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Tumorigenesis and tumor development are closely related to the abnormal regulation of ubiquitination. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin ligase critical to the ubiquitination process, plays key roles in the regulation of cancer stem cells, as well as tumor cell functions, including cell proliferation, apoptosis, cell cycle regulation, migration, invasion, epithelial–mesenchymal transition (EMT), and tumor drug resistance, by controlling subsequent protein degradation through ubiquitination. NEDD4L primarily functions as a tumor suppressor in several tumors but also plays an oncogenic role in certain tumors. In this review, we comprehensively summarize the relevant signaling pathways of NEDD4L in tumors, the regulatory mechanisms of its upstream regulatory molecules and downstream substrates, and the resulting functional alterations. Overall, therapeutic strategies targeting NEDD4L to treat cancer may be feasible.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

In view of the little research that has been conducted on the ride comfort of mini vehicles, an electric mini off-road vehicle was designed in this study and a 2 degree-of-freedom quarter car model was established to investigate the ride comfortability. The amplitude-frequency and vibration response characteristics of the suspension were analyzed with the natural frequencies of the front and rear suspensions selected in accordance with the required driving performance. A comprehensive objective function with respect to the safety and comfortability was established, and the damping ratio of the suspension was determined. The damping characteristics of the shock absorber were analyzed to derive an adjustment rule of the suspension damping ratio. The piecewise linear speed characteristics of the shock absorber were subsequently obtained, and suspension-parameter identification and ride comfort tests were conducted. The test results showed that the natural frequencies and damping ratios of the front and rear suspensions were 1.676 and 1.922 Hz, and 0.225 and 0.242, respectively. The results of a pulse input test and D-level road random running test also demonstrated the safety and good ride comfortability of the vehicle.

The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20-HETE) affected neddylation modification of E3-ligase Nedd4-2 (neural precursor cell expressed, developmentally down-regulated 4-like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20-HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4-2-mediated ubiquitin-proteasome pathway. Nedd4-2 expression is increased in the kidney and decreased in the liver of transgenic mice compared with wild-type mice. Subsequently, co-immunoprecipitation analysis indicated that Nedd4-2 was modified by Nedd8, and the level of neddylation on Nedd4-2 was reduced in the kidney and increased in the liver of transgenic mice compared with controls. In addition, sentrin-specific protease 8 (Senp8), a deneddylation enzyme, is expressed higher in the kidney and lower in the liver of transgenic mice compared with wild-type controls. The function of 20-HETE on modulation of Nedd4-2 were also confirmed in mouse M1 kidney and mouse NCTC1469 liver cell lines, and the function was restored by neddylation inhibitor MLN4924 Data from the present study demonstrated that 20-HETE upregulated the expression of Nedd4-2 in the kidney and downregulated expression in the liver through the neddylation modification pathway, at least partly, depending on the effects on Senp8 deneddylation. [ABSTRACT FROM AUTHOR]

This paper established the three degree of freedom mathematical model, based on the two degree of freedom linear model with two wheel steering. Then the dynamics differential equation is obtained. With a step input of the front wheel, observing and analyzing the yaw rate response and the side slip angle response in the whole process based on MATLAB/Simulink. Finally, by changing the position of the battery pack to transform the location of the gravity center of the whole vehicle, analyzing the impact on the electric vehicle's steering characteristic while the location of battery pack changed. [ABSTRACT FROM AUTHOR]