Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility

Merkel cell carcinoma (MCC) is an aggressive skin cancer with high rates of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases. MCPyV-induced tumourigenesis is largely dependent on the expression of the small tumour antigen (ST). Recent findings implicate MCPyV ST expression in the highly metastatic nature of MCC by promoting cell motility and migration, through differential expression of cellular proteins that lead to microtubule destabilisation, filopodium formation and breakdown of cell–cell junctions. However, the molecular mechanisms which dysregulate these cellular processes are yet to be fully elucidated. Here, we demonstrate that MCPyV ST expression activates p38 MAPK signalling to drive cell migration and motility. Notably, MCPyV ST-mediated p38 MAPK signalling occurs through MKK4, as opposed to the canonical MKK3/6 signalling pathway. In addition, our results indicate that an interaction between MCPyV ST and the cellular phospatase subunit PP4C is essential for its effect on p38 MAPK signalling. These results provide novel opportunities for the treatment of metastatic MCC given the intense interest in p38 MAPK inhibitors as therapeutic agents

SFPQ promotes an oncogenic transcriptomic state in melanoma

The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ–RNA interactions promoting the expression of numerous oncogenic transcripts

The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma

Exosomes play a crucial role in the crosstalk between cancer associated fibroblasts (CAFs) and cancer cells, contributing to carcinogenesis and the tumour microenvironment. Recent studies have revealed that CAFs, normal fibroblasts and cancer cells all secrete exosomes that contain miRNA, establishing a cell-cell communication network within the tumour microenvironment. For example, miRNA dysregulation in melanoma has been shown to promote CAF activation via induction of epithelial-mesenchymal transition (EMT), which in turn alters the secretory phenotype of CAFs in the stroma. This review assesses the roles of melanoma exosomal miRNAs in CAF formation and how CAF exosome-mediated feedback signalling to melanoma lead to tumour progression and metastasis. Moreover, efforts to exploit exosomal miRNA-mediated network communication between tumour cells and their microenvironment, and their potential as prognostic biomarkers or novel therapeutic targets in melanoma will also be considered

Regional anaesthesia training in the UK – a national survey

Background: Adequate training of anaesthetists in regional anaesthesia is important to ensure optimal patient access to regional anaesthesia. Methods: We undertook a national survey of UK trainee anaesthetists and Royal College of Anaesthetists (RCoA) tutors to assess experiences of training in regional anaesthesia. We performed descriptive statistics for baseline characteristics, and logistic regression of training indices and tutor confidence that their hospital could provide regional anaesthesia training at all three stages of the RCoA 2021 curriculum. Results: A total of 492 trainees (19.2%) and 114 tutors (45.2%) completed the survey. Trainees were less likely to have received training in chest/abdominal wall compared with upper/lower limb blocks {erector spinae vs femoral block (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.16–0.39), P<0.001}, or achieved >20 chest/abdominal wall blocks by Stage 3 of training (chest vs lower limb block [OR 0.09, 95% CI 0.05–0.15, P<0.001]. There was a strong association between training received, number of blocks performed (>20 vs 0–5 blocks), and self-reported ability to perform blocks independently, OR 20.9 (95% CI 9.38–53.2). 24/182 (13%) and 10/182 (5.5%) of trainees had performed ≥50 non-obstetric lumbar and thoracic epidurals, respectively, by Stage 3 training. There was a positive association between having a lead clinician for regional anaesthesia, particularly those with paid sessions, and reported confidence to provide regional anaesthesia training at all stages of the curriculum (Stage 3 OR 7.27 [95% CI 2.64–22.0]). Conclusion: Our results confirm the importance of clinical experience and access to training in regional anaesthesia, and support the introduction of departmental regional anaesthesia leads to improve equity and quality in training opportunities

Dialectics and contradictions in public procurement of information systems

Published version of a chapter from the book M. Janssen, H. Scholl, M. Wimmer & F. Bannister (Eds.), Electronic Government : Springer Berlin Heidelberg, 2014. Also available on SpringerLink: http://dx.doi.org/10.1007/978-3-662-44426-9_24Public procurement of Information Systems is a highly complex process. Not surprisingly, systems often fail to meet the needs for which they were procured. One of the main causes of this is the contradictions between goals of different stakeholders. Identifying and understanding these conflicts and contradictions are essential to develop strategies to improve the procurement process. In this paper, we present a case study where we examined the procurement process of a system carried out by a public entity in Norway. Using dialectic theory and stakeholder theory as interpreting lenses, we identified a number of conflicts and contradictions. Some of the contradictions resulted from conflicting and divergent goals of the various stakeholders across groups but also within groups, while others resulted from differing goals of policies and regulations