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Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate , is prescribed as a treatment for upper respiratory tract infection. Here we report the potential radioprotective effect and mechanism of Andrographolide on RILI. C57BL/6 mice were exposed to 18 Gy of whole thorax irradiation, followed by intraperitoneal injection of Andrographolide every other day for 4 weeks. Andrographolide significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release in the early phase and progressive fibrosis in the late phase. Moreover, Andrographolide markedly hampered radiation-induced activation of the AIM2 inflammasome and pyroptosis in vivo. Furthermore, bone marrow-derived macrophages (BMDMs) were exposed to 8 Gy of X-ray radiation in vitro and Andrographolide significantly inhibited AIM2 inflammasome mediated-pyroptosis in BMDMs. Mechanistically, Andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation or chemotherapeutic agents in BMDMs. Taken together, Andrographolide ameliorates RILI by suppressing AIM2 inflammasome mediated-pyroptosis in macrophage, identifying Andrographolide as a novel potential protective agent for RILI.

Radiation protection on male testis is an important task for ionizing radiation‐related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll‐like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low‐toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage‐derived exosomes protein expression. We proved that after MPLA treatment, macrophage‐derived exosomes played an important role in testis radiation protection, and specially, G‐CSF and MIP‐2 in exosomes are the core molecules in this protection effect.

Aim: In this study, we investigated expression levels of cyclooxygenase-2 (COX-2) and endothelin-1 (ET-1) genes after pelvis and heart irradiation in a rat model. These factors are involved in heart diseases (HDs). Materials and Methods: We used seven groups, including two groups of pelvic irradiation, two groups of whole body irradiation, two groups of heart irradiation, and one control nonirradiated group. Pelvis irradiations were conducted at a 2 cm × 2 cm in the pelvis area. Irradiation condition conducted using 1.25 MeV cobalt-60 gamma-rays (30 cGy/min). The changes at ET-1 and COX-2 gene expressions in heart tissue after pelvis and heart irradiation were measured and compared to the control and whole body irradiation groups at 24 h and 72 h after the exposure. Results: In heart irradiation groups, 3-fold up-regulation of both ET-1 and COX-2 was observed. In pelvis irradiation groups, 3-fold up-regulation of ET-1 was seen, but not significant changes in COX-2 gene expression have observed at distant heart tissues after pelvis irradiation. Conclusion: This study reveals that nontargeted effect induced by radiation may be considered as an important phenomenon for induction of HD after radiotherapy.

We have demonstrated chromosomal instability in the clonal descendants of hemopoietic stem cells after irradiating murine bone marrow with α -particles. However, because cells that are irradiated by α -particles are defined by a Poisson distribution of individual particle traversals, there is an inevitable proportion of unirradiated cells in the surviving population. The calculated expected proportions of irradiated and nonirradiated cells indicate that the number of clonogenic cells transmitting chromosomal instability is greater than the number expected to be hit and survive. To investigate further this discrepancy, we studied the effects of interposing a grid between the cells and the α -particle source so that the surviving population consists predominantly of untraversed stem cells. Comparison with the same irradiation conditions without the grid reveals that the same level of instability is induced. The data confirm that α -particles induce chromosomal instability but instability is demonstrated in the progeny of nonirradiated stem cells and must be due to unexpected interactions between irradiated and non-irradiated cells. This untargeted effect has important implications for mechanistic studies of radiation action and for assessment of radiation risk.

Genetic studies in the offspring of atomic bomb survivors have been conducted since 1948 at the Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, in Hiroshima and Nagasaki. Past studies include analysis of birth defects (untoward pregnancy outcome; namely, malformation, stillbirth, and perinatal death), chromosome aberrations, alterations of plasma and erythrocyte proteins as well as epidemiologic study on mortality (any cause) and cancer incidence (the latter study is still ongoing). There is, thus far, no indication of genetic effects in the offspring of survivors. Recently, the development of molecular biological techniques and human genome sequence databases made it possible to analyze DNA from parents and their offspring (trio-analysis). In addition, a clinical program is underway to establish the frequency of adult-onset multi-factorial diseases (diabetes mellitus, high blood pressure, and cardiovascular disease etc) in the offspring. The complementary kinds of data that will emerge from this three-pronged approach (clinical, epidemiologic, and molecular aspects) promise to shed light on health effects in the offspring of radiation-exposed people.

Secondary sexual characters have been hypothesized to be particularly susceptible to the deleterious effects of mutation because the expression of such characters is usually influenced by many more metabolic pathways than are ordinary morphological characters. We tested this hypothesis using the elevated mutation rates in the barn swallow (Hirundo rustica) of the Chernobyl region of Ukraine as a model system. A great deal is known about the relative importance of different characters for male mating success in this species. The importance of phenotypic characters for male mating success was quantified based on a long-term study of a Danish breeding population, by expressing phenotypic differences between mated and unmated males as the difference between log-transformed mean values. For field samples from Ukraine we likewise expressed the difference in male phenotype between individuals living in a relatively uncontaminated area and individuals from the Chernobyl region as the difference between log-transformed mean values. The standardized difference in male phenotype between the two regions in Ukraine for the 41 different characters was strongly positively correlated with the standardized difference in male phenotype between mated and unmated males from Denmark. The standardized difference in male phenotype between the two regions in Ukraine was significantly positively associated with sexual size dimorphism. However, the standardized difference in male phenotype between mated and unmated males was a much better predictor of standardized difference in male phenotype between the two regions in Ukraine than was the standardized difference in sexual size dimorphism, expressed as the difference between log-transformed mean values for males and females. These findings are consistent with the hypothesis that traits most important for sexual selection are particularly susceptible to the effects of deleterious mutations.

This article provides a broad overview of our earlier studies on the induction of tumors and congenital anomalies in the progeny of X-irradiated or chemically treated mice and our subsequent (published, hitherto unpublished and on-going) investigations aimed at identifying potential relationships between genetic changes induced in germ cells and the adverse effects manifest as tumors and congenital anomalies using cytogenetic and molecular approaches. The earlier studies document the fact that tumors and congenital anomalies can be induced by irradiation or treatment with certain chemicals such as urethane and that these phenotypes are heritable i.e., transmitted to generations beyond the first generation. These findings support the view that transmissible induced genetic changes are involved. The induced rates of congenital abnormalities and tumors are about two orders of magnitude higher than those recorded in the literature from classical mutation studies with specific locus mutations. The cytogenetic studies addressed the question of whether there were any relationships between induced translocations and induced tumors. The available data permit the inference that gross chromosomal changes may not be involved but do not exclude smaller induced genetic changes that are beyond the resolution of the techniques used in these studies. Other work on possible relationship between visible chromosomal anomalies (in bone marrow preparations) and tumors were likewise negative. However, there were indications that some induced cytogenetic changes might underlie induced congenital anomalies, i.e., trisomies, deletions and inversions were observed in induced and transmissible congenital anomalies (such as dwarfs, tail anomalies). Studies that explored possible relationships between induction of minisatellite mutations at the Pc-3 locus and tumors were negative. However, gene expression analysis of tumor (hepatoma)-susceptible offspring of progeny descended from irradiated male mice showed abnormal expression of many genes. Of these, only very few were oncogenes. This lends some support to our hypothesis that cumulative changes in gene expression of many genes, which perform normal cellular functions, may contribute to the occurrence of tumors in the offspring of irradiated or chemically treated mice.   

Parental exposure of mice to radiation and chemicals causes a variety of adverse effects (e. g. , tumors, congenital malformations and embryonic deaths) in the progeny and the tumor-susceptibility phenotype is transmissible beyond the first post-radiation generation. The induced rates of tumors were 100-fold higher than those known for mouse specific locus mutations. There were clear strain differences in the types of naturally-occurring and induced tumors and most of the latter were malignant. Another important finding was that germ-line exposure elicited very weak tumorigenic responses, but caused persistent hypersensitivity in the offspring for the subsequent development of cancer by the postnatal environment. Activations of oncogenes, ras, mos, abl, etc. and mutations in tumor suppressor genes such as p53 were also detected in specific tumors in cancer-prone descendants. However, the majority of tumors observed in the progeny were those commonly observed in the strains that were used and oncogene activations were rarely observed in these tumors. It can be hypothesized that genetic instability modifies tumor occurrence in a transgenerational manner, but so far no links could be established between chromosomal and molecular changes and transmissible tumor risks. Our data are consistent with the hypothesis that cumulative changes in many normal but cancer-related genes affecting immunological, biochemical and physiological functions may slightly elevate the incidence of tumors or fasten the tumor development. This hypothesis is supported by our GeneChip analyses which showed suppression and/or over-expression of many such genes in the offspring of mice exposed to radiation. In humans, a higher risk of leukemia and birth defects has been reported in the children of fathers who had been exposed to radionuclides in the nuclear reprocessing plants and to diagnostic radiation. These findings have not been supported in the children of atomic bomb survivors in Hiroshima and Nagasaki, who were exposed to higher doses of atomic radiation. However, it will be important to follow the human subjects, especially for adult type cancers and chronic diseases throughout their lives to determine whether the mouse studies can predict human responses.

The congenital malformation gastroschisis has a genetic disposition in the inbred mouse strain HLG/Zte. It is increased after preconceptional irradiation of males or females. Radiation exposures during the meiotic stages are most efficient. This malformation can also be induced by ionising radiation when the exposure takes place during the preimplantation period especially during the zygote stage. This latter effect can be transmitted to the next mouse generation. Other macroscopically visible or skeletal malformations are not significantly induced under these experimental conditions. These latter malformations are increased by radiation exposures during major organogenesis. The mechanisms for the development of the effects are different. Radiation exposure of the mouse zygote (1 to 3 hours p.c.) also leads to the induction of genomic instability in skin fibroblasts of the fetus. This phenomenon also occurs in a mouse strain (C57BL/6J) which is not susceptible to radiation-induced gastroschisis during the preimplantation period. The genomic instability is transmitted to the next mouse generation. During genomic instability chromatide breaks are dominating as in non-exposed cells. With respect to \"spontaneous\" malformations gastroschisis is dominating in HLG/Zte mice. Late radiation effects seem to have similar patterns as observed in non-exposed subjects, however, the rates are increased after irradiation.