Abstract
Therapeutics targeting immune checkpoints have achieved astonishing clinical success in cancer treatment. However, these therapies can hardly adapt to immunologically “cold” tumors featuring ...insufficient and exhausted tumor‐infiltrating lymphocytes as well as low immunogenicity. Herein, a two‐pronged strategy is presented by combining cryo‐shocked M1 macrophages (CSMs) and CD47‐targeted lonidamine nanodrugs (CLNDN) for reprograming the immunosuppressive tumor microenvironment (TME). CSMs induce durable polarization of tumor‐associated macrophages (TAMs) into the immunostimulatory M1 phenotype through the TLR2/MAPK signaling and also elevate CD47 expression in tumor cells, which in turn facilitates the targeted delivery of CLNDN into tumor cells. CLNDN trigger tumor cell‐specific pyroptosis through the caspase‐3/GSDME pathway and lead to the release of damage‐associated molecular patterns. Consequently, the combination of CSM and CLNDN synergistically boosts immune infiltration and tumor cell immunogenicity within the TME, effectively reverting tumor immunosuppression. This combination achieves potent antitumor effects and induces long‐term immune memory against tumor metastasis and recurrence. This work demonstrates for the first time TAM polarization by using cryo‐shocked macrophages and highlights its coordination with tumor pyroptosis for igniting tumor immunity, opening up a new avenue for robust cancer immunotherapy.
Effective delivery is the primary barrier against the clinical translation of gene therapy. Yet there remains too much unknown in the gene delivery mechanisms, even for the most investigated ...polymeric carrier (i.e., PEI). As a consequence, the conflicting results have been often seen in the literature due to the large variability in the experimental conditions and operations. Therefore, some key parameters should be identified and thus strictly controlled in the formulation process.
: The effect of the formulation processing parameters (e.g., concentration or mixture volume) and the resulting nanostructure properties on gene transfection have been rarely investigated. Two types of the PEI/DNA nanoparticles (NPs) were prepared in the same manner with the same dose but at different concentrations. The microstructure of the NPs and the transfection mechanisms were investigated through various microscopic methods. The therapeutic efficacy of the NPs was demonstrated in the cervical subcutaneous xenograft and peritoneal metastasis mouse models.
: The high-concentration process (i.e., small reaction-volume) for mixture resulted in the large-sized PEI/DNA NPs that had a higher efficiency of gene transfection, compared to the small counterpart that was prepared at a low concentration. The microstructural experiments showed that the prepared small NPs were firmly condensed, whereas the large NPs were bulky and botryoid-shaped. The large NPs entered the tumor cells via the macropinocytosis pathway, and then efficiently dissociated in the cytoplasm and released DNA, thus promoting the intranuclear delivery. The enhanced
therapeutic efficacy of the large NPs was demonstrated, indicating the promise for local-regional administration.
: This work provides better understanding of the effect of formulation process on nano-structural properties and gene transfection, laying a theoretical basis for rational design of the experimental process.
Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors characterized by tumor cells’ inadequate ...antigenicity and the tumor microenvironment’s low immunogenicity (TME). Herein, we developed a novel multifunctional nanoassembly termed FMMC through the self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan prodrug (FM), Ce6, and ionic manganese (Mn2+) via noncovalent interactions. The laser-ignited FMMC treatment could induce effective immunogenic cell death and activate the STING/MHC-I signaling pathway, thus deeply sculpting the tumor-intrinsic antigenicity to achieve dendritic cell (DC)-dependent and -independent T cell responses against tumors. Meanwhile, by inhibiting IDO-1, FMMC could lead to immunosuppressive TME reversion to an immunoactivated one. FMMC-based phototherapy led to the up-regulation of programmed death-ligand 1 (PD-L1), enhancing the sensitivity of tumors to anti-PD-1 therapy. Furthermore, the incorporation of Mn2+ into FMMC resulted in an augmented longitudinal relaxivity and enhanced the MRI for monitoring the growth of primary tumors and lung metastases. Collectively, the superior reprogramming performance of immunosuppressive tumor cells and TME, combined with excellent anticancer efficacy and MRI capability, made FMMC a promising immune nanosculptor for cancer theranostics.
One-dimensional gas injection storage building and one-cycle injection-production modeling experiment, and two-dimensional flat core storage building and multi-cycle injection-production modeling ...experiment were carried out using one-dimensional long core and large two-dimensional flat physical models to find out the effects of reservoir physical properties and injection-production balance time on reservoir pore utilization efficiency, effective reservoir capacity formation and capacity-reaching cycle. The results show that reservoir physical properties and formation water saturation are the main factors affecting the construction and operation of gas-reservoir type underground gas storage. During the construction and operation of gas-reservoir type gas storage, the reservoir space can be divided into three types of working zones: high efficiency, low efficiency and ineffective ones. The higher the reservoir permeability, the higher the pore utilization efficiency is, the smaller the ineffective working zone is, or there is no ineffective working zone; the smaller the loss of injected gas is, and the higher the utilization rate of pores is. The better the reservoir physical properties, the larger the reservoir space and the larger the final gas storage capacity is. The higher the water saturation of the reservoir, the more the gas loss during gas storage capacity building and operation is. Optimizing injection-production regime to discharge water and reduce water saturation is an effective way to reduce gas loss in gas storage. In the process of multiple cycles of injection and production, there is a reasonable injection-production balance time, further extending the injection-production balance period after reaching the reasonable time has little contribution to the expansion of gas storage capacity.
The woodwasp, Sirex noctilio Fabricius, is an exotic pest of Pinus L. in the southern hemisphere and North America, and it is an emerging threat in northeastern China. Adult woodwasps have numerous ...insect competitors for oviposition substrates, and developing larvae must compete for resources with other subcortical invaders. Its mutualistic fungus Amylostereum areolatum (Fr.) Boidon, is less competitive than many other fungal colonists present in pine ecosystems. This study investigated the effects of incidental, host-colonizing fungi on the growth and development of woodwasp larvae and A. areolatum. Fungi were isolated from dead S. noctilio larvae within galleries (primarily Trichoderma Pers, Ophiostoma Sydow, and Sphaeropsis Sacc.), and effects of these fungi on woodwasp brood survival were investigated via inoculations of S. noctilio-infested logs. Larval mortality was significantly increased in sample logs inoculated with Ophiostoma minus (Hedgc.) Sydow Phlebiopsis gigantea (Fr.) Jülich, Trichoderma atroviride Bissett, Trichoderma viride Pers, and Trichoderma harzianum Rifai. Inoculation of logs with O. minus resulted in the highest mortality and greatest reductions in wood moisture content. When grown on artificial media, these fungi grew faster than and inhibited growth of A. areolatum mycelium. We propose that the adverse effects of incidental fungi on the survival of S. noctilio larvae may be caused at least in part by an indirect mechanism involving inhibition of the fungal symbiont. The findings provide potentially valuable information for suppressing S. noctilio populations using microbial control agents.
In the present article, we have developed a facile and rapid method to fabricate a polyelectrolyte multilayer under high gravity field and investigated the difference of mass transfer in the ...diffusing process between LbL self-assembled technique under high gravity field (HG-LbL) and dipping assembly. Herein, we have employed polyethyleneimine and zinc oxide nanoparticles, which is a well-known UV blocking material with typical absorption properties in the range of 300–400 nm, as building blocks and applied hydrogen bonding as the driving force to construct the multilayer under HG-LbL and dipping assembly. The results show that, compared with dipping assembly, HG-LbL can highly improve the utilization and adsorption efficiency of building blocks by hastening the diffusing process, and meanwhile the resulting multilayer films still achieve comparable quality as those prepared from dipping assembly.
Wood-boring beetles are among the most destructive forest pests. The larvae of some species live in the trunks and are covered by bark, rendering them difficult to detect. Early detection of these ...larvae is critical to their effective management. A promising surveillance method is inspecting the vibrations induced by larval activity in the trunk to identify whether it is infected. As convenient as it seems, it has a significant drawback. The identification process is easily disrupted by environmental noise and results in low accuracy. Previous studies have proven the feasibility and necessity of adding an enhancement procedure before identification. To this end, we proposed a small yet powerful boring vibration enhancement network based on deep learning. Our approach combines frequency-domain and time-domain enhancement in a stacked network. The dataset employed in our study comprises the boring vibrations of Agrilus planipennis larvae and various environmental noises. After enhancement, the SNR (signal-to-noise ratio) increment of a boring vibration segment reaches 18.73 dB, and our model takes only 0.46 s to enhance a 5 s segment on a laptop CPU. The accuracy of several well-known classification models showed a substantial increase using clips enhanced by our model. All experimental results proved our contribution to the early detection of larvae.
Masson pine stands infected by Pine wilt disease (PWD) in the Three Gorges Reservoir Region of central China were surveyed to quantify the immediate responses and subsequent trajectories of biomass, ...carbon (C), and nitrogen (N) in stand-level major ecosystem compartments. The biomasses of above- and belowground tree components, as well as of the understory, forest floor, and mineral soil (0–40 cm), were determined within each stand. C and N storage were also estimated for each ecosystem compartment. Overstory biomass decreased steadily with the extent of PWD infection. Understory biomass ranged from 1.97 to 4.16 Mg ha
−1
, and the observed value for forest floor biomass was 12.89–22.59 Mg ha
−1
. The highest mean C and N concentrations were found in the stem bark and needles of Masson pine, respectively, while the lowest were found in the semi- to fully decomposed layer of the forest floor and stem wood of Masson pine, respectively. The C and N storage of aboveground trees, tree roots, and the aboveground ecosystem decreased with the extent of PWD infection. However, the C and N contents of the understory, forest floor, and total mineral soil initially declined after PWD infection before recovering over the following several years. Those result concluded that the biomass, C, and N storage of different forest ecosystem compartments have experienced certain variations following the PWD epidemic. This is vital to understand the shifts in stand-level C and N allocation in PWD-damaged forest stands, as well as for predicting the responses of regional and global C and N cycling.
Low-dose computed tomography (LDCT) screening is effective in reducing lung cancer mortality in smokers; however, the evidence in nonsmokers is scarce.
This study aimed to evaluate the participant ...rate and effectiveness of one-off LDCT screening for lung cancer among smokers and nonsmokers.
A population-based prospective cohort study was performed to enroll participants aged between 40 and 74 years from 2013 to 2019 from 4 cities in Zhejiang Province, China. Participants who were evaluated as having a high risk of lung cancer from an established risk score model were recommended to undergo LDCT screening. Follow-up outcomes were retrieved on June 30, 2020. The uptake rate of LDCT screening for evaluated high-risk participants and the detection rate of early-stage lung cancer (stage 0-I) were calculated. The lung cancer incidence, lung cancer mortality, and all-cause mortality were compared between the screened and nonscreened groups.
At baseline, 62.56% (18,818/30,079) of smokers and 6% (5483/91,455) of nonsmokers were identified as high risk (P<.001), of whom 41.9% (7885/18,818) and 66.31% (3636/5483) underwent LDCT screening (P<.001), respectively. After a median follow-up of 5.1 years, 1100 lung cancer cases and 456 all-cause death cases (116 lung cancer death cases) were traced. The proportion of early-stage lung cancer among smokers was 60.3% (173/287), which was lower than the proportion of 80.3% (476/593) among nonsmokers (P<.001). Among smokers, a higher proportion was found in the screened group (72/106, 67.9%) than the nonscreened group (56/114, 49.1%; P=.005), whereas no significance was found (42/44, 96% vs 10/12, 83%; P=.20) among nonsmokers. Compared with participants who were not screened, LDCT screening in smokers significantly increased lung cancer incidence (hazard ratio HR 1.39, 95% CI 1.09-1.76; P=.007) but reduced lung cancer mortality (HR 0.52, 95% CI 0.28-0.96; P=.04) and all-cause mortality (HR 0.47, 95% CI 0.32-0.69; P<.001). Among nonsmokers, no significant results were found for lung cancer incidence (P=.06), all-cause mortality (P=.89), and lung cancer mortality (P=.17).
LDCT screening effectively reduces lung cancer and all-cause mortality among high-risk smokers. Further efforts to define high-risk populations and explore adequate lung cancer screening modalities for nonsmokers are needed.
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