskar S, Stanwell P, Cordato D, Attia J, Levi C, et al. Reperfusion therapy in acute ischemic stroke: dawn of a new era? BMC Neurol. 2018;18(1):8. PMID: 29338750 https://doi.org/10.1186/s12883-017-1007-yBhaskar S, Stanwell P, Cordato D, Attia J, Levi C, et al. Reperfusion therapy in acute ischemic stroke: dawn of a new era? BMC Neurol. 2018;18(1):8. PMID: 29338750 https://doi.org/10.1186/s12883-017-1007-yWang L, Xie L, Zhang Q, Cai X, Tang Y, Wang L, et al. Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients. Coron Artery Dis. 2015; 26(4):296–300. PMID: 25714070 https://doi.org/10.1097/MCA.0000000000000231Wang L, Xie L, Zhang Q, Cai X, Tang Y, Wang L, et al. Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients. Coron Artery Dis. 2015;26(4):296–300. PMID: 25714070 https://doi.org/10.1097/MCA.0000000000000231Zemmour H, Planer D, Magenheim J, Moss J, Neiman D, Gilon D, et al. Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA. Nat Commun. 2018;9(1):1443. PMID: 29691397 https://doi.org/10.1038/s41467-018-03961-yZemmour H, Planer D, Magenheim J, Moss J, Neiman D, Gilon D, et al. Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA. Nat Commun. 2018;9(1):1443. PMID: 29691397 https://doi.org/10.1038/s41467-018-03961-yOmar AS, Mahmoud K, Hanoura S, Osman H, Sivadasan P, Sudarsanan S, et al. Acute kidney injury induces high-sensitivity troponin measurement changes after cardiac surgery. BMC Anesthesiol. 2017;17(1):15. PMID: 28143401 https://doi.org/10.1186/s12871-017-0307-5Omar AS, Mahmoud K, Hanoura S, Osman H, Sivadasan P, Sudarsanan S, et al. Acute kidney injury induces high-sensitivity troponin measurement changes after cardiac surgery. BMC Anesthesiol. 2017;17(1):15. PMID: 28143401 https://doi.org/10.1186/s12871-017-0307-5Vallabhajosyula S, Sakhuja A, Geske JB Kumar M, Poterucha JT, Kashyap R, et al. Role of Admission Troponin-T and Serial Troponin-T Testing in Predicting Outcomes in Severe Sepsis and Septic Shock. J Am Heart Assoc. 2017;6(9).pii: e005930. PMID: 28889100 https://doi.org/10.1161/JAHA.117.005930Vallabhajosyula S, Sakhuja A, Geske JB, Kumar M, Poterucha JT, Kashyap R, et al. Role of Admission Troponin-T and Serial Troponin-T Testing in Predicting Outcomes in Severe Sepsis and Septic Shock. J Am Heart Assoc. 2017;6(9).pii: e005930. PMID: 28889100 https://doi.org/10.1161/JAHA.117.005930Herman DS, Kavsak PA, Greene DN. Variability and Error in Cardiac Troponin Testing: An ACLPS Review. Am J Clin Patrol. 2017;148(4):281–295. PMID: 28967956 DOI: 10.1093/ajcp/aqx066Herman DS, Kavsak PA, Greene DN. Variability and Error in Cardiac Troponin Testing: An ACLPS Critical Review. Am J Clin Pathol. 2017, 148(4):281–295. PMID: 28967956. https://doi.org/10.1093/ajcp/aqx066Xie J, Yang J, Hu P. Correlations of Circulating Cell-Free DNA With Clinical Manifestations in Acute Myocardial Infarction. Am J Med Sci. 2018;356(2):121–129. PMID: 30219153 https://doi.org/10.1016/j.amjms.2018.04.007Xie J, Yang J, Hu P. Correlations of Circulating Cell-Free DNA With Clinical Manifestations in Acute Myocardial Infarction. Am J Med Sci. 2018;356(2):121–129. PMID: 30219153 https://doi.org/10.1016/j.amjms.2018.04.007Singer M, Deutschman CS, Seymour CW Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801–810. PMID: 26903338 https://doi.org/10.1001/jama.2016.0287Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801–810. PMID: 26903338 https://doi.org/10.1001/jama.2016.0287Angus DC, Seymour CW, Coopersmith CM, Deutschman CS, Klompas M, Levy MM, et al. A framework for the development and interpretation of different sepsis definitions and clinical criteria. Crit Care Med. 2016;44(3):e113–e121. PMID: 26901559 https://doi.org/10.1097/CCM.0000000000001730Angus DC, Seymour CW, Coopersmith CM, Deutschman CS, Klompas M, Levy MM, et al. A framework for the development and interpretation of different sepsis definitions and clinical criteria. Crit Care Med. 2016;44(3):e113–e121. PMID: 26901559. https://doi.org/10.1097/CCM.0000000000001730Avriel A, Paryente Wiessman M, Almog Y Perl Y, Novack V, Galante O, et al. Admission cell free DNA levels predict 28-day mortality in patients with severe sepsis in intensive care. PLoS One. 2014;9(6):e100514. PMID: 24955978 https://doi.org/10.1371/journal.pone.0100514Avriel A, Paryente Wiessman M, Almog Y, Perl Y, Novack V, Galante O, et al. Admission cell free DNA levels predict 28-day mortality in patients with severe sepsis in intensive care. PLoS One. 2014;9(6):e100514. PMID: 24955978. https://doi.org/10.1371/journal.pone.0100514Dwivedi DJ, Toltl LJ, Swystun LL Pogue J, Liaw KL, Weitz JI, et al. Canadian Critical Care Translational Biology Group. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. 2012;16(4):R151. PMID: 22889177 https://doi.org/10.1186/cc11466Dwivedi DJ, Toltl LJ, Swystun LL, Pogue J, Liaw KL, Weitz JI, et al. Canadian Critical Care Translational Biology Group. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. 2012;16(4):R151. PMID:22889177 https://doi.org/10.1186/cc11466Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340(3):207–214. PMID: 9895401 https://doi.org/10.1056/NEJM199901213400307Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340(3):207–214. PMID: 9895401 https://doi.org/10.1056/NEJM199901213400307Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348(2):138–150. PMID: 12519925 https://doi.org/10.1056/NEJMra021333Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348(2):138–150. PMID: 12519925 https://doi.org/10.1056/NEJMra021333Gould TJ, Vu TT, Swystun LL Dwivedi DJ, Mai SH, Weitz JI, et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34(9):1977–1984. PMID: 25012129 https://doi.org/10.1161/ATVBAHA.114.304114Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34(9):1977–1984. PMID: 25012129 https://doi.org/10.1161/ATVBAHA.114.304114Trigg RM, Martinson LJ, Parpart-Li S, Shaw JA. Factors that influence quality and yield of circulating-free DNA: A systematic review of the methodology literature. Heliyon. 2018;4(7):e00699. PMID: 30094369 https://doi.org/10.1016/j.heliyon.2018.e00699Trigg RM, Martinson LJ, Parpart-Li S, Shaw JA. Factors that influence quality and yield of circulating-free DNA: A systematic review of the methodology literature. Heliyon. 2018;4(7):e00699. PMID: 30094369 https://doi.org/10.1016/j.heliyon.2018.e00699

The authors declare that there are no conflicts of interest present.