Risultati per: Fumo e malattia coronarica: responsabile un singolo gene

‘Il drago ruba bellezza’ racconta la Colestasi Intraepatica

New England Journal of Medicine, Volume 391, Issue 12, Page 1108-1118, September 26, 2024.

Minore multimorbidità cardiometabolica

Sindrome di Leigh,progetto vincitore bando Multi-round Telethon

Uno studio pubblicato su Nature Communication fa luce su Oser1

Per l’amaurosi congenita di Leber risultati duraturi e notevoli

Al via campagna. L’8 settembre Giornata Mondiale Fisioterapia

Dalla fine della terapia non ha presentato segni clinici

Advanz Pharma, decisione mette a rischio migliaia di pazienti

This Viewpoint discusses the high cost of new gene therapies for sickle cell disease, the challenges these costs pose for health care access, and new policy approaches to ensure fair reimbursement for payers and manufacturers without further increasing health care costs or barriers to access for underserved populations.

Condizione rara, ma grave, causata da depositi di proteine anomale

Tecnologia dell’Università Carlo Bo esplora uso di globuli rossi

This cohort study investigates whether calcitonin gene-related peptide inhibition is associated with reduced rates of developing acne or rosacea in patients who experience migraines.

Objective
Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations.

Design
We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC.

Results
We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor geneTrp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth.

Conclusion
These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.