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Context. Shadows in scattered light images of protoplanetary disks are a common feature and support the presence of warps or misalignments between disk regions. These warps are possibly caused by an inclined (sub-)stellar companion embedded in the disk. Aims. We aim to study the morphology of the protoplanetary disk around the Herbig Ae star HD 139614 based on the first scattered light observations of this disk, which we model with the radiative transfer code MCMax3D. Methods. We obtained J- and H-band observations that show strong azimuthal asymmetries in polarized scattered light with VLT/SPHERE. In the outer disk, beyond similar to 30 au, a broad shadow spans a range of similar to 240 deg in position angle, in the east. A bright ring at similar to 16 au also shows an azimuthally asymmetric brightness, with the faintest side roughly coincidental with the brightest region of the outer disk. Additionally, two arcs are detected at similar to 34 and similar to 50 au. We created a simple four-zone approximation to a warped disk model of HD 139614 in order to qualitatively reproduce these features. The location and misalignment of the disk components were constrained from the shape and location of the shadows they cast. Results. We find that the shadow on the outer disk covers a range of position angles too wide to be explained by a single inner misaligned component. Our model requires a minimum of two separate misaligned zones - or a continuously warped region - to cast this broad shadow on the outer disk. A small misalignment of similar to 4 degrees between adjacent components can reproduce most of the observed shadow features. Conclusions. Multiple misaligned disk zones, potentially mimicking a warp, can explain the observed broad shadows in the HD 139614 disk. A planetary mass companion in the disk, located on an inclined orbit, could be responsible for such a feature and for the dust-depleted gap responsible for a dip in the SED.

BACKGROUND: Radiofrequency current (RFC) catheter ablation for patients with paroxysmal atrial fibrillation (AF) has been shown to be safe and effective in first-line therapy. Recent data demonstrates that RFC ablation provides better clinical outcomes compared to antiarrhythmic drug (AAD) in the treatment of early AF disease. Furthermore, studies comparing RFC and cryoballoon have established comparable efficacy and safety of pulmonary vein isolation (PVI) for patients with symptomatic paroxysmal AF. OBJECTIVE(S): The Cryo-FIRST trial was designed to compare AAD treatment against cryoballoon PVI as a first-line therapy in treatment naive patients with AF. Efficacy and safety will be compared between the two cohorts and amongst subgroups. METHOD(S): The primary hypothesis is that cryoablation is superior to AAD therapy. To test this hypothesis, patients will be randomized in a 1:1 design. Using a 90-day blanking period, primary efficacy endpoint failure is defined as (at least) one episode of atrial arrhythmia with a duration >30 sec (documented by 7-day Holter or 12-lead ECG). Secondary endpoints (Quality-of-Life, rehospitalization, arrhythmia recurrence rate, healthcare utilization, and left atrial function) and adverse events will also be evaluated. Study enrollment will include 218 patients in up to 16 centers. CONCLUSION(S): This study will be a multi-national randomized controlled trial comparing cryoablation against AAD as a first-line treatment in patients with paroxysmal AF. The results may help guide the selection of patients for early AF disease therapy via cryoballoon ablation.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chronic lymphocytic leukemia (CLL) is characterized by a low CD20 expression, in part explained by an epigenetic-driven downregulation triggered by mutations of the NOTCH1 gene. In the present study, by taking advantage of a wide and well-characterized CLL cohort (n=537), we demonstrate that CD20 expression is downregulated in SF3B1-mutated CLL in an extent similar to NOTCH1-mutated CLL. In fact, SF3B1-mutated CLL cells show common features with NOTCH1-mutated CLL cells, including a gene expression profile enriched of NOTCH1-related gene sets and elevated expression of the active intracytoplasmic NOTCH1. Activation of the NOTCH1 signaling and down-regulation of surface CD20 in SF3B1-mutated CLL cells correlate with over-expression of an alternatively spliced form of DVL2, a component of the Wnt pathway and negative regulator of the NOTCH1 pathway. These findings are confirmed by separately analyzing the CD20-dim and CD20-bright cell fractions from SF3B1-mutated cases as well as by DVL2 knock-out experiments in CLL-like cell models. Altogether, the clinical and biological features that characterize NOTCH1-mutated CLL may also be recapitulated in SF3B1-mutated CLL, contributing to explain the poor prognosis of this CLL subset and providing the rationale for expanding novel agents-based therapies to SF3B1-mutated CLL.

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n 5 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d1 subpopulation and a CD49d2 subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d1 subpopulation over time after therapy. The CD49d1 subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d2 cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d1 subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d1 CLL, both in chemoimmunotherapy (n 5 1522) and in ibrutinib (n 5 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL.

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin protein superfamily, is broadly expressed on a wide variety of cell types, such as B lymphocytes, a subset of T lymphocytes, dendritic cells, endothelial and neuronal cells. It delivers immunosuppressive signals through its receptor CD200R, which is expressed on monocytes/myeloid cells and T lymphocytes. Moreover, interaction of CD200 with CD200R has also been reported to play a role in the regulation of tumor immunity. Overexpression of CD200 has been reported in chronic lymphocytic leukemia (CLL) and hairy cell leukemia but not in mantle cell lymphoma, thus helping to better discriminate between these different B cell malignancies with different prognosis. In this review, we focus on the role of CD200 expression in the differential diagnosis of mature B-cell neoplasms and on the prognostic significance of CD200 expression in CLL, where conflicting results have been published so far. Of interest, increasing evidences indicate that anti-CD200 treatment might be therapeutically beneficial for treating CD200-expressing malignancies, such as CLL.

1. Introduzione. - 2. Il confine del Terzo Settore (e del suo diritto) alla luce della sentenza n. 131/2020 della Corte costituzionale. - 3. Ai confini del Terzo settore (e del suo diritto) - 4. Il bene comune oltre il Terzo settore: quale diritto?

CD200 is a transmembrane type Ia glycoprotein belonging to theimmunoglobulin superfamily [1].It isexpressed byvariouscell types,such as B cells, a subset of T cells including activated T cells, thymo-cytes, endothelial cells, and neurons. CD200 surface expression hasbeenshowntohavearelevantroleinthedifferentialdiagnosisofB-cellchronic lymphoproliferative disorders (B-CLPDs) [2]. The major con-tributionofCD200istheabilitytodiscriminatebetweenchroniclym-phocytic leukemia (CLL) and mantle cell lymphoma (MCL), and be-tweenhairycellleukemiaanditsvariantform[3].Furthermore,ithasbeenalsodemonstratedaroleofCD200inthedifferentialdiagnosisofother forms of B-CLPDs, when incorporated in panels including othersurface markers [4,5]. However, little is known about the prognosticsignificanceofCD200expressioninCLL