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

Identification of neoplasm-specific signatures of miRNA interactions by employing a systems biology approach

MicroRNAs represent major regulatory components of the disease epigenome and they constitute powerful biomarkers for the accurate diagnosis and prognosis of various diseases, including cancers. The advent of high-throughput technologies facilitated the generation of a vast amount of miRNA-cancer association data. Computational approaches have been utilized widely to effectively analyze and interpret these data towards the identification of miRNA signatures for diverse types of cancers. Herein, a novel computational workflow was applied to discover core sets of miRNA interactions for the major groups of neoplastic diseases by employing network-based methods. To this end, miRNA-cancer association data from four comprehensive publicly available resources were utilized for constructing miRNA-centered networks for each major group of neoplasms. The corresponding miRNA-miRNA interactions were inferred based on shared functionally related target genes. The topological attributes of the generated networks were investigated in order to detect clusters of highly interconnected miRNAs that form core modules in each network. Those modules that exhibited the highest degree of mutual exclusivity were selected from each graph. In this way, neoplasm-specific miRNA modules were identified that could represent potential signatures for the corresponding diseases

Soft Tissue Ewing Sarcoma Cell Drug Resistance Revisited: A Systems Biology Approach

Ewing sarcoma is a rare type of cancer that develops in the bones and soft tissues. Drug therapy represents an extensively used modality for the treatment of sarcomas. However, cancer cells tend to develop resistance to antineoplastic agents, thereby posing a major barrier in treatment effectiveness. Thus, there is a need to uncover the molecular mechanisms underlying chemoresistance in sarcomas and, hence, to enhance the anticancer treatment outcome. In this study, a differential gene expression analysis was conducted on high-throughput transcriptomic data of chemoresistant versus chemoresponsive Ewing sarcoma cells. By applying functional enrichment analysis and protein–protein interactions on the differentially expressed genes and their corresponding products, we uncovered genes with a hub role in drug resistance. Granted that non-coding RNA epigenetic regulators play a pivotal role in chemotherapy by targeting genes associated with drug response, we investigated the non-coding RNA molecules that potentially regulate the expression of the detected chemoresistance genes. Of particular importance, some chemoresistance-relevant genes were associated with the autonomic nervous system, suggesting the involvement of the latter in the drug response. The findings of this study could be taken into consideration in the clinical setting for the accurate assessment of drug response in sarcoma patients and the application of tailored therapeutic strategies

A Counterintuitive Neutrophil-Mediated Pattern in COVID-19 Patients Revealed through Transcriptomics Analysis

The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic “cytokine storm”. Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies

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