Search Results for: Diagnosi e gestione dell’aneurisma aorta addominale (AAA)

Dai primi risultati modello utile per la diagnosi precoce

Cruciale per questa neoplasia gravata dalla diagnosi tardiva

In Italia circa 13mila diagnosi carcinoma renale lo scorso anno

In Italia circa 13mila diagnosi carcinoma renale lo scorso anno

Circulation, Ahead of Print. BACKGROUND:The developmental diversity among smooth muscle cells (SMCs) plays a crucial role in segment-specific aortic diseases. However, traditional genetic approaches are inadequate for enabling in vivo analysis of disease susceptibility associated with cellular origin. There is an urgent need to build genetic technologies that target different developmental origins to investigate the mechanisms of aortopathies, thereby facilitating the development of effective therapeutics.METHODS:To address this challenge, we developed an advanced dual recombinase-mediated intersectional genetic system, specifically designed to precisely target SMCs from various developmental origins in mice. Specifically, we usedIsl1-Dre,Wnt1-Dre,Meox1-DreER, andUpk3b-Dreto target SMC progenitors from the second heart field, cardiac neural crest, somites, and mesothelium, respectively. This system was combined with single-cell RNA sequencing to investigate the impact of TGF-β (transforming growth factor-β) signaling in different segments of the aorta by selectively knocking out Tgfbr2 in the ascending aorta and Smad4 in the aortic arch, respectively.RESULTS:Through intersectional genetic approaches, we use theMyh11-Cre(ER) driver along with origin-specific Dre drivers to trace cells of diverse developmental origins within the SMC population. We found that a deficiency of Tgfbr2 in SMCs of the ascending aorta leads to aneurysm formation in this specific region. We also demonstrate the critical role of Smad4 in preserving aortic wall integrity and homeostasis in SMCs of the aortic arch.CONCLUSIONS:Our approach to genetically targeting SMC subtypes provides a novel platform for exploring origin-dependent or location-specific aortic vascular diseases. This genetic system enables comprehensive analysis of contributions from different cell lineages to SMC behavior and pathology, thereby paving the way for targeted research and therapeutic interventions in the future.

Circulation, Ahead of Print. BACKGROUND:The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme EZH2 (enhancer of zeste homolog 2) mediates the H3K27me3 (trimethylation of histone H3 lysine 27) and is pivotal in controlling T cell responses.METHODS:To detail the role of T cell EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2. Atherosclerosis-proneApoe(apolipoprotein E)–deficient mice with CD (cluster of differentiation) 4+or CD8+T cell–specificEzh2deletion (Ezh2cd4-knockout [KO], Ezh2cd8-KO) were analyzed to unravel the role of T cell Ezh2 in atherosclerosis and T cell–associated immune status.RESULTS:EZH2expression is elevated in advanced human atherosclerotic plaques and primarily expressed in the T cell nucleus, suggesting the importance of canonical EZH2 function in atherosclerosis. Ezh2cd4-KO, but not Ezh2cd8-KO, mice showed reduced atherosclerosis with fewer advanced plaques, which contained less collagen and macrophages, indicating that Ezh2 in CD4+T cells drives atherosclerosis. In-depth analysis of CD4+T cells of Ezh2cd4-KO mice revealed that absence of Ezh2 results in a type 2 immune response with increased Il-4 (interleukin 4) gene and protein expression in the aorta and lymphoid organs. In vitro,Ezh2-deficient T cells polarized macrophages toward an anti-inflammatory phenotype. Single-cell RNA-sequencing of splenic T cells revealed thatEzh2deficiency reduced naive, Ccl5+(C-C motif chemokine ligand 5) and regulatory T cell populations and increased the frequencies of memory T cells and invariant natural killer T (iNKT) cells. Flow cytometric analysis identified a shift toward Th2 (type 2 T helper) effector CD4+T cells in Ezh2cd4-KO mice and confirmed a profound increase in splenic iNKT cells with increased expression of Plzf (promyelocytic leukemia zinc finger), which is the characteristic marker of the iNKT2 subset. Likewise,Zbtb16([zinc finger and BTB domain containing 16], a Plzf-encoding gene) transcripts were elevated in the aorta of Ezh2cd4-KO mice, suggesting an accumulation of iNKT2 cells in the plaque. H3K27me3–chromatin immunoprecipitation followed by quantitative polymerase chain reaction showed that T cell–Ezh2 regulates the transcription of theIl-4andZbtb16genes.CONCLUSIONS:Our study uncovers the importance of T cell EZH2 in human and mouse atherosclerosis. Inhibition of Ezh2 in CD4+T cells drives type 2 immune responses, resulting in an accumulation of iNKT2 and Th2 cells, memory T cells and anti-inflammatory macrophages that limit the progression of atherosclerosis.

Circulation, Ahead of Print. BACKGROUND:Although combination antiretroviral therapy has increased life expectancy in people living with HIV, it has led to a marked increase in the prevalence of hypertension, the cause of which is unknown. Despite combination antiretroviral therapy, HIV-derived proteins remain expressed and produced by CD4+T lymphocytes in people living with HIV. However, their contribution to HIV-associated hypertension and impaired endothelium-dependent relaxation remains ill defined.METHODS:Here, we tested the hypothesis that CD4+T cells expressing viral proteins contribute to endothelial dysfunction and hypertension using the Tg26 mouse model of HIV that expresses 7 of the 9 HIV proteins under the long terminal repeat promoter. We used male and female mice, bone marrow transplantation (BMT), adoptive transfer of CD4+T cells, and aorta specimen discarded from people living with HIV.RESULTS:We reported that intact Tg26 mice and mice receiving BMT (Tg26→WT) or CD4+T cells from Tg26 mice display impaired endothelium-dependent relaxation and hypertension. Conversely, BMT from WT mice into Tg26 mice, inhibition of T cell activation, and CD4+T cell depletion restored endothelial function and blood pressure in Tg26 mice. Cytokine profiling revealed that Tg26 mice, Tg26→WT, and Tg26 CD4+T cells consistently exhibit high interleukin 1α (IL-1α) levels with no significant increase in other cytokines, whereas BMT from WT mice into Tg26 mice reduced IL-1α levels. IL-1α neutralization reduced blood pressure and restored endothelial function in Tg26 mice. To investigate the role of CD4+T cells and IL-1α in endothelial dysfunction, we developed an aorta-immune cell coculture system. Exposure of WT aortas to Tg26 CD4+T cells impaired endothelium-dependent relaxation, which was blocked by IL-1α–neutralizing antibody. While investigating the mechanisms of endothelial dysfunction, we reported that Tg26 mice, Tg26→WT aorta exhibit high NADPH oxidase (NOX) 1 expression. IL-1α exposure increased NOX1 in human microvascular endothelial cells, and NOX1 blockade restored endothelial function in Tg26 and Tg26→WT arteries, whereas NOX1 deficiency protected against Tg26 BMT-induced impaired endothelium-dependent relaxation and hypertension. Aortas from people living with HIV exhibit high NOX1 levels, and exposure of human aorta to Tg26 T cells increased NOX1 expression.CONCLUSIONS:We provide the first evidence that CD4+T cells expressing HIV viral proteins induced hypertension through IL-1α–mediated increases in vascular NOX1, which impairs endothelial function in males and females.

Il libro di Claudio Giorlandino, ‘da diagnosi per le malattie rare alle cure su misura’

Per circa il 60% degli studenti delle scuole superiori di Milano che hanno partecipato all’incontro ‘Dal Laboratorio alla vita’

Per diagnosi precoce del tumore tra i 70 e 74 anni

Stroke, Volume 56, Issue Suppl_1, Page AWP187-AWP187, February 1, 2025. Introduction:3 to 5% of patients undergoing endovascular thrombectomy present impossible catheter access to the occlusion site from transfemoral access (TFA), largely attributed to complex arterial anatomy. Radial access can be an effective bailout strategy, but intraprocedural delays may negatively impact outcomes. Novel image processing algorithms allow for advanced characterization of vascular pathways from baseline neuroimaging, enabling the exploration of predictive models of impossible TFA before arterial puncture.Methods:A retrospective cohort of patients with an anterior large vessel occlusion who received thrombectomy from TFA between 2017 and 2023 were included in this study. A previously described automatic vascular analysis software was used to generate centerline graphs from the aorta to the intracranial occlusion site from baseline CTA. ArterialGNet, a graph neural network based on graph attention designed to integrate descriptors of centerline pathways extracted at three different distance scales, was trained for impossible TFA prediction. Five-fold cross validation was used for model derivation. The method was compared to a previously introduced random forest ensemble model with extreme gradient boosting (XGBRF) based on six vascular tortuosity descriptors of the aortic and supra-aortic regions.Results:A total of 745 patients (aged 78 years IQR 68-85, 56% women) were included in this study. Patients treated between 2017 to 2022 (n=568, 3.2% with impossible TFA) were used for model training and validation. Patients treated in 2023 (n=177, 3.4% with impossible TFA) were held out for testing. In validation, the best-performing configuration of ArterialGNet achieved a C-statistic of 0.82 (95%CI 0.74-0.90), similar to the baseline model (0.82, 95%CI 0.77-0.88). Comparable outcomes were observed in the final testing for ArterialGNet (0.84, 95%CI: 0.82–0.86). In contrast, the XGBRF model exhibited signs of overfitting (0.65, 95% CI: 0.53–0.78). In final testing, ArterialGNet predicted impossible TFA with a sensitivity of 0.80 (95%CI 0.66-0.94) and a specificity of 0.84 (95%CI 0.76-0.91). Median processing time for ArterialGNet was below 4 min.Conclusions:A novel model for impossible TFA prediction was validated with a large dataset. Impossible TFA prediction before arterial puncture may assist in decision support for initial access selection in thrombectomy, reducing intraprocedural delays and potentially improving clinical outcomes.