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  Model-based integration analysis revealed presence of novel prognostic miRNA targets and important cancer driver genes in triple-negative breast cancers

  Zaka, M.; Sutton, Chris W.; Peng, Y.; Konur, Savas (2020-03)

  Background: miRNAs (microRNAs) play a key role in triple-negative breast cancer (TNBC) progression, and its heterogeneity at the expression, pathological and clinical levels. Stratification of breast cancer subtypes on the basis of genomics and transcriptomics profiling, along with the known biomarkers’ receptor status, has revealed the existence of subgroups known to have diverse clinical outcomes. Recently, several studies have analysed expression profiles of matched mRNA and miRNA to investigate the underlying heterogeneity of TNBC and the potential role of miRNA as a biomarker within cancers. However, the miRNA-mRNA regulatory network within TNBC has yet to be understood. Results and Findings: We performed model-based integrated analysis of miRNA and mRNA expression profiles on breast cancer, primarily focusing on triple-negative, to identify subtype-specific signatures involved in oncogenic pathways and their potential role in patient survival outcome. Using univariate and multivariate Cox analysis, we identified 25 unique miRNAs associated with the prognosis of overall survival (OS) and distant metastases-free survival (DMFS) with “risky” and “protective” outcomes. The association of these prognostic miRNAs with subtype-specific mRNA genes was established to investigate their potential regulatory role in the canonical pathways using anti-correlation analysis. The analysis showed that miRNAs contribute to the positive regulation of known breast cancer driver genes as well as the activation of respective oncogenic pathway during disease formation. Further analysis on the “risk associated” miRNAs group revealed significant regulation of critical pathways such as cell growth, voltage-gated ion channel function, ion transport and cell-to-cell signalling. Conclusion: The study findings provide new insights into the potential role of miRNAs in TNBC disease progression through the activation of key oncogenic pathways. The results showed previously unreported subtype-specific prognostic miRNAs associated with clinical outcome that may be used for further clinical evaluation.
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  kPWorkbench: A software suit for membrane systems

  Konur, Savas; Mierla, L.; Ipate, F.; Gheorghe, Marian (2020)

  Membrane computing is a new natural computing paradigm inspired by the functioning and structure of biological cells, and has been successfully applied to many different areas, from biology to engineering. In this paper, we present kPWorkbench, a software framework developed to support membrane computing and its applications. kPWorkbench offers unique features, including modelling, simulation, agent-based high performance simulation and verification, which allow modelling and computational analysis of membrane systems. The kPWorkbench formal verification component provides the opportunity to analyse the behaviour of a model and validate that important system requirements are met and certain behaviours are observed. The platform also features a property language based on natural language statements to facilitate property specification.
• MicroRNAs and Cancer

  Maher, S.G.; Bibby, B.A.S.; Moody, Hannah L.; Reid, G. (2015)

  MicroRNAs are a relatively new class of small, noncoding RNA species that represent a cornerstone of cell biology, with diverse roles ranging from embryonic development to aging. miRNAs function to regulate posttranscriptional gene expression, are critical to the normal function of cells, and as such are frequently dysregulated during disease processes. In this chapter, we discuss the biogenesis and mechanism of action of miRNA and their role in cancer initiation, promotion, and progression. In addition, we discuss the most recently identified dual roles of miRNA in epigenetic gene regulation; how they are both regulators and regulated. Finally, we discuss the emerging roles of miRNA as epigenetic anti-cancer therapeutics, the current research examining inhibition of oncogenic miRNAs, and studies now establishing the potential of replacing lost, tumor-suppressive miRNA.
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  MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma

  Moody, Hannah L.; Lind, M.; Maher, S.G. (2017-09-15)

  Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR-31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity.
• Ultrasonic micromoulding: Process characterisation using extensive in-line monitoring for micro-scaled products

  Gülçür, Mert; Brown, Elaine; Gough, Tim; Romano, J.-M.; Penchev, P.; Dimov, Stefan; Whiteside, Benjamin R. (2020-10)

  Industry-standard quality management systems such as Six Sigma and emerging Industry 4.0 compliant production processes demonstrate the importance of in-line condition monitoring of manufacturing methods for achieving the highest levels of product quality. Measurement data collected as the process is running can inform the operator about unexpected changes in machine operation or raw materials that could negatively impact production; and offer an opportunity for a process control intervention to stabilise production. However, micro-manufacturing production lines can pose a challenging environment for deploying such systems, since processing events can occur extremely rapidly and in harsh environments. Moreover, the small scale of micro-nano featured components can make sensor installation even more problematic. Recently, ultrasonic micromoulding has drawn attention in niche markets due to its unique advantages for processing thermoplastics as a new micro-manufacturing technology. The process differs from conventional moulding significantly by eliminating the need for a plasticising screw and using direct application of ultrasonic energy to melt the polymer. This offers numerous benefits such as decrease in energy usage, moulding at lower pressures, easier cleaning, and reduced material residence times, the latter which could be beneficial for pharma-grade polymers or polymers with active ingredients. However, very little work has been reported attempting to monitor the process using in-line measurements. This work aims to evaluate the characteristics of the ultrasonic micromoulding process for microinjection moulding of a microneedle array using a range of sensor technologies including: data recorded by the machine controller; a high-speed thermal camera and a cavity pressure transducer. The data has captured the highly dynamic process environment with a high degree of accuracy. The relationship between the process data and dimensional quality of the ultrasonically micromoulded products has been quantified and subsequently implemented as a cost-effective in-line quality assurance method.

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