MicroRNAs modulated by local mIGF-1 expression in mdx dystrophic mice

Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and miR-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle

Sex-specific predictors of PCSK9 levels in a European population:The IMPROVE study

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of low-density lipoprotein cholesterol plasma levels and circulating PCSK9, which differs between genders. PCSK9 represents a valid pharmacological target for preventing cardiovascular (CV) events. We aimed to investigate sex-related associations between PCSK9 plasma levels and biochemical and anthropomorphic factors, and familial and personal morbidities, in a large European cohort (n=3,673) of men (47.9%) and women (52.1%). Methods: Individuals (aged 54 to 79 years) free of CV diseases were enrolled in 7 centers of five European countries: Finland, France, Italy, the Netherlands, and Sweden. PCSK9 plasma levels were measured by ELISA. Results: PCSK9 was higher in women than in men. Multiple linear regression analysis showed that latitude, sex, and treatments with statins and fibrates were the strongest predictors of PCSK9 in the whole group. These variables, together with triglycerides and high-density lipoprotein cholesterol, were also associated with PCSK9 in men or women. Mean corpuscular hemoglobin concentration and pack-years were PCSK9 independent predictors in women, whereas hypercholesterolemia and physical activity were independent predictors in men. The associations between PCSK9 and latitude, uric acid, diabetes, hypercholesterolemia and physical activity were significantly different in men and women (pinteraction <0.05 for all). Conclusions: Besides confirming the association with lipids in the whole group, our study revealed previously unknown differences in PCSK9 predictors in men and women. These might be taken into account when defining individual risk for CV events and/or for refining PCSK9 lowering treatments

Sex-specific predictors of PCSK9 levels in a European population: the IMPROVE study

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of low-density lipoprotein cholesterol plasma levels and circulating PCSK9, which differs between genders. PCSK9 represents a valid pharmacological target for preventing cardiovascular (CV) events. We aimed to investigate sex-related associations between PCSK9 plasma levels and biochemical and anthropomorphic factors, and familial and personal morbidities, in a large European cohort (n=3,673) of men (47.9%) and women (52.1%). Methods: Individuals (aged 54 to 79 years) free of CV diseases were enrolled in 7 centers of five European countries: Finland, France, Italy, the Netherlands, and Sweden. PCSK9 plasma levels were measured by ELISA. Results: PCSK9 was higher in women than in men. Multiple linear regression analysis showed that latitude, sex, and treatments with statins and fibrates were the strongest predictors of PCSK9 in the whole group. These variables, together with triglycerides and high-density lipoprotein cholesterol, were also associated with PCSK9 in men or women. Mean corpuscular hemoglobin concentration and pack-years were PCSK9 independent predictors in women, whereas hypercholesterolemia and physical activity were independent predictors in men. The associations between PCSK9 and latitude, uric acid, diabetes, hypercholesterolemia and physical activity were significantly different in men and women (pinteraction <0.05 for all). Conclusions: Besides confirming the association with lipids in the whole group, our study revealed previously unknown differences in PCSK9 predictors in men and women. These might be taken into account when defining individual risk for CV events and/or for refining PCSK9 lowering treatments

Intake of food rich in saturated fat in relation to subclinical atherosclerosis and potential modulating effects from single genetic variants

The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54–79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMTmean, C-IMTmax), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMTmean (OR:1.27;1.06–1.47), CC-IMTmean (OR:1.22;1.04–1.44) and ICA-IMTmean (OR:1.26;1.07–1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis

EFFICACY, SAFETY AND COST ANALYSIS OF SUBCUTANEOUS VS INTRAVENOUS RITUXIMAB IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH RCHOP

Introduction: Rituximab (R) in combination with cyclophosphamide, doxorubicin and prednisone (R-CHOP) is the standard of care for patients (pts) with diffuse large B-cell lymphoma (DLBCL). A subcutaneous (sc) formulation that provides a fixed dose of R is being tested in a number of studies. Results indicate that the pharmacokinetics is not inferior and the response rates comparable to those obtained with the intravenous (iv) formulation. In August 2014, the Italian Medicine Agency (AIFA) approved the sc formulation for follicular lymphoma and DLBCL. We performed a retrospective analysis at our Centre in pts with DLBCL treated with RCHOP. The aim was to evaluate the costs of the 2 different formulations of R (sc vs iv) combined with CHOP and the efficacy in terms of complete response (CR) rates and toxicity. Meth- ods: We collected data from 71 consecutive pts with untreated DLBCL who received 6 cycles of RCHOP plus 2 doses of R between January 2014 and January 2016; 35 pts received iv R (375mg/mq) and 36 sc R (1400 mg) from May 2015. We compared the direct costs of the 2 for- mulations of R, the rate of CR and of adverse events (AEs) of the two subgroups of patients. Univariate analysis was used to evaluate efficacy and toxicity. Results: The clinical characteristics were well balanced be- tween the iv and sc RCHOP groups: mean age 61 years in both groups, with a mean BSA of 1.8 (1.4-2.2); IPI score ≥3, 20% vs 30%; Ann Arbor stage III-IV, 62% vs 69%. There was no significant difference in terms of efficacy: the CR rates were 30/35 (85%) and 29/36 (83%), p=0.177, respectively. Grade ≥3 AEs (45% vs 47%) were almost all hematologic (90% in both groups) and the most common AE was grade 3/4 neu- tropenia in both groups. The cost of the treatment was 472.227€ for the iv R group and 449.870€ for sc R group; with a decrease of 4.73% only of the direct costs of R. In addition, the calculated infusion time for the sc RCHOP was 135 min compared to 240 min for the iv RCHOP; this translated into a 44% chair time reduction. Conclusions: In our analysis, the use of a sc formulation of R allowed a gain of 22.357€ in terms of only direct costs compared to the schedule with iv R, with comparable response rates and similar safety profile. Given the shorter delivery time, the sc formulation could also improve pts’ comfort and reduce the burden on health care resources. Finally, the reduction in required chair time allows for a greater number of pts to be treated daily

Relationship between circulating PCSK9 and markers of subclinical atherosclerosis—the improve study

none24si(1) Background and purpose: Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: The IMPROVE study enrolled 3703 European subjects (54-79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: In the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all p < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) (p = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) (p < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both p < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: In subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries.openCoggi D.; Frigerio B.; Bonomi A.; Ruscica M.; Ferri N.; Sansaro D.; Ravani A.; Ferrante P.; Damigella M.; Veglia F.; Capra N.; Lupo M.G.; Macchi C.; Savonen K.; Silveira A.; Kurl S.; Giral P.; Pirro M.; Strawbridge R.J.; Gigante B.; Smit A.J.; Tremoli E.; Amato M.; Baldassarre D.Coggi, D.; Frigerio, B.; Bonomi, A.; Ruscica, M.; Ferri, N.; Sansaro, D.; Ravani, A.; Ferrante, P.; Damigella, M.; Veglia, F.; Capra, N.; Lupo, M. G.; Macchi, C.; Savonen, K.; Silveira, A.; Kurl, S.; Giral, P.; Pirro, M.; Strawbridge, R. J.; Gigante, B.; Smit, A. J.; Tremoli, E.; Amato, M.; Baldassarre, D

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841