12C Ions Research Articles

Carbon - 12C ion radiation-induced cell death and molecular mechanisms in malignant cells: Evidence from in vivo and in vitro

Conventional radiotherapy has been revolutionized for several decades. Recently, the delivery of high linear energy transfer (LET) radiation such as heavy carbon ion therapy has gained more attention. Among all low-energy therapies such as photon, X-ray, and gamma radiation therapy, 12C heavy carbon ion therapy is the best therapy for cancer treatment due to its high relative biological effectiveness (RBE). It has been studied that many tumors show resistance to chemotherapy and low energy transfer radiation. The unique nature of high LET shows unique Bragg peaks where very little radiation are applied on the tumor cells and better results can be achieved. It effectively kills the tumor cells without affecting the normal cells. There are some limitations to conventional radiotherapy. Radiotherapy with the low LET group may not work properly. Carbon ion radiation (CIR) induces malignant cell death in different modes, such as apoptosis, senescence, autophagy, immunogenic cell death and necrosis. Heavy carbon ion therapy enhances cell death by altering different molecular signalling pathways such as p53, AKT, MEK, caspase and STAT–3. Investigation of the major molecular cell death by carbon ion irradiation is very essential to understand the modalities of heavy carbon ion induced cell death. In this context, the investigation of different signaling cascades may open new horizons in cancer treatment. The therapeutic efficacy and application of heavy carbon ion beams along with some molecular inhibitors, radio sensitizers, and gene therapy would be helpful for future cancer treatment. Therefore, a more thorough investigation in this field is needed. The current review article highlights the recent advances in cancer therapy research based on Carbon 12C Ion radiation-induced cell death.

NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia.

Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET) particle radiation might be effective in the treatment of hypoxic solid tumors, including NSCLC. Cellular hypoxia can activate nuclear factor κB (NF-κB), which can modulate radioresistance by influencing cancer cell survival. The effect of high-LET radiation on NF-κB activation in hypoxic NSCLC cells is unclear. Therefore, we compared the effect of low (X-rays)- and high (12C)-LET radiation on NF-κB responsive genes' upregulation, as well as its target cytokines' synthesis in normoxic and hypoxic A549 NSCLC cells. The cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h, followed by irradiation with 8 Gy X-rays or 12C ions, maintaining the oxygen conditions until fixation or lysis. Regulation of NF-κB responsive genes was evaluated by mRNA sequencing. Secretion of NF-κB target cytokines, IL-6 and IL-8, was quantified by ELISA. A greater fold change increase in expression of NF-κB target genes in A549 cells following exposure to 12C ions compared to X-rays was observed, regardless of oxygenation status. These genes regulate cell migration, cell cycle, and cell survival. A greater number of NF-κB target genes was activated under hypoxia, regardless of irradiation status. These genes regulate cell migration, survival, proliferation, and inflammation. X-ray exposure under hypoxia additionally upregulated NF-κB target genes modulating immunosurveillance and epithelial-mesenchymal transition (EMT). Increased IL-6 and IL-8 secretion under hypoxia confirmed NF-κB-mediated expression of pro-inflammatory genes. Therefore, radiotherapy, particularly with X-rays, may increase tumor invasiveness in surviving hypoxic A549 cells.

Fabrication and characterization of TeO2–Na2O–BaO glass doped with Yb2O3 for optical and particulate-radiation shielding applications: Role of Bi2O3/WO3

In this research, transparent 64TeO2–15Na2O–5BaO-(10-x)Bi2O3-(x+5)WO3-1Yb2O3 glasses were prepared and analysed for their optical, structural, and radiation protection potentials. Samples of the novel glasses were produced in the laboratory, starting with the melting-quenching process. The glasses were characterised using standard laboratory procedures and dedicated software. The influence of replacing WO3 with Bi2O3 on the investigated properties was highlighted. The values of the glass density increase from 5.42 g/cm3 to 5.67 g/cm3 as the bismuth oxide concentration increases from 0 to 10 mol%. XRD spectrograms of the glass samples reveal that they have an amorphous structure. The glasses had high optical transparency, which was reduced when WO3 was replaced by Bi. The photoluminescence decay showed that the luminescence lifetime of Yb3+ decreases with increasing bismuth concentration. For electrons, the mass stopping powers (Sp) were within 1.253–8.918 MeV cm2/g, 1.241–8.721 MeV cm2/g, and 1.232–8.549 MeV cm2/g for samples containing 0, 5, and 10 mol% of Bi2O3. Generally, Sp of electrons, protons, alpha particles, and 12C ions were in the order, (Sp)TWBi−0>(Sp)TWBi−5>(Sp)TWBi−10. Increasing the concentration of Bi atomic density in the glasses improved the total interaction probability of thermal neutrons but reduced the ability of the glasses to moderate fast neutrons.

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.

Changes in molecular conformation and electronic structure of DNA under 12C ions based on first-principles calculations

Fundamental studies on the interaction between ionizing radiation and deoxyribonucleic acid (DNA) can contribute to understanding the biological effects of radiation protection and radiotherapy. The transitional process from ionized and excited DNA to DNA lesions, such as strand breaks and base lesions, remains uncertain. In this study, we focused in particular on the direct effects of radiation on DNA and calculated the number of ionizations induced within 10 base pairs of DNA using the Particle and Heavy Ion Transport code System, a general-purpose Monte Carlo code for radiation transport. The electronic structure of the ionized DNA is subsequently calculated using the first-principles calculation software OpenMX. Through these calculations, we successfully identified the redox site of DNA and quantitatively evaluated the amount of molecular bond cleavage. The scientific findings of this study will elucidate the cleavage mechanism of DNA in the high-density radiation field realized by ion beam irradiation by determining the redox sites.

Using SRIM code for calculating Bragg curve, projected range, straggling of 12C ion in biological materials

‘The Stopping and Range of Ions in Matter’ SRIM program, utilizing the built-in compound directory has been used to compute Bragg curve, projected range, longitudinal, lateral straggle of 12C ion with energies of 1 − 150 MeV in biological matter: liquid water (benchmark) human blood, skin, thyroid, and spleen are assessed. Results show that in the studied biological media for higher energy beam i): noticeable modification are seen in Bragg peak, shift in peak-position; ii) maximum projected range: 595.2 μm suggests effective use of 12C ions for cancer tumor therapy, especially for superficial cancer tumors, without much damage to healthier cells; iii) longitudinal straggling ~ 22.6 μm, low lateral straggling ~ 4.7 μm suggests potential application of 12C ions in treating cancer tumor nearby critical organs, causing minimal damage in nearby normal tissues.

Biological Response of Chinese Hamster B14-150 Cells to Sequential Combined Exposure to Protons and 12C Ions.

Proton and ion radiation therapy, when used both as single radiation and in mixed radiation mode, have a number of advantages over the conventional γ-therapy that are determined by physical characteristics of accelerated particles. The paper presents the results of an in vitro study of the effectiveness of sequential exposures of Chinese hamster tumor cells B14-150 to proton (p) and 12C ion beams. We used 4 irradiation schemes differing by the sequence of exposure and the contribution of each radiation to the total dose. Synergism was shown for 12C ions dose contribution of 45% (taking into account the coefficient of relative biological efficiency) and the sequence 12C→p.

Effect of ion-induced secondary radiations on the formation of extended defects and radiolysis beyond the range of swift 12C, 50Ti, and 52Cr ions in LiF

The objective of this research is to study the role of ion-induced secondary radiations on structural damage in LiF crystals irradiated with ∼ 10 MeV/u energy 12C, 50Ti, and 52Cr ions using experimental methods of nanoindentation, Atomic Force Microscopy, optical absorption, depth-resolved photoluminescence and chemical etching. In LiF crystals irradiated at room temperature with 50Ti and 52Cr ions, the chemical etching method revealed formation of nano-sized colloids in a wide area (up to one mm) beyond the ion penetration depth. Annealing experiments on irradiated samples at temperatures above 620 K, show enhanced manifestations of radiolysis in ion-irradiated and beyond-range areas accompanied by the emission of radiolysis residues. The multicomponent secondary radiation following the ion-induced inelastic nuclear reactions is discussed as the plausible mechanism of the observed long-range damage.

The effect of fitting the reference photon dose-response on the clonogenic survival predicted with the Mayo Clinic Florida microdosimetric kinetic model in case of accelerated ions.

The Mayo Clinic Florida microdosimetric kinetic model (MCF MKM) is a recently developed clonogenic survival model. Since the MCF MKM relies on novel strategies to a priori determine the cell-specific model parameters, the only experiment-specific input values are the α and ß terms of the linear-quadratic model (LQM) of clonogenic survival for the reference photon exposure. Because the two LQM terms are anti-correlated, the fitting process of the reference photon survival curve was found to significantly influence the MCF MKM calculations. This article reports this effect for two clinically relevant cell lines (human brain glioblastoma A-172, human healthy foreskin fibroblasts AG01522) and ions (1H and 12C ions).

Tumour status prediction by means of carbon-ion beam irradiation: comparison of washout rates between in-beam PET and DCE-MRI in rats

Objective. Tumour response to radiation therapy appears as changes in tumour vascular condition. There are several methods for analysing tumour blood circulatory changes one of which is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), but there is no method that can observe the tumour vascular condition and physiological changes at the site of radiation therapy. Positron emission tomography (PET) has been applied for treatment verification in charged particle therapy, which is based on the detection of positron emitters produced through nuclear fragmentation reactions in a patient’s body. However, the produced positron emitters are washed out biologically depending on the tumour vascular condition. This means that measuring the biological washout rate may allow evaluation of the tumour radiation response, in a similar manner to DCE-MRI. Therefore, this study compared the washout rates in rats between in-beam PET during 12C ion beam irradiation and DCE-MRI. Approach. Different vascular conditions of the tumour model were prepared for six nude rats. The tumour of each nude rat was irradiated by a 12C ion beam with simultaneous in-beam PET measurement. In 10–12 h, the DCE-MRI experiment was performed for the same six nude rats. The biological washout rate of the produced positron emitters (k 2,1st) and the MRI contrast agent (k 2a) were derived using the single tissue compartment model. Main results. A linear correlation was observed between k 2,1st and k 2a, and they were inversely related to fractional necrotic volume. Significance. This is the first animal study which confirmed the biological washout rate of in-beam PET correlates closely with tumour vascular condition measured with the MRI contrast agent administrated intravenously.

Relative efficiency of radiophotoluminescent glass detectors in low energy ion beams

In heavy charged particle dosimetry, the luminescence efficiency strongly depends on linear energy transfer (LET) and characterization of the detectors' efficiency as a function of the particle LET is very important. Available literature data for the efficiency of radiophotoluminescent (RPL) glass detectors are scarce and especially for low energy range no data was found. In this study, detectors made of the most widely known RPL material (silver activated phosphate glass) were exposed to various low energy ion beams (1H, 7Li, and 12C). For every ion beam, the linear dose (fluence) response of the RPL glass detectors was confirmed for the investigated dose (fluence) range and the RPL efficiency relative to 60Co gamma rays was evaluated. The relative efficiency decreased as LET increased but not as a unique function of LET, where the relative efficiency (expressed for doses in RPL glass) decreased from 0.85 ± 0.06 for the 5 MeV 1H ion beam (LETw = 8.1 keV/μm) to 0.017 ± 0.001 for the 15 MeV 12C ion beam (LETw = 673.8 keV/μm). More experimental data are still needed but results obtained in this study may motivate the application and testing of microdosimetric models for RPL glass detectors.

Unraveling astrocyte behavior in the space brain: Radiation response of primary astrocytes.

Exposure to space conditions during crewed long-term exploration missions can cause several health risks for astronauts. Space radiation, isolation and microgravity are major limiting factors. The role of astrocytes in cognitive disturbances by space radiation is unknown. Astrocytes' response toward low linear energy transfer (LET) X-rays and high-LET carbon (12C) and iron (56Fe) ions was compared to reveal possible effects of space-relevant high-LET radiation. Since astronauts are exposed to ionizing radiation and microgravity during space missions, the effect of simulated microgravity on DNA damage induction and repair was investigated. Primary murine cortical astrocytes were irradiated with different doses of X-rays, 12C and 56Fe ions at the heavy ion accelerator GSI. DNA damage and repair (γH2AX, 53BP1), cell proliferation (Ki-67), astrocytes' reactivity (GFAP) and NF-κB pathway activation (p65) were analyzed by immunofluorescence microscopy. Cell cycle progression was investigated by flow cytometry of DNA content. Gene expression changes after exposure to X- rays were investigated by mRNA-sequencing. RT-qPCR for several genes of interest was performed with RNA from X-rays- and heavy-ion-irradiated astrocytes: Cdkn1a, Cdkn2a, Gfap, Tnf, Il1β, Il6, and Tgfβ1. Levels of the pro inflammatory cytokine IL-6 were determined using ELISA. DNA damage response was investigated after exposure to X-rays followed by incubation on a 2D clinostat to simulate the conditions of microgravity. Astrocytes showed distinct responses toward the three different radiation qualities. Induction of radiation-induced DNA double strand breaks (DSBs) and the respective repair was dose-, LET- and time-dependent. Simulated microgravity had no significant influence on DNA DSB repair. Proliferation and cell cycle progression was not affected by radiation qualities examined in this study. Astrocytes expressed IL-6 and GFAP with constitutive NF-κB activity independent of radiation exposure. mRNA sequencing of X-irradiated astrocytes revealed downregulation of 66 genes involved in DNA damage response and repair, mitosis, proliferation and cell cycle regulation. In conclusion, primary murine astrocytes are DNA repair proficient irrespective of radiation quality. Only minor gene expression changes were observed after X-ray exposure and reactivity was not induced. Co-culture of astrocytes with microglial cells, brain organoids or organotypic brain slice culture experiments might reveal whether astrocytes show a more pronounced radiation response in more complex network architectures in the presence of other neuronal cell types.

Study of the radioprotective properties of fumaric acid and 3-hydroxypyridine fumarate under the action of ionizing radiation on human cells

In the modern world, such a situation has developed that the development of nuclear energy and the use of sources of ionizing radiation in various fields of activity have created a potential threat of radiation hazard to humans. In this connection, the actual direction is the study of ways to increase the radioresistance of human cells and tissues to the action of ionizing radiation. In addition, radioprotective compounds are also important in radiotherapy, since normal tissues of patients must be protected from radiation damage when using high doses of radiation in the treatment of malignant neoplasms. However, the radioprotectors currently used have some disadvantages. The aim of this work is to study the radioprotective properties of fumaric acid and 3-hydroxypyridine fumarate under the action of gamma radiation and radiation of 12C ions on tumor (SK-N-BE neuroblastoma) and normal (hTERT fibroblasts) human cells. The effect of radiation was evaluated according to the criteria of cell survival in culture, doubling time and clonogenic activity. It has been shown that the use of fumaric acid and 3-hydroxypyridine fumarate has a radioprotective effect on normal and tumor cells when they are irradiated with gamma radiation at doses of 1, 4, 6 and 10 Gy. The use of fumaric acid and 3-hydroxypyridine fumarate does not have a radioprotective effect on tumor cells when they are irradiated with 12C ions. A comparative analysis of the results of the action of the preparations with gamma rays and 12C ions showed a significant dependence of the manifestation of modifying properties on the quality of radiation. The study of cell doubling time showed that the presence of drugs in the control did not increase this indicator. On the contrary, under the action of gamma radiation at a dose of 10 Gy, the preparations reduced the doubling time of fibroblasts by more than two times and the doubling time of neuroblastoma cells by almost 1.5 times. The data obtained indicate that the antioxidant properties of the studied preparations open up new possibilities for modifying the action of ionizing radiation in the treatment of oncological diseases. The use of fumaric acid and 3-hydroxypyridine fumarate will reduce the radiation load on healthy cells, including reducing the effect of secondary products on healthy cells beyond the Bragg peak under the action of carbon ion therapy.

Neurobiological Effects of Combined Exposure to Antiorthostatic Suspension, Quasi-Chronic Gamma Irradiation and Heavy Ion Irradiation in Rats

We have researched neurobiological effects of physical impacts, modeling conditions of interplanetary space flight: microgravity (modeled by AntiOrthostatic Suspension, AOS) and deep space radiation (modeled by quasi-chronic gamma irradiation and head irradiation by 12C ions) taking into account typological characteristics of high nervous activity (HNA) of model animals (Long Evans male rats). Behavioral changes, as well as EEG and neurochemical changes in key brain areas are investigated. We have shown difference between control and exposed animals, as well as between animals of different HNA typologies (more or less excitable), in motoric and research activity aside as in cognitive abilities. Such difference is driven by shift in balance in main inhibition and exctitation-related neurotransmitters, GABA and GLU and dopaminergic system. In particular, more excitable rats learn faster but are more vulnerable to mentioned model impacts. As a clear sign of HNA distortion we also found some changes in EEG waves.

Measurement of thick target neutron yield from 80.5 MeV/u 12C incidence on Be, C, W, and Pb targets

Thick target neutron yield produced from 80.5 MeV/u 12C ions stopping in the thick Be, C, W, and Pb targets were measured at 0°, 37°, 60° using liquid scintillation detector and the time of flight method. The experimental data were compared with those calculations using the Liege IntraNuclear-Cascade (INCL) implemented in Geant4 and the JAERI Quantum Molecular Dynamics 2.0 (JQMD-2.0) model followed by the Generalized Evaporation Model (GEM) implemented in PHITS, and default model implemented in FLUKA. The results of the three simulation codes with different physics models are similar for beryllium and carbon targets and in good agreement with the experimental data. For tungsten and lead targets, the calculation results from PHITS and FLUKA successfully reproduced the neutron spectra. While the results from GEANT4 overestimate the experimental data above 50 MeV at 0° and significantly underestimated experimental data in the 15–60 MeV energy range at 0°, 37° and 60°. In general, the simulation results of PHITS with the JQMD-2.0 physical model are in good agreement with the experimental data for all targets.

Clonogenic Survival RBE Calculations in Carbon Ion Therapy: The Importance of the Absolute Values of α and β in the Photon Dose-Response Curve and a Strategy to Mitigate Their Anticorrelation

The computation of the relative biological effectiveness (RBE) is a fundamental step in the planning of cancer radiotherapy treatments with accelerated ions. Numerical parameters derived analyzing the dose response of the chosen cell line after irradiation to photons (i.e., α and β, namely the linear and quadratic terms of the linear-quadratic model of cell survival) are generally used as input to biophysical models to predict the ion RBE. The α/β ratio for the photon exposure is generally regarded as an indicator of cell radiosensitivity. However, previous studies suggest that α/β might not be a sufficient parameter to model the RBE of relatively high linear energy transfer (LET) radiation such as carbon ions. For a fixed α/β, the effect of the absolute values of α and β on the computed RBE is underexplored. Furthermore, since α and β are anticorrelated during the fit of the photon-exposed in vitro survival data, different linear-quadratic fits could produce different sets of α and β, thus affecting the RBE calculations. This article reports the combined effect of the α/β ratio and the absolute values α and β on the RBE computed with the Mayo Clinic Florida microdosimetric kinetic model (MCF MKM) for 12C ions of different LET. Furthermore, we introduce a theory-based strategy to potentially mitigate the anticorrelation between α and β during the fit of the photon dose-response biological data.

Monte Carlo-Based Radiobiological Investigation of the Most Optimal Ion Beam Forming SOBP for Particle Therapy.

Proton (p) and carbon (C) ion beams are in clinical use for cancer treatment, although other particles such as He, Be, and B ions have more recently gained attention. Identification of the most optimal ion beam for radiotherapy is a challenging task involving, among others, radiobiological characterization of a beam, which is depth-, energy-, and cell type- dependent. This study uses the FLUKA and MCDS Monte Carlo codes in order to estimate the relative biological effectiveness (RBE) for several ions of potential clinical interest such as p, 4He, 7Li, 10Be, 10B, and 12C forming a spread-out Bragg peak (SOBP). More specifically, an energy spectrum of the projectiles corresponding to a 5-cm SOBP at a depth of 8 cm was used. All secondary particles produced by the projectiles were considered and RBE was determined based on radiation-induced Double Strand Breaks (DSBs), as calculated by MCDS. In an attempt to identify the most optimal ion beam, using the latter data, biological optimization was performed and the obtained depth-dose distributions were inter-compared. The results showed that 12C ions are more effective inside the SOBP region, which comes at the expense of higher dose values at the tail (i.e., after the SOBP). In contrast, p beams exhibit a higher DSOPB/DEntrance ratio, if physical doses are considered. By performing a biological optimization in order to obtain a homogeneous biological dose (i.e., dose × RBE) in the SOBP, the corresponding advantages of p and 12C ions are moderated. 7Li ions conveniently combine a considerably lower dose tail and a DSOPB/DEntrance ratio similar to 12C. This work contributes towards identification of the most optimal ion beam for cancer therapy. The overall results of this work suggest that 7Li ions are of potential interest, although more studies are needed to demonstrate the relevant advantages. Future work will focus on studying more complex beam configurations.

Precision of the PET activity range during irradiation with 10C, 11C, and 12C beams

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable 12C ions, the positron emitters 10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam. Approach. An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner. Main results. High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes 11C and 10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107 ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for 10C, 11C and 12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from 11C to 10C than when going from 12C to 11C. The much better precision for 10C is due to its much shorter half-life, which, contrary to the case of 11C, also enables to include the in-spill data in the image formation. Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.

МОДЕЛИРОВАНИЕ РЕПАРАЦИИ ПОВРЕЖДЕНИЙ ДНК, ИНДУЦИРОВАННЫХ ТЯЖЕЛЫМИ ИОНАМИ В КЛЕТКАХ МЛЕКОПИТАЮЩИХ

In this paper the mathematical description of main DNA repair pathways of single-strand break (SSB), base damage (BD), and double-strand break (DSB) in mammalian and human cells are proposed. The model shows key molecular mechanisms of DNA recovery through the single-strand DNA repair, base excision repair (BER), nonhomologous end-joining (NHEJ). To formalize the molecular mechanisms the dynamic system of differential equations describing the chemical kinetics of protein interactions according the modern concepts of molecular biology is constructed. Taking into account three repair pathways it makes possible to describe the cell's response to heavy charged particles influence. The proposed model is validated for main mechanisms of SSB repair, BER, NHEJ. In the course of the work, the time-dependent dynamics of formations and repairs of key DNA damage types (BD, SSB, DSB, cluster damages) in human cells under 56Fe ions (E = 600 Mev/u) exposure are calculated. A comparative analysis of the DNA damages and theirs repair under 12C (E = 270 MeV/u) and 56Fe (E = 600 Mev/u) ions exposure at 1 Gy was carried out.

An inception network for positron emission tomography based dose estimation in carbon ion therapy

Objective. We aim to evaluate a method for estimating 1D physical dose deposition profiles in carbon ion therapy via analysis of dynamic PET images using a deep residual learning convolutional neural network (CNN). The method is validated using Monte Carlo simulations of 12C ion spread-out Bragg peak (SOBP) profiles, and demonstrated with an experimental PET image. Approach. A set of dose deposition and positron annihilation profiles for monoenergetic 12C ion pencil beams in PMMA are first generated using Monte Carlo simulations. From these, a set of random polyenergetic dose and positron annihilation profiles are synthesised and used to train the CNN. Performance is evaluated by generating a second set of simulated 12C ion SOBP profiles (one 116 mm SOBP profile and ten 60 mm SOBP profiles), and using the trained neural network to estimate the dose profile deposited by each beam and the position of the distal edge of the SOBP. Next, the same methods are used to evaluate the network using an experimental PET image, obtained after irradiating a PMMA phantom with a 12C ion beam at QST’s Heavy Ion Medical Accelerator in Chiba facility in Chiba, Japan. The performance of the CNN is compared to that of a recently published iterative technique using the same simulated and experimental 12C SOBP profiles. Main results. The CNN estimated the simulated dose profiles with a mean relative error (MRE) of 0.7% ± 1.0% and the distal edge position with an accuracy of 0.1 mm ± 0.2 mm, and estimate the dose delivered by the experimental 12C ion beam with a MRE of 3.7%, and the distal edge with an accuracy of 1.7 mm. Significance. The CNN was able to produce estimates of the dose distribution with comparable or improved accuracy and computational efficiency compared to the iterative method and other similar PET-based direct dose quantification techniques.