Search

Accumulating studies have demonstrated that CADM2 modulated malignant phenotype of various cancer cells, while its regulatory function and mechanism have not yet been reported. In this study, qRT-PCR was utilized to measure CADM2 mRNA level in normal cells and colon cancer cells, also, IHC and WB were applied to detect CADM2 protein expression in colon tissues, exhibiting low mRNA and protein levels of CADM2 in colon cancer. Applying cell function experiments, the impacts of CADM2 on colon cell phenotypes were examined, and the results illustrated that upregulating CADM2 remarkably repressed proliferation, invasion, migration, cell cycle of colon cancer cells, and facilitated cell apoptosis. Thus, it could be considered that CADM2 served as a tumor repressor gene in colon cancer. Moreover, the outcomes of dual-luciferase assay displayed that miR-17-5p could target CADM2, and overexpressing miR-17-5p could notably inhibit the mRNA and protein expression levels of CADM2. We, therefore, assumed that CADM2 was a downstream target of miR-139-5p. qRT-PCR was conducted to assess miR-17-5p level in colon cancer cells and normal cells, verifying a high miR-17-5p expression in the cancer cells. The effects of miR-17-5p on colon cell phenotypes were examined as well, where we determined that miR-17-5p served as a tumor-promoting factor. Finally, the rescue experiments exhibited that miR-17-5p could activate tumor-promoting phenotypes, while such activating effects could be reversed by upregulating CADM2. In short, the study proved that miR-17-5p facilitated malignant progression of colon cancer through targeting CADM2 at a post-transcriptional level. Our findings offer new insight into molecular therapy of colon cancer patients.

Background BRE-AS1 is a recently identified tumor suppressor in non-small cell lung cancer. It role in other human diseases remains elusive. Methods Differential expression of BRE-AS1 in with triple-negative breast cancer (TNBC) patients (n = 74, patient group) and healthy volunteers (n = 58, control group) was studied with RT-qPCR. The direct interaction between BRE-AS1 and premature microRNA-21 (miR-21) was assessed by RNA pull-down assay. The interactions among BRE-AS1, miR-21 and PTEN were evaluated by overexpression assays. CCK-8 assay and Transwell assay were used to evaluate cell behaviors. Results BRE-AS1 was downregulated in TNBC, while miR-21 was highly expressed in TNBC. Low expression levels of lncRNA BRE-AS1 and high expression levels of miR-21 were significantly correlated with unfavorable survival outcomes. BRE-AS1 and miRNA-21 were inversely correlated across TNBC samples, not control samples. BRE-AS1 decreased miR-21 expression and increased PTEN expression while miR-21showed no role in BRE-AS1 expression. RNA pull-down assay illustrated that BRE-AS1 may sponge premature miR-21 to suppress it maturation. Overexpression of BRE-AS1 decreased cell behaviors, while overexpression of miR-21 promoted cell behaviors. MiR-21 suppressed the role of BRE-AS1 in cancer cell behaviors. Conclusion Therefore, BRE-AS1 may inhibit TNBC by downregulating miR-21.

This study aims to establish a gene model that can robustly and effectively predict the prognosis of colon carcinoma patients via bioinformatics. Data along with clinical information in GSE39582 Series Matrix were firstly downloaded from Gene Expression Omnibus (GEO) database. Next, differentially expressed genes (DEGs) were obtained through “edgeR” analysis. Finally, a risk predication model was established through a series of regression analyses, and then prognostic performance of the model was comprehensively evaluated though Kaplan-Meier and receiver operating characteristic (ROC) analysis. Gene set enrichment analysis (GSEA) was further performed. Totally, 846 DEGs were obtained by analyzing the gene expression data in GSE39582 dataset. A 9-gene signature-based risk predication model was established via regression analyses, and the model-based risk score was formulated as: Riskscore = (−0.1214) * TNFRSF11A + (−0.2617) * TMEM97 + (−0.1041) * LGR5 + 0.0973 * KLK10 + 0.1655 * HOXB8 + 0.227 * FKBP10 + (−0.1312) * CXCL13 + (−0.1316) * CXCL10 + 0.2593 * CD36. Kaplan-Meier curve showed that colon carcinoma patients in the high-risk group had a lower survival rate. GSEA showed that high-risk group and low-risk group displayed significant difference in biological pathways including ECM RECEPTOR INTERACTION. Besides, correlation analysis between the riskscore of the model and clinical features of patients revealed that the model could effectively predict the prognosis of patients in different ages (age>65, age

Docetaxel (DCT) is widely adopted in chemotherapy for colon cancer (CC). However, DCT resistance can cause chemotherapy failure in CC. MicroRNAs (miRNAs) are key regulators of DCT resistance. Among them, miR-194-3p is a key tumor suppressor, but how it regulates DCT resistance has not been reported yet. This research explored the molecular mechanism of miR-194-3p/Kallikrein Related Peptidase 10 (KLK10) axis in regulating DCT resistance in CC.The expression and targeting relationship of miR-194-3p and KLK10 was dug through bioinformatics analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was adopted to determine miR-194-3p level in CC cells. The over-expressed miR-194-3p cell group was constructed to ascertain the impacts of dysregulated miR-194-3p on DCT resistance. Through dual-luciferase assay, the targeting relationship of miR-194-3p and KLK10 was uncovered. Subsequently, the in vitro cellular experiments were performed to investigate the impacts of miR-194-3p/KLK10 axis on DCT resistance in CC cells.We noticed that miR-194-3p was notably down-regulated in CC cells. The over-expressed miR-194-3p restored the DCT sensitivity of SW620/DCT and SW480/DCT cells. Dual-luciferase assay suggested the targeting relationship of miR-194-3p and KLK10. Besides, miR-194-3p negatively regulated KLK10 expression level. In vitro cellular experiments further exposed that miR-194-3p could down-regulate KLK10, thereby attenuating DCT resistance in CC cells.miR-194-3p could overcome DCT resistance in CC cells through negatively regulating KLK10. This finding offers a potential therapeutic target for clinical treatment of DCT chemoresistance in CC.

Clinical researches of stem cell-based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies.This article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell-based products, as well as the clinical review concerns of stem cell-based products in China.The current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued "Administrative Measures on Stem Cell Clinical Research" (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell-based products are supervised by Drug Administration Law (DAL).The regulatory framework of stem cell-based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well-designed and patient-focused clinical trial is required for commercially developed stem cell-based products, and definite clinical benefit evidence is crucial to obtain marketing authorization.

// Jinfeng Kong 1, 2, * , Juan Du 1, * , Yunling Wang 1 , Mingzi Yang 1 , Jianchao Gao 1 , Xiaofan Wei 1 , Weigang Fang 1, 2 , Jun Zhan 1 , Hongquan Zhang 1 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China 2 Department Pathology, Peking University Health Science Center, Beijing 100191, China * These authors have contributed equally to this work Correspondence to: Hongquan Zhang, email: Hongquan.Zhang@bjmu.edu.cn Weigang Fang, email: wgfang@bjmu.edu.cn Jun Zhan, email: Zhanjun@bjmu.edu.cn Keywords: Kindlin-1, colorectal carcinoma, TGF-β receptor I, Smad3, Smad anchor for receptor activation (SARA) Received: August 17, 2016 Accepted: October 05, 2016 Published: October 20, 2016 ABSTRACT Kindlin-1, an integrin-interacting protein, has been implicated in TGF-β/Smad3 signaling. However, the molecular mechanism underlying Kindlin-1 regulation of TGF-β/Smad3 signaling remains elusive. Here, we reported that Kindlin-1 is an important mediator of TGF-β/Smad3 signaling by showing that Kindlin-1 physically interacts with TGF-β receptor I (TβRI), Smad anchor for receptor activation (SARA) and Smad3. Kindlin-1 is required for the interaction of Smad3 with TβRI, Smad3 phosphorylation, nuclear translocation, and finally the activation of TGF-β/Smad3 signaling pathway. Functionally, Kindlin-1 promoted colorectal cancer (CRC) cell proliferation in vitro and tumor growth in vivo, and was also required for CRC cell migration and invasion via an epithelial to mesenchymal transition. Kindlin-1 was found to be increased with the CRC progression from stages I to IV. Importantly, raised expression level of Kindlin-1 correlates with poor outcome in CRC patients. Taken together, we demonstrated that Kindlin-1 promotes CRC progression by recruiting SARA and Smad3 to TβRI and thereby activates TGF-β/Smad3 signaling. Thus, Kindlin-1 is a novel regulator of TGF-β/Smad3 signaling and may also be a potential target for CRC therapeutics.

The clinical trials of CAR T-cell therapy are growing fast in recent years, and most of the trials are initiated by sponsors from the United States and China. Exhibiting the distinctions between the clinical trials in the two countries is of great value for understanding the panorama of CAR T-cell clinical trials and forecasting the future of this promising therapy. We analyzed the critical elements of 289 clinical trials posted on the clinicaltrials.gov website by sponsors from the two countries and evaluated the efficacy data in available 50 published CAR T-cell studies. Our analysis shows that China has become the country with the largest number of CAR-T cell clinical trials by the end of 2017, while overall subject sample size and study center numbers are still larger, and the design of the clinical trials is more cautious in the United States. There are obvious differences between the two countries in CAR-targeted antigens in solid tumors and genetic modifications besides CARs for enhancing the potency of CAR T-cells. Although the currently available response rates are promising in both countries, it is inexpedient to conclude that the clinical efficacy is comparable between the two countries considering the smaller patient sample sizes and discrete distribution of median cell doses in China. And finally, the flexible regulatory regime of cell therapy in China, which expedites the bursting of CAR T-cell therapy, is also firstly introduced in our study.

Epidermal growth factor receptor (EGFR) mediates multiple signaling pathways that regulate cell proliferation, migration and tumor invasion. Kindlin-2 has been known as a focal adhesion molecule that binds to integrin to control cell migration and invasion. However, molecular mechanisms underlying the role of Kindlin-2 in breast cancer progression remain elusive. Here we report that Kindlin-2 interacts with EGFR and mediates EGF-induced breast cancer cell migration. We found that EGF treatment dramatically increases Kindlin-2 expression at both mRNA and protein levels in a variety of cancer cells. Inhibitors specific for EGFR or PI3K blocked Kindlin-2 induction by EGF. Importantly, Kindlin-2 interacted with EGFR kinase domain, which was independent of Kindlin-2 binding to integrin cytoplasmic domain. Intriguingly, Kindlin-2 stabilized EGFR protein by blocking its ubiquitination and degradation. Depletion of Kindlin-2 impaired EGF-induced cell migration. Our results demonstrated that Kindlin-2 participates in EGFR signaling and regulates breast cancer progression.

The wind power generation system will play a crucial role for developing the energy conservative, environmentally friendly, and sustainable electric power system in China. However, the intermittency and unpredictability of wind power has been an obstacle to the deployment of wind power generation, especially in the winter of northern China. In northern China, a combined heat and power (CHP) unit has been widely utilized as a heat and electricity source. Considering the flexible operation of CHP with introduction of electric heat pumps (EHPs), this paper proposes a new method of electricity and heating demand side management to facilitate the wind power integration with the purpose of energy conservation in a unit-commitment problem. The thermal characteristics of demand side such as the thermal inertia of buildings and thermal comfort of end users are taken into consideration. Moreover the distributed electric heat pumps (EHPs) widely used by city dwellers are introduced into the wind-thermal power system as the heating source and spinning reserve so as to increase the flexibility of heating and electricity supply. The simulation results show that the new method can integrate more wind power into power grid for electricity and heating demand to reduce the coal consumption.

SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3′ splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is a common defect of spliceosomes with disease-causing SF3B1 mutations and, since this defect can be rescued, suggests possibilities for therapeutic intervention.

This paper presents an efficient algorithm for loss minimization in distribution network reconfiguration. The algorithm divided the initial particle swarm into two different sub-groups which perform simultaneously. So there are more particles with high inertia weights in the prophase of the evolution in order to make the large-scale searching in solution domain easily, and in the anaphase, these particles inertia weights will descend in linearity which improves the ability of local searching. As the changing of the particles quantity of the two sub-groups and the effect of the different inertia weights, it can achieve a good searching performance and overcome the limitations of PSO, which has a slow convergence velocity and easily being relapsed into local extreme. Then on the basis of improved binary particle swarm optimization algorithm and in combination with the breaking circle method, to make the updated particles meet the requirement of the radial network by hundred percent and accelerate the calculation speed. Finally a typical example of the IEEE 33-nodes network was simulated through the proposed algorithm to calculate the network power losses, and the simulation results was compared with those of modified binary PSO algorithms. The comparison results show that the proposed method has a higher searching efficiency and faster convergence rate.

To detect the methylation status of gastric cancer tissue genome by DNA methylation chip.Methylation status of 6 samples of gastric cancer tissues and their matched adjacent tissues was analyzed using methylated DNA immunoprecipitation(MeDIP) combined with NibleGen chip. Significantly different methylated genes in promoter region and CpG island between two tissues were searched. Functions of these significantly different methylated genes were analyzed by Gene Ontology and Pathway assays.In gene promoter regions, 113 significantly different methylated genes were identified in gastric cancer tissues, such as SHP1, FGF8 and CSF2RA, while 161 significantly different methylated genes were identified in their matched adjacent tissues, such as TNF, IGF2 and BMP7. In the CpG islands, 123 significantly different methylated genes were identified in gastric cancer tissues, such as WNT2B, JAK2 and TPT1, while 139 significantly different methylated genes were identified in their matched adjacent tissues, such as TNFRSF4, HOXC8 and NFYA. These genes located on different chromosomes. In gastric cancer tissues, the 1st and the 4th chromosomes had the most (both 11), the 18th and the 20th chromosomes had the least(both 1). In matched adjacent normal tissues, the 11th chromosome had the most (17), and no significantly different methylated gene was found on Y chromosome. These genes involved in many functions, such as protein phosphorylation, regulating cellular catabolism, ion transport, enzyme activity, transcriptional regulation, cell division, cell cycle regulation, and signal transduction.There are significant differences between gastric cancer tissues and their matched adjacent tissues in DNA methylation. DNA methylation genes locate on different chromosomes, and their number and distribution vary widely. These genes may be associated with many pathways in carcinogenesis.

Aiming at the challenge of large-scale wind power integration, a new method for integrating the heating load and heating storage control is proposed based on district energy system with a core of CHP. In the new method, thermal energy storage (TES) can increase the flexibility of CHP's heat output and power output to follow the fluctuation of wind power. The distributed electric heat pumps (EHPs) are used for heating load control to increase the capability to balance the wind power and electricity demand. In addition, the building thermal inertia and human thermal comfort are taken into account to make the power consumption of EHPs to follow the wind power. At last, the simulation results show the effect on balancing the wind power and electricity demand as well as the influence of space heating load characteristic.

Kindlin-2 is engaged in tumor progression. However, the mechanism accounting for Kindlin-2 regulation in tumor cells remained largely unknown. Here, we report a regulatory loop between Kindlin-2 and GLI1, an effector of Hedgehog signaling pathway. We show that Kindlin-2 is transcriptionally downregulated via GLI1 occupancy on the Kindlin-2 promoter. Adversely, we found that Kindlin-2 promotes GLI1 expression through a mechanism involving GSK3β inactivation and is independent of Smoothened. Functionally, knockdown of Kindlin-2 cooperates with cyclopamine, a Smoothened antagonist, to decrease the viability of prostate cancer cells. Taken together, targeting the Kindlin-2–GLI1 feedback loop may facilitate the killing of prostate cancer cells.

IPMC (ionic polymer metal composites), also known as artificial muscles, is one kind smart material of electric actuators, it can generates a large deformation under a relatively low input voltage (generally less than 5V). Thin IPMC strips (the thickness is usually less than 0.3mm) possess a strong hysteresis and creep characteristics which will change with the different level of water content and the environmental temperature. When it comes to thick IPMC samples (the thickness is thicker than 0.4mm), the hysteresis characteristic is relatively weaker than the creep characteristic and these properties relatively remain stable. Currently, most of the existing control methods for IPMC manipulation are complicated and they are usually adaptive ones which require complicated hardware equipments, so these kinds of controllers are not very suitable for some practical applications. This paper proposes the Periodic Output Feedback (POF) control method to regulate the IPMCs, and also develops the error integral compensation POF (IPOF) control method to deal with the gradual enhancing control error and the output oscillation problems of IPMCs with POF controller. The simulations and experiments are carried out, and good results are obtained.

This paper proposes a remote control system based on cell injection robot. Analysis of the influence of network delay to control system performance with Matlab/Simulink toolbox TrueTime is done. The adoption of UDT protocol to transfer experimental image and control information in real-time lowers the network transfer delay and makes the microscopic image displayed in client computer smoothly and stably. It chooses SELECT I/O mode supported by UDT protocol and adopts multithread programming technology to guarantee well performance of the program. As the remote control system is sensitive to network delay, the system uses event-based control mode.

IPMC is a type of electro-active polymer material, also called artificial muscle, which can generate a relatively large deformation under a relatively low input voltage (generally speaking, less than 5 V), and can be implemented in a water environment. Due to these advantages, IPMC can be used in many fields such as biomimetics, service robots, bio-manipulation, etc. Until now, most existing methods for IPMC manipulation are displacement control not directly force control, however, under most conditions, the success rate of manipulations for tiny fragile objects is limited by the contact force, such as using an IPMC gripper to fix cells. Like most EAPs, a creep phenomenon exists in IPMC, of which the generated force will change with time and the creep model will be influenced by the change of the water content or other environmental factors, so a proper force control method is urgently needed. This paper presents a novel adaptive force control method (AIPOF control—adaptive integral periodic output feedback control), based on employing a creep model of which parameters are obtained by using the FRLS on-line identification method. The AIPOF control method can achieve an arbitrary pole configuration as long as the plant is controllable and observable. This paper also designs the POF and IPOF controller to compare their test results. Simulation and experiments of micro-force-tracking tests are carried out, with results confirming that the proposed control method is viable.