The expression and role of protein kinase C (PKC) epsilon in clear cell renal cell carcinoma

Protein kinase C epsilon (PKCε), an oncogene overexpressed in several human cancers, is involved in cell proliferation, migration, invasion, and survival. However, its roles in clear cell renal cell carcinoma (RCC) are unclear. This study aimed to investigate the functions of PKCε in RCC, especially in clear cell RCC, to determine the possibility of using it as a therapeutic target. By immunohistochemistry, we found that the expression of PKCε was up-regulated in RCCs and was associated with tumor Fuhrman grade and T stage in clear cell RCCs. Clone formation, wound healing, and Borden assays showed that down-regulating PKCε by RNA interference resulted in inhibition of the growth, migration, and invasion of clear cell RCC cell line 769P and, more importantly, sensitized cells to chemotherapeutic drugs as indicated by enhanced activity of caspase-3 in PKCε siRNA-transfected cells. These results indicate that the overexpression of PKCε is associated with an aggressive phenotype of clear cell RCC and may be a potential therapeutic target for this disease

MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion

Background/Aims: To investigate the role of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in the clinical prognosis and cell biology of renal cell carcinoma (RCC). Methods: A total of 137 RCC tissues were evaluated by immunohistochemistry. The relationship between MTHFD2 overexpression and clinical parameters and vimentin expression was assessed. Kaplan-Meier curves and the log-rank test were applied for survival analysis according to MTHFD2 and vimentin expression in RCC tissues. The expression of MTHFD2 mRNA and protein was examined by quantitative reverse transcription PCR and western blotting, respectively. To determine further the biological activity of MTHFD2 in RCC, 786-O cells were transfected with short hairpin RNA specifically targeting MTHFD2 (shMTHFD2) with or without tumor necrosis factor (TNF)-α stimulation. Cell proliferation, cell migration and invasion and drug sensitivity were subsequently assessed using Cell Counting Kit-8, wound healing, and Transwell assays. Results: Immunohistochemical analysis demonstrated that both MTHFD2 and vimentin overexpression was positively associated with clinical staging, pathological grade, and poor overall survival (all P < 0.05). MTHFD2 expression was closely correlated with vimentin overexpression in RCC (r = 0.402, P < 0.001). After knocking down MTHFD2 expression in 786-O cells, decreased cell proliferation, migration, and invasion were observed and accompanied by the reduced expression of vimentin. The effects of MTHFD2 down-regulation could be partially restrained by TNF-α treatment. Vimentin expression and cell migration and invasion, but not cell proliferation, were reversed by TNF-α stimulation. Furthermore, treatment of 786-O cells with shMTHFD2 increased their sensitivity to chemotherapy drugs. Conclusion: The current results demonstrated that MTHFD2 was overexpressed in RCC and associated with poor clinical characteristics, vimentin expression, and cellular features connected to malignant disease, thus, implicating MTHFD2 as a potential target for RCC therapy

Tyrosine Kinase ETK/BMX Is Up-Regulated in Bladder Cancer and Predicts Poor Prognosis in Patients with Cystectomy

Deregulation of the non-receptor tyrosine kinase ETK/BMX has been reported in several solid tumors. In this report, we demonstrated that ETK expression is progressively increased during bladder cancer progression. We found that down-regulation of ETK in bladder cancer cells attenuated STAT3 and AKT activity whereas exogenous overexpression of ETK had opposite effects, suggesting that deregulation of ETK may attribute to the elevated activity of STAT3 and AKT frequently detected in bladder cancer. The survival, migration and invasion of bladder cancer cells were significantly compromised when ETK expression was knocked down by a specific shRNA. In addition, we showed that ETK localizes to mitochondria in bladder cancer cells through interacting with Bcl-XL and regulating ROS production and drug sensitivity. Therefore, ETK may play an important role in regulating survival, migration and invasion by modulating multiple signaling pathways in bladder cancer cells. Immunohistochemistry analysis on tissue microarrays containing 619 human bladder tissue samples shows that ETK is significantly upregulated during bladder cancer development and progression and ETK expression level predicts the survival rate of patients with cystectomy. Taken together, our results suggest that ETK may potentially serve as a new drug target for bladder cancer treatment as well as a biomarker which could be used to identify patients with higher mortality risk, who may be benefited from therapeutics targeting ETK activity

Bending and Wave Propagation Analysis of Magneto-Electro-Elastic Functionally Graded Porous Microbeams

In this paper, a microstructure-dependent magneto-electro-elastic functionally graded porous (MEEFGP) beam model is proposed using a variational approach. To account for the microstructure effect, the extended modified couple stress theory is incorporated in the new model. In addition, the porosity variation of the two-phase beam model through the thickness direction is also considered. The new developed model is verified in terms of its correctness with a FEM model. Based on the equations of motion and boundary conditions derived by Hamilton’s principle, the static bending and wave propagation behaviors of the new model are analytically determined. The results prove the existence of the microstructure effect and the magneto-electro-elastic multi-field coupling effect. There are significant differences between the new model and the classical model at the microscale. Moreover, the porosity also has an important influence on the mechanical properties of the new model. The results predicted by the new model can provide the theoretical basis for the design of microscale acoustic wave devices and micro-electro-mechanical systems

Changes of Transthyretin and Clusterin after Androgen Ablation Therapy and Correlation with Prostate Cancer Malignancy12

After androgen ablation therapy (AAT), advanced prostate cancer (Pca) eventually progresses to castration-resistant Pca (CRPC); however, the biomarkers that are used to predict its prognosis are limited. In this study, serum samples from four patients with advanced Pca were collected at the time of the initial diagnosis and 3 months after AAT. Proteomic changes were analyzed with two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Altogether, nine proteins were differentially expressed in the samples collected at diagnosis and in the samples collected after AAT. Among them, the expression of transthyretin (TTR) was 1.58-fold lower and clusterin (CLU) was 1.51-fold higher in the sera of post-AAT patients compared with those in the sera from pre-AAT patients. The significant changes in serum TTR and CLU in post-AAT patients were further confirmed by a large-scale ELISA. Immunohistochemistical staining revealed that the expression levels of TTR and CLU were significantly higher in Pca tissue than in normal and benign prostate hyperplasia tissue. The expression levels of TTR and CLU in Pca tissue were found to be associated with the grade and stage of Pca. Overall, this study indicated that TTR and CLU might be used to monitor the efficacy of AAT therapy and serve as biomarkers for the prognosis of Pca

Research on the Torque Control Strategy of a Distributed 4WD Electric Vehicle Based on Economy and Stability Control

To improve the comprehensive performance of the distributed wheel-side four-wheel-drive electric bus, the problem of optimal distribution of the driving torque of the four wheel-side motors is studied. Aiming at the poor economy and failure of switching control due to the consideration of both straight and steering conditions, this paper proposes a fuzzy yaw moment control strategy based on the golden section search algorithm. Under full working conditions, according to the efficiency characteristics of the front and rear axle drive motors, the golden section search algorithm is used to determine the best front and rear axle motor torque distribution coefficient K to distribute the front and rear axle motor torques. Given the stability problems existing in the steering conditions, based on the optimal torque distribution of the front and rear axles, fuzzy control is used to calculate the expected yaw moment, and the left and right wheel torques are adjusted in real time. The simulation is carried out through TruckSim and MATLAB/Simulink, and a hardware-in-the-loop platform is built for experimentation under step steering conditions and sine wave steering conditions. The results show that the proposed torque optimal distribution strategy can optimally distribute the torque of the four drive motors through the real-time identification of working conditions. Compared with the four-wheel equal distribution, under two different steering conditions, the torque distribution efficiency of the torque distribution strategy using the golden section search algorithm increased by 4.35% and 3.83%, respectively. The energy utilization rate of the whole vehicle is improved under all of the working conditions. Under steering conditions, compared with the four-wheel equal distribution and the torque distribution strategy using the golden section search algorithm under all of the conditions, the yaw rate deviation and the slip angle deviation can be reduced, and the yaw stability has been improved