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Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles 1 , 2 . We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and α-sarcoglycan (α-SG)–deficient mice by inducing the expression of the myostatin antagonist follistatin 3 in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.

Friedreich’s ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNγ) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNγ in Friedreich’s patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21–38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 μg) of IFNγ (human recombinant interferon 1 b gamma, trade name IMUKIN ® ), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNγ by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNγ in Friedreich’s ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich’s ataxia.

Over the past decades, research has made impressive breakthroughs towards drug delivery systems, resulting in a wide range of multifunctional engineered nanoparticles with biomedical applications such as cancer therapy. Despite these significant advances, well-designed nanoparticles rarely reach the clinical stage. Promising results obtained in standard 2D cell culture systems often turn into disappointing outcomes in in vivo models. Although the overall majority of in vitro nanoparticle research is still performed on 2D monolayer cultures, more and more researchers started acknowledging the importance of using 3D cell culture systems, as better models for mimicking the in vivo tumor physiology. In this review, we provide a comprehensive overview of the 3D cancer cell models currently available. We highlight their potential as a platform for drug delivery studies and pinpoint the challenges associated with their use. We discuss in which way each 3D model mimics the in vivo tumor physiology, how they can or have been used in nanomedicine research and to what extent the results obtained so far affect the progress of nanomedicine development. It is of note that the global scientific output associated with 3D models is limited, showing that the use of these systems in nanomedicine investigation is still highly challenging.

Chronic pressure-overload induces right ventricular (RV) adaptation to maintain RV–pulmonary arterial (PA) coupling. RV remodeling is frequently associated with secondary tricuspid regurgitation (TR) which may accelerate uncoupling. Our aim is to determine whether the non-invasive analysis of RV–PA coupling could improve risk stratification in patients with secondary TR. A total of 1,149 patients (median age 72[IQR, 63 to 79] years, 51% men) with moderate or severe secondary TR were included. RV–PA coupling was estimated using the ratio between two standard echocardiographic measurements: tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). The risk of all-cause mortality across different values of TAPSE/PASP was analyzed with a spline analysis. The cut-off value of TAPSE/PASP to identify RV–PA uncoupling was based on the spline curve analysis. At the time of significant secondary TR diagnosis the median TAPSE/PASP was 0.35 (IQR, 0.25 to 0.49) mm/mm Hg. A total of 470 patients (41%) demonstrated RV–PA uncoupling (<0.31 mm/mm Hg). Patients with RV–PA uncoupling presented more frequently with heart failure symptoms had larger RV and left ventricular dimensions, and more severe TR compared to those with RV–PA coupling. During a median follow-up of 51 (IQR, 17 to 86) months, 586 patients (51%) died. The cumulative 5-year survival rate was lower in patients with RV–PA uncoupling compared to their counterparts (37% vs 64%, p < 0.001). After correcting for potential confounders, RV–PA uncoupling was the only echocardiographic parameter independently associated with all-cause mortality (HR 1.462; 95% CI 1.192 to 1.793; p < 0.001). In conclusion, RV–PA uncoupling in patients with secondary TR is independently associated with poor prognosis and may improve risk stratification.

Left ventricular (LV) systolic dysfunction in cardiac amyloidosis (CA) is associated with poor prognosis. This study aimed to investigate the prognostic implications of right ventricular (RV) systolic dysfunction in CA. A total of 93 patients diagnosed with CA who underwent standard and speckle-tracking echocardiography were included. During a median follow-up of 17 (5 to 38) months, 42 patients (45%) died. Nonsurvivors were more likely to present with immunoglobulin light-chain amyloidosis and New York Heart Association class III to IV heart failure symptoms. Regarding the echocardiographic characteristics, nonsurvivors had a higher LV apical ratio, worse LV diastolic function, and worse RV systolic function (evaluated with both tricuspid annular plane systolic excursion and RV free wall strain). RV free wall strain was independently associated with all-cause mortality in several multivariable Cox regression models and had incremental prognostic value over conventional parameters of RV function when added to a basal model (including heart failure symptoms, amyloidosis phenotype, and LV global longitudinal strain). Based on spline curve analysis and Youden index, a value of 16% for RV free wall strain was identified as the optimal cutoff to predict outcome and patients with RV free wall strain <16% had a significantly worse short- and long-term survival during follow-up (1- and 3-year cumulative survival: 81% vs 31% and 67% vs 20%, respectively, p <0.001). In conclusion, RV systolic dysfunction is independently associated with poor outcome in patients with CA and the use of advanced echocardiographic parameters, such as RV free wall strain, may be of aid for better risk stratification.

Patients with severe aortic stenosis (AS) may show left ventricular (LV) apical longitudinal strain sparing. Transcatheter aortic valve implantation (TAVI) improves LV systolic function in patients with severe AS. However, the changes in regional longitudinal strain after TAVI have not been extensively evaluated. This study aimed to characterize the effect of the pressure overload relief after TAVI on LV apical longitudinal strain sparing. A total of 156 patients (mean age 80 ± 7 years, 53% men) with severe AS who underwent computed tomography before and within 1 year after TAVI (mean time to follow-up 50 ± 30 days) were included. LV global and segmental longitudinal strain were assessed using feature tracking computed tomography. LV apical longitudinal strain sparing was evaluated as the ratio between the apical and midbasal longitudinal strain and was defined as an LV apical to midbasal longitudinal strain ratio >1. LV apical longitudinal strain remained stable after TAVI (from 19.5 ± 7.2% to 18.7 ± 7.7%, p = 0.20), whereas LV midbasal longitudinal strain showed a significant increase (from 12.9 ± 4.2% to 14.2 ± 4.0%, p ≤0.001). Before TAVI, 88% of the patients presented with LV apical strain ratio >1% and 19% presented with an LV apical strain ratio >2. After TAVI, these percentages significantly decreased to 77% and 5% (p = 0.009, p ≤0.001), respectively. In conclusion, LV apical sparing of strain is a relatively common finding in patients with severe AS who underwent TAVI and its prevalence decreases after the afterload relief after TAVI.

Pulmonary vein isolation is the cornerstone of atrial fibrillation (AF) ablation. Radiofrequency (RF) represents a standard of care for pulmonary vein isolation, whereas cryoballoon (CB) ablation has emerged as a valid alternative. The aim of our meta-analysis was to explore the efficacy and safety of CB compared with RF as first ablation procedure for AF. We searched the literature for studies that investigated this issue. The primary efficacy outcome was AF recurrence. The safety outcomes were: pericardial effusion, cardiac tamponade, phrenic nerve palsy, vascular complications, and major bleedings. Fourteen randomized controlled studies and 34 observational studies were included in the analysis. A total of 7,951 patients underwent CB ablation, whereas 9,641 received RF ablation. Mean follow-up was 14 ± 7 months. Overall, CB reduced the incidence of AF recurrence compared with RF ablation (relative risk [RR] 0.86; 95% confidence interval [CI] 0.78 to 0.94; p = 0.001), and this result was consistent across different study design and AF type. CB had a significantly higher rate of phrenic nerve palsy, whereas it was related to a lower incidence of pericardial effusion, cardiac tamponade (RR 0.58; 95% CI 0.38 to 0.88; p = 0.011) and vascular complications (RR 0.61; 95% CI 0.48 to 0.77; p <0.001) compared with RF. There was no significant difference in major bleedings between the 2 strategies. CB ablation had a shorter procedural time compared with RF (mean difference −20.76 minutes; p <0.001). In conclusion, considered its efficacy/safety profile and short procedural time, CB ablation represents the preferable option for first AF ablation procedure.

ObjectivesCardiovascular (CV) diseases are associated with adverse outcomes. However, attention has typically focused on outcomes considered relevant by doctors, whereas the potential gap in perception and relative importance of outcomes that may exist between patients and doctors has been scarcely explored. Evidence available reports the views of either patients or doctors alone, and data are analysed in aggregate. We investigated this issue by surveying for the first time patients’ and doctors’ opinions simultaneously, on a one-to-one basis.DesignSurvey involving patients with different CV diseases. Each patient and their attending doctor were asked to simultaneously but independently gauge the importance each attached to a predetermined set of outcomes, filling out disease-specific questionnaires. Results were analysed by compositional analysis.SettingInpatients and outpatients being seen by cardiologists and internal medicine specialists at hospitals affiliated with the National Health System in Umbria, Italy.ParticipantsAll-comer patients, presenting with one of the following conditions: atrial fibrillation (AF), myocardial infarction (MI), heart failure (HF) or considered at high CV risk.Main outcome measuresImportance attached to outcomes relative to life path, quality of life, future clinical events.ResultsFrom 337 paired questionnaires returned, significant differences between patients’ and doctors’ perspectives emerged. Specifically: (1) patients with AF were significantly less concerned about the risk of stroke than doctors; (2) worsening of HF was a greater concern for doctors than patients, whereas patients weighed the risk of disability more; (3) patients with a previous MI, or at high CV risk, weighed the risk of hospitalisation less relevant than doctors, but were significantly more concerned about the risk of disability.ConclusionsSimultaneous, one-to-one assessment of patients’ and doctors’ opinion shows remarkable differences between patients’ perception and physicians’ judgement concerning the relevance of major CV outcomes. Appreciation and sharing of these issues may inform better tailoring of cardiac care.

Most targeting strategies of anticancer drug delivery systems (DDSs) rely on the surface functionalization of nanocarriers with specific ligands, which trigger the internalization in cancer cells via receptor-mediated endocytosis. The endocytosis implies the entrapment of DDSs in acidic vesicles (endosomes and lysosomes) and their eventual ejection by exocytosis. This process, intrinsic to eukaryotic cells, is one of the main drawbacks of DDSs because it reduces the drug bioavailability in the intracellular environment. The escape of DDSs from the acidic vesicles is, therefore, crucial to enhance the therapeutic performance at low drug dose. To this end, we developed a multifunctionalized DDS that combines high specificity towards cancer cells with endosomal escape capabilities. Doxorubicin-loaded mesoporous silica nanoparticles were functionalized with polyethylenimine, a polymer commonly used to induce endosomal rupture, and hyaluronic acid, which binds to CD44 receptors, overexpressed in cancer cells. We show irrefutable proof that the developed DDS can escape the endosomal pathway upon polymeric functionalization. Interestingly, the combination of the two polymers resulted in higher endosomal escape efficiency than the polyethylenimine coating alone. Hyaluronic acid additionally provides the system with cancer targeting capability and enzymatically controlled drug release. Thanks to this multifunctionality, the engineered DDS had cytotoxicity comparable to the pure drug whilst displaying high specificity towards cancer cells. The polymeric engineering here developed enhances the performance of DDS at low drug dose, holding great potential for anticancer therapeutic applications.