arXiv subjects

Ankang Hu

Publications and source records attributed to Ankang Hu.

6 recordsLinked to original sources

arXiv2025

Unraveling the Redox Mechanisms Underlying FLASH Radiotherapy: Critical Dose Thresholds and NRF2-Driven Tissue Sparing

FLASH radiotherapy (FLASH-RT) achieves tumor control comparable to conventional dose-rate irradiation (CONV-RT) while significantly reducing radiation damage to normal tissues. However, the physical conditions triggering the FLASH sparing effect remain unclear, and mechanisms related to oxidative stress and redox regulation are poorly understood. This study utilizes a murine acute intestinal toxicity model to investigate how beam parameters influence the FLASH sparing effect and tumor control using innovative FLASH-RT and CONV-RT combined irradiation. Results demonstrate for the first time that a substantially reduced FLASH dose can still elicit sparing effect, provided a total dose threshold is met. Kinetic simulation and experimental validation demonstrate that FLASH-RT enhances peroxyl radical recombination, reducing reactive oxygen species (ROS) and malondialdehyde levels. Antioxidant interventions further confirm the essential role of free radicals. RNA sequencing and molecular analyses reveal that FLASH-RT activates the nuclear factor E2-related factor 2 (NRF2) antioxidant pathway while suppressing extracellular signal-regulated kinases (ERK) signaling, thereby enhancing cellular redox defenses, reducing apoptosis, and mitigating ROS-mediated tissue injury. These findings highlight the feasibility of optimizing the FLASH-RT therapeutic window through redox modulation and provide a foundation for developing free radical-targeted strategies to improve its therapeutic efficacy.

physics.med-ph↗

arXiv2025

Impact of Oxygen on DNA Damage Distribution in 3D Genome and its Correlation to Oxygen Enhancement Ratio after High-LET Irradiation

The variation of the oxygen enhancement ratio (OER) across linear energy transfer (LET) currently lacks a comprehensive mechanistic interpretation and a mechanistic model. Our earlier research revealed a significant correlation between the distribution of double-strand breaks (DSBs) within 3D genome and radiation-induced cell death, which offers valuable insights into the oxygen effect. We propose a model where the reaction of oxygen is represented as the probability of inducing DNA strand breaks. Then it is integrated into a track-structure Monte Carlo simulation to investigate the impact of oxygen on the distribution of DSBs within 3D genome. Using the parameters from our previous study, we calculate the OER values related to cell survival. Results show that the incidence ratios of clustered DSBs within a single topologically associating domain (TAD) (case 2) and within frequently interacting TADs (case 3) under aerobic and hypoxic conditions align with the trend in the OER of cell survival across LET. Our OER curves exhibit good correspondence with experimental data. This study provides a potentially mechanistic explanation for changes in OER across LET. High-LET irradiation leads to dense ionization events, resulting in an overabundance of lesions that readily induce case 2 and case 3, which have substantially higher probabilities of cell killing than other damage patterns. This may contribute to the main mechanism governing the variation of OER for high LET. Our study further underscores the importance of the DSB distribution within 3D genome in the context of radiation-induced cell death.

physics.bio-ph↗

arXiv2024

Correlation Between DNA Double-Strand Break Distribution in 3D Genome and Radiation-Induced Cell Death

The target theory is the most classical hypothesis explaining radiation-induced cell death, the physical or biological nature of the "target" remains ambiguous. This study hypothesizes that the distribution of DNA double-strand breaks (DSBs) within the 3D genome is a pivotal factor affecting the probability of radiation-induced cell death. We propose that clustered DSBs in DNA segments with high interaction frequencies are more susceptible to leading to cell death than isolated DSBs. Topologically associating domains (TAD) can be regarded as the reference unit for evaluating the impact of DSB clustering in the 3D genome. To quantify this correlation between the DSB distribution in 3D genome and radiation-induced effect, we developed a simplified model considering the DSB distribution across TADs. Utilizing track-structure Monte Carlo codes to simulate the electron and carbon ion irradiation, we calculated the incidence of each case across a variety of radiation doses and LETs. Our simulation results indicate that DSBs in TADs with frequent interactions (case 3) are significantly more likely to induce cell death than clustered DSBs within a single TAD (case 2). Moreover, case 2 is significantly more likely to induce cell death than isolated DSBs (case 1). The curves of the incidence of case 2 and case 3 versus LETs have a similar shape to the radiation quality factor used in radiation protection. This indicates that these two cases are also associated with the stochastic effects induced by high LET irradiation. Our study underscores the significance of the 3D genome structure in the fundamental mechanisms of radiobiological effects. The hypothesis in our research offers novel perspectives on the mechanisms that regulate radiobiological effects. Moreover, it serves as a valuable reference for establishing mechanistic models that can predict cell survival under different doses and LETs.

physics.med-ph↗

arXiv2024

Influencing Factors of the FLASH Effect: Unveiling the Importance of Free Radicals

Purpose: Our aim was to elucidate the critical factors responsible for inducing the FLASH effect, focusing on the role of free radicals through simulation and experimental approaches. Methods and Materials: The whole abdomen of C57BL/6 mice was irradiated with 6 MeV electron beam. The endpoint was acute intestinal toxicity quantified by histological score. Total doses ranging from 6 to 15 Gy were evaluated. The impact of the mean dose rate (MDR) was assessed in the range of 40 to 900 Gy/s. Dose per pulse (DPP) of 0.5 Gy and 3 Gy were compared. The recombination of peroxyl radicals were simulated. Further comparisons were conducted by incorporating the antioxidant amifostine. Results: When varying total doses with a constant MDR of 900 Gy/s, the FLASH effect was not observed until the dose reached 15 Gy. For a total dose of 15 Gy and varying MDR, the FLASH effect was observed only when MDR reached 100 Gy/s. For a dose of 15 Gy and an MDR of 150 Gy/s, no significant difference in biological effect was observed between low DPP and high DPP. The simulation results indicated that the fraction of peroxyl radicals recombination remained nearly zero at conventional dose rates. For FLASH irradiation, the recombination fraction increased linearly with the dose. Notably, the dose delivery time corresponding to 50% change in the recombination fraction was approximately 300 ms. The addition of amifostine effectively eliminated the difference between FLASH group and CONV group. Conclusions: The critical requirement for observing the sparing effect at the biological endpoint is the administration of an adequate dose within the time window of the radical reaction. Additionally, the important role of free radical was verified after introducing antioxidants, suggesting that the generation and recombination of free radicals are pivotal factors influencing the FLASH sparing effect.

physics.med-ph↗

arXiv2023

Mathematical Analysis of FLASH Effect Models Based on Theoretical Hypotheses

Clinical applications of FLASH radiotherapy require formulas to describe how the FLASH radiation features and other related factors determine the FLASH effect. Mathematical analysis of the models can connect the theoretical hypotheses with the radiobiological effect, which provides the foundation for establishing clinical application models. We abstract the complex models of the oxygen depletion hypothesis and radical recombination-antioxidants hypothesis into concise mathematical equations. The equations are solved to analyze how the radiation features and other factors influence the FLASH effect. Then we propose methodologies for determining the parameters in the models and utilizing the models to predict the FLASH effect.The formulas linking the physical, chemical and biological factors to the FLASH effect are obtained through mathematical derivation of the equation. The analysis indicates that the initial oxygen concentration, radiolytic oxygen consumption and oxygen recovery are key factors for the oxygen depletion hypothesis and that the level of antioxidants is the key factor for the radical recombination-antioxidants hypothesis. According to the model derivations and analysis, the methodologies for determining parameters and predicting the FLASH effect are proposed: the criteria for data filtration, the strategy of hybrid FLASH and conventional dose rate irradiation to ensure the acquisition of effective experimental data across a wide dose range, the pipelines of fitting parameters and predicting the FLASH effect. The derived formulas can be used to calculate the FLASH effect in future clinical FLASH radiotherapy. The proposed methodologies guide to obtain sufficient high-quality datasets and utilize them to predict the FLASH effect. Furthermore, this study indicates the key factors of the FLASH effect and offers clues to further explore the FLASH mechanism.

physics.med-ph↗

arXiv2020

Oxygen depletion hypothesis remains controversial: a mathematical model of oxygen depletion during FLASH radiation

Background: Experiments have reported low normal tissue toxicities during FLASH radiation, but the mechanism has not been elaborated. Several hypotheses have been proposed to explain the mechanism. The oxygen depletion hypothesis has been introduced and mostly studied qualitatively. Methods: We present a computational model to describe the time-dependent change of oxygen concentration in the tissue. The kinetic equation of the model is solved numerically using the finite difference method. The model is used to analyze the FLASH effect with the oxygen depletion hypothesis, and the brain tissue is chosen as an example. Results: The oxygen distribution is determined by the oxygen consumption rate of the tissue and the distance between capillaries. The change of oxygen concentration with time after radiation has been found to follow a negative exponential function, and the time constant is determined by the distance between capillaries. When the dose rate is high enough, the same dose results in the same change of oxygen concentration regardless of dose rate. The analysis of FLASH effect in the brain tissue based on this model does not support the explanation of the oxygen depletion hypothesis. Conclusions: The oxygen depletion hypothesis remains controversial because oxygen in most normal tissues cannot be depleted by FLASH radiation according to the mathematical analysis with this model and experiments on the expression and distribution of the hypoxia-inducible factors.

physics.med-ph↗