The Effects of Cinobufagin on Hepatocellular Carcinoma Cells Enhanced by MRT68921, an Autophagy Inhibitor.

Cinobufagin, a cardiotonic steroid derived from toad venom extracts, exhibits significant anticancer properties by inhibiting Na[Formula: see text]/K[Formula: see text]-ATPase in cancer cells. It is frequently used in clinical settings to treat advanced-stage cancer patients, improving their quality of life and survival time. However, its long-term use can result in multidrug resistance to other chemotherapy drugs, and the exact mechanism underlying this effect remains unknown. Therefore, this study explores the molecular mechanism underlying the anticancer effects of cinobufagin in hepatocellular carcinomas (HCCs), specifically in HepG2 and Huh-7 cells. As determined using transcriptome analysis, cinobufagin-triggered protective autophagy suppressed cell apoptosis in liver cancer HepG2 and Huh-7 cells by inhibiting the phosphoinositide-3-Kinase (PI3K)-AKT serine/threonine kinase (AKT)-mammalian target of rapamycin (mTOR) pathway. Cinobufagin-inhibited cell proliferation, induced apoptosis, and generated cell autophagy by upregulating the expression of MAP1 light chain 3 protein II, Beclin1, and autophagy-related protein 12-5. In addition, the autophagy inhibitor MRT68921 improved the antiproliferative and proapoptotic effects of cinobufagin in the studied cell lines. Overall, this study suggests that combining cinobufagin with an autophagy inhibitor can effectively treat HCC, providing a potential strategy for cancer therapy.

Influence of farmland confirmation on farmland abandonment in China.

The general view is that land ownership affirmation provides incentives for farmers to internalize external benefits, optimizes farmers' allocation of agricultural production factors, and then reduces farmers' farmland wastage behavior. This study examines the influence of residual control and claim rights in farmland right confirmation on farmers' farmland wastage behavior. Results show that residual control rights guarantee the farmers' exclusive right to use the farmland independently, and residual claim stimulates the farmers to pursue the goal of agricultural production surplus value. However, the residual claim rights are related to the constraint conditions of agricultural production; thus, the farmland right confirmation is situational dependent on farmers' farmland wastage behavior. The surplus value of the farming output of low-income families is low, and the willingness to realize the surplus claim through agricultural reproduction is weak. Residual control reduces the risk of land loss, accelerates the transfer of the labor force, and shows the behavior of farmland wastage. Nonpoor households with high agricultural production surplus value tend to increase the allocation of agrarian production factors to maximize the income, improve the allocation efficiency of agricultural land resources, and reduce farmland wastage behavior. Conclusion: The implementation effect of accurate farmland affirmation is progressive and internally unbalanced. The institutional basis of matching policy should be to deal with the relationship between residual control right and residual claim right.

Epstein-Barr Virus LMP1-Activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Properties.

Epstein-Barr virus (EBV) is associated with several malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. The virus-encoded oncoprotein, LMP1, induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring cancer stem cell (CSC) characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 coregulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients. IMPORTANCE LMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 coregulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.

Performance Analysis of the Direct Position Determination Method in the Presence of Array Model Errors.

The direct position determination approach was recently presented as a promising technique for the localization of a transmitting source with accuracy higher than that of the conventional two-step localization method. In this paper, the theoretical performance of a direct position determination estimator proposed by Weiss is examined for situations in which the array model errors are present. Our study starts from a matrix eigen-perturbation result, which expresses the perturbation of eigenvalues as a function of the disturbance added to the Hermitian matrix. The first-order asymptotic expression of the positioning errors is presented, from which an analytical expression for the mean square error of the direct localization is available. Additionally, explicit formulas for computing the probabilities of a successful localization are deduced. Finally, Cramér-Rao bound expressions for the position estimation are derived for two cases: (1) array model errors are absent and (2) array model errors are present. The obtained Cramér-Rao bounds provide insights into the effects of the array model errors on the localization accuracy. Simulation results support and corroborate the theoretical developments made in this paper.