Activated Natural Killer Cells-Dependent Dendritic Cells Recruitment and Maturation by Responsive Nanogels for Targeting Pancreatic Cancer Immunotherapy.

Although enormous success has been obtained for dendritic cells (DCs)-mediated antigen-specific T cells anticancer immunotherapy in the clinic, it still faces major challenging problems: insufficient DCs in tumor tissue and low response rate for tumor cells lacking antigen expression, especially in low immunogenic tumors such as pancreatic cancer. Here, these challenges are tackled through tumor microenvironment responsive nanogels with prominent tumor-targeting capability by Panc02 cell membranes coating and inhibition of tumor-derived prostaglandin E2 (PGE2), aimed at improving natural killer (NK) cells activation and inducing activated NK cells-dependent DCs recruitment. The engineered nanogels can on-demand release acetaminophen to inhibit PGE2 secretion, thus promoting the activity of NK cells for non-antigen-specific tumor elimination. Furthermore, activated NK cells can secrete chemokines as CC motif chemokine ligand 5 and X-C motif chemokine ligand 1 to recruit immature DCs, and then promote DCs maturation and induce antigen-dependent CD8+ T cells proliferation for enhancing antigen-specific immunotherapy. Notably, these responsive nanogels show excellent therapeutic effect on Panc02 pancreatic tumor growth and postsurgical recurrence, especially combination of the programmed cell death-ligand 1 checkpoint-blockade immunotherapy. Therefore, this study provides a simple strategy for enhancing low immunogenic tumors immunotherapy through an antigen-independent way and antigen-dependent way synergetically.

Discoidin domain receptor 1 promotes lung adenocarcinoma migration via the AKT/snail signaling axis.

BACKGROUND: Discoidin domain receptor 1 (DDR1), a member of receptor tyrosine kinase, has been implicated in tumor progression. However, the function and underlying mechanism of DDR1 in lung adenocarcinoma (LUAD) progression is unclear. Thus, we explored the molecular regulatory mechanism of DDR1 in the migration of LUAD. METHODS: Transwell assays, wound healing assays and xenograft tumor assays were performed to study the function of DDR1 in the progression of LUAD. Immunoblotting and quantitative real-time polymerase chain reaction (RT-qPCR) were used to detect the expression levels of genes. Co-immunoprecipitation (co-IP) assays were performed to detect the interaction between DDR1 and AKT. Immunofluorescence and immunohistochemistry assays were used to determine the expression level of proteins in cells and tissues, respectively. RESULTS: DDR1 expression was significantly higher in LUAD tissues than in normal lung tissues, and the level of DDR1 was inversely correlated with prognosis in patients. We found that DDR1 promoted the migration and invasion of LUAD cells in vitro. Furthermore, ectopic expression of DDR1 in LUAD cells altered EMT-related markers expression. Importantly, the DDR1 protein interacted with AKT and phosphorylated AKT. The AKT inhibitor MK2206 interrupted Snail upregulation in DDR1-overexpressing LUAD cells. Finally, our study revealed that depletion of DDR1 attenuated LUAD cell migration in a tumor xenograft mouse model. CONCLUSION: Our findings uncovered that a high abundance of DDR1 increased the migration and invasion capability of LUAD cells via the AKT/Snail signaling axis and indicated that DDR1 could be a potential target for treating LUAD.

Truncating PICK1 Variant Identified in Azoospermia Affected Mitochondrial Dysfunction in Knockout Mice.

OBJECTIVE: The protein interacting with C kinase 1 (PICK1) plays a critical role in vesicle trafficking, and its deficiency in sperm cells results in abnormal vesicle trafficking from Golgi to acrosome, which eventually disrupts acrosome formation and leads to male infertility. METHODS: An azoospermia sample was filtered, and the laboratory detection and clinical phenotype indicated typical azoospermia in the patient. We sequenced all of the exons in the PICK1 gene and found that there was a novel homozygous variant in the PICK1 gene, c.364delA (p.Lys122SerfsX8), and this protein structure truncating variant seriously affected the biological function. Then we constructed a PICK1 knockout mouse model using clustered regularly interspaced short palindromic repeat cutting technology (CRISPRc). RESULTS: The sperm from PICK1 knockout mice showed acrosome and nucleus abnormalities, as well as dysfunctional mitochondrial sheath formation. Both the total sperm and motility sperm counts were decreased in the PICK1 knockout mice compared to wild-type mice. Moreover, the mitochondrial dysfunction was verified in the mice. These defects in the male PICK1 knockout mice may have eventually led to complete infertility. CONCLUSION: The c.364delA novel variant in the PICK1 gene associated with clinical infertility, and pathogenic variants in the PICK1 may cause azoospermia or asthenospermia by impairing mitochondrial function in both mice and humans.

Biomimetic microcavity interfaces for a label-free capture of pathogens in the fluid bloodstream by vortical crossflow filtration.

Bacterial sepsis is a lethal disease triggered by microbial pathogens. The blood pathogen load is a major contributor to both disease severity and mortality in patients with sepsis blood. Therefore, it is crucial to reduce the load of pathogens, in particular the drug-resistant pathogens. In this work, inspired by the crossflow filtration mechanism in suspension-feeding fish, we developed a biomimetic microcavity interface to mimic a porous gill-raker surface as a blood-cleansing dialyzer for sepsis therapy, which can rapidly, safely and efficiently clear bacteria from the fluidic blood. The microcavity interface consists of microcavity arrays, the innerface of which contains nanowire forests. By precisely controlling the pore size of the microcavity and directing the axial travel of the fluid, the bacteria can be isolated from the whole blood without disturbing any blood components or blocking the blood cell transportation. In addition, the three-dimensional nanowire forests assist in the formation of vortices with reduced blood flow velocity and increased resistance to bacterial deposition in situ. Functional modification is not required to recognize the bacteria specifically in our designed dialyzer. Moreover, the microcavity interface clears over 95% bacteria from a fluid blood sample without inducing protein adsorption or complement and platelet activation when contacting the fluid blood. The study supports this biomimetic microcavity interface to be a promising extracorporeal blood-cleansing device in clinical settings.

Platelet-Tumor Cell Hybrid Membrane-Camouflaged Nanoparticles for Enhancing Therapy Efficacy in Glioma.

PURPOSE: Cell membrane-camouflaged nanoparticles (NPs) are drawing increasing attention because their surfaces acquire some characteristics of the cell membranes, making them a unique class of biomimetic materials for diverse applications. Modification of cell membrane or combination of different types of membranes can enhance their functionality. METHODS: We prepared platelet and tumor cell membrane camouflaged ß-mangostin-loaded NPs, which were synthesized with platelet-C6 hybrid biomimetic coating, poly(lactic-co-glycolic acid), and ß-mangostin (ß-PCNPs). Then, we evaluated their targeting ability and anticancer activity against glioma in vitro and in vivo. RESULTS: Biomimetic coating enhanced active drug targeting and immune escape properties of nanocarrier in C6 and THP-1 cells, respectively, which improved their cytotoxicity. ß-PCNPs were characterized to study the inherent properties of both source cells. Compared with bare ß-NPs, ß-PCNPs exhibited high tumor-targeting capability and induced apoptosis of C6 cells in vitro. Similarly, intravenous administration of drug through ß-PCNPs resulted in enhanced tumor-targeting and exhibited excellent rate of inhibition of glioma tumor growth in mice. Moreover, the blood circulation time of drug in mice in the ß-PCNP group was markedly prolonged and these mice exhibited better outcome than those in the ß-NP group. CONCLUSION: These results provide a new strategy of utilizing PCNPs as carriers for drug delivery, which improves the targeting efficiency and therapeutic efficacy of chemotherapeutic agents for glioma therapy.

Cancer cell membrane-coated nanogels as a redox/pH dual-responsive drug carrier for tumor-targeted therapy.

Nanocarriers have shown great advantages in increasing the efficiency of drug delivery and reducing drug side effects. However, their lack of targeting and on-demand drug release abilities will seriously limit their clinical application. Herein, we report tumor cell membrane coated nanogels (NGs) with redox/pH dual-responsive behavior for enhanced tumor chemotherapy. The cell membrane coating improves the tumor targeting efficiency, and stimuli-responsive drug release enhances the therapeutic effects. These NGs are well dispersed in PBS with an average size of 109.1 ± 5.2 nm and a narrow polydispersity index of 0.12. Both in vitro and in vivo studies indicate that these NGs can responsively release the therapeutic drug DOX under acidic conditions or high GSH concentrations and effectively inhibit tumor growth. Based on the results, this nanogel shows promise as a platform for tumor-targeted chemotherapy for future clinical translation.

Application of multi-model switching predictive functional control on the temperature system of an electric heating furnace.

A method of multi-model switching based predictive functional control is proposed and applied to the temperature control system of an electric heating furnace. The control strategies provide the effective and independent control modes of the electric heating furnace temperature in order to obtain improved control performance. The method depends on conventional implementation of the multi-model switching state, which requires some endeavors to tune the switching model in the model predictive control and allows a reduction of the calculation compared with the weighted multiple model algorithms. In order to test the advantage of the proposed method, experimental equipment is set up and experiments are done on the temperature process of a heating furnace, which verify the validity and effectiveness of the proposed algorithm.