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This paper proposes a general analytical formulation for LCL filter design for grid-connected PWM-driven cascaded H-bridge inverters. The novelty of this work deals with providing some easy-of-use analytical expressions that allow for properly sizing the filter inductances and capacitance values considering the number of voltage levels, the DC-link voltage, the adopted multicarrier pulse width modulation strategy, and the switching frequency. Although multilevel inverters performance strongly depends on the adopted modulation strategy and switching frequency, a general mathematical formulation that allows for properly sizing the LCL filter by considering such parameters simultaneously is currently missing. The proposed approach is generalized for the most adopted multicarrier pulse width modulation strategies. To validate the proposed approach, an extended investigation analysis is performed by hardware-in-the-loop real-time tests. According to international standards EN50160 and IEEE Std 1547–2018, the voltage total harmonic distortion and current total rated distortion are adopted to evaluate the LCL filter performance. Tests are carried out in several working conditions, defined in terms of provided apparent power and power factor values. Finally, the proposed analytical formulation is adopted to formulate an optimized LCL filter design algorithm that allows for matching the standard requirements without oversizing the filter parameters.

To avoid leg short-circuit in inverters, dead time must be introduced on leg gate signals. Dead time affects the inverter output voltage fundamental harmonic amplitude, voltage harmonic distortion and inverter efficiency by introducing additional voltage drops. In this regard, dead time effects have been widely investigated for traditional two-level three-phase voltage source inverters in the literature but not extensively for multilevel topology structures. This paper provides a detailed analysis of dead time impact on the harmonic distortion and efficiency of Cascaded H-Bridges Multilevel Inverters (CHBMIs). For this purpose, a general mathematical formulation to determine voltage drop due to dead time effects, also taking into account the adopted Multicarrier PWM strategy, has been provided and experimentally validated for a five-level three-phase CHBMI structure. As a comparison tool between expected and ideal inverter output voltage, the percentage voltage error $e_{\%}$ is introduced. In most of the cases, $e_{\%} $ is lower than 5%, and it starts increasing for very low amplitude modulation index or for specific working points where nonlinearities occur. Furthermore, several experimental investigations have been carried out to evaluate the CHBMI performance in terms of harmonic distortion and efficiency by changing, the values of dead time, modulation index and switching frequency for ten different multi-carried PWM strategies. Experimental results confirm the strong dependency between the dead time impact on the converter performance and the adopted Multi Carrier-PWM (MC-PWM) strategy: as a way of example, converter efficiency can be reduced from 80% to 60% when dead time is increased from $0.5 \mu \text{s}$ to $1.5 \mu \text{s}$ and Phase Shifted-PWM (PS-PWM) is adopted.

Background and purpose: Radiomics features derived from medical images have the potential to act as imaging biomarkers to improve diagnosis and predict treatment response in oncology. However, the complex relationships between radiomics features and the biological characteristics of tumours are yet to be fully determined. In this study, we developed a preclinical cone beam computed tomography (CBCT) radiomics workflow with the aim to use in vivo models to further develop radiomics signatures. Materials and methods: CBCT scans of a mouse phantom were acquired using onboard imaging from a small animal radiotherapy research platform (SARRP, Xstrahl). The repeatability and reproducibility of radiomics outputs were compared across different imaging protocols, segmentation sizes, pre-processing parameters and materials. Robust features were identified and used to compare scans of two xenograft mouse tumour models (A549 and H460). Results: Changes to the radiomics workflow significantly impact feature robustness. Preclinical CBCT radiomics analysis is feasible with 119 stable features identified from scans imaged at 60 kV, 25 bin width and 0.26 mm slice thickness. Large variation in segmentation volumes reduced the number of reliable radiomics features for analysis. Standardization in imaging and analysis parameters is essential in preclinical radiomics analysis to improve accuracy of outputs, leading to more consistent and reproducible findings. Conclusions: We present the first optimised workflow for preclinical CBCT radiomics to identify imaging biomarkers. Preclinical radiomics has the potential to maximise the quantity of data captured in in vivo experiments and could provide key information supporting the wider application of radiomics.

The interest in hadron therapy is growing fast thanks to the latest technological advances in accelerators and delivery technologies, to the development of more and more efficient and comprehensive treatment planning tools, and due to its increasing clinical adoption proving its efficacy. A precise and reliable beam quality assessment and an accurate and effective inclusion of the biological effectiveness of different radiation qualities are fundamental to exploit at best its advantages with respect to conventional radiotherapy. Currently, in clinical practice, the quality assurance (QA) is carried out by means of conventional dosimetry, while the biological effectiveness of the radiation is taken into account considering the Relative Biological Effectiveness (RBE). The RBE is considered a constant value for protons and it is estimated as a function of the absorbed dose in case of carbon ions. In this framework, microdosimetry could bring a significant improvement to both QA and RBE estimation. By measuring the energy deposited by the radiation into cellular or sub-cellular volumes, microdosimetry could provide a unique characterisation of the beam quality on one hand, and a direct link to radiobiology on the other. Different detectors have been developed for microdosimetry, from the more conventional tissue equivalent proportional counter (TEPC), silicon-based and diamond-based solid-state detectors, to ΔE-E telescope detectors, gas electrons multiplier (GEM), hybrid microdosimeters and a micro-bolometer based on Superconducting QUantum Interference Device (SQUID) technology. However, because of their different advantages and drawbacks, a standard device and an accredited experimental methodology have not been unequivocally identified yet. The establishment of accepted microdosimetry standard protocols and code of practice is needed before the technique could be employed in clinical practice. Hoping to help creating a solid ground on which future research, development and collaborations could be planned and inspired, a comprehensive state of the art of the detector technologies developed for microdosimetry is presented in this review, discussing their use in clinical hadron therapy conditions and considering their advantages and drawbacks.

Abstract Purpose The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. Methods SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. Results The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P

The “Laser-hybrid Accelerator for Radiobiological Applications,” LhARA, is conceived as a novel, flexible facility dedicated to the study of radiobiology. The technologies demonstrated in LhARA, which have wide application, will be developed to allow particle-beam therapy to be delivered in a new regimen, combining a variety of ion species in a single treatment fraction and exploiting ultra-high dose rates. LhARA will be a hybrid accelerator system in which laser interactions drive the creation of a large flux of protons or light ions that are captured using a plasma (Gabor) lens and formed into a beam. The laser-driven source allows protons and ions to be captured at energies significantly above those that pertain in conventional facilities, thus evading the current space-charge limit on the instantaneous dose rate that can be delivered. The laser-hybrid approach, therefore, will allow the radiobiology that determines the response of tissue to ionizing radiation to be studied with protons and light ions using a wide variety of time structures, spectral distributions, and spatial configurations at instantaneous dose rates up to and significantly beyond the ultra-high dose-rate “FLASH” regime. It is proposed that LhARA be developed in two stages. In the first stage, a programme of in vitro radiobiology will be served with proton beams with energies between 10 and 15 MeV. In stage two, the beam will be accelerated using a fixed-field alternating-gradient accelerator (FFA). This will allow experiments to be carried out in vitro and in vivo with proton beam energies of up to 127 MeV. In addition, ion beams with energies up to 33.4 MeV per nucleon will be available for in vitro and in vivo experiments. This paper presents the conceptual design for LhARA and the R&D programme by which the LhARA consortium seeks to establish the facility.

Biologically based treatment planning is a broad term used to cover any instance in radiotherapy treatment planning where some form of biological input has been used. This is wide ranging, and the simpler forms (e.g., fractionation modification/optimization) have been in use for many years. However, there is a reluctance to use more sophisticated methods that incorporate biological models either for plan evaluation purposes or for driving plan optimizations. This is due to limited data available regarding the uncertainties in these model parameters and what impact these have clinically. This work aims to address some of these issues and to explore the role that uncertainties in individual model parameters have on the overall tissue control probability (TCP)/normal tissue control probability (NTCP) calculated, those parameters that have the largest influence and situations where extra care must be taken. In order to achieve this, a software tool was developed, which can import individual clinical DVH's for analysis using a range of different TCP/NTCP models. On inputting individual model parameters, an uncertainty can be applied. Using a normally distributed random number generator, distributions of parameters can be generated, from which TCP/NTCP values can be calculated for each parameter set for the DVH in question. These represent the spread in TCP/NTCP parameters that would be observed for a simulated population of patients all being treated with that particular dose distribution. A selection of clinical DVHs was assessed using published parameters and their associated uncertainties. A range of studies was carried out to determine the impact of individual parameter uncertainties including reduction of uncertainties and assessment of what impact fractionation and dose have on these probabilities.

With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumor niche. Advancements in the field of tissue engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, polyurethane (PU) scaffold-based, long-term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells, and stellate cells. Recognizing the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumor compartment consisting of cancer cells [fibronectin (FN)-coated] and a surrounding stromal compartment consisting of stellate and endothelial cells [collagen I (COL)-coated]. Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported timeframe in vitro. Furthermore, the hybrid model showed extensive COL production by the cells, mimicking desmoplasia, one of PDAC’s hallmark features. Fibril alignment of the stellate cells was observed, which attested to their activated state. All three cell types expressed various cell-specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low-cost tool for in vitro studies of PDAC, as well as for treatment screening.

The current climatic scenario requires the use of innovative solutions to increase the production of electricity from renewable energy sources. Multilevel Power Inverters are a promising solution to improve the penetration of renewable energy sources into the electrical grid. Moreover, the performance of MPIs is a function of the modulation strategy employed and of its features (modulation index and switching frequency). This paper presents an extended and experimental analysis of three-phase five-level Cascaded H-Bridges Multilevel Inverter performance in terms of efficiency and harmonic content considering several MC PWM modulation strategies. In detail, the CHBMI performance is analyzed by varying the modulation index and the switching frequency. For control purposes, the NI System On Module sbRIO-9651 control board, a dedicated FPGA-based control board for power electronics and drive applications programmable in the LabVIEW environment, is used. The paper describes the modulation strategies implementation, the test bench set-up, and the experimental investigations carried out. The results obtained in terms of Total Harmonic Distorsion (THD) and efficiency are analyzed, compared, and discussed.

Auger electron-emitters increasingly attract attention as potential radionuclides for molecular radionuclide therapy in oncology. The radionuclide technetium-99m is widely used for imaging; however, its potential as a therapeutic radionuclide has not yet been fully assessed. We used MDA-MB-231 breast cancer cells engineered to express the human sodium iodide symporter-green fluorescent protein fusion reporter (hNIS-GFP; MDA-MB-231.hNIS-GFP) as a model for controlled cellular radionuclide uptake. Uptake, efflux, and subcellular location of the NIS radiotracer [99mTc]TcO4− were characterised to calculate the nuclear-absorbed dose using Medical Internal Radiation Dose formalism. Radiotoxicity was determined using clonogenic and γ-H2AX assays. The daughter radionuclide technetium-99 or external beam irradiation therapy (EBRT) served as controls. [99mTc]TcO4− in vivo biodistribution in MDA-MB-231.hNIS-GFP tumour-bearing mice was determined by imaging and complemented by ex vivo tissue radioactivity analysis. [99mTc]TcO4− resulted in substantial DNA damage and reduction in the survival fraction (SF) following 24 h incubation in hNIS-expressing cells only. We found that 24,430 decays/cell (30 mBq/cell) were required to achieve SF0.37 (95%-confidence interval = [SF0.31; SF0.43]). Different approaches for determining the subcellular localisation of [99mTc]TcO4− led to SF0.37 nuclear-absorbed doses ranging from 0.33 to 11.7 Gy. In comparison, EBRT of MDA-MB-231.hNIS-GFP cells resulted in an SF0.37 of 2.59 Gy. In vivo retention of [99mTc]TcO4− after 24 h remained high at 28.0% ± 4.5% of the administered activity/gram tissue in MDA-MB-231.hNIS-GFP tumours. [99mTc]TcO4− caused DNA damage and reduced clonogenicity in this model, but only when the radioisotope was taken up into the cells. This data guides the safe use of technetium-99m during imaging and potential future therapeutic applications.

Abstract Background Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on-board CBCT image guidance. Methods In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture. Results Good agreement (between 1.7–3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time. Conclusions FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility.

Solar plants suffer of partial shading and mismatch problems. Without considering the generation of hot spots and the resulting security issues, a monitoring system for the health of a PV plant should be useful to drive a dynamic reconfiguration system (DRS) to solve bottlenecks due to different panels’ shading. Over the years different DRS architectures have been proposed, but no suggestions about costs and benefits have been provided. Starting from technical subjects such as differences of the topologies driving the hardware complexity and number of components, this paper identifies the cost of DRS and its lifetime, and based on these issues it provides an economic analysis for a 6 kWp PV plant in different European Union countries, in which the dissimilar incentive policies have been considered.

The sustainable development of our planet is considerably related to a relevant reduction of CO2 global emissions, with building consumption contributing more than 40%. In this scenario, new technological conceptions, such as building-integrated photovoltaic technology, emerged in order to satisfy the requirements of sustainability imposed by the European Union. Therefore, the aim of this work is to provide a technical and economical comparison of the performances of different vertical-mounted innovative photovoltaic systems, potentially integrated on a building instead of on traditional windows or glass walls. The proposed investigation was carried out by means of experimental tests on three different next-generation vertical structures. The related results are described and discussed, highlighting the advantages and the drawbacks of the proposed technologies.

The Field Programmable Gate Array (FPGA) represents a valid solution for the design of control systems for inverters adopted in many industry applications, because of both its high flexibility of use and its high-performance with respect to other types of digital controllers. In this context, this paper presents an experimental investigation on the harmonic content of the voltages produced by a three-phase, five level cascaded H-Bridge Multilevel inverter with an FPGA-based control board, aiming also to evaluate the performance of the FPGA through the implementation of the main common modulation techniques and the comparison between simulation and experimental results. The control algorithms are implemented by means of the VHDL programming language. The output voltage waveforms, which have been obtained by applying to the inverter the main PWM techniques, are compared in terms of THD%. Simulation and experimental results are analyzed, compared and finally discussed.

In this paper, a novel approach to low order harmonic mitigation in fundamental switching frequency modulation is proposed for high power photovoltaic (PV) applications, without trying to solve the cumbersome non-linear transcendental equations. The proposed method allows for mitigation of the first-five harmonics (third, fifth, seventh, ninth, and eleventh harmonics), to reduce the complexity of the required procedure and to allocate few computational resource in the Field Programmable Gate Array (FPGA) based control board. Therefore, the voltage waveform taken into account is different respect traditional voltage waveform. The same concept, known as “voltage cancelation”, used for single-phase cascaded H-bridge inverters, has been applied at a single-phase five-level cascaded H-bridge multilevel inverter (CHBMI). Through a very basic methodology, the polynomial equations that drive the control angles were detected for a single-phase five-level CHBMI. The acquired polynomial equations were implemented in a digital system to real-time operation. The paper presents the preliminary analysis in simulation environment and its experimental validation.

DNA damage (caused by direct cellular exposure and bystander signaling) and the complex pathways involved in its repair are critical events underpinning cellular and tissue response following radiation exposures. There are limited data addressing the dynamics of DNA damage induction and repair in the skin particularly in areas not directly exposed. Here we investigate the mechanisms regulating DNA damage, repair, intracellular signalling and their impact on premature differentiation and development of inflammatory-like response in the irradiated and surrounding areas of a 3D organotypic skin model. Following localized low-LET irradiation (225 kVp X-rays), low levels of 53BP1 foci were observed in the 3D model (3.8±0.28 foci/Gy/cell) with foci persisting and increasing in size up to 48 h post irradiation. In contrast, in cell monolayers 14.2±0.6 foci/Gy/cell and biphasic repair kinetics with repair completed before 24 h was observed. These differences are linked to differences in cellular status with variable level of p21 driving apoptotic signalling in 2D and accelerated differentiation in both the directly irradiated and bystander areas of the 3D model. The signalling pathways utilized by irradiated keratinocytes to induce DNA damage in non-exposed areas of the skin involved the NF-κB transcription factor and its downstream target COX-2.

Radiation therapy is one of the most common and effective strategies used to treat cancer. The irradiation is usually performed with a fractionated scheme, where the dose required to kill tumour cells is given in several sessions, spaced by specific time intervals, to allow healthy tissue recovery. In this work, we examined the DNA repair dynamics of cells exposed to radiation delivered in fractions, by assessing the response of histone-2AX (H2AX) phosphorylation (γ-H2AX), a marker of DNA double strand breaks. γ-H2AX foci induction and disappearance were monitored following split dose irradiation experiments in which time interval between exposure and dose were varied. Experimental data have been coupled to an analytical theoretical model, in order to quantify key parameters involved in the foci induction process. Induction of γ-H2AX foci was found to be affected by the initial radiation exposure with a smaller number of foci induced by subsequent exposures. This was compared to chromatin relaxation and cell survival. The time needed for full recovery of γ-H2AX foci induction was quantified (12 hours) and the 1:1 relationship between radiation induced DNA double strand breaks and foci numbers was critically assessed in the multiple irradiation scenarios.

It is now widely accepted that intercellular communication can cause significant variations in cellular responses to genotoxic stress. The radiation-induced bystander effect is a prime example of this effect, where cells shielded from radiation exposure see a significant reduction in survival when cultured with irradiated cells. However, there is a lack of robust, quantitative models of this effect which are widely applicable. In this work, we present a novel mathematical model of radiation-induced intercellular signalling which incorporates signal production and response kinetics together with the effects of direct irradiation, and test it against published data sets, including modulated field exposures. This model suggests that these so-called "bystander" effects play a significant role in determining cellular survival, even in directly irradiated populations, meaning that the inclusion of intercellular communication may be essential to produce robust models of radio-biological outcomes in clinically relevant in vivo situations.