1,721,008 research outputs found
Cabergoline plus lanreotide for ectopic Cushing's syndrome
No full textThis case documents the long-term effectiveness of combined treatment with a somatostatin analogue and a dopamine agonist in a patient who no longer had a response to either agent alone and supports the hypothesis that somatostatin and dopamine receptors interact and that somatostatin and dopamine agonists may potentiate actions
Somatostatin receptors: from basic science to clinical approach. Unlabeled somatostatin analogues-1: Prostate cancer
No full textNeuroendocrine cells have been found in all the stages of prostate cancer, but their clinical significance is not completely understood. Neuroendocrine cells are androgen receptor- and prostate-specific antigen-negative, do not proliferate, and secrete many neuropeptides, such as chromogranin A. Neuroendocrine differentiation of prostate cancer correlates with an advancing tumour stage, poor prognosis and tumour progression after androgen deprivation. Furthermore, neuroendocrine phenotype is associated with the increased expression of neo-angiogenesis and vascular endothelial growth factor and with an over-expression of survivin, a new anti-apoptosis protein. Chromogranin A is the quantitatively major secretory protein of the vesicles inside neuroendocrine prostate cells and it is the marker most frequently used to detect neuroendocrine features, both in tissues and in general circulation. Tumours displaying neuroendocrine phenotype tend to be more aggressive and resistant to hormone-therapy. Neuroendocrine differentiation seems to be a dynamic phenomenon: in vitro and in vivo data suggest that it can be induced by androgen suppression. Moreover, the differences in the expression of somatostatin receptors between primary and hormone-refractory prostate cancer are likely to be related to the changes in neuroendocrine phenotype during androgen deprivation. Circulating chromogranin A levels seem to be scarcely affected by endocrine- and chemotherapy, while they significantly decreased after treatment with somatostatin analogs
Natural variants of the β isoform of the human glucocorticoid receptor do not alter sensitivity to glucocorticoids
No full textThe β isoform of the human glucocorticoid receptor, hGRβ, is a product of alternative splicing of the hGR gene. The physiological function of this isoform is unknown up to now. Recent data are contradictory in that they either favor or argue against a role of hGRβ as a repressor of the functional hGRα isoform. In the present study hGRβ did not inhibit transcriptional activation of the MMTV-driven luciferase reporter gene by dexamethasone-activated hGRα in COS-1 cells. In addition, two naturally occurring variants of the hGRβ isoform associated with altered sensitivity to glucocorticoids, termed hGRβ-R23K and hGRβ-N363S, did not repress hGRα, even when overexpressed 10-fold. We conclude that the hGRβ isoform, as well as two of its natural variants, do not act as dominant negative inhibitors of hGRα function and that the β isoform does not appear to play a role in the regulation of glucocorticoid sensitivity
Clinical aspects of glucocorticoid sensitivity
No full textRecent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a 'safe' dose of glucocorticoid in individual patients. 'Resistance' to the beneficial clinical effects of glucocorticoid therapy in part of the patients with severe rheumatoid arthritis and asthma is probably rarely related to generalized primary (hereditary) glucocorticoid resistance. In the majority of patients this 'resistance' seems to be acquired and localized to the sites of inflammation, where it reflects high local cytokine production, which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance indicating as alternative drug therapy with other immune-modulating drugs like cyclosporin and methotrexate. Chronic high dose glucocorticoid treatment in such patients is ineffective in alleviating symptomatology, while generalized side effects occur, reflecting the patient's normal systemic sensitivity to these drugs
The role of somatostatin and somatostatin analogs in the pathophysiology of the human immune system.
No full textIn vivo and in vitro expression of somatostatin receptors in two human thymomas with similar clinical presentation and different histological features.
No full text[(111)In-DTPA0]octreotide scintigraphy allows the in vivo visualization of several types of SS receptor (SSR)-expressing tumors. Among these, thymomas have been recently detected. Here we report on 2 patients admitted for myasthenia gravis and radiological evidence of thymic mass. Although these patients had similar clinical presentation, in vivo SSR scintigraphy displayed a difference in the degree of the [(111)In-DTPA0]octreotide uptake. Considering that both thymic masses had comparable volume, [(111)In-DTPA0]octreotide level was significantly higher in one of the 2 tumors (tumor/background ratio of 5.7 vs 2.6). The SSR subtype expression pattern was studied in vitro on the surgically resected specimens by ligand binding techniques, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. According to the recent World Health Organization classification, the 2 tumors were classified A and B2 thymomas respectively. In membrane homogenates, we found a higher number of high affinity [125I-Tyr11]-SS-14 binding sites in the B2 thymomas (23.5+/-2.5 vs 12.0+/-0.4 fmol/mg membrane protein; p<0.05). RT-PCR analysis showed sst1, sst2A and sst3 mRNA in the 2 thymoma tissues, whereas SS mRNA was detectable only in the A thymoma. Quantitative evaluation of RT-PCR data showed a comparable expression of the relative amount of sst2A mRNA in both tumors, whereas a significant higher expression of sst3 mRNA in the B2 thymoma. Sst2A immunoreactivity was localized mainly on the endothelium of intratumoral vessels, whereas sst3 was present on either tumoral epithelial cells or normal reactive thymocytes. The expression of sst2A receptors in these tumors is in line with the in vivo visualization by [(111)In-DTPA0]octreotide, which is considered a sst2-preferring ligand. However, since radioligand uptake was significantly higher in the B2 thymoma, which expressed the largest sst3 mRNA levels, it might be possible that this subtype is involved in determining the tumor visualization during SSR scintigraphy. Apart from the affinity of the radioligand for the receptor, also the efficacy of the internalization of the radioligand-receptor complex might play a role in radioactivity accumulation during in vivo SSR scintigraphy. In fact, although octreotide binds with lower affinity to sst3 receptors, this subtype displayed the highest amount of agonist-dependent receptor internalization compared to the other SSR subtypes. Moreover, sst3 was localized on both tumor cells and reactive thymocytes, and these latter cells are characterized by a very active turnover of membrane molecules. Finally, although more cases need to be evaluated, the lack of detection of SS mRNA in the tumor presenting a more aggressive phenotype (B2 thymoma) might have physiopathological or prognostic significance
Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene
No full textCortisol resistance (CR) is a rare disease characterized by a generalized reduced sensitivity of end-organs to the actions of glucocorticoids (GCs). GC effects are mediated by the GC receptor (GR). The molecular alterations in CR described thus far were located in the hormone-binding domain of the GR gene. Recent reports of a considerable prevalence of abnormalities in the GR in patients attending the endocrine clinic prompted us to carry out further investigations with respect to GR protein and GR gene in patients attending the endocrine clinic for a broad spectrum of complaints and biochemical evidence suggesting a CR. In the present study, we describe five patients with biochemical and clinical CR. All patients showed a diurnal rhythm of serum cortisol concentrations (albeit at a high level), an insufficient suppression of serum cortisol concentration in reaction to 1 mg dexamethasone (DEX), and variable degrees of androgen overproduction, in the absence of clinical signs and symptoms of Cushing's syndrome. Three of the four female patients presented with complaints of androgen overproduction, two of them in combination with fatigue. The other female patient had severe steroid-resistant asthma. The only male patient and his son were asymptomatic. In four patients, we investigated receptor protein characteristics on mononuclear leukocytes in a whole cell DEX binding assay and studied the ability of DEX to inhibit mitogen-induced cell proliferation in mononuclear leukocytes in vitro. In all patients investigated, we found alterations in receptor number or ligand affinity and/or the ability of DEX to inhibit mitogen-induced cell proliferation. To investigate the molecular defects leading to the clinical and biochemical pictures in these patients, we screened the GR gene using PCR/single-strand conformational polymorphism/sequence analysis. No GR gene alterations were found in these patients. In conclusion, the five patients described had clinical and biochemical evidence of CR, but no abnormalities were demonstrated in the GR gene. Probably, as yet undefined alterations somewhere in the cascade of events starting with ligand binding to the GR protein, and finally resulting in the regulation of the expression of GC responsive genes, or postreceptor defects or interactions with other nuclear factors form the pathophysiologic basis of CR in these patients
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