Search Results for: Le cure a domicilio: Chi curare, cosa fare e cosa non fare

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Il Ceo della farmaceutica indiana: «l’Europa è un mercato chiave e stiamo investendo per estendere l’accesso alle cure in aree cruciali come oncologia, immunologia e diabete»

Il Ceo della farmaceutica indiana: «l’Europa è un mercato chiave e stiamo investendo per estendere l’accesso alle cure in aree cruciali come oncologia, immunologia e diabete»

Chronic hepatitis B virus (HBV) infection remains a significant global health burden, affecting over 250 million people worldwide who are at risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Currently available nucleos(t)ide analogues (NAs) are effective in controlling viraemia; however, functional cure, defined as loss of hepatitis B surface antigen (HBsAg), is rare and difficult to achieve and likely requires robust immune responses, reflecting the need for innovative therapeutic strategies.1 Thus, the future of treating chronic HBV infections relies on combination therapies that include both direct-acting antiviral agents and immunomodulatory agents.2 In this context, selgantolimod (SLGN), an agonist of Toll-like receptor 8 (TLR8), could be a promising candidate. Its efficacy in the treatment of chronic HBV infections has been investigated in preclinical models and clinical trials,3–5 but there remains limited understanding of its impact on immune effectors within the…

Objective
Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment.

Design
We identified TLR8-expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN’s indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN’s effect were validated using transcriptomic data from HBV-infected patients.

Results
Hepatic TLR8 expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg, S100A12) and downregulated genes associated with the KC identity (eg, SPIC). Treatment of hepatocytes with SLGN-CM downregulated NTCP and impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition.

Conclusion
Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection.

Circulation, Volume 150, Issue Suppl_1, Page A4136030-A4136030, November 12, 2024. Background:Almost all cardiac diseases are difficult to cure entirely because cardiomyocytes rarely proliferate to recover cardiac damage. In fact, most mammals have a capacity to regenerate cardiomyocytes immediately after birth. Newborn infant drastically changes cardiac metabolism from glycolysis to oxidative phosphorylation using fatty acids. Previous research revealed that lipid metabolism had a negative influence on cardiomyocyte cell cycle but the mechanism has not been clarified completely.Objective:This study was performed to elucidate the way fatty acid metabolism affects cardiomyocyte proliferation.Methods and results:Isolated and cultured neonatal rat cardiomyocytes (NRCM) were treated with the mixture of palmitic acid, oleic acid, and L-carnitine (FA mix) for 24 hours. Realtime RT-PCR revealed that FA mix increased the mRNA expressions of pyruvate dehydrogenase kinase 4 (PDK4), a fatty acid metabolism regulator, and HMG-CoA synthase 2 (HMGCS2), a ketogenic factor, as well as β-oxidation-related enzymes in dose dependent manner. Simultaneously, the results of immunofluorescent staining showed that FA mix decreased cardiomyocytes expressing Ki67, a cell cycle marker. GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) agonist, also increased fatty acid metabolism factors with the reduction of Ki67 positive cardiomyocytes, whereas fenofibrate, a PPARα agonist, or pioglitazone, a PPARγ agonist, caused little or no change in these phenotypes. Moreover, NRCM pretreated with GSK3787, a PPARδ antagonist, before FA mix stimulation suppressed the upregulations of fatty acid metabolism factors and the reduction of Ki67 expressing cardiomyocytes. Finally, the lentiviral vectors which expressed PDK4 or HMGCS2 were produced to investigate these proteins suppressed NRCM cell cycle directly. Either overexpressing PDK4 or HMGCS2 decreased Ki67 positive NRCM without the upregulation of each other or β-oxidation-related enzymes.Conclusion:Fatty acids disturbed NRCM proliferation by upregulating PDK4 and HMGCS2 through the activation of PPARδ independently from β-oxidation.

Circulation, Volume 150, Issue Suppl_1, Page A4114694-A4114694, November 12, 2024. Purpose:Persistent atrial fibrillation (AFib), the most common sustained cardiac arrhythmia in the United States, poses substantial health hazards, such as the formation of blood clots, stroke, and heart failure. Despite available therapies such as ablation and antiarrhythmic drugs, there still is no definitive cure for AFib. Our study aims to bridge this gap by investigating the genetic and molecular factors underlying AFib through the development of an AFib model using Yucatan mini swine as the medium that closely mimics human cardiac physiology.Methods:We selected Yucátan mini swine as animal models because they closely resemble humans physiologically and are of a convenient size for performing extended experiments. We surgically implanted pacing leads, implantable cardiac monitors (ICMs), and pacing generators into the swine, along with external Fitbark 2.0 Collars to use activity levels as a measurement of quality of life. After the procedures the swine underwent rapid atrial pacing with the intention to induce persistent atrial fibrillation.Findings:An electrocardiogram (ECG) showed that the method of stimulating the right atrium of the heart induced persistent atrial fibrillation in pigs and decreased levels of activity, indicating a decline in their general health. This continued for >7 days after atrial pacing was terminated. Overcoming challenges associated with animal dimensions and model design, we devised specific surgical techniques, including jugular cut-down, lateral cervical implantation coupled with antibiotic support, long sheaths, and customized styluses. These innovations were instrumental in achieving a successful AFib model and overcoming anatomical obstacles.Summary:Our study demonstrates the feasibility of creating a large animal model of AFib using Yucatan mini swine. This model closely resembles the clinical presentation of human AFib and could provide valuable insights into the disease mechanism and potential therapeutic strategies. Animal heart and vascular dimensions were the most challenging surgically.

Circulation, Volume 150, Issue Suppl_1, Page A4141118-A4141118, November 12, 2024. Objective:Pulmonary Arterial Hypertension (PAH) is a fatal disease with high mortality rates and late diagnosis, currently lacking complete cure. Metabolic abnormalities play a crucial role in the pathophysiological process of pulmonary vascular remodeling. This study aimed to identify metabolic-related genes that may play important roles in PAH and analyze their expression and function and the clinical significance.Methods:Transcriptomic data were retrieved from the GEO database, including tissue transcriptome data (GSE113439, GSE53408, GSE198618) and single-cell transcriptome data (GSE210248, GSE203274); “limma” and “DEseq2” packages were used to identify differentially expressed genes (DEGs); By WGCNA and Boruta algorithm, we identified feature genes related to PAH; Transcription factor network analysis was analyzed using the “RTN” package; Single-cell and single-nucleus transcriptome data were analyzed using the Seurat pipeline; Concentration of key genes’ protein level in PAH were evaluated using ELISA.Results:The study found increased glycolysis, disrupted carnitine shuttle pathway, enhanced fatty acid degradation, decreased oxidative phosphorylation, and augmented polyamine synthesis in PAH. PIGN, SLC25A24, RPL5, PIK3CA, PIK3CB, DNM1L, SETD2, TPH1, ITPR2, PRKAA1, PTPN11, and PDK4 were identified as metabolic-related genes associated with PAH. PDK4 was significantly increased in pulmonary artery endothelial cells (PAECs) and right ventricular tissues of decompensated right heart failure, mainly expressed in cardiomyocytes. PDK4 was significantly elevated in the PAH group (control group: 4.15 ± 0.53 ng/ml; idiopathic pulmonary arterial hypertension group: 5.28 ± 0.77 ng/ml, p-value

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