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

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.

This gene-environment interaction study using a case-control design investigated the interaction between oral contraceptives, the risk allele in CYP1B1, and female frontal fibrosing alopecia.

In Lombardia uno studio pilota promosso da Telethon coinvolgerà 100mila neonati. Obiettivo: validare il test per la diagnosi di leucodistrofia metacromatica

This Viewpoint presents the components of the payment model and the implementation challenges among the Center for Medicare and Medicaid Innovation, state Medicaid agencies, patients, and manufacturers.

Objective
Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice.

Design
A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T >C mouse models).

Results
The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process.

Conclusion
One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

New England Journal of Medicine, Volume 390, Issue 21, Page 2025-2027, June 6, 2024.

While many treatments are available for papules and pustules of rosacea, few are available for erythema and flushing. The 2019 Global Rosacea Consensus Panel recommends general skincare, β-blockers (eg, propranolol and carvedilol), and α-adrenergic agents (eg, brimonidine and oxymetazoline) for flushing and vascular lasers for persistent erythema. Because these treatments may not always be effective or tolerated, there remains an unmet need for additional options that can address symptoms of flushing and erythema in rosacea.

This report describes the development of an 18-gene urine panel for high-grade prostate cancer and validates its external performance relative to current guideline-endorsed biomarkers.

Tra i giovani il 30,2% usa almeno un prodotto tra sigaretta tradizionale, tabacco riscaldato o sigaretta elettronica,

Tra i giovani il 30,2% usa almeno un prodotto tra sigaretta tradizionale, tabacco riscaldato o sigaretta elettronica,

Tra i giovani il 30,2% usa almeno un prodotto tra sigaretta tradizionale, tabacco riscaldato o sigaretta elettronica,

This Viewpoint examines the appropriateness of FDA accelerated approval of novel gene therapies to treat boys with Duchenne muscular dystrophy following clinical trials with surrogate outcomes that did not demonstrate net benefits.

Studio Irccs Candiolo su nuovo meccanismo resistenza a terapia