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Anna Spada

Bio: Anna Spada is an academic researcher from University of Milan. The author has contributed to research in topics: Pituitary tumors & Acromegaly. The author has an hindex of 60, co-authored 322 publications receiving 12683 citations. Previous affiliations of Anna Spada include Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico.


Papers
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Journal ArticleDOI
31 Aug 1989-Nature
TL;DR: A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein α chain, αs, which results in the activation of adenylyl cyclase, which bypasses the cells' normal requirement for trophic hormone.
Abstract: A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s) The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone Amino acids substituted in the putative gsp oncogene identify a domain of G protein alpha-chains required for intrinsic ability to hydrolyse GTP This domain may serve as a built-in counter-part of the separate GTPase-activating proteins required for GTP hydrolysis by small GTP-binding proteins such as p21ras

1,342 citations

Journal ArticleDOI
01 Dec 1987-Nature
TL;DR: A profoundly altered Gs protein is found in a group of human growth hormone-secreting pituitary adenomas, characterized by high secretory activity and intracellular cyclic AMP levels.
Abstract: Gs and Gi are guanine nucleotide-binding, heterotrimer proteins that regulate the activity of adenylate cyclase, and are responsible for transferring stimulatory and inhibitory hormonal signals, respectively, from cell surface receptors to the enzyme catalytic unit. These proteins can be directly activated by agents such as GTP and analogues, fluoride and magnesium. Decreased amounts of Gs and Gi, and even the absence of Gs, have been described, whereas an altered Gs has been reported in a cultured cell line (UNC variant of S49 lymphoma cells), but has never been observed in human disease states. We have found a profoundly altered Gs protein in a group of human growth hormone-secreting pituitary adenomas, characterized by high secretory activity and intracellular cyclic AMP levels. In the membranes from these tumours no stimulation of adenylate cyclase activity by growth hormone-releasing hormone, by GTP or by fluoride was observed. Indeed, the last two agents caused an inhibition, probably mediated by Gi. In contrast, adenylate cyclase stimulation by Mg2+ was enormously increased. This altered pattern of adenylate cyclase regulation was reproduced when a cholate extract of the tumour membranes (which contains G proteins) was reconstituted with Gs-free, cyc- S49 cell membranes. Inasmuch as secretion from somatotrophic cells is known to be a cAMP-dependent function, the alteration of Gs could be the direct cause of the high secretory activity of the tumours in which it occurs.

490 citations

Journal ArticleDOI
TL;DR: Prisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.
Abstract: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively.

301 citations

Journal ArticleDOI
15 Mar 1979-Nature
TL;DR: It is reported here that in homogenates of human PRL adenomas, in which dopaminergic agonists act as inhibitors of PRL secretion, basal adenylate cyclase is inhibited by DA and the DA receptors mediating this inhibition have the same pharmacological properties as those regulatingPRL secretion.
Abstract: THERE is evidence for the existence of multiple forms of dopamine (DA) receptors1–3. In particular, some of these receptors are coupled to adenylate cyclase (DA-stimulating enzyme activity), whereas others seem to be independent3–5. These two classes of receptors, which have been designated D-1 and D-2, respectively, would also have different pharmacological properties3. Pituitary mammotroph DA receptors regulating prolactin (PRL) secretion are considered to be typical D-2 receptors. A DA-stimulated adenylate cyclase has not been detected in normal anterior pituitaries3,5,6; furthermore, several studies indicate that cyclic AMP is stimulatory and not inhibitory to PRL secretion7,8. We report here that in homogenates of human PRL adenomas, in which dopaminergic agonists act as inhibitors of PRL secretion, basal adenylate cyclase is inhibited by DA. The DA receptors mediating this inhibition have the same pharmacological properties as those regulating PRL secretion.

266 citations

Journal ArticleDOI
TL;DR: The results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.
Abstract: Somatic mutations in the α-chain (αs) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-rel...

265 citations


Cited by
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Journal ArticleDOI
21 Jul 1979-BMJ
TL;DR: It is suggested that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units, outpatients, and referrals to social services, but for house doctors to assess overdoses would provide no economy for the psychiatric or social services.
Abstract: admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

4,497 citations

Journal ArticleDOI
TL;DR: Target deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions and provide unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders.
Abstract: Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

3,433 citations

Journal ArticleDOI
10 Jan 1991-Nature
TL;DR: GTPases are conserved molecular switches, built according to a common structural design, and rapidly accruing knowledge of individual GTPases—crystal structures, biochemical properties, or results of molecular genetic experiments—support and generate hypotheses relating structure to function in other members of the diverse family of GTPase.
Abstract: GTPases are conserved molecular switches, built according to a common structural design. Rapidly accruing knowledge of individual GTPases--crystal structures, biochemical properties, or results of molecular genetic experiments--support and generate hypotheses relating structure to function in other members of the diverse family of GTPases.

3,236 citations

PatentDOI
13 Aug 2007-Science
TL;DR: In this paper, the authors analyzed 13,023 genes in 11 breast and 11 colorectal cancers and found that individual tumors accumulate an average of 90 mutant genes but only a subset of these contribute to the neoplastic process.
Abstract: Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

3,152 citations

Journal ArticleDOI
TL;DR: The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by gh Relin derived from the stomach, which plays important roles for maintaining GH release and energy homeostasis in vertebrates.
Abstract: Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it "ghrelin," after a word root ("ghre") in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

2,740 citations