Purpose The occurrence of thrombus migration (TM) in middle cerebral arteries (MCAs) prior to mechanical thrombectomy (MT) in patients suffering from acute ischemic strokes is a crucial aspect as TM is associated with lower rates of complete reperfusion and worse clinical outcomes. In this study, we sought to clarify whether histological thrombus composition influences TM. Methods We included 64 patients with acute MCA occlusions who had undergone MT. In 11 of the cases (17.2%) we identified TM prior to the interventions. The extracted clots were collected and histologically examined. The hematoxylin and eosin-stained specimens were quantitatively analyzed in terms of the relative fractions of the main constituents (red and white blood cells and fibrin/platelets). The histologic patterns were correlated with the occurrence of TM. Results Patients in whom TM could be observed were more often treated in a drip-and-ship fashion (90.9% vs 41.5%, p = 0.003). Stroke etiology did not differ between migrated and stable thrombi. A weak tendency for higher RBC and lower F/P content could be observed in thrombi that had migrated when compared with stable thrombi (RBC: median 41% vs 37%, p = 0.022 and F/P: median 54% vs 57%, p = 0.024). When using a cut-off of 60% RBC content for the definition of RBC-rich thrombi, a higher portion of RBC-rich thrombi could be identified in the migrated group as opposed to the stable group (36.4% vs 5.7%, p = 0.003). Conclusion Preinterventional TM may be influenced by the histological thrombus composition in a way that RBC-rich thrombi are more prone to migrate.

Curcumin (diferuloylmethane), a polyphenolic compound derived from the spice plantCurcuma longa, displays multiple actions on solid tumours including anti-angiogenic effects. Here we have studied in rodent and human pituitary tumour cells the influence of curcumin on the production of hypoxia inducible factor 1α (HIF1A) and vascular endothelial growth factor A (VEGFA), two key components involved in tumour neovascularisation through angiogenesis. Curcumin dose-dependently inhibited basal VEGFA secretion in corticotroph AtT20 mouse and lactosomatotroph GH3 rat pituitary tumour cells as well as in all human pituitary adenoma cell cultures (n=32) studied. Under hypoxia-mimicking conditions (CoCl2treatment) in AtT20 and GH3 cells as well as in all human pituitary adenoma cell cultures (n=8) studied, curcumin strongly suppressed the induction of mRNA synthesis and protein production of HIF1A, the regulated subunit of the hypoxia-induced transcription factor HIF1. Curcumin also blocked hypoxia-induced mRNA synthesis and secretion of VEGFA in GH3 cells and in all human pituitary adenoma cell cultures investigated (n=18). Thus, curcumin may inhibit pituitary adenoma progression not only through previously demonstrated anti-proliferative and pro-apoptotic actions but also by its suppressive effects on pituitary tumour neovascularisation.

Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the PKA regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto PKA activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated PKA pathway may be more efficiently targeted.