Recent studies show that exosomes are involved in intercellular communication and that abundant circular RNAs (circRNAs) are present within exosomes. However, whether these exosomal circRNAs contribute to tumor invasion and metastasis remains unclear, as do their associated mechanisms. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to measure the expression levels of circ-IARS in 85 pancreatic ductal adenocarcinoma (PDAC) tissues, plasma exosomes, and Hs 766 T, Hs 766 T-L2 and human microvascular vein endothelial (HUVECs) cells. RhoA, ZO-1 and RhoA-GTP levels were detected by qRT-PCR and western blotting (WB); RhoA activity analysis was also performed. Transwell assays were performed to examine changes in endothelial monolayer permeability, and immunofluorescence and WB were employed to evaluate F-actin expression and focal adhesion. Finally, an animal experiment was performed to detect the contribution of circ-IARS to cancer metastasis. circ-IARS expression was up-regulated in pancreatic cancer tissues and in plasma exosomes of patients with metastatic disease. Circ-IARS was found to enter HUVECs through exosomes and promote tumor invasion and metastasis. Circ-IARS expression was positively correlated with liver metastasis, vascular invasion, and tumor-node-metastasis (TNM) stage and negatively correlated with postoperative survival time. Overexpression of circ-IARS significantly down-regulated miR-122 and ZO-1 levels, up-regulated RhoA and RhoA-GTP levels, increased F-actin expression and focal adhesion, enhanced endothelial monolayer permeability, and promoted tumor invasion and metastasis. circ-IRAS accesses HUVECs via exosomes derived from pancreatic cancer cells followed by increased endothelial monolayer permeability. Furthermore, this process promotes tumor invasion and metastasis. The results of this study suggest that the presence of circRNAs in exosomes may be important indicator for early diagnosis and prognostic prediction in PDAC.

CD44 variants have been associated with tumor invasion and metastasis, but CD44 expression patterns have not been systematically investigated in pancreatic carcinoma. This study systematically investigated whether CD44 expression patterns are involved in pancreatic carcinoma metastasis and prognosis. We applied primers specific for all CD44 variants and CD44s to analyze the expression patterns of CD44 (CD44v2-CD44v10 and CD44s) using quantitative real-time PCR (qRT-PCR). We then further evaluated their roles in pancreatic carcinoma metastasis and prognosis using clinical survival analysis. Increased CD44v expression and decreased CD44s expression were found in metastatic pancreatic carcinoma in three different cell lines and in human tumor tissue. Clinical analysis showed that CD44v6+ and CD44v9+ were correlated with lymph node metastasis, liver metastasis and TNM stage. However, CD44s- was associated with liver metastasis, tumor differentiation and TNM stage. Survival analysis showed that patients with CD44v6+/CD44s- or CD44v6+/CD44s- had lower overall survival (OS) rates, although the individual expression of CD44v6, CD44v9 and CD44s was also related to decreased OS rates. Univariate analysis showed that lymph node metastasis; vessel invasion; hepatic metastases; TNM stage; and individual or co-expression of CD44v6, CD44v9 and CD44s were risk factors affecting survival. Multivariate analysis showed that CD44v6+/CD44s- was an independent predictor of survival. We found that CD44v6+, CD44v9+ and CD44s- were associated with pancreatic carcinoma metastasis and progression and that CD44v6+/CD44s- was an independent risk factor affecting survival in pancreatic carcinoma. Therefore, the different expression patterns of CD44v/CD44s may determine pancreatic carcinoma prognosis. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1579257224116287.

Background. Exosomes have been proven to play important diagnostic, regulatory, or communication roles in tumorigenesis, tumor progression, or metastasis; in recent studies, lots of molecules, including miRNAs, were found to be aberrantly expressed in tumor exosomes and were correlated with tumor development. However, studies about the expression, relationship, or control mechanisms of miRNAs in exosomes in pancreatic ductal adenocarcinoma (PDAC) are scarce and urgently needed. The aim of this article was to identify and investigate abnormally expressed miRNAs in PDAC exosomes in vivo and in vitro. Methods. Microarray studies were used to detect aberrantly expressed miRNAs in PDAC exosomes, and miR-210 expression in cells or exosomes was further analyzed by qRT-PCR. Bioinformatics analyses, dual-luciferase assays, WB, and other assays were utilized to explore the miRNA molecular mechanisms. The living cell coculture model and immunofluorescence analysis were employed to image the communication between PDAC cells and endothelial cells. Other biological experiments in the study include a real-time intravital imaging system, EdU, transwell, xenograft models, and so on. Results. miR-210 is significantly expressed in PDAC exosomes and malignant cells. High miR-210 significantly facilitated tumor angiogenesis, cell invasion, and proliferation in PDAC cells. Further mechanistic detection revealed that miR-210 negatively regulated EFNA3 expression and participated in the PI3K/AKT/VEGFA or Wnt/Β-catenin/RHOA pathways, thus promoting tumor angiogenesis and cellular permeability. PDAC cells promote endothelial angiogenesis or permeability via miR-210 transmission by tumor exosomes. Exosomal miR-210 promotes PDAC progression in vivo. Further detection of PDAC plasma exosomal miR-210 suggests that exosomal miR-210 expression was high and significantly associated with vascular invasion and TNM stage and was an independent risk factor for PDAC overall survival. Conclusions. PDAC cell-secreted exosomes could promote angiogenesis and cellular permeability of neighboring endothelial angiogenesis or permeability via miR-210 transmission. Exosomal miR-210 may play important roles in tumor biology and may be a useful prognostic marker in PDAC.

An amendment to this paper has been published and can be accessed via the original article.

Septic shock, a life-threatening intensive care unit condition characterized by persistent hypotension and organ dysfunction despite fluid resuscitation, is a leading cause of intensive care unit mortality. Vasoactive drugs are central to hemodynamic support in septic shock but their benefit-potential adverse event trade-off remains controversial; existing studies link high-dose vasopressors to increased mortality, though the association with 28-day mortality is unclear due to limitations like small sample sizes or single-center designs. This retrospective cohort study, based on the Medical Information Mart for Intensive Care-IV database (V3.1), included 2961 adult patients with septic shock who received vasoactive drugs and had hyperlactatemia between 2008 and 2022. The association between total vasoactive drug exposure and mortality was investigated using quartile grouping, Kaplan–Meier (K–M) survival analysis, restricted cubic spline regression, and subgroup analysis. Multivariable Cox proportional hazards models with incremental adjustments for demographics, comorbidities and laboratory markers were applied to evaluate hazard ratios. The overall in-hospital 28-day mortality rate was 31.37%. Mortality significantly increased across quartiles of vasoactive drug exposure, rising from 15.26% to 43.67% ( χ ² = 152.73, P < .001). Multivariable Cox models demonstrated consistently elevated mortality risks with higher exposure quartiles, showing significant dose–response trends. Restricted cubic spline analysis showed a nonlinear association between vasoactive drug exposure and 28-day mortality, with a threshold of 470.98 units: below it, lower exposure raised risk; above it, higher exposure reduced risk. Subgroup analyses found this association was more pronounced in males, patients ≤ 60 years old, those without cirrhosis, chronic kidney disease, cancer, and those with comorbid heart failure. The exposure dose of vasoactive drugs in patients with septic shock exhibits a non-linear association with 28-day mortality, with significant heterogeneity in risk characteristics across different dose ranges.

Retraction for the article MACC1 promotes angiogenesis in cholangiocarcinoma by upregulating VEGFA