AKT2S128/CCTαS315/319/323-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs).

Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance. Present study employed multi-omics, including phosphoproteomics, untargeted metabolomics and lipidomics, to demonstrate that the pAKT2 Ser128 and pCCTα Ser315/319/323-positive cancer-associated fibroblasts (CAFs) substantially release phosphatidylcholines (PCs), contributing to the resistance of focal adhesion kinase (FAK) inhibitors in esophageal squamous cell carcinoma (ESCC) treatment. Additionally, we observed extremely low levels of FAK Tyr397 expression in CAFs, potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs. Consequently, FAK inhibitor increased the intracellular concentration of Ca2+ in CAFs, promoting the formation of AKT2/CCTα complex, leading to phosphorylation of CCTα Ser315/319/323 sites and eventually enhancing stromal PC production. This activation could stimulate the intratumoral Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway, triggering resistance to FAK inhibition. Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTα Ser315/319/323 are related to the tumor malignancy and reduced patient survival. Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients. In conclusion, inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

Association of the Quantity, Duration, and Type of Alcohol Consumption on the Development of Gouty Tophi.

OBJECTIVE: To examine the association of alcohol consumption with the presence and development of ultrasound (US)-detected tophi and subcutaneous tophi in a Chinese gout population. METHODS: A total of 554 patients with gout who underwent US and physical examination of the most frequently involved joints in gout were included in this study. Multivariable analysis was performed to assess the associations of the duration, quantity, and type of alcohol consumption with the presence, size, and number of US-detected tophi and subcutaneous tophi. RESULTS: Compared to non-drinkers, excessive drinkers (>70 gm/week), long-term drinkers (≥10 years), and spirits drinkers had a greater proportion, size, and number of US-detected tophi and subcutaneous tophi (all P < 0.05). After adjusting for confounders, excessive drinking (>70 gm/week) (odds ratio [OR] 1.79 [2.00 after adjustment]), long-term alcohol consumption (≥10 years) (OR 1.96 [2.17 after adjustment]), and spirits consumption of (OR 1.81 [2.10 after adjustment]) were significantly associated with the presence of US-detected tophi and subcutaneous tophi (all P < 0.05), with the highest ORs among the identified risk factors. Among patients who already had US-detected tophi or subcutaneous tophi, moderate drinking (≤70 gm/week) was associated with larger or multiple tophi (all P < 0.05). CONCLUSION: Longer duration and higher quantity of alcohol consumption as well as spirits consumption are predictors for the development of US-detected tophi and subcutaneous tophi in patients with gout. Among individuals who have US-detected tophi and subcutaneous tophi, weekly alcohol consumption leads to the development of tophi regardless of amount consumed.

Characterization of Plasma Extrachromosomal Circular DNA in Gouty Arthritis.

Objective: Extrachromosomal circular DNA elements (eccDNAs) are known for their broad existence in cells and plasma, which may potentially play important roles in many biological processes. Our aim was to identify potentially functional or marked eccDNAs in gout patients. Methods: The Circle-Seq approach was applied for eccDNA detection from plasma in acute gout patients and healthy controls. Further analysis was performed on the distribution of genomic elements and eccDNA gene annotations in two groups. Results: We detected 57,216 and 109,683 eccDNAs from the acute gout and healthy control plasma, respectively. EccDNAs were mapped to the reference genome to identify diverse classes of genomic elements and there was no significant difference of eccDNAs on genomic element annotation between gout and control group. A total of 256 eccDNA-associated genes were detected as gout unique eccDNA genes, including COL1A1 and EPB42, which potentially contribute to hyperuricemia and gout, and a couple of genes involved in inflammation or immune response. Enrichment analysis showed that these eccDNA genes were highly correlated with defense response, stress response, and immune and inflammatory responses, including T cell receptor signaling pathway, Fc epsilon RI signaling pathway, and JAK-STAT signaling pathway. Conclusion: Our discovery reveals the novel potential biological roles of plasma eccDNAs in gouty arthritis.