Correlation of Plasma FL Expression with Bone Marrow Irradiation Dose

Sproull, Mary; Avondoglio, Dane; Kramp, Tamalee; Shankavaram, Uma; Camphausen, Kevin

doi:10.1371/journal.pone.0058558

Cited by 11 publications

(16 citation statements)

References 38 publications

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“…Pentraxin 3 (PTX3), a biomarker associated with vascular injury to the brain but previously unassociated with radiation exposure was also included in this study (2). FL is a cytokine known to induce proliferation and differentiation of bone marrow stem cells of myeloid and lymphoid origin and has recently been described as a biomarker of radiation exposure (3). The apolipoprotein SAA is a major acute phase reactant protein playing a central role in the inflammatory response and has been characterized as a marker of radiation exposure in heterogeneous radiation exposure profiles (4–6).…”

Section: Introductionmentioning

confidence: 99%

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Multivariate Analysis of Radiation Responsive Proteins to Predict Radiation Exposure in Total-Body Irradiation and Partial-Body Irradiation Models

et al. 2017

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In the event of a radiological or nuclear attack, advanced clinical countermeasures are needed for screening and medical management of the exposed population. In such a scenario, minimally invasive biomarkers that can accurately quantify radiation exposure would be useful for triage management by first responders. In this murine study, we evaluated the efficacy of a novel combination of radiation responsive proteins, Flt3 ligand (FL), serum amyloid A (SAA), matrix metalloproteinase 9 (MMP9), fibrinogen beta (FGB) and pentraxin 3 (PTX3) to predict the received dose after whole- or partial-body irradiation. Ten-week-old female C57BL6 mice received a single whole-body or partial-body dose of 18 Gy from a Pantak X-ray source at a dose rate of 2.28 Gy/min. Plasma was collected by cardiac puncture at 24, 48, 72 h and 1 week postirradiation. Plasma protein levels were determined via commercially available ELISA assay. A multivariate discriminant analysis was utilized to generate best-fit dose prediction models for whole-body exposures using the selected biomarker panel and its potential application to partial-body exposures was examined. The combination of values from FL, SAA, MMP9, FGB and PTX3 between 24 h and 1 week postirradiation yielded novel dose-response relationships. For day 1 postirradiation, the best-fit model yielded a predictive accuracy of 81% utilizing FL alone. The use of additional proteins did not enhance the model accuracy whereas, at day 2 postirradiation, the addition of PTX3 and FGB to FL increased the accuracy to 100%. At day 3 the use of FL and PTX3 yielded a predictive accuracy of 93% and at day 7 use of FL and SAA had an accuracy of 90%. Dose prediction of partial-body exposures based on the TBI model had a higher predictive accuracy when the percentage of the body exposed to radiation increased. Our findings indicate that this novel combination of radiation responsive biomarker proteins are an efficient method for predicting radiation exposure and are more accurate when used in concert compared to using any single biomarker protein alone.

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Section: Introductionmentioning

confidence: 99%

“…Flt3 Ligand, SAA, MMP9 and FGB were selected based on our previous studies which identified these proteins as being radiation responsive (3, 4). FL and SAA have also been previously characterized in other biodosimetry studies modeling total-body irradiation (TBI) and partial-body irradiation (PBI) (5, 8–10).…”

Section: Introductionmentioning

confidence: 99%

Multivariate Analysis of Radiation Responsive Proteins to Predict Radiation Exposure in Total-Body Irradiation and Partial-Body Irradiation Models

et al. 2017

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“…Partial-body exposures have also been shown to correlate with plasma expression of SAA, FL and G-CSF using a murine model ( 34 , 35 ). These studies were able to show relative increases in expression of plasma biomarkers correlating to an increasing area of partial-body exposure ( 26 , 36 ).…”

Section: Proteomicsmentioning

confidence: 94%

“…For example, several studies have shown that expression of cytokine FL, exhibits a direct relationship to the amount of radiation and has been used previously in clinical assessment of accidental exposures. (34, 36, 43). While a single marker or small panel of proteomic markers to determine dose has great utility for dose assessment, further proteomics studies are needed to evaluate internal exposures, other types of radiation exposure and preexisting clinical confounders.…”

Section: Proteomicsmentioning

confidence: 99%

State-of-the-Art Advances in Radiation Biodosimetry for Mass Casualty Events Involving Radiation Exposure

Sproull

Camphausen

2016

Radiation Research

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With the possibility of large-scale terrorist attacks around the world, the need for modeling and development of new medical countermeasures for potential future chemical, biological, radiological and nuclear (CBRN) has been well established. Project Bioshield, initiated in 2004, provided a framework to develop and expedite research in the field of CBRN exposures. To respond to large-scale population exposures from a nuclear event or radiation dispersal device (RDD), new methods for determining received dose using biological modeling became necessary. The field of biodosimetry has advanced significantly beyond this original initiative, with expansion into the fields of genomics, proteomics, metabolomics and transcriptomics. Studies are ongoing to evaluate the use of lymphocyte kinetics for dose assessment, as well as the development of field-deployable EPR technology. In addition, expansion of traditional cytogenetic assessment methods through the use of automated platforms and the development of laboratory surge capacity networks have helped to advance our biodefense preparedness. In this review of the latest advances in the field of biodosimetry we evaluate our progress and identify areas that still need to be addressed to achieve true field-deployment readiness.

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“…Serum Flt3 ligand has been shown to reflect hematopoiesis at the progenitor cell level, increasing with the severity of bone marrow failure and normalizing as patients recover; it inversely correlated with colony forming ability in patient bone marrow cells [22]. Flt3 ligand may be a surrogate marker of decreased bone marrow hematopoietic potential as the hematopoietic stem cells (HSCs) are depleted, similar to the elevated Flt3 ligand levels seen after bone marrow irradiation [23], continued exploration of Flt3 ligand levels in the setting of GATA2 deficiency may help track or predict disease evolution [21*]. …”

Section: Disease Coursementioning

confidence: 99%

GATA2 deficiency

Hsu

McReynolds

Holland

2015

Current Opinion in Allergy &Amp; Clinical Immunology

125

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Purpose of Review GATA2 deficiency is a germline disease which causes a wide spectrum of phenotypes including viral and bacterial infections, cytopenias, myelodysplasia, myeloid leukemias, pulmonary alveolar proteinosis and lymphedema. The age of clinical presentation ranges from early childhood to late adulthood, with most occurring in adolescence to early adulthood. We review the expanding GATA2 deficient phenotype, molecular genetics of disease, and developments in treatment. Recent Findings GATA2 mutations have been found in up to 10% of those with congenital neutropenia and/or aplastic anemia. Heterozygous mutations appear to cause haploinsufficiency due either to protein dysfunction or uniallelic reduced transcription. Disease-associated mutations in intronic regulatory elements or variations within the 5’ leader exons indicate that regulation of GATA2 is critical. Those with GATA2 mutations are at high risk for myelodysplasia (MDS), cytogenetic abnormalities, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). Bone marrow transplantation has been successful for both hematopoietic and pulmonary alveolar proteinosis repair. Summary GATA2 is a zinc finger transcription factor essential for embryonic and definitive hematopoiesis as well as lymphatic angiogenesis. GATA2 deficiency is caused by a variety of mutations in the GATA2 gene and can have variable presentation, onset and outcome. Patients are susceptible to mycobacterial, viral and fungal infections and can develop MDS, acute or chronic leukemias, lymphedema and pulmonary alveolar proteinosis. Hematopoietic stem cell transplantation (HSCT) reverses most of the clinical phenotype with good long-term outcomes.

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Correlation of Plasma FL Expression with Bone Marrow Irradiation Dose

Cited by 11 publications

References 38 publications

Multivariate Analysis of Radiation Responsive Proteins to Predict Radiation Exposure in Total-Body Irradiation and Partial-Body Irradiation Models

Multivariate Analysis of Radiation Responsive Proteins to Predict Radiation Exposure in Total-Body Irradiation and Partial-Body Irradiation Models

State-of-the-Art Advances in Radiation Biodosimetry for Mass Casualty Events Involving Radiation Exposure

GATA2 deficiency

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