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The dataset contains comprehensive image data for a total of nine mice, which underwent normal tissue brain irradiation with 90MeV protons. In particular, the image data comprise cone-bem computed tomographies (CBCT), Monte Carlo beam transport simulations based on those CTs, regular magnetic resonance imaging (MRI) follow-up (≥26 weeks), a co-aligned DSURQE mouse brain atlasand scanned whole-brain tissue sections with histochemical and immunofluorescent markers for morphology (H&E), cell nuclei (DAPI), astrocytes (GFAP), microglia (Iba1), the intermediate filament protein Nestin, proliferation (Ki67), neurons (NeuN) and oligodendrocytes (OSP). The volumetric image data (i.e. CBCT, MRI and brain atlas) were co-aligned using the ImageJ plugin Big Warp. The CBCT data was used as spatial reference to allow for mask-based, slice-wise alignment of CBCT and light microscopy image data in 3D with the scriptable registration tool Elastix. We provide the data in raw format and as aligned data sets, as well as their spatial transformations.

Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient’s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.

The influence of different average and bunch dose rates in electron beams on the FLASH effect was investigated. The present study measures O2 content in water at different beam pulse patterns and finds strong correlation with biological data, strengthening the hypothesis of radical-related mechanisms as a reason for the FLASH effect.

Background and purpose: Radiomics analyses have been shown to predict clinical outcomes of radiotherapy based on medical imaging-derived biomarkers. However, the biological meaning attached to such image features often remains unclear, thus hindering the clinical translation of radiomics analysis. In this manuscript, we describe a preclinical radiomics trial, which attempts to establish correlations between the expression of histological tumor microenvironment (TME)- and magnetic resonance imaging (MRI)-derived image features. Materials & Methods: A total of 114 mice were transplanted with the radioresistant and radiosensitive head and neck squamous cell carcinoma cell lines SAS and UT-SCC-14, respectively. The models were irradiated with five fractions of protons or photons using different doses. Post-treatment T1-weighted MRI and histopathological evaluation of the TME was conducted to extract quantitative features pertaining to tissue hypoxia and vascularization. We performed radiomics analysis with leave-one-out cross validation to identify the features most strongly associated with the tumor's phenotype. Performance was assessed using the area under the curve (AUCVₐlid) and F1-score. Furthermore, we analyzed correlations between TME- and MRI features using the Spearman correlation coefficient ρ. Results: TME and MRI-derived features showed good performance (AUCVₐlid, TME = 0.72, AUCVₐlid, MRI = 0.85, AUCVₐlid, Cₒmbinₑd = 0.85) individual tumor phenotype prediction. We found correlation coefficients of ρ = −0.46 between hypoxia-related TME features and texture-related MRI features. Tumor volume was a strong confounder for MRI feature expression. Conclusion: We demonstrated a preclinical radiomics implementation and notable correlations between MRI- and TME hypoxia-related features. Developing additional TME features may help to further unravel the underlying biology.

Simple Summary Radiotherapy is part of the standard of care for many solid tumors. In pancreatic ductal adenocarcinoma (PDAC), good responses to radiotherapy can only be observed in a minority of patients. In our study, we used PDAC patient-derived organoids (PDO) to investigate alternative radiotherapy approaches for PDAC, such as proton irradiation and combined radiochemotherapy (RCT). Although only very distinct differences in treatment response could be identified, we show the utility of PDOs in translational proton research and found synergistic effects of combined treatments with chemotherapy and proton irradiation in individual PDOs. To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1(nu/nu) mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research. CA extern

In the last two decades, variably doped strontium barium niobate (SBN) has attracted a lot of scientific interest mainly due to its specific non-linear optical response. Comparably, the parental compound, i.e., undoped SBN, appears to be less studied so far. Here, two different cuts of single-crystalline nominally pure strontium barium niobate in the composition Sr0.61Ba0.39Nb2O6 (SBN61) are comprehensively studied and analyzed with regard to their photoconductive responses. We present conductance measurements under systematically varied illumination conditions along either the polar z-axis or perpendicular to it (x-cut). Apart from a pronounced photoconductance (PC) already under daylight and a large effect upon super-bandgap illumination in general, we observe (i) distinct spectral features when sweeping the excitation wavelength over the sub-bandgap region as then discussed in the context of deep and shallow trap states, (ii) extremely slow long-term relaxation for both light-on and light-off transients in the range of hours and days, (iii) a critical dependence of the photoresponse on the pre-illumination history of the sample, and (iv) a current–voltage hysteresis depending on both the illumination and the electrical-measurement conditions in a complex manner.

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Challenges in the fields of renewable energy harvesting, data storage, and nanoelectronics have resparked interest in ferroelectric domain walls (DWs) as tunable, nanoscale elements. However, the s...

After the rediscovery of the normal tissue sparing effect of high dose rate radiation, i.e. the so-called FLASH effect, by Favaudon et al. in 2014, research activities on this topic have been revived and are flourishing ever since. Yet, the exact biological mechanism as well as the required boundary conditions and radiation qualities to reach said sparing remain mostly unclear. We present a laser-based irradiation platform at the Draco PW facility that enables systematic studies into the FLASH regime using proton peak dose rates of up to 10^9 Gy/s. Besides the PW class laser acceleration source, a key component is a pulsed high-field beamline to transport and shape the laser driven proton bunches spectrally and spatially in order to generate homogeneous dose distributions tailored to match the irradiation sample. Making use of the diverse capabilities of the laser driven irradiation platform a pilot experiment of highest complexity has been conducted – a systematic in-vivo tumor irradiation in a specifically developed mouse model. A plethora of online particle diagnostics, including Time-of-Flight, bulk scintillators and screens as well as ionization chambers, in conjunction with diagnostics for retrospective absolute dosimetry (radiochromic films) allowed for an unprecedented level of precision in mean dose delivery (±10 %) and dose homogeneity (±5 %) for the challenging beam qualities of a laser accelerator. The tailored detector suite is complemented by predictive simulations. The talk addresses how our interdisciplinary team overcame all hurdles from animal model development, over enhancing the laser and laser acceleration stability, to dose delivery and online dose monitoring. Results on radiation induced tumor growth delay by laser driven as well as conventionally accelerated proton beams are critically discussed.

Laser-driven proton pulse provide unique properties in terms of pulse structure (ns) and instantaneous dose rate (10^9 Gy/s) but - inherently broadband and highly divergent - pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for three-dimensional cases. We present the successful implementation and characterisation of a highly efficient and tuneable dual pulsed solenoid beamline at the Draco PW facility[1] to generate volumetric dose distribution tailored to specific applications[2]. The vast experimental scope and already successfully performed studies range from systematic volumetric in-vivo tumour irradiations in a dedicated mouse model (with a stable mean dose delivery of ±10 % and a spatial dose homogeneity of ±5 % over a cylindrical volume of 5 mm diameter and height) to high-dose-rate irradiations in the FLASH regime (using proton peak dose rates of up to 10^9 Gy/s with about 20 Gy/shot homogeneously over a cylindrical sample volume of 4.5 mm diameter and 3 mm height) as well as particle diagnostics commissioning (with a multitude of spatial and spectral dose distributions). The beamline setup is complemented by a complex beam monitoring and dosimetry detector suite adapted to the ultra-high dose rate pulses and is in its unique synergy and redundancy capable of %-level precision dose delivery to samples as required for systematic irradiation studies. In addition to established radiochromic film dosimetry, the detector suite includes saturation-corrected (transmission) ionisation chambers [3] as well as screen and bulk scintillator setups, partly with tomographic reconstruction capabilities for 3D dose distribution retrieval. Moreover, non-invasive, single-shot-capable online time-of-flight-based spectral characterisation of filtered proton pulses has proven a powerful tool for beam monitoring as well as dosimetric purposes. In this presentation the complex and versatile dose delivery system of laser-driven protons at the Draco PW using pulsed solenoids will be discussed. Its characterisation, technological development and improvement as well as the dosimetry suite as a vital part of the precise dose delivery will be addressed, while the presentation by U. Schramm covers recent experimental activities in detail. [1] T. Ziegler, et al., Proton beam quality enhancement by spectral phase control of a PW-class laser system, https://arxiv.org/abs/2007.11499 (2020) [2] Brack, et al., Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline, SciRep, 10:9118, (2020) [3] Gotz M, et al., A new model for volume recombination in plane‐parallel chambers in pulsed fields of high dose‐per‐pulse. Phys Med Biol., 62: 8634, (2017)

Purpose: To investigate experimentally, if FLASH irradiation depletes oxygen within water for different radiation types such as photons, protons and carbon ions. Methods: This study presents measurements of the oxygen consumption in sealed, 3D printed water phantoms during irradiation with X-rays, protons and carbon ions at varying dose rates up to 340 Gy/s. The oxygen measurement was performed using an optical sensor allowing for non-invasive measurements. Results: Oxygen consumption in water only depends on dose, dose rate and linear energy transfer (LET) of the irradiation. The total amount of oxygen depleted per 10 Gy was found to be 0.04 - 0.18 % atm for 225 kV photons, 0.04 - 0.25 % atm for 224 MeV protons and 0.09 - 0.17 % atm for carbon ions. consumption depends on dose rate by an inverse power law and saturates for higher dose rates because of self-interactions of radicals. Higher dose rates yield lower oxygen consumption. No total depletion of oxygen was found for clinical doses. Conclusions: FLASH irradiation does consume oxygen, but not enough to deplete all the oxygen present. For higher dose rates, less oxygen was consumed than at standard radiotherapy dose rates. No total depletion was found for any of the analyzed radiation types for 10 Gy dose delivery using FLASH., 23 pages, 7 figures

Background and purpose In consequence of a previous study, where no protecting proton Flash effect was found for zebrafish embryos, potential reasons and requirements for inducing a Flash effect should be investigated with higher pulse dose rate and partial oxygen pressure (pO2) as relevant parameters. Materials and methods The experiments were performed at the research electron accelerator ELBE, whose variable pulse structure enables dose delivery as electron Flash and quasi-continuously (reference irradiation). Zebrafish embryos were irradiated with ~26 Gy either continuously at a dose rate of ~6.7 Gy/min (reference) or by 1441 electron pulses within 111 µs at a pulse dose rate of 109 Gy/s and a mean dose rate of 105Gy/s, respectively. Using the OxyLite system to measure the pO2 a low- (pO2 ≤ 5 mmHg) and a high-pO2 group were defined on basis of the oxygen depletion kinetics in sealed embryo samples. Results A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20–25% less embryos with spinal curvature and pericardial edema, relative to reference irradiation. The reduction of pO2 below atmospheric levels (148 mmHg) resulted in higher protection, which was however more pronounced in the low-pO2 group. Conclusion The Flash experiment at ELBE showed that the zebrafish embryo model is appropriate for studying the radiobiological response of high dose rate irradiation. The applied high pulse dose rate was confirmed as important beam parameter as well as the pivotal role of pO2 during irradiation.

Simple Summary Due to higher precision and consequent sparing of normal tissue, pancreatic cancer patients might profit from proton beam radiotherapy, a treatment modality increasingly used. Since molecular data upon proton irradiation in comparison to standard photon radiotherapy are limited in pancreatic cancer, the aims of our study were to unravel differences in the effectiveness of photon versus proton irradiation and to exploit radiation type-specific molecular changes for radiosensitizing 3D PDAC cell cultures. Although protons showed a slightly higher effectiveness and a stronger induction of molecular alterations than photons, our results revealed a radiation-type independent sensitization of molecular-targeted agents selected according to the discovered molecular, radiation-induced alterations. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly therapy-resistant tumor entity of unmet needs. Over the last decades, radiotherapy has been considered as an additional treatment modality to surgery and chemotherapy. Owing to radiosensitive abdominal organs, high-precision proton beam radiotherapy has been regarded as superior to photon radiotherapy. To further elucidate the potential of combination therapies, we employed a more physiological 3D, matrix-based cell culture model to assess tumoroid formation capacity after photon and proton irradiation. Additionally, we investigated proton- and photon-irradiation-induced phosphoproteomic changes for identifying clinically exploitable targets. Here, we show that proton irradiation elicits a higher efficacy to reduce 3D PDAC tumoroid formation and a greater extent of phosphoproteome alterations compared with photon irradiation. The targeting of proteins identified in the phosphoproteome that were uniquely altered by protons or photons failed to cause radiation-type-specific radiosensitization. Targeting DNA repair proteins associated with non-homologous endjoining, however, revealed a strong radiosensitizing potential independent of the radiation type. In conclusion, our findings suggest proton irradiation to be potentially more effective in PDAC than photons without additional efficacy when combined with DNA repair inhibitors.

Optical activation of material properties illustrates the potentials held by tuning light-matter interactions with impacts ranging from basic science to technological applications. Here, we demonstrate for the first time that composite nanostructures providing nonlocal environments can be engineered to optically trigger photoinduced charge-transfer-dynamic modulations in the solid state. The nanostructures explored herein lead to out-of-phase behavior between charge separation and recombination dynamics, along with linear charge-transfer-dynamic variations with the optical-field intensity. Using transient absorption spectroscopy, up to 270% increase in charge separation rate is obtained in organic semiconductor thin films. We provide evidence that composite nanostructures allow for surface photovoltages to be created, which kinetics vary with the composite architecture and last beyond optical pulse temporal characteristics. Furthermore, by generalizing Marcus theory framework, we explain why charge-transfer-dynamic modulations can only be unveiled when optic-field effects are enhanced by nonlocal image-dipole interactions. Our demonstration, that composite nanostructures can be designed to take advantage of optical fields for tuneable charge-transfer-dynamic remote actuators, opens the path for their use in practical applications ranging from photochemistry to optoelectronics., Controlling and modulating charge transfer dynamics in composite nanostructures, though promising for optoelectronic applications, remains a challenge. Here, the authors report optical control of charge separation and recombination processes in organic semiconductor-based composite nanostructures.

Preclinical imaging and irradiation yields valuable insights into clinically relevant research topics. While complementary imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) can be combined within single devices, this is technically demanding and cost-intensive. Similarly, bedding and setup solutions are often specific to certain devices and research questions. We present a bedding platform for mice that is compatible with various preclinical imaging modalities (combined PET/MRI, cone beam CT) and irradiation with photons and protons. It consists of a 3D-printed bedding unit (acrylonitrile butadiene styrene, ABS) holding the animal and features an inhalation anesthesia mask, jaw fixation, ear pins, and immobilization for the hind leg. It can be embedded on mounting adaptors for multi-modal imaging and into a transport box (polymethyl methacrylate, PMMA) for experiments outside dedicated animal facilities while maintaining the animal’s hygiene status. A vital support unit provides heating, inhalation anesthesia, and a respiration monitor. We dosimetrically evaluated used materials in order to assess their interaction with incident irradiation. Proof-of-concept multi-modal imaging protocols were used on phantoms and mice. The measured attenuation of the bedding unit for 40/60/80/200 kV X-rays was less than 3%. The measured stopping-power-ratio of ABS was 0.951, the combined water-equivalent thickness of bedding unit and transport box was 4.2 mm for proton energies of 150 MeV and 200 MeV. Proof-of-concept imaging showed no loss of image quality. Imaging data of individual mice from different imaging modalities could be aligned rigidly. The presented bed aims to provide a platform for experiments related to both multi-modal imaging and irradiation, thus offering the possibility for image-guided irradiation which relies on precise imaging and positioning. The usage as a self-contained, stand-alone unit outside dedicated animal facilities represents an advantage over setups designed for specific devices.

Microbeam radiation therapy (MRT), a preclinical form of spatially fractionated radiotherapy, uses an array of microbeams of hard synchrotron X-ray radiation. Recently, compact synchrotron X-ray sources got more attention as they provide essential prerequisites for the translation of MRT into clinics while overcoming the limited access to synchrotron facilities. At the Munich compact light source (MuCLS), one of these novel compact X-ray facilities, a proof of principle experiment was conducted applying MRT to a xenograft tumor mouse model. First, subcutaneous tumors derived from the established squamous carcinoma cell line FaDu were irradiated at a conventional X-ray tube using broadbeam geometry to determine a suitable dose range for the tumor growth delay. For irradiations at the MuCLS, FaDu tumors were irradiated with broadbeam and microbeam irradiation at integral doses of either 3Gy or 5Gy and tumor growth delay was measured. Microbeams had a width of 50µm and a center-to-center distance of 350µm with peak doses of either 21Gy or 35Gy. A dose rate of up to 5Gy/min was delivered to the tumor. Both doses and modalities delayed the tumor growth compared to a sham-irradiated tumor. The irradiated area and microbeam pattern were verified by staining of the DNA double-strand break marker γH2AX. This study demonstrates for the first time that MRT can be successfully performed in vivo at compact inverse Compton sources.

Background and purpose Motivated by first animal trials showing the normal tissue protecting effect of electron and photon Flash irradiation relative to conventional continuous beam delivery, the feasibility of proton Flash should be assessed. Materials and methods A setup and beam parameter settings for the treatment of zebrafish embryo with proton Flash and proton beam of conventional dose rate were established at the University Proton Therapy Dresden. Zebrafish embryos were treated with graded doses and the differential effect on embryonic survival and the induction of morphological malformations was followed for up to four days after irradiation. Results Beam parameters for the realization of proton Flash were set and tested with respect to controlled dose delivery to biological samples. The dose dependent embryonic survival data obtained for protons delivered as Flash and with a beam of conventional dose rate of 5 Gy/min show not significant influence of proton dose rate. Similarly, just a trend towards a protective effect of proton Flash was revealed for the induction of pericardial oedema as one type of acute radiation effect and spinal curvature as a developmental abnormality. Conclusion The feasibility of Flash proton irradiation was successfully shown, whereas more experiments are required to understand the absence of a clear protecting effect and therefore to figure out the limits and requirements for the Flash effect.

Regarding the long-term goal to develop and establish laser-based particle accelerators for a future radiotherapeutic treatment of cancer, the radiobiological consequences of the characteristic short intense particle pulses with ultra-high peak dose rate, but low repetition rate of laser-driven beams have to be investigated. This work presents in vitro experiments performed at the radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance). This accelerator delivered 20-MeV electron pulses with ultra-high pulse dose rate of 10(10) Gy/min either at the low pulse frequency analogue to previous cell experiments with laser-driven electrons or at high frequency for minimizing the prolonged dose delivery and to perform comparison irradiation with a quasi-continuous electron beam analogue to a clinically used linear accelerator. The influence of the different electron beam pulse structures on the radiobiological response of the normal tissue cell line 184A1 and two primary fibroblasts was investigated regarding clonogenic survival and the number of DNA double-strand breaks that remain 24 h after irradiation. Thereby, no considerable differences in radiation response were revealed both for biological endpoints and for all probed cell cultures. These results provide evidence that the radiobiological effectiveness of the pulsed electron beams is not affected by the ultra-high pulse dose rates alone.

Author(s): Brack, Florian-Emanuel; Kroll, Florian; Gaus, Lennart; Bernert, Constantin; Beyreuther, Elke; Cowan, Thomas E; Karsch, Leonhard; Kraft, Stephan; Kunz-Schughart, Leoni A; Lessmann, Elisabeth; Metzkes-Ng, Josefine; Obst-Huebl, Lieselotte; Pawelke, Jorg; Rehwald, Martin; Schlenvoigt, Hans-Peter; Schramm, Ulrich; Sobiella, Manfred; Szabo, Emilia Rita; Ziegler, Tim; Zeil, Karl | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A challenge in cancer research is the definition of reproducible, reliable, and practical models, which reflect the effects of complex treatment modalities and the heterogeneous response of patients. Proton beam radiotherapy (PBRT), relative to conventional photon-based radiotherapy, offers the potential for iso-effective tumor control, while protecting the normal tissue surrounding the tumor. However, the effects of PBRT on the tumor microenvironment and the interplay with newly developed chemo- and immunotherapeutic approaches are still open for investigation. This work evaluated thin-cut tumor slice cultures (TSC) of head and neck cancer and organotypic brain slice cultures (OBSC) of adult mice brain, regarding their relevance for translational radiooncology research. TSC and OBSC were treated with PBRT and investigated for cell survival with a lactate dehydrogenase (LDH) assay, DNA repair via the DNA double strand break marker &gamma, H2AX, as well as histology with regards to morphology. Adult OBSC failed to be an appropriate model for radiobiological research questions. However, histological analysis of TSC showed DNA damage and tumor morphological results, comparable to known in vivo and in vitro data, making them a promising model to study novel treatment approaches in patient-derived xenografts or primary tumor material.

Purpose: In order to take full advantage of proton radiotherapy, the biological effect of protons in normal and tumor tissue should be investigated and understood in detail. The ongoing discussion on variable relative biological effectiveness along the proton depth dose distribution (eg, Paganetti 2015), and also the administration of concomitant treatments, demands dedicated in vitro trials that prepare the translation into the clinics. Therefore, a setup for radiobiological studies and the corresponding dosimetry should be established that enables in vitro experiments at a horizontal proton beam and a clinical 6 MV photon linear accelerator (Linac) as reference. Methods: The experimental proton beam at the University Proton Therapy Dresden is characterized by high beam availability and reliability throughout the day in parallel to patient treatment. For cell irradiation, a homogeneous 10 × 10 cm2 proton field with an optional spread-out Bragg-peak can be formed. A water-filled phantom was installed that allows for precise positioning of different sample geometries along the proton path. Results: Depth-dose profiles within the phantom and dose homogeneity over different cell samples were characterized for the proton beam and the photon reference source. A daily quality assurance protocol was implemented that provides absolute dose information required for significant and reproducible in vitro experiments. Cell survival test experiments were performed to demonstrate the feasibility of such experiments. Conclusion: In the experimental room of the University Proton Therapy Dresden, clinically relevant conditions for proton in vitro experiments have been realized. The established cell phantom and dosimetry facilitate irradiation in an aqueous environment and are transferable to other proton, photon and ion beam facilities. Precise positioning and easy exchange of cell samples, monitor unit-based dose delivery, and high beam availability allow for systematic in vitro experiments. The close vicinity to the radiotherapy and radiobiology departments provides access to clinical linacs and the interdisciplinary basis for further translational steps.

In line with the long-term aim of establishing the laser-based particle acceleration for future medical application, the radiobiological consequences of the typical ultra-short pulses and ultra-high pulse dose rate can be investigated with electron delivery.The radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance) was used to mimic the quasi-continuous electron beam of a clinical linear accelerator (LINAC) for comparison with electron pulses at the ultra-high pulse dose rate of 10(10) Gy min(-1) either at the low frequency of a laser accelerator or at 13 MHz avoiding effects of prolonged dose delivery. The impact of pulse structure was analyzed by clonogenic survival assay and by the number of residual DNA double-strand breaks remaining 24 h after irradiation of two human squamous cell carcinoma lines of differing radiosensitivity.The radiation response of both cell lines was found to be independent from electron pulse structure for the two endpoints under investigation.The results reveal, that ultra-high pulse dose rates of 10(10) Gy min(-1) and the low repetition rate of laser accelerated electrons have no statistically significant influence (within the 95% confidence intervals) on the radiobiological effectiveness of megavoltage electrons.

Cerium-doped LaMnO3 is widely discussed as one of the most prospective electron-doped thin-film prototype material that complements well-established hole-doped mixed-valence manganites. Here, we investigate La0.7Ce0.3MnO3 films with respect to their electrical properties and check whether they provide an effective electron doping with Mn-valences well below +3. Thin films of a variable thickness between 10 and 100 nm are characterized through resistance measurements over a broad temperature range between 90 and 300 K deducing their hopping energies, carrier localization lengths, and the Mn valence by comparing the experimental data to different transport models. While electronic transport above 300 K is well determined by the thermally activated diffusion of small polarons, we find the carrier localization by disorder to reveal a variable-range hopping-type transport for lower temperatures. From the several parameters investigated in the study, it is mainly the oxygen content and the degree of CeO2 phase segregation that are crucial to be controlled in such electron-doped thin-film manganites.

Only few ten radiotherapy facilities worldwide provide ion beams, in spite of their physical advantage of better achievable tumor conformity of the dose compared to conventional photon beams. Since, mainly the large size and high costs hinder their wider spread, great efforts are ongoing to develop more compact ion therapy facilities. One promising approach for smaller facilities is the acceleration of ions on micrometre scale by high intensity lasers. Laser accelerators deliver pulsed beams with a low pulse repetition rate, but a high number of ions per pulse, broad energy spectra and high divergences. A clinical use of a laser based ion beam facility requires not only a laser accelerator providing beams of therapeutic quality, but also new approaches for beam transport, dosimetric control and tumor conformal dose delivery procedure together with the knowledge of the radiobiological effectiveness of laser-driven beams. Over the last decade research was mainly focused on protons and progress was achieved in all important challenges. Although currently the maximum proton energy is not yet high enough for patient irradiation, suggestions and solutions have been reported for compact beam transport and dose delivery procedures, respectively, as well as for precise dosimetric control. Radiobiological in vitro and in vivo studies show no indications of an altered biological effectiveness of laser-driven beams. Laser based facilities will hardly improve the availability of ion beams for patient treatment in the next decade. Nevertheless, there are possibilities for a need of laser based therapy facilities in future.

In the past, surface photovoltage (SPV) analysis has been successfully applied to derive the electronic defect status of a number of wide-bandgap semiconductor surfaces. Here, the method is applied to the model perovskite strontium titanate, whose SPV phenomena are comprehensively studied over seven decades of excitation-light intensity. The SPV was recorded by a Kelvin probe setup as a function of wavelength in order to extract the energetic positions of electronic surface states within the bandgap. At selected wavelengths addressing distinct surface states, SPV transients were measured as a function of light intensity and temperature. Several models known from the literature were used to estimate and cross check surface state parameters such as surface state densities, capture cross sections for photons and electrons, and the surface band bending in the dark and under illumination. In contrast to other wide-bandgap materials, SPV transients of SrTiO3 exhibit highly complex shapes, i.e. they (i) show signatures of multiple carrier transitions, (ii) mixtures of surface and bulk contributions, as well as (iii) both ex- and intrinsic SPV processes.

No abstract available

Proton beams are a promising tool for the improvement of radiotherapy of cancer, and compact laser-driven proton radiation (LDPR) is discussed as an alternative to established large-scale technology facilitating wider clinical use. Yet, clinical use of LDPR requires substantial development in reliable beam generation and transport, but also in dosimetric protocols as well as validation in radiobiological studies. Here, we present the first dose-controlled direct comparison of the radiobiological effectiveness of intense proton pulses from a laser-driven accelerator with conventionally generated continuous proton beams, demonstrating a first milestone in translational research. Controlled dose delivery, precisely online and offline monitored for each out of ∼4,000 pulses, resulted in an unprecedented relative dose uncertainty of below 10 %, using approaches scalable to the next translational step toward radiotherapy application.

Purpose: The use of laser accelerators in radiation therapy can perhaps increase the low number of proton and ion therapy facilities in some years due to the low investment costs and small size. The laser-based acceleration technology leads to a very high peak dose rate of about 10{sup 11} Gy/s. A first dosimetric task is the evaluation of dose rate dependence of clinical dosimeters and other detectors. Methods: The measurements were done at ELBE, a superconductive linear electron accelerator which generates electron pulses with 5 ps length at 20 MeV. The different dose rates are reached by adjusting the number of electrons in one beam pulse. Three clinical dosimeters (TLD, OSL, and EBT radiochromic films) were irradiated with four different dose rates and nearly the same dose. A faraday cup, an integrating current transformer, and an ionization chamber were used to control the particle flux on the dosimeters. Furthermore two diamond detectors were tested. Results: The dosimeters are dose rate independent up to 410{sup 9} Gy/s within 2% (OSL and TLD) and up to 1510{sup 9} Gy/s within 5% (EBT films). The diamond detectors show strong dose rate dependence. Conclusions: TLD, OSL dosimeters, and EBT films are suitable for pulsedmore » beams with a very high pulse dose rate like laser accelerated particle beams.« less

Laser particle acceleration/Laser radiotherapy/Cell response to electrons/Pulsed irradiation. The notable progress in laser particle acceleration techn ology promises potential medical application in cancer therapy through compact and cost effective laser devices that are suitable for already existing clinics. Previously, consequences on the radiobiological response by laser driven particle beams characterised by an ultra high peak dose rate have to be inves tigated. Therefore, tumour and non-malignant cells were irradiated with pulsed laser accelerated electrons at the JETI facility for the comparison with continuous electrons of a conventional therapy LINAC. Dose res ponse curves were measured for the biological endpoints clonogenic survival and residual DNA double strand breaks. The overall results show no significant differences in radiobiological response for in vitro cell experiments between laser accelerated pulsed and clinical used electron beams. These first systematic in vitro cell response studies with precise dosimetry to laser driven electron beams represent a first s tep toward the long term aim of the application of laser accelerated particles in radiotherapy.

The energetic distribution of electronic defect states in oxide heterostructures made of ultrathin lanthanum manganite (La0.7Ca0.3MnO3, La0.7Ce0.3MnO3) films on SrTiO3 substrates is investigated by surface photovoltage (SPV) spectroscopy. Within a comparative evaluation of the SPV spectra of both the film/substrate structures and pure substrates at different temperatures we were able to elaborate a map of defect states across the SrTiO3-bandgap and we find that the defect state distribution is mainly affected by the substrate, i.e., no specific film-induced defect states were detected. Possible origins of the defect states are discussed within the framework of a semiconductor band scheme, taking into account complementary photoconductivity and SPV transient data.

Purpose: In recent years, laser-based acceleration of charged particles has rapidly progressed and medical applications, e.g., in radiotherapy, might become feasible in the coming decade. Requirements are monoenergetic particle beams with long-term stable and reproducible properties as well as sufficient particle intensities and a controlled delivery of prescribed doses at the treatment site. Although conventional and laser-based particle accelerators will administer the same dose to the patient, their different time structures could result in different radiobiological properties. Therefore, the biological response to the ultrashort pulse durations and the resulting high peak dose rates of these particle beams have to be investigated. The technical prerequisites, i.e., a suitable cellirradiation setup and the precise dosimetric characterization of a laser-based particle accelerator, have to be realized in order to prepare systematic cellirradiation experiments. Methods: The Jena titanium:sapphire laser system (JETI) was customized in preparation for cellirradiation experiments with laser-accelerated electrons. The delivered electron beam was optimized with regard to its spectrum, diameter, dose rate, and dose homogeneity. A custom-designed beam and dose monitoring system, consisting of a Roos ionization chamber, a Faraday cup, and EBT-1 dosimetry films, enables real-time monitoring of irradiation experiments and precise determination of the dose delivered to the cells. Finally, as proof-of-principle experiment cell samples were irradiated using this setup. Results: Laser-accelerated electron beams, appropriate forin vitro radiobiological experiments, were generated with a laser shot frequency of 2.5 Hz and a pulse length of 80 fs. After laser acceleration in the helium gas jet, the electrons were filtered by a magnet, released from the vacuum target chamber, and propagated in air for a distance of 220 mm. Within this distance a lead collimator (aperture of 35 mm) was introduced, leading, along with the optimized setup, to a beam diameter of 35 mm, sufficient for the irradiation of common cell culture vessels. The corresponding maximum dose inhomogeneity over the beam spot was less than 10% for all irradiated samples. At cell position, the electrons posses a mean kinetic energy of 13.6 MeV, a bunch length of about 5 ps (FWHM), and a mean pulse dose of 1.6 mGy/bunch. Cross correlations show clear linear dependencies for the online recorded accumulated bunch charges, pulse doses, and pulse numbers on absolute doses determined with EBT-1 films. Hence, the established monitoring system is suitable for beam control and a dedicated dose delivery. Additionally, reasonable day-to-day stable and reproducible properties of the electron beam were achieved. Conclusions: Basic technical prerequisites for future cellirradiation experiments with ultrashort pulsed laser-accelerated electrons were established at the JETI laser system. The implemented online control system is suitable to compensate beam intensity fluctuations and the achieved accuracy of dose delivery to the cells is sufficient for radiobiological cell experiments. Hence, systematicin vitrocellirradiation experiments can be performed, being the first step toward clinical application of laser-accelerated particles. Further steps, including the transfer of the established methods to experiments on higher biological systems or to other laser-based particle accelerators, will be prepared.

The application of ionising radiation for medical purposes requires the investigation of induced and persistent DNA damages, especially for soft X-rays that are assumed to be more effective than higher energy photons. Therefore, we examined the energy dependent time and dose response of residual DNA damage foci for soft X-rays in comparison to 200 kV photons.DNA damage present in cell line 184A1 within 48 h after irradiations with 10 kV, 25 kV and 200 kV photons was analysed by immunochemical detection of co-localised gamma-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein) foci.The dose dependencies of the colocated foci revealed significant energy dependent differences with increasing amounts of residual foci at decreasing X-ray energy independent on postirradiation time. Dose-dependent RBE (relative biological effectiveness) values ranging from 4 to 7 were determined for 10 kV relative to 200 kV X-rays based on the 24 hour dose responses. For 25 kV photons, ratios considerably higher than one were obtained only for doses above 2 Gy.The expected energy dependence with increasing DNA damage at decreasing photon energy was confirmed for the residual co-localised foci measured at different time points after irradiation.