The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

Inactivating germline mutations of the CDKN1B gene encoding the nuclear cyclin-dependent kinase inhibitor P27kip1 protein have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to characterize in vitro the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by primary hyperparathyroidism due to multiglandular parathyroid involvement and gastro–entero–pancreatic tumors. We carried out subcellular localization experiments by transfection with plasmid vectors expressing the WT or mutant CDKN1B cDNA into the eukaryotic human cervix adenocarcinoma (HeLa) and GH3 cell lines. Results from western blotting studies indicated that fusion proteins were expressed at equal levels. The mutated protein was shorter compared with the WT protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells, WT P27 localized in the nucleus, whereas the P27_S125X protein was retained in the cytoplasm, predicting the loss of tumor-suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, because both WT and mutant alleles were determined to be present by sequencing the somatic DNA. Immunohistochemistry revealed a complete loss of nuclear expression of P27 in a parathyroid adenoma, which had been removed by the second surgery in the patient. In conclusion, our results confirm the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.

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The prevalence of T1DM autoantibodies in FDRs of T1DM patients was very high (11.9%) in the Sardinian population, higher than in other populations from the United States and Europe, and similar to that observed in Finland. Autoantibody positivity strongly associated with HLA risk. This study provides evidence of the high risk of T1DM in FDR of T1DM patients in Sardinia and warrants longitudinal follow-up to estimate the risk of progression to T1DM in high-risk populations.

University students’ mental health has become a public health issue since increasingly students report high levels of psychological distress. Mental health difficulties influence students’ lives, such as academic performance, relationships satisfaction, and quality of life. Moreover, different kinds of obstacles often hinder help-seeking behavior. Such evidence strongly suggests the need to implement prevention and promotion strategies to increase health and well-being in educational contexts. This article presents a study protocol for implementing and evaluating NoiBene, an evidence-based group intervention that aims to promote mental health and well-being, improve a series of transversal competencies (e.g., emotional awareness, commitment to values, assertiveness, goal setting), and decrease dysfunctional transdiagnostic mechanisms (i.e., perfectionism, repetitive thinking, experiential avoidance). A randomized controlled trial will be conducted to evaluate the protocol’s efficacy. Participants will be assigned to one of the three conditions: the NoiBene Group condition (NB-G), the NoiBene guided web-based condition (NB-WB), or the waiting list condition (WLC). The NB-G intervention consists of six face-to-face group meetings, each dedicated to specific issues related to well-being or vulnerabilities. Every meeting includes an explanation of the theoretical contents, individual and group exercises, and role-plays. The NB-WB intervention covers the same topic addressed in the NB-G intervention. In this case, participants carry out a series of online modules, including theoretical explanations, practical exercises, useful activities, and self-monitoring tools. Students will individually meet the Tutor once every 2 weeks. The primary outcome will include an increase in mental health and well-being. Secondary outcomes will include changes in emotional awareness, assertiveness, perfectionism, rumination, worry, self-criticism, experiential avoidance, and academic performance and satisfaction. We expect that participants in both NoiBene conditions will show these outcomes. However, we hypothesized that the NB-G conditions will be more effective than the NB-WB in improving assertiveness. Besides treatment efficacy, we expect that students can benefit from the NB-G or NB-WB differently based on their specific behavioral and motivational patterns. Outcomes will be assessed at pre-, post-intervention and 6-months follow-up. In conclusion, we believe that NoiBene is a promising tool that can improve students’ well-being, and it could have positive implications for preventing mental health disorders among students.