Rossenhemmingsen8529

Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.Metastatic pheochromocytomas and paragangliomas are rare, highly vascular tumors that spread primarily to the lymph nodes, skeletal tissue, lungs, and liver. Tumor morbidity is related to their size, location, hormonal activity, vascular nature, and rate of progression. Systemic therapies for this indication are limited. Only high-specific-activity iodine-131 metaiodobenzylguanidine is approved in the Unites States for treatment of these patients, and not all patients are candidates for this radiopharmaceutical. Antiangiogenic medications are currently being evaluated in prospective clinical trials for patients with metastatic pheochromocytomas and paragangliomas, and preliminary results have been encouraging. Antiangiogenic medications frequently offer antineoplastic effects with sometimes durable responses. However, cardiovascular toxicity and the development of tumor resistance may limit their efficacy. Experience derived from clinical trials is being used to identify mechanisms to effectively improve drug toxicity and possibly prevent the emergence of resistance. Therefore, antiangiogenic medications represent a therapeutic option for patients with metastatic pheochromocytomas and paragangliomas. Furthermore, in the world of oncology, there is strong scientific interest in the development of clinical trials that combine antiangiogenic medications with other modalities such as immunotherapy, radiopharmaceuticals, and hypoxia inhibitors since these combinations may substantially enhance clinical outcomes, including survivorship. In this review, we examine the progress made to date on antiangiogenic treatments for patients with metastatic pheochromocytomas and paragangliomas.Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.Many solid tumors metastasize to bone, but only prostate cancer has bone as a single, dominant metastatic site. Recently, the FGF axis has been implicated in cancer progression in some tumors and mounting evidence indicate that it mediates prostate cancer bone metastases. The FGF axis has an important role in bone biology and mediates cell to cell communication. Therefore, we discuss here basic concepts of bone biology, FGF signaling axis and FGF axis function in adult bone, to integrate these concepts in our current understanding of the role of FGF axis in bone metastases.Patients with pituitary tumours, ensuing hormonal abnormalities and mass effects are usually followed in multidisciplinary pituitary clinics and can represent a management challenge even during times of non-pandemic. The COVID-19 pandemic has put on hold routine medical care for hundreds of millions of patients around the globe, while many pituitary patients' evaluations cannot be delayed for too long. Furthermore, the majority of patients with pituitary tumours have co-morbidities potentially impacting the course and management of COVID-19 (e.g. click here hypopituitarism, diabetes mellitus, hypertension, obesity, cardiovascular disease). Here, we summarize some of the diagnostic and management dilemmas for these patients, and we provide guidance on safe and as effective as possible delivery of care in the COVID-19 era. We also attempt to address how pituitary services should be remodelled in the event of similar crises, while maintaining or even improving patient outcomes. Regular review of these recommendations and further adjustments are needed, depending on the evolution of the COVID-19 pandemic status. We consider that utilization of successful models of pituitary multidisciplinary care implemented during the COVID-19 pandemic should continue after the crisis is over by using the valuable and exceptional experience gained during these challenging times.Summary Familial hypomagnesemia with secondary hypocalcemia (FHSH) is a rare autosomal recessive disorder (OMIM# 602014) characterized by profound hypomagnesemia associated with hypocalcemia. It is caused by mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6). It usually presents with neurological symptoms in the first months of life. We report a case of a neonate presenting with recurrent seizures and severe hypomagnesemia. The genetic testing revealed a novel variant in the TRPM6 gene. The patient has been treated with high-dose magnesium supplementation, remaining asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to prevent irreversible neurological damage. Learning points Loss-of-function mutations of TRPM6 are associated with FHSH. FHSH should be considered in any child with refractory hypocalcemic seizures, especially in cases with serum magnesium levels as low as 0.2 mM. Normocalcemia and relief of clinical symptoms can be assured by administration of high doses of magnesium.