Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

Naïve pluripotent embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) represent distinctive developmental stages, mimicking the pre- and the post-implantation events during the embryo development, respectively. The complex molecular mechanisms governing the transition from ESCs into EpiSCs are orchestrated by fluctuating levels of pluripotency transcription factors (Nanog, Oct4, etc.) and wide-ranging remodeling of the epigenetic landscape. Recent studies highlighted the pivotal role of microRNAs (miRNAs) in balancing the switch from self-renewal to differentiation of ESCs. Of note, evidence deriving from miRNA-based reprogramming strategies underscores the role of the non-coding RNAs in the induction and maintenance of the stemness properties. In this review, we revised recent studies concerning the functions mediated by miRNAs in ESCs, with the aim of giving a comprehensive view of the highly dynamic miRNA-mediated tuning, essential to guarantee cell cycle progression, pluripotency maintenance and the proper commitment of ESCs.

Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson’s disease, addiction, depression, schizophrenia, and others. Despite advances in the understanding of specific altered proteins and coding genes, little is known about cumulative changes in the transcriptional landscape of noncoding genes in midbrain dopamine neurons. Noncoding RNAs—specifically microRNAs and long noncoding RNAs—are emerging as crucial post-transcriptional regulators of gene expression in the brain. The identification of noncoding RNA networks underlying all stages of dopamine neuron development and plasticity is an essential step to deeply understand their physiological role and also their involvement in the etiology of dopaminergic diseases. Here, we provide an update about noncoding RNAs involved in dopaminergic development and metabolism, and the related evidence of these biomolecules for applications in potential treatments for dopaminergic neurodegeneration.

The distinct clinical features of Giant Cell Tumor of Bone in pagetic and non-pagetic patients are associated with genetic, biochemical and histological differences The distinct clinical features of Giant Cell Tumor of Bone in pagetic and non-pagetic patients are associated with genetic, biochemical and histological differences

Giant Cell Tumour of Bone (GCT) is a locally aggressive primary bone tumour that usually occurs at the epiphyses of the long bones of the appendicular skeleton with a tendency to recurrence. Recurrent somatic H3F3A mutations have been described in 92% of GCT cases. GCTs involving the Clivus are extremely rare lesions and less than 15 cases are described in the literature. They represent a surgery challenge and are easily misdiagnosed. Our aim was to reveal if the genetic bases underlying Clival GCTs were the same of GCTs of long bones to improve the diagnosis and treatment. The targeted somatic sequencing of GCT-related genes (H3F3A, H3F3B, IDH1, IDH2 and ZNF687) was performed on Clival GCT biopsies of two different cases. Histological analyses on the same tissues were used to detect the neoplastic population and its expression profile. Sanger sequencing revealed that both patients were positive for the p.Gly34Trp mutation in the H3F3A gene. Immunofluorescence assay using monoclonal antibody, specifically detecting the mutant H3.3, highlighted that the mutation only involved the mononuclear cell population and not the multinucleated giant cells. Moreover, immunohistochemistry assay showed that RANKL was highly expressed by the stromal cells within Clival GCT, mimicking what happens in GCT of the long bones. In addition, systematic literature review allowed us to generate a histology-based diagnostic algorithm of the most common clival lesions. We conclude that the Clival GCT is genetically defined by somatic mutation in the H3F3A gene, linking it to the GCT of long bones. The similarity with GCTs of long bones let us to hypothesize the utility of Denosumab therapy (already effective for GCTs) in these surgically challenging cases. Moreover, H3F3A genetic screening can be combined to the histological analysis to differentiate GCTs from morphologically similar giant cell-rich sarcomas, while the histological diagnostic algorithm could help the differential diagnosis of other clival lesions.