Chronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research

<p><b>Purpose:</b> To investigate biochemical pathways known to be involved in radiation response and in CFIDS to determine if there might be common underlying mechanisms leading to symptoms experienced by those accidentally or deliberately exposed to radiation and those suffering from CFIDS. If such a link was established to suggest testable hypotheses to investigate the mechanisms with the aim of identifying new therapeutic targets.</p> <p><b>Conclusions:</b> Evidence for involvement of the alpha-synuclein, cytochrome c oxidase, αB-crystallin, RNase L, and lactate dehydrogenase/STAT1 pathways is strong and suggests a common underlying mechanism involving mitochondrial dysfunction mediated by ROS and disruption of ATP production. The downstream effect of this is compromised energy production. Testable hypotheses are suggested to investigate the involvement of these pathways further.</p

Low-dose non-targeted radiation effects in human esophageal adenocarcinoma cell lines

<p><b>Purpose:</b> To investigate non-targeted radiation effects in esophageal adenocarcinoma cell lines (OE19 and OE33) using human keratinocyte and colorectal cancer cell reporters following γ-ray exposure.</p> <p><b>Materials and methods:</b> Both clonogenic assays and ratiometric calcium endpoints were used to check for the occurrence of bystander signals in reporter cells.</p> <p><b>Results:</b> We report data suggesting that γ-irradiation increases cell killing over the expected linear quadratic (LQ) model levels in the OE19 cell line exposed to doses below 1 Gy, i.e. which may be suggestive to be a low hyper-radiosensitive (HRS) response to direct irradiation. Both EAC cell lines (OE19 and OE33) have the ability to produce bystander signals when irradiated cell conditioned medium (ICCM) is placed onto human keratinocyte reporters, but do not seem to be capable of responding to bystander signals when placed on their autologous reporters. Further work with human keratinocyte reporter models showed statistically significant intracellular calcium fluxes following exposure of the reporters to ICCM harvested from both EAC cell lines exposed to 0.5 Gy.</p> <p><b>Conclusion:</b> These experiments suggest that the OE19 and OE33 cell lines produce bystander signals in human keratinocyte reporter cells. However, the radiosensitivity of the EAC cell lines used in this study cannot be enhanced by the bystander response since both cell lines could not respond to bystander signals.</p

Different width of the radiation paths.

<p>A) Microbeam tracks as outlined by γ-H2AX stain at 4 and 8 hours after a 350 Gy irradiation. The high dose delivered resulted in an increase in the width of the microbeam track over time. B) Intensity of the fluorescence of the areas depicted in A.</p

Mean thickness of the radiation tracks in the cerebellum.

<p>Microbeam irradiation was given to both normal (A) and tumour-bearing rats (B). The width of the microbeams was 25 μm, which is represented by the dotted line. Animals were exposed to 35, 70, or 350 Gy to their right cerebral hemisphere. Four and 8 hours indicate the two dissection times after irradiation. Different letters and different letter cases indicate significant differences between groups and within each group respectively. Error bars show SD.</p

Number of γ-H2AX positive cells per unit area.

<p>The measurements were performed in the granular layer of the cerebellum. A) Shows the number of cells in normal rats while B) shows the number of cells in tumour-bearing animals. Stars show significant differences between 4 and 8 hours. Error bars correspond to SD.</p

γ-H2AX stain comparison between micro- and broad beam configurations.

<p>Horizontal sections of the irradiated right cerebral hemisphere and the cerebellum of Wistar rats. Images A—D were obtained from the irradiated right cerebral hemisphere and cerebellum of animals exposed to 350 Gy of either microbeam or broad beam; dissected 8 hours after irradiation. For the MRT array, the center-to-center distance was 200 μm. The position and intensity of the γ-H2AX marker (green) correlate with the deposition of the peak synchrotron doses. A) Radiation tracks of the microbeams in the right cerebral hemisphere. B) Right cerebral hemisphere after broad beam irradiation C) Radiation tracks of the microbeams in the cerebellum. D) Cerebellum after broad beam irradiation. E) Horizontal section through the whole cerebellum after exposure of the right hemisphere to microbeams of 350 Gy; dissected at 4 hours after irradiation.</p

Comparison of radiation tracks produced by the same intended microbeam configuration (center-to-center distance of 200 μm).

<p>By design the collimator spatially fractionates the microbeams with a center-to-center distance of 400 μm; to generate a center-to-center distance of 200 μm the collimator moves laterally followed by a second passage of the animal through the beam. A) Variable center-to-center distance of the microbeams due to inaccurate lateral translation of the collimator (35 Gy, 4 hours after irradiation). B) Accurate delivery of the microbeams. (350 Gy, 8 hours after irradiation).</p

Schematic representation of a broad beam and a microbeam array.

<p>Schematic representation of a broad beam and a microbeam array.</p

Intensity of the fluorescence measured through a 100 μm profile line traced perpendicular to the direction of the microbeams peak radiation path.

<p>A) Intensity profile of normal rats. B) Intensity profile in tumour-bearing animals.</p

Assessing patient characteristics and radiation-induced non-targeted effects in vivo for high dose-rate (HDR) brachytherapy

<div><p><i>Purpose</i>: To test whether blood, urine, and tissue based colony-forming assays are a useful clinical detection tool for assessing fractionated treatment responses and non-targeted radiation effects in bystander cells.</p><p><i>Materials and methods</i>: To assess patients’ responses to radiation treatments, blood serum, urine, and an esophagus explant-based in vivo colony-forming assay were used from oesophageal carcinoma patients. These patients underwent three fractions of high dose rate (HDR) intraluminal brachytherapy (ILBT).</p><p><i>Results</i>: Human keratinocyte reporters exposed to blood sera taken after the third fraction of brachytherapy had a significant increase in cloning efficiency compared to baseline samples (<i>p</i> < 0.001). Such results may suggest an induced radioresistance response in bystander cells. The data also revealed a clear inverse dose-rate effect during late treatment fractions for the blood sera data only. Patient characteristics such as gender had no statistically significant effect (<i>p</i> > 0.05). Large variability was observed among the patients’ tissue samples, these colony-forming assays showed no significant changes throughout fractionated brachytherapy (<i>p</i> > 0.05).</p><p><i>Conclusion</i>: Large inter-patient variability was found in the urine and tissue based assays, so these techniques were discontinued. However, the simple blood-based assay had much less variability. This technique may have future applications as a biological dosimeter to predict treatment outcome and assess non-targeted radiation effects.</p></div