La mielofibrosi nell’era degli inibitori di JAK2: efficacia ed aspetti molecolari della terapia con Ruxolitinib.

La mielofibrosi è una neoplasia mieloproliferativa cronica caratterizzata da variabile fibrosi midollare, presenza nel sangue periferico di elementi immaturi della linea granulocitaria ed eritroblastica, evidente anisopoichilocitosi ed emopoiesi extramidollare, con associata epatosplenomegalia. Esistono forme di mielofibrosi primitiva (MFI) e mielofibrosi secondaria ad altre neoplasie mieloproliferative croniche, quali la policitemia vera (MF-post-PV) e la trombocitemia essenziale (MF post-TE). Recentemente è stato identificato giocare un ruolo importante nella patogenesi della MF il gene JAK2, la cui mutazione in posizione V617F ne provoca una costante iperattivazione. A seguito di tale scoperta, è stato messo a punto Ruxolitinib, farmaco capace di inibire JAK1 e 2, attualmente in indicazione negli U.S.A. ed in Europa per il trattamento della mielofibrosi. I nostri obiettivi sono stati: 1) confronto dei dati sulla sicurezza e tossicità del farmaco ruxolitinib (INC424) somministrato all’interno dello studio in aperto, multicentrico, di accesso allargato CINC424A2401 a pazienti con mielofibrosi primaria e secondaria seguiti presso la UO Ematologia di Pisa, con i risultati degli studi COMFORT I e COMFORT II (i trials che hanno portato all'approvazione di ruxolitinib); 2) studio dei profili di espressione dei miRNA negli stessi pazienti di cui sopra con l'intento di investigarne la funzione in relazione ai geni targets. Dai dati raccolti è emerso che i risultati ottenuti dai 14 pazienti in trattamento con Ruxolitinib, seguiti presso UO Ematologia di Pisa, sono per la maggior parte sovrapponibili a quelli degli studi COMFORT. In particolar modo possiamo affermare che la diminuzione della splenomegalia, così come dei sintomi sistemici, è stata, in media, del 32,3% vs il 35% dei risultati degli studi COMFORT. Per quanto riguarda lo studio dei profili di espressione dei miRNA, effettuato su 4 dei 14 pazienti in trattamento con Ruxolitinib, è emerso che 9 miRNA risultano significativamente deregolati nella mielofibrosi, attribuendo ad essi un possibile ruolo di biomarkers all’interno della terapia farmacologica con anti-JAK2

Reconstructing eruptive source parameters from tephra deposit: a numerical study of medium-sized explosive eruptions at Etna volcano

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Rapid emergency assessment of ash and gas hazard for future eruptions at Santorini Volcano, Greece

Hazard assessments for long-dormant volcanoes, where information is rarely available, typically have to be made rapidly and in the face of considerable uncertainty and often poor information. A conditional (assuming an eruption), scenario-based probabilistic approach to such an assessment is presented here for Santorini volcano (Greece). The rapid assessment was developed and implemented in response to the 2011-2012 unrest crisis in order to inform emergency management and planning. This paper synthesises the results presented to the Greek National Committee and scientific community involved. Two plausible eruptions at Santorini were investigated, using multiple inputs and dispersal models, based on observations of historic eruptions and expert judgement. For ash hazard, a 'most likely' eruption scenario was developed, characterised by slow lava extrusion over periods of one to two years with weak but persistent explosions and ash venting up to 3 km. A second 'largest considered' sub-Plinian explosive scenario assumed a 12 km high column of 4-h duration. For gas hazard, constant fluxes of 200 and 800 tons/day SO2 were assumed for the duration of the eruption scenarios, noting that there is very little evidence to constrain SO2 flux from Santorini eruptions. Statistical models of likely wind conditions with height and season were developed from decadal reanalysis time series showing that consistent low-altitude winds were rarely maintained for more than a few days. Stochastic models of ash (TEPHRA2, VOL-CALPUFF) and gas (AERMOD) dispersal provided outputs in the form of probability maps and exceedance probability curves for key loading and concentration thresholds at important locations on the island. The results from the rapid assessments presented in this paper confirm that ash and gas hazard is likely to be of concern if an eruption of Santorini occurs. Higher hazard may be expected to the south and east of the volcano, notably at important tourist and transport hubs. Low hazard to the north and northwest suggests that these may be suitable locations for emergency response centres and emergency critical infrastructure. This approach may provide a blueprint for rapid ash and gas assessment for other long-dormant volcanoes and we provide suggestions for refining the methods used.</p

Ruolo dell'imaging nella diagnosi di iperparatiroidismo

Abstract non disponibil

Combining robotics with enhanced serotonin-driven cortical plasticity improves post-stroke motor recovery.

Despite recent progresses in robotic rehabilitation technologies, their efficacy for post-stroke motor recovery is still limited. Such limitations might stem from the insufficient enhancement of plasticity mechanisms, crucial for functional recovery. Here, we designed a clinically relevant strategy that combines robotic rehabilitation with chemogenetic stimulation of serotonin release to boost plasticity. These two approaches acted synergistically to enhance post-stroke motor performance. Indeed, mice treated with our combined therapy showed substantial functional gains that persisted beyond the treatment period and generalized to non-trained tasks. Motor recovery was associated with a reduction in electrophysiological and neuroanatomical markers of GABAergic neurotransmission, suggesting disinhibition in perilesional areas. To unveil the translational potentialities of our approach, we specifically targeted the serotonin 1A receptor by delivering Buspirone, a clinically approved drug, in stroke mice undergoing robotic rehabilitation. Administration of Buspirone restored motor impairments similarly to what observed with chemogenetic stimulation, showing the immediate translational potential of this combined approach to significantly improve motor recovery after stroke

Surveying volcanic crises exercises: From open-question questionnaires to a prototype checklist

Volcanic crisis exercises are usually run to test response capabilities, communication protocols, and decision-making procedures by agencies with responsibilities to cope with scenarios of volcanic unrest with inherent uncertainty, such as volcano observatories and/or civil protection authorities. During the last decades, the use of questionnaires has been increased to evaluate people's knowledge on volcanic hazards and their perception of risk, to better understand their preparedness to respond to emergency measures plans. In this paper, we present a study carried out within the European Network of Observatories and Research Infrastructures for Volcanology project (EUROVOLC) focused on extracting information on the experience gained during volcanic-crisis exercises by the project's participants and beyond. An open-ended question questionnaire was firstly distributed for a survey within the project community. Through the results obtained, we developed a user-friendly online multi-choice questionnaire that was submitted to the volcanological communities within and outside EUROVOLC. Analyzing the answers to the online questionnaire, we extracted a prototype checklist for guiding the design of such exercises in the future. Our results confirm this type of survey as a very useful tool for gathering information on participants' experience and knowledge, able to understand which data and information may be useful when designing exercises for scientists, emergency managers and decision makers. In particular, the main lessons learnt regard the need i) to increase training activities involving people exposed to volcanic hazards and media, ii) to improve external communication tools (between players and public/media), equipment and protocols and iii) to better define decision-makers' needs

Increased respiratory morbidity associated with exposure to a mature volcanic plume from a large Icelandic fissure eruption.

The 2014-15 Holuhraun eruption in Iceland was the largest fissure eruption in over 200 years, emitting prodigious amounts of gas and particulate matter into the troposphere. Reykjavík, the capital area of Iceland (250 km from eruption site) was exposed to air pollution events from advection of (i) a relatively young and chemically primitive volcanic plume with a high sulphur dioxide gas (SO2) to sulphate PM (SO42-) ratio, and (ii) an older and chemically mature volcanic plume with a low SO2/SO42- ratio. Whereas the advection and air pollution caused by the primitive plume were successfully forecast and forewarned in public advisories, the mature plume was not. Here, we show that exposure to the mature plume is associated with an increase in register-measured health care utilisation for respiratory disease by 23% (95% CI 19.7-27.4%) and for asthma medication dispensing by 19.3% (95% CI 9.6-29.1%). Absence of public advisories is associated with increases in visits to primary care medical doctors and to the hospital emergency department. We recommend that operational response to volcanic air pollution considers both primitive and mature types of plumes

REFIR- a multi-parameter system for near real-time estimates of plume-height and mass eruption rate during explosive eruptions

Meaningful forecasting of the atmospheric concentration and ground accumulation of volcanic ash during explosive eruptions requires detailed knowledge of the eruption source parameters. However, due to the large uncertainties in observations and limitations of current models used to make inferences from these, monitoring an ongoing eruption and quantifying the mass eruption rate in real-time is a considerable challenge. Within the EU supersite project “FutureVolc”, an integrated approach has been applied to develop a quasi-autonomous multi-parameter system, denoted “REFIR”, for monitoring volcanic eruptions in Iceland and assessing the eruption mass flow rate by inverting the plume height information and taking account of these uncertainties. REFIR has the capability to ingest and process streaming plume-height data provided by a multitude of ground based sensors, including C– and X-band radars and web-cam based plume height tracking systems. These observational data are used with a suite of plume models that also consider the current wind and other atmospheric conditions, providing statistically assessed best estimates of plume height and mass eruption rate. Provided instrumental data is available, near real-time estimates are obtained (the delay corresponding to the scan rate of data-providing instruments, presently of the order of minutes). Using the Hekla 2000, and Eyjafjallajökull 2010 eruptions in Iceland, the potential of REFIR is demonstrated and discussed through application to three scenarios. The system has been developed to provide maximum flexibility. A setup script assists the user in adapting to local conditions, allowing implementation of REFIR for any volcanic eruption site worldwide. REFIR is designed to be easily upgradable, allowing future extension of monitoring networks, learning from new events, and incorporation of new technologies and model improvements. This article gives an overview of the basic structure, models implemented, functionalities and the computational techniques of REFIR

D-aspartate oxidase gene duplication induces social recognition memory deficit in mice and intellectual disabilities in humans

The D-aspartate oxidase (DDO) gene encodes the enzyme responsible for the catabolism of D-aspartate, an atypical amino acid enriched in the mammalian brain and acting as an endogenous NMDA receptor agonist. Considering the key role of NMDA receptors in neurodevelopmental disorders, recent findings suggest a link between D-aspartate dysmetabolism and schizophrenia. To clarify the role of D-aspartate on brain development and functioning, we used a mouse model with constitutive Ddo overexpression and D-aspartate depletion. In these mice, we found reduced number of BrdU-positive dorsal pallium neurons during corticogenesis, and decreased cortical and striatal gray matter volume at adulthood. Brain abnormalities were associated with social recognition memory deficit at juvenile phase, suggesting that early D-aspartate occurrence influences neurodevelopmental related phenotypes. We corroborated this hypothesis by reporting the first clinical case of a young patient with severe intellectual disability, thought disorders and autism spectrum disorder symptomatology, harboring a duplication of a chromosome 6 region, including the entire DDO gene