Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells.

The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.

CD57-positive CD8 + T cells define the response to anti-programmed cell death protein-1 immunotherapy in patients with advanced non-small cell lung cancer.

Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC). However, accurately identifying patients who will benefit from immunotherapy remains a challenge. This study aimed to discover potential biomarkers for predicting immunotherapy response in NSCLC patients. Single-cell mass cytometry (CyTOF) was utilized to analyze immune cell subsets in peripheral blood mononuclear cells (PBMCs) obtained from NSCLC patients before and 12 weeks after single-agent immunotherapy. The CyTOF findings were subsequently validated using flow cytometry and multiplex immunohistochemistry/immunofluorescence in PBMCs and tumor tissues, respectively. RNA sequencing (RNA-seq) was performed to elucidate the underlying mechanisms. In the CyTOF cohort (n = 20), a high frequency of CD57+CD8+ T cells in PBMCs was associated with durable clinical benefit from immunotherapy in NSCLC patients (p = 0.034). This association was further confirmed in an independent cohort using flow cytometry (n = 27; p < 0.001), with a determined cutoff value of 12.85%. The cutoff value was subsequently validated in another independent cohort (AUC = 0.733). We also confirmed the CyTOF findings in pre-treatment formalin-fixed and paraffin-embedded tissues (n = 90; p < 0.001). RNA-seq analysis revealed 475 differentially expressed genes (DEGs) between CD57+CD8+ T cells and CD57-CD8+ T cells, with functional analysis identifying DEGs significantly enriched in immune-related signaling pathways. This study highlights CD57+CD8+ T cells as a promising biomarker for predicting immunotherapy success in NSCLC patients.

Overview of Health-Monitoring Technology for Long-Distance Transportation Pipeline and Progress in DAS Technology Application.

There are various health issues associated with the different stages of long-distance pipeline transportation. These issues pose potential risks to environmental pollution, resource waste, and the safety of human life and property. It is essential to have real-time knowledge of the overall health status of pipelines throughout their entire lifecycle. This article investigates various health-monitoring technologies for long-distance pipelines, providing references for addressing potential safety issues that may arise during long-term transportation. This review summarizes the factors and characteristics that affect pipeline health from the perspective of pipeline structure health. It introduces the principles of major pipeline health-monitoring technologies and their respective advantages and disadvantages. The review also focuses on the application of Distributed Acoustic Sensing (DAS) technology, specifically time and space continuous monitoring technology, in the field of pipeline structure health monitoring. This paper discusses the process of commercialization development of DAS technology, the main research progress in the experimental field, and the open research issues. DAS technology has broad application prospects in the field of long-distance transportation pipeline health monitoring.

Evolution Characteristics of Void in the Caving Zone Using Fiber Optic Sensing.

Addressing the issue of low filling efficiency in gangue slurry backfilling due to unclear evolution characteristics of voids in the overlying collapsed rock mass during mining, this study utilizes fiber optic sensing technology to monitor real-time strain changes within the rock mass. It proposes a void zoning method based on fiber optic sensing for mining the overlying rock and, in combination with physical model experiments, systematically investigates the dimensions, distribution, and deformation characteristics of rock mass voids. By analyzing fiber optic sensing data, the correlation between the rate of void expansion and the stress state of the rock mass is revealed. The research results demonstrate that as mining progresses, the internal voids of the rock mass gradually expand, exhibiting complex spatial distribution patterns. During the mining process, the expansion of voids within the overlying collapsed rock mass is closely related to the stress state of the rock mass. The rate of void expansion is influenced by changes in stress, making stress regulation a key factor in preventing void expansion and rock mass instability. The application of fiber optic sensing technology allows for more accurate monitoring of changes in rock mass voids, enabling precise zoning of voids in the overlying collapsed rock mass during mining. This zoning method has been validated against traditional theoretical calculations and experimental results. This research expands our understanding of the evolution characteristics of voids in overlying collapsed rock mass and provides valuable reference for backfilling engineering practices and backfilling parameter optimization.

CPT1A induction following epigenetic perturbation promotes MAVS palmitoylation and activation to potentiate antitumor immunity.

Targeting epigenetic regulators to potentiate anti-PD-1 immunotherapy converges on the activation of type I interferon (IFN-I) response, mimicking cellular response to viral infection, but how its strength and duration are regulated to impact combination therapy efficacy remains largely unknown. Here, we show that mitochondrial CPT1A downregulation following viral infection restrains, while its induction by epigenetic perturbations sustains, a double-stranded RNA-activated IFN-I response. Mechanistically, CPT1A recruits the endoplasmic reticulum-localized ZDHHC4 to catalyze MAVS Cys79-palmitoylation, which promotes MAVS stabilization and activation by inhibiting K48- but facilitating K63-linked ubiquitination. Further elevation of CPT1A incrementally increases MAVS palmitoylation and amplifies the IFN-I response, which enhances control of viral infection and epigenetic perturbation-induced antitumor immunity. Moreover, CPT1A chemical inducers augment the therapeutic effect of combined epigenetic treatment with PD-1 blockade in refractory tumors. Our study identifies CPT1A as a stabilizer of MAVS activation, and its link to epigenetic perturbation can be exploited for cancer immunotherapy.

Multi-method joint monitoring study on strata behavior in shallow seam mining under bedrock gully.

The Baijigou Coal Mine in Helan mountain mining area is alpine gully landform, and the double key stratums are cut by the gully. A two-dimensional physical similarity model under this condition was established in the laboratory. The strain field, deformation field and pressure field of the model are jointly and accurately monitored by BOTDA, DIC and pressure sensors. The rock behavior in shallow coal seam mining under bedrock gullies are studied. In the mining stage under the gully, the deformation of overburden is intense because overburden is thin, and the surface is easy to form a depression basin. In the mining stage far away from the gully, the deformed rock mass lacks horizontal support in the process of deflecting to the lower goaf, and the movement rock is in a multilateral block. The multilateral block rock periodically deflects and rotates, resulting in the periodic deformation and break of the inferior key stratum. At the mining stage of away from the gully, nine times of roof weighting occurred. And there are large and small periodic weighting phenomenon with the average roof pressure concentration coefficient is 1.37. The distance between the peak point of advance abutment pressure and the coal wall is 6-18 cm, and the influence distance decreases with the advancing of the working face. The inferior key stratum has a significant impact on the weighting process and the weighting strength. In the mining stage under the mountaintop, large downward inclined tension crack is prone to produce in the slope on the side of the stope line, and the roof weighting is the most severe. In the mining stage close to the gully, the overburden falls in layers from bottom to top, and the overburden at the slope toe is prone to slip. At the mining stage under the mountaintop and close to the gully, five times of roof weighting occurred. And the roof weighting concentration coefficient is 1.46 on average. The distance between the peak point of advance abutment pressure and the coal wall is always kept at 6-16 cm, and the influence distance is 33-41 cm. The study can provide a reference for mining design and ensures safe and efficient mining in this condition.

Grouting mechanism and experimental study of goaf considering filtration effect.

The filtration effect significantly affects the gangue slurry velocity and concentration, making it difficult to evaluate the gangue slurry diffusion range. Based on the Darcy seepage law, a seepage theoretical calculation model is established considering the filtration time and space effect. And the "water-cement ratio change matrix" in the seepage process of coal gangue slurry is deduced, revealing the basic mechanism of the porous media filtration effect, and the water-cement ratio gradually increases in the seepage process of gangue slurry. The visual test platform for slurry diffusion in goaf was independently developed for testing. The active heating optical fiber method (AHFO) was used to monitor the flow and diffusion of coal gangue slurry in the collapse zone of goaf, and the gravity gradient and water cement ratio of slurry in goaf were measured. The law of particle sedimentation in the gangue slurry flow process under the filtration effect was revealed, and engineering verification was carried out. The results show that the average slope of the gangue slurry in the gangue accumulation is 6.34%, and the overall flow law of the gangue slurry in the goaf is the first longitudinal expansion and then transverse diffusion. The water-cement ratio near the grouting mouth is smaller than the initial water-cement ratio, the near-end water-cement ratio is smaller, and the far-end water-cement ratio is larger. During on-site filling, the accumulated grouting volume of a single hole is 700 m3, and the gangue slurry diffusion distance is greater than 45m, indicating that the gangue slurry has good fluidity.

Coal seam in-situ inorganic analysis based on least angle regression and competitive adaptive reweighted sampling algorithm by XRF-visNIR fusion.

The fusion of X-ray fluorescence spectroscopy (XRF) and visible near infrared spectroscopy (visNIR) has been widely used in geological exploration. The outer product analysis (OPA) has a good effect in the fusion. The dimension of the spectral matrix obtained by OPA is large, and the Competitive Adaptive Reweighted Sampling (CARS) cannot cover the whole spectrum. As a result, the selected variables by the method are inconsistent each time. In this paper, a new feature variable screening method is proposed, which uses the Least Angle Regression (LAR) to select the high dimensional spectral matrix first, and then uses CARS to complete the secondary selection of the spectral matrix, forming the LAR-CARS algorithm. The purpose is to make the sampling method cover all the spectral data. XRF and visNIR tests were carried out on three cores in two boreholes, and a cross-validation set, validation set and a test set were established by combining the results of wavelength dispersion X-ray fluorescence spectrometer and ITRAX Core scanner in the laboratory. The quantitative model was established with the Extreme Gradient Boosting (XGBoost) and LAR-CARS was compared to these other algorithms (LAR, Successive Projections Algorithm, Monte Carlo uninformative variables elimination and CARS). The results showed that the RMSEP values of the models established by the LAR-CARS for six rock-forming elements (Si, Al, K, Ca, Fe, Ti) were relatively small, and the RPD ranges from 1.424 to 2.514. All these results show that the high-dimensional matrix formed by XRF and visNIR integration combined with LAR-CARS can be used for quantitative analysis of rock forming elements in in-situ coal seam cores, and the analysis results can be used as the basis for judging lithology. The research will provide necessary technical support for digital mine construction.

Grouting slurry diffusion range based on active heating fiber optics monitoring.

To quantify the diffusion range of slurry in grouting engineering, an active heating optical fiber (AHFO) monitoring method is proposed. The AHFO is arranged on the coal seam floor. The temperature is taken as the monitoring parameter to monitor the diffusion range and state of slurry in the injected medium. Considering the time-varying characteristics of slurry rheological parameters, the theoretical calculation formula of spherical diffusion radius based on the power-law fluid is deduced. The relationship between the void ratio and grouting diffusion radius is discussed. Considering the influence of the seepage effect, the "water cement ratio change matrix" in the process of mud seepage is derived, and the influence of the space-time change of the slurry water cement ratio on the temperature gradient of the injected medium is studied. According to the factors affecting grouting diffusion, four groups of small three-dimensional simulation tests and one large three-dimensional grouting test are designed to verify the feasibility of the proposed method. The results show that the relative error of the AHFO monitoring radius is between 3.00 and 14.67%, based on the actual diffusion radius. In the large-scale three-dimensional grouting test, the data from AHFO is used to generate the two-dimensional surface of the grouting diffusion form, and the grouting diffusion range is asymmetric oval. Compared with the theoretical calculation results, the maximum relative error of grouting diffusion radius is 9.6%, and AHFO shows prediction accuracy. With the decrease in the water-cement ratio of slurry, the temperature gradient of the injection medium monitored by AHFO increases, showing an obvious space-time effect. The application of AHFO in the grouting simulation test can effectively analyze slurry diffusion in the injected medium.

EZH2 inhibition activates dsRNA-interferon axis stress and promotes response to PD-1 checkpoint blockade in NSCLC.

Lung cancer is the leading cause of cancer death and immunotherapy had been approved be a useful approach for NSCLC therapy. However, only part of the patients responds to checkpoint inhibitors. The EZH2, as a histone modification regulator, is overexpressed in NSCLC and negatively regulates the interferon-stimulated genes. Here, we demonstrate that EZH2 inhibition increases the double-strand RNA (dsRNA) level and then triggers the IFN pathway stress which is dependent on the pattern recognition receptors (TLR3, MDA5). The antigen presentation genes and PDL1 were also upregulated by inhibition of EZH2. Furthermore, in the immunocompetent LLC tumor model, the inhibition of EZH2 causes tumor regression and enhances the CD8+T cell infiltration. The EZH2 depletion triggers significant responses of the LLC mouse model to anti-PD1 therapy. This study identifies that inhibition of EZH2 promotes the dsRNA interferon driven antitumor immunity and enhances the anti-PD1 antitumor efficacy in NSCLC. These data suggest that EZH2 inhibition combined with anti-PD1/PDL1 is a promising lung cancer treatment strategy.

Hemorrhagic fever with renal syndrome complicated with aortic dissection: A case report.

BACKGROUND: Hemorrhagic fever with renal syndrome is caused by hantaviruses presenting with high fever, hemorrhage, and acute kidney injury. Microvascular injury and hemorrhage in mucus were often observed in patients with hantavirus infection. Infection with bacterial and virus related aortic aneurysm or dissection occurs sporadically. Here, we report a previously unreported case of hemorrhagic fever with concurrent aortic dissection. CASE SUMMARY: A 56-year-old man complained of high fever and generalized body ache, with decreased platelet counts of 10 × 109/L and acute kidney injury. The enzyme-linked immunosorbent assays test for immunoglobulin M and immunoglobulin G hantavirus-specific antibodies were both positive. During the convalescent period, he complained sudden onset acute chest pain radiating to the back, and the computed tomography angiography revealed an aortic dissection of the descending aorta extending to iliac artery. He was diagnosed with hemorrhagic fever with renal syndrome and Stanford B aortic dissection. The patient recovered completely after surgery with other support treatments. CONCLUSION: Hemorrhagic fever with renal syndrome complicated with aortic dissection is rare and a difficult clinical condition. Hantavirus infection not only causes microvascular damage presenting with hemorrhage but may be risk factor for acute macrovascular detriment. A causal relationship has yet to be confirmed.

Gypenosides induce apoptosis by ca2+ overload mediated by endoplasmic-reticulum and store-operated ca2+ channels in human hepatoma cells.

Gypenosides (Gyps) are triterpenoid saponins contained in an extract from Gynostemma pentaphyllum Makino and reported to induce apoptosis in human hepatoma cells through Ca(2+)-implicated endoplasmic reticulum (ER) stress and mitochondria-dependent pathways. The mechanism underlying the Gyp-increased intracellular Ca(2+) concentration ([Ca(2+)]i) is unclear. Here, we examined Gyp-induced necrosis and apoptosis in human hepatoma HepG2 cells. Gyp-induced apoptotic cell death was accompanied by a sustained increase in [Ca(2+)]i level. Gyp-increased [Ca(2+)]i level was partly inhibited by removal of extracellular Ca(2+) by Ca(2+) chelator EGTA, store-operated Ca(2+) channel (SOC) inhibitor 2- aminoethoxydiphenyl borate (2-APB), and ER Ca(2+)-release-antagonist 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester (TMB-8). The strongest inhibitory effect was observed with TMB-8. EGTA, 2-APB, and TMB-8 also protected against Gyp-induced apoptosis in HepG2 cells. The combination of 2-APB and TMB-8 almost completely abolished the Gyp-induced Ca(2+) response and apoptosis. In contrast, the sarco/endoplasmic-reticulum-Ca(2+)-ATPase (SERCA) inhibitor thapsigargin slightly elevated Gyp-induced [Ca(2+)]i increase and apoptosis in HepG2 cells. Exposure to 300 µg/mL Gyp for 24 hours upregulated protein levels of inositol 1,4,5-trisphosphate receptor and SOC and downregulated that of SERCA for at least 72 hours. Thus, Gyp-induced increase in [Ca(2+)]i level and consequent apoptosis in HepG2 cells may be mainly due to enhanced Ca(2+) release from ER stores and increased store-operated Ca(2+) entry.

Adenovirus-mediated delivery of CALR and MAGE-A3 inhibits invasion and angiogenesis of glioblastoma cell line U87.

BACKGROUND: The management of patients with glioblastoma multiforme is difficult. Poor results have led to a search for novel therapeutic approaches. Gene therapy that could be both anti-invasive and antiangiogenic would be ideal. In this study, we constructed the recombinant adenoviral vector Ad-CALR/MAGE-A3 and evaluated its antitumor effects on glioblastoma in vitro and in vivo. METHODS: In this study, CALR and MAGE-A3 genes were delivered to the glioblastoma cell line U87, using adenovirus (Ad-CALR/MAGE-A3). U87 glioblastoma cells were transfected with Ad-green fluorescent protein to identify the multiplicity of infection. The expressions of CALR and MAGE-A3 were detected by PCR and Western blot. Cell proliferation was measured by MTT assay. Cell apoptosis was assessed by Annexin-V FITC/PI double staining flow cytometry. The invasive potential of U87 cells was determined by Matrigel invasion assay. Tube formation assay was used to detect the effects on angiogenesis of human umbilical vein endothelial cells. Protein expressions of PI3K/AKT, Erk1/2 and MMP-2/-9 in transfected cells were detected by Western blot. In vivo, the effects of Ad-CALR/MAGE-A3 on tumor growth and angiogenesis of U87 glioblastoma xenografts in nude mice were investigated. RESULTS: The expressions of CALR and MAGE-A3 in U87 cells resulted in the suppression of cell proliferation and invasion properties, and induced cell apoptosis. The Erk MAPK, PI3K/AKT pathways and expressions of MMP-2/-9 were inhibited in Ad-CALR/MAGE-A3-transfected cells. Outcomes of the tube formation assay confirmed the antiangiogenic effect of CALR. Moreover, in the in vivo model of glioblastoma, intratumoral injection of Ad-CALR/MAGE-A3 suppressed tumor growth and angiogenesis. CONCLUSION: Although Ad-CALR/MAGE-A3 and Ad-CALR demonstrated antiangiogenic effects on U87 cells, the repression of invasion was significant only in Ad-CALR/MAGE-A3-treated cells. To our knowledge, this is the first description of a role for combined CALR and MAGE-A3 in the anti-invasion and antiangiogenesis of U87.