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Introduction: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. Methods: PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay.

Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.

In light of the high incidence and mortality rates of cancer, early and accurate diagnosis is an important priority for assigning optimal treatment for each individual with suspected illness. Biomarkers are crucial in the screening of patients with a high risk of developing cancer, diagnosing patients with suspicious tumours at the earliest possible stage, establishing an accurate prognosis, and predicting and monitoring the response to specific therapies. Epigenetic alterations are innovative biomarkers for cancer, due to their stability, frequency, and noninvasive accessibility in bodily fluids. Epigenetic modifications are also reversible and potentially useful as therapeutic targets. Despite this, there is still a lack of accurate biomarkers for the conclusive diagnosis of most cancer types; thus, there is a strong need for continued investigation to expand this area of research. In this review, we summarise current knowledge on methylated DNA and its implications in cancer to explore its potential as an epigenetic biomarker to be translated for clinical application. We propose that the identification of biomarkers with higher accuracy and more effective detection methods will enable improved clinical management of patients and the intervention at early-stage disease.

MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets.MethodsUtilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy.ResultsWe identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration.ConclusionThese functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0529-z) contains supplementary material, which is available to authorized users.

Objective: “13 Reasons Why,” a Netflix series, included a controversial depiction of suicide that has raised fears about possible contagion. Studies of youth suicide in the United States found an increase on the order of 10% following release of the show, but this has not been replicated in other countries. This study aims to begin to address that gap by examining the relationship between the show’s release and youth suicide in Canada’s most populous province. Methods: Suicides in young people (under the age of 30) in the province of Ontario following the show’s release on March 31, 2017, were the outcome of interest. Time-series analyses were performed using data from January 2013 to March 2017 to predict expected deaths from April to December 2017 with a simple seasonal model (stationary R 2 = 0.732, Ljung-Box Q = 15.1, df = 16, P = 0.52, Bayesian information criterion = 3.09) providing the best fit/used for the primary analysis. Results: Modeling predicted 224 suicides; however, 264 were observed corresponding to 40 more deaths or an 18% increase. In the primary analysis, monthly suicides exceeded the 95% confidence limit for 3 of the 9 months (May, July, and October). Conclusion: The statistical strength of the findings here is limited by small numbers; however, the results are in line with what has been observed in the United States and what would be expected if contagion were occurring. Further research in other locations is needed to increase confidence that the associations found here are causal.

Objective: A growing body of research has established that specific elements of suicide-related news reporting can be associated with increased or decreased subsequent suicide rates. This has not been systematically investigated for social media. The aim of this study was to identify associations between specific social media content and suicide deaths. Methods: Suicide-related tweets ( n = 787) geolocated to Toronto, Canada and originating from the highest level influencers over a 1-year period (July 2015 to June 2016) were coded for general, putatively harmful and putatively protective content. Multivariable logistic regression was used to examine whether tweet characteristics were associated with increases or decreases in suicide deaths in Toronto in the 7 days after posting, compared with a 7-day control window. Results: Elements independently associated with increased subsequent suicide counts were tweets about the suicide of a local newspaper reporter (OR = 5.27, 95% CI = [1.27, 21.99]), ‘other’ social causes of suicide (e.g. cultural, relational, legal problems; OR = 2.39, 95% CI = [1.17, 4.86]), advocacy efforts (OR = 2.34, 95% CI = [1.48, 3.70]) and suicide death (OR = 1.52, 95% CI = [1.07, 2.15]). Elements most strongly independently associated with decreased subsequent suicides were tweets about murder suicides (OR = 0.02, 95% CI = [0.002, 0.17]) and suicide in first responders (OR = 0.17, 95% CI = [0.05, 0.52]). Conclusions: These findings largely comport with the theory of suicide contagion and associations observed with traditional news media. They specifically suggest that tweets describing suicide deaths and/or sensationalized news stories may be harmful while those that present suicide as undesirable, tragic and/or preventable may be helpful. These results suggest that social media is both an important exposure and potential avenue for intervention.