The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models

Abstract Many neurological disorders of gluten-related diseases (GRD), not directly referable to the gastrointestinal tract, have been reported in association with celiac disease (CD), including ataxia, neuropathy and epilepsy. In particular, people with epilepsy diagnosed with CD seems to be characterized by intractable seizure. In these patients, gluten restriction diet has resulted in a reduction of both seizure frequency and antiepileptic medication. Many hypotheses have been suggested, however, molecular mechanisms that associates GRD and epileptogenesis are yet unknown. In this study, we examined the effects of the toxic gliadin peptide 31-43 in in vivo and in vitro models of kainate-induced-epilepsy. We observed that p31-43 exacerbates kainate neurotoxicity in epilepsy models, through the involvement of the enzymatic activity of transglutaminases. Moreover, electrophysiological recordings in CA3 pyramidal neurons of organotypic hippocampal slices show that p31-43 increases the inward current induced by kainate, the average sEPSC amplitude and the total number of evoked action potentials when applicated alone, thus suggesting that p31-43 is able to influence CA3-CA1 neurotransmission and can potentiate postsynaptic kainate receptors. Our results suggest a possible mechanism underlying the relationship between GRD and epilepsy through a potentiation of kainate-induced neurotoxicity and links the toxic effects of gluten to epilepsy

Anticancer activities of anthocyanin extract from genotyped Solanum tuberosum L. "Vitelotte"

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RINTC-E: Towards seismic risk assessment of existing residential reinforced concrete buildings in Italy

The RINTC research project (RINTC Workgroup, 2018), financed by the Italian Department of Civil Protection, is aimed at evaluating the seismic risk of buildings conforming to the Italian building code. Within the framework of this project, the attention has been recently focused on existing buildings, too. In this study, case-study structures, representative of the existing residential reinforced concrete (RC) building stock in Italy, are analyzed. These structures are three-storey buildings with compact rectangular plan, and they have been defined through a simulated design process, in order to represent two types of buildings, namely designed for gravity loads only during 1970s (gravity load designed, GLD) or for moderate seismic loads during 1990s (seismic load designed, SLD). GLD buildings are assumed to be located in three different sites, namely Milan, Naples and Catania, in increasing order of seismic hazard. SLD buildings are assumed to be located in L'Aquila. The assumed design typologies are consistent with the seismic classification of the sites at the assumed ages of construction. The presence of typical nonstructural masonry infill walls (uniformly distributed in plan as external enclosure walls) is taken into account, assuming three configurations along height, namely “bare” (without infills), uniformly infilled and “pilotis” (without infills at the bottom storey) buildings. Two (not code-based) Limit States are investigated, namely Usability-Preventing Damage, corresponding to an interruption of the building use, and Collapse. RC elements are modelled with a lumped plasticity approach, through an empirical-based macromodel. The possible occurrence of shear failures in columns is taken into account through a preliminary classification of the expected failure mode (flexure- or shear-controlled, in the latter case prior to or following flexural yielding) and, if needed, a modification of the backbone of the nonlinear moment-chord rotation response, through empirical models providing the expected deformation capacity at shear and axial failure, the latter meant as the (initiation of) loss of axial-load-carrying-capacity. The nonlinear response of beam-column joints is modelled, too, with a “scissors model” based on concentrated springs representing the nonlinear response of the joint panel, at the intersection of beams' and columns' centerlines, through a preliminary evaluation of the expected failure mode (i.e. prior to or following yielding of adjacent beam/column elements). Materials properties are provided by literature studies, consistent with the age of construction of the buildings. The in-plane response of infills is modelled, taking into account the presence of openings, too. Modeling should be considered as simplified and, from some points of view, still preliminary, since advances are foreseen within the project in order to capture further failure modes that can occur in structural and nonstructural elements of older, nonductile RC buildings. Nonlinear static analyses, allowing to identify the (top) displacement capacity at the investigated Limit States, are carried out. Multiple stripe nonlinear time history bi-directional analyses of the three-dimensional structural models are carried out in order to evaluate the demand, for ten stripes - each corresponding to a return period ranging from 10 to 105 years - and for twenty couples of records for each stripe. Records were selected, within the activities of the research project, based on a Probabilistic Seismic Hazard Analysis at the sites of interest for the selected return periods. Results are illustrated, highlighting the role of a - although obsolete - seismic design in the response of the buildings and in their capacity, more specifically in terms of displacement capacity at Collapse, but also in terms of demand estimated from multiple stripe analyses. Finally, demand-to-capacity ratios at the investigated Limit States are analyzed, which allow, within the scope of the project, the assessment of the seismic risk of the case study structures

Pegaso: an ultra-light long duration stratospheric

Launched from the Mario Zuccelli Station (Baia Terra Nova) in Antarctica during the 2005/06 austral summer, the PEGASO-D payload lifted into the stratospheric anticyclone over the southern polar region. This effort marks the first Long Duration Scientific payload to be launched from this location and is the fourth such payload launched in the polar regions. Performing in the framework of the NOBILE/AMUNDSEN collaborative LDB development between ASI-ARR. The Italian Institute of Geophysics and Volcanology (INGV), with the sponsorship of the Italian Antarctic Program (PNRA) and the Italian Space Agency (ASI),designed and built the Ultra-Light system together with three Universities in Italy. The Pegaso program has been created to investigate the Earth magnetic field and provide a precursor series of small payload launches for the bigger LDB program such as OLIMPO, BOOMERanG and BArSPOrt through this collaboration between ASI and ARR. The Italian scientific community, aware of the big advantages that LDB balloons can offer to their experiments, proposed to extend the LDB program to Southern polar regions, besides performing launches from the newly initiated Nobile/Amundsen Stratospheric Balloon Center in Svalbard, Norway.Three PEGASO (Polar Explorer for Geomagnetics And other Scientific Observations) payloads have been launched from the Svalbard (No) in collaboration with Andoya Rocket Range, ASI and ISTAR (Operations and logistics) during the past two northern summers. These stratospheric (altitude m.35000) small 10kmc balloons have floated in the stratosphere between 14 to 39 days measuring the magnetic field of polar regions, by means of a 3-axys-fluxgate magnetometer, during a three year campaign. The study of the magnetic field and its variations is done through permanent observatories. They provide us with high quality data but their spatial distribution is not quite regular, specially in Antarctica due to logistic difficulties. The coverage is improved through marine and aeromagnetic surveys, and also through satellite missions. There exists nevertheless a gap in the wavelengths of the magnetic field represented by these kind of measurements. Satellite data are too far away from Earth's surface to individuate wavelengths lower than 1000 km, and near-ground sur- veys are not able to represent wavelengths longer than the dimensions of the surveyed area. Moreover, there is a region empty of data around the geographical pole for the satellite measurements. The size of these gaps depends on the orbital parameters, but it can reach up to 10 degrees around the pole. PEGASO allows to bridge this gap in the measurements of the magnetic field. Surveys carried out at 35 km height allow the study of crustal anomalies in the range between, we can say, 60 and 1000 km. Taking into account that pathfinders (smaller non-recoverable balloon systems) are usually sent to explore the atmospheric currents, the use of PEGASO as pathfinder allows us to obtain all these results at a very affordable cost. The PEGASO payload was also developed as a single source system integrating science, housekeeping and operational control of the entire balloon borne configuration.Satellite telemetry sent the scientific (magnetometric) data, house-keeping (temperature, solar panel voltage and current, altitude and time) and telecommand (four ballast, two parachute release system, system reset), and powered the terminate system. Data flows through the IRIDIUM telephone service. The onboard systems were kept inside a vessel (white painted and pressurizzed vessel due to power dissipation) except for external flexible solar panels and magnetometer, attached to an external boom. Two redundant tracking systems have been used: a first GPS was integrated inside the on-board telemetry system, necessary to reconstruct position and time of scientific data, while an independent GPS-ARGOS system gave the balloon trajectory, including its descent. Continuous trajectory predictions were made during the missions; they have been necessary, in particular, for the flight safety requirements of the northern hemisphere. The evaluation of the statistical error is proposed. The PEGASO payload was developed to be a light, cost effective way to explore the potential of Ultra-Light Long Duration Ballooning for science as well as an introduction to the earth-space possibilities for students.PublishedBeijing, China1A. Geomagnetismo e Paleomagnetism

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer

A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects

Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study

Background: Molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. Patients and methods: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. Results: High PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15-1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). Conclusions: To our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors

Stereotactic MR-guided adaptive radiotherapy (SMART) for primary rectal cancer: evaluation of early toxicity and pathological response

Background: The purpose of this study is to measure the effects of stereotactic MR-guided adaptive radiotherapy (SMART) for rectal cancer patients in terms of early toxicity and pathological response. Materials and methods: For this prospective pilot study, patients diagnosed with locally advanced rectal cancer (LARC) with positive lymph node clinical staging underwent SMART on rectal lesion and mesorectum using hybrid MR-Linac (MRIdian ViewRay). Dose prescription at 80% isodose for the rectal lesion and mesorectum was 40 Gy (8 Gy/fr) and 25 Gy (5 Gy/fr), respectively, delivered on 5 days (3 fr/week). Response assessment by MRI was performed 3 weeks after SMART, then patients fit for surgery underwent total mesorectal excision. Primary endpoint was evaluation of adverse effect of radiotherapy. Secondary endpoint was pathological complete response rate. Early toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Results: From October 2020 to January 2022, twenty patients underwent rectal SMART. No grade 3–5 toxicity was recorded. Twelve patients were eligible for total mesorectal excision (TME). Mean interval between the completion of SMART and surgery was 4 weeks. Pathological downstaging occurred in all patients; rate of pathological complete response (pCR) was 17%. pCR occurred with a prolonged time to surgery (> 7 weeks). Conclusion: To our knowledge, this is the first study to use stereotactic radiotherapy for primary rectal cancer. SMART for rectal cancer is well tolerated and effective in terms of tumor regression, especially if followed by delayed surgery.

Nernst-Planck Based Description of Transport, Coulombic Interactions and Geochemical Reactions in Porous Media: Modeling Approach and Benchmark Experiments

Transport of multicomponent electrolyte solutions in saturated porous media is affected by the electrostatic interactions between charged species. Such Coulombic interactions couple the displacement of the different ions in the pore water and remarkably impact mass transfer not only under diffusion, but also under advection-dominated flow regimes. To accurately describe charge effects in flow-through systems, we propose a multidimensional modeling approach based on the Nernst-Planck formulation of diffusive/dispersive fluxes. The approach is implemented with a COMSOL-PhreeqcRM coupling allowing us to solve multicomponent ionic conservative and reactive transport problems, in domains with different dimensionality (1-D, 2-D, and 3-D), and in homogeneous and heterogeneous media. The Nernst-Planck-based coupling has been benchmarked with analytical solutions, numerical simulations with another code, and high-resolution experimental data sets. The latter include flow-through experiments that have been carried out in this study to explore the effects of electrostatic interactions in fully three-dimensional setups. The results of the simulations show excellent agreement for all the benchmarks problems, which were selected to illustrate the capabilities and the distinct features of the Nernst-Planck-based reactive transport code. The outcomes of this study illustrate the importance of Coulombic interactions during conservative and reactive transport of charged species in porous media and allow the quantification and visualization of the specific contributions to the diffusive/dispersive Nernst-Planck fluxes, including the Fickian component, the term arising from the activity coefficient gradients, and the contribution due to electromigration