In non-cooperative scenarios, wideband frequency hopping (FH) communication reconnaissance including FH signal detection, parameter estimation, and network sorting under single-channel reception is challenging. The FH pattern contains the most information about FH signals. So it is the core of FH parameter estimation. Based on the task analysis, this paper proposes a blind prediction framework combining deep learning (DL) and clustering methods to improve the accuracy and efficiency of FH pattern estimation for mixed signals in the wideband spectrum. The unique advantage of this framework is that it requires no prior signal information and anchors but exploits the inherent time-frequency (TF) properties of asynchronous FH signals. It has a strong generalization ability and can adapt to signals of any shape. Moreover, a new comprehensive evaluation metric, normalized root mean square error including missed detection (NRMSE-MD), suitable for sequence data prediction is proposed to evaluate the level of missed detection and false detection in signal monitoring. Experimental results demonstrate the superiority of the proposed framework and the effectiveness of the proposed evaluation metric.
The 90-kDa heat shock protein (Hsp90) assists in the proper folding of numerous mutated or overexpressed signal transduction proteins that are involved in cancer. Consequently, there is considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90. Here, we investigated the extent to which a novel novobiocin-derived C-terminal Hsp90 inhibitor, designated KU135, induced antiproliferative effects in Jurkat T-lymphocytes. The results indicated that KU135 bound directly to Hsp90, caused the degradation of known Hsp90 client proteins, and induced more potent antiproliferative effects than the established N-terminal Hsp90 inhibitor 17-allylamino-demethoxygeldanamycin (17-AAG). Closer examination of the cellular response to KU135 and 17-AAG revealed that only 17-AAG induced a strong up-regulation of Hsp70 and Hsp90. In addition, KU135 caused wild-type cells to undergo G2/M arrest, whereas cells treated with 17-AAG accumulated in G1. Furthermore, KU135 but not 17-AAG was found to be a potent inducer of mitochondria-mediated apoptosis as evidenced, in part, by the fact that cell death was inhibited to a similar extent by Bcl-2/Bcl-xL overexpression or the depletion of apoptotic protease-activating factor-1 (Apaf-1). Together, these data suggest that KU135 inhibits cell proliferation by regulating signaling pathways that are mechanistically different from those targeted by 17-AAG and as such represents a novel opportunity for Hsp90 inhibition.
Although both excision repair cross-complementing group 1 (ERCC1) and breast cancer susceptibility gene 1 (BRCA1) can be effective biomarkers for chemosensitivity in primary malignant tumors, their applicability to metastases is poorly understood. Here, ERCC1 and BRCA1, which are linked to lymph node metastasis (LNM) in colorectal cancer (CRC), were evaluated in primary CRC samples from Chinese patients with LNM (LNM CRC) or without LNM (non-LNM CRC). mRNA levels of ERCC1 and BRCA1 in CRC samples, and their relationships to primary CRC and LNM, were also examined.Differences in BRCA1 and ERCC1 gene expression between primary CRC with or without LNM were assessed in CRC samples from 120 Chinese patients, using real-time polymerase chain reaction. Relationships between ERCC1 and BRCA1 expression and clinicopathological parameters and prognoses were also examined.ERCC1 and BRCA1 were significantly down-regulated in LNM CRC compared with non-LNM CRC. Down-expression of ERCC1 and BRCA1 was significantly associated with LNM (P < 0.001), advanced TNM stage (P < 0.001), and decreased 5-year overall survival rate (P < 0.001). Univariate and multivariate analyses showed ERCC1 and BRCA1 expression as independent predictors of recurrence and survival in CRC patients (P < 0.05).ERCC1 and BRCA1 mRNA expression levels correlate inversely to CRC metastasis. ERCC1 and BRCA1 might serve as biomarkers for LNM and as prognostic indicators for CRC; their down-expressions are predictors of poor outcome in CRC patients.
Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN.
Background: As key molecules that drive progression and chemoresistance in gastrointestinal cancers, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (Her2) have become efficacious drug targets in this setting. But
Abstract Background Tumor necrosis factor receptor-associated protein 1 (TRAP1) is highly-expressed during epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC). Here, we investigated the mechanism underlying the high expression of TRAP1 during EMT and evaluated the potential of TRAP1 as a therapeutic target for metastatic CRC treatment. Moreover, we discussed ways to improve the clinical effectiveness of CRC treatments. Methods HCT116 colon cancer cell lines (either over-expressing or lacking TRAP1), nude mouse tumor experiments, and human CRC tissue were used. The effect of TRAP1 gene expression on the migration of CRC cells was studied using methods characterizing cellular function. The mechanism of the effect of TRAP1 expression on EMT in CRC was studied using immunohistochemistry, immunofluorescence, and western blotting methods. Results High TRAP1 expression was found to increase the migration of CRC cells, reduce apoptosis rates, regulate the E-cadherin and vimentin expression in opposite directions, as well as increase expression levels of hypoxia inducible factor 1α (HIF-1α), extracellular signal-regulated kinase 1/2 (ERK1/2), Twist, forkhead box protein C2 (FoxC2), and reduce the expression of succinate dehydrogenase complex flavoprotein subunit A (SDHA) proteins. These results indicate that TRAP1 regulates EMT in CRC by affecting the crosstalk between SDHA/HIF-1α, HIF/ERK1/2/Twist, and HIF/FOXC/Twist pathways. Conclusion High TRAP1 expression was found to promote EMT in CRC. TRAP1 activates expression of genes encoding proteins involved in SDHA/HIF-1α, HIF-1α/ERK1/2/Twist/Snail, and HIF-1α/FoxC/Twist/Snail pathways via HIF-1α. TRAP1 also regulates the expression of E-cadherin, the downstream protein of EMT.
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