Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model

Clonal myeloproliferation and development of bone marrow (BM) fibrosis are the major pathogenetic events in myelofibrosis (MF). The identification of novel antifibrotic strategies is of utmost importance since the effectiveness of current therapies in reverting BM fibrosis is debated. We previously demonstrated that osteopontin (OPN) has a profibrotic role in MF by promoting mesenchymal stromal cells proliferation and collagen production. Moreover, increased plasma OPN correlated with higher BM fibrosis grade and inferior overall survival in MF patients. To understand whether OPN is a druggable target in MF, we assessed putative inhibitors of OPN expression in vitro and identified ERK1/2 as a major regulator of OPN production. Increased OPN plasma levels were associated with BM fibrosis development in the Romiplostim-induced MF mouse model. Moreover, ERK1/2 inhibition led to a remarkable reduction of OPN production and BM fibrosis in Romiplostim-treated mice. Strikingly, the antifibrotic effect of ERK1/2 inhibition can be mainly ascribed to the reduced OPN production since it could be recapitulated through the administration of anti-OPN neutralizing antibody. Our results demonstrate that OPN is a novel druggable target in MF and pave the way to antifibrotic therapies based on the inhibition of ERK1/2-driven OPN production or the neutralization of OPN activity

Cerebral large-vessel vasculitis as an unusual manifestation of POEMS syndrome

non present

MAORY science merit function for the one vs two post-focal DMs configurations

Documento tecnico presentato come parte della documentazione per la Preliminary Design Review di MORFEO (MAORY) alla commissione ESO. Questo documento è stato discusso e quindi accettato in fase di chiusura della Preliminary Design Review e distribuito all'interno di ESO.MORFEO, formerly known as MAORY, is the multi-conjugate adaptive optics module for the ESO Extremely Large Telescope (ELT). We present the description of the analysis to compare on a scientific basis the one and two post-focal Deformable Mirrors (DM) configurations of MAORY. We aim to compare the two configurations proposed for the MAORY adaptive optics design, including in the optical path one or two post-focal DMs

MAORY + MICADO scientific analysis of the 1pfDM versus 2pfDM performance with realistic atmospheric profiles

Documento tecnico presentato alla preliminary design review di MORFEO (MAORY) a sostegno della soluzione a due specchi deformabili post focali. Il documento è stato accettato dalla commissione ESO e quindi presentato e distribuito all'interno di ESO.This document shows that the implementation of a 2nd pfDM in MAORY would have an impressive impact on the scientific productivity of MAORY+MICADO. An exhaustive analysis of the 1pfDM versus 2pfDM photometric, astrometric and sky coverage performances was carried out based on realistic atmospheric profiles that take into account a wide range of observing conditions. The effect of the 2nd pfDM is to increase image quality and its stability under variations of atmospheric turbulence and seeing conditions, and more dramatically for bluer filters than for redder ones. The 2nd pfDM also significantly improves the spatial homogeneity of the point spread function, allowing for the restoration of the full 2 arcmin MAORY field of view, with consequent impact on the natural reference stars region and on the sky coverage. In terms of scientific performances, this means: ●The sensitivity one can expect for a typical target in typical conditions will increase by 1 mag in K-band (equivalently 2 mag in H-band and over 3 mag in J-band). A 1 mag difference corresponds to a factor 6 reduction in telescope time to reach the same signal-to-noise on faint point sources. This is invaluable for deep integrations on faint targets as well as efficient use of telescope time. ● The fraction of targets for which a scientifically useful minimum Strehl ratio can be achieved (sky coverage) will increase by a factor 2-6 in K-band. This is invaluable for target selection as well as programme scheduling on the telescope. ● The astrometric accuracy over the (zoomed-in, reduced) MICADO FoV will be impacted by 20% in high SNR conditions (>200) corresponding to the range baseline-goal of the MAORY requirements. These results are of extreme importance because they are related to the selection of targets based primarily on astrophysical rather than on technical criteria as well as to the need to achieve good AO performance in moderate atmospheric conditions to enable efficient long integrations, as highlighted by Davies & Kasper (2012) among the lessons learned in their adaptive optics review. Indeed, without the 2nd pfDM there will be a significant loss for science cases about the dynamics of dense stellar systems and black holes in galaxies, while resolved stellar population, Galactic Centre, and galaxy evolution studies will be affected in a major way

Mechanical thrombectomy in patients with heart failure: the Italian registry of Endovascular Treatment in Acute Stroke

Background: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF. Methods: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed. Results: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0-2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24-1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05-1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results. Conclusion: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments

Association between procedural time and outcome in unsuccessful mechanical thrombectomy for acute ischemic stroke: analysis from the Italian Registry of Endovascular Treatment in Acute Stroke

Background We aim to assess the association between procedural time and outcomes in patients in unsuccessful mechanical thrombectomy (MT) for anterior circulation acute stroke. Methods We conducted a cohort study on prospectively collected data from patients with M1 and/or M2 segment of middle cerebral artery occlusion with a thrombolysis in cerebral infarction 0-1 at the end of procedure. Primary outcome was 90-day poor outcome. Secondary outcomes were early neurological deterioration (END), symptomatic intracranial hemorrhage (sICH) according to ECASS II and sICH according to SITS-MOST. Results Among 852 patients, after comparing characteristics of favourable and poor outcome groups, logistic regression analysis showed age (OR: 1.04; 95%CI: 1.02-1.05; p < 0.001), previous TIA/stroke (OR: 0.23; 95%CI: 0.12-0.74; p = 0.009), M1 occlusion (OR: 1.69; 95%CI: 1.13-2.50; p = 0.01), baseline NIHSS (OR: 1.01; 95%CI: 1.06-1.13; p < 0.001) and procedural time (OR:1.00; 95% CI: 1.00-1.01; p = 0.003) as independent predictors poor outcome at 90 days. Concerning secondary outcomes, logistic regression analysis showed NIHSS (OR:0.96; 95%CI: 0.93-0.99; p = 0.008), general anaesthesia (OR:2.59; 95%CI: 1.52-4.40; p < 0.001), procedural time (OR: 1.00; 95% CI: 1.00-1.01; p = 0.002) and intraprocedural complications (OR: 1.89; 95%CI: 1.02-3.52; p = 0.04) as independent predictors of END. Bridging therapy (OR:2.93; 95%CI: 1.21-7.09; p = 0.017) was associated with sICH per SITS-MOST criteria whereas M1 occlusion (OR: 0.35; 95%CI: 0.18-0.69; p = 0.002), bridging therapy (OR: 2.02; 95%CI: 1.07-3.82; p = 0.03) and intraprocedural complications (OR: 5.55; 95%CI: 2.72-11.31; p < 0.001) were independently associated with sICH per ECASS II criteria. No significant association was found between the number of MT attempts and analyzed outcomes. Conclusions Regardless of the number of MT attempts and intraprocedural complications, procedural time was associated with poor outcome and END. We suggest a deeper consideration of procedural time when treating anterior circulation occlusions refractory to MT