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Osteoclasts are highly specialized cells of the bone, with a unique apparatus responsible for resorption in the process of bone remodeling. They are derived from differentiation and fusion of hematopoietic precursors, committed to form mature osteoclasts in response to finely regulated stimuli produced by bone marrow–derived cells belonging to the stromal lineage. Despite a highly specific function confined to bone degradation, emerging evidence supports their relevant implication in bone tumors and metastases. In this review, we summarize the physiological role of osteoclasts and then focus our attention on their involvement in skeletal tumors, both primary and metastatic. We highlight how osteoclast-mediated bone erosion confers increased aggressiveness to primary tumors, even those with benign features. We also outline how breast and pancreas cancer cells promote osteoclastogenesis to fuel their metastatic process to the bone. Furthermore, we emphasize the role of osteoclasts in reactivating dormant cancer cells within the bone marrow niches for manifestation of overt metastases, even decades after homing of latent disseminated cells. Finally, we point out the importance of counteracting tumor progression and dissemination through pharmacological treatments based on a better understanding of molecular mechanisms underlying osteoclast lytic activity and their recruitment from cancer cells.

MicroRNAs (miRNAs) were shown to be important for pancreas development, yet their roles in differentiated β‐cells remain unclear. Here, we show that miRNA inactivation in β‐cells of adult mice results in a striking diabetic phenotype. While islet architecture is intact and differentiation markers are maintained, Dicer1‐deficient β‐cells show a dramatic decrease in insulin content and insulin mRNA. As a consequence of the change in insulin content, the animals become diabetic. We provide evidence for involvement of a set of miRNAs in regulating insulin synthesis. The specific knockdown of miR‐24, miR‐26, miR‐182 or miR‐148 in cultured β‐cells or in isolated primary islets downregulates insulin promoter activity and insulin mRNA levels. Further, miRNA‐dependent regulation of insulin expression is associated with upregulation of transcriptional repressors, including Bhlhe22 and Sox6. Thus, miRNAs in the adult pancreas act in a new network that reinforces insulin expression by reducing the expression of insulin transcriptional repressors. A pancreatic β‐cell‐specific knockout of Dicer with a diabetic phenotype reveals critical roles for specific miRNAs in the regulation of insulin expression.

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC. Patients with primary sclerosing cholangitis (PSC) harboring Klebsiella pneumoniae (Kp) exhibit poor clinical outcomes. Here, the authors show that administration of a phage cocktail targeting PSC-derived Kp reduces bacterial burden in Kp-colonized mice and alleviates liver injury.

The serum or plasma microRNA (miRNA) molecules have been suggested as diagnostic and prognostic biomarkers, in various pathological conditions. However, these molecules are also found in different serum fractions, such as exosomes and Argonaute (Ago) protein complexes. Ago1 is the predominant Ago protein expressed in heart tissue. The objective of the study was to examine the hypothesis that Ago1‐associated miRNAs may be more relevant to cardiac disease and heart failure compared with the serum. In total, 84 miRNA molecules were screened for their expression in the whole serum, exosomes and Ago1, and Ago2 complexes. Ago1‐bound miR‐222‐3p, miR‐497‐5p and miR‐21‐5p were significantly higher, and let‐7a‐5p was significantly lower in HF patients compared with healthy controls, whereas no such difference was observed for those markers in the serum samples among the groups. A combination of these 4 miRNAs into an Ago1‐HF score provided a ROC curve with an AUC of 1, demonstrating clear discrimination between heart failure patients and healthy individuals. Ago1 fraction might be a better and more specific platform for identifying HF‐related miRNAs compared with the whole serum.

A review of the literature shows that the model for the Unified Theory of Acceptance and Use of Technology (UTAUT) has received only limited validation in educational contexts. This limitation led to this study to determine the applicability of the UTAUT model with an educational perspective and to statistically explain the factors affecting student teachers' intentions to use interactive whiteboards. The research project comprised a cohort of 159 student teachers who undertook a questionnaire designed to measure their responses to performance expectancy, effort expectancy, social influence, facilitating condition and behavioural intention. Structural equation modelling was used as the main technique for data analysis. According to the result of the goodness-of-fit test, the findings led to the conclusion that the model was endorsed by the data. Overall, the model accounted for 59.6 % of the variance in intention of student teachers to use interactive whiteboards in their teaching. The findings also demonstrated the important distinction of performance expectancy, effort expectancy and user's experiences in interactive whiteboard adoption amongst student teachers. The theoretical and practical implications of the model are discussed.

In-vitro expansion of β cells from adult human pancreatic islets could provide abundant cells for cell replacement therapy of diabetes. However, proliferation of β-cell-derived (BCD) cells is associated with dedifferentiation. Here we analyzed changes in microRNAs (miRNAs) during BCD cell dedifferentiation and identified miR-375 as one of the miRNAs greatly downregulated. We hypothesized that restoration of miR-375 expression in expanded BCD cells may contribute to their redifferentiation. Our findings demonstrate that overexpression of miR-375 alone leads to activation of β-cell gene expression, reduced cell proliferation, and a switch from N-cadherin to E-cadherin expression, which characterizes mesenchymal-epithelial transition. These effects, which are reproducible in cells derived from multiple human donors, are likely mediated by repression of PDPK1 transcripts and indirect downregulation of GSK3 activity. These findings support an important role of miR-375 in regulation of human β-cell phenotype, and suggest that miR-375 upregulation may facilitate the generation of functional insulin-producing cells following ex-vivo expansion of human islet cells.

This study evaluated the epidemiology and seasonal patterns of respiratory viruses in adults hospitalized with acute respiratory tract infections during two consecutive post-COVID-19 pandemic seasons. A retrospective study was conducted at the University Hospital “P. Giaccone”, Palermo, from September 2022 to September 2024. Multiplex molecular assays were used to detect the ten respiratory viruses most relevant from an epidemiological perspective in respiratory samples (n = 1110) of 1081 patients. A respiratory viral infection was identified in 29.6% of patients. The highest viral infection rate was observed in the 31–50 age group. Human rhinovirus/enterovirus (HRV/EV) was the most frequently detected (40%), followed by influenza A virus (IAV; 18.4%) and human coronaviruses (HuCoVs; 12.8%). Viral co-infections were identified in 10.9% of positive cases, with HRV/EV, adenovirus (ADV), and parainfluenza virus (PIV) being most frequently involved. Influenza and respiratory syncytial viruses (RSVs) showed a winter seasonality, while diverse circulation patterns were revealed for the other viruses. This study demonstrated a sustained circulation of respiratory viruses in adults hospitalized with severe respiratory symptoms, with HRV/EV accounting for most of them. Syndromic multiplex molecular testing, although limited to the detection of a small fraction of epidemiologically relevant known viruses, has proven to be a valuable tool, not only for diagnostic purposes but also for acquiring genotyping data and implementing epidemiological information from sentinel surveillance systems.

Paget’s disease (PDB) is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications. One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene. Although the genetic involvement of ZNF687 in PDB has been extensively studied, the molecular mechanisms underlying this association remain unclear. Here, we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype, resulting in severely altered bone remodeling. Through microcomputed tomography analysis, we observed that 8-month-old mutant mice showed a mainly osteolytic phase, with a significant decrease in the trabecular bone volume affecting the femurs and the vertebrae. Conversely, osteoblast activity was deregulated, producing disorganized bone. Notably, this phenotype became pervasive in 16-month-old mice, where osteoblast function overtook bone resorption, as highlighted by the presence of woven bone in histological analyses, consistent with the PDB phenotype. Furthermore, we detected osteophytes and intervertebral disc degeneration, outlining for the first time the link between osteoarthritis and PDB in a PDB mouse model. RNA sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687, e.g., Tspan7, Cpe, Vegfc, and Ggt1, confirming its role in this process. Strikingly, in this mouse model, the mutation was also associated with a high penetrance of hepatocellular carcinomas. Thus, this study established an essential role of Zfp687 in the regulation of bone remodeling, offering the potential to therapeutically treat PDB, and underlines the oncogenic potential of ZNF687.

Osteosarcoma is a highly malignant bone tumor which primarily affects the juvenile population and is characterized by high rate of recurrence and metastasis. RNA editing has emerged as a key process in cancer progression. Herein, we investigated the role of RNA editing enzyme ADAR2 (Adenosine Deaminase Acting on RNA 2) in osteosarcoma. We demonstrated that ADAR2 expression increases during osteoblast differentiation and inversely correlates with the aggressiveness of osteosarcoma cells. Interestingly, the overexpression of ADAR2 in osteosarcoma cell lines reduces their tumoral properties and promotes their differentiation in osteoblast-like cells, as shown by gene expression analysis and mineralization assays. These results were also confirmed by in vivo experiments; indeed, intratibial injection of ADAR2-overexpressing osteosarcoma cells in NSG mice resulted in less aggressive tumors compared to mice injected with pEmpty or pInactive ADAR2 E/A vector-transfected cells. To elucidate the mechanisms by which ADAR2 overexpression induces osteogenic terminal differentiation of osteosarcoma cells, we performed RNA-seq analysis of Saos-2 cells and identified IGFBP7 (Insulin-like Growth Factor Binding Protein 7) as the most highly edited transcript in ADAR2-overexpressing cells. We showed that the editing activity of ADAR2 on IGFBP7 abolishes its proliferative effect on osteosarcoma cells and triggers terminal differentiation. Overall, our results indicate that ADAR2 acts as a tumor suppressor in osteosarcoma and may represent a novel therapeutic target for this aggressive pediatric tumor.

Profilin 1—encoded by PFN1— is a small actin-binding protein with a tumour suppressive role in various adenocarcinomas and pagetic osteosarcomas. However, its contribution to tumour development is not fully understood. Using fix and live cell imaging, we report that Profilin 1 inactivation results in multiple mitotic defects, manifested prominently by anaphase bridges, multipolar spindles, misaligned and lagging chromosomes, and cytokinesis failures. Accordingly, next-generation sequencing technologies highlighted that Profilin 1 knock-out cells display extensive copy-number alterations, which are associated with complex genome rearrangements and chromothripsis events in primary pagetic osteosarcomas with Profilin 1 inactivation. Mechanistically, we show that Profilin 1 is recruited to the spindle midzone at anaphase, and its deficiency reduces the supply of actin filaments to the cleavage furrow during cytokinesis. The mitotic defects are also observed in mouse embryonic fibroblasts and mesenchymal cells deriving from a newly generated knock-in mouse model harbouring a Pfn1 loss-of-function mutation. Furthermore, nuclear atypia is also detected in histological sections of mutant femurs. Thus, our results indicate that Profilin 1 has a role in regulating cell division, and its inactivation triggers mitotic defects, one of the major mechanisms through which tumour cells acquire chromosomal instability. A detailed characterization of in vitro and in vivo phenotypes of Pfn1 knockout cells demonstrates that loss of this gene results in cytoskeletal alterations, leading to mitotic defects and genome instability.