While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used ...for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.
In order to obtain conductive concrete with good electrical conductivity and good mechanical properties, nanographite and magnetite sand excited by different activators and their combinations are ...added to ordinary concrete to obtain high quality and efficient conductive concrete. The optimal mixture ratio of alkali-excited conductive concrete and the effects of different activators and their combinations on the mechanics and electrical conductivity of concrete were studied. The microstructure of alkali-excited conductive concrete was analyzed by scanning electron microscope (SEM) to study its conductive mechanism. Results show that the conductive concrete obtained by compounding sodium hydroxide, sodium sulfate and calcium hydroxide has optimal mechanical and electrical properties when the graphite is 6% cement, and magnetite sand is 40% fine aggregate. The conductive concrete sample prepared by this method has a flexural strength of 6.84 MPa, a compressive strength of 47.79 MPa and a resistivity of 4805 Ω·cm (28 days). Compared with ordinary concrete (no nanographite and no magnetite sand), the compressive strength of conductive concrete is increased by 122.3%, the bending strength is increased by 116.5%, and the resistivity is reduced by 99.1%. SEM shows that the distribution of conductive materials in concrete is more uniform due to alkali excitation and calcium silicate hydrate (CSH) gel can be formed, which leads to better performance. The research in this paper is only a preliminary exploration of the characteristics of green conductive concrete, and the conductive heating characteristics and electromagnetic wave absorption properties of concrete, along with strength characteristics after adding conductive fillers, need to be further studied. It is suggested that further research should be carried out on the deicing characteristics of conductive concrete and the electromagnetic wave absorption properties used in stealth military engineering.
High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is ...rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9
tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.
PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti-PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We ...fortuitously observed that anti-PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti-PD-1-induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1-laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1-laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1-laIL-2. Collectively, these results highlight that PD-1-laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.
Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the ...mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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•dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β•Knockout of cGAS or STING in dMLH tumor cells renders resistance to checkpoint blockade•Downregulating cGAS-STING in human dMLH1 cancers impairs checkpoint blockade therapy
About 50% of patients with dMMR cancers are objectively responsive to immunotherapy. In addition to neoantigens, Lu et al. find that dMMR-mediated cytosolic DNA sensing by cGAS-STING pathway in tumor cells contributes to such clinical benefits, while impaired expression of cGAS-STING pathway is associated with drug resistance.
In order to explore the corrosion resistance of duplex stainless steel under seawater corrosion and the compressive stiffness of its reinforced concrete columns, this study first performed seawater ...corrosion resistance tests on HRB400 ordinary steel rebar and S32205 duplex stainless steel rebar. The effect of the corrosion product film on the corrosion behavior was investigated through polarization curve tests and electrochemical impedance spectroscopy tests. The results showed that the corrosion rate of S32205 duplex stainless steel in a seawater environment was approximately 1/15 that of the HRB400 ordinary steel rebar. The anodic polarization curve of duplex stainless steel rebars exhibited a greater slope than that of carbon steel rebars. In the simulated seawater environment, the corrosion rate of these two kinds of steel bars showed different trends. The corrosion rate of ordinary steel bar HRB400 first decreased and then increased, while that of duplex stainless steel S2205 increased steadily. Furthermore, 18 short concrete columns reinforced with ordinary and duplex stainless steel rebars were subjected to the axial compression test and stiffness analysis; the stiffness of the short columns was calculated from the test data. The theoretical values agreed with the test values, with a stiffness calculation error of less than 5%.
CD47 on tumor cells protects from phagocytosis, while PD-L1 dampens T cell-mediated tumor killing. However, whether and how CD47 and PD-L1 coordinate is poorly understood. We reveal that CD47 and ...PD-L1 on tumor cells coordinately suppress innate and adaptive sensing to evade immune control. Targeted blockade of both CD47 and PD-L1 on tumor cells with a bispecific anti-PD-L1-SIRPα showed significantly enhanced tumor targeting and therapeutic efficacy versus monotherapy. Mechanistically, systemic delivery of the dual-targeting heterodimer significantly increased DNA sensing, DC cross-presentation, and anti-tumor T cell response. In addition, chemotherapy that increases “eat me” signaling further synergizes with the bispecific reagent for better tumor control. Our data indicate that tumor cells evolve to utilize both innate and adaptive checkpoints to evade anti-tumor immune responses and that tumor cell-specific dual-targeting of both checkpoints represents an improved strategy for tumor immunotherapy.
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•CD47 and PD-L1 checkpoints on tumor cells coordinate to suppress immune sensing•The bispecific antibody enables better targeting on tumor cells than on non-tumor cells•Dual targeting increases cytosolic DNA sensing in DCs for an anti-tumor T cell response•Chemotherapy induces danger signals that synergize with bispecific antibody
CD47 and PD-L1 serve as critical innate and adaptive checkpoints, respectively. Liu et al. show CD47 and PD-L1 coordinate in tumor cells to evade immune response. Furthermore, a bispecific antibody design enables better targeting on tumor cells, but less on non-tumor cells, and enhanced therapeutic efficacy.
Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete ...activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
Rationale and objective
Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological ...mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders.
Methods
We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue.
Results
Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients’ BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α.
Conclusion
Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.
Olfactory dysfunction occurs frequently in Parkinson's disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of ...olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice.
MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP
). Next, prok2R overexpression (prok2R
) and knockdown (prok2R
) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP
were evaluated in prok2R overexpression (prok2R
) HEK293T cell lines.
Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R
and prok2R
HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R
HEK293T cells were resistant to MPP
-induced apoptosis.
This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.
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