Low Linear Energy Transfer Radiation Research Articles

OSLD nanoDot characterization for carbon radiotherapy dosimetry

Objective. This study characterized optically-stimulated luminescent dosimeter (OSLD) nanoDots for use in a therapeutic carbon beam using the Imaging and Radiation Oncology Core (IROC) framework for remote output verification. Approach. The absorbed dose correction factors for OSLD (fading, linearity, beam quality, angularity, and depletion), as defined by AAPM TG 191, were characterized for carbon beams. For the various correction factors, the effect of linear energy transfer (LET) was examined by characterizing in both a low and high LET setting. Main results. Fading was not statistically different between reference photons and carbon, nor between low and high LET beams; thus, the standard IROC-defined exponential function could be used to characterize fading. Dose linearity was characterized with a linear fit; while low and high LET carbon linearity was different, these differences were small and could be rolled into the uncertainty budget if using a single linearity correction. A linear fit between beam quality and dose-averaged LET was determined. The OSLD response at various angles of incidence was not statistically different, thus a correction factor need not be applied. There was a difference in depletion between low and high LET irradiations in a primary carbon beam, but this difference was small over the standard five readings. The largest uncertainty associated with the use of OSLDs in carbon was because of the k Q correction factor, with an uncertainty of 6.0%. The overall uncertainty budget was 6.3% for standard irradiation conditions. Significance. OSLD nanoDot response was characterized in a therapeutic carbon beam. The uncertainty was larger than for traditional photon applications. These findings enable the use of OSLDs for carbon absorbed dose measurements, but with less accuracy than conventional OSLD audit programs.

Impact of radiation therapy on healthy and cancerous cell dynamics: a Mathematical analysis

This study proposes a novel therapeutic model for cancer treatment with radiation therapy by analyzing the interactions among cancer, immune and healthy cells through a system of three ordinary differential equations. In this model, the natural influx rate of mature immune cells is assumed constant and is denoted by, a. The overall effect of radiation therapy on cancer cells is represented by a parameter, s; which is the surviving fraction of cells as determined by the Linear Quadratic (LQ) model. Conditions for the stability of equilibria in the interaction model modified to include the surviving fraction, are systematically established in terms of the dose and model parameters. Numerical simulations are performed in Wolfram MATHEMATICA software, investigating a spectrum of initial cell population values irradiated with 60Co γ -ray Low-LET radiation and High-LET 165 keV / μ m Ni-ion radiation to facilitate improved visualization and in-depth analysis. By analyzing the model, this study identifies threshold values for the absorbed dose D for particular values of the model and radiation parameters for both High Linear Energy Transfer (high-LET) and Low Linear Energy Transfer (low-LET) radiations that ensure either eradication or minimization of cancer cells from a patient’s body, providing valuable insights for designing effective cancer treatments.

Hypoxia Modulates Radiosensitivity and Response to Different Radiation Qualities in A549 Non-Small Cell Lung Cancer (NSCLC) Cells.

Hypoxia-induced radioresistance reduces the efficacy of radiotherapy for solid malignancies, including non-small cell lung cancer (NSCLC). Cellular hypoxia can confer radioresistance through cellular and tumor micro-environment adaptations. Until recently, studies evaluating radioresistance secondary to hypoxia were designed to maintain cellular hypoxia only before and during irradiation, while any handling of post-irradiated cells was carried out in standard oxic conditions due to the unavailability of hypoxia workstations. This limited the possibility of simulating in vivo or clinical conditions in vitro. The presence of molecular oxygen is more important for the radiotoxicity of low-linear energy transfer (LET) radiation (e.g., X-rays) than that of high-LET carbon (12C) ions. The mechanisms responsible for 12C ions' potential to overcome hypoxia-induced radioresistance are currently not fully understood. Therefore, the radioresistance of hypoxic A549 NSCLC cells following exposure to X-rays or 12C ions was investigated along with cell cycle progression and gene expression by maintaining hypoxia before, during and after irradiation. A549 cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h and then irradiated with X-rays (200 kV) or 12C ions (35 MeV/n, LET ~75 keV/µm). Cell survival was evaluated using colony-forming ability (CFA) assays immediately or 24 h after irradiation (late plating). DNA double-strand breaks (DSBs) were analyzed using γH2AX immunofluorescence microscopy. Cell cycle progression was determined by flow cytometry of 4',6-diamidino-2-phenylindole-stained cells. The global transcription profile post-irradiation was evaluated by RNA sequencing. When hypoxia was maintained before, during and after irradiation, hypoxia-induced radioresistance was observed only in late plating CFA experiments. The killing efficiency of 12C ions was much higher than that of X-rays. Cell survival under hypoxia was affected more strongly by the timepoint of plating in the case of X-rays compared to 12C ions. Cell cycle arrest following irradiation under hypoxia was less pronounced but more prolonged. DSB induction and resolution following irradiation were not significantly different under normoxia and hypoxia. Gene expression response to irradiation primarily comprised cell cycle regulation for both radiation qualities and oxygen conditions. Several PI3K target genes involved in cell migration and cell motility were differentially upregulated in hypoxic cells. Hypoxia-induced radioresistance may be linked to altered cell cycle response to irradiation and PI3K-mediated changes in cell motility and migration in A549 cells rather than less DNA damage or faster repair.

Effects of tissue heterogeneity and comparisons of collapsed cone and Monte Carlo fast neutron patient dosimetry using the University of Washington clinical neutron therapy system (CNTS)

Fast neutron therapy is a high linear energy transfer (LET) radiation treatment modality offering advantages over low LET radiations. Multileaf collimator technology reduces normal-tissue dose (toxicity) and makes neutron therapy more comparable to MV x-ray treatments. Published clinical-trial and other experiences with fast neutron therapy are reported. Early comparative studies failed to consider differences in target-dose spatial conformality between x-ray and neutron treatments, which is especially important for organs-at-risk close to tumor targets. Treatments planning systems (TPS) for high-energy neutrons lag behind TPS tools for MV x-rays, creating challenges for comparative studies of clinical outcomes. A previously published Monte Carlo model of the University of Washington (UW) Clinical Neutron Therapy System (CNTS) is refined and integrated with the RayStation TPS as an external dose planning/verification tool. The collapsed cone (CC) dose calculations in the TPS are based on measured dose profiles and output factors in water, with the absolute dose determined using a tissue-equivalent ionization chamber. For comparison, independent (external) Monte Carlo simulation computes dose on a voxel-by-voxel basis using an atlas that maps Hounsfield Unit (HU) numbers to elemental composition and density. Although the CC algorithm in the TPS accurately computes neutron dose to water compared to Monte Carlo calculations, calculated dose to water differs from bone or tissue depending largely on hydrogen content. Therefore, the elemental composition of tissue and bone, rather than the material or electron density, affects fast neutron dose. While the CC algorithm suffices for reproducible patient dosimetry in fast neutron therapy, adopting methods that consider tissue heterogeneity would enhance patient-specific neutron dose accuracy relative to national standards for other types of ionizing radiation. Corrections for tissue composition have a significant impact on absolute dose and the relative biological effectiveness (RBE) of neutron treatments compared to other radiation types (MV x-rays, protons, and carbon ions).

Comparison of radiation protection effects between epigallocatechin gallate and ascorbic acid

Ionizing radiation can originate from naturally occurring radiation sources on the earth or it can be from man-made sources. When interacting with cells and living organisms, ionizing radiation produces free radicals, impacting biological molecules such as proteins, lipids, and DNA in the cell nucleus and membrane, leading to cell death or causing cell mutations. Epigallocathecin gallate (EGCG) and ascorbic acid (AA) are well-known natural antioxidants that have been studied and applied as potential radical scavengers. In this study, the radiation protection effects in the presence of EGCG and AA via the scavenging process of free radicals (mainly hydroxyl radicals) were examined. Saccharomyces cerevisiae yeast cells were grown in YDP liquid medium containing yeast extract, peptone, and dextrose/glucose that supplemented with EGCG and AA at different concentrations. Then, the cell cultures were irradiated with both low (gamma) and high (helium ion beam) linear energy transfer (LET) radiations to evaluate the radiation effect on the survival of the yeast cell. Both of EGCG and AA play effectively important roles as radiation-protective agent for yeast cells and the effectiveness in radiation protection of EGCG and AA at the same concentration was almost the same between these two additives.

Equivalent Uniform Dose (EUD) and the Evaluation of Cell Survival in Spatially Fractionated Radiotherapy (SFRT)

SFRT has shown promise as a treatment modality to decrease normal tissue sparing without compromising tumor coverage, i.e., an increase in the therapeutic window compared to more conventional uniform radiation therapy (RT). The aim of this work is to examine and test several alternative bio-dosimetric parameters for the prediction of cell survival for normal-tissue and tumor cell lines irradiated in vitro with uniform and microbeam radiotherapy (MRT). A bespoke tungsten collimator with 50 parallel, 50 µm wide slits and 400 µm slit spacing was mounted into an x-ray cabinet. Human fibroblast (MRC5) and two human tumor cell lines (LN18 and A549) were irradiated with a range of doses (< 10 Gy) for uniform and MRT (50um slits, 400um center spacing) using kV X-rays. Average, mean and valley dose as useful predictive metrics of cell survival are compared to the equivalent uniform dose (EUD) with biological parameters estimated from uniform-dose experiments. We find that EUD, with linear-quadratic (LQ) model parameters, is more predictive for survival after SFRT than maximum, minimum or average dose. The maximum and average doses are correlated very poorly with in vitro cell survival. The difference in cell survival between uniform and MRT irradiation as a function of EUD is cell-type and dose dependent. The report results suggest that MRT is more effective at cell killing of tumor-cell lines than uniform irradiation for both tumor cell lines. However, MRT is less effective at killing normal tissue cells than uniform irradiation. EUD is a superior predictor of in vitro cell survival than other metrics sometimes used in the SFRT literature, including mean dose, maximum dose, and valley dose. The reported studies provide some evidence that SFRT may increase the therapeutic ratio by producing spatial dose distributions that effectively reduce normal-tissue damage with little or no change in biological damage to tumor cells. Additional studies are needed to further extend and generalize our results and to test our conclusions against a larger dose range, low and high linear energy transfer (LET) radiations and additional cell lines.

Adineta vaga under fire: simulating the impact of radiation

AbstractPrevious studies have demonstrated the remarkable resistance of bdelloid rotifers to ionizing radiation, making them an interesting model system for studying radiation effects on living organisms. In this study, we use simulations, instead of direct experimental exposures, to examine whether all bdelloids are affected equally by radiation exposure and to explore the relationship between biological data and energy deposition patterns induced by low and high linear energy transfer (LET) radiation. To this end, tool for particle simulation (TOPAS) a simulation tool, widely used in the field of medical physics and radiation therapy, was utilized. Using simulations for proton, iron ions, and X-ray exposure, our findings showed that all individuals, cells, and nuclei were effectively hit by the administered doses of 4 MeV protons, 0.5 GeV/n 56Fe, and X-ray radiation. The results support that the impact on survival and fertility rate measured in Adineta vaga is caused by radiation-induced damage rather than the absence of hits in certain individuals or germinal cells. Notably, simulations revealed significant differences between low- and high-LET radiation concerning irradiated individuals' nuclei. Specifically, for an equivalent dose, high-LET radiation requires fewer incident particles compared to low-LET radiation, resulting in a sparser distribution of radiation hits on the nucleus surface. In conclusion, the study supports the idea that reduced fertility described in high-LET exposed samples is associated with complex DNA damage caused by the condensed energy deposition pattern of high-LET radiation compared to low-LET.

Mechanistic insights from high resolution DNA damage analysis to understand mixed radiation exposure

Cells exposed to densely ionising high and scattered low linear energy transfer (LET) radiation (50 % dose of each) react more strongly than to the same dose of each separately. The relationship between DNA double strand break location inside the nucleus and chromatin structure was evaluated, using high-resolution transmission electron microscopy (TEM) in breast cancer MDA-MB-231 cells at 30 min post 5 Gy. Additionally, response to high and/or low LET radiation was assessed using single (1 ×1.5 Gy) versus fractionated dose delivery (5 ×0.3 Gy). By TEM analysis, the highest total number of γH2AX nanobeads were found in cells irradiated with alpha radiation just prior to gamma radiation (called mixed beam), followed by alpha, then gamma radiation. γH2AX foci induced by mixed beam radiation tended to be surrounded by open chromatin (lighter TEM regions), yet foci containing the highest number of beads, i.e. larger foci representing complex damage, remained in the heterochromatic areas. The γH2AX large focus area was also greater in mixed beam-treated cells when analysed by immunofluorescence. Fractionated mixed beams given daily induced the strongest reduction in cell viability and colony formation in MDA-MB-231 and osteosarcoma U2OS cells compared to the other radiation qualities, as well as versus acute exposure. This may partially be explained by recurring low LET oxidative DNA damage by every fraction together with a delay in recompaction of chromatin after high LET, demonstrated by low levels of heterochromatin marker H3K9me3 at 2 h after the last mixed beam fraction in MDA-MB-231. In conclusion, early differences in response to complex DNA damage may lead to a stronger cell kill induced by fractionated exposure, which suggest a therapeutic potential of combined high and low LET irradiation.

Comparative analysis of the molecular response characteristics in Platycodon grandiflorus irradiated with heavy ion beams and X-rays

The response of plants to radiation is an essential topic in both space plant cultivation and mutation breeding by radiation. In this study, heavy ion beams (HIB) generated by the ground accelerator and X-rays (XR) were used as models of high linear energy transfer (LET) and low LET radiation to study the molecular response mechanism of Platycodon grandiflorus (P. grandiflorus) seedlings after irradiation. The gene and protein expression profiles of P. grandiflorus after 15 Gy HIB and 20 Gy XR radiation were analyzed by transcriptome and proteome. The results showed that the number of differentially expressed genes (DEGs) induced by HIB radiation was less than that of XR group, but HIB radiation induced more differentially expressed proteins (DEPs). Both HIB and XR radiation activated genes of RNA silencing, double-strand break repair and cell catabolic process. DNA replication and cell cycle related genes were down-regulated. The genes of cell wall and external encapsulating structure were up-regulated after HIB radiation. The gene expression of protein folding and glucan biosynthesis increased after XR radiation. Protein enrichment analysis indicated that HIB radiation resulted in differential protein enriched in photosynthesis and secondary metabolite biosynthesis pathways, while XR radiation induced differential protein of glyoxylate and dicarboxylate metabolism and carbon metabolism. After HIB and XR radiation, the genes of antioxidant system and terpenoid and polyketide metabolic pathways presented different expression patterns. HIB radiation led to the enrichment of non-homologous end-joining pathway. The results will contribute to understanding the biological effects of plants under space radiation.

Atmosphere and dose effects on the SHI irradiation of atactic polystyrene

This article deals with Swift Heavy Ion (SHI) irradiation of atactic polystyrene at different doses, up to about 10 MGy, under an inert and oxidative atmosphere. The effect of the irradiation is analyzed using various tools such as high-resolution gas mass spectrometry, gel fraction, size exclusion chromatography, and Fourier Transform InfraRed spectroscopy. Previous research has shown that under SHI and in conditions of homogenous oxidation, two kinds of defects can be identified: those commonly observed under an oxidative atmosphere with low linear energy transfer irradiations (hydroperoxides and carbonyl bonds, for instance), and those evidenced under inert atmosphere (C=C bonds …). These latter defects are assigned to the heterogeneous structure of energy deposition with ion beams because of ion tracks' high ionization and excitation density. Polystyrene (PS) is known to be very radiation-resistant under inert atmosphere. Although degradation is increased under oxidative atmosphere, the oxidation remains very low compared to the one observed in polyethylene, even at doses as high as 10 MGy. The global low oxidation of PS under oxidative atmosphere is explained, as under inert atmosphere, by the presence of aromatic rings that confers efficient radiation resistence to the polymer.

DNA polymerase θ-mediated repair of high LET radiation-induced complex DNA double-strand breaks.

DNA polymerase θ (POLQ) is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). However, the biological significance of the TLS activity is currently unknown. Herein we provide evidence that the TLS activity of POLQ plays a critical role in repairing complex DNA double-strand breaks (DSBs) induced by high linear energy transfer (LET) radiation. Radiotherapy with high LET radiation such as carbon ions leads to more deleterious biological effects than corresponding doses of low LET radiation such as X-rays. High LET-induced DSBs are considered to be complex, carrying additional DNA damage such as AP site and Tg in close proximity to the DSB sites. However, it is not clearly understood how complex DSBs are processed in mammalian cells. We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation. At the biochemical level, POLQ was able to bypass an AP site and Tg during end-joining and was able to anneal two single-stranded DNA tails when DNA lesions were located outside the microhomology. This study offers evidence that POLQ is directly involved in the repair of complex DSBs.

Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses.

For advanced hepatocellular carcinoma (HCC), resistance to conservative treatments remains a challenge. In previous studies, the therapeutic effectiveness and DNA damage responses of boric acid-mediated boron neutron capture therapy (BA-BNCT) in HCC have been demonstrated in animal models and HCC cell line. On the other hand, numerous studies have shown that high linear energy transfer (LET) radiation can overcome tumor resistance. Since BNCT yields a mixture of high and low LET radiation, we aimed to explore whether and how BA-BNCT could eliminate radioresistant HCC cells. Radioresistant human HCC (HepG2-R) cells were established from HepG2 cells via intermittent irradiation. HepG2 and HepG2-R cells were then irradiated with either γ-ray or neutron radiation of BA-BNCT. Colony formation assays were used to assess cell survival and the relative biological effectiveness (RBE). The expression of phosphorylated H2AX (γH2AX) was also examined by immunocytochemistry and Western blot assays to evaluate the extent of DNA double-strand breaks (DSBs). Finally, the expression levels of DNA damage response-associated proteins were determined, followed by cell cycle analysis and caspase-3 activity analysis. Our data demonstrated that under the same dose by γ-ray, BNCT effectively eliminated radioresistant HCC by increasing the number of DNA DSBs (p < 0.05) and impeding their repair (p < 0.05), which verified the high RBE of BNCT. We also found that BNCT resulted in delayed homologous recombination (HR) and inhibited the nonhomologous end-joining (NHEJ) pathway during DNA repair. Markedly, BNCT increased cell arrest (p < 0.05) in the G2/M phase by altering G2 checkpoint signaling and increased PUMA-mediated apoptosis (p < 0.05). Our data suggest that DNA damage and repair responses could affect the anticancer efficiency of BNCT in radioresistant HepG2-R cells, which highlights the potential of BNCT as a viable treatment option for recurrent HCC.

Ionizing Radiation-Induced DNA Damage Response in Primary Melanocytes and Keratinocytes of Human Skin

Currently, our knowledge of how different cell types in a tissue microenvironment respond to low and high linear energy transfer (LET) radiation is highly restricted. In this study, a comparative analysis was performed on γ-ray-induced DNA damage and repair in primary human melanocytes and keratinocytes isolated from 3 donors. Our study demonstrates a modest interindividual variability in both melanocytes and keratinocytes in terms of both spontaneous and ionizing radiation (IR)-induced 53BP1 foci formation and persistence. Melanocytes, in general, showed a slightly elevated (1.66–2.79 folds more) 53BP1 foci induction relative to keratinocytes after exposure to different doses of γ-rays (0.1–2.5 Gy) radiation. To verify the influence of ATM kinase on IR-induced 53BP1 foci formation, melanocytes and keratinocytes were treated with a specific ATM kinase inhibitor (KU55993, 10 μM) for 1 h prior to radiation. ATM kinase inhibition resulted in the reduction of both spontaneous and IR-induced 53BP1 foci by 17–42% in both melanocytes and keratinocytes of all the 3 donors. Increased persistence of IR-induced 53BP1 foci number was observed in ATM-inhibited melanocytes and keratinocytes after different post exposure times (6 h and 24 h). Taken together, our study suggests that interindividual variations exist in the induction and repair of DNA double-strand breaks (DSBs) in melanocytes and keratinocytes and that ATM is crucial for an optimal DSB repair efficiency in both human skin cell types.

Comparison of the Medical Uses and Cellular Effects of High and Low Linear Energy Transfer Radiation.

Exposure to ionizing radiation can occur during medical treatments, from naturally occurring sources in the environment, or as the result of a nuclear accident or thermonuclear war. The severity of cellular damage from ionizing radiation exposure is dependent upon a number of factors including the absorbed radiation dose of the exposure (energy absorbed per unit mass of the exposure), dose rate, area and volume of tissue exposed, type of radiation (e.g., X-rays, high-energy gamma rays, protons, or neutrons) and linear energy transfer. While the dose, the dose rate, and dose distribution in tissue are aspects of a radiation exposure that can be varied experimentally or in medical treatments, the LET and eV are inherent characteristics of the type of radiation. High-LET radiation deposits a higher concentration of energy in a shorter distance when traversing tissue compared with low-LET radiation. The different biological effects of high and low LET with similar energies have been documented in vivo in animal models and in cultured cells. High-LET results in intense macromolecular damage and more cell death. Findings indicate that while both low- and high-LET radiation activate non-homologous end-joining DNA repair activity, efficient repair of high-LET radiation requires the homologous recombination repair pathway. Low- and high-LET radiation activate p53 transcription factor activity in most cells, but high LET activates NF-kB transcription factor at lower radiation doses than low-LET radiation. Here we review the development, uses, and current understanding of the cellular effects of low- and high-LET radiation exposure.

THE ROLE OF DNA DOUBLE-STRAND BREAK REPAIR THROUGH NON-HOMOLOGOUS END JOINING IN THE DOSE-RATE EFFECT IN TERMS OF CLONOGENIC ABILITY

Abstract It is generally and widely accepted that the biological effects of a given dose of ionizing radiation, especially those of low linear energy transfer radiations like X-ray and gamma ray, become smaller as the dose rate becomes lower. This phenomenon, known as ‘dose-rate effect (DRE),’ is considered due to the repair of sublethal damage during irradiation but the precise mechanisms for DRE have remained to be clarified. We recently showed that DRE in terms of clonogenic cell survival is diminished or even inversed in rodent cells lacking Ku, which is one of the essential factors in the repair of DNA double-strand breaks (DSBs) through non-homologous end joining (NHEJ). Here we review and discuss the involvement of NHEJ in DRE, which has potential implications in radiological protection and cancer therapeutics.

A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy – including photon and proton therapy – for the treatment of radioresistant tumors: the ETOILE trial

BackgroundSome cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy.MethodsThe ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas.In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France.The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted.To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study.DiscussionSo far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors.Trial registrationClinicalTrials.gov identifier: NCT02838602. Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects

Glioblastoma is a deadly cancer tumor in the brain and has a survival rate of about 15 months. Despite the high mortality rate, temozolomide has proven to increase the survival rate of patients when combined with radiotherapy. However, its effects may be limited because some patients develop therapeutic resistance. Curcumin has proven to be a cancer treatment due to its broad anticancer spectrum, high efficiency and low toxic level. Additionally, curcumin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, curcumin increased the cell population in the sub-G1 phase and the reactive oxygen species (ROS) level, ultimately increasing GBM cellular apoptosis. The radiosensitizing effects of curcumin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Curcumin plus neutron combination significantly inhibited cell invasion compared with that of single treatment or curcumin combined γ-ray treatment. Curcumin enhances the radiosensitivity of Glioblastoma (GBM), suggesting it may have clinical utility in combination cancer treatment with neutron high-LET radiation.

Optical and thermal luminescence efficiencies of BeO exposed to low-energy protons and carbon ions

Optically stimulated luminescence (OSL) and thermoluminescence (TL) are well-described phenomena utilized to measure the absorbed dose of crystalline materials. The techniques are used to monitor low linear energy transfer (LET) radiation (β, γ) as well as high-LET heavy charged particles (HCPs). Detector efficiency ƞdet, defined as the ratio of the luminescence per unit dose from a non-reference radiation field compared to the identical quantity from the reference field, is particle and energy dependent. The responses of BeO ceramics exposed to low-energy HCPs were investigated in this work. Dosimeters were bombarded with 1, 2, and 4 MeV protons, as well as 2 and 4 MeV carbon ions; these radiation qualities constitute a mean LET range of 37.6 keV/μm - 628 keV/μm and were realized using the 2 MV tandem Pelletron particle accelerator at East Carolina University. Each dosimeter was calibrated using a dose response constructed with a90Sr/90Y β source, which was calibrated against a137Cs γ source. This enabled ƞdet to be calculated. It was observed that optical and thermal signal shape and magnitude depend on the mean LET. Furthermore, thermal efficiencies are significantly higher than optical efficiencies for all ions investigated.

Particle radiotherapy and molecular therapies: mechanisms and strategies towards clinical applications.

Immunotherapy and targeted therapy are now commonly used in clinical trials in combination with radiotherapy for several cancers. While results are promising and encouraging, the molecular mechanisms of the interaction between the drugs and radiation remain largely unknown. This is especially important when switching from conventional photon therapy to particle therapy using protons or heavier ions. Different dose deposition patterns and molecular radiobiology can in fact modify the interaction with drugs and their effectiveness. We will show here that whilst the main molecular players are the same after low and high linear energy transfer radiation exposure, significant differences are observed in post-exposure signalling pathways that may lead to different effects of the drugs. We will also emphasise that the problem of the timing between drug administration and radiation and the fractionation regime are critical issues that need to be addressed urgently to achieve optimal results in combined treatments with particle therapy.

Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response.

Simple SummaryRadiation therapy can modulate anti-tumor immune responses. In this study, we investigated the relationship between the anti-tumor immune response and tumor fibrosis after X-ray or neutron radiation therapy. Neutron radiation therapy resulted in lesser fibrosis and greater anti-tumor immunity compared to X-ray irradiation. Radiation therapy-induced fibrotic changes within the tumor environment and tumor regrowth were suppressed by specifically deleting Trp53 in endothelial cells. In particular, the upregulation of PD-L1 expression after X-ray radiation therapy was significantly suppressed via EC-Trp53 deletion. Understanding the effects of different radiation therapy types on the tumor microenvironment provides strategies for enhancing the efficacy of combined radio- and immunotherapy. High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the radioresistance of tumors. However, this effect was attenuated in tumors of endothelial-specific Trp53-knockout mice. Herein, we report that compared to X-ray irradiation, neutron radiation therapy reduced collagen deposition and suppressed EndMT in tumors. In addition to the fewer fibrotic changes, more cluster of differentiation (CD8)-positive cytotoxic T cells were observed in neutron-irradiated regrowing tumors than in X-ray-irradiated tumors. Furthermore, lower programmed death-ligand 1 (PD-L1) expression was noted in the former. Endothelial-specific Trp53 deletion suppressed fibrotic changes within the tumor environment following both X-ray and neutron radiation therapy. In particular, the upregulation in PD-L1 expression after X-ray radiation therapy was significantly dampened. Our findings suggest that compared to low LET radiation therapy, high LET radiation therapy can efficiently suppress profibrotic changes and enhance the anti-tumor immune response, resulting in delayed tumor regrowth.