Using nanotechnology for improving the immunotherapy efficiency represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to ...fulfill all the requirements in the complicated immune activation processes. Herein, a supramolecular assembled programmable immune activation nanomedicine (PIAN) for sequentially finishing multiple steps after intravenous injection and eliciting robust antitumor immunity in situ is reported. The programmable nanomedicine is constructed by supramolecular assembly via host–guest interactions between poly‐(N‐2‐hydroxyethyl)‐aspartamide‐Pt(IV)/β‐cyclodextrin (PPCD), CpG/polyamidoamine‐thioketal‐adamantane (CpG/PAMAM‐TK‐Ad), and methoxy poly(ethylene glycol)‐thioketal‐adamantane (mPEG‐TK‐Ad). After intravenous injection and accumulation at the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes PIAN dissociation and the release of PPCD (mediating tumor cell killing and antigen release) and CpG/PAMAM (mediating antigen capturing and transferring to the tumor‐draining lymph nodes). This results in antigen‐presenting cell activation, antigen presentation, and robust antitumor immune responses. In combination with anti‐PD‐L1 antibody, the PIAN cures 40% of mice in a colorectal cancer model. This PIAN provides a new framework for designing programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy.
A novel strategy to use programmable nanomedicine for cancer immunotherapy is presented. A programmable immune activation nanomedicine (PIAN) is constructed through supramolecular modular assembly, which automatically transforms after intravenous injection and finishes sequential multiple steps for eliciting robust immune responses in vivo.
Using nanotechnology for cancer vaccine design holds great promise because of the intrinsic feature of nanoparticles in being captured by antigen-presenting cells (APCs). However, there are still ...obstacles in current nanovaccine systems in achieving efficient tumor therapeutic effects, which could partially be attributed to the unsatisfactory vaccine carrier design. Herein, we report a mannan-decorated pathogen-like polymeric nanoparticle as a protein vaccine carrier for eliciting robust anticancer immunity. This nanovaccine was constructed as a core-shell structure with mannan as the shell, polylactic acid-polyethylenimine (PLA-PEI) assembled nanoparticle as the core, and protein antigens and Toll-like receptor 9 (TLR9) agonist CpG absorbed onto the PLA-PEI core via electrostatic interactions. Compared to other hydrophilic materials, mannan decoration could greatly enhance the lymph node draining ability of the nanovaccine and promote the capturing by the CD8+ dendritic cells (DCs) in the lymph node, while PLA-PEI as the inner core could enhance antigen endosome escape thus promoting the antigen cross-presentation. In addition, mannan itself as a TLR4 agonist could synergize with CpG for maximally activating the DCs. Excitingly, we observed in several murine tumor models that using this nanovaccine alone could elicit robust immune response in vivo and result in superior anti-tumor effects with 50% of mice completely cured. This study strongly evidenced that mannan decoration and a rationally designed nanovaccine system could be quite robust in tumor vaccine therapy.
Adenosine-to-inosine (A-to-I) RNA editing regulates miRNA biogenesis and function. To date, fewer than 160 miRNA editing sites have been identified. Here, we present a quantitative atlas of miRNA ...A-to-I editing through the profiling of 201 pri-miRNA samples and 4694 mature miRNA samples in human, mouse, and
We identified 4162 sites present in ∼80% of the pri-miRNAs and 574 sites in mature miRNAs. miRNA editing is prevalent in many tissue types in human. However, high-level editing is mostly found in neuronal tissues in mouse and
Interestingly, the edited miRNAs in neuronal and non-neuronal tissues in human gain two distinct sets of new targets, which are significantly associated with cognitive and organ developmental functions, respectively. Furthermore, we reveal that miRNA editing profoundly affects asymmetric strand selection. Altogether, these data provide insight into the impact of RNA editing on miRNA biology and suggest that miRNA editing has recently gained non-neuronal functions in human.
Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death (ICD), which provides a promising alternative way for cancer ...immunotherapy. However, the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone. Herein, we proposed a trinity immune enhancing nanoparticles (TIENs) for boosting antitumor immune responses of chemo agents. The TIENs was constructed with Food and Drug Administration (FDA) approved polylactic acid (PLA), canonical proton-sponging cationic polymer polyethyleneimine (PEI), and Toll-like receptor 9 (TLR9) agonist cytosine phosphate guanine oligodeoxynucleotide (CpG-ODN). In
in vitro
studies, the TIENs was proved to (1) promote antigen capturing, (2) antigen-presenting cells (APCs) activation, and (3) antigen cross-presentation. In
in vivo
studies, intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models, respectively. Furthermore, after decoration with a detachable shielding, the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection. The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.
Functional materials and nanostructures have been widely used for enhancing the therapeutic potency and safety of current cancer immunotherapy. While profound nanostructures have been developed to ...participate in the development of cancer immunotherapy, the construction of intricate nanostructures with easy fabrication and functionalization properties to satisfy the diversified requirements in cancer immunotherapy are highly required. Hierarchical self-assembly using supramolecular interactions to manufacture organized architectures at multiple length scales represents an interesting and promising avenue for sophisticated nanostructure construction. In this mini-review, we will outline the recent progress made in the development of supramolecular self-assembled nanostructures for cancer immunotherapy, with special focus on the supramolecular interactions including supramolecular peptide assembly, supramolecular DNA assembly, lipid hydrophobic assembly, host-guest assembly, and biomolecular recognition assembly.
Adenosine-to-inosine (A-to-I) RNA editing plays important roles in diversifying the transcriptome and preventing MDA5 sensing of endogenous dsRNA as nonself. To date, few studies have investigated ...the population genomic signatures of A-to-I editing due to the lack of editing sites overlapping with SNPs.
In this study, we applied a pipeline to robustly identify SNP editing sites from population transcriptomic data and combined functional genomics, GWAS, and population genomics approaches to study the function and evolution of A-to-I editing. We find that the G allele, which is equivalent to edited I, is overrepresented in editing SNPs. Functionally, A/G editing SNPs are highly enriched in GWAS signals of autoimmune and immune-related diseases. Evolutionarily, derived allele frequency distributions of A/G editing SNPs for both A and G alleles as the ancestral alleles are skewed toward intermediate frequency alleles relative to neutral SNPs, a hallmark of balancing selection, suggesting that both A and G alleles are functionally important. The signal of balancing selection is confirmed by a number of additional population genomic analyses.
We uncovered a hidden layer of A-to-I RNA editing SNP loci as a common target of balancing selection, and we propose that the maintenance of such editing SNP variations may be at least partially due to constraints on the resolution of the balance between immune activity and self-tolerance.
In the process of deep cooling and liquefaction of low-concentration (concentration <30 %) oxygen-bearing coal bed methan, there is a risk of explosion because the methane concentration in the ...ultra-low temperature environment is within the explosion limit. It is of great guiding significance to study the occurrence mechanism and accident-causing process of such accidents. Firstly, the experimental system of low-temperature methane explosion characteristics is constructed, and it is found that when ignition energy exceeds a certain range, the process of deep cooling and liquefaction of low-concentration oxygen-bearing coal bed methane will cause explosion. Then, the occurrence of the gas explosion accident in low-temperature environment is briefly described, and the causes of the accident are analyzed preliminarily, and the dynamic characteristics of methane explosion propagation under ultra-low temperature conditions are studied by Fluent numerical simulation, and it is obtained that ultra-low temperature conditions have a promotion effect on the explosion pressure. Finally, based on the analysis of catastrophe theory, the traditional accident causation cusp catastrophe model is improved, and the “experimental safety state" and the “internal causes of explosion-external cause of explosion" are taken as the state variables and control variables respectively, and the explosion risk analysis model for deep cooling and liquefaction of low-concentration oxygen-bearing coal bed methane based on the cusp catastrophe theory is constructed. Based on the accident case, the process of accidents caused by risk factors is described, and the evolution mechanism of such disasters and accidents is clarified. Finally, the hazard state evaluation method for liquefaction explosion of low-concentration oxygen-bearing coal bed methane is proposed based on the catastrophe theory, and this evaluation model is applied to evaluate and analyze the hazard state of accident case. The evaluation results are consistent with the actual hazard state, confirming the rationality and feasibility of this evaluation method. In this paper, the key hazards of such accidents are found out in detail and provides support for safety decision-making in the deep cooling and liquefaction process of low-concentration oxygen-bearing coal bed methane.
Passive explosion-isolation facilities in underground coal mines, such as explosion-proof water troughs and bags, face challenges aligned with current trends in intelligent and unmanned technologies, ...due to restricted applicability and structural features. Grounded in the propagation laws and disaster mechanisms of gas explosions, the device in this paper enables accurate identification of explosion flames and pressure information. Utilizing a high-speed processor for rapid logical processing enables judgments within 1 ms. Graded activation of the operating mechanism is enabled by the device. The tunnel flame-proof device’s flame-extinguishing agent has a continuous action time of 6075 ms. Experiments on the active flame-proof effect of a 100 m3 gas explosion were conducted using a cross-sectional 7.2 m2 large-tunnel test system. With a dosage of 5.6 kg/m2, the powder flame-extinguishing agent completely extinguished the explosion flame within a 20 m range behind the explosion isolator. Numerical calculations unveiled the gas-phase chemical suppression mechanism of the powder flame-extinguishing agent NH4H2PO4 in suppressing methane explosions. Building upon these findings, application technology for active flame-proofing was developed, offering technical support for intelligent prevention and control of gas explosions in underground coal mines.
For women of childbearing age, the biggest problem caused by polycystic ovary syndrome (PCOS) is infertility, which is mainly caused by anovulation, abnormal follicular development, proliferation of ...small antral follicles, and cystic follicles. The mechanism underlying its occurrence is not clear. The abnormal proliferation and development of follicles in PCOS patients is a complex process, which is affected by many factors. The objective of this study was to investigate the relationship between the Hippo pathway and follicular development in PCOS, and to further explore this relationship by using the YAP inhibitor verteporfin (VP).
30 3-week-old BALB/C female rats were randomly divided into control group (n = 10), DHEA group (n = 10) and DHEA + VP group (n = 10). The morphology of ovary and the degree of follicular development were observed by HE staining, and the expression and location of AMH in ovarian follicles were observed by immunofluorescence. The ovarian reserve function index AMH, cell proliferation index PCNA and the ratio of Hippo pathway related proteins MST, LATS, YAP, P-YAP and P-YAP/YAP were detected by Western blot.
After dividing 30 3-week-old female mice into control, dehydroepiandrosterone (DHEA; model of PCOS), and DHEA + VP groups, we found that the number of small follicles increased in the DHEA group compared to the control group. Additionally, in the DHEA group compared to the control group, anti-müllerian hormone (AMH; ovarian reserve index) increased, proliferating cell nuclear antigen (PCNA; cell proliferation index) decreased, and upstream (MST and LATS) and downstream (YAP and p-YAP) proteins in the Hippo pathway increased, though the p-YAP/YAP ratio decreased. VP ameliorated the increases in AMH, MST, LATS, YAP and p-YAP, but did not ameliorate the decrease in the p-YAP/YAP ratio.
This study indicates that the increased small follicles in the ovaries and changes in ovarian reserve and cell proliferation may be closely related to Hippo pathway activation. This suggests that the Hippo pathway may be an important pathway affecting the proliferation and development of follicles and the occurrence of PCOS.
During the process of coal spontaneous combustion (CSC), a plethora of combustible gases alongside inert gases, such as CO2, are copiously generated. However, prior investigations have regrettably ...overlooked the pivotal influence of inert gas production on the propensity for methane explosions during CSC. To investigate the impact of the flue gas environment generated by CSC, containing both combustible and inert gases, on the risk of methane explosion, a high-temperature programmed heating test system for CSC was employed to analyze the generation pattern of flue gas. It was found that CO, CO2, and CH4 were continuously generated in large quantities during the process of CSC, which are the main components of CSC flue gas. The effect of the concentration and component ratio (CCO2/CCO) of the flue gas on the methane explosion limit was tested. It was found that the CSC flue gas led to a decrease in the methane explosion limit, and that the explosion limit range was facilitated at 0 < CCO2/CCO < 0.543 and suppressed at CCO2/CCO > 0.543. As the temperature of CSC increases, the risk of methane explosion is initially suppressed. When the coal temperature exceeds 330~410 °C, the explosion risk rapidly expands.
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