Objective. The purpose of this study was to evaluate the contrast-enhanced ultrasonographic (CEUS) characteristics of metastatic lymph nodes (LNs) and to determine the correlation of CEUS parameters with the tumor aggressiveness in patients with breast cancer. Methods. Real-time gray scale CEUS of axillary LNs was preoperatively performed in 51 consecutive patients with breast carcinoma who were scheduled for axillary lymph node dissection. The CEUS characteristics assessed by a direct visualization method and quantification software were compared with pathologic findings. Expression of human epidermal growth factor receptor 2 (HER-2/neu) in the primary tumor was detected by immunohistochemical analysis. Correlation analysis of CEUS parameters with HER-2/neu expression and the LN stage was performed. Results. Of the LNs examined, 27 were metastatic, and 25 were diagnosed as reactive hyperplasia. Lymph nodes with metastasis were characterized by centripetal progress (66.7%) and a heterogeneous pattern (55.6%) or no or scarce perfusion (25.9%). However, LNs with nonmetastases were characterized by with centrifugal enhancement (56.0%) and a homogeneous pattern (80.0%). The difference between the hyperintense and hypointense regions was higher in metastatic LNs than nonmetastatic ones (P < .001). No significant differences were found in the arrival time, time to peak intensity, and peak intensity between the two groups. A histopathologic diagnosis could be predicted with sensitivity, specificity, and accuracy of 92.6%, 76.0%, and 84.6% respectively, by a standardized difference between maximum and minimum signal intensity (SI max -SI min ) value of 28. Human epidermal growth factor receptor 2 expression and the LN histopathologic stage were significantly associated with the SI max -SI min . In metastatic LNs, the relationship between the diagnostic sensitivity of CEUS and the transverse diameter of LNs remained statistically significant (P < .05). Conclusions. Noninvasive CEUS can play a role in discriminating metastatic from nonmetastatic LNs and predicting the aggressiveness in patients with breast cancer. Key words: breast neoplasm; contrast-enhanced ultrasonography; human epidermal growth factor receptor 2; lymph node metastasis; reactive hyperplasia lymph node. Abbreviations ALND, axillary lymph node dissection; AT, arrival time; CEUS, contrast-enhanced ultrasonography; HER-2/neu, human epidermal growth factor receptor 2; LN, lymph node; MRI, magnetic resonance imaging; PI, peak signal intensity; PT, time to peak intensity; ROC, receiver operating characteristic; SI max -SI min , difference between maximum and minimum signal intensity he detection of metastasis in lymph nodes (LNs) is critical for tumor staging and preoperative planning in patients with breast cancer. Because of the lack of accurate noninvasive methods for diagnosing LN metastasis, axillary lymph node dissection (ALND) is performed routinely in cases of invasive breast cancer.1 However, ALND is a costly procedure associated with various side ef...
Objective. Toll-like receptor 9 (TLR9) is involved in many inflammatory diseases, but its role in atherosclerosis remains controversial. This study aimed to investigate the role of TLR9 in atherosclerosis development and macrophage polarization. Methods. ApoE−/− mice were treated with vehicle or IRS869 for 12 weeks. Plaque vulnerability was assessed with immunohistochemical analysis, picro-sirius red, and oil red O staining. The expressions of M1- and M2-associated markers in plaques were detected by RT-PCR and immunofluorescence. The aorta TLR9 and its downstream molecules including myeloid differentiation protein 88 (MyD88), phosphorylated nuclear factor-kappa B (p-NF-κB), and interferon regulatory factor 7 (IRF7) were determined by western blot analysis. The frequency of M1 and M2 subtype in RAW264.7 cells treated with IRS869 and/or ODN1826 was evaluated with flow cytometry. Results. In ApoE−/− mice, functional inactivation of TLR9 pathway resulted in attenuated atherosclerosis development, as manifested by reduced plaque burden and by decreased plaque vulnerability. Mechanistically, TLR9 inhibition prevented the activation of MyD88/NF-κB pathway and shifted the balance of M1/M2 toward M2 macrophages that were involved. Conclusions. Our data indicated that TLR9 inactivation ameliorated atherosclerosis via skewing macrophage plasticity to M2 phenotype in ApoE-deficient mice. These findings may provide a promising therapeutic strategy for atherosclerosis.
Apolipoprotein E deficiency (ApoE−/−) combined with a high-fat Western-type diet (WD) is known to activate the toll-like receptor (TLR4) pathway and promote atherosclerosis. However, to date, the pathogenic effects of these conditions on the lung have not been extensively studied. Therefore, the present study examined the effects of ApoE−/− and a WD on lung injury and investigated the underlying mechanisms. ApoE−/− and wild-type mice were fed a WD or normal chow diet for 4, 12 and 24 weeks. Lung inflammation, lung cholesterol content and cytokines profiles in bronchoalveolar lavage fluid (BALF) were determined. TLR4 and its main downstream molecules were analyzed with western blot analysis. In addition, the role of the TLR4 pathway was further validated using TLR4-targeted gene silencing. The results showed that ApoE−/− mice developed lung lipidosis following 12 weeks of receiving a WD, as evidenced by an increased lung cholesterol content. Moreover, dependent on the time period of receiving the diet, those mice exhibited pulmonary inflammation, which was manifested by initial leukocyte recruitment (at 4 weeks), by increased alveolar septal thickness and mean linear intercept as well as elevated production of inflammation mediators (at 12 weeks), and by granuloma formation (at 24 weeks). The expression levels of TLR4, myeloid differentiation primary response 88 (MyD88) and nuclear factor kappa B were markedly upregulated in ApoE−/− WD mice at week 12. However, these effects were ameliorated by shRNA-mediated knockdown of TLR4. By contrast, ApoE−/− ND or wild-type WD mice exhibited low-grade or no inflammation and mild lipidosis. The levels of TLR4 and MyD88 in those mice showed only minor changes. In conclusion, ApoE deficiency acts synergistically with a WD to trigger lung lipidosis and inflammation at least in part via TLR4 signaling.
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