Combined therapy of CAR-IL-15/IL-15Rα-T cells and GLIPR1 knockdown in cancer cells enhanced anti-tumor effect against gastric cancer.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown remarkable responses in hematological malignancies with several approved products, but not in solid tumors. Patients suffer from limited response and tumor relapse due to low efficacy of CAR-T cells in the complicated and immunosuppressive tumor microenvironment. This clinical challenge has called for better CAR designs and combined strategies to improve CAR-T cell therapy against tumor changes. METHODS: In this study, IL-15/IL-15Rα was inserted into the extracellular region of CAR targeting mesothelin. In-vitro cytotoxicity and cytokine production were detected by bioluminescence-based killing and ELISA respectively. In-vivo xenograft mice model was used to evaluate the anti-tumor effect of CAR-T cells. RNA-sequencing and online database analysis were used to identify new targets in residual gastric cancer cells after cytotoxicity assay. CAR-T cell functions were detected in vitro and in vivo after GLI Pathogenesis Related 1 (GLIPR1) knockdown in gastric cancer cells. Cell proliferation and migration of gastric cancer cells were detected by CCK-8 and scratch assay respectively after GLIPR1 were overexpressed or down-regulated. RESULTS: CAR-T cells constructed with IL-15/IL-15Rα (CAR-ss-T) showed significantly improved CAR-T cell expansion, cytokine production and cytotoxicity, and resulted in superior tumor control compared to conventional CAR-T cells in gastric cancer. GLIPR1 was up-regulated after CAR-T treatment and survival was decreased in gastric cancer patients with high GLIPR1 expression. Overexpression of GLIPR1 inhibited cytotoxicity of conventional CAR-T but not CAR-ss-T cells. CAR-T treatment combined with GLIPR1 knockdown increased anti-tumor efficacy in vitro and in vivo. CONCLUSIONS: Our data demonstrated for the first time that this CAR structure design combined with GLIPR1 knockdown in gastric cancer improved CAR-T cell-mediated anti-tumor response.

Notch Signaling Regulates the Function and Phenotype of Dendritic Cells in Helicobacter pylori Infection.

Notch signaling manipulates the function and phenotype of dendritic cells (DCs), as well as the interaction between DCs and CD4+ T cells. However, the role of Notch signaling in Helicobacter pylori (H. pylori) infection remains elusive. Murine bone marrow-derived dendritic cells (BMDCs) were pretreated in the absence or presence of Notch signaling inhibitor DAPT prior to H. pylori stimulation and the levels of Notch components, cytokines and surface markers as well as the differentiation of CD4+ T cells in co-culture were measured using quantitative real-time PCR (qRT-PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Compared with the control, the mRNA expression of all Notch receptors and Notch ligands Dll4 and Jagged1 was up-regulated in H. pylori-stimulated BMDCs. The blockade of Notch signaling by DAPT influenced the production of IL-1ß and IL-10 in H. pylori-pulsed BMDCs, and reduced the expression of Notch1, Notch3, Notch4, Dll1, Dll3 and Jagged2. In addition, DAPT pretreatment decreased the expression of maturation markers CD80, CD83, CD86, and major histocompatibility complex class II (MHC-II) of BMDCs, and further skewed Th17/Treg balance toward Treg. Notch signaling regulates the function and phenotype of DCs, thus mediating the differentiation of CD4+ T cells during H. pylori infection.

Circular RNAs in vascular diseases.

Vascular diseases are the leading cause of morbidity and mortality worldwide and are urgently in need of diagnostic biomarkers and therapeutic strategies. Circular RNAs (circRNAs) represent a unique class of RNAs characterized by a circular loop configuration and have recently been identified to possess a wide variety of biological functions. CircRNAs exhibit exceptional stability, tissue specificity, and are detectable in body fluids, thus holding promise as potential biomarkers. Their encoding function and stable gene expression also position circRNAs as an excellent alternative to gene therapy. Here, we briefly review the biogenesis, degradation, and functions of circRNAs. We summarize circRNAs discovered in major vascular diseases such as atherosclerosis and aneurysms, with a particular focus on molecular mechanisms of circRNAs identified in vascular endothelial cells and smooth muscle cells, in the hope to reveal new directions for mechanism, prognosis and therapeutic targets of vascular diseases.

[Notch signaling regulates macrophages during inflammation and infection: An update].

Macrophage as a crucial component of innate immunity, plays an important role in inflammation and infection immunity. Notch signal pathway is a highly conserved pathway, which regulates cellular fate and participates in numerous pathological processes. At present, a lot of literature has confirmed the role of Notch signaling in regulating the differentiation, activation and metabolism of macrophage during inflammation and infection. This review focuses on how Notch signaling promotes macrophage pro-inflammatory and anti-infective immune function in different inflammatory and infectious diseases. In this regulation, Notch signaling interact with TLR signaling in macrophages or inflammatory-related cytokines including IL-6, IL-12, and TNF-α. Additionally, the potential application and challenges of Notch signaling as a therapeutic target against inflammation and infectious diseases are also discussed.

Mesenchymal Stem Cell-Secreted Exosome Promotes Chemoresistance in Breast Cancer via Enhancing miR-21-5p-Mediated S100A6 Expression.

Emerging evidence has shown the role of mesenchymal stem cell-derived exosome (MSC-exo) in inducing resistance of cancer cells to chemotherapy. However, it remains unclear whether the change of MSC-exo in response to chemotherapy also contributes to chemoresistance. In this study, we investigated the effect of a standard-of-care chemotherapeutic agent, doxorubicin (Dox), on MSC-exo and its contribution to the development of Dox resistance in breast cancer cells (BCs). We found that the exosome secreted by Dox-treated MSCs (Dt-MSC-exo) induced a higher degree of Dox resistance in BCs when compared with non-treated MSC-exo. By analysis of the MSC-exo-induced transcriptome change in BCs, we identified S100A6, a chemoresistant gene, as a top-ranked gene induced by MSC-exo in BCs, which was further enhanced by Dt-MSC-exo. Furthermore, we found that Dox induced the expression of miR-21-5p in MSCs and MSC-exo, which was required for the expression of S100A6 in BCs. Importantly, silencing of miR-21-5p expression in MSCs and MSC-exo abolished the resistance of BCs to Dox, indicating an exosomal miR-21-5p-regulated S100A6 in chemoresistance. Our study thus uncovered a novel mechanistic insight into the role of MSC-secreted exosome in the development of chemoresistance in the tumor microenvironment.

Statistical Scene-Based Non-Uniformity Correction Method with Interframe Registration.

The non-uniform response in infrared focal plane array (IRFPA) detectors inevitably produces corrupted images with a fixed-pattern noise. In this paper, we present a novel and adaptive scene-based non-uniformity correction (NUC) method called Correction method with Statistical scene-based and Interframe Registration (CSIR) , which realizes low delay calculation of correction coefficient for infrared image. This method combines the statistical method and registration method to achieve a better NUC performance. Specifically, CSIR estimates the gain coefficient with statistical method to give registration method an appropriate initial value. This combination method not only reduces the need of interactive pictures, which means lower time delay, but also achieves better performance compared to the statistical method and other single registration methods. To verify this, real non-uniformity infrared image sequences collected by ourselves were used, and the advantage of CSIR was compared thoroughly on frame number (corresponding to delay time) and accuracy. The results show that the proposed method could achieve a significantly fast and reliable fixed-pattern noise reduction with the effective gain and offset.

Protective skin aging effects of cherry blossom extract (Prunus Yedoensis) on oxidative stress and apoptosis in UVB-irradiated HaCaT cells.

Extracts of the cherry blossom plant have been reported to exert various biological effects on human cells. However, no previous investigations have examined the antioxidant and anti-apoptotic effects of these extracts on ultraviolet B (UVB) radiation-induced skin aging. This study explores the underlying mechanisms of the antioxidant and anti-apoptotic effects of cherry blossom extract (CBE) in human keratinocyte (HaCaT) cells. HaCaT cells were treated with CBE at concentrations of 0.5, 1.0, and 2.0% for 24 h and then irradiated with UVB (40 mJ/cm2). CBE effectively and dose-dependently decreased the levels of reactive oxygen species and malondialdehyde, while increasing the activities of superoxide dismutase and glutathione peroxidase. Pretreatment with 1 and 2% CBE attenuated UVB-induced DNA damage by reducing the formation of cyclobutane pyrimidine dimers and 8-hydroxy-20-deoxyguanosine. Furthermore, CBE also prevented UVB-induced apoptosis and significantly downregulated B cell lymphoma 2 (Bcl-2)-associated X, cytochrome-c, and caspase-3 expression, while upregulating Bcl-2 expression. Taken together, these results indicate that CBE protects HaCaT cells from UVB-induced oxidative stress and apoptosis and suggest that CBE could be a potent antioxidant against skin aging.

Sequential Monte Carlo-guided ensemble tracking.

A great deal of robustness is allowed when visual tracking is considered as a classification problem. This paper combines a finite number of weak classifiers in a SMC framework as a strong classifier. The time-varying ensemble parameters (confidence of weak classifiers) are regarded as sequential arriving states and their posterior distribution is estimated in a Bayesian manner. Therefore, both the adaptiveness and stability are kept for the ensemble classification in handling scene changes and target deformation. Moreover, to increase the tracking accuracy, weak classifiers including Support Vector Machine (SVM) and Large Margin Distribution Machine (LDM) are combined as a hybrid strong one, with adaptiveness to the sample scales. Comprehensive experiments are performed on benchmark videos with various tracking challenges, and the proposed method is demonstrated to be better than or comparable to the state-of-the-art trackers.

Optimal Appearance Model for Visual Tracking.

Many studies argue that integrating multiple cues in an adaptive way increases tracking performance. However, what is the definition of adaptiveness and how to realize it remains an open issue. On the premise that the model with optimal discriminative ability is also optimal for tracking the target, this work realizes adaptiveness and robustness through the optimization of multi-cue integration models. Specifically, based on prior knowledge and current observation, a set of discrete samples are generated to approximate the foreground and background distribution. With the goal of optimizing the classification margin, an objective function is defined, and the appearance model is optimized by introducing optimization algorithms. The proposed optimized appearance model framework is embedded into a particle filter for a field test, and it is demonstrated to be robust against various kinds of complex tracking conditions. This model is general and can be easily extended to other parameterized multi-cue models.