Diacylglycerol kinase epsilon suppresses expression of p53 and glycerol kinase in mouse embryo fibroblasts.

The incorporation of glycerol into lipid was measured using SV40 transformed mouse embryo fibroblasts (MEFs) from either wild-type (WT) mice or from mice in which the epsilon isoform of diacylglycerol kinase (DGKε) was knocked out (DGKε-/-). We present an explanation for our finding that DGKε-/- MEFs exhibited greater uptake of 3H-glycerol into the cell and a greater incorporation into lipids compared with their WT counterparts, with no change in the relative amounts of various lipids between the DGKε-/- and WT MEFs. Glycerol kinase is more highly expressed in the DGKε-/- cells than in their WT counterparts. In addition, the activity of glycerol kinase is greater in the DGKε-/- cells than in their WT counterparts. Other substrates that enter the cell independent of glycerol kinase, such as pyruvate or acetate, are incorporated into lipid to the same extent between DGKε-/- and WT cell lines. We also show that expression of p53, a transcription factor that increases the synthesis of glycerol kinase, is increased in DGKε-/- MEFs in comparison to WT cells. We conclude that the increased incorporation of glycerol into lipids in DGKε-/- cells is a consequence of up-regulation of glycerol kinase and not a result of an increase in the rate of lipid synthesis. Furthermore, increased expression of the pro-survival gene, p53, in cells knocked out for DGKε suggests that cells over-expressing DGKε would have a greater propensity to become tumorigenic.

Diacylglycerol kinase delta promotes lipogenesis.

We have studied the relationship between diacylglycerol kinase delta (DGKδ) and lipogenesis. There is a marked increase in the expression of DGKδ during the differentiation of 3T3-L1 cells to adipocytes, as well as in the synthesis of neutral and polar lipids. When 3T3-L1 undifferentiated fibroblasts are transfected to express DGKδ, there is increased triglyceride synthesis without differentiation to adipocytes. Hence, expression of DGKδ promotes lipogenesis. Lipid synthesis is decreased in DGKδ knockout mouse embryo fibroblasts, especially for lipids with shorter acyl chains and limited unsaturation. This reduction occurs for both neutral and polar lipids. These findings suggest reduced de novo lipid synthesis. This is confirmed by measuring the incorporation of glycerol into polar and neutral lipids, which is higher in the wild type cells than in the DGKδ knockouts. In comparison, there was no change in lipid synthesis in DGKε knockout mouse embryo fibroblasts. We also demonstrate that the DGKδ knockout cells had a lower expression of acetyl-CoA carboxylase and fatty acid synthase as well as a lower degree of activation by phosphorylation of ATP citrate lyase. These three enzymes are involved in the synthesis of long chain fatty acids. Our results demonstrate that DGKδ markedly increases lipid synthesis, at least in part as a result of promoting the de novo synthesis of fatty acids.

Global health training in Canadian family medicine residency programmes.

Objective: Canadian family medicine (FM) residency programmes are responding to the growing demand to provide global health (GH) education to their trainees; herein, we describe the various GH activities (GHAs) offered within Canadian FM programmes. Design: A bilingual online survey was sent out to all 17 Canadian FM program directors (PDs) and/or an appointed GH representative. Setting: Online survey via Qualtrics. Participants: All 17 Canadian FM PDs and/or an appointed GH representative. Results: The response rate was 100% and represented 3250 first-year and second-year FM residents across English and French Canada. All schools stated that they participate in some form of GHAs. There was variation in the level of organisation, participation and types of GHAs offered. Overall, most GHAs are optional, and there is a large amount of variation in terms of resident participation. Approximately one third of programmes receive dedicated funding for their GHAs, and two thirds wish to increase the scope/variety of GHAs. Conclusion: These results suggest nationwide interest in developing a workforce trained in GH, but show great discrepancies in training, implementation and education.

Training of oncologists: results of a global survey.

While several studies have highlighted the global shortages of oncologists and their workload, few have studied the characteristics of current oncology training. In this study, an online survey was distributed through a snowball method for cancer care providing physicians in 57 countries. Countries were classified into low- or lower-middle-income countries (LMICs), upper-middle-income countries (UMICs) and high-income countries (HICs) based on World Bank criteria. A total of 273 physicians who were trained in 57 different countries responded to the survey: 33% (90/273), 32% (87/273) and 35% (96/273) in LMICs, UMICs and HICs, respectively. About 60% of respondents were practising physicians and 40% were in training. The proportion of responding trainees was higher in LMICs (51%; 45/89) and UMICs (42%; 37/84), than HICs (19%; 28/96; p = 0.013). A higher proportion of respondents from LMICs (37%; 27/73) self-fund their core oncology training compared to UMICs (13%; 10/77) and HICs (11%; 10/89; p < 0.001). Respondents from HICs were more likely to complete an accepted abstract, poster and publication from their research activities compared to respondents from UMICs and LMICs. Respondents identified several barriers to effective training, including skewed service to education ratio and burnout. With regard to preparedness for practice, mean scores on a 5-point Likert scale were low for professional tasks like supervision and mentoring of trainees, leadership and effective management of an oncology practice and understanding of healthcare systems irrespective of country grouping. In conclusion, the investment in training by the public sector is vital to decreasing the prevalence of self-funding in LMICs. Gaps in research training and enhancement of competencies in research dissemination in LMICs require attention. The instruction on cancer care systems and leadership needs to be incorporated in training curricula in all countries.