Apoptotic cell-free DNA promotes inflammation in haemodialysis patients

Atamaniuk, Johanna; Kopecky, Chantal; Skoupy, Sonja; Säemann, Marcus D.; Weichhart, Thomas

doi:10.1093/ndt/gfr695

Cited by 86 publications

(82 citation statements)

References 20 publications

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“…First discovered in 1948 by Mandel and Metais, fragmented DNA or cfDNA has since been associated with a number of conditions, including end-stage renal disease, myocardial infarction, stroke, and trauma [2][3][4][5][6][7]. Multiple studies have shown a correlation between the levels of cfDNA and cellular injury and necrosis, processes relevant in cancer cell survival and propagation.…”

Section: Cfdnamentioning

confidence: 99%

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Levy

Cordova

et al. 2016

The Oncologist

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A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non-small cell lung cancer. Historically, the reference standard for the diagnosis and genetic interrogation for advanced-stage patients has been tissue acquisition via computed tomography-guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood-based diagnostics or “liquid biopsies” with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell-free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high-risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.

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Section: Cfdnamentioning

confidence: 99%

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Levy

Cordova

et al. 2016

The Oncologist

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“…Other studies have shown that cfDNA exists at a ready-state level in clinical scenarios such as myocardial infarction, surgery, trauma and stroke. Cellfree DNA may increase dramatically with cellular injury or necrosis [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Detection and characterization of circulating cell free tumor DNA in cancer patients with malignant solid tumors. Liquid biopsy: a new tool in molecular pathology?

Hinrichsen

Dworniczak

Wachter

et al. 2016

LaboratoriumsMedizin

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Abstract:The term liquid biopsy comprises methods of blood-based analysis of nucleic acids, which are increasingly under discussion in oncology and personalized medicine, and are already applied in individual cases. The analysis of tumor markers, which in certain tumor diseases can be found as protein markers in vast amounts in the blood, constitutes a primary form of liquid biopsy. Cell-free circulating DNA fragments in the blood (ctDNA), which reflect the genetic profile of a tumor cell and are released in different ways by the tumor, represent a new class of more specific and sensitive biomarkers that can be correlated with the dynamics of the tumor disease. New technologies based on PCR and sequencing techniques pave the way for diagnostic approaches to define molecular tumor characteristics, not only in tumor tissue but also in the blood, by analyzing cell-free circulating DNA.The combination of molecular profiling of the tumor with ctDNA analytics by liquid biopsy is a promising step in the advancement of precision medicine.

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“…6,[17][18][19][20][21] NETs are composed of extracellular DNA, histones, and neutrophil granular proteins. CFDNA, either in the presence or absence of histones, has been shown to modulate several procoagulant pathways.…”

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Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

Gould

Stafford

et al. 2015

ATVB

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144

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Objectives-Sepsis is characterized by systemic activation of inflammation and coagulation in response to infection. In sepsis, activated neutrophils extrude neutrophil extracellular traps composed of cell-free DNA (CFDNA) that not only trap pathogens but also provide a stimulus for clot formation. Although the effect of CFDNA on coagulation has been extensively studied, much less is known about the impact of CFDNA on fibrinolysis. To address this, we (1) investigated the relationship between CFDNA levels and fibrinolytic activity in sepsis and (2) determined the mechanisms by which CFDNA modulates fibrinolysis. Approach and Results-Plasma was collected from healthy and septic individuals, and CFDNA was quantified. Clot lysis assays were performed in plasma and purified systems, and lysis times were determined by monitoring absorbance. Clot morphology was assessed using scanning electron microscopy. Clots formed in plasma from septic patients containing >5 µg/mL CFDNA were dense in structure and resistant to fibrinolysis, a phenomenon overcome by deoxyribonuclease addition. These effects were recapitulated in control plasma supplemented with CFDNA. In a purified system, CFDNA delayed fibrinolysis but did not alter tissue-type plasminogen activator-induced plasmin generation. Using surface plasmon resonance, CFDNA bound plasmin with a K d value of 4.2±0.3 µmol/L, and increasing concentrations of CFDNA impaired plasmin-mediated degradation of fibrin clots via the formation of a nonproductive ternary complex between plasmin, CFDNA, and fibrin. Conclusions-Our studies suggest that the increased levels of CFDNA in sepsis impair fibrinolysis by inhibiting plasmin-mediated fibrin degradation, thereby identifying CFDNA as a potential therapeutic target for sepsis treatment. Gould et al DNA Impairs Fibrinolysis in Sepsis 2545patients increase thrombin generation by activating the intrinsic pathway of blood coagulation, 26 whereas DNA-histone complexes trigger platelet activation and aggregation by signaling through toll-like receptor-2 and toll-like receptor-4. [26][27][28] In addition, recent evidence suggests that fibrin, along with von Willebrand factor and chromatin, form a colocalized network within the thrombus that provides a scaffold for localized coagulation activation coupled with platelet and red blood cell adhesion, thereby promoting thrombus formation. 16,20,29 Although the contributions of CFDNA to coagulation activation and thrombus formation have been well characterized, studies on the influence of CFDNA on the fibrinolytic system are limited. NETs have previously been shown to intercalate with fibrin to form a structural network that is resistant to lysis by tissue-type plasminogen activator (tPA) or degradation by DNase. 20 Conversely, CFDNA has been shown to facilitate the recruitment of profibrinolytic enzymes, such as tPA, urokinase plasminogen activator, plasminogen, and plasmin, and their endogenous inhibitors, plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin.30 Thus, although CFDNA may...

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Apoptotic cell-free DNA promotes inflammation in haemodialysis patients

Abstract: We provide the first evidence that cfDNA has selective immunostimulatory effects on human monocytes. This process may contribute to the proinflammatory milieu observed in HD patients.

Cited by 86 publications

References 20 publications

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Detection and characterization of circulating cell free tumor DNA in cancer patients with malignant solid tumors. Liquid biopsy: a new tool in molecular pathology?

Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

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