Balanced Spectral Feature Selection.

In many real-world unsupervised learning applications, given data with balanced distribution, that is, there are an approximately equal number of instances in each class, we often need to construct a model to reveal such balance. However, in many data, especially the high-dimensional ones, the data in the original feature space often do not present such balance due to the redundant and noisy features. To tackle this problem, we apply an unsupervised spectral feature selection method to select some informative features, which can better reveal the balanced structure of data. Although spectral feature selection is one of the most popular unsupervised feature selection methods and has been widely studied, none of the existing spectral feature selection methods consider the balance property of data. To address this issue, in this article, we propose a novel balanced spectral feature selection (BSFS) method, which not only selects the discriminative features but also picks those to reveal the balanced structure of data. To the best of our knowledge, this is the first spectral feature selection method considering balance structure of data. By introducing a balanced regularization term, we integrate the balanced spectral clustering and feature selection into a unified framework seamlessly. At last, the experiments on benchmark datasets show that the proposed one outperforms the conventional feature selection methods in both clustering performance and balance, which demonstrates the effectiveness and efficiency of the proposed method.

miRNA-200c-3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts.

Increasing evidence has suggested a critical role for endothelial-to-mesenchymal transition (EndoMT) in a variety of pathological conditions. MicroRNA-200c-3p (miR-200c-3p) has been implicated in epithelial-to-mesenchymal transition. However, the functional role of miR-200c-3p in EndoMT and neointimal hyperplasia in artery bypass grafts remains largely unknown. Here we demonstrated a critical role for miR-200c-3p in EndoMT. Proteomics and luciferase activity assays revealed that fermitin family member 2 (FERM2) is the functional target of miR-200c-3p during EndoMT. FERMT2 gene inactivation recapitulates the effect of miR-200c-3p overexpression on EndoMT, and the inhibitory effect of miR-200c-3p inhibition on EndoMT was reversed by FERMT2 knockdown. Further mechanistic studies revealed that FERM2 suppresses smooth muscle gene expression by preventing serum response factor nuclear translocation and preventing endothelial mRNA decay by interacting with Y-box binding protein 1. In a model of aortic grafting using endothelial lineage tracing, we observed that miR-200c-3p expression was dramatically up-regulated, and that EndoMT contributed to neointimal hyperplasia in grafted arteries. MiR-200c-3p inhibition in grafted arteries significantly up-regulated FERM2 gene expression, thereby preventing EndoMT and reducing neointimal formation. Importantly, we found a high level of EndoMT in human femoral arteries with atherosclerotic lesions, and that miR-200c-3p expression was significantly increased, while FERMT2 expression levels were dramatically decreased in diseased human arteries. Collectively, we have documented an unexpected role for miR-200c-3p in EndoMT and neointimal hyperplasia in grafted arteries. Our findings offer a novel therapeutic opportunity for treating vascular diseases by specifically targeting the miR-200c-3p/FERM2 regulatory axis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

SOX9 promotes epithelial-mesenchymal transition in non-small cell lung cancer A549 cells via Wnt/β-catenin pathway / 中国肿瘤生物治疗杂志

@#Objective:To explore the mechanism by which SRY-related high mobility group-box 9 (SOX9) promotes the epithelial mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC) A549 cells via the Wnt/β-catenin pathway. Methods: The human NSCLCA549 cell line was divided into three groups: OE-NC group, OE-SOX9 group and OE-SOX9+XAV-939 group. The cells in OESOX9 group were transfected with SOX9 pcDNA plasmid to up-regulate the expression level of SOX9; The cells in OE-SOX9+XAV939 group were transfected with SOX9 pcDNA plasmid while the β-catenin inhibitor XAV-939 (1.0 μmol/L) was added to the medium. qPCR was used to detect SOX9 mRNA levels; CCK-8 was used to examine the proliferation of A549 cells; Wound-healing assay and Transwell chamber assay were used to detect the migration and invasion ofA549 cells, respectively; and WB was used to detect protein expressions of SOX9, β-catenin, E-cadherin, γ-catenin, N-cadherin and vimentin. Results: The mRNA and protein levels of SOX9 in OE-SOX9 group and OE-SOX9+XAV-939 group were significantly higher than those in the OE-NC group after transfection (all P< 0.05), while there was no significant difference between the OE-SOX9 group and the OE-SOX9+XAV-939 group (P>0.05). The proliferation, migration and invasion of cells in OE-SOX9 group were significantly higher than those in OE-NC group; however, those abilities in OE-SOX9+XAV-939 group were significantly lower than those in OE-SOX9 group (all P<0.05). The level of β-catenin protein in OE-SOX9 group was significantly higher than that in the OE-NC group, while the level of β-catenin protein in OE-SOX9+XAV-939 group was lower than that in OE-SOX9 group (all P<0.05). Compared with the OE-NC group, the levels of phenotypic markers of epithelial cells, E-cadherin and γ-catenin, were down-regulated, and the phenotypic markers of mesenchymal cells, N-cadherin and vimentin, were up-regulated in cells of OE-SOX9 group; however, E-cadherin and γ-catenin were higher, and N-cadherin and vimentin were lower in OE-SOX9+XAV-939 group than those in OE-SOX9 group (all P<0.05). Conclusion: SOX9 could promote proliferation, migration and EMT of NSCLCA549 cells by activating the Wnt/β-catenin pathway. ··

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis.

BACKGROUND: To investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved. METHODS AND RESULTS: NE genetic-deficient mice (Apolipoprotein E-/-/NE-/- mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high-fat diet (HFD)-fed wild-type (WT) (Apolipoprotein E-/-) mice but, as expected, not in NE-deficient mice. Selective NE knockout markedly reduced HFD-induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE-deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE-/- bone marrow cells significantly reduced HFD-induced atherosclerosis, while bone marrow reconstitution of NE-/- mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE-deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP-binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux. CONCLUSIONS: We outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

Cbx3 inhibits vascular smooth muscle cell proliferation, migration, and neointima formation.

AIMS: To investigate the role of chromobox protein homolog 3 (Cbx3) in vascular smooth muscle cell (VSMC) proliferation, migration, and neointima formation following vascular injury. METHODS AND RESULTS: Overexpression of Cbx3 led to a significant increase in VSMC contractile gene expression and VSMC apoptosis as well as a dramatic decrease in collagen gene expression, VSMC proliferation, and migration. Meanwhile, the opposite was observed following inhibition of endogenous Cbx3. Luciferase activity assays revealed that Notch signalling, but neither ß-catenin nor NF-κB signalling, is regulated by Cbx3 in VSMCs, and among the four Notch receptors, Notch3 is selectively down-regulated by Cbx3 through a transcriptional repression mechanism. Notch3 gene activation recapitulates the effects of Cbx3 knockdown on VSMC proliferation and migration. Consequently, the inhibitory effects of Cbx3 over-expression on VSMC proliferation and migration were reversed by Notch3 gene reactivation. In a model of vascular damage by carotid wire injury, we observed that Cbx3 expression was dramatically down-regulated in the injured arteries. Local ectopic over-expression of Cbx3 in the injured arteries significantly inhibited Notch3 expression, thereby reducing VSMCs proliferation and causing an overall decrease in neointima formation. Additionally, injury-induced neointimal SMC hyperplasia was significantly reduced by aortic inhibition of Notch3. Importantly, a decreased expression level of Cbx3, but an increased expression level of Notch3, was observed in human femoral arteries with atherosclerotic lesions. CONCLUSION: Cbx3 modulates VSMC contractile and collagen gene expression, as well as VSMC proliferation, migration, and apoptosis via a Notch3 pathway, and plays an important role in controlling injury-induced neointima formation.

[Down-regulation of TIPE2 promotes the proliferation and immune activity of T lymphocytes].

Objective To utilize specific small interfering RNA (siRNA) to silence the expression of tumor necrosis factor α-induced protein 8 like-2 (TIPE2) gene of T lymphocytes and investigate the effect of TIPE2 targeting siRNA on T lymphocyte proliferation and immune function. Methods Mouse spleen T lymphocytes were sorted by magnetic beads. Western blotting was used to screen and validate an effective siRNA to silence the TIPE2 gene expression of T lymphocytes. Twenty-four hours after transfection with the siRNA into T lymphocytes, the expression of CD69 in each group was detected by flow cytometry. Seventy-two hours after transfection, the proliferation of the T lymphocytes was measured with CCK-8 assay; meanwhile, the secretion levels of interleukin 2 (IL-2) and interferon γ (IFN-γ) in each group were measured by ELISA. Results We obtained TIPE2 targeting siRNA sequences and effectively silenced the expression of TIPE2 gene. After TIPE2 gene expression was down-regulated, the expression of the CD69 on T lymphocytes increased, and the proliferation of T lymphocytes and the secretion of IL-2 and IFN-γ were enhanced. Conclusion Down-regulation of TIPE2 gene expression can promote the T lymphocyte proliferation and immune activity.

[Intraoperative methylene blue and (99m)Tc-sulfur colloid isotope tracing for sentinel node mapping in early-stage non-small cell lung cancer].

OBJECTIVE: To compare the accuracy of intaoperative methylene blue alone and in combination with (99m)Tc-sulfur colloid isotopic tracing for detection of sentinel lymph nodes (SLNs) in early-stage non-small cell lung cancer (NSCLC). METHODS: Sixty-one patients with operable NSCLC who did not receive previous radiotherapy or chemotherapy were enrolled. Methylene blue and (99m)Tc-sulfur colloid were injected into the subserosal layer adjacent to the tumor, and SLNs were defined as those with blue staining or those containing 3 times more radioactivity than the surrounding tissue detected with a gamma probe. The SLN were removed with systematic lymph node dissection. All the removed lymph nodes were examined histopathologically with HE staining and immunohistochemistry. RESULTS: Methylene blue alone showed a low detection rate (60.0%) and sensitivity (58.33%) for SLNs compared with the combination of methylene blue and isotope tracing (96.15% and 92.86%, respectively). CONCLUSION: The combination of methylene blue and (99m)Tc-sulfur colloid isotopic tracing allows accurate detection of the SLNs in early-stage NSCLC.