Low Doses of Ionizing Radiation Promote Tumor Growth and Metastasis by Enhancing Angiogenesis

Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk. The biological effects of these low doses of IR on the healthy tissue surrounding the tumor area, and in particular on the vasculature remain largely to be determined. We found that doses of IR lower or equal to 0.8 Gy enhance endothelial cell migration without impinging on cell proliferation or survival. Moreover, we show that low-dose IR induces a rapid phosphorylation of several endothelial cell proteins, including the Vascular Endothelial Growth Factor (VEGF) Receptor-2 and induces VEGF production in hypoxia mimicking conditions. By activating the VEGF Receptor-2, low-dose IR enhances endothelial cell migration and prevents endothelial cell death promoted by an anti-angiogenic drug, bevacizumab. In addition, we observed that low-dose IR accelerates embryonic angiogenic sprouting during zebrafish development and promotes adult angiogenesis during zebrafish fin regeneration and in the murine Matrigel assay. Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis and that these effects were prevented by the administration of a VEGF receptor-tyrosine kinase inhibitor immediately before IR exposure. These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR and may provide a new rationale basis to the improvement of current radiotherapy protocols.     

Bioassay Approach to Prescribe Safe-limits of Exposure to Non Ionizing Radiation in Ecosystems

A biological assay that quantifies hazardous response in living matter to an electromagnetic stimulus, is evolved. Considering the various susceptible aspects of physio-anatomical systems constituting a living subject, a dominance criterion to determine an optimum all-or-none response limit of exposure to electromagnetic pollutions is established. Based on the statistics of proneness and susceptibility of discrete physio-anatomical parts of living systems (biotic components) to polluting radiations (abiotic environment), the stochastic nature of damage involved is considered to formulate a quantal index which specifies a “safe” intensity-level of electromagnetic radiation to which living systems can be exposed without encountering any deleterious effects. The locations of vulnerable parts which are affected by radiation are identified through random mosaic modeling of a test subject. Using this model, a susceptance priority sequence of biotic components is constructed. This sequence is then terminated at a point of weightage proportional to the diversity of victim population. The biotic species falling within this limit of truncation are subsequently studied to assay the tolerance (optimum lethal dose) of the test subject to the radiation in question. The possibility of simulating the entire ecological system under consideration by means of a microprocessor is suggested.     

Escherichia coli Genes and Pathways Involved in Surviving Extreme Exposure to Ionizing Radiation

To further an improved understanding of the mechanisms used by bacterial cells to survive extreme exposure to ionizing radiation (IR), we broadly screened nonessential Escherichia coli genes for those involved in IR resistance by using transposon-directed insertion sequencing (TraDIS). Forty-six genes were identified, most of which become essential upon heavy IR exposure. Most of these were subjected to direct validation. The results reinforced the notion that survival after high doses of ionizing radiation does not depend on a single mechanism or process, but instead is multifaceted. Many identified genes affect either DNA repair or the cellular response to oxidative damage. However, contributions by genes involved in cell wall structure/function, cell division, and intermediary metabolism were also evident. About half of the identified genes have not previously been associated with IR resistance or recovery from IR exposure, including eight genes of unknown function.     

Evaluation of the Contribution of Homologous Recombination in DNA Double-Strand Break Repair in Human Fibroblasts after Exposure to Low and Intermediate Doses of X-ray Radiation

Biology Bulletin - Abstract—Studies of the changes in the number of γH2AX foci (a DNA double-strand break protein-marker), and Rad51 foci (a key homologous recombination protein) were...     

The Frequency, Dynamics, and Structure of Congenital Malformations in Populations under Long-Term Exposure to Ionizing Radiation

Information on the dynamics, frequency, and structure of congenital malformations (CMs) and chromosomal diseases in two generations of rural populations from the Semipalatinsk region was obtained for the first time. The tests performed in the Semipalatinsk nuclear test site (STS) for many years were demonstrated to deteriorate the genetic health of the populations of the zones of extreme and maximum radiation risks. Mutagenic and teratogenic effects of long-term ionizing irradiation were detected. These were mainly expressed as an increase in the frequencies of strictly registered CMs (SR CMs), including the Down syndrome, multiple malformations (MMs) and microcephaly (1.45 ± 0.11, 1.39 ± 0.01, and 0.77 ± 0.05 per 1000 births, respectively). SR CMs exhibited linear trends toward higher frequencies in two generations of exposed persons after surface nuclear tests in 1949–1963. Their frequency was strongly correlated with the effective population dose of radiation; the main population genetic parameters (inbreeding coefficient, endogamy index, etc.) had less pronounced effects on Cms.     

Altered Telomere Nuclear Matrix Interactions and Nucleosomal Periodicity in Ataxia Telangiectasia Cells before and after Ionizing Radiation Treatment

Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G(1), G(2), and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene.     

Possible Relationships between Plasma Glutathione Levels and Cytogenetic Indices in Peripheral Blood Lymphocytes of Children Exposed to Low Doses of Radiation

An analysis of correlations between cytogenetic indices in lymphocytes and levels of reduced glutathione in the plasma of peripheral blood in children born after the Chernobyl accident is presented. The studied systems in the child population demonstrated different responses to low-level radiation of their mothers living in conditions of radionuclide contamination (1–20 Ci/km² of ¹³⁷Cs). Low doses of radiation accumulated by mothers (below 30 cSv) proved to have a more pronounced effect on the studied systems in children as compared to high doses (from 30 to 60 cSv).     

The Mechanical Characteristics of Human Endothelial Cells in Response to Single Ionizing Radiation Doses By Using Micropipette Aspiration Technique

The mechanical properties of living cells are known to be promising biomarkers when investigating the health and functions of the human body. Ionizing irradiation results in vascular injury due to endothelial damage. Thus, the current study objective was to evaluate the influence of continuous radiation doses on the mechanical properties of human umbilical vein endothelial cells (HUVECs), and to identify Young’s modulus (E) and viscoelastic behavior. Single-dose (0, 2, 4, 6, and 8 Gy) radiation was applied to HUVECs using a Cobalt-60 treatment machine in the current vitro irradiation study. Thereafter, a micropipette-aspiration technique was used to measure the elastic modulus of the HUVECs in control and radiation-induced samples. Confocal imaging was then performed for following of the cytoskeletal reorganization of the HUVECs in response to the different radiation doses. Significant enhanced adhesion of the elastic modulus of the HUVECs was observed. The dose value was seen to increase from 0 Gy to 8 Gy. A linear relationship was observed between the 0 Gy and 8 Gy doses following an examination of the dose-response curve for elastic modulus after irradiation. The correlation coefficient was found to be 0.955 and the sensitivity of the dose-elastic modulus to be 7.69 Pa..Gy-1 following analysis of the linear portion of the response curve. Also, a significant increment in stiffness accompanied with the considerable drop in creep compliance curve was detected in radiation-induced groups. Biomechanics-based analysis can provide a platform from which to assess the response of the endothelium to radiation when studying vascular system behavior during the cancer therapy process.     

Effects of Aluminum Exposure on Bone Mineral Density,Mineral, and Trace Elements in Rats

The purpose of the study was to investigate the effects of aluminum (Al) exposure on bone mineral elements, trace elements, and bone mineral density (BMD) in rats. One hundred Wistar rats were divided randomly into two groups. Experimental rats were given drinking water containing aluminum chloride (AlCl₃, 430 mg Al³⁺/L), whereas control rats were given distilled water for up to 150 days. Ten rats were sacrificed in each group every 30 days. The levels of Al, calcium (Ca), phosphorus (P), magnesium (Mg), zinc (Zn), iron (Fe), copper (Cu), manganese (Mn), selenium (Se), boron (B), and strontium (Sr) in bone and the BMD of femur were measured. Al-treated rats showed lower deposition of Ca, P, and Mg compared with control rats. Levels of trace elements (Zn, Fe, Cu, Mn, Se, B, and Sr) were significantly lower in the Al-treated group than in the control group from day 60, and the BMD of the femur metaphysis in the Al-treated group was significantly lower than in the control group on days 120 and 150. These findings indicate that long-term Al exposure reduces the levels of mineral and trace elements in bone. As a result, bone loss was induced (particularly in cancellous bone).     

Effects of Low Doses of Fluoride on Serum Proteins and a Serum Enzyme in Man

FLUORIDE ions have long been known to exert an inhibitory effect on the activity of certain enzymes-Frajola¹ lists ten human enzymes which are definitely inhibited in vitro and suggests that there may be more. In an experiment in one subject receiving 36 mg of sodium fluoride daily for 18 days Frajola was able to show that the activities of the serum enzymes lactic dehydrogenase, acid phosphatase and glutamic transaminase were reduced, but he does not say whether the general health of the subject was affected. Opponents of fluoridation as a public health measure argue that the action as an enzyme inhibitor will affect general health and they quote instances of subjectively assessed ill-health and allergylike reactions following fluoridation of public water supplies, but careful medical observations in fluoridated areas have shown no increase of systemic disease and no significant variation in mortality rates. It has been stated² that there is no evidence that fluoride ingested at 1 p.p.m. in drinking water has any effect on human enzyme activity, but there are no specific experimental data on this question.     

Chronic Exposure to Low Doses of HgCl2 Avoids Calcium Handling Impairment in the Right Ventricle after Myocardial Infarction in Rats

Right ventricle systolic dysfunction is a major risk factor for death and heart failure after myocardial infarction (MI). Heavy metal exposure has been associated with the development of several cardiovascular diseases, such as MI. The aim of this study was to investigate whether chronic exposure to low doses of mercury chloride (HgCl₂) enhances the functional deterioration of right ventricle strips after MI. Male Wistar rats were divided into four groups: Control (vehicle); HgCl₂ (exposure during 4 weeks- 1st dose 4.6 µg/kg, subsequent dose 0.07 µg/kg/day, i.m. to cover daily loss); MI surgery induced and HgCl₂-MI groups. One week after MI, the morphological and hemodynamic measurements and isometric tension of right ventricle strips were investigated. The chronic HgCl₂ exposure did not worsen the injury compared with MI alone in the morphological or hemodynamic parameters evaluated. At basal conditions, despite similar maximum isometric force at L-max, relaxation time was increased in the MI group but unaffected in the HgCl₂-MI compared to the Control group. Impairment of the sarcoplasmic reticulum (SR) function and reduction in the sarcolemmal calcium influx were observed in MI group associated with SERCA2a reduction and increased PLB protein expression. Induction of MI in chronic HgCl₂ exposed rats did not cause any alteration in the developed force at L-max, lusitropic function or −dF/dt except for a tendency of a reduction SR function. These findings could be partially explained by the normalization in the sarcolemmal calcium influx and the increase in NCX protein expression observed only in this group. These results suggest that chronic exposure to low doses of HgCl₂ prevents the impaired SR function and the reduced sarcolemmal calcium influx observed in MI likely by acting on NCX, PLB and SERCA2a protein expression.     

Serum Concentrations of Trace Elements Zinc,Copper, Selenium,and Manganese in Critically Ill Patients

Biological Trace Element Research - We measured serum concentrations of trace elements and evaluated their clinical significance in relation to treatment outcomes of critically ill patients. A...     

Altered Plasma Concentrations of Trace Elements in Ulcerative Colitis Patients Before and After Surgery

Ileal pouch-anal anastomosis (IPAA) is a classical surgery for ulcerative colitis patients. However, knowledge on trace element alteration in patients who had undergone this surgery is limited. This study was conducted to assess trace element alteration in patients with ulcerative colitis before and after ileal pouch-anal anastomosis. Preoperative (40) and postoperative (35) ulcerative colitis patients were studied. The dietary assessment of trace element intake was undertaken by a semiquantitative food frequency questionnaire. Patients' trace element status of zinc, copper, manganese, selenium, calcium, iron, and vitamin D₃ was assessed by measuring their blood concentrations. We found that with the similar dietary intake, there was no statistical difference in the concentrations of plasma copper, iron, calcium, and vitamin D₃ in the two groups (P?>?0.05). Compared with preoperative patients, postoperative patients had higher concentrations of plasma zinc (14.51?±?4.75 μmol/l) and manganese (0.21?±?0.11 μmol/l) and lower concentrations of plasma selenium (0.86?±?0.58 μmol/l). Both preoperative and postoperative mean concentrations of plasma calcium and vitamin D₃ were below their reference range, respectively. We conclude that IPAA does not seem to alter patients' abnormal trace elements completely. It is important to monitor and supply some specified trace elements even in postoperative patients.     

The Effects of Whole Body Cell Phone Exposure on the T1 Relaxation Times and Trace Elements in the Serum of Rats

The objective of this study was to investigate the effects of radiofrequency radiation emitted from cellular phones on: (1) trace elements such as manganese, iron, copper, zinc, (2) T1 relaxation times in serum, and (3) rectal temperature of rats exposed to microwave radiation emitted from cellular phones. Sixteen Spraque–Dawley rats were separated into two groups of eight, one sham-exposed (control) and one exposed (experimental). The rats were confined in Plexiglas cages and a cellular phone was placed 0.5 cm under the cage. For the experimental group, cellular phones were activated 20 min per day, 7 days a week, for 1 month. For the control group, a cellular phone placed beneath the cage for 20 min a day was turned off. Rectal temperatures were measured weekly. For 250-mW-radiated powers, the whole body average specified absorption rate (SAR) (rms) is 0.52 W/kg and 1-g-averaged peak SAR (rms) is 3.13 W/kg. The Mann-Whitney U test was used for statistical comparisons of groups. T1 relaxation time and the values of iron and copper in the serum of the experimental group were not changed compared to the control group (p > 0.05). However, manganese and zinc values in the serum of the experimental group were significantly different from the control group (p < 0.05). The difference in rectal temperature measured before and after exposure in the experimental groups was not statistically different from control (p > 0.05).     

Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: I. Radiation-Induced Genomic Instability and Bystander Effects In Vitro

A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.     

Formation of Lipofuscin in Drosophila after Exposure to Elevated Temperatures and UV Radiation

Biophysics - Abstract—A spectroscopic study of the manner in which exposure to elevated temperature or intense UV radiation leads to the occurrence of lipofuscin debris in the bodies and...