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.

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.

Novel integrated workflow allows production and in-depth quality assessment of multifactorial reprogrammed skeletal muscle cells from human stem cells.

Skeletal muscle tissue engineering aims at generating biological substitutes that restore, maintain or improve normal muscle function; however, the quality of cells produced by current protocols remains insufficient. Here, we developed a multifactor-based protocol that combines adenovector (AdV)-mediated MYOD expression, small molecule inhibitor and growth factor treatment, and electrical pulse stimulation (EPS) to efficiently reprogram different types of human-derived multipotent stem cells into physiologically functional skeletal muscle cells (SMCs). The protocol was complemented through a novel in silico workflow that allows for in-depth estimation and potentially optimization of the quality of generated muscle tissue, based on the transcriptomes of transdifferentiated cells. We additionally patch-clamped phenotypic SMCs to associate their bioelectrical characteristics with their transcriptome reprogramming. Overall, we set up a comprehensive and dynamic approach at the nexus of viral vector-based technology, bioinformatics, and electrophysiology that facilitates production of high-quality skeletal muscle cells and can guide iterative cycles to improve myo-differentiation protocols.

Evaluation of intraoperative ketamine on the prevention of severe rebound pain upon cessation of peripheral nerve block: a prospective randomised, double-blind, placebo-controlled study.

BACKGROUND: Pain after resolution of peripheral nerve block, known as 'rebound pain' (RP), is a major problem in outpatient surgery. The primary objective was to evaluate the benefit of intraoperative ketamine at an anti-hyperalgesic dose on the incidence of rebound pain after upper limb surgery under axillary plexus block in ambulatory patients. The secondary objective was to better understand the rebound pain phenomenon (individual risk factors). METHODS: In this prospective, double-blind study, patients were randomised to receive either a single dose of i.v. ketamine (0.3 mg kg-1) or a placebo. Preoperative mechanical temporal summation and central sensitization inventory were applied to question underlying central sensitisation. Pain catastrophising and Douleur Neuropathique 4 questionnaires were used. Rebound pain was defined as pain intensity score >7 (numeric rating scale, 0-10) after block resolution. Postoperative pain was recorded at Days 1, 4, and 30 after discharge. RESULTS: A total of 109 subjects completed the study, and 40.4% presented with rebound pain. Ketamine administration did not reduce rebound pain incidence or intensity. Temporal summation and central sensitisation inventory scores did not differ between subjects with and without rebound pain. The predictive risk factors were bone surgery (odds ratio [OR]=5.2; confidence interval [CI], 1.9-14.6), severe preoperative pain (OR=4.2; CI, 1.5-11.7), and high pain catastrophising (OR=4.8; CI, 1.0-22.3). At Day 30, the average daily pain was higher in the rebound pain group involving neuropathic characteristics. CONCLUSION: Ketamine at an anti-hyperalgesic dose showed no benefit on rebound pain development. Although central sensitisation might not be involved, preoperative pain intensity, and catastrophising stand as risk factors. Because rebound pain remains frequent despite adequate procedure-specific postoperative analgesia, future studies should focus on patient-specific pain management.

Polycystic οvary syndrome revisited: An interactions network approach.

BACKGROUND: The polycystic ovary syndrome (PCOS) has genetic, epigenetic, metabolic and reproductive aspects, while its complex pathophysiology has not been conclusively deciphered. AIM: The goal of this research was to screen the gene/gene products associated with PCOS and to predict any possible interactions with the highest possible fidelity. MATERIALS AND METHODS: STRING v10.5 database and a confidence level of 0.7 were used. RESULTS: A highly interconnected network of 48 nodes was created, where insulin (INS) appears to be the major hub. INS upstream and downstream defects were analysed and revealed that only the kisspeptin- and glucagon-coding genes were upstream of INS. CONCLUSION: A metabolic dominance was inferred and discussed herein with its implications in puberty, obesity, infertility and cardiovascular function. This study, thus, may contribute to the resolution of a scientific conflict between the USA and EU definitions of the syndrome and/or provide a new P4 medicine approach.

Evaluation of virtual reality combining music and a hypnosis session to reduce anxiety before hand surgery under axillary plexus block: A prospective study.

AIMS: Preoperative anxiety, which can affect postoperative recovery, is often present in patients undergoing surgery under loco-regional anaesthesia (LRA). Minimising preoperative anxiety with premedication can be effective but results in drug-related side effects. Therefore, the use of non-pharmacological techniques should be encouraged. METHODS: We evaluated whether a virtual reality (VR) incorporating music and a hypnosis session, provided during the performance of LRA, can reduce preoperative anxiety. Fifty patients scheduled for elective hand surgery under an axillary plexus block were enrolled (March-June 2019). The primary outcome measure was the change in the Amsterdam Anxiety and Preoperative Information Scale (APAIS) questionnaire 5 min after the VR session as compared to before the VR session. The secondary outcome measures were the visual analog scale (VAS) for anxiety before and 2 h after the surgery and the Evaluation du Vécu de l'ANesthésie-LocoRégionale (EVAN-LR) satisfaction score. RESULTS: Data from 48 patients were analysed. The APAIS score as well as VAS for anxiety were significantly reduced after a VR session (p < .001 for both scores). Patients were very satisfied (EVAN-LR: 92 (88, 94)). CONCLUSIONS: The use of VR incorporating music and a hypnosis session could be an effective tool in the management of a patient's preoperative anxiety during the performance of an axillary plexus block.

In Silico Methods for the Identification of Diagnostic and Favorable Prognostic Markers in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML), the most common type of acute leukemia in adults, is mainly asymptomatic at early stages and progresses/recurs rapidly and frequently. These attributes necessitate the identification of biomarkers for timely diagnosis and accurate prognosis. In this study, differential gene expression analysis was performed on large-scale transcriptomics data of AML patients versus corresponding normal tissue. Weighted gene co-expression network analysis was conducted to construct networks of co-expressed genes, and detect gene modules. Finally, hub genes were identified from selected modules by applying network-based methods. This robust and integrative bioinformatics approach revealed a set of twenty-four genes, mainly related to cell cycle and immune response, the diagnostic significance of which was subsequently compared against two independent gene expression datasets. Furthermore, based on a recent notion suggesting that molecular characteristics of a few, unusual patients with exceptionally favorable survival can provide insights for improving the outcome of individuals with more typical disease trajectories, we defined groups of long-term survivors in AML patient cohorts and compared their transcriptomes versus the general population to infer favorable prognostic signatures. These findings could have potential applications in the clinical setting, in particular, in diagnosis and prognosis of AML.

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.

Interactome of Obesity: Obesidome : Genetic Obesity, Stress Induced Obesity, Pathogenic Obesity Interaction.

Obesity is a chronic disease of increasing prevalence reaching epidemic proportions. Genetic defects as well as epigenetic effects contribute to the obesity phenotype. Investigating gene (e.g. MC4R defects)-environment (behavior, infectious agents, stress) interactions is a relative new field of great research interest. In this study, we have made an effort to create an interactome (henceforth referred to as "obesidome"), where extrinsic stressors response, intrinsic predisposition, immunity response to inflammation and autonomous nervous system implications are integrated. These pathways are presented in one interactome network for the first time. In our study, obesity-related genes/gene products were found to form a complex interactions network.

Progression of mouse skin carcinogenesis is associated with the orchestrated deregulation of mir-200 family members, mir-205 and their common targets.

MicroRNAs are small, non-coding RNAs which regulate post-transcriptionally hundreds of target mRNAs. Given that their expression is deregulated in several cancer types, they represent potential diagnostic, prognostic, and predictive biomarkers, as well as next-generation therapeutic targets. Nevertheless, the involvement of miRNAs in non-melanoma skin cancer, a cancer type with increasing prevalence, is not extensively studied, and their comprehensive characterization as regard to the initiation, promotion, and progression stages is missing. To this end, we exploited a well-established multistage mouse skin carcinogenesis model in order to identify miRNAs consistently implicated in different stages of skin carcinogenesis. The cell lines comprising this model were subjected to miRNA expression profiling using microarrays, followed by bioinformatics analysis and validation with Q-PCR, as well as treatment with miRNA modulators. We showed that among all deregulated miRNAs in our system, only a functionally coherent group consisting of the miR-200 family members and miR-205-5p displays a pattern of progressive co-downregulation from the early toward the most aggressive stages of carcinogenesis. Their overlapping, co-regulated putative targets are potentially inter-associated and, of these, the EMT-related Rap1a is overexpressed toward aggressive stages. Ectopic expression of miR-205-5p in spindle cancer cells reduces Rap1a, mitigates cell invasiveness, decreases proliferation, and delays tumor onset. We conclude that deregulation of this miRNA group is primarily associated with aggressive phenotypes of skin cancer cells. Restoration of the miR-205-5p member of this group in spindle cells reduces the expression of critical, co-regulated targets that favor cancer progression, thus reversing the EMT characteristics. © 2015 Wiley Periodicals, Inc.

3D molecular modeling and evolutionary study of the Trypanosoma brucei DNA Topoisomerase IB, as a new emerging pharmacological target.

In the present study, an outline is proposed that may lead to specific drug design targeting of the Trypanosoma brucei DNA Topoisomerase IB. In this direction, an unequivocally specific platform was designed for the development of selective modulators. The designed platform is focused on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all available published genomes indicated a broad distribution of DNA topoisomerases across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the mechanism of the T. brucei DNA Topoisomerase IB. Based on the above, we propose a comprehensive in silico 3D model for the structure of the T. brucei DNA Topoisomerase IB. Our approach provides an efficient intergraded platform with both evolutionary and structural insights for the rational design of pharmacophore models as well as novel modulators as the anti-T. brucei DNA Topoisomerase IB agents with therapeutic potential.

Functions, divergence and clinical value of TAp73 isoforms in cancer.

The p73 gene encodes the tumour suppressive full-length TAp73 and N-terminal-truncated DNp73 isoforms that act as dominant negative inhibitors of TAp73. The overall effect of p73 in oncogenesis is thought to depend on the TAp73 to DNp73 isoforms' ratio. TAp73 isoforms include a number of C-terminal variants as a result of alternative splicing in 3'-end. TAp73 isoforms protect cells from oncogenic alterations in a multifaceted way since they are implicated in the suppression of all demonstrated hallmarks and enabling characteristics of cancer. Their best established role is in apoptosis, a process which seems to be differently affected by each TAp73 C-terminal variant. Based on previous findings and our thorough bioinformatics analysis, we highlight that TAp73 variants are functionally non-equivalent, since they present major differences in their transactivation efficiencies, protein interactions, response to DNA damage and apoptotic effects that are attributable to the primary structure of their C terminus. In this review, we summarise these differences and we unveil the link between crucial C-terminal motifs/residues and the oncosuppressive potential of TAp73 isoforms, emphasising on the importance of considering C terminus during the development of p73-based anticancer biologics.

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.

"In the light of evolution:" keratins as exceptional tumor biomarkers.

Keratins (KRTs) are the intermediate filament-forming proteins of epithelial cells, classified, according to their physicochemical properties, into "soft" and "hard" keratins. They have a key role in several aspects of cancer pathophysiology, including cancer cell invasion and metastasis, and several members of the KRT family serve as diagnostic or prognostic markers. The human genome contains both, functional KRT genes and non-functional KRT pseudogenes, arranged in two uninterrupted clusters on chromosomes 12 and 17. This characteristic renders KRTs ideal for evolutionary studies. Herein, comprehensive phylogenetic analyses of KRT homologous proteins in the genomes of major taxonomic divisions were performed, so as to fill a gap in knowledge regarding the functional implications of keratins in cancer biology among tumor-bearing species. The differential expression profiles of KRTs in diverse types of cancers were investigated by analyzing high-throughput data, as well. Several KRT genes, including the phylogenetically conserved ones, were found to be deregulated across several cancer types and to participate in a common protein-protein interaction network. This indicates that, at least in cancer-bearing species, these genes might have been under similar evolutionary pressure, perhaps to support the same important function(s). In addition, semantic relations between KRTs and cancer were detected through extensive text mining. Therefore, by applying an integrative in silico pipeline, the evolutionary history of KRTs was reconstructed in the context of cancer, and the potential of using non-mammalian species as model organisms in functional studies on human cancer-associated KRT genes was uncovered.

Whole Genome Analysis of Dizygotic Twins With Autism Reveals Prevalent Transposon Insertion Within Neuronal Regulatory Elements: Potential Implications for Disease Etiology and Clinical Assessment.

Transposable elements (TEs) have been implicated in autism spectrum disorder (ASD). However, our understanding of their roles is far from complete. Herein, we explored de novo TE insertions (dnTEIs) and de novo variants (DNVs) across the genomes of dizygotic twins with ASD and their parents. The neuronal regulatory elements had a tendency to harbor dnTEIs that were shared between twins, but ASD-risk genes had dnTEIs that were unique to each twin. The dnTEIs were 4.6-fold enriched in enhancers that are active in embryonic stem cell (ESC)-neurons (p < 0.001), but DNVs were 1.5-fold enriched in active enhancers of astrocytes (p = 0.0051). Our findings suggest that dnTEIs and DNVs play a role in ASD etiology by disrupting enhancers of neurons and astrocytes.

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.

An in silico approach to the identification of diagnostic and prognostic markers in low-grade gliomas.

Low-grade gliomas (LGG) are central nervous system Grade I tumors, and as they progress they are becoming one of the deadliest brain tumors. There is still great need for timely and accurate diagnosis and prognosis of LGG. Herein, we aimed to identify diagnostic and prognostic biomarkers associated with LGG, by employing diverse computational approaches. For this purpose, differential gene expression analysis on high-throughput transcriptomics data of LGG versus corresponding healthy brain tissue, derived from TCGA and GTEx, respectively, was performed. Weighted gene co-expression network analysis of the detected differentially expressed genes was carried out in order to identify modules of co-expressed genes significantly correlated with LGG clinical traits. The genes comprising these modules were further used to construct gene co-expression and protein-protein interaction networks. Based on the network analyses, we derived a consensus of eighteen hub genes, namely, CD74, CD86, CDC25A, CYBB, HLA-DMA, ITGB2, KIF11, KIFC1, LAPTM5, LMNB1, MKI67, NCKAP1L, NUSAP1, SLC7A7, TBXAS1, TOP2A, TYROBP, and WDFY4. All detected hub genes were up-regulated in LGG, and were also associated with unfavorable prognosis in LGG patients. The findings of this study could be applicable in the clinical setting for diagnosing and monitoring LGG.

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.

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.

Thrombocytopenia in COVID­19 and vaccine­induced thrombotic thrombocytopenia.

The highly heterogeneous symptomatology and unpredictable progress of COVID­19 triggered unprecedented intensive biomedical research and a number of clinical research projects. Although the pathophysiology of the disease is being progressively clarified, its complexity remains vast. Moreover, some extremely infrequent cases of thrombotic thrombocytopenia following vaccination against SARS­CoV­2 infection have been observed. The present study aimed to map the signaling pathways of thrombocytopenia implicated in COVID­19, as well as in vaccine­induced thrombotic thrombocytopenia (VITT). The biomedical literature database, MEDLINE/PubMed, was thoroughly searched using artificial intelligence techniques for the semantic relations among the top 50 similar words (>0.9) implicated in COVID­19­mediated human infection or VITT. Additionally, STRING, a database of primary and predicted associations among genes and proteins (collected from diverse resources, such as documented pathway knowledge, high­throughput experimental studies, cross­species extrapolated information, automated text mining results, computationally predicted interactions, etc.), was employed, with the confidence threshold set at 0.7. In addition, two interactomes were constructed: i) A network including 119 and 56 nodes relevant to COVID­19 and thrombocytopenia, respectively; and ii) a second network containing 60 nodes relevant to VITT. Although thrombocytopenia is a dominant morbidity in both entities, three nodes were observed that corresponded to genes (AURKA, CD46 and CD19) expressed only in VITT, whilst ADAM10, CDC20, SHC1 and STXBP2 are silenced in VITT, but are commonly expressed in both COVID­19 and thrombocytopenia. The calculated average node degree was immense (11.9 in COVID­19 and 6.43 in VITT), illustrating the complexity of COVID­19 and VITT pathologies and confirming the importance of cytokines, as well as of pathways activated following hypoxic events. In addition, PYCARD, NLP3 and P2RX7 are key potential therapeutic targets for all three morbid entities, meriting further research. This interactome was based on wild­type genes, revealing the predisposition of the body to hypoxia­induced thrombosis, leading to the acute COVID­19 phenotype, the 'long­COVID syndrome', and/or VITT. Thus, common nodes appear to be key players in illness prevention, progression and treatment.