Baseline Cardiac Parameters as Biomarkers of Radiation Cardiotoxicity in Lung Cancer: An NI-HEART Analysis.

Background: Radiation-induced cardiotoxicity poses a significant challenge in lung cancer management because of the close anatomical proximity of the heart to the lungs, compounded by a high prevalence of cardiovascular risk factors among patients.

Objectives: The aim of this study was to assess the predictive value of routinely available clinical and imaging-based cardiac parameters in identifying "high risk" patients for major adverse cardiac events (MACE) and mortality following radiation therapy (RT).

Methods: The medical records of patients who underwent definitive RT for non-small cell lung cancer using modern planning techniques at a single center between 2015 and 2020 were retrospectively reviewed.

Inter-school variations in the standard of examiners' graduation-level OSCE judgements.

Introduction: Ensuring equivalence in high-stakes performance exams is important for patient safety and candidate fairness. We compared inter-school examiner differences within a shared OSCE and resulting impact on students' pass/fail categorisation.

Methods: The same 6 station formative OSCE ran asynchronously in 4 medical schools, with 2 parallel circuits/school.

D-MAINS: A Deep-Learning Model for the Label-Free Detection of Mitosis, Apoptosis, Interphase, Necrosis, and Senescence in Cancer Cells.

Background: Identifying cells engaged in fundamental cellular processes, such as proliferation or living/death statuses, is pivotal across numerous research fields. However, prevailing methods relying on molecular biomarkers are constrained by high costs, limited specificity, protracted sample preparation, and reliance on fluorescence imaging.

Methods: Based on cellular morphology in phase contrast images, we developed a deep-learning model named Detector of Mitosis, Apoptosis, Interphase, Necrosis, and Senescence (D-MAINS).

A realist evaluation of how, why and when objective structured clinical exams (OSCEs) are experienced as an authentic assessment of clinical preparedness.

Introduction: Whilst rarely researched, the authenticity with which Objective Structured Clinical Exams (OSCEs) simulate practice is arguably critical to making valid judgements about candidates' preparedness to progress in their training. We studied how and why an OSCE gave rise to different experiences of authenticity for different participants under different circumstances.

Methods: We used Realist evaluation, collecting data through interviews/focus groups from participants across four UK medical schools who participated in an OSCE which aimed to enhance authenticity.

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression.

Unlabelled: p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1-S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway.

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation.

Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation.

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.

ATR promotes mTORC1 activity via cholesterol synthesis.

DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined.

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

p16 is a tumor suppressor encoded by the gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway.

Feasibility of home-based exercise training during adjuvant treatment for metastatic castrate-resistant prostate cancer patients treated with an androgen receptor pathway inhibitor (EXACT).

Background: Exercise is an effective adjuvant therapy that can alleviate treatment-related toxicities for men with prostate cancer (PC). However, the feasibility of delivering exercise training to men with advanced disease and the wider impact on clinical outcomes remain unknown. The purpose of the EXACT trial was to determine the feasibility and effects of home-based exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC).

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study.

Introduction: Radiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients' cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events.

Methods: Patients treated between 2015-2020 at a regional center were identified.

A pulmonary vein atlas for radiotherapy planning.

Background And Purpose: Cardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated.

A Randomized Feasibility Trial of Stereotactic Prostate Radiation Therapy With or Without Elective Nodal Irradiation in High-Risk Localized Prostate Cancer (SPORT Trial).

Purpose: The aim of this study was to establish the feasibility of a randomized clinical trial comparing SABR with prostate-only (P-SABR) or with prostate plus pelvic lymph nodes (PPN-SABR) in patients with unfavorable intermediate- or high-risk localized prostate cancer and to explore potential toxicity biomarkers.

Methods And Materials: Thirty adult men with at least 1 of the following features were randomized 1:1 to P-SABR or PPN-SABR: clinical magnetic resonance imaging stage T3a N0 M0, Gleason score ≥7 (4+3), and prostate-specific antigen >20 ng/mL. P-SABR patients received 36.

Enhancing authenticity, diagnosticity and quivalence (AD-Equiv) in multicentre OSCE exams in health professionals education: protocol for a complex intervention study.

Introduction: Objective structured clinical exams (OSCEs) are a cornerstone of assessing the competence of trainee healthcare professionals, but have been criticised for (1) lacking authenticity, (2) variability in examiners' judgements which can challenge assessment equivalence and (3) for limited diagnosticity of trainees' focal strengths and weaknesses. In response, this study aims to investigate whether (1) sharing integrated-task OSCE stations across institutions can increase perceived authenticity, while (2) enhancing assessment equivalence by enabling comparison of the standard of examiners' judgements between institutions using a novel methodology (video-based score comparison and adjustment (VESCA)) and (3) exploring the potential to develop more diagnostic signals from data on students' performances.

Methods And Analysis: The study will use a complex intervention design, developing, implementing and sharing an integrated-task (research) OSCE across four UK medical schools.

ATM inhibition drives metabolic adaptation via induction of macropinocytosis.

Macropinocytosis is a nonspecific endocytic process that may enhance cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that has been previously shown to play a role in cellular metabolic reprogramming. We report that the suppression of ATM increases macropinocytosis to promote cancer cell survival in nutrient-poor conditions.

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.

Validation of an established deep learning auto-segmentation tool for cardiac substructures in 4D radiotherapy planning scans.

Background: Emerging data suggest that dose-sparing several key cardiac regions is prognostically beneficial in lung cancer radiotherapy. The cardiac substructures are challenging to contour due to their complex geometry, poor soft tissue definition on computed tomography (CT) and cardiorespiratory motion artefact. A neural network was previously trained to generate the cardiac substructures using three-dimensional radiotherapy planning CT scans (3D-CT).

LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition.

The immune checkpoint receptor lymphocyte activation gene 3 protein (LAG3) inhibits T cell function upon binding to major histocompatibility complex class II (MHC class II) or fibrinogen-like protein 1 (FGL1). Despite the emergence of LAG3 as a target for next-generation immunotherapies, we have little information describing the molecular structure of the LAG3 protein or how it engages cellular ligands. Here we determined the structures of human and murine LAG3 ectodomains, revealing a dimeric assembly mediated by Ig domain 2.

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.

Dose estimation after a mixed field exposure: Radium-223 and intensity modulated radiotherapy.

Introduction: Radium-223 dichloride ([Ra]RaCl), a radiopharmaceutical that delivers α-particles to regions of bone metastatic disease, has been proven to improve overall survival of men with metastatic castration resistant prostate cancer (mCRPC). mCRPC patients enrolled on the ADRRAD clinical trial are treated with a mixed field exposure comprising radium-223 (Ra) and intensity modulated radiotherapy (IMRT). While absorbed dose estimation is an important step in the characterisation of wider systemic radiation risks in nuclear medicine, uncertainties remain for novel radiopharmaceuticals such as Ra.

Radiation oncology teaching provision and practice prior to and during the first wave of the COVID-19 pandemic in medical schools in the United Kingdom and the Republic of Ireland: a cross-sectional survey.

Objectives: Radiotherapy is a key cancer treatment modality but is poorly understood by doctors. We sought to evaluate radiation oncology (RO) teaching in medical schools within the United Kingdom (UK) and Republic of Ireland (RoI), as well as any impacts on RO teaching delivery from the coronavirus disease 2019 (COVID-19) pandemic.

Methods: A bespoke online survey instrument was developed, piloted and distributed to oncology teaching leads at all UK and RoI medical schools.

Domain-specific biochemical and serological characterization of SARS-CoV-2 nucleocapsid protein.

Nucleocapsid proteins are essential for SARS-CoV-2 life cycle. Here, we describe protocols to gather domain-specific insights about essential properties of nucleocapsids. These assays include dynamic light scattering to characterize oligomerization, fluorescence polarization to quantify RNA binding, hydrogen-deuterium exchange mass spectrometry to map RNA binding regions, negative-stain electron microscopy to visualize oligomeric species, interferon reporter assay to evaluate interferon signaling modulation, and a serology assay to reveal insights for improved sensitivity and specificity.

Lrp1 is a host entry factor for Rift Valley fever virus.

Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection.

Coincidental splenic irradiation and risk of functional hyposplenism in oesophageal cancer treatment.

Introduction: Definitive chemoradiotherapy (dCRT) and radical radiotherapy are central to the management of distal oesophageal carcinoma. This study sought to establish whether the spleen receives a significant incidental radiation dose when treating distal oesophageal carcinoma with the standardised dCRT or radical radiotherapy doses.

Methods: In this single-centre retrospective study, all patients (n = 34) with distal oesophageal cancer, treated with either dCRT or radical radiotherapy over an 18-month period using a volumetric modulated arc therapy (VMAT) planning technique, were included.