Establishment of Early Endpoints in Mouse Total-Body Irradiation Model

Koch, Amory; Gulani, Jatinder; King, Gregory L.; Hieber, Kevin; Chappell, Mark C.; Ossetrova, Natalia I.

doi:10.1371/journal.pone.0161079

Cited by 60 publications

(50 citation statements)

References 25 publications

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“…To obtain a positive control for DNA damage accumulation in mouse spinal cords, Non-Tg mice (n = 3) were irradiated for 10 min at 10Gy of γ-rays. Animals were perfused within 2 hours after irradiation and processed for immunofluorescence staining using anti-γH2A.X and −53BP1 antibodies as previously described ( Ahmed et al., 2017 , Koch et al., 2016 ).…”

Section: Methodsmentioning

confidence: 99%

ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

López-Erauskin

Tadokoro

Baughn

et al. 2018

Neuron

194

152

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SummaryThrough the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs.Video Abstract

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Section: Methodsmentioning

confidence: 99%

ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

López-Erauskin

Tadokoro

Baughn

et al. 2018

Neuron

194

152

View full text Add to dashboard Cite

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“…To do so, we focused on a mouse model of radiation-induced enteropathy 41,42 . Weight loss of animals following irradiation is an important parameter in evaluating the severity of radiation-induced damage [43][44][45][46] . Modeling of weight measurements established a significant difference between the two dose rates from 0.5 to 6 weeks after irradiation, this loss of weight being systematically greater for the higher dose rate.…”

Section: Discussionmentioning

confidence: 99%

Variation of 4 MV X-ray dose rate strongly impacts biological response both in vitro and in vivo

Kacem¹,

Benadjaoud²,

Santos³

et al. 2020

Sci Rep

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Whereas an RBE > 1 is described for very low-energy X-ray beams (in the range of 25-50 kV), there is a consensus that the RBE of X-rays (from 0.1 to 3 MeV) is equal to 1, whatever the energy or dose rate of the beam. Comparisons of X-ray beam dose rates are scarce even though these beams are widely used in medical diagnosis or radiotherapy. By using two dose rates (0.63 and 2.5 Gy.min −1) of high-energy X-rays on normal endothelial cells (HUVECs), we have studied the clonogenic assay, but also viability/ mortality, cell cycle analysis and measured cellular senescence by flow cytometry, and have performed gene analysis on custom arrays. In order to consolidate these data, we performed localized irradiation of exteriorized small intestine at 0.63 and 2.5 Gy.min −1. Interestingly, in vivo validation has shown a significantly higher loss of weight at the higher dose when irradiating to 19 Gy a small fragment of exteriorized small intestine of C57Bl6J mice. Nevertheless, no significant differences were observed in lesioned scores between the two dose rates, while bordering epithelium staining indicated twofold greater severe damage at 2.5 Gy.min −1 compared to 0.63 Gy.min −1 at one week post-irradiation. Taken together, these experiments systematically show that the relative biological effectiveness of photons is different from 1 when varying the dose rate of high-energy X-rays. Moreover, these results strongly suggest that, in support of clonogenic assay, multiparametric analysis should be considered to provide an accurate evaluation of the outcome of irradiated cells. Relative biological effectiveness (RBE) is the ratio of the dose of one kind of ionizing radiation relative to another to produce the same biological effect. Several studies have focused on dose rate effects, but they were mainly performed at low dose rates and by using 137 Cs 1,2 or 60 Co 3,4 sources. A few studies have directly compared the in vitro effects of different dose rates of X-rays on cancer cells, but not on normal human cells 5-9. It is also known that RBE increases as LET increases up to 100 KeV.µm −1 , above which RBE decreases because of cellular overkill 10. Moreover, RBE for protons is also described as endpoint-dependent 11 , while there is a consensus that the RBE of X-rays (photons; energy from 0.1 to 3 MeV) is equal to 1, whatever the energy or dose rate of the beam 12. Importantly, higher RBE is described for very low-energy X-ray beams (in the range of 25-50 kV) 13-16. Nevertheless, modern radiotherapy uses medical devices (mostly 6-10 MV) able to deliver doses up to 20 Gy. min −1 , assuming that the RBE of the X-ray beam remains equal to 1 whatever the energy and/or dose rate. To verify this, and build a proof of concept both in vitro and in vivo, we set as our reference a beam of high energy X-rays (4 MV) at 0.63 Gy.min −1 on a Linear Accelerator (LINAC) Elekta Synergy Platform. Independently of the radiation type and delivery technique, several dosimetric studies of water phantoms or of real treatment planning conditions 17-1...

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“…Two factors critical to successful allogeneic bone marrow reconstitution in host mice are (1) sufficient bone marrow ablation to make space for donor bone marrow as well as prohibit bone marrow rejection and (2) adequately suppressed host hematopoietic activity so that the transplanted donor bone marrow can out compete any residual host bone marrow cells and splenocytes in repopulating the host's hematopoietic cells. 16 Our results suggest that unlike filtered high-energy Cs-137 g-ray photons, X-RAD 320-Unit, X-ray photons (with some low-energy photons removed via filtration) may still not have high-enough energy for successful allogeneic bone marrow transplantation studies in small rodents. The intended doses (target doses) of g rays were selected based on findings from a literature search and the desired doses of X-rays were chosen based on our preliminary estimate of the X-ray RBE (¼1.3) relative to g rays.…”

Section: Discussionmentioning

confidence: 81%

A Comparison of Cs-137 γ Rays and 320-kV X-Rays in a Mouse Bone Marrow Transplantation Model

et al. 2020

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US homeland security concerns regarding the potential misuse of some radiation sources used in radiobiological research, for example, cesium-137 (137Cs), have resulted in recommendations by the National Research Council to conduct studies into replacing these sources with suitable X-ray instruments. The objective of this research is to compare the effectiveness of an X-RAD 320 irradiator (PXINC 2010) with a 137Cs irradiator (Gammacell-1000 Unit) using an established bone marrow chimeric model. Using measured radiation doses for each instrument, we characterized the dose–response relationships for bone marrow and splenocyte ablation, using a cytotoxicity-hazard model. Our results show that the X-RAD 320 photon energy spectrum was suitable for ablating bone marrow at the 3 exposure levels used, similar to that of 137Cs photons. However, the 320-kV X-rays were not as effective as the much higher energy γ rays at depleting mouse splenocytes. Furthermore, the 3 X-ray levels used were less effective than the higher energy γ rays in allowing the successful engraftment of donor bone marrow, potentially as a result of the incomplete depletion of the spleen cells. More defined studies are warranted for determining whether bone marrow transplantation in mice can be successfully achieved using 320-kV X-rays. A higher X-ray dose then used is likely needed for transplantation success.

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Establishment of Early Endpoints in Mouse Total-Body Irradiation Model

Cited by 60 publications

References 25 publications

ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

Variation of 4 MV X-ray dose rate strongly impacts biological response both in vitro and in vivo

A Comparison of Cs-137 γ Rays and 320-kV X-Rays in a Mouse Bone Marrow Transplantation Model

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