Abstract In this contribution we describe the implementation of a novel solution for image guided particle therapy, designed to ensure the maximal accuracy in patient setup. The presented system is ...installed in the central treatment room at Centro Nazionale di Adroterapia Oncologica (CNAO, Italy), featuring two fixed beam lines (horizontal and vertical) for proton and carbon ion therapy. Treatment geometry verification is based on robotic in-room imaging acquisitions, allowing for 2D/3D registration from double planar kV-images or 3D/3D alignment from cone beam image reconstruction. The calculated six degrees-of-freedom correction vector is transferred to the robotic patient positioning system, thus yielding automated setup error compensation. Sub-millimetre scale residual errors were measured in absolute positioning of rigid phantoms, in agreement with optical- and laser-based assessment. Sub-millimetre and sub-degree positioning accuracy was achieved when simulating setup errors with anthropomorphic head, thorax and pelvis phantoms. The in-house design and development allowed a high level of system customization, capable of replicating the clinical performance of commercially available products, as reported with preliminary clinical results in 10 patients.
Interacting in the peripersonal space requires coordinated arm and eye movements to visual targets in depth. In primates, the medial posterior parietal cortex (PPC) represents a crucial node in the ...process of visual-to-motor signal transformations. The medial PPC area V6A is a key region engaged in the control of these processes because it jointly processes visual information, eye position and arm movement related signals. However, to date, there is no evidence in the medial PPC of spatial encoding in three dimensions. Here, using single neuron recordings in behaving macaques, we studied the neural signals related to binocular eye position in a task that required the monkeys to perform saccades and fixate targets at different locations in peripersonal and extrapersonal space. A significant proportion of neurons were modulated by both gaze direction and depth, i.e., by the location of the foveated target in 3D space. The population activity of these neurons displayed a strong preference for peripersonal space in a time interval around the saccade that preceded fixation and during fixation as well. This preference for targets within reaching distance during both target capturing and fixation suggests that binocular eye position signals are implemented functionally in V6A to support its role in reaching and grasping.
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as a transcription corepressor or coactivator by regulating the methylation status of histone H3 lysines K4 and K9, ...respectively. KDM1A represents an attractive target for cancer therapy. While, in the past, the main medicinal chemistry strategy toward KDM1A inhibition was based on the optimization of ligands that irreversibly bind the FAD cofactor within the enzyme catalytic site, we and others have also identified reversible inhibitors. Herein we reported the discovery of 5-imidazolylthieno3,2-bpyrroles, a new series of KDM1A inhibitors endowed with picomolar inhibitory potency, active in cells and efficacious after oral administration in murine leukemia models.
Oral FEES (O-FEES) is an endoscopic procedure conceived to directly visualise the oral phase of swallowing. In the perspective of clinical use, the feasibility, safety and acceptability of O-FEES has ...been evaluated. Subsequently, the procedure was compared with the radiological gold standard. The acceptability of O-FEES was compared to that of FEES using a 10 point questionnaire submitted to a sample of 52 outpatients complaining of swallowing disorders. Repeated measure analysis of variance (rm-ANOVA) models were used to test the mean difference of acceptability in the same subjects after FEES and O-FEES. Subsequently, another sample of 8 male outpatients underwent a simultaneous O-FEES and videofluoroscopic study (VFSS). The inter-rater reliability using 10 radiological landmarks, compared to O-FEES, was blindly determined between two raters. Inter-rater agreement between the two judges for O-FEES and VFSS scores was assessed with the single score intra-class correlation coefficient (ICC). Differences between FEES and O-FEES answers for each question and among all the items considered overall were statistically significant (rm-ANOVA; F-statistic p < 0.001). The inter-rater agreement concerning endoscopic and radiological evaluations between the two raters showed strong values of intra-class correlation coefficient (ICC) (95% confidence interval): 0.875 (0.373-0.979) and 0.921 (0.542-0.986), respectively. The Bland-Altman test showed a bias of -0.24 (95% limits of agreement; -1.77 to +1.19), which suggests that both methods produced almost identical results. In clinical practice and compared with FEES, O-FEES is a well tolerated and safe procedure. Compared with the radiological gold standard, O-FEES offers reliable information about oral preparation and oral propulsion of the bolus.
The indoline dyes D102, D131, D149, and D205 have been characterized when adsorbed on fluorine-doped tin oxide (FTO) and TiO2 electrode surfaces. Adsorption from 50:50 acetonitrile−tert-butanol onto ...fluorine-doped tin oxide (FTO) allows approximate Langmuirian binding constants of 6.5 × 104, 2.0 × 103, 2.0 × 104, and 1.5 × 104 mol−1 dm3, respectively, to be determined. Voltammetric data obtained in acetonitrile/0.1 M NBu4PF6 indicate reversible one-electron oxidation at E mid = 0.94, 0.91, 0.88, and 0.88 V vs Ag/AgCl(3 M KCl), respectively, with dye aggregation (at high coverage) causing additional peak features at more positive potentials. Slow chemical degradation processes and electron transfer catalysis for iodide oxidation were observed for all four oxidized indolinium cations. When adsorbed onto TiO2 nanoparticle films (ca. 9 nm particle diameter and ca. 3 μm thickness on FTO), reversible voltammetric responses with E mid = 1.08, 1.16, 0.92, and 0.95 V vs Ag/AgCl(3 M KCl), respectively, suggest exceptionally fast hole hopping diffusion (with D app > 5 × 10−9 m2 s−1) for adsorbed layers of all four indoline dyes, presumably due to π−π stacking in surface aggregates. Slow dye degradation is shown to affect charge transport via electron hopping. Spectroelectrochemical data for the adsorbed indoline dyes on FTO-TiO2 revealed a red-shift of absorption peaks after oxidation and the presence of a strong charge transfer band in the near-IR region. The implications of the indoline dye reactivity and fast hole mobility for solar cell devices are discussed.
Post-traumatic stress disorder (PTSD) in the occupational context, especially following workplace robbery, is still under-investigated.
To evaluate PTSD incidence and risk factors among bank employee ...victims of robbery voluntarily joining an employer-sponsored post-robbery support programme.
The programme entailed a structured support interview with robbery victims within 15 days of the robbery and a follow-up psychological assessment 45 days after. A self-reported questionnaire on personal variables and robbery characteristics was administered to participants at the first support session (T1). Interviews on employees' psychophysical health and their opinion about the support programme were administered individually at follow-up (T2). The Impact of Event Scale (IES) was administered both at T1 and T2.
There were 383 participants. At T2, 13% of subjects had an IES score >34, a cut-off suggestive of PTSD. In a multi-variate model, feelings of helplessness and terror during the robbery and the number of previous robberies were associated with a PTSD diagnosis. After including IES score at T1, other variables lost statistical significance.
Our findings showed that PTSD is common among employee victims of workplace robbery. Our results also suggest the importance of subjective variables, such as personal perception of robbery severity and early emotional reaction, in identifying people at higher risk of developing PTSD.
Maresin-2 (MaR2) is a specialized pro-resolution lipid mediator (SPM) that reduces neutrophil recruitment in zymosan peritonitis. Here, we investigated the analgesic effect of MaR2 and its mechanisms ...in different mouse models of pain. For that, we used the lipopolysaccharide (LPS)-induced mechanical hyperalgesia (electronic version of the von Frey filaments), thermal hyperalgesia (hot plate test) and weight distribution (static weight bearing), as well as the spontaneous pain models induced by capsaicin (TRPV1 agonist) or AITC (TRPA1 agonist). Immune cell recruitment was determined by immunofluorescence and flow cytometry while changes in the pro-inflammatory mediator landscape were determined using a proteome profiler kit and ELISA after LPS injection. MaR2 treatment was also performed in cultured DRG neurons stimulated with capsaicin or AITC in the presence or absence of LPS. The effect of MaR2 on TRVP1- and TRPA1-dependent CGRP release by cultured DRG neurons was determined by EIA. MaR2 inhibited LPS-induced inflammatory pain and changes in the cytokine landscape as per cytokine array assay. MaR2 also inhibited TRPV1 and TRPA1 activation as observed by a reduction in calcium influx in cultured DRG neurons, and the number of flinches and time spent licking the paw induced by capsaicin or AITC. In corroboration, MaR2 reduced capsaicin- and AITC-induced CGRP release by cultured DRG neurons and immune cell recruitment to the paw skin close the CGRP+ fibers. In conclusion, we show that MaR2 is an analgesic SPM that acts by targeting leukocyte recruitment, nociceptor TRPV1 and TRPA1 activation, and CGRP release in mice.
•Maresin-2 (MaR2) reduces pain and inflammation caused by the microbial product LPS.•MaR2 reduces TRPV1 and TRPA1 activation in mouse dorsal root ganglion (DRG) neurons.•MaR2 reduces pain-like behavior triggered by TRPV1 and TRPA1 agonists.•MaR2 inhibits CGRP release by mouse DRG neurons.•MaR2 reduces recruitment of CD11b+ cells close to CGRP + nociceptors.
Significance
This work provides a report of accumulation of unconventional CD56
−
CD16
+
NK cells in nonvirally induced malignancies. Increased frequency of CD56
−
CD16
+
NK cells is associated with ...adverse clinical outcome in AML, as well as other maturation defects, and might contribute to a defective control of AML progression. Pseudotime analysis highlights a disruption in the maturation process of conventional NK cells in AML patients, leading to a bifurcation point absent in healthy subjects. This analysis, combined with the reduced frequency of conventional NK cells observed in AML patients, suggests that unconventional CD56
−
CD16
+
NK cells derive from an aberrant maturation of conventional NK cells. Overall, accumulation of CD56
−
CD16
+
NK cells could be an important feature of immune escape from innate immunity.
Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56
−
CD16
+
unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML (
n
= 48, HEMATOBIO cohort, NCT02320656) and healthy subjects (
n
= 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56
−
CD16
+
unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56
−
CD16
+
NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13;
P
= 0.0002) and event-free survival (HR = 0.33;
P
= 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56
−
CD16
+
NK cells. Overall, our data suggest that the accumulation of CD56
−
CD16
+
NK cells may be the consequence of immune escape from innate immunity during AML progression.
Disordered mesoporous silica (DMS), prepared by the sol–gel method, was chemically modified with ensal functional groups. Copper complexes were formed on the surface of the resulting material. A ...homogeneous mixture of the DMS/(ensal)2Cu with ultra pure graphite (99.99%) was pressed in disk format in order to fabricate a working electrode that displayed an excellent specific electrocatalytic response to dopamine (DA) oxidation. Under optimized conditions, at −20mV vs. SCE in 0.04molL−1 Britton–Robinson buffer (BRB) solution (pH 7.0) containing 200μmolL−1 of H2O2, a linear response range for dopamine from 5 up to 130μmolL−1 was obtained with a sensitivity of 21.2 (±0.003)nALμmol−1cm−2 and the limit of detection LOD was 0.52μmolL−1. The sensors presented stable response during successive determinations. The repeatability, evaluated in terms of relative standard deviation of <3% for n=10 and 10μmolL−1 dopamine. The response time was 1s and life time at least 6months. Finally, the sensor was tested to determine dopamine in the sample, showing a good performance for its determination. The presence of ascorbic acid and NADH did not show any interference in the detection of dopamine on this electrode, even in the same concentration as the dopamine.
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