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Objective: To evaluate activity and safety of obinutuzumab-miniCHOP (Ga101-miniCHOP) combination in older patients with Diffuse Large B-Cell Lymphoma (DLBCL) unfit to receive full dose immunochemotherapy., Materials and Methods: We conducted a Simon's two-stage phase II multicenter trial to investigate response rate (primary endpoint) and safety of six courses of Ga101-miniCHOP in older patients with DLBCL (≥65 years), prospectively defined as unfit according to a simplified Comprehensive Geriatric Assessment (sCGA)., Results: Overall, 34 patients were enrolled (median age 82 years; range 68-89), with 27 out of the 33 eligible patients completing all six planned courses. Complete Remission (CR) rate was reported in fourteen patients (42%). After a median follow-up of sixteen months, the two-year Progression Free and Overall Survival (PFS and OS) were 49% (95% Confidence Interval (CI), 28 to 67) and 68% (95% CI, 49 to 81), respectively. The most frequent grade 3-4 adverse event was neutropenia in thirteen patients (26%)., Conclusions: Based on the observed CR rate, study accrual was interrupted due to the very low probability of demonstrating the initial study hypothesis that Ga101-miniCHOP could improve results of historical data obtained with R-miniCHOP in this group of patients. Nonetheless, results achieved with the 33 treated patients confirm activity and good tolerability of the Ga101-miniCHOP regimen for older unfit adult patients with DLBCL., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression., Methods and Results: Apolipoprotein-E (ApoE) -/- mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE -/- /ICAM-1 -/- ) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1., Conclusions: Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Drospirenone (DRSP) is an antialdosterone agent with progestogenic and antiandrogenic effects. This compound, has been recently used in combination with 17β-estradiol (E2) as hormonal therapy in postmenopausal women and has been shown to exert a significant antihypertensive effect in hypertensive post-menopausal women. Aim of the present study was to compare the effect of DRSP/E2 with those of Tibolone (T) on endothelial function, arterial stiffness, and lipid profile of early postmenopausal women naïve on post-menopausal hormonal therapy. Twenty-four women met the inclusion criteria and entered the study. Women were randomized to receive either DRSP/E2 or T for 6months. Blood pressure and heart rate were similar in both groups at baseline and at the end of the study. Compared to baseline, endothelial function assessed by Reactive Hyperemia (RH) significantly improved in women receiving E2/DRSP, whereas no significant differences between baseline and follow up were detected in women receiving Tibolone. Women receiving E2/DRSP showed a significant decrease in pulse wave velocity and Augmentation Index compared to baseline while no changes were observed in women receiving Tibolone. The capacity of sera to trigger endothelial cells apoptosis in vitro measured by cell death assay was significantly reduced by E/DRSP but not by T (HFA-E 70±5,6% vs HFD-E 41±4,5%, p<0,001). In conclusion, the present study shows that the association of Estradiol and Drospirenone as hormonal replacement therapy significantly improves vascular parameters and the composition of sera relevant for vascular protection in early post-menopausal normotensive women. These effects are not shared by Tibolone., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Endothelial cells (ECs) represent a major source of actively secreted adenosine triphosphate (ATP). Natural killer (NK) cells can mediate vascular injury in several pathologic conditions, including cytomegalovirus infection and vascular leak syndrome. We studied NK-cell expression of P2 receptors and the role of these nucleotide receptors in the regulation of endothelial-NK cell cross-talk. NK cells from healthy subjects expressed P2Y(₁,₂,₄,₆,₁₁,₁₂,₁₃,₁₄) and P2X(₁,₄,₅,₆,₇) receptors. NK cells stimulated with ATP, but not uridine triphosphate, increased intracellular Ca²(+) and chemokinesis. Moreover, ATP, but not uridine triphosphate, inhibited NK chemotaxis in response to CX₃CL1, whereas chemotaxis to CXCL12 was increased. CX₃CL1 elicited killing of human umbilical vein ECs and human coronary artery ECs by NK cells. However, in the presence of ATP, CX₃CL1 failed to stimulate killing of ECs. Such inhibitory effect was lost on exogenous addition of the ATP-hydrolyzing enzyme apyrase or by pharmacologic inhibition of the P2Y₁₁R, and correlated with increased intracellular cyclic adenosine monophosphate concentrations induced by ATP or other P2Y₁₁R agonists, including NAD(+). Extracellular ATP regulates NK-cell cytotoxicity via P2Y₁₁R activation, protecting ECs from CX₃CL1-elicited NK cell-mediated killing. These findings point out the P2Y₁₁R as a potential target for pharmacologic intervention aimed at reducing NK-mediated vascular injury.

Aims: To evaluate whether metabolic syndrome MS has a gender dependent effect on the recovery of functional capacity in patients (pts) with coronary heart disease (CHD) undergoing a cardiac rehabilitation program., Methods and Results: We studied 286 CHD patients, age 66.2+/-10.6 (median+/-SD); M/F 187/99. Patients were divided into two groups according to the presence (MS, 48%) or not (nMS, 52%) of MS. MS was present in 48% of patients. Functional capacity was assessed by the distance walked at six minute walking test (6MWT), and by a maximal exercise test. Compared to patients without MS, those with MS walked a lower distance at 6MWT (438+/-110 vs 408+/-123 m; p<0.05), had a lower maximal exercise capacity (7.6+/-1.8 vs 9.3+/-1.2 MET; p<0.05) and a lower heart rate recovery (HRR) (16+/-9 vs 22+/-8; p<0.05). Male patients with or without MS had a similar degree of functional recovery (51%) while women with MS had a significantly lower recovery than nMS (20% vs 40%). In a multivariate logistic regression model, including body mass index, age, gender hypertension, ejection fraction and diabetes, MS predicted a reduced performance at 6MWT in the overall population (OR 1.4, 95% CI 1.7 to 2.4) and in women (OR 1.31; 95% CI 1.20-1.62), while it was not predictive in males., Conclusions: CAD patients with MS have lower functional recovery and HRR than nMS. However MS is an independent predictor of lower exercise capacity only in female gender.

Background: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas., Methods: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine., Results: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent., Conclusions: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS--at least within the limits clinically attainable without stem cell rescue--does not improve results.