Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer

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.

Leggi
Luglio 2024

Risk-reducing salpingo-oophorectomy among diverse patients with BRCA mutations at an urban public hospital: a mixed methods study

Objectives
To assess the association of socioeconomic demographics with recommendation for and uptake of risk-reducing bilateral salpingo-oophorectomy (rrBSO) in patients with BRCA1 and BRCA2 (BRCA1/2) mutations.

Design
Retrospective cohort, semistructured qualitative interviews.

Setting and participants
BRCA1/2 mutation carriers at an urban, public hospital with a racially and socioeconomically diverse population.

Intervention
None.

Primary and secondary outcomes
The primary outcomes were rate of rrBSO recommendation and completion. Secondary outcomes were sociodemographic variables associated with rrBSO completion.

Results
The cohort included 167 patients with BRCA1/2 mutations of whom 39% identified as black (n=65), 35% white (n=59) and 19% Hispanic (n=32). Over 95% (n=159) received the recommendation for age-appropriate rrBSO, and 52% (n=87) underwent rrBSO. Women who completed rrBSO were older in univariable analysis (p=0.05), but not in multivariable analysis. Completion of rrBSO was associated with residence in zip codes with lower unemployment and documented recommendation for rrBSO (p

Leggi
Giugno 2024

Decision aids for female BRCA mutation carriers: a scoping review

Objectives
Women who inherit a pathogenic BRCA1 or BRCA2 mutation are at substantially higher risk of developing breast and ovarian cancer than average. Several cancer risk management strategies exist to address this increased risk. Decisions about which strategies to choose are complex, personal and multifactorial for these women. Decision aids (DAs) are tools that assist patients in making health-related decisions. The aim of this scoping review was to map evidence relating to the development and testing of patient DAs for cancer unaffected BRCA mutation carriers.

Design
Scoping review conducted according to the Joanna Briggs Institute’s (JBI’s) scoping review methodological framework.

Data sources
MEDLINE, EMBASE, CINAHL, Web of Science. No restrictions applied for language or publication date. A manual search was also performed.

Eligibility criteria for selecting studies
Studies on DAs for cancer risk management designed for or applicable to women with a pathogenic BRCA1 or BRCA2 mutation who are unaffected by breast or ovarian cancer.

Data extraction and synthesis
Data were extracted using a form based on the JBI instrument for extracting details of studies’ characteristics and results. Data extraction was performed independently by two reviewers. Extracted data were tabulated.

Results
32 evidence sources relating to development or testing of 21 DAs were included. Four DAs were developed exclusively for cancer unaffected BRCA mutation carriers. Of these, two covered all guideline recommended risk management strategies for this population though only one of these was readily available publicly in its full version. All studies investigating DA effectiveness reported a positive effect of the DA under investigation on at least one of the outcomes evaluated, however only six DAs were tested in randomised controlled trials.

Conclusion
This scoping review has mapped the landscape of the literature relating to developing and testing, DAs applicable to cancer unaffected BRCA mutation carriers.

Leggi
Giugno 2024

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice

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.

Leggi
Giugno 2024

Calcitonin Gene-Related Peptide Inhibitors for Treatment of Rosacea

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.

Leggi
Giugno 2024