The aim of this study is to assess the predictive efficacy of a radiomics model utilizing magnetic resonance imaging (MRI) for predicting locally advanced cervical squamous cell carcinoma response to concurrent chemoradiotherapy. We enrolled a cohort of 139 patients diagnosed with stage IIB to IV cervical squamous cell carcinoma, based on the 2018 FIGO classification, who underwent concurrent chemoradiotherapy and pre-/post-treatment MRI examinations. These patients were divided into complete response and partial response groups. Prior to the initiation of treatment, the areas of interest within the lesion were delineated on T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and enhanced T1-weighted imaging (T1WI) sequences, from which radiomic features were extracted. The group was randomly divided into training (n = 111) and validation (n = 28) sets (8:2 ratio) to identify the optimal features. Logistic regression models were constructed to predict treatment response, with distinct models based on the following imaging modalities: enhanced T1WI, T2WI, DWI, a combination of T2WI and enhanced T1WI (joint model 1), and a combination of T2WI, DWI, and enhanced T1WI (joint model 2). Model fitness and predictive performance were assessed using receiver operating characteristic curves, while the clinical applicability of the models was analyzed using decision curve analysis. A cumulative count of 2,264 radiomic features was derived from the region of interest in each imaging sequence. Subsequently, 18, 16, 15, 16, and 13 optimal features were selectively identified from the five models. These selected features were employed to formulate a radiomics model designed for the prediction of treatment response. These selected features were used to construct individual radiomics models aimed at predicting treatment response. Subsequently, all models achieved AUCs > 0.8 in the validation set, with Joint Model 2 demonstrating the highest performance (AUC = 0.939, 95% CI: 0.826-1; sensitivity = 0.773, specificity = 0.833). No significant differences were observed between Joint Model 2 and other models (P > 0.05). The MRI-based radiomics model has high potential in effectively predicting the efficacy of concurrent chemoradiotherapy for locally advanced cervical squamous cell carcinoma.
Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is known for high levels of disease recurrence and resistance to conventional fractionated radiation therapy. In an analysis of primary patient HPV-negative HNSCC biopsies from our institutional tumor bank, we observed circulating and tumor-resident monocytic myeloid-derived suppressor cells (M-MDSCs) were enriched in patient samples from recurrent HPV-negative HNSCCs relative to treatment-naïve samples. To determine if radiation exposure alters myeloid chemotaxis to the tumor site, we measured myeloid chemotactic factor transcript expression in eight cancer-associated fibroblast (CAF) and EpCAM-expressing patient-derived malignant cell lines. In malignant cell lines, radiation exposure increased transcriptional expression of CCL5 and C-X-C ligand receptor 2 (CXCR2) ligands CXCL2 and CXCL8 (IL-8). Based on this finding, we evaluated whether an antagonist of CXCR2 (SB225002) in combination with radiation blocked murine MDSC chemotaxis in vivo and in vitro. Antagonism of CXCR2 signaling with SB225002, in combination with radiation, suppressed tumor growth, improved survival, and reduced intra-tumoral macrophages in a murine MOC1 model. Additionally, radiation-induced MDSC chemotaxis was inhibited by SB225002 in a transwell assay. Together, these data suggest CXCR2 inhibition in combination with radiation has therapeutic potential for treatment of HPV-negative HNSCC.
Several radiation medical countermeasures (MCMs) are currently approved by the United States Food and Drug Administration (US FDA) for the mitigation of hematopoietic acute radiation syndrome (H-ARS). Continued development of additional candidates remains a priority to enhance force protection capabilities, combat readiness, and operational preparedness in nuclear/radiological threat environments. One such candidate under development is BBT-059, a long-acting PEGylated interleukin-11 (IL-11) analog with known hematopoietic-promoting and anti-apoptotic properties. BBT-059 is under advanced development as a potential radiation MCM for H-ARS and has been shown to improve survival in lethally irradiated murine models; however, its proteomic responses after irradiation have not been fully characterized in nonhuman primates (NHPs). In this study, NHPs exposed to 4 Gy total-body gamma radiation were subsequently treated with a single subcutaneous dose of either 37.5 or 75 µg/kg of BBT-059 at 24 h postirradiation, and longitudinal serum proteomic profiling was performed using a mass spectrometry (MS)-based approach. Proteomic changes were compared to baseline levels to comprehensively identify time-dependent changes induced by irradiation and BBT-059 administration. These analyses revealed changes in proteins related to inflammation, innate immune activation, and hematological and platelet functions, which peaked at days 2 and 4 and gradually decreased to near baseline levels by the end of the study. Pathway enrichment analysis identified consistent activation of neutrophil degranulation, platelet degranulation, insulin-like growth factor transport, and calcium signaling pathways.
Normal tissues exposed to radiation during radiotherapy or radiation accidents are susceptible to chronic inflammation, which poses a significant health concern. Here, we used the mouse mammary gland as a model to investigate radiation-induced damage to normal tissue. Five-week-old mice were chosen to capture the radiation-sensitive pubertal developmental window, and transcriptomic sequencing was used to profile gene expression changes at 1-5 months postirradiation. Single-cell RNA sequencing was performed to identify immune cell populations and characterize their transcriptional features at the subpopulation level. By combining transcriptomic data with morphological analysis of the irradiated mammary gland, we identified gene expression signatures of specific macrophage and T cell subtypes within the postirradiation microenvironment and highlighted their roles in modulating inflammation and maintaining cell junction homeostasis. Notably, dysregulation of adipocyte differentiation and lipid metabolism pathways was observed as early as 1 month postirradiation, and this metabolic disturbance was associated with persistently elevated oxidative stress in the tissue. Single-cell analysis showed that CD163+ macrophages were functionally enriched in lipid metabolism pathways, and immunofluorescence staining confirmed their significant accumulation in the irradiated mammary gland. Overall, these findings suggest that CD163+macrophages are key mediators of chronic tissue inflammation after irradiation. This study offers a comprehensive characterization of microenvironmental changes in the irradiated mammary gland and identifies potential targets for radioprotection strategies to modulate tissue microenvironment factors.
To clarify the mechanisms of FLASH radiotherapy using C ion beams (373 MeV/u and 90 MeV/u), we investigated the dose rate dependence of yields of water radiolysis species (OH radicals, hydrated electrons, and hydrogen peroxide). Additionally, we evaluated changes in the induction rate of DNA strand breaks as a function of dose rate using pBR322 plasmid DNA in solutions. Average dose rates were 0.2 Gy/s [conventional (CONV)] and 75 Gy/s [ultra-high dose rate (UHDR)] for 373 MeV/u, and 0.3 Gy/s (CONV) and 100 Gy/s (UHDR) for 90 MeV/u. The G values of water radiolysis species decreased with UHDR irradiation compared to CONV dose rate, except for hydrogen peroxide exposed to 90 MeV/u C ions, whose yield remained independent of dose rate. Furthermore, the induction rate of single-strand breaks (SSB) was unaffected by dose rate, while the induction of double-strand breaks (DSB) decreased after UHDR irradiation. These findings suggest that radical-radical reactions occur more efficiently with increasing dose rate, resulting in a reduced contribution of water radiolysis species to DNA strand breaks, especially DSBs, after irradiation with C ions. Therefore, changes in the contribution of water radiolysis species to DNA strand breaks could play a crucial role in the sparing effects observed after UHDR irradiation.
Cervical squamous cell carcinoma (CESC), a subtype of cervical cancer, is an aggressive cancer. Radiotherapy is a key treatment for locally advanced cases, but its success is often limited by radioresistance. Therefore, this study explores whether the intermediate filament protein KRT6A increases the radioresistance of CESC cells by regulating lipid metabolism. The expression profile of KRT6A was analyzed using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets via the University of California Santa Clara UCSC Xena platform, while associated signaling pathways were identified through gene set enrichment analysis (GSEA) based on the GSE44001 dataset. Radioresistant SiHa cells (SiHa-R) were developed from the parental human CESC SiHa cell line. KRT6A mRNA levels were measured by qRT-PCR. Protein expression of KRT6A, γH2AX, and key lipogenic enzymes fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC1) was detected through Western blotting. Cell viability and proliferation were assessed using CCK-8 and colony formation assays, respectively. Apoptosis was evaluated with Annexin V-FITC/PI staining. Lipogenesis was examined by BODIPY staining and Acetyl-CoA measurement. Fatty acid composition was analyzed using liquid chromatography-mass spectrometry (LC-MS). KRT6A was found to be upregulated in CESC tissues compared to normal tissues and was further increased in radioresistant cells compared to radiosensitive cells. Its knockdown in radioresistant SiHa cells reduced cell viability and proliferation, increased apoptosis, and enhanced radiation-induced DNA damage. GSEA indicated KRT6A's involvement in fatty acid metabolism. LC-MS analysis showed that reducing KRT6A expression led to the overall decrease in multiple fatty acids. Overexpression of KRT6A increased FASN and ACC1 levels, promoted lipid droplet formation, and decreased radiation damage. These resistance effects were effectively reversed by the lipogenesis inhibitor C75. Therefore, KRT6A promotes radioresistance in CESC by activating lipogenesis.
Pentaazamacrocyclic Mn (II)-containing (MnPAM) superoxide dismutase mimetics can selectively modulate the effects of radiotherapy in tumors and normal tissues by enhancing oxidative stress in tumors and mitigating it in normal tissues. However, radiosensitizing effects in tumors are only achieved with stereotactic body radiotherapy-type dosing (≥7 Gy per fraction). These effects are limited at lower fractional doses that are clinically relevant for many tumors, including locally advanced rectal cancer. Here, we show that combining the MnPAM dismutase mimetic, rucosopasem manganese (GC4711), with pharmacological ascorbate significantly enhances radiosensitization to fractionated radiation doses relevant in colorectal cancer treatment (2–5 Gy) compared to either agent alone in multiple tumor models in vitro and significantly prolongs tumor growth delay in vivo. Mechanistically, enhanced radiosensitization with combination therapy is mediated by increased oxygen consumption and hydrogen peroxide generation. Despite having no effect on oxygen consumption in tumor cell media on its own, GC4711 significantly increases pharmacological ascorbate-induced oxygen consumption. Inducible catalase expression, or administration of exogenous catalase, attenuates the anti-cancer activity when combined. As predicted, increased peroxide fluxes with combination therapy enhanced postirradiation DNA damage and G 2 /M cell cycle accumulation. Importantly, treatment with pharmacological ascorbate and/or GC4711 had no significant effect on postirradiation clonogenic survival or DNA damage in non-malignant FHs74 enterocytes. These results support the hypothesis that adding pharmacological ascorbate to MnPAM dismutase mimetics selectively induces more peroxide-mediated radiosensitization than either agent alone in tumors without increasing radiosensitivity in cells treated with clinically relevant radiation fraction sizes used for radiotherapy of colorectal cancers.
Radiotherapy is a widely used cancer treatment modality with more than 70% of head and neck cancer (HNC) patients receiving it in either the definitive or adjuvant settings. Currently, all HNC patients, regardless of human papillomavirus (HPV) status, are treated with the same radiation dose, yet treatment response remains highly variable across patients and radiation-induced treatment toxicities continue to pose significant clinical challenges. To date, there are no clinically approved methods or biomarkers that can predict patient response to radiation, hindering the development of personalized radiation treatment strategies. In our recent publication in the International Journal of Radiation Oncology, Biology, Physics (1), we approached this clinical problem by focusing on a biological characteristic occurring in nearly all cancer cells to different degrees; chromosomal instability (CIN). CIN is defined as an ongoing rate of chromosome missegregation events over consecutive cell divisions, and is a type of genomic instability, which is a hallmark of cancer. One consequence of CIN is aneuploidy, or a state of abnormal chromosome content. It is important to distinguish CIN from aneuploidy as we discovered it is the rate of chromosome missegregation during mitosis (CIN) that determines cell fate after radiation.
Radiation has beneficial medical and industrial applications; however, high-dose exposure during accidents can result in severe outcomes, including fatal bone marrow failure. Total-body irradiation (TBI) of 6-10 Gy induces hematopoietic failure, primarily due to oxidative stress caused by excessive reactive oxygen species. This study aimed to evaluate the protective potential of probucol, a potent antioxidant, against lethal ionizing radiation-induced damage. Eight-week-old mice received 8 Gy TBI. Two probucol treatment strategies were tested: pretreatment, in which the drug was administered daily for 4 days before irradiation, and post-treatment, in which the drug was administered 4 h after irradiation and continued for 4 days. Survival rates, peripheral blood cell counts, bone marrow and spleen morphology, and urinary excretion levels of 8-hydroxy-2'-deoxyguanosine (oxidative DNA damage) were analyzed. Probucol pretreatment improved survival in mice that received 8 Gy TBI, whereas most of the mice in the post-treatment group and all of the mice in vehicle control group died within 30 days after exposure. Probucol pretreatments also significantly decreased the urinary excretion of 8-hydroxy-2'-deoxyguanosine compared with untreated control mice. Although TBI caused pancytopenia in both groups, peripheral blood cell counts showed no difference between the groups on day 14 postirradiation. Probucol pretreatment preserved nucleated bone marrow cells and showed extramedullary hematopoiesis in the spleen. These findings suggest that probucol pretreatment exert beneficial effects by mitigating radiation-induced bone marrow suppression and promoting compensatory extramedullary hematopoiesis within the spleen through its antioxidative action.
Rapid molecular biodosimetry may support radiation exposure assessment during mass casualty or mixed-field radiological incidents, but how gene expression responses vary across radiation qualities and dose rates remains incompletely characterized. Gene expression biodosimetry, including transcript-variant-aware measurements resulting from alternative splicing, may improve sensitivity for determining radiation quality and dose rate. We profiled nine radiation-responsive genes (AEN, APOBEC3H, DDB2, EDA2R, FDXR, PCNA, RPS27L, TRIAP1, ZMAT3) and six FDXR transcript variants using custom 384-well microfluidic RT-qPCR array cards (TaqMan Low Density Array, TLDA) of ex vivo leukopak-derived samples (leukocyte-enriched blood products) from three healthy donors, harvested 24 h after irradiation. Samples received an acute exposure of X rays (0.1-4 Gy), a protracted exposure of X rays (2 Gy at 0.1, 0.01, 0.004 Gy·min-1), and a mixed neutron field exposure with approximately 81% neutrons and 19% concomitant γ-rays (0.1-2 Gy at 0.6-1 Gy·h-1). In a separate experiment, gene expression of leukopaks was concordant with whole blood responses for FDXR and CDKN1A, with FDXR exceeding a 30-fold induction after exposure to 4 Gy of X rays. In the TLDA dataset, all targets were upregulated in a dose-dependent manner. Over the range of 0.1-1 Gy, neutrons elicited higher induction than X rays for APOBEC3H, DDB2, and FDXR, with convergence at 2 Gy as X-ray responses plateaued. Variant-level analysis showed isoform-specific behavior: FDXR-203 and FDXR-206 mRNA isoforms were induced by neutrons (especially at higher doses), while FDXR-202, FDXR-205, and FDXR-217 responded preferentially to X rays and FDXR-204 was moderately upregulated after X-ray irradiation. After protracted X-ray exposure, most genes were up-regulated with minimal dose-rate effects; AEN was the only target that differed significantly between 0.004 and 0.01 Gy·min-1, and FDXR-202/-204/-205 showed a higher fold change at the lowest dose rate. Analysis of dose-response behavior and derived relative biological effectiveness (RBE) values revealed three patterns when comparing neutrons with X rays. First, FDXR, DDB2 and EDA2R were more responsive to neutrons than to X rays at low doses (0.1-1 Gy), with fold changes increasing faster for neutrons. Depending on the gene, neutrons were equivalent to X-ray doses that were approximately 2-4 times higher, consistent with results reported previously for cytogenetic endpoints. Second, APOBEC3H, FDXR-217, RPS27L, PCNA and FDXR-203 showed similar dose-response behavior after exposure to neutrons and X rays, with occasional plateau differences. Third, AEN, TRIAP1 and the remaining assayed FDXR variants showed high variability and were not studied further here. Overall, several genes showed little discrimination across low dose rates, supporting their use for estimating total dose, while others showed clear differences between radiations of different qualities. Taken together, our results support the further development of multi-gene, variant-resolved approaches for radiation exposure assessment in mixed-field scenarios.
Previously, we demonstrated that continuous oral delivery of quercetin attenuated radiation-induced dermal fibrosis in C3H/HeN mice exposed to 35 Gy of ionizing radiation. Quercetin was rapidly metabolized and primarily detected in plasma, liver, and urine as methylated metabolites. The current study aimed to investigate the biological effects of methylated quercetin on radiation-induced cellular senescence and macrophage polarization, and to evaluate its therapeutic potential for ameliorating radiation-induced skin fibrosis. Skin tissue was collected from C3H/HeN mice fed quercetin-formulated or control chow and exposed to 0 Gy or 35 Gy at 150 days postirradiation. In mice irradiated with 35 Gy, quercetin chow administration reduced epidermis thickness, the number of cells that were positive for senescent markers (p21, p16) positive cells and vimentin-positive cells in the skin, compared with control chow administration. Also, the number of cells positive for macrophage markers (F4/80, CD206) were decreased. These in vivo results were consistent with findings in NIH/3T3 fibroblasts irradiated with either 0 Gy or 17.5 Gy in the presence of 3-O-methylquercetin (MQ) or vehicle. X-gal staining and p21 expression detected by Western blotting indicated that radiation-induced cellular senescence, but it was decreased by pretreatment of MQ. Senescence-associated secretory phenotype (SASP) factors including TGF-β1 and Pai-1 were significantly higher in the irradiated fibroblasts but decreased in the presence of MQ. In addition, MQ pretreatment reduced cell proliferation and vimentin expression via canonical TGF-β1 signaling. Furthermore, conditioned media (CM) from irradiated fibroblasts induced M2 polarization of Raw264.7 macrophages, whereas CM from MQ-treated irradiated fibroblasts decreased M2 macrophage expression. Taken together, these results indicate that MQ is a potential senomorphic agent, reducing SASP expression to mitigate radiation-induced skin senescence and macrophage polarization, and exerting protective effects against radiation-induced skin fibrosis.
Blood is the standard matrix for gene expression (GE)-based biodosimetry, but less invasive sampling methods are needed in emergency settings and for longitudinal monitoring. Saliva, which contains leukocytes and an ultrafiltrate of blood, is a promising alternative. In this human in vivo study, we analyzed radiation-induced shifts in salivary gene expression for biodosimetric applications and evaluated their similarity to gene expression patterns in blood. Beyond dose estimation, such saliva-based gene expression signatures may support risk stratification and early prediction of clinical outcomes, particularly when repeated sampling is required or blood collection is not feasible. Matched blood and saliva samples were collected from leukemia patients (n = 31) undergoing fractionated total-body irradiation (TBI) for their myeloablative treatment (1.5-4 Gy total dose, 1.5-2 Gy per fraction). Samples were taken before and 24 h after the first day of radiation treatment. The expression of radiation-responsive genes (GADD45A, CCNG1, CDKN1A, PHPT1, SESN1, FDXR, DDB2, POU2AF1, and WNT3) was analyzed for 28 patients (three patients excluded) using quantitative real-time PCR (RT-qPCR). Significant upregulation was observed for GADD45A (median fold change = 1.52, P = 0.003), CCNG1 (median fold change = 1.73; P = 0.003), and DDB2 (median fold change = 1.60; P = 0.05), as well as WNT3 (median fold change = 1.84; P = 0.038), demonstrating that saliva shows molecular responses to radiation exposure. Notably, 54% of the patients exhibited radiation-responsive upregulation of GADD45A and CCNG1, indicating that saliva can detect radiation-responsive gene expression despite substantial inter-individual variability. Corresponding blood samples were obtained from 16 patients. Statistically significant upregulation of multiple radiation-responsive genes was observed: GADD45A (median fold change = 2.25; P < 0.001), CCNG1 (median fold change = 1.64; P = 0.010), DDB2 (median fold change = 1.91; P < 0.001), CDKN1A (median fold change = 2.45; P = 0.001), SESN1 (median fold change = 1.75; P < 0.001), and FDXR (median fold change = 2.53; P = 0.001). A significant downregulation was observed for POU2AF1 (median fold change = 0.49; P = 0.013). In conclusion, detection of radiation-induced gene expression changes in saliva may serve as a minimally invasive tool for biodosimetry. However, given the greater inter-individual variability observed in saliva compared to blood, further optimization and validation is essential before clinical implementation.
Glioblastoma WHO CNS Grade 4 (GBM) is associated with poor prognosis and high recurrence rates despite the current therapeutic interventions. Conventional imaging bears restrictions in detecting tumor recurrence and discriminating it from tissue necrosis and post-operative scar tissues. In a previous study, we conducted a whole-transcriptome screening using next-generation sequencing (NGS) on whole blood samples (n = 33) from seven patients and tumor biopsies to identify tumor-specific gene expression patterns. This revealed downregulation post-surgery, with a return to pre-surgery baseline levels at the time of tumor recurrence. In the screening phase, we were able to identify 374 genes across all patients, and in this study, we aimed to validate the most predictive genes identified in the screening phase using the same samples with qRT-PCR (customized TaqMan array cards). A subset of candidate genes was selected for each patient to reduce the number of screening genes to be validated, resulting in a total of 94 genes for validation using qRT-PCR. All genes were measured in all samples, thus allowing a search for genes methodologically confirming the NGS candidate genes as well as examining qRT-PCR-based gene expression patterns, which were not captured by NGS in certain patients. Filter criteria included a post-surgery fold change (FC) ≤ 0.6 across all or most time points and already cited GBM-related genes. From whole blood, total RNA was isolated, converted into cDNA, and 6,270 gene expression measurements were performed employing custom TaqMan array cards (qRT-PCR). We were able to successfully validate NGS candidate genes for three patients out of seven. Differential gene expression (DGE) of both methods was comparable for these patients (e.g., r2 = 0.76, P < 0.001 for patient #1). Between 38-62% of NGS candidate genes per patient could be successfully validated, but only in patients where the screening comprised ≥20 NGS candidate genes. QRT-PCR also detected tumor recurrence-associated expression patterns in genes that were not captured by NGS, but 2-9-fold more candidates were observed for NGS-selected genes. Furthermore, in a patient receiving additional chemotherapy (CTx) during the tumor recurrence phase, a reduction in DGE of 13 genes was observed. In another patient, DGE indicated recurrence 13 days before radiological examinations confirmed it. The evidence, based on screening and validated, suggests a potential association, but a coincidental link cannot be ruled out. Our findings may point to the possible utility of gene expression measurements in peripheral whole blood as a simplified liquid biopsy method for GBM tumor recurrence. However, further prospective cohort studies with improved control of sampling during clinical follow-up and radiological examinations are needed to strengthen the presumed causality and the clinical value of early gene expression changes as an indicator of tumor recurrence.
The potential use of tactical nuclear weapons or improvised nuclear devices in conflict scenarios could cause mass casualties, exposing victims to both physical trauma and ionizing radiation, resulting in complex injuries related to irradiation. Due to the synergistic and deleterious effects of radiation combined injuries, including higher mortality and impaired tissue repair, these injuries must be considered in victim management and triage strategies. While muscle injuries are often reported in conflict zones, their interaction with total-body irradiation (TBI) remains poorly understood. In this study, we developed a new in vivo rat model combining total-body irradiation with localized muscle injury. Animals were exposed to 8 Gy of gamma radiation from a cobalt-60 source, causing hematopoietic acute radiation syndrome (H-ARS). Muscle injury was induced by intramuscular injection of notexin into the left soleus muscle. Clinical assessments were performed at multiple time points over 63 days after irradiation and/or muscle injury, with blood, bone marrow, and muscle samples harvested. Total-body irradiation alone caused about 15% lethality, significant weight loss, and temporary bone marrow aplasia, consistent with H-ARS. Notexin-induced muscle injury caused acute muscle necrosis followed by complete regeneration, as shown by the restoration of muscle mass and normal tissue structure. However, under the combined radiation and injury condition, muscle regeneration was markedly impaired. By day 63, the animals had lost about 20% of muscle mass, with ongoing necrotic fibers, chronic inflammation, thickening of the extracellular matrix in the perimysium, and smaller myofibers, indicating long-term functional impairment. This preclinical model captures radiation combined with muscle injury in the context of H-ARS and shows a lasting impairment of muscle regeneration after irradiation. It offers a useful tool to explore underlying mechanisms and improve medical support during future radiological or nuclear mass casualty events.
In the event of incidents involving nuclear hazards, the correct use of the devices deployed for measuring and monitoring γ-radiation fields is important for the safety of all people involved. Accordingly, realistic training is essential for all personnel who may face such scenarios. Unfortunately, this is currently not feasible on a regular basis, as appropriate radioactive sources are only available at a few training sites and the use of high-activity γ-radiation sources for this purpose imposes unnecessary safety and health risks. Furthermore, commercially available training equipment is too expensive for widespread use and covers only a few aspects. The goal of the SIEVERT project is to create an inexpensive and easy-to-use device for the realistic emulation of dose rate meters in freely definable scenarios. Using low-cost, readily available components, we have already developed a prototype of a device that is able to emulate radiometers using high-precision satellite navigation. It allows any number, kind, activity and age of point sources as well as shielding elements of different nature and thickness, e.g., house walls, to be defined and their coordinates stored. The portable emulators determine their positions relative to the virtual sources and the shields in real-time with a precision of a few centimeters. So, they can continuously calculate and display the equivalent γ-ray dose rates and the resulting doses that would be received at the respective locations in a real scenario. The system also accounts for effects such as inertia, limited measurement accuracy, and background radiation.
Radiological emergencies, such as nuclear power plant accidents or the detonation of radiation-dispersive devices, can release radionuclides into the environment, with Cesium-137 (137Cs) of particular concern due to its long half-life (30.17 years), high water solubility, and widespread dispersibility. Once incorporated, 137Cs distributes in soft tissues and exhibits a long biological half-life. The approved commercial countermeasure for internal decorporation is Radiogardase®-Cs, the insoluble Prussian Blue (PB; ferric hexacyanoferrate(II)), which binds radiocesium and thallium in the gastrointestinal tract. Since absorption occurs mainly in the small intestine and redistribution via enterohepatic circulation prolongs retention, effective decorporation strategies remain essential. In this study, insoluble PB nanoparticles were synthesized via an optimized indirect route employing hydrogen peroxide treatment, and their structure characteristics were compared to those of Radiogardase®-Cs, followed using an in vivo C57Bl6 mouse model for acute internal 137Cs decorporation assessment. Initially, the elimination kinetics for the ingestion of 137Cs was assessed using control animals. The results revealed a decrease of half of the radionuclides' initial activity within a period of approximately 3.4 days. Following therapeutic effect tests of 1-to-4-day treatment of contaminated mice with Nano-PB formulation indicated by 1.2- to 1.9-fold higher excretion rate of 137Cs compared to that when Radiogardase®-Cs was used. Although the short-term elimination profiles of Nano-PB and Radiogardase®-C appeared comparable, the overall results for the nanosized particles indicated an advantage in enhanced radiocesium decorporation. This effect may be attributed to the higher density of active binding sites, enhancing binding efficiency, while future perspectives should include comparison of absorption capacity and comprehensive toxicity assessments of the nanosized PB formulations.
Conventional radiation emergency medical education has relied on mannequin-based simulations and table-top exercises, which have limitations in reproducing complex contaminated casualty scenarios. To address these limitations, a virtual reality/augmented reality (VR/AR)-based training simulator was developed and implemented in the 2024 regular training curriculum at the Korea Institute of Radiological and Medical Sciences (KIRAMS). This study focused on two VR modules: the treatment process for radiation exposure patients and VR TRIAGE. Both modules were technically refined in 2024, including scenario expansion (e.g., cardiac arrest events), difficulty adjustment, enhanced trauma representation, personal protective equipment donning/doffing procedures, video reference functions, and integration of vital sign monitoring. The VR modules were deployed in radiation emergency training programs for radiological emergency medical personnel and first responders, with structured proficiency and effectiveness evaluations. For the VR treatment process, 45 trainees completed pre- and post-training assessments, showing significant improvement in all five assessment items, including sequential management steps, wound decontamination, and knowledge of required equipment (all P < 0.001). Similar gains were observed in VR TRIAGE, where understanding and confidence in casualty classification improved consistently. Educational effectiveness evaluation across the total curriculum (n = 120 in 2024) showed higher scores compared with the 2023 pilot (n = 151), particularly for presence (from 4.13 to 4.51) and reduced simulation sickness (from 3.26 to 3.96). The integration of VR/ AR-based modules into radiation emergency medical education demonstrated improvements in learner proficiency, usability, and overall satisfaction. These results emphasize VR/AR-based training programs as sustainable educational tools for enhancing preparedness and response capacity in radiation emergency medicine.
BBT-059 is a long-acting PEGylated interleukin-11 (IL-11) analog that is believed to have hematopoietic-promoting and anti-apoptotic properties, making it an ideal candidate for further development as a potential radiation medical countermeasure (MCM) for the hematopoietic acute radiation syndrome (H-ARS). The efficacy of BBT-059 has been previously established in an H-ARS murine model and in a nonhuman primate (NHP) model through pharmacokinetic and pharmacodynamic (PK/PD) studies. In the current study, a total of 12 naïve NHPs (rhesus macaques) were administered a single 37.5 µg/kg, 75 µg/kg, or 150 µg/kg dose of BBT-059 (n = 4 animals per group) subcutaneously and monitored for 21 days post-administration. To further evaluate the safety profile of BBT-059 and better understand its mechanism of action, proteomic analyses were performed to assess the impact of BBT-059 on proteins, pathways, and any dose-dependent differences. Blood samples were collected and serum was isolated and analyzed using trapped ion mobility time-of-flight mass spectrometry (timsTOF-MS). Statistically significant time-dependent changes were present in all dose groups when comparing pre-administration to post-administration samples, peaking around 3 days post-administration and reverting to near-normal levels by the end of the study period. Any dose of BBT-059 triggered a robust, acute-phase proteomic response characterized by an increase in platelet and neutrophil counts, elevated IL-6 expression, and an activation of the neutrophil degranulation and platelet activation, signaling and aggregation pathways. Taken together, these observations suggest that BBT-059 has a good safety profile for further development as a radiation MCM.
Acquired radioresistance remains a major obstacle to effective radiotherapy for cervical cancer, often driven by epithelial-mesenchymal transition (EMT). This study reveals TSPAN8 as a novel regulator of EMT-mediated radioresistance, offering new insights for overcoming treatment failure. Radioresistant subclones of HeLa-R25 and SiHa-R25 cells were established by repeated 2 Gy fractions. Radioresistance, apoptosis, EMT, and stemness were assessed by clonogenic survival, flow cytometry, immunoblotting, and immunofluorescence. Differentially expressed genes were identified by microarray, validated by protein-protein interaction analysis and co-immunoprecipitation, and functionally examined via TSPAN8 overexpression/knockdown, xenograft models, and immunohistochemistry of primary, metastatic, and recurrent post-radiotherapy specimens. Prognostic relevance was analyzed in the TCGA-CESC cohort. Fractionated irradiation induced EMT and radioresistance, with significantly higher clonogenic survival in R25 cells (P < 0.05), characterized by E-cadherin loss, N-cadherin/Vimentin upregulation, and increased CD44/Oct4. TSPAN8 was the most upregulated gene and directly interacted with E-cadherin. Overexpression enhanced EMT, invasion, and resistance to apoptosis, while knockdown reversed these effects and restored radiosensitivity in vivo. TSPAN8 knockdown in radioresistant xenografts significantly suppressed tumor growth (P < 0.05), and combined knockdown with irradiation further reduced tumor volume (P < 0.05). In patient samples, post-radiotherapy recurrences and metastases exhibited high TSPAN8 and vimentin with reduced E-cadherin. TCGA data confirmed that elevated TSPAN8 was associated with worse outcomes, including shorter disease-specific survival (HR = 2.02, 95% CI 1.01-3.71, P = 0.02) and progression-free survival (HR = 3.09, 95% CI 1.80-5.30, P < 0.001). These data suggest that TSPAN8 drives EMT-mediated radioresistance in cervical cancer, is associated with recurrence and poor survival, and represents a potential biomarker and therapeutic target. Targeting TSPAN8 may enhance radiosensitivity and improve personalized radiotherapy outcomes.
