Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: the paradigm of radiotherapy.

Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of CVDs. Stressed and dying irradiated cells produce 'danger' signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors.

RadPhysBio: A Radiobiological Database for the Prediction of Cell Survival upon Exposure to Ionizing Radiation.

Based on the need for radiobiological databases, in this work, we mined experimental ionizing radiation data of human cells treated with X-rays, γ-rays, carbon ions, protons and α-particles, by manually searching the relevant literature in PubMed from 1980 until 2024. In order to calculate normal and tumor cell survival α and ß coefficients of the linear quadratic (LQ) established model, as well as the initial values of the double-strand breaks (DSBs) in DNA, we used WebPlotDigitizer and Python programming language. We also produced complex DNA damage results through the fast Monte Carlo code MCDS in order to complete any missing data. The calculated α/ß values are in good agreement with those valued reported in the literature, where α shows a relatively good association with linear energy transfer (LET), but not ß. In general, a positive correlation between DSBs and LET was observed as far as the experimental values are concerned. Furthermore, we developed a biophysical prediction model by using machine learning, which showed a good performance for α, while it underscored LET as the most important feature for its prediction. In this study, we designed and developed the novel radiobiological 'RadPhysBio' database for the prediction of irradiated cell survival (α and ß coefficients of the LQ model). The incorporation of machine learning and repair models increases the applicability of our results and the spectrum of potential users.

DExplore: An Online Tool for Detecting Differentially Expressed Genes from mRNA Microarray Experiments.

Microarray experiments, a mainstay in gene expression analysis for nearly two decades, pose challenges due to their complexity. To address this, we introduce DExplore, a user-friendly web application enabling researchers to detect differentially expressed genes using data from NCBI's GEO. Developed with R, Shiny, and Bioconductor, DExplore integrates WebGestalt for functional enrichment analysis. It also provides visualization plots for enhanced result interpretation. With a Docker image for local execution, DExplore accommodates unpublished data. To illustrate its utility, we showcase two case studies on cancer cells treated with chemotherapeutic drugs. DExplore streamlines microarray data analysis, empowering molecular biologists to focus on genes of biological significance.

Differential Gene Expression in Human Fibroblasts Simultaneously Exposed to Ionizing Radiation and Simulated Microgravity.

During future space missions, astronauts will be exposed to cosmic radiation and microgravity (µG), which are known to be health risk factors. To examine the differentially expressed genes (DEG) and their prevalent biological processes and pathways as a response to these two risk factors simultaneously, 1BR-hTERT human fibroblast cells were cultured under 1 gravity (1G) or simulated µG for 48 h in total and collected at 0 (sham irradiated), 3 or 24 h after 1 Gy of X-ray or Carbon-ion (C-ion) irradiation. A three-dimensional clinostat was used for the simulation of µG and the simultaneous radiation exposure of the samples. The RNA-seq method was used to produce lists of differentially expressed genes between different environmental conditions. Over-representation analyses were performed and the enriched biological pathways and targeting transcription factors were identified. Comparing sham-irradiated cells under simulated µG and 1G conditions, terms related to response to oxygen levels and muscle contraction were identified. After irradiation with X-rays or C-ions under 1G, identified DEGs were found to be involved in DNA damage repair, signal transduction by p53 class mediator, cell cycle arrest and apoptosis pathways. The same enriched pathways emerged when cells were irradiated under simulated µG condition. Nevertheless, the combined effect attenuated the transcriptional response to irradiation which may pose a subtle risk in space flights.

Dual Targeting of DNA Damage Response Proteins Implicated in Cancer Radioresistance.

Ionizing radiation can induce different types of DNA lesions, leading to genomic instability and ultimately cell death. Radiation therapy or radiotherapy, a major modality in cancer treatment, harnesses the genotoxic potential of radiation to target and destroy cancer cells. Nevertheless, cancer cells have the capacity to develop resistance to radiation treatment (radioresistance), which poses a major obstacle in the effective management of cancer. It has been shown that administration of platinum-based drugs to cancer patients can increase tumor radiosensitivity, but despite this, it is associated with severe adverse effects. Several lines of evidence support that activation of the DNA damage response and repair machinery in the irradiated cancer cells enhances radioresistance and cellular survival through the efficient repair of DNA lesions. Therefore, targeting of key DNA damage repair factors would render cancer cells vulnerable to the irradiation effects, increase cancer cell killing, and reduce the risk of side effects on healthy tissue. Herein, we have employed a computer-aided drug design approach for generating ab initio a chemical compound with drug-like properties potentially targeting two proteins implicated in multiple DNA repair pathways. The findings of this study could be taken into consideration in clinical decision-making in terms of co-administering radiation with DNA damage repair factor-based drugs.

The Role of Human Endogenous Retroviruses in Cancer Immunotherapy of the Post-COVID-19 World.

At the outbreak of the COVID-19 global crisis, diverse scientific groups suggested that this unprecedented emergency could act as a 'blessing in disguise' [...].

More than Meets the Eye: Integration of Radiomics with Transcriptomics for Reconstructing the Tumor Microenvironment and Predicting Response to Therapy.

For over a decade, large cancer-related datasets (big data) have continuously been produced and made publicly available to the scientific community [...].

Clustered DNA Damage Patterns after Proton Therapy Beam Irradiation Using Plasmid DNA.

Modeling ionizing radiation interaction with biological matter is a major scientific challenge, especially for protons that are nowadays widely used in cancer treatment. That presupposes a sound understanding of the mechanisms that take place from the early events of the induction of DNA damage. Herein, we present results of irradiation-induced complex DNA damage measurements using plasmid pBR322 along a typical Proton Treatment Plan at the MedAustron proton and carbon beam therapy facility (energy 137-198 MeV and Linear Energy Transfer (LET) range 1-9 keV/µm), by means of Agarose Gel Electrophoresis and DNA fragmentation using Atomic Force Microscopy (AFM). The induction rate Mbp-1 Gy-1 for each type of damage, single strand breaks (SSBs), double-strand breaks (DSBs), base lesions and non-DSB clusters was measured after irradiations in solutions with varying scavenging capacity containing 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris) and coumarin-3-carboxylic acid (C3CA) as scavengers. Our combined results reveal the determining role of LET and Reactive Oxygen Species (ROS) in DNA fragmentation. Furthermore, AFM used to measure apparent DNA lengths provided us with insights into the role of increasing LET in the induction of highly complex DNA damage.

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues.

Ionizing radiation (IR) is a genuine genotoxic agent and a major modality in cancer treatment. IR disrupts DNA sequences and exerts mutagenic and/or cytotoxic properties that not only alter critical cellular functions but also impact tissues proximal and distal to the irradiated site. Unveiling the molecular events governing the diverse effects of IR at the cellular and organismal levels is relevant for both radiotherapy and radiation protection. Herein, we address changes in the expression of mammalian genes induced after the exposure of a wide range of tissues to various radiation types with distinct biophysical characteristics. First, we constructed a publicly available database, termed RadBioBase, which will be updated at regular intervals. RadBioBase includes comprehensive transcriptomes of mammalian cells across healthy and diseased tissues that respond to a range of radiation types and doses. Pertinent information was derived from a hybrid analysis based on stringent literature mining and transcriptomic studies. An integrative bioinformatics methodology, including functional enrichment analysis and machine learning techniques, was employed to unveil the characteristic biological pathways related to specific radiation types and their association with various diseases. We found that the effects of high linear energy transfer (LET) radiation on cell transcriptomes significantly differ from those caused by low LET and are consistent with immunomodulation, inflammation, oxidative stress responses and cell death. The transcriptome changes also depend on the dose since low doses up to 0.5 Gy are related with cytokine cascades, while higher doses with ROS metabolism. We additionally identified distinct gene signatures for different types of radiation. Overall, our data suggest that different radiation types and doses can trigger distinct trajectories of cell-intrinsic and cell-extrinsic pathways that hold promise to be manipulated toward improving radiotherapy efficiency and reducing systemic radiotoxicities.

FDXR Gene Expression after in Vivo Radiation Exposure of Pediatric Patients Undergoing Interventional Cardiology Procedures.

BACKGROUND: Ferredoxin reductase (FDXR) has already been reported as a promising biomarker for estimating radiation doses in radiotherapy. This study aimed to investigate the responsiveness of FDXR on pediatric population exposed to ionizing radiation (X-rays) during pediatric interventional cardiology (IC) procedures. PATIENTS AND METHODS: Peripheral blood was collected by venipuncture from 24 pediatric donors before and 24 hours after the IC procedure. To estimate the effective dose, demographic data and Air Kerma-Area Product (PKA) were recorded for each patient. The relative quantification (RQ) of the FDXR gene in irradiated patient blood samples compared to the non-irradiated blood samples was determined using qPCR analysis. The relative values of FDXR were log- transformed. RESULTS: The effective dose ranged from 0.002 mSv to 8.004 mSv. Over this radiation exposure range, the FDXR gene expression varied randomly with the effective dose. Up-regulation in FDXR expression was observed in 17 patients and down-regulation in 7 patients. CONCLUSIONS: Further studies in a larger cohort of pediatric patients along with the record of clinical data are needed to determine whether FDXR gene expression is an effective biomarker for radiation exposure estimation in pediatric imaging.

Biological Response of Human Cancer Cells to Ionizing Radiation in Combination with Gold Nanoparticles.

In the context of improving radiation therapy, high-atomic number (Z) metallic nanoparticles and, more importantly, gold-based nanostructures are developed as radiation enhancers/radiosensitizers. Due to the diversity of cell lines, nanoparticles, as well as radiation types or doses, the resulting biological effects may differ and remain obscure. In this multiparameter study, we aim to shed light on these effects and investigate them further by employing X-irradiation and three human cancer cell lines (PC3, A549, and U2OS cells) treated by multiple techniques. TEM experiments on PC3 cells showed that citrate-capped AuNPs were found to be located mostly in membranous structures/vesicles or autophagosomes, but also, in the case of PEG-capped AuNPs, inside the nucleus as well. The colony-forming capability of cancer cells radiosensitized by AuNPs decreased significantly and the DNA damage detected by cytogenetics, γH2AX immunostaining, and by single (γH2AX) or double (γH2AX and OGG1) immunolocalization via transmission electron microscopy (TEM) was in many cases higher and/or persistent after combination with AuNPs than upon individual exposure to ionizing radiation (IR). Moreover, different cell cycle distribution was evident in PC3 but not A549 cells after treatment with AuNPs and/or irradiation. Finally, cellular senescence was investigated by using a newly established staining procedure for lipofuscin, based on a Sudan Black-B analogue (GL13) which showed that based on the AuNPs' concentration, an increased number of senescent cells might be observed after exposure to IR. Even though different cell lines or different types and concentrations of AuNPs may alter the levels of radiosensitization, our results imply that the complexity of damage might also be an important factor of AuNP-induced radiosensitization.

p73 isoforms meet evolution of metastasis.

Cancer largely adheres to Darwinian selection. Evolutionary forces are prominent during metastasis, the final and incurable disease stage, where cells acquire combinations of advantageous phenotypic features and interact with a dynamically changing microenvironment, in order to overcome the metastatic bottlenecks, while therapy exerts additional selective pressures. As a strategy to increase their fitness, tumors often co-opt developmental and tissue-homeostasis programs. Herein, 25 years after its discovery, we review TP73, a sibling of the cardinal tumor-suppressor TP53, through the lens of cancer evolution. The TP73 gene regulates a wide range of processes in embryonic development, tissue homeostasis and cancer via an overwhelming number of functionally divergent isoforms. We suggest that TP73 neither merely mimics TP53 via its p53-like tumor-suppressive functions, nor has black-or-white-type effects, as inferred by the antagonism between several of its isoforms in processes like apoptosis and DNA damage response. Rather, under dynamic conditions of selective pressure, the various p73 isoforms which are often co-expressed within the same cancer cells may work towards a common goal by simultaneously activating isoform-specific transcriptional and non-transcriptional programs. Combinatorial co-option of these programs offers selective advantages that overall increase the likelihood for successfully surpassing the barriers of the metastatic cascade. The p73 functional pleiotropy-based capabilities might be present in subclonal populations and expressed dynamically under changing microenvironmental conditions, thereby supporting clonal expansion and propelling evolution of metastasis. Deciphering the critical p73 isoform patterns along the spatiotemporal axes of tumor evolution could identify strategies to target TP73 for prevention and therapy of cancer metastasis.

Immunogenic Cell Death, DAMPs and Prothymosin α as a Putative Anticancer Immune Response Biomarker.

The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A distinct characteristic of ICD is the release of danger-associated molecular patterns (DAMPs) by dying and/or dead cells. Thus, several members of the DAMP family, such as the well-characterized heat shock proteins (HSPs) HSP70 and HSP90, the high-mobility group box 1 protein and calreticulin, and the thymic polypeptide prothymosin α (proTα) and its immunoreactive fragment proTα(100-109), are being studied as potential diagnostic tools and/or possible therapeutic agents. Here, we present the basic aspects and mechanisms of both ICD and other immunogenic RCD forms; denote the role of DAMPs in ICD; and further exploit the relevance of human proTα and proTα(100-109) in ICD, highlighting their possible clinical applications. Furthermore, we present the preliminary results of our in vitro studies, which show a direct correlation between the concentration of proTα/proTα(100-109) and the levels of cancer cell apoptosis, induced by anticancer agents and γ-radiation.

Ginger for Healthy Ageing: A Systematic Review on Current Evidence of Its Antioxidant, Anti-Inflammatory, and Anticancer Properties.

The world's population is ageing at an accelerated pace. Ageing is a natural, physiological but highly complex and multifactorial process that all species in the Tree of Life experience over time. Physical and mental disabilities, and age-related diseases, would increase along with the increasing life expectancy. Ginger (Zingiber officinale) is a plant that belongs to the Zingiberaceae family, native to Southeast Asia. For hundreds of years, ginger has been consumed in various ways by the natives of Asian countries, both as culinary and medicinal herb for the treatment of many diseases. Mounting evidence suggests that ginger can promote healthy ageing, reduce morbidity, and prolong healthy lifespan. Ginger, a well-known natural product, has been demonstrated to possess antioxidant, anti-inflammatory, anticancer, and antimicrobial properties, as well as an outstanding antiviral activity due to a high concentration of antiviral compounds. In this review, the current evidence on the potential role of ginger and its active compounds in the prevention of ageing is discussed.

Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair.

DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.

The Role of Ionizing Radiation for Diagnosis and Treatment against COVID-19: Evidence and Considerations.

The Coronavirus disease 2019 (COVID-19) pandemic continues to spread worldwide with over 260 million people infected and more than 5 million deaths, numbers that are escalating on a daily basis. Frontline health workers and scientists diligently fight to alleviate life-threatening symptoms and control the spread of the disease. There is an urgent need for better triage of patients, especially in third world countries, in order to decrease the pressure induced on healthcare facilities. In the struggle to treat life-threatening COVID-19 pneumonia, scientists have debated the clinical use of ionizing radiation (IR). The historical literature dating back to the 1940s contains many reports of successful treatment of pneumonia with IR. In this work, we critically review the literature for the use of IR for both diagnostic and treatment purposes. We identify details including the computed tomography (CT) scanning considerations, the radiobiological basis of IR anti-inflammatory effects, the supportive evidence for low dose radiation therapy (LDRT), and the risks of radiation-induced cancer and cardiac disease associated with LDRT. In this paper, we address concerns regarding the effective management of COVID-19 patients and potential avenues that could provide empirical evidence for the fight against the disease.

Temporal evolution and adaptation of SARS-CoV-2 codon usage.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in Wuhan (China) in December of 2019. Since the outbreak, it has accumulated mutations on its coding sequences to optimize its adaptation to the human host. The identification of its genetic variants has become crucial in tracking and evaluating their spread across the globe. METHODS: In this study, we compared 320,338 SARS-CoV-2 genomes isolated from all over the world to the first sequenced genome in Wuhan, China. To this end, we analysed over time the codon usage patterns of SARS-CoV-2 genes encoding for the membrane protein (M), envelope (E), spike surface glycoprotein (S), nucleoprotein (N), RNA-dependent RNA polymerase (RdRp) and ORF1ab. RESULTS: We found that genes coding for the proteins N and S diverged more rapidly since the outbreak by accumulating mutations. Interestingly, all genes show a deoptimization of their codon usage with respect to the human host. Our findings suggest a general evolutionary trend of SARS-CoV-2, which evolves towards a sub-optimal codon usage bias to favour the host survival and its spread. Furthermore, we found that S protein and RdRp are more subject to an increasing purifying pressure over time, which implies that these proteins will reach a lower tendency to accept mutations. In contrast, proteins N and M tend to evolve more under the action of mutational bias, thus exploring a large region of their sequence space. CONCLUSIONS: Overall, our study shed more light on the evolution of SARS-CoV-2 genes and their adaptation to humans, helping to foresee their mutation patterns and the emergence of new variants.

In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach.

Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as "clustered/complex DNA damage" and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients.