The radiation-induced bystander effect (RIBE) is a destructive reaction in nonirradiated cells and is one primary factor in determining the efficacy and success of radiation therapy in the field of cancer treatment. Previously reported studies have shown that the RIBE can be mediated by exosomes that carry miRNA components within. Exosomes, which are one type of cell-derived vesicle, exist in different biological conditions and serve as an important additional pathway for signal exchange between cells. In addition, exosome-derived miRNAs are confirmed to play an important role in RIBE, activating the bystander effect and genomic instability after radiotherapy. After investigating the field of RIBE, it is important to understand the mechanisms and consequences of biological effects as well as the role of exosomes and exosomal miRNAs therein, from different sources and under different circumstances, respectively. More discoveries could help to establish early interventions against RIBE while improving the efficacy of radiotherapy. Meanwhile, measures that would alleviate or even inhibit RIBE to some extent may exist in the near future.

The cellular response to ionizing radiation continues to be of significant research interest in cancer radiotherapy, and DNA is recognized as the critical target for most of the biologic effects of radiation. Incident particles can cause initial DNA damages through physical and chemical interactions within a short time scale. Initial DNA damages can undergo repair via different pathways available at different stages of the cell cycle. The misrepair of DNA damage results in genomic rearrangement and causes mutations and chromosome aberrations, which are drivers of cell death. This work presents an integrated study of simulating cell response after proton irradiation with energies of 0.5–500 MeV (LET of 60–0.2 keV/µm). A model of a whole nucleus with fractal DNA geometry was implemented in TOPAS-nBio for initial DNA damage simulations. The default physics and chemistry models in TOPAS-nBio were used to describe interactions of primary particles, secondary particles, and radiolysis products within the nucleus. The initial DNA double-strand break (DSB) yield was found to increase from 6.5 DSB/Gy/Gbp at low-linear energy transfer (LET) of 0.2 keV/µm to 21.2 DSB/Gy/Gbp at high LET of 60 keV/µm. A mechanistic repair model was applied to predict the characteristics of DNA damage repair and dose response of chromosome aberrations. It was found that more than 95% of the DSBs are repaired within the first 24 h and the misrepaired DSB fraction increases rapidly with LET and reaches 15.8% at 60 keV/µm with an estimated chromosome aberration detection threshold of 3 Mbp. The dicentric and acentric fragment yields and the dose response of micronuclei formation after proton irradiation were calculated and compared with experimental results.

Breast tissue is very susceptible to radiation-induced carcinogenesis, and mammary stem/progenitor cells are potentially important targets of this. The mammary epithelium is maintained as two mostly independent lineages of luminal and basal cells. To elucidate their immediate radiation responses, we analyzed the mammary glands of female Sprague-Dawley rats, a radiation carcinogenesis model, using colony formation, flow cytometry and immunofluorescence. The results revealed that flow cytometry successfully fractionates rat mammary cells into CD49f^hi CD24^lo basal, CD49f^med CD24^hi luminal progenitor, and CD49f^lo CD24^hi mature luminal populations, resembling human breast, rather than mouse tissues. The colony-forming ability of the basal cells was more radiosensitive than the luminal progenitor cells. Flow cytometry and immunofluorescence showed more efficient cell cycle arrest, γ-H2AX responses, and apoptosis in the irradiated luminal progenitor cells, than in the basal cells. These results provide important insights into the early phase of radiation-induced breast cancer.

Recently reported studies considering nonlinearity in the effects of low-dose space radiation have assumed a nontargeted mechanism. To date, few analyses have been performed to assess whether a nontargeted term is supported by the available data. The Harderian gland data from Alpen et al. (published in 1993 and 1994), and Chang et al. (2016) provide the most diversity of ions and energies in a tumor induction model, including multiple high-energy and charge particles. These data can be used to investigate various nonlinearity assumptions against a linear model, including nontargeted effects in the low-dose region or cell sterilization at high doses. In this work, generalized linear models were used with the log complement link function to analyze the binomial data from the studies independently and combined. While there was some evidence of nonlinearity that was best described by a cell-sterilization model, the linear model was adequate to describe the data. The current data do not support the addition of a nontargeted effects term in any model. While adequate data are available in the low-dose region (<0.5 Gy) to support a nontargeted effects term if valid, additional data in the 1–2 Gy region are necessary to achieve power for cell-sterilization analysis validation. The current analysis demonstrates that the Harderian gland tumor data do not support the use of a nontargeted effects term in human cancer risk models.

Radiation pneumonitis is a common complication of thoracic irradiation for lung cancer patients. The healthy gut microbiota plays an important role in the local mucosal defense process as well as pulmonary immunomodulation of the host. However, the effect of the intestinal microbiota on radiation pneumonitis is not well understood. Here we studied how the intestinal microbiota affected the host response to radiation pneumonitis. C57BL/6 mice were administered antibiotics to induce disequilibrium in the gut microbiota, and subsequently irradiated. We found that the intestinal microbiota served as a protective mediator against radiation pneumonitis, as indicated by decreased body weight and increased mortality in antibiotic-treated mice. In mice with gut microbiota disequilibrium, more serious pathological lung damage was observed at two and four weeks postirradiation. Fecal microbiota transplantation into irradiated mice led to improvement from radiation-induced inflammation two weeks postirradiation. High-throughput sequencing of murine feces displayed conversion of flora diversity, bacterial composition and community structure in the absence of normal intestinal flora. We filtered the potentially important species among the gut microbiota and considered that the tissue-type plasminogen activator might be involved in the inflammatory process. This study reveals that the gut microbiota functions as a protective regulator against radiation pneumonitis. Additionally, fecal microbiota transplantation was shown to alleviate lung injury in the irradiated model. The protective role of the healthy gut microbiota and the utilization of the gut–lung axis show potential for innovative therapeutic strategies in radiation-induced lung injury.

To investigate the effects of low-dose γ irradiation on apoptosis and development of the brain in zebrafish embryos, cumulative 15 mGy doses of γ rays from a ¹³⁷Cs source were used to irradiate zebrafish embryos at 2 h post-fertilization (hpf) for 120 h. Apoptosis of the brain, brain morphological development, cell submicroscopic structure and mRNA expression were analyzed, respectively. Results indicate that after 15 mGy exposure, the apoptosis of zebrafish brain increased, vacuoles appeared in brain tissue, some organelles were damaged and vacuoles appeared locally in brain cells. The mRNA expression level of axin2 was significantly upregulated, and those of frizzled, β-catenin, camk2, TCF/ LEF and bcl9 were significantly downregulated in brain tissue. These genes are involved in the Wnt signaling pathway. The findings of this work suggest that low-dose radiation may influence the apoptosis and development of the brain in the zebrafish embryo by inhibiting the Wnt signaling pathway.

Numerous studies have shown that exosomes play important roles in tumor biology development. However, the function of exosomal protein in cancer progression under different oxygen condition after irradiation is poorly understood. In this study, non-small cell lung cancer (NSCLC) A549 cells were γ-ray irradiated under normoxic or hypoxic conditions, then the exosomes released from the irradiated cells were collected and co-cultured with nonirradiated A549 cells or human umbilical vein endothelial cells (HUVECs). It was found that the exosomes significantly promoted the proliferation, migration and invasion of A549 cells as well as the proliferation and angiogenesis of HUVECs. Moreover, the exosomes released from hypoxic cells and/or irradiated cells had more powerful driving force in tumor progression compared to that generated from normoxia cells. Meanwhile, the proteins contained in the exosomes derived from A549 cells under different conditions were detected using tandem mass tag (TMT), and their expression profiles were analyzed. It was found that the exosome-derived protein of angiopoietin-like 4 (ANGPTL4) contributed to the migration of A549 cells as well as the angiogenesis of HUVECs, suggesting its potential as an effective diagnostic biomarker of metastasis and even a therapeutic target of lung cancer.

Inflammatory cytokines have been suggested to play important roles in radiation-induced lung injury (RILI). Identifying significantly changed circulating and tissue cytokines after thoracic irradiation will aid in deciphering the mechanism of RILI and identifying potential biomarkers to predict clinical outcome. Herein, the levels of 24 cytokines were measured in serial plasma samples and lung tissue samples collected from a pilot study where nonhuman primates (NHPs) received 11.5 Gy whole thoracic lung irradiation (WTLI) and were then treated with or without a medical countermeasure, AEOL 10150 [a superoxide dismutase (SOD) mimetic]. Seven plasma cytokines (i.e., IP-10, MCP-1, IL-12, IL-15, IL-16, IL-7 and IL-6) were found to be significantly changed at different time points due to WTLI. Plasma IP-10 and MDC were significantly changed between the vehicle group and the drug group. The levels of IP-10, MCP-1, MIP-1α, TARC, IL-17, TNF-β and IL-6 were significantly elevated in the lung tissue lysates of NHPs that received WTLI versus radiation-naïve NHPs. The terminal plasma concentrations of IP-10, MDC, TARC, IL-12, IL-15 and IL-6 were significantly correlated with their levels in the lung tissue. The levels of four cytokines (MCP-4, IL-17, TNF-β and IL-2) at early time points (≤8 weeks postirradiation) were significantly correlated with their terminal plasma levels, respectively. Statistical analysis indicated that circulating cytokines could be discriminatory predictors of AEOL 10150 treatment. Taken together, our data suggested that the cytokine profiles were significantly changed after WTLI as well as mitigator treatment, and that the plasma cytokine profiles could potentially be used to distinguish vehicle or mitigator treatment after WTLI in a NHP model.