Search

Abstract A fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with therapeutic beams of positron-emitters of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. An experimental study was performed at the FRS fragment-separator of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of $$^{14}$$ 14 O and $$^{15}$$ 15 O ion beams in a PMMA phantom. The positron activity profile was imaged by a dual-panel version of a Siemens Biograph mCT PET scanner. Results from a similar experiment using ion beams of carbon positron-emitters $$^{11}$$ 11 C and $$^{10}$$ 10 C performed at the same experimental setup were used for comparison. Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for $$^{10}$$ 10 C compared to $$^{11}$$ 11 C and likewise for $$^{14}$$ 14 O compared to $$^{15}$$ 15 O, but their lower production cross-sections make it difficult to produce them at therapeutically relevant intensities. With a similar production cross-section and a 10 times shorter half-life than $$^{11}$$ 11 C, $$^{15}$$ 15 O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to $$^{11}$$ 11 C. A figure of merit formulation was developed for the quantitative comparison of therapy-relevant positron-emitting beams in the context of quasi-real-time beam monitoring. In conclusion, this study demonstrates that among the positron emitters of carbon and oxygen, $$^{15}$$ 15 O is the most feasible candidate for quasi-real-time range monitoring by in-beam PET that can be produced at therapeutically relevant intensities. Additionally, this study demonstrated that the in-flight production and separation method can produce beams of therapeutic quality, in terms of purity, energy, and energy spread.

Introduction: Charged Particle Therapy plays a key role in the treatment of deep-seated tumours, because of the advantageous energy deposition culminating in the Bragg peak. However, knowledge of the dose delivered in the entrance channel is limited by the lack of data on the beam and fragmentation of the target.Methods: The FOOT experiment has been designed to measure the cross sections of the nuclear fragmentation of projectile and target with two different detectors: an electronic setup for the identification of Z ≥ 3 fragments and a nuclear emulsion spectrometer for Z ≤ 3 fragments. In this paper, we analyze the data taken by exposing four nuclear emulsion spectrometers, with C and C2H4 targets, to 200 MeV/n and 400 MeV/n oxygen beams at GSI Helmholtzzentrum für Schwerionenforschung (Darmstadt, Germany), and we report the charge identification of produced fragments based on the controlled fading induced on nuclear emulsion films.Results: The goal of identifying fragments as heavy as lithium has been achieved.Discussion: The results will contribute to a better understanding of the nuclear fragmentation process in charged particle therapy and have implications for refining treatment planning in the presence of deep-seated tumors.

The study of nuclear fragmentation plays a central role in many important applications: from the study of Particle Therapy (PT) up to radiation protection for space (RPS) missions and the design of shielding for nuclear reactors. The FragmentatiOn Of Target (FOOT) collaboration aims to study the nuclear reactions that describe the interactions with matter of different light ions (like H1, He4, C12, O16) of interest for such applications, performing double differential fragmentation cross section measurements in the energy range of interest for PT and RPS. In this manuscript, we present the analysis of the data collected in the interactions of an oxygen ion beam of 400 MeV/u with a graphite target using a partial FOOT setup, at the GSI Helmholtz Center for Heavy Ion Research facility in Darmstadt. During the data taking the magnets, the silicon trackers and the calorimeter foreseen in the final FOOT setup were not yet available, and hence precise measurements of the fragments kinetic energy, momentum and mass were not possible. However, using the FOOT scintillator detectors for the time of flight (TOF) and energy loss (ΔE) measurements together with a drift chamber, used as beam monitor, it was possible to measure the elemental fragmentation cross sections. The reduced detector set-up and the limited available statistics allowed anyway to obtain relevant results, providing statistically significant measurements of cross sections eagerly needed for PT and RPS applications. Whenever possible the obtained results have been compared with existing measurements helping in discriminating between conflicting results in the literature and demonstrating at the same time the proper functioning of the FOOT ΔE-TOF system. Finally, the obtained fragmentation cross sections are compared to the Monte Carlo predictions obtained with the FLUKA software.

Dose build-up effects in the entrance channel of proton Bragg curves were investigated in detail by means of simulations and experiments. There are two relevant dose build-up effects. Firstly, the δ-electron build-up effect which takes place in the first few millimeters of the tissue until an equilibrium state of the forward-scattered δ-electrons is reached. Secondly, the target fragment build-up effect that covers the first centimeters in the entrance channel of the proton Bragg curve. These target fragments are created in inelastic interactions of the beam protons with the target nuclei and partially have low kinetic energies and/or high atomic numbers compared to the incident beam protons. Consequently, the target fragments possess high LET values and thus an increased RBE. However, the production cross sections relevant for target fragmentation in ion beam therapy still have large uncertainties. Therefore, in this work target fragmentation was investigated indirectly by measuring low-noise proton Bragg curves with the focus placed on their build-up regions. The measurements clearly show the magnitude and shape of the two different build-up effects. Additionally, with the application of a magnetic filter, it was possible to separate the measurement of the target fragment build-up effect from the δ-electron build-up effect. Corresponding FLUKA Monte Carlo simulations were carried out for the experimental setup. A comparison of the experimental results with the FLUKA predictions enabled the assessment of the precision of FLUKA models, e.g. the δ-electron production models and the nuclear event generators which are responsible for target fragmentation reactions. It could be shown that the relevant models worked well to reproduce both build-up effects. [ABSTRACT FROM AUTHOR]

In this paper we report the re-analysis of the data published in Piersanti et al (2014 Phys. Med. Biol. 59 1857) documenting the charged secondary particles production induced by the interaction of a 220 MeV/u 12C ion beam impinging on a polymethyl methacrylate (PMMA) target, measured in 2012 at the GSI facility in Darmstadt (Germany). This re-analysis takes into account the inhomogeneous light response of the LYSO crystal in the experimental setup measured in a subsequent experiment (2014) performed in the Heidelberg Ion-Beam Therapy Center. A better description of the detector and re-calculation of the geometrical efficiencies have been implemented as well, based on an improved approach that accounts also for the energy dependence of the emission spectrum. The new analysis has little effect on the total secondary charged flux, but has an impact on the production yield and emission velocity distributions of the different particle species (protons, deuterons and tritons) at different angles with respect to the beam direction ( and ). All these observables indeed depend on the particle identification algorithms and hence on the LYSO detector energy response. The results of the data re-analysis presented here are intended to supersede and replace the results published in Piersanti et al (2014 Phys. Med. Biol. 59 1857). [ABSTRACT FROM AUTHOR]

Background and Purpose: In recent years, ultra-high dose rate (UHDR) irradiation has emerged as a promising innovative approach to cancer treatment. Characteristic feature of this regimen, commonly referred to as FLASH effect, demonstrated primarily for electrons, photons or protons, is the improved normal tissue sparing, while the tumor control is similar to the one of the conventional dose-rate (CDR) treatments. The FLASH mechanism is, however, unknown. One major question is whether this effect is maintained when using densely ionizing (high-LET) heavy nuclei., Materials and Methods: Here we report the effects of 20 Gy UHDR heavy ion irradiation in clinically relevant conditions, i.e., at high-LET in the spread-out Bragg peak (SOBP) of a 12 C beam using an osteosarcoma mouse model., Results: We show that UHDR irradiation was less toxic in the normal tissue compared to CDR while maintaining tumor control. The immune activation was also comparable in UHDR and CDR groups. Both UHDR and CDR exposures steered the metagenome toward a balanced state., Conclusions: These results suggest that the UHDR irradiations can improve the safety and effectiveness of heavy ion therapy, and provide a crucial benchmark for current mechanistic FLASH models. However, additional experiments are needed to validate these findings across other animal and tumor models., (Copyright © 2024. Published by Elsevier Inc.)

Background: Motion of lung tumors during radiotherapy leads to decreased accuracy of the delivered dose distribution. This is especially true for proton radiotherapy due to the finite range of the proton beam. Methods for mitigating motion rely on knowing the position of the tumor during treatment., Purpose: Proton radiography uses the treatment beam, at an energy high enough to traverse the patient, to produce a radiograph. This work shows the first results of using an integrated-mode proton radiography system to track the position of moving objects in an experimental phantom study; demonstrating the potential of using this method for measuring tumor motion., Methods: Proton radiographs of an anthropomorphic lung phantom, with a motor-driven tumor insert, were acquired approximately every 1 s, using tumor inserts of 10, 20, and 30 mm undergoing a known periodic motion. The proton radiography system used a monolithic scintillator block and digital cameras to capture the residual range of each pencil beam passing through the phantom. These ranges were then used to produce a water equivalent thickness map of the phantom. The centroid of the tumor insert in the radiographs was used to determine its position. This measured position was then compared to the known motion of the phantom to determine the accuracy., Results: Submillimeter accuracy on the measurement of the tumor insert was achieved when using a 30 mm tumor insert with a period of 24 s and was found to be improved for decreasing motion amplitudes with a mean absolute error (MAE) of 1.0, 0.9, and 0.7 mm for 20, 15, and 10 mm respectively. Using smaller tumor inserts reduced the accuracy with a MAE of 1.8 and 1.9 mm for a 20 and 10 mm insert respectively undergoing a periodic motion with an amplitude of 20 mm and a period of 24 s. Using a shorter period resulted in significant motion artifacts reducing the accuracy to a MAE of 2.2 mm for a 12 s period and 3.1 mm for a 6 s period for the 30 mm insert with an amplitude of 20 mm., Conclusions: This work demonstrates that the position of a lung tumor insert in a realistic anthropomorphic phantom can be measured with high accuracy using proton radiographs. Results show that the accuracy of the position measurement is the highest for slower tumor motions due to a reduction in motion artifacts. This indicates that the primary obstacle to accurate measurement is the speed of the radiograph acquisition. Although the slower tumor motions used in this study are not clinically realistic, this work demonstrates the potential for using proton radiography for measuring tumor motion with an increased scanning speed that results in a decreased acquisition time., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

A 3D range-modulator (RM), optimized for a single energy and a specific target shape, is a promising and viable solution for the ultra-fast dose delivery in particle therapy. The aim of this work was to investigate the impact of potential beam and modulator misalignments on the dose distribution. Moreover, the FLUKA Monte Carlo model, capable of simulating 3D RMs, was adjusted and validated for the 250 MeV single-energy proton irradiation from a Varian ProBeam system. A 3D RM was designed for a cube target shape rotated 45° around two axes using a Varian-internal research version of the Eclipse treatment planning software, and the resulting dose distribution was simulated in a water phantom. Deviations from the ideal alignment were introduced, and the dose distributions from the modified simulations were compared to the original unmodified one. Finally, the FLUKA model and the workflow were validated with base-line data measurements and dose measurements of the manufactured modulator prototype at the HollandPTC facility in Delft. The adjusted FLUKA model, optimized particularly in the scope of a single-energy FLASH irradiation with a PMMA pre-absorber, demonstrated very good agreement with the measured dose distribution resulting from the 3D RM. Dose deviations resulting from modulator-beam axis misalignments depend on the specific 3D RM and its shape, pin aspect ratio, rotation angle, rotation point, etc. A minor modulator shift was found to be more relevant for the distal dose distribution than for the spread-out Bragg Peak (SOBP) homogeneity. On the other hand, a modulator tilt (rotation away from the beam axis) substantially affected not only the depth dose profile, transforming a flat SOBP into a broad, Gaussian-like distribution with increasing rotation angle, but also shifted the lateral dose distribution considerably. This work strives to increase awareness and highlight potential pitfalls as the 3D RM method progresses from a purely research concept to pre-clinical studies and human trials. Ensuring that gantry rotation and the combined weight of RM, PMMA, and aperture do not introduce alignment issues is critical. Given all the other range and positioning uncertainties, etc., not related to the modulator, the RM must be aligned with an accuracy below 1° in order to preserve a clinically acceptable total uncertainty budget. Careful consideration of critical parameters like the pin aspect ratio and possibly a novel robust modulator geometry optimization are potential additional strategies to mitigate the impact of positioning on the resulting dose. Finally, even the rotated cube 3D modulator with high aspect ratio pin structures (~80 mm height to 3 mm pin base width) was found to be relatively robust against a slight misalignment of 0.5° rotation or a 1.5 mm shift in one dimension perpendicular to the beam axis. Given a reliable positioning and QA concept, the additional uncertainties introduced by the 3D RM can be successfully managed adopting the concept into the clinical routine.

Purpose: The present study aimed to develop a porous structure with plug-ins (PSP) to broaden the Bragg peak width (BPW, defined as the distance in water between the proximal and distal 80% dose) of the carbon ion beam while maintaining a sharp distal falloff width (DFW, defined as the distance along the beam axis where the dose in water reduces from 80% to 20%)., Methods: The binary voxel models of porous structure (PS) and PSP were established in the Monte Carlo code FLUKA and the corresponding physical models were manufactured by 3D printing. Both experiment and simulation were performed for evaluating the modulation capacity of PS and PSP. BPWs and DFWs derived from each integral depth dose curves were compared. Fluence homogeneity of 430 MeV/u carbon-ion beam passing through the PSP was recorded by analyzing radiochromic films at six different locations downstream the PSP in the experiment. Additionally, by changing the beam spot size and incident position on the PSP, totally 48 different carbon-ion beams were simulated and corresponding deviations of beam metrics were evaluated to test the modulating stability of PSP., Results: According to the measurement data, the use of PSP resulted in an average increase of 0.63 mm in BPW and a decrease of 0.74 mm in DFW compared to PS. The 2D radiation field inhomogeneities were lower than 3 % when the beam passing through a ≥ 10 cm PMMA medium. Furthermore, employing a spot size of ≥ 6 mm ensures that beam metric deviations, including BPW, DFW, and range, remain within a deviation of 0.1 mm across various incident positions., Conclusion: The developed PSP demonstrated its capability to effectively broaden the BPW of carbon ion beams while maintaining a sharp DFW comparing to PS. The superior performance of PSP, indicates its potential for clinical use in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation can affect surface-exposed antigen, thereby reducing vaccine efficacy. Gamma rays have been used in the past to inactivate viruses. We recently proposed that high-energy heavy ions may be more suitable as an inactivation method because they increase the damage ratio between the viral nucleic acid and surface proteins. Here, we demonstrate that irradiation of the influenza virus using heavy ion beams constitutes a suitable method to develop effective vaccines, since immunization of mice by the intranasal route with the inactivated virus resulted in the stimulation of strong antigen-specific humoral and cellular immune responses.

The generation of space radiation on Earth is essential to study and predict the effects of radiation on space travelers, electronics, or materials during future long-term space missions. Next to the heavy ions of the galactic cosmic rays, solar particle events play a major role concerning the radiation risk in space, which consist of intermediate-energy protons with broad spectra and energies up to a few hundred MeV. This work describes an approach for the ground-based generation of solar particle events. As a proof of principle, a passive beam modulator with a specific funnel-shaped periodic structure was designed and is used to convert a monoenergetic proton beam into a spectral proton energy distribution, mimicking a solar particle event from August 1972, which is known as one of the strongest recorded SPE events. The required proton beam of 220 MeV can be generated at many existing particle accelerators at research or particle therapy facilities. The planning, manufacturing and testing of the modulator is described step by step. Its correct manufacturing and the characteristics of the solar particle event simulator are tested experimentally and by means of Monte Carlo simulations. Future modulators will follow the same concept with minor adjustments such as a larger lateral extension. As of now, the presented beam modulator is available to the research community to conduct experiments at GSI for exposure under solar particle event conditions. In addition, researchers can use and apply the described concept to design and print their individualized modulator to reproduce any desired solar particle event spectrum or request the presented modulator geometry from the authors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

A fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with therapeutic beams of positron-emitters of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. An experimental study was performed at the FRS fragment-separator of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of [Formula: see text]O and [Formula: see text]O ion beams in a PMMA phantom. The positron activity profile was imaged by a dual-panel version of a Siemens Biograph mCT PET scanner. Results from a similar experiment using ion beams of carbon positron-emitters [Formula: see text]C and [Formula: see text]C performed at the same experimental setup were used for comparison. Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for [Formula: see text]C compared to [Formula: see text]C and likewise for [Formula: see text]O compared to [Formula: see text]O, but their lower production cross-sections make it difficult to produce them at therapeutically relevant intensities. With a similar production cross-section and a 10 times shorter half-life than [Formula: see text]C, [Formula: see text]O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to [Formula: see text]C. A figure of merit formulation was developed for the quantitative comparison of therapy-relevant positron-emitting beams in the context of quasi-real-time beam monitoring. In conclusion, this study demonstrates that among the positron emitters of carbon and oxygen, [Formula: see text]O is the most feasible candidate for quasi-real-time range monitoring by in-beam PET that can be produced at therapeutically relevant intensities. Additionally, this study demonstrated that the in-flight production and separation method can produce beams of therapeutic quality, in terms of purity, energy, and energy spread., (© 2023. The Author(s).)

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15 O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10 -4 15 O fragments per primary 16 O ion accelerated in the synchrotron SIS18 was reached., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objective . Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable 12 C ions, the positron emitters 10,11 C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam. Approach. An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner. Main results. High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes 11 C and 10 C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 10 7 ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for 10 C, 11 C and 12 C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from 11 C to 10 C than when going from 12 C to 11 C. The much better precision for 10 C is due to its much shorter half-life, which, contrary to the case of 11 C, also enables to include the in-spill data in the image formation. Significance . Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics., (Creative Commons Attribution license.)

Purpose: Radiotherapy escalating dose rates above 50Gys -1 , might offer a great potential in treating tumours while further sparing healthy tissue. However, these ultra-high intensities of FLASH-RT lead to new challenges with regard to dosimetry and beam monitoring. FLASH experiments at HIT (Heidelberg Ion Beam Therapy Center) and at GSI (GSI Helmholtz Centre for Heavy Ion Research) have shown a significant loss of signal in the beam monitoring system due to recombination effects. To enable accurate beam monitoring, this work investigates the recombination loss of different fill gases in the plane parallel ionisation chambers (ICs)., Methods: Therefore, saturation curves at high intensities were measured for the currently used fill gases Ar/CO 2 (80/20) and pure He and also for He/CO 2 mixtures as alternative fill gases. Furthermore, breakdown voltages and ion mobilities were measured in ICs filled with He/CO 2 mixtures. A numerical model for volume recombination in plane parallel ionisation chambers was developed and implemented in Python. This includes a novel simulation method of the space charge effect from the charge carriers in the detector volume and predicts a significant effect on the electric field for high intensity beams., Results: Even at high intensities the He/CO 2 mixtures allow operation of the ICs at an electric field strength of 2 kVcm -1 or more which reduces recombination to negligible levels at intensities larger than 3 × 10 10 C-ions per second. Our measurements show that added fractions of CO 12 C-ions per second. Our measurements show that added fractions of CO 2 to He decrease the ion mobility in the fill gas but significantly increase the breakdown voltage in the ICs compared to pure He., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Owing to the favorable depth-dose distribution and the radiobiological properties of heavy ion radiation, ion beam therapy shows an improved success/toxicity ratio compared to conventional radiotherapy. The sharp dose gradients and very high doses in the Bragg peak region, which represent the larger physical advantage of ion beam therapy, make it also extremely sensitive to range uncertainties. The use of β + C and 11 C beams were produced and isotopically separated with the FRagment Separator (FRS) at GSI. The 10 C beams were produced and isotopically separated with the FRagment Separator (FRS) at GSI. The β + C and ∼ 10 6 particle per spill for the 10 C beam, respectively. The impact of different ion optical parameters on the depth dose distribution was studied with a precision water column system. In this work, the measured depth dose distributions are presented together with results from Monte Carlo simulations using the FLUKA software.7 particle per spill for the 11 C beam, respectively. The impact of different ion optical parameters on the depth dose distribution was studied with a precision water column system. In this work, the measured depth dose distributions are presented together with results from Monte Carlo simulations using the FLUKA software., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marco Durante reports financial support was provided by European Research Council.

Background and Purpose: The FLASH effect is a potential breakthrough in radiotherapy because ultra-high dose-rate irradiation can substantially widen the therapeutic window. While the normal tissue sparing at high doses and short irradiation times has been demonstrated with electrons, photons, and protons, so far evidence with heavy ions is limited to in vitro cell experiments. Here we present the first in vivo results with high-energy 12 C-ions delivered at an ultra-high dose rate., Materials and Methods: LM8 osteosarcoma cells were subcutaneously injected in the posterior limb of female C3H/He mice 7 days before radiation exposure. Both hind limbs of the animals were irradiated with 240 MeV/n 12 C-ions at ultra-high (18 Gy in 150 ms) or conventional dose rate (∼18 Gy/min). Tumor size was measured until 28 days post-exposure, when animals were sacrificed and lungs, limb muscles, and tumors were collected for further histological analysis., Results: Irradiation with carbon ions was able to control the tumour both at conventional and ultra-high dose rate. FLASH decreases normal tissue toxicity as demonstrated by the reduced structural changes in muscle compared to conventional dose-rate irradiation. Carbon ion irradiation in FLASH conditions significantly reduced lung metastasis compared to conventional dose-rate irradiation and sham-irradiated animals., Conclusions: We demonstrated the FLASH effect in vivo with high-energy carbon ions. In addition to normal tissue sparing, we observed tumor control and a substantial reduction of lung metastasis in an osteosarcoma mouse model., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Helium ion beam therapy for the treatment of cancer was one of several developed and studied particle treatments in the 1950s, leading to clinical trials beginning in 1975 at the Lawrence Berkeley National Laboratory. The trial shutdown was followed by decades of research and clinical silence on the topic while proton and carbon ion therapy made debuts at research facilities and academic hospitals worldwide. The lack of progression in understanding the principle facets of helium ion beam therapy in terms of physics, biological and clinical findings persists today, mainly attributable to its highly limited availability. Despite this major setback, there is an increasing focus on evaluating and establishing clinical and research programs using helium ion beams, with both therapy and imaging initiatives to supplement the clinical palette of radiotherapy in the treatment of aggressive disease and sensitive clinical cases. Moreover, due its intermediate physical and radio-biological properties between proton and carbon ion beams, helium ions may provide a streamlined economic steppingstone towards an era of widespread use of different particle species in light and heavy ion therapy. With respect to the clinical proton beams, helium ions exhibit superior physical properties such as reduced lateral scattering and range straggling with higher relative biological effectiveness (RBE) and dose-weighted linear energy transfer (LET d ) ranging from ∼4 keV μ m -1 to ∼40 keV μ m -1 . In the frame of heavy ion therapy using carbon, oxygen or neon ions, where LET d increases beyond 100 keV μ m -1 , helium ions exhibit similar physical attributes such as a sharp lateral penumbra, however, with reduced radio-biological uncertainties and without potentially spoiling dose distributions due to excess fragmentation of heavier ion beams, particularly for higher penetration depths. This roadmap presents an overview of the current state-of-the-art and future directions of helium ion therapy: understanding physics and improving modeling, understanding biology and improving modeling, imaging techniques using helium ions and refining and establishing clinical approaches and aims from learned experience with protons. These topics are organized and presented into three main sections, outlining current and future tasks in establishing clinical and research programs using helium ion beams-A. Physics B. Biological and C. Clinical Perspectives., (Creative Commons Attribution license.)

Galactic cosmic rays (GCR) are among the main deterrents to manned space exploration. Currently, the most realistic way to reduce the dangers caused by GCR to acceptable levels is passive shielding. Light materials guarantee the strongest dose attenuation per unit mass. High-density polyethylene is considered the gold standard for radiation protection in space. Nevertheless, accelerator-based experimental campaigns already showed the advantages of more hydrogen-rich innovative shielding materials such as lithium hydride. The experimental campaigns of this work focused on the absorbed dose attenuation properties of lithium-based hydrides chemically stabilized with a paraffin matrix. Such materials were compared to pure lithium-based hydrides, polyethylene, structural materials such as spacecraft aluminum alloys and lithium batteries, and in situ shielding materials such as Moon regolith and its main components silicon and silicon dioxide. The experimental results were compared to simulations performed with PHITS, FLUKA, and Geant4, which are among the most used Monte Carlo codes for radiation protection in space. The simulations showed systematic differences and highlighted the pressing need for reliable nuclear cross-section models., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

The exposure to galactic cosmic radiation (GCR) is a major health concern for astronauts. Crewed missions with durations of several years are foreseen in future space exploration projects such as permanent habitats on the Moon and flights to Mars. This aim requires elaborate space radiation shielding concepts and a proper understanding of the underlying radiation physics and radiobiology as well as their interplay. In the present work, Monte Carlo simulations to assess the performance of different materials (polyethylene, aluminum, Moon regolith) as thick shields (up to 400 g/cm 2 ) against GCR were conducted using the FLUKA code. Absorbed dose, dose equivalent and the mean quality factor at 1 cm depth in the ICRU sphere as a function of shielding thickness were calculated in a spherical shell configuration for both solar minimum and solar maximum GCR conditions. Large differences were observed in the performance of the studied materials as thick GCR shields. Special attention was paid to the build-up and moderation of secondary neutrons. A method to reduce the neutron contributions to ambient dose equivalent by means of a two-layer shielding combination is proposed. The present study can be useful for considerations on thick shielding of Moon or Mars habitats built from local regolith., (Copyright © 2022. Published by Elsevier B.V.)

Fiducial markers are used for image guidance to verify the correct positioning of the target for the case of tumors that can suffer interfractional motion during proton therapy. The markers should be visible on daily imaging, but at the same time, they should produce minimal streak artifacts in the CT scans for treatment planning and induce only slight dose perturbations during particle therapy. In this work, these three criteria were experimentally investigated at the Heidelberg Ion Beam Therapy Center. Several small fiducial markers with different geometries and materials (gold, platinum, and carbon-coated ZrO 2 ) were evaluated. The streak artifacts on treatment planning CT were measured with and without iMAR correction, showing significantly smaller artifacts from markers lighter than 6 mg and a clear improvement with iMAR correction. Daily imaging as X-ray projections and in-room mobile CT were also performed. Markers heavier than 6 mg showed a better contrast in the X-ray projections, whereas on the images from the in-room mobile CT, all markers were clearly visible. In the other part of this work, fluence perturbations of proton beams were measured for the same markers by using a tracker system of several high spatial resolution CMOS pixel sensors. The measurements were performed for single-energy beams, as well as for a spread-out Bragg peak. Three-dimensional fluence distributions were computed after reconstructing all particle trajectories. These measurements clearly showed that the ZrO 2 markers and the low-mass gold/platinum markers (0.35mm diameter) induce perturbations being 2-3 times lower than the heavier gold or platinum markers of 0.5mm diameter. Monte Carlo simulations, using the FLUKA code, were used to compute dose distributions and showed good agreement with the experimental data after adjusting the phase space of the simulated proton beam compared to the experimental beam., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Reidel, Horst, Schuy, Jäkel, Ecker, Henkner, Brons, Durante and Weber.)

Purpose: To establish a beam monitoring and dosimetry system to enable the FLASH dose rate carbon ion irradiation and investigate, at different oxygen concentrations, the in vitro biological response in comparison to the conventional dose rate., Methods and Materials: CHO-K1 cell response to irradiation at different dose rates and at different levels of oxygenation was studied using clonogenic assay. The Heidelberg Ion-Beam Therapy Center (HIT) synchrotron, after technical improvements, was adjusted to extract ≥5 × 10 8 12 C ions within approximately 150 milliseconds. The beam monitors were filled with helium., Results: The FLASH irradiation with beam scanning yields a dose of 7.5 Gy (homogeneity of ±5%) for a 280 MeV/u beam in a volume of at least 8 mm in diameter and a corresponding dose rate of 70 Gy/s (±20%). The dose repetition accuracy is better than 2%, the systematic uncertainty is better than 2%. Clonogenic assay demonstrates a significant FLASH sparing effect which is strongly oxygenation-dependent and mostly pronounced at 0.5% O 2 but absent at 0% and 21% O 2 ., Conclusion: The FLASH dose rates >40 Gy/s were achieved with carbon beams. Cell survival analysis revealed FLASH dose rate sparing in hypoxia (0.5%-4% O 2 )., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The purpose of this work was to develop and manufacture a 3D range-modulator (3D RM) for a complex target contour for scanned proton therapy. The 3D RM is considered to be a viable technique for the very fast dose application in patient-specific tumors with only one fixed energy. The RM was developed based on a tumor from a patient CT and manufactured with high-quality 3D printing techniques with both polymer resin and aluminum. Monte Carlo simulations were utilized to investigate its modulating properties and the resulting dose distribution. Additionally, the simulation results were validated with measurements at the Marburg Ion-Beam Therapy Centre. For this purpose, a previously developed water phantom was used to conduct fast, automated high-resolution dose measurements. The results show a very good agreement between simulations and measurements and indicate that highly homogeneous dose distributions are possible. The delivered dose is conformed to the distal as well as to the proximal edge of the target. The 3D range-modulator concept combines a high degree of dose homogeneity and conformity, comparable to standard IMPT with very short irradiation times, promising clinically applicable dose distributions for lung and/or FLASH treatment, comparable and competitive to those from conventional irradiation techniques., (Creative Commons Attribution license.)

Carbon therapy is a promising treatment option for cancer. The physical and biological properties of carbon ions can theoretically allow for the delivery of curative doses to the tumor, while simultaneously limiting risks of toxicity to adjacent healthy structures. The treatment effectiveness can be further improved by decreasing the uncertainties stemming from several sources, including the modeling of tissue heterogeneity. Current treatment plans employ density-based conversion methods to translate patient-specific anatomy into a water system, where dose distribution is calculated. This approach neglects differences in nuclear interactions stemming from the elemental composition of each tissue. In this work, we investigated the interaction of therapeutic carbon ions with bone-like materials. The study concentrated on nuclear interactions and included attenuation curves of 200 and 400 AMeV beams in different types of bones, as well as kinetic energy spectra of all charged fragments produced up to 29 degrees from the beam direction. The comparison between measurements and calculations of the treatment planning system TRiP98 indicated that bone tissue causes less fragmentation of carbon ions than water. Overall, hydrogen and helium particles were found to be the most abundant species, while heavier fragments were mostly detected within 5 degrees from the beam direction. We also investigated how the presence of a soft tissue-bone interface could affect the depth-dose profile. The results revealed a dose spike in the transition region, that extended from the entry channel to the target volume. The findings of this work indicated that the tissue-to-water conversion method based only on density considerations can result in dose inaccuracies. Tissue heterogeneity regions containing bones can potentially produce dose spikes, whose magnitude will depend on the patient anatomy. Dose uncertainties can be decreased by modeling nuclear interactions directly in bones, without applying the tissue-to-water conversion., (© 2021 Institute of Physics and Engineering in Medicine.)

Several techniques are under development for image-guidance in particle therapy. Positron (β + ) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by β + -emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using β + -radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy., Competing Interests: Author AP was employed by company MedAuston GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boscolo, Kostyleva, Safari, Anagnostatou, Äystö, Bagchi, Binder, Dedes, Dendooven, Dickel, Drozd, Franczack, Geissel, Gianoli, Graeff, Grahn, Greiner, Haettner, Haghani, Harakeh, Horst, Hornung, Hucka, Kalantar-Nayestanaki, Kazantseva, Kindler, Knöbel, Kuzminchuk-Feuerstein, Lommel, Mukha, Nociforo, Ishikawa, Lovatti, Nitta, Ozoemelam, Pietri, Plaß, Prochazka, Purushothaman, Reidel, Roesch, Schirru, Schuy, Sokol, Steinsberger, Tanaka, Tanihata, Thirolf, Tinganelli, Voss, Weber, Weick, Winfield, Winkler, Zhao, Scheidenberger, Parodi, Durante and the Super-FRS Experiment Collaboration.)

This paper introduces the concept of a 2D range-modulator as a static device for generating spread-out Bragg peaks at very small distances to the target. The 2D range-modulator has some distinct advantages that can be highly useful for different research projects in particle therapy facilities. Most importantly, it creates an instantaneous, quasi-static irradiation field with only one energy, thus decreasing irradiation time tremendously. In addition, it can be manufactured fast and cost efficiently and its SOBP width and shape can be adjusted easily for the specific purpose/experiment. As the modulator is a static element, there is no need for rotation (e.g. like in a modulation wheel) or lateral oscillation and due to the small base structure period it can be positioned close to the target. Two different rapid prototyping manufacturing techniques were utilized. The modulation properties of one polymer and one steel modulator were investigated with both simulations and measurements. For this purpose, a sophisticated water phantom system (WERNER), that can perform fast, completely automated and high resolution dose measurements, was developed. Using WERNER, the dose distribution of a modulator can be verified quickly and reliably, both during experiments, as well as in a time constrained clinical environment. The maximum deviation between the Monte Carlo simulations and dose measurements in the spread-out Bragg peak region was 1.4% and 4% for the polymer and steel modulator respectively. They were able to create spread-out Bragg peaks with a high degree of dose homogeneity, thus validating the whole process chain, from the mathematical optimization and modulator development, to manufacturing, MC simulations and dose measurements. Combining the convenience, flexibility and cost-effectiveness of rapid prototyping with the advantages of highly customizable modulators, that can be adapted for different experiments, the 2D range-modulator is considered a very useful tool for a variety of research objectives. Moreover, we have successfully shown that the manufacturing of 2D modulators with high quality and high degree of homogeneity is possible, paving the way for the further development of the more complex 3D range-modulators, which are considered a viable option for the very fast treatment of moving targets and/or FLASH irradiation., (Copyright © 2020. Published by Elsevier GmbH.)

There is increasing interest in using helium ions for radiotherapy, complementary to protons and carbon ions. A large number of patients were treated with 4 He ions in the US heavy ion therapy project and novel 4 He ion treatment programs are under preparation, for instance in Germany and Japan. 3 He ions have been proposed as an alternative to 4 He ions because the acceleration of 3 He is technically less difficult than 4 He. In particular, beam contaminations have been pointed out as a potential safety issue for 4 He ion beams. This motivated a series of experiments with 3 He ion beams at Gesellschaft für Schwerionenforschung (GSI), Darmstadt. Measured 3 He Bragg curves and fragmentation data in water are presented in this work. Those experimental data are compared with FLUKA Monte Carlo simulations. The physical characteristics of 3 He ion beams are compared to those of 4 He, for which a large set of data became available in recent years from the preparation work at the Heidelberger Ionenstrahl-Therapiezentrum (HIT). The dose distributions (spread out Bragg peaks, lateral profiles) that can be achieved with 3 He ions are found to be competitive to 4 He dose distributions. The effect of beam contaminations on 4 He depth dose distribution is also addressed. It is concluded that 3 He ions can be a viable alternative to 4 He, especially for future compact therapy accelerator designs and upgrades of existing ion therapy facilities., (Creative Commons Attribution license.)

Purpose: Three-dimensional (3D) dosimetry is a necessity to validate patient-specific treatment plans in particle therapy as well as to facilitate the development of novel treatment modalities. Therefore, a vendor-agnostic water phantom was developed and verified to measure high resolution 3D dose distributions., Methods: The system was experimentally validated at the Marburger Ionenstrahl-Therapiezentrum using two ionization chamber array detectors (PTW Octavius 1500XDR and 1000P) with 150.68 MeV proton and 285.35 MeV/u 12 C beams. The dose distribution of several monoenergetic and complex scanned fields were measured with different step sizes to assess the reproducibility, absolute positioning accuracy, and general performance of the system., Results: The developed system was successfully validated and used to automatically measure high resolution 3D dose distributions. The reproducibility in depth was better than ±25 micron. The roll and tilt uncertainty of the detector was estimated to be smaller than ±3 mrad., Conclusions: The presented system performed fully automated, high resolution 3D dosimetry, suitable for the validation of complex radiation fields in particle therapy. The measurement quality is comparable to commercially available systems., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Fiducial markers are nowadays a common tool for patient positioning verification before radiotherapy treatment. These markers should be visible on x-ray projection imaging, produce low streak artifacts on CTs and induce small dose perturbations due to edge-scattering effects during the ion-beam therapy treatment. In this study, the latter effect was investigated and the perturbations created by the markers were evaluated with a new measurement method using a tracker system composed of six CMOS pixel sensors. The present method enables the determination of the particle trajectory before and after the target. The experiments have been conducted at the Marburg Ion Beam Therapy Center with carbon ion beams and the measurement concept was validated by comparison with radiochromic films. This work shows that the new method is very efficient and precise to measure the perturbations due to fiducial markers with a tracker system. Three dimensional fluence distributions of all particle trajectories were reconstructed and the maximum cold spots due to the markers and their position along the beam axis were quantified. In this study, four small commercial markers with different geometries and materials (gold and carbon-coated ZrO 2 ) were evaluated. The gold markers showed stronger perturbations than the lower density ones. However, it is important to consider that low density and low atomic number fiducial markers are not always visible on x-ray projections.

Measured cross sections for the production of the PET isotopes [Formula: see text], [Formula: see text] and [Formula: see text] from carbon and oxygen targets induced by protons (40-220 [Formula: see text]) and carbon ions (65-430 [Formula: see text]) are presented. These data were obtained via activation measurements of irradiated graphite and beryllium oxide targets using a set of three scintillators coupled by a coincidence logic. The measured cross sections are relevant for the PET particle range verification method where accurate predictions of the [Formula: see text] emitter distribution produced by therapeutic beams in the patient tissue are required. The presented dataset is useful for validation and optimization of the nuclear reaction models within Monte Carlo transport codes. For protons the agreement of a radiation transport calculation using the measured cross sections with a thick target PET measurement is demonstrated.

Tocopherols and tocotrienols, commonly referred to as vitamin E, are essential compounds in food and feed. Due to their lipophilic nature they protect biomembranes by preventing the propagation of lipid-peroxidation especially during oxidative stress. Since their synthesis is restricted to photosynthetic organisms, plant-derived products are the major source of natural vitamin E. In the present study the genetic basis for high vitamin E accumulation in leaves and grains of different barley (Hordeum vulgare L.) accessions was uncovered. A genome wide association study (GWAS) allowed the identification of two genes located on chromosome 7H, homogentisate phytyltransferase (HPT-7H) and homogentisate geranylgeranyltransferase (HGGT) that code for key enzymes controlling the accumulation of tocopherols in leaves and tocotrienols in grains, respectively. Transcript profiling showed a correlation between HPT-7H expression and vitamin E content in leaves. Allele sequencing allowed to decipher the allelic variation of HPT-7H and HGGT genes corresponding to high and low vitamin E contents in the respective tissues. Using the obtained sequence information molecular markers have been developed which can be used to assist smart breeding of high vitamin E barley varieties. This will facilitate the selection of genotypes more tolerant to oxidative stress and producing high-quality grains.

The harmful effects of space radiation pose a serious health risk to astronauts participating in future long-term missions. Such radiation effects must be considered in the design phase of space vessels as well as in mission planning. Crew radioprotection during long periods in deep space (e.g., transit to Mars) represents a major challenge, especially because of the strong restrictions on the passive shielding load allowed on-board the vessel. Novel materials with better shielding performance compared to the "gold standard" high-density polyethylene are therefore greatly needed. Because of the high hydrogen content of hydrides, lithium hydride has been selected as a starting point for further studies of promising candidates to be used as passive shielding materials. In the current experimental campaign, the shielding performance of lithium hydride was assessed by measuring normalized dose, primary beam attenuation and neutron ambient dose equivalent using 430 MeV/u 12 C, 600 MeV/u 12 C and 228 MeV proton beams. The experimental data were then compared to predictions from the Monte Carlo transport codes PHITS and GRAS. The experimental results show an increased shielding effectiveness of lithium hydride compared to reference materials like polyethylene. For instance, the attenuation length for 600 MeV/u 12 C primary particles in lithium hydride is approximately 20% shorter compared to polyethylene. Furthermore, the comparison results between both transport codes indicates that the standard Tripathi-based total reaction cross-section model of PHITS cannot accurately reproduce the presented experimental data, whereas GRAS shows reasonable agreement.

The roadmap for space exploration foresees longer journeys and further excursions outside low-Earth orbit as well as the establishment of permanent outposts on other celestial bodies, such as the Moon or Mars. The design of spacecrafts and habitats depends heavily on the mission scenario and must consider the radiation protection properties of the structural components as well as dedicated shielding. In fact, short- and long-term effects caused by exposure to cosmic radiation are now considered among the main health risks of space travel. One of the current strategies is to find multifunctional materials that combine excellent mechanical properties with a high shielding effectiveness to minimize the overall load. In this work, the shielding effectiveness of a wide variety of single and multilayer materials of interest for different mission scenarios has been characterized. In the experimental campaign, reference and innovative materials, as well as simulants of Moon and Mars in situ resources, were irradiated with 1,000 MeV/u 4 He, 430 MeV/u 12 C and 962-972 MeV/u 56 Fe. The results are presented in terms of Bragg curves and dose reduction per unit area density. To isolate the shielding effectiveness only due to nuclear fragmentation, a correction for the energy loss in the material is also considered. These findings indicate that the best shield is lithium hydride, which performs even better than polyethylene. However, the technical feasibility of shielding needs to be investigated. The classification of all materials in terms of shielding effectiveness is not influenced by the ion species, but the value changes dramatically depending on the beam energy. The output of this investigation represents a useful database for benchmarking Monte Carlo and deterministic transport codes used for space radiation transport calculations. These findings also contribute to recommendations for optimizing the design of space vessels and habitats in different radiation environments.

Dose build-up effects in the entrance channel of proton Bragg curves were investigated in detail by means of simulations and experiments. There are two relevant dose build-up effects. Firstly, the δ-electron build-up effect which takes place in the first few millimeters of the tissue until an equilibrium state of the forward-scattered δ-electrons is reached. Secondly, the target fragment build-up effect that covers the first centimeters in the entrance channel of the proton Bragg curve. These target fragments are created in inelastic interactions of the beam protons with the target nuclei and partially have low kinetic energies and/or high atomic numbers compared to the incident beam protons. Consequently, the target fragments possess high LET values and thus an increased RBE. However, the production cross sections relevant for target fragmentation in ion beam therapy still have large uncertainties. Therefore, in this work target fragmentation was investigated indirectly by measuring low-noise proton Bragg curves with the focus placed on their build-up regions. The measurements clearly show the magnitude and shape of the two different build-up effects. Additionally, with the application of a magnetic filter, it was possible to separate the measurement of the target fragment build-up effect from the δ-electron build-up effect. Corresponding FLUKA Monte Carlo simulations were carried out for the experimental setup. A comparison of the experimental results with the FLUKA predictions enabled the assessment of the precision of FLUKA models, e.g. the δ-electron production models and the nuclear event generators which are responsible for target fragmentation reactions. It could be shown that the relevant models worked well to reproduce both build-up effects.

Geminiviral single-stranded circular DNA genomes replicate in nuclei so that the progeny DNA has to cross both the nuclear envelope and the plasmodesmata for systemic spread within plant tissues. For intra- and intercellular transport, two proteins are required: a nuclear shuttle protein (NSP) and a movement protein (MP). New characteristics of ectopically produced Abutilon mosaic virus (AbMV) MP (MP AbMV ), either authentically expressed or fused to a yellow fluorescent protein or epitope tags, respectively, were determined by localization studies in mammalian cell lines in comparison to plant cells. Wild-type MP AbMV and the distinct MP AbMV : reporter protein fusions appeared as curled threads throughout mammalian cells. Co-staining with cytoskeleton markers for actin, intermediate filaments, or microtubules identified these threads as re-organized microtubules. These were, however, not stabilized by the viral MP, as demonstrated by nocodazole treatment. The MP of a related bipartite New World begomovirus, Cleome leaf crumple virus (ClLCrV), resulted in the same intensified microtubule bundling, whereas that of a nanovirus did not. The C-terminal section of MP AbMV , i.e., the protein's oligomerization domain, was dispensable for the effect. However, MP expression in plant cells did not affect the microtubules network. Since plant epidermal cells are quiescent whilst mammalian cells are proliferating, the replication-associated protein Rep AbMV protein was then co-expressed with MP AbMV to induce cell progression into S-phase, thereby inducing distinct microtubule bundling without MP recruitment to the newly formed threads. Co-immunoprecipitation of MP AbMV in the presence of Rep AbMV , followed by mass spectrometry identified potential novel MP AbMV -host interaction partners: the peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (Pin4) and stomatal cytokinesis defective 2 (SCD2) proteins. Possible roles of these putative interaction partners in the begomoviral life cycle and cytoskeletal association modes are discussed., Competing Interests: The authors declare no conflict of interest.