-
Clinical and Translational Medicine Nov 2023Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors,...
BACKGROUND
Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up-regulate pro-inflammatory cytokines and activate NF-κB signaling. Meanwhile, the PIEZO1 upregulation and cancer-associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated.
METHODS
The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF-κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1-CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co-culture system and animal studies. Patient-derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1-YAP1-CTGF cascade in GC.
RESULTS
Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF-κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF-κB into YAP1 signaling, a well-documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c-Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen-enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5-FU in suppressing the GC cell peritoneal metastasis.
CONCLUSION
This study elucidates a novel driving PIEZO1-YAP1-CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori-NF-κB activates the PIEZO1-YAP1-CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1-YAP1-CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.
Topics: Animals; Humans; NF-kappa B; Stomach Neoplasms; Helicobacter pylori; Cancer-Associated Fibroblasts; Helicobacter Infections; Peritoneal Neoplasms; Tumor Microenvironment; Ion Channels
PubMed: 37983931
DOI: 10.1002/ctm2.1481 -
Journal of Veterinary Internal Medicine 2023Nucleoside analog GS-441524 is effective in treating cats with feline infectious peritonitis (FIP). Investigation into the use of parent nucleotide analog remdesivir...
BACKGROUND
Nucleoside analog GS-441524 is effective in treating cats with feline infectious peritonitis (FIP). Investigation into the use of parent nucleotide analog remdesivir (GS-5734) is needed.
OBJECTIVES
To assess efficacy and tolerability of remdesivir with or without transition to GS-441524 in cats with FIP and document clinical and clinicopathologic progression over 6 months.
ANIMALS
Twenty-eight client-owned cats with FIP.
METHODS
Cats were prospectively recruited between May 2021 and May 2022. An induction dosage of remdesivir 10 to 15 mg/kg intravenously or subcutaneously q24h was utilized for 4 doses, with a maintenance dosage of remdesivir (6-15 mg/kg SC) or GS-441524 (10-15 mg/kg per os) every 24 hours continued for at least 84 days. Laboratory testing, veterinary, and owner assessments were recorded.
RESULTS
Twenty-four cats survived to 6 months (86%). Three cats died within 48 hours. Excluding these, survival from 48 hours to 6 months was 96% (24/25). Remission was achieved by day 84 in 56% (14/25). Three cats required secondary treatment for re-emergent FIP. Remission was achieved in all 3 after higher dosing (15-20 mg/kg). Adverse reactions were occasional site discomfort and skin irritation with remdesivir injection. Markers of treatment success included resolution of pyrexia, effusions, and presenting signs of FIP in the first half of treatment and normalization of globulin concentration, and continued body weight gains in the latter half of the treatment period.
CONCLUSIONS AND CLINICAL IMPORTANCE
Parenteral administration of remdesivir and oral administration of GS-441524 are effective and well-tolerated treatments for FIP. Early emphasis on clinical, and later emphasis on clinicopathologic response, appears prudent when monitoring treatment efficacy.
Topics: Humans; Cats; Animals; Feline Infectious Peritonitis; Exudates and Transudates; Coronavirus, Feline; Cat Diseases
PubMed: 37439383
DOI: 10.1111/jvim.16803 -
La Tunisie Medicale Oct 2023Peritoneal dialysis (PD) is the method of choice for extra-renal replacement therapy (ERT) for children with end-stage renal disease (ESRD), because of its various...
INTRODUCTION
Peritoneal dialysis (PD) is the method of choice for extra-renal replacement therapy (ERT) for children with end-stage renal disease (ESRD), because of its various advantages. However, it presents different infectious and non-infectious complications, causes of important morbidity and mortality.
AIM
To determine the mechanical complications of PD in our center and to identify risk factors of their occurrence.
METHODS
We retrospectively collected the records of 99 patients who were treated with PD within the past eleven years in the department of pediatrics of the University Hospital Charles Nicolle of Tunis. Analysis examining possible risque factors were performed using parametric and non-parametric tests.
RESULTS
A total of 63 patients had mechanical complications with an incidence of peritoneal dialysis catheter revision of 1 procedure every 38 months. The causes were dominated by catheter migration (27.5%) and obstruction by fibrin or blood clotting (19.8%). A history of peritonitis (p=0.046) and the presence of comorbidity (p=0.008) were the two independent risk factors for catheter revision. Inguinal hernia was noted in six patients. No patient presented with a hydrothorax. Seven patients presented an episode of hemoperitoneum.
CONCLUSION
Our results lead us to focus our efforts on preventing peritonitis and controlling morbidity. Prospective studies will enable us to confirm our results.
Topics: Humans; Child; Retrospective Studies; Prospective Studies; Peritoneal Dialysis; Kidney Failure, Chronic; Peritonitis
PubMed: 38465752
DOI: No ID Found