Evaluation of Vitamin D (25OHD), Bone Alkaline Phosphatase (BALP), Serum Calcium, Serum Phosphorus, Ionized Calcium in Patients with Mandibular Third Molar Impaction. An Observational Study

The aim of this study was to evaluate the levels of vitamin D (25OHD) and other bone biomarkers in patients with third molar impaction (TMI). Thirty males and 30 females with unilateral or bilateral impacted mandibular third molar, and 15 males and 15 females as a control group (CG) were recruited. Rx-OPT was used to evaluate dental position and Pederson index to measure the difficulty of the intervention. Bone biomarkers were measured through blood venous sample in TMI group and CG. Mann-Whitney test, Pearson’s correlation coefficient, linear regression model were used to compare the different parameters in the two groups. 25OHD showed lower values in TMI group than in CG (p < 0.05) with values significantly lower in bilateral impaction (p < 0.05). Pearson’s coefficient for 25OHD presented a negative correlation with the Pederson index ($ = 0.75). Bone alkaline phosphatase (BALP) showed significantly lower dosage in TMI group than CG (p = 0.02), Pearson’s coefficient for BALP presented a negative correlation with the Pederson index. Serum calcium, serum phosphorus, ionized calcium levels in TMI and CG groups were similar and Mann- Whitney test did not significantly differ between TMI and CG. TMI could be a sign of vitamin D deficiency and of low BALP levels that should be investigated

Proof-of-Concept Study on the Use of Tangerine-Derived Nanovesicles as siRNA Delivery Vehicles toward Colorectal Cancer Cell Line SW480

In the last years, the field of nanomedicine and drug delivery has grown exponentially, providing new platforms to carry therapeutic agents into the target sites. Extracellular vesicles (EVs) are ready-to-use, biocompatible, and non-toxic nanoparticles that are revolutionizing the field of drug delivery. EVs are involved in cell-cell communication and mediate many physiological and pathological processes by transferring their bioactive cargo to target cells. Recently, nanovesicles from plants (PDNVs) are raising the interest of the scientific community due to their high yield and biocompatibility. This study aims to evaluate whether PDNVs may be used as drug delivery systems. We isolated and characterized nanovesicles from tangerine juice (TNVs) that were comparable to mammalian EVs in size and morphology. TNVs carry the traditional EV marker HSP70 and, as demonstrated by metabolomic analysis, contain flavonoids, organic acids, and limonoids. TNVs were loaded with DDHD1-siRNA through electroporation, obtaining a loading efficiency of 13%. We found that the DDHD1-siRNA complex TNVs were able to deliver DDHD1-siRNA to human colorectal cancer cells, inhibiting the target expression by about 60%. This study represents a proof of concept for the use of PDNVs as vehicles of RNA interference (RNAi) toward mammalian cells

Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum

Extracellular vesicles (EVs) are mediators of intercellular communication under bothhealthy and pathological conditions, including the induction of pro-metastatic traits,but it is not yet known how and where functional cargoes of EVs are delivered to theirtargets in host cell compartments. We have described that after endocytosis, EVsreach Rab+late endosomes and a fraction of these enter the nucleoplasmic reticu-lum and transport EV biomaterials to the host cell nucleoplasm. Their entry thereinand docking to outer nuclear membrane occur through a tripartite complex formedby the proteins VAP-A, ORP and Rab (VOR complex). Here, we report that theantifungal compound itraconazole (ICZ), but not its main metabolite hydroxy-ICZor ketoconazole, disrupts the binding of Rab to ORP–VAP-A complexes, leadingto inhibition of EV-mediated pro-metastatic morphological changes including cellmigration behaviour of colon cancer cells. With novel, smaller chemical drugs, inhi-bition of the VOR complex was maintained, although the ICZ moieties responsiblefor antifungal activity and interference with intracellular cholesterol distributionwere removed. Knowing that cancer cells hijack their microenvironment and thatEVs derived from them determine the pre-metastatic niche, small-sized inhibitors ofnuclear transfer of EV cargo into host cells could nd cancer therapeutic applications,particularly in combination with direct targeting of cancer cell

A Proton Recoil Telescope for Neutron Spectroscopy

The N2P research program funded by the INFN committee for Experimental Nuclear Physics (CSNIII) has among his goals the construction of a Proton Recoil Telescope (PRT), a detector to measure neutron energy spectra. The interest in such a detector is primarily related to the SPES project for rare beams production at the Laboratori Nazionali di Legnaro. For the SPES project it is, in fact, of fundamental importance to have reliable information about energy spectra and yield for neutrons produced by d or p projectiles on thick light targets to model the ''conversion target'' in which the p or d are converted in neutrons. These neutrons, in a second stage, will induce the Uranium fission in the ''production target''. The fission products are subsequently extracted, selected and re-accelerated to produce the exotic beam. The neutron spectra and angular distribution are important parameters to define the final production of fission fragments. In addition, this detector can be used to measure neutron spectra in the field of cancer therapy (this topic is nowadays of particular interest to INFN, for the National Centre for Hadron therapy (CNAO) in Pavia) and space applications

The Pharmacological Chaperone N-butyldeoxynojirimycin Enhances Enzyme Replacement Therapy in Pompe Disease Fibroblasts

In spite of the progress in the treatment of lysosomal storage diseases (LSDs), in some of these disorders the available therapies show limited efficacy and a need exists to identify novel therapeutic strategies. We studied the combination of enzyme replacement and enzyme enhancement by pharmacological chaperones in Pompe disease (PD), a metabolic myopathy caused by the deficiency of the lysosomal acid α-glucosidase. We showed that coincubation of Pompe fibroblasts with recombinant human α-glucosidase and the chaperone N-butyldeoxynojirimycin (NB-DNJ) resulted in more efficient correction of enzyme activity. The chaperone improved α-glucosidase delivery to lysosomes, enhanced enzyme maturation, and increased enzyme stability. Improved enzyme correction was also found in vivo in a mouse model of PD treated with coadministration of single infusions of recombinant human α-glucosidase and oral NB-DNJ. The enhancing effect of chaperones on recombinant enzymes was also observed in fibroblasts from another lysosomal disease, Fabry disease, treated with recombinant α-galactosidase A and the specific chaperone 1-deoxygalactonojirimycin (DGJ). These results have important clinical implications, as they demonstrate synergy between pharmacological chaperones and enzyme replacement. A synergistic effect of these treatments may result particularly useful in patients responding poorly to therapy and in tissues in which sufficient enzyme levels are difficult to obtain

Comparative study of T84 and T84SF human colon carcinoma cells: in vitro and in vivo ultrastructural and functional characterization of cell culture and metastasis

To better understand the relationship between tumor heterogeneity, differentiation, and metastasis, suitable experimental models permitting in vitro and in vivo studies are necessary. A new variant cell line (T84SF) exhibiting an altered phenotype was recently selected from a colon cancer cell line (T84) by repetitive plating on TNF-alpha treated human endothelial cells and subsequent selection for adherent cells. The matched pair of cell lines provides a useful system to investigate the extravasation step of the metastatic cascade. Since analysis of morphological differences can be instructive to the understanding of metastatic potential of tumor cells, we compared the ultrastructural and functional phenotype of T84 and T84SF cells in vitro and in vivo. The reported ultrastructural features evidence differences between the two cell lines; selected cells showed a marked pleomorphism of cell size and nuclei, shape, and greater surface complexity. These morphological differences were also coupled with biochemical data showing a distinct tyrosine phosphorylation-based signaling, an altered localization of beta-catenin, MAPK, and AKT activation, as well as an increased expression in T84SF cells of Bcl-X-L, a major regulator of apoptosis. Therefore, these cell lines represent a step forward in the development of appropriate models in vitro and in vivo to investigate colon cancer progression

Measuring the free fall of antihydrogen

After the first production of cold antihydrogen by the ATHENA and ATRAP experiments ten years ago, new second-generation experiments are aimed at measuring the fundamental properties of this anti-atom. The goal of AEGIS (Antimatter Experiment: Gravity, Interferometry, Spectroscopy) is to test the weak equivalence principle by studying the gravitational interaction between matter and antimatter with a pulsed, cold antihydrogen beam. The experiment is currently being assembled at CERN's Antiproton Decelerator. In AEGIS, antihydrogen will be produced by charge exchange of cold antiprotons with positronium excited to a high Rydberg state (n > 20). An antihydrogen beam will be produced by controlled acceleration in an electric-field gradient (Stark acceleration). The deflection of the horizontal beam due to its free fall in the gravitational field of the earth will be measured with a moire deflectometer. Initially, the gravitational acceleration will be determined to a precision of 1%, requiring the detection of about 105 antihydrogen atoms. In this paper, after a general description, the present status of the experiment will be reviewed

Natural History of Malignant Bone Disease in Renal Cancer: Final Results of an Italian Bone Metastasis Survey

Abstract Background: Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as diseaserelated survival improves. There are few data on the natural history of bone disease in RCC

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57