The contribution of high-LET track to DNA damage formation and cell death for Monoenergy and SOBP carbon ion irradiation.

Carbon ion radiotherapy (CIRT) is a heavy ion charge particle therapy with 29 years of prominent use. Despite advantages like high relative biological effectiveness (RBE), improved quality of life, and reduced treatment time, challenges persist, especially regarding heavy nuclear fragments. Our research addresses these challenges in horizontal irradiation, aiming to comprehend Monoenergetic and Spread-Out Bragg peak (SOBP) carbon ion beam trajectories using cell survival analysis and visualizing biological effects through DNA damage (γ-H2AX). This reveals repair-related protein foci near the Bragg peak. CR-39, a plastic nuclear track detector, was explored to understand high-linear energy transfer (LET) tracks and radiation quality near the Bragg peak. Findings unveil high-LET DNA damage signatures through aligned γ-H2AX foci, correlating with LET values in SOBP. CR-39 visualized high-LET particle exposure, indicating comet-type etch-pits at the Bragg peak and suggesting carbon ion fragmentation. Unexpectedly, dot-type etch-pits in irradiated and post-Bragg peak regions indicated high-LET neutron production. This investigation highlights the intricate interplay of carbon ion beams, stressing the importance of understanding LET variations, DNA damage patterns, and undesired secondary exposure.

Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development.

Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, and craniofacial and/or renal defects. Variants in the transcription factor Six1 and its co-factor Eya1, both of which are required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 co-factor, and SOBP variants in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-immunoprecipitation and immunofluorescence experiments demonstrate that Sobp binds to and colocalizes with Six1 in the cell nucleus. Luciferase assays show that Sobp interferes with the transcriptional activation of Six1+Eya1 target genes. Experiments in Xenopus embryos that either knock down or increase expression of Sobp show that it is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression of Xenopus Sobp containing the human variant disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function and is required for vertebrate craniofacial development, and identify Sobp as a potential candidate gene for BOR.

Using Xenopus to discover new candidate genes involved in BOR and other congenital hearing loss syndromes.

Hearing in infants is essential for brain development, acquisition of verbal language skills, and development of social interactions. Therefore, it is important to diagnose hearing loss soon after birth so that interventions can be provided as early as possible. Most newborns in the United States are screened for hearing deficits and commercially available next-generation sequencing hearing loss panels often can identify the causative gene, which may also identify congenital defects in other organs. One of the most prevalent autosomal dominant congenital hearing loss syndromes is branchio-oto-renal syndrome (BOR), which also presents with defects in craniofacial structures and the kidney. Currently, mutations in three genes, SIX1, SIX5, and EYA1, are known to be causative in about half of the BOR patients that have been tested. To uncover new candidate genes that could be added to congenital hearing loss genetic screens, we have combined the power of Drosophila mutants and protein biochemical assays with the embryological advantages of Xenopus, a key aquatic animal model with a high level of genomic similarity to human, to identify potential Six1 transcriptional targets and interacting proteins that play a role during otic development. We review our transcriptomic, yeast 2-hybrid, and proteomic approaches that have revealed a large number of new candidates. We also discuss how we have begun to identify how Six1 and co-factors interact to direct developmental events necessary for normal otic development.

Proton therapy induces a local microglial neuroimmune response.

BACKGROUND AND PURPOSE: Although proton therapy is increasingly being used in the treatment of paediatric and adult brain tumours, there are still uncertainties surrounding the biological effect of protons on the normal brain. Microglia, the brain-resident macrophages, have been shown to play a role in the development of radiation-induced neurotoxicity. However, their molecular and hence functional response to proton irradiation remains unknown. This study investigates the effect of protons on microglia by comparing the effect of photons and protons as well as the influence of age and different irradiated volumes. MATERIALS AND METHODS: Rats were irradiated with 14 Gy to the whole brain with photons (X-rays), plateau protons, spread-out Bragg peak (SOBP) protons or to 50 % anterior, or 50 % posterior brain sub-volumes with plateau protons. RNA sequencing, validation of microglial priming gene expression using qPCR and high-content imaging analysis of microglial morphology were performed in the cortex at 12 weeks post irradiation. RESULTS: Photons and plateau protons induced a shared transcriptomic response associated with neuroinflammation. This response was associated with a similar microglial priming gene expression signature and distribution of microglial morphologies. Expression of the priming gene signature was less pronounced in juvenile rats compared to adults and slightly increased in rats irradiated with SOBP protons. High-precision partial brain irradiation with protons induced a local microglial priming response and morphological changes. CONCLUSION: Overall, our data indicate that the brain responds in a similar manner to photons and plateau protons with a shared local upregulation of microglial priming-associated genes, potentially enhancing the immune response to subsequent inflammatory challenges.

Calculation of biological effectiveness of SOBP proton beams: a TOPAS Monte Carlo study.

Objective.This study aims to investigate the biological effectiveness of Spread-Out Bragg-Peak (SOBP) proton beams with initial kinetic energies 50-250 MeV at different depths in water using TOPAS Monte Carlo code.Approach.The study modelled SOBP proton beams using TOPAS time feature. Various LET-based models and Repair-Misrepair-Fixation model were employed to calculate Relative Biological Effectiveness (RBE) for V79 cell lines at different on-axis depths based on TOPAS. Microdosimetric Kinetic Model and biological weighting function-based models, which utilize microdosimetric distributions, were also used to estimate the RBE. A phase-space-based method was adopted for calculating microdosimetric distributions.Main results.The trend of variation of RBE with depth is similar in all the RBE models, but the absolute RBE values vary based on the calculation models. RBE sharply increases at the distal edge of SOBP proton beams. In the entrance region of all the proton beams, RBE values at 4 Gy i.e. RBE(4 Gy) resulting from different models are in the range of 1.04-1.07, comparable to clinically used generic RBE of 1.1. Moving from the proximal to distal end of the SOBP, RBE(4 Gy) is in the range of 1.15-1.33, 1.13-1.21, 1.11-1.17, 1.13-1.18 and 1.17-1.21, respectively for 50, 100, 150, 200 and 250 MeV SOBP beams, whereas at the distal dose fall-off region, these values are 1.68, 1.53, 1.44, 1.42 and 1.40, respectively.Significance.The study emphasises application of depth-, dose- and energy- dependent RBE values in clinical application of proton beams.

Prompt X-ray imaging during irradiation with spread-out Bragg peak (SOBP) beams of carbon ions.

Prompt secondary electron bremsstrahlung X-ray (prompt X-ray) imaging using a low-energy X-ray camera is a promising method for observing a beam shape from outside the subject. However, such imaging has so far been conducted only for pencil beams without a multi-leaf collimator (MLC). The use of spread-out Bragg peak (SOBP) with an MLC may increase the scattered prompt gamma photons and decrease the contrast of the images of prompt X-rays. Consequently, we performed prompt X-ray imaging of SOBP beams formed with an MLC. This imaging was carried out in list mode during irradiation of SOBP beams to a water phantom. An X-ray camera with a 1.5-mm diameter as well as 4-mm-diameter pinhole collimators was used for the imaging. List mode data were sorted to obtain the SOBP beam images as well as energy spectra and time count rate curves. Due to the high background counts from the scattered prompt gamma photons penetrating the tungsten shield of the X-ray camera, the SOBP beam shapes were difficult to observe with a 1.5-mm-diameter pinhole collimator. With the 4-mm-diameter pinhole collimators, images of SOBP beam shapes at clinical dose levels could be obtained with the X-ray camera. The use of a 4-mm-diameter pinhole collimator attached to the X-ray camera is effective for prompt X-ray imaging with high sensitivity and low background counts. This approach makes it possible to image SOBP beams with an MLC when the counts are low and the background levels are high.

Direct determination ofkQfor Farmer-type ionization chambers in a clinical scanned carbon-ion beam using water calorimetry.

Within two studies,kQfactors for two Farmer-type ionization chambers have been experimentally determined by means of water calorimetry in the entrance channel (EC) of a monoenergetic carbon-ion beam (Osinga-Blättermannet al2017Phys. Med. Biol.622033-54) and for a passively modulated spread-out Bragg peak (SOBP) (Holmet al2021Phys. Med. Biol.66145012). Both studies were performed at the Heidelberg Ion Beam Therapy Center (HIT) using the PTB portable water calorimeter but applying different initial beam energies of 429 MeV u-1for the EC and 278 MeV u-1for the SOBP as well as different scanning patterns of the irradiated field. Comparing their results revealed differences between the experimentalkQfactors of up to 1.9% between the EC and the SOBP. To further investigate this unexpected difference, we performed additionalkQdeterminations for the EC of an 278 MeV u-1monoenergetic carbon-ion beam and reevaluated the original data of Osinga-Blättermannet al(2017Phys. Med. Biol.622033-54). This new experimental data indicated no difference between thekQfactors for the EC and the SOBP and the reevaluation led to a substantial reduction of the originally publishedkQfactors for the EC of the 429 MeV u-1beam (Osinga-Blättermannet al2017Phys. Med. Biol.622033-54). Finally, no significant difference between the data for the EC and the data for the SOBP can be found within the standard measurement uncertainty of experimentalkQfactors of 0.8%. The results presented here are intended to correct and replace thekQdata published by Osinga-Blättermannet al(2017Phys. Med. Biol.622033-54) and in Osinga-Blättermann and Krauss (2018Phys. Med. Biol.64015009).

Optimization of FLASH proton beams using a track-repeating algorithm.

BACKGROUND: Radiation with high dose rate (FLASH) has shown to reduce toxicities to normal tissues around the target and maintain tumor control with the same amount of dose compared to conventional radiation. This phenomenon has been widely studied in electron therapy, which is often used for shallow tumor treatment. Proton therapy is considered a more suitable treatment modality for deep-seated tumors. The feasibility of FLASH proton therapy has recently been demonstrated by a series of pre- and clinical trials. One of the challenges is to efficiently generate wide enough dose distributions in both lateral and longitudinal directions to cover the entire tumor volume. The goal of this paper is to introduce a set of automatic FLASH proton beam optimization algorithms developed recently. PURPOSE: To develop a fast and efficient optimizer for the design of a passive scattering proton FLASH radiotherapy delivery at The University of Texas MD Anderson Proton Therapy Center, based on the fast dose calculator (FDC). METHODS: A track-repeating algorithm, FDC, was validated versus Geant4 simulations and applied to calculate dose distributions in various beamline setups. The design of the components was optimized to deliver homogeneous fields with well-defined diameters between 11.0 and 20.5 mm, as well as a spread-out Bragg peak (SOBP) with modulations between 8.5 and 39.0 mm. A ridge filter, a high-Z material scatterer, and a collimator with range compensator were inserted in the beam path, and their shapes and sizes were optimized to spread out the Bragg peak, widen the beam, and reduce the penumbra. The optimizer was developed and tested using two proton energies (87.0 and 159.5 MeV) in a variety of beamline arrangements. Dose rates of the optimized beams were estimated by scaling their doses to those of unmodified beams. RESULTS: The optimized 87.0-MeV beams, with a distance from the beam pipe window to the phantom surface (window-to-surface distance [WSD]) of 550 mm, produced an 8.5-mm-wide SOBP (proximal 90% to distal 90% of the maximum dose); 14.5, 12.0, and 11.0-mm lateral widths at the 50%, 80%, and 90% dose location, respectively; and a 2.5-mm penumbra from 80% to 20% in the lateral profile. The 159.5-MeV beam had an SOBP of 39.0 mm and lateral widths of 20.5, 15.0, and 12.5 mm at 50%, 80%, and 90% dose location, respectively, when the WSD was 550 mm. Wider lateral widths were obtained with increased WSD. The SOBP modulations changed when the ridge filters with different characteristics were inserted. Dose rates on the beam central axis for all optimized beams (other than the 87.0-MeV beam with 2000-mm WSD) were above that needed for the FLASH effect threshold (40 Gy/s) except at the very end of the depth dose profile scaling with a dose rate of 1400 Gy/s at the Bragg peak in the unmodified beams. The optimizer was able to instantly design the individual beamline components for each of the beamline setups, without the need of time intensive iterative simulations. CONCLUSION: An efficient system, consisting of an optimizer and an FDC have been developed and validated in a variety of beamline setups, comprising two proton energies, several WSDs, and SOBPs. The set of automatic optimization algorithms produces beam shaping element designs efficiently and with excellent quality.

Biological effects of passive scattering and spot scanning proton beams at the distal end of the spread-out Bragg peak in single cells and multicell spheroids.

PURPOSE: The present study investigated the biological effects of spot scanning and passive scattering proton therapies at the distal end region of the spread-out Bragg peak (SOBP) using single cell and multicell spheroids. MATERIALS AND METHODS: The Geant4 Monte Carlo simulation was used to calculate linear energy transfer (LET) values in passive scattering and spot scanning beams. The biological doses of the two beam options at various points of the distal end region of SOBP were investigated using EMT6 single cells and 0.6-mm V79 spheroids irradiated with 6 and 15 Gy, respectively, by inserting the fractions surviving these doses onto dose-survival curves and reading the corresponding dose. RESULTS: LET values in the entrance region of SOBP were similar between the two beam options and increased at the distal end region of SOBP, where the LET value of spot scanning beams was higher than that of passive scattering beams. Increases in biological effects at the distal end region were similarly observed in single cells and spheroids; biological doses at 2-10 mm behind the distal end were 4.5-57% and 5.7-86% higher than physical doses in passive scattering and spot scanning beams, respectively, with the biological doses of spot scanning beams being higher than those of passive scattering beams (p < .05). CONCLUSIONS: In single cells and spheroids, the effects of proton irradiation were stronger than expected from measured physical doses at the distal end of SOBP and were correlated with LET increases.

Therapeutic Efficacy of Variable Biological Effectiveness of Proton Therapy in U-CH2 and MUG-Chor1 Human Chordoma Cell Death.

BACKGROUND: Chordoma is a cancer of spinal cord, skull base, and sacral area. Currently, the standard of care to treat chordoma is resection followed by radiation therapy. Since, chordoma is present in the spinal cord and these are very sensitive structures and often complete removal by surgery is not possible. As a result, chordoma has a high chance of recurrence and developing resistance to radiation therapy. In addition, treatment of chordoma by conventional radiation therapy can also damage normal tissues surrounding chordoma. Thus, current therapeutic options to treat chordoma are insufficient and novel therapies are desperately needed to treat locally advanced and metastatic chordoma. (2) Methods: In the present investigation, human chordoma cell lines of sacral origin MUG-Chor1 and U-CH2 were cultured and irradiated with Proton Beam Radiation using the clinical superconducting cyclotron and pencil-beam (active) scanning at Middle and End of the Spread-Out Bragg Peak (SOBP). Proton radiation was given at the following doses: Mug-Chor1 at 0, 1, 2, 4, and 8 Gy and U-CH2 at 0, 4, 8, 12, and 16 Gy. These doses were selected based on a pilot study in our lab and attempted to produce approximate survival fractions in the range of 1, 0.9, 0.5, 0.1, and 0.01, respectively, chosen for linear quadratic model fitting of the dose response. (3) Results: In this study, we investigated relative biological effectiveness (RBE) of proton radiation at the end of Spread Out Bragg Peak assuming that the reference radiation is a proton radiation in the middle of the SOBP. We observed differences in the survival of both Human chordoma cell lines, U-CH2 and MUG-Chor1. The data showed that there was a significantly higher cell death at the end of the Bragg peak as compared to middle of the Bragg peak. Based on the linear quadratic (LQ) fit for cell survival we calculated the RBE between M-SOBP and E-SOBP at 95% CI level and it was observed that RBE was higher than 1 at E-SOBP and caused significantly higher cell killing. Proton field at E-SOBP caused complex DNA damage in comparison to M-EOBP and the genes such as DNA topoisomerase 1, GTSE1, RAD51B were downregulated in E-SOBP treated cells. Thus, we conclude that there seems to be substantial variation in RBE (1.3-1.7) at the E-SOBP compared with the M-SOBP.

Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma.

Expression of intragenic exon rearrangements (IERs) has reportedly been detected in both normal and cancer cells. However, there have been few reports of occurrence of these rearrangements specific to neoplasms including malignant lymphoma. In this study, we detected IERs of ten genes (NBPF8, SOBP, AUTS2, RAB21, SPATA13, ABCC4, WDR7, PHLPP1, NFATC1 and MAGED1) in non-Hodgkin B cell lymphoma (B-NHL) cell line KPUM-UH1 using a high-resolution single nucleotide polymorphism array and reverse transcription polymerase chain reaction using reversely directed divergent primers within exons involved in genomic intragenic gains followed by sequencing analysis. Among them, the IERs involved in SOBP (6q21) exon 2 and 3 and AUTS2 (7q11.22) exon 2-4 were the molecular lesions specific to tumors and were frequently detected in B-NHL samples. These IERs constitute novel genetic alterations of B-NHL, which might be associated with tumorigenesis and be useful as genetic biological markers.

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining.

Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons and protons remain elusive. We compared the differences in DNA double strand break (DSB) repair and survival of cells compromised in non-homologous end joining (NHEJ), homologous recombination repair (HRR) or both, after irradiation with an equal dose of X-ray photons, entrance plateau (EP) protons, and mid spread-out Bragg peak (SOBP) protons. We used super-resolution microscopy to investigate potential differences in spatial distribution of DNA damage foci upon irradiation. While DNA damage foci were equally distributed throughout the nucleus after X-ray photon irradiation, we observed more clustered DNA damage foci upon proton irradiation. Furthermore, deficiency in essential NHEJ proteins delayed DNA repair kinetics and sensitized cells to both, X-ray photon and proton irradiation, whereas deficiency in HRR proteins sensitized cells only to proton irradiation. We assume that NHEJ is indispensable for processing DNA DSB independent of the irradiation source, whereas the importance of HRR rises with increasing energy of applied irradiation.

Secondary particle production and physical properties during dose enhancement for spread-out Bragg peaks.

BACKGROUND: The proton therapy is a form of particle radiation therapy that dose enhancement to improve therapeutic ratio (TR) is obtained by high-Z materials. This study evaluated the physical properties of dose enhancement and the resulting changes in the secondary particle production using the spread-out Bragg peak (SOBP). METHODS: Monte Carlo simulations were performed using the Geant4 software and the medical internal radiation dose head phantom. Gold and gadolinium were applied as enhancement materials at concentrations of 10, 20, and 30 mg/g in the tumor volume, and the composition of soft tissue was varied in parallel. The ratio of changes in the reaction caused by the interaction of the initial particles with the enhancement materials was calculated. RESULTS: Among the physical interaction processes, inelastic Coulomb scattering by electrical action occurred with the highest frequency of 99.02%, and elastic collisions, nuclear inelastic collisions, and multiple Coulomb scatterings appeared with low frequencies of 0.633%, 0.334%, and 0.006%, respectively. The use of gold as the enhancement material increased the frequency of interactions by a factor of 1.14-1.18 for inelastic Coulomb scattering, 1.05-1.30 for elastic collision, and 1.03-1.37 for nuclear inelastic collision. Furthermore, the use of gadolinium as the enhancement material increased the frequency of interactions by a factor of 1.08-1.14 for inelastic Coulomb scattering, 1.03-1.25 for elastic collision, and 1.01-1.34 for nuclear inelastic collision. Regarding the dose by the production of secondary particles, the equivalent dose increased by a factor of 1.032-1.070 for alpha particles, 1.133-1.860 for neutrons, and 1.030-1.053 for deuterons when gold was used as the enhancement material. When gadolinium was used as the enhancement material, the equivalent dose increased by a factor of 1.015-1.043 for alpha particles, 1.075-1.478 for neutrons, and 1.021-1.036 for deuterons. CONCLUSIONS: Based on this study's findings, the dose enhancement simulations correspond to the physical characteristics of energy transmission. The study's results can be used as basic data for in vivo and in vitro experiments investigating the effects of dose enhancement.

The FGF1/CPP-C chimera protein protects against intestinal adverse effects of C-ion radiotherapy without exacerbating pancreatic carcinoma.

BACKGROUND AND PURPOSE: Carbon ion (C-ion) beams are concentrated to irradiate pancreatic carcinoma in the upper abdomen; however, this radiotherapy potentially causes adverse reactions in the gastrointestinal tract. FGF1 is a candidate radioprotector for radiation-induced intestinal damage, but may promote the malignancy of pancreatic cancer. An FGF1/CPP-C chimeric protein was created to enhance the intracellular signaling mode of FGF1 instead of FGFR signaling. The present study investigated the effects of FGF1/CPP-C on the intestinal adverse reactions of C-ion radiotherapy as well as its influence on the malignancy of pancreatic cancer. MATERIALS AND METHODS: FGF1/CPP-C was administered intraperitoneally to BALB/c mice without heparin 12 h before total body irradiation (TBI) with low-LET C-ion (17 keV/µm) at 6-8 Gy. Several radioprotective effects were examined in the jejunum. The invasion and migration of the human pancreatic carcinoma cell lines MIAPaCa-2 and PANC-1 were assessed using Boyden chambers after cultures with FGF1/CPP-C. RESULTS: The FGF1/CPP-C treatment promoted crypt survival after C-ion irradiation at 7-8 Gy significantly more than the FGF1 treatment. FGF1/CPP-C also inhibited C-ion radiotherapy-induced apoptosis and reduced γH2AX foci in crypt cells more than FGF1. However, FGF1/CPP-C inhibited the downstream signaling pathways of FGFRs and suppressed the activation of cell-cycle regulatory molecules in the intestine until 4 h after TBI. Furthermore, IEC6 cells were arrested in G2M after cultures with FGF1/CPP-C or FGF1, suggesting that DNA repair after irradiation is promoted by FGF1/CPP-C-induced G2M arrest. In contrast, FGF1/CPP-C appeared to be internalized into MIAPaCa-2 and PANC-1 cells more efficiently than FGF1. Therefore, FGF1/CPP-C reduced the in vitro proliferation, invasion, and migration of MIAPaCa-2 and PANC-1 cells significantly more than FGF1 through the cellular internalization of FGF1. CONCLUSION: These results suggest that the intracellular signaling mode of FGF1/CPP-C attenuates the intestinal adverse effects of C-ion radiotherapy without enhancing the malignancy of pancreatic carcinoma.

Measurements of 2D distributions of absorbed dose in protontherapy with Gafchromic EBT3 films.

A study of the response of EBT3 films to protons has been carried out with the aim of finding a simple modality to achieve dose images in which the effect of the film sensitivity dependence on radiation LET is amended. Light transmittance images (around 630 nm) were acquired by means of a CCD camera and the difference of optical density was assumed as dosimeter response. The calibration of EBT3 film was performed by means of protons of 173.61 MeV. Some EBT3 films were exposed, in a solid-water phantom, to proton beams of three different energies (89.17 MeV, 110.96 MeV and 130.57 MeV) and the obtained depth-dose profiles were compared with the calculated profiles. From the ratios of calculated and measured Bragg peaks, a trend of the decrease in EBT3 sensitivity with increasing peak depth has been deduced. A method for correcting the data measured with EBT3 films, utilizing the file of irradiation planning data, has been proposed and tested. The results confirm that the method can be advantageously applied for obtaining spatial distribution of the absorbed dose in proton therapy.

Using Xenopus to discover new genes involved in branchiootorenal spectrum disorders.

Congenital hearing loss is an important clinical problem because, without early intervention, affected children do not properly acquire language and consequently have difficulties developing social skills. Although most newborns in the US are screened for hearing deficits, even earlier diagnosis can be made with prenatal genetic screening. Genetic screening that identifies the relevant mutated gene can also warn about potential congenital defects in organs not related to hearing. We will discuss efforts to identify new candidate genes that underlie the Branchiootorenal spectrum disorders in which affected children have hearing deficits and are also at risk for kidney defects. Mutations in two genes, SIX1 and EYA1, have been identified in about half of the patients tested. To uncover new candidate genes, we have used the aquatic animal model, Xenopus laevis, to identify genes that are part of the developmental genetic pathway of Six1 during otic and kidney development. We have already identified a large number of potential Six1 transcriptional targets and candidate co-factor proteins that are expressed at the right time and in the correct tissues to interact with Six1 during development. We discuss the advantages of using this system for gene discovery in a human congenital hearing loss syndrome.

Effects of defining realistic compositions of the ocular melanoma on proton therapy.

BACKGROUND: Recent studies in eye plaque brachytherapy have shown a considerable difference between the dosimetric results using water phantom and a model of human eye containing realistic materials. In spite of this fact, there is a lack of simulation studies based on such a model in proton therapy literatures. In the presented work, the effect of utilizing an eye model with ocular media on proton therapy is investigated using the MCNPX Monte Carlo Code. METHODS: Two different eye models are proposed to study the effect of defining realistic materials on dose deposition due to utilizing pencil beam scanning (PBS) method for proton therapy of ocular melanoma. The first model is filled with water, and the second one contains the realistic materials of tumor and vitreous. Spread out Bragg peaks (SOBP) are created to cover a typical tumor volume. Moreover, isodose curves are figured in order to evaluate planar variations of absorbed dose in two models. RESULTS: The results show that the maximum delivered dose in ocular media is approximately 12-32% more than in water phantom. Also it is found that using the optimized weighted beams in water phantom leads to disturbance of uniformity of SOBP in ocular media. CONCLUSION: Similar to the results reported in eye brachytherapy published papers, considering the ocular media in simulation studies leads to a more realistic assessment of sufficiency of the designed proton beam in tissue. This effect is of special importance in creating SOBP, as well as in delivered dose in the tumor boundaries in proton pencil beam scanning method.