Background Early metastasis is a key factor contributing to poor breast cancer (BC) prognosis. Circulating tumor cells (CTCs) are regarded as the precursor cells of metastasis, which are ultimately responsible for the main cause of death in BC. However, to date molecular mechanisms underlying CTC formation in BC have been insufficiently defined. Methods RNA-seq was carried out in primary tissues from early-stage BC patients (with CTCs≥5 and CTCs = 0, respectively) and the validation study was conducted in untreated 80 BC patients. Multiple in vitro and in vivo models were used in functional studies. Luciferase reporter, ChIP-seq, CUT&Tag-seq, and GST-pulldown, etc. were utilized in mechanistic studies. CTCs were counted by the CanPatrol™ CTC classification system or LiquidBiospy™ microfluidic chips. ERK1/2 inhibitor SCH772984 was applied to in vivo treatment. Results Highly expressed FOXD1 of primary BC tissues was observed to be significantly associated with increased CTCs in BC patients, particularly in early BC patients. Overexpressing FOXD1 enhanced the migration capability of BC cells, CTC formation and BC metastasis, via facilitating epithelial-mesenchymal transition of tumor cells. Mechanistically, FOXD1 was discovered to induce RalA expression by directly bound to RalA promotor. Then, RalA formed a complex with ANXA2 and Src, promoting the interaction between ANXA2 and Src, thus increasing the phosphorylation (Tyr23) of ANXA2. Inhibiting RalA-GTP form attenuated the interaction between ANXA2 and Src. This cascade culminated in the activation of ERK1/2 signal that enhanced metastatic ability of BC cells. In addition, in vivo treatment with SCH772984, a specific inhibitor of ERK1/2, was used to dramatically inhibit the CTC formation and BC metastasis. Conclusion Here, we report a FOXD1-dependent RalA-ANXA2-Src complex that promotes CTC formation via activating ERK1/2 signal in BC. FOXD1 may serve as a prognostic factor in evaluation of BC metastasis risks. This signaling cascade is druggable and effective for overcoming CTC formation from the early stages of BC.

Vulnerable carotid plaque is closely related to the occurrence of Ischemic stroke. Therefore, accurate and rapid identification of the nature of carotid plaques is essential. AS is a chronic immune inflammatory process. Systemic immune-inflammation index (SII) is a novel index of immune inflammation obtained from routine whole blood cell count analysis, which comprehensively reflects the state of inflammation and immune balance in the body. This study sought to explore the relationship between SII level and carotid plaque vulnerability, plaque composition characteristics, and acute ischemic stroke (AIS) severity. A total of 131 patients diagnosed with AIS presenting with a carotid atherosclerotic plaque were enrolled in this study. Using carotid ultrasound (CDU) to assess the carotid-responsible plaque properties, we divided the patients into stable plaques group and vulnerable plaques group, and analyzed the correlation between SII levels and plaque vulnerability. And we further analyzed to evaluate the correlation between high SII levels and plaque characteristics and AIS severity. In addition, Cohen's Kappa statistics was used to detect the consistency of Carotid ultrasound (US) and cervical High-resolution magnetic resonance imaging (HRMRI) in evaluating plaque vulnerability. The findings showed that the vulnerable group had higher levels of SII compared with the stable group. The high SII group had more vulnerable plaques and a high frequency of plaque fibrous cap rupture compared with the low SII group. Logistic analysis showed that a high SII level was an independent risk factor for vulnerable plaques (odds ratio [OR] = 2.242) and plaque fibrous cap rupture (OR=3.462). The results also showed a high consistency between Carotid US and HRMRI methods in the assessment of plaque vulnerability [Cohen's kappa value was 0.89 (95% CI = 0.78–0.97)] and the level of SII was positively associated with NIHSS score (r = 0.473, P < 0.001). Our study suggests that elevated levels of SII may have adverse effects on the vulnerability of carotid plaques, especially in stroke patients with vulnerable plaques with ruptured fibrous caps, which may aggravate the severity of AIS.

Objectives This study aimed to compare the diagnostic accuracy of shear wave elastography (SWE) with that of shear wave dispersion (SWD) in evaluation of hepatic parenchyma in patients with liver tumors before resection. Methods A total of 174 patients with liver tumors were prospectively enrolled. SWE and SWD examinations were performed. Fibrosis stage and necroinflammatory activity were determined histopathologically according to the Scheuer standard. We compared the diagnostic accuracy of SWE and SWD. Results Both SWE and SWD values of the liver were highly correlated with liver fibrosis stage (P < .05, respectively). Both SWE and SWD values of the liver were moderately correlated with necroinflammatory activity (P < .05, respectively). Both SWE and SWD values of the liver were not correlated with steatosis (P > .05, respectively). Both SWE and SWD values were significantly different among the patients with different stages of liver fibrosis (P < .001, respectively). The area under the receiver operating characteristic (ROC) curve of SWE value was 0.982, 0.977, 0.969, and 0.984 for predicting S ≥ 1, S ≥ 2, S ≥ 3, and S = 4, respectively. The optimal cutoff SWE values were 6.9, 7.9, 8.7, and 10.6 kPa for S ≥ 1, S ≥ 2, S ≥ 3, and S = 4, respectively. The area under the ROC curve of SWD value was 0.967, 0.960, 0.925, and 0.954 for predicting S ≥ 1, S ≥ 2, S ≥ 3, and S = 4, respectively. The optimal cutoff SWD values were 11.2, 12.0, 13.2, and 16.0 m/s/kHz for S ≥ 1, S ≥ 2, S ≥ 3, and S = 4, respectively. Conclusions SWE and SWD could be noninvasive and accurate for predicting the stage of liver fibrosis in patients with liver tumors before surgery. SWE was more accurate than SWD in predicting severe fibrosis (S ≥ 3) and cirrhosis (S = 4).