The Role of Cell-Free Plasma DNA in Critically Ill Patients with Sepsis

Background: The identification of highly reliable outcome predictors in severe sepsis is important to define disease severity, predict bedside prognosis and monitor response to treatment. Cell-free plasma DNA (cfDNA) has been recently proposed as a possible prognostic marker of clinical outcome in septic patients. In this study, we investigated the prognostic value of cfDNA in patients with sepsis and its possible correlation with caspase-3, IL-6 and IL-18 levels. Methods: We enrolled 34 patients admitted to the intensive care unit (ICU). Out of these 34, 27 patients were septic and 7 were non-septic. cfDNA was extracted from plasma and quantified by real time PCR. Plasma levels of caspase-3, IL-6 and IL-18 were measured by ELISA. Results: We observed significantly higher levels of cfDNA in septic patients. No significant differences were found between cfDNA levels in patients with Gram+, Gram- and fungal infections. Out of the 27 septic patients, 12 developed acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT), and cfDNA levels resulted to be higher in this group. Out of the 27 septic patients, 11 had a negative outcome during the ICU stay. The cfDNA concentrations at admission were higher in non-survivors than in survivors. Caspase-3, IL-6 and IL-18 levels were significantly higher in septic patients when compared to these levels in non-septic patients and correlated with cfDNA levels. Conclusion: cfDNA can be considered a good prognostic marker of clinical outcome in septic patients. Its levels increase in case of AKI complicating sepsis, in particular if CRRT is needed, and are associated with poor outcome. Caspase-3, IL-6 and IL-18 levels are higher in septic patients and correlate to cfDNA concentrations.

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The Role of Cell-Free Plasma DNA in Patients with Cardiorenal Syndrome Type 1

Cardiorenal Medicine ◽

10.1159/000518553 ◽

2021 ◽

pp. 1-8

Author(s):

Grazia Maria Virzì ◽

Anna Clementi ◽

Sabrina Milan Manani ◽

Chiara Castellani ◽

Giovanni Giorgio Battaglia ◽

...

Keyword(s):

Caspase 3 ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Plasma Dna ◽

Apoptosis And Inflammation ◽

Factor Α ◽

Clinical Conditions

Background: Recent research highlighted the potential role of circulating cell-free DNA (cfDNA), resulted by apoptosis or cell necrosis, as a prognostic marker in the setting of different clinical conditions. Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Apoptosis of renal epithelial cells is proposed as a mechanism involved in CRS type 1. In this study, we investigated cfDNA levels in patients with acute heart failure (AHF) and CRS type 1 and the possible correlation between cfDNA levels and inflammatory and apoptotic parameters. Methods: We enrolled 17 AHF patients and 15 CRS type 1 who exhibited AKI at the time of admission (caused by AHF) or developed AKI during the first 48 h from admission. cfDNA was extracted from plasma and quantified by real-time polymerase chain reaction. Plasma levels of NGAL, tumor necrosis factor-α, interleukin (IL)-6, IL-18, and caspase-3 were measured. Results: We observed significantly higher levels of cfDNA in patients with CRS type 1 than patients with AHF. Caspase-3, IL-6, IL-18, and NGAL levels resulted significantly increased in patients with CRS type 1. Moreover, a positive correlation between cfDNA levels and caspase-3 levels was found, as well as between cfDNA levels and IL-6 and renal parameters. Conclusion: Our study explores the premise of cfDNA as a marker for apoptosis and inflammation in CRS type 1 patients. cfDNA could potentially serve as an index for noninvasive monitoring of tissue damage and apoptosis in patients with AKI induced by AHF.

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Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-020-00309-w ◽

2021 ◽

Author(s):

M. Del Re ◽

V. Conteduca ◽

S. Crucitta ◽

G. Gurioli ◽

C. Casadei ◽

...

Keyword(s):

Androgen Receptor ◽

Clinical Outcome ◽

Liquid Biopsy ◽

Response To Treatment ◽

First Line ◽

Primary Resistance ◽

Circulating Free Dna ◽

Free Dna ◽

Signaling Inhibitors

Abstract Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

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Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Experimental & Molecular Medicine ◽

10.1038/s12276-020-0426-9 ◽

2020 ◽

Vol 52 (4) ◽

pp. 702-712

Author(s):

Zhifeng Liu ◽

Jingjing Ji ◽

Dong Zheng ◽

Lei Su ◽

Tianqing Peng ◽

...

Keyword(s):

Acute Kidney Injury ◽

Caspase 3 ◽

Kidney Injury ◽

Protective Role ◽

Inos Expression ◽

Calpain Inhibitor ◽

Ros Production ◽

Enos Expression ◽

Cellular Apoptosis

Abstract To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4−/−), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4−/−). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogen-activated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4−/− and Tg-CAST mice but not in LYZ/Capn4−/− mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.

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Cell-Free Plasma DNA as a Prognostic Marker in Intensive Treatment Unit Patients

Annals of the New York Academy of Sciences ◽

10.1196/annals.1318.036 ◽

2004 ◽

Vol 1022 (1) ◽

pp. 232-238 ◽

Cited By ~ 40

Author(s):

S WIJERATNE ◽

A BUTT ◽

S BURNS ◽

K SHERWOOD ◽

O BOYD ◽

...

Keyword(s):

Prognostic Marker ◽

Intensive Treatment ◽

Plasma Dna ◽

Treatment Unit ◽

Free Plasma

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Role of Cell-Free Plasma DNA as a Diagnostic Marker for Prostate Cancer

Annals of the New York Academy of Sciences ◽

10.1196/annals.1318.013 ◽

2004 ◽

Vol 1022 (1) ◽

pp. 76-80 ◽

Cited By ~ 57

Author(s):

DARRELL ALLEN ◽

ASIF BUTT ◽

DECLAN CAHILL ◽

MIKE WHEELER ◽

RICK POPERT ◽

...

Keyword(s):

Prostate Cancer ◽

Diagnostic Marker ◽

Plasma Dna ◽

Free Plasma

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The Role of Cell-Free Plasma DNA in Peritoneal Dialysis Patients with Peritonitis

Peritoneal Dialysis International ◽

10.3747/pdi.2014.00245 ◽

2015 ◽

Vol 35 (7) ◽

pp. 755-758

Author(s):

Grazia Maria Virzì ◽

Sabrina Milan Manani ◽

Vincenzo Cantaluppi ◽

Alessandra Brocca ◽

Massimo de Cal ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Plasma Dna ◽

Dialysis Patients ◽

Free Plasma

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Role of surgical modality and timing of surgery as clinical outcome predictors following acute subdural hematoma evacuation

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.36.3.1771 ◽

2020 ◽

Vol 36 (3) ◽

Author(s):

Imran Altaf ◽

Shahzad Shams ◽

Anjum Habib Vohra

Keyword(s):

Clinical Outcome ◽

Decompressive Craniectomy ◽

Subdural Hematoma ◽

Demographic Data ◽

Timing Of Surgery ◽

Acute Subdural Hematoma ◽

Outcome Predictors ◽

Surgical Evacuation ◽

Surgical Modality

Background & Objective: A Craniotomy (CO) or decompressive craniectomy (DC) are the two main surgical procedures employed for evacuation of acute traumatic subdural hematoma (ASDH). However, the optimal surgical procedure remains controversial. The beneficial effect of early surgical evacuation of acute subdural hematoma in improving outcome also remains unclear. Our objective was to study the role of these two parameters in determining the outcome in patients undergoing surgical evacuation of acute traumatic subdural hematoma. Methods: A retrospective analysis of 58 patients presenting with acute traumatic subdural hematoma and with presenting Glasgow Coma Scale (GCS) ≤ 8 that had been operated in Lahore General Hospital between June 2014 and July 2015 was performed. The demographic data, preoperative GCS, type of surgical procedure performed and timing of surgery were analysed. Results: Forty (69%) patients underwent CO, and eighteen (31%) patients underwent DC. The CO and DC groups showed no difference in the demographic data and preoperative GCS. Six patients survived in the craniotomy group, while none survived in the decompressive craniectomy group (p=0.083). The relationship of timing of surgery with survival in the craniotomy group was found not to be clinically significant (p=0.87). Conclusion: In this study craniotomy was associated with a better outcome as compared to decompressive craniectomy, however, the difference did not reach statistical significance. Early surgery was also found not to be associated with an improved outcome. doi: https://doi.org/10.12669/pjms.36.3.1771 How to cite this:Altaf I, Shams S, Vohra AH. Role of surgical modality and timing of surgery as clinical outcome predictors following acute subdural hematoma evacuation. Pak J Med Sci. 2020;36(3):---------. doi: https://doi.org/10.12669/pjms.36.3.1771 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation

Cell Death and Disease ◽

10.1038/s41419-021-03431-2 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Weiwei Xia ◽

Yuanyuan Li ◽

Mengying Wu ◽

Qianqian Jin ◽

Qian Wang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Caspase 3 ◽

Inflammatory Diseases ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Epithelial Cells ◽

Regulated Cell Death ◽

Deficient Mice

AbstractPyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.

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l-Proline Alleviates Kidney Injury Caused by AFB1 and AFM1 through Regulating Excessive Apoptosis of Kidney Cells

Toxins ◽

10.3390/toxins11040226 ◽

2019 ◽

Vol 11 (4) ◽

pp. 226 ◽

Cited By ~ 5

Author(s):

Huiying Li ◽

Songli Li ◽

Huaigu Yang ◽

Yizhen Wang ◽

Jiaqi Wang ◽

...

Keyword(s):

Cell Apoptosis ◽

Caspase 3 ◽

Cell Model ◽

Kidney Injury ◽

Kidney Damage ◽

Aflatoxin M1 ◽

Proline Dehydrogenase ◽

Hek 293 ◽

Model Cell

The toxicity and related mechanisms of aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) in the mouse kidney were studied, and the role of l-proline in alleviating kidney damage was investigated. In a 28-day toxicity mouse model, thirty mice were divided into six groups: control (without treatment), l-proline group (10 g/kg body weight (b.w.)), AFB1 group (0.5 mg/kg b.w.), AFM1 (3.5 mg/kg b.w.), AFB1 + l-proline group and AFM1 + l-proline group. Kidney index and biochemical indicators were detected, and pathological staining was observed. Using a human embryonic kidney 293 (HEK 293) cell model, cell apoptosis rate and apoptotic proteins expressions were detected. The results showed that AFB1 and AFM1 activated pathways related with oxidative stress and caused kidney injury; l-proline significantly alleviated abnormal expressions of biochemical parameters and pathological kidney damage, as well as excessive cell apoptosis in the AF-treated models. Moreover, proline dehydrogenase (PRODH) was verified to regulate the levels of l-proline and downstream apoptotic factors (Bax, Bcl-2, and cleaved Caspase-3) compared with the control (p < 0.05). In conclusion, l-proline could protect mouse kidneys from AFB1 and AFM1 through alleviating oxidative damage and decreasing downstream apoptosis, which deserves further research and development.

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Critical evaluation of p53 as a prognostic marker in ovarian cancer

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399404007781 ◽

2004 ◽

Vol 6 (12) ◽

pp. 1-20 ◽

Cited By ~ 28

Author(s):

Jacqueline Hall ◽

Jim Paul ◽

Robert Brown

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Clinical Outcome ◽

Prognostic Marker ◽

Clinical Studies ◽

Critical Evaluation ◽

Experimental Studies ◽

Minimum Criteria

The tumour suppressor gene encoding p53 has been shown from experimental studies to have a crucial role in how cells respond to DNA damage. p53 has important functions in apoptosis, cell-cycle arrest and DNA repair, largely mediated by its activity on gene transcription. However, despite this wealth of in vitro data, its role in how tumours respond to DNA damage induced by chemotherapeutic drugs remains controversial. In this review, we highlight some of the problems surrounding design and analysis of studies of p53 as a prognostic marker of clinical outcome, using ovarian cancer as an example. We aim to build on the knowledge of the published literature in ovarian cancer to identify criteria for clinical studies that should give a more definitive estimate of the role of p53 in clinical drug resistance. A search of three public databases using keywords combined with Boolean operators identified 64 clinical publications investigating the relationship of p53 to clinical outcome following chemotherapy in ovarian cancer. Although 43% of 215 published analyses from the 64 papers reported a significant correlation between p53 status and a clinical endpoint relevant to chemoresistance, only six analyses fulfil minimum criteria and none of these finds a statistically significant correlation of p53 with chemotherapy-resistance endpoints. The results from published clinical studies suggest a more complex role of p53 mutation in the mechanism of resistance in ovarian cancer than is suggested by in vitro studies.

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