Risultati per: Scoperta una nuova molecola anti-cancro

Circulation, Volume 150, Issue Suppl_1, Page A4129709-A4129709, November 12, 2024. Background:The current unmet needs for aspirin usage in atherosclerosis lie in its short half-life and narrow indication for anti-platelet effects. Daily aspirin intake is mandatory, and the anti-inflammatory effects of aspirin for atherosclerosis have not successfully translated to clinical practice. Nanoparticles remain in circulation for 2-3 days, with a large portion being cleared by splenic monocytes, which are known to inherently target inflamed sites.Hypothesis:By altering the pharmacokinetics of aspirin through loading into nanoparticles, aspirin-nanoparticles can exert prolonged anti-platelet effects and target atherosclerosis sites via monocyte carriers for anti-inflammatory effects, resulting in dual therapies.Methods:Splenic monocytes were loaded with aspirin-liposomes and co-cultured with endothelial cells or platelets to examine the interactions between them using high-resolution time-series microscopy. Prolonged anti-platelet effects and targeted anti-inflammatory effects of aspirin were validated in intact mice and hindlimb ischemia models, respectively. Furthermore, the dual therapies of aspirin-liposomes were validated in an atherosclerotic mouse model created by partial carotid ligation and a western diet in apoE gene knock-out mice.Results:When splenic monocytes were loaded with aspirin-liposomes, they emitted extracellular vesicles (EVs) loaded with aspirin towards endothelial cells or platelets. As inflamed cells upregulate caveolin expression, they uptake an increased amount of transferred EVs compared to non-inflamed cells. Additionally, aspirin-liposomes showed prolonged circulation time and increased splenic accumulation compared to aspirin itself, resulting in prolonged anti-platelet effects ( >7 days) and targeted anti-inflammatory effects at inflamed sites. Compared to the daily oral aspirin group in the atherosclerosis model, the weekly intravenous aspirin-liposome group showed superior therapeutic effects, including attenuated systemic and local inflammation and patent lumen in atherosclerotic sites.Conclusion:Aspirin-nanoparticles can exert prolonged anti-platelet effects combined with targeted anti-inflammatory effects, resulting in superior therapeutic effects on atherosclerosis.

Circulation, Volume 150, Issue Suppl_1, Page A4141387-A4141387, November 12, 2024. Background and Objective:To investigate the differences in Ambulatory Blood Pressure Monitoring (ABPM) parameters in patients affected by VEGFR-TKI and tumors, and to summarize the relationship between VEGFR-TKI, tumors, and blood pressure.Methods:43 patients who received VEGFR-TKI anti-tumor treatment and developed induced hypertension were selected for ABPM. Additionally, 94 cases of tumor-associated hypertension and 96 cases of primary hypertension were randomly selected for comparison. The ambulatory blood pressure-related parameters between the VEGFR-TKI-related hypertension group and the tumor-associated hypertension group, as well as between the tumor-associated hypertension group and the primary hypertension group, were analyzed.Results:Compared with the tumor-associated hypertension group, the VEGFR-TKI-related hypertension group showed higher 24-hour average diastolic blood pressure [(85.37±13.21) vs. (80.41±10.71) mmHg,t=2.332,P=0.021], daytime average diastolic blood pressure [(85.98±13.19) vs. (80.69±10.98) mmHg,t=2.452,P=0.015]. Multivariate linear regression analysis revealed that after adjusting for tumor type and BMI, the use of VEGFR-TKI remained independently associated with nighttime average diastolic blood pressure (B=5.921,P=0.021). Compared with the primary hypertension group, the tumor-associated hypertension group exhibited significantly reduced nighttime systolic blood pressure decline rate [(1.10±9.01) vs. (6.33±6.87),t=-4.508,P

Circulation, Volume 150, Issue Suppl_1, Page A4147319-A4147319, November 12, 2024. Introduction:Historically, the pathogenesis of atherosclerotic disease has been characterized as an inflammatory process that drives the formation, progression, and rupture of plaques. Despite the recognized role of the immune response, current guidelines primarily emphasize statin and non-statin lipid lowering agents for the prevention of atherosclerotic disease. However, the utilization of anti-inflammatory agents and their effects on inflammation with respect to the attenuation of atherosclerosis has been recently highlighted in the literature.Aim:We aimed to investigate the role of immunomodulating agents in the prevention of atherosclerotic disease by means of a systematic review.Methods:We conducted a systematic search of MEDLINE, Cochrane, and Scopus databases through June 2024, for randomized control trials (RCTs) that assessed immunomodulating agents on outcomes of cardiovascular disease (CVD). Keywords included “anti-inflammatory therapy”, “immunomodulator therapy”, and “atherosclerotic disease”. Inclusion criteria involved participants aged 19 years and older with CVD and studies that assessed major adverse cardiovascular events (MACE), or atherosclerotic biomarkers.Results:Five RCTs were included in our systematic review, including CANTOS, COLCOT, LoDoCo2, RESCUE, and CIRT. Two RCT’s evaluated immunomodulating agents, including the CANTOS trial which assessed canakinumab, an IL-1β inhibitor and the RESCUE trial which assessed ziltivekimab, an IL-6 inhibitor. The COLCOT and LoDoCo2 trials assessed colchicine while CIRT assessed methotrexate. All trials assessed the primary endpoint of MACE, except the RESCUE trial. The primary endpoint for the RESCUE trial was the percent change in high sensitivity CRP. All trials, except CIRT had statistically significant reductions in their primary endpoints.Conclusion:The advancements in targeted immune therapies offer promising new avenues in cardiovascular medicine. Our systematic review of RCTs suggests that anti-inflammatory agents have a beneficial role in the reduction of cardiovascular events and the progression of CVD in patients with atherosclerotic disease. While the majority of the included RCTs support the use of these agents, the heterogeneity in the individual studies emphasize the need for further research to investigate the role of immunomodulating agents on CVD outcomes.

Circulation, Volume 150, Issue Suppl_1, Page A4147456-A4147456, November 12, 2024. Background:Cardiac fibrosis is a condition characterized by deposition of extracellular matrix proteins and myofibroblasts, leading to scar formation, cardiac dysfunction and arrhythmogenesis. Various cardiometabolic stressors can promote fibrosis and scarring, including MI, hypertension, diabetes and obesity. Targeted therapy to prevent cardiac fibrosis is therefore an important unmet medical need. In a mouse model of obesity-related atrial fibrillation (AF), inhibition of SGK1 reduced markers of inflammation and fibrosis, suggesting SGK1 as a novel target. Several SGK1 inhibitors are being evaluated in clinical studies for the treatment of long QT syndrome, paroxysmal AF, and heart failure.Hypothesis:SGK1 activation is a significant driver of inflammation and fibrosis, and its inhibition may offer a new therapeutic strategy for treating fibrotic diseases, including those of the cardiovascular system.Methods:Primary hepatic stellate cells, lung fibroblasts, and proximal tubule cells were treated with TGFβ for 24-48 hours to induce fibrosis and measure the effects of SGK1 inhibition on markers of fibrosis (alpha SMA and collagen 1). Three, selective and potent, SGK1 inhibitors (SGK1-I 1,2,3) were tested in a BioMAP fibrosis panel at concentrations ranging from 0.3 to 10 µM. The fibrosis panel includes three systems that model TGFβ and TNFα driven myofibroblast differentiation during chronic inflammation and wound healing. Markers of fibrosis, tissue remodeling, myofibroblast activation, and inflammation were measured quantitatively. IC50s were determined using GraphPad Prism.Results:In primary human stellate cells, SGK1-I,1,2,3 inhibited αSMA and collagen 1 mRNAs with IC50s ranging from 0.1- 0.8 µM and 1.0-3.0 µM, respectively. In primary lung fibroblasts, treatment with SGK1-I reduced the mRNA and protein expression of αSMA. Treatment of cells from different tissues with TGFβ resulted in a 1.5-to-3.0-fold increase in SGK1 mRNA and protein and this was blocked by the TGFβ receptor inhibitor SB525334. SGK1 inhibitors displayed anti-inflammatory and anti-fibrotic properties in the BioMAP panel, with inhibition of IL-6, IL-8, MCP-1, and αSMA, collagen 1, and TIMP1 respectively.Conclusion:SGK1 is an important effector of TGFβ signaling. The development of SGK1 inhibitors may represent a new therapeutic strategy for treating fibrotic diseases. Additional studies are warranted to further evaluate novel SGK1 inhibitors in cardiac fibrosis

Circulation, Volume 150, Issue Suppl_1, Page A4114505-A4114505, November 12, 2024. Introduction:Idecabtagene vicleucel (Ide-Cel) and ciltacabtagene autoleucel (Cilta-cel) are novel CAR-T therapies targeting B-cell maturation antigen (BCMA) and approved for relapsed and refractory multiple myeloma (RRMM). While cardiovascular adverse events (CVAE) are relatively common with CD-19 CAR-T, the incidence of CVAE in the real-world setting for anti-BCMA CAR-T in RRMM is largely unknown. This study aims to determine the incidence of CVAE and its associated risk factors in patients treated with ide-cel and cilta-cel.Method:This single-center retrospective cohort study evaluated RRMM patients treated with ide-cel and cilta-cel from May 2021 to December 2023. We assessed baseline cardiac and oncologic characteristics and clinical outcomes post-CAR-T. Cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome (ICANS) grading followed ASTCT consensus guidelines.Result:A total of 164 RRMM patients treated with ide-cel (N=109) or cilta-cel (N=55) with at least 6 months follow-up were included. The average age was 63 years, and 57% were male. Advanced RRMM stage (R-ISS III) was present in 17% with a median of 6 prior lines of therapy. CRS grade equal or greater than 2 occurred in 22%, and ICANS grade equal or greater than 3 in 6.7%. Twenty patients (12.2%) experienced CVAE, including atrial fibrillation (7.9%), non-sustained ventricular arrhythmia (3.0%), heart failure (3.7%), and cardiovascular death (0.6%). R-ISS III was associated with increased CVAE (52.9% vs. 11.5%; P=0.001). Patients with CVAE had higher baseline ferritin and CRP levels and a higher incidence of CRS grade ≥ 2 (60% vs. 16.7%; P

Circulation, Volume 150, Issue Suppl_1, Page A4137045-A4137045, November 12, 2024. The formation of occlusive thrombi resulting in myocardial infarction or stroke present a significant challenge for the healthcare community. Activation of the prostacyclin (IP) receptor has been shown to decrease platelet reactivity, however current IP agonists lack a sustained effect in the blood. We have developed CS585, an IP receptor agonist with sustained anti-thrombotic effects in the blood, which could represent a novel prevention strategy in targeting thrombosis. We sought to assess the anti-thrombotic efficacy and pharmacodynamic stability of IP agonists CS585, iloprost and selexipag, in bothex vivoandin vivomodels.We evaluated the timeframe of effect of CS585, iloprost, and selexipag in mice following a single IV dose. Inhibition of thrombus formation was measuredex vivoin whole blood under arterial shear rates.In vivo, CS585, iloprost, or selexipag, were administered prior to labeling of platelets and fibrin. Thrombus formation at the site of injury was measured using the cremaster arteriole injury thrombosis assay.CS585 administered to mice prior to blood draw decreases platelet adhesion and blood clot formation under arterial shear conditions. These effects are observed up to 24 hours post-administration; however, the effects of iloprost and selexipag return to pre-treatment levels by 24 hours.In vivo, mice administered iloprost or selexipag demonstrated a decrease in platelet accumulation and fibrin formation, however the effects were abrogated post-administration by 10 minutes and 4 hours, respectively. Administration of CS585, however, demonstrated sustained inhibition of thrombus formation at the site of injury, with inhibitory effects observed at 18 hours post-administration.We have used bothin vivoandex vivomodels to demonstrate the anti-thrombotic efficacy of IP receptor agonists. Our results suggest that CS585, a novel IP receptor agonist, sustainably inhibits platelet activation and clot formation for extended periods, in contrast to existing alternatives. This demonstrates a significant improvement in the pharmacodynamic effects of IP receptor agonists in the blood, highlighting CS585 as a novel anti-platelet therapeutic with the potential to treat thrombotic diseases.

Circulation, Volume 150, Issue Suppl_1, Page A4146104-A4146104, November 12, 2024. Background:There is substantial imbalance between the prevalence and treatment of overweight/obesity. Team-based remote care programs have shown promise in closing healthcare delivery gaps for several cardiometabolic disorders, but whether this strategy can enhance the uptake of guideline-directed therapy for weight management remains uncertain.Methods:In this quality improvement program, we developed and deployed a remote, patient navigator and pharmacist-led, pharmacotherapy-oriented weight management intervention (Supplementary Anti-Obesity Integration into a Longitudinal Weight Loss [SAIL] program). SAIL was conducted within the Partnerships for Reducing Overweight and Obesity with Patient-Centered Strategies 2.0 (PROPS 2.0) program, an ongoing 12-month digital health program pairing an online weight management program (RestoreHealth; HealthFleet, Inc.) with personalized support from health coaches. After 6 months, PROPS 2.0 participants who did not experience weight reduction were offered possible enrollment in SAIL. Pharmacists, enabled by a collaborative drug therapy management program, prescribed, titrated, and monitored anti-obesity medications (AOM) with physician (cardiologist) supervision.Results:Overall, 2,540 invitations for participation in SAIL were sent to the 5,061 patients enrolled in PROPS 2.0, of whom 200 responded. Of the respondents, 98 (49%) were eligible for SAIL, and 75 patients were enrolled. Based randomly by enrollment period, 45 patients participated without a remote physician visit, while 30 had a video telemedicine visit. Among the 75 program participants, 70 (93%) received a prescription for AOM (29/30 with a visit vs. 41/45 without; P=0.64). After a median follow-up of 143 days (IQR 79-193), 61/70 were taking prescribed AOM (26/29 with a visit vs. 35/41 without; P=0.73) (Figure).Conclusion:This study extends prior experiences leveraging remote, team-based care, emphasizing the potential of this approach to enhance weight management. Given the dramatic cardiometabolic detriments of prolonged exposure to overweight and obesity, innovative approaches are necessary to meet demand. Remote and team-based care are proven methods to improve care and outcomes and may provide a novel model for delivering care for overweight and obesity. Further studies are needed to ascertain the effectiveness of this strategy on weight-related health outcomes.

Circulation, Volume 150, Issue Suppl_1, Page A4138339-A4138339, November 12, 2024. Introduction:Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies are increasingly used in anti-cancer therapy. However, several cardiovascular adverse effects can occur with the use of ICIs, including new-onset heart failure.Hypothesis:We hypothesized that prior myocardial ischemic injury could exacerbate cardiac dysfunction and inflammation caused by anti-PD-1 treatment. Moreover, we investigated whether abatacept, a T-cell co-stimulation blocker, can prevent ICI-induced cardiac effects.Methods:To induce reversible cardiac ischemia, C57Bl/6J mice were treated with isoprenaline (ISOP group) or with PBS (CON group), followed by 16 weeks of recovery period. Following this, mice from both groups were divided into three further treatment groups: isotype control, anti-PD-1, or anti-PD-1 combined with abatacept, and were treated for two weeks, with three weekly intraperitoneal injections. Echocardiography was performed to evaluate cardiac function while myocardial inflammation was assessed by qRT-PCR and immunohistochemistry. Flow cytometry and Western blot were used to investigate changes occurring in the thymus.Results:Mice with normal heart function but with prior ischemic injury and anti-PD-1 treatment (ISOP + anti-PD-1) showed significantly decreased fractional shortening and cardiac index on echocardiography, while in animals with abatacept co-treatment (ISOP+anti-PD-1+abatacept) cardiac function was not altered. Increased immune cell infiltration was seen in the myocardium of the ISOP+anti-PD-1 treated group compared to CON animals, including T-cells and macrophages, with increased expression of pro-inflammatory cytokines, while co-treatment with abatacept ameliorated the inflammatory response. In the thymus, increased expression of PD-1 was found after abatacept co-treatment.Conclusion:Prior myocardial ischemic injury was associated with cardiac dysfunction and inflammation after anti-PD-1 treatment, which was ameliorated by abatacept co-treatment. Patients with prior cardiac ischemic events may be at greater risk for developing ICI-induced cardiotoxicity, including new-onset HF.

Circulation, Volume 150, Issue Suppl_1, Page A4119262-A4119262, November 12, 2024. Background:Impediment in the excretion of lipid deposits within SMC-derived foam cells (SMC-FCs) is one of the reasons for the continuous expansion of the plaque necrotic core. This study aims to explore the effect and underlying mechanimsm of exosomes secreted by M2 macrophage (M2-exos) on SMC-FCs lipid metabolism and plaque stability.Methods:First, immunofluorescence was used to detect the expression levels of CD45 (a recognized differentially expressed molecule of myeloid and SMC-FCs) and the key proteins of cholesterol efflux pathway, ABCA1 and ABCG1, in human early and late plaques. Exosomes derived from M0 and M2 macrophages were purified by sucrose density gradient centrifugation, and characterized based on specific morphology and surface markers. Western blot, Oil red O staining and cell total cholesterol assay were used to assess the effects of M2-exos on the lipid mechanism of SMC-FCs. RNA-seq was used to detect the miRNA profiles of M2-exos. Quantitative real-time PCR was used to identify candidate miRNAs. The dual-luciferase reporting system was utilized to assess the regulatory effect of candidate miRNA on target gene. Then, the effect of M2-exos on the progression and stability of plaques in ApoE-/-mice was evaluated using Oil red O, H&E, Masson, Movat and immunohistochemistry.Results:Immunofluorescence revealed that compared with early plaques, VSMC-FCs (CD45-) were significantly increased in late plaques, and the expression levels of ABCG1 and ABCA1 were marked lower than those in macrophage-derived foam cells (CD45+). Purified M2-exos treatment significantly promoted the cholesterol efflux of SMC-FCs in vitro. In high-fat-fed ApoE-/-mice, M2-exos significantly reduced the VSMC-FCs, delayed the progression of plaques, decreased necrotic core area and enhanced plaque stability. MiRNA profiling and comprehensive analysis of signaling pathways showed that M2-exos were rich in miR-7683-3p, which played a key role in regulating SMC-FCs lipid metabolism through PPARγ-LXRα-ABCA1/ABCG1 pathway. Dual-luciferase reporting assay showed that miR-7683-3p can specifically bind to the promoter region of homeobox genes A1(HoxA1), an inhibitor of PPARγ-LXRα-ABCA1/ABCG1 pathway.Conclusion:M2-exos exerted an obvious atherosclerotic protective effect, and the underlying mechanism was closely related to MiR-7683-3p, which targeted the 3’UTR of HoxA1 mRNA and activated the PPARγ-LXRα-ABCA1/ABCG1 mediated cholesterol efflux in SMC-FCs.

Background
Patient medication knowledge and health literacy affect patient safety. Taking angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin II receptor blockers (ARBs), with diuretics and non-steroidal anti-inflammatory medications (NSAIDs) is nephrotoxic. Patients may not know of this risk. An eHealth information package was developed to inform patients at risk of taking this combination of medication.

Objective
To assess the impact of the eHealth information package on patient knowledge and behaviour.

Design
This was a two-arm, parallel, randomised control trial. A knowledge quiz and NSAID use survey were undertaken at baseline, and repeated after two weeks. The intervention group accessed the information package after completing the baseline assessment. The control group received normal care.

Setting and participants
Primary healthcare patients prescribed an ACE-i or ARB plus a diuretic in Aotearoa New Zealand.

Intervention
A novel eHealth information package was made available to participants in the intervention group consisting of a downloadable PDF and online education activity. This took approximately 15 min for participants to complete.

Primary outcome measures
Change in knowledge scores and in NSAID use between pre-intervention and post-intervention assessment.

Secondary outcome measures
Self-reported patient intentions regarding future NSAID use

Results
The 201 participants who completed the study had high baseline NSAID medication knowledge, which did not substantially change at follow-up. The intervention group had a 0.35 (95% CI: -0.18, 0.88) higher knowledge score than the control group. NSAID use decreased over the study; the intervention group had 62% lower odds of NSAID use at follow-up assessment compared with the control group (OR=0.37, 95% CI: 0.14, 1.03). There was no substantial difference between study groups at follow-up for self-reported action. The information package was considered acceptable and useful.

Conclusion
This tailored eHealth information package may reduce NSAID use in patients at increased risk from NSAID-related harm.

Trial registration number
Australian New Zealand Clinical Trial Registry (ACTRN:12622001132730).

Chi ne consuma molti ha rischio ridotto di avere vari tumori

Chi ne consuma molti ha rischio ridotto di avere vari tumori

Stroke, Ahead of Print. BACKGROUND:Contemporary thrombolytics in acute ischemic stroke are limited to administration within 4.5 hours of last known normal. JX10 (formerly TMS-007), aStachybotrys microsporatriprenyl phenol family member, may extend this therapeutic window.METHODS:In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2a study, JX10 or placebo was administered as a single intravenous infusion to Japanese patients with acute ischemic stroke who were unable to receive tissue-plasminogen activator or thrombectomy within 12 hours of last known normal. Primary end point was incidence of symptomatic intracranial hemorrhage with a worsening National Institutes of Health Stroke Scale score of ≥4 points within 24 hours of drug administration (symptomatic intracranial hemorrhage incidence).RESULTS:Ninety patients received either placebo (n=38; female 26.3%) or JX10 at 1, 3, or 6 mg/kg (n=6, 18, 28; female 0%, 33.3%, and 42.9%, respectively). Median age (range) and baseline median (range) National Institutes of Health Stroke Scale scores were respectively 76.5 (42–87) and 8 (6–21) for the combined JX10 cohort (JX10 Cohorts) and 75.0 (34–85) and 8 (6–22) for placebo. Median (range) dosing time since last known normal was 9.5 (5.0–12.1) and 10.0 (3.7–12.0) hours for JX10 Cohorts and placebo, respectively. Symptomatic intracranial hemorrhage incidence was 0% (0/52 [95% CI, 0.0–5.6]) for JX10 Cohorts versus 2.6% (1/38 [95% CI, 0.1–13.8]) for placebo (P=0.42). Vessel patency at 24 hours (secondary end point) in patients with baseline arterial occlusive lesion score

Il numero 1 al mondo per l’iniziativa ‘Un ace per la ricerca’