The active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms

Oxaliplatin-induced neuropathy (OXAIN) is a major adverse effect of this antineoplastic drug, widely used in the treatment of colorectal cancer. Although its molecular mechanisms remain poorly understood, recent evidence suggest that maladaptive neuroplasticity and oxidative stress may participate to the development of this neuropathy. Given the role played on protein remodeling by ubiquitin–proteasome system (UPS) in response to oxidative stress and in neuropathic pain, we investigated whether oxaliplatin might cause alterations in the UPS-mediated degradation pathway, in order to identify new pharmacological tools useful in OXAIN. In a rat model of OXAIN (2.4 mg kg−1 i.p., daily for 10 days), a significant increase in chymotrypsin-(β5) like activity of the constitutive proteasome 26S was observed in the thalamus (TH) and somatosensory cortex (SSCx). In addition, the selective up-regulation of β5 and LMP7 (β5i) subunit gene expression was assessed in the SSCx. Furthermore, this study revealed that oprozomib, a selective β5 subunit proteasome inhibitor, is able to normalize the spinal prodynorphin gene expression upregulation induced by oxaliplatin, as well as to revert mechanical allodynia and thermal hyperalgesia observed in oxaliplatin-treated rats. These results underline the relevant role of UPS in the OXAIN and suggest new pharmacological targets to counteract this severe adverse effect. This preclinical study reveals the involvement of the proteasome in the oxaliplatin-induced neuropathy and adds useful information to better understand the molecular mechanism underlying this pain condition. Moreover, although further evidence is required, these findings suggest that oprozomib could be a therapeutic option to counteract chemotherapy-induced neuropathy

Exercise Increases Markers of Spermatogenesis in Rats Selectively Bred for Low Running Capacity

The oxidative stress effect of exercise training on testis function is under debate. In the present study we used a unique rat model system developed by artificial selection for low and high intrinsic running capacity (LCR and HCR, respectively) to evaluate the effects of exercise training on apoptosis and spermatogenesis in testis. Twenty-four 13-month-old male rats were assigned to four groups: control LCR (LCR-C), trained LCR (LCR-T), control HCR (HCR-C), and trained HCR (HCR-T). Ten key proteins connecting aerobic exercise capacity and general testes function were assessed, including those that are vital for mitochondrial biogenesis. The VO2 max of LCR-C group was about 30% lower than that of HCR-C rats, and the SIRT1 levels were also significantly lower than HCR-C. Twelve weeks of training significantly increased maximal oxygen consumption in LCR by nearly 40% whereas HCR remained unchanged. LCR-T had significantly higher levels of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1α), decreased levels of reactive oxygen species and increased acetylated p53 compared to LCR-C, while training produced no significant changes for these measures in HCR rats. BAX and Blc-2 were not different among all four groups. The levels of outer dense fibers -1 (Odf-1), a marker of spermatogenesis, increased in LCR-T rats, but decreased in HCR-TR rats. Moreover, exercise training increased the levels of lactate dehydrogenase C (LDHC) only in LCR rats. These data suggest that rats with low inborn exercise capacity can increase whole body oxygen consumption and running exercise capacity with endurance training and, in turn, increase spermatogenesis function via reduction in ROS and heightened activity of p53 in testes

The impact of COVID-19 on radiological findings in patients accessing the emergency department: a multicentric study

The aim of this multicentric study is to illustrate how the COVID-19 pandemic lockdown affected the workload and outcomes of radiological examinations in emergency radiology

Integrins and Cadherins could be important regulators of osteogenic differentiation and bone formation in dental stem cells

Regenerative medicine aims to translate the regeneration of tissues and organs into clinical application. Numerous studies have reported beneficial effects of Adult stem cells therapy in the treatment of disease and disabilities. New sources of mesenchymal stem cells (MSCs) are emerging in adult organisms, and dental tissues, that are easily accessible, have been identified as a source of postnatal MSCs capable of self-renewal and multipotency. Dental Follicle Stem Cells (DFSCs) isolated from tooth buds of healthy paediatric patients showed ≥95% expression of stemness makers (CD73, CD90, CD146, CD44, CD105, and HLA-I) [1]. Moreover DFSCs differentiated into osteoblastlike cells, produced mineralized matrix nodules and expressed typical osteoblastic markers. Cell interactions with extracellular matrix (ECM) and neighbor cells are critical for tissue morphogenesis and architecture, and are mediated by two classes of adhesion molecules, respectively Integrins and Cadherins, which also act intracellularly by modulating crucial pathways of proliferation and differentiation. Thus, in this study, DFSCs were characterized for the expression of adhesion molecules Cadherins and Integrins. In basal conditions DFSCs expressed higher levels of N-Cadherin and Cadherin-11 in comparison to E-Cadherin and P-Cadherin, which were low expressed. The examined Cadherins showed different behaviours during DFSCs osteogenic differentiation: N-cadherin expression was high during the first steps, while decreased at the later times; Cadherin-11 progressively increased; E-Cadherin and P-Cadherin did not change a Cadherin profile reflecting the osteoblastic commitment of the cells. DFSCs expressed the Integrin subunits alpha V, beta 3, alpha 5, and beta 1 in basal undifferentiated conditions but their expression increased time-dependently under osteogenic treatment. In addition we found that the subunits alpha V and beta 3 associated and formed the functional integrin, which localized at the focal adhesion in response to osteogenic trigger; similarly, alpha 5 and beta 1 subunits were found to associate and localize at the cell borders mostly in differentiated cells. Finally we found that osteogenic differentiation of DFSCs was prompted out by seeding the cells on ECM protein coated surfaces. Functional tissue engineering for bone regeneration requires the appropriate combination of MSCs with biocompatible scaffolds, thus acting on cell surface and ECM molecules could optimize osteogenic differentiation of MSCs and contribute to the successful regeneration of damaged bone tissue

The Present Development of CsI Rich Detectors for the ALICE Experiment at CERN

The ALICE Collaboration plans to implement a 12m^2 array consisting of 7 proximity focussed C6F^14 liquid radiator RICH modules devoted to the particle identification in the momentum range: 1 GeV/c - 3.5 GeV/c for pions and kaons. A large area CSI-RICH prototype has been designed and built with the aim to validate the detector parameter assumptions made to predict the performance of the High Momentum Particle Identification System (HMPID) of the ALICE Experiment. The main elements of the prototype will be described with emphasis on the engineering solutions adopted. First results from the analysis of multitrack events recorded with this prototype exposed to hadron beams at the CERN SPS will be discussedList of FiguresFigure 1 General view of the ALICE lay-outFigure 2 Schematic layout of the fast CsI-RICHFigure 3 Perspective view of the HMPID layout with the seven RICH modules tilted according to their position with respect to the interaction vertex. The frame that supports the detectors is also shownFigure 4 Top view of the photodetector anode plane with the wire support spacer. One CsI board, out of six forming the pad cathode plane, is also shown.Figure 5 Perspective view of the HMPID honeycomb panel with the three radiator vesselsFigure 6 Cut away view of the HMPID CsI-RICH showing separately each detector component. Kapton buses that carry signals from the pads to the readout electronics are also shownFigure 7 a)number of resolved photoelectrons per event, b)reconstructed Cherenkov angle per photonFigure 8 C6F14 transmission plots before and after the molecular sieve purificationFigure 9 Display plot showing an SPS event. Three tracks are reconstructed by using the tracking chamber telescope, the associated rings are shown in the HMPID prototypeThis publication also appears as INT-98-20

Charged Particle Production in Proton-, Deuteron-, Oxygen- and Sulphur-Nucleus Collisions at 200 GeV per Nucleon

The transverse momentum and rapidity distributions of net protons and negatively charged hadrons have been measured for minimum bias proton-nucleus and deuteron-gold interactions, as well as central oxygen-gold and sulphur-nucleus collisions at 200 GeV per nucleon. The rapidity density of net protons at midrapidity in central nucleus-nucleus collisions increases both with target mass for sulphur projectiles and with the projectile mass for a gold target. The shape of the rapidity distributions of net protons forward of midrapidity for d+Au and central S+Au collisions is similar. The average rapidity loss is larger than 2 units of rapidity for reactions with the gold target. The transverse momentum spectra of net protons for all reactions can be described by a thermal distribution with `temperatures' between 145 +- 11 MeV (p+S interactions) and 244 +- 43 MeV (central S+Au collisions). The multiplicity of negatively charged hadrons increases with the mass of the colliding system. The shape of the transverse momentum spectra of negatively charged hadrons changes from minimum bias p+p and p+S interactions to p+Au and central nucleus-nucleus collisions. The mean transverse momentum is almost constant in the vicinity of midrapidity and shows little variation with the target and projectile masses. The average number of produced negatively charged hadrons per participant baryon increases slightly from p+p, p+A to central S+S,Ag collisions.Comment: 47 pages, submitted to Z. Phys.

A progress report on the development of the CsI-RICH detector for the ALICE experiment at LHC

The particle identification in ALICE (A Large Ion Collider Experiment) at LHC will be achieved by two complementary systems based on time of flight measurement, at low $p_t$, and on the Ring Imaging Cherenkov (RICH) technique, at $p_t$ ranging from 2 to 5 GeV/$c$, respectively. The High Momentum PID (HMPID) system will cover $\sim$5\% of the phase space, the single arm detector array beeing composed by seven 1.3$\times$1.3 m$^2$ CsI-RICH modules placed at 4.7 m from the interaction point where a density of about 50 particles/m$^2$ is expected.\\ A 1 m$^2$ prototype, 2/3 of HMPID module size, has been successfully tested at the CERN/PS beam where 18 photoelectrons per event have been obtained with 3 GeV/c pions and 10 mm liquid $\mathrm{C}_6\mathrm{F}_{14}$ radiator. Mechanical problems related to the liquid radiator vessel construction have been solved and the prototype, fully equipped, will be tested at the CERN/SPS to investigate the PID capability in high particle density events.\\ In this report, after an introductory discussion on the requirements for PID in ALICE, the HMPID prototype is described and the main results of beam tests on large area CsI photocathodes, operated in RICH detectors, are given

Strange particle production in 158 and 40 AA GeV/cc Pb-Pb and p-Be collisions

Results on strange particle production in Pb-Pb collisions at 158 and 40 $A$ GeV/$c$ beam momentum from the NA57 experiment at CERN SPS are presented. Particle yields and ratios are compared with those measured at RHIC. Strangeness enhancements with respect to p-Be reactions at the same beam momenta have been also measured: results about their dependence on centrality and collision energy are reported and discussed.Comment: Contribution to the proceedings of the "Hot Quarks 2004" Conference, July 18-24 2004, New Mexico, USA, submitted to Journal of Physics G 7 pages, 5 figure

Study of the transverse mass spectra of strange particles in Pb-Pb collisions at 158 A GeV/c

The NA57 experiment has collected high statistics, high purity samples of \PKzS and \PgL, $\Xi$ and $\Omega$ hyperons produced in Pb-Pb collisions at 158 $A$ GeV/$c$. In this paper we present a study of the transverse mass spectra of these particles for a sample of events corresponding to the most central 53% of the inelastic Pb-Pb cross-section. We analyse the transverse mass distributions in the framework of the blast-wave model for the full sample and, for the first time at the SPS, as a function of the event centrality.Comment: 22 pages, 14 figures, submitted to J. Phys. G: Nucl. Phy