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Marco Locatelli,
Stefano Ferrero,
Filippo Martinelli Boneschi,
Leonardo Boiocchi,
Mario Zavanone,
Sergio Maria Gaini,
Lorenzo Bello,
Sonia Valentino,
Elisa Barbati,
Manuela Nebuloni,
Alberto Mantovani,
Cecilia Garlanda
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ABSTRACT: Inflammation is a component of glioma microenvironment. PTX3 is a component of the humoral arm of innate immunity and a candidate marker of inflammation. In the present study we assessed the expression of PTX3 in gliomas by immunohistochemistry. PTX3 expression differed across low and high-grade tumors based on histopathological diagnosis and clinical severity, positively correlating with tumor grade and severity. In a multivariate logistic regression model, only the PTX3 score was significantly associated with the presence of a high-grade tumor. Thus, PTX3 may represent a new marker of cancer-related inflammation and glioma malignancy.
Journal of neuroimmunology 05/2013; · 2.84 Impact Factor
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ABSTRACT: BACKGROUND: Transphenoidal surgery is an effective treatment for acromegalic patients with growth hormone (GH) producing pituitary adenomas. Since acromegaly is a systemic disease which causes multiple bony alterations, we hypothesized that it could affect the sphenoid sinus anatomy. The aim of the study was to determine whether acromegalic patients have sphenoid sinus alterations with potential surgical impact. METHODS: Fourty-six consecutive patients (23 acromegalics-GH group, 23 non-acromegalics-nGH group) undergoing transphenoidal surgery were included in this study. Pre-operative volumetric CT scan of the head was used to assess the following anatomic characteristics: type of sphenoid sinus (sellar, pre-sellar, conchal); number of intrasphenoid septa; number of carotid-directed septa; intercarotid distance; depth of the sphenoid sinus; depth and size of the sella. RESULTS: The sphenoid sinus was of the pre-sellar/conchal type in 26 % of the patients with acromegaly (n = 23) versus 9 % of the patients of the nGH group (n = 23). The number of intrasphenoid septations was significantly higher in the GH group than in the nGH group (P = .03). Interestingly, the intercarotid distance was smaller in GH patients than in nGH displaying a trend toward significance (P = .05). The sphenoid bone was deeper in the GH group as compared to the nGH group (P = .01) but the distance sphenoid sinus-sella was reduced (P < .01). Finally, the sella was not deeper, nor larger in acromegalic patients. CONCLUSIONS: The sphenoid sinus of acromegalic patients resulted in being deeper, characterized by more septa and by a reduced intercarotid distance. These alterations deserve special pre- and intraoperative care, being potentially responsible for surgical difficulties.
Acta Neurochirurgica 11/2012; · 1.52 Impact Factor
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Gaia Giannicola,
Manuela Rosa,
Sara Marceglia,
Emma Scelzo,
Lorenzo Rossi,
Domenico Servello,
Claudia Menghetti,
Claudio Pacchetti,
Roberta Zangaglia, Marco Locatelli,
Elena Caputo,
Filippo Cogiamanian,
Gianluca Ardolino,
Sergio Barbieri,
Alberto Priori
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ABSTRACT: New adaptive systems for deep brain stimulation (DBS) could in the near future optimize stimulation settings online so as to achieve better control over the clinical fluctuations in Parkinson's disease (PD). Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) in PD patients show that levodopa and DBS modulate STN oscillations. Because previous research has shown that levodopa and DBS variably influence beta LFP activity (8-20 Hz), we designed this study to find out how they affect low-frequency (LF) oscillations (2-7 Hz). STN LFPs were recorded in 19 patients with PD during DBS, after levodopa medication, and during DBS and levodopa intake combined. We investigated the relationship between LF modulations, DBS duration and levodopa intake. We also studied whether LF power depended on disease severity, the patient's clinical condition and whether LF modulations were related to electrode impedances. LF power increased during DBS, after levodopa intake and under both experimental conditions combined. The LF power increase correlated with the levodopa-induced clinical improvement and the higher the electrode impedance, the greater was the LF power change. These data suggest that the LF band could be useful as a control neurosignal for developing novel adaptive DBS systems for patients with PD.
Neurosignals 04/2012; · 2.11 Impact Factor
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09/2011; , ISBN: 978-953-307-736-9
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ABSTRACT: Tumor-associated macrophages (TAMs) are key components of the tumor macroenvironment. Cancer- and host cell-derived signals generally drive the functions of TAMs towards an M2-like polarized, tumor-propelling mode; however, when appropriately re-educated. TAMs also have the potential to elicit tumor destructive reactions. Here, we discuss recent advances regarding the immunobiology of TAMs and highlight open questions including the mechanisms of their accumulation (recruitment versus proliferation), their diversity and how to best therapeutically target these cells.
European Journal of Immunology 09/2011; 41(9):2522-5. · 5.10 Impact Factor
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ABSTRACT: The endoscopic transnasal, transsphenoidal approach is considered by many a valid option to reach the sellar region and, in selected cases, to decompress the optic nerve. However, few data are available in literature about the real effectiveness of the procedure and the extent of nerve decompression needed to obtain a clinical result. The aim of this anatomical study was to describe the most important landmarks of the endoscopic transsphenoidal approach to the optic nerve.
Six silicone-injected cadaver heads were dissected via the endoscopic transnasal approach, performing a bilateral optic nerve decompression. The lateral optocarotid recess (OCR) and optic canal were identified in each case. Moreover, the relationship between the ophthalmic artery at its origin and the optic nerve was examined.
Twelve decompressions of the optic nerve were performed, obtaining the following measurements: intercarotid distance 12 mm ± 1.5, median length of OCR 5 mm ± 1 and average length of optic nerve decompression 15 mm ± 2. The ophthalmic artery was observed emerging from the internal carotid artery (ICA) medially in six cases, ventrally in four cases and laterally in two cases.
A wide optic nerve decompression may be obtained with transsphenoidal approach. However, the risk of ophthalmic artery injury seems to be more relevant than with supratentorial approaches, due to the intimate relationship between artery and nerve on its inferior surface. Knowledge of anatomical landmarks, such as lateral OCR and the position of the ophthalmic artery, is useful to prevent this injury.
Anatomia Clinica 04/2011; 33(3):257-62. · 0.93 Impact Factor
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ABSTRACT: Cavernous hemangioma are the most common benign lesions of the orbit. Their surgical resection is still challenging and several surgical approaches have been proposed.
We present the case of a 59-year-old woman with a cavernous hemangioma of the orbital apex, which was diagnosed incidentally. The hemangioma was extraconal and involved mainly the medial orbital apex; it also extended to the pterygoid fossa, to the middle fossa, to the maxillary and sphenoid sinuses. The surgical resection was performed by a pure endoscopic transphenoidal, transmaxillary, transethmoidal approach, achieving a total removal. The patient had a transient and incomplete paresis of the VI cranial nerve on the left side and did not experience other postoperative complications.
The endoscopic endonasal approach proved successful in the management of this case and it should be considered in the surgical management of extraconal orbital apex lesions with medial or inferior extension.
Surgical neurology international. 01/2011; 2:58.
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ABSTRACT: CX3CL1 or Fractalkine is a peculiar chemokine that can exist either in a soluble form, like all the other chemokines, and as a cell membrane molecule. CX3CL1 is one of the most expressed chemokines in the central nervous system, where it regulates the communication between neurons, glia and microglia. CX3CR1-expressing microglia may have an important role in limiting tissue injury during inflammation and neuro-degeneration. Recent evidence has implicated CX3CL1 and its cognate receptor CX3CR1 in cancer. Tumors of neural origin (glioma, neuroblastoma) express CX3CR1 which is involved in the adhesion, transendothelial migration and mobilization of tumor cells. In addition, tumors of non-neural origin, like prostate, pancreas and breast carcinoma express high levels of the CX3CR1 receptor. As for other chemokine receptors, CX3CR1 expression is associated with increased migration and site specific dissemination. In pancreatic cancer, receptor expression is involved in the perineural invasion and dissemination of neoplastic cells along intra- and extra-pancreatic nerves. This peculiar route of tumor spread is used also by other carcinomas (e.g. prostate, head and neck) and may represent a target for therapeutic intervention.
Journal of neuroimmunology 07/2010; 224(1-2):39-44. · 2.84 Impact Factor
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ABSTRACT: The chemokine receptor CX3CR1 and its cognate ligand CX3CL1 (also known as fractalkine), are involved in central nervous system pathophysiology, in particular, in the cross-talk between neurons and microglia. It was therefore important to investigate the expression of CX3CR1 in gliomas, the most frequently occurring, malignant brain tumors. In a consecutive series of 70 patients with primary, central nervous glial tumors, CX3CR1 was highly expressed in tumor cells as assessed by RT-PCR mRNA and protein levels, and by immunohistochemistry, while the corresponding normal cells were negative. Receptor immuno-positivity did not correlate with histology, grade, chromosomal (1p,19q) deletion, or with methylation of the DNA repair gene promoter MGMT (O6-methylguanine-DNA methyltransferase). Thus, CX3CR1 expression is a frequent event in gliomas, irrespective of tumor classification and clinical severity. The molecular basis underlying CX3CR1 up-regulation and its functional biological significance remain to be determined.
European cytokine network. 03/2010; 21(1):27-33.
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ABSTRACT: The study investigated the effects of the dopamine-somatostatin chimeric compound BIM-23A760 on cell proliferation and apoptosis in cultured cells from human non-functioning pituitary tumors (NFPTs). Both BIM-23A760 and the dopaminergic agonist BIM-53097 induced a significant inhibition of cell proliferation associated with increased p27 expression, together with a significant increase in caspase-3 activity. Conversely, null or marginal effects were elicited by somatostatin analogs. Moreover, BIM-23A760 and BIM-53097 induced ERK1/2 and p38 phosphorylation and the blockade of these pathways prevented both the antiproliferative and the pro-apoptotic effects of these drugs. In conclusions the chimeric compound BIM-23A760 is able to exert cytostatic and cytotoxic effects in NFPTs, these phenomena being mainly mediated by DR2D and involving ERK1/2 and p38 pathways activation.
Cancer letters 08/2009; 288(2):170-6. · 4.86 Impact Factor
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ABSTRACT: The orbitofrontal cortex (OFC) plays a major role in the pathophysiology of obsessive-compulsive disorder (OCD); functional neuroimaging studies indicate that OCD symptoms are associated with increased activity in the OFC, caudate nucleus, thalamus, and anterior cingulate gyrus. The goal of our single-blind study was to assess whether repetitive transcranial magnetic stimulation (rTMS) over the left OFC would influence OCD symptoms in drug-resistant patients.
Twenty-three consecutively admitted right-handed inpatients with DSM-IV-TR-diagnosed drug-resistant OCD were given rTMS (80% motor threshold, 1 Hz seconds per minute for 10 minutes every day for 15 days) to the left OFC parallel (active: n = 16) or perpendicular (sham: n = 7) to the scalp. The patients' OCD symptoms, mood, and anxiety were rated at baseline, at the end of treatment, and once every 2 weeks for 3 months after treatment. Data were gathered from June 2006 to November 2007.
Considering changes in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores with 2-way analysis of variance for repeated measures for a total of 8 observations (before rTMS, after treatment, and every 2 weeks for 12 weeks' follow-up), we found significant reduction of YBOCS scores comparing active versus sham treatment for 10 weeks after the end of rTMS (P < .02), with loss of significance after 12 weeks (P < .06). We also found a reduction of anxiety and depression symptoms but not a significant difference in the 2 groups.
Low-frequency rTMS of the left OFC produced significant but time-limited improvement in OCD patients compared to sham treatment.
The Primary Care Companion to The Journal of Clinical Psychiatry 01/2009; 11(5):226-30.
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Simona Mrakic-Sposta,
Sara Marceglia,
Marcello Egidi,
Giorgio Carrabba,
Paolo Rampini, Marco Locatelli,
Guglielmo Foffani,
Ettore Accolla,
Filippo Cogiamanian,
Filippo Tamma,
Sergio Barbieri,
Alberto Priori
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ABSTRACT: Intraoperative neuronal microrecordings can help in localizing the subthalamic nucleus (STN) during stereotactic neurosurgery for deep-brain stimulation (DBS) in Parkinson's disease. To obtain quantitative information on neuronal spike descriptors, we systematically analysed neuronal spikes in the STN and substantia nigra pars reticulata (SNr) in 31 sides of the brain in awake patients undergoing stereotactic neurosurgery for DBS electrode implantation. In these two structures we evaluated spike amplitude, area, duration, rise time and mean total firing rate. The recording spike density was higher in the STN than in the SNr (94% vs. 28%). Microelectrode recordings showed a larger spike area and amplitude in the SNr than in the STN ([mean+/-SD] amplitude: 46.7+/-31.1 vs. 36.3+/-29.6 microV; area: 25.6+/-24.2 vs. 36.7+/-21.4 microVmsec), a higher total firing rate at rest in the SNr than in the STN (78.6+/-53.5 vs. 61.9+/-40.8 Hz), and a longer duration and rise time in the SNr than in the STN (duration: 2.0+/-1 vs. 1.3+/-0.6 ms; rise time: 0.95+/-0.6 vs. 0.67+/-0.3 ms). Our analysis also revealed sex-related differences in the studied spike descriptors, paralleling recent findings from deep electroencephalography recordings. In the STN, males had larger spike area and amplitude (amplitude: 41.97+/-32.57 vs. 26.2+/-19.7 microV; area: 31.8+/-26.4 vs. 13.0+/-10.6 microVmsec), whereas females had higher mean total firing rate (66.7+/-53.4 vs. 82.8+/-50.8 Hz). Our results have implications for clinical practice and the development of algorithms for the neurophysiological identification of the STN during stereotactic neurosurgery for Parkinson's disease, based on the on-line automated computation of multiple spike-variables.
Journal of Clinical Neuroscience 06/2008; 15(5):559-67. · 1.25 Impact Factor
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Sara Bondioni,
Anita R Angioni,
Sabrina Corbetta, Marco Locatelli,
Stefano Ferrero,
Emanuele Ferrante,
Giovanna Mantovani,
Luca Olgiati,
Paolo Beck-Peccoz,
Anna Spada,
Andrea G Lania
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ABSTRACT: The dopamine receptor subtype 2 (D2R) promoter contains a functional retinoic acid response element involved in the control of D2R expression. The aim of the study was to evaluate the effect of 9-cis retinoic acid (9-cis RA) on D2R protein expression in human pituitary adenomas and GH3 cell line. Treatment with 9-cis RA (100 nM for 48 hrs) caused a 109 +/- 32% increase of basal D2R levels in five of eight growth hormone (GH)-secreting adenomas (GH-omas), a 129 +/- 28% increase in 7 of 11 nonfunctioning adenomas, and no effect in two resistant prolactinomas by Western blotting. The lack of D2R induction in some tumors was not associated with a different pattern of retinoid x receptor (RXR) and retinoic acid receptor (RAR) isoform expression that was similar in all tumors by immunohistochemistry. While the induction of D2R did not affect the slight but significant inhibitory effect exerted by dopamine (10 nM) on in vitro GH release by GH-oma cultured cells, in pituitary GH3 cell lines cis-9 RA enhanced the dopamine-induced inhibition of in vitro GH release (% inhibition: 16 +/- 2 versus 26 +/- 5, P < 0.05), cell proliferation (25 +/- 2% versus 44 +/- 5%, P < 0.05) and cell viability (16 +/- 0.8% versus 29 +/- 1%, P < 0.05), likely by activating caspase-3 (28 +/- 3% versus basal, P < 0.05). In conclusion, this study provides novel evidence for a permissive role of retinoids on the expression of D2R in a good proportion of pituitary tumors and on the generation of pro-apoptotic signals in GH3 cell line.
Experimental Biology and Medicine 04/2008; 233(4):439-46. · 2.64 Impact Factor
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ABSTRACT: To evaluate if timing of chemotherapy with Temozolomide (TMZ) was able to modify the outcome of glioblastoma (GBM), we analyzed two comparable series of supratentorial GBM patients, treated with surgery and radiotherapy, in which the administration of TMZ has been performed in the first group at first relapse and in the second group in newly diagnosed cases. The end-points were the median survival, the time tumor progression (TTP) and also the Karnofsky (KPS) scale and the Mini Mental State Examination (MMSE) scale at follow-up. From December 1999 to December 2001 30 patients with recurrent GBM received TMZ until progression. From January 2002 to January 2004 38 newly diagnosed patients received a first cycle of TMZ immediately after surgery, and additional cycles after completing radiotherapy until recurrence. In order to obtain a greater drug exposure we adopted a once-daily 10 days schedule of TMZ every 28 days as follows: 150 mg/m(2)/day (day 1-5) and 75 mg/m(2)/day (day 6-10). The first group had a median overall survival of 14 months and a median TTP of 6. The second group had a median survival of 16 months and a median TTP of 10. The difference of TTP was statistically significant (P < 0.001), while the overall survival was not. The values of KPS and MMSE at 12 months demonstrated a better quality of life in the second group (P < 0.01). Our regimen permitted to cover the therapeutic "window" between surgery and the beginning of radiotherapy in newly diagnosed cases and is well tolerated by the patients with limited side effects. We will propose as alternative option when the concomitant radio-chemotherapic protocol is not feasible.
Journal of Neuro-Oncology 08/2007; 84(1):71-7. · 3.21 Impact Factor
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ABSTRACT: We investigated gender-differences in clinical phenomenology and response to deep brain stimulation (DBS) of the subthalamic nucleus (STN) in a group of patients with advanced Parkinson's disease (PD). Thirty-eight consecutive patients with PD (22 men and 16 women), bilaterally implanted for DBS of the STN, were evaluated 1 month before and 11 to 14 months after surgery. Gender differences in severity of the disease (HY and UPDRS), ability in the activities of daily living (ADL, UPDRS II), tremor and rigidity (UPDRS III), bradykinesia (UPDRS III and hand tapping test), levodopa-induced dyskinesias (LIDs, UPDRS IV), and levodopa equivalent daily dosage (LEDD) were analyzed before and after intervention. We found a predominantly male population, with no gender-related differences in age at onset, disease progression rate, or severity of disease. Nevertheless, women had more severe LIDs than men, only before the intervention. Bradykinesia was significantly less responsive to any kind of treatment (pharmacologic and neurosurgical) in women than in men. Finally, although STN-DBS induced similar total benefits in both genders, postoperative assessment suggested that the ADL improved more in women than in men. Women and men with advanced PD appear to differ in some clinical features and in response to dopaminergic and STN-DBS treatment.
Movement Disorders 07/2007; 22(8):1150-6. · 4.51 Impact Factor
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ABSTRACT: Transsphenoidal surgery is currently the primary therapeutic option for Cushing's disease. Despite considerable initial success, 10-30% of patients fail to achieve lasting remission.
We evaluated a strategy of immediate reoperation in surgical failures judged by plasma cortisol levels that did not fall to 2 microg/dl or less within 72 h of surgery. Of 215 patients with presumed ACTH microadenomas, treated between 1993 and 2004, 12 met inclusion criteria and had prompt (within 15 d) reoperation for residual or missed ACTH microadenoma. These 12 patients represent 28% of those who did not have evidence of postoperative adrenal insufficiency.
Based on an outcome measure of sustained subnormal or normal plasma cortisol levels, eight of 12 patients (67%) achieved remission from the two operations. Adjunctive therapies (radiotherapy, gamma knife radiosurgery, and adrenalectomy) led to remission in another three patients. It is recognized that this outcome required either total hypophysectomy (one patient) or postoperative hypopituitarism (all patients in remission).
Magnetic resonance imaging was not usually helpful in determining therapeutic strategies; however, inferior petrosal sinus sampling was critical in providing confidence that the disease was of pituitary origin. A treatment algorithm is recommended, based on this study.
Journal of Clinical Endocrinology & Metabolism 10/2005; 90(9):5478-82. · 6.50 Impact Factor
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ABSTRACT: A grading system, called the Clinical-Radiological Grading System (CRGS), has been developed to standardize surgical indications in elderly patients harboring intracranial meningiomas. Patients with a score lower than 10 had a bad prognosis regardless of surgical treatment, those with a score between 10 and 12 had a prognosis positively influenced by surgery, and those with a score higher than 12 had a good prognosis regardless of surgical treatment. The authors performed a prospective cross-sectional study to validate further the use of the CRGS as a clinical tool to orientate surgical decision making in elderly patients and to explore prognostic factors of survival.
From 1990 to 2000 the authors consecutively recruited and surgically treated 90 patients 70 years of age or older with neuroimaging findings of intracranial meningiomas and a preoperative evaluation based on the CRGS. The surgical mortality rate, which covers deaths within 3 months after surgical intervention, was 7.8%, and the 1-year mortality rate was 15.6%. Female sex and a higher CRGS score were associated with a higher probability of survival. Among the different subset items of the CRGS score, no peritumoral edema for surgical survival and no concomitant diseases for 1-year survival provide the strongest predictive contribution, even if not at a statistically significant level.
The CRGS score is a useful and practical tool for the selection of elderly patients affected by intracranial meningiomas as surgical candidates. A CRGS score higher than 10 and female sex are good prognostic factors of survival. whereas age is not a contraindication to surgery.
Journal of Neurosurgery 03/2005; 102(2):290-4. · 2.96 Impact Factor
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ABSTRACT: Ghrelin, an endogenous ligand of the GH secretagogue receptor that exerts orexigenic activity, is negatively correlated with body mass index (BMI) and insulin resistance. Conversely, low levels of adiponectin (ApN), a circulating adipocytokine with antidiabetic, antiatherogenic and anti-inflammatory properties, have been found in several insulin-resistant conditions. Although Cushing's syndrome causes several metabolic and hormonal changes leading to insulin resistance and central obesity, few data concerning the impact of glucocorticoid excess on ghrelin and ApN levels are so far available.
We evaluated ghrelin and ApN levels in 14 women (age +/- SE 39.5 +/- 3.9 years, BMI +/- SE 25.8 +/- 1.4 kg/m2) with Cushing's disease (CD) at baseline and after successful transsphenoidal surgery (TSS) and in 14 age- and BMI-matched healthy women.
Despite similar levels of fasting glucose, insulin, homeostatic model assessment-estimated insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) values, patients with CD had ghrelin levels lower than controls (117.8 +/- 21.5 vs. 269.6 +/- 51.4 pmol/l, P < 0.01), and ghrelin levels did not correlate with ACTH, cortisol, androgen and GH levels. Patients and controls showed similar ApN levels (11.1 +/- 1.6 vs. 11.5 +/- 2.0 mg/l), which correlated negatively with insulin, HOMA-IR and BMI and positively with QUICKI and high density lipoprotein (HDL)-cholesterol only in controls. At 10.2 +/- 0.7 months after successful TSS, patients showed a significant increase in ghrelin levels compared to pretreatment values (342.5 +/- 25.6 vs. 117.8 +/- 21.5 pmol/l, P < 0.005) along with significant modifications in BMI, insulin, HOMA-IR and HDL-cholesterol and no change in ApN levels. In two patients tested on days 2-4 after TSS, no modification in ghrelin and ApN levels was observed, despite a dramatic reduction in cortisol levels.
Cortisol excess did not directly affect ghrelin and ApN levels in patients with CD. The observation that ghrelin levels were low during the active phase of CD and increased after recovery suggests that glucocorticoids may influence ghrelin levels indirectly by modulating adiposity and metabolic signals over the long term.
Clinical Endocrinology 02/2005; 62(1):30-6. · 3.17 Impact Factor
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Andrea G Lania,
Giovanna Mantovani,
Stefano Ferrero,
Caterina Pellegrini,
Sara Bondioni,
Erika Peverelli,
Paola Braidotti, Marco Locatelli,
Mario L Zavanone,
Emanuela Ferrante,
Silvano Bosari,
Paolo Beck-Peccoz,
Anna Spada
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ABSTRACT: The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By real-time PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.
Cancer Research 01/2005; 64(24):9193-8. · 7.86 Impact Factor
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ABSTRACT: Mutations of the Gsalpha gene inherited from the mother lead to pseudohypoparathyroidism (PHP) type Ia (PHP Ia), in which Albright's hereditary osteodistrophy is associated to resistance to the action of different hormones, whereas the same mutations inherited from the father lead to isolated Albright's hereditary osteodistrophy [pseudo-PHP (PPHP)]. Accordingly, it has been suggested that Gsalpha is under tissue-specific imprinting control, and recent studies provided evidence for a predominant maternal origin of Gsalpha transcripts in different endocrine organs involved in the PHP Ia phenotype. To establish whether Gsalpha is imprinted also in tissues that are site of alteration both in PHP Ia and PPHP, we selected 20 bone and 10 adipose tissue samples, which were heterozygous for a known polymorphism in exon 5. Expression from both parental alleles was evaluated by RT-PCR and enzymatic digestion of the resulting fragments. By this approach, the great majority of the samples analyzed showed an equal expression of the two alleles. Our results provide evidence for the absence of Gsalpha imprinting in human bone and fat and suggest that the clinical finding of osteodystrophy and obesity in PHP Ia and PPHP patients despite the presence of a normal Gsalpha allele is likely due to Gsalpha haploinsufficiency in these tissues.
Journal of Clinical Endocrinology & Metabolism 01/2005; 89(12):6316-9. · 6.50 Impact Factor
