Formulation of Time-Dependent Cell Survival with Saturable Repairability of Radiation Damage.

This study aims to provide a model that compounds historically proposed ideas regarding cell survival irradiated with X rays or particles. The parameters used in this model have simple meanings and are closely related to cell death-related phenomena. The model is adaptable to a wide range of doses and dose rates and thus can consistently explain previously published cell survival data. The formulas of the model were derived by using five basic ideas: 1. "Poisson's law"; 2. "DNA affected damage"; 3. "repair"; 4. "clustered affected damage"; and 5. "saturation of reparability". The concept of affected damage is close to but not the same as the effect caused by the double-strand break (DSB). The parameters used in the formula are related to seven phenomena: 1. "linear coefficient of radiation dose"; 2. "probability of making affected damage"; 3. "cell-specific repairability", 4. "irreparable damage by adjacent affected damage"; 5. "recovery of temporally changed repairability"; 6. "recovery of simple damage which will make the affected damage"; 7. "cell division". By using the second parameter, this model includes cases where a single hit results in repairable-lethal and double-hit results in repairable-lethal. The fitting performance of the model for the experimental data was evaluated based on the Akaike information criterion, and practical results were obtained for the published experiments irradiated with a wide range of doses (up to several 10 Gy) and dose rates (0.17 Gy/h to 55.8 Gy/h). The direct association of parameters with cell death-related phenomena has made it possible to systematically fit survival data of different cell types and different radiation types by using crossover parameters.

Implementation of simplified stochastic microdosimetric kinetic models into PHITS for application to radiation treatment planning.

PURPOSE: The stochastic microdosimetric kinetic (SMK) model is one of the most sophisticated and precise models used in the estimation of the relative biological effectiveness of carbon-ion radiotherapy (CRT) and boron neutron capture therapy (BNCT). However, because of its complicated and time-consuming calculation procedures, it is nearly impractical to directly incorporate this model into a radiation treatment-planning system. MATERIALS AND METHODS: Through the introduction of Taylor expansion (TE) or fast Fourier transform (FFT), we developed two simplified SMK models and implemented them into the Particle and Heavy Ion Transport code System (PHITS). To verify the implementation, we calculated the photon isoeffective doses in a cylindrical phantom placed in the radiation fields of passive CRT and accelerator-based BNCT. RESULTS AND DISCUSSION: Our calculation suggested that both TE-based and FFT-based SMK models can reproduce the data obtained from the original SMK model very well for absorbed doses approximately below 5 Gy, whereas the TE-based SMK model overestimates the original data at higher doses. In terms of computational efficiency, the TE-based SMK model is much faster than the FFT-based SMK model. CONCLUSION: This study enables the instantaneous calculation of the photo isoeffective dose for CRT and BNCT, considering their cellular-scale dose heterogeneities. Treatment-planning systems that use the improved PHITS as a dose-calculation engine are under development.

Computational evaluation of dose distribution for BNCT treatment combined with X-ray therapy or proton beam therapy.

In this study, we performed Monte Carlo simulations to accurately reflect the beam delivery systems including patient-specific irradiation devices of X-ray and proton beam therapies. The dose distributions obtained from the simulations for X-rays or proton beams were successfully combined to the dose distribution of boron neutron capture therapy (BNCT), which was calculated by a treatment planning system called Tsukuba Plan. The results demonstrate the feasibility of dose evaluation for BNCT combined with other radiotherapy modalities using the Tsukuba Plan.

Verification for dose estimation performance of a Monte-Carlo based treatment planning system in University of Tsukuba.

The University of Tsukuba is developing not only a linac-based neutron source for BNCT (iBNCT) but also a multi-modal treatment planning system (Tsukuba-Plan) for BNCT. We are currently performing several verifications. Phantom experiments performed in iBNCT were simulated by the Tsukuba-Plan, and the calculation results were compared with the measurements from the experiments. The calculations were in good agreement with the measurements. The results demonstrated that the Tsukuba-Plan can perform to estimate doses properly for BNCT treatment at iBNCT.

Evaluation of the characteristics of the neutron beam of a linac-based neutron source for boron neutron capture therapy.

The linac-base neutron source "iBNCT" developed by the Tsukuba team has begun to generate a large intensity of neutrons. To confirm the applicability of the device to BNCT, several characteristic measurements have been implemented. In a water phantom experiment, when the accelerator was operated with an average current of 1.4 mA, the maximum thermal neutron flux was approximately 7.8 × 108 (n/cm2/s). Results demonstrate the stability of the linac over time, showing its promising potential for future patient treatment.

Monitoring patient movement with boron neutron capture therapy and motion capture technology.

In boron neutron capture therapy (BNCT), a patient must remain in a fixed position during the irradiation process. In this study, a system was devised that can guide a patient to the correct position and the patient can be monitored during the irradiation process. This is achieved by using motion capture technology that consists of many cameras. The discrepancy of the measured coordinates for each marker on a phantom by the system was less than 5 mm. For practical applications, further research and verification are required.

3D-printable lung phantom for distal falloff verification of proton Bragg peak.

In proton therapy, the Bragg peak of a proton beam reportedly deteriorates when passing though heterogeneous structures such as human lungs. Previous studies have used heterogeneous random voxel phantoms, in which soft tissues and air are randomly allotted to render the phantoms the same density as human lungs, for conducting Monte Carlo (MC) simulations. However, measurements of these phantoms are complicated owing to their difficult-to-manufacture shape. In the present study, we used Voronoi tessellation to design a phantom that can be manufactured, and prepared a Voronoi lung phantom for which both measurement and MC calculations are possible. Our aim was to evaluate the effectiveness of this phantom as a new lung phantom for investigating proton beam Bragg peak deterioration. For this purpose, we measured and calculated the percentage depth dose and the distal falloff widths (DFW) passing through the phantom. For the 155 MeV beam, the measured and calculated DFW values with the Voronoi lung phantom were 0.40 and 0.39 cm, respectively. For the 200 MeV beam, the measured and calculated DFW values with the Voronoi lung phantom were both 0.48 cm. Our results indicate that both the measurements and MC calculations exhibited high reproducibility with plastinated lung sample from human body in previous studies. We found that better results were obtained using the Voronoi lung phantom than using other previous phantoms. The designed phantom may contribute significantly to the improvement of measurement precision. This study suggests that the Voronoi lung phantom is useful for simulating the effects of the heterogeneous structure of lungs on proton beam deterioration.

Establishment of a New Three-Dimensional Dose Evaluation Method Considering Variable Relative Biological Effectiveness and Dose Fractionation in Proton Therapy Combined with High-Dose-Rate Brachytherapy.

PURPOSE: The purpose of this study is to evaluate the influence of variable relative biological effectiveness (RBE) of proton beam and dose fractionation has on dose distribution and to establish a new three-dimensional dose evaluation method for proton therapy combined with high-dose-rate (HDR) brachytherapy. MATERIALS AND METHODS: To evaluate the influence of variable RBE and dose fractionation on dose distribution in proton beam therapy, the depth-dose distribution of proton therapy was compared with clinical dose, RBE-weighted dose, and equivalent dose in 2 Gy fractions using a linear-quadratic-linear model (EQD2LQL). The clinical dose was calculated by multiplying the physical dose by RBE of 1.1. The RBE-weighted dose is a biological dose that takes into account RBE variation calculated by microdosimetric kinetic model implemented in Monte Carlo code. The EQD2LQL is a biological dose that makes the RBE-weighted dose equivalent to 2 Gy using a linear-quadratic-linear (LQL) model. Finally, we evaluated the three-dimensional dose by taking into account RBE variation and LQL model for proton therapy combined with HDR brachytherapy. RESULTS: The RBE-weighted dose increased at the distal of the spread-out Bragg peak (SOBP). With the difference in the dose fractionation taken into account, the EQD2LQL at the distal of the SOBP increased more than the RBE-weighted dose. In proton therapy combined with HDR brachytherapy, a divergence of 103% or more was observed between the conventional dose estimation method and the dose estimation method we propose. CONCLUSIONS: Our dose evaluation method can evaluate the EQD2LQL considering RBE changes in the dose distribution.

Thermal-history-dependent Phase Behavior of Ceramide Molecular Assembly in a UV-curable Acrylic Adhesive Resin.

The structure and thermal behavior of a synthetic D-erythro-ceramide [NDS], (2S,3R)-2-octadecanoylamino-octadecane-1,3-diol (CER), molecular assembly in a UV-curable acrylic adhesive resin (acResin®) were investigated by differential scanning calorimetry (DSC), polarized-light microscopy, and X-ray diffraction (XRD). CER in the resin was found to exhibit a thermal-history-dependent polymorphic phase behavior that is similar but not identical to that observed for pure CER. The melting temperatures of the in-resin CER samples were lower than those of pure CER samples. Maintaining a melt-quenched in-resin CER sample at 60°C for 5-6 days induced a transformation from a metastable phase to a stable phase, where CER formed an ordered lamellar structure. The lamellar structure differed from that observed in the stable solid phase of pure CER samples. The findings of this study are expected to be useful for developing new medical tapes or sheets with ceramides added to the adhesives to protect skin.

Characterisation of an aptamer against the Runt domain of AML1 (RUNX1) by NMR and mutational analyses.

Since the invention of systematic evolution of ligands by exponential enrichment, many short oligonucleotides (or aptamers) have been reported that can bind to a wide range of target molecules with high affinity and specificity. Previously, we reported an RNA aptamer that shows high affinity to the Runt domain (RD) of the AML1 protein, a transcription factor with roles in haematopoiesis and immune function. From kinetic and thermodynamic studies, it was suggested that the aptamer recognises a large surface area of the RD, using numerous weak interactions. In this study, we identified the secondary structure by nuclear magnetic resonance spectroscopy and performed a mutational study to reveal the residue critical for binding to the RD. It was suggested that the large contact area was formed by a DNA-mimicking motif and a multibranched loop, which confers the high affinity and specificity of binding.

Validation of the physical and RBE-weighted dose estimator based on PHITS coupled with a microdosimetric kinetic model for proton therapy.

The microdosimetric kinetic model (MKM) is widely used for estimating relative biological effectiveness (RBE)-weighted doses for various radiotherapies because it can determine the surviving fraction of irradiated cells based on only the lineal energy distribution, and it is independent of the radiation type and ion species. However, the applicability of the method to proton therapy has not yet been investigated thoroughly. In this study, we validated the RBE-weighted dose calculated by the MKM in tandem with the Monte Carlo code PHITS for proton therapy by considering the complete simulation geometry of the clinical proton beam line. The physical dose, lineal energy distribution, and RBE-weighted dose for a 155 MeV mono-energetic and spread-out Bragg peak (SOBP) beam of 60 mm width were evaluated. In estimating the physical dose, the calculated depth dose distribution by irradiating the mono-energetic beam using PHITS was consistent with the data measured by a diode detector. A maximum difference of 3.1% in the depth distribution was observed for the SOBP beam. In the RBE-weighted dose validation, the calculated lineal energy distributions generally agreed well with the published measurement data. The calculated and measured RBE-weighted doses were in excellent agreement, except at the Bragg peak region of the mono-energetic beam, where the calculation overestimated the measured data by ~15%. This research has provided a computational microdosimetric approach based on a combination of PHITS and MKM for typical clinical proton beams. The developed RBE-estimator function has potential application in the treatment planning system for various radiotherapies.

DEVELOPMENT OF A MULTIMODAL MONTE CARLO BASED TREATMENT PLANNING SYSTEM.

To establish boron neutron capture therapy (BNCT), the University of Tsukuba is developing a treatment device and peripheral devices required in BNCT, such as a treatment planning system. We are developing a new multimodal Monte Carlo based treatment planning system (developing code: Tsukuba Plan). Tsukuba Plan allows for dose estimation in proton therapy, X-ray therapy and heavy ion therapy in addition to BNCT because the system employs PHITS as the Monte Carlo dose calculation engine. Regarding BNCT, several verifications of the system are being carried out for its practical usage. The verification results demonstrate that Tsukuba Plan allows for accurate estimation of thermal neutron flux and gamma-ray dose as fundamental radiations of dosimetry in BNCT. In addition to the practical use of Tsukuba Plan in BNCT, we are investigating its application to other radiation therapies.

Conjugation of two RNA aptamers improves binding affinity to AML1 Runt domain.

To develop a high-affinity aptamer against AML1 Runt domain, two aptamers were conjugated based on their structural information. The newly designed aptamer Apt14 was generated by the conjugation of two RNA aptamers (Apt1 and Apt4) obtained by SELEX against AML1 Runt domain, resulting in improvement in its binding performance. The residues of AML1 Runt domain in contact with Apt14 were predicted in silico and confirmed by mutation and NMR analyses. It was suggested that the conjugated internal loop renders additional contacts and is responsible for the enhancement in the binding affinity. Conjugation of two aptamers that bind to different sites of the target protein is a facile and robust strategy to develop an aptamer with higher performance.

Neutron spectral fluence measurements using a Bonner sphere spectrometer in the development of the iBNCT accelerator-based neutron source.

The neutron spectral fluence of an accelerator-based neutron source facility for boron neutron capture therapy (BNCT) based on a proton linac and a beryllium target was evaluated by the unfolding method using a Bonner sphere spectrometer (BSS). A 3He-proportional-counter-based BSS was used with weak beam during the development of the facility. The measured epithermal neutron spectra were consistent with calculations. The epithermal neutron intensity at the beam port was estimated and the results gave a numerical target for the enhancement of the proton beam intensity and will be used as reference data for measurements performed after the completion of the facility.

Development of Monte Carlo based real-time treatment planning system with fast calculation algorithm for boron neutron capture therapy.

PURPOSE: We simulated the effect of patient displacement on organ doses in boron neutron capture therapy (BNCT). In addition, we developed a faster calculation algorithm (NCT high-speed) to simulate irradiation more efficiently. METHODS: We simulated dose evaluation for the standard irradiation position (reference position) using a head phantom. Cases were assumed where the patient body is shifted in lateral directions compared to the reference position, as well as in the direction away from the irradiation aperture. For three groups of neutron (thermal, epithermal, and fast), flux distribution using NCT high-speed with a voxelized homogeneous phantom was calculated. The three groups of neutron fluxes were calculated for the same conditions with Monte Carlo code. These calculated results were compared. RESULTS: In the evaluations of body movements, there were no significant differences even with shifting up to 9mm in the lateral directions. However, the dose decreased by about 10% with shifts of 9mm in a direction away from the irradiation aperture. When comparing both calculations in the phantom surface up to 3cm, the maximum differences between the fluxes calculated by NCT high-speed with those calculated by Monte Carlo code for thermal neutrons and epithermal neutrons were 10% and 18%, respectively. The time required for NCT high-speed code was about 1/10th compared to Monte Carlo calculation. CONCLUSIONS: In the evaluation, the longitudinal displacement has a considerable effect on the organ doses. We also achieved faster calculation of depth distribution of thermal neutron flux using NCT high-speed calculation code.

Kinetic and Thermodynamic Analyses of Interaction between a High-Affinity RNA Aptamer and Its Target Protein.

AML1 (RUNX1) protein is an essential transcription factor involved in the development of hematopoietic cells. Several genetic aberrations that disrupt the function of AML1 have been frequently observed in human leukemia. AML1 contains a DNA-binding domain known as the Runt domain (RD), which recognizes the RD-binding double-stranded DNA element of target genes. In this study, we identified high-affinity RNA aptamers that bind to RD by systematic evolution of ligands by exponential enrichment. The binding assay using surface plasmon resonance indicated that a shortened aptamer retained the ability to bind to RD when 1 M potassium acetate was used. A thermodynamic study using isothermal titration calorimetry (ITC) showed that the aptamer-RD interaction is driven by a large enthalpy change, and its unfavorable entropy change is compensated by a favorable enthalpy change. Furthermore, the binding heat capacity change was identified from the ITC data at various temperatures. The aptamer binding showed a large negative heat capacity change, which suggests that a large apolar surface is buried upon such binding. Thus, we proposed that the aptamer binds to RD with long-range electrostatic force in the early stage of the association and then changes its conformation and recognizes a large surface area of RD. These findings about the biophysics of aptamer binding should be useful for understanding the mechanism of RNA-protein interaction and optimizing and modifying RNA aptamers.

Effect of biological factors on successful measurements with skeletal-muscle (1)H-MRS.

BACKGROUND: Our purpose in this study was to clarify whether differences in subject group attributes could affect data acquisition in proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Subjects without diabetes mellitus (DM) were divided into two groups (group A, in their 20s; group B, 30-60 years old). Subjects with DM formed group C (30-60 years old). The numbers of subjects were 19, 27, and 22 for group A, B, and C respectively. For all subjects, (1)H-MRS measurements were taken of the soleus muscle (SOL) and the anterior tibial muscle (AT). We defined the success of the measurements by the detection of intramyocellular lipids. Moreover, we also measured the full width at half maximum of the water peaks for all subjects. RESULTS: The success rate was significantly higher for the AT (100%) than for the SOL (81.6%) (P<0.01). For the SOL, the success rate was 100% in group A, 85.2% in group B, and 77.3% in group C. There was a significant difference (P<0.05) between groups A and B, as well as between groups A and C. In all subjects, there was a significant difference (P<0.01) in the full width at half maximum (Hz) of the water peak between the AT and SOL measurements. CONCLUSION: We conclude that differences in the age and DM history of subjects could affect the probability of successful (1)H-MRS data acquisition.

Development of simple high-precision two-dimensional dose-distribution measurement method for proton beam therapy using imaging plate and EBT3.

Although there are several two-dimensional (2D) dose-distribution measurement methods using proton beam therapy, they all have drawbacks; hence, there is no standard method established worldwide. The purpose of this study was to develop a simple, high-precision 2D distribution measurement method for proton beam therapy that uses an imaging plate and EBT3. First, we expanded the maximum readable dose (saturation dose) in the imaging plate. The method involves (i) the control of the fading phenomenon by an annealing process and (ii) the control of the photostimulated luminescence (PSL) phenomenon using a longpass filter (LPF). In method (i), upon heating at 80 °C, the PSL became 0.485 times the room temperature, and in method (ii), we attenuated the PSL by a factor of 0.245 using an LPF. Thus, by combining methods (i) and (ii), we expanded the saturation dose to 2 Gy. Thus, it was possible to measure the imaging plate and EBT3 in the same dose range. We simultaneously measured the percent depth dose using imaging plate and EBT3. We defined a correction factor to match the measured values-which had a reduced sensitivity because of the linear energy transfer (LET) dependence of the imaging plate and EBT3-with reference data and developed a correction factor function. Subsequently, by defining the relative LET dependence of imaging plate and EBT3 as the relative sensitivity and converting the relationship imaging plate between the relative sensitivity and correction factor into a function, we obtained a sensitivity-correction function. By employing this function, measurements with the same accuracy as the reference data were performed using the imaging plate and EBT3.