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See detailStable GPR101 over-Expressing Cell Lines As an Invaluable Tool for Functional Studies, Ligand Screening, and the Identification of Deregulated Genes/Pathways in Patients with X-Linked Acrogigantism
Trivellin, Giampaolo; Janjic, Maria; Larco, Darwin et al

Poster (2017, April 02)

Background: GPR101 is an orphan G protein-coupled receptor (GPCR) that is duplicated in patients with X-linked acrogigantism (X-LAG) and over-expressed in their GH- and PRL-secreting tumors. GPR101 is a ... [more ▼]

Background: GPR101 is an orphan G protein-coupled receptor (GPCR) that is duplicated in patients with X-linked acrogigantism (X-LAG) and over-expressed in their GH- and PRL-secreting tumors. GPR101 is a constitutively active GPCR that strongly activates the cAMP pathway. To elucidate the mechanisms through which GPR101 causes GH over-secretion we generated HEK293 and GH/PRL-secreting (GH3) cells with stable GPR101 expression. Methods: Both cell lines were created via direct integration of a human GPR101-coding sequence into their genome. In HEK293 cells this was achieved by transient transfection of a GPR101-expressing plasmid, while GH3 were transduced with GPR101 lentiviral particles. Cells were selected with appropriate antibiotics and the surviving clones expanded. GPR101 expression was quantified by RT-qPCR and immunofluorescence/western blotting. Cell proliferation (MTT assay), cAMP levels (125I-labeled cAMP tracer), and calcium signaling (FURA 2 AM) were determined. RNA was extracted from both cell lines and subjected to RNA-seq. Differential gene expression between control and GPR101-expressing cells and pathway analysis was carried out with the Stirplate and MetaCore softwares, respectively. De-regulated genes were validated by RT-qPCR. Results: High GPR101 expression was achieved in both cell lines and confirmed at the mRNA and protein level. GPR101-expressing cells proliferated at different rates from the respective controls: GPR101-HEK293 cells were slow-dividing, while GPR101-GH3 divided faster. cAMP production was enhanced in GPR101-GH3 and accompained by increased excitability of cells. Differential expression analysis in HEK293 cells revealed several up-regulated and few down-regulated genes. Among the genes with high expression, several were linked to the cAMP pathway: CGA, PCK1, LINC00473 and PDE3A. Enrichment analysis ranked cytoskeleton remodeling and cell cycle regulation (inhibition of G1/S transition) as the most relevant pathways. In GH3 cells most of the genes with a significantly different expression encoded for membrane-localized proteins, among which were ion channels (Trpm8, Kcnj1), GPCRs (Trhr), and calcium sensors (Syt4, Anxa1). Biological processes associated with these genes are: vesicle transport and fusion, cytoskeleton organization, and energy homeostasis. Conclusions: These results show that the intrinsic activity of GPR101 strongly stimulates cAMP production and this in turn facilitates voltage-gated calcium influx. Changes in cAMP/calcium signaling are accompanied with faster/slower cell division depending on the cell type. Accordingly, several genes associated with these and related pathways are differentially expressed. The establishment of these cell lines will be of paramount importance to validate putative GPR101 ligands and to conduct functional studies. [less ▲]

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See detailThe dual SSTR2/5 specific somatostatin analog, AP102, does not affect glucose metabolism in diabetic ZDF rats: a comparative 14-day infusion study versus pasireotide
Daly, Adrian ULg; Sumeray, Mark

in Abstract Book of the 15th International Pituitary Congress (2017, March 29)

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See detailGenetics of Pituitary Tumor Syndromes
Daly, Adrian ULg; BECKERS, Albert ULg

in Melmed, Shlomo (Ed.) The Pituitary (2017)

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See detailPaleogenetic study of ancient DNA suggestive of X-Linked acrogigantism
Beckers, Albert ULg; Fernandes, Daniel; Fina, Frederic et al

in Endocrine-Related Cancer (2017)

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See detailSomatic mosaicism is implicated in the etiology of XLAG syndrome
Rostomyan, Liliya ULg; Daly, Adrian ULg; Yuan, Bo et al

in Abstract book : Symposium "Perspectives in Endocrinology" (2017, January)

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See detailGenetic predisposition to breast cancer occuring in a male-to-female transsexual patient
Potorac, Iulia ULg; CORMAN, Vinciane ULg; Manto, Florence ULg et al

in Abstract book : Symposium "Perspectives in Endocrinology" (2017, January)

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See detailA multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues
Franck, Sanne Elisabeth; Korevaar, Tim; PETROSSIANS, Patrick ULg et al

in European Journal of Endocrinology (2017)

Background: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and ... [more ▼]

Background: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. Objective: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). 188) were meta-analysed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n=83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. <0.001, p=<0.001, p=0.028 and p=0.047, respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of +/- 60 mg/week (21.3% within a range of +/- 20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (p=<0.001) and predicted this dosage correctly in 77.1% of all patients within a range of +/- 60 mg/week (31.3% within a range of +/- 20 mg/week). Conclusion: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose in order to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage. [less ▲]

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See detailTransdifferentiation of Neuroendocrine Cells: Gangliocytoma Associated With Two Pituitary Adenomas of Different Lineage in MEN1.
Sergeant, Camille; Jublanc, Christel; Leclercq, Delphine et al

in American Journal of Surgical Pathology (2017)

Gangliocytomas are rare and benign neuronal cell tumors, mostly found in the hypothalamic and sellar regions. Their histogenesis is still the subject of discussions. Herein we present a unique case of a ... [more ▼]

Gangliocytomas are rare and benign neuronal cell tumors, mostly found in the hypothalamic and sellar regions. Their histogenesis is still the subject of discussions. Herein we present a unique case of a pituitary gangliocytoma associated with a prolactinoma and a corticotroph adenoma in a patient affected by MEN1. The histologic study revealed shared features between adenomatous and neuronal cells, supporting the etiological hypothesis of a common origin or a phenomenon of transdifferentiation. Furthermore, gangliocytoma could be a new tumor related to MEN1. The clinical and histologic observations are discussed and the literature on the topic is reviewed. [less ▲]

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See detailThe role of AIP mutations in pituitary adenomas: 10 years on
Daly, Adrian ULg; BECKERS, Albert ULg

in Endocrine (2016)

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See detailProspective, long-term study of the effect of cabergoline on valvular status in patients with prolactinoma and idiopathic hyperprolactinemia.
VROONEN, Laurent ULg; Lancellotti, Patrizio ULg; Garcia, Monica Tome et al

in Endocrine (2016)

Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated ... [more ▼]

Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated in Parkinson's disease patients treated with dopamine agonists. Retrospective studies in prolactinoma patients treated with cabergoline at lower doses did not show such an effect. However, few prospective data with long-term follow-up are available. The aim of this study was to assess the safety of cabergoline regarding cardiac valvular status during prospective follow-up in patients treated for prolactinoma or idiopathic hyperprolactinemia. We report here a series of 100 patients (71F; median age at diagnosis: 41.5 years) treated with cabergoline for endocrine diseases (prolactinoma n = 89, idiopathic hyperprolactinemia n = 11). All patients underwent complete transthoracic echocardiographic studies at baseline and during long-term prospective surveillance using the same equipment and performed by the same technicians. The median interval between baseline and last follow-up echocardiographic studies while on cabergoline was 62.5 months (interquartile range: 34.75-77.0). The median total duration of cabergoline treatment was 124.5 months (interquartile range: 80.75-188.75) and the median cumulative total dose of cabergoline was 277.8 mg (interquartile range : 121.4-437.8 mg) at last follow-up. We found no clinically relevant alterations in cardiac valve function or valvular calcifications with cabergoline treatment. Our data suggest that findings from retrospective analyses are correct and that cabergoline is a safe chronic treatment at the doses used typically in endocrinology. [less ▲]

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See detailSomatic mosaicism is implicated in the etiology of XLAG syndrome
Rostomyan, Liliya ULg; Daly, Adrian ULg; Yuan, Bo et al

in 26nd meeting of the Belgian Endocrine Society - Abstract book (2016, October)

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See detailHypogonadism due to a novel inactivating mutation of the luteinizing hormone beta subunit (LHB) gene leading to impaired protein trafficking
Potorac, Iulia ULg; Rivero-muller, a; Trehan, A et al

in 26nd meeting of the Belgian Endocrine Society - Abstract book (2016, October)

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See detailT2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.
Potorac, Iulia ULg; PETROSSIANS, Patrick ULg; Daly, Adrian ULg et al

in Endocrine-Related Cancer (2016), 23(11), 871881

GH-secreting pituitary adenomas can be hypo-, iso- or hyperintense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the ... [more ▼]

GH-secreting pituitary adenomas can be hypo-, iso- or hyperintense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyperintense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypointense adenoma had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyperintense groups (p<0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypointense group (38%) compared with the T2-iso- and hyperintense groups (8% and 3%, respectively; p<0.0001). The response to SSA correlated with the calculated T2-intensity: the lower the T2-weighted intensity, the greater the decrease of random GH (p<0.0001, r=0.22), IGF-1 (p<0.0001, r=0.14) and adenoma volume (p<0.0001, r=0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with the hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly. [less ▲]

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See detailCharacterization of GPR101 transcripts structure and expression patterns
Trivellin, Giampaolo; Ivana, Bjelobaba; Daly, Adrian ULg et al

in Journal of Molecular Endocrinology (2016)

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See detailGenetic predisposition to breast cancer occurring in a male-to-female transsexual patient
Potorac, Iulia ULg; CORMAN, Vinciane ULg; Manto, Florence et al

Poster (2016, May)

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See detailMANAGEMENT OF ENDOCRINE DISEASE: Pituitary "incidentaloma": Neuroradiological assessment and differential diagnosis.
Vasilev, Vladimir; Rostomyan, Liliya ULg; Daly, Adrian ULg et al

in European Journal of Endocrinology (2016), 175(4), 171184

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See detailSomatic mosaicism underlies X-linked acrogigantism (XLAG) syndrome in sporadic male subjects
Daly, Adrian ULg; Yuan, Bo; Fina, Frederic et al

in Endocrine-Related Cancer (2016)

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric ... [more ▼]

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (N=18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (ddPCR) technique. Using a separate ddPCR technique we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism and identified one female gigantism patient that had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. [less ▲]

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