Conventional cancer therapy strategies, although centered around killing tumor cells, often lead to severe side effects on surrounding normal tissues, thus compromising the chronic quality of life in cancer survivors. Hydrogen peroxide (H2O2) is a secondary signaling molecule that has an array of functions in both tumor and normal cells, including the promotion of cell survival pathways and immune cell modulation in the tumor microenvironment. H2O2 is a reactive oxygen species (ROS) crucial in cellular homeostasis and signaling (at concentrations maintained under nM levels), with increased steady-state levels in tumors relative to their normal tissue counterparts. Increased steady-state levels of H2O2 in tumor cells, make them vulnerable to oxidative stress and ultimately, cell death. Recently, H2O2-producing therapies-namely, pharmacological ascorbate and superoxide dismutase mimetics-have emerged as compelling complementary treatment strategies in cancer. Both pharmacological ascorbate and superoxide dismutase mimetics can generate excess H2O2 to overwhelm the impaired H2O2 removal capacity of cancer cells. This review presents an overview of H2O2 metabolism in the physiological and malignant states, in addition to discussing the anti-tumor and normal tissue-sparing mechanism(s) of, and clinical evidence for, two H2O2-based therapies, pharmacological ascorbate and superoxide dismutase mimetics.

BACKGROUND: Central nervous system (CNS) injury following brain-directed radiotherapy remains a major challenge. Proton radiotherapy (PRT) minimizes radiation to healthy brain, potentially limiting sequelae. We characterized CNS radiotoxicity, including radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB), in glioma patients treated with PRT or photons (XRT).
METHODS: Thirty-four patients (19 male; median age 39.6 years) with WHO grade 2-3 gliomas treated with partial cranial radiotherapy (XRT [n = 17] vs PRT[n = 17]) were identified and matched by demographic/clinical criteria. Radiotoxicity was assessed longitudinally for 3 years post-radiotherapy via serial analysis of T2/FLAIR- (for RIL), contrast-enhanced T1- (for TN), and susceptibility (for CMB)-weighted MRI sequences. RIL was rated at whole-brain and hemispheric levels using a novel Fazekas scale-informed scoring system.
RESULTS: The scoring system proved reliable (ICC > 0.85). Both groups developed moderate-to-severe RIL (62%[XRT]; 71%[PRT]) within 3 years; however, XRT was associated with persistent RIL increases in the contralesional hemisphere, whereas contralesional hemispheric RIL plateaued with PRT at 1-year post-radiotherapy (t = 2.180; P = .037). TN rates were greater with PRT (6%[XRT] vs 18%[PRT]; P = ns). CMB prevalence (76%[XRT]; 71%[PRT]) and burden (mean #CMB: 4.0[XRT]; 4.2[PRT]) were similar; however, XRT correlated with greater contralesional hemispheric CMB burden (27%[XRT]; 17%[PRT]; X2 = 4.986; P = .026), whereas PRT-specific CMB clustered at the radiation field margin (X2 = 14.7; P = .002).
CONCLUSIONS: CNS radiotoxicity is common and progressive in glioma patients. Injury patterns suggest radiation modality-specificity as RIL, TN, and CMB exhibit unique spatiotemporal differences following XRT vs PRT, likely reflecting underlying dosimetric and radiobiological differences. Familiarity with such injury patterns is essential to improve patient management. Prospective studies are needed to validate these findings and assess their impacts on neurocognitive function.

The risks of severe ionizing radiation exposure are increasing due to the involvement of nuclear powers in combat operations, the increasing use of nuclear power, and the existence of terrorist threats. Exposure to a whole-body radiation dose above about 0.7 Gy results in H-ARS (hematopoietic acute radiation syndrome), which is characterized by damage to the hematopoietic system; higher doses result in further damage to the gastrointestinal and nervous systems. Only a few medical countermeasures for ARS are currently available and approved for use, although others are in development. Cell therapies (cells or products produced by cells) are complex therapeutics that show promise for the treatment of radiation injury and have been shown to reduce mortality and morbidity in animal models. Since clinical trials for ARS cannot be ethically conducted, animal testing is extremely important. Here, we describe cell therapies that have been tested in animal models. Both cells and cell products appear to promote survival and lessen tissue damage after whole-body irradiation, although the mechanisms are not clear. Because radiation exposure often occurs in conjunction with other traumatic injuries, animal models of combined injury involving radiation and future countermeasure testing for these complex medical problems are also discussed.

To date, few FDA-approved medical countermeasures are available for addressing hematopoietic acute radiation syndrome (H-ARS). In this study, we present our latest research findings focusing on the evaluation of a novel radiation mitigator known as the mitigating amino acid mixture (MAAM). MAAM is composed of five amino acids as the recently reported amino acid-based oral rehydration solution for mitigating gastrointestinal (GI)-ARS. CD2F1 male and female mice were exposed to 60Co-γ total body irradiation (TBI) at 9.0 or 9.5 Gy. Following irradiation, mice were orally administered with MAAM or a saline vehicle control once daily for a duration of 14 days, commencing 24 h after TBI. Mouse survival and body weight change were monitored for 30 days after irradiation. Complete blood counts (CBCs), bone marrow (BM) stem and progenitor cell survival (clonogenicity), and a serum cytokine antibody array were analyzed using samples from day 30 surviving mice. Our data revealed that MAAM treatment significantly enhanced survival rates in irradiated male CD2F1 mice, and the survival rate increased from 25% in the vehicle control group to 60% in the MAAM-treated group (p < 0.05) after 9.0 Gy TBI. The number of BM colonies significantly increased from 41.8 ± 6.4 /104 cells (in the vehicle group) to 78.5 ± 17.0 /104 cells (in the MAAM group) following 9.0 Gy TBI. Furthermore, MAAM treatment led to a decrease in the levels of six cytokines/proteins [cluster of differentiation 40 (CD40), interleukin (IL)-17A, C-X-C motif chemokine 10 (CXCL10/CRG-2), cutaneous T cell-attracting chemokine (CTACK), macrophage inflammatory protein (MIP)-3β, and IL-1β] and an increase in the levels of five other cytokines/proteins [IL-3Rβ, IL-5, leptin, IL-6, and stem cell factor (SCF)] in mouse serum compared to the vehicle group after 9.0 Gy TBI. However, similar alleviating effects of MAAM were not observed in the irradiated CD2F1 female mice. The serum cytokine profile in the irradiated female mice was different compared to the irradiated male mice. In summary, our data suggest that the beneficial effects of the mitigative amino acid combination treatment after radiation exposure may depend on sex.

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent\'s use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.

Exposure to ionizing radiation, accidental or intentional, may lead to delayed effects of acute radiation exposure (DEARE) that manifest as injury to organ systems, including the kidney, heart, and brain. This study examines the role of activated protein C (APC), a known mitigator of radiation-induced early toxicity, in long-term plasma metabolite and lipid panels that may be associated with DEARE in APCHi mice. The APCHi mouse model used in the study was developed in a C57BL/6N background, expressing the D168F/N173K mouse analog of the hyper-activatable human D167F/D172K protein C variant. This modification enables increased circulating APC levels throughout the mouse\'s lifetime. Male and female cohorts of C57BL/6N wild-type and APCHi transgenic mice were exposed to 9.5 Gy γ-rays with their hind legs shielded to allow long-term survival that is necessary to monitor DEARE, and plasma was collected at 6 months for LC-MS-based metabolomics and lipidomics. We observed significant dyslipidemia, indicative of inflammatory phenotype, upon radiation exposure. Additionally, observance of several other metabolic dysregulations was suggestive of gut damage, perturbations in TriCarboxylic Acid (TCA) and urea cycles, and arginine metabolism. We also observed gender- and genotype-modulated metabolic perturbations post radiation exposure. The APCHi mice showed near-normal abundance for several lipids. Moreover, restoration of plasma levels of some metabolites, including amino acids, citric acid, and hypoxanthine, in APCHi mice is indicative of APC-mediated protection from radiation injuries. With the help of these findings, the role of APC in plasma molecular events after acute γ-radiation exposure in a gender-specific manner can be established for the first time.

UNASSIGNED: Radiation injury (RI) is a common occurrence in malignant tumors patients receiving radiation therapy. While killing tumor cells, normal tissue surrounding the target area is inevitably irradiated at a certain dose, which can cause varying results of radiation injury. Currently, there are limited clinical treatments available for radiation injuries. In recent years, the negative effects of stem cell therapy have been reported more clearly and non-cellular therapies such as exosomes have become a focus of attention for researchers. As a type of vesicle-like substances secreted by mesenchymal stem cells (MSC), MSC derived exosomes (MSC-exo) carry DNA, mRNA, microRNA (miRNAs), specific proteins, lipids, and other active substances involved in intercellular information exchange. miRNAs released by MSC-exo are capable of alleviating and repairing damaged tissues through anti-apoptosis, modulating immune response, regulating inflammatory response and promoting angiogenesis, which indicates that MSC-exo miRNAs have great potential for application in the prevention and treatment of radiation injury. Therefore, it is necessary to explore the underlying therapeutic mechanisms of MSC-exo miRNAs in this process, which may shed new lights on the treatment of radiation injury.
UNASSIGNED: Increasing evidence confirms that MSC-exo has shown encouraging applications in tissue repair due to the anti-apoptotic, immunoreactive, and pro-angiogenesis effects of the miRNAs it carries as intercellular communication carriers. However, miRNA-based therapeutics are still in their infancy and many practical issues remain to be addressed for clinical applications.

OBJECTIVE: The objective of this study was to assess voice changes in patients with nasopharyngeal carcinoma (NPC) using subjective and objective assessment tools and to make inferences regarding the underlying pathological causes for different phases of radiotherapy (RT).
METHODS: A total of 187 (123 males and 64 females) patients with post-RT NPC with no recurrence of malignancy or other voice diseases and 17 (11 males and 6 females) healthy individuals were included in this study. The patients were equally divided into 11 groups according to the number of years after RT. The acoustic analyses, GRBAS (grade, roughness, breathiness, asthenia, and strain) scales, and Voice Handicap Index (VHI)-10 scores were collected and analyzed.
RESULTS: The fundamental frequency (F0) parameters in years 1 and 2 and year 11 were significantly lower in patients with NPC than in healthy individuals. The maximum phonation times in years 1 and 11 were significantly shorter than those in healthy individuals. The jitter parameters were significantly different between year 1 and from years 8 to 11 and the healthy individuals. The shimmer parameters were significantly different between years 1, from years 9 to 11, and healthy individuals. Hoarseness was the most prominent problem compared to other items of the GRBAS. The VHI-10 scores were significantly different between years 1 and 2 and year 11 after RT in patients with NPC.
CONCLUSIONS: Voice quality was worse in the first 2 years and from years 8 to 11 but remained relatively normal from years 3 to 7 after RT. Patient-reported voice handicaps began during year 3 after RT. The most prominent problem was perceived hoarseness, which was evident in the first 2 years and from years 9 to 11 after RT. The radiation-induced mucous edema, laryngeal intrinsic muscle fibrosis, nerve injuries, upper respiratory tract changes, and decreased lung capacity might be the pathological reasons for voice changes in post-RT patients with NPC.

BACKGROUND: Human hematopoietic organoids have a wide application value for modeling human bone marrow diseases, such as acute hematopoietic radiation injury. However, the manufacturing of human hematopoietic organoids is an unaddressed challenge because of the complexity of hematopoietic tissues.
METHODS: To manufacture hematopoietic organoids, we obtained CD34+ hematopoietic stem and progenitor cells (HSPCs) from human embryonic stem cells (hESCs) using stepwise induction and immunomagnetic bead-sorting. We then mixed these CD34+ HSPCs with niche-related cells in Gelatin-methacryloyl (GelMA) to form a three-dimensional (3D) hematopoietic organoid. Additionally, we investigated the effects of radiation damage and response to granulocyte colony-stimulating factor (G-CSF) in hematopoietic organoids.
RESULTS: The GelMA hydrogel maintained the undifferentiated state of hESCs-derived HSPCs by reducing intracellular reactive oxygen species (ROS) levels. The established hematopoietic organoids in GelMA with niche-related cells were composed of HSPCs and multilineage blood cells and demonstrated the adherence of hematopoietic cells to niche cells. Notably, these hematopoietic organoids exhibited radiation-induced hematopoietic cell injury effect, including increased intracellular ROS levels, γ-H2AX positive cell percentages, and hematopoietic cell apoptosis percentages. Moreover, G-CSF supplementation in the culture medium significantly improved the survival of HSPCs and enhanced myeloid cell regeneration in these hematopoietic organoids after radiation.
CONCLUSIONS: These findings substantiate the successful manufacture of a preliminary 3D hematopoietic organoid from hESCs-derived HSPCs, which was utilized for modeling hematopoietic radiation injury and assessing the radiation-mitigating effects of G-CSF in vitro. Our study provides opportunities to further aid in the standard and scalable production of hematopoietic organoids for disease modeling and drug testing.

Objective: To explore the diagnostic value of whole blood cell parameters logistic regression model for radiation injury on radiation workers by comparing the differences of whole blood cell parameters between occupational radiation injury population and occupational health examination population. Methods: In February 2023, 184 radiation workers who received occupational health examinations in our hospital and occurrenced chromosome aberration from July 2021 to July 2022 were retrospectively selected as the radiation injury group. And other 184 radiation workers encountered in the same period without chromosome aberration occurrence were selected as the control group. Collected whole blood cell parameters from two groups of research subjects, conducted comparative analysis, constructed a logistic regression model, and evaluated the diagnostic value of the logistic regression model for radiation injury on radiation workers by receiver operating characteristic curve (ROC) and area under curve (AUC) . In addition, with the same standard, 60 radiation workers with chromosome aberration and 60 radiation workers without chromosome aberration from August 2022 to January 2023 were included in the validation queue to validate the logistic regression model. Results: Neu_X, Neu_Y, Neu_Z, Lym_X, Lym_Y, Lym_Z, Mon_X, Mon_Y, Mon_Z, Micro, MCHC in the radiation injury group were significantly higher than those in the control group, and the difference was statistically significant (P<0.05) . And MCV and Macro in the radiation injury group were lower than those in the control group, and the difference was statistically significant (P<0.05) . Moreover, logistic regression analysis showed that Lym_X, Lym_Y, Lym_Z, MCHC, Micro were all independent risk factors for diagnosing radiation injury on radiation workers (OR=1.08、1.02、0.99、1.06、51.32, P<0.05) . ROC curve analysis showed that the AUC, sensitivity, specificity, and accuracy of the logistic regression model based by Lym_X, Lym_Y, Lym_Z, MCHC and Micro in diagnosing radiation injury on radiation workers were 0.80, 85.9%, 65.8% and 75.9% respectively. The validation queue verified the logistic regression model and the AUC, sensitivity, specificity, and accuracy of the logistic regression model were 0.80, 81.7%, 71.7% and 76.7% respectively, the model fitted well. Conclusion: Radiation damage can cause changes in multiple whole blood cell parameters of radiation workers. The logistic regression model based by Lym_X, Lym_Y, Lym_Z, MCHC and Micro showed good diagnosis ability and can be used for the screening of radiation injury on radiation workers.
目的： 通过比较辐射损伤人群与职业性健康体检人群的全血细胞参数，探讨全血细胞参数Logistic回归模型对放射工作人员辐射损伤的诊断价值。 方法： 于2023年2月，回顾性选取2021年7月至2022年7月在我院进行职业健康检查且发生染色体畸变的放射工作人员184例作为辐射损伤组，纳入同期在我院进行职业健康检查且未发生染色体畸变的放射工作人员184例作为对照组，收集两组研究对象的全血细胞参数，进行比较分析，构建logistic回归模型，运用受试者工作特征曲线（ROC）及曲线下面积（AUC）评价logistic回归模型对放射工作人员辐射损伤的诊断价值。再以相同的评定标准，纳入2022年8月至2023年1月在我院进行职业健康检查且发生染色体畸变的放射工作人员60例和未发生染色体畸变的放射工作人员60例作为验证队列，对Logistic回归模型进行验证。 结果： 辐射损伤组中性粒细胞（Neu）_X、Neu_Y、Neu_Z、淋巴细胞（Lym）_X、Lym_Y、Lym_Z、单核细胞（Mon）_X、Mon_Y、Mon_Z、小红细胞（Micro）、平均红细胞血红蛋白浓度（MCHC）水平均明显高于对照组（P<0.05），辐射损伤组平均红细胞体积（MCV）、大红细胞（Macro）水平均明显低于对照组（P<0.05）。logistic回归分析显示Lym_X、Lym_Y、Lym_Z、MCHC、Micro均是诊断放射工作人员辐射损伤的独立影响因素（OR=1.08、1.02、0.99、1.06、51.32，P<0.05）。ROC曲线分析显示，基于Lym_X、Lym_Y、Lym_Z、MCHC、Micro构建的logistic回归模型诊断放射工作人员辐射损伤的AUC为0.80，敏感度为85.9%，特异度为65.8%，准确度为75.9%。验证队列验证logistic回归模型，AUC为0.80，敏感度为81.7%，特异度为71.7%，准确度为76.7%，模型拟合较好。 结论： 辐射损伤会导致放射工作人员多种全血细胞参数发生改变，基于Lym_X、Lym_Y、Lym_Z、MCHC和Micro构建的logistic回归模型对放射工作人员辐射损伤具有良好的诊断价值，可用于放射工作人员辐射损伤的筛查。.