NK Cell Levels Correlate with Disease Activity in Patients with Multiple Sclerosis on Ocrelizumab/Rituximab Therapy

Background: Recently, research on the pathogenesis of multiple sclerosis (MS) has focused on the role of B lymphocytes and the possibility of using specific drugs, such as Ocrelizumab and Rituximab, directed toward these cells to reduce inflammation and to slow disease progression. Objective: We aimed to evaluate the effect of Ocrelizumab/Rituximab on laboratory immune parameters and identify the predictors of treatment responses. Methods: A retrospective single-center study was conducted among patients who received infusion therapy with an anti-CD20 drug to treat MS. Results: A total of 64 patients met the inclusion criteria, with 277 total cycles of therapy studied. Compared with the baseline values, anti-CD20 infusions resulted in absolute-value and percentage decreases in B lymphocyte levels and increased the absolute and percentage levels of NK cells 3 and 5 months after therapy (p < 0.001). After multivariate logistic regression analysis, a reduced percentage level of NK cells 3 months after infusion could predict disease activity 6 months after Ocrelizumab/Rituximab administration (p = 0.041). Conclusions: Lower percentage levels of NK cells 3 months after anti-CD20 infusion correlate with the presence of disease activity 6 months after therapy, confirming a possible protective role of NK cells in MS

C7 is expressed on endothelial cells as a trap for the assembling terminal complement complex and may exert anti-inflammatory function

We describe a novel localization of C7 as a membrane-bound molecule on endothelial cells (ECs). Data obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot analysis, Northern blot analysis, and mass spectrometry revealed that membrane- associated C7 (mC7) was indistinguish-able from soluble C7 and was associated with vimentin on the cell surface. mC7 interacted with the other late complement components to form membrane-bound TCC (mTCC). Unlike the soluble SC5b-9, mTCC failed to stimulate ECs to express adhesion molecules, to secrete IL-8, and to induce albumin leakage through a monolayer of ECs, and more importantly protected ECs from the proinflammatory effect of SC5b-9. Our data disclose the possibility of a novel role of mC7 that acts as a trap for the late complement components to control excessive inflammation induced by SC5b-9. \ua9 2009 by The American Society of Hematology

Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma

A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases

Relationship between cytokine release and stress hyperglycemia in patients hospitalized with COVID-19 infection

Introduction: Stress hyperglycemia is a frequent finding in patients with COVID-19 infection and could affect the outcome of disease. Cytokines released in response to infection could have adverse effects on insulin sensitivity and pancreatic beta-cell function. The aim of the study was to examine the relationships of stress hyperglycemia with cytokines and clinical outcomes in hospitalized patients with COVID-19. Methods: In a cross-sectional analysis of 150 patients hospitalized for COVID-19 infection who were included in the GIRA-COVID database, we identified patients with stress hyperglycemia by calculation of the Stress Hyperglycemia Ratio (SHR) and use of a cut-off of 1.14. Plasma levels of cytokines principally involved in COVID-19 infection-related cytokine storm were measured. Outcome variables were use of mechanical ventilation and death within 60 days from hospital admission. Results: Patients with SHR > 1.14 had significantly higher plasma insulin, HOMA-index, and levels of interleukin-10 (IL-10), interleukin-10/tumor necrosis factor-a ratio (IL-10/TNF-α), and CXC motif chemokine ligand 10 (CXCL10) than patients with SHR ≤ 1.14. IL-10, IL-10/TNF-α ratio, CXCL10, and IFN-γ were significantly and directly related with SHR in univariate analysis and multivariate logistic regression models showed that IL-10, IL-10/TNF-α ratio, and CXCL10 were independently associated with SHR>1.14. In a multivariate logistic model, stress hyperglycemia predicted use of mechanical ventilation (OR 2.453; CI 1.078–6.012) and death (OR 2.281; CI 1.049–7.369) independently of diabetes and other major confounders. Conclusions: In patients hospitalized for COVID-19 infection, stress hyperglycemia is associated with worse clinical outcomes and is independently related to levels of cytokines that might impair glucose homeostasis

Local variability of the ground shaking during the 2009 L’Aquila earthquake (April 6, 2009—Mw 6.3): the case study of Onna and Monticchio villages

The 2009 Mw 6.3 L’Aquila event caused extensive damage in the city of L’Aquila and in some small towns in its vicinity. The most severe damage was recognized SE of L’Aquila town along the Aterno river valley. Although building vulnerability and near-source effects are strongly responsible for the high level of destruction, site effects have been invoked to explain the damage heterogeneities and the similarities between the 2009 macroseismic field with the intensities of historical earthquakes. The small village of Onna is settled on quaternary alluvium and suffered during the L’Aquila event an extremely heavy damage in the masonry structures with intensity IX–X on the Mercalli-Cancani-Sieberg (MCS) scale. The village of Monticchio, far less than 1.3 km from Onna, is mostly situated on Meso- zoic limestone and suffered a smaller level of damaging (VI MCS). In the present paper, we analyze the aftershock recordings at seismic stations deployed in a small area of the middle-Aterno valley including Onna and Monticchio. The aim is to investigate local ampli-fication effects caused by the near-surface geology. Because the seismological stations are close together, vulnerability and near-source effects are assumed to be constant. The wave- form analysis shows that the ground motion at Onna is systematically characterized by large high-frequency content. The frequency resonance is varying from 2 to 3 Hz and it is related to alluvial sediments with a thickness of about 40 m that overlay a stiffer Pleistocene substrate. The ground motion recordings of Onna are well reproduced by the predictive equation for the Italian territory.Published783-8072T. Sorgente SismicaJCR Journalreserve

Overview of the first HyMeX Special Observation Period over Italy: observations and model results

Abstract. The Special Observation Period (SOP1), part of the HyMeX campaign (Hydrological cycle in the Mediterranean Experiments, 5 September–6 November 2012), was dedicated to heavy precipitation events and flash floods in the western Mediterranean, and three Italian hydro-meteorological monitoring sites were identified: Liguria–Tuscany, northeastern Italy and central Italy. The extraordinary deployment of advanced instrumentation, including instrumented aircrafts, and the use of several different operational weather forecast models, including hydrological models and marine models, allowed an unprecedented monitoring and analysis of high-impact weather events around the Italian hydro-meteorological sites. This activity has seen strong collaboration between the Italian scientific and operational communities. In this paper an overview of the Italian organization during SOP1 is provided, and selected Intensive Observation Periods (IOPs) are described. A significant event for each Italian target area is chosen for this analysis: IOP2 (12–13 September 2012) in northeastern Italy, IOP13 (15–16 October 2012) in central Italy and IOP19 (3–5 November 2012) in Liguria and Tuscany. For each IOP the meteorological characteristics, together with special observations and weather forecasts, are analyzed with the aim of highlighting strengths and weaknesses of the forecast modeling systems, including the hydrological impacts. The usefulness of having different weather forecast operational chains characterized by different numerical weather prediction models and/or different model set up or initial conditions is finally shown for one of the events (IOP19)

NERA project - Deliverable D11.4: Array measurements

The aim of this Task is to present the seismological data and some preliminary empirical results related to two deployed specific arrays; (a) the Argostoli seismological array and (b) the Fucino seismological array. Both experiment arrays provided high quality data that along with corresponding geological and geophysical measurements may serve to critical evaluation of site effects and basin effects. In addition, work on modelling of basin effects may be significantly benefited by the observed acquired in both sites. Given that the analyses of the data obtained during the aforementioned experimental arrays will be performed in close link with activity of NERA-JRA3, the following goals are set: To investigate the link between ground motion spatial variability, strains, seismic wavefield and subsurface properties To compare numerical estimates of ground strain with actual measurements To investigate the capability of estimating ground strains from noise correlation studies. In order to organize and accomplish the work according to the initial schedule, several meetings (actual or/and Skype) among the participants took place during the 2nd year of the NERA-JRA1 project. Minutes of these meetings are given in Appendices 1, 2, 3 and 4.Network of European Research Infrastructures for Earthquake Risk Assessment and Mitigation Project, Seventh Framework Programme EC project number: 262330Published4T. Sismologia, geofisica e geologia per l'ingegneria sismic

Le reti sismica e geodetica di pronto intervento dell’INGV: un primo impiego a seguito del terremoto de L’Aquila del 6 aprile 2009

Durante gli ultimi due anni l’Istituto Nazionale di Geofisica e Vulcanologia (INGV) ha sviluppato un importante infrastruttura di pronto intervento (la Rete Mobile Real-Time di Pronto Intervento), al fine di incrementare il numero di stazioni della Rete Sismica Nazionale dell’INGV (RSN) in zona epicentrale a seguito di eventi sismici rilevanti. Gli obiettivi principali della Rete Mobile Real-Time di Pronto Intervento sono il miglioramento delle localizzazioni epicentrali calcolate dalla Sala di Monitoraggio dell’INGV e l’abbassamento della soglia di detezione della micro-sismicità in area epicentrale durante una sequenza sismica. La Rete Mobile Real-Time di Pronto Intervento è composta da stazioni sismiche remote i cui dati sono telemetrati tramite ponte radio UHF (Ultra High Frequency) presso dei centri d’acquisizione intermedi (definiti “sottonodi”). I sottonodi sono a loro volta connessi tramite Wi-Fi ad un “centro stella” (nodo), ove è situato un sistema di trasmissione satellitare (Libra VSAT Nanometrics), tramite il quale vengono inviati i dati in tempo reale al centro acquisizione della Sala di Monitoraggio dell’INGV di Roma. L’acquisizione dati è ridondata inoltre presso la sala Disaster Recovery dell’Osservatorio di Grottaminarda. Il sistema d’acquisizione di dati sismici è costituito da un datalogger a tre canali, equipaggiato con un convertitore AD ad alta risoluzione (a 24 bit), dotato di un clock di precisione basato su timing GPS. I sensori sismici utilizzati presso le stazioni remote sono accelerometri Episensor FBA ES-T (Kinemetrics) con fondo scala a 2G e velocimetri a corto periodo (Lennartz Le Lite 3D). Il sistema di trasmissione dati, come accennato, si avvale di diversi apparati installati presso le stazioni remote, i sottonodi, ed il centro stella. Presso le stazioni remote è installato un radio modem operante in banda UHF (da 380 a 470 MHz), per il trasferimento trasparente di dati asincroni in modalità half-duplex. L’apparato modula in etere a 9.600 bps, realizzando collegamenti da 2 a 50 chilometri, in funzione dell’orografia locale e del sistema d’antenna utilizzato. Presso i sottonodi viene utilizzato un apparato WiFi (Wireless Fidelity) operante con frequenza di 2.4 GHz per collegamenti IP fino a 54 Mbit/s. Presso i sottonodi i dati sismici ricevuti dalle stazioni remote vengono inviati, tramite ponte Wi-Fi, al centro stella. Presso il centro stella la trasmissione dati avviene tramite il ricetrasmettitore Cygnus Nanometrics. Esso permette l’invio dei dati ricevuti alla Sala di Monitoraggio tramite collegamento satellitare. Il protocollo di trasmissione satellitare dedicato sul link VSAT è di tipo IP, ma può avvenire anche su apparati esterni quali fibra ottica, linee telefoniche, ecc. Per conseguire una maggiore flessibilità d’impiego, tale sistema dispone di due differenti frequenze di trasmissione, disponibili su satellite Intelsat ed HellaSat. Tutto ciò permette di orientare la parabola in due diverse direzioni, in modo da poter ovviare l’eventuale presenza di ostacoli come alberi, montagne o edifici. L’intera struttura racchiude queste tre diverse tecnologie di trasmissione dati (UHF, Wi-Fi e satellitare) al fine di garantire maggiore flessibilità di utilizzo; questo permette di affrontare l’emergenza sismica in tutte le condizioni logistiche e/o meteorologiche mirando a rapidi tempi di intervento (raggiungimento della zona epicentrale e istallazione). L’installazione della Rete Mobile Real-Time di Pronto Intervento viene gestita e coordinata all’interno di un Sistema Informativo Geografico (GIS) che consente la scelta della disposizione geografica ottimale delle stazioni della rete di pronto intervento intorno all’area epicentrale. Il database geografico utilizzato durante l’emergenza sismica contiene informazioni territoriali di vario tipo in area epicentrale. L’INGV dispone infatti di database geografici contenenti dati territoriali di tutto il territorio nazionale le cui categorie, utili ai fini della gestione dell’emergenza sismica, sono: Ubicazione delle stazioni delle reti di monitoraggio; Cartografia topografica IGM (1:25000, 1:50000, 1:100000); Modello digitale del terreno IGM; Uso del suolo; Viabilità e grafo stradale; Catologhi di sismicità storica e strumentale; Mappe di pericolosità sismica e del territorio; Database delle Sorgenti sismogenetiche; Mappe di scuotimento; Mappe di osservazioni macrosismiche. I dati sopra elencati sono utilizzati per la realizzazione di analisi di superficie (surface spatial analysis, Viewshed, Observer Point) che consentono la produzione di scenari utili per l’individuazione delle aree più favorevoli alla collocazione degli apparati della rete Real Time. Il terremoto de L’Aquila del 6 aprile 2009 è stato il primo caso di utilizzo dell’intera infrastruttura di pronto intervento. A meno di 6 ore dalla scossa principale (Mw 6.3 delle ore 01:32 GMT) il primo accelerometro inviava già dati alla Sala di Monitoraggio dell’INGV di Roma. A 3 giorni dall’evento la struttura di pronto intervento installata era costituita da 9 stazioni sismiche real-time. Oltre alla Rete Real Time di Pronto Intervento l’INGV ha installato 5 nuove stazioni GPS permanenti nel territorio abruzzese a seguito dell’evento del 6 aprile (Fig. 3). Le stazioni GPS permanenti presenti nel settore aquilano precedentemente al terremoto erano infatti caratterizzate da un’interdistanza troppo elevata, tale da non consentire una risoluzione spaziale adeguata del campo di spostamento co- e postsismico. A poche ore di distanza dall’evento sismico del 6 aprile si è quindi attivata una squadra di pronto intervento dell’INGV coadiuvata anche da personale del DPC-Ufficio Sismico e dell’ISPRA. A partire dal 7 aprile 2009, e fino al 17 dello stesso mese, sono state installate 5 nuove stazioni GPS permanenti (3 stazioni appartenenti alla Rete Integrata Nazionale GPS dell’INGV, 1 stazione del DPC-Ufficio Sismico ed una stazione dell’ISPRA) nei settori limitrofi all’epicentro della scossa principale della sequenza dell’aquilano. In tutte e 5 i casi la stazione GPS è stata monumentata, installata e avviata nell’arco di 5-6 ore. Su tutte le stazioni GPS è stata impostata sia un’acquisizione del dato GPS a 30 secondi sia un ringbuffer con campionamento a 10 Hz, in modo da permettere la registrazione dell’intera deformazione cosismica (sia statica che dinamica) in caso di ulteriore evento sismico. Nelle settimane successive è stata poi ottimizzata la trasmissione dei dati GPS, utilizzando un sistema di trasmissione dati via GPRS/UMTS implementato dal ST-Osservatorio di Grottaminarda.PublishedTrieste- Italy1.1. TTC - Monitoraggio sismico del territorio nazionaleope

Evaluation of the local site effects in the upper and middle Aterno valley

In the months following the April 6th, 2009, L’Aquila earthquake, several Italian and foreign research institutions installed dozens of seismic stations to monitor more than 100 localities with the aim of studying the local site effects in the epicentral area (upper and middle Aterno valley). The stations (accelerometers and velocimeters) have been deployed inside or very close to the inhabited areas. Among the investigated sites there are Onna, where almost the totality of the buildings collapsed, and the historic centre of L’Aquila, both towns suffering many casualties. The preliminary results for the examined sites show an extreme variability of ground motion and significant amplification for the most damaged localities.In press4.1. Metodologie sismologiche per l'ingegneria sismicaN/A or not JCRope