Federica Cioppi

Two Novel Mutations at Exon 8 of the Sequestosome 1 (SQSTM1) Gene in an Italian Series of Patients Affected by Paget's Disease of Bone (PDB)†

PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Pagets in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder.

Azidothymidine Induces Apoptosis and Inhibits Cell Growth and Telomerase Activity of Human Parathyroid Cancer Cells in Culture

Telomerase activity has been correlated to parathyroid carcinoma. Because its role in acquisition of a malignant phenotype by parathyroid cells is unclear, we treated telomerase‐positive cultured human parathyroid cancer cells with the telomerase inhibitor AZT, evaluating cell telomerase activity, cytotoxic effects, growth, and morphological changes. In vitro exposure of these cells to AZT correlated with inhibition of cell proliferation.

A patient with MEN1-associated hyperparathyroidism, responsive to cinacalcet

Background A 30-year-old woman with suspected multiple endocrine neoplasia type 1 (MEN1) was referred to our center in 2001 with primary hyperparathyroidism caused by a multiglandular parathyroid adenoma. The patient also had hyperprolactinemia caused by an anterior pituitary macroadenoma. The patient underwent a parathyroidectomy with autotransplantation of parathyroid fragments into the nondominant forearm, resulting in resolution of the primary hyperparathyroidism. MEN1 was confirmed by analysis of the MEN1 gene, which revealed a 1555insG frameshift mutation. In 2006 serum calcium and parathyroid hormone (PTH) levels were again found to be high.Investigations After parathyroidectomy in 2001, the patient underwent regular measurements of PTH levels from both forearms, of serum calcium, prolactin and phosphate levels, and of urinary calcium and phosphate levels. When serum calcium and PTH levels were found to be elevated in 2006, circulating PTH levels were similar in both forearms. Ultrasound scan and technetium-99m-labeled hexakis-2-methoxyisobutylisonitrile (99mTc MIBI) scintigraphy evidenced a metabolically active parathyroid nodule in the neck.Diagnosis Local recurrence of a parathyroid adenoma associated with MEN1.Management Because the patient refused a further operation, we decided to initiate pharmacological treatment with cinacalcet. After 1 month of therapy, serum calcium and PTH levels returned to normal. The patient has now been closely monitored for 1 year. During this time calcium and PTH levels remained normal, morphologically the parathyroid nodular lesion remained unchanged and cinacalcet was well tolerated without the occurrence of adverse events. Cinacalcet could represent an important pharmacological intervention in MEN1-associated primary hyperparathyroidism before surgery and in postsurgical recurrences.

ENETS Consensus Guidelines for the Management of Peritoneal Carcinomatosis from Neuroendocrine Tumors

ENETS Consensus Guidelines for the Management of Peritoneal Carcinomatosis from Neuroendocrine Tumors

Uteroglobin reverts the transformed phenotype in the endometrial adenocarcinoma cell line HEC‐1A by disrupting the metabolic pathways generating platelet‐activating factor

Uteroglobin, originally named blastokinin, is a protein synthesized and secreted by most epithelia, including the endometrium. Uteroglobin has strong anti‐inflammatory properties that appear to be due, at least in part, to its inhibitory effect on the activity of the enzyme phospholipase A2. In addition, recent experimental evidence indicates that uteroglobin exerts antiproliferative and antimetastatic effects in different cancer cells via a membrane receptor. The human endometrial adenocarcinoma cell line HEC‐1A does not express uteroglobin. Thus, we transfected HEC‐1A cells with human uteroglobin cDNA. The transfectants showed a markedly reduced proliferative potential as assessed by impaired plating efficiency as well as by reduced growth in soft agar. Cytofluorimetric analysis clearly indicated that in uteroglobin‐transfected cells the time for completion of the cell cycle was increased. We previously demonstrated that HEC‐1A cells actively synthesize platelet‐activating factor, one of the products of phospholipase A2 activity. In addition, we demonstrated that platelet‐activating factor stimulates the proliferation of these cells through an autocrine loop. In uteroglobin transfectants, the activity of phospholipase A2 and platelet‐activating factor acetyl‐transferase, which are involved in the synthesis of platelet‐activating factor, was significantly reduced compared with wild‐type and vector‐transfected cells (p < 0.05). Our results indicate that enforced expression of uteroglobin in HEC‐1A cells markedly reduced their growth potential and significantly impaired the synthesis of platelet‐activating factor, an autocrine growth factor for these cells. These data suggest that one possible mechanism for the recently observed antineoplastic properties of uteroglobin may be the inhibition of the synthesis of platelet‐activating factor. Int. J. Cancer 88:525–534, 2000.

Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database

ObjectiveThe aim of this study was to integrate European epidemiological data on patients with multiple endocrine neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management.MethodsClinical, familial and genetic data of patients with multiple endocrine neoplasia type 1, diagnosed, treated, and followed-up for a mean time of 11.3 years, in 14 Italian referral endocrinological centers, were collected, over a 3-year course (2011–2013), to build a national electronic database.ResultsThe Italian multiple endocrine neoplasia type 1 database includes 475 patients (271 women and 204 men), of whom 383 patients (80.6%) were classified as familial cases (from 136 different pedigrees), and 92 (19.4%) patients were sporadic cases. A MEN1 mutation was identified in 92.6% of familial cases and in 48.9% of sporadic cases. Four hundred thirty-six patients were symptomatic, presenting primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumors and pituitary tumors in 93, 53, and 41% of cases, respectively. Thirty-nine subjects, belonging to affected pedigrees positive for a MEN1 mutation, were asymptomatic at clinical and biochemical screening. Age at diagnosis of multiple endocrine neoplasia type 1 probands was similar for both familial and simplex cases (mean age 47.2 ± 15.3 years). In familial cases, diagnosis of multiple endocrine neoplasia type 1 in relatives of affected probands was made more than 10 years in advance (mean age at diagnosis 36.5 ± 17.6 years).ConclusionsThe analysis of Italian registry of multiple endocrine neoplasia type 1 patients revealed that clinical features of Italian multiple endocrine neoplasia type 1 patients are similar to those of other western countries, and confirmed that the genetic test allowed multiple endocrine neoplasia type 1 diagnosis 10 years earlier than biochemical or clinical diagnosis.

Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

The effects of an autocrine loop mediated by platelet-activating factor (PAF) in HEC-1A cells are reverted by uteroglobin

Platelet-Activating Factor (PAF), a proinflammatory phospholipid, is produced in high amount by endometrial cells both in basal conditions and following different stimulations”.”. In the same tissue, specilic PAF receptors have been demonstrated”. Several studies have suggested a role for PAF in implantation”, 5, although more recent evidences indicate a prominent role of this phospholipid in angiogenesis‘. We have studied PAF production, expression of PAF receptors and the role of PAF/PAF receptor system in growth processes in the human endometrial adenocarcinoma cell line HEC-lA, which was established by Kuramoto et al, in 1972’. Early studies performed by our group, demonstrated that HEC-lA cells are able to synthesize PAI?” at least through the remodelling pathway of PAF synthesis. Indeed, the activity of PAF acetyltransferase, the main enzyme involved in PAF synthesis through the remodelling pathway together J

Correction to: Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database

The original version of this article unfortunately contained a mistake in Table 2. The table 2 was truncated in the original publication. The full table 2 is given below.

Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database

PurposeMultiple endocrine neoplasia type 1 (MEN1) is caused by germline inactivating mutations of the MEN1 gene. Currently, no direct genotype–phenotype correlation is identified. We aim to analyze MEN1 mutation site and features, and possible correlations between the mutation type and/or the affected menin functional domain and clinical presentation in patients from the Italian multicenter MEN1 database, one of the largest worldwide MEN1 mutation series published to date.MethodsThe study included the analysis of MEN1 mutation profile in 410 MEN1 patients [370 familial cases from 123 different pedigrees (48 still asymptomatic at the time of this study) and 40 single cases].ResultsWe identified 99 different mutations: 41 frameshift [small intra-exon deletions (28) or insertions (13)], 13 nonsense, 26 missense and 11 splicing site mutations, 4 in-frame small deletions, and 4 intragenic large deletions spanning more than one exon. One family had two different inactivating MEN1 mutations on the same allele. Gastro-entero-pancreatic tumors resulted more frequent in patients with a nonsense mutation, and thoracic neuroendocrine tumors in individuals bearing a splicing-site mutation.ConclusionsOur data regarding mutation type frequency and distribution are in accordance with previously published data: MEN1 mutations are scattered through the entire coding region, and truncating mutations are the most common in MEN1 syndrome. A specific direct correlation between MEN1 genotype and clinical phenotype was not found in all our families, and wide intra-familial clinical variability and variable disease penetrance were both confirmed, suggesting a role for modifying, still undetermined, factors, explaining the variable MEN1 tumorigenesis.