High Linear Energy Transfer Particles Research Articles

10255-BOT-5 EXOSOMAL MIRNAS RELEASED FROM GLIOBLASTOMA CELLS AFTER BNCT TARGET CELL PROLIFERATION AND SURVIVAL SIGNALS

Abstract Boron neutron capture therapy (BNCT) is a tumor -selective particle radiation therapy. In BNCT, p-boronophenyl alanine, which is actively taken up by tumor cells through LAT1 transporter, a member of the system L family of heterodimeric, sodium-independent, amino acid transporters, is administrated to patients, and thermal or epithermal neutron is irradiated to tumor tissue of the patients. Nuclear capture and fission reactions between boron-10 and thermal neutron occurred only in tumor cells produce high- linear energy transfer (LET) alpha particles and recoiling lithium-7 (7Li). These high LET particles have very short pathlength (5-9 μmeter), and kill boron-10 containing tumor cells sparing adjacent normal tissue cells. BNCT was applied to malignant glioma, the most devastating tumor and has prolonged the survival of malignant glioma patients. In this study, we comprehensively investigated the micro RNAs (miRNAs) in exosomes derived from BNCT-treated glioblastoma U87 MG cells using microarray. Comparing with non-treated cells, more than 300 up-regulated miRNAs or 100 down-regulated miRNAs were detected in BNCT-treated cells. From the results of the prediction analysis of the target genes which interact with the miRNAs, the pathway analysis was performed. We found significantly associated pathways, such as Focal adhesion-PI3K-Akt-mTOR, Ras, MAPK, etc. miRNAs in exosomes released from BNCT-treated glioblastoma cells may suppress such essential pathways for cell proliferation and survival.

Alpha‐emitters and targeted alpha therapy in cancer treatment

AbstractAlpha emitters are radionuclides with good pharmacological characteristics for the treatment of cancer because they decay by emitting high linear energy transfer particles. Recent advancements in isotope production and purification and the generation of novel techniques for optimum targeting have led to the development of targeted alpha therapy (TAT). The great cytotoxic potential of α‐particle emissions combined with monoclonal antibodies, peptides, small compounds, or nanoparticles has led to investigations of TAT in the pre‐clinical context and more recently, in oncology clinical trials. Numerous studies have shown that TAT is effective both in vitro and in vivo. The first α‐emitter to obtain FDA approval for the treatment of prostate cancer with metastatic bone lesions was radium‐223 dichloride. Many clinical trials are being conducted to evaluate the efficiency and safety of several radionuclides in cancer treatment, including radium‐223, astatine‐211, actinium‐225, bismuth‐213, lead‐212, and thorium‐227. This review provides an overview of the therapeutic use of these radionuclides and a summary of the studies that lay the groundwork for future clinical advancement.

A Review of Boron Neutron Capture Therapy: Its History and Current Challenges.

Mechanism of ActionExternal beam, whether with photons or particles, remains as the most common type of radiation therapy. The main drawback is that radiation deposits dose in healthy tissue before reaching its target. Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when 10B is irradiated with low-energy (0.0025 eV) thermal neutrons. The resulting 10B(n,α)7Li capture reaction produces high linear energy transfer (LET) α particles, helium nuclei (4He), and recoiling lithium-7 (7Li) atoms. The short range (5-9 μm) of the α particles limits the destructive effects within the boron-containing cells. In theory, BNCT can selectively destroy malignant cells while sparing adjacent normal tissue at the cellular levels by delivering a single fraction of radiation with high LET particles.HistoryBNCT has been around for many decades. Early studies were promising for patients with malignant brain tumors, recurrent tumors of the head and neck, and cutaneous melanomas; however, there were certain limitations to its widespread adoption and use.Current Limitations and ProspectsRecently, BNCT re-emerged owing to several developments: (1) small footprint accelerator-based neutron sources; (2) high specificity third-generation boron carriers based on monoclonal antibodies, nanoparticles, among others; and (3) treatment planning software and patient positioning devices that optimize treatment delivery and consistency.

Carbon ion radiation and clustered DNA double-strand breaks.

A carbon ion categorized as a heavy ion particle has been used for cancer radiotherapy. High linear energy transfer (LET) carbon ion irradiation deposits energy at a high density along a particle track, generating multiple types of DNA damage. Complex DNA lesions, comprising DNA double-strand breaks (DSBs), single-strand breaks, and base damage within 1-2 helical turns (<3-4nm), are thought to be difficult to repair and critically influence cell viability. In addition to the effect of lesion complexity, the most recent studies have demonstrated another characteristic of high LET particle radiation-induced DNA damage, clustered DSBs. Clustered DSBs are defined as the formation of multiple DSBs in close proximity where the scale of clustering is approximately 1-2μm3, i.e., the scale of the event is estimated to be > ∼1Mbp. This chapter reviews the hallmarks of clustered DSBs and how such DNA damage influences genome instability and cell viability in the context of high LET carbon ion radiotherapy.

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts.

Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.

Molecular Mechanisms of Specific Cellular DNA Damage Response and Repair Induced by the Mixed Radiation Field During Boron Neutron Capture Therapy.

The impact of a mixed neutron-gamma beam on the activation of DNA damage response (DDR) proteins and non-coding RNAs (ncRNAs) is poorly understood. Ionizing radiation is characterized by its biological effectiveness and is related to linear energy transfer (LET). Neutron-gamma mixed beam used in boron neutron capture therapy (BNCT) can induce another type of DNA damage such as clustered DNA or multiple damaged sites, as indicated for high LET particles, such as alpha particles, carbon ions, and protons. We speculate that after exposure to a mixed radiation field, the repair capacity might reduce, leading to unrepaired complex DNA damage for a long period and may promote genome instability and cell death. This review will focus on the poorly studied impact of neutron-gamma mixed beams with an emphasis on DNA damage and molecular mechanisms of repair. In case of BNCT, it is not clear which repair pathway is involved, and recent experimental work will be presented. Further understanding of BNCT-induced DDR mechanisms may lead to improved therapeutic efficiency against different tumors.

Harm of high LET radiation to the lens of the human eye

The biological effects of ionising radiation vary according to its linear energy transfer (LET) density, with higher LET radiation having stronger biological effects than lower LET radiation at the same absorbed dose. Though we have done more research in the area of radiation effects on the ocular lens, we know little about the effects of high LET on the ocular lens. This article briefly describes the historical changes in the dose limits of the human ocular lens, investigates the epidemiology of high LET radiation eye lens, summarizes various biological experiments of high LET particles, and briefly analyzes the reasons for the high prevalence of cataracts in the plateau. It also discusses the factors that need to be considered in the future research on high LET, aiming to provide valuable information for the future research of high LET eye lens in China. 摘要： 眼晶状体是人体对辐射最敏感的组织之一, 电离辐射的生物效应因其传能线密度 (linear energy transfer, LET) 的不同而不同, 同等吸收剂量条件下, 高 LET 辐射生物效应比低 LET 辐射更强, 尽管目前辐射对眼晶状体的影响这一 领域己经有了较多研宄, 但对于高 LET 对眼晶状体的影响知之甚少。本文简述人眼晶状体剂量限值的历史变化情况, 综述各种高 LET 粒子的生物学实验, 调查高 LET 辐射眼晶状体的流行病学, 简要分析高原白内障高患病率的原因, 并 初步讨论未来研宄高 LET 需要考虑的因素, 旨在为国内今后开展高 LET 辐射对人眼晶状体的研宄提供有价值的信息。

Relative Biological Effectiveness of High LET Particles on the Reproductive System and Fetal Development.

During a space mission, astronauts are inevitably exposed to space radiation, mainly composed of the particles having high values of linear energy transfer (LET), such as protons, helium nuclei, and other heavier ions. Those high-LET particles could induce severer health damages than low-LET particles such as photons and electrons. While it is known that the biological effectiveness of a specified type of radiation depends on the distribution of dose in time, type of the cell, and the biological endpoint in respect, there are still large uncertainties regarding the effects of high-LET particles on the reproductive system, gamete, embryo, and fetal development because of the limitation of relevant data from epidemiological and experimental studies. To safely achieve the planned deep space missions to the moon and Mars that would involve young astronauts having reproductive functions, it is crucial to know exactly the relevant radiological effects, such as infertility of the parent and various diseases of the child, and then to conduct proper countermeasures. Thus, in this review, the authors present currently available information regarding the relative biological effectiveness (RBE) of high-LET particles on the deterministic effects related to the reproductive system and embryonic/fetal development for further discussions about the safety of being pregnant after or during a long-term interplanetary mission.

Soft X-ray Radiation and Monte Carlo Simulations: Good Tools to Describe the Radiation Chemistry of Sub-keV Electrons.

The description of the biological effects of ionizing radiation requires a good knowledge of the dose deposition processes at both the cellular and molecular scales. However, experimental studies on the energy deposition specificity of sub-keV electrons, produced by most radiations, including high-energy photons and heavy ions, are scarce. Soft X-rays (0.2-2 keV) are here used to probe the physical and physico-chemical events occurring upon exposure of liquid water to sub-keV electrons. Liquid water samples were irradiated with a monochromatic photon beam at the SOLEIL synchrotron. Hydroxyl radical quantification was conducted through HO• scavenging using benzoate to form fluorescent hydroxybenzoate. The yields of HO• radicals exhibit a minimum around 1.5 keV, in good agreement with indirect observation. Moreover, they are relatively independent of the benzoate concentration in the range investigated, which corresponds to scavenging times of 170 ns to 170 ps. These results provide evidence that sub-keV electrons behave as high linear energy transfer particles, since they are able to deposit tens to hundreds of electronvolts in nanometric volumes.

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids.

Radiation-induced normal tissue toxicity often limits the curative treatment of cancer. Moreover, normal tissue relative biological effectiveness data for high-linear energy transfer particles are urgently needed. We propose a strategy based on transcriptome analysis of patient-derived human intestinal organoids (HIO) to determine molecular surrogates for radioresponse of gastrointestinal (GI) organs at risk in a personalized manner. HIO were generated from induced pluripotent stem cells (iPSC), which were derived from skin biopsies of three patients, including two patients with FANCA deficiency as a paradigm for enhanced radiosensitivity. For the two Fanconi anemia (FA) patients (HIO-104 and 106, previously published as FA-A#1 IND-iPS1 and FA-A#2 IND-iPS3), FANCA expression was reconstituted as a prerequisite for generation of HIO via lentiviral expression of a doxycycline inducible construct. For radiosensitivity analysis, FANCA deficient and FANCA rescued as well as wtHIO were sham treated or irradiated with 4Gy photon, proton or carbon ions at HIT, respectively. Immunofluorescence staining of HIO for 53BP1-foci was performed 1 h post IR and gene expression analyses was performed 12 and 48 h post IR. 53BP1-foci numbers and size correlated with the higher RBE of carbon ions. A FANCA dependent differential gene expression in response to radiation was found (p < 0.01, ANOVA; n = 1071 12 h; n = 1100 48 h). Pathways associated with FA and DNA-damage repair i.e., transcriptional coupled nucleotide excision repair, homology-directed repair and translational synthesis were found to be differentially regulated in FANCA deficient HIO. Next, differential regulated genes were investigated as a function of radiation quality (RQ, p < 0.05, ANOVA; n = 742 12 h; n = 553 48 h). Interestingly, a gradual increase or decrease of gene expression was found to correlate with the three main qualities, from photon to proton and carbon irradiation. Clustering separated high-linear energy transfer irradiation with carbons from proton and photon irradiation. Genes associated with dual incision steps of TC-NER were differentially regulated in photon vs. proton and carbon irradiation. Consequently, SUMO3, ALC1, POLE4, PCBP4, MUTYH expression correlated with the higher RBE of carbon ions. An interaction between the two studied parameters FA and RQ was identified (p < 0.01, 2-way ANOVA n = 476). A comparison of genes regulated as a function of FA, RQ and RBE suggest a role for p53 interacting genes BRD7, EWSR1, FBXO11, FBXW8, HMGB1, MAGED2, PCBP4, and RPS27 as modulators of FA in response to radiation. This proof of concept study demonstrates that patient tailored evaluation of GI response to radiation is feasible via generation of HIO and comparative transcriptome profiling. This methodology can now be further explored for a personalized assessment of GI radiosensitivity and RBE estimation.

Concepts and terms for dose/volume parameters in carbon-ion radiotherapy: Conclusions of the ULICE taskforce

PurposeThe Union of Light Ion Centers in Europe (ULICE) program addressed the need for uniting scientific results for carbon-ion radiation therapy obtained by several institutions worldwide in different fields of excellence, and translating them into a real benefit to the community. Particularly, the concepts for dose/volume parameters developed in photon radiotherapy cannot be extrapolated to high linear energy transfer particles. Methods and MaterialsThe ULICE-WP2 taskforce included radiation oncologists involved in carbon-ion radiation therapy and International Commission on Radiation Units and Measurements, radiation biologists, expert physicists in the fields of carbon-ion radiation therapy, microdosimetry, biological modeling and image-guided radiotherapy. Consensual reports emerged from multiple discussions within both the restricted group and the wider ULICE community. Public deliverables were produced and disseminated to the European Commission. ResultsHere we highlight the disparity in practices between treating centers, then address the main topics to finally elaborate specific recommendations. Although it appears relatively simple to add geometrical margins around the clinical target volume to obtain the planning target volume as performed in photon radiotherapy, this procedure is not appropriate for carbon-ion radiation therapy. Due to the variation of the radiation quality in depth, there is no generic relative biological effectiveness value for carbon-ions outside of an isolated point, for a given fractionation and specific experimental conditions. Absorbed dose and “equieffective dose” for specified conditions must always be reported. ConclusionsThis work contributed to the development of standard operating procedures for carbon-ion radiation therapy clinical trials. These procedures are now being applied, particularly in the first phase III international, multicenter trial (PHRC Étoile).

Effect of Transistor Variants on Single-Event Transients at the 14-/16-nm Bulk FinFET Technology Generation

Single-event transient (SET) data for the 14-/16-nm bulk finFET technology generation are presented and analyzed for variations in threshold voltage and number of fins in the transistor. The heavy-ion experimental data over a range of supply voltage allows for a comparison of the impact of drive current on the SET response of each transistor variant. The results show that the transistor drive current is a key factor for determining SET pulsewidths and cross sections for high linear energy transfer particle irradiation. Transistor variant data that result in matching transistor drive current show an excellent match for SET pulsewidths and cross sections.

Impact of oxygen status on 10B-BPA uptake into human glioblastoma cells, referring to significance in boron neutron capture therapy.

Boron neutron capture therapy (BNCT) can potentially deliver high linear energy transfer particles to tumor cells without causing severe damage to surrounding normal tissue, and may thus be beneficial for cases with characteristics of infiltrative growth, which need a wider irradiation field, such as glioblastoma multiforme. Hypoxia is an important factor contributing to resistance to anticancer therapies such as radiotherapy and chemotherapy. In this study, we investigated the impact of oxygen status on 10B uptake in glioblastoma cells in vitro in order to evaluate the potential impact of local hypoxia on BNCT. T98G and A172 glioblastoma cells were used in the present study, and we examined the influence of oxygen concentration on cell viability, mRNA expression of L-amino acid transporter 1 (LAT1), and the uptake amount of 10B-BPA. T98G and A172 glioblastoma cells became quiescent after 72 h under 1% hypoxia but remained viable. Uptake of 10B-BPA, which is one of the agents for BNCT in clinical use, decreased linearly as oxygen levels were reduced from 20% through to 10%, 3% and 1%. Hypoxia with <10% O2 significantly decreased mRNA expression of LAT1 in both cell lines, indicating that reduced uptake of 10B-BPA in glioblastoma in hypoxic conditions may be due to reduced expression of this important transporter protein. Hypoxia inhibits 10B-BPA uptake in glioblastoma cells in a linear fashion, meaning that approaches to overcoming local tumor hypoxia may be an effective method of improving the success of BNCT treatment.

3D-structured illumination microscopy reveals clustered DNA double-strand break formation in widespread γH2AX foci after high LET heavy-ion particle radiation.

DNA double-strand breaks (DSBs) induced by ionising radiation are considered the major cause of genotoxic mutations and cell death. While DSBs are dispersed throughout chromatin after X-rays or γ-irradiation, multiple types of DNA damage including DSBs, single-strand breaks and base damage can be generated within 1–2 helical DNA turns, defined as a complex DNA lesion, after high Linear Energy Transfer (LET) particle irradiation. In addition to the formation of complex DNA lesions, recent evidence suggests that multiple DSBs can be closely generated along the tracks of high LET particle irradiation. Herein, by using three dimensional (3D)-structured illumination microscopy, we identified the formation of 3D widespread γH2AX foci after high LET carbon-ion irradiation. The large γH2AX foci in G2-phase cells encompassed multiple foci of replication protein A (RPA), a marker of DSBs undergoing resection during homologous recombination. Furthermore, we demonstrated by 3D analysis that the distance between two individual RPA foci within γH2AX foci was approximately 700 nm. Together, our findings suggest that high LET heavy-ion particles induce clustered DSB formation on a scale of approximately 1 μm3. These closely localised DSBs are considered to be a risk for the formation of chromosomal rearrangement after heavy-ion irradiation.

High Linear Energy Transfer Particle Irradiation Leads to Increased Expression of In Vitro Markers of Immunogenic Cell Death

Radiotherapy (RT) fosters a form of tumor cell death that results in dendritic cell activation, effector T-cell cross priming/tumor trafficking, and the formation of a tumor cell/T-cell immune response. This type of immunogenicity is comprised of the release of immune modulating signals, which include the release of high mobility group box 1 (HMGB1), ATP, and the translocation of calreticulin to the cell surface. Previous studies have demonstrated a positive correlation between markers of immunogenic cell death (ICD) and radiation dose with X-rays. Less is known about the effect of higher energies using charged particle irradiation and ICD. In this study, we explore whether varying linear energy transfer (LET) greater than 60 keV/μm with helium ion irradiation would impact immunogenicity in tumor cells as measured by levels of calreticulin translocation, ATP release, and HMGB1 release. Reporter cell lines designed to detect ATP luminescence (RLUs), red fluorescence protein tagged HMGB1 (relative fluorescent units [RFUs]), and cell surface calreticulin (percentage of calreticulin positive cells [%CRT+]) were derived from TSA (murine mammary carcinoma; syngeneic to BALB/c mice) cells. Prior to irradiation, the cells were seeded on six micron thick Mylar attached to 1.5 cm metal rings. The cells were then irradiated at the Radiological Research Accelerator Facility (RARAF) through a Track Segment Charged-Particle Irradiator. ATP and HMGB1 levels were measured 72 hours after RT and calreticulin was measured 24 hours after RT. Various doses of 250kV X-rays and LETs of helium ions were delivered and levels of these tumor ICD markers were determined. For ATP measurements, when compared to non-irradiated controls, cells irradiated with 5 and 20 Gy X-rays and with 5 Gy 65, 80, 110, and 160 keV/μm helium ions resulted in RLU fold-changes of 1.00 ± 0.05 (non-irradiated), 2.33 ± 0.08, 3.27 ± 0.19, 3.24 ± 0.10, 3.99 ± 0.33, 4.12 ± 0.32, and 2.91 ± 0.16 respectively. For HMGB1 measurements, when compared to controls, cells irradiated with 5 and 20 Gy X-rays and with 5 Gy 65, 80, 110, and 160 keV/μm helium ions resulted in RFU fold-changes of 1.00 ± 0.02 (non-irradiated), 1.43 ± 0.03, 1.72 ± 0.03, 1.97 ± 0.06, 1.64 ± 0.03, 1.61 ± 0.04, and 1.51 ± 0.03, respectively. For calreticulin measurements, when compared to controls, cells irradiated with 5 and 20 Gy X-rays and with 5 Gy 65, 80, 110, and 160 keV/μm helium ions resulted in %CRT+ fold-changes of 1.00 ± 0.12 (non-irradiated), 2.32 ± 0.15, 3.07 ± 0.32, 3.16 ± 0.17, 3.01 ± 0.12, 2.74 ± 0.39, and 1.61 ± 0.15, respectively. Immunogenicity of tumor cells as measured by immune cell death signals increases with high LET ion irradiation when compared to low LET X-ray irradiation at the same dose. These marker levels appear to decrease at LETs greater than 110 keV/μm. Further investigation is warranted on the effects of high LET charged particle irradiation on the tumor immune response.

Neutron Radiation Therapy for Treatment of Refractory Merkel Cell Carcinoma.

We describe the first reported use of neutron radiation therapy for successful palliation of treatment refractory Merkel cell carcinoma. The patient was a 78-year-old man with Merkel cell carcinoma involving the scalp and bilateral cervical lymph nodes. The extensive coalescing scalp lesions were locally destructive, painful, and highly detrimental to his overall quality of life, and he had previously progressed through 3 courses of conventional x-ray-based radiation therapy and multiple immunotherapy regimens. We treated him with neutron radiation therapy, and he experienced a complete and durable local response with minimal toxicity. High linear energy transfer particle therapy approaches deserve consideration as a treatment option in cancers that are refractory to standard radiation therapy.

A monochromatic x-ray irradiation system for in vitro studies at synchrotron beamlines

The use of synchrotron light in radiobiological keV x-ray in vitro studies has been accompanied by compromises in culture conditions and sample handling procedures. The presented monochromatic x-ray system bridges the gap between synchrotron science and cell biology by facilitating the irradiation of adherent cells uninterruptedly maintained under cell type-specific conditions throughout the entire experiment. The system for horizontal irradiations consists of a single crystal Laue monochromator, a beam monitor, and a scanning sample stage. As implemented at the BMIT-BM beamline, the system enables homogeneous cell culture irradiations with intense and purely monochromatic x-ray beams (10–30 keV). The first MCF-7 dose-response study demonstrates how the establishment of a stress-minimized experimental procedure leads to accurate and precise in vitro irradiation results. The cell survival as a function of the surface dose is well described by a first-order exponential decay, indicating that the cellular damage induced by 11.9 keV x-rays is comparable to the lethal effects caused by high linear energy transfer particles. The system design opens up the pathway for combined live-cell imaging and monochromatic keV x-ray applications, while the implementation of the system at insertion device beamlines can help to establish novel investigations on the fundamental role of photonactivation agents in an energy regime up to 100 keV.

A Comparison of the SEU Response of Planar and FinFET D Flip-Flops at Advanced Technology Nodes

Heavy-ion experimental results were used to characterize single-event upset trends in 16 nm bulk FinFET, 20 nm bulk planar, and 28 nm bulk planar D flip-flops. Experimental data show that 16 nm bulk FinFET flip-flops have considerably lower SEU cross sections than their sub-32 nm planar counterparts for linear energy transfer (LET) less than $10~\hbox{MeV-{cm}}^{2}/\hbox{mg}$ . However, FinFET SEU cross section improvement compared to the planar technologies is weak for high LET particles. Three-dimensional technology computer-aided design simulations are used to investigate charge collection mechanisms and single-event transient (SET) pulse widths at these advanced fabrication nodes. Simulation results show that SETs follow conventional scaling trends, which are that SET pulse widths reduce with technology scaling.

A numerical model of initial recombination for high-LET irradiation: Application to liquid-filled ionization chambers

Abstract In this paper we present a numerical model of initial recombination in media irradiated with high linear energy transfer (LET) ions, which relies on an amorphous track model of ionization of high LET particles, and diffusion, drift and recombination of ionized charge carriers. The model has fundamental applications for the study of recombination in non-polar liquids, as well as practical ones, like in modelling hadrontherapy dosimetry with ionization chambers. We have used it to study the response of liquid-filled ionization chambers to hadrontherapy beams: dependence of initial recombination on ion species, energy and applied external electric field.

Radiation environment at aviation altitudes and in space.

On the Earth, protection from cosmic radiation is provided by the magnetosphere and the atmosphere, but the radiation exposure increases with increasing altitude. Aircrew and especially space crew members are therefore exposed to an increased level of ionising radiation. Dosimetry onboard aircraft and spacecraft is however complicated by the presence of neutrons and high linear energy transfer particles. Film and thermoluminescent dosimeters, routinely used for ground-based personnel, do not reliably cover the range of particle types and energies found in cosmic radiation. Further, the radiation field onboard aircraft and spacecraft is not constant; its intensity and composition change mainly with altitude, geomagnetic position and solar activity (marginally also with the aircraft/spacecraft type, number of people aboard, amount of fuel etc.). The European Union Council directive 96/29/Euroatom of 1996 specifies that aircrews that could receive dose of >1 mSv y(-1) must be evaluated. The dose evaluation is routinely performed by computer programs, e.g. CARI-6, EPCARD, SIEVERT, PCAire, JISCARD and AVIDOS. Such calculations should however be carefully verified and validated. Measurements of the radiation field in aircraft are thus of a great importance. A promising option is the long-term deployment of active detectors, e.g. silicon spectrometer Liulin, TEPC Hawk and pixel detector Timepix. Outside the Earth's protective atmosphere and magnetosphere, the environment is much harsher than at aviation altitudes. In addition to the exposure to high energetic ionising cosmic radiation, there are microgravity, lack of atmosphere, psychological and psychosocial components etc. The milieu is therefore very unfriendly for any living organism. In case of solar flares, exposures of spacecraft crews may even be lethal. In this paper, long-term measurements of the radiation environment onboard Czech aircraft performed with the Liulin since 2001, as well as measurements and simulations of dose rates on and outside the International Space Station were presented. The measured and simulated results are discussed in the context of health impact.