Simultaneous Activation of Pyroptosis and cGAS-STING Pathway with Epigenetic/ Photodynamic Nanotheranostic for Enhanced Tumor Photoimmunotherapy.

Promoting innate immunity through pyroptosis induction or the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway activation has emerged as a potent approach to counteract the immunosuppressive tumor microenvironment and elicit systemic antitumor immunity. However, current pyroptosis inducers and STING agonists often suffer from limitations including instability, unpredictable side effects, or inadequate intracellular expression of gasdermin and STING. Here, a tumor-specific nanotheranostic platform that combines photodynamic therapy (PDT) with epigenetic therapy to simultaneously activate pyroptosis and the cGAS-STING pathway in a light-controlled manner is constructed. This approach involves the development of oxidation-sensitive nanoparticles (NP1) loaded with the photosensitizer TBE, along with decitabine nanomicelles (NP2). NP2 enables the restoration of STING and gasdermin E (GSDME) expression, while NP1-mediated PDT facilitates the release of DNA fragments from damaged mitochondria to potentiate the cGAS-STING pathway, and promotes the activation of caspase-3 to cleave the upregulated GSDME into pore-forming GSDME-N terminal. Subsequently, the released inflammatory cytokines facilitate the maturation of antigen-presentation cells, triggering T cell-mediated antitumor immunity. Overall, this study presents an elaborate strategy for simultaneous photoactivation of pyroptosis and the cGAS-STING pathway, enabling targeted photoimmunotherapy in immunotolerant tumors. This innovative approach holds significant promise in overcoming the limitations associated with existing therapeutic modalities and represents a valuable avenue for future clinical applications.

Tailoring Electronic Structure to Achieve Maximum Utilization of Transition Metal Redox for High-Entropy Na Layered Oxide Cathodes.

Charge compensation from cationic and anionic redox couples accompanying Na+ (de)intercalation in layered oxide cathodes contributes to high specific capacity. However, the engagement level of different redox couples remains unclear and their relationship with Na+ content is less studied. Here we discover that it is possible to take full advantage of the high-voltage transition metal (TM) redox reaction through low-valence cation substitution to tailor the electronic structure, which involves an increased ratio of Na+ content to available charge transfer number of TMs. Taking NaxCu0.11Ni0.11Fe0.3Mn0.48O2 as the example, the Li+ substitution increases the ratio to facilitate the high-voltage TM redox activity, and further F-ion substitution decreases the covalency of the TM-O bond to relieve structural changes. As a consequence, the final high-entropy Na0.95Li0.07Cu0.11Ni0.11Fe0.3Mn0.41O1.97F0.03 cathode demonstrates ∼29% capacity increase contributed by the high-voltage TMs and exhibits excellent long-term cycling stability due to the improved structural reversibility. This work provides a paradigm for the design of high-energy-density electrodes by simultaneous electronic and crystal structure modulation.

Conversion of Surface Residual Alkali to Solid Electrolyte to Enable Na-Ion Full Cells with Robust Interfaces.

The deposition of volatilized Na+ on the surface of the cathode during sintering results in the formation of surface residual alkali (NaOH/Na2 CO3 NaHCO3 ) in layered cathode materials, leading to serious interfacial reactions and performance degradation. This phenomenon is particularly evident in O3-NaNi0.4 Cu0.1 Mn0.4 Ti0.1 O2 (NCMT). In this study, a strategy is proposed to transform waste into treasure by converting residual alkali into a solid electrolyte. Mg(CH3 COO)2 and H3 PO4 are reacted with surface residual alkali to generate the solid electrolyte NaMgPO4 on the surface of NCMT, which can be labeled as NaMgPO4@NaNi0.4 Cu0.1 Mn0.4 Ti0.1 O2 -X (NMP@NCMT-X, where X indicates the different amounts of Mg2+ and PO4 3- ). NaMgPO4 acts as a special ionic conductivity channel on the surface to improve the kinetics of the electrode reactions, remarkably improving the rate capability of the modified cathode at a high current density in the half-cell. Additionally, NMP@NCMT-2 enables a reversible phase transition from the P3 to OP2 phase in the charge-discharge process above 4.2 V and achieves a high specific capacity of 157.3 mAh g-1 and outstanding capacity retention in the full cell. The strategy can effectively and reliably stabilize the interface and improve the performance of layered cathodes for Na-ion batteries (NIBs).

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer.

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

Restoration of the Immunogenicity of Tumor Cells for Enhanced Cancer Therapy via Nanoparticle-Mediated Copper Chaperone Inhibition.

Recent progress in studying copper-dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper-dependent disease vulnerabilities and pharmacological manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed reactive oxygen species (ROS)-sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1-ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicits intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle-mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.

Using High-Entropy Configuration Strategy to Design Na-Ion Layered Oxide Cathodes with Superior Electrochemical Performance and Thermal Stability.

Na-ion layered oxide cathodes (NaxTMO2, TM = transition metal ion(s)), as an analogue of lithium layered oxide cathodes (such as LiCoO2, LiNixCoyMn1-x-yO2), have received growing attention with the development of Na-ion batteries. However, due to the larger Na+ radius and stronger Na+-Na+ electrostatic repulsion in NaO2 slabs, some undesired phase transitions are observed in NaxTMO2. Herein, we report a high-entropy configuration strategy for NaxTMO2 cathode materials, in which multicomponent TMO2 slabs with enlarged interlayer spacing help strengthen the whole skeleton structure of layered oxides through mitigating Jahn-Teller distortion, Na+/vacancy ordering, and lattice parameter changes. The strengthened skeleton structure with a modulated particle morphology dramatically improves the Na+ transport kinetics and suppresses intragranular fatigue cracks and TM dissolution, thus leading to highly improved performances. Furthermore, the elaborate high-entropy TMO2 slabs enhance the TM-O bonding energy to restrain oxygen release and thermal runaway, benefiting for the improvement of thermal safety.

O3-NaFe(1/3-x)Ni1/3Mn1/3AlxO2 Cathodes with Improved Air Stability for Na-Ion Batteries.

Na-ion batteries (NIBs) have been considered as potential candidates for large-scale energy storage, where O3-type Na-based layered oxide cathodes have attracted great attention due to their high capacity and low cost. However, O3-NaxTMO2 materials still suffer from insufficient air stability, which could lead to deteriorative electrochemical properties and thus hinder their practical application. In this work, a series of Al-doped O3-NaFe(1/3-x)Ni1/3Mn1/3AlxO2 cathodes prepared by a co-precipitation method were investigated to enhance their electrochemical performance and air stability through stabilizing their structural and interface chemical properties. The Al-doped O3-NaFe(1/3-0.01)Ni1/3Mn1/3Al0.01O2 (NFNMA0.01) cathode delivers a comparable capacity of 138 mAh g-1 and keeps a capacity retention of 85.88% after 50 cycles at 0.2 C, while the undoped O3-NaFe1/3Ni1/3Mn1/3O2 (NFNM) can only keep a capacity retention of 71.02%, although with an initial capacity of 141 mAh g-1 at 0.2 C. For the air stability, the capacity decay rates are 58.87 and 5.07% for the undoped NFNM and Al-doped NFNMA0.01 after the air exposure for 30 days, respectively. The greatly decaying electrochemical performance could be due to the formation of carbonates during air exposure, which can be efficiently suppressed by Al doping. The doped Al3+ has been confirmed to be inserted into the NFNM crystal lattice, inducing the reduced values of lattice parameters a and c due to the smaller ionic radius of Al3+ (53.5 pm) vs Fe3+ (55.0 pm). This study demonstrates that Al doping plays an important role in the air stability and cycling stability for layered cathode materials, which offers an efficient strategy to optimize the material design for their practical application in NIBs.

Rational design of layered oxide materials for sodium-ion batteries.

Sodium-ion batteries have captured widespread attention for grid-scale energy storage owing to the natural abundance of sodium. The performance of such batteries is limited by available electrode materials, especially for sodium-ion layered oxides, motivating the exploration of high compositional diversity. How the composition determines the structural chemistry is decisive for the electrochemical performance but very challenging to predict, especially for complex compositions. We introduce the "cationic potential" that captures the key interactions of layered materials and makes it possible to predict the stacking structures. This is demonstrated through the rational design and preparation of layered electrode materials with improved performance. As the stacking structure determines the functional properties, this methodology offers a solution toward the design of alkali metal layered oxides.

High-Entropy Layered Oxide Cathodes for Sodium-Ion Batteries.

Material innovation on high-performance Na-ion cathodes and the corresponding understanding of structural chemistry still remain a challenge. Herein, we report a new concept of high-entropy strategy to design layered oxide cathodes for Na-ion batteries. An example of layered O3-type NaNi0.12 Cu0.12 Mg0.12 Fe0.15 Co0.15 Mn0.1 Ti0.1 Sn0.1 Sb0.04 O2 has been demonstrated, which exhibits the longer cycling stability (ca. 83 % of capacity retention after 500 cycles) and the outstanding rate capability (ca. 80 % of capacity retention at the rate of 5.0 C). A highly reversible phase-transition behavior between O3 and P3 structures occurs during the charge-discharge process, and importantly, this behavior is delayed with more than 60 % of the total capacity being stored in O3-type region. Possible mechanism can be attributed to the multiple transition-metal components in this high-entropy material which can accommodate the changes of local interactions during Na+ (de)intercalation. This strategy opens new insights into the development of advanced cathode materials.

Slope-Dominated Carbon Anode with High Specific Capacity and Superior Rate Capability for High Safety Na-Ion Batteries.

The comprehensive performance of carbon anodes for Na-ion batteries (NIBs) is largely restricted by their inferior rate capability and safety issues. Herein, a slope-dominated carbon anode is achieved at a low temperature of 800 °C, which delivers a high reversible capacity of 263 mA h g-1 at 0.15C with an impressive initial Coulombic efficiency (ICE) of 80 %. When paired with the NaNi1/3 Fe1/3 Mn1/3 O2 cathode, the reversible capacity at 6C is still 75 % of that at 0.15C, and 73 % of the capacity is retained after 1000 cycles at 3C. The enhanced Na storage performance could be attributed to the unique microstructure with randomly oriented short carbon layers and the relatively higher defect concentration. Given its robustness, such a low-temperature carbonization strategy could also be applicable to other precursors and provide a new opportunity to design slope-dominated carbon anodes for high safety, low-cost NIBs with excellent ICE and superior rate capability.

Surface Heterostructure Induced by PrPO4 Modification in Li1.2[Mn0.54Ni0.13Co0.13]O2 Cathode Material for High-Performance Lithium-Ion Batteries with Mitigating Voltage Decay.

Lithium-rich layered oxides (LLOs) have been attractive cathode materials for lithium-ion batteries because of their high reversible capacity. However, they suffer from low initial Coulombic efficiency and capacity/voltage decay upon cycling. Herein, facile surface modification of Li1.2Mn0.54Ni0.13Co0.13O2 cathode material is designed to overcome these defects by the protective effect of a surface heterostructure composed of an induced spinel layer and a PrPO4 modification layer. As anticipated, a sample modified with 3 wt % PrPO4 (PrP3) shows an enhanced initial Coulombic efficiency of 90% compared to 81.8% for the pristine one, more excellent cycling stability with a capacity retention of 89.3% after 100 cycles compared to only 71.7% for the pristine one, and less average discharge voltage fading from 0.6353 to 0.2881 V. These results can be attributed to the fact that the modification nanolayers have moved amounts of oxygen and lithium from the lattice in the bulk crystal structure, leading to a chemical activation of the Li2MnO3 component previously and forming a spinel interphase with a 3D fast Li+ diffusion channel and stable structure. Moreover, the elaborate surface heterostructure on a lithium-rich cathode material can effectively curb the undesired side reactions with the electrolyte and may also extend to other layered oxides to improve their cycling stability at high voltage.

A preliminary study on the activation and antigen presentation of hepatitis B virus core protein virus-like particle-pulsed bone marrow-derived dendritic cells.

Hepatitis B virus core protein virus-like particles (HBc-VLPs) act as a strong immunogen and are suitable for uptake by dendritic cells (DCs), in which they directly promote DC maturation and migration. To illustrate the utility of global proteomic analysis techniques in elucidating the molecular events that are altered in HBc-VLP-pulsed bone marrow-derived DCs (BMDCs) and to gain a better understanding of the molecular mechanisms of capture and processing of HBc-VLP-pulsed BMDCs, an antigen (Ag) delivery system based on HBc-VLP-pulsed BMDCs was developed. Two-dimensional electrophoresis (2-DE) and tandem mass spectrometry (MS/MS) analyses were utilized to analyze the differential protein expression patterns between HBc-VLP-pulsed and untreated BMDCs. Protein spots with significantly altered expression levels were detected, identified and validated. The results showed that exogenous HBc-VLPs were phagocytosed efficiently by BMDCs and enhanced the efficacy of BMDC maturation and Ag presentation, VLPs also induced high levels of Ag-specific CD8(+) T cells that displayed high cytotoxic T lymphocyte (CTL) activity in vivo. Several differentially expressed proteins, including growth factor receptor bound protein 2 (Grb2) and annexin A2 (AnxA2), were detected by proteomic analysis, identified by mass spectrometry and validated by western blot.

Production of biologically active recombinant annexin B1 with enhanced stability via a tagging system.

Annexin B1 is a novel Ca(2+)-dependent phospholipid-binding protein from metacestodes of Taenia solium and has been shown to have many potential biomedical applications. Although annexin B1 has been produced successfully in Escherichia coli, the purified protein has poor stability at room temperature, which has hindered our attempts to further study its structure-function relationship. To increase the stability of the protein, the construction and purification procedures were examined and changed to hopefully increase its effectiveness. In this study, we describe a new recombinant annexin B1 expressed with a hexahistidine tag fused to its N-terminal end, which was purified to homogeneity in two steps using immobilized metal affinity followed by size exclusion chromatography. The final yield was approximately 23 mg/L of bacterial culture. Isoelectric focusing and mass spectrometry analysis showed that the protein purified by this method was quite stable at room temperature, even greater than 3 days later. A series of functional tests indicated that the recombinant protein had high anticoagulant activity, and fluorescence-labeled annexin B1 could bind to the outer membranes of apoptotic mammalian cells and efficiently detect them in the early stages of apoptosis.

Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis.

We here report that miR-17-92 cluster is a novel target for p53-mediated transcriptional repression under hypoxia. We found the expression levels of miR-17-92 cluster were reduced in hypoxia-treated cells containing wild-type p53, but were unchanged in hypoxia-treated p53-deficient cells. The repression of miR-17-92 cluster under hypoxia is independent of c-Myc. Luciferase reporter assays mapped the region responding to p53-mediated repression to a p53-binding site in the proximal region of the miR-17-92 promoter. Chromatin immunoprecipitation (ChIP), Re-ChIP and gel retardation assays revealed that the binding sites for p53- and the TATA-binding protein (TBP) overlap within the miR-17-92 promoter; these proteins were found to compete for binding. Finally, we show that pri-miR-17-92 expression correlated well with p53 status in colorectal carcinomas. Over-express miR-17-92 cluster markedly inhibits hypoxia-induced apoptosis, whereas blocked miR-17-5p and miR-20a sensitize the cells to hypoxia-induced apoptosis. These data indicated that p53-mediated repression of miR-17-92 expression likely has an important function in hypoxia-induced apoptosis, and thus further our understanding of the tumour suppressive function of p53.

Screen of multifunctional monoclonal antibodies against hepatitis B core virus-like particles.

HBc-VLP can be used in an epitope presentation system to carry foreign epitopes and mimic live virus in order to study viral particle uptake, virion-mediated activation and antigen presentation by dendritic cells. In this study, a multifunctional mAb was produced using a novel research strategy. A truncated HBc-VLP bone vector with a special conformation was used as an immunogen and the target hybridoma cell lines were screened by a series of tests; including ELISA, Western blot, and cellular immunofluorescence based on the epitope presentation system. The screened monoclonal antibody was used to identify the HBc-VLP vector, a fusion HBc-VLP vaccine, and intracellular HBV capsids. The new strategy facilitated acquisition of the desired mAbs and will serve as a reference for other VLP-related research.

Expression of annexin a5 is associated with higher tumor stage and poor prognosis in colorectal adenocarcinomas.

GOALS: To gain an insight into the putative role of annexin A5 (ANXA5) in the tumor stage and its clinical outcome. BACKGROUND: ANXA5 is a calcium-binding protein, which has been implicated in the carcinogenesis of several carcinomas. However, the role of ANXA5 in colorectal cancer (CRC) is unclear. STUDY: We investigated the expression of ANXA5 in colorectal adenocarcinoma. This study included 207 consecutive patients with sporadic CRC. Paired colorectal tissue samples and corresponding nonmalignant tissues were obtained by surgical resection. ANXA5 mRNA and protein expression in each tissue were assessed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical staining. Data were statistically correlated with pathologic parameters and clinical outcome. RESULTS: Real-time reverse transcriptase polymerase chain reaction showed that there is an up-regulation in the mRNA level of ANXA5 in tumors (P<0.001). Immunohistochemical study revealed that high ANXA5 expression was present in 40.58% (84 of 207) of tumors. Univariate analysis showed increased ANXA5 expression correlated with pT stage (P=0.008), liver metastasis (P=0.024), pathologic tumor-node-metastasis stage (P=0.015), Dukes' stage (P=0.017), recurrence (P=0.024), cancer-related death (P=0.028), recurrence-free probability (P=0.003), and overall survival (P=0.005). Multivariate analysis showed that ANXA5 expression and liver metastasis significantly correlated with recurrence-free probability (P=0.039 and P=0.048, respectively) and overall survival (P=0.012 and P=0.021, respectively) independent of pT stage and pN stage. CONCLUSIONS: From these findings ANXA5 expression seems to be related to the tumor stage and clinical outcome of CRC. Thus ANXA5 could serve as a prognostic marker for tumor progression.

Multiepitope peptide-loaded virus-like particles as a vaccine against hepatitis B virus-related hepatocellular carcinoma.

UNLABELLED: To develop a hepatitis B virus (HBV) therapeutic vaccine that can induce a broad but specific immune response and significant antitumor effects both in vivo and in vitro, we inserted HBV X protein (HBx)-derived epitopes HBx(52-60), HBx(92-100), and HBx(115-123); a novel subdominant cytolytic T lymphocyte (CTL) epitope HBx(140-148); and the universal T helper epitope pan human leukocyte antigen DR-binding epitope into HBV core protein to form multiepitope peptide-loaded virus-like particles (VLPs). CTL responses against epitope-loaded VLPs were elicited by priming with VLP-pulsed dendritic cells in both HLA-A*0201 transgenic (Tg) mice and peripheral blood lymphocytes from HLA-A2(+)/HBx(+) HBV-infected hepatocellular carcinoma (HCC) patients. The multiepitope peptide-loaded VLPs demonstrated significantly higher immunogenicity in Tg mice than any single responsive epitope. Significant antitumor effects were demonstrated both with primary cultured autologous HCC cells in vitro and tumor-bearing Tg mice in vivo in an HLA-A2-restricted and epitope-specific fashion. CONCLUSION: The significant antitumor effects both in vivo and in vitro demonstrate the potential of multiepitope peptide-loaded VLPs as a vaccine against HCC.

Calcium-dependent proapoptotic effect of Taenia solium metacestodes annexin B1 on human eosinophils: a novel strategy to prevent host immune response.

Annexins are a family of calcium-dependent phospholipid-binding proteins that have been proposed to be involved in a wide range of important biological processes. At present, only a few annexins have been identified in parasites, and the physiological roles of these annexins are obscure. Earlier, we cloned a novel annexin (annexin B1) from Taenia solium metacestodes and found that annexin B1 was detectable in the surrounding host-derived layer with granulomaous infiltration. The objective of this study was to investigate the secretion and physiological function of annexin B1. We expressed a green fluorescent protein-tagged annexin B1 (GFP-anxB1) in living SiHa cells and showed that it was secreted upon stimulation with dexamethasone (Dex). This secretion was not inhibited by brefeldin A but was blocked by pre-treatment with the intracellular calcium-specific chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Furthermore, we describe for the first time that annexin B1 can bind to the extracellular surface of human eosinophils and produce Ca(2+)-influx. The Ca(2+)-influx induced apoptosis in eosinophils, which was inhibited by pre-loading the Ca(2+) channel blocker 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-metho-xyphenethyl]-1H-imidazole, HCl (SKF-96365). In conclusion, these findings represent direct and substantial evidence for the secretion of annexin B1 by living cells; the apoptosis in eosinophil induced by annexin B1 might be a novel strategy for T. solium metacestodes to prevent the host's immune attack.

Translocation of annexin B1 in response to the stimulation of PMA and ionomycin in cervical cancer cells.

Annexin B1 is a novel member of the annexin superfamily which was isolated from a Cysticercus cellulosae cDNA library. To investigate the physiological roles of annexin B1, we firstly performed immunohistochemical analysis on frozen Cysticercus cellulosae sections and found that annexin B1 was present not only in the tegument of the bladder wall, but also in the host-derived inflammatory layer; In addition, ELISA analysis revealed that annexin B1 could be detected in the cystic fluid of Cysticercus cellulosae and the sera of pigs with cysticercosis. These findings indicated that annexin B1 might be a secretary protein. We further constructed a pEGFP-annexin B1 plasmid and transfected it into SiHa cells. We found that GFP-annexin B1 was stimulated to translocate to the plasma membrane by phorbol 12-myristate 13-acetate (PMA). By contrast, it was induced to distribute at the plasma and nuclear membranes by treatment with calcium ionophore ionomycin. PMA increased annexin B1 membrane binding, which might facilitate exocytosis. Moreover, translocation of the protein to the plasma and nuclear membranes after stimulated by ionomycin, was predicted to be related to an additional function.