👤 Paolo Poggio

Aortic valve sclerosis affects 30 % of individuals over 65 and is associated with coronary artery disease, with risk of progression to aortic stenosis. Endothelial dysfunction, mediated by oxidative stress, impaired nitric oxide (NO) signaling, inflammation, and lipoprotein deposition, plays a central role in disease initiation and progression. This study investigated whether a combination of bioactive compounds could counteract these mechanisms and support vascular health. The effects of curcuma longa, coenzyme Q10, black garlic, vitamin B1, and vitamin D3 were tested in vitro on aortic valve endothelial cells. Cell viability, reactive oxygen species (ROS), and NO levels were quantified by commercially available kits, while gene expression was analyzed by RNA sequencing. A 4-week prospective pilot clinical study in 10 healthy volunteers without cardiovascular disease evaluated endothelial function and arterial stiffness. The compounds reduced ROS production (>27 %; p < 0.05), enhanced endothelial viability (>33 %; p < 0.05; except curcuma and black garlic), and increased NO production (>6 %; p < 0.05; except black garlic). Beneficial effects were reflected in upregulation of anti-atherosclerotic (GIPR, +0.058 copies per million, CPM; p < 0.05), antioxidant (GADL1, +0.55 CPM; p < 0.001), and anti-inflammatory (IL12A, +0.17 CPM; p < 0.01) genes. Clinically, daily supplementation improved endothelial function in participants found to have pre-existing endothelial dysfunction (p = 0.0336), with 50 % achieving normal levels after 4 weeks, while all subjects exhibited reduced arterial stiffness (p = 0.0016) without hepatic toxicity. The oral supplementation of the combination of these bioactive compounds improved endothelial function and vascular health, particularly in individuals with endothelial dysfunction, offering potential therapeutic benefits for cardiovascular health. Show less

Aortic valve stenosis (AS) is a progressive valvular disease characterized by fibrocalcific remodeling of the aortic valve leaflets, contributing to significant cardiovascular morbidity and mortality. While valve calcification has been extensively studied, the relationship between valve fibrosis, lipoprotein(a) [Lp(a)], systemic inflammation, sex differences, and valve morphology remains less explored. We prospectively enrolled 45 patients with severe AS undergoing preoperative echocardiography and contrast-enhanced cardiac computed tomography (CT) at Centro Cardiologico Monzino. Aortic valve calcium and fibrosis volumes were quantified using threshold-based segmentation on CT images. Lp(a) was measured by ELISA, while a multiplex Luminex assay measured a panel of 44 cytokines. Patients were stratified by Lp(a) levels (≤ 50 vs. > 50 mg/dL), sex, and valve morphology (bicuspid vs. tricuspid) to explore associations with the fibrocalcific components of stenotic aortic valves. The median Lp(a) level was 34.4 mg/dL (12.6; 93.4). No significant differences in valvular calcium load were observed between low and high Lp(a) groups. However, a modest increase in fibrotic volume was noted in patients with elevated Lp(a), particularly among men (p = 0.075). Several cytokines, including IL-1RA, IL-8, and TGF-α in men, and EGF, GM-CSF, IP-10, and IL-10 in women, were positively correlated with calcium burden. Fibrotic volume was associated with elevated eotaxin and PDGF-AA levels, with sex-specific patterns. Patients with bicuspid valve exhibited higher fibrocalcific volumes but lower circulating levels of several cytokines compared to patients with tricuspid valve morphology. In patients with severe AS, circulating cytokine profiles show sex- and valve-morphology-specific associations with the fibrocalcific composition of the valve. However, Lp(a) was not associated with valvular calcification, and any relationship with fibrosis appeared at most modest, more evident in men. These results support the relevance of inflammatory profiling in assessing AS pathophysiology. Show less

Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib. This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics. Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. gov identifier: NCT02974725. Show less