I moderni dispositivi permettono di adattare la terapia insulinica alle esigenze individuali di ciascun paziente, migliorando l’efficacia del trattamento
Search Results for: Scoperto bersaglio per il trattamento del cancro al pancreas
Here's what we've found for you
Linea guida sulla diagnosi e gestione dell’endometriosi
Questa linea guida riguarda la diagnosi e la gestione dell’endometriosi, anche quando […]
CD64+ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8+ T cells
Objective
The objective of this study is to improve the efficacy of CLDN18.2/CD3 bispecific T-cell engagers (BiTEs) as a promising immunotherapy against pancreatic ductal adenocarcinoma (PDAC).
Design
Humanised hCD34+/hCD3e+, Trp53R172HKrasG12DPdx1-Cre (KPC), pancreas-specific Cldn18.2 knockout (KO), fibroblast-specific Fcgr1 KO and patient-derived xenograft/organoid mouse models were constructed. Flow cytometry, Masson staining, Cell Titer Glo assay, virtual drug screening, molecular docking and chromatin immunoprecipitation were conducted.
Results
CLDN18.2 BiTEs effectively inhibited early tumour growth, but late-stage efficacy was significantly diminished. Mechanically, the Fc fragment of BiTEs interacted with CD64+ cancer-associated fibroblasts (CAFs) via activation of the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A-α-SMA/collagen-I pathway, which enhanced desmoplasia and limited late-stage infiltration of T cells. Molecular docking analysis found that vilanterol suppressed BiTEs-induced phosphorylation of VAV2 (Y172) in CD64+ CAFs and weakened desmoplasia. Additionally, decreased cyclic guanosine-adenosine monophosphate synthase/stimulator of interferon genes (STING) activity reduced proliferation of TCF-1+PD-1+ stem-like CD8+ T cells, which limited late-stage effects of BiTEs. Finally, vilanterol and the STING agonist synergistically boosted the efficacy of BiTEs by inhibiting the activation of CD64+ CAFs and enriching proliferation of stem-like CD8+ T cells, resulting in sustained anti-tumour activity.
Conclusion
Vilanterol plus the STING agonist sensitised PDAC to CLDN18.2 BiTEs and augmented efficacy as a potential novel strategy.
Abstract 4143006: Systemic Vascular Damage and Cardiac Dysfunction in a Mouse Severe Acute Pancreatitis Model
Circulation, Volume 150, Issue Suppl_1, Page A4143006-A4143006, November 12, 2024. Background and Objective:Decline of cardiovascular (CV) function is commonly observed in patients with severe acute pancreatitis (AP), which is associated with high mortality and morbidity. While the pathological changes in the pancreas during severe AP have been extensively studied, the impact on the CV system has not been well characterized. Furthermore, obesity is a major risk factor for severe AP. Hereby we utilized an obesity-associated mouse AP model to assess potential alterations in vascular integrity and cardiac function, two major components of circulatory failure.Methods:Wild-type male C57BL6J mice were fed a normal or a high fat (to induce obesity) diet. Both groups received intraperitoneal injection of cerulein (100 mg/kg/h x12) to induce AP. H&E and TUNEL staining of pancreas were performed to assess histology and cell death. To measure vascular integrity, we measured the leakiness of a fluorescein-conjugated dextran (70 kDa) in tissue parenchyma and serum levels of soluble vascular endothelial (VE)-cadherin, which has recently shown to be shed from endothelial cells with disrupted adherens junctions. Cardiac systolic and diastolic function were assessed by echocardiography at baseline and post-AP induction.Results:Compared to lean mice, obese mice developed more severe pancreatic edema, cell death and inflammatory cell infiltration, along with significantly increased accumulation of fluorescent dextran in multiple organs including pancreas, heart, lung, and kidney, suggesting systemic disruption of vascular integrity. Increased serum levels of soluble VE-cadherin in obese mice (vs. lean) after AP induction further supported compromised endothelial cell barrier function. At baseline, obese mice exhibited similar cardiac function to lean mice. However, obese mice, but not lean mice, developed impaired systolic and diastolic function post-AP induction, as supported by decreased ejection fraction and e’ velocity respectively.Conclusion:In this obesity-associated severe AP mouse model, systemic vascular permeability is increased, and cardiac function is substantially compromised. Systemic vascular hyperpermeability and cardiac dysfunction may represent therapeutic targets to enhance the outcomes in severe AP.
Linee guida sull’identificazione e gestione della menopausa
Questa linea guida pubblicata da NICE, riguarda l’identificazione e la […]
Tumore al seno, nuovo farmaco blocca metastasi in animali
In Italia 37mila persone con cancro metastatico della mammella
Da salmone a frutta secca, grassi buoni difendono dal cancro
Chi ne consuma molti ha rischio ridotto di avere vari tumori
Da salmone a frutta secca, grassi buoni difendono dal cancro
Chi ne consuma molti ha rischio ridotto di avere vari tumori
Cura del cancro, Sinner a Candiolo per il lancio della Biobanca
Il numero 1 al mondo per l’iniziativa ‘Un ace per la ricerca’
Pancreatite acuta: diagnosi, valutazione di gravità, terapia medica ed endoscopica e gestione del post-acuzie
La presente Linea Guida affronta il tema della gestione ospedaliera […]
Linea guida per la terapia del sovrappeso e dell’obesità resistenti al trattamento comportamentale nella popolazione adulta con comorbilità metaboliche
Lo scopo della presente Linea Guida è produrre raccomandazioni operative […]
Acidi grassi Omega-3 e Omega-6 associati a un rischio inferiore di cancro
Uno studio condotto dai ricercatori dell’University of Georgia su oltre 250.000 […]
Riviste le linee guida diagnostiche per l’Alzheimer
L’International Working Group ha aggiornato le linee guida diagnostiche per […]
La terapia del diabete mellito di tipo 1
Lo scopo della Linea Guida è quello di fornire un […]
Gestione terapeutica del paziente adulto con ipotiroidismo primario non in gravidanza
Lo scopo della seguente linea guida è produrre raccomandazioni operative […]
Linee guida Diverticolosi e Malattia diverticolare del colon
La Società Italiana di Gastroenterologia ed Endoscopia Digestiva (SIGE) nell’ambito […]