Low Linear Energy Transfer Values Research Articles

Data-driven ion-independent relative biological effectiveness modeling using the beam quality Q

Beam quality Q = Z2/E (Z = ion charge, E = energy), an alternative to the conventionally used linear energy transfer (LET), enables ion-independent modeling of the relative biological effectiveness (RBE) of ions. Therefore, the Q concept, i.e. different ions with similar Q have similar RBE values, could help to transfer clinical RBE knowledge from better-studied ion types (e.g. carbon) to other ions. However, the validity of the Q concept has so far only been demonstrated for low LET values. In this work, the Q concept was explored in a broad LET range, including the so-called overkilling region. The particle irradiation data ensemble (PIDE) was used as experimental in vitro dataset. Data-driven models, i.e. neural network (NN) models with low complexity, were built to predict RBE values for H, He, C and Ne ions at different in vitro endpoints taking different combinations of clinically available candidate inputs: LET, Q and linear-quadratic photon parameter α x/β x. Models were compared in terms of prediction power and ion dependence. The optimal model was compared to published model data using the local effect model (LEM IV). The NN models performed best for the prediction of RBE at reference photon doses between 2 and 4 Gy or RBE near 10% cell survival, using only α x/β x and Q instead of LET as input. The Q model was not significantly ion dependent (p > 0.5) and its prediction power was comparable to that of LEM IV. In conclusion, the validity of the Q concept was demonstrated in a clinically relevant LET range including overkilling. A data-driven Q model was proposed and observed to have an RBE prediction power comparable to a mechanistic model regardless of particle type. The Q concept provides the possibility of reducing RBE uncertainty in treatment planning for protons and ions in the future by transferring clinical RBE knowledge between ions.

Analysis of Ion-Induced SEFI and SEL Phenomena in 90 nm NOR Flash Memory

This article mainly focuses on the single event function interruption (SEFI) and single event latch-up (SEL) of 90 nm NOR flash memories. Devices were irradiated by ions with different linear energy transfer (LET) values from 12.9 to $65.8~MeV\cdot cm^{2}$ /mg. SEFI observed in the device is further divided into bit SEFI, column SEFI, and sector SEFI by severity of data corruption. Under irradiation with low LET value ions, SEL propagation-like phenomena were observed in this work, which was recognized as the process from local latch-up to global latch-up in the peripheral circuits. The underlying mechanisms for SEFI and SEL in NOR flash are discussed. Results indicate that the radiation-induced transient current should be responsible for SEFI, and different forms of SEFI depend on in which part of the circuit that transient current occurred. Besides, SEL in NOR flash is considered to be triggered from the peripheral circuits.

Single-Event Upsets in a 7-nm Bulk FinFET Technology With Analysis of Threshold Voltage Dependence

In this work, single-event upset (SEU) responses of D flip-flop (FF) designs with different threshold-voltage options in a 7-nm bulk FinFET technology are examined. Experimental data imply that single-event (SE) cross section depends heavily on supply voltage and particle linear energy transfer (LET) values. For close-to-nominal supply voltages and low-LET particles, the SEU response differs very little between threshold-voltage options; however, for low supply voltages and high-LET particles, experimental data indicate that FFs are more susceptible to SEUs at higher threshold voltages. These results are consistent with schematic-level simulations run to estimate the effect of threshold voltage on SE transient (SET) pulsewidth (PW) and D-FF feedback-loop delay. Additional technology computer-aided design (TCAD) simulations show that SET current PWs for worst case strikes on an inverter are largely independent on threshold voltage at low LET values. All these results together suggest that the weak dependence of SEU response on threshold voltage is due to the FinFET structure and charge-collection mechanisms.

Differences in Linear Energy Transfer Affect Cell-killing and Radiosensitizing Effects of Spread-out Carbon-ion Beams.

The cell-killing and radiosensitizing effects of carbon-ion (C-ion) beams with low linear energy transfer (LET) are underexplored. We aimed to demonstrate the cell-killing effects of 60Co gamma rays and C-ion beams at various LET values and the radiosensitizing effect of C-ion beams at various LET and cisplatin levels. Human uterine cervical cancer cells were irradiated with 60Co gamma rays and C-ion beams at different levels of LET, with and without cisplatin treatment. Low-LET C-ion beams had a superior cell-killing effect compared to 60Co gamma rays. Survival curves under low-LET C-ion beams were more similar to that of 60Co gamma rays than that of high-LET C-ion beams. Cisplatin significantly reduced cell survival after 1, 2, and 3 Gy C-ion beam irradiations at LET values of 13/30/70 keV/μm, 13/30 keV/μm, and 13 keV/μm, respectively. Low-LET C-ion beams combined with cisplatin have higher radiosensitizing effects than high-LET C-ion beams.

Clinical implications of variable relative biological effectiveness in proton therapy for prostate cancer

Purpose To study the potential consequences of differences in the evaluation of variable versus uniform relative biological effectiveness calculations in proton radiotherapy for prostate cancer. Methods and material Experimental data with proton beams suggest that relative biological effectiveness increases with linear energy transfer. This relation also depends on the ratio, characteristic of a tissue and a considered endpoint. Three phenomenological models (Carabe et al., Wedenberg et al. and McNamara et al.) are compared to a mechanistic model based on microdosimetry (microdosimetric kinetic model) and to the current assumption of uniform relative biological effectiveness equal to 1.1 in a prostate case. Results and conclusions Phenomenological models clearly predict higher relative biological effectiveness values compared to microdosimetric kinetic model, that seems to approach to the constant value of 1.1 adopted in the clinics, at least for low linear energy transfer values achieved in typical prostate proton plans. All models predict a higher increase of the relative biological effectiveness-weighted dose for the prostate tumor than for the rest of structures involved due to its lower ratio, even when linear energy transfer is, in general, lower in the tumor than on the surroundings tissues. Prostate cancer is, therefore, a good candidate to take advantage of variable relative biological effectiveness, especially if linear energy transfer is enhanced within the tumor. However, the discrepancies among models hinder the clinical implementation of variable relative biological effectiveness.

SE Response of Guard-Gate FF in 16- and 7-nm Bulk FinFET Technologies

Single-event (SE) performance of the guard-gate flip-flop (GG-FF) and conventional D-FF designs is evaluated at the 16- and 7-nm FinFET technology nodes. The heavy-ion test results show that at the 16-nm node, the GG-FF shows better SE performance for low-linear energy transfer (LET) particles and similar performance for high-LET particles compared with D-FF design. However, at the 7-nm node, the GG-FF shows better SE performance than the D-FF across a wide range of particle LET values. This behavior is due to the higher number of short SE transient (SET) pulses for high-LET particles at the 7-nm node. The heavy-ion test results are used to estimate the number of short SET pulses as a function of particle LET values.

Both irradiated and bystander effects link with DNA repair capacity and the linear energy transfer

AimsIn comparison with a low linear energy transfer (LET) radiation, a high-LET radiation induces more complex DNA damage. This study wonders whether radiation-induced bystander effect (RIBE) is dependent of LET. Materials and methodsChinese hamster ovary CHO-9 cells and its subline EM-C11 cells (SSB repair deficient) and XR-C1 cells (DSB repair deficient) were irradiated by γ-rays, α-particles, or carbon ions with different LETs of 13, 30 and 70 keV/μm. Cell proliferation, cell death, DNA damage, cell cycle distribution and some protein expressions were measured with the cell counting kit-8 (CCK-8), colony formation, micronuclei (MN), flow cytometry and western blot, respectively. Key findingsA series of cell responses were induced by these radiations in a LET-dependent manner, including proliferation inhibition, cell death, MN induction, G2/M phase arrest and the expression of γH2AX protein. These cell injuries were also depended on DNA repair capacity, and XR-C1 cells were the most sensitive to each radiation. Furthermore, when the cells were treated with the conditioned medium (CM) collected from irradiated CHO-9 cells, the MN induction and cell death response in the bystander cells of EM-C11 or XR-C1 increased along with LET of irradiation, and the bystander damage was easier to be induced in EM-C11 and XR-C1 cells than that in CHO-9 cells. SignificanceBoth cellular DNA repair capacity and the LET value of radiation could deeply influence damage extents of not only the irradiated cells but also the bystander cells.

Experimental characterization of the dominant multiple nodes charge collection mechanism in metal oxide-semiconductor transistors

We propose an experimental method to investigate the dominant multiple node charge collection mechanism. A transistor array-based test structure is used to distinguish charge collection owing to the drift-diffusion and parasitic bipolar amplification effect. Heavy ion experimental results confirm that drift-diffusion dominates multiple node charge collection at low linear energy transfer (LET). However, the parasitic bipolar amplification effect dominates it at high LET. We also propose simple equations to determine the critical LET which may change the dominant multiple node charge collection mechanism. The calculated LET value is consistent with the heavy ion experimental results.

Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos.

Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET) value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio) as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf) revealed through acridine orange (AO) staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy) and alpha-particle (4.4 mGy) exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis.

Impact of Temporal Masking of Flip-Flop Upsets on Soft Error Rates of Sequential Circuits

Reductions in single-event (SE) upset (SEU) rates for sequential circuits due to temporal masking effects are evaluated. The impacts of supply voltage, combinational-logic delay, flip-flop (FF) SEU performance, and particle linear energy transfer (LET) values are analyzed for SE cross sections of sequential circuits. Alpha particles and heavy ions with different LET values are used to characterize the circuits fabricated at the 40-nm bulk CMOS technology node. Experimental results show that increasing the delay of the logic circuit present between FFs and decreasing the supply voltage are two effective ways of reducing SE error rates for sequential circuits for particles with low LET values due to temporal masking. SEU-hardened FFs benefit less from temporal masking than conventional FFs. Circuit hardening implications for SEU-hardened and unhardened FFs are discussed.

LET dependence of the response of a PTW-60019 microDiamond detector in a 62 MeV proton beam

This study was initiated following conclusions from earlier experimental work, performed in a low-energy carbon ion beam, indicating a significant LET dependence of the response of a PTW-60019 microDiamond detector. The purpose of this paper is to present a comparison between the response of the same PTW-60019 microDiamond detector and an IBA Roos-type ionization chamber as a function of depth in a 62MeV proton beam. Even though proton beams are considered as low linear energy transfer (LET) beams, the LET value increases slightly in the Bragg peak region. Contrary to the observations made in the carbon ion beam, in the 62MeV proton beam good agreement is found between both detectors in both the plateau and the distal edge region. No significant LET dependent response of the PTW-60019 microDiamond detector is observed consistent with other findings for proton beams in the literature, despite this particular detector exhibiting a substantial LET dependence in a carbon ion beam.

A Simpler Energy Transfer Efficiency Model to Predict Relative Biological Effect for Protons and Heavier Ions.

The aim of this work is to predict relative biological effectiveness (RBE) for protons and clinically relevant heavier ions, by using a simplified semi-empirical process based on rational expectations and published experimental results using different ion species. The model input parameters are: Z (effective nuclear charge) and radiosensitivity parameters αL and βL of the control low linear energy transfer (LET) radiation. Sequential saturation processes are assumed for: (a) the position of the turnover point (LETU) for the LET–RBE relationship with Z, and (b) the ultimate value of α at this point (αU) being non-linearly related to αL. Using the same procedure for β, on the logical assumption that the changes in β with LET, although smaller than α, are symmetrical with those of α, since there is symmetry of the fall off of LET–RBE curves with increasing dose, which suggests that LETU must be identical for α and β. Then, using iso-effective linear quadratic model equations, the estimated RBE is scaled between αU and αL and between βU and βL from for any input value of Z, αL, βL, and dose. The model described is fitted to the data of Barendsen (alpha particles), Weyrather et al. (carbon ions), and Todd for nine different ions (deuterons to Argon), which include variations in cell surviving fraction and dose. In principle, this new system can be used to complement the more complex methods to predict RBE with LET such as the local effect and MKM models which already have been incorporated into treatment planning systems in various countries. It would be useful to have a secondary check to such systems, especially to alert clinicians of potential risks by relatively easy estimation of relevant RBEs. In clinical practice, LET values smaller than LETU are mostly encountered, but the model extends to higher values beyond LETU for other purposes such as radiation, protection, and astrobiology. Considerable further research is required, perhaps in a dedicated international laboratory, using a basket of different models to determine what the best system or combination of systems will be to make proton and ion beam radiotherapy as safe as possible and to produce the best possible clinical results.

The principles of Katz's cellular track structure radiobiological model.

The cellular track structure theory (TST), introduced by Katz in 1968, applies the concept of action cross section as the probability of targets in the radiation detector being activated to elicit the observed endpoint (e.g. cell killing). The ion beam radiation field is specified by the charge Z, speed β (or energy), fluence and linear energy transfer (LET) of the ion, rather than by its total absorbed dose or dose-averaged LET. The detector is represented by radiosensitive elements of size a0 and radiosensitivity D0, its gamma-ray response being represented by c-hit or multi-target expressions rather than by the linear-quadratic formula. Key to TST is the Dδ(r) formula describing the radial distribution of delta-ray dose (RDD) around the ion path. This formula, when folded with the dose response of the detector and radially integrated, yields the 'point target' action cross section value, σPT. The averaged value of the cross section, σ, is obtained by radially integrating the a0-averaged RDD. In the 'track width' regime which may occur at the distal end of the ion's path, the value of σ may considerably exceed its geometrical value, [Formula: see text]. Several scaling principles are applied in TST, resulting in its simple analytic formulation. Multi-target detectors, such as cells, are represented in TST by m, D0, σ0 (the 'saturation value' of the cross section which replaces a0) and κ (a 'detector saturation index'), as the fourth model parameter. With increasing LET of the ion, the two-component formulation of TST allows for successive transition from shouldered survival curves at low LET values to exponential ones at radiobiological effectiveness (RBE) maximum, followed by 'thindown' at the end of the ion track. For a given cell line, having best-fitted the four model parameters (m, D0, σ0 and κ) to an available data set of measured survival curves, TST is able to quantitatively predict cell survival and RBE for this cell line after any other ion irradiation.

A 2D DNA Lattice as an Ultrasensitive Detector for Beta Radiations

There is growing demand for the development of efficient ultrasensitive radiation detectors to monitor the doses administered to individuals during therapeutic nuclear medicine which is often based on radiopharmaceuticals, especially those involving beta emitters. Recently biological materials are used in sensors in the nanobio disciplines due to their abilities to detect specific target materials or sites. Artificially designed two-dimensional (2D) DNA lattices grown on a substrate were analyzed after exposure to pure beta emitters, (90)Sr-(90)Y. We studied the Raman spectra and reflected intensities of DNA lattices at various distances from the source with different exposure times. Although beta particles have very low linear energy transfer values, the significant physical and chemical changes observed throughout the extremely thin, ∼0.6 nm, DNA lattices suggested the feasibility of using them to develop ultrasensitive detectors of beta radiations.

Adaptive Response of Low Linear Energy Transfer X-rays for Protection Against High Linear Energy Transfer Accelerated Heavy Ion-Induced Teratogenesis

Adaptive response (AR) of low linear energy transfer (LET) irradiations for protection against teratogenesis induced by high LET irradiations is not well documented. In this study, induction of AR by X-rays against teratogenesis induced by accelerated heavy ions was examined in fetal mice. Irradiations of pregnant C57BL/6J mice were performed by delivering a priming low dose from X-rays at 0.05 or 0.30 Gy on gestation day 11 followed one day later by a challenge high dose from either X-rays or accelerated heavy ions. Monoenergetic beams of carbon, neon, silicon, and iron with the LET values of about 15, 30, 55, and 200keV/μm, respectively, were examined. Significant suppression of teratogenic effects (fetal death, malformation of live fetuses, or low body weight) was used as the endpoint for judgment of a successful AR induction. Existence of AR induced by low-LET X-rays against teratogenic effect induced by high-LET accelerated heavy ions was demonstrated. The priming low dose of X-rays significantly reduced the occurrence of prenatal fetal death, malformation, and/or low body weight induced by the challenge high dose from either X-rays or accelerated heavy ions of carbon, neon or silicon but not iron particles. Successful AR induction appears to be a radiation quality event, depending on the LET value and/or the particle species of the challenge irradiations. These findings would provide a new insight into the study on radiation-induced AR in utero.

Dosimetry and microdosimetry of 10–220 MeV proton beams with CR-39 and their verifications by calculation of reaction cross sections using ALICE, TALYS and GEANT4 codes

Abstract High- and intermediate-energy protons are not able to directly form a track in a CR-39 etch detector (TED). Such detectors, however, can be used for the detection and dosimetry of the beams of these particles through the registration of secondary charged particles with sufficiently high values of linear energy transfer (LET). High-energy protons (72–220 MeV) and Intermediate-energy protons (10–30 MeV) with low LET values ranging from 1.1 down to 0.4 keV/μm and 5.87 down to 2.40 keV/μm, respectively are considered in this study. It seems to be sufficient to create secondary particles, although the LET values are low. This phenomenon can modify the characteristics of the energy transfer process due to these particles, which should be taken into account when such particles are used for radiobiology studies or for radiotherapy. The importance of these secondary particles was investigated experimentally by means of an LET spectrometer based on a chemically etched track detector in which the tracks of the primary protons are not revealed. Experiments were performed with proton beams available at the Nuclear Research Center for Agriculture and Medicine (NRCAM) in Karaj, Iran and at the National Cancer Center (NCC) in Seoul, Korea with protons of primary energies of about 10–30 MeV and 72–220 MeV respectively. The contribution of the secondary particle dose increases as the proton energy decreases. The origin of the secondary particles in interactions with protons having high and intermediate energies due to various nuclear reactions was calculated by the both ALICE and TALYS computer codes. The secondary microdosimetry doses were also calculated by GEANT4 code. There is large discrepancy between experimental and calculated results in low proton energies. It has been verified that there is a good correlation between the experimentally obtained results and the reaction cross sections predicted by ALICE and TALYS codes.

In vitro H2AX phosphorylation and micronuclei induction in human fibroblasts across the Bragg curve of a 577 MeV/nucleon Fe incident beam

The space environment consists of a varying field of radiation particles including high-energy ions, with spacecraft shielding material providing the only major protection to astronauts from harmful exposure. Unlike low-linear energy transfer (LET) γ or X-rays, the presence of shielding does not always reduce the radiation risks for energetic charged particle exposure, since the dose delivered by the charged particle increases sharply as the particle approaches the end of its range, a position known as the Bragg peak. The Bragg curve does not necessarily represent the biological damage along the particle traversal, and the “biological Bragg curve” is dependent on the energy and the type of the primary particle, and may vary for different biological endpoints. Here we used a unique irradiation geometry to measure the biological response across the Bragg curve in human fibroblasts exposed to 577 MeV/nucleon incident Fe ions in vitro. Polyethylene shielding was used to achieve a Bragg curve distribution with the beam geometry parallel to a monolayer of fibroblast cells. Qualitative analyses of γ -H2AX fluorescence, a known marker of DSBs, indicated increased clustering of DNA damage before the Bragg peak, enhanced homogenous distribution at the peak, and provided visual evidence of high-LET particle traversal of cells beyond the Bragg peak in agreement with one-dimensional transport approximations. A quantitative biological response curve generated for micronuclei induction across the Bragg curve did not reveal an increased yield of micronuclei at the location of the Bragg peak. However, the percentage of mononucleated cells, which indicates inhibition in cell progression, increased at the location of the peak. These results confirm the argument that severely damaged cells at the Bragg peak, as observed by increased γ -H2AX formation, are likely to go through reproduction death. Depending on the LET value of the primary particles, the yield of the biological endpoint of interest (micronuclei formation in the present study) may or may not increase at the location of the Bragg peak.