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Background: The 2014 British Thyroid Association guidelines acknowledged the value of risk-stratifying thyroid nodules by utilising an ultrasound reporting system ('U' classification). This study assessed whether using pre-existing parameters in combination can better stratify patients' malignancy and completion thyroidectomy risks., Method: A multicentre, retrospective, observational review identified 936 NHS Greater Glasgow and Clyde patients from pathology records who underwent hemithyroidectomy between 1 January 2014 and 31 December 2019., Results: A total of 308 patients had thyroid malignancy, 180 (58.4 per cent) progressed to completion thyroidectomy. A nodule classified as 'U3' (indeterminate) was associated with a 35.4 per cent chance of malignancy and a 21.6 per cent risk of requiring completion surgery. Amalgamation of 'U' score with Thy score enhanced risk prediction. The malignancy rate in U3, Thy-3f nodules was 38 per cent, and 21 per cent required completion surgery. The malignancy and completion thyroidectomy rates were comparatively lower for U3, Thy-3a nodules (22 per cent and 14.3 per cent, respectively)., Conclusion: Combining ultrasound 'U' score and Thy score improves pre-operative thyroid nodule risk stratification, leading to better informed patients regarding the risks of malignancy and completion surgery. A move towards an integrated assessment approach should be considered.

Two mitotic cyclin types, cyclin A and B, exist in higher eukaryotes, but their specialised functions in mitosis are incompletely understood. Using degron tags for rapid inducible protein removal, we analyse how acute depletion of these proteins affects mitosis. Loss of cyclin A in G2-phase prevents mitotic entry. Cells lacking cyclin B can enter mitosis and phosphorylate most mitotic proteins, because of parallel PP2A:B55 phosphatase inactivation by Greatwall kinase. The final barrier to mitotic establishment corresponds to nuclear envelope breakdown, which requires a decisive shift in the balance of cyclin-dependent kinase Cdk1 and PP2A:B55 activity. Beyond this point, cyclin B/Cdk1 is essential for phosphorylation of a distinct subset of mitotic Cdk1 substrates that are essential to complete cell division. Our results identify how cyclin A, cyclin B and Greatwall kinase coordinate mitotic progression by increasing levels of Cdk1-dependent substrate phosphorylation., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.