Modelling and calculation of dna damage and repair in mammalian cells induced by ionizing radiation of different quality

Recent experimental data have revealed a wealth of information that provides an exceptional opportunity to construct a mechanistic model of DNA repair. The cellular response to radiation exposure starts with repair of DNA damage and cell signalling that may lead to mutation, or cell death. The purpose of this work was to construct a mechanistic mathematical model of DNA repair in mammalian cells. The repair m odel is based on biochemical action of repair proteins to examin e the hypotheses regarding two or more components of double strand break ( DSB ) repair kinetics. The mechanistic mathematical model of repair proposed in this thesis is part of a bottom - up appr oach that assumes the cell is a complex system. In this approach radiation induces DNA damage, and the cellular response to radiation perturbation was modelled in terms of activating repair processes. A b iochemical kinetic method based on law of mass actio n was employed to model the repair pathways. The repair model consists of a set of nonlinear differential equations that calculates and explains protein act ivity on the damage step by step. The model takes into account complexity of the DSB, topology of da mage in the cell nucleus, and cell cycle . The solution of the model in terms of overall kinetics of DSB repair was compared with pulsed - field gel electrophoresis measurements. The repair model was integrated with the track structure model to calculate the damage spectrum and repair kinetics for every individual DSB induced by monoenergetic electrons, and ultrasoft X - rays. For this purpose we proposed a method to sample the protein repair actions for every individual DSB, and finally calculate the total repa ir time for that specific DSB. The DSB - repair kinetics for the number of DSB induced by 500 track s of monoenergetic electrons and ultrasoft X - rays were calculated and compared with experimental results for cell s irradiated with Al K , C K , and Ti K ultrasoft X - rays. The results presented here form the first example of mechanistic modelling and calculations for NHEJ, HR and MMEJ repair pathways. The results, for the first time , quantitatively confirm the hypothesis that the complex type double strand breaks play a major role in the slow kinetics of DSB repair. The results also confirm that simple DSB located in the heterocromatin delay the repair process due to a series of processes that are required for the relaxation of the heterochromatin. The rep air model established in this work provides a unique opportunity to continue this study of cellular responses to radiation furth er downstream that may have important implications for human risk estimation and radiotherapy

Mitigating disruptions, and scalability of radiation oncology physics work during the COVID-19 pandemic

PURPOSE: The COVID-19 pandemic has led to disorder in work and livelihood of a majority of the modern world. In this work, we review its major impacts on procedures and workflow of clinical physics tasks, and suggest alternate pathways to avoid major disruption or discontinuity of physics tasks in the context of small, medium, and large radiation oncology clinics. We also evaluate scalability of medical physics under the stress of social distancing . METHODS: Three models of facilities characterized by the number of clinical physicists, daily patient throughput, and equipment were identified for this purpose. For identical objectives of continuity of clinical operations, with constraints such as social distancing and unavailability of staff due to system strain, however with the possibility of remote operations, the performance of these models was investigated. General clinical tasks requiring on-site personnel presence or otherwise were evaluated to determine the scalability of the three models at this point in the course of disease spread within their surroundings. RESULTS: The clinical physics tasks within three models could be divided into two categories. The former, which requires individual presence, include safety-sensitive radiation delivery, high dose per fraction treatments, brachytherapy procedures, fulfilling state and nuclear regulatory commission\u27s requirements, etc. The latter, which can be handled through remote means, include dose planning, physics plan review and supervision of quality assurance, general troubleshooting, etc. CONCLUSION: At the current level of disease in the United States, all three models have sustained major system stress in continuing reduced operation. However, the small clinic model may not perform if either the current level of infections is maintained for long or staff becomes unavailable due to health issues. With abundance, and diversity of innovative resources, medium and large clinic models can sustain further for physics-related radiotherapy services

Inducing Accelerated Lung Toxicity in Mice Using a Partial Arc SBRT Technique

Background Radiation-induced pulmonary fibrosis (RIPF) is a frequent outcome of thoracic radiation therapy, constraining safe tumor radiation dosage. Various animal models, such as mice, rats, and pigs, have been devised to study RIPF Current methods for inducing lung fibrosis in mice involve whole lung irradiation with doses between 2-20 Gy. These methods used fixed anterior and posterior (AP/PA) x-ray beams at 0º and 180º with analysis typically commencing 24 to 52 weeks post-radiation Current methods are unrepresentative of modern radiation therapy techniques and are limited by the associated long latency of RIPFhttps://jdc.jefferson.edu/radoncposters/1000/thumbnail.jp

Characterization of Dynamic Regulatory Gene and Protein Networks in Wheat Roots Upon Perceiving Water Deficit Through Comparative Transcriptomics Survey

A well-developed root system benefits host plants by optimizing water absorption and nutrient uptake and thereby increases plant productivity. In this study we have characterized the root transcriptome using RNA-seq and subsequential functional analysis in a set of drought tolerant and susceptible genotypes. The goal of the study was to elucidate and characterize water deficit-responsive genes in wheat landraces that had been through long-term field and biochemical screening for drought tolerance. The results confirm genotype differences in water-deficit tolerance in line with earlier results from field trials. The transcriptomics survey highlighted a total of 14,187 differentially expressed genes (DEGs) that responded to water deficit. The characterization of these genes shows that all chromosomes contribute to water-deficit tolerance, but to different degrees, and the B genome showed higher involvement than the A and D genomes. The DEGs were mainly mapped to flavonoid, phenylpropanoid, and diterpenoid biosynthesis pathways, as well as glutathione metabolism and hormone signaling. Furthermore, extracellular region, apoplast, cell periphery, and external encapsulating structure were the main water deficit-responsive cellular components in roots. A total of 1,377 DEGs were also predicted to function as transcription factors (TFs) from different families regulating downstream cascades. TFs from the AP2/ERF-ERF, MYB-related, B3, WRKY, Tify, and NAC families were the main genotype-specific regulatory factors. To further characterize the dynamic biosynthetic pathways, protein-protein interaction (PPI) networks were constructed using significant KEGG proteins and putative TFs. In PPIs, enzymes from the CYP450, TaABA8OH2, PAL, and GST families play important roles in water-deficit tolerance in connection with MYB13-1, MADS-box, and NAC transcription factors

Spatial mapping of the biologic effectiveness of scanned particle beams: towards biologically optimized particle therapy

The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE