A collimation system for ELI-NP Gamma Beam System - design and simulation of performance

The purpose of this study was to evaluate the performance and refine the design of the collimation system for the gamma radiation source (GBS) currently being realised at ELI-NP facility. The gamma beam, produced by inverse Compton scattering, will provide a tunable average energy in the range between 0.2 and 20 MeV, an energy bandwidth 0.5% and a flux of about 108 photons/s. As a result of the inverse Compton interaction, the energy of the emitted radiation is related to the emission angle, it is maximum in the backscattering direction and decreases as the angle increase [1,2]. Therefore, the required energy bandwidth can be obtained only by developing a specific collimation system of the gamma beam, i.e. filtering out the radiation emitted at larger angles. The angular acceptance of the collimation for ELI-NP-GBS must be continuously adjustable in a range from about 700 to 60 μrad, to obtain the required parameters in the entire energy range. The solution identified is a stack of adjustable slits, arranged with a relative rotation around the beam axis to obtain an hole with an approximately circular shape. In this contribution, the final collimation design and its performance evaluated by carrying out a series of detailed Geant4 simulations both of the high-energy and the low-energy beamline are presented

Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases

The conversion of peptides or proteins from their soluble native states into intractable amyloid deposits is associated with a wide range of human disorders. Misfolded protein oligomers formed during the process of aggregation have been identified as the primary pathogenic agents in many such conditions. Here, we show the existence of a quantitative relationship between the degree of binding to neuronal cells of different types of oligomers formed from a model protein, HypF-N, and the GM1 content of the plasma membranes. In addition, remarkably similar behavior is observed for oligomers of the Aβ(42) peptide associated with Alzheimer’s disease. Further analysis has revealed the existence of a linear correlation between the level of the influx of Ca(2+) across neuronal membranes that triggers cellular damage, and the fraction of oligomeric species bound to the membrane. Our findings indicate that the susceptibility of neuronal cells to different types of misfolded oligomeric assemblies is directly related to the extent of binding of such oligomers to the cellular membrane

Within-breath oscillometry for identifying exercise-induced bronchoconstriction in pediatric patients reporting symptoms with exercise

Background: Evaluating oscillometry parameters separately for the inspiratory and expiratory breath phases and their within-breath differences can help to identify exercise-induced bronchoconstriction (EIB) in pediatric outpatients disclosing exercise-induced symptoms (EIS). Aims: To assess the response in impedance parameters following an exercise challenge in patients reporting EIS. Methods: Sixty-eight patients reporting EIS (34 asthmatics and 34 suspected of asthma, age mean = 10.8 years, range = 6.0-16.0) underwent an incremental treadmill exercise test. Spirometry was performed at baseline and 1, 5-, 10-, 15-, and 20-min post exercise. Oscillometry was performed at baseline and at 3- and 18-min post exercise. Bronchodilator response to 200 μg albuterol was then assessed. EIB was defined as a forced expiratory volume in 1 s (FEV1) fall ≥10% from baseline. Expiratory and inspiratory resistance (Rrs) and reactance (Xrs), their z-score (Ducharme et al. 2022), and their mean within-breath differences (ΔRrs = Rrsexp-Rrsinsp, ΔXrs = Xrsexp-Xrsinsp) were calculated. Receiver operating characteristic (ROC) curves and their areas (AUCs) were used to evaluate impedance parameters' performances in classifying EIB. Results: Asthmatic patients developed EIB more frequently than those suspected of asthma [18/34 (52.9%) vs. 2/34 (5.9%), p < 0.001]. In the 20 subjects with EIB, Rrsinsp, Rrsexp, Xrsinsp, and Xrsexp peaked early (3'), and remained steady except for Xrsinsp, which recovered faster afterward. ΔXrs widened 18 min following the exercise and reversed sharply after bronchodilation (BD) (-1.81 ± 1.60 vs. -0.52 ± 0.80 cmH2O × s/L, p < 0.001). Cutoffs for EIB leading to the highest AUCs were a rise of 0.41 in z-score Rrsinsp (Se: 90.0%, Sp: 66.7%), and a fall of -0.64 in z-score Xrsinsp (Se: 90.0%, Sp: 75.0%). Accepting as having "positive" postexercise oscillometry changes those subjects who had both z-scores beyond respective cutoffs, sensitivity for EIB was 90.0% (18/20) and specificity, 83.3% (40/48). Conclusion: Oscillometry parameters and their within-breath differences changed markedly in pediatric patients presenting EIB and were restored after the bronchodilator. Strong agreement between z-scores of inspiratory oscillometry parameters and spirometry supports their clinical utility, though larger studies are required to validate these findings in a broader population

Glucose-Coated Superparamagnetic Iron Oxide Nanoparticles Prepared by Metal Vapour Synthesis Are Electively Internalized in a Pancreatic Adenocarcinoma Cell Line Expressing GLUT1 Transporter

Iron oxide nanoparticles (IONP) can have a variety of biomedical applications due to their visualization properties through Magnetic Resonance Imaging (MRI) and heating with radio frequency or alternating magnetic fields. In the oncological field, coating IONP with organic compounds to provide specific features and to achieve the ability of binding specific molecular targets appears to be very promising. To take advantage of the high avidity of tumor cells for glucose, we report the development of very small glucose-coated IONP (glc-IONP) by employing an innovative technique, Metal Vapor Synthesis (MVS). Moreover, we tested the internalization of our gl-IONP on a tumor line, BxPC3, over-expressing GLUT 1 transporter. Both glc-IONP and polyvinylpyrrolidone-IONP (PVP-IONP), as control, were prepared with MVS and were tested on BxPC3 at various concentrations. To evaluate the role of GLUT-1 transporter, we also investigated the effect of adding a polyclonal anti-GLUT1 antibody. After proper treatment, the iron value was assessed by atomic absorption spectrometer, reported in mcg/L and expressed in mg of protein. Our IONP prepared with MVS were very small and homogeneously distributed in a narrow range (1.75-3.75 nm) with an average size of 2.7 nm and were super-paramagnetic. Glc-IONP were internalized by BxPC3 cells in a larger amount than PVP-IONP. After 6h of treatment with 50 mcg/mL of IONPs, the content of Fe was 1.5 times higher in glc-IONP-treated cells compared with PVP-IONP-treated cells. After 1h pre-treatment with anti-GLUT1, a reduction of 41% cellular accumulation of glc-IONP was observed. Conversely, the uptake of PVP-IONPs was reduced only by 14% with antibody pretreatment. In conclusion, MVS allowed us to prepare small, homogeneous, super-paramagnetic glc-IONP, which are electively internalized by a tumor line over-expressing GLUT1. Our glc-IONP appear to have many requisites for in vivo use

Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma

Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS