2024 |
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Proton-FLASH: effects of ultra-high dose rate irradiation on an in-vivo mouse ear model S. Rudigkeit, T.E. Schmid, A.C. Dombrowsky, J. Stolz, S. Bartzsch, C.-B. Chen, N. Matejka, M. Sammer, A. Bergmaier, G. Dollinger and J. Reindl; Scientific Reports 14 (1) (2024) 1418. |
| Abstract: FLASH-radiotherapy may provide significant sparing of healthy tissue through ultra-high dose rates in protons, electrons, and x-rays while maintaining the tumor control. Key factors for the FLASH effect might be oxygen depletion, the immune system, and the irradiated blood volume, but none could be fully confirmed yet. Therefore, further investigations are necessary. We investigated the protective (tissue sparing) effect of FLASH in proton treatment using an in-vivo mouse ear model. The right ears of Balb/c mice were irradiated with 20 MeV protons at the ion microprobe SNAKE in Garching near Munich by using three dose rates (Conv = 0.06 Gy/s, Flash9 = 9.3 Gy/s and Flash930 = 930 Gy/s) at a total dose of 23 Gy or 33 Gy. The ear thickness, desquamation, and erythema combined in an inflammation score were measured for 180 days. The cytokines TGF-β1, TNF-α, IL1α, and IL1β were analyzed in the blood sampled in the first 4 weeks and at termination day. No differences in inflammation reactions were visible in the 23 Gy group for the different dose rates. In the 33 Gy group, the ear swelling and the inflammation score for Flash9 was reduced by (57 ± 12) % and (67 ± 17) % and for Flash930 by (40 ± 13) % and (50 ± 17) % compared to the Conv dose rate. No changes in the cytokines in the blood could be measured. However, an estimation of the irradiated blood volume demonstrates, that 100-times more blood is irradiated when using Conv compared to using Flash9 or Flash930. This indicates that blood might play a role in the underlying mechanisms in the protective effect of FLASH. |
BibTeX:
@article{Rudigkeit2024,
author = {Rudigkeit, Sarah and Schmid, Thomas E. and Dombrowsky, Annique C. and Stolz, Jessica and Bartzsch, Stefan and Chen, Ce-Belle and Matejka, Nicole and Sammer, Matthias and Bergmaier, Andreas and Dollinger, Günther and Reindl, Judith},
title = {Proton-FLASH: effects of ultra-high dose rate irradiation on an in-vivo mouse ear model},
journal = {Scientific Reports},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2024},
volume = {14},
number = {1},
pages = {1418},
url = {https://www.nature.com/articles/s41598-024-51951-6},
doi = {https://doi.org/10.1038/s41598-024-51951-6}
}
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Chromatin Organization after High-LET Irradiation Revealed by Super-Resolution STED Microscopy B. Schwarz, N. Matejka, S. Rudigkeit, M. Sammer and J. Reindl; International Journal of Molecular Sciences 25 (1) (2024) 628. |
| Abstract: Ion-radiation-induced DNA double-strand breaks can lead to severe cellular damage ranging from mutations up to direct cell death. The interplay between the chromatin surrounding the damage and the proteins responsible for damage recognition and repair determines the efficiency and outcome of DNA repair. The chromatin is organized in three major functional compartments throughout the interphase: the chromatin territories, the interchromatin compartment, and the perichromatin lying in between. In this study, we perform correlation analysis using super-resolution STED images of chromatin; splicing factor SC35, as an interchromatin marker; and the DNA repair factors 53BP1, Rad51, and γH2AX in carbon-ion-irradiated human HeLa cells. Chromatin and interchromatin overlap only in protruding chromatin branches, which is the same for the correlation between chromatin and 53BP1. In contrast, between interchromatin and 53BP1, a gap of (270 ± 40) nm is visible. Rad51 shows overlap with decondensed euchromatic regions located at the borders of condensed heterochromatin with further correlation with γH2AX. We conclude that the DNA damage is repaired in decondensed DNA loops in the perichromatin, located in the periphery of the DNA-dense chromatin compartments containing the heterochromatin. Proteins like γH2AX and 53BP1 serve as supporters of the chromatin structure. |
BibTeX:
@article{Schwarz2024,
author = {Schwarz, Benjamin and Matejka, Nicole and Rudigkeit, Sarah and Sammer, Matthias and Reindl, Judith},
title = {Chromatin Organization after High-LET Irradiation Revealed by Super-Resolution STED Microscopy},
journal = {International Journal of Molecular Sciences},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2024},
volume = {25},
number = {1},
pages = {628},
url = {https://www.mdpi.com/1422-0067/25/1/628},
doi = {https://doi.org/10.3390/ijms25010628}
}
|
2023 |
|
Radiobiology of Combining Radiotherapy with Other Cancer Treatment Modalities V. Ahire, N. Ahmadi Bidakhvidi, T. Boterberg, P. Chaudhary, F. Chevalier, N. Daems, W. Delbart, S. Baatout, C.M. Deroose, C. Fernandez-Palomo, N.A.P. Franken, U.S. Gaipl, L. Geenen, N. Heynickx, I. Koniarová, V.K. Selvaraj, H. Levillain, A.J. Michaelidesová, A. Montoro, A.L. Oei, S. Penninckx, J. Reindl, F. Rödel, P. Sminia, K. Tabury, K. Vermeulen, K. Viktorsson and A. Waked; In: S. Baatout (Ed.), Radiobiology Textbook , p. 311-386 , Springer International Publishing , 2023. |
| Abstract: In this chapter, we address the role of radiation as treatment modality in the context of oncological treatments given to patients. Physical aspects of the use of ionizing radiation (IR)---by either photons, neutrons, or charged (high linear energy transfer) particles---and their clinical application are summarized. Information is also provided regarding the radiobiological rationale of the use of conventional fractionation as well as alternative fractionation schedules using deviating total dose, fraction size, number of fractions, and the overall treatment time. Pro- and contra arguments of hypofractionation are discussed. In particular, the biological rationale and clinical application of Stereotactic Body Radiation Therapy (SBRT) are described. Furthermore, background information is given about FLASH radiotherapy (RT), which is an emerging new radiation method using ultra-high dose rate allowing the healthy, normal tissues and organs to be spared while maintaining the antitumor effect. Spatial fractionation of radiation in tumor therapy, another method that reduces damage to normal tissue is presented. Normal tissue doses could also be minimized by interstitial or intraluminal irradiation, i.e., brachytherapy, and herein an overview is given on the principles of brachytherapy and its clinical application. Furthermore, details are provided regarding the principles, clinical application, and limitations of boron neutron capture therapy (BNCT). Another important key issue in cancer therapy is the combination of RT with other treatment modalities, e.g., chemotherapy, targeted therapy, immunotherapy, hyperthermia, and hormonal therapy. Combination treatments are aimed to selectively enhance the effect of radiation in cancer cells or to trigger the immune system but also to minimize adverse effects on normal cells. The biological rationale of all these combination treatments as well as their application in clinical settings are outlined. To selectively reach high concentrations of radionuclides in tumor tissue, radioembolization is a highly interesting approach. Also, radioligand therapy which enables specific targeting of cancer cells, while causing minimal harm surrounding healthy tissues is presented. A brief overview is provided on how nanotechnology could contribute to the diagnosis and treatment of cancer. Last but not least, risk factors involved in acquiring secondary tumors after RT are discussed. |
BibTeX:
@incollection{Ahire2023,
author = {Ahire, Vidhula and Ahmadi Bidakhvidi, Niloefar and Boterberg, Tom and Chaudhary, Pankaj and Chevalier, Francois and Daems, Noami and Delbart, Wendy and Baatout, Sarah and Deroose, Christophe M. and Fernandez-Palomo, Cristian and Franken, Nicolaas A. P. and Gaipl, Udo S. and Geenen, Lorain and Heynickx, Nathalie and Koniarová, Irena and Selvaraj, Vinodh Kumar and Levillain, Hugo and Michaelidesová, Anna Jelínek and Montoro, Alegría and Oei, Arlene L. and Penninckx, Sébastien and Reindl, Judith and Rödel, Franz and Sminia, Peter and Tabury, Kevin and Vermeulen, Koen and Viktorsson, Kristina and Waked, Anthony},
title = {Radiobiology of Combining Radiotherapy with Other Cancer Treatment Modalities},
booktitle = {Radiobiology Textbook},
publisher = {Springer International Publishing},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2023},
pages = {311--386},
editor = {Baatout, Sarah},
url = {https://link.springer.com/chapter/10.1007/978-3-031-18810-7_6},
doi = {https://doi.org/10.1007/978-3-031-18810-7_6}
}
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Basic Concepts of Radiation Biology A. Baeyens, A.M. Abrantes, V. Ahire, E.A. Ainsbury, S. Baatout, B. Baselet, M.F. Botelho, T. Boterberg, F. Chevalier, F. Da Pieve, W. Delbart, N.F.J. Edin, C. Fernandez-Palomo, L. Geenen, A.G. Georgakilas, N. Heynickx, A.D. Meade, A.J. Michaelidesova, D. Mistry, A. Montoro, C. Mothersill, A.S. Pires, J. Reindl, G. Schettino, Y. Socol, V.K. Selvaraj, P. Sminia, K. Vermeulen, G. Vogin, A. Waked and A.-S. Wozny; In: S. Baatout (Ed.), Radiobiology Textbook , p. 25-81 , Springer International Publishing , 2023. |
| Abstract: Radiation biology is the study of the effects of ionizing radiation on biological tissues and living organisms. It combines radiation physics and biology. The purpose of this chapter is to introduce the terminology and basic concepts of radiobiology to create a better understanding of the ionizing radiation interactions with a living organism. This chapter firstly describes the different types of radiation, the sources, and the radiation interactions with matter. The basic concepts of radioactivity and its applications are also included. Ionizing radiation causes significant physical and chemical modifications, which eventually lead to biological effects in the exposed tissue or organism. The physical quantities and units needed to describe the radiation are introduced here. Eventually, a broad range of biological effects of the different radiation types are addressed. This chapter concludes with a specific focus on the effects of low doses of radiation. |
BibTeX:
@incollection{Baeyens2023,
author = {Baeyens, Ans and Abrantes, Ana Margarida and Ahire, Vidhula and Ainsbury, Elizabeth A. and Baatout, Sarah and Baselet, Bjorn and Botelho, Maria Filomena and Boterberg, Tom and Chevalier, Francois and Da Pieve, Fabiana and Delbart, Wendy and Edin, Nina Frederike Jeppesen and Fernandez-Palomo, Cristian and Geenen, Lorain and Georgakilas, Alexandros G. and Heynickx, Nathalie and Meade, Aidan D. and Michaelidesova, Anna Jelinek and Mistry, Dhruti and Montoro, Alegría and Mothersill, Carmel and Pires, Ana Salomé and Reindl, Judith and Schettino, Giuseppe and Socol, Yehoshua and Selvaraj, Vinodh Kumar and Sminia, Peter and Vermeulen, Koen and Vogin, Guillaume and Waked, Anthony and Wozny, Anne-Sophie},
title = {Basic Concepts of Radiation Biology},
booktitle = {Radiobiology Textbook},
publisher = {Springer International Publishing},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2023},
pages = {25--81},
editor = {Baatout, Sarah},
url = {https://link.springer.com/chapter/10.1007/978-3-031-18810-7_2},
doi = {https://doi.org/10.1007/978-3-031-18810-7_2}
}
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A carbon minibeam irradiation facility concept M. Mayerhofer, V. Bencini, M. Sammer and G. Dollinger; Journal of Physics: Conference Series 2420 (1) (2023) 012097. |
| Abstract: In minibeam therapy, the sparing of deep-seated normal tissue is limited by transverse beam spread caused by small-angle scattering. Contrary to proton minibeams, helium or carbon minibeams experience less deflection, which potentially reduces side effects. To verify this potential, an irradiation facility for preclinical and clinical studies is needed. This manuscript presents a concept for a carbon minibeam irradiation facility based on a LINAC design for conventional carbon therapy. A quadrupole triplet focuses the LINAC beam to submillimeter minibeams. A scanning and a dosimetry unit are provided to move the minibeam over the target and monitor the applied dose. The beamline was optimized by TRAVEL simulations. The interaction between beam and these components and the resulting beam parameters at the focal plane is evaluated by TOPAS simulations. A transverse beamwidth of < 100 μm (sigma) and a peak-to-valley (energy) dose ratio of > 1000 results for carbon energies of 100 MeV/u and 430 MeV/u (∼ 3 cm and 30 cm range in water) whereby the average beam current is ∼ 30 nA. Therefore, the presented irradiation facility exceeds the requirements for hadron minibeam therapy. |
BibTeX:
@article{Mayerhofer2023,
author = {Mayerhofer, M. and Bencini, V. and Sammer, M. and Dollinger, G.},
title = {A carbon minibeam irradiation facility concept},
journal = {Journal of Physics: Conference Series},
publisher = {IOP Publishing},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2023},
volume = {2420},
number = {1},
pages = {012097},
url = {https://iopscience.iop.org/article/10.1088/1742-6596/2420/1/012097},
doi = {https://doi.org/10.1088/1742-6596/2420/1/012097}
}
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First high quality DTL cavity additively manufactured from pure copper M. Mayerhofer, J. Mitteneder, C. Wittig, I. Prestes, E. Jägle and G. Dollinge; In: , R. Assmann, P. McIntosh, G. Bisoffi, Elettra-Sincrotrone, I. Andrian and G. Vinicola (Eds.), Proc. 14th International Particle Accelerator Conference (IPAC'23) , JACoW 14 (2023) 4967-4970 , JACoW Publishing, Geneva, Switzerland. |
| Abstract: Recently presented RF cavity prototypes printed entirely from pure copper illustrate the potential of additive manufacturing (AM), and particularly laser powder bed fusion (L-PBF), for accelerator technology. Thereby, the design freedom of L-PBF is only limited by overhanging geometries, which have to be printed with supporting structures to ensure sufficient accuracy. However, subsequent removal of these support structures is a major challenge for cm-sized GHz cavities. Therefore, our approach is to design self-supporting geometries. In this contribution we present a DTL cavity geometry as used in e.g. proton therapy linac systems that can be fabricated by L-PBF without support structures. A 5-cell prototype was manufactured from high-purity copper using L-PBF. It is shown that the developed geometry allows a print accuracy sufficient to reach the defined resonance frequency. A chemical, as well as dynamic electrochemical finishing process, was applied to optimize the prototypes surface quality. Thus, the CST simulated figures of merit (e.g., Q_0, Z_eff) were obtained for the first time with a printed cavity. |
BibTeX:
@inproceedings{Mayerhofer2023b,
author = {Mayerhofer, M. and Mitteneder, J. and Wittig, C. and Prestes, I. and Jägle, E. and Dollinge, G.},
title = {First high quality DTL cavity additively manufactured from pure copper},
booktitle = {Proc. 14th International Particle Accelerator Conference (IPAC'23)},
journal = {JACoW},
publisher = {JACoW Publishing, Geneva, Switzerland},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2023},
volume = {14},
number = {13},
pages = {4967-4970},
editor = {Ralph Assmann and Peter McIntosh and Giovanni Bisoffi and Elettra-Sincrotrone and Ivan Andrian and Giulia Vinicola},
url = {https://accelconf.web.cern.ch/ipac2023/doi/jacow-ipac2023-thpm035/},
doi = {https://doi.org/10.18429/JACoW-IPAC2023-THPM035}
}
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Molecular Radiation Biology J. Reindl, A.M. Abrantes, V. Ahire, O. Azimzadeh, S. Baatout, A. Baeyens, B. Baselet, V. Chauhan, F. Da Pieve, W. Delbart, C.P. Dobney, N.F.J. Edin, M. Falk, N. Foray, A. François, S. Frelon, U.S. Gaipl, A.G. Georgakilas, O. Guipaud, M. Hausmann, A.J. Michaelidesova, M. Kadhim, I.A. Marques, M. Milic, D. Mistry, S. Moertl, A. Montoro, E. Obrador, A.S. Pires, R. Quintens, N. Rajan, F. Rödel, P. Rogan, D. Savu, G. Schettino, K. Tabury, G.I. Terzoudi, S. Triantopoulou, K. Viktorsson and A.-S. Wozny; In: S. Baatout (Ed.), Radiobiology Textbook , p. 83-189 , Springer International Publishing , 2023. |
| Abstract: Various exogeneous and endogenous factors constantly cause damages in the biomolecules within a cell. For example, per day, 10,000--100,000 molecular lesions occur in DNA per cell. The molecule modifications that are formed disturb the structure and function of the affected molecules. The purpose of this chapter is to introduce the damages to biomolecules caused by radiation, the associated repair pathways, and the effect on the cellular function. Special interest lies on the damages induced to DNA, the carrier of the human genome, and the consequence to genomic integrity, cell death, and cell survival. Additionally, related effects regarding inflammation and immunity, epigenetic factors, and omics are discussed. The chapter concludes with an explanation of the molecular factors of cellular hyper-radiosensitivity and induced radiation resistance. |
BibTeX:
@incollection{Reindl2023,
author = {Reindl, Judith and Abrantes, Ana Margarida and Ahire, Vidhula and Azimzadeh, Omid and Baatout, Sarah and Baeyens, Ans and Baselet, Bjorn and Chauhan, Vinita and Da Pieve, Fabiana and Delbart, Wendy and Dobney, Caitlin Pria and Edin, Nina Frederike Jeppesen and Falk, Martin and Foray, Nicolas and François, Agnès and Frelon, Sandrine and Gaipl, Udo S. and Georgakilas, Alexandros G. and Guipaud, Olivier and Hausmann, Michael and Michaelidesova, Anna Jelinek and Kadhim, Munira and Marques, Inês Alexandra and Milic, Mirta and Mistry, Dhruti and Moertl, Simone and Montoro, Alegría and Obrador, Elena and Pires, Ana Salomé and Quintens, Roel and Rajan, Nicholas and Rödel, Franz and Rogan, Peter and Savu, Diana and Schettino, Giuseppe and Tabury, Kevin and Terzoudi, Georgia I. and Triantopoulou, Sotiria and Viktorsson, Kristina and Wozny, Anne-Sophie},
title = {Molecular Radiation Biology},
booktitle = {Radiobiology Textbook},
publisher = {Springer International Publishing},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2023},
pages = {83--189},
editor = {Baatout, Sarah},
url = {https://link.springer.com/chapter/10.1007/978-3-031-18810-7_3},
doi = {https://doi.org/10.1007/978-3-031-18810-7_3}
}
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Beam optimization of a heavy ion microbeam for targeted irradiation of mitochondria in human cells S. Rudigkeit, N. Matejka, M. Sammer, D.W.M. Walsh, G. Dollinger and J. Reindl; Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms 542 (2023) 195-205. |
| Abstract: Mitochondria, organelles of the cytoplasm, are the power plants of the cell and thus their function is important for the survival of cells. Mitochondria are known to depolarize after targeted irradiation, but the effects on cells are still unclear. The aim of this work is to investigate the effects of mitochondrial depolarization on growth and survival of cells. We performed targeted irradiation with 55 MeV C5+-ions at the ion-microbeam SNAKE at the 14 MV tandem accelerator in Garching near Munich, with a beam spot size of ∼1 µm. Approx. 6% of the mitochondrial area was irradiated in 74 cells with 5,120 carbon ions homogenously distributed over a square area of 13.2 µm2. Cell growth was investigated by observing the cells for 3.5 days via live-cell phase-contrast microscopy and evaluating the number of vital cells. While the number of irradiated cells remained constant during the observation, the unirradiated control group showed exponential growth. An additional particle track detector test with polycarbonate revealed that 4% parasitic ions hit the cells up to 500 µm away from the target, forming a so-called halo and inducing a mean parasitic dose of (2 ± 2) Gy on the cells. This dose alone, when applied in cell nuclei, is large enough to reduce the survival and growth of cells significantly and overrides any effects caused by targeted irradiation of mitochondria. Subsequently, several methods to reduce the halo were investigated. A significant reduction in halo size and number of ions in the halo could be achieved by using C6+-ions instead of C5+-ions. The slit openings, correction of lens errors, and the beam spot size had minor influence on the halo size but could achieve a reduction in halo dose. Overall, a 97% reduction in halo area and a halving of halo dose were achieved. |
BibTeX:
@article{Rudigkeit2023,
author = {Rudigkeit, Sarah and Matejka, Nicole and Sammer, Matthias and Walsh, Dietrich W. M. and Dollinger, Günther and Reindl, Judith},
title = {Beam optimization of a heavy ion microbeam for targeted irradiation of mitochondria in human cells},
journal = {Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2023},
volume = {542},
pages = {195-205},
url = {https://www.sciencedirect.com/science/article/pii/S0168583X23003129},
doi = {https://doi.org/10.1016/j.nimb.2023.07.004}
}
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Single-Cell Radiation Response Scoring with the Deep Learning Algorithm CeCILE 2.0 S. Rudigkeit and J. Reindl; Cells 12 (24) (2023) 2782. |
| Abstract: External stressors, such as ionizing radiation, have massive effects on life, survival, and the ability of mammalian cells to divide. Different types of radiation have different effects. In order to understand these in detail and the underlying mechanisms, it is essential to study the radiation response of each cell. This allows abnormalities to be characterized and laws to be derived. Tracking individual cells over several generations of division generates large amounts of data that can no longer be meaningfully analyzed by hand. In this study, we present a deep-learning-based algorithm, CeCILE (Cell classification and in vitro lifecycle evaluation) 2.0, that can localize, classify, and track cells in live cell phase-contrast videos. This allows conclusions to be drawn about the viability of the cells, the cell cycle, cell survival, and the influence of X-ray radiation on these. Furthermore, radiation-specific abnormalities during division could be characterized. In summary, CeCILE 2.0 is a powerful tool to characterize and quantify the cellular response to external stressors such as radiation and to put individual responses into a larger context. To the authors knowledge, this is the first algorithm with a fully integrated workflow that is able to do comprehensive single-cell and cell composite analysis, allowing them to draw conclusions on cellular radiation response. |
BibTeX:
@article{Rudigkeit2023a,
author = {Rudigkeit, Sarah and Reindl, Judith},
title = {Single-Cell Radiation Response Scoring with the Deep Learning Algorithm CeCILE 2.0},
journal = {Cells},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2023},
volume = {12},
number = {24},
pages = {2782},
url = {https://www.mdpi.com/2073-4409/12/24/2782},
doi = {https://doi.org/10.3390/cells12242782}
}
|
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Range verification of a clinical proton beam in an abdominal phantom by co-registration of ionoacoustics and ultrasound J. Schauer, H.-P. Wieser, J. Lascaud, Y. Huang, M. Vidal, J. Herault, V. Ntziachristos, G. Dollinger and K. Parodi; Physics in Medicine & Biology 68 (12) (2023) 125009. |
| Abstract: Objective. The range uncertainty in proton radiotherapy is a limiting factor to achieve optimum dose conformity to the tumour volume. Ionoacoustics is a promising approach for in situ range verification, which would allow to reduce the size of the irradiated volume relative to the tumour volume. The energy deposition of a pulsed proton beam leads to an acoustic pressure wave (ionoacoustics), the detection of which allows conclusion about the distance between the Bragg peak and the acoustic detector. This information can be transferred into a co-registered ultrasound image, marking the Bragg peak position relative to the surrounding anatomy. Approach. A CIRS 3D abdominal phantom was irradiated with 126 MeV protons at a clinical proton therapy centre. Acoustic signals were recorded on the beam axis distal to the Bragg peak with a Cetacean C305X hydrophone. The ionoacoustic measurements were processed with a correlation filter using simulated filter templates. The hydrophone was rigidly attached to an ultrasound device (Interson GP-C01) recording ultrasound images of the irradiated region. Main results. The time of flight obtained from ionoacoustic measurements were transferred to an ultrasound image by means of an optoacoustic calibration measurement. The Bragg peak position was marked in the ultrasound image with a statistical uncertainty of σ = 0.5 mm of 24 individual measurements depositing 1.2 Gy at the Bragg peak. The difference between the evaluated Bragg peak position and the one obtained from irradiation planning (1.0 mm) is smaller than the typical range uncertainty (≈4 mm) at the given penetration depth (10 cm). Significance. The measurements show that it is possible to determine the Bragg peak position of a clinical proton beam with submillimetre precision and transfer the information to an ultrasound image of the irradiated region. The dose required for this is smaller than that used for a typical irradiation fraction. |
BibTeX:
@article{Schauer2023,
author = {Jannis Schauer and Hans-Peter Wieser and Julie Lascaud and Yuanhui Huang and Marie Vidal and Joel Herault and Vasilis Ntziachristos and Günther Dollinger and Katia Parodi},
title = {Range verification of a clinical proton beam in an abdominal phantom by co-registration of ionoacoustics and ultrasound},
journal = {Physics in Medicine & Biology},
publisher = {IOP Publishing},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2023},
volume = {68},
number = {12},
pages = {125009},
url = {https://iopscience.iop.org/article/10.1088/1361-6560/acd834},
doi = {https://doi.org/10.1088/1361-6560/acd834}
}
|
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Mechanistic, Modeling, and Dosimetric Radiation Biology G. Schettino, S. Baatout, F. Caramelo, F. Da Pieve, C. Fernandez-Palomo, N.F.J. Edin, A.D. Meade, Y. Perrot, J. Reindl and C. Villagrasa; In: S. Baatout (Ed.), Radiobiology Textbook , p. 191-236 , Springer International Publishing , 2023. |
| Abstract: The ultimate aim of radiobiological research is to establish a quantitative relationship between the radiation dose absorbed by biological samples (being this a cell, a tissue, an organ, or a body) and the effect caused. Therefore, radiobiological investigations need to be supported by accurate and precise dosimetric measurements. A rigorous standardized methodology has been established to assess and quantify the radiation dose absorbed by biological samples and these will be reviewed and discussed in this chapter. Dosimetric concepts at the macro- and microscopic levels are discussed with a focus on key physical quantities, their measurement technologies, and the link to the biological damage and response. This chapter will also include a description of state-of-the-art irradiation facilities (e.g., mini- and micro-beams) used for probing mechanisms underpinning radiobiological responses. Finally, the link between energy deposition events and detectable biological effects (from the molecular to the organism level) is investigated using Monte Carlo simulation codes and macroscopic radiobiological models. |
BibTeX:
@incollection{Schettino2023,
author = {Schettino, Giuseppe and Baatout, Sarah and Caramelo, Francisco and Da Pieve, Fabiana and Fernandez-Palomo, Cristian and Edin, Nina Frederike Jeppesen and Meade, Aidan D. and Perrot, Yann and Reindl, Judith and Villagrasa, Carmen},
title = {Mechanistic, Modeling, and Dosimetric Radiation Biology},
booktitle = {Radiobiology Textbook},
publisher = {Springer International Publishing},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2023},
pages = {191--236},
editor = {Baatout, Sarah},
url = {https://link.springer.com/chapter/10.1007/978-3-031-18810-7_4},
doi = {https://doi.org/10.1007/978-3-031-18810-7_4}
}
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High-LET targeted microbeam irradiation induces local chromatin reorganization in living cells showing active basal mechanisms at highly complex DNA damage sites0 B. Schwarz, N. Matejka, M. Sammer, S. Rudigkeit and J. Reindl; Journal of Radiation Research and Imaging 2 (1) (2023) 1-8. |
| Abstract: DNA repair eukaryotic cells have additional protective mechanisms that avoid uncontrolled interaction of different parts of the chromatin and damaged regions. Key factors here are the regulation of chromatin density and mobility. The 4D (temporal and spatial) organization of chromatin is controlling this security barrier by regulating the accessibility of genes, flexibility of DNA, and its ability to move inside the nucleus. How this regulation mechanisms are involved in DNA repair upon radiation damage is until now rarely known but an important part to understand the enhanced effectiveness of high linear energy transfer (LET) particles. The damage recognition via PARP1 and the subsequent chromatin decondensation via PARylation is a crucial step in the DNA damage response (DDR). Upon We used the SNAKE microbeam with a beam spot size of <1 µm to induce highly localized DNA damage in living cells using 55 MeV Carbon ions to investigate the chromatin rearrangements in the early stage of DDR. The nuclei were irradiated with a cross pattern consisting of 1000 ions per spot and 25 spots per cell either with one (11 000 Gy), two (22 000 Gy), or three crosses (33 000 Gy). The chromatin rearrangement was imaged live for several minutes after irradiation at the beam using SiR chromatin stain. Upon 91% of the cells show a localized decondensation starting from a few seconds up to minutes after irradiation. The chromatin is decondensed by 6%-8% in the beam path with a local condensation at the edges of up to 8%. Our results suggest that chromatin decondensation is a fast process in the first few seconds after damage induction. Furthermore, decondensation status does not change over minutes, which gives evidence that this process and therefore DDR is paused or even stopped. In combination with the existing knowledge about early reactions to damage induction our data support the model of PARP induced chromatin decondensation. Furthermore, it is evident that also ultra-high doses of radiation are, in first place not able to inactivate initial basal mechanisms as response to damage induction. |
BibTeX:
@article{Schwarz2023,
author = {Schwarz, Benjamin and Matejka, Nicole and Sammer, Matthias and Rudigkeit, Sarah and Reindl, Judith},
title = {High-LET targeted microbeam irradiation induces local chromatin reorganization in living cells showing active basal mechanisms at highly complex DNA damage sites0},
journal = {Journal of Radiation Research and Imaging},
publisher = {ProBiologists LLC.},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2023},
volume = {2},
number = {1},
pages = {1-8},
url = {https://probiologists.com/Article/High-LET-targeted-microbeam-irradiation-induces-local-chromatin-reorganization-in-living-cells-showing-active-basal-mechanisms-at-highly-complex-DNA-damage-sites},
doi = {https://doi.org/10.46439/radiation.2.006}
}
|
2022 |
|
Höchstauflösende STED Mikroskopie von Strahlungsgeschädigten Zellen zur Biodosimetrie Nicolai Heßmann; Masters-Thesis, Universität der Bundeswehr München, 2022. [BibTeX] |
BibTeX:
@mastersthesis{Hessmann2022,
author = {Heßmann, Nicolai},
title = {Höchstauflösende STED Mikroskopie von Strahlungsgeschädigten Zellen zur Biodosimetrie},
school = {Universität der Bundeswehr München},
year = {2022}
}
|
|
A 3D printed pure copper drift tube linac prototype M. Mayerhofer, J. Mitteneder and G. Dollinger; Review of Scientific Instruments 93 (2) (2022) 023304. |
| Abstract: Radio frequency cavities are among the most challenging and costly components of an accelerator facility. They are usually manufactured in individual parts, which are then joined by complex processes, e.g., several brazing steps. 3D printing has become an alternative to these conventional manufacturing methods due to higher cost efficiency, freedom in design, and recent achievement of high print quality for pure copper. A fully functional 3 GHz drift tube linac (DTL) prototype was 3D printed in one piece, made from pure copper by selective laser melting (SLM). To achieve a higher surface quality, the DTL geometry was optimized for the SLM process. The DTL design is related to the design of the DTL part of the side-coupled DTL modules used in linac-based proton therapy facilities. The quality factor (8750) and the shunt impedance per unit length (102 mΩ/m) of the printed prototype are already comparable to traditionally manufactured DTL structures and can be further enhanced by surface treatments. |
BibTeX:
@article{Mayerhofer2022,
author = {Mayerhofer, Michael and Mitteneder, Johannes and Dollinger, Günther},
title = {A 3D printed pure copper drift tube linac prototype},
journal = {Review of Scientific Instruments},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2022},
volume = {93},
number = {2},
pages = {023304},
url = {https://aip.scitation.org/doi/full/10.1063/5.0068494},
doi = {https://doi.org/10.1063/5.0068494}
}
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|
A Carbon Minibeam Irradiation Facility Concept M. Mayerhofer, V. Bencini, G. Dollinger and M.A. Sammer; In: Proc. 13th International Particle Accelerator Conference (IPAC'22) , JACoW (2022) 2947-2950 , JACoW Publishing, Geneva, Switzerland. |
| Abstract: In minibeam therapy, the sparing of deep-seated normal tissue is limited by transverse beam spread caused by small-angle scattering. Contrary to proton minibeams, helium or carbon minibeams experience less deflection, which potentially reduces side effects. To verify this potential, an irradiation facility for preclinical and clinical studies is needed. This manuscript presents a concept for a carbon minibeam irradiation facility based on a LINAC design for conventional carbon therapy. A quadrupole triplet focuses the LINAC beam to submillimeter minibeams. A scanning and a dosimetry unit are provided to move the minibeam over the target and monitor the applied dose. The beamline was optimized by TRAVEL simulations. The interaction between beam and these components and the resulting beam parameters at the focal plane is evaluated by TOPAS simulations. A transverse beamwidth of < 100 µm (σ) and a peak-to-valley (energy) dose ratio of > 1000 results for carbon energies of 100 MeV/u and 430 MeV/u (about 3 cm and 30 cm range in water) whereby the average beam current is about 30 nA. Therefore, the presented irradiation facility exceeds the requirements for hadron minibeam therapy. |
BibTeX:
@inproceedings{Mayerhofer2022a,
author = {Mayerhofer, M. and Bencini, V. and Dollinger, G. and Sammer, M. A.},
title = {A Carbon Minibeam Irradiation Facility Concept},
booktitle = {Proc. 13th International Particle Accelerator Conference (IPAC'22)},
journal = {JACoW},
publisher = {JACoW Publishing, Geneva, Switzerland},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2022},
number = {13},
pages = {2947--2950},
url = {https://jacow.org/ipac2022/papers/thpoms006.pdf},
doi = {https://doi.org/10.18429/JACoW-IPAC2022-THPOMS006}
}
|
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Dosimetry of heavy ion exposure to human cells using nanoscopic imaging of double strand break repair protein clusters J. Reindl, P. Kundrat, S. Girst, M. Sammer, B. Schwarz and G. Dollinger; Scientific Reports 12 (1) (2022) 1305. |
| Abstract: The human body is constantly exposed to ionizing radiation of different qualities. Especially the exposure to high-LET (linear energy transfer) particles increases due to new tumor therapy methods using e.g. carbon ions. Furthermore, upon radiation accidents, a mixture of radiation of different quality is adding up to human radiation exposure. Finally, long-term space missions such as the mission to mars pose great challenges to the dose assessment an astronaut was exposed to. Currently, DSB counting using γH2AX foci is used as an exact dosimetric measure for individuals. Due to the size of the γH2AX IRIF of 0.6 µm, it is only possible to count DSB when they are separated by this distance. For high-LET particle exposure, the distance of the DSB is too small to be separated and the dose will be underestimated. In this study, we developed a method where it is possible to count DSB which are separated by a distance of 140 nm. We counted the number of ionizing radiation-induced pDNA-PKcs (DNA-PKcs phosphorylated at T2609) foci (size = 140 nm ± 20 nm) in human HeLa cells using STED super-resolution microscopy that has an intrinsic resolution of 100 nm. Irradiation was performed at the ion microprobe SNAKE using high-LET 20 MeV lithium (LET = 116 keV/µm) and 27 MeV carbon ions (LET = 500 keV/µm). pDNA-PKcs foci label all DSB as proven by counterstaining with 53BP1 after low-LET γ-irradiation where separation of individual DSB is in most cases larger than the 53BP1 gross size of about 0.6 µm. Lithium ions produce (1.5 ± 0.1) IRIF/µm track length, for carbon ions (2.2 ± 0.2) IRIF/µm are counted. These values are enhanced by a factor of 2-3 compared to conventional foci counting of high-LET tracks. Comparison of the measurements to PARTRAC simulation data proof the consistency of results. We used these data to develop a measure for dosimetry of high-LET or mixed particle radiation exposure directly in the biological sample. We show that proper dosimetry for radiation up to a LET of 240 keV/µm is possible. |
BibTeX:
@article{Reindl2022,
author = {Reindl, Judith and Kundrat, P. and Girst, S. and Sammer, M. and Schwarz, B. and Dollinger, G.},
title = {Dosimetry of heavy ion exposure to human cells using nanoscopic imaging of double strand break repair protein clusters},
journal = {Scientific Reports},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2022},
volume = {12},
number = {1},
pages = {1305},
url = {https://www.nature.com/articles/s41598-022-05413-6},
doi = {https://doi.org/10.1038/s41598-022-05413-6}
}
|
|
Status and Perspectives of Combining Proton Minibeam with Flash Radiotherapy J. Reindl and S. Girst; In: , I. Toma-Dasu (Ed.), FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021 , Physica Medica: European Journal of Medical Physics 94 (2022) S51 , Elsevier. |
| Abstract: Background and Aims: Proton minibeam radiotherapy (pMBRT) is an external beam radiotherapy method with reduced side effects by taking advantage of spatial fractionation in the normal tissue. Due to scattering, the delivered small beams widen in the tissue ensuring a homogeneous dose distribution in the tumor. In the last decade, several preclinical studies have been conducted addressing normal tissue sparing and tumor control in-vitro and in-vivo, using human skin tissue and mouse or rat models. In some of the studies due to application requirements the dose-rates are high such that additionally the FLASH effect comes into play. The aim is to investigate how the two effects of spatial and temporal focussing can interact and further widen the therapeutic window. Methods: Results: Conclusions: |
BibTeX:
@inproceedings{Reindl2022a,
author = {Reindl, J. and Girst, S.},
title = {Status and Perspectives of Combining Proton Minibeam with Flash Radiotherapy},
booktitle = {FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021},
journal = {Physica Medica: European Journal of Medical Physics},
publisher = {Elsevier},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2022},
volume = {94},
number = {Suppl1},
pages = {S51},
editor = {Iuliana Toma-Dasu},
url = {https://www.physicamedica.com/article/S1120-1797(22)01547-2/fulltext#relatedArticles},
doi = {https://doi.org/10.1016/s1120-1797(22)01547-2}
}
|
|
Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation S. Rudigkeit, N. Matejka, C.-B. Chen, A. Dombrowsky, M. Sammer, T. Schmid, G. Dollinger and J. Reindl; In: , I. Toma-Dasu (Ed.), FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021 , Physica Medica: European Journal of Medical Physics 94 (2022) S44 , Elsevier. |
| Abstract: Introduction The application of radiation with ultra-high dose-rates in radiotherapy shows a sparing effect of healthy tissue compared to cancerous tissue. This so-called FLASH-effect is mainly studied by using electrons or x-rays. Radiotherapy using protons already shows benefits in the low dose-rate application compared to conventional treatment. Therefore, a combination of both the particle based sparing and the FLASH effect could further widen the therapeutic window. Here, we investigated the FLASH effect in proton treatment using an in-vivo mouse ear model. Materials & Methods Results Summary |
BibTeX:
@inproceedings{Rudigkeit2022,
author = {Rudigkeit, Sarah and Matejka, Nicole and Chen, Ce-Belle and Dombrowsky, Annique and Sammer, Matthias and Schmid, Thomas and Dollinger, Günther and Reindl, Judith},
title = {Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation},
booktitle = {FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021},
journal = {Physica Medica: European Journal of Medical Physics},
publisher = {Elsevier},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2022},
volume = {94},
number = {Suppl1},
pages = {S44},
editor = {Iuliana Toma-Dasu},
url = {https://www.physicamedica.com/article/S1120-1797(22)01528-9/fulltext#relatedArticles},
doi = {https://doi.org/10.1016/S1120-1797(22)01528-9}
}
|
|
Auswirkung chronischer Strahlenexposition auf das Wachstumsverhalten von Nutzpflanzen Raphael Rücker; Masters-Thesis, Universität der Bundeswehr München, 2022. [BibTeX] |
BibTeX:
@mastersthesis{Ruecker2022,
author = {Rücker, Raphael},
title = {Auswirkung chronischer Strahlenexposition auf das Wachstumsverhalten von Nutzpflanzen},
school = {Universität der Bundeswehr München},
year = {2022}
}
|
|
Bildbasierte Auswertung von Filopodien in der Glioblastomaforschung Florian Rüdele; Bachelors-Thesis, Universität der Bundeswehr München, 2022. |
BibTeX:
@mastersthesis{Ruedele2022,
author = {Rüdele, Florian},
title = {Bildbasierte Auswertung von Filopodien in der Glioblastomaforschung},
school = {Universität der Bundeswehr München},
year = {2022}
}
|
|
Longitudinally Heterogeneous Tumor Dose Optimizes Proton Broadbeam, Interlaced Minibeam, and FLASH Therapy M. Sammer, A. Rousseti, S. Girst, J. Reindl and G. Dollinger; Cancers 14 (20) (2022) 5162. |
| Abstract: The prerequisite of any radiation therapy modality (X-ray, electron, proton, and heavy ion) is meant to meet at least a minimum prescribed dose at any location in the tumor for the best tumor control. In addition, there is also an upper dose limit within the tumor according to the International Commission on Radiation Units (ICRU) recommendations in order to spare healthy tissue as well as possible. However, healthy tissue may profit from the lower side effects when waving this upper dose limit and allowing a larger heterogeneous dose deposition in the tumor, but maintaining the prescribed minimum dose level, particularly in proton minibeam therapy. Methods: Three different longitudinally heterogeneous proton irradiation modes and a standard spread-out Bragg peak (SOBP) irradiation mode are simulated for their depth-dose curves under the constraint of maintaining a minimum prescribed dose anywhere in the tumor region. Symmetric dose distributions of two opposing directions are overlaid in a 25 cm-thick water phantom containing a 5 cm-thick tumor region. Interlaced planar minibeam dose distributions are compared to those of a broadbeam using the same longitudinal dose profiles. Results and Conclusion: All longitudinally heterogeneous proton irradiation modes show a dose reduction in the healthy tissue compared to the common SOBP mode in the case of broad proton beams. The proton minibeam cases show eventually a much larger mean cell survival and thus a further reduced equivalent uniform dose (EUD) in the healthy tissue than any broadbeam case. In fact, the irradiation mode using only one proton energy from each side shows better sparing capabilities in the healthy tissue than the common spread-out Bragg peak irradiation mode with the option of a better dose fall-off at the tumor edges and an easier technical realization, particularly in view of proton minibeam irradiation at ultra-high dose rates larger than 10 Gy/s (so-called FLASH irradiation modes). |
BibTeX:
@article{Sammer2022,
author = {Sammer, Matthias and Rousseti, Aikaterini and Girst, Stefanie and Reindl, Judith and Dollinger, Günther},
title = {Longitudinally Heterogeneous Tumor Dose Optimizes Proton Broadbeam, Interlaced Minibeam, and FLASH Therapy},
journal = {Cancers},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2022},
volume = {14},
number = {20},
pages = {5162},
url = {https://www.mdpi.com/2072-6694/14/20/5162},
doi = {https://doi.org/10.3390/cancers14205162}
}
|
|
Feasability Study of Ionoacoustic Signal Detection uner Flash Conditions at a Clinical Synchrocylotron Facility J. Schauer, J. Lascaud, Y. Huang, M. Vidal, J. Hérault, G. Dollinger, K. Parodi and H.-P. Wieser; In: , I. Toma-Dasu (Ed.), FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021 , Physica Medica: European Journal of Medical Physics 94 (2022) S111-S112 , Elsevier. |
| Abstract: Background and aims: Ionoacoustics is a promising approach for online range verification using pulsed ion beams. The deposited kinetic energy converts to heat energy and results in a thermal expansion thereby initiating an acoustic wave. Its detection provides information about the Bragg peak location, which can be used for adaptive treatment strategies. A major challenge in ionoacoustics is the poor signal-to-noise ratio (SNR) at clinically relevant dose levels. Adapting the pulsing structure and maximising the instantaneous beam current provides ideal conditions for SNR maximisation. Methods: Ionoacoustic signals of 220MeV protons in water were simulated using an acoustic propagation simulation software (k-wave) and validated with experimental measurements. As high temporal gradients and pulse width influence the ionoacoustic amplitude, various beam currents and pulse widths were modelled in the remaining simulations assuming band-limited Gaussian noise for a synchrocyclotron facility under FLASH conditions. Results: FIG1 shows the expected signals and corresponding SNRs from different pulsing structures assuming a total dose deposition of 5Gy. For a constant instantaneous current, different pulse widths influence the signal amplitude. Suitable pulse widths for ionoacoustics lie between 2 and 10µs, which relates back to the spatial expansion of the Bragg peak. SNR improved drastically for an increased instantaneous beam current compared to previous experimental irradiation conditions. Conclusion: FLASH RT conditions with an increased instantaneous beam current alongside a suitable pulse width are beneficial for ionoacoustic signal generation. These conditions allow increased signal detection, range verification and could enable dose reconstruction for clinically relevant settings. Funded by DFG. |
BibTeX:
@inproceedings{Schauer2022,
author = {Schauer, Jannis and Lascaud, Julie and Huang, Yuanhui and Vidal, Marie and Hérault, Joël and Dollinger, Günther and Parodi, Katia and Wieser, Hans-Peter},
title = {Feasability Study of Ionoacoustic Signal Detection uner Flash Conditions at a Clinical Synchrocylotron Facility},
booktitle = {FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021},
journal = {Physica Medica: European Journal of Medical Physics},
publisher = {Elsevier},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2022},
volume = {94},
number = {Suppl1},
pages = {S111--S112},
editor = {Iuliana Toma-Dasu},
url = {https://www.physicamedica.com/article/S1120-1797(22)01696-9/fulltext#relatedArticles},
doi = {https://doi.org/10.1016/S1120-1797(22)01696-9}
}
|
|
Proton beam range verification by means of ionoacoustic measurements at clinically relevant doses using a correlation-based evaluation J. Schauer, H.-P. Wieser, Y. Huang, H. Ruser, J. Lascaud, M. Würl, A. Chmyrov, M. Vidal, J. Herault, V. Ntziachristos, W. Assmann, K. Parodi and G. Dollinger; Frontiers in Oncology 12:925542 (2022) 1-18. |
| Abstract: |
BibTeX:
@article{Schauer2022a,
author = {Schauer, Jannis and Wieser, Hans-Peter and Huang, Yuanhui and Ruser, Heinrich and Lascaud, Julie and Würl, Matthias and Chmyrov, Andriy and Vidal, Marie and Herault, Joel and Ntziachristos, Vasilis and Assmann, Walter and Parodi, Katia and Dollinger, Günther},
title = {Proton beam range verification by means of ionoacoustic measurements at clinically relevant doses using a correlation-based evaluation},
journal = {Frontiers in Oncology},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2022},
volume = {12:925542},
pages = {1--18},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2022.925542},
doi = {https://doi.org/10.3389/fonc.2022.925542}
}
|
|
Planar Proton Minibeam Irradiation Elicits Spatially Confined DNA Damage in a Human Epidermis Model H. Scherthan, S.-Q. Wagner, J. Grundhöfer, N. Matejka, J. Müller, S. Müller, S. Rudigkeit, M. Sammer, S. Schoof, M. Port and J. Reindl; Cancers 14 (6) (2022) 1545. |
| Abstract: Purpose: High doses of ionizing radiation in radiotherapy can elicit undesirable side effects to the skin. Proton minibeam radiotherapy (pMBRT) may circumvent such limitations due to tissue-sparing effects observed at the macro scale. Here, we mapped DNA damage dynamics in a 3D tissue context at the sub-cellular level. Methods: Epidermis models were irradiated with planar proton minibeams of 66 µm, 408 µm and 920 µm widths and inter-beam-distances of 2.5 mm at an average dose of 2 Gy using the scanning-ion-microscope SNAKE in Garching, GER. γ-H2AX + 53BP1 and cleaved-caspase-3 immunostaining revealed dsDNA damage and cell death, respectively, in time courses from 0.5 to 72 h after irradiation. Results: Focused 66 µm pMBRT induced sharply localized severe DNA damage (pan-γ-H2AX) in cells at the dose peaks, while damage in the dose valleys was similar to sham control. pMBRT with 408 µm and 920 µm minibeams induced DSB foci in all cells. At 72 h after irradiation, DNA damage had reached sham levels, indicating successful DNA repair. Increased frequencies of active-caspase-3 and pan-γ-H2AX-positive cells revealed incipient cell death at late time points. Conclusions: The spatially confined distribution of DNA damage appears to underlie the tissue-sparing effect after focused pMBRT. Thus, pMBRT may be the method of choice in radiotherapy to reduce side effects to the skin. |
BibTeX:
@article{Scherthan2022,
author = {Scherthan, Harry and Wagner, Stephanie-Quinta and Grundhöfer, Jan and Matejka, Nicole and Müller, Jessica and Müller, Steffen and Rudigkeit, Sarah and Sammer, Matthias and Schoof, Sarah and Port, Matthias and Reindl, Judith},
title = {Planar Proton Minibeam Irradiation Elicits Spatially Confined DNA Damage in a Human Epidermis Model},
journal = {Cancers},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2022},
volume = {14},
number = {6},
pages = {1545},
url = {https://www.mdpi.com/2072-6694/14/6/1545},
doi = {https://doi.org/10.3390/cancers14061545}
}
|
|
New R&D Platform with Unique Capabilities for Electron FLASH and VHEE Radiation Therapy and Radiation Biology under Preparation at PITZ F. Stephan, Z. Aboulbanine, Z. Amirkhanyan, J. Good, M. Gross, M. Krasilnikov, O. Lishilin, A. Oppelt, S. Philipp, H. Qian, C. Stegmann, S. Worm, W. Leemans, M. Schmitz, T. Schnautz, H. Weise, V. Budach, V. Ehrhardt, M.-C. Vozenin, A. Faus-Golfe, G. Tsakanova, A. Schüller, M. Frohme, A. Grebinyk, J. Reindl, F. Grüner and T. Staufer; In: , I. Toma-Dasu (Ed.), FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021 , Physica Medica: European Journal of Medical Physics 94 (2022) S36-S37 , Elsevier. |
| Abstract: At the Photo Injector Test facility at DESY in Zeuthen (PITZ, near Berlin, Germany), the realization of an R&D platform for electron FLASH radiation therapy, VHEE radiation therapy and radiation biology is under preparation. The name of the new platform is HP²eFLASH-RT@PITZ, which stands for high power, high performance electron FLASH radiation therapy at PITZ. The beam parameters that PITZ can provide are unique in the world: ps scale electron bunches with up to 5nC bunch charge at MHz repetition rate in bunch trains of up to 1 ms in length. The individual bunches can produce dose rates up to 1014 Gy/s and dose deposition up to 1000 Gy. Upon demand, each bunch of the bunch train can be guided to a different location on the tumor, so that either a “painting” with micro beams, or a cumulative increase of absorbed dose using a wide beam distribution can be realized at the tumor. Full tumor treatment can hence be finished in a time interval of 1 ms, mitigating organ movement issues . Together with 20 years of operational experience at PITZ, and availability of detailed beam characterization and extremely flexible beam manipulation capabilities, this R&D platform will cover current parameter range of successfully demonstrated FLASH effects and extend the parameter range towards yet unexplored and unexploited short treatment times and high dose rates. A summary of the plans for HP²eFLASH-RT@PITZ and the status of the preparations will be presented, with as goal to stimulate interest and broaden out our cooperation. |
BibTeX:
@inproceedings{Stephan2022,
author = {Stephan, F. and Aboulbanine, Z. and Amirkhanyan, Z. and Good, J. and Gross, M. and Krasilnikov, M. and Lishilin, O. and Oppelt, A. and Philipp, S. and Qian, H. and Stegmann, C. and Worm, S. and Leemans, W. and Schmitz, M. and Schnautz, T. and Weise, H. and Budach, V. and Ehrhardt, V. and Vozenin, M.-C. and Faus-Golfe, A. and Tsakanova, G. and Schüller, A. and Frohme, M. and Grebinyk, A. and Reindl, J. and Grüner, F. and Staufer, T.},
title = {New R&D Platform with Unique Capabilities for Electron FLASH and VHEE Radiation Therapy and Radiation Biology under Preparation at PITZ},
booktitle = {FRPT 2021 (Flash Radiotherapy and Particle Therapy Conference), Wien, 1.-3.12.2021},
journal = {Physica Medica: European Journal of Medical Physics},
publisher = {Elsevier},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2022},
volume = {94},
number = {Suppl1},
pages = {S36--S37},
editor = {Iuliana Toma-Dasu},
url = {https://www.physicamedica.com/article/S1120-1797(22)01512-5/fulltext#relatedArticles},
doi = {https://doi.org/10.1016/s1120-1797(22)01512-5}
}
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FLASHlab@PITZ: New R&D platform with unique capabilities for electron FLASH and VHEE radiation therapy and radiation biology under preparation at PITZ F. Stephan, M. Gross, A. Grebinyk, Z. Aboulbanine, Z. Amirkhanyan, V. Budach, V.H. Ehrhardt, A. Faus-Golfe, M. Frohme, J.-F. Germond, J.D. Good, F. Grüner, D. Kaul, M. Krasilnikov, R. Leavitt, W. Leemans, X. Li, G. Loisch, F. Müller, G. Müller, F. Obier, A. Oppelt, S. Philipp, H. Qian, J. Reindl, F. Riemer, M. Sack, M. Schmitz, T. Schnautz, A. Schüller, T. Staufer, C. Stegmann, G. Tsakanova, M.-C. Vozenin, H. Weise, S. Worm and D. Zips; Physica Medica 104 (2022) 174-187. |
| Abstract: At the Photo Injector Test facility at DESY in Zeuthen (PITZ), an R&D platform for electron FLASH and very high energy electron radiation therapy and radiation biology is being prepared (FLASHlab@PITZ). The beam parameters available at PITZ are worldwide unique. They are based on experiences from 20 + years of developing high brightness beam sources and an ultra-intensive THz light source demonstrator for ps scale electron bunches with up to 5 nC bunch charge at MHz repetition rate in bunch trains of up to 1 ms length, currently 22 MeV (upgrade to 250 MeV planned). Individual bunches can provide peak dose rates up to 1014 Gy/s, and 10 Gy can be delivered within picoseconds. Upon demand, each bunch of the bunch train can be guided to a different transverse location, so that either a “painting” with micro beams (comparable to pencil beam scanning in proton therapy) or a cumulative increase of absorbed dose, using a wide beam distribution, can be realized at the tumor. Full tumor treatment can hence be completed within 1 ms, mitigating organ movement issues. With extremely flexible beam manipulation capabilities, FLASHlab@PITZ will cover the current parameter range of successfully demonstrated FLASH effects and extend the parameter range towards yet unexploited short treatment times and high dose rates. A summary of the plans for FLASHlab@PITZ and the status of its realization will be presented. |
BibTeX:
@article{Stephan2022a,
author = {Stephan, Frank and Gross, Matthias and Grebinyk, Anna and Aboulbanine, Zakaria and Amirkhanyan, Zohrab and Budach, Volker and Ehrhardt, Vincent Henrique and Faus-Golfe, Angeles and Frohme, Marcus and Germond, Jean-Francois and Good, James David and Grüner, Florian and Kaul, David and Krasilnikov, Mikhail and Leavitt, Ron and Leemans, Wim and Li, Xiangkun and Loisch, Gregor and Müller, Frieder and Müller, Georg and Obier, Frank and Oppelt, Anne and Philipp, Sebastian and Qian, Houjun and Reindl, Judith and Riemer, Felix and Sack, Martin and Schmitz, Michael and Schnautz, Tobias and Schüller, Andreas and Staufer, Theresa and Stegmann, Christian and Tsakanova, Gohar and Vozenin, Marie-Catherine and Weise, Hans and Worm, Steven and Zips, Daniel},
title = {FLASHlab@PITZ: New R&D platform with unique capabilities for electron FLASH and VHEE radiation therapy and radiation biology under preparation at PITZ},
journal = {Physica Medica},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2022},
volume = {104},
pages = {174-187},
url = {https://www.sciencedirect.com/science/article/pii/S1120179722020877},
doi = {https://doi.org/10.1016/j.ejmp.2022.10.026}
}
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Optimierung der Detektionsgenauigkeit des KI-basierten Objekterkennungsalgorithmus CeCILE Lucas Villaverde Zimmermann; Masters-Thesis, Universität der Bundeswehr München, 2022. [BibTeX] |
BibTeX:
@mastersthesis{Zimmermann2022,
author = {Zimmermann, Lucas Villaverde},
title = {Optimierung der Detektionsgenauigkeit des KI-basierten Objekterkennungsalgorithmus CeCILE},
school = {Universität der Bundeswehr München},
year = {2022}
}
|
2021 |
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Focused Ion Microbeam Irradiation Induces Clustering of DNA Double-Strand Breaks in Heterochromatin Visualized by Nanoscale-Resolution Electron Microscopy Y. Lorat, J. Reindl, A. Isermann, C. Rübe, A.A. Friedl and C.E. Rübe; International Journal of Molecular Sciences 22 (14) (2021) 7638. |
| Abstract: Background: Charged-particle radiotherapy is an emerging treatment modality for radioresistant tumors. The enhanced effectiveness of high-energy particles (such as heavy ions) has been related to the spatial clustering of DNA lesions due to highly localized energy deposition. Here, DNA damage patterns induced by single and multiple carbon ions were analyzed in the nuclear chromatin environment by different high-resolution microscopy approaches. Material and Methods: Using the heavy-ion microbeam SNAKE, fibroblast monolayers were irradiated with defined numbers of carbon ions (1/10/100 ions per pulse, ipp) focused to micrometer-sized stripes or spots. Radiation-induced lesions were visualized as DNA damage foci (γH2AX, 53BP1) by conventional fluorescence and stimulated emission depletion (STED) microscopy. At micro- and nanoscale level, DNA double-strand breaks (DSBs) were visualized within their chromatin context by labeling the Ku heterodimer. Single and clustered pKu70-labeled DSBs were quantified in euchromatic and heterochromatic regions at 0.1 h, 5 h and 24 h post-IR by transmission electron microscopy (TEM). Results: Increasing numbers of carbon ions per beam spot enhanced spatial clustering of DNA lesions and increased damage complexity with two or more DSBs in close proximity. This effect was detectable in euchromatin, but was much more pronounced in heterochromatin. Analyzing the dynamics of damage processing, our findings indicate that euchromatic DSBs were processed efficiently and repaired in a timely manner. In heterochromatin, by contrast, the number of clustered DSBs continuously increased further over the first hours following IR exposure, indicating the challenging task for the cell to process highly clustered DSBs appropriately. Conclusion: Increasing numbers of carbon ions applied to sub-nuclear chromatin regions enhanced the spatial clustering of DSBs and increased damage complexity, this being more pronounced in heterochromatic regions. Inefficient processing of clustered DSBs may explain the enhanced therapeutic efficacy of particle-based radiotherapy in cancer treatment. |
BibTeX:
@article{Lorat2021,
author = {Lorat, Yvonne and Reindl, Judith and Isermann, Anna and Rübe, Christian and Friedl, Anna A. and Rübe, Claudia E.},
title = {Focused Ion Microbeam Irradiation Induces Clustering of DNA Double-Strand Breaks in Heterochromatin Visualized by Nanoscale-Resolution Electron Microscopy},
journal = {International Journal of Molecular Sciences},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
volume = {22},
number = {14},
pages = {7638},
url = {https://www.mdpi.com/1422-0067/22/14/7638},
doi = {https://doi.org/10.3390/ijms22147638}
}
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Influence of α-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells N. Matejka and J. Reindl; In: , D. Geort and W. Birkfellner (Eds.), Joint Conference of the ÖGMP, DGMP & SGSMP Dreiländertagung der Medizinischen Physik 19.–22. September 2021 (2021) 58 . |
| Abstract: Introduction The aggressive nature of glioblastoma, a common brain tumor, is composed of several features like uncontrolled cell-growth, high infiltration rates and their strong ability to develop therapy resistance. For their organization, an effective cell-to-cell communication among the cancerous cells is essential. One remarkable communication mechanism of cells are tunneling nanotubes (TNTs). These ultra-fine membrane connections with a diameter from 50 to 1500 nm enable cells to network very strongly with each other and thus ensure their survival. Here, we study the response of TNT communication networks in glioblastoma cells on radiative stress induced by α-particle radiation. The aim was to figure out whether cellular TNT-networks are influenced by radiation and if cellular communication is enhanced upon radiation treatment. Materials & Methods Results Summary |
BibTeX:
@conference{Matejka2021,
author = {Matejka, Nicole and Reindl, Judith},
title = {Influence of α-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells},
booktitle = {Joint Conference of the ÖGMP, DGMP & SGSMP Dreiländertagung der Medizinischen Physik 19.–22. September 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
pages = {58},
editor = {Dietmar Geort and Wolfgang Birkfellner},
url = {https://www.dgmp.de/de-DE/131/dgmp-tagungsbaende/}
}
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Influence of α-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells N. Matejka and J. Reindl; In: 59th Annual Conference of the Particle Thereapy Co-Operative Group 4-7 June 2021 (2021) . |
| Abstract: Introduction The aggressive nature of glioblastoma, a common brain tumor, is composed of several features like uncontrolled cell-growth, high infiltration rates and their strong ability to develop therapy resistance. For their organization, an effective cell-to-cell communication among the cancerous cells is essential. One remarkable communication mechanism of cells are tunneling nanotubes (TNTs). These ultra-fine membrane connections with a diameter from 50 to 1500 nm enable cells to network very strongly with each other and thus ensure their survival. Here, we study the response of TNT communication networks in glioblastoma cells on radiative stress induced by α-particle radiation. The aim was to figure out whether cellular TNT-networks are influenced by radiation and if cellular communication is enhanced upon radiation treatment. Materials & Methods Results Summary |
BibTeX:
@conference{Matejka2021a,
author = {Matejka, Nicole and Reindl, Judith},
title = {Influence of α-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells},
booktitle = {59th Annual Conference of the Particle Thereapy Co-Operative Group 4-7 June 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
url = {https://www.ptcog59.org/}
}
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Influence of α-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells N. Matejka and J. Reindl; In: DeGBS Annual Meeting – 27-29 September 2021 (2021) . |
| Abstract: Introduction The aggressive nature of glioblastoma, a common brain tumor, is composed of several features like uncontrolled cell-growth, high infiltration rates and their strong ability to develop therapy resistance. For their organization, an effective cell-to-cell communication among the cancerous cells is essential. One remarkable communication mechanism of cells are tunneling nanotubes (TNTs). These ultra-fine membrane connections with a diameter from 50 to 1500 nm enable cells to network very strongly with each other and thus ensure their survival. Here, we study the response of TNT communication networks in glioblastoma cells on radiative stress induced by α-particle radiation. The aim was to figure out whether cellular TNT-networks are influenced by radiation and if cellular communication is enhanced upon radiation treatment. Materials & Methods Results Summary |
BibTeX:
@conference{Matejka2021b,
author = {Matejka, Nicole and Reindl, Judith},
title = {Influence of α-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells},
booktitle = {DeGBS Annual Meeting – 27-29 September 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
url = {https://degbs.de/?page_id=1455}
}
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Magnetically focused 70 MeV proton minibeams for preclinical experiments combining a tandem accelerator and a 3 GHz linear post-accelerator M. Mayerhofer, G. Datzmann, A. Degiovanni, V. Dimov and G. Dollinger; Medical Physics 48 (6) (2021) 2733-2749. |
| Abstract: Purpose Radiotherapy plays an important role for the treatment of tumor diseases in two-thirds of all cases, but it is limited by side effects in the surrounding healthy tissue. Proton minibeam radiotherapy (pMBRT) is a promising option to widen the therapeutic window for tumor control at reduced side effects. An accelerator concept based on an existing tandem Van de Graaff accelerator and a linac enables the focusing of 70 MeV protons to form minibeams with a size of only 0.1 mm for a preclinical small animal irradiation facility, while avoiding the cost of an RFQ injector. Methods The tandem accelerator provides a 16 MeV proton beam with a beam brightness of as averaged from 5 µs long pulses with a flat top current of 17 µA at 200 Hz repetition rate. Subsequently, the protons are accelerated to 70 MeV by a 3 GHz linear post-accelerator consisting of two Side Coupled Drift Tube Linac (SCDTL) structures and four Coupled Cavity Linac (CCL) structures [design: AVO-ADAM S.A (Geneva, Switzerland)]. A 3 GHz buncher and four magnetic quadrupole lenses are placed between the tandem and the post-accelerator to maximize the transmission through the linac. A quadrupole triplet situated downstream of the linac structure focuses the protons into an area of (0.1 × 0.1) mm2. The beam dynamics of the facility is optimized using the particle optics code TRACE three-dimensional (3D). Proton transmission through the facility is elaborated using the particle tracking code TRAVEL. Results A study about buncher amplitude and phase shift between buncher and linac is showing that 49% of all protons available from the tandem can be transported through the post-accelerator. A mean beam current up to 19 nA is expected within an area of (0.1 × 0.1) mm2 at the beam focus. Conclusion An extension of existing tandem accelerators by commercially available 3 GHz structures is able to deliver a proton minibeam that serves all requirements to obtain proton minibeams to perform preclinical minibeam irradiations as it would be the case for a complete commercial 3 GHz injector-RFQ–linac combination. Due to the modularity of the linac structure, the irradiation facility can be extended to clinically relevant proton energies up to or above 200 MeV. |
BibTeX:
@article{Mayerhofer2021,
author = {Mayerhofer, Michael and Datzmann, Gerd and Degiovanni, Alberto and Dimov, Veliko and Dollinger, Günther},
title = {Magnetically focused 70 MeV proton minibeams for preclinical experiments combining a tandem accelerator and a 3 GHz linear post-accelerator},
journal = {Medical Physics},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2021},
volume = {48},
number = {6},
pages = {2733-2749},
url = {https://aapm.onlinelibrary.wiley.com/doi/abs/10.1002/mp.14854},
doi = {https://doi.org/10.1002/mp.14854}
}
|
|
Concept and performance evaluation of two 3 GHz buncher units optimizing the dose rate of a novel preclinical proton minibeam irradiation facility M. Mayerhofer, A. Bergmaier, G. Datzmann, H. Hagn, R. Helm, J. Mitteneder, R. Schubert, L. Picardi, P. Nenzi, C. Ronsivalle, H.-F. Wirth and G. Dollinger; PLOS ONE 16 (10) (2021) 1-19. |
| Abstract: To demonstrate the large potential of proton minibeam radiotherapy (pMBRT) as a new method to treat tumor diseases, a preclinical proton minibeam radiation facility was designed. It is based on a tandem Van-de-Graaff accelerator providing a 16 MeV proton beam and a 3 GHz linac post-accelerator (designs: AVO-ADAM S.A, Geneva, Switzerland and ENEA, Frascati, Italy). To enhance the transmission of the tandem beam through the post-accelerator by a factor of 3, two drift tube buncher units were designed and constructed: A brazed 5-gap structure (adapted SCDTL tank of the TOP-IMPLART project (ENEA)) and a non-brazed low budget 4-gap structure. Both are made of copper. The performance of the two differently manufactured units was evaluated using a 16 MeV tandem accelerator beam and a Q3D magnetic spectrograph. Both buncher units achieve the required summed voltage amplitude of 42 kV and amplitude stability at a power feed of less than 800 W. |
BibTeX:
@article{Mayerhofer2021a,
author = {Mayerhofer, Michael and Bergmaier, Andreas and Datzmann, Gerd and Hagn, Hermann and Helm, Ricardo and Mitteneder, Johannes and Schubert, Ralf and Picardi, Luigi and Nenzi, Paolo and Ronsivalle, Concetta and Wirth, Hans-Friedrich and Dollinger, Günther},
title = {Concept and performance evaluation of two 3 GHz buncher units optimizing the dose rate of a novel preclinical proton minibeam irradiation facility},
journal = {PLOS ONE},
publisher = {Public Library of Science},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2021},
volume = {16},
number = {10},
pages = {1-19},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258477},
doi = {https://doi.org/10.1371/journal.pone.0258477}
}
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Eine präklinische Protonen-Minibeam-Bestrahlungsanlage Michael Mayerhofer; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2021. |
| Abstract: Studien in einem Mausohrmodell, an Rattenhirnen und in in-vitro Modellen der menschlichen Haut haben gezeigt, dass die Protonen-Minibeam-Strahlentherapie (pMBRT) das Potential hat, Normalgewebekomplikationen im Vergleich zur herkömmlichen Protonentherapie zu reduzieren. Das Ziel dieser Arbeit war die Konzeption einer präklinischen Protonen-Minibeam-Bestrahlungsanlage, die es ermöglicht, weiterführende Studien in einem Kleintier-Tumormodell durchzuführen. Das Konzept der präklinischen Bestrahlungsanlage basiert auf einem Tandem-Beschleuniger, der als Injektor einen 16 MeV Protonen-Strahl liefert, dessen Energie anschließend durch einen linearen 3 GHz Nachbeschleuniger (engl.: linear accelerator (Linac)) auf 70 MeV erhöht wird. Das entspricht einer Reichweite der Protonen in Wasser von mehr als 40 mm. Der Linac besteht aus zwei Side Coupled Drift Tube Linac (SCDTL) Strukturen und vier Coupled Cavity Linac (CCL) Strukturen, welche vom für die herkömmliche Protonentherapie entwickelten All-Linac-System LIGHT (AVO-ADAM SA, Genf, Schweiz) übernommen werden. Um die Transmission durch den Linac zu erhöhen, wird der Phasenraum des Tandemstrahls mithilfe einer 3 GHz Buncher-Einheit und einem Quadrupol-Quartett auf den akzeptierten Phasenraum des Linacs optimiert. Ein stromabwärts nach dem Linac positioniertes Quadrupol-Triplett fokussiert den Protonenstrahl zu Minibeams. Strahldynamik-Simulationen zeigen, dass die Transmission durch den Linac bei einer Buncher-Amplitude von 42 kV um einen Faktor 3 erhöht wird und insgesamt 54 % aller Tandem-Protonen (Strahlstrom ca. 21 nA) in einen Strahlfleck mit einer transversalen Ausdehnung von 77 µm (FWHM) fokussiert werden. Ein Scanning-System, bestehend aus vier Dipolmagneten, das zwischen Linac und Quadrupol-Triplett positioniert ist, ermöglicht das Verfahren des Strahls über eine Fläche von 30 mm x 30 mm am Fokus. Nach der Strahlextraktion an Luft hat der maximal ausgelenkte Strahl eine transversale Ausdehnung von 204 µm (FWHM). Bei der Applikation mehrerer solcher Protonen-Minibeams mit einem Center-to-Center-Abstand von 1,2 mm wird an der Fokusebene ein Peak-to-Valley-Verhältnis von ca. 780 erreicht. So erfüllt die entwickelte präklinische Protonen-Minibeam-Bestrahlungsanlage alle Voraussetzungen für zukünftige präklinische Experimente. Weitere Simulationen zeigen, dass sich auch das kommerziell erhältliche All-Linac-System LIGHT als präklinische Protonen-Minibeam-Bestrahlungsanlage eignet. Im Falle eines bestehenden Tandem-Injektors ist die entwickelte Tandem-Linac-Kombination jedoch deutlich günstiger zu realisieren. Das einzige zusätzlich nötige Element für die Tandem-Linac-Kombination, das nicht kommerziell erhältlich ist, ist die Buncher-Einheit, weshalb im Rahmen dieser Arbeit zwei Prototypen entwickelt und gefertigt werden. Beide Prototypen beruhen auf dem Prinzip des Drift-Röhren-Linac (engl.: drift tube linac (DTL)). Ein Prototyp ist als kostengünstiges Studienobjekt konzipiert, dessen Hohlraumresonator durch Schrauben zusammengepresst wird, was eine einfache Demontage erlaubt. Der Hohlraumresonator des anderen Prototyps ist hartgelötet, um die elektrische Oberflächenleitfähigkeit zu maximieren und ein Kühlsystem zu integrieren. Die Performance der beiden Prototypen wird mit einem Q3D-Magnetspektrographen evaluiert, wobei beide die geforderte Buncher-Amplitude (42 kV) bei einer Eingangsleistung unter 800 W erreichen. Der aufwendige Hartlötprozess bei der traditionellen Herstellung war Motivation zu evaluieren, ob sich auch 3D-Druck-Verfahren zur Fertigung von Hohlraumresonatoren eignen. Ein 3 GHz DTL-Prototyp wird entwickelt und für den 3D-Druck durch selektives Laserschmelzen optimiert. Der aus hochreinem Kupfer gedruckte DTL-Prototyp erreicht einen Gütefaktor von 8750 und eine Shunt-Impedanz von 53 MOhm/m, was das große Potential von 3D-Druck-Verfahren zur Herstellung von Hohlraumresonatoren zeigt. Im Hinblick auf die stark reduzierten Herstellungskosten und die große Designfreiheit motivieren die Ergebnisse, dieses Potential für die Herstellung noch komplexerer Hohlraumresonator-Geometrien weiter zu evaluieren. |
BibTeX:
@phdthesis{Mayerhofer2021diss,
author = {Mayerhofer, Michael},
title = {Eine präklinische Protonen-Minibeam-Bestrahlungsanlage},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2021},
url = {https://nbn-resolving.org/urn/resolver.pl?urn:nbn:de:bvb:706-7876}
}
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|
Preclinical proton minibeam radiotherapy: Biomedical aspects J. Reindl, G. Datzmann, S. Girst, M. Sammer and G. Dollinger; In: 59th Annual Conference of the Particle Thereapy Co-Operative Group 4-7 June 2021 (2021) . |
| Abstract: The concept of spatial fractionation in radiotherapy was developed for better sparing of normal tissue in the entrance channel of radiation. Spatial fractionation utilizing proton minibeam radiotherapy (pMBRT) promises to be advantageous compared to X-ray minibeams due to higher dose conformity at the tumor. Preclinical in-vivo experiments conducted with pMBRT in mouse ear models or in rat brains support the prospects. However, the research on radiobiological mechanisms and the search for adequate application parameters delivering the most beneficial minibeam therapy is still in its infancy. Progressing towards clinical usage, pMBRT research should overcome technical and biomedical limitations of the current irradiation test stages and animal models. This work discusses results achieved so far in human skin tissue, in-vivo mouse ear and rat brain models. It further gives insight in the next steps and provides suggestions for biomedical research , which in our opinion has to be conducted for bringing pMBRT into clinical use. We consider glioma, non-small cell lung cancer and hepatocellular carcinoma as the most promising targets for preclinical and later clinical use. We furthermore propose an in-depth investigation of proton minibeams on healthy tissue. Especially neuronal cells and abdominal organs – both in in-vitro studies using artificial organoids as well as in in-vivo animal studies – need further testing. |
BibTeX:
@conference{Reindl2021,
author = {Reindl, J. and Datzmann, G. and Girst, S. and Sammer, M. and Dollinger, G.},
title = {Preclinical proton minibeam radiotherapy: Biomedical aspects},
booktitle = {59th Annual Conference of the Particle Thereapy Co-Operative Group 4-7 June 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
url = {https://www.ptcog59.org/}
}
|
|
The use of AI in Cell Biology: Needs and Solutions, International E-Conference on AI and Machine Learning J. Reindl; In: International E-Conference on AI and Machine Learning, 14.-15.12.2021 (2021) . [BibTeX] |
BibTeX:
@conference{Reindl2021b,
author = {Reindl, Judith},
title = {The use of AI in Cell Biology: Needs and Solutions, International E-Conference on AI and Machine Learning},
booktitle = {International E-Conference on AI and Machine Learning, 14.-15.12.2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021}
}
|
|
CeCILE - An Artificial Intelligence Based Cell-Detection for the Evaluation of Radiation Effects in Eucaryotic Cells S. Rudigkeit, J.B. Reindl, N. Matejka, R. Ramson, M. Sammer, G. Dollinger and J. Reindl; Frontiers in Oncology 11 (2021) 2327. |
| Abstract: The fundamental basis in the development of novel radiotherapy methods is in-vitro cellular studies. To assess different endpoints of cellular reactions to irradiation like proliferation, cell cycle arrest, and cell death, several assays are used in radiobiological research as standard methods. For example, colony forming assay investigates cell survival and Caspase3/7-Sytox assay cell death. The major limitation of these assays is the analysis at a fixed timepoint after irradiation. Thus, not much is known about the reactions before or after the assay is performed. Additionally, these assays need special treatments, which influence cell behavior and health. In this study, a completely new method is proposed to tackle these challenges: A deep-learning algorithm called CeCILE (Cell Classification and In-vitroLifecycle Evaluation), which is used to detect and analyze cells on videos obtained from phase-contrast microscopy. With this method, we can observe and analyze the behavior and the health conditions of single cells over several days after treatment, up to a sample size of 100 cells per image frame. To train CeCILE, we built a dataset by labeling cells on microscopic images and assign class labels to each cell, which define the cell states in the cell cycle. After successful training of CeCILE, we irradiated CHO-K1 cells with 4 Gy protons, imaged them for 2 days by a microscope equipped with a live-cell-imaging set-up, and analyzed the videos by CeCILE and by hand. From analysis, we gained information about cell numbers, cell divisions, and cell deaths over time. We could show that similar results were achieved in the first proof of principle compared with colony forming and Caspase3/7-Sytox assays in this experiment. Therefore, CeCILE has the potential to assess the same endpoints as state-of-the-art assays but gives extra information about the evolution of cell numbers, cell state, and cell cycle. Additionally, CeCILE will be extended to track individual cells and their descendants throughout the whole video to follow the behavior of each cell and the progeny after irradiation. This tracking method is capable to put radiobiologic research to the next level to obtain a better understanding of the cellular reactions to radiation. |
BibTeX:
@article{Rudigkeit2021,
author = {Rudigkeit, Sarah and Reindl, Julian B. and Matejka, Nicole and Ramson, Rika and Sammer, Matthias and Dollinger, Günther and Reindl, Judith},
title = {CeCILE - An Artificial Intelligence Based Cell-Detection for the Evaluation of Radiation Effects in Eucaryotic Cells},
journal = {Frontiers in Oncology},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
volume = {11},
pages = {2327},
url = {https://www.frontiersin.org/article/10.3389/fonc.2021.688333},
doi = {https://doi.org/10.3389/fonc.2021.688333}
}
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Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation S. Rudigkeit, N. Matejka, C.-B. Chen, A. Dombrowsky, M. Sammer, T. Schmid, G. Dollinger and J. Reindl; In: 59th Annual Conference of the Particle Thereapy Co-Operative Group 4-7 June 2021 (2021) . |
| Abstract: Introduction The application of radiation with ultra-high dose-rates in radiotherapy shows a sparing effect of healthy tissue compared to cancerous tissue. This so-called FLASH-effect is mainly studied by using electrons or x-rays. Radiotherapy using protons already shows benefits in the low dose-rate application compared to conventional treatment. Therefore, a combination of both the particle based sparing and the FLASH effect could further widen the therapeutic window. Here, we investigated the FLASH effect in proton treatment using an in-vivo mouse ear model. Materials & Methods Results Summary |
BibTeX:
@conference{Rudigkeit2021a,
author = {Rudigkeit, Sarah and Matejka, Nicole and Chen, Ce-Belle and Dombrowsky, Annique and Sammer, Matthias and Schmid, Thomas and Dollinger, Günther and Reindl, Judith},
title = {Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation},
booktitle = {59th Annual Conference of the Particle Thereapy Co-Operative Group 4-7 June 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2021},
url = {https://www.ptcog59.org/}
}
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Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation S. Rudigkeit, N. Matejka, C.-B. Chen, A. Dombrowsky, M. Sammer, T. Schmid, G. Dollinger and J. Reindl; In: , D. Geort and W. Birkfellner (Eds.), Joint Conference of the ÖGMP, DGMP & SGSMP Dreiländertagung der Medizinischen Physik 19.–22. September 2021 (2021) 118 . |
| Abstract: Introduction The application of radiation with ultra-high dose-rates in radiotherapy shows a sparing effect of healthy tissue compared to cancerous tissue. This so-called FLASH-effect is mainly studied by using electrons or x-rays. Radiotherapy using protons already shows benefits in the low dose-rate application compared to conventional treatment. Therefore, a combination of both the particle based sparing and the FLASH effect could further widen the therapeutic window. Here, we investigated the FLASH effect in proton treatment using an in-vivo mouse ear model. Materials & Methods Results Summary |
BibTeX:
@conference{Rudigkeit2021b,
author = {Rudigkeit, Sarah and Matejka, Nicole and Chen, Ce-Belle and Dombrowsky, Annique and Sammer, Matthias and Schmid, Thomas and Dollinger, Günther and Reindl, Judith},
title = {Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation},
booktitle = {Joint Conference of the ÖGMP, DGMP & SGSMP Dreiländertagung der Medizinischen Physik 19.–22. September 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2021},
pages = {118},
editor = {Dietmar Geort and Wolfgang Birkfellner},
url = {https://www.dgmp.de/de-DE/131/dgmp-tagungsbaende/}
}
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CeCILE – An artificial intelligence based cell-detection for the evaluation of radiation effects in eucaryotic cells S. Rudigkeit, J.B. Reindl, N. Matejka, M. Sammer, G. Dollinger and J. Reindl; In: DeGBS Annual Meeting – 27-29 September 2021 (2021) . |
| Abstract: Introduction: In radiobiologic research important endpoints of the cellular reactions to irradiation are proliferation, cell cycle arrest, and cell death. To assess these endpoints several assays are used as standard methods. For example colony forming assay for investigating the cell survival and Caspase3/7-Sytox assay for the cell death. However, these assays have major limitations as they are analysed at a fixed timepoint after irradiation and each assay addresses a very special endpoint. Therefore, not much is known before and after the assay is performed and more assays are needed to cover more endpoints. Another issue is, that these assays require special treatments, which influence the cell behaviour. To tackle these challenges we propose here a complete new method. A deep-learning based algorithm called CeCILE (Cell Classification and In-vitro Lifecycle Evaluation), which is used to detect and analyse cells on videos obtained from live-cell phase-contrast microscopy. With this method, we can observe and analyse the behaviour and the health conditions of single cells over several days after treatment. Methods: Results: Conclusion: |
BibTeX:
@conference{Rudigkeit2021c,
author = {Rudigkeit, Sarah and Reindl, Julian B. and Matejka, Nicole and Sammer, Matthias and Dollinger, Günther and Reindl, Judith},
title = {CeCILE – An artificial intelligence based cell-detection for the evaluation of radiation effects in eucaryotic cells},
booktitle = {DeGBS Annual Meeting – 27-29 September 2021},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2021},
url = {https://degbs.de/?page_id=1455}
}
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Normal Tissue Response of Combined Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy M. Sammer, A.C. Dombrowsky, J. Schauer, K. Oleksenko, S. Bicher, B. Schwarz, S. Rudigkeit, N. Matejka, J. Reindl, S. Bartzsch, A. Blutke, A. Feuchtinger, S.E. Combs, G. Dollinger and T.E. Schmid; International Journal of Radiation Oncology, Biology, Physics 109 (1) (2021) 76-83. |
| Abstract: Purpose Proton minibeam radiation therapy, a spatial fractionation concept, widens the therapeutic window. By reducing normal tissue toxicities, it allows a temporally fractionated regime with high daily doses. However, an array shift between daily fractions can affect the tissue-sparing effect by decreasing the total peak-to-valley dose ratio. Therefore, combining temporal fractions with spatial fractionation raises questions about the impact of daily applied dose modulations, reirradiation accuracies, and total dose modulations. Methods and Materials Healthy mouse ear pinnae were irradiated with 4 daily fractions of 30 Gy mean dose, applying proton pencil minibeams (pMB) of Gaussian σ = 222 μm in 3 different schemes: a 16 pMB array with a center-to-center distance of 1.8 mm irradiated the same position in all sessions (FS1) or was shifted by 0.9 mm to never hit the previously irradiated tissue in each session (FS2), or a 64 pMB array with a center-to-center distance of 0.9 mm irradiated the same position in all sessions (FS3), resulting in the same total dose distribution as FS2. Reirradiation positioning and its accuracy were obtained from image guidance using the unique vessel structure of ears. Acute toxicities (swelling, erythema, and desquamation) were evaluated for 153 days after the first fraction. Late toxicities (fibrous tissue, inflammation) were analyzed on day 153. Results Reirradiation of highly dose-modulated arrays at a positioning accuracy of 110 ± 52 μm induced the least severe acute and late toxicities. A shift of the same array in FS2 led to significantly inducted acute toxicities, a higher otitis score, and a slight increase in fibrous tissue. FS3 led to the strongest increase in acute and late toxicities. Conclusions The highest normal-tissue sparing is achieved after accurate reirradiation of a highly dose modulated pMB array, although high positioning accuracies are challenging in a clinical environment. Nevertheless, the same integral dose applied in highly dose-modulated fractions is superior to low daily dose-modulated fractions. |
BibTeX:
@article{Sammer2021,
author = {Sammer, Matthias and Dombrowsky, Annique C. and Schauer, Jannis and Oleksenko, Kateryna and Bicher, Sandra and Schwarz, Benjamin and Rudigkeit, Sarah and Matejka, Nicole and Reindl, Judith and Bartzsch, Stefan and Blutke, Andreas and Feuchtinger, Annette and Combs, Stephanie E. and Dollinger, Günther and Schmid, Thomas E.},
title = {Normal Tissue Response of Combined Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy},
journal = {International Journal of Radiation Oncology, Biology, Physics},
publisher = {Elsevier},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2021},
volume = {109},
number = {1},
pages = {76--83},
url = {http://www.sciencedirect.com/science/article/pii/S036030162034116X},
doi = {https://doi.org/10.1016/j.ijrobp.2020.08.027}
}
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Optimizing proton minibeam radiotherapy by interlacing and heterogeneous tumor dose on the basis of calculated clonogenic cell survival M. Sammer, S. Girst and G. Dollinger; Scientific Reports 11 (1) (2021) 3533. |
| Abstract: Proton minibeam radiotherapy (pMBRT) is a spatial fractionation method using sub-millimeter beams at center-to-center (ctc) distances of a few millimeters to widen the therapeutic index by reduction of side effects in normal tissues. Interlaced minibeams from two opposing or four orthogonal directions are calculated to minimize side effects. In particular, heterogeneous dose distributions applied to the tumor are investigated to evaluate optimized sparing capabilities of normal tissues at the close tumor surrounding. A 5 cm thick tumor is considered at 10 cm depth within a 25 cm thick water phantom. Pencil and planar minibeams are interlaced from two (opposing) directions as well as planar beams from four directions. An initial beam size of σ0 = 0.2 mm (standard deviation) is assumed in all cases. Tissue sparing potential is evaluated by calculating mean clonogenic cell survival using a linear-quadratic model on the calculated dose distributions. Interlacing proton minibeams for homogeneous irradiation of the tumor has only minor benefits for the mean clonogenic cell survival compared to unidirectional minibeam irradiation modes. Enhanced mean cell survival, however, is obtained when a heterogeneous dose distribution within the tumor is permitted. The benefits hold true even for an elevated mean tumor dose, which is necessary to avoid cold spots within the tumor in concerns of a prescribed dose. The heterogeneous irradiation of the tumor allows for larger ctc distances. Thus, a high mean cell survival of up to 47% is maintained even close to the tumor edges for single fraction doses in the tumor of at least 10 Gy. Similar benefits would result for heavy ion minibeams with the advantage of smaller minibeams in deep tissue potentially offering even increased tissue sparing. The enhanced mean clonogenic cell survival through large ctc distances for interlaced pMBRT with heterogeneous tumor dose distribution results in optimum tissue sparing potential. The calculations show the largest enhancement of the mean cell survival in normal tissue for high-dose fractions. Thus, hypo-fractionation or even single dose fractions become possible for tumor irradiation. A widened therapeutic index at big cost reductions is offered by interlaced proton or heavy ion minibeam therapy. |
BibTeX:
@article{Sammer2021a,
author = {Sammer, Matthias and Girst, Stefanie and Dollinger, Günther},
title = {Optimizing proton minibeam radiotherapy by interlacing and heterogeneous tumor dose on the basis of calculated clonogenic cell survival},
journal = {Scientific Reports},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2021},
volume = {11},
number = {1},
pages = {3533},
url = {https://www.nature.com/articles/s41598-021-81708-4},
doi = {https://doi.org/10.1038/s41598-021-81708-4}
}
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Tissue-sparing of Proton Minibeam Therapy depends on beam size, fractionation scheme and interlacing geometry Matthias Sammer; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2021. |
| Abstract: Proton Minibeam Radiotherapy (pMBRT) is a spatial fractionation method that widens the therapeutic window in the radiation therapy of cancers. Sub-millimeter planar or pencil proton beams (minibeams) are applied to the patient with a few mm center-to-center distances (ctc). Due to the small-angle scattering of protons, the submillimeter beams increase in size with depth. Adjusting the ctc distances to the tumor depth and its size yields an overlapping, up to homogeneous dose distribution in the tumor volume. Therefore, a tumor dose coverage as in conventional radiotherapy approaches can be maintained while the minibeam pattern within the entrance channel spares healthy tissues and reduces side effects due to the low dose regions in the valleys between the minibeams. The goal of this work was to improve the understanding of the sparing potential of spatial fractionation by conducting experiments at the ion microprobe SNAKE as well as further developing proton minibeams based on theoretical dose and cell survival calculations. In the first experiment, the dependence of the radiation response on the dose modulation within an in-vivo mouse ear model of healthy BALB/c mice was investigated. Proton pencil minibeam sizes from σ = 95 µm to σ = 883 µm (standard deviation) were applied with a 60 Gy mean dose on a 4×4 grid with 1.8 mm center-to-center distance ctc, corresponding to σ/ctc ratios between 0.05 and 0.5. The largest σ/ctc of 0.5 corresponds to a homogeneous irradiation. The results provide an insight into the sparing effect of different dose distributions of minibeam irradiations as they could be applied on the skin or as they occur in depth due to the lateral spread of the minibeams. Visible skin reactions and ear swelling were observed for 90 days post-irradiation. The results state that the closer the dose modulation is to that of a homogeneous irradiation (σ/ctc = 0.5), the stronger the tissue toxicities. Transferred to patient irradiation, the tissue-sparing potential of proton minibeams decreases with depth but proton minibeams are still superior to conventional proton irradiations even at large depths. The σ/ctc ratio without any side effects in the mouse model was extrapolated to σ/ctc = 0.032. In the second animal trial, the combination of temporal and spatial fractionation was studied within the BALB/c mouse ear model. Four daily fractions of 30 Gy mean dose were applied to the ears with 16 proton minibeams (σ = 222 µm; ctc = 1.8 mm). The minibeams were reirradiated accurately (fractionation scheme 1; FS1) or with a maximum spatial shift between the temporal fractions (FS2). The third irradiation group (FS3) accurately reirradiated the resulting 64 proton minibeam positions from FS2 (σ = 222 µm; ctc = 0.9 mm) with 30 Gy mean dose per fraction. Due to the halving of the ctc in FS3, the daily dose distribution changed with increased valley doses compared to FS1 and FS2. However, the integral dose distributions after the full treatment were equal to the integral dose distribution of FS2, allowing to evaluate the influence of different daily dose distributions. The achieved reirradiation accuracy of (110±52) µm led to a maximum ear swelling of only 1.6-fold for the strongly modulated dose distributions of FS1. The irradiation with maximally shifted minibeams (FS2) led to a swelling of 2.4-fold ear thickness compared to sham irradiated ears. The accurate irradiation of the weaker dose modulations of FS3 yielded even three times the ear thickness of sham irradiated ears. An increased ear thickness was found for FS2 ( 1.4-fold) and FS3 ( 1.7-fold) ears at the end of the observational period of 160 days. In FS2 and FS3, histological sections confirmed a significantly increased amount of fibrotic tissue at the end of the observational period. The results suggest that most tissue-sparing in temporally fractionated proton minibeam therapy is achieved for accurate reirradiation of strong daily dose modulations (FS1). The same daily dose modulations as in FS1 but maximally shifted (FS2) are also of advantage compared to accurately reirradiated but weaker dose modulations (FS3). Hence, fractionated proton minibeam therapy presumably also has an advantage over fractionated conventional radiotherapy. In theoretical proton minibeam dose calculations, further developments and potential application variations were considered. In a 5 cm thick tumor located at 10 cm depth, interlaced minibeams from two opposing or four orthogonal directions were calculated to maximize the clonogenic cell survival. Additionally, the combination of interlacing and heterogeneous tumor dose was examined to evaluate optimized tissuesparing capabilities at the close tumor vicinity. The computed dose distributions were biologically weighted by the calculated clonogenic cell survival. Interlacing proton minibeams with homogeneous tumor irradiation was only of minor benefit in terms of mean clonogenic cell survival compared to unidirectional minibeam irradiations. Allowing a heterogeneous dose distribution within the tumor enabled larger ctc distances between the minibeams. This resulted in enhanced cell survival even for an elevated mean tumor dose, which was necessary to cover the tumor with a prescribed minimum dose. Interlaced minibeams with at least 10 Gy minimum tumor dose could still maintain a mean cell survival of up to 47% even close to the tumor margin. According to the calculations, the sparing-effect of proton minibeams is of most advantage for high dose fractions, which brings hypo- or even single-fractionated radiotherapy into reach. Similar benefits as for proton minibeams are expected for heavy-ion minibeams with the advantage of lower scattering and, therefore, smaller, less harmful minibeams in deeper tissues. The elaborated results within this thesis elucidate in detail the sparing potential of proton Minibeam Radiotherapy. The resolution of proton minibeam dose distributions and their effect on biological tissue paves the way for a deeper understanding of the sparing potential of spatial fractionation. A first-of-its-kind temporal fractionation of proton minibeams suggests that the sparing effect of minibeam irradiation is preserved also when fractionated compared to conventional radiotherapy. Substantial improvements to conventional radiotherapy are revealed by dose simulations. Nevertheless, the experimental results need to be validated in other and human tissues. The theoretical cell survival calculations must also be placed in the context of a complex biological system. Furthermore, the technical feasibility of a clinically applicable proton or heavy ion minibeam needs to be elucidated, in particular for potential interlaced irradiation approaches. Zusammenfassung Die Protonen-Minibeamtherapie ist eine räumliche Fraktionierungsmethode der Strahlentherapie von Tumoren um das therapeutische Fenster zu erweitern. Die submillimeter großen Protonenbeams (Minibeams) werden als planare oder Pencil Beams mit einem Abstand (Mitte zu Mitte; engl.: center-to-center ctc) von wenigen mm auf den Patienten appliziert. Aufgrund der Kleinwinkelstreuung der Protonen weiten diese Kanäle mit zunehmender Tiefe auf und erlauben, durch die Anpassung der ctc-Abstände an die Tumortiefe und Tumorgröße, eine überlappende und bis zu homogene Dosisverteilung im Tumorvolumen. Somit kann der Tumor wie bei der konventionellen Strahlentherapie homogen bestrahlt werden, gleichzeitig sorgt das Minibeammuster, aufgrund der Niedrigdosisbereiche zwischen den Minibeams, für eine Schonung des gesunden Gewebes und führt zur Reduzierung der Nebenwirkungen. |
BibTeX:
@phdthesis{Sammer2021diss,
author = {Sammer, Matthias},
title = {Tissue-sparing of Proton Minibeam Therapy depends on beam size, fractionation scheme and interlacing geometry},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2021},
url = {https://nbn-resolving.org/urn/resolver.pl?urn:nbn:de:bvb:706-7780}
}
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Proton minibeam radiation therapy-an innovative strategy in cancer treatment T. Schmid, A. Dombrowsky, M. Sammer, J. Reindl, S. Bartzsch, G. Dollinger and S. Combs; In: DEGRO 2021 (27. Jahrestagung der Deutschen Gesellschaft Für Radioonkologie, 24.-26.06.2021) , Strahlentherapie und Onkologie 197 (2021) S211 , Springer Heidelberg. |
| Abstract: Fragestellung: Normal tissue complications are a common side effect after conventional radiotherapy. Proton minibeam radiotherapy (pMBRT) is a spatial fractionation method that widens the therapeutic window. By using submillimeter proton beams the treatment dose can be modulated, known as spatial fractionation. This is based on the dose-volume effect, which says that the tissue tolerance increases for smaller irradiation fields. The aim of this study was to analyze if normal tissue complications depend on the irradiation accuracies of a radiation treatment combining spatial fractionation with temporal fractionation. Methodik: Four fractions of 20 MeV pencil proton minibeams with a size of σ = 222 ± 5 μm were delivered daily to healthy ears of Balb/c mice in three different schemes. A total of 6 to 8 mice were assigned to each group. Ears were positioned in each fraction according to the Ergebnis: A pattern of 16 minibeams with a center-to-center (ctc) distance of 1.8 mm was delivered to the same position in every fraction and induced the lowest swelling while a pattern shift by ctc/2 between the fractions led to a significant stronger acute reaction. The highest increase in ear thickness and additionally in fibrosis induction was measured when 64 minibeams with a ctc of 0.9 mm were irradiated. At the end of the follow-up, the ears which were irradiated four times at the same position were 265.8 ± 3.6 μm thick which was not different to the sham-irradiated ears (266.1 ± 7.2 μm). These results demonstrate that Schlussfolgerung: In conclusion, both acute and late normal tissue complications depend on the accuracy of the reirradiation positon of proton minibeams. By using a high reirradiation accuracy, ear swelling and the amount of fibrotic tissue were almost on the same level as sham-irradiated mice. However, a lack of accuracy slightly increased the normal tissue complications when a highly dose modulated minibeam pattern is applied. |
BibTeX:
@inproceedings{Schmid2021,
author = {Schmid, T. and Dombrowsky, A. and Sammer, M. and Reindl, J. and Bartzsch, S. and Dollinger, G. and Combs, S.},
title = {Proton minibeam radiation therapy-an innovative strategy in cancer treatment},
booktitle = {DEGRO 2021 (27. Jahrestagung der Deutschen Gesellschaft Für Radioonkologie, 24.-26.06.2021)},
journal = {Strahlentherapie und Onkologie},
publisher = {Springer Heidelberg},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2021},
volume = {197},
number = {SUPPL 1},
pages = {S211},
url = {https://link.springer.com/article/10.1007/s00066-021-01791-4},
doi = {https://doi.org/10.1007/s00066-021-01791-4}
}
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An innovative strategy in cancer treatment: Proton minibeam radiation therapy T. Schmid, A. Dombrowsky, M. Sammer, J. Reindl, G. Dollinger, S. Bartzsch and S. Combs; In: ESTRO 2021, 28.- 31. August 2021 , Radiotherapy and Oncology 161 (2021) S338 , Elsevier. |
| Abstract: Purpose or Objective Normal tissue complications are a common side effect after conventional radiotherapy. Proton minibeam radiotherapy (pMBRT) is a spatial fractionation method that widens the therapeutic window. By using submillimeter proton beams the treatment dose can be modulated, known as spatial fractionation. This is based on the dose-volume effect, which says that the tissue tolerance increases for smaller irradiation fields. The aim of this study was to analyze if normal tissue complications depend on the irradiation accuracies of a radiation treatment combining spatial fractionation with temporal fractionation. Materials and Methods Results Conclusion |
BibTeX:
@inproceedings{Schmid2021a,
author = {Schmid, T. and Dombrowsky, A. and Sammer, M. and Reindl, J. and Dollinger, G. and Bartzsch, S. and Combs, S.},
title = {An innovative strategy in cancer treatment: Proton minibeam radiation therapy},
booktitle = {ESTRO 2021, 28.- 31. August 2021},
journal = {Radiotherapy and Oncology},
publisher = {Elsevier},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2021},
volume = {161},
number = {Suppl1},
pages = {S338},
url = {https://www.sciencedirect.com/science/article/abs/pii/S0167814021073308?via%3Dihub},
doi = {https://doi.org/10.1016/S0167-8140(21)07330-8}
}
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Nanoskopische Charakterisierung von strahlungsinduzierten DNA Schäden im Kontext der Chromatinstruktur und Reparaturproteinorganisation Benjamin Schwarz; Dissertation, Universität der Bundeswehr München, 2021. |
| Abstract: Ionizing radiation and DNA double-strand breaks (DSB) induced by radiation are part of the everyday stresses of an organism. Every cell has different repair mechanisms to counteract this health threat. However, ionizing radiation also offers potentially important medical applications such as radiation therapy for the treatment of tumours. Researching the underlying DNA repair processes not only makes it possible to provide better protection against ionizing radiation in the future, but also to make the targeted use of radiation in medical settings even more efficient. Not only the identification of individual DNA repair proteins and the quantification of the induced damage is important, but also the localization of the damage in the context of chromatin helps to better understand the repair processes and to optimize medical approaches. This work focuses on three main aspects for the characterization of DSB repair mechanisms. A new method for the quantitative measurement of high-LET (Linear Energy Transfer) induced radiation damage was developed and the corresponding proof of principle was provided. Using in situ ligation techniques in combination with in situ DNA blunting, it was possible to couple so-called DNA oligo probes, consisting of short single-stranded DNA sequences that form hairpin structures in solution, with fluorophores and specifically bind them to double-strand breaks. The reduced size and the reduced number of binding sites allows an accurate and reliable DSB detection using STED microscopy (Stimulated Emission Depletion). In addition, irradiation experiments with focused carbon ions made it possible not only to trigger the most basic reactions of chromatin to irradiation with high-LET radiation and to document them by live cell microscopy, but also to observe these chromatin remodeling processes from a few seconds to several minutes after irradiation and to compare them with characteristics of several repair proteins. It was also possible to establish a detailed model for DNA repair in the context of chromatin organisation and in accordance with the latest chromatin organisation models by the high-resolution analysis of overlapping regions of the DNA repair proteins BRCA1, Rad51, 53BP1, γH2AX and components of the chromatin. In addition, in the course of this work, ∝ - irradiation of cell nuclei - was used for the first time to document a migration of difficult to repair DSB repair sites from the cell nucleus interior to the cell nucleus envelope and presumably to specialized repair centers. Also, it was possible to match them temporally into existing DSB repair processes using STED microscopy. Zusammenfassung Ionisierende Strahlung und durch diese induzierte DNA Doppelstrangbrüche (DSB) gehören zu den alltäglichen Belastungen eines Organismus. Jede Zelle besitzt verschiedene Reparaturmechanismen, um dieser gesundheitlichen Bedrohung zu begegnen. Jedoch birgt ionisierende Strahlung auch potentiell wichtige medizinische Anwendungen wie beispielsweise Strahlentherapie zur Behandlung von Tumorerkrankungen. Die Erforschung der zu Grunde liegenden DNA-Reparaturprozesse ermöglicht es hierbei nicht nur in Zukunft einen besseren Schutz vor ionisierender Strahlung zu ermöglichen, sondern die gezielte Anwendung von Strahlung im medizinischen Rahmen noch effizienter zu gestalten. Hierfür ist nicht nur die Identifikation einzelner DNA-Reparaturproteine und die Quantifizierung des induzierten Schadens wichtig, sondern auch die Lokalisation des Schadens im Kontext des Chromatins hilft dabei, die Reparaturprozesse besser zu verstehen und medizinische Ansätze zu optimieren. Diese Arbeit beschäftigt sich mit drei Hauptaspekten zur Charakterisierung von DSB-Reparaturmechanismen. Es konnte eine neue Methode zur quantitativen Messung von hoch-LET (Linearer Energietransfer) induzierten Strahlenschäden entwickelt und der dazugehörige Grundsatzbeweis erbracht werden. Durch In-Situ Ligationsverfahren in Kombination mit In-Situ DNA-Blunting, war es möglich, so genannte DNA Oligo Sonden, bestehend aus kurzen einzelsträngigen DNA-Sequenzen, welche sich in Lösung zu Haarnadelstrukturen ausbilden, mit Fluorophoren zu koppeln und spezifisch an Doppelstrangbrüche zu binden. Die reduzierte Größe und das reduzierte Bindestellenvorkommen ermöglicht hierbei eine genaue und verlässliche DSB Detektion mittels STED-Mikroskopie (eng. Stimulated Emission Depletion). Des Weiteren war es durch Bestrahlungsexperimente mit fokussierten Kohlenstoffionen möglich, nicht nur die grundlegendsten Reaktionen des Chromatins auf Bestrahlung mit hoch-LET Strahlung auszulösen und durch Lebendzellmikroskopie zu dokumentieren, sondern diese Chromatinremodellierungsprozesse auch zeitlich ab wenigen Sekunden bis mehreren Minuten nach Bestrahlung zu beobachten und mit Charakteristika mehrerer Reparaturproteine zu vergleichen. Ebenso war es möglich, durch die höchstauflösende Analyse von Überschneidungsbereichen der DNA-Reparaturproteine BRCA1, Rad51, 53BP1, γH2AX und Bestandteile des Chromatins, ein detailliertes Modell zur DNA-Reparatur im Kontext der Chromatinorganisation und im Einklang neuster Chromatinorganisationsmodelle, aufzustellen. Zusätzlich konnte im Laufe dieser Arbeit erstmals mittels ∝ - Bestrahlung von Zellkernen eine Migration von schwer reparierbaren DSB-Reparaturstellen vom Zellkerninneren zur Zellkernhülle und dort vermutlich zu spezialisierten Reparaturzentren dokumentiert und mittels STED-Mikroskopie zeitlich in existierende DSB-Reparaturprozesse eingeordnet werden. |
BibTeX:
@phdthesis{Schwarz2021diss,
author = {Schwarz, Benjamin},
title = {Nanoskopische Charakterisierung von strahlungsinduzierten DNA Schäden im Kontext der Chromatinstruktur und Reparaturproteinorganisation},
school = {Universität der Bundeswehr München},
year = {2021},
url = {https://nbn-resolving.org/urn/resolver.pl?urn:nbn:de:bvb:706-7318}
}
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2020 |
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Preclinical Challenges in Proton Minibeam Radiotherapy: Physics and Biomedical Aspects G. Datzmann, M. Sammer, S. Girst, M. Mayerhofer, G. Dollinger and J. Reindl; Frontiers in Physics 8 (2020) 471. |
| Abstract: The concept of spatial fractionation in radiotherapy was developed for better sparing of normal tissue in the entrance channel of radiation. Spatial fractionation utilizing proton minibeam radiotherapy (pMBRT) promises to be advantageous compared to X-ray minibeams due to higher dose conformity at the tumor. Preclinical in vivo experiments conducted with pMBRT in mouse ear models or in rat brains support the prospects, but the research about the radiobiological mechanisms and the search for adequate application parameters delivering the most beneficial minibeam therapy is still in its infancy. Concerning preclinical research, we consider glioma, non-small cell lung cancer and hepatocellular carcinoma as the most promising targets and propose investigating the effects on healthy tissue, especially neuronal cells and abdominal organs. The experimental setups for preclinical pMBRT used so far follow different technological approaches, and experience technical limitations when addressing the current questions in the field. We review the crucial physics parameters necessary for proton minibeam production and link them to the technological challenges to be solved for providing an optimal research environment. We consider focusing of pencil or planar minibeams in a scanning approach superior compared to collimation due to less beam halos, higher peak-to-valley dose ratios and higher achievable dose rates. A possible solution to serve such a focusing system with a high-quality proton beam at all relevant energies is identified to be a 3 GHz radio-frequency linear accelerator. We propose using a 16 MeV proton beam from an existing tandem accelerator injected into a linear post-accelerator, boosted up to 70 MeV, and finally delivered to an imaging and positioning end-station suitable for small animal irradiation. Ion-optical simulations show that this combination can generate focused proton minibeams with sizes down to 0.1 mm at 18 nA mean proton current - sufficient for all relevant preclinical experiments. This technology is expected to offer powerful and versatile tools for unleashing structured and advanced preclinical pMBRT studies at the limits and also has the potential to enable a next step into precision tumor therapy. |
BibTeX:
@article{Datzmann2020,
author = {Datzmann, Gerd and Sammer, Matthias and Girst, Stefanie and Mayerhofer, Michael and Dollinger, Günther and Reindl, Judith},
title = {Preclinical Challenges in Proton Minibeam Radiotherapy: Physics and Biomedical Aspects},
journal = {Frontiers in Physics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
volume = {8},
pages = {471},
url = {https://www.frontiersin.org/article/10.3389/fphy.2020.568206},
doi = {https://doi.org/10.3389/fphy.2020.568206}
}
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Author Correction: DNA damage interactions on both nanometer and micrometer scale determine overall cellular damage T. Friedrich, K. Ilicic, C. Greubel, S. Girst, J. Reindl, M. Sammer, B. Schwarz, C. Siebenwirth, D.W.M. Walsh, T.E. Schmid, M. Scholz and G. Dollinger; Scientific Reports 10 (1) (2020) 19552. |
| Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. |
BibTeX:
@article{Friedrich2020,
author = {Friedrich, Thomas and Ilicic, Katarina and Greubel, Christoph and Girst, Stefanie and Reindl, Judith and Sammer, Matthias and Schwarz, Benjamin and Siebenwirth, Christian and Walsh, Dietrich W. M. and Schmid, Thomas E. and Scholz, Michael and Dollinger, Günther},
title = {Author Correction: DNA damage interactions on both nanometer and micrometer scale determine overall cellular damage},
journal = {Scientific Reports},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
volume = {10},
number = {1},
pages = {19552},
url = {https://www.nature.com/articles/s41598-020-76568-3#citeas},
doi = {https://doi.org/10.1038/s41598-020-76568-3}
}
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Die Gewebeschonung bei Protonen-Minibeam-Bestrahlungen hängt von Strahlgrößeund -abstand sowie von der Positioniergenauigkeit bei zeitlicher Fraktionierung ab S. Girst, M. Sammer, C. Greubel, J. Schauer, B. Schwarz, N. Matejka, S. Rudigkeit, C. Siebenwirth, D.W.M. Walsh, A. Dombrowsky, K. Teiluf, K. Ilicic, S. Dobiasch, E. Zahnbrecher, K. Oleksenko, S. Bicher, M. Aichler, A. Blutke, A. Feuchtinger, A. Walch, S. Bartzsch, J.J. Wilkens, S.E. Combs, T.E. Schmid, J. Reindl and G. Dollinger; In: , U. Wolf and B. Sattler (Eds.), 51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020 (2020) . |
| Abstract: Einleitung Die Protonen Minibeam Therapie reduziert die Schädigung des Normalgewebes bei gleichbleibender Tumorkontrolle gegenüber konventioneller Protonen Therapie. Diese Gewebeschonung wurde im Mausmodell untersucht, um den Einfluss von Pencil-Minibeam Größen, Minibeam Abstand und von zeitlicher Fraktionierung zu bestimmen. Material und Methoden Ergebnisse Zusammenfassung Literatur |
BibTeX:
@conference{Girst2020,
author = {Girst, S. and Sammer, M. and Greubel, C. and Schauer, J. and Schwarz, B. and Matejka, N. and Rudigkeit, S. and Siebenwirth C. and Walsh, D. W. M. and Dombrowsky, A. and Teiluf, K. and Ilicic, K. and Dobiasch S. and Zahnbrecher E. and Oleksenko, K. and Bicher, S. and Aichler, M. and Blutke, A. and Feuchtinger, A. and Walch, A. and Bartzsch, S. and Wilkens, J. J. and Combs, S. E. and Schmid, T. E. and Reindl, J. and Dollinger, G.},
title = {Die Gewebeschonung bei Protonen-Minibeam-Bestrahlungen hängt von Strahlgrößeund -abstand sowie von der Positioniergenauigkeit bei zeitlicher Fraktionierung ab},
booktitle = {51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
editor = {Wolf, Ulrich and Sattler, Bernhard},
url = {https://www.dgmp.de/de-DE/131/dgmp-tagungsbaende/}
}
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Dosimetrie zur Gewebebestrahlung mit Protonen Minibieams und FLASH Jan Grundhöfer; Bachelors-Thesis, Universität der Bundeswehr München, 2020. |
| Abstract: Diese Arbeit beschreibt die Dosimetrie zu einem Protonen Minibeam und einem FLASH Experiment, welche beide mit 21 MeV Protonen durchgeführt wurden. Zur Dosimetrie wurden Filme vom Modell GAFChromic EBT3 (EBT3 Filme) verwendet. Bei dem Protonen Minibeam Experiment wird untersucht, inwieweit die tatsächlich bestrahlten Minibeams hinsichtlich Breite, Abstand und der applizierten Dosis mit den geplanten Bestrahlungsmustern übereinstimmen. Dabei wurden Strahlbreiten von 100, 500 und 1250 μm für die Minibeams geplant. Die EBT3 Filme mit 1250 μm Strahlbreite wurden mit einer mittleren Dosis von 5 und 2 Gy bestrahlt, die EBT3 Filme mit 500 μm Strahlbreite mit 2,76 und 2 Gy und die EBT3 Filme mit 100 μm Strahlbreite mit 0,5 und 2 Gy. Die unterschiedlichen Strahlbreiten wurde jeweils als einzelne Linie sowie als Muster aus vier parallelen Linien mit einem Abstand von 2,5 mm auf die EBT3 Filme bestrahlt. Das Protonen FLASH Experiment beschäftig sich mit dem Vergleich unterschiedlicher Dosisraten, weshalb bei jeder Bestrahlung ein homogenes Feld verwendet wurde. Dieses homogene Feld wurde mit Dosisraten von 1 Gy/s und 40 Gy/s appliziert. Die Analyse der mit Minibeams bestrahlten EBT3 Filme ergab bei der Bestimmung der Linienbreiten deutlich schmalere Werte als im Bestrahlungsplan. Diese lagen mit Tiefstwerten von 65,4±0,6 μm bei den 100 μm EBT3 Filmen, 407,9±0,9 μm bei den 500 μm EBT3 Filmen und 914,3±2,1 μm bei den 1250 μm EBT3 Filmen unter den geplanten Werten. Die Messungen der Höhen der Dosismaxima sind aufgrund der Tatsache, dass die EBT3 Filme ab einer Dosis von 8 Gy in Sättigung gehen und somit keine exakte Dosisbestimmung mehr möglich ist, nur bedingt aussagekräftig. Die Dosismaxima befinden sich bei sämtlichen Filmen mit Ausnahme von Film Nummer 5 über dieser Sättigungsgrenze. Bei der Bestimmung der Abstände der Dosismaxima waren keine Abweichungen vom Bestrahlungsplan festzustellen. Alle Abstände schwanken nur sehr schwach um die geplanten 2,5 mm bei einem sehr geringen Fehler von maximal 0,06 mm. Die Analyse des FLASH Experiments ergab abweichende Dosisraten, die teilweise über und teilweise unter den Dosisraten des Bestrahlungsplans lagen. Bei einer Soll-Dosisrate von 1 Gy/s wurde eine tatsächliche Dosisrate von 0,65 Gy/s festgestellt und beim EBT3 Film, welcher mit einer Soll-Dosisrate von 40 Gy/s bestrahlt werden sollte, ergab die Analyse eine Dosisrate von 107,9 Gy/s. |
BibTeX:
@mastersthesis{Grundhoefer2020ba,
author = {Grundhöfer, Jan},
title = {Dosimetrie zur Gewebebestrahlung mit Protonen Minibieams und FLASH},
school = {Universität der Bundeswehr München},
year = {2020}
}
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Influence of α-Particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells N. Matejka and J. Reindl; Frontiers in Oncology 10 (2020) 1691. |
| Abstract: Cellular communication plays a crucial role in the coordination and organization of cancer cells. Especially processes such as uncontrolled cell growth, invasion, and therapy resistance (development), which are features of very malignant tumors like glioblastomas, are supported by an efficient cell-to-cell communication in the tumor environment. One powerful way for cells to communicate are tunneling nanotubes (TNTs). These tiny membrane tunnels interconnect cells over long distances and serve as highways for information exchange between distant cells. Here, we study the response of cellular communication via TNTs in U87 glioblastoma cells to homogeneous irradiation with α-particles as a stress factor. We describe the development of TNT networks in certain time steps after irradiation using confocal live-cell imaging and suggest an evaluation method to characterize these communication networks. Our results show that irradiated cells establish their network faster and have more cell-to-cell connections with high TNT content than sham-irradiated controls within the first 24 h. These findings suggest that there is an additional trigger upon radiation damage which results in fast and intensive network formation by TNTs as a radiation damage response mechanism. |
BibTeX:
@article{Matejka2020,
author = {Matejka, Nicole and Reindl, Judith},
title = {Influence of α-Particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells},
journal = {Frontiers in Oncology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2020},
volume = {10},
pages = {1691},
url = {https://www.frontiersin.org/article/10.3389/fonc.2020.01691},
doi = {https://doi.org/10.3389/fonc.2020.01691}
}
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Influence of Alpha-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells N. Matejka and J. Reindl; In: ERRS 2020 digital (2020) 70 . |
| Abstract: Introduction: Cellular communication plays a crucial role in the coordination and organization of cancer cells. Especially processes such as uncontrolled cell-growth, invasion and therapy resistance, which are features of malignant tumors as glioblastomas, are supported by an efficient cell-to-cell communication. One powerful way for cells to communicate are tunneling nanotubes (TNTs). These tiny cytoplasmic membrane bridges with a diameter from 50 to 1500 nm directly connect cells over long distances up to several cell diameters and serve as highways for information and material exchange between them. We study the response of TNT communication networks in glioblastoma cells on radiative stress induced by α-particle radiation. The aim was to figure out whether cell-to- cell connections via TNTs are influenced by radiation and if cellular communication was enhanced upon irradiation. Methods: U87 glioblastoma cells were irradiated using high-LET α-particles to a dose of 1.2 Gy. After irradiation cells were labeled with CellMask™ Orange plasma membrane stain. The TNT network was examined using live-cell confocal microscopy up to 72 h after irradiation and compared to sham irradiated controls. We quantify the development of TNT networks and suggest an evaluation method to characterize these communication networks. Results: Our results show that irradiated cells establish their network faster and have more cell-to- cell connections with a high TNT content than sham irradiated controls within the first 24 h. Conclusion: These findings suggest that there is an additional trigger upon radiation damage which results in fast and intensive network formation by TNTs as a radiation damage response mechanism. |
BibTeX:
@conference{Matejka2020a,
author = {Matejka, Nicole and Reindl, Judith},
title = {Influence of Alpha-particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells},
booktitle = {ERRS 2020 digital},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2020},
pages = {70},
url = {https://www.errs2020.eu/app/netattm/attendee/page/89323}
}
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Protonen Minibeam. Therapie, Konzept und Anwendung J. Reindl, S. Girst, M. Sammer and G. Dollinger; In: , U. Wolf and B. Sattler (Eds.), 51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020 (2020) . |
| Abstract: Einleitung Protonen Minibeam Therapie (engl. Proton minibeam radiotherapy, pMBRT) ist eine Form der externen Strahlentherapie, welche Nebenwirkungen durch räumliche Fraktionierung der Strahlung reduziert. Aufgrund der im Gewebe auftretenden Kleinwinkelstreuung weiten die applizierten, submillimeter großen Protonen-Minibeams auf, so dass eine homogene Bestrahlung des Tumors ermöglicht wird. Diese neuartige Form der Strahlentherapie wurde 2013 parallel von den Gruppen um Günther Dollinger[1] und Yolanda Prezado[2] eingeführt. Hier wird das pMBRT-Konzept vorgestellt und ein Überblick über Potential, Herausforderungen und zukünftig notwendige Entwicklungsschritte gegeben. Material und Methoden Ergebnisse Zusammenfassung Literatur |
BibTeX:
@conference{Reindl2020,
author = {Reindl, J. and Girst, S. and Sammer, M. and Dollinger, G.},
title = {Protonen Minibeam. Therapie, Konzept und Anwendung},
booktitle = {51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
editor = {Wolf, Ulrich and Sattler, Bernhard},
url = {https://www.dgmp.de/de-DE/131/dgmp-tagungsbaende/}
}
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Radiobiological and Medical Research at the Ion Microprobe Snake J. Reindl, K. Ilicic, S. Girst, M. Sammer, C. Siebenwirth and G. Dollinger; In: ICNMTA 2020 on-line (2020) . |
BibTeX:
@conference{Reindl2020a,
author = {Reindl, Judith and Ilicic, Katarina and Girst, Stefanie and Sammer, Matthias and Siebenwirth, Christian and Dollinger, Günther},
title = {Radiobiological and Medical Research at the Ion Microprobe Snake},
booktitle = {ICNMTA 2020 on-line},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
url = {https://www.icnmta2020.org}
}
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Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation S. Rudigkeit, N. Matejka, C.-B. Chen, P. Hosseinpour, A. Hunger, M. Sammer, T. Schmid, G. Dollinger and J. Reindl; In: ERRS 2020 digital (2020) 88 . |
| Abstract: Introduction: Tissue sparing by irradiation with ultra-high dose-rates – the so-called FLASH-effect - is investigated since several years using electrons or x-rays. Since protons already show advantageous effects compared to conventional therapy, we designed a study to test the FLASH- effect with protons in-vivo and in-vitro. Methods: We performed irradiation with 20 MeV protons at the ion microprobe SNAKE at the 14 MV tandem accelerator in Garching near Munich using three different dose-rates (2 Gy/min, 10 Gy/s and 1000 Gy/s). In the in-vitro experiments we compared genetic damage measured by micronuclei induction to cell survival using colony forming assay and cell death using a caspase 3/7- sytox assay on a flowcytometer. For the in-vivo study we irradiated the right ears of 63 Balb/c mice and measured the ear thickness, desquamation and erythema over 180 days. Results: No difference in cell survival was visible. Whereas, early apoptotic and late apoptotic cells were reduced after irradiation with 1000 Gy/s to base level of sham irradiated controls. In the in-vivo study we obtained a 16 % reduction of the earthickness after 32 Gy irradiation with 1000 Gy/s and a 22 % reduction for 10 Gy/s compared to the conventional dose-rate of 2 Gy/min. Desquamation and erythema was reduced by half for both higher dose-rates. Conclusion: By using FLASH dose-rates for low-LET proton irradiation a tissue sparing effect can be achieved. But especially the in-vitro experiments showed more diverse results than expected. Therefore, further investigations are necessary to understand the underlying mechanisms and interactions in the tissue after FLASH-irradiation. |
BibTeX:
@conference{Rudigkeit2020,
author = {Rudigkeit, Sarah and Matejka, Nicole and Chen, Ce-Belle and Hosseinpour, Parisa and Hunger, Annique and Sammer, Matthias and Schmid, Thomas and Dollinger, Günther and Reindl, Judith},
title = {Proton-FLASH – Radiation effects of ultrahigh dose-rate irradiation},
booktitle = {ERRS 2020 digital},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
pages = {88},
url = {https://www.errs2020.eu/app/netattm/attendee/page/89323}
}
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Optimierte Protonen-Minibeam-Therapie durch ineinander verschachtelte Bestrahlung und heterogene Tumordosis M. Sammer, S. Girst, J. Reindl and G. Dollinger; In: , U. Wolf and B. Sattler (Eds.), 51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020 (2020) . |
| Abstract: Einleitung Die Protonen Minibeam Therapie ist eine räumlich fraktionierte Bestrahlungsmethode, in welcher das gesunde Gewebe im Vergleich zur konventionellen Therapie geschont wird. Diese Gewebeschonung verstärkt sich mit abnehmender Minibeamgröße und zunehmendem Abstand zwischen den Minibeams (ctc; engl. center-to-center). Wir stellen die Dosisberechnung für die einseitige und für die ineinander verschachtelte Bestrahlung zur Optimierung der Protonen Minibeam Therapie vor. Material und Methoden Ergebnisse Zusammenfassung |
BibTeX:
@conference{Sammer2020,
author = {Sammer, M. and Girst, S. and Reindl, J. and Dollinger, G.},
title = {Optimierte Protonen-Minibeam-Therapie durch ineinander verschachtelte Bestrahlung und heterogene Tumordosis},
booktitle = {51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2020},
editor = {Wolf, Ulrich and Sattler, Bernhard},
url = {https://www.dgmp.de/de-DE/131/dgmp-tagungsbaende/}
}
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Reichweitenbestimmung eines Protonenstrahls durch ionoakustische Messungen fürklinisch relevante Dosen J. Schauer, H.P.W. , J. Lascaud, Y. Huang, W. Assmann, K. Parodi, A. Chmyrov, V.Ntziachristos and G. Dollinger; In: , U. Wolf and B. Sattler (Eds.), 51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020 (2020) . |
| Abstract: Einleitung: Der Bragg-Peak, der sich am Ende eines Ionenstrahls befindet, ist einer der Hauptvorteile der Ionenstrahltherapie im Vergleich zur konventionellen Radiotherapie. Die Echtzeit-Bestimmung der Bragg-Peak Position innerhalb des Patienten ist eine große Herausforderung, deren Bewältigung eine sicherere und effektivere Ionenstrahltherapie ermöglichen würde. Ein vielversprechender Ansatz der Reichweitenverifizierung ist die Ionoakustik. Durch die Energiedeposition des Ionenstrahls wird ein lokaler Druckanstieg verursacht, der als Ultraschallwelle detektiert werden kann. Die Messung der Flugzeit der Ultraschallwellen ermöglicht eine direkte Lokalisierung des Bragg-Peaks. Diese Arbeit untersucht die idealen Strahlkonfigurationen und einen Signalverarbeitungsalgorithmus um das Signal-Rausch-Verhältnis des Signals für klinisch relevante Dosen zu optimieren. Methode: Ergebnisse: Zusammenfassung: |
BibTeX:
@conference{Schauer2020,
author = {Schauer, J. and , H. P. Wieser and Lascaud, J. and Huang, Y. and Assmann, W. and Parodi, K. and Chmyrov, A. and V.Ntziachristos and Dollinger, G.},
title = {Reichweitenbestimmung eines Protonenstrahls durch ionoakustische Messungen fürklinisch relevante Dosen},
booktitle = {51. Jahrestagung der Deutschen Gesellschaft für Medizinische Physik (DGMP) e. V. 09.–11. September 2020},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2020},
editor = {Wolf, Ulrich and Sattler, Bernhard},
url = {https://www.dgmp.de/de-DE/131/dgmp-tagungsbaende/}
}
|
2019 |
|
Proton minibeam radiotherapy - A big step into the future of precision tumor therapy G. Datzmann, A. Degiovanni and J. Reindl; ENLIGHT Highlights 12 (12) (2019) 13-18. |
BibTeX:
@article{Datzmann2019,
author = {Datzmann, Gerd and Degiovanni, Alberto and Reindl, Judith},
title = {Proton minibeam radiotherapy - A big step into the future of precision tumor therapy},
journal = {ENLIGHT Highlights},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2019},
volume = {12},
number = {12},
pages = {13-18},
url = {https://enlight.web.cern.ch/sites/enlight.web.cern.ch/files/media/downloads/december_2019.pdf},
doi = {https://doi.org/10.5281/zenodo.3540930}
}
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Acute Skin Damage and Late Radiation-Induced Fibrosis and Inflammation in Murine Ears after High-Dose Irradiation C.A. Dombrowsky, J. Schauer, M. Sammer, A. Blutke, W.D. Walsh, B. Schwarz, S. Bartzsch, A. Feuchtinger, J. Reindl, E.S. Combs, G. Dollinger and E.T. Schmid; Cancers 11 (5) (2019) 727. |
| Abstract: The use of different scoring systems for radiation-induced toxicity limits comparability between studies. We examined dose-dependent tissue alterations following hypofractionated X-ray irradiation and evaluated their use as scoring criteria. Four dose fractions (0, 5, 10, 20, 30 Gy/fraction) were applied daily to ear pinnae. Acute effects (ear thickness, erythema, desquamation) were monitored for 92 days after fraction 1. Late effects (chronic inflammation, fibrosis) and the presence of transforming growth factor beta 1 (TGFβ1)-expressing cells were quantified on day 92. The maximum ear thickness displayed a significant positive correlation with fractional dose. Increased ear thickness and erythema occurred simultaneously, followed by desquamation from day 10 onwards. A significant dose-dependency was observed for the severity of erythema, but not for desquamation. After 4 × 20 and 4 × 30 Gy, inflammation was significantly increased on day 92, whereas fibrosis and the abundance of TGFβ1-expressing cells were only marginally increased after 4 × 30 Gy. Ear thickness significantly correlated with the severity of inflammation and fibrosis on day 92, but not with the number of TGFβ1-expressing cells. Fibrosis correlated significantly with inflammation and fractional dose. In conclusion, the parameter of ear thickness can be used as an objective, numerical and dose-dependent quantification criterion to characterize the severity of acute toxicity and allow for the prediction of late effects. |
BibTeX:
@article{Dombrowsky2019,
author = {Dombrowsky, C. Annique and Schauer, Jannis and Sammer, Matthias and Blutke, Andreas and Walsh, W. Dietrich and Schwarz, Benjamin and Bartzsch, Stefan and Feuchtinger, Annette and Reindl, Judith and Combs, E. Stephanie and Dollinger, Günther and Schmid, E. Thomas},
title = {Acute Skin Damage and Late Radiation-Induced Fibrosis and Inflammation in Murine Ears after High-Dose Irradiation},
journal = {Cancers},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2019},
volume = {11},
number = {5},
pages = {727},
url = {https://www.mdpi.com/2072-6694/11/5/727},
doi = {https://doi.org/10.3390/cancers11050727}
}
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Zellschädigung von gesundem Gewebe bei der Protonen Minibeam Therapie - eine in-vitro Gewebsstudie Jan Grundhöfer; Studienarbeit, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2019. |
| Abstract: Diese Arbeit beschreibt die in-vitro Untersuchung der Zellschädigung von gesundem Gewebe bei der Protonen Minibeam Therapie. Dazu wurden Hautmodelle mit 2 Gy mit unterschiedlich breiten Minibeams bestrahlt, um die Auswirkungen der Protonenstrahlung im Gewebe auszuwerten. Protonenstrahlung wirkt ionisierend und verursacht beim Durchlaufen von menschlichen Zellen Doppelstrangbrüche. Die Verteilung der Doppelstrangbrüche im Gewebe ist vom linearen Energietransfer der Protonen abhängig. Um einen Zusammenhang zwischen den Bestrahlungsmustern und der Verteilung der Doppelstrangbrüche herstellen zu können, wurden die Hautmodelle einer Immunfluoreszenzfärbung unterzogen, welche die Reparaturproteine, die sich an den Doppelstrangbrüchen anlagern, in den Zellen sichtbar macht. Die Auswertung der gefärbten Proben erfolgte mithilfe der Epifluoreszenzmikroskopie, bei der hochauflösende Aufnahmen der Querschnitte von den bestrahlten Hautmodellen erstellt wurden. Um die Bestrahlungsmuster mit entsprechender Präzision auf die Hautmodelle zu projizieren, wurde die Bestrahlung an dem Rasterionenmikroskop SNAKE (Supraleitendes Nanoskop für angewandte kernphysikalische Experimente) am 14 MV Tandem-van de Graaff Beschleuniger des Maier-Leibnitz-Laboratoriums in Garching durchgeführt. Mit dieser Versuchsanordnung konnte detailliert untersucht werden, wie die Strahlbreiten der Minibeams mit der gewünschten Verringerung von Gewebeschäden zwischen den Strahlkanälen zusammenhängen. Die Verteilung der Doppelstrangbrüche bei den Gewebeproben spiegelt in den durchgeführten Versuchen die Anordnung und Dosisverteilung der Minibeams wider. Dabei wurden für die Minibeams Breiten von 100 μm und 500 μm verwendet. Diese wurden mit einer annähernd homogenen Dosisverteilung von 1250 μm Strahlbreite verglichen, um zu erfahren, ob zwischen den Minibeams eine verringerte Anzahl von Doppelstrangbrüchen auftritt. Die Strahlbreiten sind durch die Standardabweichung (σ) des Maximums eines Minibeams definiert. Es zeigte sich, dass bei den Proben, die mit Minibeams mit einer Linienbreite von 500 μm und einem Linienabstand von 2500 μm bestrahlt wurden, die Maxima der Focizahl nicht die Maxima in den homogen bestrahlten Proben überschreiten. Das Maximum der Messpunkte lag bei den homogen bestrahlten Proben bei 6,60 ± 3,96 Foci pro Zellkern und bei den Minibeam Proben mit 500 μm Strahlbreite bei 6,58 ± 3,72 Foci pro Zellkern. Zwischen den Peaks der Fociverteilung sinkt die Anzahl der Foci zwar ab, jedoch erreicht sie nicht das Hintergrundniveau, welches der Zellschädigung einer nicht bestrahlten Probe entspricht. Bei den Proben mit einer Linienbreite von 100 μm und identischem Linienabstand von 2500 μm konnte eine komplette Gewebeschonung zwischen den Strahlkanälen der Minibeams festgestellt werden. Die Anzahl der Foci pro Zellkern fiel also zwischen den Minibeams auf das Hintergrundniveau von 0,188 Foci pro Zellkern ab. Des Weiteren fallen die Maxima der Fociverteilung bei den Proben mit 100 μm Strahlbreite deutlich niedriger aus als bei denen mit 500 μm Strahlbreite. Der größte Messpunkt betrug nur 1,56 ± 2,05 Foci pro Zellkern. Der Zusammenhang zwischen den Bestrahlungsmustern und der Verteilung der Doppelstrangbrüche hinsichtlich der Breite der Bestrahlung und der Abstände der Minibeams konnte bei unterschiedlichen Hautmodellen nachgewiesen werden. |
BibTeX:
@thesis{Grundhoefer2019sa,
author = {Jan Grundhöfer},
title = {Zellschädigung von gesundem Gewebe bei der Protonen Minibeam Therapie - eine in-vitro Gewebsstudie},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2019}
}
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Perspectives of cellular communication through tunneling nanotubes in cancer cells and the connection to radiation effects N. Matejka and J. Reindl; Radiation Oncology 14 (1) (2019) 218. |
| Abstract: Direct cell-to-cell communication is crucial for the survival of cells in stressful situations such as during or after radiation exposure. This communication can lead to non-targeted effects, where non-treated or non-infected cells show effects induced by signal transduction from non-healthy cells or vice versa. In the last 15 years, tunneling nanotubes (TNTs) were identified as membrane connections between cells which facilitate the transfer of several cargoes and signals. TNTs were identified in various cell types and serve as promoter of treatment resistance e.g. in chemotherapy treatment of cancer. Here, we discuss our current understanding of how to differentiate tunneling nanotubes from other direct cellular connections and their role in the stress reaction of cellular networks. We also provide a perspective on how the capability of cells to form such networks is related to the ability to surpass stress and how this can be used to study radioresistance of cancer cells. |
BibTeX:
@article{Matejka2019,
author = {Matejka, Nicole and Reindl, Judith},
title = {Perspectives of cellular communication through tunneling nanotubes in cancer cells and the connection to radiation effects},
journal = {Radiation Oncology},
type = {Open Access},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2019},
volume = {14},
number = {1},
pages = {218},
url = {https://ro-journal.biomedcentral.com/articles/10.1186/s13014-019-1416-8},
doi = {https://doi.org/10.1186/s13014-019-1416-8}
}
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The Influence of High-LET Particle Radiation on Cellular Communication via Tunneling Nanotubes Nicole Matejka; Masters-Thesis, Technische Universität München, 2019. |
| Abstract: Cell-to-cell communication is crucial for the survival of cells in stressful situations such as during or after radiation exposure. In 2004, a new kind of intercellular communication was reported and termed as tunneling nanotubes (TNTs). TNTs are thin membrane channels with a diameter in the nanometer range that directly connect cells over long-distances. They facilitate the direct cell-to-cell transfer of several cargoes such as organelles, viruses and signals. This thesis deals with the role of TNTs in radio-biology. It has the aim to investigate the influence of radiation on communication networks built up by TNTs and to figure out to what extent cellular communication via TNTs can interfere the cellular survival upon radiation exposure. Several membrane markers are tested in order to identify the most suitable TNT marker. Here, the CellMask© plasma membrane stain shows excellent properties. This non-toxic dye enables an uniform and intensive labeling of the cell membrane within 15 minutes. Due to its robustness against dye internalization by endocytosis, the staining offers the opportunity to study TNTs over long time periods. Furthermore, TNTs in U87 glioblastoma cells are characterized using confocal and STED microscopy. Cell-to-cell connections can consist of one single TNT or of several dense packed TNTs. The appearance of TNTs is not always straight and stretched, instead they can have kinks, junctions and noodles. TNT formation by cell-dislodgement as well as the transport of a gondola are successfully imaged. The formation of the TNT occurs within one hour and the gondola moves along the TNT with an average speed of (14.5 ± 0.7) nm/s . In addition, the cytoskeleton content of TNTs is studied by additional labeling of F-actin and microtublin. Thick TNTs contain microtubules as well as F-actin. In thin TNTs, F-actin is only found as fragments at their origins close to the cell body. This finding indicates that F-actin is only needed at the TNT formation, but not for stability of TNTs. An accurate TNT diameter of 195 nm is measured by STED nanoscopy. Although, TNTs are smaller than the resolution of a confocal microscope, in combination with bright and stable labeling they can be identified by confocal microscopy, when no accurate thickness measurement is needed. Additionally, a first pilot experiment on the investigation of the impact of radiation on TNTs is performed. U87 glioblastoma cells are irradiated with -particles to a dose of 1.2 Gy at the -particle irradiation setup located in Neubiberg. After irradiation cells are labeled with CellMask© orange plasma membrane stain. The TNT network is then examined using livecell confocal microscopy and compared to sham irradiated controls. In order to follow the evolution and expansion of the TNT network, samples are analyzed 1 h, 6 h, 24 h and 72 h after irradiation. The results of this experiment show that irradiated cells establish their network faster within the first 6 h and have more cell-to-cell connections, which have a high TNT density, than sham irradiated controls after 24 h. These findings suggest that there is an additional trigger upon radiation damage, which results in fast and intensive network formation by TNTs, as an additional damage response mechanism. |
BibTeX:
@mastersthesis{Matejka2019ma,
author = {Matejka, Nicole},
title = {The Influence of High-LET Particle Radiation on Cellular Communication via Tunneling Nanotubes},
school = {Technische Universität München},
year = {2019}
}
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Training eines Deep Learning Algorithmus zur automatisierten Zellerkennung in Phasenkontrastaufnahmen von lebenden Zellen Rika Ramson; Masters-Thesis, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2019. |
| Abstract: Bei der Bestrahlung von Zellen mit ionisierender Strahlung werden die Zellen geschädigt. Solche Schädigungsprozesse werden bei einer Strahlentherapie gezielt eingesetzt, um Tumorzellen zu schädigen. Diese Zellschädigung wird jedoch z.B. während eines Fluges zum Mars für die Astronauten zum Problem, da diese über einen längeren Zeitraum der kosmischen Strahlung ausgesetzt sind. Deshalb ist es wichtig, ein besseres Verständis für die Reaktionen von Zellen auf eine Bestrahlung zu erlangen, um damit den Strahlenschutz und die Strahlentherapie verbessern zu können. In dieser Arbeit wurde ein Deep Learning Algorithmus so angelernt, dass er die Strahlenschäden in lebenden Zellen auf Einzelzellebene charakterisieren konnte. Dazu wurde ein Trainingsdatensatz erstellt, der aus Phasenkontrastaufnahmen von bestrahlten und unbehandelten Zellen bestand. Mit diesem Datensatz wurde anschließend ein Convolutional Neural Network trainiert. Abschließend wurden die Ergebnisse des Trainings evaluiert. Dabei zeigte sich, dass der Algorithmus in allen erlernten Klassen Evaluationswerte von mindestens 94 % erreichte. Er konnte somit als sehr zuverlässig charakterisiert werden. Zusätzlich wurde für die Generierung einer Datenbasis die mittlere Dauer des Zellzyklus der unbehandelten Zellen bestimmt. Diese Datenbasis soll der Bestimmung strahlenbiologischer Größen dienen, da so Aussagen über eine veränderte Dauer von Zellzyklen oder das Vorliegen eines Zellarrests getroffen werden können. Als mittlere Zellzyklusdauer wurden 19 h ermittelt. When cells are irradiated with ionising radiation, the cells are damaged. This process is purposefully used in radiation therapy to treat tumour cells. However, this cell damage causes a problem for astronauts flying to Mars, since these are exposed to cosmic radiation for a long period of time. Therefore, it is important to gain a better understanding of the reactions of the cells to irradiation in order to be in a position to improve radiation protection and radiotherapy. |
BibTeX:
@mastersthesis{Ramson2019ma,
author = {Ramson, Rika},
title = {Training eines Deep Learning Algorithmus zur automatisierten Zellerkennung in Phasenkontrastaufnahmen von lebenden Zellen},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2019}
}
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Membrane Hsp70-supported Cell-to-cell Connections Via Tunneling Nanotubes Revealed by Live-cell Sted Nanoscopy J. Reindl, M. Shevtsov, G. Dollinger, S. Stangl and G. Multhoff; Cell Stress and Chaperones 24 (1) (2019) 213-221. |
| Abstract: Heat shock protein Hsp70 (Hsp70) is found on the cell surface of a large variety of human and mouse tumor cell types including U87, GL261 glioblastoma, and 4T1 mammary carcinoma cells. We studied the role of membrane-bound Hsp70 (mHsp70) in the formation of cell-to-cell connections via tunneling nanotubes (TNTs) using live-cell STED nanoscopy. This technique allows the visualization of microstructures in the 100-nm range in the living cells. We could show that the presence of tumor-derived mHsp70 in TNTs with a diameter ranging from 120 to 140 nm predominantly originates from cholesterol-rich-microdomains containing the lipid compound globoyltriaosylceramide (Gb3). Under non-stress conditions, Hsp70 and Gb3 are structurally clustered in the membrane of TNTs of tumor cells that showed tumor type specific variations in the amount of cell-to-cell connection networks. Furthermore depletion of cholesterol and ionizing radiation as a stress factor results in a complete loss of Hsp70-containing TNTs. |
BibTeX:
@article{Reindl2019,
author = {Reindl, Judith and Shevtsov, Maxim and Dollinger, Günther and Stangl, Stefan and Multhoff, Gabriele},
title = {Membrane Hsp70-supported Cell-to-cell Connections Via Tunneling Nanotubes Revealed by Live-cell Sted Nanoscopy},
journal = {Cell Stress and Chaperones},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2019},
volume = {24},
number = {1},
pages = {213--221},
url = {https://link.springer.com/article/10.1007/s12192-018-00958-w?wt_mc=Internal.Event.1.SEM.ArticleAuthorOnlineFirst&utm_source=ArticleAuthorOnlineFirst&utm_medium=email&utm_content=AA_en_06082018&ArticleAuthorOnlineFirst_20190113},
doi = {https://doi.org/10.1007/s12192-018-00958-w}
}
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pMB FLASH - Status and Perspectives of Combining Proton Minibeam with FLASH Radiotherapy J. Reindl and S. Girst; Journal of Cancer Immunology 1 (1) (2019) 14-23. |
| Abstract: Proton minibeam radiotherapy (pMBRT) is an external beam radiotherapy method with reduced side effects by taking advantage of spatial fractionation in the normal tissue. Due to scattering, the delivered small beams widen in the tissue ensuring a homogeneous dose distribution in the tumor. In this review, the physical and biological principles regarding dose distribution and healing effects are explained. In the last decade, several preclinical studies have been conducted addressing normal tissue sparing and tumor control in-vitro and in-vivo, using human skin tissue and mouse or rat models. The major results acquired in these studies are summarized. A further newly emerging therapy method is FLASH radiotherapy, i.e. the treatment using ultra-high dose rates. The possibility of combining these methods in proton minibeam FLASH therapy (pMB FLASH) is worked out. Additionally, technical feasibility and limitations will be discussed by looking at simulations as well as preclinical studies and also pointing out new ways of delivering the desired tumor dose, such as interlacing. We will also highlight the opportunities that emerge regarding high dose radiation, hypofractionation and the combination with immunotherapy. |
BibTeX:
@article{Reindl2019a,
author = {Reindl, Judith and Girst, Stefanie},
title = {pMB FLASH - Status and Perspectives of Combining Proton Minibeam with FLASH Radiotherapy},
journal = {Journal of Cancer Immunology},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Reindl, Judith},
year = {2019},
volume = {1},
number = {1},
pages = {14--23},
url = {https://www.scientificarchives.com/article/pmb-flash--status-and-perspectives-of-combining-proton-minibeam-with-flash-radiotherapy},
doi = {https://doi.org/10.33696/cancerimmunol.1.003}
}
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Beam size limit for pencil minibeam radiotherapy determined from side effects in an in-vivo mouse ear model M. Sammer, K. Teiluf, S. Girst, C. Greubel, J. Reindl, K. Ilicic, D.W.M. Walsh, M. Aichler, A. Walch, S.E. Combs, J.J. Wilkens, G. Dollinger and T.E. Schmid; PLoSONE 14 (e0221454) (2019) e0221454. |
| Abstract: Side effects caused by radiation are a limiting factor to the amount of dose that can be applied to a tumor volume. A novel method to reduce side effects in radiotherapy is the use of spatial fractionation, in which a pattern of sub-millimeter beams (minibeams) is applied to spare healthy tissue. In order to determine the skin reactions in dependence of single beam sizes, which are relevant for spatially fractionated radiotherapy approaches, single pencil beams of submillimeter to 6 millimeter size were applied in BALB/c mice ears at a Small Animal Radiation Research Platform (SARRP) with a plateau dose of 60 Gy. Radiation toxicities in the ears were observed for 25 days after irradiation. Severe radiation responses were found for beams ≥ 3 mm diameter. The larger the beam diameter the stronger the observed reactions. No ear swelling and barely reddening or desquamation were found for the smallest beam sizes (0.5 and 1 mm). The findings were confirmed by histological sections. Sub-millimeter beams are preferred in minibeam therapy to obtain optimized tissue sparing. The gradual increase of radiation toxicity with beam size shows that also larger beams are capable of healthy tissue sparing in spatial fractionation. © 2019 Sammer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
BibTeX:
@article{Sammer2019,
author = {Sammer, M. and Teiluf, K. and Girst, S. and Greubel, C. and Reindl, J. and Ilicic, K. and Walsh, D. W. M. and Aichler, M. and Walch, A. and Combs, S. E. and Wilkens, J. J. and Dollinger, G. and Schmid, T. E.},
title = {Beam size limit for pencil minibeam radiotherapy determined from side effects in an in-vivo mouse ear model},
journal = {PLoSONE},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2019},
volume = {14},
number = {e0221454},
pages = {e0221454},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221454},
doi = {https://doi.org/10.1371/journal.pone.0221454}
}
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Proton pencil minibeam irradiation of an in-vivo mouse ear model spares healthy tissue dependent on beam size M. Sammer, E. Zahnbrecher, S. Dobiasch, S. Girst, C. Greubel, K. Ilicic, J. Reindl, B. Schwarz, C. Siebenwirth, D.W.M. Walsh, S.E. Combs, G. Dollinger and T.E. Schmid; PLoSONE 14 (2019) e0224873. |
| Abstract: Side effects caused by radiation are a limiting factor to the amount of dose that can be applied to a tumor volume. A novel method to reduce side effects in radiotherapy is the use of spatial fractionation, in which a pattern of sub-millimeter beams (minibeams) is applied to spare healthy tissue. In order to determine the skin reactions in dependence of single beam sizes, which are relevant for spatially fractionated radiotherapy approaches, single pencil beams of submillimeter to 6 millimeter size were applied in BALB/c mice ears at a Small Animal Radiation Research Platform (SARRP) with a plateau dose of 60 Gy. Radiation toxicities in the ears were observed for 25 days after irradiation. Severe radiation responses were found for beams ≥ 3 mm diameter. The larger the beam diameter the stronger the observed reactions. No ear swelling and barely reddening or desquamation were found for the smallest beam sizes (0.5 and 1 mm). The findings were confirmed by histological sections. Sub-millimeter beams are preferred in minibeam therapy to obtain optimized tissue sparing. The gradual increase of radiation toxicity with beam size shows that also larger beams are capable of healthy tissue sparing in spatial fractionation. |
BibTeX:
@article{Sammer2019a,
author = {Sammer, Matthias and Zahnbrecher, Esther and Dobiasch, Sophie and Girst, Stefanie and Greubel, Christoph and Ilicic, Katarina and Reindl, Judith and Schwarz, Benjamin and Siebenwirth, Christian and Walsh, Dietrich W. M. and Combs, Stephanie E. and Dollinger, Günther and Schmid, Thomas E.},
title = {Proton pencil minibeam irradiation of an in-vivo mouse ear model spares healthy tissue dependent on beam size},
journal = {PLoSONE},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2019},
volume = {14},
pages = {e0224873},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224873},
doi = {https://doi.org/10.1371/journal.pone.0224873}
}
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Pre-experiment for fractionated proton-minibeam-irradiation Jannis Schauer; Masters-Thesis, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2019. |
| Abstract: Fractionation is a well established approach to reduce adverse side effects during an radiotherapeutic tumor treatment. In fractionated radiotherapy the entire dose is delivered in several fractions over several days or even weeks. A necessity during fractionated irradiation is the precise positioning of the patient to allow the irradiation of the tumor and spare healthy tissues and organs at risk. In clinical radiotherapy this is done with lasers which are aligned with corresponding marks on the skin. An accuracy of a few millimetres can be achieved using this technique [1]. A technique which is currently under investigation is spatial fractionation. In spatially fractionated irradiation the total dose is not delivered homogeneously over a certain area but in certain minibeams or lines. A procedure which has shown extraordinarily good results in former experiments is proton minibeam irradiation [2]. The small angle scattering allows for a homogeneous dose distribution in the tumor while healthy tissue is spared. In particular one experiment by Girst et.al. has shown tissue sparing effects using the model of a female BALB/c mouse [2]. The combination of spatial and temporal fractionation is still uninvestigated. This thesis covers all necessary preparations in order to perform fractionated proton minibeam irradiation in an in vivo BALB/c mouse ear model. The dose determination was done by performing a pre-experiment investigating the dose response of the ears of BALB/c mice after being irradiated with four fractions of X-Ray radiation. A first positioning mechanism was established for the pre-experiment which was improved for the final setup of the proton minibeam irradiation experiemnt in order to position the ear with sufficient accuracy. The pre-experiment serves to find an applicable dose for the fractionated proton minibeam experiment. 6 groups of 7 mice each were irradiated with doses of 0, 5, 10, 20, 30 and 40 Gy in each of the four fractions to cover a broad field of doses. The irradiated ears were measured 92 long in terms of of reddening (erythema), crust formation (desquamation) and thickness. Below 10 Gy per fraction (40 Gy total dose), disproportionate protection of the ear was observed. A continuous increase in swelling and inflammation was observed for the doses between 10 Gy per fraction and 30 Gy per fraction. The mice irradiated with 40 Gy per fraction showed the highest reaction and in addition suffered from necrosis as a unique characteristic of the 4*40 Gy mice. The dose for the fractionated proton minibeam irradiation experiment was set to be 30 Gy per fraction as effects like necrosis should be avoided. The first positioning setup for the pre-experiment allows to reproduce the initial field with an accuracy of around 250 μm which was sufficiently accurate for the X-Ray irradiation asthe ear was irradiated with a homogeneous field of 7.2 mm*7.2 mm. In the last part of this thesis an improved positioning setup is presented that allows for precise irradiation for the proton minibeam irradiation. As these minibeams are only around 200 μm in width a positioning accuracy in the order of 100 μm is obligatory. The needed hardware consisting of a translation and a rotation stage included in a self designed holder is presented. In addition the corresponding software is introduced and explained. The experiment will be performed in the the beginning of April at the tandem accelerator in Garching. [1] Nagamine, Yoshihiko ; Fujitaka, Shinichiro ; Honda, Takurou ; Akiyama, Hiroshi: Patient positioning device and patient positioning method. Mai 1 2007. – US Patent 7,212,608 |
BibTeX:
@mastersthesis{Schauer2019ma,
author = {Schauer, Jannis},
title = {Pre-experiment for fractionated proton-minibeam-irradiation},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2019}
}
|
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Nanoscopic analysis of 53BP1, BRCA1 and Rad51 reveals new insights in temporal progression of DNA-repair and pathway choice B. Schwarz, A.A. Friedl, S. Girst, G. Dollinger and J. Reindl; Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 816-818 (2019) 111675. |
| Abstract: The accumulation and spatial distribution of 53BP1, BRCA1 and Rad51, key proteins in DNA double-strand break (DSB) repair, was investigated with high temporal resolution over a time span of 24 h, using STED nanoscopy. DNA lesions were induced by irradiation with high-LET (linear energy transfer) α-particles. We show that 53BP1 IRIF formation occurs quickly in almost all cells and after about 6 h the fraction of 53BP1 IRIF positive cells slowly declines. Against the expectations BRCA1 and Rad51 IRIF formation is only shortly delayed but with the maximum of cells showing foci after 6 and 8 h after irradiation. At this stage, almost all IRIF in a given Rad51-positive cell show Rad51 accumulation, suggesting that repair via homologous recombination is attempted at almost all residual DSB sites. The frequency of BRCA1 IRIF positive cells increases much earlier and remains high after Rad51 positive cells start to decline, supporting models claiming that functional roles of BRCA1 change over time. Correlation analysis showed a high degree of correlation of Rad51 with BRCA1, while the exclusion of 53BP1 from the actual resection-zone is demonstrated by anti-correlation of Rad51 and 53BP1. Interestingly, these correlation and anti-correlation patterns exhibit complementary temporal variation. |
BibTeX:
@article{Schwarz2019,
author = {Schwarz, Benjamin and Friedl, Anna A. and Girst, Stefanie and Dollinger, Günther and Reindl, Judith},
title = {Nanoscopic analysis of 53BP1, BRCA1 and Rad51 reveals new insights in temporal progression of DNA-repair and pathway choice},
journal = {Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2019},
volume = {816-818},
pages = {111675},
url = {http://www.sciencedirect.com/science/article/pii/S0027510719300272},
doi = {https://doi.org/10.1016/j.mrfmmm.2019.111675}
}
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Local inhibition of rRNA transcription without nucleolar segregation after targeted ion irradiation of the nucleolus C. Siebenwirth, C. Greubel, G.A. Drexler, J. Reindl, D.W.M. Walsh, B. Schwarz, M. Sammer, I. Baur, H. Pospiech, T.E. Schmid, G. Dollinger and A.A. Friedl; Journal of cell science 132 (19) (2019) 232181. |
| Abstract: Nucleoli have attracted interest for their role as cellular stress sensors and as potential targets for cancer treatment. The effect of DNA double-strand breaks (DSBs) in nucleoli on rRNA transcription and nucleolar organisation appears to depend on the agent used to introduce DSBs, DSB frequency and the presence (or not) of DSBs outside the nucleoli. To address the controversy, we targeted nucleoli with carbon ions at the ion microbeam SNAKE. Localized ion irradiation with 1-100 carbon ions per point (about 0.3-30 Gy per nucleus) did not lead to overall reduced ribonucleotide incorporation in the targeted nucleolus or other nucleoli of the same cell. However, both 5-ethynyluridine incorporation and Parp1 protein levels were locally decreased at the damaged nucleolar chromatin regions marked by γH2AX, suggesting localized inhibition of rRNA transcription. This locally restricted transcriptional inhibition was not accompanied by nucleolar segregation, a structural reorganisation observed after inhibition of rRNA transcription by treatment with actinomycin D or UV irradiation. The presented data indicate that even multiple complex DSBs do not lead to a pan-nucleolar response if they affect only a subnucleolar region. |
BibTeX:
@article{Siebenwirth2019,
author = {Siebenwirth, C. and Greubel, C. and Drexler, G. A. and Reindl, J. and Walsh, D. W. M. and Schwarz, B. and Sammer, M. and Baur, I. and Pospiech, H. and Schmid, T. E. and Dollinger, G. and Friedl, A. A.},
title = {Local inhibition of rRNA transcription without nucleolar segregation after targeted ion irradiation of the nucleolus},
journal = {Journal of cell science},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther ; Reindl, Judith},
year = {2019},
volume = {132},
number = {19},
pages = {232181},
url = {https://jcs.biologists.org/content/132/19/jcs232181},
doi = {https://doi.org/10.1242/jcs.232181}
}
|
2018 |
|
Physics at the Munich Tandem Accelerator Laboratory G. Dollinger and T. Faestermann; Nuclear Physics News 28 (1) (2018) 5-12. |
| Abstract: The Tandem accelerator situated in Garching, just 20 km north of Munich, is of the “Emperor” (MP) series manufactured by High Voltage Engineering Corporation (HVEC). It delivered the first beams for experiments in 1970 and came close to its design voltage of 10 MV. In 1991 the tubes were exchanged to the extended version of HVEC. Routine operation at a terminal voltage of 14 MV was then possible. |
BibTeX:
@article{Dollinger2018,
author = {Günther Dollinger and Thomas Faestermann},
title = {Physics at the Munich Tandem Accelerator Laboratory},
journal = {Nuclear Physics News},
publisher = {Taylor & Francis},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2018},
volume = {28},
number = {1},
pages = {5-12},
url = {https://www.tandfonline.com/doi/full/10.1080/10619127.2018.1427405},
doi = {https://doi.org/10.1080/10619127.2018.1427405}
}
|
|
Physics at the Munich Tandem Accelerator Laboratory G. Dollinger and T. Faestermann; ArXiv (v2) (2018) . |
| Abstract: This review reports on the science performed in various fields at the Munich tandem accelerator during the past decade. It covers nuclear structure studies, also with respect to astro- and particle physics as well as for the understanding of fundamental symmetries, the extremely sensitive detection of long-lived radionuclides from Supernova or r-process production with accelerator mass spectrometry and studies of the elemental composition of thin films with extreme depth resolution and sensitivity by elastic recoil detection (ERD). The ion microbeam is used for 3D hydrogen microscopy as well as in radiobiology to study the response of living cells on well-defined irradiations. In medical research new therapeutic methods of tumour irradiation are tested using proton minibeams as well as the determination of ion ranges in tissue with iono-acoustics. Primary and secondary beams from the accelerator are also used for development and testing of detector components in large setups, e.g. at the LHC, and for testing new kinds of fuel materials of high uranium density to use them as medium enriched fuels at the Munich research reactor FRM II in the future. |
BibTeX:
@openaccess{Dollinger2018a,
author = {Günther Dollinger and Thomas Faestermann},
title = {Physics at the Munich Tandem Accelerator Laboratory},
journal = {ArXiv},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2018},
number = {v2},
url = {https://arxiv.org/abs/1802.07057}
}
|
|
Modeling Studies on Dicentrics Induction After Sub-micrometer Focused Ion Beam Grid Irradiation W. Friedland, P. Kundrát, E. Schmitt, J. Becker, K. Ilicic, C. Greubel, J. Reindl, C. Siebenwirth, T.E. Schmid and G. Dollinger; rpd 183 (1-2) (2018) 40-44. |
| Abstract: The biophysical simulation tool PARTRAC contains modules for DNA damage response representing non-homologous end joining of DNA double-strand breaks (DSB) and the formation of chromosomal aberrations. Individual DNA ends from the induced DSB are followed regarding both their enzymatic processing and spatial mobility, as is needed for chromosome aberrations to arise via ligating broken ends from different chromosomes. In particular, by tracking the genomic locations of the ligated fragments and the positions of centromeres, the induction of dicentrics can be modeled. In recent experiments, the impact of spatial clustering of DNA damage on dicentric yields has been assessed in AL human-hamster hybrid cells: Defined numbers of 20 MeV protons (linear energy transfer, LET 2.6 keV/μm), 45 MeV Li ions (60 keV/μm) and 55 MeV C ions (310 keV/μm) focused to sub-μm spot sizes were applied with the ion microbeam SNAKE in diverse grid modes, keeping the absorbed dose constant. The impact of the μm-scaled spatial distribution of DSB (focusing effect) has thus been separated from nm-scaled DSB complexity (LET effect). The data provide a unique benchmark for the model calculations. Model and parameter refinements are described that enabled the simulations to largely reproduce both the LET-dependence and the focusing effect as well as the usual biphasic rejoining kinetics. The predictive power of the refined model has been benchmarked against dicentric yields for photon irradiation. |
BibTeX:
@article{Fiedland2018,
author = {Friedland, W. and Kundrát, P. and Schmitt, E. and Becker, J. and Ilicic, K. and Greubel, C. and Reindl, J. and Siebenwirth, C. and Schmid, T. E. and Dollinger, G.},
title = {Modeling Studies on Dicentrics Induction After Sub-micrometer Focused Ion Beam Grid Irradiation},
journal = {rpd},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2018},
volume = {183},
number = {1-2},
pages = {40--44},
url = {https://academic.oup.com/rpd/article/183/1-2/40/5307683},
doi = {https://doi.org/10.1093/rpd/ncy266}
}
|
|
DNA damage interactions on both nanometer and micrometer scale determine overall cellular damage T. Friedrich, K. Ilicic, C. Greubel, S. Girst, J. Reindl, M. Sammer, B. Schwarz, C. Siebenwirth, D.W.M. Walsh, T.E. Schmid, M. Scholz and G. Dollinger; Scientific Reports 8 (1) (2018) 16063. |
| Abstract: DNA double strand breaks (DSB) play a pivotal role for cellular damage, which is a hazard encountered in toxicology and radiation protection, but also exploited e.g. in eradicating tumors in radiation therapy. It is still debated whether and in how far clustering of such DNA lesions leads to an enhanced severity of induced damage. Here we investigate - using focused spots of ionizing radiation as damaging agent - the spatial extension of DNA lesion patterns causing cell inactivation. We find that clustering of DNA damage on both the nm and µm scale leads to enhanced inactivation compared to more homogeneous lesion distributions. A biophysical model interprets these observations in terms of enhanced DSB production and DSB interaction, respectively. We decompose the overall effects quantitatively into contributions from these lesion formation processes, concluding that both processes coexist and need to be considered for determining the resulting damage on the cellular level. |
BibTeX:
@article{Friedrich2018,
author = {Friedrich, Thomas and Ilicic, Katarina and Greubel, Christoph and Girst, Stefanie and Reindl, Judith and Sammer, Matthias and Schwarz, Benjamin and Siebenwirth, Christian and Walsh, Dietrich W. M. and Schmid, Thomas E. and Scholz, Michael and Dollinger, Günther},
title = {DNA damage interactions on both nanometer and micrometer scale determine overall cellular damage},
journal = {Scientific Reports},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2018},
volume = {8},
number = {1},
pages = {16063},
url = {https://www.nature.com/articles/s41598-018-34323-9#auth-6},
doi = {https://doi.org/10.1038/s41598-018-34323-9}
}
|
|
Nanoscopic Analysis of Chromatin Organization during DNA Double-Strand Break Repair using STED Microscopy Mario Köhler; Masters-Thesis, Ludwig-Maximilians-Universität München, 2018. |
| Abstract: DNA double-strand breaks (DSB) are considered the most critical damage to DNA caused by can be caused by ionizing radiation. This is constantly exposed to every organism. Incorrect repair of the DSB can lead to mutations and thus to the development of cancer. An important part of DNA DSB repair is the interaction between the proteins involved in the repair and chromatin. In this thesis the connection between the deposition of the repair protein 53BP1 and the superior chromatin structure was investigated by STED nanoscopy. 53BP1 plays an important role in the main mechanisms (non-homologous end joining and homologous recombination) of DNA double strand break repair and can therefore be used as a marker for DNA damage. The connection between the deposition of 53BP1 and the higher order chromatin structure after DSB induction by radiation with different linear energy transfer (LET) has not yet been investigated. However, this plays a central role in the modelling of DNA repair and chromatin structure (based on the models of T. Cremer [1] and J. Reindl [2]). The HeLa cells used were each treated with 2.7 MeV alpha particles with a linear energy transfer of 138 keV/µm , 20 MeV protons (LET=2.6 keV/µm ), 55 MeV carbon (LET=414 keV/µm ) and 33 MeV lithium ions (LET=85 keV/µm). This made it possible to investigate the correlation between chromatin and 53BP1 during DNA double strand break repair. The results showed that for all radiation types a high anticorrelation (86.9% ± 2.1% to 94.7% ± 0.6%) between 53BP1 and EdU stained chromatin occurs within the irradiated areas. This confirms the assumption that there are distinct compartments in which chromatin alone could be detected (chromatin territories), areas which contain only 53BP1 (intermediate interchromatin areas), but also a third area in which both chromatin and 53BP1 occur (perichromatin) and which accounts for 5%-15% of the irradiated areas. It was also found that although the correlation or anti-correlation differs for different types of radiation, this is LET independent, because no pattern can be derived. The results obtained confirm the previous model regarding the relationship between DNA repair and chromatin structure, but go even further. Intensity measurements of the superimposed regions showed that more EdU is incorporated in the correlated region (between 53BP1 and chromatin) than on average in the rest of the nucleus. This is a strong indication that the repair takes place exclusively in these regions. This region can be called the active perichromatin area. Furthermore, these intensity analyses confirmed the structure-preserving function of 53BP1, since the average 53BP1 concentration in the correlated and anticorrelated areas within the irradiated area remains constant. |
BibTeX:
@mastersthesis{Koehler2018ma,
author = {Köhler, Mario},
title = {Nanoscopic Analysis of Chromatin Organization during DNA Double-Strand Break Repair using STED Microscopy},
school = {Ludwig-Maximilians-Universität München},
year = {2018}
}
|
|
Auswirkungen ionisierender Strahlung auf Mitochondrien und ihre Rolle beim Zellüberleben Sarah Rudigkeit; Masters-Thesis, Technische Universität München, 2018. |
| Abstract: glqq The central dogma of radiation biologygrqq [1,2,3,4] states, that the radiotoxic effects from ionizing radiation originate from damage to the nucleus. Therefore only little research has investigated the role of cytoplasm. As the mitochondria are the power plants of the cell, they are necessary for the survival of cells and play an important role in signaling pathways such as the initialization of apoptosis [5], the programmed cell death. Furthermore mitochondria build highly dynamic networks over the whole cytoplasm, which react to the energy demand of the cell. Hence the morphology of the mitochondrial networks is an indicator for the cells stress level and healthiness [6,7]. These are the reasons why the mitochondria are an interesting target to investigate the radiation effects on the cytoplasm. Therefore, in this thesis a method was developed, with which the mitochondrial networks of living cells were imaged with confocal microscopy also over time and were analyzed with regard to various morphological parameters like the mitochondrial network size, to investigate the cells stress level before and after irradiation. So I concluded that the morphological parameters of a single unirradiated cell oscillates over time up to 40 % around a constant value. Also between different cells the results vary and result in high standard deviations from 12.5 % up to 68 %. A repetition of this experiment showed reproducible results and so this method is suitable for analyzing high morphological differences in the mitochondrial networks. Now it can be investigated which changes occur in the mitochondrial networks after irradiation. Thus an approach will be described in the second part of this thesis, with which a targeted irradiation of mitochondria followed by longterm imaging is possible. For the targeted irradiation the ionmicrobeam SNAKE at the tandem accelerator of the Maier-Leibnitz-Laboratory in Garching was used, which is able to focus 55 MeV carbon ions to a beam spot size of about 1 micro m. This is suitable to irradiate subcompartments of cells. But such an irradiation takes a high effort, so in this thesis a method for seeding only small cell numbers (approx. 100) on four small areas (diameter: 0.4 mm) was etablished. In a first testexperiment every single cell was irradiated in the mitochondrial area with 5120 carbon ions distributed in one of three different areas (13.2 micro m², 7.0 micro m² und 2.7 micro m²). After that the cells were observed with phase contrast microscopy for 3.5 days. During the observation the cell number of the irradiated cells stays constant, while the unirradiated control group shows an exponential growth. Then the accuracy of the microbeam targeting was checked with a nuclear track detector, which shows, that 3 % of the ions were scattered up to 570 micro m away from target. This results in a dose of (1 ± 1) micro m over the cell area, that originated only from scattered ions. So the probability of hitting a cell nucleus became very likely. Therefore the microbeam was optimized in further experiments by using instead of 5-times positively charged carbon ions 6-times positively charged carbon ions. Additionally the slit positions were adjusted and lens errors due to focusing of the beam were corrected. With this changes the number of non-focused ions was reduced to 1 % and the maximal scattered distance to 180 micro m away from target. |
BibTeX:
@mastersthesis{Rudigkeit2018ma,
author = {Rudigkeit, Sarah},
title = {Auswirkungen ionisierender Strahlung auf Mitochondrien und ihre Rolle beim Zellüberleben},
school = {Technische Universität München},
year = {2018}
}
|
|
Targeted Irradiation of Mitochondria Dietrich Wyndham Michael Walsh; Dissertation, Technische Universität München, 2018. |
| Abstract: Targeted mitochondrial irradiation has been performed using protons and carbon ions at two separate ion microbeam facilities. Live cell imaging of mitochondria in cancerous and non-cancerous cells has been developed and performed to analyze mitochondrial factors in situ.Among the traits analyzed are mitochondrial membrane potential (polarization state), mitochondrial membrane integrity, plasma membrane integrity and mitochondrial reactive oxygen species production. The results from the experiments have shown that polarized and functional mitochondria can be depolarized and deactivated by targeted irradiation with both protons and carbon ions. The results indicate that the total energy deposited in the mitochondria is the factor which dictates the mitochondrial depolarization response not the particle specific LET. In addition there was no sign of mitochondrial membrane integrity change or plasma membrane integrity change after irradiation. The targeted irradiation and concurrent live cell imaging of mitochondria has also enabled the detection of mitochondria specific superoxide (O2-) production during irradiation. In conclusion, this thesis is the first documentation of targeted irradiation of mitochondria and the radiation induced superoxide production and mitochondrial depolarization following irradiation. |
BibTeX:
@phdthesis{Walsh2018diss,
author = {Walsh, Dietrich Wyndham Michael},
title = {Targeted Irradiation of Mitochondria},
school = {Technische Universität München},
year = {2018},
url = {http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:91-diss-20180514-1379509-1-4}
}
|
|
Evaluation of radiation-related invasion in primary patient-derived glioma cells and validation with established cell lines: impact of different radiation qualities with differing LET M. Wank, D. Schilling, J. Reindl, B. Meyer, J. Gempt, S. Motov, F. Alexander, J.J. Wilkens, J. Schlegel, T.E. Schmid and S.E. Combs; Journal of Neuro-Oncology 139 (3) (2018) 583-590. |
| Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor and has a very poor overall prognosis. Multimodal treatment is still inefficient and one main reason is the invasive nature of GBM cells, enabling the tumor cells to escape from the treatment area causing tumor progression. This experimental study describes the effect of low- and high-LET irradiation on the invasion of primary GBM cells with a validation in established cell systems. |
BibTeX:
@article{Wank2018,
author = {Wank, M. and Schilling, D. and Reindl, J. and Meyer, B. and Gempt, J. and Motov, S. and Alexander, F. and Wilkens, J. J. and Schlegel, J. and Schmid, T. E. and Combs, S. E.},
title = {Evaluation of radiation-related invasion in primary patient-derived glioma cells and validation with established cell lines: impact of different radiation qualities with differing LET},
journal = {Journal of Neuro-Oncology},
type = {OpenAccess},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2018},
volume = {139},
number = {3},
pages = {583--590},
url = {https://link.springer.com/article/10.1007%2Fs11060-018-2923-4},
doi = {https://doi.org/10.1007/s11060-018-2923-4}
}
|
2017 |
|
Microbeam radiation therapy at a laser-based compact synchrotron x-ray source K. Burger, K. Ilicic, A. Hunger, M. Dierolf, B. Günther, E. Schmid, D.W.M. Walsh, T. Urban, S. Bartzsch, A. Radtke, E. Eggl, K. Achterhold, B. Gleich, S.E. Combs, M.M. Molls, T.E. Schmid, F. Pfeiffer and J.J. Wilkens; In: 2017 Conference on Lasers and Electro-Optics Europe & European Quantum Electronics Conference (CLEO/Europe-EQEC) (2017) , IEEE. |
| Abstract: Summary form only given. X-ray microbeam radiation therapy (MRT) is a preclinical approach for tumor treatment based on spatial dose redistribution. In-vitro and in-vivo studies suggest higher tumor control and less normal tissue complications compared to conventional radiotherapy [1]. Due to high requirements on dose rate and x-ray beam collimation, most of the research on MRT has been performed at large-scale synchrotron facilities. We conducted first successful in-vitro experiments at a laser-based Compact Light Source (CLS). This unique system is based on inverse Compton scattering of infrared laser photons, enhanced with a high-finesse bowtie-cavity, with relativistic electrons of 20-45 MeV [2]. Here, the magnetic field created by undulators at standard synchrotrons is replaced by the electro-magnetic field of the laser photons. Due to the significantly lower period of the laser undulator, these low electron energies are sufficient to achieve quasi-monochromatic x-rays of 15-35 keV with a source size of about 45×45 μm 2 yielding a photon flux of 1×10 10 ph/s. As this x-ray source bridges the gap between laboratory x-ray sources and large-scale synchrotron facilities, it is well suited to deepen the knowledge about radiobiological effects of MRT in in-vitro studies using cells or tissue models or in-vivo using small animals. |
BibTeX:
@inproceedings{Burger2017,
author = {Burger, Karin and Ilicic, Katarina and Hunger, Annique and Dierolf, Martin and Günther, Benedikt and Schmid, Ernst and Walsh, Dietrich W. M. and Urban, Theresa and Bartzsch, Stefan and Radtke, Amira and Eggl, Elena and Achterhold, Klaus and Gleich, Bernhard and Combs, Stephanie Elisabeth and Molls, Michael M. and Schmid, Thomas Ernst and Pfeiffer, Franz and Wilkens, Jan J.},
title = {Microbeam radiation therapy at a laser-based compact synchrotron x-ray source},
booktitle = {2017 Conference on Lasers and Electro-Optics Europe & European Quantum Electronics Conference (CLEO/Europe-EQEC)},
publisher = {IEEE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
url = {https://ieeexplore.ieee.org/document/8087793},
doi = {https://doi.org/10.1109/CLEOE-EQEC.2017.8087793}
}
|
|
Low LET proton microbeam to understand high-LET RBE by shaping spatial dose distribution C. Greubel, K. Ilicic, T. Rösch, J. Reindl, C. Siebenwirth, M. Moser, S. Girst, D.W. Walsh, T.E. Schmid and G. Dollinger; Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms 404 (Supplement C) (2017) 155 - 161. |
| Abstract: High LET radiation, like heavy ions, are known to have a higher biological effectiveness (RBE) compared to low LET radiation, like X- or γ-rays. Theories and models attribute these higher effectiveness mostly to their extremely inhomogeneous dose deposition, which is concentrated in only a few micron sized spots. At the ion microprobe SNAKE, low LET 20 MeV protons (LET in water of 2.6 keV/μm) can be applied to cells either randomly distributed or focused to submicron spots, approximating heavy ion dose deposition. Thus, the transition between low and high LET energy deposition is experimentally accessible and the effect of different spatial dose distributions can be analysed. Here, we report on the technical setup to cultivate and irradiate 104 cells with submicron spots of low LET protons to measure cell survival in unstained cells. In addition we have taken special care to characterise the beam spot of the 20 MeV proton microbeam with fluorescent nuclear track detectors. |
BibTeX:
@article{Greubel2017,
author = {Christoph Greubel and Katarina Ilicic and Thomas Rösch and Judith Reindl and Christian Siebenwirth and Marcus Moser and Stefanie Girst and Dietrich W.M. Walsh and Thomas E. Schmid and Günther Dollinger},
title = {Low LET proton microbeam to understand high-LET RBE by shaping spatial dose distribution},
journal = {Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
volume = {404},
number = {Supplement C},
pages = {155 - 161},
note = {Proceedings of the 15th International Conference on Nuclear Microprobe Technology and Applications},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X16305109},
doi = {https://doi.org/10.1016/j.nimb.2016.11.032}
}
|
|
Chromatin organization revealed by nanostructure of irradiation induced γH2AX, 53BP1 and Rad51 foci J. Reindl, S. Girst, D.W.M. Walsh, C. Greubel, B. Schwarz, C. Siebenwirth, G.A. Drexler, A.A. Friedl and G. Dollinger; Scientific Reports 7 (2017) 40616. |
| Abstract: The spatial distribution of DSB repair factors γH2AX, 53BP1 and Rad51 in ionizing radiation induced foci (IRIF) in HeLa cells using super resolution STED nanoscopy after low and high linear energy transfer (LET) irradiation was investigated. 53BP1 and γH2AX form IRIF with same mean size of (540 ± 40) nm after high LET irradiation while the size after low LET irradiation is significantly smaller. The IRIF of both repair factors show nanostructures with partial anti-correlation. These structures are related to domains formed within the chromatin territories marked by γH2AX while 53BP1 is mainly situated in the perichromatin region. The nanostructures have a mean size of (129 ± 6) nm and are found to be irrespective of the applied LET and the labelled damage marker. In contrast, Rad51 shows no nanostructure and a mean size of (143 ± 13) nm independent of LET. Although Rad51 is surrounded by 53BP1 it strongly anti-correlates meaning an exclusion of 53BP1 next to DSB when decision for homologous DSB repair happened. |
BibTeX:
@article{Reindl2017,
author = {Reindl, Judith and Girst, Stefanie and Walsh, Dietrich W. M. and Greubel, Christoph and Schwarz, Benjamin and Siebenwirth, Christian and Drexler, Guido A. and Friedl, Anna A. and Dollinger, Günther},
title = {Chromatin organization revealed by nanostructure of irradiation induced γH2AX, 53BP1 and Rad51 foci},
journal = {Scientific Reports},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
volume = {7},
pages = {40616},
url = {http://www.nature.com/articles/srep40616},
doi = {https://doi.org/10.1038/srep40616}
}
|
|
Nanoskopische Analyse von DNA Doppelstrangbrüchen in menschlichen Krebszellen nach Ionenbestrahlung Judith Reindl; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2017. |
| Abstract: Ionisierende Strahlung induziert beim Durchgang durch menschliche Zellen Doppelstrangbrüche mit unterschiedlicher Dichte und Komplexität abhängig vom Linearen Energietransfer (LET) der Teilchen. Diese Arbeit beschreibt die quantitative, höchstauflösende STED (engl.: stimulated emission depletion) Mikroskopie an menschlichen Zellen mit einer lateralen Auflösung von 100 nm. Die Zellen wurden hierzu am Rasterionenmikroskop SNAKE am 14 MV Tandembeschleuniger in Garching oder der alpha-Bestrahlungsquelle an der Universität der Bundeswehr München bestrahlt. Damit konnten strukturelle und funktionale Domänen der Anlagerung von Proteinen, welche für das Auffinden und die Reparatur von Doppelstrangbrüchen verantwortlich sind, detailliert untersucht werden.Weitergehend konnten diese Domänen mit der Chromatinstruktur höherer Ordnung, also der Lage der DNA innerhalb des Zellkerns, verknüpft werden. Hierzu wurde die Korrelation der wichtigen Reparaturproteine 53BP1,γH2AX, Rad51 sowie Brca1 nach hoch- und niedrig-LET Bestrahlungen untersucht. Hierbei zeigen γH2AX und 53BP1, obwohl sie der gleichen Reparaturdomäne, dem sogenannten ''flanking chromatin'' zugeordnet werden nur teilweise Korrelation, welche unabhängig vom linearen Energietransfer der Teilchen ist. 53BP1 und Rad51 schließen sich ebenso LET unabhängig gegenseitig aus, was deren unterschiedliche Rolle während der Reparatur und die Zugehörigkeit zu verschiedenen Domänen widerspiegelt. Als Mediator zwischen den beiden Proteinen und somit Domänen wurde Brca1 identifiziert, welches ähnliche Zeitverläufe, wie Rad51 zeigt, jedoch nur teilweise räumlich mit Rad51 korreliert. Weitergehend wurden bei den Proteinen 53BP1 und γ-H2AX, welche sich nach Kohlenstoffbestrahlung in (540 ± 60) nm großen IRIF (engl.: ionizing radiation induced foci) und nach Protonenbestrahlung in (410 ± 30) nm großen IRIF anlagern, Nanostrukturen innerhalb der IRIF identifiziert. Diese Strukturen haben unabhängig vom LET eine Größe von 120 nm - 140 nm und entsprechen der ebenso LET unabhängigen IRIF Größe von Rad51 von (142 ± 13) nm, welche selbst keine Nanostruktur zeigen. Diese Strukturen in Kombination mit den Korrelationsmessungen lassen sich mit der Chromatinstruktur höherer Ordnung verbinden. So konnte Rad51 als direkte Markierung des Schadensorts identifiziert werden, welche in einer Region von dekondensierter DNA liegt, dem sogenannten Perichromatin. Dies hat eine Breite von 100 nm - 200 nm und wird um den Schaden in einem größeren Bereich durch das Protein 53BP1 stabilisiert. Das phosphorylierte Histon H2AX (γ-H2AX) markiert hingegen direkt die Chromatin Territorien und somit die DNA. Als zweites wesentliches Ergebnis wurde die initiale Anzahl an IRIF des Schadensmarkers DNA-PKcs wenige Minuten nach Bestrahlung mit Hilfe höchstauflösender STED Mikroskopie bestimmt. Die IRIF haben eine mittlere Größe von 190 nm, was die Trennung von DSB ermöglicht, welche nur durch solch kleine Abstände getrennt sind. Für 27 MeV Kohlenstoffbestrahlung (LET = 500 keV/μm) am Rasterionenmikroskop SNAKE in Garching wurden (4,5 ± 0,9) IRIF/μm und für 20 MeV Lithiumbestrahlung (LET = 116 keV/μm) wurden (2,8 ± 0,5) IRIF/μm . Beides verbessert nicht nur bisherige Messungen um einen Faktor 3 sondern übersteigt auch die Anzahl von durch Monte- Carlo basierten Simulationen mit PARTRAC vorhergesagten Schadenszahlen um einen Faktor 2 - 2,5. Diese Messungen stellen damit eine gegenüber bisherigen Messungen essentiell verbesserte Datenbasis dar, um die erhöhte relative biologische Wirksamkeit von hoch-LET Strahlung besser modellieren und damit verstehen zu können. |
BibTeX:
@phdthesis{Reindl2017diss,
author = {Judith Reindl},
title = {Nanoskopische Analyse von DNA Doppelstrangbrüchen in menschlichen Krebszellen nach Ionenbestrahlung},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
url = {https://athene-forschung.rz.unibw-muenchen.de/node?id=120718}
}
|
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Optimization of beam arrangements in proton minibeam radiotherapy by cell survival simulations M. Sammer, C. Greubel, S. Girst and G. Dollinger; Medical Physics 44 (11) (2017) 6096-6104. |
| Abstract: Purpose: Proton minibeam radiotherapy using submillimeter beam dimensions allows to enhance tissue sparing in the entrance channel by spatial fractionation additionally to advantageous proton depth dose distribution. In the entrance channel, spatial fractionation leads to reduced side effects compared to conventional proton therapy. The submillimeter sized beams widen with depth due to small angle scattering and enable therefore, in contrary to x-ray microbeam radiation therapy (MRT), the homogeneous irradiation of a tumor. Proton minibeams can either be applied as planar minibeams or pencil shaped with an additional possibility to vary between a quadratic and a hexagonal arrangement for pencil minibeams. The purpose of this work is to deduce interbeam distances to achieve a homogeneous dose distribution for different tumor depths and tumor thicknesses. Furthermore, we aim for a better understanding of the sparing effect on the basis of surviving cells calculated by the linear-quadratic model. Methods: Two-dimensional dose distributions are calculated for proton minibeams of different shapes and arrangements. For a tumor in 10-15 cm depth, treatment plans are calculated with initial beam size of σ0 = 0.2 mm in a water phantom. Proton minibeam depth dose distributions are finally converted into cell survival using a linear-quadratic model. Results: Inter proton beam distances are maximized under the constraint of dose homogeneity in the tumor for tumor depths ranging from 4 to 15 cm and thickness ranging from 0.5 to 10 cm. Cell survival calculations for a 5 cm thick tumor covered by 10 cm healthy tissue show less cell death by up to 85%, especially in the superficial layers, while keeping the cell death in the tumor as in conventional therapy. In the entrance channel, the pencil minibeams result in higher cell survival in comparison to the planar minibeams while all proton minibeam irradiations show higher cell survival than conventional broadbeam irradiation. Conclusion: The deduced constraints for interbeam distances simplify treatment planning for proton minibeam radiotherapy applications in future studies. The cell survival results indicate that proton minibeam radiotherapy reduces side effects but keeps tumor control as in conventional proton therapy. It makes proton minibeam, especially pencil minibeam radiotherapy a potentially attractive new approach for radiation therapy. |
BibTeX:
@article{Sammer2017,
author = {Sammer, M. and Greubel, C. and Girst, S. and Dollinger, G.},
title = {Optimization of beam arrangements in proton minibeam radiotherapy by cell survival simulations},
journal = {Medical Physics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
volume = {44},
number = {11},
pages = {6096-6104},
note = {cited By 0},
url = {http://onlinelibrary.wiley.com/doi/10.1002/mp.12566/abstract;jsessionid=36AD12B1DEFB0CD51C862B75F5B5EF5D.f02t01},
doi = {https://doi.org/10.1002/mp.12566}
}
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The influence of reference radiation photon energy on high-LET RBE: comparison of human peripheral lymphocytes and human--hamster hybrid AL cells T.E. Schmid, C. Greubel, G. Dollinger and E. Schmid; Radiation and Environmental Biophysics 56 (2017) 79-87. |
| Abstract: The relative biological effectiveness (RBE) based on the induction of dicentrics in any cell type is principally an important information for the increasing application of high-LET radiation in cancer therapy. Since the standard system of human lymphocytes for measuring dicentrics are not compatible with our microbeam irradiation setup where attaching cells are essential, we used human--hamster hybrid AL cells which do attach on foils and fulfil the special experimental requirement for microbeam irradiations. In this work, the dose--response of AL cells to photons of different energy, 70 and 200 kV X-rays and 60Co γ-rays, is characterized and compared to human lymphocytes. The total number of induced dicentrics in AL cells is approximately one order of magnitude smaller. Despite the smaller α and β parameters of the measured linear--quadratic dose--response relationship, the α/β-ratio versus photon energy dependence is identical within the accuracy of measurement for AL cells and human lymphocytes. Thus, the influence of the reference radiation used for RBE determination is the same. For therapy relevant doses of 2 Gy (60Co equivalent), the difference in RBE is around 20% only. These findings indicate that the biological effectiveness in AL cells can give important information for human cells, especially for studies where attaching cells are essential. |
BibTeX:
@article{Schmid2017,
author = {Schmid, T. E. and Greubel, C. and Dollinger, G. and Schmid, E.},
title = {The influence of reference radiation photon energy on high-LET RBE: comparison of human peripheral lymphocytes and human--hamster hybrid AL cells},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
volume = {56},
pages = {79--87},
url = {http://link.springer.com/article/10.1007%2Fs00411-016-0680-3},
doi = {https://doi.org/10.1007/s00411-016-0680-3}
}
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Gezielte Bestrahlung zellulärer und nukleärer Substrukturen am Ionenmikrostrahl SNAKE Christian Siebenwirth; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2017. |
| Abstract: In dieser Arbeit wurde ein Aufbau zur gezielten Bestrahlung von zellulären und nukleären Substrukturen am Rasterionenmikroskop SNAKE entwickelt, erfolgreich installiert und charakterisiert. Diese Entwicklung bildete die methodische Grundlage für die Untersuchung der Sensitivität des Nucleolus im Zellkern auf ionisierende Strahlung. Das präsentierte neue Zielbestrahlungskonzept ermöglicht es, Substrukturen in Zellen mit einer Genauigkeit von besser als (0,4 ± 0,7) μm in X-Richtung und (-0,2 ± 0,8) μm in Y-Richtung mit einzelnen, abgezählten Ionen zu bestrahlen. So wird ein Nucleolus mit 3 μm Durchmesser von einem einzeln applizierten Ion zu mehr als 80% Wahrscheinlichkeit getroffen. Die Bestrahlung von 15-20 Zellen eines Kamerablickfeldes dauert dabei etwa 1 min, wodurch auf einer Probe mehr als 1000 Zellen pro Stunde gezielt bestrahlt werden können. Diese methodische Entwicklung macht die Behandlung neuer Fragestellungen in der Strahlenbiologie möglich und wird schon erfolgreich für Projekte, wie der Untersuchung der Strahlensensitivität von Mitochondrien oder dem Vergleich von UV-Mikrobestrahlungen mit Ionenbestrahlungen angewendet. Als treibende Idee dieser Entwicklung wurde in dieser Arbeit erstmals mit einer gezielten Nucleolusbestrahlung mit 55 MeV Kohlenstoffionen die Hypothese getestet, ob der Zellkern homogen auf Strahlung sensitiv ist. Dazu wurde gezielt der Nucleolus oder der Zellkern mit ausgesparten Nucleoli mit 3 Ionen auf einen Punkt bestrahlt, was auf den Zellkern gemittelt etwa 1,1 Gy entspricht, und ein Zytokineseblock-Mikrokerntest durchgeführt. Es ergaben sich mit (0,34 ± 0,04) nach Nucleolusbestrahlung (NB) und (0,35 ± 0,04) nach „Zellkern ohne Nucleolus“-Bestrahlung (ZB) die gleichen Mikrokernraten pro doppelkerniger Zelle, die aber deutlich erhöht zu den Kontrollpositionen mit (0,073 ± 0,019) und (0,073 ± 0,022) sind. Nach NB wurde eine signifikant höhere Doppelkernrate von (0,60 ± 0,04) pro bestrahlter Zelle beobachtet als nach ZB mit (0,508 ± 0,023). Bei unbestrahlten Zellen lag die Doppelkernrate bei (0,600 ± 0,024). Offensichtlich wird der Zellzyklus nach NB etwas weniger verzögert als nach ZB. Bei beiden Endpunkten ist der Unterschied jedoch deutlich geringer als man anhand des DNADichteunterschieds annehmen würde (DNA-Dichte im Nucleolus ≈ 5% DNA-Dichte im Zellkern). Damit wirken sich im Nucleolus erzeugte DNA-Schäden scheinbar schwerer aus als im restlichen Zellkern. Zusätzlich wurde überprüft, ob eine gezielte Bestrahlung des Nucleolus mit 1, 10, 50 und 100 Kohlenstoffionen eine Stressantwort der Nucleoli in der Zelle hervorruft. Eine auftretende nucleoläre Segregation mittels Färbung des UBF-Proteins, wie nach UV-Bestrahlung beobachtet wird, wurde weder in allen Nucleoli eines Zellkerns noch an dem bestrahlten Nucleolus in Folge der Ionenbestrahlung beobachtet. Jedoch ergab die Analyse der Transkription, dass an der Stelle eines Nucleolustreffer zu mehr als (90 ± 20)% das Signal des 5EU-Einbaus in die rRNA des Nucleolus verringert ist. Während-auch keine generelle Umverteilung des Parp1-Proteins über den kompletten bestrahlten Nucleolus beobachtet wurde, kam es jedoch zu (57 ± 15)% lokal an der Stelle-des reduzierten 5EU-Signals zu einer lokalen Verringerung des Parp1-Signals. Dies lässt auf eine von der Ionenzahl unabhängige lokale Hemmung der rRNA-Transkription -im Nucleolus schließen. Abstract: In this thesis, a setup for targeted irradiation of cellular and nuclear substructures at the ion microbeam SNAKE was developed, successfully installed and characterized. This development builds the methodical basis for investigations into the sensitivity of the nucleolus, which is in the nucleus, to ionizing radiation. The presented new targeted irradiation concept enables the irradiation of substructures in the nucleus with an accuracy of less than (0.4 ± 0.7) μm in X-direction and (-0.2 ± 0.8) μm in Y-direction with single counted ions. Thus a nucleolus of 3 μm diameter is hit by a single applied ion with a probability of more than 80%. Irradiation of 15-20 cells in one field of view of the microscope camera takes about 1 min, whereby in one sample more than 1000 cells per hour can be irradiated. This methodical development enables the investigation of new questions in radiobiologyand is successfully used in projects like the investigation of the radiation sensitivity of mitochondria or the comparison of UV microirradiations with ion irradiations. For the first time, as the main motivation for this development, in this Additionally, it was tested, if targeted irradiation of the nucleolus with 1, 10, 50 and100 carbon ions induces a stress response in the nucleoli. An occurring nucleolar segregationusing a staining of the protein UBF, as observed after UV irradiation, couldnot be observed in all nucleoli of the nucleus nor in the irradiated nucleolus using ions. However, analysis of the transcription showed, that at the spot of a nucleolus hit with more than (90 ± 20)% probability the signal of the incorporation of 5EU in the rRNA of the nucleolus is decreased. While no general reorganization of Parp1 in the complete irradiated nucleolus was observed, (57 ± 15)% of the spots with reduced 5EU signal showed a local reduction of the Parp1 signal. Thus, independent of the ion number the rRNA transcription in the nucleolus was locally inhibited. |
BibTeX:
@phdthesis{Siebenwirth2017diss,
author = {Christian Siebenwirth},
title = {Gezielte Bestrahlung zellulärer und nukleärer Substrukturen am Ionenmikrostrahl SNAKE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
url = {http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:706-5214}
}
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Live cell imaging of mitochondria following targeted irradiation in situ reveals rapid and highly localized loss of membrane potential D.W.M. Walsh, C. Siebenwirth, C. Greubel, K. Ilicic, J. Reindl, S. Girst, G. Muggiolu, M. Simon, P. Barberet, H. Seznec, H. Zischka, G. Multhoff, T.E. Schmid and G. Dollinger; Scientific Reports 7 (2017) 46684. |
| Abstract: The reliance of all cell types on the mitochondrial function for survival makes mitochondria an interesting target when trying to understand their role in the cellular response to ionizing radiation. By harnessing highly focused carbon ions and protons using microbeams, we have performed in situ live cell imaging of the targeted irradiation of individual mitochondria stained with Tetramethyl rhodamine ethyl ester (TMRE), a cationic fluorophore which accumulates electrophoretically in polarized mitochondria. Targeted irradiation with both carbon ions and protons down to beam spots of <1 μm induced a near instant loss of mitochondrial TMRE fluorescence signal in the targeted area. The loss of TMRE after targeted irradiation represents a radiation induced change in mitochondrial membrane potential. This is the first time such mitochondrial responses have been documented in situ after targeted microbeam irradiation. The methods developed and the results obtained have the ability to shed new light on not just mitochondria’s response to radiation but to further elucidate a putative mechanism of radiation induced depolarization and mitochondrial response. |
BibTeX:
@article{Walsh2017,
author = {Walsh, Dietrich W. M. and Siebenwirth, Christian and Greubel, Christoph and Ilicic, Katarina and Reindl, Judith and Girst, Stefanie and Muggiolu, Giovanna and Simon, Marina and Barberet, Philippe and Seznec, Hervé and Zischka, Hans and Multhoff, Gabriele and Schmid, Thomas E. and Dollinger, Guenther},
title = {Live cell imaging of mitochondria following targeted irradiation in situ reveals rapid and highly localized loss of membrane potential},
journal = {Scientific Reports},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2017},
volume = {7},
pages = {46684},
url = {https://www.nature.com/articles/srep46684},
doi = {https://doi.org/10.1038/srep46684}
}
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2016 |
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A New Nanobody-Based Biosensor to Study Endogenous PARP1 In Vitro and in Live Human Cells A. Buchfellner, L. Yurlova, S. Nüske, A.M. Scholz, J. Bogner, B. Ruf, K. Zolghadr, S.E. Drexler, G.A. Drexler, S. Girst, C. Greubel, J. Reindl, C. Siebenwirth, T. Romer, A.A. Friedl and U. Rothbauer; PLOS ONE 11 (3) (2016) 1-23. |
| Abstract: Poly(ADP-ribose) polymerase 1 (PARP1) is a key player in DNA repair, genomic stability and cell survival and it emerges as a highly relevant target for cancer therapies. To deepen our understanding of PARP biology and mechanisms of action of PARP1-targeting anti-cancer compounds, we generated a novel PARP1-affinity reagent, active both in vitro and in live cells. This PARP1-biosensor is based on a PARP1-specific single-domain antibody fragment ( 15 kDa), termed nanobody, which recognizes the N-terminus of human PARP1 with nanomolar affinity. In proteomic approaches, immobilized PARP1 nanobody facilitates quantitative immunoprecipitation of functional, endogenous PARP1 from cellular lysates. For cellular studies, we engineered an intracellularly functional PARP1 chromobody by combining the nanobody coding sequence with a fluorescent protein sequence. By following the chromobody signal, we were for the first time able to monitor the recruitment of endogenous PARP1 to DNA damage sites in live cells. Moreover, tracing of the sub-nuclear translocation of the chromobody signal upon treatment of human cells with chemical substances enables real-time profiling of active compounds in high content imaging. Due to its ability to perform as a biosensor at the endogenous level of the PARP1 enzyme, the novel PARP1 nanobody is a unique and versatile tool for basic and applied studies of PARP1 biology and DNA repair. |
BibTeX:
@article{Buchfellner2016,
author = {Buchfellner, Andrea AND Yurlova, Larisa AND Nüske, Stefan AND Scholz, Armin M. AND Bogner, Jacqueline AND Ruf, Benjamin AND Zolghadr, Kourosh AND Drexler, Sophie E. AND Drexler, Guido A. AND Girst, Stefanie AND Greubel, Christoph AND Reindl, Judith AND Siebenwirth, Christian AND Romer, Tina AND Friedl, Anna A. AND Rothbauer, Ulrich},
title = {A New Nanobody-Based Biosensor to Study Endogenous PARP1 In Vitro and in Live Human Cells},
journal = {PLOS ONE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016},
volume = {11},
number = {3},
pages = {1-23},
url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151041},
doi = {https://doi.org/10.1371/journal.pone.0151041}
}
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Proton Minibeam Radiation Therapy Reduces Side Effects in an In Vivo Mouse Ear Model S. Girst, C. Greubel, J. Reindl, C. Siebenwirth, O. Zlobinskaya, D. Walsh, K. Ilicic, M. Aichler, A. Walch, J. Wilkens, G. Multhoff, G. Dollinger and T. Schmid; International Journal of Radiation Oncology * Biology * Physics 95 (2016) 234-241. |
| Abstract: Purpose: Proton minibeam radiation therapy is a novel approach to minimize normal tissue damage in the entrance channel by spatial fractionation while keeping tumor control through a homogeneous tumor dose using beam widening with an increasing track length. In the present study, the dose distributions for homogeneous broad beam and minibeam irradiation sessions were simulated. Also, in an animal study, acute normal tissue side effects of proton minibeam irradiation were compared with homogeneous irradiation in a tumor-free mouse ear model to account for the complex effects on the immune system and vasculature in an in vivo normal tissue model. Methods and Materials: At the ion microprobe SNAKE, 20-MeV protons were administered to the central part (7.2 × 7.2 mm2) of the ear of BALB/c mice, using either a homogeneous field with a dose of 60 Gy or 16 minibeams with a nominal 6000 Gy (4 × 4 minibeams, size 0.18 × 0.18 mm2, with a distance of 1.8 mm). The same average dose was used over the irradiated area. Results: No ear swelling or other skin reactions were observed at any point after minibeam irradiation. In contrast, significant ear swelling (up to fourfold), erythema, and desquamation developed in homogeneously irradiated ears 3 to 4 weeks after irradiation. Hair loss and the disappearance of sebaceous glands were only detected in the homogeneously irradiated fields. Conclusions: These results show that proton minibeam radiation therapy results in reduced adverse effects compared with conventional homogeneous broad-beam irradiation and, therefore, might have the potential to decrease the incidence of side effects resulting from clinical proton and/or heavy ion therapy. |
BibTeX:
@article{Girst2016,
author = {Girst, S. and Greubel, C. and Reindl, J. and Siebenwirth, C. and Zlobinskaya, O. and Walsh, D.W.M. and Ilicic, K. and Aichler, M. and Walch, A. and Wilkens, J.J. and Multhoff, G. and Dollinger, G. and Schmid, T.E.},
title = {Proton Minibeam Radiation Therapy Reduces Side Effects in an In Vivo Mouse Ear Model},
journal = {International Journal of Radiation Oncology * Biology * Physics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016},
volume = {95},
pages = {234--241},
url = {http://www.sciencedirect.com/science/article/pii/S0360301615265856},
doi = {https://doi.org/10.1016/j.ijrobp.2015.10.020}
}
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Proton Minibeam Radiotherapy Stefanie Girst; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2016. |
| Abstract: The risk of developing adverse side effects in the normal tissue after radiotherapy is often limiting for the dose that can be applied to the tumor. Proton minibeam radiotherapy, a spatially fractionated radiotherapy method using sub-millimeter proton beams, similar to grid therapy or microbeam radiation radiotherapy (MRT) using X-rays, has recently been invented at the ion microprobe SNAKE in Munich. The aim of this new concept is to minimize normal tissue injuries in the entrance channel and especially in the skin by irradiating only a small percentage of the cells in the total irradiation field, while maintaining tumor control via a homogeneous dose in the tumor, just like in conventional broad beam radiotherapy. This can be achieved by optimizing minibeam sizes and distances according to the prevailing tumor size and depth such that after widening of the minibeams due to proton interactions in the tissue, the overlapping minibeams produce a homogeneous dose distribution throughout the tumor. The aim of this work was to elucidate the prospects of minibeam radiation therapy compared to conventional homogeneous broad beam radiotherapy in theory and in experimental studies at the ion microprobe SNAKE. Treatment plans for model tumors of different sizes and depths were created using the planning software LAP-CERR, to elaborate suitable minibeam sizes and distances for the individual tumors. Radiotherapy-relevant inter-beam distances required to obtain a homogeneous dose in the target volume were found to be in the millimeter range. First experiments using proton minibeams of only 10 μm and 50 μm size (termed microchannels in the corresponding publication Zlobinskaya et al. 2013) and therapy-conform larger dimensions of 100 μm and 180 μm were performed in the artificial human in-vitro skin model EpiDermFTTM (MatTek). The corresponding inter-beam distances were 500 μm, 1 mm and 1.8 mm, respectively, leading to irradiation of only a few percent of the cells in the skin tissue, but with significantly increased doses (up to 5000 Gy) compared to the average dose of 2 Gy, which was applied homogeneously in further skin samples for comparison. Gaussian-shaped minibeams of even larger sizes (σ = 260 μm and 520 μm, inter-beam distance 1.8 mm) were analyzed in further experiments to evaluate the effect of increasing beam sizes as in deeper-lying tissues. Acute side effects were quantified via the MTT tissue viability test and the release of inflammatory proteins into the culture medium and showed improved results for minibeam compared to homogeneous irradiation. Genetic damage, an indicator for secondary tumor induction, was analyzed via the micronucleus test in the epidermal keratinocytes and was less than half for minibeams up to 180 μm size compared to homogeneous fields. Increasing minibeam sizes, i.e. increasing fractions of irradiated skin receiving a dose higher than the average dose of 2 Gy) increased the number of micronuclei per divided cell, but never exceeded the genetic damage induced by a homogeneous dose distribution. A more authentic and representative in-vivo skin model, accounting for higher complexity with blood vessels, further cell types, follicles glands and especially a working immune system, was used in the next step to further examine the side effects of minibeam radiotherapy compared to homogeneous irradiation. The central part of the ear of adult BALB/c mice was irradiated with 20 MeV protons, using an average dose of 60 Gy in a field of 7.2×7.2 mm2. The 4×4 minibeams of nominal 6000 Gy had a size of 180×180 μm2 and inter-beam distances of 1.8 mm, as in previous in-vitro skin experiments. Minibeam irradiation induced no ear swelling or other visible skin reaction at any time, while significant ear swelling (up to 4-fold), skin reddening (erythema) and desquamation developed in homogeneously irradiated ears 3-4 weeks after irradiation. Loss of hair and sebaceous glands only occurred in the homogeneous irradiation fields and did not recover during the monitoring phase of 90 days. Taken together all theoretical considerations and experimental findings, proton minibeam radiation therapy appears suitable for the implementation in clinical tumor therapy using protons and/or heavy ions, as it reduces side effects in the normal tissue compared to conventional broad beam irradiation. However, the upper limit of the minibeam size for tissue sparing and the technical feasibility are still to be elucidated as current technologies might have to be improved and adapted for the generation of sub-millimeter proton beams of energies up to 250 MeV at therapy plants. |
BibTeX:
@phdthesis{Girst2016diss,
author = {Stefanie Girst},
title = {Proton Minibeam Radiotherapy},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016},
url = {http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:706-4569}
}
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Double-Strand Break Distributions along high-LET Particle Tracks in Human HeLa Cells Josef Huber; Masters-Thesis, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2016. |
| Abstract: Ionizing radiation finds widespread application in cancer treatment because it induces DNA double-strand breaks (DSB), which are causal to the killing of tumor cells and are ultimately required for a patient’s recovery. Based on its clinical relevance, it is of great importance to study the influence of radiation quality on the number of induced DSB. In previous experiments, the number of observed damage sites in the cell for low-LET X-rays matched well with the number of DSB predicted by simulations. However, for high-LET ionizing radiation, a saturation in the number of damage sites was observed that is less than the predicted number of DSB. The cause of this saturation is attributed to the method of visualizing DSB. It is performed by imaging the distribution of proteins like 53BP1 and γH2AX, which are involved in DSB-signalling and form 1 μm-sized ionizing radiation induced foci (IRIF) at these sites. Due to a decreased spacing between consecutive DSB with increasing LET, single DSB can no longer be resolved within the IRIF. The proteins KU70/80 and DNA-PKcs might be a promising alternative to these conventional damage markers, since one copy each binds to the end of double-stranded DNA immediately after damage induction. Thus, for these proteins significantly smaller IRIF are expected, which might allow the visual- ization of single DSB. The aim of this work was to count every DSB that is induced by high-LET ionizing radiation in human HeLa cells. For this, the IRIF-formation of DNA-PKcs and KU70/80 was tested and examined. Induction of DSB was achieved by irradiation with α-particles and small angle irradiation at the ion microprobe SNAKE with lithium and carbon ions. Visualization of the target proteins’ distribution in the cell was accom- plished through the method of indirect secondary immunofluorescence staining and imaging was performed with the help of a super-resolution STED-microscope. In the experiments, no IRIF-formation was detected for primary antibodies specifically targeting KU80 and DNA-PKcs after α-irradiation. The abundant presence of 400000 proteins of each type masked the signal of single proteins bound to double-stranded DNA, indicating that the proteins are not suitable for the counting of single DSB in their indistinguishable collective natural state. DNA-PKcs bound to DSB reportedly undergo phosphorylation at Thr2609, which leads to the dissociation from the DSB. Although this way the expected strong localisation at sites of DSB is lost, it allows for the discrimination of DNA-PKcs proteins that are not involved in damage response. Based on these findings in the relevant literature, the experiments were carried out and IRIF-formation for a primary antibody specific to phosphorylated DNA-PKcs was tested positive after α-particle irradiation. Furthermore, particle tracks were visible after lithium and carbon ion irradiation for samples fixed 2, 3 and 5 minutes post- irradiation. Evaluation of 30 particle tracks for each time point yielded an average number of 2.5±0.4 IRIF per micron after 2 minutes, which increased to 3.2±0.6 IRIF per micron 5 minutes after irradiation for lithium ions with LET=116±10 keV/μm. For carbon ions with LET=500±80 keV/μm , the number of observed IRIF increased from 4.1±0.6 per micron to 4.5±0.7 per micron from 2 to 5 minutes after irradiation. The increase for both ion types can be attributed to a delayed accumulation of protein to a fraction of DSB, which become accessible by changes in the conformation of hete- rochromatin at later times. PARTRAC simulations predict 2.7±0.4 DSB per micron for lithium and 10.2±2.2 DSB per micron for carbon ions. The number of observed IRIF for lithium ions exceeded the number from linear scaling of low-LET X-rays and matched well with the predicted number from PARTRAC. However, the observed number of IRIF for carbon ions was only half the number of the predicted DSB by PARTRAC. Thus, it is concluded that the goal of counting single DSB for high-LET irradiation can only be partly fulfilled: up to LET=116±10 keV/μm , the average spacing between DSB can be resolved by the IRIF-size with diameters from 188±36 nm to 205±49 nm. However, at LET=500±80 keV/μm , the decreased average spacing between consecutive DSB can no longer be resolved and is exceeded by the minimal observed IRIF-diameter of 178±40 nm. PARTRAC takes into account that DSB in close vicinity may not be resolvable and provides a reduced number of observable IRIF, which is derived by assigning all DSB within 150 nm to one observable cluster. This results in a predicted number of 3.3±0.3 observable IRIF per micron for carbon ions, which is matched and partly exceeded by the actual observed number of IRIF per micron. This indicates that the experimental results of this thesis are compatible with PARTRAC simulations. |
BibTeX:
@mastersthesis{Huber2016ma,
author = {Huber, Josef},
title = {Double-Strand Break Distributions along high-LET Particle Tracks in Human HeLa Cells},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016}
}
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Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair C. Penterling, G.A. Drexler, C. Böhland, R. Stamp, C. Wilke, H. Braselmann, R.B. Caldwell, J. Reindl, S. Girst, C. Greubel, C. Siebenwirth, W.Y. Mansour, K. Borgmann, G. Dollinger, K. Unger and A.A. Friedl; PLoS ONE 11 (6) (2016) e0156599. |
| Abstract: Histone demethylases have recently gained interest as potential targets in cancer treatment and several histone demethylases have been implicated in the DNA damage response. We investigated the effects of siRNA-mediated depletion of histone demethylase Jarid1A (KDM5A, RBP2), which demethylates transcription activating tri- and dimethylated lysine 4 at histone H3 (H3K4me3/me2), on growth characteristics and cellular response to radiation in several cancer cell lines. In unirradiated cells Jarid1A depletion lead to histone hyperacetylation while not affecting cell growth. In irradiated cells, depletion of Jarid1A significantly increased cellular radiosensitivity. Unexpectedly, the hyperacetylation phenotype did not lead to disturbed accumulation of DNA damage response and repair factors 53BP1, BRCA1, or Rad51 at damage sites, nor did it influence resolution of radiation-induced foci or rejoining of reporter constructs. We conclude that the radiation sensitivity observed following depletion of Jarid1A is not caused by a deficiency in repair of DNA double-strand breaks. |
BibTeX:
@article{Penterling2016,
author = {Penterling, Corina and Drexler, Guido A. and Böhland, Claudia and Stamp, Ramona and Wilke, Christina and Braselmann, Herbert and Caldwell, Randolph B. and Reindl, Judith and Girst, Stefanie and Greubel, Christoph and Siebenwirth, Christian and Mansour, Wael Y. and Borgmann, Kerstin and Dollinger, Günther and Unger, Kristian and Friedl, Anna A.},
title = {Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair},
journal = {PLoS ONE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016},
volume = {11},
number = {6},
pages = {e0156599},
url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156599},
doi = {https://doi.org/10.1371/journal.pone.0156599}
}
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Superresolution light microscopy shows nanostructure of carbon ion radiation-induced DNA double-strand break repair foci R.L. Perez, G. Best, N.H. Nicolay, C. Greubel, S. Rossberger, J. Reindl, G. Dollinger, K.-J. Weber, C. Cremer and P.E. Huber; Faseb 30 (2016) 2767-2776. |
| Abstract: Carbon ion radiation is a promising new form of radiotherapy for cancer, but the central question about the biologic effects of charged particle radiation is yet incompletely understood. Key to this question is the understanding of the interaction of ions with DNA in the cell’s nucleus. Induction and repair of DNA lesions including double-strand breaks (DSBs) are decisive for the cell. Several DSB repair markers have been used to investigate these processes microscopically, but the limited resolution of conventional microscopy is insufficient to provide structural insights. We have applied superresolution microscopy to overcome these limitations and analyze the fine structure of DSB repair foci. We found that the conventionally detected foci of the widely used DSB marker γH2AX (Ø700-1000 nm) were composed of elongated subfoci with a size of 100 nm consisting of even smaller subfoci elements (Ø40-60 nm). The structural organization of the subfoci suggests that they could represent the local chromatin structure of elementary DSB repair units at the DSB damage sites. Subfoci clusters may indicate induction of densely spaced DSBs, which are thought to be associated with the high biologic effectiveness of carbon ions. Superresolution microscopy might emerge as a powerful tool to improve our knowledge of interactions of ionizing radiation with cells. |
BibTeX:
@article{Perez2016,
author = {Ramon Lopez Perez and Gerrit Best and Nils H. Nicolay and Christoph Greubel and Sabrina Rossberger and Judith Reindl and Günther Dollinger and Klaus-Josef Weber and Christoph Cremer and Peter E. Huber},
title = {Superresolution light microscopy shows nanostructure of carbon ion radiation-induced DNA double-strand break repair foci},
journal = {Faseb},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016},
volume = {30},
pages = {2767-2776},
url = {http://www.fasebj.org/content/30/8/2767},
doi = {https://doi.org/10.1096/fj.201500106R}
}
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Geometrical Constraints for Proton Minibeam Radiotherapy Matthias Sammer; Masters-Thesis, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2016. |
| Abstract: A novel approach to reduce (often limiting) side effects in radiotherapy is the proton minibeam radiotherapy. The application of sub-millimeter proton beams spares a large number of cells within the irradiation fi especially in the entrance channel, result- ing in a lower response effect. Moreover, due to Multiple Coulomb scatter, the proton minibeams spread with depth and by adjusting the inter beam distances, a homogeneous dose distribution in the tumor can be achieved. Thus, proton minibeam radiotherapy reduces side effects due to spatial fractionation while a homogeneous dose distribution in the tumor delivers a well-known tumor control. The aim of this work was to carry out detailed investigations of geometrical constraints in proton minibeam radiotherapy in simulations and in experiments. The simulations of proton minibeam scenarios were analyzed for different beam arrangements. Pencil minibeams were arranged on a quadratic and a hexagonal lattice. Planar line minibeams were arranged on a simple grid. First, a homogeneity constraint was elaborated for the different scenarios. Adjusting the scenarios so that all arrangements are homogeneous for the same beam size, the pure dose distributions were analyzed and delivered the fi hint that the best tissue sparing appears for the hexagonally arranged pencil minibeams. Moreover, a comparison was established by the calculation of idealized but realistic dimen- sioned treatment plans for the different minibeam arrangements (hexagonal, quadratic and line with initial minibeam size of 200 µm and a second line minibeam of 75 µm width) as well as for a conventional broadbeam scenario in a water phantom. The dose simulations were used to calculate a mean cell survival over depth, using the linear-quadratic model, for a 2 Gy and 10 Gy tumor dose. This allows the direct comparison of dose distributions on a modeled cellular level. The cell survival shows a tremendous effect, especially in the entrance channels (σ0 = 200 µm), with up to 91 % (87 %) cell survival for hexagonally arranged pencil beams, 90 % (86 %) for quadratic arranged pencil beams, 77 % (68 %) for the line beam arrangement with σ0 = 200 µm and 58 % (2 %) for the broadbeam irradi- ation with a tumor dose of 2 Gy (10 Gy). The pencil minibeams result in the best cell survival curves with small benefit for the hexagonal arrangement. In the second part of the work, an experimental approach of geometrical constraints on single channels is investigated. Within an in-vivo mouse skin model the irradiation of mice ears with only one single channel of diff t sizes was investigated. 70 kV x-rays were applied on the ear with an average beam dose of 60 Gy for 7 different beam sizes (0.5, 1, 2, 3, 4, 5, 6 mm). No ear swelling was measured for irradiated ears with beamsizes ≤ 2 mm and no ear reddening was observed for beamsizes ≤ 1 mm over the monitoring time of 25 days after irradiation. Histological sections were made on day 25, which is the time-point for the expected maximum reaction, and did not deliver any hints on radiation damage for beamsizes ≤ 1 mm. |
BibTeX:
@mastersthesis{Sammer2016ma,
author = {Sammer, Matthias},
title = {Geometrical Constraints for Proton Minibeam Radiotherapy},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2016}
}
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Feinstruktur von BRCA1- und Rad51-Foci nach α-Bestrahlung Benjamin Schwarz; Masters-Thesis, Ludwig-Maximilians-Universität München, 2016. |
| Abstract: DNA-Doppelstrangbrüche (DSB) sind kritische Schäden für das Überleben einer Zelle, wobei eine Vielzahl von extra- und intrazellulärer Faktoren zu einem DSB führen können. Aus diesem Grund hat die Natur besonders spezialisierte und dadurch gleichfalls komplexe Methoden zur DSB-Reparatur entwickelt. Einer dieser Prozesse ist die Homologe Rekombination (HR), bei welcher durch ein komplexes Zusammenspiel verschiedenster Proteine, akkumuliert in so genannten Foci, unter Verwendung des homologen Schwesterchromatids, die losen DNA-Enden wieder zusammengefügt werden. Wichtige Schlüsselfunktionen übernehmen dabei die Proteine Rad51 und BRCA1, wobei ihr gesamtes Aufgabenspektrum noch nicht bekannt ist. Die geringe Größe solcher Foci von wenigen 100 nm macht eine Abbildung ihrer inneren Strukturen für herkömmliche Lichtmikroskopie aufgrund der beugungsbegrenzten Auflösung von 250 nm unmöglich. In dieser Arbeit wurden immunhistochemische Methoden in Kombination mit STED Mikroskopie (STimulated Emission Depletion) verwendet, um die Feinstruktur der Reparaturfoci α-strahlungsinduzierter DSB an Hand von BRCA1 und Rad51 unterhalb der Beugungsgrenze abzubilden und über die Zeit von 24h zu charakterisieren. Dabei deuten die Ergebnisse der Korrelationsanalyse auf drei Phasen gemeinsamer Aktion am Doppelstrangbruch hin, welche in Early Stage, Processing Stage und Late Stage aufgeteilt werden können. Des Weiteren weisen Intensitätsplots quer durch einzelne Foci gemessen, auf eine lokale Exklusion der beiden Proteine im Zentrum des DSB hin und stärken Hypothesen, welche keinen direkten Protein-Protein-Kontakt beschreiben. DNA Double-Strand Breaks (DSB) are critical damages for a living cell. A variety of extra- and intracellular factors are able to induce DSB. Therefore, nature developed several specific and complex DSB-Repair mechanisms. One of them is homologous recombination (HR). It depends on a complex interaction between different proteins, accumulating in so called foci. These proteins use the homologous sister chromatid as a template to rejoin the loose DNA ends. The proteins BRCA1 and Rad51 have a key function in HR, but their specific responsibilities are not completely understood yet. The small size of the foci (few 100 nm) rules out a resolution via light microscopy because of the diffraction barrier of 250 nm. During this thesis, immunohistochemistry and STED microscopy (STimulated Emission Depletion) was used to image foci of BRCA1 and Rad51 during the repair of α-radiation induced DSB with a resolution below the diffraction limit. The resulting data of the correlation analysis of BRCA1 and Rad51 imply a subdivision of BRCA1 and Rad51 interaction in 3 phases during HR (early stage, processing stage, late stage). Intensity plots of the localization of BRCA1 and Rad51 show local exclusion within the foci and therefore support predictions of non-existing direct protein interaction. |
BibTeX:
@mastersthesis{Schwarz2016ma,
author = {Schwarz, Benjamin},
title = {Feinstruktur von BRCA1- und Rad51-Foci nach α-Bestrahlung},
school = {Ludwig-Maximilians-Universität München},
year = {2016}
}
|
2015 |
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Live cell imaging at the Munich ion microbeam SNAKE - a status report G.A. Drexler, C. Siebenwirth, S.E. Drexler, S. Girst, C. Greubel, G. Dollinger and A.A. Friedl; Radiation Oncology 10 (2015) 42. |
| Abstract: Ion microbeams are important tools in radiobiological research. Still, the worldwide number of ion microbeam facilities where biological experiments can be performed is limited. Even fewer facilities combine ion microirradiation with live-cell imaging to allow microscopic observation of cellular response reactions starting very fast after irradiation and continuing for many hours. At SNAKE, the ion microbeam facility at the Munich 14 MV tandem accelerator, a large variety of biological experiments are performed on a regular basis. Here, recent developments and ongoing research projects at the ion microbeam SNAKE are presented with specific emphasis on live-cell imaging experiments. An overview of the technical details of the setup is given, including examples of suitable biological samples. By ion beam focusing to submicrometer beam spot size and single ion detection it is possible to target subcellular structures with defined numbers of ions. Focusing of high numbers of ions to single spots allows studying the influence of high local damage density on recruitment of damage response proteins. |
BibTeX:
@article{Drexler2015,
author = {Drexler, Guido A. and Siebenwirth, Christian and Drexler, Sophie E. and Girst, Stefanie and Greubel, Christoph and Dollinger, Günther and Friedl, Anna A.},
title = {Live cell imaging at the Munich ion microbeam SNAKE - a status report},
journal = {Radiation Oncology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {10},
pages = {42},
url = {http://ro-journal.biomedcentral.com/articles/10.1186/s13014-015-0350-7},
doi = {https://doi.org/10.1186/s13014-015-0350-7}
}
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Improved normal tissue protection by proton and X-ray microchannels compared to homogeneous field irradiation S. Girst, C. Marx, E. Bräuer-Krisch, A. Bravin, S. Bartzsch, U. Oelfke, C. Greubel, J. Reindl, C. Siebenwirth, O. Zlobinskaya, G. Multhoff, G. Dollinger, T. Schmid and J. Wilkens; Physica Medica 31 (0) (2015) 615-620. |
| Abstract: The risk of developing normal tissue injuries often limits the radiation dose that can be applied to the tumour in radiation therapy. Microbeam Radiation Therapy (MRT), a spatially fractionated photon radiotherapy is currently tested at the European Synchrotron Radiation Facility (ESRF) to improve normal tissue protection. MRT utilizes an array of microscopically thin and nearly parallel X-ray beams that are generated by a synchrotron. At the ion microprobe SNAKE in Munich focused proton microbeams (“proton microchannels”) are studied to improve normal tissue protection. Here, we comparatively investigate microbeam/microchannel irradiations with sub-millimetre X-ray versus proton beams to minimize the risk of normal tissue damage in a human skin model, in vitro. Skin tissues were irradiated with a mean dose of 2 Gy over the irradiated area either with parallel synchrotron-generated X-ray beams at the ESRF or with 20 MeV protons at SNAKE using four different irradiation modes: homogeneous field, parallel lines and microchannel applications using two different channel sizes. Normal tissue viability as determined in an MTT test was significantly higher after proton or X-ray microchannel irradiation compared to a homogeneous field irradiation. In line with these findings genetic damage, as determined by the measurement of micronuclei in keratinocytes, was significantly reduced after proton or X-ray microchannel compared to a homogeneous field irradiation. Our data show that skin irradiation using either X-ray or proton microchannels maintain a higher cell viability and DNA integrity compared to a homogeneous irradiation, and thus might improve normal tissue protection after radiation therapy. |
BibTeX:
@article{Girst2015,
author = {Girst, S. and Marx, C. and Bräuer-Krisch, E. and Bravin, A. and Bartzsch, S. and Oelfke, U. and Greubel, C. and Reindl, J. and Siebenwirth, C. and Zlobinskaya, O. and Multhoff, G. and Dollinger, G. and Schmid, T.E. and Wilkens, J.J.},
title = {Improved normal tissue protection by proton and X-ray microchannels compared to homogeneous field irradiation},
journal = {Physica Medica},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {31},
number = {0},
pages = {615--620},
url = {http://www.sciencedirect.com/science/article/pii/S1120179715000952},
doi = {https://doi.org/10.1016/j.ejmp.2015.04.004}
}
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The influence of the channel size on the reduction of side effects in microchannel proton therapy S. Girst, C. Greubel, J. Reindl, C. Siebenwirth, O. Zlobinskaya, G. Dollinger and T.E. Schmid; Radiation and Environmental Biophysics 54 (3) (2015) 335-342. |
| Abstract: The potential of proton microchannel radiotherapy to reduce radiation effects in the healthy tissue but to keep tumor control the same as in conventional proton therapy is further elucidated. The microchannels spread on their way to the tumor tissue resulting in different fractions of the healthy tissue covered with doses larger than the tumor dose, while the tumor gets homogeneously irradiated. The aim of this study was to evaluate the effect of increasing channel width on potential side effects in the normal tissue. A rectangular 180 × 180 µm2 and two Gaussian-type dose distributions of σ = 260 µm and σ = 520 µm with an interchannel distance of 1.8 mm have been applied by 20-MeV protons to a 3D human skin model in order to simulate the widened channels and to compare the irradiation effects at different endpoints to those of a homogeneous proton irradiation. The number of protons applied was kept constant at all irradiation modes resulting in the same average dose of 2 Gy. All kinds of proton microchannel irradiation lead to higher cell viability and produce significantly less genetic damage than homogeneous proton irradiation, but the reduction is lower for the wider channel sizes. Our findings point toward the application of microchannel irradiation for clinical proton or heavy ion therapy to further reduce damage of normal tissues while maintaining tumor control via a homogeneous dose distribution inside the tumor. |
BibTeX:
@article{Girst2015a,
author = {Girst, Stefanie and Greubel, Christoph and Reindl, Judith and Siebenwirth, Christian and Zlobinskaya, Olga and Dollinger, Günther and Schmid, Thomas E.},
title = {The influence of the channel size on the reduction of side effects in microchannel proton therapy},
booktitle = {Radiation and Environmental Biophysics},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {54},
number = {3},
pages = {335--342},
url = {http://link.springer.com/article/10.1007%2Fs00411-015-0600-y},
doi = {https://doi.org/10.1007/s00411-015-0600-y}
}
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Nanoscopic exclusion between Rad51 and 53BP1 after ion irradiation in human HeLa cells J. Reindl, G.A. Drexler, S. Girst, C. Greubel, C. Siebenwirth, S.E. Drexler, G. Dollinger and A.A. Friedl; Physical Biology 12 (6) (2015) 066005. |
| Abstract: Many proteins involved in detection, signalling and repair of DNA double-strand breaks (DSB) accumulate in large number in the vicinity of DSB sites, forming so called foci. Emerging evidence suggests that these foci are sub-divided in structural or functional domains. We use stimulated emission depletion (STED) microscopy to investigate localization of mediator protein 53BP1 and recombination factor Rad51 after irradiation of cells with low linear energy transfer (LET) protons or high LET carbon ions. With a resolution better than 100 nm, STED microscopy and image analysis using a newly developed analyzing algorithm, the reduced product of the differences from the mean, allowed us to demonstrate that with both irradiation types Rad51 occupies spherical regions of about 200 nm diameter. These foci locate within larger 53BP1 accumulations in regions of local 53BP1 depletion, similar to what has been described for the localization of Brca1, CtIP and RPA. Furthermore, localization relative to 53BP1 and size of Rad51 foci was not different after irradiation with low and high LET radiation. As expected, 53BP1 foci induced by low LET irradiation mostly contained one Rad51 focal structure, while after high LET irradiation, most foci contained >1 Rad51 accumulation. |
BibTeX:
@article{Reindl2015,
author = {Judith Reindl and Guido A Drexler and Stefanie Girst and Christoph Greubel and Christian Siebenwirth and Sophie E Drexler and Günther Dollinger and Anna A Friedl},
title = {Nanoscopic exclusion between Rad51 and 53BP1 after ion irradiation in human HeLa cells},
journal = {Physical Biology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {12},
number = {6},
pages = {066005},
url = {http://stacks.iop.org/1478-3975/12/i=6/a=066005},
doi = {https://doi.org/10.1088/1478-3975/12/6/066005}
}
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Investigation of EBT2 and EBT3 films for proton dosimetry in the 4–20 MeV energy range S. Reinhardt, M. Würl, C. Greubel, N. Humble, J. Wilkens, M. Hillbrand, A. Mairani, W. Assmann and K. Parodi; Radiation and Environmental Biophysics 54 (1) (2015) 71-79. |
| Abstract: Radiochromic films such as Gafchromic EBT2 or EBT3 films are widely used for dose determination in radiation therapy because they offer a superior spatial resolution compared to any other digital dosimetric 2D detector array. The possibility to detect steep dose gradients is not only attractive for intensity-modulated radiation therapy with photons but also for intensity-modulated proton therapy. Their characteristic dose rate-independent response makes radiochromic films also attractive for dose determination in cell irradiation experiments using laser-driven ion accelerators, which are currently being investigated as future medical ion accelerators. However, when using these films in ion beams, the energy-dependent dose response in the vicinity of the Bragg peak has to be considered. In this work, the response of these films for low-energy protons is investigated. To allow for reproducible and background-free irradiation conditions, the films were exposed to mono-energetic protons from an electrostatic accelerator, in the 4–20 MeV energy range. For comparison, irradiation with clinical photons was also performed. It turned out that in general, EBT2 and EBT3 films show a comparable performance. For example, dose–response curves for photons and protons with energies as low as 11 MeV show almost no differences. However, corrections are required for proton energies below 11 MeV. Care has to be taken when correction factors are related to an average LET from depth–dose measurements, because only the dose-averaged LET yields similar results as obtained in mono-energetic measurements. |
BibTeX:
@article{Reinhardt2015,
author = {Reinhardt, S. and Würl, M. and Greubel, C. and Humble, N. and Wilkens, J.J. and Hillbrand, M. and Mairani, A. and Assmann, W. and Parodi, K.},
title = {Investigation of EBT2 and EBT3 films for proton dosimetry in the 4–20 MeV energy range},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {54},
number = {1},
pages = {71--79},
url = {http://link.springer.com/article/10.1007%2Fs00411-014-0581-2},
doi = {https://doi.org/10.1007/s00411-014-0581-2}
}
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Sub-micrometer 20 MeV protons or 45 MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks T. Schmid, W. Friedland, C. Greubel, S. Girst, J. Reindl, C. Siebenwirth, K. Ilicic, E. Schmid, G. Multhoff, E. Schmitt, P. Kundrát and G. Dollinger; Mutation Research/Genetic Toxicology and Environmental Mutagenesis 793 (2015) 30-40. |
| Abstract: Abstract In conventional experiments on biological effects of radiation types of diverse quality, micrometer-scale double-strand break (DSB) clustering is inherently interlinked with clustering of energy deposition events on nanometer scale relevant for DSB induction. Due to this limitation, the role of the micrometer and nanometer scales in diverse biological endpoints cannot be fully separated. To address this issue, hybrid human-hamster AL cells have been irradiated with 45 MeV (60 keV/μm) lithium ions or 20 MeV (2.6 keV/μm) protons quasi-homogeneously distributed or focused to 0.5 × 1 μm2 spots on regular matrix patterns (point distances up to 10.6 × 10.6 μm), with pre-defined particle numbers per spot to provide the same mean dose of 1.7 Gy. The yields of dicentrics and their distribution among cells have been scored. In parallel, track-structure based simulations of DSB induction and chromosome aberration formation with PARTRAC have been performed. The results show that the sub-micrometer beam focusing does not enhance DSB yields, but significantly affects the DSB distribution within the nucleus and increases the chance to form DSB pairs in close proximity, which may lead to increased yields of chromosome aberrations. Indeed, the experiments show that focusing 20 lithium ions or 451 protons per spot on a 10.6 μm grid induces two or three times more dicentrics, respectively, than a quasi-homogenous irradiation. The simulations reproduce the data in part, but in part suggest more complex behavior such as saturation or overkill not seen in the experiments. The direct experimental demonstration that sub-micrometer clustering of DSB plays a critical role in the induction of dicentrics improves the knowledge on the mechanisms by which these lethal lesions arise, and indicates how the assumptions of the biophysical model could be improved. It also provides a better understanding of the increased biological effectiveness of high-LET radiation. |
BibTeX:
@article{Schmid2015,
author = {Schmid, T.E. and Friedland, W. and Greubel, C. and Girst, S. and Reindl, J. and Siebenwirth, C. and Ilicic, K. and Schmid, E. and Multhoff, G. and Schmitt, E. and Kundrát, P. and Dollinger, G.},
title = {Sub-micrometer 20 MeV protons or 45 MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks},
booktitle = {Insights into formation and consequences of chromosome aberrations: Report on the 11th International Symposium on Chromosomal Aberrations (ISCA 11), Rhodes , Greece, September 12-14, 2014},
journal = {Mutation Research/Genetic Toxicology and Environmental Mutagenesis},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {793},
pages = {30--40},
url = {http://www.sciencedirect.com/science/article/pii/S1383571815002053},
doi = {https://doi.org/10.1016/j.mrgentox.2015.07.015}
}
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Determination of the accuracy for targeted irradiations of cellular substructures at SNAKE C. Siebenwirth, C. Greubel, S. Drexler, S. Girst, J. Reindl, D. Walsh, G. Dollinger, A. Friedl, T. Schmid and G. Drexler; Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms 348 (0) (2015) 137-142. |
| Abstract: In the last 10 years the ion microbeam SNAKE, installed at the Munich 14 MV tandem accelerator, has been successfully used for radiobiological experiments by utilizing pattern irradiation without targeting single cells. Now for targeted irradiation of cellular substructures a precise irradiation device was added to the live cell irradiation setup at SNAKE. It combines a sub-micrometer single ion irradiation facility with a high resolution optical fluorescence microscope. Most systematic errors can be reduced or avoided by using the same light path in the microscope for beam spot verification as well as for and target recognition. In addition online observation of the induced cellular responses is possible. The optical microscope and the beam delivering system are controlled by an in-house developed software which integrates the open-source image analysis software, CellProfiler, for semi-automatic target recognition. |
BibTeX:
@article{Siebenwirth2015,
author = {Siebenwirth, C. and Greubel, C. and Drexler, S.E. and Girst, S. and Reindl, J. and Walsh, D.W.M. and Dollinger, G. and Friedl, A.A. and Schmid, T.E. and Drexler, G.A.},
title = {Determination of the accuracy for targeted irradiations of cellular substructures at SNAKE},
journal = {Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2015},
volume = {348},
number = {0},
pages = {137--142},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X15000865},
doi = {https://doi.org/10.1016/j.nimb.2015.01.064}
}
|
2014 |
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The Effects of Ultra-High Dose Rate Proton Irradiation on Growth Delay in the Treatment of Human Tumor Xenografts in Nude Mice O. Zlobinskaya, C. Siebenwirth, C. Greubel, V. Hable, R. Hertenberger, N. Humble, S. Reinhardt, D. Michalski, B. Röper, G. Multhoff, G. Dollinger, J. Wilkens and T. Schmid; Radiation Research 181 (2) (2014) 177-183. |
| Abstract: The new technology of laser-driven ion acceleration (LDA) has shown the potential for driving highly brilliant particle beams. Laser-driven ion acceleration differs from conventional proton sources by its ultra-high dose rate, whose radiobiological impact should be investigated thoroughly before adopting current clinical dose concepts. The growth of human FaDu tumors transplanted onto the hind leg of nude mice was measured sonographically. Tumors were irradiated with 20 Gy of 23 MeV protons at pulsed mode with single pulses of 1 ns duration or continuous mode (?100 ms) in comparison to controls and to a dose-response curve for 6 MV photons. Tumor growth delay and the relative biological effectiveness (RBE) were calculated for all irradiation modes. The mean target dose reconstructed from Gafchromic films was 17.4 ± 0.8 Gy for the pulsed and 19.7 ± 1.1 Gy for the continuous irradiation mode. The mean tumor growth delay was 34 ± 6 days for pulsed, 35 ± 6 days for continuous protons, and 31 ± 7 days for photons 20 ± 1.2 Gy, resulting in RBEs of 1.22 ± 0.19 for pulsed and 1.10 ± 0.18 for continuous protons, respectively. In summary, protons were found to be significantly more effective in reducing the tumor volume than photons (P < 0.05). Together with the results of previous in vitro experiments, the in vivo data reveal no evidence for a substantially different radiobiology that is associated with the ultra-high dose rate of protons that might be generated from advanced laser technology in the future. The new technology of laser-driven ion acceleration (LDA) has shown the potential for driving highly brilliant particle beams. Laser-driven ion acceleration differs from conventional proton sources by its ultra-high dose rate, whose radiobiological impact should be investigated thoroughly before adopting current clinical dose concepts. The growth of human FaDu tumors transplanted onto the hind leg of nude mice was measured sonographically. Tumors were irradiated with 20 Gy of 23 MeV protons at pulsed mode with single pulses of 1 ns duration or continuous mode (?100 ms) in comparison to controls and to a dose-response curve for 6 MV photons. Tumor growth delay and the relative biological effectiveness (RBE) were calculated for all irradiation modes. The mean target dose reconstructed from Gafchromic films was 17.4 ± 0.8 Gy for the pulsed and 19.7 ± 1.1 Gy for the continuous irradiation mode. The mean tumor growth delay was 34 ± 6 days for pulsed, 35 ± 6 days for continuous protons, and 31 ± 7 days for photons 20 ± 1.2 Gy, resulting in RBEs of 1.22 ± 0.19 for pulsed and 1.10 ± 0.18 for continuous protons, respectively. In summary, protons were found to be significantly more effective in reducing the tumor volume than photons (P < 0.05). Together with the results of previous in vitro experiments, the in vivo data reveal no evidence for a substantially different radiobiology that is associated with the ultra-high dose rate of protons that might be generated from advanced laser technology in the future. |
BibTeX:
@article{Zlobinskaya2014,
author = {Zlobinskaya, O. and Siebenwirth, C. and Greubel, C. and Hable, V. and Hertenberger, R. and Humble, N. and Reinhardt, S. and Michalski, D. and Röper, B. and Multhoff, G. and Dollinger, G. and Wilkens, J.J. and Schmid, T.E.},
title = {The Effects of Ultra-High Dose Rate Proton Irradiation on Growth Delay in the Treatment of Human Tumor Xenografts in Nude Mice},
booktitle = {Radiation Research},
journal = {Radiation Research},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2014},
volume = {181},
number = {2},
pages = {177--183},
url = {http://www.rrjournal.org/doi/abs/10.1667/RR13464.1},
doi = {https://doi.org/10.1667/RR13464.1}
}
|
2013 |
|
Subdiffusion Supports Joining Of Correct Ends During Repair Of DNA Double-Strand Breaks S. Girst, V. Hable, G.A. Drexler, C. Greubel, C. Siebenwirth, M. Haum, A.A. Friedl and G. Dollinger; Scientific Reports 3 (2013) 2511. |
| Abstract: The mobility of damaged chromatin regions in the nucleus may affect the probability of mis-repair. In this work, live-cell observation and distance tracking of GFP-tagged DNA damage response protein MDC1 was used to study the random-walk behaviour of chromatin domains containing radiation-induced DNA double-strand breaks (DSB). Our measurements indicate a subdiffusion-type random walk process with similar time dependence for isolated and clustered DSBs that were induced by 20 MeV proton or 43 MeV carbon ion micro-irradiation. As compared to normal diffusion, subdiffusion enhances the probability that both ends of a DSB meet, thus promoting high efficiency DNA repair. It also limits their probability of long-range movements and thus lowers the probability of mis-rejoining and chromosome aberrations. |
BibTeX:
@article{Girst2013,
author = {Girst, S. and Hable, V. and Drexler, G. A. and Greubel, C. and Siebenwirth, C. and Haum, M. and Friedl, A. A. and Dollinger, G.},
title = {Subdiffusion Supports Joining Of Correct Ends During Repair Of DNA Double-Strand Breaks},
journal = {Scientific Reports},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2013},
volume = {3},
pages = {2511},
url = {http://www.nature.com/articles/srep02511},
doi = {https://doi.org/10.1038/srep02511}
}
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Einfluss der zeitlichen und räumlichen Fokussierung auf die strahlenbiologische Wirksamkeit von Protonen. Christoph Greubel; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2013. |
| Abstract: In dieser Arbeit wurde der Einfluss von auf Nanosekunden gepulster (zeitlich fokussierter) Dosisdeposition, im zweiten Teil von auf Submikrometer (räumlich) fokussierter Dosisdeposition auf die relative biologische Wirksamkeit, RBE, studiert. Die Effekte gepulster Bestrahlung auf Nanosekunden Zeitskala sind vor allem für eine mögliche Anwendung der Laserbeschleunigung von Ionen in der Tumortherapie, welche die Dosisdeposition auf einer Nanosekunden Zeitskala erwarten lässt, von Bedeutung. Zur Untersuchung wurde die Wachstumsverzögerung von zwei menschlichen Plattenepitelkarzinomen aus dem Mund- und Rachenraum, FaDu und XF354, im Mausmodell nach Bestrahlung mit einer Fraktion von nominell 20 Gy gemessen. In Ermangelung geeigneter lasergetriebener Ionenstrahlen wurde hierzu mittels konventioneller Technik am Rasterionenmikroskop SNAKE am Müchener Tandembeschleuniger ein auf 1,3 ns (volle Halbwertsbreite) gepulster 23 MeV Protonenstrahl mit einer Fluenz pro Einzelpuls von bis zu 109 cm-2 präpariert, sowie ein kontinuierlicher Protonenstrahl zur Dosisdeposition auf Millisekunden Zeitskala für direkte Vergleichsmessungen. Die Bestrahlung der maximal 4 mm tiefen und 7 mm im Durchmesser messenden Tumore erfolgt voxelweise, wobei die komplette Fluenz eines Voxels mit einem Nanosekunden Puls appliziert wird. An jedem Punkt im Tumor deponiert mindestens ein Puls eine Dosis zwischen 1,0 Gy und 2,7 Gy. Der RBE für die Wachstumsverzögerung von FaDu Tumoren bezüglich 6 MV Röntgenstrahlung wurde nach kontinuierlicher Dosisdeposition zu 1,10 ± 0,14, nach gepulster Dosisdeposition zu 1,22 ± 0,17 gemessen. Auch für die XF354 Tumore konnte kein signifikanter Unterschied in der Wachstumsverzögerung gemessen werden. Die Messungen zeigen keine Anzeichen für eine geänderte Wirksamkeit von Nanosekunden gepulster Dosisdeposition. Im zweiten Teil der Arbeit wurden die Auswirkungen von räumlich fokussierter Dosisdeposition am Endpunkt der Induktion von dizentrischen Chromosomen und Mikrokernen untersucht. Durch die Submikrometer Fokussierung von niedrig-LET 20 MeV Protonen kann eine räumliche Dosisverteilung generiert werden, welche qualitativ jener von Schwerionen mit hohem LET ähnelt, so dass die Wirkung von dichtionisierender hoch-LET Strahlung modelliert werden kann. Hierzu wurden AL-Zellen mit einer Dosis von jeweils 1,7 Gy in drei verschiedenen Modi bestrahlt: Die Bestrahlung mit Submikrometer fokussierten 20 MeV Protonen folgt einer 5,4 µm x 5,4 µm Matrix, wobei 117 Protonen pro Matrixpunkt appliziert werden. Die Bestrahlung mit 55 MeV Kohlenstoffionen erfolgt im selben Muster mit je einem Ion pro Matrixpunkt. Zufällig verteilte 20 MeV Protonen werden mit einer Fluenz von 4,01 µm-2 appliziert. Der RBE für die Induktion von Mikrokernen steigt durch die Fokussierung der Protonen von 1,28 ± 0,07 nach zufällig verteilter Protonenbestrahlung auf 1,48 ± 0,07 nach fokussierter Protonenapplikation, der RBE für die Induktion von dizentrischen Chromosomen steigt von 1,41 ± 0,14 auf 1,92 ± 0,15. Der von Kohlenstoffionen induzierte RBE ist mit 2,20 ± 0,09 für Mikrokerne und 3,21 ± 0,27 für dizentrische Chromosomen nochmal deutlich höher. Die signifikante Erhöhung der Induktion von Chromosomenaberrationen alleine durch die Fokussierung der Protonen und damit der räumlichen Dosisverteilung zeigt, dass die räumliche Dosisverteilung für den RBE maßgeblich ist. Die Experimente stellen somit die erste experimentelle Bestätigung der Grundannahme des Local Effect Models dar, welches in der Tumortherapie mit schweren Ionen zur Modellierung des RBE für die Dosisplanung verwendet wird. Rechnungen mit dem Local Effect Model III zeigen jedoch, dass dieses den RBE für die Endpunkte der Chromosomenaberrationen für die drei Bestrahlungsmodi zwar qualitativ, nicht aber quantitativ beschreiben kann. |
BibTeX:
@phdthesis{Greubel2013diss,
author = {Greubel, Christoph},
title = {Einfluss der zeitlichen und räumlichen Fokussierung auf die strahlenbiologische Wirksamkeit von Protonen.},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2013},
url = {http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:706-3415}
}
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Reduced side effects by proton microchannel radiotherapy: Study in a human skin model O. Zlobinskaya, S. Girst, C. Greubel, V. Hable, C. Siebenwirth, D. Walsh, G. Multhoff, J. Wilkens, T. Schmid and G. Dollinger; Radiation and Environmental Biophysics 52 (1) (2013) 123-133. |
| Abstract: The application of a microchannel proton irradiation was compared to homogeneous irradiation in a three-dimensional human skin model. The goal is to minimize the risk of normal tissue damage by microchannel irradiation, while preserving local tumor control through a homogeneous irradiation of the tumor that is achieved because of beam widening with increasing track length. 20 MeV protons were administered to the skin models in 10- or 50-μm-wide irradiation channels on a quadratic raster with distances of 500 μm between each channel (center to center) applying an average dose of 2 Gy. For comparison, other samples were irradiated homogeneously at the same average dose. Normal tissue viability was significantly enhanced after microchannel proton irradiation compared to homogeneous irradiation. Levels of inflammatory parameters, such as Interleukin-6, TGF-Beta, and Pro-MMP1, were significantly lower in the supernatant of the human skin tissue after microchannel irradiation than after homogeneous irradiation. The genetic damage as determined by the measurement of micronuclei in keratinocytes also differed significantly. This difference was quantified via dose modification factors (DMF) describing the effect of each irradiation mode relative to homogeneous X-ray irradiation, so that the DMF of 1.21 ± 0.20 after homogeneous proton irradiation was reduced to 0.23 ± 0.11 and 0.40 ± 0.12 after microchannel irradiation using 10- and 50-μm-wide channels, respectively. Our data indicate that proton microchannel irradiation maintains cell viability while significantly reducing inflammatory responses and genetic damage compared to homogeneous irradiation, and thus might improve protection of normal tissue after irradiation. |
BibTeX:
@article{Zlobinskaya2013,
author = {Zlobinskaya, O. and Girst, S. and Greubel, C. and Hable, V. and Siebenwirth, C. and Walsh, D.W.M. and Multhoff, G. and Wilkens, J.J. and Schmid, T.E. and Dollinger, G.},
title = {Reduced side effects by proton microchannel radiotherapy: Study in a human skin model},
booktitle = {Radiation and Environmental Biophysics},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2013},
volume = {52},
number = {1},
pages = {123--133},
url = {http://link.springer.com/article/10.1007%2Fs00411-012-0450-9},
doi = {https://doi.org/10.1007/s00411-012-0450-9}
}
|
2012 |
|
A laser-driven nanosecond proton source for radiobiological studies J. Bin, K. Allinger, W. Assmann, G. Dollinger, G.A. Drexler, A.A. Friedl, D. Habs, P. Hilz, R. Hoerlein, N. Humble, S. Karsch, K. Khrennikov, D. Kiefer, F. Krausz, W. Ma, D. Michalski, M. Molls, S. Raith, S. Reinhardt, B. Roeper, T.E. Schmid, T. Tajima, J. Wenz, O. Zlobinskaya, J. Schreiber and J.J. Wilkens; Applied Physics Letters 101 (24) (2012) 243701. |
| Abstract: Ion beams are relevant for radiobiological studies and for tumor therapy. In contrast to conventional accelerators, laser-driven ion acceleration offers a potentially more compact and cost-effective means of delivering ions for radiotherapy. Here, we show that by combining advanced acceleration using nanometer thin targets and beam transport, truly nanosecond quasi-monoenergetic proton bunches can be generated with a table-top laser system, delivering single shot doses up to 7Gy to living cells. Although in their infancy, laser-ion accelerators allow studying fast radiobiological processes as demonstrated here by measurements of the relative biological effectiveness of nanosecond proton bunches in human tumor cells. |
BibTeX:
@article{Bin2012,
author = {Bin, Jianhui and Allinger, Klaus and Assmann, Walter and Dollinger, Guenther and Drexler, Guido A. and Friedl, Anna A. and Habs, Dieter and Hilz, Peter and Hoerlein, Rainer and Humble, Nicole and Karsch, Stefan and Khrennikov, Konstantin and Kiefer, Daniel and Krausz, Ferenc and Ma, Wenjun and Michalski, Doerte and Molls, Michael and Raith, Sebastian and Reinhardt, Sabine and Roeper, Barbara and Schmid, Thomas E. and Tajima, Toshiki and Wenz, Johannes and Zlobinskaya, Olga and Schreiber, Joerg and Wilkens, Jan J.},
title = {A laser-driven nanosecond proton source for radiobiological studies},
journal = {Applied Physics Letters},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2012},
volume = {101},
number = {24},
pages = {243701},
url = {http://link.aip.org/link/doi/10.1063/1.4769372},
doi = {https://doi.org/10.1063/1.4769372}
}
|
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Recruitment kinetics of DNA repair proteins Mdc1 and Rad52 but not 53BP1 depend on damage complexity V. Hable, G.A. Drexler, T. Brüning, C. Burgdorf, C. Greubel, A. Derer, J. Seel, H. Strickfaden, T. Cremer, A.A. Friedl and G. Dollinger; PLoS One 7 (7) (2012) e41943. |
| Abstract: The recruitment kinetics of double-strand break (DSB) signaling and repair proteins Mdc1, 53BP1 and Rad52 into radiation-induced foci was studied by live-cell fluorescence microscopy after ion microirradiation. To investigate the influence of damage density and complexity on recruitment kinetics, which cannot be done by UV laser irradiation used in former studies, we utilized 43 MeV carbon ions with high linear energy transfer per ion (LET = 370 keV/μm) to create a large fraction of clustered DSBs, thus forming complex DNA damage, and 20 MeV protons with low LET (LET = 2.6 keV/μm) to create mainly isolated DSBs. Kinetics for all three proteins was characterized by a time lag period T0 after irradiation, during which no foci are formed. Subsequently, the proteins accumulate into foci with characteristic mean recruitment times τ1. Mdc1 accumulates faster (T0 = 17±2 s, τ1 = 98±11 s) than 53BP1 (T0 = 77±7 s, τ1 = 310±60 s) after high LET irradiation. However, recruitment of Mdc1 slows down (T0 = 73±16 s, τ1 = 1050±270 s) after low LET irradiation. The recruitment kinetics of Rad52 is slower than that of Mdc1, but exhibits the same dependence on LET. In contrast, the mean recruitment time τ1 of 53BP1 remains almost constant when varying LET. Comparison to literature data on Mdc1 recruitment after UV laser irradiation shows that this rather resembles recruitment after high than low LET ionizing radiation. So this work shows that damage quality has a large influence on repair processes and has to be considered when comparing different studies. |
BibTeX:
@article{Hable2012,
author = {Hable, Volker and Drexler, Guido A. and Brüning, Tino and Burgdorf, Christian and Greubel, Christoph and Derer, Anja and Seel, Judith and Strickfaden, Hilmar and Cremer, Thomas and Friedl, Anna A. and Dollinger, Günther},
title = {Recruitment kinetics of DNA repair proteins Mdc1 and Rad52 but not 53BP1 depend on damage complexity},
journal = {PLoS One},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2012},
volume = {7},
number = {7},
pages = {e41943},
url = {http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041943},
doi = {https://doi.org/10.1371/journal.pone.0041943}
}
|
|
Super resolution microscopy of repair foci after ion irradiation of human HeLa cells Judith (Seel) Reindl; Masters-Thesis, Ludwigs-Maximilians-Universität München, 2012. |
| Abstract: High LET (linear energy transfer) irradiation of living cells using heavy ions generates a high amount of DNA double-strand breaks (DSB) in close vicinity to each other along the ion track. Various repair proteins cluster to the damage sites, such as gH2AX and 53BP1, forming so-called repair foci of a gross size of about 1 µm. Due to the fact that one focus covers more than one DSB, a fine-structure within the focus can be expected. First indications for such a fine-structure were found in wide field images of cells taken one hour after irradiation with 55MeV carbon ions in a 5x5 µm matrix performed at the ion microprobe SNAKE. While a typical focus with the diameter of about 1 µm can be easily resolved using a conventional fluorescence microscope, its substructures cannot be resolved due to the diffraction limit of about 250 nm in conventional fluorescence microscopy. Therefore, for analyzing foci fine-structures systematically, super-resolution microscopy techniques like structured illumination microscopy (SIM), stimulation emission depletion microscopy (STED) or localization microscopy (SPDM) which provide a lateral resolution of about 130 nm (SIM) to 50 nm (SPDM) fwhm are utilized. Since with these techniques the lateral resolution is even better than the z-resolution we used an irradiation configuration, where the cells are irradiated at a small angle to the image plane. Thus, the complete ion track appears as a line within one layer of a 3D microscope image. Due to these improvements the super resolution images clearly indicate a fine-structure when e. g. 53BP1 is stained with two colors. For quantification of the results the Pearson correlation coefficient is calculated for a pixel wise shift in x-direction as well as in y-direction of one color channel with respect to the other (Van Steensel approach). This proves the existence of a fine-structure of a scale of about 200-230 nm, which becomes obvious by an extra correlation peak with a fwhm of this size. Using the same Van Steensel approach with images where one color marks 53BP1 and the other gH2AX, it can be shown that there is no total correlation of the fine-structure between 53BP1 and gH2AX on the small scale. Using the product of the difference of the mean (PDM) for 2D profiles the images where one protein is labeled with two colors show large regions with total correlation of the to color channels and only small regions at the rim of the focus with no total correlation. In addition, in the PDM approach two different damage markers each labeled in one color show colocalisation in small regions inside the focus but anticorrelation in the outer regions of the focus. These analysis lead to different results: first of all a single repair marker seems to cluster systematically to the damage site and not in a random way. Secondly 53BP1 and gH2AX cluster in a different way and therefore no full colocalisation can be reached. With this experimental and analytical methods it is possible to determine the way of clustering to DSB of one single DNA damage marker to clarify the structure of a DSB and the structure of the chromatin architecture as well as the comparison of two damage markers to get deeper understanding to the interaction of repair markers and repair proteins and at the end decode the way of DNA repair. |
BibTeX:
@mastersthesis{Reindl2012ma,
author = {Reindl, Judith (Seel)},
title = {Super resolution microscopy of repair foci after ion irradiation of human HeLa cells},
school = {Ludwigs-Maximilians-Universität München},
year = {2012}
}
|
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Low LET protons focused to submicrometer shows enhanced radiobiological effectiveness T.E. Schmid, C. Greubel, V. Hable, O. Zlobinskaya, D. Michalski, S. Girst, C. Siebenwirth, E. Schmid, M. Molls, G. Multhoff and G. Dollinger; Physics in Medicine and Biology 57 (19) (2012) 5889-5907. |
| Abstract: This study shows that enhanced radiobiological effectiveness (RBE) values can be generated focusing low linear energy transfer (LET) radiation and thus changing the microdose distribution. 20 MeV protons (LET = 2.65 keV µm −1 ) are focused to submicrometer diameter at the ion microprobe superconducting nanoprobe for applied nuclear (Kern) physics experiments of the Munich tandem accelerator. The RBE values, as determined by measuring micronuclei (RBE MN = 1.48 ± 0.07) and dicentrics (RBE D = 1.92 ± 0.15), in human–hamster hybrid (A L ) cells are significantly higher when 117 protons were focused to a submicrometer irradiation field within a 5.4 × 5.4 µm 2 matrix compared to quasi homogeneous in a 1 × 1 µm 2 matrix applied protons (RBE MN = 1.28 ± 0.07; RBE D = 1.41 ± 0.14) at the same average dose of 1.7 Gy. The RBE values are normalized to standard 70 kV (dicentrics) or 200 kV (micronuclei) x-ray irradiation. The 117 protons applied per point deposit the same amount of energy like a 12 C ion with 55 MeV total energy (4.48 MeV u −1 ). The enhancements are about half of that obtained for 12 C ions (RBE MN = 2.20 ± 0.06 and RBE D = 3.21 ± 0.10) and they are attributed to intertrack interactions of the induced damages. The measured RBE values show differences from predictions of the local effect model (LEM III) that is used to calculate RBE values for irradiation plans to treat tumors with high LET particles. |
BibTeX:
@article{Schmid2012,
author = {Schmid, T. E. and Greubel, C. and Hable, V. and Zlobinskaya, O. and Michalski, D. and Girst, S. and Siebenwirth, C. and Schmid, E. and Molls, M. and Multhoff, G. and Dollinger, G.},
title = {Low LET protons focused to submicrometer shows enhanced radiobiological effectiveness},
journal = {Physics in Medicine and Biology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2012},
volume = {57},
number = {19},
pages = {5889-5907},
url = {http://stacks.iop.org/0031-9155/57/i=19/a=5889},
doi = {https://doi.org/10.1088/0031-9155/57/19/5889}
}
|
|
Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams O. Zlobinskaya, G. Dollinger, D. Michalski, V. Hable, C. Greubel, G. Du, G. Multhoff, B. Röper, M. Molls and T.E. Schmid; Radiation and Environmental Biophysics 51 (1) (2012) 23-32. |
| Abstract: In particle tumor therapy including beam scanning at accelerators, the dose per voxel is delivered within about 100 ms. In contrast, the new technology of laser plasma acceleration will produce ultimately shorter particle packages that deliver the dose within a nanosecond. Here, possible differences for relative biological effectiveness in creating DNA double-strand breaks in pulsed or continuous irradiation mode are studied. HeLa cells were irradiated with 1 or 5 Gy of 20-MeV protons at the Munich tandem accelerator, either at continuous mode (100 ms), or applying a single pulse of 1-ns duration. Cells were fixed 1 h after 1-Gy irradiation and 24 h after 5-Gy irradiation, respectively. A dose–effect curve based on five doses of X-rays was taken as reference. The total number of phosphorylated histone H2AX (gamma-H2AX) foci per cell was determined using a custom-made software macro for gamma-H2AX foci counting. For 1 h after 1-Gy 20-MeV proton exposures, values for the relative biological effectiveness (RBE) of 0.97 ± 0.19 for pulsed and 1.13 ± 0.21 for continuous irradiations were obtained in the first experiment 1.13 ± 0.09 and 1.16 ± 0.09 in the second experiment. After 5 Gy and 24 h, RBE values of 0.99 ± 0.29 and 0.91 ± 0.23 were calculated, respectively. Based on the gamma-H2AX foci numbers obtained, no significant differences in RBE between pulsed and continuous proton irradiation in HeLa cells were detected. These results are well in line with our data on micronucleus induction in HeLa cells. |
BibTeX:
@article{Zlobinskaya2012,
author = {Zlobinskaya, O. and Dollinger, G. and Michalski, D. and Hable, V. and Greubel, C. and Du, G. and Multhoff, G. and Röper, B. and Molls, M. and Schmid, T. E.},
title = {Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2012},
volume = {51},
number = {1},
pages = {23--32},
url = {http://link.springer.com/article/10.1007%2Fs00411-011-0398-1},
doi = {https://doi.org/10.1007/s00411-011-0398-1}
}
|
2011 |
|
Survival of tumor cells after proton irradiation with ultra-high dose rates S. Auer, V. Hable, C. Greubel, G.A. Drexler, T.E. Schmid, C. Belka, G. Dollinger and A.A. Friedl; Radiation Oncology 6 (1) (2011) 139. |
| Abstract: Background Laser acceleration of protons and heavy ions may in the future be used in radiation therapy. Laser-driven particle beams are pulsed and ultra high dose rates of >109 Gy s-1may be achieved. Here we compare the radiobiological effects of pulsed and continuous proton beams. Methods The ion microbeam SNAKE at the Munich tandem accelerator was used to directly compare a pulsed and a continuous 20 MeV proton beam, which delivered a dose of 3 Gy to a HeLa cell monolayer within < 1 ns or 100 ms, respectively. Investigated endpoints were G2 phase cell cycle arrest, apoptosis, and colony formation. Results At 10 h after pulsed irradiation, the fraction of G2 cells was significantly lower than after irradiation with the continuous beam, while all other endpoints including colony formation were not significantly different. We determined the relative biological effectiveness (RBE) for pulsed and continuous proton beams relative to x-irradiation as 0.91 ± 0.26 and 0.86 ± 0.33 (mean and SD), respectively. Conclusions At the dose rates investigated here, which are expected to correspond to those in radiation therapy using laser-driven particles, the RBE of the pulsed and the (conventional) continuous irradiation mode do not differ significantly. |
BibTeX:
@article{Auer2011,
author = {Auer, Susanne and Hable, Volker and Greubel, Christoph and Drexler, Guido A. and Schmid, Thomas E. and Belka, Claus and Dollinger, Günther and Friedl, Anna A.},
title = {Survival of tumor cells after proton irradiation with ultra-high dose rates},
journal = {Radiation Oncology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011},
volume = {6},
number = {1},
pages = {139},
url = {http://ro-journal.biomedcentral.com/articles/10.1186/1748-717X-6-139},
doi = {https://doi.org/10.1186/1748-717X-6-139}
}
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|
Spatial Dynamics of DNA Damage Response Protein Foci along the Ion Trajectory of High-LET Particles G. Du, G.A. Drexler, W. Friedland, C. Greubel, V. Hable, R. Krücken, A. Kugler, L. Tonelli, A.A. Friedl and G. Dollinger; Radiation Research 176 (6) (2011) 706-715. |
| Abstract: High-linear energy transfer (LET) ion irradiation of cell nuclei induces complex and severe DNA lesions, and foci of repair proteins are formed densely along the ion trajectory. To efficiently discriminate the densely distributed/overlapping foci along the ion trajectory, a focus recognition algorithm called FociPicker3D based on a local fraction thresholding technique was developed. We analyzed high-resolution 3D immunofluorescence microscopic focus images and obtained the kinetics and spatial development of γ-H2AX, 53BP1 and phospho-NBS1 foci in BJ1-hTERT cells irradiated with 55 MeV carbon ions and compared the results with the dynamics of double-strand break (DSB) distributions simulated using the PARTRAC model. Clusters consisting of several foci were observed along the ion trajectory after irradiation. The spatial dynamics of the protein foci supports that the foci clusters are not formed by neighboring foci but instead originate from the DSB cluster damage induced by high-LET radiations. |
BibTeX:
@article{Du2011,
author = {Du, Guanghua and Drexler, Guido A. and Friedland, Werner and Greubel, Christoph and Hable, Volker and Krücken, Reiner and Kugler, Alexandra and Tonelli, Laura and Friedl, Anna A. and Dollinger, Günther},
title = {Spatial Dynamics of DNA Damage Response Protein Foci along the Ion Trajectory of High-LET Particles},
booktitle = {Radiation Research},
journal = {Radiation Research},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011},
volume = {176},
number = {6},
pages = {706--715},
url = {http://www.bioone.org/doi/10.1667/RR2592.1},
doi = {https://doi.org/10.1667/RR2592.1}
}
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Anomalous subdiffusion of DNA repair protein foci after ion microirradiation. Stefanie Girst; Diplomarbeit, Technische Universität München, 2011. |
| Abstract: DNA repair processes, starting after the irradiation of cell nuclei, can be made visible by tagging DNA repair proteins (here MDC1) with the green fluorescent protein GFP, so that microscopic accumulations of the repair proteins ( at the ion-induced damages (mostly DNA double-strand breaks) can be observed and analyzed "live" under a fluorescence microscope. The aim of this work is to determine the dynamics of the MDC1-foci in the nucleus. Living U2OS osteosarcoma cells were irradiated in a 5x5 µm^2 matrix pattern with one carbon ion (43MeV) per point or 32 protons (20 MeV) respectively at the ion microprobe SNAKE at the Munich 14MV Tandem accelerator. The relative movement (i.e. the distance) of neighboring foci within the living cells was monitored over several hours "online" at the irradiation site at SNAKE. This relative measure is more robust against cell movement than absolute position determination. The distribution of the change of distance dl between two foci in a time interval dt is a measure for the underlying diffusion. The square of its standard deviation sigma^2(dt) is in general described by sigma^2(dt) = G*dt^a, with a = 1 for normal, a < 1 for anomalous subdiffusion. The diffusion data gathered in the performed experiments are in agreement with an anomalous subdiffusion. The anomalous diffusion exponent found is a = 0.50 +/- 0.04 for both proton and carbon irradiation on a time scale of dt =10 s till 10 000 s, indicating that the degree of anomality does not depend on the density of double-strand breaks. The transport coefficient G and thus the apparent and the instantaneous diffusion coefficient, however, were clearly bigger in proton-irradiated cell nuclei (G = (7+/-2)x10^(-3) µm^2/s^0.5) than in those irradiated with the higher-LET carbon ions (G = (3 +/- 1) x 10^(-3) µm^2/s^0.5). This probably arises from the fact that protons produce isolated double-strand breaks (DSBs) which move faster than the larger number of DSBs that form the foci in a carbon ion track. |
BibTeX:
@mastersthesis{Girst2011da,
author = {Girst, Stefanie},
title = {Anomalous subdiffusion of DNA repair protein foci after ion microirradiation.},
school = {Technische Universität München},
year = {2011}
}
|
|
Scanning irradiation device for mice in vivo with pulsed and continuous proton beams C. Greubel, W. Assmann, C. Burgdorf, G. Dollinger, G. Du, V. Hable, A. Hapfelmeier, R. Hertenberger, P. Kneschaurek, D. Michalski, M. Molls, S. Reinhardt, B. Röper, S. Schell, T.E. Schmid, C. Siebenwirth, T. Wenzl, O. Zlobinskaya and J.J. Wilkens; Radiation and Environmental Biophysics 50 (3) (2011) 339-344. |
| Abstract: A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 μm2, the necessary fluence of 109 protons per cm2 to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth–dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed. |
BibTeX:
@article{Greubel2011,
author = {Greubel, Christoph and Assmann, Walter and Burgdorf, Christian and Dollinger, Günther and Du, Guanghua and Hable, Volker and Hapfelmeier, Alexander and Hertenberger, Ralf and Kneschaurek, Peter and Michalski, Dörte and Molls, Michael and Reinhardt, Sabine and Röper, Barbara and Schell, Stefan and Schmid, Thomas E. and Siebenwirth, Christian and Wenzl, Tatiana and Zlobinskaya, Olga and Wilkens, Jan J.},
title = {Scanning irradiation device for mice in vivo with pulsed and continuous proton beams},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011},
volume = {50},
number = {3},
pages = {339--344},
url = {http://link.springer.com/article/10.1007%2Fs00411-011-0365-x},
doi = {https://doi.org/10.1007/s00411-011-0365-x}
}
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Echtzeitbeobachtung schneller Reaktionskinetiken in lebenden Zellen nach Ionenmikrobestrahlung Volker Hable; Dissertation, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2011. |
| Abstract: Diese Arbeit beschreibt den Aufbau einer Lebendzellmikroskopieumgebung am Rasterionenmikroskop SNAKE, welches am Münchner 14 MV Tandembeschleuniger installiert ist. An dessen Zellbestrahlungsplatz können lebende Zellen mit Protonen und Schwerionen unter Lebendbedingungen mit einer Genauigkeit von ca. 0,5 µm und mit genau definierter Dosis bestrahlt werden. Die nach der Bestrahlung im Zellkern ablaufenden Reparaturvorgänge können durch eine mikroskopische Betrachtung der an der Reparatur beteiligten Proteine analysiert werden. Hierfür ist die Markierung dieser Proteine mittels Fluoreszenzfarbstoffen nötig. Dazu werden die Zellen auf gentechnischem Wege so verändert, dass an Proteine, die an der Reparatur der ioneninduzierten Schäden beteiligt sind, Fluoreszenzproteine (z. B. GFP, green fluorescent protein) angehängt werden. Mikroskopische Proteinanlagerungen an die Schadensorte, sogenannte Foci, können mit dem im Rahmen dieser Arbeit realisierten Aufbau unmittelbar nach und sogar während der Bestrahlung "online“ analysiert werden. Ein kommerziell erhältliches Fluoreszenzmikroskop (Zeiss Axiovert 200M) wurde hierzu am Bestrahlungsplatz angebracht. An dessen Probentisch befinden sich die Zellen während der Bestrahlung und der nachfolgenden Mikroskopie unter optimalen Umgebungsbedingungen in neu entwickelten Zellkulturgefäßen. Erste Experimente an dem neuen Aufbau dienten der Untersuchung von Kinetiken (= zeitlicher Ablauf der Focibildung) der Proteine Mdc1, 53BP1 und Rad52. Nach Applizierung einer mittleren Dosis von 4,4 Gy mit 55 MeV Kohlenstoffionen mit einem linearen Energietransfer LET = 310 keV/µm beginnt Mdc1 nach T0 = 17 ± 2 s mit der Anlagerung an die Schadensorte. Dies geschieht mit einer Zeitkonstante t = 98 ± 11 s. Wird dieselbe Dosis mit 20 MeV Protonen appliziert (LET = 2,65 keV/µm), läuft die Focibildung langsamer ab (T0 = 73 ± 16 s, t = 1050 ± 270 s). Eine höhere Bestrahlungsdosis durch Erhöhung der pro Punkt applizierten Protonen beschleunigt die Kinetik. Die Zeitkonstanten des Proteins 53BP1 weisen keine solch ausgeprägte Abhängigkeit von der Bestrahlungsart auf. Für alle Bestrahlungsbedingungen liegt hier T0 in der Größenordnung von 100 s und t in der Größenordnung von 300 s. Das nur qualitativ betrachtete Reparaturprotein Rad52 zeigt eine deutlich langsamere Kinetik, die allerdings wieder stark von der Dosis und vom LET der Strahlung abhängt. Während bereits ca. zehn Minuten nach Bestrahlung mit 4,7 Gy mit 55 MeV Kohlenstoffionen erste Foci sichtbar werden, dauert deren Erscheinen nach Applizierung von 5,7 Gy durch 20 MeV Protonen (117 Protonen pro Punkt) ca. drei Stunden. Eine Erhöhung der pro Punkt applizierten Protonenzahl auf 256 (und somit der Dosis auf 12 Gy) verkürzt diese Zeit auf ca. eine Stunde. Eine weitere Verdopplung von Protonenzahl und Dosis führt zu einem Sichtbarwerden der Foci nach weniger als zehn Minuten. |
BibTeX:
@phdthesis{Hable2011diss,
author = {Hable, Volker},
title = {Echtzeitbeobachtung schneller Reaktionskinetiken in lebenden Zellen nach Ionenmikrobestrahlung},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011},
url = {http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:706-2487}
}
|
|
Subdiffusion von DNS-Doppelstrangbrüchen unter dem Einfluss von Zellkernverformungen Michael Haum; Bachelors-Thesis, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2011. |
| Abstract: Die Untersuchung von Schäden an biologischem Material durch ionisierende Strahlung stellt immer noch ein großes Forschungsgebiet von Medizin und Biologie dar. Insbesondere die Reparaturvorgänge nach der Schädigung der DNS im Zellkern werfen noch viele offene Fragen auf, dabei vor allem die der gefährlichsten Doppelstrangbrüche (DSB). Für ein besseres Verständnis der raumzeitlichen Dynamik der DSB wurden lebende Zellen am Münchner 14 MV Tandembeschleuniger mit 43 MeV Kohlenstoff-Ionen beschossen, um so die DNS gezielt zu schädigen und die erzeugten DSB über die sich dort gebildeten fluoreszenzmarkierten Reparaturproteincluster („Foci“) zu beobachten. Für die Analyse der Dynamik wurde die zeitliche Änderung der Abstände benachbarter Foci ( l≈5μm ) herangezogen. Die Standardabweichung der Abstandsänderung über ein Zeitintervall dt kann mit der Gleichung sigma^2= G * dt^a beschrieben werden, die eine Aussage über die Art der Diffusion macht. Es zeigte sich, dass der Diffusionsexponent mit a=0,49±0,05 deutlich kleiner ist als der einer normalen Diffusion ( a=1 ) und der Transportkoeffizient bei G=(1,7± 0,6) x 10^(−3) μm^2/s^0,49 liegt, sodass der Bewegung eine anomale Subdiffusion zugrunde liegt [S. Girst, 2011]. Durch die Betrachtung der Abstände anstelle von absoluten Positionen soll ausgeschlossen werden, dass eine Bewegung oder Deformation der gesamten Zelle unbeabsichtigt in die Auswertung mit einfließt. Ziel dieser Arbeit war es zu untersuchen, ob auch bei der Auswertung von größeren Foci-Abständen eine anomale Subdiffusion vorliegt. Hierfür wurden die Abstandsänderungen eines Foci zu seinem übernächsten Nachbarn ( l≈10μm ) herangezogen. Es ergab sich, dass auch hier eine anomale Subdiffusion vorliegt, mit dem Diffusionsexponenten a=0,58± 0,03 und dem Transportkoeffizienten G=(1,6± 0,3) x 10^(−3) μm^2 /s^0,58 . Trotz des größeren Diffusionsexponenten liegt auch nach dieser Auswertung eine anomale Subdiffusion vor, sodass das für kleine Abstände gefundene Ergebnis bestätigt wird. Der größere Diffusionsexponent ist allerdings ein Hinweis darauf, dass sich bei großen Foci-Abständen eine Verformung der Zelle in der Auswertung stärker bemerkbar macht. |
BibTeX:
@mastersthesis{Haum2011ba,
author = {Haum, Michael},
title = {Subdiffusion von DNS-Doppelstrangbrüchen unter dem Einfluss von Zellkernverformungen},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011}
}
|
|
The effectiveness of 20 MeV protons at nanosecond pulse lengths in producing chromosome aberrations in human-hamster hybrid cells T.E. Schmid, G. Dollinger, V. Hable, C. Greubel, O. Zlobinskaya, D. Michalski, S. Auer, A.A. Friedl, E. Schmid, M. Molls and B. Röper; Radiation Research 175 (6) (2011) 719-727. |
| Abstract: Laser accelerated radiotherapy is a potential cancer treatment with proton and carbon-ion beams that is currently under development. Ultra-fast high-energy laser pulses will accelerate ion beams that deliver their dose to a patient in a “pulsed mode” that is expected to differ from conventional irradiation by increasing the dose delivery rate to a tissue voxel by approximately 8 orders of magnitude. In two independently performed experiments at the ion microprobe SNAKE of the 14 MV Munich tandem accelerator, AL cells were exposed either to protons with 1-ns pulse durations or to protons applied over 150 ms in continuous irradiation mode. A slightly but consistently lower aberration yield was observed for the pulsed compared to the continuous mode of proton irradiation. This difference was not statistically significant when each aberration type was analyzed separately (P values between 0.61 and 0.85 in experiment I and P values between 0.32 and 0.64 in experiment II). However, excluding the total aberrations, which were not analyzed as independent radiation-induced effects, the mean ratio of the yields of dicentrics, centric rings and excess acentrics scored together showed (with 95% CI) a significant difference of 0.90 (0.81; 0.98) between the pulsed and the continuous irradiation modes. A similar tendency was also determined for the corresponding RBE values relative to 70 kV X rays. Since the different findings for the comparisons of individual chromosome aberration types and combined comparisons could be explained by different sample sizes with the consequence that the individual comparisons had less statistical power to identify a difference, it can be concluded that 20 MeV protons may be slightly less effective in the pulsed mode. |
BibTeX:
@article{Schmid2011,
author = {Schmid, T. E. and Dollinger, G. and Hable, V. and Greubel, C. and Zlobinskaya, O. and Michalski, D. and Auer, S. and Friedl, A. A. and Schmid, E. and Molls, M. and Röper, B.},
title = {The effectiveness of 20 MeV protons at nanosecond pulse lengths in producing chromosome aberrations in human-hamster hybrid cells},
booktitle = {Radiation Research},
journal = {Radiation Research},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011},
volume = {175},
number = {6},
pages = {719--727},
url = {http://www.bioone.org/doi/10.1667/RR2465.1},
doi = {https://doi.org/10.1667/RR2465.1}
}
|
|
Double-strand break-induced transcriptional silencing is associated with loss of tri-methylation at H3K4 D. Seiler, J. Rouquette, V. Schmid, H. Strickfaden, C. Ottmann, G. Drexler, B. Mazurek, C. Greubel, V. Hable, G. Dollinger, T. Cremer and A. Friedl; Chromosome Research 19 (7) (2011) 883-899. |
| Abstract: Epigenetic alterations induced by ionizing radiation may contribute to radiation carcinogenesis. To detect relative accumulations or losses of constitutive post-translational histone modifications in chromatin regions surrounding DNA double-strand breaks (DSB), we developed a method based on ion microirradiation and correlation of the signal intensities after immunofluorescence detection of the histone modification in question and the DSB marker γ-H2AX. We observed after ionizing irradiation markers for transcriptional silencing, such as accumulation of H3K27me3 and loss of active RNA polymerase II, at chromatin regions labeled by γ-H2AX. Confocal microscopy of whole nuclei and of ultrathin nuclear sections revealed that the histone modification H3K4me3, which labels transcriptionally active regions, is underrepresented in γ-H2AX foci. While some exclusion of H3K4me3 is already evident at the earliest time amenable to this kind of analysis, the anti-correlation apparently increases with time after irradiation, suggesting an active removal process. Focal accumulation of the H3K4me3 demethylase, JARID1A, was observed at damaged regions inflicted by laser irradiation, suggesting involvement of this enzyme in the DNA damage response. Since no accumulation of the repressive mark H3K9me2 was found at damaged sites, we suggest that DSB-induced transcriptional silencing resembles polycomb-mediated silencing rather than heterochromatic silencing. |
BibTeX:
@article{Seiler2011,
author = {Seiler, D.M. and Rouquette, J. and Schmid, V.J. and Strickfaden, H. and Ottmann, C. and Drexler, G.A. and Mazurek, B. and Greubel, C. and Hable, V. and Dollinger, G. and Cremer, T. and Friedl, A.A.},
title = {Double-strand break-induced transcriptional silencing is associated with loss of tri-methylation at H3K4},
journal = {Chromosome Research},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2011},
volume = {19},
number = {7},
pages = {883--899},
url = {http://link.springer.com/article/10.1007%2Fs10577-011-9244-1},
doi = {https://doi.org/10.1007/s10577-011-9244-1}
}
|
2010 |
|
Quantitative Analyse der LET- und Strahlungsdosisabhängigkeit von Proteinkinetiken nach Ionenmikrobestrahlung Christian Burgdorf; Diplomarbeit, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2010. |
| Abstract: In dieser Arbeit wurde eine quantitative Analyse von Proteinkinetiken nach Ionenmikrobestrahlung hinsichtlich einer LET- und Strahlungsdosisabhängigkeit durchgeführt. Zur Auswertung der ablaufenden Reparaturprozesse wurden die mit dem Rasterionenmikroskop SNAKE fluoreszenzmikroskopisch aufgenommenen Zeitserien analysiert. In diesen Zeitserien bildeten sich in bestrahlten Bereichen innerhalb von verschiedenen Zeitintervallen Foci aus. Diese Foci beschreiben Orte, in denen sich die Konzentration von Proteinen erhöht, was mit der Anlagerung von Reparaturproteinen an beschädigten DNA-Sequenzen gleich zusetzen ist. Bei Beobachtung dieser Focibildung wurde des Weiteren deutlich, dass die Foci mit den Bestrahlungsorten kolokalisieren. In dieser Arbeit wurden die Kinetiken der Proteine MDC1 und 53BP1 mit Hilfe von Helligkeitsmessungen ihrer Foci ausgewertet. Eine entwickelte Modellfunktion wurde an die gemessenen Helligkeitsverläufe angepasst. Die Proteinanlagerung und der Proteinabbau wurden mit Hilfe von zwei Zeitkonstanten Tau_1 und Tau_2 charakterisiert. Eine mögliche zeitliche Verzögerung beim Start des Reparaturvorganges konnte mit einem Zeitoffset T0 modelliert werden. Zum Abschluss der Helligkeitsmessungen wurden probenübergeifend einzelne Bestrahlungsexperimente zusammengefasst, die unter gleichen biophysikalischen Bedingungen durchgeführt wurden. Die Klassifizierung erfolgte nach der verwendeten Strahlungsart und -dosis sowie nach dem untersuchten Reparaturprotein. Hinsichtlich einer LET- und Strahlungsdosisabhängigkeit konnten für das Reparaturprotein MDC1 nach 20MeV H+, wie auch bei einer 55MeV C+ Bestrahlung, Abhängigkeiten festgestellt werden. Dabei zeigte sich für die Bestrahlung mit H+, dass die Erhöhung der Strahlungsdosis von 4,8 Gy auf 12,05 Gy (Faktor 2,5) eine Beschleunigung der Anlagerungszeit Tau_1,( 4,8 Gy) = 1052 ± 272 s zu Tau_1,(12,05 Gy) = 522 ± 148 s zur Folge hatte. Das Starten der Reparaturprozesse hingegen war nahezu konstant nach einem Zeitoffset von T0,(4,8 Gy) = 73 ± 16 s und T0,(12,05 Gy) = 80 ± 11 s. Für die Zeitkonstanten nach 55MeV C+ Bestrahlung zeigte sich ein ähnliches Bild, wobei deutlich wurde, dass weitaus geringere Strahlungsdosen nötig waren, um vergleichsweise schnelle Reaktionen für die Proteinanlagerung zu erreichen. Die Zeit für den Anlagerungsprozess wurde mit steigender Strahlungsdosis weiter verringert. Bei einer Dosis von 3,1Gy betrug Tau_1,(3,1 Gy) = 218 ± 55 s, die sich bei der Dosis von 4,4 Gy auf Tau_1,(4,4 Gy) = 98 ± 11 s verringerte. Eine signifikante Dosisabhängigkeit für die Offset-Zeiten T0 konnte nicht bestimmt werden (T0,(3,1 Gy) = 14 ± 4 s, T0,(4,4 Gy) = 17 ± 2 s). Die Auswertung des zweiten Reparaturproteins 53BP1 erbrachte für die Bestrahlung mit 20MeV H+ keine linearen Dosisabhängigkeiten. Die Werte für die Zeitkonstanten Tau_1 liegen in niedrigen (3,4 Gy) und hohen Strahlungsdosisbereichen (13,7 Gy) nahezu konstant bei Tau_1,(3,4 Gy) = 237 ± 33 s und Tau_1,(13,7 Gy) = 226 ± 60 s. Für den mittleren Dosisbereich ist mit Tau_1,(6,9 Gy) = 460 ± 100 s die benötigte Zeit für die Proteinanlagerung doppelt so groß. Derselbe Effekt ist auch bei der Offset-Zeit T0 zu erkennen (T0, 3,4 Gy = 118 ± 14 s, T0, 6,9 Gy = 160 ± 12 s, T0, 13,7 Gy = 120 ± 22 s). Die Auswertung des 53BP1 nach 55 MeVC+ Bestrahlung erbrachte ein Tau_1,(6,3 Gy) = 375 ± 58 s und einen Zeitoffset T0,(6,3 Gy) = 89 ± 8 s. Dabei wurde deutlich, dass sich die Zeitkonstanten für unterschiedliche Strahlungsarten trotz einer ähnlichen applizierten Strahlungsdosis stark unterschieden. Dennoch zeigte sich, wie bei der Untersuchung von MDC1, dass 55MeV C+ bestrahlte 53BP1 Proben eine schnellere Reaktion zeigten. |
BibTeX:
@mastersthesis{Burgdorf2010da,
author = {Burgdorf, Christian},
title = {Quantitative Analyse der LET- und Strahlungsdosisabhängigkeit von Proteinkinetiken nach Ionenmikrobestrahlung},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2010}
}
|
|
Life cell micro-irradiation G. Dollinger; Nuclear Physics News 20 (3) (2010) 27-32. |
| Abstract: A main subject of modern experiments in radiobiology is the detailed investigation of the biological response on a microscopic scale when a living organism is irradiated by ionizing radiation. As known for long, a DNA double strand break (DSB) is one of the most harmful threats that can be induced by ionizing radiation (Figure 1a). Thus, the response of cells to DSBs on a microscopic scale interests in view of cell surveillance strategies. There are already a lot of proteins known that are omnipresent in cell nuclei and that are involved in the repair of DSBs. Some of them cluster around a DSB forming a “repair focus” (Figure 1b). The spatio-temporal development of the repair processes and the interaction of the different proteins within repair pathways are to a large extent still unknown. A precise irradiation of cells by means of a nuclear microprobe, for example, using SNAKE ( S uperconducting N anoscope for A pplied nuclear ( K ern-) physics E xperiments) at the Munich tandem accelerator, is an ideal tool to perform accurate radiobiological experiments and to investigate cell surveillance strategies in general [1]. |
BibTeX:
@article{Dollinger2010,
author = {Dollinger, G.},
title = {Life cell micro-irradiation},
journal = {Nuclear Physics News},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2010},
volume = {20},
number = {3},
pages = {27--32},
note = {cited By (since 1996)0},
url = {http://www.nupecc.org/index.php?display=npn/issues},
doi = {https://doi.org/10.1080/10619127.2010.506125}
}
|
|
Differences in the kinetics of γ-H2AX fluorescence decay after exposure to low and high LET radiation T.E. Schmid, G. Dollinger, W. Beisker, V. Hable, C. Greubel, S. Auer, A. Mittag, A. Tarnok, A.A. Friedl, M. Molls and B. Röper; International Journal of Radiation Biology 86 (8) (2010) 682-691. |
| Abstract: Purpose: In order to obtain more insight into heavy ion tumour therapy, some features of the underlying molecular mechanisms controlling the cellular response to high linear energy transfer (LET) radiation are currently analysed. Materials and methods: Results: Conclusion: |
BibTeX:
@article{Schmid2010,
author = {Schmid, Thomas E. and Dollinger, Günther and Beisker, Wolfgang and Hable, Volker and Greubel, Christoph and Auer, Susanne and Mittag, Anja and Tarnok, Attila and Friedl, Anna A. and Molls, Michael and Röper, Barbara},
title = {Differences in the kinetics of γ-H2AX fluorescence decay after exposure to low and high LET radiation},
journal = {International Journal of Radiation Biology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2010},
volume = {86},
number = {8},
pages = {682--691},
note = {PMID: 20569192},
url = {http://informahealthcare.com/doi/abs/10.3109/09553001003734543},
doi = {https://doi.org/10.3109/09553001003734543}
}
|
|
Relative biological effectiveness of pulsed and continuous 20 MeV protons for micronucleus induction in 3D human reconstructed skin tissue T.E. Schmid, G. Dollinger, V. Hable, C. Greubel, O. Zlobinskaya, D. Michalski, M. Molls and B. Röper; Radiotherapy and Oncology 95 (1) (2010) 66-72. |
| Abstract: Background and purpose: Laser accelerated radiotherapy is a prospect for cancer treatment with proton and/or carbon ion beams that is currently under fast development. In principal, ultra fast, high-energy laser pulses will lead to a "pulsed" delivery of the induced ion beam with pulse durations of 1 ns and below, whereas conventional proton beams deriving from a cyclotron or synchrotron apply the dose within 100 ms ("continuous"). Materials and methods: A simulation of both irradiation modes could be established at the Munich tandem accelerator with a 20 MeV proton beam, and a wide-field fast scanning system was implemented that allowed for application of up to 5 Gy per tissue voxel in a single pulse. The relative biological effectiveness (RBE) of pulsed and continuous modes of irradiation with 20 MeV protons relative to the reference radiation 70 kV X-rays was examined in a human tissue model (3D human reconstructed skin, EpiDermFT™) which preserves the three-dimensional geometric arrangement and communication of cells present in tissues in vivo. Using the induction of micronuclei (MN) in keratinocytes as the biological endpoint, the RBE was calculated as the ratio between the dose of 70 kV X-rays and 3 Gy of 20 MeV protons (pulsed or continuous) which produced equal response. Results: For pulsed and continuous 20 MV proton exposures of the human skin model, RBE values of 1.08 ± 0.20 and 1.22 ± 0.15 versus 70 kV X-rays were obtained in a first experiment and 1.00 ± 0.14 and 1.13 ± 0.14 in a second experiment during distinct beam access times, respectively. The ∼10% difference in RBE between the respective irradiation modes in both experiments was associated with large uncertainties which were not statistically significant (p ≈ 0.5). Conclusion: These findings represent an important step on the way towards application of laser-accelerated protons for clinical radiotherapy. Further clinically relevant endpoints in normal and tumor tissue have to be evaluated. |
BibTeX:
@article{Schmid2010a,
author = {Schmid, Thomas E. and Dollinger, Günther and Hable, Volker and Greubel, Christoph and Zlobinskaya, Olga and Michalski, Dörte and Molls, Michael and Röper, Barbara},
title = {Relative biological effectiveness of pulsed and continuous 20 MeV protons for micronucleus induction in 3D human reconstructed skin tissue},
journal = {Radiotherapy and Oncology},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2010},
volume = {95},
number = {1},
pages = {66--72},
url = {http://www.sciencedirect.com/science/article/pii/S0167814010001623},
doi = {https://doi.org/10.1016/j.radonc.2010.03.010}
}
|
|
Tumorbestrahlung mit gepulsten und kontinuierlichen Protonen am Mausmodell. Christian Siebenwirth; Diplomarbeit, Technische Universität München, 2010. |
| Abstract: Zur Qualifizierung der Tumortherapie mit gepulsten Protonenstrahlen mit Pulsbreiten von 1 ns, wie sie bei der Laserbeschleunigung erzeugt werden, wurden am Münchner 14 MV Tandembeschleuniger menschliche Tumore am Mausmodell mit 20 Gy bestrahlt. Anhand des Parameters der Tumorwachstumsverzögerung wurde überprüft, ob ein Unterschied in der relativen biologischen Wirksamkeit (RBW) zwischen Protonenstrahlung, die ihre Dosis in Pulsen der Breite von 1 ns applizieren, und kontinuierlicher Protonenbestrahlung auftritt. Da es noch keine laserbeschleunigten Ionenstrahlen in hinreichender Qualität gibt, um eine Tumorbestrahlung durchzuführen, wurde am Rasterionenmikroskop SNAKE ein laserbeschleunigter Protonenstrahl simuliert. Dazu wurde das 5 MHz Pulsungssystem des Tandembeschleunigers verwendet, das ein 23 MeV Protonenstrahl mit einer Pulsbreite von 1 ns erzeugt. Durch die Fokussierung des Strahls an SNAKE auf einen Durchmesser von 100 μm konnte in einem einzelnen Puls eine Ionenstrahldichte von 10^9 Protonen/cm² erreicht werden und so eine Dosis von 20 Gy mit einem Puls im Target deponiert werden. Die Strahlflecke wurden in lateraler Richtung durch Strahlablenkung und Bewegen des Tumors inklusive Maus zu einem homogenen Feld von ca. 1 cm² zusammengesetzt. Die homogene Tiefendosis wurde mittels Aluminiumplättchen als diskrete Energieabsorber kurz vor dem Target verwirklicht. So besaß das homogen bestrahlte Gesamtvolumen eine Tiefe von 4,8 mm und einen Durchmesser von 9 mm. Durch die Realisierung der kontinuierlichen Protonenbestrahlung am selben Gerät, wurden systematische Fehler im Vergleich der beiden Bestrahlungsarten minimiert. Zur Kontrolle der Protonenfluenz diente ein vor dem Tumor platzierter Gafchromic EBT2 Film, der in Abhängigkeit von der durch die Protonen deponierten Dosis verdunkelt. Damit konnte die Dosis der gepulsten und kontinuierlichen Bestrahlung mit einer relativen Genauigkeit von 3 % rekonstruiert werden. Es wurden insgesamt 11 XF354 und 12 FaDu Tumore bestrahlt, davon 12 im gepulsten und 11 im kontinuierlichen Modus. Die sich aus der Dosisrekonstruktion ergebende mittlere Tiefendosis lag für die gepulsten Bestrahlungen durchschnittlich bei 17,6 Gy mit einer Breite von 0,2 Gy bzw. für die kontinuierliche Bestrahlung bei 19,6 Gy mit einer Breite von 0,3 Gy. Annähernd die Hälfte des 10 % Dosisunterschieds zwischen gepulst und kontinuierlicher Bestrahlung konnten auf systematische Fehler der Bestrahlungsdurchführung und der Dosisrekonstruktion zurückgeführt werden. Diese sind in zukünftigen Experimenten einfach zu korrigieren. Die andere Hälfte liegt vermutlich in der Strahlstrommessung begründet und sollte nach näheren Untersuchungen ebenfalls reduziert werden können. Bei den XF354 Tumoren erreichte ein Tumor je Bestrahlungsmodus das dreifache Bestrahlungsvolumen, das für die Wachstumsverzögerung als Bezugspunkt dient, wobei die Wachstumsverzögerung 103 d für die gepulste und 35 d für die kontinuierliche Bestrahlung ergab. Die übrigen Tumore wurden kontrolliert, wodurch sich wegen der geringen Statistik keine Aussage über eine unterschiedliche RBW treffen lässt. Für die FaDu Tumore konnte eine mittlere Wachstumsverzögerung von (34 ± 4) d aus fünf gepulst bestrahlten und (36 ± 4) d aus vier kontinuierlich bestrahlten nicht kontrollierten Tumoren bestimmt werden. Die gewonnenen Ergebnisse zeigen keinen signifikanten Unterschied bezüglich der Tumorwachstumsverzögerung von gepulster und kontinuierlicher Protonenbestrahlung. |
BibTeX:
@mastersthesis{Siebenwirth2010da,
author = {Siebenwirth, Christian},
title = {Tumorbestrahlung mit gepulsten und kontinuierlichen Protonen am Mausmodell.},
school = {Technische Universität München},
year = {2010}
}
|
2009 |
|
Nanosecond pulsed proton microbeam G. Dollinger, A. Bergmaier, V. Hable, R. Hertenberger, C. Greubel, A. Hauptner and P. Reichart; Nuclear Instruments and Methods in Physics Research Section B 267 (12-13) (2009) 2008-2012. |
| Abstract: We show the preparation of a pulsed 20 MeV proton beam at the Munich tandem accelerator which offers a fluence of more than 1 × 10e9 protons/cm2 being deposited in a beam spot smaller than 100 μm in diameter and within a time span of 0.9 ns fwhm. Such a beam is produced by an ECR type proton source using charge exchange in cesium vapor to obtain a beam of negative hydrogen of high brightness that is bunched, chopped, accelerated and then focused by the superconducting multipole lens of the microprobe SNAKE. Single beam pulses are generated in order to irradiate cell samples or tissue and to measure their biological effect in comparison to continuous proton or X-ray irradiation. |
BibTeX:
@article{Dollinger2009,
author = {Dollinger, G. and Bergmaier, A. and Hable, V. and Hertenberger, R. and Greubel, C. and Hauptner, A. and Reichart, P.},
title = {Nanosecond pulsed proton microbeam},
booktitle = {Proceedings of the 11th International Conference on Nuclear Microprobe Technology and Applications and the 3rd International Workshop on Proton Beam Writing},
journal = {Nuclear Instruments and Methods in Physics Research Section B},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2009},
volume = {267},
number = {12-13},
pages = {2008--2012},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X09003310},
doi = {https://doi.org/10.1016/j.nimb.2009.03.006}
}
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|
The live cell irradiation and observation setup at SNAKE V. Hable, C. Greubel, A. Bergmaier, P. Reichart, A. Hauptner, R. Krücken, H. Strickfaden, S. Dietzel, T. Cremer, G. Drexler, A. Friedl and G. Dollinger; Nuclear Instruments and Methods in Physics Research Section B 267 (12-13) (2009) 2090-2097. |
| Abstract: We describe a new setup at the ion microprobe SNAKE (Superconducting Nanoscope for Applied nuclear (Kern-) physics Experiments) at the Munich 14 MV Tandem accelerator that facilitates both living cell irradiation with sub micrometer resolution and online optical imaging of the cells before and after irradiation by state of the art phase contrast and fluorescence microscopy. The cells are kept at standard cell growth conditions at 37 °C in cell culture medium. After irradiation it is possible to switch from single ion irradiation conditions to cell observation within 0.5 s. First experiments were performed targeting substructures of a cell nucleus that were tagged by TexasRed labeled nucleotides incorporated in the cellular DNA by 55 MeV single carbon ion irradiation. In addition we show first online sequences of short time kinetics of Mdc1 protein accumulation in the vicinity of double strand breaks after carbon ion irradiation. |
BibTeX:
@article{Hable2009,
author = {Hable, V. and Greubel, C. and Bergmaier, A. and Reichart, P. and Hauptner, A. and Krücken, R. and Strickfaden, H. and Dietzel, S. and Cremer, T. and Drexler, G.A. and Friedl, A.A. and Dollinger, G.},
title = {The live cell irradiation and observation setup at SNAKE},
booktitle = {Proceedings of the 11th International Conference on Nuclear Microprobe Technology and Applications and the 3rd International Workshop on Proton Beam Writing},
journal = {Nuclear Instruments and Methods in Physics Research Section B},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2009},
volume = {267},
number = {12-13},
pages = {2090--2097},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X09003504},
doi = {https://doi.org/10.1016/j.nimb.2009.03.071}
}
|
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No Evidence for a Different RBE between Pulsed and Continuous 20 MeV Protons T.E. Schmid, G. Dollinger, A. Hauptner, V. Hable, C. Greubel, S. Auer, A.A. Friedl, M. Molls and B. Röper; Radiation Research 172 (5) (2009) 567-574. |
| Abstract: To obtain greater insight into the future potential of tumor radiotherapy using proton beams generated from high-intensity lasers, it is important to characterize the ionization quality of the new beams by measuring the relative biological effectiveness (RBE) under conditions where the full dose at one irradiation site will be deposited by a few proton pulses less than 1 ns in duration. HeLa cells attached to a Mylar foil were irradiated with 70 kV X rays to obtain a reference dose–response curve or with 3 Gy of 20 MeV protons at the Munich tandem accelerator (Garching), either using a continuous mode where a cell sample was irradiated within a 100-ms time span or using a pulsed mode where radiation was given in a single proton pulse of about 1 ns. After irradiation cytochalasin B was added; 24 h later cells were fixed and stained with acridine orange and micronuclei were counted. The X-ray dose–response curve for the production of micronuclei in HeLa cells followed a linear-quadratic model. The corresponding RBE values for 20 MeV protons in pulsed and continuous irradiation modes were 1.07 ± 0.08 and 1.06 ± 0.10 in the first proton experiment and 1.09 ± 0.08 and 1.05 ± 0.11 in the second, respectively. There was no evidence for a difference in the RBE for pulsed and continuous irradiation of HeLa cells with 20 MeV protons. |
BibTeX:
@article{Schmid2009,
author = {Schmid, T. E. and Dollinger, G. and Hauptner, A. and Hable, V. and Greubel, C. and Auer, S. and Friedl, A. A. and Molls, M. and Röper, B.},
title = {No Evidence for a Different RBE between Pulsed and Continuous 20 MeV Protons},
booktitle = {Radiation Research},
journal = {Radiation Research},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2009},
volume = {172},
number = {5},
pages = {567--574},
note = {cited By (since 1996)18},
url = {http://www.bioone.org/doi/10.1667/RR1539.1},
doi = {https://doi.org/10.1667/RR1539.1}
}
|
|
Differences in gamma-H2AX foci formation after irradiation with continuous and pulsed proton beams O. Zlobinskaya, T. Schmid, G. Dollinger, V. Hable, C. Greubel, D. Michalski, J. Wilkens, G. Du, M. Molls and B. Röper; In: , O. Dössel and W.C. Schlegel (Eds.), IFMBE Proceedings 25 (2009) 142-145 , Springer International Publishing AG. |
| Abstract: Introduction: Classical particle accelerators offer proton pulses of some milliseconds duration. In contrast, the new technology of the high-intensity laser acceleration will produce ultimately shorter particle packages (up to one nanosecond) with substantially lower pulse frequency and higher pulse-dose achievement. Very little is known about the relative biological effectiveness (RBE) of this new beam quality, which could be a possible future application in radiation oncology. In our present study we investigate possible differences based on quantitative analysis of γ-H2AX fluorescence - a known marker of DNA double strand breaks (DSBs). Methods: HeLa cells were irradiated with 1 Gy of 20 MeV protons at the Munich tandem accelerator, either at continuous mode (100 ms), or at pulsed mode with a single pulse of 1 ns duration. A dose-effect-curve based on five doses of 75 kV x-rays served for reference. The total number of γ-H2AX foci per cell was determined using a self-developed macro (ImageJ, NIH, USA). Results: Quantitative analysis of γ-H2AX fluorescence revealed no significant difference (p=0.16) in yield of foci formation after irradiation with pulsed or continuous proton beams. γ-H2AX data for cell samples exposed to 1 Gy of 20 MeV protons at pulsed or continuous irradiation modes were 23.29 ± 2.04 and 26.54 ± 2.54 foci per cell, respectively. The corresponding RBE values for 20 MeV protons were 0.96 ± 0.18 and 1.13 ± 0.21 (p=0.21) for pulsed and continuous irradiation modes. However, the percentage of foci smaller than 5-10 pixels was slightly decreased and foci tended to cluster after irradiation with pulsed protons. Conclusions: Based on γ-H2AX foci formation no significant difference in the RBE between pulsed and continuous proton irradiation beams in HeLa cells has been detected so far. These results are well in line with our data on micronucleus induction in HeLa cells. |
BibTeX:
@inproceedings{Zlobinskaya2009,
author = {Zlobinskaya, O. and Schmid, T.E. and Dollinger, G. and Hable, V. and Greubel, C. and Michalski, D. and Wilkens, J. and Du, G. and Molls, M. and Röper, B.},
title = {Differences in gamma-H2AX foci formation after irradiation with continuous and pulsed proton beams},
booktitle = {IFMBE Proceedings},
publisher = {Springer International Publishing AG},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2009},
volume = {25},
number = {3},
pages = {142--145},
editor = {Olaf Dössel and Wolfgang C. Schlegel},
note = {World Congress on Medical Physics and Biomedical Engineering: Radiation Protection and Dosimetry, Biological Effects of Radiation; Munich; Germany; 7 September 2009 through 12 September 2009;},
url = {http://link.springer.com/book/10.1007/978-3-642-03902-7},
doi = {https://doi.org/10.1007/978-3-642-03902-7}
}
|
2008 |
|
Quantitative Analyse von Proteinkinetiken nach Bestrahlung lebender Zellen mit energetischen Schwerionen am Rasterionenmikroskop SNAKE Tino Brüning; Diplomarbeit, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2008. |
BibTeX:
@mastersthesis{Bruening2008da,
author = {Brüning, Tino},
title = {Quantitative Analyse von Proteinkinetiken nach Bestrahlung lebender Zellen mit energetischen Schwerionen am Rasterionenmikroskop SNAKE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2008}
}
|
|
Realisierung einer Schnittstelle für die externe Steuerung der Software AxioVision 4.6.3 in Verbindung mit dem Rasterionenmikroskop SNAKE Christian Burgdorf; Studienarbeit, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2008. |
BibTeX:
@thesis{Burgdorf2008sa,
author = {Burgdorf, Christian},
title = {Realisierung einer Schnittstelle für die externe Steuerung der Software AxioVision 4.6.3 in Verbindung mit dem Rasterionenmikroskop SNAKE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2008}
}
|
|
Quantitative analysis of DNA-damage response factors after sequential ion microirradiation C. Greubel, V. Hable, G.A. Drexler, A. Hauptner, S. Dietzel, H. Strickfaden, I. Baur, R. Krücken, T. Cremer, A.A. Friedl and G. Dollinger; Radiation and Environmental Biophysics 47 (4) (2008) 415-422. |
| Abstract: Several proteins are known to form foci at DNA sites damaged by ionizing radiation. We study DNA damage response by immunofluorescence microscopy after microirradiation of cells with energetic ions. By using microirradiation, it is possible to irradiate different regions on a single dish at different time-points and to differentiate between cells irradiated earlier and later. This allows to directly compare immunofluorescence intensities in both subsets of cells with little systematic error because both subsets are cultivated and stained under identical conditions. In addition, by using irradiation patterns such as crossing lines, it is possible to irradiate individual cells twice and to differentiate between immunofluorescence signals resulting from the cellular response to the earlier and to the later irradiation event. Here, we describe the quantitative evaluation of immunofluorescence intensities after sequential irradiation. |
BibTeX:
@article{Greubel2008,
author = {Greubel, Christoph and Hable, Volker and Drexler, Guido A. and Hauptner, Andreas and Dietzel, Steffen and Strickfaden, Hilmar and Baur, Iris and Krücken, Reiner and Cremer, Thomas and Friedl, Anna A. and Dollinger, Günther},
title = {Quantitative analysis of DNA-damage response factors after sequential ion microirradiation},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2008},
volume = {47},
number = {4},
pages = {415--422},
url = {http://link.springer.com/article/10.1007%2Fs00411-008-0181-0},
doi = {https://doi.org/10.1007/s00411-008-0181-0}
}
|
|
Competition effect in DNA damage response C. Greubel, V. Hable, G. Drexler, A. Hauptner, S. Dietzel, H. Strickfaden, I. Baur, R. Krücken, T. Cremer, G. Dollinger and A. Friedl; Radiation and Environmental Biophysics 47 (4) (2008) 423-429. |
| Abstract: We have built an ion-microbeam for studies of the nuclear topography and kinetics of double-strand break repair at the single cell level. Here, we show that a first and a second, delayed single ion exposure at different nuclear sites led to comparable accumulations of phospho-ATM, γ-H2AX and Mdc1 at both earlier (e) and later (l) microirradiated sites. In contrast, accumulations of 53BP1 and the recombination protein Rad51 were strongly reduced at l-sites. This apparent competition effect is accompanied by a reduced amount of 53BP1 in undamaged areas of the irradiated nuclei. We suggest that a critically limited pool size combined with strong binding at irradiated sites leads to the exhaustion of unbound factors freely roaming the nuclear space. The undersupply of these factors at l-sites requires in addition a long-lasting binding at e-sites or a weaker binding at l-sites. The observed effects suggest that DNA damage response at individual nuclear sites depends on the time course of damage load. This may have implications for therapeutic radiation treatments. |
BibTeX:
@article{Greubel2008a,
author = {Greubel, C. and Hable, V. and Drexler, G.A. and Hauptner, A. and Dietzel, S. and Strickfaden, H. and Baur, I. and Krücken, R. and Cremer, T. and Dollinger, G. and Friedl, A.A.},
title = {Competition effect in DNA damage response},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2008},
volume = {47},
number = {4},
pages = {423--429},
url = {http://link.springer.com/article/10.1007%2Fs00411-008-0182-z},
doi = {https://doi.org/10.1007/s00411-008-0182-z}
}
|
|
Relative biological effectiveness (RBE) of 20 MeV protons for induction of micronuclei in HeLa cells at continuous and pulsed irradiation modes T.E. Schmid, G. Dollinger, A. Hauptner, V. Hable, C. Greubel, A.A. Friedl, M. Molls and B. Röper; In: , M. Baumann (Ed.), Proceedings des 17. Symposiums Experimentelle Strahlentherapie und Klinische Strahlenbiologie : Dresden, 28. Februar - 01. März 2008 17 (2008) 105-108 , Inst. für Biophysik u. Strahlenbiologie. |
BibTeX:
@inproceedings{Schmid2008,
author = {Schmid, T. E. and Dollinger, G. and Hauptner, A. and Hable, V. and Greubel, C. and Friedl, A. A. and Molls, M. and Röper, B.},
title = {Relative biological effectiveness (RBE) of 20 MeV protons for induction of micronuclei in HeLa cells at continuous and pulsed irradiation modes},
booktitle = {Proceedings des 17. Symposiums Experimentelle Strahlentherapie und Klinische Strahlenbiologie : Dresden, 28. Februar - 01. März 2008},
publisher = {Inst. für Biophysik u. Strahlenbiologie},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2008},
volume = {17},
number = {17},
pages = {105--108},
editor = {Baumann, Michael}
}
|
2007 |
|
Entwicklung von Auswertemethoden zur Bestimmung von Proteinkinetiken nach Zellbestrahlungen am Rasterionenmikroskop SNAKE Tino Brüning; Studienarbeit, Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther, 2007. |
BibTeX:
@thesis{Bruening2007sa,
author = {Brüning, Tino},
title = {Entwicklung von Auswertemethoden zur Bestimmung von Proteinkinetiken nach Zellbestrahlungen am Rasterionenmikroskop SNAKE},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2007}
}
|
2006 |
|
Hydrogen microscopy and analysis of DNA repair using focused high energy ion beams G. Dollinger, A. Bergmaier, A. Hauptner, S. Dietzel, G. Drexler, C. Greubel, V. Hable, P. Reichart, R. Krücken, T. Cremer and A. Friedl; Nuclear Instruments and Methods in Physics Research Section B 249 (1-2) (2006) 270-277. |
| Abstract: The ion microprobe SNAKE (Supraleitendes Nanoskop für Angewandte Kernphysikalische Experimente) at the Munich 14 MV tandem accelerator achieves beam focussing by a superconducting quadrupole doublet and can make use of a broad range of ions and ion energies, i.e. 4-28 MeV protons or up to 250 MeV gold ions. Due to these ion beams, SNAKE is particularly attractive for ion beam analyses in various fields. Here we describe two main applications of SNAKE. One is the unique possibility to perform three-dimensional hydrogen microscopy by elastic proton-proton scattering utilizing high energy proton beams. The high proton energies allow the analysis of samples with a thickness in the 100 μm range with micrometer resolution and a sensitivity better than 1 ppm. In a second application, SNAKE is used to analyse protein dynamics in cells by irradiating live cells with single focussed ions. Fluorescence from immunostained protein 53BP1 is used as biological track detector after irradiation of HeLa cells. It is used to examine the irradiated region in comparison with the targeted region. Observed patterns of fluorescence foci agree reasonably well with irradiation patterns, indicating an overall targeting accuracy of about 2 μm while the beam spot size is less than 0.5 μm in diameter. This performance shows successful adaptation of SNAKE for biological experiments where cells are targeted on a sub-cellular level by energetic ions. |
BibTeX:
@article{Dollinger2006,
author = {Dollinger, G. and Bergmaier, A. and Hauptner, A. and Dietzel, S. and Drexler, G.A. and Greubel, C. and Hable, V. and Reichart, P. and Krücken, R. and Cremer, T. and Friedl, A.A.},
title = {Hydrogen microscopy and analysis of DNA repair using focused high energy ion beams},
booktitle = {Proceedings of the Seventeenth International Conference on Ion Beam Analysis},
journal = {Nuclear Instruments and Methods in Physics Research Section B},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {249},
number = {1-2},
pages = {270--277},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X06004587},
doi = {https://doi.org/10.1016/j.nimb.2006.04.012}
}
|
|
Radiobiological Experiments at the Munich Microprobe SNAKE A.A. Friedl, G.A. Drexler, M. Deutsch, H. Strickfaden, S. Dietzel, T. Cremer, A. Hauptner, R. Krücken, C. Greubel, V. Hable and G. Dollinger; In: Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response , Radiation Research 166 (2006) 668 , Radiation Research Society. |
BibTeX:
@inproceedings{Friedl2006,
author = {Friedl, A. A. and Drexler, G. A. and Deutsch, M. and Strickfaden, H. and Dietzel, S. and Cremer, T. and Hauptner, A. and Krücken, R. and Greubel, C. and Hable, V. and Dollinger, G.},
title = {Radiobiological Experiments at the Munich Microprobe SNAKE},
booktitle = {Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response},
journal = {Radiation Research},
publisher = {Radiation Research Society},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {166},
number = {4},
pages = {668},
url = {http://www.bioone.org/doi/abs/10.1667/RR0683.1},
doi = {https://doi.org/10.1667/RR0683.1}
}
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The Munich Microprobe SNAKE, a Single-Ion Cell Irradiation Facility C. Greubel, V. Hable, G. Dollinger, A. Hauptner, R. Krücken, H. Strickfaden, S. Dietzel, T. Cremer, G.A. Drexler, M. Deutsch and A.A. Friedl; In: Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response , Radiation Research 166 (2006) 654 , Radiation Research Society. |
BibTeX:
@inproceedings{Greubel2006,
author = {Greubel, C. and Hable, V. and Dollinger, G. and Hauptner, A. and Krücken, R. and Strickfaden, H. and Dietzel, S. and Cremer, T. and Drexler, G. A. and Deutsch, M. and Friedl, A. A.},
title = {The Munich Microprobe SNAKE, a Single-Ion Cell Irradiation Facility},
booktitle = {Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response},
journal = {Radiation Research},
publisher = {Radiation Research Society},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {166},
number = {4},
pages = {654},
url = {http://www.bioone.org/doi/abs/10.1667/RR0683.1},
doi = {https://doi.org/10.1667/RR0683.1}
}
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Dynamics of DNA Repair Proteins after Directed Heavy-Ion Cell Irradiation. V. Hable, G. Dollinger, C. Greubel, A. Hauptner, R. Krücken, S. Dietzel, T. Cremer, G.A. Drexler and A.A. Fried; In: Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response , Radiation Research 166 (2006) 676 , Radiation Research Society. |
BibTeX:
@inproceedings{Hable2006,
author = {Hable, V. and Dollinger, G. and Greubel, C. and Hauptner, A. and Krücken, R. and Dietzel, S. and Cremer, T. and Drexler, G. A. and Fried, A. A.},
title = {Dynamics of DNA Repair Proteins after Directed Heavy-Ion Cell Irradiation.},
booktitle = {Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response},
journal = {Radiation Research},
publisher = {Radiation Research Society},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {166},
number = {4},
pages = {676},
url = {http://www.bioone.org/doi/abs/10.1667/RR0683.1},
doi = {https://doi.org/10.1667/RR0683.1}
}
|
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Methods for quantitative evaluation of dynamics of repair proteins within irradiated cells V. Hable, G. Dollinger, C. Greubel, A. Hauptner, R. Krücken, S. Dietzel, T. Cremer, G. Drexler, A. Friedl and R. Löwe; Nuclear Instruments and Methods in Physics Research Section B 245 (1) (2006) 298-301. |
| Abstract: Living HeLa cells are irradiated well directed with single 100 MeV oxygen ions by the superconducting ion microprobe SNAKE, the Superconducting Nanoscope for Applied Nuclear (=Kern-) Physics Experiments, at the Munich 14 MV tandem accelerator. Various proteins, which are involved directly or indirectly in repair processes, accumulate as clusters (so called foci) at DNA-double strand breaks (DSBs) induced by the ions. The spatiotemporal dynamics of these foci built by the phosphorylated histone γ-H2AX are studied. For this purpose cells are irradiated in line patterns. The γ-H2AX is made visible under the fluorescence microscope using immunofluorescence techniques. Quantitative analysis methods are developed to evaluate the data of the microscopic images in order to analyze movement of the foci and their changing size. |
BibTeX:
@article{Hable2006a,
author = {Hable, V. and Dollinger, G. and Greubel, C. and Hauptner, A. and Krücken, R. and Dietzel, S. and Cremer, T. and Drexler, G.A. and Friedl, A.A. and Löwe, R.},
title = {Methods for quantitative evaluation of dynamics of repair proteins within irradiated cells},
booktitle = {Proceedings of the Sixth International Symposium on Swift Heavy Ions in Matter (SHIM 2005)},
journal = {Nuclear Instruments and Methods in Physics Research Section B},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {245},
number = {1},
pages = {298--301},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X05020628},
doi = {https://doi.org/10.1016/j.nimb.2005.11.118}
}
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Spatial Distribution of DNA Double-Strand Breaks from Ion Tracks A. Hauptner, W. Friedland, S. Dietzel, G.A. Drexler, C. Greubel, V. Hable, H. Strickfaden, T. Cremer, A.A. Friedl, R. Krücken, H.G. Paretzke and G. Dollinger; In: P. Sigmund (Ed.), Ion Beam Science: Solved and Unsolved Problems , Vol. 52 , p. 59-85 , Royal Danish Academy of Sciences and Letter , 2006. |
| Abstract: Theoretical and experimental approaches are developed to investigate the spatial distribution of DNA damage induced by energetic ions in cell nuclei, with a special emphasis on DNA double-strand breaks (DSB). Using a phenomenological description for the relationship between energy dose and DSB induction, the total number of DSBs and their average number per unit pathlength can be calculated analytically for single ion tracks in cell nuclei. A simple approach to microscopic DNA damage description is offered by analytical representations which give the average energy dose in dependence of the radial distance from the ion track. However, the extreme fluctuations in the DNA damage per volume, which is due to the inhomogeneous ionisation events of the individual secondary electron paths and the structure of chromatin in the nucleus, make a true follow-up of the ionisation and excitation events desirable, e.g. by using Monte Carlo methods. The visualisation of DSBs by staining proteins which accumulate in large amounts at DSB repair sites, thus forming so-called foci, allows to analyse the spatial distribution of DSB sites under the fluorescence microscope. With this method, generally a much lower number of DSB sites along an ion track is observed than expected on basis of calculations. This observation hints at insufficient consideration of gross structures in the organisation of nuclear DNA or at a fast clustering of DSBs, possibly to form repair factories. |
BibTeX:
@incollection{Hauptner2006,
author = {Hauptner, A. and Friedland, W. and Dietzel, S. and Drexler, G. A. and Greubel, C. and Hable, V. and Strickfaden, H. and Cremer, T. and Friedl, A. A. and Krücken, R. and Paretzke, H. G. and Dollinger, G.},
title = {Spatial Distribution of DNA Double-Strand Breaks from Ion Tracks},
booktitle = {Ion Beam Science: Solved and Unsolved Problems},
publisher = {Royal Danish Academy of Sciences and Letter},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {52},
pages = {59--85},
editor = {P. Sigmund},
url = {http://www.sdu.dk/Bibliotek/matfys}
}
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DNA-repair protein distribution along the tracks of energetic ions A. Hauptner, R. Krücken, C. Greubel, V. Hable, G. Dollinger, G. Drexler, M. Deutsch, R. Löwe, A. Friedl, S. Dietzel, H. Strickfaden and T. Cremer; Radiation Protection Dosimetry 122 (1-4) (2006) 147-149. |
| Abstract: A simple model of homogenous chromatin distribution in HeLa-cell nuclei suggests that the track of an energetic ion hits 30 nm chromatin fibers with a mean distance of 0.55 μm. To test this assumption, living HeLa-cells were irradiated at the irradiation setup of the ion microprobe SNAKE using the ion beams provided by the Munich 14 MV tandem accelerator. After irradiation, the distribution of 53BP1 protein foci was studied by immunofluorescence. The observed 53BP1 distribution along the tracks of 29 MeV 7Li ions and 24 MeV 12C ions differed significantly from the expectations resulting from the simple chromatin model, suggesting that the biological track structure is determined by cell nuclear architecture with higher order organisation of chromatin. |
BibTeX:
@article{Hauptner2006a,
author = {Hauptner, A. and Krücken, R. and Greubel, C. and Hable, V. and Dollinger, G. and Drexler, G.A. and Deutsch, M. and Löwe, R. and Friedl, A.A. and Dietzel, S. and Strickfaden, H. and Cremer, T.},
title = {DNA-repair protein distribution along the tracks of energetic ions},
journal = {Radiation Protection Dosimetry},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {122},
number = {1-4},
pages = {147--149},
url = {http://rpd.oxfordjournals.org/content/122/1-4/147.abstract},
doi = {https://doi.org/10.1093/rpd/ncl420}
}
|
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Irradiation of living cells with single ions at the ion microprobe SNAKE A. Hauptner, T. Cremer, M. Deutsch, S. Dietzel, G. Drexler, C. Greubel, V. Hable, R. Krücken, R. Löwe, H. Strickfaden, G. Dollinger and A. Friedl; Acta Physica Polonica A 109 (3) (2006) 273-278. |
| Abstract: The irradiation setup at the ion microprobe SNAKE is used to irradiate living cells with single energetic ions. The irradiation accuracy of 0.55 µm and respectively 0.40 µm allows to irradiate substructures of the cell nucleus. By the choice of ion atomic number and energy the irradiation can be performed with a damage density adjustable over more than three orders of magnitude. Immunofluorescence detection techniques show the distribution of proteins involved in the repair of DNA double-strand breaks. In one of the first experiments the kinetics of appearance of irradiation-induced foci in living HeLa cells was examined. In other experiments a new effect was detected which concerned the interaction between irradiation events performed at different time points within the same cell nucleus. |
BibTeX:
@article{Hauptner2006b,
author = {Hauptner, A. and Cremer, T. and Deutsch, M. and Dietzel, S. and Drexler, G.A. and Greubel, C. and Hable, V. and Krücken, R. and Löwe, R. and Strickfaden, H. and Dollinger, G. and Friedl, A.A.},
title = {Irradiation of living cells with single ions at the ion microprobe SNAKE},
journal = {Acta Physica Polonica A},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2006},
volume = {109},
number = {3},
pages = {273--278},
note = {Proceedings of the XL Zakopane School of Physics, Zakopane 2005},
url = {http://przyrbwn.icm.edu.pl/APP/SPIS/a109-3.html},
doi = {0.12693/APhysPolA.109.273}
}
|
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Mikroskopisch genaue Zellbestrahlung mit hochenergetischen Ionen. Andreas Hauptner; Dissertation, Technische Universität München, 2006. |
| Abstract: Im Rahmen der Arbeit wurde die physikalisch-biologische Schädigungswirkung von hochenergetischer Ionenstrahlung in Modell-Zellkernen auf mikroskopischer Ebene abgeschätzt. Zur Durchführung von Bestrahlungsexperimenten wurde am Rasterionenmikroskop SNAKE des Münchener 14 MV Tandembeschleunigers ein Einzel-Ionen-Bestrahlungsaufbau für lebende Zellen realisiert. An HeLa-Zellen konnten damit Bestrahlungen mit einer räumlichen Auflösung von 0,5 µm durchgeführt und mittels Immunofluoreszenz-Methoden Proteine nachgewiesen werden, die an der Reparatur von DNA-Doppelstrangbrüchen beteiligt sind. Dies ermöglichte das Studium der Chromatin-Dynamik an geschädigten Zellkernbereichen sowie die Charakterisierung eines neu entdeckten "Konkurrenzeffekts" der DNA-Reparatur nach fraktionierter Bestrahlung. Durch Änderung der Bestrahlungsgeometrie konnten Schädigungsereignisse in Form sogenannter Foci entlang von Ionenspuren mit hoher Auflösung untersucht und mit Modellrechnungen verglichen werden. |
BibTeX:
@phdthesis{Hauptner2006diss,
author = {Hauptner, Andreas},
title = {Mikroskopisch genaue Zellbestrahlung mit hochenergetischen Ionen.},
school = {Technische Universität München},
year = {2006},
url = {http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:91-diss20060915-1726116123}
}
|
2005 |
|
Microirradiation of cells with energetic heavy ions G. Dollinger, V. Hable, A. Hauptner, R. Krücken, P. Reichart, A. Friedl, G. Drexler, T. Cremer and S. Dietzel; Nuclear Instruments and Methods in Physics Research Section B 231 (1-4) (2005) 195-201. |
| Abstract: The ion microprobe SNAKE (superconducting nanoscope for applied nuclear (Kern) physics experiments) at the Munich 14 MV tandem accelerator achieves beam focusing by a superconducting quadrupole doublet and can make use of a broad range of ions and ion energies, from 20 MeV protons to 200 MeV gold ions. This allows to adjust the number of DNA single strand breaks (SSBs) and double strand breaks (DSBs) per ion and per cell nucleus from about 0.1 DSBs per ion to several 100 DSBs per ion. When irradiating with single 100 MeV 16O ions, the adapted setup permits a fwhm irradiation accuracy of 0.55 μm in x-direction and 0.4 μm in y-direction, as demonstrated by retrospective track etching of polycarbonate foils. The experiments point to investigate protein dynamics after targeted irradiation. As an example for such experiments we show a kind of three dimensional representation of foci of γ-H2AX which are visible 0.5 h after the irradiation with 100 MeV 16O ions took place. It shows the gross correlation with the irradiation pattern but also distinct deviations which are attributed to protein dynamics in the cell. |
BibTeX:
@article{Dollinger2005,
author = {Dollinger, G. and Hable, V. and Hauptner, A. and Krücken, R. and Reichart, P. and Friedl, A.A. and Drexler, G. and Cremer, T. and Dietzel, S.},
title = {Microirradiation of cells with energetic heavy ions},
booktitle = {Proceedings of the 9th International Conference on Nuclear Microprobe Technology and Applications},
journal = {Nuclear Instruments and Methods in Physics Research Section B},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2005},
volume = {231},
number = {1-4},
pages = {195--201},
url = {http://www.sciencedirect.com/science/article/pii/S0168583X05000765},
doi = {https://doi.org/10.1016/j.nimb.2005.01.056}
}
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Dynamik der Verteilung von DNA-Reparaturfaktoren in lebenden Zellen nach fraktionierter Bestrahlung am Rasterionenmikroskop SNAKE Christoph Greubel; Diplomarbeit, Technische Universität München, 2005. |
BibTeX:
@mastersthesis{Greubel2005da,
author = {Greubel, Christoph},
title = {Dynamik der Verteilung von DNA-Reparaturfaktoren in lebenden Zellen nach fraktionierter Bestrahlung am Rasterionenmikroskop SNAKE},
school = {Technische Universität München},
year = {2005}
}
|
2004 |
|
Untersuchung der Dynamik von DNA-Reparaturproteinen nach Bestrahlung lebender Zellen am Rasterionenmikroskop SNAKE. Volker Hable; Diplomarbeit, Technische Universität München, 2004. |
| Abstract: In dieser Arbeit wurde die Dynamik der Reparaturvorgänge von DNA-Schäden in biologischen Zellen nach Schwerionenbestrahlung untersucht. Dazu wurden lebende HeLa-Zellen am Rasterionenmikroskop SNAKE mit 100MeV Sauerstoff-Ionen des Münchner 14MV Tandembeschleuniger bestrahlt. Die dort installierte Bestrahlungseinrichtung ermöglicht es, Zellkernen eine definierte Anzahl von Ionen und somit eine definierte Dosis mikroskopisch genau zu applizieren. Die erreichbare Strahlauflösung konnte im Rahmen dieser Arbeit mittels einer 50 Hz-Pulsung in x auf 0.55μm fwhm und in y auf 0.40μm verbessert werden. Durch die Entwicklung mikrostrukturierter Zellträgerfolien wurde das Auffinden der bestrahlten Zellen deutlich erleichtert und somit erstmals Experimente zur gezielten Bestrahlung einzelner Zellkerne ermöglicht. Die schwersten Schäden, die hochenergetische Ionen in Zellkernen bewirken, sind Doppelstrangbrüche der DNA. Zu deren Reparatur stehen der Zelle verschiedene Mechanismen zur Verfügung. An der Reparatur direkt oder indirekt beteiligte Proteine wie gH2AX, 53BP1, Rad51 und Mdc1 werden an Doppelstrangbrüchen angehängt und bilden sogenannte Foci aus. Ihre Funktion und Dynamik wurde in dieser Arbeit untersucht. Mittels biochemischer Prozesse wurden diese Proteine nach der Bestrahlung angefärbt und unter dem Fluoreszenzmikroskop in einer Fokusserie abgebildet. So gewonnene und rechnergestützt entfaltete, dreidimensionale Bilder lieferten die Grundlage für eine quantitative Auswertung der Proteinverteilungen, um so die Dynamik der Reparaturproteine zu studieren. In Zeitreihenstudien wurde in der Zellkernmitte innerhalb der ersten 2 – 4 Stunden nach Bestrahlung ein Anwachsen der Focigröße (fwhm) von 1.2μm auf 1.5μm bei gH2AX und von 0.8μm auf 1.1μm bei 53BP1 beobachtet. In den folgenden zwei Stunden fällt sie wieder in etwa auf den Anfangswert ab, und bleibt über 24 Stunden nahezu konstant. Am Zellkernrand wächst die Größe der gH2AX-Foci von ebenfalls 1.2μm innerhalb der ersten Stunde um knapp 0.1μm an und fällt daraufhin auf ca. 0.8μm ab. Des weiteren wurde die Bewegung der geschädigten DNA im Zellkern untersucht. Die hierbei gewonnenen Ergebnisse sind mit dem Modell einer Diffusion verträglich. Die Diffusionskonstante ließ sich zu (7 · 10^(−7) ± 4 · 10^(−7))μm^2/s bestimmen. Dabei waren keine signifikanten Unterschiede zwischen Zellkernmitte und -rand erkennbar. Darüber hinaus wurde durch markiertes Bestrahlen zu zwei verschiedenen Zeitpunkten festgestellt, dass in Zellkernen, die gerade Doppelstrangbrüche reparieren, neu hinzukommende Strahlenschäden eine Unterversorgung von Protein 53BP1 erleiden. Dieser Effekt tritt auf, wenn die Zeitdauer zwischen den beiden Bestrahlungen unter einer Stunde liegt. |
BibTeX:
@mastersthesis{Hable2004da,
author = {Hable, Volker},
title = {Untersuchung der Dynamik von DNA-Reparaturproteinen nach Bestrahlung lebender Zellen am Rasterionenmikroskop SNAKE.},
school = {Technische Universität München},
year = {2004}
}
|
|
Microirradiation of cells with energetic heavy ions A. Hauptner, S. Dietzel, G.A. Drexler, P. Reichart, R. Krücken, T. Cremer, A.A. Friedl and G. Dollinger; Radiation and Environmental Biophysics 42 (4) (2004) 237-245. |
| Abstract: The ion microprobe SNAKE at the Munich 14 MV tandem accelerator achieves beam focussing by a superconducting quadrupole doublet and can make use of a broad range of ions and ion energies, from 20 MeV protons to 200 MeV gold ions. Because of these properties, SNAKE is particularly attractive for biological microbeam experiments. Here we describe the adaptation of SNAKE for microirradiation of cell samples. This includes enlarging of the focal distance in order to adjust the focal plane to the specimen stage of a microscope, construction of a beam exit window in a flexible nozzle and of a suitable cell containment, as well as development of procedures for on-line focussing of the beam, preparation of single ions and scanning by electrostatic deflection of the beam. When irradiating with single 100 MeV 16O ions, the adapted set-up permits an irradiation accuracy of 0.91 µm (full width at half maximum) in the x-direction and 1.60 µm in the y-direction, as demonstrated by retrospective track etching of polycarbonate foils. Accumulation of the repair protein Rad51, as detected by immunofluorescence, was used as a biological track detector after irradiation of HeLa cells with geometric patterns of counted ions. Observed patterns of fluorescence foci agreed reasonably well with irradiation patterns, indicating successful adaptation of SNAKE. In spite of single ion irradiation, we frequently observed split fluorescence foci which might be explained by small-scale chromatin movements. |
BibTeX:
@article{Hauptner2004,
author = {Hauptner, A. and Dietzel, S. and Drexler, G. A. and Reichart, P. and Krücken, R. and Cremer, T. and Friedl, A. A. and Dollinger, G.},
title = {Microirradiation of cells with energetic heavy ions},
journal = {Radiation and Environmental Biophysics},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2004},
volume = {42},
number = {4},
pages = {237--245},
url = {http://link.springer.com/article/10.1007%2Fs00411-003-0222-7},
doi = {https://doi.org/10.1007/s00411-003-0222-7}
}
|
|
The Munich Microprobe Setup for Single-Ion Irradiation of Cells A. Hauptner, G. Dollinger, G. Datzmann, H.-J. Körner, R. Krücken and P. Reichart; In: Proceedings of the 6th International Workshop/12th L. H. Gray Workshop: Microbeam Probes of Cellular Radiation ResponseMarch 29–31, 2003 , Radiation Research 161 (2004) 98 , Radiation Research Society. |
BibTeX:
@inproceedings{Hauptner2004a,
author = {Hauptner, A. and Dollinger, G. and Datzmann, G. and Körner, H.-J. and Krücken, R. and Reichart, P.},
title = {The Munich Microprobe Setup for Single-Ion Irradiation of Cells},
booktitle = {Proceedings of the 6th International Workshop/12th L. H. Gray Workshop: Microbeam Probes of Cellular Radiation ResponseMarch 29–31, 2003},
journal = {Radiation Research},
publisher = {Radiation Research Society},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2004},
volume = {161},
number = {1},
pages = {98},
url = {http://www.rrjournal.org/toc/rare/161/1},
doi = {https://doi.org/10.1667/RR3091}
}
|
2002 |
|
Design of the munich microprobe facility for single-ion irradiation of cells A. Hauptner, G. Datzmann, G. Dollinger, H.-J. Körner, P. Reichart and O. Schmelmer; In: Proceedings of the 5th International Workshop: Microbeam Probes of Cellular Radiation Response , Radiation Research 158 (2002) 367 , Radiation Research Society. |
BibTeX:
@inproceedings{Hauptner2002,
author = {Hauptner, A. and Datzmann, G. and Dollinger, G. and Körner, H.-J. and Reichart, P. and Schmelmer, O.},
title = {Design of the munich microprobe facility for single-ion irradiation of cells},
booktitle = {Proceedings of the 5th International Workshop: Microbeam Probes of Cellular Radiation Response},
journal = {Radiation Research},
publisher = {Radiation Research Society},
school = {Universität der Bundeswehr München, Fakultät für Luft- und Raumfahrttechnik, LRT 2 - Institut für Angewandte Physik und Messtechnik, Professur: Dollinger, Günther},
year = {2002},
volume = {158},
number = {3},
pages = {367},
note = {Stresa, Lago Maggiore, Italy,May 26–27, 2001},
url = {http://www.rrjournal.org/toc/rare/158/3},
doi = {https://doi.org/10.1667/0033-7587(2002)158%5B0365:POTIWM%5D2.0.CO;2}
}
|
1999 |
|
Der 0°-Spektrograph am Raster-Ionenmikroskop SNAKE. Andreas Hauptner; Diplomarbeit, Technische Universität München, 1999. |
| Abstract: Das Ziel dieser Arbeit bestand im Aufbau und der Inbetriebnahme des 0°-Spektrographen am Raster-Ionenmikroskop SNAKE. Dieses Instrument erweitert die vielfältigen Anwendungsmöglichkeiten des Ionenmikroskops um Transmissionsmessungen mit einer Energieauflösung im Bereich von dE/E 1 x 10^(-5). Dadurch werden sowohl Dickenmessungen mit Auflösungen bis zu einatomaren Schichten als auch ganz grundlegende Experimente möglich, die sich mit der Wechselwirkung zwischen hochenergetischen Ionen und Materie beschäftigen. Die ionenoptischen Grundlagen des Spektrographen werden ausführlich behandelt. Der vertikale 90°-Magnet als zentrales Element erlaubt dabei eine ionenoptische Abbildung in die Fokalebene mit hoher Qualität. Um die projektierte Energieauflösung zu erreichen, ist jedoch eine weitergehende, flexible Fokussierung des Ionenstrahls notwendig. Daher wurde der Spektrograph durch zwei Quadrupol-Linsen vervollständigt. Um den Spektrographen betreiben zu können, wurde ein CCD (charge coupled device) Zeilensensor als Fokalebenendetektor gewählt. Dieser bietet eine Ortsauflösung von 14µm. Seine prinzipielle Eignung für die Detektion sowohl von leichten wie auch von schweren Ionen wurde experimentell mit 20 MeV Protonen und 90 MeV Schwefelionen nachgewiesen. Bei 20 MeV Protonen konnten dabei effektive Zählraten von ca. 100kHz erreicht werden. Es zeigte sich, dass die Strahlenbeständigkeit des CCD- Detektors ausreicht, um auf einem Pixel des Detektors zwischen 10^7 und 10^8 Protonen nachzuweisen. In ersten Experimenten konnte die Einsetzbarkeit des Spektrographen einschließlich des Fokalebenendetektors demonstriert werden. Mit 20 MeV Protonen wurde eine relative Energieauflösung von dE_(FWHM)/E = 1.3 x 10^(-4) erreicht und Energieverlustmessungen an Goldfolien durchgeführt. Die Auflösung war hier noch durch den Strahl beschränkt. In einer Strahlzeit mit 90 MeV Schwefelionen wurde eine relative Energieauflösung von dE_(FWHM)/E = 3.8 x 10^(-5) erreicht. Dadurch scheint die projektierte Energieauflösung und damit auch der Einsatz des 0°-Spektrographen für die geplanten Experimente in absehbarer Zeit möglich. |
BibTeX:
@mastersthesis{Hauptner1999da,
author = {Hauptner, Andreas},
title = {Der 0°-Spektrograph am Raster-Ionenmikroskop SNAKE.},
school = {Technische Universität München},
year = {1999}
}
|