Response to Ling et al. regarding “An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses”

In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤500 ms) of radiation delivered at ultrahigh dose rate (≥40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc+ orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor–β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor–α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.

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Idiorrhythmic dose-rate variability in dietary zinc intake generates a different response pattern of zinc metabolism than conventional dose–response feeding

British Journal Of Nutrition ◽

10.1079/bjn19970128 ◽

1997 ◽

Vol 78 (1) ◽

pp. 173-191 ◽

Cited By ~ 8

Author(s):

Berislav MomČilović ◽

Philip G. Reeves ◽

Michael J. Blake

Keyword(s):

Dose Rate ◽

Dose Response ◽

Male Rats ◽

Metabolic Efficiency ◽

Zinc Metabolism ◽

Deficient Diet ◽

Zinc Intake ◽

Conventional Dose ◽

Zn Concentration ◽

Different Response

We compared the effects of idiorrhythmic dose-rate feeding and conventional dose-response on the induction of intestinal metallothionein (IMT), expression of aortal heat-shock protein mRNA (HSP70mRNA) induced by restraint stress, and accumulation of Zn in the femur and incisor of young growing male rats. An idiorrhythmic approach requires that the average dietary Zn concentration (modulo, M) over the whole experiment (epoch, E) is kept constant across different groups. This is done by adjusting the Zn concentration of the supplemented diet supplied to compensate for the reduction in the number of days on which Zn-supplemented diet is fed, the latter being spread evenly over the experiment. Idiorrhythms involve offering the diet with n times theoverall Zn concentration (M) only every nth day with Zn-deficient diet offered on other days. Idiorrythmic Zn dose-rate feeding changed Zn accumulation in the femur and incisor in a complexbi-modal fashion, indicating that metabolic efficiency of dietary Zn is not constant but depends on Zn dose-rate. In contrast to feeding Zn in the conventional dose-response scheme, iMT and HSP7OmRNA were not affected by idiorrhythmic dose-rate feeding. Idiorrhythmic cycling in dietary Zn load posed no risk of a biochemical overload nor caused the animals to be stressed. Idiorrhythmic dose-rate feeding brings the dimension of time to the conventional dose-response

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