Protocol for a realist review of workplace learning in postgraduate medical education and training

Postgraduate medical education and training (PGMET) is a complex social process which happens predominantly during the delivery of patient care. The clinical learning environment (CLE), the context for PGMET, shapes the development of the doctors who learn and work within it, ultimately impacting the quality and safety of patient care. Clinical workplaces are complex, dynamic systems in which learning emerges from non-linear interactions within a network of related factors and activities. Those tasked with the design and delivery of postgraduate medical education and training need to understand the relationship between the processes of medical workplace learning and these contextual elements in order to optimise conditions for learning. We propose to conduct a realist synthesis of the literature to address the overarching questions; how, why and in what circumstances do doctors learn in clinical environments? This review is part of a funded projected with the overall aim of producing guidelines and recommendations for the design of high quality clinical learning environments for postgraduate medical education and training

Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential biomarker for isocitrate dehydrogenase (IDH1/2) mutant cholangiocarcinoma

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients. Results were validated in cohorts of CCA and clear cell renal cell carcinoma (ccRCC) patients. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for IDHmt glioma patients, while circulating rRS was elevated in IDHmt CCA patients. There were overlap distributions of circulating R2HG and total 2HG (t2HG) in both IDHmt and wild-type (IDHwt) CCA patients, while there was minimal overlap in rRS values between IDHmt and IDHwt CCA patients. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in IDHmt CCA patients compare to IDHwt CCA patients. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy

BRAFΔβ3−αC^{Δβ3-αC} in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF$^{Δβ3-αC}$ oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF$^{Δβ3-αC}$ oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF$^{ΔLNVTAP>F}$ and two novel mutants, BRAF$^{delinsFS}$ and BRAF$^{ΔLNVT>F}$, and compare them with other BRAF$^{Δβ3-αC}$ oncoproteins. We show that BRAF$^{Δβ3-αC}$ oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAF$^{Δβ3-αC}$ oncoproteins, e.g., BRAF$^{ΔLNVTAP>F}$, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAF$^{Δβ3-αC}$ mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds