The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells

Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy.Grant support: This study was supported in part by Chongqing Natural Science Foundation (CSTC, 2011BB5030), and by the Scientific Funds of Third Military Medical University (2011XHG02)

Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling

Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer cells and tumors. Consequently, Lip-FLLL32 suppressed pancreatic cancer cell growth, and exhibited synergetic effects with gemcitabine and radiation treatment in vitro and in vivo. Furthermore, Lip-FLLL32 reduced ALDH1-positive CSC population and modulated several potential stem cell markers. These results demonstrate that Lip-FLLL32 suppresses pancreatic tumor growth and sensitizes pancreatic cancer cells to radiotherapy through inhibition of CSCs in a STAT3-dependent manner. By targeting pancreatic CSCs, Lip-FLLL32 provides a novel strategy for pancreatic cancer therapy via overcoming radioresistance

Reduced Energy Metabolism Impairs T Cell-Dependent B Cell Responses in Patients With Advanced HBV-Related Cirrhosis

Background and AimsPatients with decompensated HBV-related liver cirrhosis (HBV D-LC) showed compromised immune responses, which manifested as a proneness to develop infections and hyporesponsiveness to vaccines, resulting in accelerated disease progression. The alterations in T cell-dependent B cell responses in this pathophysiological process were not well understood. This study aimed to investigate T cell-dependent B cell responses in this process and discuss the mechanism from the perspective of metabolism.MethodsChanges in phenotypes and subsets of peripheral B cells between HBV D-LC patients and healthy controls (HCs) were compared by flow cytometry. Isolated B cells were activated by coculture with circulating T follicular (cTfh) cells. After coculture, the frequencies of plasmablasts and plasma cells and immunoglobin levels were analyzed. Oxidative phosphorylation (OXPHOS) and glycolysis were analyzed by a Seahorse analyzer. Mitochondrial function and the AKT/mTOR pathway were analyzed by flow cytometry.ResultsThe proliferation and differentiation capacities of B cells after T cell stimulation were impaired in D-LC. Furthermore, we found that B cells from D-LC patients showed reductions in OXPHOS and glycolysis after activation, which may result from reduced glucose uptake, mitochondrial dysfunction and attenuated activation of the AKT/mTOR pathway.ConclusionsB cells from HBV D-LC patients showed dysfunctional energy metabolism after T cell-dependent activation. Understanding the regulations of B cell metabolic pathway and their changes may provide a new direction to rescue B cell hyporesponsiveness in patients with HBV D-LC, preventing these patients be infected and improving sensitivity to vaccines

MiR-137 Targets Estrogen-Related Receptor Alpha and Impairs the Proliferative and Migratory Capacity of Breast Cancer Cells

ERRα is an orphan nuclear receptor emerging as a novel biomarker of breast cancer. Over-expression of ERRα in breast tumor is considered as a prognostic factor of poor clinical outcome. The mechanisms underlying the dysexpression of this nuclear receptor, however, are poorly understood. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. In the present study, we have identified that the expression of ERRα is regulated by miR-137, a potential tumor suppressor microRNA. The bioinformatics search revealed two putative and highly conserved target-sites for miR-137 located within the ERRα 3′UTR at nt 480–486 and nt 596–602 respectively. Luciferase-reporter assay demonstrated that the two predicted target sites were authentically functional. They mediated the repression of reporter gene expression induced by miR-137 in an additive manner. Moreover, ectopic expression of miR-137 down-regulated ERRα expression at both protein level and mRNA level, and the miR-137 induced ERRα-knockdown contributed to the impaired proliferative and migratory capacity of breast cancer cells. Furthermore, transfection with miR-137mimics suppressed at least two downstream target genes of ERRα–CCNE1 and WNT11, which are important effectors of ERRα implicated in tumor proliferation and migration. Taken together, our results establish a role of miR-137 in negatively regulating ERRα expression and breast cancer cell proliferation and migration. They suggest that manipulating the expression level of ERRα by microRNAs has the potential to influence breast cancer progression

Material Cost Advantage and Development of Small Printing Industry: Based on the Case of Xinhua Phenomenon

Based on the survey of small printing industry in Beijing, Xi’an and Zhengzhou, this paper analyses the development of Xinhua Phenomenon as one case of Rural Migration Entrepreneurship and find that group culture is an important factor to promote the development of Xinhua Phenomenon. Through the econometric analysis, the research finds that Xinhua printing group offers better services than non-Xinhua group to gain the material cost advantage and promote the development of Xinhua Phenomenon

Material Cost Advantage and Development of Small Printing Industry: Based on the Case of Xinhua Phenomenon

Based on the survey of small printing industry in Beijing, Xi’an and Zhengzhou, this paper analyses the development of Xinhua Phenomenon as one case of Rural Migration Entrepreneurship and find that group culture is an important factor to promote the development of Xinhua Phenomenon. Through the econometric analysis, the research finds that Xinhua printing group offers better services than non-Xinhua group to gain the material cost advantage and promote the development of Xinhua Phenomenon

Design and Fabrication of a Differential Electrostatic Accelerometer for Space-Station Testing of the Equivalence Principle

The differential electrostatic space accelerometer is an equivalence principle (EP) experiment instrument proposed to operate onboard China’s space station in the 2020s. It is designed to compare the spin-spin interaction between two rotating extended bodies and the Earth to a precision of 10−12, which is five orders of magnitude better than terrestrial experiment results to date. To achieve the targeted test accuracy, the sensitive space accelerometer will use the very soft space environment provided by a quasi-drag-free floating capsule and long-time observation of the free-fall mass motion for integration of the measurements over 20 orbits. In this work, we describe the design and capability of the differential accelerometer to test weak space acceleration. Modeling and simulation results of the electrostatic suspension and electrostatic motor are presented based on attainable space microgravity condition. Noise evaluation shows that the electrostatic actuation and residual non-gravitational acceleration are two major noise sources. The evaluated differential acceleration noise is 1.01 × 10−9 m/s2/Hz1/2 at the NEP signal frequency of 0.182 mHz, by neglecting small acceleration disturbances. The preliminary work on development of the first instrument prototype is introduced for on-ground technological assessments. This development has already confirmed several crucial fabrication processes and measurement techniques and it will open the way to the construction of the final differential space accelerometer

Bayesian Network-Based Knowledge Graph Inference for Highway Transportation Safety Risks

Accurate inference of knowledge about highway transportation safety risks forms a crucial aspect of building a knowledge graph. Based on the data related to highway transportation accidents, this study has developed a Bayesian network model. The initial identification of the network nodes is through expert scoring. The network structure is then constructed by utilizing the prior expert knowledge and K2 greedy search algorithm. Later, the network parameters are trained via the expectation-maximization (EM) algorithm. Finally, knowledge about highway transportation safety risks is inferred using the junction tree algorithm. A comparison is made between the trained conditional and actual probabilities during the network parameter training to verify the validity of the proposed model that accords with expert experience, thereby proving the model validity. Further, its main “causal chain” is inferred to be an improper emergency response-human failure-accident occurrence, where the probability of driver failure is 82%, and the probability of accident occurrence is 68% by taking “a certain road traffic accident” as an example. There is consistency between the inference results and the actual accident sequence that suggests the effectiveness of the proposed knowledge inference method

Hybrid Transverse Polar Navigation for High-Precision and Long-Term INSs

Transverse navigation has been proposed to help inertial navigation systems (INSs) fill the gap of polar navigation ability. However, as the transverse system does not have the ability of navigate globally, a complicated switch between the transverse and the traditional algorithms is necessary when the system moves across the polar circles. To maintain the inner continuity and consistency of the core algorithm, a hybrid transverse polar navigation is proposed in this research based on a combination of Earth-fixed-frame mechanization and transverse-frame outputs. Furthermore, a thorough analysis of kinematic error characteristics, proper damping technology and corresponding long-term contributions of main error sources is conducted for the high-precision INSs. According to the analytical expressions of the long-term navigation errors in polar areas, the 24-h period symmetrical oscillation with a slowly divergent amplitude dominates the transverse horizontal position errors, and the first-order drift dominates the transverse azimuth error, which results from the g 0 gyro drift coefficients that occur in corresponding directions. Simulations are conducted to validate the theoretical analysis and the deduced analytical expressions. The results show that the proposed hybrid transverse navigation can ensure the same accuracy and oscillation characteristics in polar areas as the traditional algorithm in low and mid latitude regions