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- Jernberg, Emma, et al.
(författare)
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Clinical relevance of androgen receptor alterations in prostate cancer
- 2017
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Ingår i: Endocrine Connections. - 2049-3614. ; 6:8, s. R146-R161
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Forskningsöversikt (refereegranskat)abstract
- Prostate cancer (PC) remains a leading cause of cancer-related deaths among men worldwide, despite continuously improved treatment strategies. Patients with metastatic disease are treated by androgen deprivation therapy (ADT) that with time results in the development of castration-resistant prostate cancer (CRPC) usually established as metastases within bone tissue. The androgen receptor (AR) transcription factor is the main driver of CRPC development and of acquired resistance to drugs given for treatment of CRPC, while a minority of patients have CRPC that is non-AR driven. Molecular mechanisms behind epithelial AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intra-tumoural and adrenal androgen synthesis and promiscuous AR activation by other factors. This review will summarize AR alterations of clinical relevance for patients with CRPC, with focus on constitutively active AR variants, their possible association with AR amplification and structural rearrangements as well as their ability to predict patient resistance to AR targeting drugs. The review will also discuss AR signalling in the tumour microenvironment and its possible relevance for metastatic growth and therapy.
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| 4. |
- Koffert, Jukka, et al.
(författare)
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Effects of meal and incretins in the regulation of splanchnic blood flow
- 2017
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Ingår i: Endocrine Connections. - 2049-3614. ; 6:3, s. 179-187
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Meal ingestion is followed by a redistribution of blood flow (BF) within the splanchnic region contributing to nutrient absorption, insulin secretion and glucose disposal, but factors regulating this phenomenon in humans are poorly known. The aim of the present study was to evaluate the organ-specific changes in BF during a mixed-meal and incretin infusions. Design: A non-randomized intervention study of 10 healthy adults to study splanchnic BF regulation was performed. Methods: Effects of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) infusions and mixed-meal were tested in 10 healthy, glucose tolerant subjects using PET-MRI multimodal imaging technology. Intestinal and pancreatic BF and blood volume (BV) were measured with 15O-water and 15O-carbon monoxide, respectively. Results: Ingestion of a mixed-meal led to an increase in pancreatic and jejunal BF, whereas duodenal BF was unchanged. Infusion of GIP and GLP-1 reduced BF in the pancreas. However, GIP infusion doubled blood flow in the jejunum with no effect of GLP-1. Conclusion: Together, our data suggest that meal ingestion leads to increases in pancreatic BF accompanied by a GIP-mediated increase in jejunal but not duodenal blood flow.
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- Lundqvist, Anette, et al.
(författare)
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The relationship between weight gain during pregnancy and allopregnanolone levels : a longitudinal study
- 2017
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Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 6:4, s. 253-259
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Large weight gain during pregnancy is a risk factor for complications for mother and fetus. Hunger and satiety are regulated in the hypothalamus, where the gamma-amino-butyric acid system (GABA) has an important role. Allopregnanolone, a progesterone metabolite, increases during pregnancy and is a potent GABA-A receptor modulating steroid. Allopregnanolone has been shown to induce overeating in rodents. The aim was to investigate whether there is a relationship between weight gain and allopregnanolone concentrations during pregnancy in humans. Design: A longitudinal, cohort study. Methods: Pregnant women (n = 56) were recruited in primary care in northern Sweden. Allopregnanolone concentrations in plasma were measured using radioimmunoassay and weight was measured in gestational weeks 12 and 35. Results: Weight increase correlated significantly to allopregnanolone in late pregnancy increase (r(s) = 0.320; P = 0.016), indicating a positive relationship between weight increase and allopregnanolone increase. A positive relationship was also noted between allopregnanolone in the 35th gestational week and weight increase. Women who gained = 11 kg during pregnancy showed higher allopregnanolone concentrations in week 35 and higher increase compared to women who increased < 11 kg (P = 0.006 and P = 0.009 resp.). There was no difference in weight or allopregnanolone concentrations at the onset of pregnancy. Conclusions: The results show a relationship between weight gain during pregnancy and increase in allopregnanolone concentrations.
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- Oleröd, Göran, et al.
(författare)
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The variation in free 25-hydroxy vitamin D and vitamin D-binding protein with season and vitamin D status.
- 2017
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Ingår i: Endocrine connections. - 2049-3614. ; 6:2, s. 111-120
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Tidskriftsartikel (refereegranskat)abstract
- Serum 25-hydroxy vitamin D [25(OH)D] varies greatly with season at northern latitudes. The purpose of this study was to determine if the seasonal variations in serum total 25(OH)D are followed by a concomitant variation in free 25(OH)D or if the variation is damped by alterations in the binding capacity of DBP.Serum was collected from 540 healthy blood donors (60% men; mean age 41 ± 13 years) during 12 months and analyzed for total 25(OH)D, directly measured free 25(OH)D, vitamin D-binding protein (DBP) and albumin. Calculated free 25(OH)D was estimated.The UV-B radiation during the sampling month was positively correlated with the serum levels of total 25(OH)D (r = 0.355,P < 0.001), directly measured free (r = 0.336,P < 0.001) and calculated free 25(OH)D (r = 0.275,P < 0.001), but not with DBP and albumin. The percentage of free 25(OH)D was higher during the winter months than that during the summer months (0.020 ± 0.005% vs 0.019 ± 0.004%;P = 0.007) and higher in participants with a serum 25(OH)D below 25 nmol/L than that in participants with a serum 25(OH)D above 75 nmol/L (0.031 ± 0.007% vs 0.017 ± 0.003%;P < 0.001). iPTH was correlated with directly measured free 25(OH)D (r = -0.226;P < 0.001), but only weakly with calculated free 25(OH)D (r = -0.095;P = 0.027).Directly measured free serum 25(OH)D was highly correlated with total serum 25(OH)D and followed the same seasonal variation, whereas the serum concentrations of DBP and albumin were stable. The fluctuation in free 25(OH)D was only marginally damped with an increase in the percentage of free 25(OH)D during the winter months and in participants with vitamin D deficiency.
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- Paschou, Stavroula A, et al.
(författare)
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On type 1 diabetes mellitus pathogenesis
- 2017
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Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614.
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of β cells of the endocrine pancreas. Pathogenesis of type 1 diabetes mellitus is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the β cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy β cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occurs after a long latency period, which reflects the large percentage of β cells that need to be destroyed before overt diabetes become evident.
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- Quinkler, Marcus, et al.
(författare)
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Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency
- 2017
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Ingår i: Endocrine Connections. - : BIOSCIENTIFICA LTD. - 2049-3614. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). Design/methods: EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3-6 mg/day, n = 50) or hydrocortisone (15-30 mg/day, n = 909) were identified and grouped at a ratio of 1: 3 (prednisolone: hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. Results: Significantly higher mean +/- s. d. total (6.3 +/- 1.6 vs 5.4 +/- 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 +/- 1.4 vs 3.2 +/- 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. Conclusions: This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group.
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| 10. |
- Ullsten, Sara, et al.
(författare)
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Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.
- 2017
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Ingår i: Endocrine Connections. - : BIOSCIENTIFICA LTD. - 2049-3614. ; 6:7, s. 458-468
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Tidskriftsartikel (refereegranskat)abstract
- Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.
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