Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Oncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.</p> <p>Results</p> <p>The observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The <it>in vivo </it>assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the <it>in vitro </it>studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.</p> <p>Conclusions</p> <p>These data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.</p

Continual Exposure to Cigarette Smoke Extracts Induces Tumor-Like Transformation of Human Nontumor Bronchial Epithelial Cells in a Microfluidic Chip

IntroductionHeavy cigarette smoking-related chronic obstructive pulmonary disease is an independent risk factor for lung squamous carcinoma. However, the mechanisms underlying the malignant transformation of bronchial epithelial cells are unclear.MethodsIn our study, human tumor-adjacent bronchial epithelial cells were obtained from 10 cases with smoking-related chronic obstructive pulmonary disease and lung squamous carcinoma and cultured in an established microfluidic chip for continual exposure to cigarette smoke extracts (CSE) to investigate the potential tumor-like transformation and mechanisms. The integrated microfluidic chip included upstream concentration gradient generator and downstream cell culture chambers supplied by flowing medium containing different concentrations of CSE.ResultsOur results showed that continual exposure to low doses of CSE promoted cell proliferation whereas to high doses of CSE triggered cell apoptosis. Continual exposure to CSE promoted reactive oxygen species production in human epithelial cells in a dose-dependent manner. More importantly, continual exposure to low dose of CSE promoted the epithelial-to-mesenchymal transition process and anchorage-independent growth, and increased chromosome instability in bronchial epithelial cells, accompanied by activating the GRP78, NF-κB, and PI3K pathways.ConclusionsThe established microfluidic chip is suitable for primary culture of human tumor-adjacent bronchial epithelial cells to investigate the malignant transformation. Continual exposure to low doses of CSE promoted tumor-like transformation of human nontumor bronchial epithelial cells by inducing reactive oxygen species production and activating the relevant signaling

Design and Analysis of a Permanent Magnet Vernier Machine with Non-Uniform Tooth Distribution

To improve the torque performance of the permanent magnet vernier machine in the direct-drive system for Unmanned Aerial Vehicle (UAV), this paper proposes the topology of non-uniform tooth distribution. This distribution, considering the additional flux harmonics, aims to contribute to torque improvement, whereas the cogging torque also increases at the same time. A phasors method is proposed to solve the issue caused by the non-uniform structure, adjusting the mechanic angle of each tooth reasonably to restrict the cogging torque. In addition, the non-uniform design is illustrated in detail, which includes the method of grouping the teeth, considering the factors of series pole ratio and winding layout. By using the three-dimensional finite element method, torque is significantly increased without additional torque ripple, which satisfies the desired design target

MOESM2 of The chimeric multi-domain proteins mediating specific DNA transfer for hepatocellular carcinoma treatment

Additional file 2: Figure S2. The schematic representation of plasmid chimera and fusion protein transfection into human HepG-2 cells

Effects of bradykinin on the survival of multiterritory perforator flaps in rats

Abstract Background Bradykinin, a vasoactive peptide, has many biological functions. For example, it accelerates angiogenesis. Thus, we studied the effects of bradykinin on the survival of perforator flaps. Methods Averagely, 50 male Sprague–Dawley rats were divided into control and bradykinin groups and underwent procedures to the multiterritory perforator flap. Areas of flap survival were tested 7 days later. Flap perfusion was evaluated by laser Doppler imaging. We assessed the extent of autophagy by determining LC3-II/I, Beclin 1, and p62. Flap angiogenesis was assessed by immunohistochemistry and H&E staining. We measured the level of vascular endothelial growth factor (VEGF) protein using western blot. We assessed oxidative stress by measuring the activity of superoxide dismutase (SOD) and malondialdehyde (MDA) levels. The apoptotic index was also evaluated by western blot, and we determined nitric oxide (NO) production using an NO assay kit. Results The bradykinin group exhibited significantly larger areas of flap survival, higher blood supply, and more neovascularization. The bradykinin group also had higher SOD activity, higher VEGF expression and NO content, and reduced MDA compared to the control group. Rats treated with bradykinin also had lower levels of apoptosis and autophagy relative to the control group. Conclusion Our results suggest that bradykinin promotes the survival of multiterritory perforator flaps by increasing angiogenesis, promoting the release of NO, suppressing apoptosis, reducing oxidative stress, and inhibiting autophagy

Investigation of Predictive Regulation Strategy of Secondary Loop in District Heating Systems

The urban energy system is greatly dependent on the District Heating System (DHS). However, many difficulties with regulation and control are caused by its large scale and numerous coupling variables. Additionally, reliance on manual experience means it can be challenging to guarantee heating comfort and effectiveness in the regulation of DHS. This paper proposes a data-driven temperature response prediction model to predict secondary loop supply temperature based on the heating substation’s historical operating status, valve opening degree, weather conditions, etc. Further, the XGBoost model was established in this article with different input and prediction steps. The results show that the XGBoost model with 72 input steps and 24 prediction steps has better performance. As an application example, the model was applied to an urban central heating system. Based on this data-driven model, different operation strategies on primary loop valve opening are compared for temperature response analysis. Operators can check the temperature responses of different valve control strategies before being applied. This paper guides the regulation behavior of the DHS, which is of great significance for the operation of the actual DHS

More but Correct: Generating Diversified and Entity-revised Medical Response

Medical Dialogue Generation (MDG) is intended to build a medical dialogue system for intelligent consultation, which can communicate with patients in real-time, thereby improving the efficiency of clinical diagnosis with broad application prospects. This paper presents our proposed framework for the Chinese MDG organized by the 2021 China conference on knowledge graph and semantic computing (CCKS) competition, which requires generating context-consistent and medically meaningful responses conditioned on the dialogue history. In our framework, we propose a pipeline system composed of entity prediction and entity-aware dialogue generation, by adding predicted entities to the dialogue model with a fusion mechanism, thereby utilizing information from different sources. At the decoding stage, we propose a new decoding mechanism named Entity-revised Diverse Beam Search (EDBS) to improve entity correctness and promote the length and quality of the final response. The proposed method wins both the CCKS and the International Conference on Learning Representations (ICLR) 2021 Workshop Machine Learning for Preventing and Combating Pandemics (MLPCP) Track 1 Entity-aware MED competitions, which demonstrate the practicality and effectiveness of our method.Comment: 12 pages, 4 figures, 7 table

Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform.

Tumor stroma and growth factors provide a survival environment to tumor cells and can modulate their chemoresistance by dysregulating several signal pathways. In this study, we fabricated a three-dimensional (3D) microfluidic chip using polydimethylsiloxane (PDMS) to investigate the impact of hepatocyte growth factor (HGF) from cancer-associated fibroblasts (CAF) on the Met/PI3K/AKT activation, glucose regulatory protein (GRP78) expression and the paclitaxel-induced A549 cell apoptosis. With a concentration gradient generator, the assembled chip was able to reconstruct a tumor microenvironment in vitro. We found high levels of HGF in the supernatants of CAF and the CAF matrix from the supernatants of activated HFL1 fibroblasts or HGF enhanced the levels of Met, PI3K and AKT phosphorylation and GRP78 expression in A549 cells cultured in a 3D cell chamber, which was abrogated by anti-HGF. Inhibition of Met attenuated the CAF matrix-enhanced PI3K/AKT phosphorylation and GRP78 expression while inhibition of PI3K reduced GRP78 expression, but not Met phosphorylation in A549 cells. Inhibition of GRP78 failed to modulate the CAF matrix-enhanced Met/PI3K/AKT phosphorylation in A549 cells. Furthermore, inhibition of PI3K or GRP78 enhanced spontaneous and paclitaxel-induced A549 cell apoptosis. Moreover, treatment with the CAF matrix inhibited spontaneous and medium or high dose of paclitaxel-induced A549 cell apoptosis. Inhibition of PI3K or GRP78 attenuated the CAF matrix-mediated inhibition on paclitaxel-induced A549 cell apoptosis. Our data indicated that HGF in the CAF matrix activated the Met/PI3K/AKT and up-regulated GRP78 expression, promoting chemoresistance to paclitaxel-mediated apoptosis in A549 cells. Our findings suggest that the microfluidic system may represent an ideal platform for signaling research and drug screening