A translatable predictor of human radiation injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58613 | GEO | 2014/10/21
SECONDARY ACCESSION(S): PRJNA253060
REPOSITORIES: GEO
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Project description:The development of a biodosimetric assay based on the combined gene expression analysis of ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation has been developed. Gene expression profile signature of human radiation injury into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) has been shown to discriminate 6 radiation dose levels in human PB. Candidate gene lists were first developed assaying human ex vivo and human TBI samples on the Affymetrix platform. For the Ex Vivo samples, healthy consented adult donor was randomly assigned to a radiation group and labeled with the target dose of 0 cGy, 150 cGy, 300 cGy, or 600 cGy. In addition to the radiation exposures, the samples were also treated with either no treatment, GCSF, or LPS at time points 6 hours and 24 hours. Radiation expire times from the Cs137 irradiator were calculated to achieve target doses specific for tubes filled with blood and inserted in the roaring test tube holder. The dose rate was 480 cGy/min for the duration of the study. The healthy donors were enrolled to participate in this study following a protocol to collect PB samples that was previously approved by the Duke University Institutional Review Board. For the TBI samples, adult patients, ages 21 to 66, were evaluated at the Duke University Adult Bone Marrow Transplantation Program enrolled in a Duke IRB-approved protocol to collect PB prior to and post TBI conditioning. With approval from the Duke University Institutional Review Board (IRB), between 5-12 mL of peripheral blood was collected from consented patients prior to and 6 hours following TBI with 150-200 cGy as part of their pre-transplantation conditioning. All patients receiving non-myeloablative conditioning were treated with 200 cGy of TBI from a linear accelerator at a dose rate of 20 cGy/min. All patients who underwent TBI-based myeloablative allogeneic or autologous stem-cell transplantation received radiation fractionated at 150 cGy per fraction at 20 cGy/min. All patients had PB collected (50 ml) prior to and 6 hours following exposure to either 200 cGy or 150 cGy radiation treatment. The dose exposure for TBI patients used in this study were 0 cGy, 150 cGy, 450 cGy and 1050 cGy at 0, 6, 30 and 78 hours post irradiation. Total RNA was extracted and assayed on the Affymetrix platform.
2014-10-21 | E-GEOD-58613 | biostudies-arrayexpress
Project description:Gene expression analysis of peripheral blood leukocytes (PB MNCs) to develop expression profiles that accurately reflect prior radiation exposure. Keywords: Comparative, exposure dosage, C57BI6 Murine Irradiation Studies We have made use of gene expression analysis of peripheral blood mononuclear cells (PB MNCs) to develop expression profiles that accurately reflect prior radiation exposure. Importantly, we demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from non-irradiated samples with an accuracy of 90%, sensitivity of 85% and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and non-irradiated human patients with an accuracy of 77%, sensitivity of 82% and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated which are highly predictive of different levels of radiation exposure in mice and humans. Mouse Dataset only
2010-06-11 | E-GEOD-6873 | biostudies-arrayexpress
Project description:After defining a gene expression signature that predicted radiation exposure dose with high accuracy in human peripheral white blood cells irradiated ex vivo, we now demonstrate the predictive power of gene expression signatures in blood from patients undergoing total body irradiation. Using whole genome microarray analysis, we have identified genes that respond to radiation exposure in cancer patients in vivo. A 3-nearest neighbor classifier built from these genes correctly predicted samples as exposed to 0, 1.25 or 3.75 Gy with 94% accuracy even when samples from healthy donor controls were included. The same samples were classified with 98% accuracy using a signature previously defined from ex vivo irradiation data. The samples could also be classified as exposed or not exposed with 100% accuracy using multiple methods. The demonstration that ex vivo irradiation is an appropriate model that can provide meaningful prediction of in vivo exposure, and that the signatures are robust across diverse disease states, is an important advance in the application of gene expression for biodosimetry. Translation of these signatures to a fully automated “lab-on-a-chip” device will enable high-throughput screening for large-scale radiological emergencies, as well as making such tests practical for clinical uses. Radiation induced gene expression was measured in vivo in TBI patients at 4 hours after 1.25Gy exposure or at 24 hours after 3.75Gy exposure with three 1.25Gy split doses (approximately 4 hours apart). A total of 18 TBI patients, diagnosed with a variety of cancers were used in this study. Blood from 14 healthy control individuals was also used for comparison.
2011-01-31 | E-GEOD-20162 | biostudies-arrayexpress
Project description:Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Keywords: peripheral blood, gene expression study, radiation reponse We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Neither genotype differences nor the time of PB sampling caused any lessening of the accuracy of PB signatures to predict radiation exposure, but sex difference did influence the accuracy of the prediction of radiation exposure at the lowest level (50 cGy). A PB signature of sepsis was also generated and both the PB signature of radiation and the PB signature of sepsis were found to be 100% specific at distinguishing irradiated from septic animals. We also identified human PB signatures of radiation exposure and chemotherapy treatment which distinguished irradiated patients and chemotherapy-treated individuals within a heterogeneous population with accuracies of 90% and 81%, respectively. Human and Murine samples used in models Peripheral blood was collected from patients prior to and 6 hrs following total body irradiation with 150 to 200 cGy as part of their pre-transplantation conditioning. For additional comparison, peripheral blood was obtained from healthy volunteers and an additional cohort of patients prior to and 6 hrs following the initiation of alkylator-based chemotherapy alone (without radiotherapy).
2010-05-17 | E-GEOD-10640 | biostudies-arrayexpress
Project description:There is a need to identify biomarkers of radiation exposure for use in development of circulating biodosimeters for radiation exposure and for clinical use as markers of radiation injury. Most research approaches for biomarker discovery rely on a single animal model. The current study sought to take advantage of a novel aptamer-based proteomic assay which has been validated for use in many species to characterize changes to the blood proteome after total-body irradiation (TBI) across four different mammalian species including humans. Plasma was collected from C57BL6 mice, Sinclair minipigs, and Rhesus non-human primates (NHPs) receiving a single dose of TBI at a range of 3.3 Gy to 4.22 Gy at 24 h postirradiation. NHP and minipig models were irradiated using a 60Co source at a dose rate of 0.6 Gy/min, the C57BL6 mouse model using an X-ray source at a dose rate of 2.28 Gy/min and clinical samples from a photon source at 10 cGy/min. Plasma was collected from human patients receiving a single dose of 2 Gy TBI collected 6 h postirradiation. Plasma was screened using the aptamer-based SomaLogic SomaScan® proteomic assay technology to evaluate changes in the expression of 1,310 protein analytes. Confirmatory analysis of protein expression of biomarker HIST1H1C, was completed using plasma from C57BL6 mice receiving a 2, 3.5 or 8 Gy TBI collected at days 1, 3, and 7 postirradiation by singleplex ELISA. Summary of key pathways with altered expression after radiation exposure across all four mammalian species was determined using Ingenuity Pathway Analysis (IPA). Detectable values were obtained for all 1,310 proteins in all samples included in the SomaScan assay. A subset panel of protein biomarkers which demonstrated significant (p < 0.05) changes in expression of at least 1.3-fold after radiation exposure were characterized for each species. IPA of significantly altered proteins yielded a variety of top disease and biofunction pathways across species with the organismal injury and abnormalities pathway held in common for all four species. The HIST1H1C protein was shown to be radiation responsive within the human, NHP and murine species within the SomaScan dataset and was shown to demonstrate dose dependent upregulation at 2, 3.5 and 8 Gy at 24 h postirradiation in a separate murine cohort by ELISA. The SomaScan proteomics platform is a useful screening tool to evaluate changes in biomarker expression across multiple mammalian species. In our study, we were able to identify a novel biomarker of radiation exposure, HIST1H1C, and characterize panels of radiation responsive proteins and functional proteomic pathways altered by radiation exposure across murine, minipig, NHP and human species. Our study demonstrates the efficacy of using a multispecies approach for biomarker discovery.
2024-01-03 | GSE252430 | GEO
Project description:Development of radiation medical countermeasures under the U.S. Food and Drug Administration Animal Rule requires the capability to translate an effective animal to human drug dose. One method of human dose translation is using a biomarker and determining drug doses that modulate the biomarker to the desired level. BIO 300 Oral Powder (BIO 300) is a prophylactic radiation medical countermeasure that is currently being developed following the Animal Rule. The present study aimed to identify biomarkers that can be used for human dose conversion by conducting transcriptomics of whole blood collected from BIO 300-treated CD2F1 mice in the presence and absence of total-body irradiation (TBI). Mice were treated with vehicle or 50, 100 or 200 mg/kg BIO 300, twice daily, for 6 days. Whole blood samples were collected 24 and 48 h after the last dose of the drug. Animals were also treated with vehicle or 200 mg/kg BIO 300 for 6 days prior to 9.2 Gy TBI 24 h after the last dose, with blood collection 24 h after irradiation. RNA sequencing demonstrated 100 – 200 mg/kg doses caused significantly more differential gene expression at 48 h post-drug dose compared to 50 mg/kg. Pathway analysis of the transcriptome profile from vehicle-treated/radiation-exposed mice revealed that many inflammatory signaling pathways were activated in these animals. Signaling pathways enriched in BIO 300-treated/TBI mice were involved in cellular stress and immune response and were predicted to be inhibited. We also identified pathways that were in inverse states (activation/inhibition) in vehicle and BIO 300-treated mice with TBI. There were two pathways specifically activated in vehicle-treated animals with TBI and inhibited in BIO 300-treated animals (with or without TBI), pathogen-induced cytokine storm signaling and S100 family signaling. In comparison to previously published human data, pulmonary fibrosis idiopathic signaling and wound healing signaling were enriched in healthy volunteers treated with BIO 300 and BIO 300-treated mice with TBI. In all, four signaling pathways were identified that were activated in vehicle-treated animals exposed to total body radiation but inhibited in irradiated animals or healthy humans treated with BIO 300. These pathways should be explored to identify potential biomarkers of BIO 300 that can be used for human dose translation.
2024-08-14 | GSE268247 | GEO
Project description:To compare human memory CD4+ T cell subsets in peripheral blood (PB) and bone marrow (BM) of healthy individuals at transcriptional level, we analyzed the global gene expression of ex vivo PB CD69- as well as BM CD69- and CD69+ memory CD4+ T cells from 4 paired PB and BM samples. The gene expression of these subsets was additionally compared to the transcriptional profile of 8 PB samples taken ex vivo or stimulated with phorbol myristate acetate (PMA) and Ionomycin for 3 hours.
2014-06-17 | GSE50677 | GEO
Project description:Early diagnosis of lethal radiation is imperative since its intervention time windows are considerably short. Hence, ideal diagnostic candidates of radiation should be easily accessible, enable to inform about the stress history and objectively triage subjects in a time-efficient manner. Therefore, the small molecules such as metabolites and microRNAs (miRNAs) from plasma are legitimate biomarker candidate for lethal radiation. Our objectives were to comprehend the radiation-driven molecular pathogenesis and thereby determine biomarkers of translational potential. We investigated an established minipig model of LD70/45 total body irradiation (TBI). In this pilot study, plasma was collected pre-TBI and at multiple time points, post-TBI. The majority of differentially expressed miRNAs and metabolites were perturbed immediately after TBI that potentially underlined the severity of its acute impact. The integrative network analysis of miRNA and metabolites showed a cohesive response; the early and consistent perturbations of networks were linked to cancer and the shift in musculoskeletal atrophy synchronized with the comorbidity-networks associated with inflammation and bioenergy synthesis. Subsequent comparative pipeline delivered 92 miRNAs, which demonstrated sequential homology between human and minipig, and potentially similar responses to lethal radiation across these two species. This panel promised to retrospectively inform the time since the radiation occurred; thereby could facilitate knowledge-driven intervention.
2023-11-16 | GSE244507 | GEO
Project description:There is a perceived need to develop tools for high-throughput radiation biodosimetry. In the case of an improvised nuclear device or a dirty bomb in a major city, potentially hundreds of thousands of people would have to be screened to assign exposed individuals to appropriate treatment. Gene expression represents an emerging approach to biodosimetry and could potentially provide an estimate of both absorbed dose and individual radiation-induced injury. Mice have been used as an in vivo model to elucidate the radiation response and to construct biodosimetric gene expression profiles. However, while most studies have used mouse strains with “average” radiation sensitivity, 2-4% of humans are thought to be radiosensitive. Such individuals would suffer greater radiological injury at a given dose than members of the general population, so it is of interest to determine how such sensitivity may impact the biodosimetric gene expression signatures being developed. Here, we use wild-type mice and genetically engineered mouse models deficient in two DNA repair pathways that can contribute to radiation sensitivity. Humans with ataxia telangiectasia or Atm-/- mice are deficient in double-strand break repair and show increased radiosensitivity. Atm-/- mice have a LD50/30 of 4 Gy compared with 8 Gy in the parental wild-type (WT) C57BL/6 mice. Humans with SCID, or Prkdcscid mice are deficient in non-homologous end joining, and are also radiosensitive. SCID mice have a LD50/30 of 3 Gy. These animal models represent a “worse-case” scenario, and should be viewed as an extreme of radiation sensitivity. Most radiosensitive members of the population will not have full-blown DNA repair deficiency syndromes, but these extreme models should help to define the maximum impact of DNA repair deficiency on gene expression following radiation exposure.
2018-01-17 | GSE99176 | GEO
Project description:Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Keywords: peripheral blood, gene expression study, radiation reponse
2008-11-29 | GSE10640 | GEO