Coordinating gene expression during the cell cycle.

Cell cycle-dependent gene transcription is tightly controlled by the retinoblastoma (RB):E2F and DREAM complexes, which repress all cell cycle genes during quiescence. Cyclin-dependent kinase (CDK) phosphorylation of RB and DREAM allows for the expression of two gene sets. The first set of genes, with peak expression in G1/S, is activated by E2F transcription factors (TFs) and is required for DNA synthesis. The second set, with maximum expression during G2/M, is required for mitosis and is coordinated by the MuvB complex, together with B-MYB and Forkhead box M1 (FOXM1). In this review, we summarize the key findings that established the distinct control mechanisms regulating G1/S and G2/M gene expression in mammals and discuss recent advances in the understanding of the temporal control of these genes.

Non-cell-autonomous regulation of petal initiation in Arabidopsis thaliana.

In many flowering plants, petals initiate in alternate positions from first whorl sepals, suggesting possible signaling between sepal boundaries and petal initiation sites. PETAL LOSS (PTL) and RABBIT EARS (RBE) regulate petal initiation in Arabidopsis thaliana and their transcripts are expressed in sepal boundary and petal initiation sites, respectively, suggesting that PTL acts in a non-cell-autonomous manner. Here, we determined that cells expressing PTL and RBE fusion proteins did not overlap but were adjacent, confirming the non-cell-autonomous function of PTL. Genetic ablation of intersepal cells by expressing the diphtheria toxin-A chain gene driven by the PTL promoter resulted in flowers lacking petals, suggesting these cells are required for petal initiation. Transcriptome analysis combined with a PTL induction system revealed 42 genes that were upregulated under PTL activation, including UNUSUAL FLORAL ORGANS (UFO), which likely plays an important role in petal initiation. These findings suggest a molecular mechanism in which PTL indirectly regulates petal initiation and UFO mediates positional signaling between the sepal boundary and petal initiation sites.

Incorporating variable RBE in IMPT optimization for ependymoma.

PURPOSE: To study the dosimetric impact of incorporating variable relative biological effectiveness (RBE) of protons in optimizing intensity-modulated proton therapy (IMPT) treatment plans and to compare it with conventional constant RBE optimization and linear energy transfer (LET)-based optimization. METHODS: This study included 10 pediatric ependymoma patients with challenging anatomical features for treatment planning. Four plans were generated for each patient according to different optimization strategies: (1) constant RBE optimization (ConstRBEopt) considering standard-of-care dose requirements; (2) LET optimization (LETopt) using a composite cost function simultaneously optimizing dose-averaged LET (LETd ) and dose; (3) variable RBE optimization (VarRBEopt) using a recent phenomenological RBE model developed by McNamara et al.; and (4) hybrid RBE optimization (hRBEopt) assuming constant RBE for the target and variable RBE for organs at risk. By normalizing each plan to obtain the same target coverage in either constant or variable RBE, we compared dose, LETd , LET-weighted dose, and equivalent uniform dose between the different optimization approaches. RESULTS: We found that the LETopt plans consistently achieved increased LET in tumor targets and similar or decreased LET in critical organs compared to other plans. On average, the VarRBEopt plans achieved lower mean and maximum doses with both constant and variable RBE in the brainstem and spinal cord for all 10 patients. To compensate for the underdosing of targets with 1.1 RBE for the VarRBEopt plans, the hRBEopt plans achieved higher physical dose in targets and reduced mean and especially maximum variable RBE doses compared to the ConstRBEopt and LETopt plans. CONCLUSION: We demonstrated the feasibility of directly incorporating variable RBE models in IMPT optimization. A hybrid RBE optimization strategy showed potential for clinical implementation by maintaining all current dose limits and reducing the incidence of high RBE in critical normal tissues in ependymoma patients.

The sensitivity of radiobiological models in carbon ion radiotherapy (CIRT) and its consequences on the clinical treatment plan: Differences between LEM and MKM models.

PURPOSE: Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)-weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE-distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE-weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE-weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions. METHODS: Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT-geometry, optimizing LEM RBE-weighted dose first and recomputing MKM thereafter. Dose-averaged linear energy transfer (LETd) distributions were also assessed. RESULTS: Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM-dose distributions lead to markedly different MKM-dose distributions and variations in LETd. Generally, a homogeneous LEM RBE-weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution. CONCLUSIONS: Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE-weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes.

Radiation exposure of astronauts following an intense solar particle event: analysis and comparison of doses in male and female voxel phantoms.

According to NASA's plans, a human travel to the Moon is planned by the end of 2025 with the Artemis II mission, and humans should land on the Moon again in 2026. Exposure to space radiation is one of the main risks for the crew members; while for these short missions the doses from galactic cosmic rays would be relatively low, the possible occurrence of an intense solar particle event (SPE) represents a major concern, especially considering that in 2025 the Sun activity will be at its peak. Quantifying the amount and the effects of such exposure is therefore crucial, to identify shielding conditions that allow respecting the dose limits established by the various space agencies. By exploiting an interface between the BIANCA biophysical model and the FLUKA Monte Carlo radiation transport code, in this work we implemented a male and a female voxel phantom and we calculated absorbed doses and Gy-Eq doses in the various tissues/organs, as well as effective doses, following exposure to the August 1972 SPE, the most intense event of the modern era. The calculations were performed respect the organ dose limits for 30 d missions. A detailed comparison between male and female doses was then carried out, also considering that the Artemis II crew will include a woman. The results showed that female doses tend to be higher than male doses, especially with light shielding. This should be taken into account in mission design, also considering that, in a typical lunar mission, up to 15% of time may be spent in extra-vehicular activities, and thus with light shielding. More generally, this work outlines the importance of performing separate calculations for male and female astronauts when dealing with radiation doses and effects.

Treatment of primary or recurrent non-resectable pancreatic cancer with proton beam irradiation combined with gemcitabine-based chemotherapy.

BACKGROUND: Pancreatic cancer accounts for around 4.6% of cancers deaths worldwide per year. Despite many advances in treatment regimes, the prognosis is still poor. Only 20% of tumors are primarily resectable. Recurrences-both with distant metastasis as well as locoregional-are frequent. For patients with primary nonresectable localized disease or localized recurrences, we offered chemoradiation to achieve local control over a long period of time. We here report our results on combined chemoradiation of pancreatic tumors and local recurrences using proton beam therapy. MATERIALS AND METHODS: We report on 25 patients with localized nonresectable pancreatic cancer (15 patients) or local recurrent disease (10 patients). All patients were treated with combined proton radiochemotherapy. Overall survival, progression-free survival, local control, and treatment-related toxicity were analyzed using statistically methods. RESULTS: Median RT dose was 54.0 Gy (RBE) for proton irradiation. The toxicity of treatment was acceptable. Four CTCAE grade III and IV adverse events (bone marrow disfunction, gastrointestinal [GI] disorders, stent dislocation, myocardial infarction) were recorded during or directly after the end of radiotherapy; two of them were related to combined chemoradiation (bone marrow disfunction, GI disorders). Six weeks after radiotherapy, one additional grade IV toxicity was reported (ileus, caused by peritoneal carcinomatosis, not treatment related). The median progression-free survival was 5.9 months and median overall survival was 11.0 months. The pretherapy CA19­9 level was a statistically significant prognostic factor for enhanced overall survival. Local control at 6 months and 12 months were determined to be 86% and 80%, respectively. CONCLUSION: Combined proton chemoradiation leads to high local control rates. Unfortunately, PFS and OS are driven by distant metastasis and were not improved compared to historical data and reports. With this in mind, enhanced chemotherapeutical regimes, in combination with local irradiation, should be evaluated.

Relative biological effectiveness of low-energy X-rays (25 kV) in mutant p53 cancer cells.

Low-energy X-rays as used in radiation therapy and diagnostics such as mammography are associated with a certain risk of promoting tumour development, especially in patients with mutations in cancer-related genes like TP53. The present study therefore addressed the relative biological effectiveness (RBE) of low-energy X-rays for two human adenocarcinoma cell lines of the breast (MDA-MB-468) and pancreas (BxPC-3) with a mutation in the TP53 gene. Clonogenic survival and cytogenetic changes in terms of micronuclei (MN) formation were determined following irradiation with 25 kV X-rays and 200 kV reference irradiation in the dose range of 1-8 Gy. Except the frequency of MN-containing binucleated cells (BNC) (BNC + MN/BNC) in breast cancer cells yielding an RBE between 0.6 and 0.8, both cell lines displayed dose-dependent variations of RBE values between 1 and 2 for all biological end points (cell survival, (BNC + MN/BNC), MN/BNC, MN/(BNC + MN)) with increased effectiveness of 25 kV irradiation in pancreatic compared to breast cancer cells. The results confirm previous findings indicating increased effectiveness of low-energy X-rays and underline the necessity of careful risk estimation for cancer screening programmes.

Calculating dose-averaged linear energy transfer in an analytical treatment planning system for carbon-ion radiotherapy.

BACKGROUND: Compelling evidence shows the association between the relative biological effectiveness (RBE) of carbon-ion radiotherapy (CIRT) and the dose averaged linear energy transfer (LETd). However, the ability to calculate the LETd in commercially available treatment planning systems (TPS) is lacking. PURPOSE: This study aims to develop a method of calculating the LETd of CIRT plans that could be robustly carried out in RayStation (V10B, Raysearch, Sweden). METHODS: The calculation used the fragment spectra in RayStation for the CIRT treatment planning. The dose-weighted averaging procedure was supported by the microdosimetric kinetic model (MKM). The MKM-based pencil beam dose engine (PBA, v4.2) for calculating RBE-weighted doses was reformulated to become a LET-weighted calculating engine. A separate module was then configured to inversely calculate the LETd from the absorbed dose of a plan and the associated fragment spectra. In this study, the ion and energy-specific LET table in the LETd module was further matched with the values decoded from the baseline data of the Syngo TPS (V13C, Siemens, Germany). The LETd distributions of several monoenergetic and modulated beams were calculated and validated against the values derived from the Syngo TPS and the published data. RESULTS: The differences in LETds of the monoenergetic beams between the new method and the traditional method were within 3% in the entrance and Bragg-peak regions. However, a larger difference was observed in the distal region. The results of the modulated beams were in good agreement with the works from the published literature. CONCLUSIONS: The method presented herein reformulates the MKM dose engine in the RayStation TPS to inversely calculate LETds. The robustness and accuracy were demonstrated.

X-ray and DNA Damage: Limitations of the Dose as a Parameter for In Vitro Studies.

A century of studies has demonstrated that the magnitude of a radiation dose determines the extent of its biological effect. However, different types of radiation show different levels of effectiveness. Although all types of X-rays are usually considered to be equivalent, several authors have demonstrated an inverse relationship between photon energy and the biological effectiveness of the X-ray. Nonetheless, the differences among 50-100 keV X-rays are usually considered absent. However, comparing different types of X-rays with different energies is not easy since they are often used with different dose rates, and the latter can be a confounding factor. We compared the biological effectiveness of X-rays with different photon energies but with the same dose rate. Moreover, we also studied X-ray with different dose rates but the same photon energy. Biological effectiveness was assessed measuring DNA damage and cell survival. We confirmed that both the dose rate and photon energy influence the effectiveness of an X-ray. Moreover, we observed that differences in the 50-100 keV range are detectable after controlling for dose-rate variations. Our results, confirming those of previous studies in a more consistent way (and accompanied by hypotheses on the importance of the number of incident photons), underline the limitations of using the dose as the sole parameter for in vitro studies.

New operational quantities (RBE ×Dp lens/Φ) for eye lens neutron dosimetry as a function of energy and angle of incidence in the ICRU 95 formalism.

This paper is a continuation of a study published recently by the authors. It presents and discusses computed personal absorbed dose in the lens of the eye (Dp lens/Φ), and a relative biological effectiveness (RBE)-weighted absorbed dose (in terms of an newly proposed operational quantity RBE ×Dp lens/Φ), conversion coefficients for the lens of the eye for neutron exposure at incident energies from thermal to ∼20 MeV and at angles of incidence from 0°to 90°in 15° increments, at 180° and for rotational incidence irradiation geometry (from 0°to 360°in 5°increments). These conversion coefficients were obtained from a simulation model developed for this study that contains the stylised eye model, embedded in the adult UF-ORNL mathematical phantom, whereby the previously stated RBE-weighted absorbed dose was obtained using the proposed RBE versus neutron energy distribution compiled in a previous paper by the authors. The simulations carried out for this study using the Monte Carlo N-Particle transport code version 6.2, were conducted in a realistic human eye model, for the left and right sensitive and whole volume of the lens of the eye, considering the recent proposed redefinition of the operational quantities for external radiation exposure in International Commission on Radiation Units and Measurements (ICRU) report 95. A comprehensive set of tabulated data for neutron fluence-to-dose conversion coefficients (Dp lens/Φin pGy cm2) and RBE-weighted absorbed dose (RBE ×Dp lens/Φin pGy cm2) conversion coefficients is included in this paper as a function of incident neutron energy and angle of incidence. Data forDp lens/Φ(pGy cm2) are compared to similar data from the literature for validation of our model. Data for RBE ×Dp lens/Φ(in pGy cm2), were also compared to the equivalent operational quantityHp(3,α)/Φ(in pSv cm2) conversion coefficients calculated at 3 mm depth in a cylindrical phantom for different incident neutron energies and angles of incidence from 0°to 75°in 15°increments to demonstrate the relevance of this newly proposed operational quantity for doses resulting in tissue reactions (deterministic effects) which should be quoted in Gray (RBE-weighted absorbed dose, RBE ×D(Gy)), rather than Sievert (Sv) which is reserved for stochastic effects. The current neutron weighted absorbed dose (RBE ×Dp lens) is proposed for the tissue reactions in the eye-lens for neutron radiation as per National Council on Radiation Protection and Measurements report 180 and in line with the recent proposal for the review and revision of the System of Radiological Protection to Keeping the International Commission on Radiological Protection (ICRP) recommendations fit for purpose. This method would bring better alignment between the dose limits in ICRP 118 and the new operational quantity consistent with the units of the new eye-lens dose limits without being overly conservative. The utilization of the proposed new operational quantities, as outlined in ICRU 95, has the potential to address the ongoing challenge in enforcing regulatory limits for neutron eye dose, specifically the use of Gy instead of Sv. It should be noted that the applicability of this will vary from country to country as in many countries the legislation is likely to mandate the use ofHp(3) until the regulation is amended. This approach can serve as an interim solution while awaiting the issuance of the new ICRP general recommendations, which is expected to take several years. Implementing the new operational quantities can contribute to enhancing the accuracy and effectiveness of neutron eye dose limit enforcement.

Anti-tumor Effect of High Doses of Carbon Ions and X-Rays during Irradiation of Ehrlich Ascites Carcinoma Cells Ex Vivo.

The effect of carbon ions (12C) with the energy of 400 MeV/nucleon on the dynamics of induction and growth rate of solid tumors in mice under irradiation of Ehrlich ascites carcinoma cells (EAC) ex vivo at doses of 5-30 Gy relative to the action of equally effective doses of X-ray radiation was studied. The dynamics of tumor induction under the action of 12C and X-rays had a similar character and depended on the dose during 3 months of observation. The value of the latent period, both when irradiating cells with 12C and X-ray, increased with increasing dose, and the interval for tumor induction decreased. The rate of tumor growth after ex vivo irradiation of EAC cells was independent of either dose or type of radiation. The dose at which EAC tumors are not induced within 90 days was 30 Gy for carbon ions and 60 Gy for X-rays. The value of the relative biological effectiveness of carbon ions, calculated from an equally effective dose of 50% probability of tumors, was 2.59.

Towards harmonizing clinical linear energy transfer (LET) reporting in proton radiotherapy: a European multi-centric study.

BACKGROUND: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed. MATERIALS AND METHODS: Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters. RESULTS: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using non-harmonized LET calculations increased inter-center dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1. CONCLUSION: Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.

RBE-weighted dose and its impact on the risk of acute coronary event for breast cancer patients treated with intensity modulated proton therapy.

PURPOSE: To evaluate the relative biological effectiveness (RBE)-weighted dose to the heart and to estimate RBE uncertainties when assuming a constant RBE of 1.1, for breast cancer patients receiving intensity-modulated proton therapy (IMPT). Further, to study the impact of RBE uncertainties on the risk of an acute coronary event (ACE). MATERIAL AND METHODS: We analyzed 20 patients who received IMPT to either the left breast (n = 10) or left chest wall (n = 10) and regional lymph nodes. The Monte Carlo simulation engine, MCsquare, was used to simulate the dose-averaged linear energy transfer (LETd) map. The RBE-weighted dose to the heart and its substructures was calculated using three different RBE models. The risk of ACE was estimated per its linear relationship with mean heart dose (MHD) as established by Darby et al. RESULTS: The median MHD increased from 1.33 GyRBE assuming an RBE of 1.1 to 1.64, 1.87, and 1.99 GyRBE when using the RBE-weighted dose models. The median values (and ranges) of the excess absolute risk of ACE were 0.4% (0.1%-0.8%) when assuming an RBE of 1.1, and 0.6% (0.2%-1.0%), 0.6% (0.2%-1.1%), and 0.7% (0.2%-1.1%) with the RBE-weighted models. For our patient cohort, the maximum excess absolute risk of ACE increased by 0.3% with the RBE-weighted doses compared to the constant RBE of 1.1, reaching an excess absolute ACE risk of 1.1%. The interpatient LETd variation was small for the relevant high-dose regions of the heart. CONCLUSION: All three RBE models predicted a higher biological dose compared to the clinical standard dose assuming a constant RBE of 1.1. An underestimation of the biological dose results in underestimation of the ACE risk. Analyzing the voxel-by-voxel biological dose and the LET map alongside clinical outcomes is warranted in the development of a more accurate normal-tissue complication probability model.

High-Accuracy Relative Biological Effectiveness Values Following Low-Dose Thermal Neutron Exposures Support Bimodal Quality Factor Response with Neutron Energy.

Theoretical evaluations indicate the radiation weighting factor for thermal neutrons differs from the current International Commission on Radiological Protection (ICRP) recommended value of 2.5, which has radiation protection implications for high-energy radiotherapy, inside spacecraft, on the lunar or Martian surface, and in nuclear reactor workplaces. We examined the relative biological effectiveness (RBE) of DNA damage generated by thermal neutrons compared to gamma radiation. Whole blood was irradiated by 64 meV thermal neutrons from the National Research Universal reactor. DNA damage and erroneous DNA double-strand break repair was evaluated by dicentric chromosome assay (DCA) and cytokinesis-block micronucleus (CBMN) assay with low doses ranging 6-85 mGy. Linear dose responses were observed. Significant DNA aberration clustering was found indicative of high ionizing density radiation. When the dose contribution of both the 14N(n,p)14C and 1H(n,γ)2H capture reactions were considered, the DCA and the CBMN assays generated similar maximum RBE values of 11.3 ± 1.6 and 9.0 ± 1.1, respectively. Consequently, thermal neutron RBE is approximately four times higher than the current ICRP radiation weighting factor value of 2.5. This lends support to bimodal peaks in the quality factor for RBE neutron energy response, underlining the importance of radiological protection against thermal neutron exposures.

Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE.

Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are rarely considered. The ion beam RBE-model within our "UNIfied and VERSatile bio response Engine" (UNIVERSE) is extended by including DNA damage repair kinetics to investigate the impact of dose-rate effects on the predicted RBE. It was found that dose-rate effects increase with dose and biological effects saturate at high dose-rates, which is consistent with data- and model-based studies in the literature. In a comparison with RBE measurements from a high dose in-vivo study, the predictions of the presented modification were found to be improved in comparison to the previous version of UNIVERSE and existing clinical approaches that disregard dose-rate effects. Consequently, DNA repair kinetics and the different dose rates applied by the reference and ion beams might need to be considered in biophysical models to accurately predict the RBE. Additionally, this study marks an important step in the further development of UNIVERSE, extending its capabilities in giving theoretical guidance to support progress in ion beam therapy.

On the operational quantity for eye lens neutron dosimetry considering ICRU 95 report.

For planned occupational exposure situations, the International Commission on Radiological Protection (ICRP) publication 118 recommends an equivalent dose limit for the lens of the eye of 20 mSv yr-1averaged over 5 yr with no single year exceeding 50 mSv. Regulatory authorities of various jurisdictions worldwide followed some or all, of the ICRP recommendations and implemented reduced occupational lens of eye dose limits in their legislation. As compliance with the eye-lens dose limit will be based on the summation of doses received from all types of radiation, applicable to a variety of workplaces, the contribution of neutrons to eye lens dose will be important where it contributes a significant fraction of the total dose to the eye lens. This work presents and discusses computed personal absorbed dose (Dlens/Φ), and personal dose equivalent (Hp(3)/Φ) as well as a newly proposed relative biological effectiveness (RBE)-weighted absorbed dose (RBE ×Dlens/Φ) conversion coefficients for the lens of the eye for neutron exposure at incident energies from thermal to ∼20 MeV. TheDlens/Φ coefficients were obtained from a simulation model developed for this study that contains the stylised eye model embedded in the adult UF-ORNL mathematical phantom. The modelling techniques used in these simulations were also used to calculateHp(3)/Φ for the International Commission on Radiation Units and Measurements (ICRU) slab and cylinder phantoms. All simulations carried out for this study utilised the Monte Carlo N-Particle (MCNP) series of codes. The results are compared with the related published data. The issue of compliance with the current equivalent dose limit for the lens of the eye is addressed from a neutron perspective considering the recent proposed redefinition of the operational quantities for external radiation exposure in ICRU report 95. The use of a radiation weighted absorbed dose (RBE ×Dlens, in Gy) is proposed for the tissue reactions in the eye-lens for neutron radiation as per the National Council on Radiation Protection and Measurements report 180, and in line with the recent review and revision of the System of Radiological Protection To Keeping the ICRP Recommendations Fit for Purpose, which states that RBE weighted dose should be used for high-Linear energy transfer (LET) radiations such as neutrons. This confirms the earlier statement in ICRP publication 92, paragraph 297 and reiterated in the Executive summary, paragraph (q) of ICRP publication 118. The proposed approach would provide an operational quantity consistent with the units of the new eye-lens dose limits without being overly conservative.

Variation in relative biological effectiveness for cognitive structures in proton therapy of pediatric brain tumors.

BACKGROUND: Clinically, a constant value of 1.1 is used for the relative biological effectiveness (RBE) of protons, whereas in vitro the RBE has been shown to vary depending on physical dose, tissue type, and linear energy transfer (LET). As the LET increases at the distal end of the proton beam, concerns exist for an elevated RBE in normal tissues. The aim of this study was therefore to investigate the heterogeneity of RBE to brain structures associated with cognition (BSCs) in pediatric suprasellar tumors. MATERIAL AND METHODS: Intensity-modulated proton therapy (IMPT) plans for 10 pediatric craniopharyngioma patients were re-calculated using 11 phenomenological and two plan-based variable RBE models. Based on LET, tissue dependence and number of data points used to fit the models, the three RBE models considered the most relevant for the studied endpoint were selected. Thirty BSCs were investigated in terms of RBE and dose/volume parameters. RESULTS: For a representative patient, the median (range) dose-weighted mean RBE (RBEd) across all BSCs from the plan-based models was among the lowest (1.09 (1.02-1.52) vs. the phenomenological models at 1.21 (0.78-2.24)). Omitting tissue dependency resulted in RBEd at 1.21 (1.04-2.24). Across all patients, the narrower RBE model selection gave median RBEd values from 1.22 to 1.30. CONCLUSION: For all BSCs, there was a systematic model-dependent variation in RBEd, mirroring the uncertainty in biological effects of protons. According to a refined selection of in vitro models, the RBE variation across BSCs was in effect underestimated when using a fixed RBE of 1.1.

All-Trans Retinoic Acid Prevented Vein Grafts Stenosis by Inhibiting Rb-E2F Mediated Cell Cycle Progression and KLF5-RARα Interaction in Human Vein Smooth Muscle Cells.

PURPOSE: Vein graft failure (VGF) is an important limitation for coronary artery bypass graft (CABG) surgery. Inhibition of the excessive proliferation and migration of venous smooth muscle cells (SMCs) is an effective strategy to alleviate VGF during the CABG perioperative period. In the present study, we aimed to explore the role and potential mechanism of all-trans retinoic acid (ATRA) on preventing vein grafts stenosis. METHODS: The autogenous vein grafts model was established in the right jugular artery of rabbits. Immunohistochemistry staining and western blot assays were used to detected the protein expression, while real-time PCR assay was applied for mRNAs expression detection. The interaction between proteins was identified by co-immunoprecipitation assay. The Cell Counting Kit-8 and wound-healing assays were used to investigate the role of ATRA on human umbilical vein smooth muscle cells (HUVSMCs) function. Cell cycle progression was identified by flow cytometry assay. RESULTS: Vein graft stenosis and SMCs hyperproliferation were confirmed in vein grafts by histological and Ki-67 immunohistochemistry assays. Treatment of ATRA (10 mg/kg/day) significantly mitigated the stenosis extent of vein grafts, demonstrated by the decreased thickness of intima-media, and decreased Ki-67 expression. ATRA could repress the PDGF-bb-induced excessive proliferation and migration of HUVSMCs, which was mediated by Rb-E2F dependent cell cycle inhibition. Meanwhile, ATRA could reduce the interaction between KLF5 and RARα, thereby inhibiting the function of cis-elements of KLF5. KLF5-induced inducible nitric oxide synthase (iNOS) expression activation could be significantly inhibited by ATRA. CONCLUSIONS: These results suggested that ATRA treatment may represent an effective prevention and therapy avenue for VGF.

Physical and biological beam modeling for carbon beam scanning at Osaka Heavy Ion Therapy Center.

We have developed physical and biological beam modeling for carbon scanning therapy at the Osaka Heavy Ion Therapy Center (Osaka HIMAK). Carbon beam scanning irradiation is based on continuous carbon beam scanning, which adopts hybrid energy changes using both accelerator energy changes and binary range shifters in the nozzles. The physical dose calculation is based on a triple Gaussian pencil-beam algorithm, and we thus developed a beam modeling method using dose measurements and Monte Carlo simulation for the triple Gaussian. We exploited a biological model based on a conventional linear-quadratic (LQ) model and the photon equivalent dose, without considering the dose dependency of the relative biological effectiveness (RBE), to fully comply with the carbon passive dose distribution using a ridge filter. We extended a passive ridge-filter design method, in which carbon and helium LQ parameters are applied to carbon and fragment isotopes, respectively, to carbon scanning treatment. We then obtained radiation quality data, such as the linear energy transfer (LET) and LQ parameters, by Monte Carlo simulation. The physical dose was verified to agree with measurements to within ±2% for various patterns of volume irradiation. Furthermore, the RBE in the middle of a spread-out Bragg peak (SOBP) reproduced that from passive dose distribution results to within ±1.5%. The developed carbon beam modeling and dose calculation program was successfully applied in clinical use at Osaka HIMAK.

Separation and Identification of Resveratrol Butyrate Ester Complexes and Their Bioactivity in HepG2 Cell Models.

Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica gel, high-performance liquid chromatography, and 1H nuclear magnetic resonance were used for separation and identification of RBE complex components. With the exception of resveratrol, five different structures of ester derivatives were separated from silica gel: 3,4'-di-O-butanoylresveratrol (ED2, 18.8%), 3-O-butanoylresveratrol (ED4, 35.7%), 4'-O-butanoylresveratrol (ED5, 4.4%), 3,5,4'-tri-O-butanoylresveratrol (ED6, 1.5%), and 3,5-di-O-butanoylresveratrol (ED7, 0.7%). Among the ester derivatives obtained, ED2 and ED4 were the main ester derivatives in the RBE complex. Thus, the cellular antioxidant activities of the RBE mixture, ED2, and ED4 were evaluated. Results showed that the antioxidant capacity of ED2 and ED4 was higher than that of the RBE mixture, demonstrating that the number and position of butyrate esterification sites are related to cell survival rate and antioxidant capacity. This study is the first to report the successful isolation, structural identification, and cellular biological antioxidant activity of RBE complex derivatives, which are key characteristics for the potential practical application of RBE complexes.