Both emerin and lamin C depend on lamin A for localization at the nuclear envelope. (57/605)

Physical interactions between lamins and emerin were investigated by co-immunoprecipitation of in vitro translated proteins. Emerin interacted with in vitro translated lamins A, B1 and C in co-immunprecipitation reactions. Competition reactions revealed a clear preference for interactions between emerin and lamin C. Structural associations between lamins and emerin were investigated in four human cell lines displaying abnormal expression and/or localisation of lamins A and C. In each cell line absence of lamins A and C from the nuclear envelope (NE) was correlated with mis-localisation of endogenous and exogenous emerin to the ER. In two cell lines that did not express lamin A but did express lamin C, lamin C as well as emerin was mis-localised. When GFP-lamin A was expressed in SW13 cells (which normally express only very low levels of endogenous lamin A and mis-localise endogenous emerin and lamin C), all three proteins became associated with the NE. When GFP-lamin C was expressed in SW13 cells neither the endogenous nor the exogenous lamin C was localised to the NE and emerin remained in the ER. Finally, lamins A and C were selectively eliminated from the NE of HeLa cells using a dominant negative mutant of lamin B1. Elimination of these lamins from the lamina led to the accumulation of emerin as aggregates within the ER. Our data suggest that lamin A is essential for anchorage of emerin to the inner nuclear membrane and of lamin C to the lamina.  (+info)

Localization of the endothelin system in aldosterone-producing adenomas. (58/605)

Endothelin-1 (ET-1) could play a role in the regulation of aldosterone secretion of the human adrenal gland. The presence of the endothelin-converting enzyme 1 (ECE-1) and ET-1 suggests that there is a local ET system in the adrenal cortex, but the in situ synthesis of ET-1 remains to be confirmed. The cellular distribution of the whole ET system was evaluated in 20 cases of aldosterone-producing adenomas. Polymerase chain reaction studies gave strong signals for ECE-1 mRNA and the mRNAs for endothelin type A (ET(A)) and B (ET(B)) receptors and faint signals for prepro-ET-1 mRNA. In situ hybridization showed ET(A) receptors scattered throughout the adenoma, in both secretory cells and vascular structures (score, +). There were more ET(B) receptors (score, ++), but they were restricted mainly to the endothelium. ECE-1 mRNA and protein were ubiquitous and abundant in secretory cells (score, +++) and vascular structures (score, ++); the enzyme was active on big ET-1. There was no prepro-ET-1 mRNA in the cortex, except in the thickened precapillary arterioles present in only 30% of the aldosterone-producing adenomas studied. ET-1 immunoreactivity was detected in vascular structures (score, +), probably bound to receptors, suggesting that ET-1 has an endocrine action. The low concentrations of ET-1 could also indicate that it acts in a paracrine-autocrine fashion to control adrenal blood flow. The discrepancy between the concentrations of ECE-1 and its substrate suggests that ECE-1 has another role in the adrenal secretory cells. Our data indicate that ET probably is not a primary cause of the development or maintenance of the adenoma.  (+info)

Scintigraphic patterns of adrenocortical carcinoma: morpho-functional correlates. (59/605)

OBJECTIVE: Adrenocortical scintigraphy has demonstrated clinical utility in the morpho-functional characterization of adrenal tumors. The aim of this study was to identify possible relationships between the scintigraphic pattern and endocrine and/or morphological data in a series of adrenocortical carcinomas. DESIGN AND METHODS: Twenty-one patients with adrenocortical carcinoma (11 nonfunctioning and 10 hormone-secreting) were investigated with 75Se-methyl-nor-cholesterol scintigraphy. Clinical, hormonal, radiological, and pathological data were analyzed. RESULTS: The adrenal mass showed no radiocholesterol uptake in 18 cases (11 nonfunctioning and 7 functioning lesions). Contralateral normal adrenal gland was visualized in all patients with nonfunctioning tumors, whereas classic bilateral nonvisualization was observed in the 7 cases with hyperfunctioning masses. Three patients with cortisol-producing carcinomas showed radiotracer uptake by the mass, without visualization of the contralateral gland. At histology, the tumors were shown to be undifferentiated adrenocortical carcinomas; they had an aggressive clinical behavior. CONCLUSIONS: Radiocholesterol scintigraphy has an important role in diagnosing adrenocortical carcinomas, which typically are not visualized. However, 30% of hypersecreting adrenocortical carcinomas show an atypical increased tracer uptake, not predictive of the biochemical and histological features of the tumor.  (+info)

Primary aldosteronism and malignant adrenocortical neoplasia. (60/605)

Our experience indicates that although adrenal carcinoma is not a common cause of primary aldosteronism, 4 to 5% of patients in a single large series may have a malignant adrenocortical tumor. The magnitude of the hypokalemia and the hyperaldosteronuria tends to be greater in patients with malignant tumors, but these patients cannot be clearly separated from those with benign tumors or hyperplasia on this basis. Patients who have malignant tumors may have no chemical evidence of adrenocortical dysfunction other than excessive aldosterone secretion. Finally, a good response to spironolactone for months does not exclude adrenal carcinoma as the cause of primary aldosteronism.  (+info)

Selection of patients and operative approach in primary aldosteronism. (61/605)

A system for discriminating between adrenal adenoma and hyperplasia based on the levels of aldosterone production, plasma renin concentration, severity of electrolyte disturbances, plasma aldosterone patterns during recumbency and after assuming erect posture, and 131I-19-iodocholesterol scan has been developed. Indicated for operation are patients with adenomas whose elevated blood pressure cannot be continuously controlled with usual doses of medication and patients with documented deterioration of target organ function. Adrenalectomy has been performed 83 times in 81 patients with a diagnosis of primary hyperaldosteronism. Results of excision of adrenal adenomas have been excellent with significant lowering of blood pressure in all cases and cure of hypertension in over 60%. Results of total or subtotal adrenalectomy for hyperplasia have been poor with almost all patients still requiring medication for hypertension. Adenomas have always been unilateral, and usually can be localized so that unilateral exploration is curative. Therefore, we have tried to distinguish preoperatively between adenoma and hyperplasia. Anterior transperitoneal adrenalectomy has been effective with few complications, and no postoperative hypercortisolism after unilateral adrenalectomy for adenoma. The unilateral extraperitoneal approach gives shorter morbidity and potentially fewer serious complications.  (+info)

Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. (62/605)

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P =.005). The phenotype Ki-67(-)p53(-)mdm-2(+)cyclinD1(-)Bcl-2(-)p21(-)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P =.01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.  (+info)

Maintenance of integrated proviral gene expression requires Brm, a catalytic subunit of SWI/SNF complex. (63/605)

We show here that murine leukemia virus-based retrovirus vector transgene expression is rapidly silenced in human tumor cell lines lacking expression of Brm, a catalytic subunit of the SWI/SNF chromatin remodeling complex, even though these vectors can successfully enter, integrate, and initiate transcription. We detected this gene silencing as a reduction in the ratio of cells expressing the exogenous gene rather than a reduction in the average expression levels, indicating that down-regulation occurs in an all-or-none manner. Retroviral gene expression was protected from silencing and maintained in Brm-deficient host cells by exogenous expression of Brm but not BRG1, an alternative ATPase subunit in the SWI/SNF complex. Introduction of exogenous Brm to these cells suppressed recruitment of protein complexes containing YY1 and histone deacetylase (HDAC) 1 and 2 to the 5'-long terminal repeat region of the integrated provirus, leading to the enhancement of acetylation of specific lysine residues in histone H4 located in this region. Consistent with these observations, treatment of Brm-deficient cells with HDAC inhibitors but not DNA methylation inhibitors suppressed retroviral gene silencing. These results suggest that the Brm-containing SWI/SNF complex subfamily (trithorax-G) and a complex including YY1 and HDACs (Polycomb-G) counteract each other to maintain transcription of exogenously introduced genes.  (+info)

Management of massive retroperitoneal hemorrhage from an adrenal tumor. (64/605)

Spontaneous massive retroperitoneal hemorrhage from an adrenal gland is a rare event. A thoughtful and meticulous approach to such a patient, with appropriate diagnostic studies, ICU and surgical care are essential for patient survival. In patients with active bleeding, angiographic embolization is a valuable adjunct to achieve hemostasis, to allow for further work-up of the adrenal tumor, and an improved subsequent oncologic resection. Hemodynamically unstable patients, however, may require supportive transfusions in the intensive care unit, potential embolization if deemed feasible, or urgent surgical exploration. If possible, however, the acute surgical removal of an adrenal tumor within a large retroperitoneal hematoma should be avoided, as under such conditions a proper oncologic resection may not be possible. The possibility of a pheochromocytoma must always be entertained. Early recognition and treatment of patients with presumed adrenal insufficiency may decrease patient morbidity and mortality.  (+info)