Publications by authors named "Melmed S"

The aim of this study was to localize various growth factors and cytokines in paragangliomas and pheochromocytomas in order to understand their possible autocrine or paracrine functions, and to compare sustentacular cells of the adrenal medulla with pituitary stellate cells. Thirteen resected tumors, 11 paragangliomas and 2 pheochromocytomas of the adrenal medulla, were studied. In addition, five surgically removed nontumorous adrenals and five nontumorous pituitaries were studied.

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Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied.

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Proteasome inhibitors induce apoptosis in some malignant cells, and we show here that these inhibitors induce apoptosis in rat pituitary MMQ and GH3 tumor cells but not in normal pituitary cells. Three proteasome inhibitors, PSI, MG-132, and lactacystin, but not the calpain inhibitor, ALLM, dose- and time-dependently caused apoptosis in these cells, and 10 microM PSI caused apoptosis in 70% of MMQ cells and in 25% of GH3 cells within 24 h. A lower PSI dose (10 nM) inhibited GH3 cell growth without causing significant apoptosis or affecting prolactin secretion.

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Octreotide, a somatostatin analog used to treat acromegalic patients harboring a pituitary tumor, acts via somatostatin subtype 2 receptor (SSTR2) and causes significant decrease of circulating GH levels and sometimes mild to moderate tumor shrinkage. To further elucidate the mechanism of octreotide action, we studied GH and SSTR2 mRNAs by in situ hybridization in densely and sparsely granulated somatotroph adenomas removed by surgery from 14 treated and 14 untreated patients. Only in densely granulated adenomas were the GH and SSTR2 mRNA signals mildly decreased relative to untreated matched adenomas.

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The neuroendocrine and immune systems communicate bidirectionally. The neuro-immune-endocrine interface is mediated by cytokines acting as auto/paracrine or endocrine factors regulating pituitary development, cell proliferation, hormone secretion, and feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. At birth or during neonatal ontogenesis, cytokines produce permanent alterations of HPA axis function and the stress response.

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We have shown that leukemia inhibitory factor (LIF) and suppressor of cytokine signaling (SOCS)-3 are expressed in the hypothalamus and pituitary and that LIF induces proopiomelanocortin (POMC) and ACTH, whereas SOCS-3 abrogates corticotroph POMC gene transcription and ACTH secretion. Here, we determined the role of pituitary LIF and SOCS-3 in regulating hypothalamo-pituitary-adrenal (HPA) axis inflammatory responses. Murine pituitary LIF expression was induced up to eightfold after intraperitoneal injection of lipopolysaccharide or tumor necrosis factor-alpha, concordant with elevated plasma levels of ACTH and corticosterone.

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Pituitary hyperplasia and lactotroph replication are induced by estrogen. The product of the pituitary tumor transforming gene (PTTG) exhibits in vitro and in vivo transforming activity and induces basic bFGF secretion, thereby modulating pituitary angiogenesis and tumor formation. We demonstrated previously that pituitary pttg is induced by estrogen and bFGF, the latter being expressed in a concordant fashion with pttg in experimental and human pituitary adenomas.

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Background: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.

Methods: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months.

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In this study we show that activation of p38MAPK by IL-6 acts as an inhibitory signal on IL-6-mediated activation of STAT and the alpha2-macroglobulin promoter. We analyzed the role of MKK6/p38MAPK for IL-6 signal transduction and transcriptional activation of the suppressor of cytokine signaling (SOCS) 3 promoter. Pretreatment of cells with the p38MAPK-specific inhibitor SB202190 downregulates the induction of SOCS3-mRNA expression by IL-6.

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The hypothalamo-pituitary-adrenal (HPA) axis maintains a homeostatic response to stress, infection, or neoplasia. Inflammatory cytokines, including leukemia inhibitory factor (LIF), stimulate the HPA axis either directly at the pituitary corticotroph, or indirectly through induction of CRH or sympathetic noradrenergic neurons, and mediate the immuno-neuroendocrine interface. Unrestrained HPA axis activation leads, however, to immunosuppression.

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Tumorigenic pituitary tumor transforming gene (PTTG) is a mammalian homolog of Xenopus securin that inhibits chromatid separation, is overexpressed in many human tumor types, and mediates transcriptional activation. Loss of yeast securin Pds1p or Drosophila securin pimples is lethal. Here we show that mice lacking PTTG (PTTG -/-) are, surprisingly, viable and fertile; but they have testicular and splenic hypoplasia, thymic hyperplasia, and thrombocytopenia.

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Acromegaly.

Endocrinol Metab Clin North Am

September 2001

Acromegaly is a slow developing disease caused by hypersecretion of growth hormone and insulin-like growth factor 1. Increased morbidity and mortality associated with the disease make early diagnosis and treatment crucial. This article reviews the etiology, clinical manifestations, and diagnosis of acromegaly, with an emphasis on newly available therapeutic options.

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Pituitary tumors constitute 10% of intracranial neoplasms and are mostly benign, monoclonal adenomas derived from single mutant cells. Pituitary oncogenes have been intensively studied and three of them, gsp, ccnd1, and PTTG are abundant in significant numbers of cases. gsp is present in approximately 40% of Caucasian patients with GH-secreting tumors and results from a mutated, constitutively active alpha subunit of Gs protein.

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The hypothalamic peptide PRL-releasing peptide (PrRP) has recently been cloned and identified as a ligand of an orphan pituitary receptor that stimulates in vitro PRL secretion. PrRP also induces PRL release in rats in vivo, especially in normal cycling females. However, no information on the effects of PrRP in the human is available.

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Several members of the newly characterized family of suppressor of cytokine signaling (SOCS) proteins-such as SOCS-1, SOCS-3, and CIS-act as negative regulators of the cytokine-induced Jak-STAT signaling cascade. The expression of SOCS proteins is stimulated by a variety of cytokines and hormones in a tissue-specific manner. This article reviews our current understanding of SOCS proteins and their role as modulators of neuroimmunoendocrine functions, for example, in signaling of leptin, growth hormone, and prolactin, specially focusing on the impact of SOCS proteins on corticotroph leukemia inhibitory factor (LIF) signaling.

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Angiogenesis is a key determinant and rate-limiting step in tumor progression and metastatic spread. As pituitary tumor-transforming gene (PTTG) induces basic fibroblast growth factor (bFGF), we tested angiogenesis induced by conditioned medium (CM) derived from NIH-3T3 transfectants overexpressing wild-type human PTTG (WT-hPTTG-CM). We also examined the relationship between PTTG expression and tumor vascularity in a series of human tumors.

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Neuroendocrine ACTH secretion responds to peripheral inflammatory and stress signals. We previously demonstrated that the proinflammatory cytokine, leukemia inhibitory factor (LIF), affects the hypothalamo-pituitary-adrenal axis (HPA) by stimulating in vitro and in vivo pituitary proopiomelanocortin (POMC) gene expression and ACTH secretion and by potentiating the action of hypothalamic corticotropin releasing hormone (CRH). Whereas pathways shown thus far to regulate POMC expression exclusively involve cAMP or calcium, we here describe a direct and indirect STAT3-dependent regulation of POMC transcription by LIF.

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The pleiotropic cytokine leukemia inhibitory factor (LIF) is expressed in murine hypothalamus and pituitary and increases POMC gene transcription and ACTH secretion in vitro and in vivo. As hypothalamic pituitary adrenal (HPA) axis activation during inflammation is an important protective mechanism, we determined whether LIF stimulates the HPA inflammatory stress response. Two experimental models were employed: s.

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Acromegaly is generally caused by growth hormone (GH) hypersecretion from a benign, monoclonal pituitary adenoma. As in other neoplastic conditions, pituitary tumor formation and dysregulated hormone secretion are most likely the ultimate result of a series of genetic alterations. A number of molecular and biochemical defects have been associated with pituitary tumorigenesis.

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Leukemia inhibitory factor (LIF) is a pleiotropic, neuropoietic cytokine found in bovine, murine, and human fetal and adult pituitary cells, mostly in corticotrophs and somatotrophs. In addition, it has been found in a few GH- and ACTH-producing human pituitary adenomas. The aim of our study was to investigate the presence of LIF in various morphologic types of human pituitary adenomas.

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