IntroductionWe investigated Nestin expression in triple-negative breast cancer and examined how the modulation of Nestin expression affects cell cycle progression, survival, invasion and regulatory signaling in breast cancer stem cells (CSC) in vitro.MethodsNestin expression in 150 triple-negative breast cancer specimens were examined by immunohistochemistry. The role of Nestin expression in tumorigenesis was examined by assaying naturally occurring Nestinhigh/Nestinlow CSC from 12 breast cancer tissues, as well as CSC from 26 clinical specimens, where Nestin overexpression and silencing was achieved by genetic manipulation, for their ability to form mammospheres and induce solid tumors. Cell cycle progression, spontaneous apoptosis and invasiveness of Nestin-silenced breast CSC were investigated by flow cytometry and transwell assays. The relative levels of expression of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related molecules were determined by western blotting.ResultsNestin expression was significantly associated with poor survival in patients with triple-negative breast cancer (P = 0.01). Nestinhigh breast CSC rapidly formed typical mammospheres in vitro. Nestinhigh, but not Nestinlow CSC, efficiently formed solid tumors in vivo. Nestin silencing induced cell cycle arrest at G2/M (52.03% versus 19.99% in controls) and promoted apoptosis (36.45% versus 8.29% in controls). Nestin silencing also inhibited breast CSC invasiveness, and was associated with significantly upregulated E-cadherin, while N-cadherin, vimentin, a-smooth muscle actin (a-SMA), matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF) expression was downregulated (P <0.05 for all). Nestin silencing also upregulated Axin, glycogen synthase kinase-3 beta (GSK-3β), adenomatous polyposis coli (APC), and peroxisome proliferator-activated receptor alpha (PPARa), and downregulated β-catenin, c-Myc, cyclin D and MMP-7 expression in CSC. Inhibition of the Wnt/β-catenin pathway mitigated mammosphere formation in Nestinhigh CSC, while inhibition of GSK-3β promoted the mammosphere formation in Nestinlow CSC (P <0.05 for all).ConclusionsOur data indicates that Nestin positively regulates the proliferation, survival and invasiveness of breast CSC by enhancing Wnt/β-catenin activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0408-8) contains supplementary material, which is available to authorized users.
Thoracic endovascular aortic repair (TEVAR) is commonly applied in type-B aortic dissection. For patients with dissection affects descending aorta and extends downward to involve abdominal aorta and possibly iliac arteries, false lumen (FL) expansion might occur post-TEVAR. Predictions of dissection development may assist in medical decision on re-intervention or surgery. In this study, two patients are selected with similar morphological features at initial presentation but with different long-term FL development post-TEVAR (stable and enlarged FL). Patient-specific models are established for each of the follow-ups. Flow boundaries and computational validations are obtained from Doppler ultrasound velocimetry. By analyzing the hemodynamic parameters, the false-to-true luminal pressure difference (PDiff) and particle relative residence time (RRT) are found related to FL remodeling. It is found that (i) the position of the first FL flow entry is the watershed of negative-and-positive PDiff and, in long-term follow-ups, and the position of largest PDiff is consistent with that of the greatest increase of FL width; (ii) high RRT occurs at the FL proximal tip and similar magnitude of RRT is found in both stable and enlarged cases; (iii) comparing to the RRT at 7days post-TEVAR, an increase of RRT afterwards in short-term is found in the stable case while a slight decrease of this parameter is found in the enlarged case, indicating that the variation of RRT in short-term post-TEVAR might be potential to predict long-term FL remodeling.
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