172 results on '"Schuemann, Jan"'
Search Results
2. Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations
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McCullum, Lucas, Shin, Jungwook, Xing, Stella, Beekman, Chris, Schuemann, Jan, Hong, Theodore, Duda, Dan, Mohan, Radhe, Lin, Steven H., Correa-Alfonso, Camilo M., Domal, Sean, Withrow, Julia, Bolch, Wesley, Paganetti, Harald, and Grassberger, Clemens
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- 2023
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3. Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA
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Sakata, Dousatsu, Hirayama, Ryoichi, Shin, Wook-Geun, Belli, Mauro, Tabocchini, Maria A., Stewart, Robert D., Belov, Oleg, Bernal, Mario A., Bordage, Marie-Claude, Brown, Jeremy M.C., Dordevic, Milos, Emfietzoglou, Dimitris, Francis, Ziad, Guatelli, Susanna, Inaniwa, Taku, Ivanchenko, Vladimir, Karamitros, Mathieu, Kyriakou, Ioanna, Lampe, Nathanael, Li, Zhuxin, Meylan, Sylvain, Michelet, Claire, Nieminen, Petteri, Perrot, Yann, Petrovic, Ivan, Ramos-Mendez, Jose, Ristic-Fira, Aleksandra, Santin, Giovanni, Schuemann, Jan, Tran, Hoang N., Villagrasa, Carmen, and Incerti, Sebastien
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- 2023
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4. A computational approach to quantifying miscounting of radiation-induced double-strand break immunofluorescent foci
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Ingram, Samuel P., Warmenhoven, John-William, Henthorn, Nicholas T., Chadiwck, Amy L., Santina, Elham E., McMahon, Stephen J., Schuemann, Jan, Kirkby, Norman F., Mackay, Ranald I., Kirkby, Karen J., and Merchant, Michael J.
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- 2022
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5. Dose Rate Effects from the 1950s through to the Era of FLASH.
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Held, Kathryn D., McNamara, Aimee L., Daartz, Juliane, Bhagwat, Mandar S., Rothwell, Bethany, and Schuemann, Jan
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RADIOBIOLOGY ,RADIOISOTOPE brachytherapy ,RADIOTHERAPY ,ONCOLOGY ,TISSUES ,RADIATION protection - Abstract
Numerous dose rate effects have been described over the past 6–7 decades in the radiation biology and radiation oncology literature depending on the dose rate range being discussed. This review focuses on the impact and understanding of altering dose rates in the context of radiation therapy, but does not discuss dose rate effects as relevant to radiation protection. The review starts with a short historic review of early studies on dose rate effects, considers mechanisms thought to underlie dose rate dependencies, then discusses some current issues in clinical findings with altered dose rates, the importance of dose rate in brachytherapy, and the current timely topic of the use of very high dose rates, so-called FLASH radiotherapy. The discussion includes dose rate effects in vitro in cultured cells, in in vivo experimental systems and in the clinic, including both tumors and normal tissues. Gaps in understanding dose rate effects are identified, as are opportunities for improving clinical use of dose rate modulation. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Brain Necrosis in Adult Patients After Proton Therapy: Is There Evidence for Dependency on Linear Energy Transfer?
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Niemierko, Andrzej, Schuemann, Jan, Niyazi, Maximilian, Giantsoudi, Drosoula, Maquilan, Genevieve, Shih, Helen A., and Paganetti, Harald
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- 2021
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7. Extended Pharmacokinetics Improve Site-Specific Prodrug Activation Using Radiation.
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Quintana, Jeremy M., Kang, Mikyung, Hu, Huiyu, Ng, Thomas S. C., Wojtkiewicz, Gregory R., Scott, Ella, Parangi, Sareh, Schuemann, Jan, Weissleder, Ralph, and Miller, Miles A.
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- 2024
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8. Sustained and Localized Drug Depot Release Using Radiation‐Activated Scintillating Nanoparticles.
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Kang, Mikyung, Quintana, Jeremy, Hu, Huiyu, Teixeira, Verônica C., Olberg, Sven, Banla, Leou Ismael, Rodriguez, Victoria, Hwang, William L., Schuemann, Jan, Parangi, Sareh, Weissleder, Ralph, and Miller, Miles A.
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- 2024
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9. End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer
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Wang, Chia-Chun, McNamara, Aimee L., Shin, Jungwook, Schuemann, Jan, Grassberger, Clemens, Taghian, Alphonse G., Jimenez, Rachel B., MacDonald, Shannon M., and Paganetti, Harald
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- 2020
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10. The TOPAS tool for particle simulation, a Monte Carlo simulation tool for physics, biology and clinical research
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Faddegon, Bruce, Ramos-Méndez, José, Schuemann, Jan, McNamara, Aimee, Shin, Jungwook, Perl, Joseph, and Paganetti, Harald
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- 2020
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11. Computational Modeling and Clonogenic Assay for Radioenhancement of Gold Nanoparticles Using 3D Live Cell Images
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Sung, Wonmo, Jeong, Yoon, Kim, Hyejin, Jeong, Hoibin, Grassberger, Clemens, Jung, Seongmoon, Ahn, G-One, Kim, Il Han, Schuemann, Jan, Lee, Kangwon, and Ye, Sung-Joon
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- 2018
12. Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
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Al Zubaidi, Tara, Gehrisch, O. H. Fiete, Genois, Marie-Michelle, Liu, Qi, Lu, Shan, Kung, Jong, Xie, Yunhe, Schuemann, Jan, Lu, Hsiao-Ming, Hata, Aaron N., Zou, Lee, Borgmann, Kerstin, and Willers, Henning
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- 2021
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13. Multi-scale Monte Carlo simulations of gold nanoparticle-induced DNA damages for kilovoltage X-ray irradiation in a xenograft mouse model using TOPAS-nBio
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Klapproth, Alexander P., Schuemann, Jan, Stangl, Stefan, Xie, Tianwu, Li, Wei Bo, and Multhoff, Gabriele
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- 2021
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14. Corrigendum to “Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA” [Phys. Med. 105 (2023) 102508]
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Sakata, Dousatsu, Hirayama, Ryoichi, Shin, Wook-Geun, Belli, Mauro, Tabocchini, Maria A., Stewart, Robert D., Belov, Oleg, Bernal, Mario A., Bordage, Marie-Claude, Brown, Jeremy M.C., Dordevic, Milos, Emfietzoglou, Dimitris, Francis, Ziad, Guatelli, Susanna, Inaniwa, Taku, Ivanchenko, Vladimir, Karamitros, Mathieu, Kyriakou, Ioanna, Lampe, Nathanael, Li, Zhuxin, Meylan, Sylvain, Michelet, Claire, Nieminen, Petteri, Perrot, Yann, Petrovic, Ivan, Ramos-Mendez, Jose, Ristic-Fira, Aleksandra, Santin, Giovanni, Schuemann, Jan, Tran, Hoang N., Villagrasa, Carmen, and Incerti, Sebastien
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- 2024
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15. Monte Carlo Processing on a Chip (MCoaC)-preliminary experiments toward the realization of optimal-hardware for TOPAS/Geant4 to drive discovery
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Abhyankar, Yogindra S., Dev, Sachin, Sarun, O.S., Saxena, Amit, Joshi, Rajendra, Darbari, Hemant, Sajish, C., Sonavane, U.B., Gavane, Vivek, Deshpande, Abhay, Dixit, Tanuja, Harsh, Rajesh, Badwe, Rajendra, Rath, G.K., Laskar, Siddhartha, Faddegon, Bruce, Perl, Joseph, Paganetti, Harald, Schuemann, Jan, Srivastava, Anil, Obcemea, Ceferino, Nath, Asheet K., Sharma, Ashok, and Buchsbaum, Jeffrey
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- 2019
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16. Voxel-wise dose rate calculation in clinical pencil beam scanning proton therapy.
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Daartz, Juliane, Madden, Thomas M, Lalonde, Arthur, Cascio, Ethan, Verburg, Joost, Shih, Helen, MacDonald, Shannon, Hachadorian, Rachael, and Schuemann, Jan
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PROTON therapy ,RADAR cross sections ,PROTON beams ,TREATMENT effectiveness ,COMPUTATIONAL neuroscience - Abstract
Objective. Clinical outcomes after proton therapy have shown some variability that is not fully understood. Different approaches have been suggested to explain the biological outcome, but none has yet provided a comprehensive and satisfactory rationale for observed toxicities. The relatively recent transition from passive scattering (PS) to pencil beam scanning (PBS) treatments has significantly increased the voxel-wise dose rate in proton therapy. In addition, the dose rate distribution is no longer uniform along the cross section of the target but rather highly heterogeneous, following the spot placement. We suggest investigating dose rate as potential contributor to a more complex proton RBE model. Approach. Due to the time structure of the PBS beam delivery the instantaneous dose rate is highly variable voxel by voxel. Several possible parameters to represent voxel-wise dose rate for a given clinical PBS treatment plan are detailed. These quantities were implemented in the scripting environment of our treatment planning system, and computations experimentally verified. Sample applications to treated patient plans are shown. Main results. Computed dose rates we experimentally confirmed. Dose rate maps vary depending on which method is used to represent them. Mainly, the underlying time and dose intervals chosen determine the topography of the resultant distributions. The maximum dose rates experienced by any target voxel in a given PBS treatment plan in our system range from ∼100 to ∼450 Gy(RBE)/min, a factor of 10–100 increase compared to PS. These dose rate distributions are very heterogeneous, with distinct hot spots. Significance. Voxel-wise dose rates for current clinical PBS treatment plans vary greatly from clinically established practice with PS. The exploration of different dose rate measures to evaluate potential correlations with observed clinical outcomes is suggested, potentially adding a missing component in the understanding of proton relative biological effectiveness (RBE). [ABSTRACT FROM AUTHOR]
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- 2024
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17. SO015 / #788 - PROTON FLASH-ARC THERAPY: MEETING THE CHALLENGE OF FLASH DOSE-RATE REQUIREMENTS IN THE CLINIC
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Bertolet, Alejandro and Schuemann, Jan
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- 2024
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18. P051 / #309 - MULTI-INSTITUTIONAL ANALYSIS OF SOURCE MODEL PARAMETERS FOR BEAM COMMISSIONING OF SCANNING PROTON THERAPY TREATMENT PLANNING SYSTEM
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Chang, Chih-Wei, Lin, Liyong, Dong, Lei, Li, Heng, Schuemann, Jan, Shen, Jiajian, and Ding, Xuanfeng
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- 2024
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19. P011 / #837 - A PLATFORM TO FACILITATE MULTI-INSTITUTIONAL STUDIES TO BOOST PARTICLE THERAPY
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Titt, Uwe, Cristancho, Juan Diego, Schuemann, Jan, Mcnamara, Aimee, and Mohan, Radhe
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- 2024
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20. Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH.
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Zhu, Hongyu, Schuemann, Jan, Zhang, Qixian, and Gerweck, Leo E.
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OXYGEN , *TUMOR growth , *CELL survival , *RADIATION tolerance , *TISSUES , *DOSE-response relationship (Radiation) - Abstract
Background: Ultra‐high dose rate (FLASH) radiation has been reported to efficiently suppress tumor growth while sparing normal tissue; however, the mechanism of the differential tissue sparing effect is still not known. Oxygen has long been known to profoundly impact radiobiological responses, and radiolytic oxygen depletion has been considered to be a possible cause or contributor to the FLASH phenomenon. Purpose: This work investigates the impact of tissue pO2 profiles, oxygen depletion per unit dose (g), and the oxygen concentration yielding half‐maximum radiosensitization (the average of its maximum value and one) (k) in tumor and normal tissue. Methods: We developed a model that considers the dependent relationship between oxygen depletion and change of radiosensitivity by FLASH irradiation. The model assumed that FLASH irradiation depletes intracellular oxygen more rapidly than it diffuses into the cell from the extracellular environment. Cell survival was calculated based on the linear quadratic‐linear model and the radiosensitivity related parameters were adjusted in 1 Gy increments of the administered dose. The model reproduced published experimental data that were obtained with different cell lines and oxygen concentrations, and was used to analyze the impact of parameter uncertainties on the radiobiological responses. This study expands the oxygen depletion analysis of FLASH to normal human tissue and tumor based on clinically determined aggregate and individual patient pO2 profiles. Results: The results show that the pO2 profile is the most essential factor that affects biological response and analyses based on the median pO2 rather than the full pO2 profile can be unreliable and misleading. Additionally, the presence of a small fraction of cells on the threshold of radiobiologic hypoxia substantially alters biological response due to FLASH oxygen depletion. We found that an increment in the k value is generally more protective of tumor than normal tissue due to a higher frequency of lower pO2 values in tumors. Variation in the g value affects the dose at which oxygen depletion impacts response, but does not alter the dose‐dependent response trends, if the g value is identical in both tumor and normal tissue. Conclusions: The therapeutic efficacy of FLASH oxygen depletion is likely patient and tissue‐dependent. For breast cancer, FLASH is beneficial in a minority of cases; however, in a subset of well oxygenated tumors, a therapeutic gain may be realized due to induced normal tissue hypoxia. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Effects of Differing Underlying Assumptions in In Silico Models on Predictions of DNA Damage and Repair.
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Warmenhoven, John W., Henthorn, Nicholas T., McNamara, Aimee L., Ingram, Samuel P., Merchant, Michael J., Kirkby, Karen J., Schuemann, Jan, Paganetti, Harald, Prise, Kevin M., and McMahon, Stephen J.
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DNA damage ,DNA repair ,DOUBLE-strand DNA breaks ,DAMAGE models ,PREDICTION models - Abstract
The induction and repair of DNA double-strand breaks (DSBs) are critical factors in the treatment of cancer by radiotherapy. To investigate the relationship between incident radiation and cell death through DSB induction many in silico models have been developed. These models produce and use custom formats of data, specific to the investigative aims of the researchers, and often focus on particular pairings of damage and repair models. In this work we use a standard format for reporting DNA damage to evaluate combinations of different, independently developed, models. We demonstrate the capacity of such inter-comparison to determine the sensitivity of models to both known and implicit assumptions. Specifically, we report on the impact of differences in assumptions regarding patterns of DNA damage induction on predicted initial DSB yield, and the subsequent effects this has on derived DNA repair models. The observed differences highlight the importance of considering initial DNA damage on the scale of nanometres rather than micrometres. We show that the differences in DNA damage models result in subsequent repair models assuming significantly different rates of random DSB end diffusion to compensate. This in turn leads to disagreement on the mechanisms responsible for different biological endpoints, particularly when different damage and repair models are combined, demonstrating the importance of inter-model comparisons to explore underlying model assumptions. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.
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Diaz Garcia-Prada, Clara, Carmes, Léna, Atis, Salima, Parach, Ali, Bertolet, Alejandro, Jarlier, Marta, Poty, Sophie, Suarez Garcia, Daniel, Wook-Geun Shin, Du Manoir, Stanislas, Schuemann, Jan, Tillement, Olivier, Lux, François, Constanzo, Julie, and Pouget, Jean-Pierre
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- 2023
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23. Roadmap to Clinical Use of Gold Nanoparticles for Radiation Sensitization
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Schuemann, Jan, Berbeco, Ross, Chithrani, Devika B., Cho, Sang Hyun, Kumar, Rajiv, McMahon, Stephen J., Sridhar, Srinivas, and Krishnan, Sunil
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- 2016
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24. Use of a lipid nanoparticle system as a Trojan horse in delivery of gold nanoparticles to human breast cancer cells for improved outcomes in radiation therapy
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Bromma, Kyle, Rieck, Kristy, Kulkarni, Jayesh, O’Sullivan, Connor, Sung, Wonmo, Cullis, Pieter, Schuemann, Jan, and Chithrani, Devika B.
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- 2019
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25. Assessing the Clinical Impact of Approximations in Analytical Dose Calculations for Proton Therapy
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Schuemann, Jan, Giantsoudi, Drosoula, Grassberger, Clemens, Moteabbed, Maryam, Min, Chul Hee, and Paganetti, Harald
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- 2015
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26. Time‐resolved diode dosimetry calibration through Monte Carlo modeling for in vivo passive scattered proton therapy range verification
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Toltz, Allison, Hoesl, Michaela, Schuemann, Jan, Seuntjens, Jan, Lu, Hsiao‐Ming, and Paganetti, Harald
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- 2017
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27. The complexity of DNA damage by radiation follows a Gamma distribution: insights from the Microdosimetric Gamma Model.
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Bertolet, Alejandro, Chamseddine, Ibrahim, Paganetti, Harald, and Schuemann, Jan
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DNA damage ,GAMMA distributions ,GAMMA rays ,RADIATION damage ,ALPHA rays - Abstract
Introduction: DNA damage is the main predictor of response to radiation therapy for cancer. Its Q8 quantification and characterization are paramount for treatment optimization, particularly in advanced modalities such as proton and alpha-targeted therapy. Methods: We present a novel approach called the Microdosimetric Gamma Model (MGM) to address this important issue. The MGM uses the theory of microdosimetry, specifically the mean energy imparted to small sites, as a predictor of DNA damage properties. MGM provides the number of DNA damage sites and their complexity, which were determined using Monte Carlo simulations with the TOPAS-nBio toolkit for monoenergetic protons and alpha particles. Complexity was used together with a illustrative and simplistic repair model to depict the differences between high and low LET radiations. Results: DNA damage complexity distributions were were found to follow a Gamma distribution for all monoenergetic particles studied. The MGM functions allowed to predict number of DNA damage sites and their complexity for particles not simulated with microdosimetric measurements (yF) in the range of those studied. Discussion: Compared to current methods, MGM allows for the characterization of DNA damage induced by beams composed of multi-energy components distributed over any time configuration and spatial distribution. The output can be plugged into ad hoc repair models that can predict cell killing, protein recruitment at repair sites, chromosome aberrations, and other biological effects, as opposed to current models solely focusing on cell survival. These features are particularly important in targeted alpha-therapy, for which biological effects remain largely uncertain. The MGM provides a flexible framework to study the energy, time, and spatial aspects of ionizing radiation and offers an excellent tool for studying and optimizing the biological effects of these radiotherapy modalities. [ABSTRACT FROM AUTHOR]
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- 2023
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28. An integrated Monte Carlo track-structure simulation framework for modeling inter and intra-track effects on homogenous chemistry.
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D-Kondo, J Naoki, Garcia-Garcia, Omar R, LaVerne, Jay A, Faddegon, Bruce, Schuemann, Jan, Shin, Wook-Geun, and Ramos-Méndez, José
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DISSOLVED oxygen in water ,CHEMICAL yield ,RADIATION chemistry ,SOLUTION (Chemistry) ,PHYSICAL & theoretical chemistry ,ANALYTICAL solutions - Abstract
Objective. The TOPAS-nBio Monte Carlo track structure simulation code, a wrapper of Geant4-DNA, was extended for its use in pulsed and longtime homogeneous chemistry simulations using the Gillespie algorithm. Approach. Three different tests were used to assess the reliability of the implementation and its ability to accurately reproduce published experimental results: (1) a simple model with a known analytical solution, (2) the temporal evolution of chemical yields during the homogeneous chemistry stage, and (3) radiolysis simulations conducted in pure water with dissolved oxygen at concentrations ranging from 10 μ M to 1 mM with [H
2 O2 ] yields calculated for 100 MeV protons at conventional and FLASH dose rates of 0.286 Gy s−1 and 500 Gy s−1 , respectively. Simulated chemical yield results were compared closely with data calculated using the Kinetiscope software which also employs the Gillespie algorithm. Main results. Validation results in the third test agreed with experimental data of similar dose rates and oxygen concentrations within one standard deviation, with a maximum of 1% difference for both conventional and FLASH dose rates. In conclusion, the new implementation of TOPAS-nBio for the homogeneous long time chemistry simulation was capable of recreating the chemical evolution of the reactive intermediates that follow water radiolysis. Significance. Thus, TOPAS-nBio provides a reliable all-in-one chemistry simulation of the physical, physico-chemical, non-homogeneous, and homogeneous chemistry and could be of use for the study of FLASH dose rate effects on radiation chemistry. [ABSTRACT FROM AUTHOR]- Published
- 2023
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29. TOPAS-imaging: extensions to the TOPAS simulation toolkit for medical imaging systems.
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Lee, Hoyeon, Cheon, Bo-Wi, Feld, Joseph W, Grogg, Kira, Perl, Joseph, Ramos-Méndez, José A, Faddegon, Bruce, Min, Chul Hee, Paganetti, Harald, and Schuemann, Jan
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MEDICAL imaging systems ,POSITRON emission tomography ,IMAGE-guided radiation therapy ,MEDICAL simulation ,MEDICAL physics ,PHOTON beams - Abstract
Objective. The TOol for PArticle Simulation (TOPAS) is a Geant4-based Monte Carlo software application that has been used for both research and clinical studies in medical physics. So far, most users of TOPAS have focused on radiotherapy-related studies, such as modeling radiation therapy delivery systems or patient dose calculation. Here, we present the first set of TOPAS extensions to make it easier for TOPAS users to model medical imaging systems. Approach. We used the extension system of TOPAS to implement pre-built, user-configurable geometry components such as detectors (e.g. flat-panel and multi-planar detectors) for various imaging modalities and pre-built, user-configurable scorers for medical imaging systems (e.g. digitizer chain). Main results. We developed a flexible set of extensions that can be adapted to solve research questions for a variety of imaging modalities. We then utilized these extensions to model specific examples of cone-beam CT (CBCT), positron emission tomography (PET), and prompt gamma (PG) systems. The first of these new geometry components, the FlatImager, was used to model example CBCT and PG systems. Detected signals were accumulated in each detector pixel to obtain the intensity of x-rays penetrating objects or prompt gammas from proton-nuclear interaction. The second of these new geometry components, the RingImager, was used to model an example PET system. Positron–electron annihilation signals were recorded in crystals of the RingImager and coincidences were detected. The simulated data were processed using corresponding post-processing algorithms for each modality and obtained results in good agreement with the expected true signals or experimental measurement. Significance. The newly developed extension is a first step to making it easier for TOPAS users to build and simulate medical imaging systems. Together with existing TOPAS tools, this extension can help integrate medical imaging systems with radiotherapy simulations for image-guided radiotherapy. [ABSTRACT FROM AUTHOR]
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- 2023
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30. Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.
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Zhang, Qixian, Gerweck, Leo E., Cascio, Ethan, Gu, Liqun, Yang, Qingyuan, Dong, Xinyue, Huang, Peigen, Bertolet, Alejandro, Nesteruk, Konrad Pawel, Sung, Wonmo, McNamara, Aimee L., and Schuemann, Jan
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ANIMAL experimentation ,RADIATION ,IMMUNOSUPPRESSION ,PROTONS ,RADIATION doses ,HYPOTHESIS ,RESEARCH funding ,INTESTINES ,MICE - Abstract
Simple Summary: The normal tissue-sparing effect of ultra-high dose rate irradiation (i.e., FLASH effect) has been widely reported. However, our data suggest that not all irradiations with a dose rate above 40 Gy/s can confer benefits. We found that partial abdominal FLASH proton irradiation neither improved survival nor preserved circulating lymphocytes. These findings highlight the necessity to understand the conditions that induce the FLASH effect, for successful clinical translation. Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm
2 elliptical field with a dose rate of ~120 Gy/s was provided by a 228 MeV proton pencil beam. Partial abdominal irradiation was delivered to C57BL/6j and immunodeficient Rag1−/− /C57 mice. Proliferating crypt cells were counted at 2 days post exposure, and the thickness of the muscularis externa was measured at 280 days following irradiation. FLASH irradiation did not reduce the morbidity or mortality of conventional irradiation in either strain of mice; in fact, a tendency for worse survival in FLASH-irradiated mice was observed. There were no significant differences in lymphocyte numbers between FLASH and conventional-dose-rate mice. A similar number of proliferating crypt cells and a similar thickness of the muscularis externa following FLASH and conventional dose rate irradiation were observed. Partial abdominal FLASH proton irradiation at 120 Gy/s did not spare normal intestinal tissue, and no difference in lymphocyte depletion was observed. This study suggests that the effect of FLASH irradiation may depend on multiple factors, and in some cases dose rates of over 100 Gy/s do not induce a FLASH effect and can even result in worse outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2023
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31. HERMAN D. SUIT, MD, DPhil 1929–2022 A Giant of Modern Radiation Oncology.
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Kirsch, David G., Willett, Christopher, Paganetti, Harald, Schuemann, Jan, Held, Kathryn D., and Jain, Rakesh
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ACTIONS & defenses (Law) ,RADIATION ,SCIENCE museums ,SCIENTIFIC knowledge ,ONCOLOGY ,EXTRACELLULAR fluid - Published
- 2022
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32. Impact of DNA Geometry and Scoring on Monte Carlo Track-Structure Simulations of Initial Radiation-Induced Damage.
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Bertolet, Alejandro, Ramos-Méndez, José, McNamara, Aimee, Yoo, Dohyeon, Ingram, Samuel, Henthorn, Nicholas, Warmenhoven, John-William, Faddegon, Bruce, Merchant, Michael, McMahon, Stephen J, Paganetti, Harald, and Schuemann, Jan
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MONTE Carlo method ,DNA ,DNA damage ,IONIZING radiation ,CELL nuclei ,CHARGE transfer - Abstract
Track structure Monte Carlo simulations are a useful tool to investigate the damage induced to DNA by ionizing radiation. These simulations usually rely on simplified geometrical representations of the DNA subcomponents. DNA damage is determined by the physical and physicochemical processes occurring within these volumes. In particular, damage to the DNA backbone is generally assumed to result in strand breaks. DNA damage can be categorized as direct (ionization of an atom part of the DNA molecule) or indirect (damage from reactive chemical species following water radiolysis). We also consider quasi-direct effects, i.e., damage originated by charge transfers after ionization of the hydration shell surrounding the DNA. DNA geometries are needed to account for the damage induced by ionizing radiation, and different geometry models can be used for speed or accuracy reasons. In this work, we use the Monte Carlo track structure tool TOPAS-nBio, built on top of Geant4-DNA, for simulation at the nanometer scale to evaluate differences among three DNA geometrical models in an entire cell nucleus, including a sphere/spheroid model specifically designed for this work. In addition to strand breaks, we explicitly consider the direct, quasi-direct, and indirect damage induced to DNA base moieties. We use results from the literature to determine the best values for the relevant parameters. For example, the proportion of hydroxyl radical reactions between base moieties was 80%, and between backbone, moieties was 20%, the proportion of radical attacks leading to a strand break was 11%, and the expected ratio of base damages and strand breaks was 2.5–3. Our results show that failure to update parameters for new geometric models can lead to significant differences in predicted damage yields. [ABSTRACT FROM AUTHOR]
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- 2022
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33. TOPAS-nBio simulation of temperature-dependent indirect DNA strand break yields.
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Ramos-MĂ©ndez, JosĂ©, GarcĂ-a-GarcĂ-a, Omar, DomĂ-nguez-Kondo, Jorge, LaVerne, Jay A, Schuemann, Jan, Moreno-Barbosa, Eduardo, and Faddegon, Bruce
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SINGLE-strand DNA breaks ,PHYSIOLOGICAL effects of radiation ,ETHYLENEDIAMINETETRAACETIC acid ,MONTE Carlo method ,DNA ,TEMPERATURE effect ,CHEMICAL species ,LINEAR energy transfer - Abstract
Current Monte Carlo simulations of DNA damage have been reported only at ambient temperature. The aim of this work is to use TOPAS-nBio to simulate the yields of DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) produced in plasmids under low-LET irradiation incorporating the effect of the temperature changes in the environment. A new feature was implemented in TOPAS-nBio to incorporate reaction rates used in the simulation of the chemical stage of water radiolysis as a function of temperature. The implemented feature was verified by simulating temperature-dependent G -values of chemical species in liquid water from 20 °C to 90 °C. For radiobiology applications, temperature dependent SSB and DSB yields were calculated from 0 °C to 42 °C, the range of available published measured data. For that, supercoiled DNA plasmids dissolved in aerated solutions containing EDTA irradiated by Cobalt-60 gamma-rays were simulated. TOPAS-nBio well reproduced published temperature-dependent G -values in liquid water and the yields of SSB and DSB for the temperature range considered. For strand break simulations, the model shows that the yield of SSB and DSB increased linearly with the temperature at a rate of (2.94 ± 0.17) × 10
â'10 Gyâ€"1 Daâ€"1 °Câ€"1 (R2  = 0.99) and (0.13 ± 0.01) Ă— 10â'10 Gyâ€"1 Daâ€"1 °Câ€"1 (R2  = 0.99), respectively. The extended capability of TOPAS-nBio is a complementary tool to simulate realistic conditions for a large range of environmental temperatures, allowing refined investigations of the biological effects of radiation. [ABSTRACT FROM AUTHOR]- Published
- 2022
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34. Monte Carlo methods for device simulations in radiation therapy.
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Park, Hyojun, Paganetti, Harald, Schuemann, Jan, Jia, Xun, and Min, Chul Hee
- Subjects
RADIOTHERAPY ,MEDICAL physics ,MEDICAL coding ,MONTE Carlo method - Abstract
Monte Carlo (MC) simulations play an important role in radiotherapy, especially as a method to evaluate physical properties that are either impossible or difficult to measure. For example, MC simulations (MCSs) are used to aid in the design of radiotherapy devices or to understand their properties. The aim of this article is to review the MC method for device simulations in radiation therapy. After a brief history of the MC method and popular codes in medical physics, we review applications of the MC method to model treatment heads for neutral and charged particle radiation therapy as well as specific in-room devices for imaging and therapy purposes. We conclude by discussing the impact that MCSs had in this field and the role of MC in future device design. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
35. The relation between microdosimetry and induction of direct damage to DNA by alpha particles.
- Author
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Bertolet, Alejandro, Ramos-Méndez, José, Paganetti, Harald, and Schuemann, Jan
- Subjects
ALPHA rays ,DNA damage ,MICRODOSIMETRY ,DNA structure ,IONIZING radiation - Abstract
In radiopharmaceutical treatments α-particles are employed to treat tumor cells. However, the mechanism that drives the biological effect induced is not well known. Being ionizing radiation, α-particles can affect biological organisms by producing damage to the DNA, either directly or indirectly. Following the principle that microdosimetry theory accounts for the stochastic way in which radiation deposits energy in sub-cellular sized volumes via physical collisions, we postulate that microdosimetry represents a reasonable framework to characterize the statistical nature of direct damage induction by α-particles to DNA. We used the TOPAS-nBio Monte Carlo package to simulate direct damage produced by monoenergetic alpha particles to different DNA structures. In separate simulations, we obtained the frequency-mean lineal energy () and dose-mean lineal energy () of microdosimetric distributions sampled with spherical sites of different sizes. The total number of DNA strand breaks, double strand breaks (DSBs) and complex strand breaks per track were quantified and presented as a function of either or The probability of interaction between a track and the DNA depends on how the base pairs are compacted. To characterize this variability on compactness, spherical sites of different size were used to match these probabilities of interaction, correlating the size-dependent specific energy () with the damage induced. The total number of DNA strand breaks per track was found to linearly correlate with and when using what we defined an effective volume as microdosimetric site, while the yield of DSB per unit dose linearly correlated with or being larger for compacted than for unfolded DNA structures. The yield of complex breaks per unit dose exhibited a quadratic behavior with respect to and a greater difference among DNA compactness levels. Microdosimetric quantities correlate with the direct damage imparted on DNA. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
36. Improving proton dose calculation accuracy by using deep learning.
- Author
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Chao Wu, Dan Nguyen, Yixun Xing, Montero, Ana Barragan, Schuemann, Jan, Haijiao Shang, Yuehu Pu, and Jiang, Steve
- Published
- 2021
- Full Text
- View/download PDF
37. Challenges in the quantification approach to a radiation relevant adverse outcome pathway for lung cancer.
- Author
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Stainforth, Robert, Schuemann, Jan, McNamara, Aimee L., Wilkins, Ruth C., and Chauhan, Vinita
- Subjects
- *
MONTE Carlo method , *LUNG cancer , *LINEAR energy transfer , *IONIZING radiation , *CELL nuclei , *RADIATION - Abstract
Adverse outcome pathways (AOPs) provide a modular framework for describing sequences of biological key events (KEs) and key event relationships (KERs) across levels of biological organization. Empirical evidence across KERs can support construction of quantified AOPs (qAOPs). Using an example AOP of energy deposition from ionizing radiation onto DNA leading to lung cancer incidence, we investigate the feasibility of quantifying data from KERs supported by all types of stressors. The merits and challenges of this process in the context of AOP construction are discussed. Empirical evidence across studies of dose-response from four KERs of the AOP were compiled independently for quantification. Three upstream KERs comprised of evidence from various radiation types in line with AOP guidelines. For these three KERs, a focused analysis of data from alpha-particle studies was undertaken to better characterize the process to the adverse outcome (AO) for a radon gas stressor. Numerical information was extracted from tables and graphs to plot and tabulate the response of KEs. To complement areas of the AOP quantification process, Monte Carlo (MC) simulations in TOPAS-nBio were performed to model exposure conditions relevant to the AO for an example bronchial compartment of the lung with secretory cell nuclei targets. Quantification of AOP KERs highlighted the relevance of radiation types under the stressor-agnostic intent of AOP design, motivating a focus on specific types. For a given type, significant differences of KE response indicate meaningful data to derive linkages from the MIE to the AO is lacking and that better response-response focused studies are required. The MC study estimates the linear energy transfer (LET) of alpha-particles emitted by radon-222 and its progeny in the secretory cell nuclei of the example lung compartment to range from 94 − 5 + 5 to 192 − 18 + 15 keV/µm. Quantifying AOP components provides a means to assemble empirical evidence across different studies. This highlights challenges in the context of studies examining similar endpoints using different radiation types. Data linking KERs to a MIE of 'deposition of energy' is shown to be non-compatible with the stressor-agnostic principles of AOP design. Limiting data to that describing response-response relationships between adjacent KERs may better delineate studies relevant to the damage that drives a pathway to the next KE and still support an 'all hazards' approach. Such data remains limited and future investigations in the radiation field may consider this approach when designing experiments and reporting their results and outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
38. FLASH Investigations Using Protons: Design of Delivery System, Preclinical Setup and Confirmation of FLASH Effect with Protons in Animal Systems.
- Author
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Zhang, Qixian, Cascio, Ethan, Li, Chengming, Yang, Qingyuan, Gerweck, Leo E., Huang, Peigen, Gottschalk, Bernard, Flanz, Jacob, and Schuemann, Jan
- Subjects
PROTONS ,PHOTON emission ,CYCLOTRONS ,PROTON beams ,RADIATION dosimetry - Abstract
Extremely high-dose-rate irradiation, referred to as FLASH, has been shown to be less damaging to normal tissues than the same dose administrated at conventional dose rates. These results, typically seen at dose rates exceeding 40 Gy/s (or 2,400 Gy/min), have been widely reported in studies utilizing photon or electron radiation as well as in some proton radiation studies. Here, we report the development of a proton irradiation platform in a clinical proton facility and the dosimetry methods developed. The target is placed in the entry plateau region of a proton beam with a specifically designed double-scattering system. The energy after the double-scattering system is 227.5 MeV for protons that pass through only the first scatterer, and 225.5 MeV for those that also pass through the second scatterer. The double-scattering system was optimized to deliver a homogeneous dose distribution to a field size as large as possible while keeping the dose rate >100 Gy/s and not exceeding a cyclotron current of 300 nA. We were able to obtain a collimated pencil beam (1.6 × 1.2 cm
2 ellipse) at a dose rate of ∼120 Gy/s. This beam was used for dose-response studies of partial abdominal irradiation of mice. First results indicate a potential tissue-sparing effect of FLASH. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
39. Roadmap for metal nanoparticles in radiation therapy: current status, translational challenges, and future directions.
- Author
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Schuemann, Jan, Bagley, Alexander F, Berbeco, Ross, Bromma, Kyle, Butterworth, Karl T, Byrne, Hilary L, Chithrani, B Devika, Cho, Sang Hyun, Cook, Jason R, Favaudon, Vincent, Gholami, Yaser H, Gargioni, Elisabetta, Hainfeld, James F, Hespeels, Félicien, Heuskin, Anne-Catherine, Ibeh, Udoka M, Kuncic, Zdenka, Kunjachan, Sijumon, Lacombe, Sandrine, and Lucas, Stéphane
- Subjects
- *
METAL nanoparticles , *RADIOTHERAPY , *DRUG carriers , *RADIATION doses , *NANOPARTICLES , *MAGNETIC nanoparticle hyperthermia , *BISMUTH - Abstract
This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
40. Cellular Response to Proton Irradiation: A Simulation Study with TOPAS-nBio.
- Author
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Zhu, Hongyu, McNamara, Aimee L., McMahon, Stephen J., Ramos-Mendez, Jose, Henthorn, Nicholas T., Faddegon, Bruce, Held, Kathryn D., Perl, Joseph, Li, Junli, Paganetti, Harald, and Schuemann, Jan
- Subjects
DOUBLE-strand DNA breaks ,CHROMOSOME abnormalities ,DNA mismatch repair ,CHEMICAL models ,DNA repair ,PROTONS ,DNA damage ,RADIOBIOLOGY - Abstract
The cellular response to ionizing radiation continues to be of significant research interest in cancer radiotherapy, and DNA is recognized as the critical target for most of the biologic effects of radiation. Incident particles can cause initial DNA damages through physical and chemical interactions within a short time scale. Initial DNA damages can undergo repair via different pathways available at different stages of the cell cycle. The misrepair of DNA damage results in genomic rearrangement and causes mutations and chromosome aberrations, which are drivers of cell death. This work presents an integrated study of simulating cell response after proton irradiation with energies of 0.5–500 MeV (LET of 60–0.2 keV/µm). A model of a whole nucleus with fractal DNA geometry was implemented in TOPAS-nBio for initial DNA damage simulations. The default physics and chemistry models in TOPAS-nBio were used to describe interactions of primary particles, secondary particles, and radiolysis products within the nucleus. The initial DNA double-strand break (DSB) yield was found to increase from 6.5 DSB/Gy/Gbp at low-linear energy transfer (LET) of 0.2 keV/µm to 21.2 DSB/Gy/Gbp at high LET of 60 keV/µm. A mechanistic repair model was applied to predict the characteristics of DNA damage repair and dose response of chromosome aberrations. It was found that more than 95% of the DSBs are repaired within the first 24 h and the misrepaired DSB fraction increases rapidly with LET and reaches 15.8% at 60 keV/µm with an estimated chromosome aberration detection threshold of 3 Mbp. The dicentric and acentric fragment yields and the dose response of micronuclei formation after proton irradiation were calculated and compared with experimental results. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
41. Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy.
- Author
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BANNISTER, AARON HENRY, BROMMA, KYLE, WONMO SUNG, MONICA, MESA, CICON, LEAH, HOWARD, PERRY, CHOW, ROBERT L., SCHUEMANN, JAN, and CHITHRANI, DEVIKA BASNAGGE
- Abstract
Objective: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. Methods: We used HeLa and MDA-MB- 231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. Results: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. Conclusion: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. Advances in knowledge: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
42. Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons
- Author
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Lin, Yuting, Paganetti, Harald, McMahon, Stephen J., and Schuemann, Jan
- Subjects
Radiation Therapy Physics ,Photons ,Radiation-Sensitizing Agents ,Dose-Response Relationship, Drug ,Proton Therapy ,Blood Vessels ,Humans ,Metal Nanoparticles ,Gold ,Particle Size ,Models, Biological ,Monte Carlo Method - Abstract
The purpose of this work is to investigate the radiosensitizing effect of gold nanoparticle (GNP) induced vasculature damage for proton, megavoltage (MV) photon, and kilovoltage (kV) photon irradiation.Monte Carlo simulations were carried out using tool for particle simulation (TOPAS) to obtain the spatial dose distribution in close proximity up to 20 μm from the GNPs. The spatial dose distribution from GNPs was used as an input to calculate the dose deposited to the blood vessels. GNP induced vasculature damage was evaluated for three particle sources (a clinical spread out Bragg peak proton beam, a 6 MV photon beam, and two kV photon beams). For each particle source, various depths in tissue, GNP sizes (2, 10, and 20 nm diameter), and vessel diameters (8, 14, and 20 μm) were investigated. Two GNP distributions in lumen were considered, either homogeneously distributed in the vessel or attached to the inner wall of the vessel. Doses of 30 Gy and 2 Gy were considered, representing typical in vivo enhancement studies and conventional clinical fractionation, respectively.These simulations showed that for 20 Au-mg/g GNP blood concentration homogeneously distributed in the vessel, the additional dose at the inner vascular wall encircling the lumen was 43% of the prescribed dose at the depth of treatment for the 250 kVp photon source, 1% for the 6 MV photon source, and 0.1% for the proton beam. For kV photons, GNPs caused 15% more dose in the vascular wall for 150 kVp source than for 250 kVp. For 6 MV photons, GNPs caused 0.2% more dose in the vascular wall at 20 cm depth in water as compared to at depth of maximum dose (Dmax). For proton therapy, GNPs caused the same dose in the vascular wall for all depths across the spread out Bragg peak with 12.7 cm range and 7 cm modulation. For the same weight of GNPs in the vessel, 2 nm diameter GNPs caused three times more damage to the vessel than 20 nm diameter GNPs. When the GNPs were attached to the inner vascular wall, the damage to the inner vascular wall can be up to 207% of the prescribed dose for the 250 kVp photon source, 4% for the 6 MV photon source, and 2% for the proton beam. Even though the average dose increase from the proton beam and MV photon beam was not large, there were high dose spikes that elevate the local dose of the parts of the blood vessel to be higher than 15 Gy even for 2 Gy prescribed dose, especially when the GNPs can be actively targeted to the endothelial cells.GNPs can potentially be used to enhance radiation therapy by causing vasculature damage through high dose spikes caused by the addition of GNPs especially for hypofractionated treatment. If GNPs are designed to actively accumulate at the tumor vasculature walls, vasculature damage can be increased significantly. The largest enhancement is seen using kilovoltage photons due to the photoelectric effect. Although no significant average dose enhancement was observed for the whole vasculature structure for both MV photons and protons, they can cause high local dose escalation (15 Gy) to areas of the blood vessel that can potentially contribute to the disruption of the functionality of the blood vessels in the tumor.
- Published
- 2015
43. Computational models and tools.
- Author
-
Schuemann, Jan, Bassler, Niels, and Inaniwa, Taku
- Subjects
- *
LINEAR energy transfer , *MONTE Carlo method , *RADIOTHERAPY treatment planning , *DOSE-response relationship in ionizing radiation , *ION beams - Abstract
In this chapter, we describe two different methods, analytical (pencil beam) algorithms and Monte Carlo simulations, used to obtain the intended dose distributions in patients and evaluate their strengths and shortcomings. We discuss the difference between the prescribed physical dose and the biologically effective dose, the relative biological effectiveness (RBE) between ions and photons and the dependence of RBE on the linear energy transfer (LET). Lastly, we show how LET‐ or RBE‐based optimization can be used to improve treatment plans and explore how the availability of multimodality ion beam facilities can be used to design a tumor‐specific optimal treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
44. Dependence of gold nanoparticle radiosensitization on cell geometry.
- Author
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Sung, Wonmo, Ye, Sung-Joon, McNamara, Aimee L., McMahon, Stephen J., Hainfeld, James, Shin, Jungwook, Smilowitz, Henry M., Paganetti, Harald, and Schuemann, Jan
- Published
- 2017
- Full Text
- View/download PDF
45. Validation of the radiobiology toolkit TOPAS-nBio in simple DNA geometries.
- Author
-
McNamara, Aimee, Geng, Changran, Turner, Robert, Mendez, Jose Ramos, Perl, Joseph, Held, Kathryn, Faddegon, Bruce, Paganetti, Harald, and Schuemann, Jan
- Abstract
Computational simulations offer a powerful tool for quantitatively investigating radiation interactions with biological tissue and can help bridge the gap between physics, chemistry and biology. The TOPAS collaboration is tackling this challenge by extending the current Monte Carlo tool to allow for sub-cellular in silico simulations in a new extension, TOPAS-nBio. TOPAS wraps and extends the Geant4 Monte Carlo simulation toolkit and the new extension allows the modeling of particles down to vibrational energies ( ∼ 2 eV) within realistic biological geometries. Here we present a validation of biological geometries available in TOPAS-nBio, by comparing our results to two previously published studies. We compare the prediction of strand breaks in a simple linear DNA strand from TOPAS-nBio to a published Monte Carlo track structure simulation study. While TOPAS-nBio confirms the trend in strand break generation, it predicts a higher frequency of events below an energy of 17.5 eV compared to the alternative Monte Carlo track structure study. This is due to differences in the physics models used by each code. We also compare the experimental measurement of strand breaks from incident protons in DNA plasmids to TOPAS-nBio simulations. Our results show good agreement of single and double strand breaks predicting a similar increase in the strand break yield with increasing LET. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
46. Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries.
- Author
-
Butterworth, Karl T., McGarry, Conor K., Clasie, Ben, Carabe-Fernandez, Alejandro, Schuemann, Jan, Depauw, Nicolas, Tang, Shikui, McMahon, Stephen J., Schettino, Giuseppe, O'Sullivan, Joe M., Hsaio-Ming Lu, Hanne Kooy, Paganetti, Harald, Hounsell, Alan R., Held, Kathryn D., and Prise, Kevin M.
- Subjects
RELATIVE biological effectiveness (Radiobiology) ,EFFECT of radiation on cells ,PROTON therapy ,PHOTONS ,CELL populations ,DATA analysis - Abstract
The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in- and outof- field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
47. Range uncertainty in proton therapy due to variable biological effectiveness.
- Author
-
Carabe, Alejandro, Moteabbed, Maryam, Depauw, Nicolas, Schuemann, Jan, and Paganetti, Harald
- Subjects
RADIOTHERAPY ,ENERGY transfer ,DRUG dosage ,MONTE Carlo method ,TREATMENT effectiveness ,ELECTROTHERAPEUTICS - Abstract
Traditionally, dose in proton radiotherapy is prescribed as Gy(RBE) by scaling up the physical dose by 10%. The relative biological effectiveness (RBE) of protons is considered to vary with dose-averaged linear energy transfer (LET
d ), dose (d) and (α/β)x . The increase of RBE with depth causes a shift of the falloff of the beam, i.e. a change of the beam range. The magnitude of this shift will depend on dose and (α/β)x . The aim of this project was to quantify the dependence of the range shift on these parameters. Three double-scattered beams of different ranges incident on a computational phantom consisting of different regions of interest (ROIs) were used. Each ROI was assigned with (α/β)x values between 0.5 and 20 Gy. The distribution of LETd within each ROI was obtained from a Monte Carlo simulation. The LETd distribution depends on the beam energy and thus its nominal range. The RBE values within the ROIs were calculated for doses between 1 and 15 Gy using an in-house developed biophysical model. Dose-volume histograms of the RBEweighted doses were extracted for each ROI for a 'fixed RBE' (RBE = 1.1) and a 'variable RBE' (RBE = f (d, α/β, LETd )), and the percentage difference in range was obtained from the difference of the percentage volumes at the distal 80% of the dose. Range differences in normal tissue ((α/β)x = 3 Gy) of the order of 3-2 mm were obtained, respectively, for a shallow (physical range 4.8 cm) and a deep (physical range 12.8 cm) beam, when a dose of 1 Gy normalized to the mid-SOBP was delivered. As the dose increased to 15 Gy, the variable RBE decreases below 1.1 which induces ranges of about 1 mm shorter than those obtained with an RBE of 1.1. The shift in the range of an SOBP when comparing biological dose distributions obtained with a fixed or a variable RBE was quantified as a function of dose, (α/β)x and physical range (as a surrogate of the initial beam energy). The shift increases with the physical range but decreases with increasing dose or (α/β)x . The results of our study allow a quantitative consideration of RBE-caused range uncertainties as a function of treatment site and dose in treatment planning. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
48. Application of High-Z Gold Nanoparticles in Targeted Cancer Radiotherapy—Pharmacokinetic Modeling, Monte Carlo Simulation and Radiobiological Effect Modeling.
- Author
-
Li, Wei Bo, Stangl, Stefan, Klapproth, Alexander, Shevtsov, Maxim, Hernandez, Alicia, Kimm, Melanie A., Schuemann, Jan, Qiu, Rui, Michalke, Bernhard, Bernal, Mario A., Li, Junli, Hürkamp, Kerstin, Zhang, Yibao, and Multhoff, Gabriele
- Subjects
XENOGRAFTS ,MATHEMATICAL models ,ANTINEOPLASTIC agents ,IRON oxide nanoparticles ,CELL survival ,THEORY ,TUMORS ,NANOPARTICLES ,MICE - Abstract
Simple Summary: High-Z gold nanoparticles show potential as radiosensitizers in the radiotherapy of cancer. In this paper, we introduce the benefits and procedures for the application of gold nanoparticles in targeted cancer radiotherapy. Based on microscopic images of the distribution of antibody-conjugated nanoparticles, we established pharmacokinetic models simulating the biodistribution of nanoparticle conjugates in the tumor and tumor environment in preclinical models. This information has been implemented in radiation transport Monte Carlo simulation codes for further investigating physical and chemical enhancement and radiobiological effects, such as DNA strand breaks and cell survival. Future perspectives and challenges of translating this promising gold nanoparticle-aided radiotherapy into clinical practice are also discussed. High-Z gold nanoparticles (AuNPs) conjugated to a targeting antibody can help to improve tumor control in radiotherapy while simultaneously minimizing radiotoxicity to adjacent healthy tissue. This paper summarizes the main findings of a joint research program which applied AuNP-conjugates in preclinical modeling of radiotherapy at the Klinikum rechts der Isar, Technical University of Munich and Helmholtz Zentrum München. A pharmacokinetic model of superparamagnetic iron oxide nanoparticles was developed in preparation for a model simulating the uptake and distribution of AuNPs in mice. Multi-scale Monte Carlo simulations were performed on a single AuNP and multiple AuNPs in tumor cells at cellular and molecular levels to determine enhancements in the radiation dose and generation of chemical radicals in close proximity to AuNPs. A biologically based mathematical model was developed to predict the biological response of AuNPs in radiation enhancement. Although simulations of a single AuNP demonstrated a clear dose enhancement, simulations relating to the generation of chemical radicals and the induction of DNA strand breaks induced by multiple AuNPs showed only a minor dose enhancement. The differences in the simulated enhancements at molecular and cellular levels indicate that further investigations are necessary to better understand the impact of the physical, chemical, and biological parameters in preclinical experimental settings prior to a translation of these AuNPs models into targeted cancer radiotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
49. Modulation of gold nanoparticle mediated radiation dose enhancement through synchronization of breast tumor cell population.
- Author
-
Rieck, Kristy, Bromma, Kyle, Sung, Wonmo, Bannister, Aaron, Schuemann, Jan, and Chithrani, Devika Basnagge
- Subjects
LINEAR accelerators ,MONTE Carlo method ,CELL populations ,BREAST tumors ,RADIATION doses ,TRIPLE-negative breast cancer ,DRUG side effects - Abstract
The incorporation of high atomic number materials such as gold nanoparticles (GNPs) into tumor cells is being tested to enhance the local radiotherapy (RT) dose. It is also known that the radiosensitivity of tumor cells depends on the phase of their cell cycle. Triple combination of GNPs, phase of tumor cell population, and RT for improved outcomes in cancer treatment. We used a double-thymidine block method for synchronization of the tumor cell population. GNPs of diameters 17 and 46 nm were used to capture the size dependent effects. A radiation dose of 2 Gy with 6 MV linear accelerator was used to assess the efficacy of this proposed combined treatment. A triple negative breast cancer cell line, MDA-MB-231 was chosen as the model cell line. Monte Carlo (MC) calculations were done to predict the GNP-mediated cell death using the experimental GNP uptake data. There was a 1.5- and 2- fold increase in uptake of 17 and 46 nm GNPs in the synchronized cell population, respectively. A radiation dose of 2 Gy with clinically relevant 6 MV photons resulted in a 62 and 38 % enhancement in cell death in the synchronized cell population with the incorporation of 17 and 46 nm GNPs, respectively. MC data supported the experimental data, but to a lesser extent. A triple combination of GNPs, cell cycle synchronization, and RT could pave the way to enhance the local radiation dose while minimizing side effects to the surrounding healthy tissue. This is the first study to show that the combined use of GNPs, phase of tumor cell population, and RT could enhance tumor cell death. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
50. Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies.
- Author
-
Yang, Celina, Bromma, Kyle, Sung, Wonmo, Schuemann, Jan, and Chithrani, Devika
- Subjects
CISPLATIN ,TUMOR treatment ,CELL lines ,GOLD ,DOSE-response relationship (Radiation) ,NANOPARTICLES ,RADIATION dosimetry ,CHEMORADIOTHERAPY - Abstract
Combined use of chemotherapy and radiation therapy is commonly used in cancer treatment, but the toxic effects on normal tissue are a major limitation. This study assesses the potential to improve radiation therapy when combining gold nanoparticle (GNP) mediated radiation sensitization with chemoradiation compared to chemoradiation alone. Incorporation of GNPs with 2 Gy, 6 MV (megavoltage) radiation resulted in a 19 ± 6% decrease in survival of MDA-MB-231 cells. Monte-Carlo simulations were performed to assess dosimetric differences in the presence of GNPs in radiation. The results show that physics dosimetry represents a small fraction of the observed effect. The survival fraction of the cells exposed to GNPs, cisplatin, and radiation was 0.16 ± 0.007, while cells treated with cisplatin and radiation only was 0.23 ± 0.011. The presence of GNPs resulted in a 30 ± 6% decrease in the survival, having an additive effect. The concentration of the GNPs and free drug used for this study was 0.3 and 435 nM, respectively. These concentrations are relatively lower and achievable in an in vivo setting. Hence, the results of our study would accelerate the incorporation of GNP-mediated chemoradiation into current cancer therapeutic protocols in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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