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Background: We evaluated reporting of diagnostic test accuracy (DTA) systematic reviews using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-DTA and PRISMA-DTA for abstracts., Methods: We searched MEDLINE for recent DTA systematic reviews (September 2023-Mar 2024) to achieve a sample size of 100. Analyses evaluated adherence to PRISMA-DTA (and abstracts), on a per-item basis. Association of reporting with journal, country, impact factor (IF), index-test type, subspecialty area, use of supplemental material, PRISMA citation, word count, and PRISMA adoption was evaluated. Comparison to the baseline evaluation from 2019 was done. Protocol: https://doi.org/10.17605/OSF.IO/P25TE., Results: Overall adherence (n = 100) was 78% (20.3/26.0 items, SD = 2.0) for PRISMA-DTA and 52% (5.7/11.0 items, SD = 1.6) for abstracts. Infrequently reported items (<33% of studies): eligibility criteria, definitions for data extraction, synthesis of results, and characteristics of the included studies. Infrequently reported items in abstracts were characteristics of the included studies, strengths and limitations, and funding. Reporting completeness for full text was minimally higher in studies in higher IF journals [20.7 vs 19.8 items; 95% confidence interval (95%CI) (0.09; 1.77)], as well as studies that cited PRISMA [21.1 vs 20.1 items; 95%CI (0.04; 1.95)], or used supplemental material (20.7 vs 19.2 items; 95%CI (0.63; 2.35)]. Variability in reporting was not associated with author country, journal, abstract word count limitations, PRISMA adoption, structured abstracts, study design, subspecialty, open-access status, or index test. No association with word counts was observed among full text or abstracts. Compared to the baseline evaluation, reporting was improved for full texts [71% to 78%; 95%CI (1.18; 2.26)] but not for abstracts [50% to 52%; 95%CI (-0.20; 0.60)]., Conclusions: Compared to the baseline evaluation published in 2019, we observed modest improved adherence to PRISMA-DTA and no improvement in PRISMA-DTA for abstracts reporting., (© Association for Diagnostics & Laboratory Medicine 2024.)

The transition to a circular economy requires new materials and products with new production designs, technologies, and processes. In order to create new materials with physico-chemical qualities suitable for application in the building materials engineering sector, stone dust and polymer waste-two environmentally hazardous industrial wastes-were combined in this study. The materials obtained were evaluated based on an analysis performed using the Micro-Deval test. The results obtained showed a Micro-Deval coefficient value of 7.7%, indicating that these artificial aggregates can replace the natural aggregates used in road construction. Additionally, it was shown that the stone dust used could be applied as a sorbent for dyes without later leaching this dye from the final synthetic stones. Another category of materials that meets the principles of the circular economy and was developed in this study is bituminous mastic, which is currently used for the hot sealing of joints in road infrastructure. For this purpose, a composite material was developed using stone dust and cooking oil to replace the filler, a non-regenerable source used for obtaining bituminous mixtures. Specific standard methods were used to assess the degree to which the new materials approach the behavior of commercially available products.

Radiology in Canada is advancing through innovations in clinical practices and research methodologies. Recent developments focus on refining evidence-based practice guidelines, exploring innovative imaging techniques and enhancing diagnostic processes through artificial intelligence. Within the global radiology community, Canadian institutions play an important role by engaging in international collaborations, such as with the American College of Radiology to refine implementation of the Ovarian-Adnexal Reporting and Data System for ultrasound and magnetic resonance imaging. Additionally, researchers have participated in multidisciplinary collaborations to evaluate the performance of artificial intelligence-driven diagnostic tools for chronic liver disease and pediatric brain tumors. Beyond clinical radiology, efforts extend to addressing gender disparities in the field, improving educational practices, and enhancing the environmental sustainability of radiology departments. These advancements highlight Canada's role in the global radiology community, showcasing a commitment to improving patient outcomes and advancing the field through research and innovation. This update underscores the importance of continued collaboration and innovation to address emerging challenges and further enhance the quality and efficacy of radiology practices worldwide., Competing Interests: Declaration of competing interest Dr. McInnes received support from the Ottawa Department of Radiology Research Stipend Program. Dr. Patlas received royalties from Springer and Elsevier., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Muscle wasting, a prevalent issue in hemodialysis patients, is effectively assessed by measuring quadriceps muscle thickness, a crucial health indicator. This meta-analysis integrates findings from various studies on the application of ultrasonography (US) for measuring the thickness of quadriceps muscles in patients undergoing maintenance hemodialysis., Design and Methods: We conducted a thorough literature search across PubMed, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science up to April 2023. The R software's Meta package was used for mean difference analysis of quadriceps rectus femoris thickness (QRFT) and quadriceps vastus intermedius thickness (QVIT) between hemodialysis patients and healthy controls. All of the patients entered the meta-analysis are Caucasians. Sub-group analyses based on measurement sites and pre- and post-dialysis comparisons were performed., Results: Among 15 studies with 1584 patients, a significant decrease in QRFT and QVIT was observed in hemodialysis patients compared to healthy controls (mean difference = 0.40 cm, 95% CI: -0.49 to -0.31 and 0.46 cm, respectively). Right and left QRFT were notably thinner in hemodialysis patients (RT: mean difference = 0.39 cm; LT: mean difference = 0.42 cm). Similarly, right and left QVIT were notably thinner in hemodialysis patients (RT: mean difference = 0.45 cm; LT: mean difference = 0.47 cm). No significant pre- and post-dialysis QRFT differences were found., Conclusion: Ultrasonography is a reliable, accessible tool for assessing quadriceps muscle thickness in hemodialysis patients, revealing consistent muscle thickness reduction. These findings emphasize the need for routine muscle health monitoring in this population and support ultrasound use for regular assessments., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background and Objectives : Secretory carcinoma of the breast is an uncommon histological subtype of breast cancer. There is little research on this entity and only a few larger studies, which lack consensus. We aim to report a particular apocrine differentiation in this subtype and ponder upon the clinical outcome of this case. Case presentation : We report the case of a 72-year-old female patient who presented to our hospital with a suspicious breast tumor. Core biopsy and mastectomy showed a low-grade breast carcinoma, a secretory subtype with apocrine differentiation. Immunohistochemistry confirmed both the secretory nature and the apocrine nature of the tumor cells. Surgical excision was considered curative and the patient is under long-term surveillance for any recurrences. Conclusions : There is very little research on the clinical behavior of secretory carcinomas with apocrine differentiation. The clinical outcome is unknown and, unfortunately, besides surgery, no other adjuvant treatments have shown efficacy. Further studies on long-term clinical progression are required for this rare entity.

Objective: To evaluate open science policies of imaging journals, and compliance to these policies in published articles. Methods: From imaging journals listed we extracted open science policy details: protocol registration, reporting guidelines, funding, ethics and conflicts of interest (COI), data sharing, and open access publishing. The 10 most recently published studies from each journal were assessed to determine adherence to these policies. We calculated the proportion of open science policies into an Open Science Score (OSS) for all journals and articles. We evaluated relationships between OSS and journal/article level variables. Results: 82 journals/820 articles were included. The OSS of journals and articles was 58.3% and 31.8%, respectively. Of the journals, 65.9% had registration and 78.1% had reporting guideline policies. 79.3% of journals were members of COPE, 81.7% had plagiarism policies, 100% required disclosure of funding, and 97.6% required disclosure of COI and ethics approval. 81.7% had data sharing policies and 15.9% were fully open access. 7.8% of articles had a registered protocol, 8.4% followed a reporting guideline, 77.4% disclosed funding, 88.7% disclosed COI, and 85.6% reported ethics approval. 12.3% of articles shared their data. 51% of articles were available through open access or as a preprint. OSS was higher for journal with DOAJ membership (80% vs 54.2%; P  < .0001). Impact factor was not correlated with journal OSS. Knowledge synthesis articles has a higher OSS scores (44.5%) than prospective/retrospective studies (32.6%, 30.0%, P  < .0001). Conclusion: Imaging journals endorsed just over half of open science practices considered; however, the application of these practices at the article level was lower., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In December 2019 the World Health Organization announced that the widespread severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection had become a global pandemic. The most affected organ by the novel virus is the lung, and imaging exploration of the thorax using computer tomography (CT) scanning and X-ray has had an important impact., Materials and Methods: We assessed the prevalence of lung lesions in vaccinated versus unvaccinated SARS-CoV-2 patients using an artificial intelligence (AI) platform provided by Medicai. The software analyzes the CT scans, performing the lung and lesion segmentation using a variant of the U-net convolutional network., Results: We conducted a cohort study at a tertiary lung hospital in which we included 186 patients: 107 (57.52%) male and 59 (42.47%) females, of which 157 (84.40%) were not vaccinated for SARS-CoV-2. Over five times more unvaccinated patients than vaccinated ones are admitted to the hospital and require imaging investigations. More than twice as many unvaccinated patients have more than 75% of the lungs affected. Patients in the age group 30-39 have had the most lung lesions at almost 69% of both lungs affected. Compared to vaccinated patients with comorbidities, unvaccinated patients with comorbidities had developed increased lung lesions by 5%., Conclusion: The study revealed a higher percentage of lung lesions among unvaccinated SARS-CoV-2-positive patients admitted to The National Institute of Pulmonology "Marius Nasta" in Bucharest, Romania, underlining the importance of vaccination and also the usefulness of artificial intelligence in CT interpretation.

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.

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., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Brown K et al.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

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 (HD 95p ) 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 HD 95p 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.

Objective: This study aims to analyze the contribution and application of forced oscillation technique (FOT) devices in lung cancer assessment. Two devices and corresponding methods can be feasible to distinguish among various degrees of lung tissue heterogeneity., Methods: The outcome respiratory impedance Z rs (in terms of resistance R rs and reactance X rs ) is calculated for FOT and is interpreted in physiological terms by being fitted with a fractional-order impedance mathematical model (FOIM). The non-parametric data obtained from the measured signals of pressure and flow is correlated with an analogous electrical model to the respiratory system resistance, compliance, and elastance. The mechanical properties of the lung can be captured through G r to define the damping properties and H r to describe the elastance of the lung tissue, their ratio representing tissue heterogeneity η r ., Results: We validated our hypotheses and methods in 17 lung cancer patients where we showed that FOT is suitable for non-invasively measuring their respiratory impedance. FOIM models are efficient in capturing frequency-dependent impedance value variations. Increased heterogeneity and structural changes in the lungs have been observed. The results present inter- and intra-patient variability for the performed measurements., Conclusion: The proposed methods and assessment of the respiratory impedance with FOT have been demonstrated useful for characterizing mechanical properties in lung cancer patients., Significance: This correlation analysis between the measured clinical data motivates the use of the FOT devices in lung cancer patients for diagnosis of lung properties and follow-up of the respiratory function modified due to the applied radiotherapy treatment.

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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Materials used in the marine industry are exposed to extreme conditions, so it is necessary to meet remarkable characteristics, such as mechanical resistance, low density, and good corrosion resistance. The challenging environment requires continuous performance improvements, so this work is focused on developing new materials with superior properties, using the electrochemical deposition technique, which are convenient for marine engineering. High-entropy alloys have been attracting tremendous interest in many applications, due to their simple crystal structures and advantageous physical-chemical properties, such as high strength, anti-corrosion, erosion, and electro-magnetic capabilities. To identify the most appropriate compositions, MatCalc software was used to predict the structure and characteristics of the required materials, and thermodynamic and kinetic criteria calculations were performed. The modelling processes generated a series of optimal compositions in the AlCrCuFeNi alloy system, that are suitable to be used in anticorrosive and tribological applications. The composition and morphology of the obtained high entropy alloy thin films revealed a uniform structure, with a small grain profile. The corrosion resistance was investigated in artificial seawater to observe the behavior of the newly developed materials in demanding conditions, and the results showed improved results compared to the copper foil substrate.

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., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Individual curves for tumor growth can be expressed as mathematical models. Herein we exploited a pharmacokinetic-pharmacodynamic (PKPD) model to accurately predict the lung growth curves when using data from a clinical study. Our analysis included 19 patients with non-small cell lung cancer treated with specific hypofractionated regimens, defined as stereotactic body radiation therapy (SBRT). The results exhibited the utility of the PKPD model for testing growth hypotheses of the lung tumor against clinical data. The model fitted the observed progression behavior of the lung tumors expressed by measuring the tumor volume of the patients before and after treatment from CT screening. The changes in dynamics were best captured by the parameter identified as the patients' response to treatment. Median follow-up times for the tumor volume after SBRT were 126 days. These results have proven the use of mathematical modeling in preclinical anticancer investigations as a potential prognostic tool.

To investigate minimal required sub milli-Sievert (mSv) ultra-low dose CT and corresponding tube current and voltage for reliable attenuation correction and semi- quantitation in 18 F-FDG PET-CT in an effort for radiation dose reduction. Methods: We performed a PET-CT investigational study using a NEMA torso phantom containing six spheres (diameter: 10, 13, 17, 22, 28, 37 mm) filled with a fixed concentration of 60 kBq/ml and a background of 15 kBq/ml of 18 F-FDG. Two sets of PET images, separated by 2 hours, were acquired for 3 minutes in a single bed position using 3-D mode with and without time-of-flight in a GE D-690 scanner. Several sets of CT images were acquired for attenuation correction with different combinations of tube voltage (80, 100, 120 kVp) and effective mAs (tube current-time product divided by pitch), using the maximum beam collimation (64 x 0.625 mm). The lowest CT acquisition technique available on this scanner is 10 mA, 0.4 s and 1.375 for the tube current, tube rotation time and pitch, respectively. The CT radiation dose was estimated based on the computed tomography dose index volume (CTDIvol) measurements performed following the standard methodology and the Imaging Performance Assessment of CT Scanners (ImPACT) calculator. Each of the CT techniques was used for attenuation correction to the same PET acquisition, using ordered-subset expectation maximum (OSEM) algorithm with 24 subsets and 2 iterations. The maximal and average radioactivity (kBq/ml) and standardized uptake values (SUV) of the spheres were measured. The minimal ultra-low dose CT for attenuation correction was determined by reproducible SUV measurements (±10%) compared to our reference CT protocol of 100 kVp and 80 mA for 0.5 s rotation. Results: The minimal ultra-low dose of CT for reproducible quantification in all spheres (<10% relative difference) was determined to be 0.3 mSv for a combination of 100 kVp and 10 mA at 0.5 s rotation, 0.984 helical pitch (0.26 mGy measured CTDIvol) . Based on these results we could confidently determine the CT parameters for reliable attenuation correction of PET images while significantly reducing the associated radiation dose. Conclusion: Our phantom study provided guidance in using ultra-low dose CT for precise attenuation correction and semi-quantification of 18 F-FDG PET imaging, which can further reduce CT dose and radiation exposure to patients in clinical PET-CT studies. Clinical application: Based on the data, we can further reduce the radiation dose to sub-mSv using an ultra-low dose CT protocol for reliable attenuation correction in clinical 18 F-FDG PET-CT studies., (Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

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 HeLa subclone . 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Adrian, Konradsson, Beyer, Wittrup, Butterworth, McMahon, Ghita, Petersson and Ceberg.)

Quality and food safety represent a major stake and growing societal challenge in the world. Bacterial contamination of food and water resources is an element that pushes scientists to develop new means for the rapid and efficient detection and identification of these pathogens. Conventional detection tools are often bulky, laborious, expensive to buy, and, above all, require an analysis time of a few hours to several days. The interest in developing new, simple, rapid, and nonlaborious bacteriological diagnostic methods is therefore increasingly important for scientists, industry, and regulatory bodies. In this study, antibiotic-functionalized metallic nanoparticles were used to isolate and identify the foodborne bacterial strains Bacillus cereus and Shigella flexneri . With this aim, a new diagnostic tool for the rapid detection of foodborne pathogenic bacteria, gold nanoparticle-based centri-chronoamperometry, has been developed. Vancomycin was first stabilized at the surface of gold nanoparticles and then incubated with the bacteria B. cereus or S. flexneri to form the AuNP@vancomycin/bacteria complex. This complex was separated by centrifugation, then treated with hydrochloric acid and placed at the surface of a carbon microelectrode. The gold nanoparticles of the formed complex catalyzed the hydrogen reduction reaction, and the generated current was used as an analytical signal. Our results show the possibility of the simple and rapid detection of the S. flexneri and B. cereus strains at very low numbers of 3 cells/mL and 12 cells/mL, respectively. On the other hand, vancomycin-capped magnetic beads were easily synthesized and then used to separate the bacteria from the culture medium. The results show that vancomycin at the surface of these metallic nanoparticles is able to interact with the bacteria membrane and then used to separate the bacteria and to purify an inoculated medium.

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.

Background: Our objective was to perform a systematic review and meta-analysis comparing the breast cancer detection rate (CDR), invasive CDR, recall rate, and positive predictive value 1 (PPV1) of digital mammography (DM) alone, combined digital breast tomosynthesis (DBT) and DM, combined DBT and synthetic 2-dimensional mammography (S2D), and DBT alone., Methods: MEDLINE and Embase were searched until April 2020 to identify comparative design studies reporting on patients undergoing routine breast cancer screening. Random effects model proportional meta-analyses estimated CDR, invasive CDR, recall rate, and PPV1. Meta-regression modeling was used to compare imaging modalities. All statistical tests were 2-sided., Results: Forty-two studies reporting on 2 606 296 patients (13 003 breast cancer cases) were included. CDR was highest in combined DBT and DM (6.36 per 1000 screened, 95% confidence interval [CI] = 5.62 to 7.14, P < .001), and combined DBT and S2D (7.40 per 1000 screened, 95% CI = 6.49 to 8.37, P < .001) compared with DM alone (4.68 per 1000 screened, 95% CI = 4.28 to 5.11). Invasive CDR was highest in combined DBT and DM (4.53 per 1000 screened, 95% CI = 3.97 to 5.12, P = .003) and combined DBT and S2D (5.68 per 1000 screened, 95% CI = 4.43 to 7.09, P < .001) compared with DM alone (3.42 per 1000 screened, 95% CI = 3.02 to 3.83). Recall rate was lowest in combined DBT and S2D (42.3 per 1000 screened, 95% CI = 37.4 to 60.4, P<.001). PPV1 was highest in combined DBT and DM (10.0%, 95% CI = 8.0% to 12.0%, P = .004), and combined DBT and S2D (16.0%, 95% CI = 10.0% to 23.0%, P < .001), whereas no difference was detected for DBT alone (7.0%, 95% CI = 6.0% to 8.0%, P = .75) compared with DM alone (7.0%, 95.0% CI = 5.0% to 8.0%)., Conclusions: Our findings provide evidence on key performance metrics for DM, DBT alone, combined DBT and DM, and combined DBT and S2D, which may inform optimal application of these modalities for breast cancer screening., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate Prostate Imaging Reporting and Data System (PI-RADS) category 3 lesions' impact on the diagnostic test accuracy (DTA) of MRI for prostate cancer (PC) and to derive the prevalence of PC within each PI-RADS category., Methods: MEDLINE and Embase were searched until April 10, 2020 for studies reporting on the DTA of MRI by PI-RADS category. Accuracy metrics were calculated using a bivariate random-effects meta-analysis with PI-RADS three lesions treated as a positive test, negative test, and excluded from the analysis. Differences in DTA were assessed utilizing meta-regression. PC prevalence within each PI-RADS category was estimated with a proportional meta-analysis., Results: In total, 26 studies reporting on 12,913 patients (4,853 with PC) were included. Sensitivities for PC in the positive, negative, and excluded test groups were 96% (95% confidence interval [CI] 92-98), 82% (CI 75-87), and 95% (CI 91-97), respectively. Specificities for the positive, negative, and excluded test groups were 33% (CI 23-44), 71% (CI 62-79), and 52% (CI 37-66), respectively. Meta-regression demonstrated higher sensitivity ( p < 0.001) and lower specificity ( p < 0.001) in the positive test group compared to the negative group. Clinically significant PC prevalences were 5.9% (CI 0-17.1), 11.4% (CI 6.5-17.3), 24.9% (CI 18.4-32.0), 55.7% (CI 47.8-63.5), and 81.4% (CI 75.9-86.4) for PI-RADS categories 1, 2, 3, 4 and 5, respectively., Conclusion: PI-RADS category 3 lesions can significantly impact the DTA of MRI for PC detection. A low prevalence of clinically significant PC is noted in PI-RADS category 1 and 2 cases., Advances in Knowledge: Inclusion or exclusion of PI-RADS category 3 lesions impacts the DTA of MRI for PC detection.

Introduction: As pulmonary dysfunctions are prospective factors for developing cancer, efforts are needed to solve the limitations regarding applications in lung cancer. Fractional order respiratory impedance models can be indicative of lung cancer dynamics and tissue heterogeneity., Objective: The purpose of this study is to investigate how the existence of a tumorous tissue in the lung modifies the parameters of the proposed models. The first use of a prototype forced oscillations technique (FOT) device in a mimicked lung tumor setup is investigated by comparing and interpreting the experimental findings., Methods: The fractional order model parameters are determined for the mechanical properties of the healthy and tumorous lung. Two protocols have been performed for a mimicked lung tumor setup in a laboratory environment. A low frequency evaluation of respiratory impedance model and nonlinearity index were assessed using the forced oscillations technique., Results: The viscoelastic properties of the lung tissue change, results being mirrored in the respiratory impedance assessment via FOT. The results demonstrate significant differences among the mimicked healthy and tumor measurements, ( p -values < 0.05 ) for impedance values and also for heterogeneity index. However, there was no significant difference in lung function before and after immersing the mimicked lung in water or saline solution, denoting no structural changes., Conclusion: Simulation tests comparing the changes in impedance support the research hypothesis. The impedance frequency response is effective in non-invasive identification of respiratory tissue abnormalities in tumorous lung, analyzed with appropriate fractional models., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

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.

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 (R 2  < 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This paper introduces a mathematical compartmental formulation of dose-effect synergy modelling for multiple therapies in non small cell lung cancer (NSCLC): antiangiogenic, immuno- and radiotherapy. The model formulates the dose-effect relationship in a unified context, with tumor proliferating rates and necrotic tissue volume progression as a function of therapy management profiles. The model accounts for inter- and intra-response variability by using surface model response terms. Slow acting peripheral compartments such as fat and muscle for drug distribution are not modelled. This minimal pharmacokinetic-pharmacodynamic (PKPD) model is evaluated with reported data in mice from literature. A systematic analysis is performed by varying only radiotherapy profiles, while antiangiogenesis and immunotherapy are fixed to their initial profiles. Three radiotherapy protocols are selected from literature: (1) a single dose 5 Gy once weekly; (2) a dose of 5 Gy × 3 days followed by a 2 Gy × 3 days after two weeks and (3) a dose of 5 Gy + 2 × 0.075 Gy followed after two weeks by a 2 Gy + 2 × 0.075 Gy dose. A reduction of 28% in tumor end-volume after 30 days was observed in Protocol 2 when compared to Protocol 1. No changes in end-volume were observed between Protocol 2 and Protocol 3, this in agreement with other literature studies. Additional analysis on drug interaction suggested that higher synergy among drugs affects up to three-fold the tumor volume (increased synergy leads to significantly lower growth ratio and lower total tumor volume). Similarly, changes in patient response indicated that increased drug resistance leads to lower reduction rates of tumor volumes, with end-volume increased up to 25-30%. In conclusion, the proposed minimal PKPD model has physiological value and can be used to study therapy management protocols and is an aiding tool in the clinical decision making process. Although developed with data from mice studies, the model is scalable to NSCLC patients.

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.

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 (r 2 = 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.

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., (Copyright © 2019 Ghita, Copot, Ghita, Derom and Ionescu.)

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 G 1 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.

Purpose: The aim of this study was to define the dose and dose-volume relationship of radiation-induced pulmonary toxicities occurring in and out-of-field in mouse models of early inflammatory and late fibrotic response., Materials and Methods: Early radiation-induced inflammation and fibrosis were investigated in C3H/NeJ and C57BL/6J mice, respectively. Animals were irradiated with 20 Gy delivered to the upper region of the right lung as a single fraction or as 3 consecutive fractions using the Small Animal Radiation Research Platform (Xstrahl Inc, Camberley, UK). Cone beam computed tomography was performed for image guidance before irradiation and to monitor late toxicity. Histologic sections were examined for neutrophil and macrophage infiltration as markers of early inflammatory response and type I collagen staining as a marker of late-occurring fibrosis. Correlation was evaluated with the dose-volume histogram parameters calculated for individual mice and changes in the observed cone beam computed tomography values., Results: Mean lung dose and the volume receiving over 10 Gy (V10) showed significant correlation with late responses for single and fractionated exposures in directly targeted volumes. Responses observed outside the target volume were attributed to nontargeted effects and showed no dependence on either mean lung dose or V10., Conclusions: Quantitative assessment of normal tissue response closely correlates early and late pulmonary response with clinical parameters, demonstrating this approach as a potential tool to facilitate clinical translation of preclinical studies. Out-of-field effects were observed but did not correlate with dosimetric parameters, suggesting that nontargeted effects may have a role in driving toxicities outside the treatment field., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: The authors declare no conflict of interest.

A key component of seed germination is the interplay of mechanical forces governing embryo growth and the surrounding restraining endosperm tissue. Endosperm cell separation is therefore thought to play a critical role in the control of this developmental transition. Here we demonstrate that in Arabidopsis thaliana seeds, endosperm cell expansion is a key component of germination. Endosperm cells expand to accommodate embryo growth prior to germination. We show that this is an actively regulated process supported by spatiotemporal control of the cell expansion gene EXPANSIN 2 (EXPA2). The NAC transcription factors NAC25 and NAC1L were identified as upstream regulators of EXPA2 expression, gibberellin-mediated endosperm expansion, and seed germination. The DELLA protein RGL2 repressed activation of the EXPA2 promoter by NAC25/NAC1L. Taken together, our findings uncover a key role of the GA/DELLA-NAC25/NAC1L-EXPA2 network in regulating endosperm cell expansion to control the seed-to-seedling transition., (Copyright © 2018 The Author. Published by Elsevier Inc. All rights reserved.)

Rare ocular pathology has an important impact on the quality of life of patients because often the damage is bilateral and, although asymmetric, causes a significant decrease in visual acuity. Because it may be asymptomatic until a relatively late stage, diagnosis is frequently delayed. A general understanding of the disease pathophysiology, diagnosis, and treatment may assist primary care physicians in referring high-risk patients for comprehensive ophthalmological examination and for a more active involvement in their care. Moreover, a significant percentage of these orphan diseases do not have treatment approved by the FDA. The examination and monitoring of patients with rare ophthalmological disorders represents a key component of an ongoing project at the University Emergency Hospital, Bucharest, Romania - Ophthalmology Clinic. Rare disease registries are leading tools for the development of clinical research for rare diseases, improvement of patient access to new diagnostic methods, follow-up and new emerging therapies. As of this moment, the European list of rare diseases includes 53 ophthalmological diseases, which are classified as rare diseases and another 103 systemic diseases with ophthalmological involvement, out of a total of 7000 rare diseases.

Purpose: This review follows the development of microbeam technology from the early days of single cell irradiations, to investigations of specific cellular mechanisms and to the development of new treatment modalities in vivo. A number of microbeam applications are discussed with a focus on pre-clinical modalities and translation towards clinical application., Conclusions: The development of radiation microbeams has been a valuable tool for the exploration of fundamental radiobiological response mechanisms. The strength of micro-irradiation techniques lies in their ability to deliver precise doses of radiation to selected individual cells in vitro or even to target subcellular organelles. These abilities have led to the development of a range of microbeam facilities around the world allowing the delivery of precisely defined beams of charged particles, X-rays, or electrons. In addition, microbeams have acted as mechanistic probes to dissect the underlying molecular events of the DNA damage response following highly localized dose deposition. Further advances in very precise beam delivery have also enabled the transition towards new and exciting therapeutic modalities developed at synchrotrons to deliver radiotherapy using plane parallel microbeams, in Microbeam Radiotherapy (MRT).

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.

Advanced radiotherapy techniques such as intensity modulated radiation therapy achieve highly conformal dose distributions within target tumor volumes through the sequential delivery of multiple spatially and temporally modulated radiation fields and have been shown to influence radiobiological response. The goals of this study were to determine the effect of hypoxia on the cell survival responses of different cell models (H460, DU145, A549, MDA231 and FADU) to modulated fields and to characterize the time dependency of signaling under oxic conditions, following reoxygenation and after prolonged hypoxia. Hypoxia was induced by incubating cells at 95% nitrogen and 5% carbon dioxide for 4 h prior to irradiation. The out-of-field response in MDA231 cells was oxygen dependent and therefore selected for co-culture studies to determine the signaling kinetics at different time intervals after irradiation under oxic and hypoxic conditions. Under both oxic and hypoxic conditions, significant increases in cell survival were observed in-field with significant decreases in survival observed out-of-field (P < 0.05), which were dependent on intercellular communication. The in-field response of MDA231 cells showed no significant time dependency up to 24 h postirradiation, while out-of-field survival decreased significantly during the first 6 h postirradiation (P < 0.05). While in-field responses were oxygen dependent, out-of-field effects were observed to be independent of oxygen, with similar or greater cell killing under hypoxic conditions. This study provides further understanding of intercellular signaling under hypoxic conditions and highlights the need for further refinement of established radiobiological models for future applications in advanced radiotherapies.

Penicillin-resistant Streptococcus pneumoniae strains are found at high rates in Romania and Iran. The mosaic structure of PBP2x was investigated in 9 strains from Iran and in 15 strains from Romania to understand their evolutionary history. Mutations potentially important for β-lactam resistance were identified by comparison of the PBP2x sequences with the sequence of the related PBP2x of reference penicillin-sensitive S. mitis strains. Two main PBP2x mosaic gene families were recognized. Eight Iranian strains expressed PBP2x variants in group 1, which had a mosaic block highly related to PBP2x of the Spain 23F -1 clone, which is widespread among international penicillin-resistant S. pneumoniae clones. A second unique PBP2x group was observed in Romanian strains; furthermore, three PBP2x single mosaic variants were found. Sequence blocks of penicillin-sensitive strain S. mitis 658 were common among PBP2x variants from strains from both countries. Each PBP2x group contained specific signature mutations within the transpeptidase domain, documenting the existence of distinct mutational pathways for the development of penicillin resistance., (Copyright © 2017 Mousavi et al.)

Background and Purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis., Materials and Methods: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining., Results: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p<0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p>0.5) and histological scoring of radiation induced fibrosis (p>0.5)., Conclusion: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Gold nanoparticles (GNPs) have been demonstrated as effective radiosensitizing agents in a range of preclinical models using broad field sources of various energies. This study aimed to distinguish between these mechanisms by applying subcellular targeting using a soft X-ray microbeam in combination with GNPs. DNA damage and repair kinetics were determined following nuclear and cytoplasmic irradiation using a soft X-ray (carbon K-shell, 278 eV) microbeam in MDA-MB-231 breast cancer and AG01522 fibroblast cells with and without GNPs. To investigate the mechanism of the GNP induced radiosensitization, GNP-induced mitochondrial depolarisation was quantified by TMRE staining, and levels of DNA damage were compared in cells with depolarised and functional mitochondria. Differential effects were observed following radiation exposure between the two cell lines. These findings were validated 24 hours after removal of GNPs by flow cytometry analysis of mitochondrial depolarisation. This study provides further evidence that GNP radiosensitisation is mediated by mitochondrial function and it is the first report applying a soft X-ray microbeam to study the radiobiological effects of GNPs to enable the separation of physical and biological effects.