Journal Issue: Dose-Response: An International Journal: Volume 12, Issue 1
No Thumbnail Available
Volume
Number
Issue Date
2014-31-03
Journal Title
Journal ISSN
Journal Volume
Articles
Dose-Response Vol 12, no 1, Table of Contents
(2014-03-31)
DOSE CALCULATIONS FOR [131I] META-IODOBENZYLGUANIDINEINDUCED BYSTANDER EFFECTS
(2014-03-31) Gow, M.D.; Seymour, CB; Boyd, M.; Mairs, RJ; Prestiwch, WV; Mothersill, CE
Targeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier – Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 - 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 - 0.75 Gy/h for UVW/NAT and 0.07 - 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 - 0.23 Gy for UVW and 0.03 - 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander doseresponse profile similar to that generated by external beam gamma irradiation but with significantly greater cell death.
ADAPTATION AND SENSITIZATION TO PROTEOTOXIC STRESS
(2014-03-31) Leak, Rehana K.
Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.
RESVERATROL ATTENUATES EXERCISE-INDUCED ADAPTIVE RESPONSES IN RATS SELECTIVELY BRED FOR LOW RUNNING PERFORMANCE
(2014-03-31) Hart, Nikolett; Sarga, Linda; Csende, Zsolt; Koch, Lauren G.; Britton, Steven L.; Radak, Zsolt
Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPTFOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control.
TRANSMISSION OF SIGNALS FROM RATS RECEIVING HIGH DOSES OF MICROBEAM RADIATION TO CAGE MATES: AN INTER-MAMMAL BYSTANDER EFFECT
(2014-03-31) Mothersill, Carmel; Fernandez-Palomo, Cristian; Fazzari, Jennifer; Smith, Richard; Schültke, Elisabeth; Bräuer-Krisch, Elke; Laissue, Jean; Schroll, Christian; Seymour, Colin
Inter-animal signaling from irradiated to non-irradiated organisms has been demonstrated for whole body irradiated mice and also for fish. The aim of the current study was to look at radiotherapy style limited exposure to part of the body using doses relevant in preclinical therapy. High dose homogenous field irradiation and the use of irradiation in the microbeam radiation therapy mode at the European Synchrotron Radiation Facility (ESRF) at Grenoble was tested by giving high doses to the right brain hemisphere of the rat. The right and left cerebral hemispheres and the urinary bladder were later removed to determine whether abscopal effects could be produced in the animals and also whether effects occurred in cage mates housed with them. The results show strong bystander signal production in the contra-lateral brain hemisphere and weaker effects in the distant bladder of the irradiated rats. Signal strength was similar or greater in each tissue in the cage mates housed for 48hrs with the irradiated rats. Our results support the hypothesis that proximity to an irradiated animal induces signalling changes in an unirradiated partner. If similar signaling occurs between humans, the results could have implications for caregivers and hospital staff treating radiotherapy patients.