Eckert, D. | Search bioRxiv

bioRxiv2024

FLASH Bragg-peak irradiation with a therapeutic carbon ion beam: first in vivo results

Background and purposeIn recent years, ultra-high dose rate (UHDR) irradiation has emerged as a promising innovative approach to cancer treatment. Characteristic feature of this regimen, commonly referred to as FLASH effect, demonstrated primarily for electrons, photons or protons, is the improved normal tissue sparing, while the tumor control is similar to the one of the conventional dose-rate (CDR) treatments. The FLASH mechanism is, however, unknown. One major question is whether this effect is maintained when using densely ionizing (high-LET) heavy nuclei. Materials and MethodsHere we report the effects of 20 Gy UHDR heavy ion irradiation in clinically relevant conditions, i.e., at high-LET in the spread-out Bragg peak (SOBP) of a 12C beam using an osteosarcoma mouse model. ResultsWe show that UHDR irradiation was less toxic in the normal tissue compared to CDR while maintaining tumor control. The immune activation was also comparable in UHDR and CDR groups. We observed that the gut microbiome was altered in mice injected with the tumor compared to healthy animals, but both UHDR and CDR exposures steered the metagenome toward a balanced state. ConclusionsThe results show that the FLASH effect is safe and effective in heavy ion therapy and provide an important benchmark for the current mechanistic FLASH models. Highlights- FLASH irradiation with SOBP carbon ions spares normal tissue in mouse - Tumor control, immune response, and gut microbioma changes are induced at the same extent both at conventional and ultra-high dose rate - FLASH carbon ion irradiation is a safe and effective alternative to conventional radiotherapy.

cancer biology↗

bioRxiv2019

A small viral potassium ion channel with an inherent inward rectification

Some algal viruses have coding sequences for K+ channels with structural and functional characteristics of pore modules of complex K+ channels. Here we exploit the immense structural diversity of natural channel orthologs to discover new basic principles of structure/function correlates in K+ channels. The comparative analysis of three similar K+ channels with monomer sizes [≤] 86 amino acids (AA) shows that one channel (Kmpv1) generates an ohmic conductance in HEK293 cells while the other two channels (KmpvSP1, KmpvPL1) exhibit typical features of canonical Kir channels. Like Kir channels, the rectification of the viral channels is a function of the K+ driving force. Reconstitution of KmpvSP1 and KmpvPL1 in planar lipid bilayers showed rapid channel fluctuations only at voltages negative of the K+ reversal voltage. This rectification was maintained in KCl buffer with 1 mM EDTA, which excludes blocking cations as the source of rectification. This means that rectification of the viral channels must be, unlike Kir channels, an inherent property of the channel proteins. The structural basis for rectification was investigated by a chimera between rectifying and non-rectifying channels as well as point mutations, which made the rectifying channels similar to the ohmic conducting channel. The results of these experiments exclude the domain, which connects the two transmembrane helixes and which includes the pore helix and the selectivity filter, as playing a major role in rectification; inward rectification must be conferred by the transmembrane domains. The finding that a swapping of the AA, which is typical for the two inward rectifiers, with the respective AA from Kmpv1 did not compromise rectification suggests that tertiary or quaternary structural interactions are responsible for this type of gating.

biophysics↗