The Chromosome Passenger Complex (CPC) Components and Its Associated Pathways Are Promising Candidates to Differentiate Between Normosensitive and Radiosensitive ATM-Mutated Cells.

Background: Sensitivity to ionizing radiation differs between individuals, but there is a limited understanding of the biological mechanisms that account for these variations. One example of such mechanisms are the mutations in the ATM (mutated ataxia telangiectasia) gene, that cause the rare recessively inherited disease Ataxia telangiectasia (AT). Hallmark features include chromosomal instability and increased sensitivity to ionizing radiation (IR).

Radiation Adverse Outcome pathways (AOPs): examining priority questions from an international horizon-style exercise.

Purpose: The Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) Development Programme is being explored in the radiation field, as an overarching framework to identify and prioritize research needs that best support strengthening of radiation risk assessment and risk management strategies. To advance the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Radiation/Chemical AOP Joint Topical Group (JTG) formed by the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The intent of the HSE was to identify key research questions for consideration in AOP development that would help to reduce uncertainties in estimating the health risks following exposures to low dose and low dose-rate ionizing radiation.

Radiotherapy for non-cancer diseases: benefits and long-term risks.

Purpose: The discovery of X-rays was followed by a variety of attempts to treat infectious diseases and various other non-cancer diseases with ionizing radiation, in addition to cancer. There has been a recent resurgence of interest in the use of such radiotherapy for non-cancer diseases. Non-cancer diseases for which use of radiotherapy has currently been proposed include refractory ventricular tachycardia, neurodegenerative diseases (e.

Late Effects of Chronic Low Dose Rate Total Body Irradiation on the Heart Proteome of ApoE Mice Resemble Premature Cardiac Ageing.

Recent epidemiologic studies support an association between chronic low-dose radiation exposure and the development of cardiovascular disease (CVD). The molecular mechanisms underlying the adverse effect of chronic low dose exposure are not fully understood. To address this issue, we have investigated changes in the heart proteome of ApoE deficient (ApoE) C57Bl/6 female mice chronically irradiated for 300 days at a very low dose rate (1 mGy/day) or at a low dose rate (20 mGy/day), resulting in cumulative whole-body doses of 0.

Towards unravelling biological mechanisms behind radiation-induced oral mucositis via mass spectrometry-based proteomics.

Objective: Head and neck cancer (HNC) accounts for almost 890,000 new cases per year. Radiotherapy (RT) is used to treat the majority of these patients. A common side-effect of RT is the onset of oral mucositis, which decreases the quality of life and represents the major dose-limiting factor in RT.

Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease.

Background: Epidemiological studies have indicated that exposure of the heart to doses of ionizing radiation as low as 0.5 Gy increases the risk of cardiac morbidity and mortality with a latency period of decades. The damaging effects of radiation to myocardial and endothelial structures and functions have been confirmed radiobiologically at high dose, but much less are known at low dose.

Development of an adverse outcome pathway for radiation-induced microcephaly via expert consultation and machine learning.

Background: Brain development during embryogenesis and in early postnatal life is particularly complex and involves the interplay of many cellular processes and molecular mechanisms, making it extremely vulnerable to exogenous insults, including ionizing radiation (IR). Microcephaly is one of the most frequent neurodevelopmental abnormalities that is characterized by small brain size, and is often associated with intellectual deficiency. Decades of research span from epidemiological data on exposure of the A-bomb survivors, to studies on animal and cellular models that allowed deciphering the most prominent molecular mechanisms leading to microcephaly.

Irradiated Triple-Negative Breast Cancer Co-Culture Produces a Less Oncogenic Extracellular Matrix.

Triple-negative breast cancer is the most common and most deadly cancer among women. Radiation is a mainstay of treatment, administered after surgery, and used in the hope that any remaining cancer cells will be destroyed. While the cancer cell response is normally the focus of radiation therapy, little is known about the tumor microenvironment response after irradiation.

A systems radiation biology approach to unravel the role of chronic low-dose-rate gamma-irradiation in inducing premature senescence in endothelial cells.

Purpose: The aim of this study was to explore the effects of chronic low-dose-rate gamma-radiation at a multi-scale level. The specific objective was to obtain an overall view of the endothelial cell response, by integrating previously published data on different cellular endpoints and highlighting possible different mechanisms underpinning radiation-induced senescence.

Materials And Methods: Different datasets were collected regarding experiments on human umbilical vein endothelial cells (HUVECs) which were chronically exposed to low dose rates (0, 1.

Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy.

Irreparable DNA damage following ionizing radiation (IR) triggers prolonged DNA damage response and induces premature senescence. Cellular senescence is a permanent state of cell-cycle arrest characterized by chromatin restructuring, altered nuclear morphology and acquisition of secretory phenotype, which contributes to senescence-related inflammation. However, the mechanistic connections for radiation-induced DNA damage that trigger these senescence-associated hallmarks are poorly understood.

Activation of PPARα by Fenofibrate Attenuates the Effect of Local Heart High Dose Irradiation on the Mouse Cardiac Proteome.

Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics.

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults.

The heart tissue is a potential target of various noxae contributing to the onset of cardiovascular diseases. However, underlying pathophysiological mechanisms are largely unknown. Human stem cell-derived models are promising, but a major concern is cell immaturity when estimating risks for adults.

Expert consultation is vital for adverse outcome pathway development: a case example of cardiovascular effects of ionizing radiation.

Background: The circulatory system distributes nutrients, signaling molecules, and immune cells to vital organs and soft tissues. Epidemiological, animal, and in vitro cellular mechanistic studies have highlighted that exposure to ionizing radiation (IR) can induce molecular changes in cellular and subcellular milieus leading to long-term health impacts, particularly on the circulatory system. Although the mechanisms for the pathologies are not fully elucidated, endothelial dysfunction is proven to be a critical event via radiation-induced oxidative stress mediators.

Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response.

The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and double knockout (LDH) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1.

Data-Independent Acquisition Proteomics Reveals Long-Term Biomarkers in the Serum of C57BL/6J Mice Following Local High-Dose Heart Irradiation.

Cardiotoxicity is a well-known adverse effect of radiation therapy. Measurable abnormalities in the heart function indicate advanced and often irreversible heart damage. Therefore, early detection of cardiac toxicity is necessary to delay and alleviate the development of the disease.

Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis.

The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved.

Impact of DNA repair and reactive oxygen species levels on radioresistance in pancreatic cancer.

Purpose: Radioresistance in pancreatic cancer patients remains a critical obstacle to overcome. Understanding the molecular mechanisms underlying radioresistance may achieve better response to radiotherapy and thereby improving the poor treatment outcome. The aim of the present study was to elucidate the mechanisms leading to radioresistance by detailed characterization of isogenic radioresistant and radiosensitive cell lines.

Quantitative Proteomic Analysis Using Formalin-Fixed, Paraffin-Embedded (FFPE) Human Cardiac Tissue.

Clinical tissue archives represent an invaluable source of biological information. Formalin-fixed, paraffin-embedded (FFPE) tissue can be used for retrospective investigation of biomarkers of diseases and prognosis.Recently, the number of studies using proteome profiling of samples from clinical archives has markedly increased.

A Five-Year report on the conception and establishment of the MSc Radiation Biology at the Technical University of Munich.

Purpose: The MSc Radiation Biology course is a highly interdisciplinary degree program placing radiation biology at the interface between biology, medicine, and physics, as well as their associated technologies. The goal was to establish an internationally acknowledged program with diverse and heterogeneous student cohorts, who benefit from each other academically as well as culturally. We have completed a Five-Year evaluation of the program to assess our qualification profile and the further direction we want to take.

Radiation Response of Human Cardiac Endothelial Cells Reveals a Central Role of the cGAS-STING Pathway in the Development of Inflammation.

Radiation-induced inflammation leading to the permeability of the endothelial barrier may increase the risk of cardiovascular disease. The aim of this study was to investigate potential mechanisms in vitro at the level of the proteome in human coronary artery endothelial cells (HCECest2) that were exposed to radiation doses of 0, 0.25, 0.

Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5.

The triple-negative breast tumor boundary is made of aligned, linear collagen. The pro-oncogenic impact of linear collagen is well established; however, its mechanism of formation is unknown. An in vitro analogue of the tumor border is created by a co-culture of MDA-MB-231 cells, adipose derived stem cells, and dermal fibroblasts.