Journal of IiMER Volume 10 Issue 1 the ability to confirm a result derived from one patient cohort with the other cohort of our second pilot study supports further analysis. MicroRNAs are of great interest as potential disease biomarkers since they are present and highly stable in virtually all biofluids, and appear to be acutely sensitive to changes in various physiological processes 18-19. They have emerged as important biomarkers and modulators of numerous pathophysiological processes. Our approach, guided by the ‘precision medicine’ methodology aims to investigate any correlation between circulating cytokines and miRNAs in plasma samples from individual patients within our two study groups. In our ME/CFS pilot studies for example, we have found differences between multiple cytokines and a particular microRNA. This implies a connection between these cytokines with the microRNA. Of interest for our initial results is a recent study by Su et al. 201520 where two cytokines were shown to induce a microRNA in macrophages in chronic inflammation. Recently, perhaps relevant to ME/CFS a number of dysregulations in microRNAs have been reported in patients suffering from pain - in complex regional pain syndrome, cystitis-induced chronic pain, and irritable bowel disorder, both in the affected tissues, and reflected in the circulation. Such microRNAs are implicated functionally in pain processing based on studies in animal models of inflammatory and neuropathic pain, and in vivo studies have found dysregulated microRNAs influence the post-transcriptional June 2016 modulation of genes implicated in pain generation and maintenance21. Several clinical studies have highlighted the potential of plasma microRNAs to be biomarkers for complex regional pain syndrome and for fibromyalgia. For example, Orlova et al. (2011)22 used whole blood samples from 41 patients with complex regional pain syndrome and 20 controls in a study analysing miRNA, cytokines and correlations with numerous clinical parameters. Unsurprisingly, expected cytokines such as VEGF were elevated in the disease group compared to controls and a miRNA-signature was evident. Extensive correlation analyses revealed that 4 miRNAs were positively correlated with disease-associated pain level, one other was correlated with the occurrence of migraine within the patient cohort and an extensive array of miRNAs was found to correlate with the levels of circulating cytokines22. A similarly designed 2013 study investigated the miRNA profile of the cerebrospinal fluid in fibromyalgia patients23, a disease with many commonalities to ME/CFS, identified 10 miRNAs differentially expressed between affected patients and healthy controls. Most notably, the study found that decreased levels of miR-145-5p in the CSF were associated with reported symptomatology such as pain intensity and fatigue24. To investigate changes in miRNA expression, we used TaqMan® Array MicroRNA cards to assay for 754 human miRNAs in the plasma samples. Megaplex™ RT Primers complement the assays on the cards Invest in ME (Charity Nr. 1114035) www.investinme.org Page 51 of 77

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