Search

Mothers can influence offspring phenotypes by transferring non-genetic information to the young, which provides them with a flexible tool to adjust the developmental trajectory of the young in fluctuating environments. Mothers can differentially deposit their resources in the same reproductive attempt in relation to the offspring position in the sibling hierarchy. However, whether embryos from different positions can be plastic in their response to the maternal signals, potentially leading to a mother–offspring conflict, is yet unclear. We used Rock pigeons (Columba livia), that lay two egg clutches where maternal androgen levels in second laid eggs at oviposition are higher than in first laid eggs, and investigated the plasticity of embryonic metabolism of maternal androgens. We experimentally elevated androstenedione and testosterone levels in first eggs to that present in second eggs and measured the change in androgen levels and its main metabolites (etiocholanolone and conjugated testosterone) after 3.5 days of incubation. We found that eggs with increased androgens show a different degree of androgen metabolism depending either on the egg laying sequence or initial androgen levels or both. Our findings indicate that embryos have certain plasticity in response to maternal androgen levels depending on maternal signals.

Glucocorticoids prescribed to limit inflammation, have significant adverseeffects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regeneratesactive glucocorticoid, we investigated whether 11β-HSD1 inhibition withAZD4017 could mitigate adverse glucocorticoid effectswithout compromisingtheir anti-inflammatory actions. We conducted a proof-of-concept, randomized,double-blind, placebo-controlled study at Research Unit, ChurchillHospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomizedto AZD4017 or placebo, alongside prednisolone treatment. Althoughthe primary endpoint of the study (change in glucose disposal during a twostephyperinsulinemic, normoglycemic clamp) wasn’t met, hepatic insulinsensitivity worsened in the placebo-treated but not in the AZD4017-treatedgroup. Protective effects of AZD4017 onmarkers of lipid metabolism and boneturnover were observed. Night-time blood pressure was higher in the placebotreatedbut not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratiowas lower in the AZD4017-treated but remained the same in the placebotreatedgroup. Most anti-inflammatory actions of prednisolone persisted withAZD4017 co-treatment. Four adverse events were reported with AZD4017 andno serious adverse events. Here we show that co-administration of AZD4017with prednisolone in men is a potential strategy to limit adverse glucocorticoideffects.

Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in