The class IA isoforms of phosphoinositide 3-kinase (p110α, p110β and p110δ) often have non-redundant functions in a given cell type. However, for reasons that are unclear, the role of a specific PI3K isoform can vary between cell types. Here, we compare the relative contributions of PI3K isoforms in primary and immortalised macrophages. In primary macrophages stimulated with the tyrosine kinase ligand colony-stimulating factor 1 (CSF1), all class IA PI3K isoforms participate in the regulation of Rac1, whereas p110δ selectively controls the activities of Akt, RhoA and PTEN, in addition to controlling proliferation and chemotaxis. The prominent role of p110δ in these cells correlates with it being the main PI3K isoform that is recruited to the activated CSF1 receptor (CSF1R). In immortalised BAC1.2F5 macrophages, however, the CSF1R also engages p110α, which takes up a more prominent role in CSF1R signalling, in processes including Akt phosphorylation and regulation of DNA synthesis. Cell migration, however, remains dependent mainly on p110δ. In other immortalised macrophage cell lines, such as IC-21 and J774.2, p110α also becomes more prominently involved in CSF1-induced Akt phosphorylation, at the expense of p110δ.These data show that PI3K isoforms can be differentially regulated in distinct cellular contexts, with the dominant role of the p110δ isoform in Akt phosphorylation and proliferation being lost upon cell immortalisation. These findings suggest that p110δ-selective PI3K inhibitors may be more effective in inflammation than in cancer.

Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.

The COVID‐19 pandemic has necessitated intensified handwashing and mask usage for healthcare staff. A retrospective cross‐sectional study was performed primarily to investigate the potential skin damage and secondary impacts on wellbeing of staff resulting from these practices. Additionally the availability and uptake of occupational health services and moisturisers in the work place was also assessed. The survey was distributed to NHS staff between April and May 2020 and asked questions regarding skin damage, impact on wellbeing and availability and utilisation of occupational health input and moisturisers. Of the 211 responders, 167 washed their hands more than ten times per shift. Three quarters of these reported cracks or fissures in one or more regions of their hands, most frequently to the back of the hands or web spaces. Amongst the 157 staff who wore FFP3 masks, redness of the nasal area was most frequently reported with 8% reporting facial blisters. 36% of staff reported a substantial impact on one or more aspects of their wellbeing. Only 7% of respondents had received specialist advice, yet a quarter (26%) had made or anticipated needing changes to their occupational duties. The majority (63%) felt they required no specialist input, despite 38% of these reporting a substantial detriment to their wellbeing. Handwashing and face mask use is resulting in skin damage amongst healthcare workers during the COVID‐19 pandemic, with associated detriment to wellbeing. Healthcare services need to take action to implement measures to prevent, reduce and treat damage including promotion of available specialist support.

No abstract

The RET receptor tyrosine kinase is crucial for embryonic and adult development, with mutations in both the extracellular and kinase domains leading to several types of cancer. In order to understand the mechanisms of RET activation in more detail, we have investigated how RET interacts with its bipartite ligand comprising of a glial cell line derived neurotrophic factor (GDNF) family ligand and a GDNF family receptor (GFRalpha). To visualise this interaction, we have reconstituted two vertebrate RET ternary complexes containing both ligand and co-receptor and have determined a pseudo-atomic model for a mammalian RET ternary complex using electron microscopy. Our structures reveal the basis for ligand recognition and will be presented. As RET is a validated anti-cancer target, we are actively investigating RET chemical inhibitors in collaboration with several chemistry laboratories. We have determined structures of a diverse set of chemical scaffolds bound to RET leading to an improved RET pharmacophore based on crystallographic, biochemical and cell-based data. As current FDA-approved drugs for RET-dependent metastatic thyroid cancer suffer from off-target dose-dependent toxicity and lack of specificity, we hope our data will usefully contribute to the design of second generation RET chemical inhibitors.[1] Knowles P et al, J Biol Chem. 2 6 Nov 3;[2][3][4][5][6][7]