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Down-regulation of cell cycle control genes by ionizing radiation.

The cellular responses to ionizing radiation include growth arrest, DNA repair, and lethality. However, little is known about the signaling events responsible for these responses. The present studies have examined the effects of ionizing radiation on the expression of genes involved in cell cycle control. The results demonstrate that the treatment of asynchronous cells with 20 Gy ionizing radiation is associated with transient down-regulation of the cdc2, cyclin A, cyclin B, and cdc25 genes. This effect was associated with transient induction of the c-jun gene. RNA stability studies demonstrate that the down-regulation of gene expression following ionizing radiation exposure is at least in part due to a decrease in transcript half-life. Other studies were performed with elutriated cells enriched for populations in G1 and S phases. Treatment of G1 enriched cell populations with 10 Gy resulted in a selective decrease in cyclin B mRNA levels, whereas this effect on cyclin B expression was less pronounced at 5 Gy and undetectable at 1 Gy. Similar results were obtained with S phase enriched cells. Taken together with clonogenic survival studies, these findings indicate that down-regulation of cell cycle control gene expression is associated with lethality, whereas lower doses of ionizing radiation have little, if any, effect on the expression of these genes. The findings also suggest that DNA damage may activate signaling events which regulate expression of cell cycle control genes.

CDC2 Protein Kinase

[Inactivation of isogenous strains of Bacillus subtilis and their mixtures by ionizing radiation].

Resistance to ionizing radiation of vegetative cells, spores and dehydrated cultures was studied with isogenous strains of Bacillus subtilis with defects in the repair systems. In vegetative cells of different classes of the recombination deficient mutants, DL90 was 31-35% of LD90 of the wild type cells. Differences in radiosensitivity of the vegetative cells were more pronounced cf. the spores and dehydrated cells: LD90 of rec- mutants was 55-88%; LD90 of uvr- mutants was 120% of LD90 of the parent bacterial cells.

Bacillus subtilis

Fixation for biological ultrastructure. II. Cross-linking of bovine serum albumin by nanosecond pulses of ionizing radiation.

Very large doses of ionizing radiation were delivered quickly to concentrated albumin solutions by pulses of 500 keV in air. The electrons penetrated the aluminium foil bottom of the test cell and into the solution. A dose of 4.6 Mrad (4.6 x 10(4) Gy) produced a gel in the albumin solution comparable to the long-term effect of 0.36% glutaraldehyde in the same albumin solution. The cross-links created by the radiation leading to gel formation are probably irreversible and quite different from those leading to gelation in the glutaraldehyde-albumin reaction. Single large pulses of ionizing radiation may be useful for fast fixation of cells and tissues for microscopy.

Equipment Design

The new special names of SI units in the field of ionizing radiations.

New SI units for ionizing radiations have been recommended by the internation Commission on Radiation Units and Measurements (ICRU). These are the becquerel (symbol Bq), equal to the second to the power -1, and the gray (symbol Gy), equal to the joule per kilogram. It was recommended that the roentgen be replaced as the unit of exposure by the coulomb per kilogram (C/kg), for which no new name was proposed. The ICRU recommends that the units rad, roentgen, and curie be gradually abandoned over a period of ten years and that preparatory steps to this end be taken as soon as possible by various national and international bodies in order to facilitate a smooth, safe, and efficient transition.

Radiation Dosage

Studies on the sterilization of pharmaceutical base materials with ionizing radiation and ethylene oxide.

The use of ionizing radiation and ethylene oxide for the sterilization of pharmaceutical base materials of animal origin, used to produce organopreparations, was studied. The materials included liver extract, pancreas extract, dried thyroid and intrinsic factor. The effective sterilizing doses for the examined materials and dependence between effective ionizing radiation dose and primary contamination were determined.

Animals

Infrared spectral characterization of peptidic material produced by ionizing radiation in aqueous cyanides.

Oligomers formed by ionizing radiation in aqueous cyanide solutions, under various experimental conditions, have been characterized by infrared spectroscopy. IR bands appear in the region known to be characteristic for amides and peptides. The results are discussed in relation to radiation-induced formation of peptidic material and the potential role of ionizing radiation as an energy source for some processes in prebiotic molecular evolution.

Cyanides

Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death.

Very little is known regarding the effects of ionizing radiation on cytoplasmic signal transduction pathways. Here, we show that ionizing radiation induces enhanced tyrosine phosphorylation of multiple substrates in human B-lymphocyte precursors. This response to ionizing radiation was also observed in cells pretreated with vanadate, a potent protein-tyrosine-phosphatase (PTPase) inhibitor, and phosphotyrosyl [Val5]angiotensin II phosphatase assays showed no decreased PTPase activity in irradiated cells. Thus, enhanced tyrosine phosphorylation in irradiated B-lymphocyte precursors is not triggered by inhibition of total cellular PTPase activity. Immune-complex kinase assays using anti-phosphotyrosine antibodies demonstrated enhanced protein-tyrosine kinase (PTK) activity in the immunoprecipitates from irradiated cells, and the PTK inhibitors genistein and herbimycin effectively prevented radiation-induced tyrosine phosphorylation. Immune-complex kinase assays on irradiated and unirradiated B-lymphocyte precursors using antibodies prepared against unique amino acid sequences of p59fyn, p56/p53lyn, p55blk, and p56lck demonstrated that these Src-family tyrosine kinases were not the primary PTKs responsible for enhanced tyrosine kinase activity in the anti-phosphotyrosine antibody immunoprecipitates or for enhanced tyrosine phosphorylation of multiple substrates. Thus, our findings favor the hypothesis that ionizing radiation induces enhanced tyrosine phosphorylation in B-lymphocyte precursors by stimulation of as yet unidentified PTKs. Tyrosine phosphorylation appears to be an important proximal step in radiation-induced apoptosis and clonogenic cell death because inhibition of PTK prevents DNA fragmentation and loss of clonogenicity of irradiated B-lymphocyte precursors. Since PTKs play myriad roles in the regulation of cell function and proliferation, the activation of a PTK cascade, as detailed in this report, may explain some of the pleiotropic effects of ionizing radiation on cellular functions of B-lymphocytes and their precursors.

Apoptosis

No adaptive response of Chinese hamster ovary cells to low doses of ionizing radiation.

Chinese hamster ovary (CHO) cells that had been exposed to very low doses of ionizing radiation from incorporated tritiated thymidine or X-rays were shown not to be more resistant to the induction of chromatid aberrations by a subsequent higher dose of ionizing radiation than previously untreated cells. The adaptive response to ionizing radiation was absent both in cells challenged with high doses of X-rays (1.25 Gy) and in cells post-treated with thermal neutrons (0.5-1 x 10(12) n/cm2). In agreement with these observations in CHO cells we were unable to demonstrate an adaptive response to X-rays also in human lymphocytes from five different donors.

Adaptation, Physiological

[Radiation therapy in patients with electronic cardiac pacemakers: interferences with the pacemaker's function by ionizing radiation and other sources of disturbances (author's transl)].

In the course of radiation therapy and connected diagnostical measures ionizing radiation and other sources of disturbance may interfere with the function of permanent pacemakers. The conditions of such hazards are investigated in theory and practice making allowance for the different susceptibility to trouble of various models of permanent pacemakers. It appears that no extension of long-term follow-up of the cardiac pacemaker's function is needed with regard to possible late effects of ionizing radiation, but that the follow-up of pacemaker-patients during their first period of treatment should not be neglected, since other sources of electronic interference may be present. Routine checks as radiotherapy installations should also include possible sources of disturbance to electronic pacemakers.

Aged

[Modification of the body's resistance to acute ionizing radiation by synthetic beta-carotene].

Radiomodifying efficiency of short-term and chronic medicinal and treatment-prophylactic enrichment of rations with artificial beta-carotene, administered at single doses of 0.1-10.0 mg, were studied after acute external gamma-irradiation of adult nonlinear and Wistar rats (0.029 Gy/s) or female SBA mice (0.0037 Gy/s), where the absorbed dose was equal to 8-3 Gy or 9.9-9.5 Gy, respectively. Suspension of beta-carotene paste in olive oil accelerated death of rats irradiated at doses of 8 and 7 Gy (P = 0.04), and shortened their lifespan. At a dose of 6 Gy single and long-term enrichment of rations with beta-carotene decreased the rate of rat death within 30 days from 33.3% to 16.7% (P = 0.14) and 3.3% (P = 0.01), while their life time was increased from 48 days to 67 days (P = 0.05) and 508 days (P = 0.01). beta-Carotene was found to affect favourably the radiation-induced (5 Gy) leukocytopenia, and decreased thymus mass (6 Gy) and body weight (8 Gy). In treatment-prophylactic enrichment with beta-carotene of mice (9.9 Gy) ration their survival was increased from 15% to 30% and lifespan from 14.4 days to 28.9 days (P = 0.05). During medicinal or treatment-prophylactic courses of beta-carotene death of mice (9.7 Gy) was decreased from 75% to 35% (P = 0.01) or 60% and life time was increased from 16.7 days to 22.17 days or 39.9 days (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

[State of hemodynamics, according to radiocardiographic data, in persons working in contact with ionizing radiation sources].

The presented results illustrate the study of the cardiovascular system by means of radiocardiography conducted in normal individuals working in contact with sources of ionizing radiation. The study includes 51 persons in the test group and 42 in the control group that was similar to the test one in terms of age, sex and type of work performed, with the only exception that these in the control group had no contact with ionizing radiation. Persons working under the effect of ionizing radiation displayed a moderate increase in the stroke and minute index and the circulating blood volume, with the blood flow rate somewhat decelerated. The changes were deeper in those with over 5 years of service, and in those with functional changes in the nervous system, like neurocirculatory dystonia. The moderate level of these reactions and their reversibility permit to interpret them as an adaptative reaction to the effect of low doses of ionizing radiation.

Angiocardiography

Brain myelination in rats treated with ionizing radiation in utero.

Effects of ionizing radiation on brain myelination and some physical development parameters were studied in laboratory rats (Fisher F-344 inbred strain). Rats were treated with three different doses of radiation (150 rad, 15 rad, and 6.8 rad) delivered on the 20th day of prenatal life. Exposure to 150 rad reduced body, brain, ovary, kidney, heart and spleen weights. Prenatal exposure to 150 rad of radiation reduced the cerebral cortex weight by 22 percent at 30 days of age, and 20 percent at 52 days of age which caused a reduction in cerebral cortex myelin content by 20 and 23 percent at the ages of 30 and 52 days respectively. This dose did not affect the myelin content of the cerebellum or the brain stem, or the myelin concentration (mg myelin/g brain tissue) of the cerebral cortex, cerebellum, and the brain stem. The cerebral cortex weight of the 15 rad treated rats was reduced at the age of 30 days. Exposure to 15 rad, and 6.8 rad did not affect either the myelin content or the myelin concentration of these brain areas.

Animals

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.

Amphetamine

Enhanced induction of tissue-type plasminogen activator in normal human cells compared to cancer-prone cells following ionizing radiation.

Normal human fibroblast (i.e., GM2936B, GM2907A, and IMR-90) and cancer-prone human fibroblast (i.e., Fanconi's anemia, Bloom's syndrome, and Ataxia telangiectasia) cells demonstrated the induction of intracellular and extracellular levels of tissue-type plasminogen activator (t-PA) at 6 and 12 hr, respectively, following ionizing radiation. Induced t-PA enzymatic activities following ionizing radiation were blocked by actinomycin D treatments. t-PA enzymatic activities were induced over 14-fold in Ataxia telangiectasia cells, over 9-fold in Bloom's syndrome cells, and over 6-fold in Fanconi's anemia cells, as compared to normal human fibroblasts. Similarly, the induction of t-PA mRNA levels in cancer-prone cells were between 5- to 10-fold higher than those observed in normal cells following equitoxic doses of ionizing radiation. Temporal induction of t-PA mRNA levels for normal and cancer-prone human cells were consistent with quantifiable enzymatic activities. The elevated induction of an intracellular protease (i.e., t-PA) in cancer-prone human cells is reminiscent of an "SOS"-like response observed in yeast and bacteria.

Ataxia Telangiectasia

Ionizing radiation perturbs the switch-on of transcriptase in a model transcription complex in vitro.

Ionizing radiation markedly alters the response of the reovirus transcriptase unblocking mechanism to stimulation by K+ ions, which normally trigger the switch-on of transcription in this system. In irradiated subviral particles the concentration of K+ ions needed to trigger switch-on is reduced in a dose-dependent way. The observed alteration of switch-on characteristics appears to correlate with alteration of the electrophoretic behaviour of a single major polypeptide species. These observations have important implications for understanding some of the effects of ionizing radiation on cells, most notably the induction of both latent virus and cell differentiation.

DNA-Directed RNA Polymerases

Ultrastructural alterations in ciliary cells exposed to ionizing radiation. A scanning and transmission electron microscopic study.

Early effects of ionizing radiation were investigated in an experimental in vitro system using the ciliary cells of the tracheal mucous membrane of the rabbit, irradiated at 30 degrees C and at more than 90% humidity. The changes in physiological activities of the ciliary cells caused by irradiation were continuously registered during the irradiation. The specimens were examined immediately after irradiation electron microscopically. The morphological changes in irradiated material after 10-70 Gy are compared with normal material. After 40-70 Gy, scanning electron microscopy revealed the formation of vesicles on cilia, and club-like protrusions and adhesion of their tips. After 30-70 Gy, a swelling of mitochondrial membranes and cristae was apparent transmission electron microscopically. The membrane alterations caused by irradiation are assumed to disturb the permeability and flow of ATP from the mitochondria, which in turn leads to the recorded changes in the activity of the ciliated cells.

Adenosine Triphosphate