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Purpose: The major goal was to evaluate effects of various radiation regimens on leukocyte populations relatively long-term after whole-body irradiation., Materials and Methods: C57BL/6 mice were exposed to-low-dose/low-dose rate (LDR) (57)Co γ-rays (0.01 Gy, 0.03 cGy/h), with and without acute 2 Gy proton (1 Gy/min) or γ-ray (0.9 Gy/min) irradiation; analyses were done on days 21 and 56 post-exposure., Results: Numerous radiation-induced changes were noted at one or both time points. Among the most striking differences (P < 0.05) were: (i) High percentage of CD4(+)CD25(+)Foxp3(+) T cells in spleens from the Proton vs. LDR, Gamma and LDR + Proton groups (day 56); (ii) high interleukin-2 (IL-2) in spleen supernatants from the LDR and LDR + Proton groups vs. 0 Gy (day 56), whereas IL-10 was high in the LDR + Gamma group vs. 0 Gy (day 56); (iii) difference in transforming growth factor-β1 (TGF-β1) in spleen supernatants from Proton and LDR + Proton groups vs. Gamma and LDR + Gamma groups (both days); (iv) low TGF-β1 in blood from LDR + Proton vs. LDR + Gamma group (day 21); and (v) high level of activated cJun N-terminal kinase (JNK) in CD4(+) T cells from LDR + Proton vs. LDR + Gamma group (day 21)., Conclusions: The findings demonstrate that at least some immune responses to acute 2 Gy radiation were dependent on radiation quality time of assessment, and pre-exposure to LDR γ-rays.

Purpose: To determine whether differences exist between proton and electron radiations on biological responses after total-body exposure., Materials and Methods: ICR mice (n=45) were irradiated to 2 Gray (Gy) using fully modulated 70 MeV protons (0.5 Gy/min) and 21 MeV electrons (3 Gy/min). At 36 h post-irradiation liver gene expression, white blood cell (WBC), natural killer (NK) cell and other analyses were performed., Results: Oxidative stress-related gene expression patterns were strikingly different for irradiated groups compared to 0 Gy (P<0.05). Proton radiation up-regulated 15 genes (Ctsb, Dnm2, Gpx5, Il19, Il22, Kif9, Lpo, Nox4, Park7, Prdx4, Prdx6, Rag2, Sod3, Srxn1, Xpa) and down-regulated 2 genes (Apoe, Prdx1). After electron irradiation, 20 genes were up-regulated (Aass, Ctsb, Dnm2, Gpx1, Gpx4, Gpx5, Gpx6, Gstk1, Il22, Kif9, Lpo, Nox4, Park7, Prdx3, Prdx4, Prdx5, Rag2, Sod1, Txnrd3, Xpa) and 1 was down-regulated (Mpp4). Of the modified genes, only 11 were common to both forms of radiation. Comparison between the two irradiated groups showed that electrons significantly up-regulated three genes (Gstk1, Prdx3, Scd1). Numbers of WBC and major leukocyte types were low in the irradiated groups (P<0.001 vs. 0 Gy). Hemoglobin and platelet counts were low in the electron-irradiated group (P<0.05 vs. 0 Gy). However, spleens from electron-irradiated mice had higher WBC and lymphocyte counts, as well as enhanced NK cell cytotoxicity, compared to animals exposed to protons (P<0.05). There were no differences between the two irradiated groups in body mass, organ masses, and other assessed parameters, although some differences were noted compared to 0 Gy., Conclusion: Collectively, the data demonstrate that at least some biological effects induced by electrons may not be directly extrapolated to protons.

Purpose: Our aim was to define dose-dependent and genotype-dependent components of radiosensitivity by resolving patterns of radiation-induced clonal inactivation into specific responses., Methods: In a set of 10 tumour cells with varying expression of radiosensitivity and genotype, we identified doses at which all tumour cells change in their rate of clonogenic inactivation. We tested intervening dose-segments as to whether inactivation was constant, expressing inactivation as a log-linear function of dose. We compared these segments to components proposed in the Hit-target (HT) model and the Linear-quadratic (LQ) model. Temporal changes in redistribution in cell-cycle prevalence and apoptosis were examined as essential components of cellular radiosensitivity., Results: We identified four distinct responses induced sequentially in all cells independent of genotype. Rates of inactivation within each response varied with expression of genotype and identified: (i) A hypersensitive component H (0.0-0.10 Gy); (ii) a resistant component R (0.1-0.2 Gy); (iii) an induced repair response alpha* (0.2 Gy and higher); and (iv) a more sensitive component omega* (3.0 Gy and higher). The H, alpha* and omega* components were fitted well by log-linear patterns, the R response did not., Conclusions: Four distinct, sequentially-induced responses comprise cellular radiosensitivity. H and R responses are associated with low dose hyper-radiosensitivity and early apoptosis, while the alpha* and omega* responses share characteristics of the HT and LQ models and are associated with post-repair apoptosis. Radiation induces these four responses at the same doses in all cells, but the rate of inactivation over each response depends on genotype.

Purpose: Astronauts on missions are exposed to low-dose/low-dose-rate (LDR) radiation and could receive high doses during solar particle events (SPE). This study investigated T cell function in response to LDR radiation and simulated SPE (sSPE) protons, alone and in combination., Materials and Methods: C57BL/6 mice received LDR γ-radiation (⁵⁷Co) to a total dose of 0.01 Gray (Gy) at 0.179 mGy/h, either with or without subsequent exposure to 1.7 Gy sSPE protons delivered over 36 h. Mice were euthanised on days 4 and 21 post-exposure. T cells with cluster of differentiation 4 (CD4(+)) were negatively isolated from spleens and activated with anti-CD3 antibody. Cells and supernatants were evaluated for survival/signalling proteins and cytokines., Results: The most striking effects were noted on day 21. In the survival pathway, nuclear factor-kappaB (NF-κB; total and active forms) and p38 mitogen activated protein kinase (p38MAPK; total) were significantly increased and cJun N-terminal kinase (JNK; total and active) was decreased when mice were primed with LDR γ-rays prior to sSPE exposure (P < 0.001). Evaluation of the T cell antigen receptor (TCR) signalling pathway revealed that LDR γ-ray exposure normalised the high sSPE proton-induced level of lymphocyte specific protein tyrosine kinase (Lck; total and active) on day 21 (P < 0.001 for sSPE vs. LDR + sSPE), while radiation had no effect on active zeta-chain-associated protein kinase 70 (Zap-70). There was increased production of interleukin-2 (IL-2) and IL-4 and decreased transforming growth factor-β1 in the LDR + sSPE group compared to the sSPE group., Conclusion: The data demonstrate, for the first time, that protracted exposure to LDR γ-rays can significantly modify the effects of sSPE protons on critical survival/signalling proteins and immunomodulatory cytokines produced by CD4(+) T cells.

Purpose: We examined the effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin, a metalloporphyrin antioxidant (MPA), on neural tissue radiation toxicity in vivo and on tumour cell radiosensitivity in vitro., Materials and Methods: MPA was administered directly into the right lateral ventricle of young adult, male Sprague-Dawley rats (0 or 3.4 microg) 3 h before treatment with a single fraction, 100 Gy radiation dose delivered to the left brain hemisphere. The effects of treatment on radiation responses were assessed at different time points following irradiation., Results: MPA treatment prior to brain irradiation protected against acute radiation-induced apoptosis and ameliorated delayed damage to the blood-brain barrier and radiation necrosis, but without producing a discernible increase in tissue superoxide disumtase (SOD) activity. In vitro, MPA pretreatment protected against radiation-induced apoptosis in primary neuronal cultures and increased clonogenic survival of irradiated rat glioma C6 cells, but had no discernible effect on radiation-induced DNA double-strand breaks. MPA, a low molecular weight SOD mimic, significantly increased mitochondrial SOD activity in C6 cells, but not total cellular SOD activity. MPA up-regulated C6 expression of heme-oxygenase 1 (HO-1), an endogenous radioprotectant, but had no effect on HO-1 levels in human astrocytoma U-251 cells, human prostatic carcinoma LNCaP cells, or primary rat brain microvascular endothelial cells in vitro, nor on brain tissue HO-1 expression levels in vivo., Conclusions: Metalloporphyrin antioxidants merit further exploration as adjunctive radioprotectants for cranial radiotherapy/radiosurgery applications, although the potential for tumour protection must be carefully considered.

Purpose: To evaluate cluster of differentiation 4(+) (CD4(+)) T cell gene expression and related parameters after whole-body exposure to proton radiation as it occurs in the spaceflight environment., Materials and Methods: C57BL/6 mice were irradiated to total doses of 0, 0.01, 0.05, and 0.1 gray (Gy) at 0.1 cGy/h. On day 0 spleens were harvested from a subset in the 0, 0.01 and 0.1 Gy groups; (CD4(+)) T cells were isolated; and expression of 84 genes relevant to T helper (Th) cell function was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). Remaining mice were euthanized on days 0, 4, and 21 for additional analyses., Results: Genes with >2-fold difference and p < 0.05 compared to 0 Gy were noted. After 0.01 Gy, five genes were up-regulated (Ccr5, Cd40, Cebpb, Igsf6, Tnfsf4) and three were down-regulated (Il4ra, Mapk8, Nfkb1). After 0.1 Gy there were nine up-regulated genes (Ccr4, Cd40, Cebpb, Cxcr3, Socs5, Stat4, Tbx21, Tnfrsf4, Tnfsf4); none were down-regulated. On day 0 after 0.01 Gy, CD4(+) T cell counts and CD4:CD8 ratio were low in the spleen (p < 0.05). Spontaneous DNA synthesis in both spleen and blood was lowest in the 0.01 Gy group on day 0; on days 4 and 21 all p values were >0.1., Conclusion: The data show that the pattern of gene expression in CD4(+) T cells after protracted low-dose proton irradiation was significantly modified and highly dependent upon total dose. The findings also suggest that low-dose radiation, especially 0.01 Gy, may enhance CD4(+) T cell responsiveness.

Replacing the sugar-phosphodiester backbone of nucleic acids with a pyrrolidine-amide backbone results in an oligonucleotide mimic POM 1 which binds with high affinity and specificity to complementary DNA and RNA. Unlike other modified oligonucleotides, POM binds much more rapidly to single stranded RNA than DNA.