Early Biomarkers Associated with P53 Signaling for Acute Radiation Injury

Accurate dose assessment within 1 day or even 12 h after exposure through current methods of dose estimation remains a challenge, in response to a large number of casualties caused by nuclear or radiation accidents. P53 signaling pathway plays an important role in DNA damage repair and cell apoptosis induced by ionizing radiation. The changes of radiation-induced P53 related genes in the early stage of ionizing radiation should compensate for the deficiency of lymphocyte decline and γ-H2AX analysis as novel biomarkers of radiation damage. Bioinformatic analysis was performed on previous data to find candidate genes from human peripheral blood irradiated in vitro. The expression levels of candidate genes were detected by RT-PCR. The expressions of screened DDB2, AEN, TRIAP1, and TRAF4 were stable in healthy population, but significantly up-regulated by radiation, with time specificity and dose dependence in 2–24 h after irradiation. They are early indicators for medical treatment in acute radiation injury. Their effective combination could achieve a more accurate dose assessment for large-scale wounded patients within 24 h post exposure. The effective combination of p53-related genes DDB2, AEN, TRIAP1, and TRAF4 is a novel biodosimetry for a large number of people exposed to acute nuclear accidents.

Influence of Drinking Water Quality on the Current of Acute Radiation Disease in Mice

Purpose: Assessing the role of various factors in the formation of radioresistance is an important branch of radiobiology. The quality of drinking water, as it turned out, can significantly affect radioresistance. Against the background of studying the antiradiation properties of various types of water, differing in mineral and isotopic composition, the problem of the influence of tap water on the course of radiation injury remained underestimated. This circumstance determined the purpose of the work: to evaluate the modifying effect of tap water on the course of acute radiation sickness after X-ray irradiation of mice at an average lethal dose. Material and methods: Female ICR (CD-1) mice were irradiated with an average lethal dose once – 6.5 Gy of X-ray irradiation. After irradiation, half of the mice received tap water as drinking water, and the other half received artificially mineralized drinking water. Results: Keeping animals on tap water significantly reduced the survival rate of mice both with a single dose (log-rank test p=0.02, χ2=5.38) compared with animals receiving artificially mineralized distilled water. In addition, in the group of mice that received tap water, an increase in the rate of death of mice and a lower preservation of the group mass of animals during the development of acute radiation injury was noted. Conclusion: Tap water, used as drinking water, increases the damaging effect of radiation when X-rays are irradiated in mice.

Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury

Radiation can be applied for therapeutic benefit against cancer or may result in devastating harm due to accidental or intentional release of nuclear energy. In all cases, radiation exposure causes molecular and cellular damage, resulting in the production of inflammatory factors and danger signals. Several classes of innate immune receptors sense the released damage associated molecules and activate cellular response pathways, including the induction of inflammasome signaling that impacts IL-1β/IL-18 maturation and cell death. A previous report indicated inflammasomes aggravate acute radiation syndrome. In contrast, here we find that inflammasome components do not exacerbate gamma-radiation-induced injury by examining heterozygous and gene-deletion littermate controls in addition to wild-type mice. Absence of some inflammasome genes, such as caspase-1/11 and Nlrp3, enhance susceptibility of treated mice to acute radiation injury, indicating importance of the inflammasome pathway in radioprotection. Surprisingly, we discover that the survival outcome may be sex-dependent as more inflammasome-deficient male mice are susceptible to radiation-induced injury. We discuss parameters that may influence the role of inflammasomes as radioprotective or radioexacerbating factors in recovery from radiation injury including the use of littermate controls, the sex of the animals, differences in microbiota within the colonies and other experimental conditions. Under the conditions tested, inflammasome components do not exacerbate radiation injury, but rather provide protective benefit.

Early Biomarkers Associated with P53 Signaling for Acute Radiation Injury

Background: Rapid and accurate high-throughput estimation of radiation dose aims to help medical rescue in nuclear radiation accident. However, current methods of dose estimation are still lacking of speedy or accuracy. P53 signaling pathway plays an important role in DNA damage repair and cell apoptosis induced by ionizing radiation. The changes of radiation-induced P53 related genes in the early stage of ionizing radiation should compensate for the deficiency of lymphocyte decline and γ-H2AX analysis as novel biomarkers of radiation damage. Methods: Bioinformatic analysis was performed on previous data to find candidate genes from human peripheral blood irradiated in vitro. The radiation sensitivity and baseline levels of candidate genes were verified. The approximate threshold for guiding medical treatment was estimated for each gene, and four genes were combined to construct an effectively early dose estimation model of radiation.Results: Four p53-related genes, DDB2, AEN, TRIAP1 and TRAF4, were screened and verified their significant radiosensitivity. Their expressions were stable without gender or age difference in healthy population, but significantly up-regulated by radiation, with time specificity and dose dependence in 2h-24h after irradiation. Further studies showed these genes can be used as indicators for early medical treatment in acute radiation injury. The effective combination of the four genes could achieve a more accurate dose assessment and injury classification for large-scale wounded patients within 24 hours post exposure.Conclusions: This is the first time to investigate the potential biomarkers of ionizing radiation by systematic study. The effective combination of the four genes provides a new model for dose estimation and injury classification of a large number of exposed population in acute nuclear accidents, and also provides a new idea and method.

Alrn-6924, a Dual Inhibitor of MDMX and MDM2, Transiently Induces Cell Cycle Arrest in Bone Marrow and Prevents Toxicity in Mouse Models of Acute Radiation Injury

Background: Myelosuppression is a common sequela of acute radiation injury due to sensitivity of proliferating bone marrow cells to ionizing radiation. ALRN-6924 is a clinical-stage, first-in-class, stabilized cell-permeating alpha-helical peptide drug that disrupts the interaction of the p53 tumor suppressor protein with its endogenous inhibitors, MDMX and MDM2, to induce transient, dose-dependent cell cycle arrest in p53-wild-type tissues. ALRN-6924 is being evaluated in clinical trials as a selective chemoprotection agent for patients with p53-mutant cancers to protect healthy normal cells from chemotherapy while not protecting p53-mutant cancer cells. We tested whether ALRN-6924 may similarly protect against radiation-induced toxicity in mouse models of acute radiation injury. Materials and methods: Activation of p21 (CDKN1A), a cell cycle regulator under transcriptional control of p53, was measured in formalin-fixed mouse bone marrow by immunohistochemistry analysis (IHC). Proliferation and apoptosis in bone marrow were measured by IHC of Ki67 and cleaved PARP, respectively. Cell cycle arrest was measured in the bone marrow of ALRN-6924-treated C57BL/6 mice by flow cytometry using EdU incorporation. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation, were measured by ELISA. As a model of radiation-induced toxicity, C57BL/6 mice (n=7/group) were treated with one or more intravenous 2.4 mg/kg doses of ALRN-6924 at 24, 16, 8, or 1 hour (or combinations thereof) or placebo prior to a 15 Gy shielded-body radiation dose and then monitored for body weight (BW) changes. Results: ALRN-6924 induced cell cycle arrest in mouse bone marrow with a maximum effect at 8 hrs post-dose. Repeated doses of ALRN-6924 every 8 hrs elevated p21 levels in bone marrow that correlated with reduced Ki67 positivity and increased serum MIC-1 levels. Treatment-dependent changes in cPARP expression in bone marrow were evident, but minimal in magnitude. In a nonlethal radiation exposure model, ALRN-6924 yielded significant protection from radiation-induced BW loss in a schedule-dependent manner. Placebo-treated mice showed 10% to 15% BW loss five days after irradiation, while mice receiving one or more ALRN-6924 doses 8 hrs prior to irradiation had an average of 4% BW loss (p=0.008, two-sided t test). Conclusions: ALRN-6924 mitigated toxicity in a mouse model of acute radiation injury. The observed radioprotection effect was correlated with cell cycle arrest in bone marrow after one or more doses of ALRN-6924. These results support further investigation of ALRN-6924 as a radioprotective agent. Disclosures Annis: Aileron Therapeutics, Inc.: Current Employment. Sutton: Aileron Therapeutics, Inc.: Consultancy; Kriya Therapeutics: Consultancy; First Light Pharmaceuticals: Consultancy; Cygnal Therapeutics: Consultancy. Aivado: Aileron Therapeutics, Inc.: Current Employment. Vukovic: Aileron Therapeutics, Inc.: Current Employment.

Identification of multi-omics molecular signature of acute radiation injury using nonhuman primate model

The availability of validated biomarkers to assess radiation exposure and to assist in developing medical countermeasures remains an unmet need. We used a cobalt 60 gamma irradiated nonhuman primate model to delineate a multi-omics based serum probability index of radiation exposure. Both male and female NHPs were irradiated with different doses ranging from 6.0 to 8.5 Gray, with 0.5 Gray increments between doses. We leveraged high resolution mass spectrometry for analysis of metabolites, lipids, and proteins at 1, 2, and 6 days post irradiation in NHP serum. A logistic regression model was implemented to develop a 4 analyte panel to stratify irradiated NHPs from unirradiated with high accuracy that was agnostic for all doses of gamma rays tested in the study, up to six days after exposure. This panel was comprised of Serpin Family A9, acetylcarnitine, PC (16:0/22:6), and suberylglycine, which showed 2 to 4 fold elevation in serum abundance upon irradiation in NHPs, and can potentially be translated for human use following larger validation studies. Taken together, this study, for the first time, demonstrates the utility of a combinatorial molecular characterization approach using an nonhuman primate model for developing minimally invasive assays from small volumes of blood that can be effectively used for radiation exposure assessments.

Peculiarities of Using Lymphocyte Test to Predict the Severity of Acute Radiation Injury

One of the methods of biological dosimetry is the use of information on the concentration of lymphocytes in the peripheral blood of victims in the first days after irradiation. The aim of the study was to validate the lymphocyte test method for predicting the severity of acute radiation injury, taking into account the dose rate factor. Materials and research methods. The method of investigation was a correlational analysis of clinical, dosimetric and laboratory data of the victims of the accident at the Chernobyl nuclear power plant in 1986 (n=65) and in radiation accidents with gamma-neutron irradiation (n=19). The data were taken from the database of acute radiation injuries in humans of A.I. Burnazyan Federal Medical Biophysical Center of the Federal Medical and Biological Agency of Russia. Results of the study and their analysis. The results of correlation analysis indicated that average lymphocyte concentration in the range of 0.4-0.8×109/l on day 3-6 post-irradiation with dose rates greater than 2 Gy/h resulted in an average dose estimate which was 40.0% higher than that for dose rates of less than 2 Gy/h. Absolute error of dose estimation is (±1.0-1.5) Gy. For lymphocyte concentrations higher than 0.8×109/l the prognosis is uncertain: the range of dose assessment variability is 1-4 Gy. At a lymphocyte concentration of less than 0.4×109/l the average dose estimate is more than 4.0 Gy, corresponding to a severe or extremely severe degree of acute radiation disease. The predicted degree of severity of radiation injuries in the presence of the neutron component of radiation is lower in comparison with the predictions based on the data on the victims of the Chernobyl accident. It is concluded that the identified dependencies can be used for medical triage of the victims at advanced stages of medical evacuation. For the purpose of correct routing of medical evacuation to specialized centers, it is advisable to allocate 4 treatment-evacuation groups.

Rehabilitation Nursing Intervention Can Improve Dysphagia and Quality of Life of Patients Undergoing Radiotherapy for Esophageal Cancer

Objective. To seek the improvement of rehabilitation nursing intervention on dysphagia and quality of life of patients with esophageal cancer undergoing radiotherapy. Methods. A total of 109 patients with esophageal cancer undergoing radiotherapy were selected as research objects. According to the random number table, they were separated into the control group (CG) and intervention group (IG), with 45 cases in CG and 64 cases in IG. In CG, patients were given routine nursing intervention, while those in IG were given rehabilitation nursing intervention. After intervention, the degree of acute radiation injury and the improvement of swallowing function were observed to compare the self-nursing ability, quality of life, and incidence of complications between the two groups. Results. The degree of injury in CG was heavier than that in IG. The improvement of swallowing function in IG was better than that in CG. The scores of self-nursing ability and life quality in IG were higher than those in CG, with statistically significant differences ( p < 0.05 ). The incidence of complications in IG was obviously lower than that in CG ( p < 0.05 ). Conclusion. Rehabilitation nursing intervention can ameliorate dysphagia, improve the quality of life, and reduce the incidence of complications for patients with esophageal cancer undergoing radiotherapy. It is worthy of clinical application.

A retrospective study of hypofractionated radiotherapy for keloids in 100 cases

At present, the consensus on the best treatment for keloids is the combination of clinical and surgical therapies, if necessary, associated with adjuvant radiotherapy like brachytherapy. Whereas, the uniform scheme of radiotherapy in keloids is unclear. Here, we conducting a retrospective analysis to assess the efficacy and safety of a specific treatment regimen (20 Gy in 5 fractions) in keloid patients. We retrospectively analysed the medical records of keloid patients receiving auxiliary postoperative radiotherapy (PORT) treatment from 2009 to 2019. The patients were treated with the hypofractionation method of 20 Gy in 5 fractions. We compared the local control rate and complications, using the chi-square test and logistic regression analyses. After screening, we identified 100 keloid patients in this study, with a median follow-up of 59 months. In this study, the overall local control rate of keloid lesions was 84.8%. After multivariate analyses (primary keloid or not, family history, interval from surgery to irradiation and site), our research showed that primary keloid, site and interval from surgery to irradiation were significantly related to recurrence. Acute radiation injury and late radiation injury accounted for 3% (erythema) and 1% (skin sclerosis) of the total cases, respectively. Our results indicate that a postoperative hypofractionation with radiation dose of 20 Gy in 5 fractions may be effective, easy to accept and safe for keloid patients.

Effect of Mexidol-Vet® on the course and outcome of acute radiation injury in rats

This paper presents experimental data on the effect of the drug Mexidol-Vet® on the course and outcome of acute radiation damage in rats caused by a single, general, external gamma radiation. There was a 20 % decrease in mortality in animals relative to the control values, activation of erythropoiesis, and a decrease in the severity of erythrocytopenia, leukocytopenia, and thrombocytopenia with the use of Mexidol-Vet®. The supposed mechanism of radioprotective and therapeutic action is the pronounced antioxidant and membrane-protective properties of the drug.