From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

: Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity

Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial

The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest.This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin.Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards.After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p 0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p 0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [pThe presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391)

A case study on Toxascaris leonine in big felids: inessicacy of a single-dose treatment with pyrantel pamoate

Elimination of helminthiasis from zoological collections is a challenging issue and often the eradication of the infection is not completely and definitely achieved. Maintenance of ascaridiosis in a facility is helped by the great resistance of the parasite's eggs, the wide host spectrum and a non-strictly monoxenous life cycle. In this case study, copromicroscopic examinations carried out in a facility hosting large felids in Northeastern Italy showed that 14/29 animals were positive for Toxascaris leonina. Following AZA manual recommendations, all positive animals were treated with pyrantel pamoate at 5 mg/kg PO for one or three consecutive days depending on the species and the efficacy of the treatment was proved by the complete absence of eggs in stool samples after 10 days. Nevertheless, faecal egg shedding reoccurred after 60 days, an insufficient period for the development of reinfection from environmental contamination. We hypothesize that two consequential treatments with Pyrantel pamoate are thus to be considered essential to eliminate larval stages of the parasite lodging in the gut walls. These larvae could indeed give origin to new patent infection after 60 days, making the single treatment ineffective in reducing the parasitic environmental burden

New Insights into the Activities of D-Chiro-Inositol: A Narrative Review

D-chiro-inositol (DCI) is a natural compound detectable in cell membranes, which is highly conserved as a biological signaling molecule. In mammals, its function is primarily characterized in the intracellular transduction cascade of insulin. In particular, insulin signal promotes the release of pivotal DCI-containing molecules. In fact, impaired release of DCI is a common feature of insulin-resistant tissues, and insulin-sensitizing pharmaceuticals induce higher concentrations of free DCI. Moreover, it also plays important roles in several other processes. DCI is involved in the regulation of steroidogenesis, due to its regulatory effects on steroidogenic enzymes, including 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and aromatase. Such regulation of various enzymes indicates a mechanism by which the body regulates different processes via a single molecule, depending on its concentration. DCI also reduces the expression of integrin β3, which is an adhesion molecule involved in embryo implantation and cellular phenomena such as survival, stemness, and invasiveness. In addition, DCI seems to have important anti-inflammatory activities, like its 3-O-methyl-ether, called pinitol. In vitro evidence demonstrates that treatment with both compounds induces a reduction in pro-inflammatory factors—such as Nf-κB—and cytokines—such as TNF-α. DCI then plays important roles in several fundamental processes in physiology. Therefore, research on such molecule is of primary importance

Long-term outcome of 'super-responder' patients to cardiac resynchronization therapy.

AIMS: To evaluate the long-term changes of clinical and echocardiographic parameters, the incidence of cardiac events and parameters associated with late cardiac events in 'super-responders' to cardiac resynchronization therapy (CRT) with [CRT defibrillator (CRT-D)] or without defibrillator back-up. METHODS AND RESULTS: In all consecutive patients treated with CRT in two Italian centres (Trieste and Udine) with left ventricular ejection fraction (LVEF) 640.35 at implantation (Timp) and LVEF > 0.50 1 and/or 2 years (Tnorm) after implantation, the long-term outcome and the evolution of echocardiographic parameters were assessed; factors associated with a higher risk of cardiac events, defined as hospitalization or death for heart failure (HF), sudden death, or CRT-D appropriate interventions, were also analysed. Among the 259 patients evaluated, 62 (24%) had LVEF 65 0.50 at Tnorm (n = 44 with at 1 year, n = 18 at 2 years). During a mean follow-up of 68 \ub1 30 months, one cardiac death (for HF) and eight cardiovascular events (two hospitalization for HF and six appropriate CRT-D interventions) occurred. At the last echo evaluation (Tfup) performed 51 \ub1 26 months after Timp, LVEF was 0.45 in four of them). At univariable analysis, only LV end-systolic volume evaluated at Tfup was associated with a higher risk of cardiac events during follow-up. CONCLUSION: In 'super-responders' to CRT long-term outcome is excellent. However, cardiac events, mainly CRT-D appropriate interventions, can occur despite the persistence of LVEF > 0.50. Early identification of these patients is still an unsolved issu

Magnetization Transfer BOOST Noncontrast Angiography Improves Pulmonary Vein Imaging in Adults With Congenital Heart Disease

Cardiac MRI plays an important role in the diagnosis and follow-up of patients with congenital heart disease (CHD). Gadolinium-based contrast agents are often needed to overcome flow-related and off-resonance artifacts that can impair the quality of conventional noncontrast 3D imaging. As serial imaging is often required in CHD, the development of robust noncontrast 3D MRI techniques is desirable. To assess the clinical utility of noncontrast enhanced magnetization transfer and inversion recovery prepared 3D free-breathing sequence (MTC-BOOST) compared to conventional 3D whole heart imaging in patients with CHD. Prospective, image quality. A total of 27 adult patients (44% female, mean age 30.9 ± 14.8 years) with CHD. A 1.5 T; free-breathing 3D MTC-BOOST sequence. MTC-BOOST was compared to diaphragmatic navigator-gated, noncontrast T2 prepared 3D whole-heart imaging sequence (T2prep-3DWH) for comparison of vessel dimensions, lumen-to-myocardium contrast ratio (CR), and image quality (vessel wall sharpness and presence and type of artifacts) assessed by two experienced cardiologists on a 5-point scale. Mann-Whitney test, paired Wilcoxon signed-rank test, Bland-Altman plots. P  MTC-BOOST significantly improved image quality and CR of the right-sided pulmonary veins (PV): (CR: right upper PV 1.06 ± 0.50 vs. 0.58 ± 0.74; right lower PV 1.32 ± 0.38 vs. 0.81 ± 0.73) compared to conventional T2prep-3DWH imaging where the PVs were not visualized in some cases due to off-resonance effects. MTC-BOOST demonstrated resistance to degradation of luminal signal (assessed by CR) secondary to accelerated or turbulent flow conditions. T2prep-3DWH had higher image quality scores than MTC-BOOST for the aorta and coronary arteries; however, great vessel dimensions derived from MTC-BOOST showed excellent agreement with standard T2prep-3DWH imaging. MTC-BOOST allows for improved contrast-free imaging of pulmonary veins and regions characterized by accelerated or turbulent blood flow compared to standard T2prep-3DWH imaging, with excellent agreement of great vessel dimensions. 1 TECHNICAL EFFICACY: Stage 2

Cannabidiol as Self-Assembly Inducer for Anticancer Drug-Based Nanoparticles

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N-desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI(50) values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B, confirming the involvement of paclitaxel in cytotoxicity and cell death mechanis

Validity and reliability of the Italian translation of the Yale Pharyngeal Residue Severity Rating Scale

Objective: In the dysphagic patient, pharyngeal residues (PR) are associated with aspiration and poor quality of life. The assessment of PR using validated scales during flexible endoscopic evaluation of swallowing (FEES) is crucial for rehabilitation. This study aims to validate and test the reliability of the Italian version of the Yale Pharyngeal Residue Severity Rating Scale (IT-YPRSRS). The effects of training and experience in FEES on the scale were also determined. Methods: The original YPRSRS was translated into Italian according to standardised guidelines. Thirty FEES images were selected after consensus and proposed to 22 naive raters who were asked to assess the severity of PR in each image. Raters were divided into two subgroups by years of experience at FEES, and randomly by training. Construct validity, inter-rater, and intra-rater reliability were assessed by kappa statistics. Results: IT-YPRSRS showed substantial to almost perfect agreement (kappa &gt; 0.75) in validity and reliability for both the overall sample (660 ratings), and valleculae/pyriform sinus sites (330 ratings each). No significant differences emerged between groups considering years of experience, and variable differences were observed by training. Conclusions: The IT-YPRSRS demonstrated excellent validity and reliability in identifying location and severity of PR

Cannabidiol as Self-Assembly Inducer for Anticancer Drug-Based Nanoparticles

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N-desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI50 values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B, confirming the involvement of paclitaxel in cytotoxicity and cell death mechanis