A multimodality assessment of the protective capacity of statin therapy in a mouse model of radiation cardiotoxicity.

PURPOSE: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. MATERIALS AND METHODS: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. RESULTS: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. CONCLUSIONS: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

Parametric Modeling and Deep Learning for Enhancing Pain Assessment in Postanesthesia.

OBJECTIVE: The problem of reliable and widely accepted measures of pain is still open. It follows the objective of this work as pain estimation through post-surgical trauma modeling and classification, to increase the needed reliability compared to measurements only. METHODS: This article proposes (i) a recursive identification method to obtain the frequency response and parameterization using fractional-order impedance models (FOIM), and (ii) deep learning with convolutional neural networks (CNN) classification algorithms using time-frequency data and spectrograms. The skin impedance measurements were conducted on 12 patients throughout the postanesthesia care in a proof-of-concept clinical trial. Recursive least-squares system identification was performed using a genetic algorithm for initializing the parametric model. The online parameter estimates were compared to the self-reported level by the Numeric Rating Scale (NRS) for analysis and validation of the results. Alternatively, the inputs to CNNs were the spectrograms extracted from the time-frequency dataset, being pre-labeled in four intensities classes of pain during offline and online training with the NRS. RESULTS: The tendency of nociception could be predicted by monitoring the changes in the FOIM parameters' values or by retraining online the network. Moreover, the tissue heterogeneity, assumed during nociception, could follow the NRS trends. The online predictions of retrained CNN have more specific trends to NRS than pain predicted by the offline population-trained CNN. CONCLUSION: We propose tailored online identification and deep learning for artefact corrupted environment. The results indicate estimations with the potential to avoid over-dosing due to the objectivity of the information. SIGNIFICANCE: Models and artificial intelligence (AI) allow objective and personalized nociception-antinociception prediction in the patient safety era for the design and evaluation of closed-loop analgesia controllers.

Assessment of Variabilities in Lung-Contouring Methods on CBCT Preclinical Radiomics Outputs.

Radiomics image analysis has the potential to uncover disease characteristics for the development of predictive signatures and personalised radiotherapy treatment. Inter-observer and inter-software delineation variabilities are known to have downstream effects on radiomics features, reducing the reliability of the analysis. The purpose of this study was to investigate the impact of these variabilities on radiomics outputs from preclinical cone-beam computed tomography (CBCT) scans. Inter-observer variabilities were assessed using manual and semi-automated contours of mouse lungs (n = 16). Inter-software variabilities were determined between two tools (3D Slicer and ITK-SNAP). The contours were compared using Dice similarity coefficient (DSC) scores and the 95th percentile of the Hausdorff distance (HD95p) metrics. The good reliability of the radiomics outputs was defined using intraclass correlation coefficients (ICC) and their 95% confidence intervals. The median DSC scores were high (0.82-0.94), and the HD95p metrics were within the submillimetre range for all comparisons. the shape and NGTDM features were impacted the most. Manual contours had the most reliable features (73%), followed by semi-automated (66%) and inter-software (51%) variabilities. From a total of 842 features, 314 robust features overlapped across all contouring methodologies. In addition, our results have a 70% overlap with features identified from clinical inter-observer studies.

Invasive fusariosis in acute leukaemia patients-An outbreak in the haematology ward.

Fusarium, a common fungus, emerges as a pathogen in severely immunocompromised patients. We present a series of patients who developed invasive fusariosis (IF) during admission to an acute leukaemia ward: an outbreak of 12 cases in June and July 2018, followed by four sporadic cases until 2021. No case was reported earlier. All patients were clustered in the same location with indoor air and water installations found to be contaminated with Fusarium spp. thus a nosocomial outbreak was assumed. Following the water installation replacement, the number of Fusarium cases dramatically dropped to one or two isolated instances per year in the same location. All 16 patients had acute leukaemia and developed IF during severe neutropenia following induction therapy. IF diagnosis was based on positive blood cultures (14 patients) and/or on tissue biopsies (3 patients). The median time from admission to the IF onset was 20 days, and from the first day of severe neutropenia (≤500/mm3) was 11.5 days. All patients were febrile, eight had moderate-to-severe myalgias, eight had respiratory involvements: lung lesions and/or sinusitis and seven had characteristic skin lesions. Follow-up: 12 out of 16 (75%) were alive on Day 90; nine out of 15 (60%) were alive on Month 6. All with intractable neutropenia died. In severely neutropenic febrile patients, the triad of respiratory involvement/skin lesions/severe myalgia may suggest Fusarium aetiology. The ability to recover from neutropenia is critical to surmount IF. The indoor environment in immunocompromised dedicated settings must be constantly controlled.

Development and optimisation of a preclinical cone beam computed tomography-based radiomics workflow for radiation oncology research.

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.

Spatial Gene Expression Changes in the Mouse Heart After Base-Targeted Irradiation.

PURPOSE: Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity. METHODS AND MATERIALS: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions. RESULTS: Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities. CONCLUSIONS: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.

Feasibility and guidelines for the use of an injectable fiducial marker (BioXmark ®) to improve target delineation in preclinical radiotherapy studies using mouse models.

BACKGROUND: Preclinical models of radiotherapy (RT) response are vital for the continued success and evolution of RT in the treatment of cancer. The irradiation of tissues in mouse models necessitates high levels of precision and accuracy to recapitulate clinical exposures and limit adverse effects on animal welfare. This requirement has been met by technological advances in preclinical RT platforms established over the past decade. Small animal RT systems use onboard computed tomography (CT) imaging to delineate target volumes and have significantly refined radiobiology experiments with major 3Rs impacts. However, the CT imaging is limited by the differential attenuation of tissues resulting in poor contrast in soft tissues. Clinically, radio-opaque fiducial markers (FMs) are used to establish anatomical reference points during treatment planning to ensure accuracy beam targeting, this approach is yet to translate back preclinical models. METHODS: We report on the use of a novel liquid FM BioXmark ® developed by Nanovi A/S (Kongens Lyngby, Denmark) that can be used to improve the visualisation of soft tissue targets during beam targeting and minimise dose to surrounding organs at risk. We present descriptive protocols and methods for the use of BioXmark ® in experimental male and female C57BL/6J mouse models. RESULTS: These guidelines outline the optimum needle size for uptake (18-gauge) and injection (25- or 26-gauge) of BioXmark ® for use in mouse models along with recommended injection volumes (10-20 µl) for visualisation on preclinical cone beam CT (CBCT) scans. Injection techniques include subcutaneous, intraperitoneal, intra-tumoral and prostate injections. CONCLUSIONS: The use of BioXmark ® can help to standardise targeting methods, improve alignment in preclinical image-guided RT and significantly improve the welfare of experimental animals with the reduction of normal tissue exposure to RT.

Lumped Parametric Model for Skin Impedance Data in Patients with Postoperative Pain.

The societal and economic burden of unassessed and unmodeled postoperative pain is high and predicted to rise over the next decade, leading to over-dosing as a result of subjective (NRS-based) over-estimation by the patient. This study identifies how post-surgical trauma alters the parameters of impedance models, to detect and examine acute pain variability. Model identification is performed on clinical data captured from post-anesthetized patients, using Anspec-PRO prototype apriori validated for clinical pain assessment. The multisine excitation of this in-house developed device enables utilizing the complex skin impedance frequency response in data-driven electrical models. The single-dispersion Cole model is proposed to fit the clinical curve in the given frequency range. Changes in identified parameters are analyzed for correlation with the patient's reported pain for the same time moment. The results suggest a significant correlation for the capacitor component. Clinical Relevance- Individual model parameters validated on patients in the post-anesthesia care unit extend the knowledge for objective pain detection to positively influence the outcome of clinical analgesia management.

Murine models of radiation cardiotoxicity: A systematic review and recommendations for future studies.

BACKGROUND AND PURPOSE: The effects of radiation on the heart are dependent on dose, fractionation, overall treatment time, and pre-existing cardiovascular pathology. Murine models have played a central role in improving our understanding of the radiation response of the heart yet a wide range of exposure parameters have been used. We evaluated the study design of published murine cardiac irradiation experiments to assess gaps in the literature and to suggest guidance for the harmonisation of future study reporting. METHODS AND MATERIALS: A systematic review of mouse/rat studies published 1981-2021 that examined the effect of radiation on the heart was performed. The protocol was published on PROSPERO (CRD42021238921) and the findings were reported in accordance with the PRISMA guidance. Risk of bias was assessed using the SYRCLE checklist. RESULTS: 159 relevant full-text original articles were reviewed. The heart only was the target volume in 67% of the studies and simulation details were unavailable for 44% studies. Dosimetry methods were reported in 31% studies. The pulmonary effects of whole and partial heart irradiation were reported in 13% studies. Seventy-eight unique dose-fractionation schedules were evaluated. Large heterogeneity was observed in the endpoints measured, and the reporting standards were highly variable. CONCLUSIONS: Current murine models of radiation cardiotoxicity cover a wide range of irradiation configurations and latency periods. There is a lack of evidence describing clinically relevant dose-fractionations, circulating biomarkers and radioprotectants. Recommendations for the consistent reporting of methods and results of in vivo cardiac irradiation studies are made to increase their suitability for informing the design of clinical studies.

A scoping review of small animal image-guided radiotherapy research: Advances, impact and future opportunities in translational radiobiology.

Background and purpose: To provide a scoping review of published studies using small animal irradiators and highlight the progress in preclinical radiotherapy (RT) studies enabled by these platforms since their development and commercialization in 2007. Materials and methods: PubMed searches and manufacturer records were used to identify 907 studies that were screened with 359 small animal RT studies included in the analyses. These articles were classified as biology or physics contributions and into subgroups based on research aims, experimental models and other parameters to identify trends in the preclinical RT research landscape. Results: From 2007 to 2021, most published articles were biology contributions (62%) whilst physics contributions accounted for 38% of the publications. The main research areas of physics articles were in dosimetry and calibration (24%), treatment planning and simulation (22%), and imaging (22%) and the studies predominantly used phantoms (41%) or in vivo models (34%). The majority of biology contributions were tumor studies (69%) with brain being the most commonly investigated site. The most frequently investigated areas of tumor biology were evaluating radiosensitizers (33%), model development (30%) and imaging (21%) with cell-line derived xenografts the most common model (82%). 31% of studies focused on normal tissue radiobiology and the lung was the most investigated site. Conclusions: This study captures the trends in preclinical RT research using small animal irradiators from 2007 to 2021. Our data show the increased uptake and outputs from preclinical RT studies in important areas of biology and physics research that could inform translation to clinical trials.

Cancer Cells Can Exhibit a Sparing FLASH Effect at Low Doses Under Normoxic In Vitro-Conditions.

BACKGROUND: Irradiation with ultra-high dose rate (FLASH) has been shown to spare normal tissue without hampering tumor control in several in vivo studies. Few cell lines have been investigated in vitro, and previous results are inconsistent. Assuming that oxygen depletion accounts for the FLASH sparing effect, no sparing should appear for cells irradiated with low doses in normoxia. METHODS: Seven cancer cell lines (MDA-MB-231, MCF7, WiDr, LU-HNSCC4, HeLa [early passage and subclone]) and normal lung fibroblasts (MRC-5) were irradiated with doses ranging from 0 to 12 Gy using FLASH (≥800 Gy/s) or conventional dose rates (CONV, 14 Gy/min), with a 10 MeV electron beam from a clinical linear accelerator. Surviving fraction (SF) was determined with clonogenic assays. Three cell lines were further studied for radiation-induced DNA-damage foci using a 53BP1-marker and for cell cycle synchronization after irradiation. RESULTS: A tendency of increased survival following FLASH compared with CONV was suggested for all cell lines, with significant differences for 4/7 cell lines. The magnitude of the FLASH-sparing expressed as a dose-modifying factor at SF=0.1 was around 1.1 for 6/7 cell lines and around 1.3 for the HeLasubclone. Similar cell cycle distributions and 53BP1-foci numbers were found comparing FLASH to CONV. CONCLUSION: We have found a FLASH effect appearing at low doses under normoxic conditions for several cell lines in vitro. The magnitude of the FLASH effect differed between the cell lines, suggesting inherited biological susceptibilities for FLASH irradiation.

Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells.

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 < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 µg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05). CONCLUSIONS: SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

Bioimpedance Sensor and Methodology for Acute Pain Monitoring.

The paper aims to revive the interest in bioimpedance analysis for pain studies in communicating and non-communicating (anesthetized) individuals for monitoring purpose. The plea for exploitation of full potential offered by the complex (bio)impedance measurement is emphasized through theoretical and experimental analysis. A non-invasive, low-cost reliable sensor to measure skin impedance is designed with off-the-shelf components. This is a second generation prototype for pain detection, quantification, and modeling, with the objective to be used in fully anesthetized patients undergoing surgery. The 2D and 3D time-frequency, multi-frequency evaluation of impedance data is based on broadly available signal processing tools. Furthermore, fractional-order impedance models are implied to provide an indication of change in tissue dynamics correlated with absence/presence of nociceptor stimulation. The unique features of the proposed sensor enhancements are described and illustrated here based on mechanical and thermal tests and further reinforced with previous studies from our first generation prototype.

Cardiac sub-volume targeting demonstrates regional radiosensitivity in the mouse heart.

BACKGROUND AND PURPOSE: Radiation-induced cardiac toxicity (RICT) remains one of the most critical dose limiting constraints in radiotherapy. Recent studies have shown higher doses to the base of the heart are associated with worse overall survival in lung cancer patients receiving radiotherapy. This work aimed to investigate the impact of sub-volume heart irradiation in a mouse model using small animal image-guided radiotherapy. MATERIALS AND METHODS: C57BL/6 mice were irradiated with a single fraction of 16 Gy to the base, middle or apex of the heart using a small animal radiotherapy research platform. Cone beam CT and echocardiography were performed at baseline and at 10 week intervals until 50 weeks post-treatment. Structural and functional parameters were correlated with mean heart dose (MHD) and volume of heart receiving 5 Gy (V5). RESULTS: All irradiated mice showed a time dependent increase in left ventricle wall thickness in diastole of ~0.2 mm detected at 10 weeks post-treatment, with the most significant and persistent changes occurring in the heart base-irradiated animals. Similarly, statistically different functional effects (p < 0.01) were observed in base-irradiated animals which showed the most significant decreases compared to controls. The observed functional changes did not correlate with MHD and V5 (R2 < 0.1), indicating that whole heart dosimetry parameters do not predict physiological changes resulting from cardiac sub-volume irradiation. CONCLUSIONS: This is the first report demonstrating the structural and functional consequences of sub-volume targeting in the mouse heart and reverse translates clinical observations indicating the heart base as a critical radiosensitive region.

Evaluation of a Novel Liquid Fiducial Marker, BioXmark®, for Small Animal Image-Guided Radiotherapy Applications.

BioXmark® (Nanovi A/S, Denmark) is a novel fiducial marker based on a liquid, iodine-based and non-metallic formulation. BioXmark® has been clinically validated and reverse translated to preclinical models to improve cone-beam CT (CBCT) target delineation in small animal image-guided radiotherapy (SAIGRT). However, in phantom image analysis and in vivo evaluation of radiobiological response after the injection of BioXmark® are yet to be reported. In phantom measurements were performed to compare CBCT imaging artefacts with solid fiducials and determine optimum imaging parameters for BioXmark®. In vivo stability of BioXmark® was assessed over a 5-month period, and the impact of BioXmark® on in vivo tumour response from single-fraction and fractionated X-ray exposures was investigated in a subcutaneous syngeneic tumour model. BioXmark® was stable, well tolerated and detectable on CBCT at volumes ≤10 µL. Our data showed imaging artefacts reduced by up to 84% and 89% compared to polymer and gold fiducial markers, respectively. BioXmark® was shown to have no significant impact on tumour growth in control animals, but changes were observed in irradiated animals injected with BioXmark® due to alterations in dose calculations induced by the sharp contrast enhancement. BioXmark® is superior to solid fiducials with reduced imaging artefacts on CBCT. With minimal impact on the tumour growth delay, BioXmark® can be implemented in SAIGRT to improve target delineation and reduce set-up errors.

Pain Detection with Bioimpedance Methodology from 3-Dimensional Exploration of Nociception in a Postoperative Observational Trial.

Although the measurement of dielectric properties of the skin is a long-known tool for assessing the changes caused by nociception, the frequency modulated response has not been considered yet. However, for a rigorous characterization of the biological tissue during noxious stimulation, the bioimpedance needs to be analyzed over time as well as over frequency. The 3-dimensional analysis of nociception, including bioimpedance, time, and frequency changes, is provided by ANSPEC-PRO device. The objective of this observational trial is the validation of the new pain monitor, named as ANSPEC-PRO. After ethics committee approval and informed consent, 26 patients were monitored during the postoperative recovery period: 13 patients with the in-house developed prototype ANSPEC-PRO and 13 with the commercial device MEDSTORM. At every 7 min, the pain intensity was measured using the index of Anspec-pro or Medstorm and the 0-10 numeric rating scale (NRS), pre-surgery for 14 min and post-anesthesia for 140 min. Non-significant differences were reported for specificity-sensitivity analysis between ANSPEC-PRO (AUC = 0.49) and MEDSTORM (AUC = 0.52) measured indexes. A statistically significant positive linear relationship was observed between Anspec-pro index and NRS (r2 = 0.15, p < 0.01). Hence, we have obtained a validation of the prototype Anspec-pro which performs equally well as the commercial device under similar conditions.

Low Frequency Forced Oscillation Lung Function Test Can Distinguish Dynamic Tissue Non-linearity in COPD Patients.

This paper introduces the use of low frequencies forced oscillation technique (FOT) in the presence of breathing signal. The hypothesis tested is to evaluate the sensitivity of FOT to various degrees of obstruction in COPD patients. The measurements were performed in the frequency range 0-2 Hz. The use of FOT to evaluate respiratory impedance has been broadly recognized and its complementary use next to standardized method as spirometry and body plethysmography has been well-documented. Typical use of FOT uses frequencies between 4-32 Hz and above. However, interesting information at frequencies below 4 Hz is related to viscoelastic properties of parenchyma. Structural changes in COPD affect viscoelastic properties and we propose to investigate the use of FOT at low frequencies with a fourth generation fan-based FOT device. The generator non-linearity introduced by the device is separated from the linear approximation of the impedance before evaluating the results on patients. Three groups of COPD obstruction, GOLD II, III, and IV are evaluated. We found significant differences in mechanical parameters (tissue damping, tissue elasticity, hysteresivity) and increased degrees of non-linear dynamic contributions in the impedance data with increasing degree of obstruction (p < 0.01). The results obtained suggest that the non-linear index correlates better with degrees of heterogeneity linked to COPD GOLD stages, than the currently used hysteresivity index. The protocol and method may prove useful to improve current diagnosis percentages for various COPD phenotypes.

Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.

In advanced radiotherapy, intensity modulated radiation fields and complex dose-delivery are utilized to prescribe higher doses to tumours. Here, we investigated the impact of modulated radiation fields on radio-sensitivity and cell recovery during dose delivery. We generated experimental survival data after single-dose, split-dose and fractionated irradiation in normal human skin fibroblast cells (AGO1522) and human prostate cancer cells (DU145). The dose was delivered to either 50% of the area of a T25 flask containing the cells (half-field) or 100% of the flask (uniform-field). We also modelled the impact of dose-rate effects and intercellular signalling on cell-killing. Applying the model to the survival data, it is found that (i) in-field cell survival under half-field exposure is higher than uniform-field exposure for the same delivered dose; (ii) the importance of sub-lethal damage repair (SLDR) in AGO1522 cells is reduced under half-field exposure; (iii) the yield of initial DNA lesions measured with half-field exposure is smaller than that with uniform-field exposure. These results suggest that increased cell survival under half-field exposure is predominantly attributed not to rescue effects (increased SLDR) but protective effects (reduced induction of initial DNA lesions). In support of these protective effects, the reduced DNA damage leads to modulation of cell-cycle dynamics, i.e., less G1 arrest 6 h after irradiation. These findings provide a new understanding of the impact of dose-rate effects and protective effects measured after modulated field irradiation.

Integrating Small Animal Irradiators withFunctional Imaging for Advanced Preclinical Radiotherapy Research.

Translational research aims to provide direct support for advancing novel treatment approaches in oncology towards improving patient outcomes. Preclinical studies have a central role in this process and the ability to accurately model biological and physical aspects of the clinical scenario in radiation oncology is critical to translational success. The use of small animal irradiators with disease relevant mouse models and advanced in vivo imaging approaches offers unique possibilities to interrogate the radiotherapy response of tumors and normal tissues with high potential to translate to improvements in clinical outcomes. The present review highlights the current technology and applications of small animal irradiators, and explores how these can be combined with molecular and functional imaging in advanced preclinical radiotherapy research.

Preclinical models of radiation-induced lung damage: challenges and opportunities for small animal radiotherapy.

Despite a major paradigm shift in radiotherapy planning and delivery over the past three decades with continuing refinements, radiation-induced lung damage (RILD) remains a major dose limiting toxicity in patients receiving thoracic irradiations. Our current understanding of the biological processes involved in RILD which includes DNA damage, inflammation, senescence and fibrosis, is based on clinical observations and experimental studies in mouse models using conventional radiation exposures. Whilst these studies have provided vital information on the pulmonary radiation response, the current implementation of small animal irradiators is enabling refinements in the precision and accuracy of dose delivery to mice which can be applied to studies of RILD. This review presents the current landscape of preclinical studies in RILD using small animal irradiators and highlights the challenges and opportunities for the further development of this emerging technology in the study of normal tissue damage in the lung.