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T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways.

In order to reveal the distribution and migration law of downwind and upwind coal cutting, total dust (TD) and respirable dust (RD) concentration distribution and migration on the leeward side of the rear drum in the fully mechanized coal mining faces was tested by innovatively adopting the method of synchronous measurement at multiple measuring points on-site. Seven measuring points were arranged specifically in this area. The CCZ20 dust sampler was used for dust concentration sampling, and the filter weighing method was adopted to test the dust. Based on the statistical analysis of a large number of data, it is concluded for the first time that downwind coal cutting or upwind coal cutting has an insignificant influence on TD production, yet it exerts an obvious effect on RD production. According to the test results, the dust distribution in downwind coal cutting is divided into three areas, while that in upwind coal cutting is divided into four areas. Targeted dust suppression strategies for different areas were proposed based on the above law. Moreover, a dust suppression scheme consisting of high-pressure spray on the shearer and support spray based on auto-tracking of the shearer were designed and applied in accordance with the actual field conditions.

In order to investigate the effects of turbulent airflow from coal cutting (TACC) on the pollution characteristics of coal dust, the pollution behaviors of coal dust under the action of system ventilation airflow (SVA) only (Condition 1) and the addition of TACC disturbance (Condition 2) were respectively simulated and verified through a comparison with the field measurement data. The results show that the effects of TACC on the pollution characteristics of coal dust cannot be ignored on the operation site. TACC could not only enhance the turbulent intensity in the flow field, but also induce the positive deviation of airflow. The airflow with a velocity of about 1.0∼1.75 m/s in the footway space moved from the region X=0.3∼36.8 m, Y=4.1∼4.5 m under Condition 1 to the region X=-5.1∼26.5 m, Y=3.8∼4.5 m under Condition 2. After the addition of TACC disturbance, the absolute value of positively-deviated airflow velocity component in the operational range of rear drum driver rose from 0∼0.8 m/s to 0.2∼1.8 m/s. Meanwhile, the flow field under Condition 2 could effectively cause lateral dispersion of coal dust to the footway space, which led to an increase in the lateral dispersion scale of coal dust. Under Condition 2, the region polluted by cutting-induced coal dust moved forward by 11.3 m along the negative direction of X-axis, and the peak coal dust concentration along the footway space was approximately doubled.

To obtain the optimal dust-exhausting airflow volume on the premise that the gas concentration in the fully mechanized caving face of high-gas coal mine can be fully diluted to the safe range, gas-respirable dust (RD) coupling dispersion under various inlet airflow volumes (Q) were simulated numerically. The results show that when Q≥2100 m3/min, the gas concentration in the mining face is fully diluted. RD is distributed in basically the same way under various airflow volumes. When Q is raised from 2100 m3/min to 2500 m3/min, the RD concentration falls continuously. However, Q continues to increase, RD concentrations no longer decrease significantly. when Q is promoted to 2700 m3/min, the phenomenon of dust reentrainment occurs. Therefore, 2500 m3/min can be regarded as the optimal dust-exhausting airflow volume. Field measurement and verification shows hat the average relative errors between the simulated results and measured results of airflow velocity, gas concentration and RD concentration are 5.8 %, 4.13 % and 5.18 % respectively, which means that the numerical simulation results boast high reliability.

To explore the effects of downwind and upwind coal cutting on dust pollution in a fully mechanized mining face, the airflow-dust migration was simulated by using ANSYS-FLUENT software, and the follow-up spraying dust control method was optimized according to the differences in dust concentration distribution during downwind and upwind coal cutting. The results show that during downwind and upwind coal cutting, the average airflow velocity of the fully mechanized mining face is about 1.053 m/s. During downwind coal cutting, the dust generated by the shearer mainly pollutes the mining area and the area within 0–50 m on its downwind side, while the dust generated by the advancing support mainly pollutes the mining area and the sidewalk area within 0–20 m on the downwind side of shearer. During upwind coal cutting, the dust generated by the shearer mainly pollutes the vicinity of the drum and the area within 0–45 m on its downwind side, while the dust generated by the advancing support mainly pollutes the sidewalk area within 0–30 m on the downwind side of shearer. In view of the differences in dust concentration during downwind and upwind coal cutting, the dust concentration in the working face was divided into four areas and the follow-up spraying dust control method was optimized. The field measurement results indicate that compared with the original spraying facility, the optimized opening mode raises the average dust removal rates of total dust and respirable dust in the working face by 52.1% and 43.8% during downwind coal cutting and by 53.6% and 42.3% during upward coal cutting.

To explore the rule of airflow-dust-gas dispersion and interaction in a fully mechanized mining face, the airflow current vector, the dust trajectory, and the gas spatial distribution were numerically simulated by Fluent. The results show that under the influence of airflow, respiratory dust diffuses to the leeward side of each dust-producing point and footway space and forms a high-concentration (peak concentration 2000 mg/m3) dust mass at 2 m on the leeward side of the advancing support. Gas tends to accumulate near the coal cutter drum, the roof, and the return air corner of the mining face, and the peak concentration exceeds the lower limit of explosion. Near the rear drum of the coal cutter and at the advancing support, considering that the gas and coal dust concentrations are both high and dust and gas can reduce each other’s explosion limit, serious gas and coal dust explosions are extremely likely to occur in the presence of a fire source, which may result in serious consequences. Therefore, the two areas can be regarded as key areas of gas and coal dust explosion prevention and control.

Background IDO1 (Indoleamine 2,3-dioxygenase 1) inhibits host anti-tumor immune response by exhausting tryptophan in tumor microenvironment, but the pathogenic mechanisms of IDO1 in gastric cancer (GC) cells need to be further explored. Methods The aim of this study was to use CCLE (Cancer Cell Line Encyclopedia) transcriptomic data of GC cell lines for WGCNA (Weighted Gene Co-expression Network Analysis) analysis, and explore the potential functions and mechanisms of IDO1 in GC progression in vitro and in vivo. Results The higher expression level of IDO1 was identified in 4 out of 7 GC cell lines. Increased IDO1 expression strongly promoted cell migration via its metabolite kynurenine and was associated with pathways of immune activation according to GSEA (Gene Set Enrichment Analysis). The functions of IDO1 were closely associated with extracellular matrix, collagen metabolic and catabolic process by WGCNA analysis. Among five hub genes (AXL, SGCE, COL12A1, ANTXR1, LOXL2), COL12A1 and LOXL2 were upregulated in GC tissues. IDO1 disclosed positive correlation with six collagen genes by coefficient matrix diagram. Knockdown of IDO1 decreased the expression of LOXL2, COL6A1, COL6A2 and COL12A1 in GC cells in both mRNA and protein levels. Of them, knockdown of COL12A1 inhibited cell migration more apparently than knockdown of others. IDO1 and COL12A1 revealed synergistic efficacy on promoting cell migration via a positive feedback sustained by MAPK pathway. This bioprocess was mediated by IDO1 metabolite kynurenine and integrin β1. A popliteal lymph nodemetastasis model was established for verifying metastatic promotion of IDO1 and COL12A1 in GC. Conclusions IDO1 and COL12A1 synergistically promoted GC metastasis. The novel findings suggested that both IDO1 and COL12A1 may be promising targets on anti-cancer treatment in GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1318-5) contains supplementary material, which is available to authorized users.

IPO-38 is a potential biomarker for early diagnosis of gastric cancer that we recently identified. Although we characterized its chemical nature as a nucleosome histone, we suspected the existence of histone modification for the IPO-38 antibody-labeled protein. Here, we used a commercially available modified histone peptide array to identify the type and site of histone modification labeled by the IPO-38 monoclonal antibody. In protein array analysis, the citrulline modification of histone 3 on arginine 26 (H3R26Cit) yielded the strongest signal. Although peptidyl arginine deiminase-2 and -4 (PADI2 and PADI4, respectively) can catalyze the conversion of arginine to citrulline, we observed that only PADI4 expression correlated with the citrulline histone modification of H3R26Cit. Overexpression of PADI4, via transfection of a eukaryotic expression vector, and knockdown of PADI4 gene expression, by a PADI4 CRISPR/Cas9 vector, confirmed the crucial function of PADI4 on the increased level of H3R26Cit in gastric cancer cell lines. By immunoprecipitation and immunoblotting, we found an interaction between H3R26Cit and H3K27me3. Our study established the first link between the IPO-38 antigen and citrullinated histone 3, and clarified the upstream regulatory enzyme PADI4. The new findings suggest an important role for the citrullination modification of histone in gastric cancer biology, and should help us optimize the development of a sensitive and specific diagnostic reagent.

Lapatinib is a small molecule inhibitor of EGFR (HER1) and ERBB2 (HER2) receptors, which is used for treatment of advanced or metastatic breast cancer. To find the drug resistance mechanisms of treatment for EGFR/ERBB2 positive tumors, we analyzed the possible effects of lncRNAs. In this study, using CCLE (Cancer Cell Line Encyclopedia) database, we explored the relationship between the lncRNAs and Lapatinib sensitivity/resistance, and then validated those findings through in vitro experiments. We found that the expression of EGFR/ERBB2 and activation of ERBB pathway was significantly related to Lapatinib sensitivity. GO (Gene Oncology) analysis of top 10 pathways showed that the sensitivity of Lapatinib was positively correlated with cell keratin, epithelial differentiation, and cell-cell junction, while negatively correlated with signatures of extracellular matrix. Forty-four differentially expressed lncRNAs were found between the Lapatinib sensitive and resistant groups (fold-change > 1.5, P < 0.01). Gene set variation analysis (GSVA) was performed based on 44 lncRNAs and genes in the top 10 pathways. Five lncRNAs were identified as hub molecules. Co-expression network was constructed by more than five lncRNAs and 199 genes in the top 10 pathways, and three lncRNAs (GIHCG, SPINT1-AS1, and MAGI2-AS3) and 47 genes were identified as close-related molecules. The three lncRNAs in epithelium-derived cancers were differentially expressed between sensitive and resistant groups, but no significance was found in non-epithelium-derived cancer cells. Correlation analysis showed that SPINT1-AS1 (R = −0.715, P < 0.001) and GIHCG (R = 0.557, P = 0.013) were correlated with the IC50 of epithelium-derived cancer cells. In further experiments, GIHCG knockdown enhanced cancer cell susceptibility to Lapatinib, while high level of SPINT1-AS1 was a sensitive biomarker of NCI-N87 and MCF7 cancer cells to Lapatinib. In conclusions, lncRNAs GIHCG and SPINT1-AS1 were involved in regulating Lapatinib sensitivity. Up-regulation of GIHCG was a drug-resistant biomarker, while up-regulation of SPINT1-AS1 was a sensitive indicator.

Figure S3. Kynurenine mediates IDO1-induced GC cell proliferation. a) After knockdown of IDO1 by siRNA for 48 h, GC cells were treated by 10 μM L-kynurenine. CCK8 assay was performed to evaluate proliferation capacity of GC cells. b) After enforcing expression of IDO1 by overexpressing eukaryotic plasmid for 48 h, GC cells were treated by 1 μM SR1. CCK8 assay was conducted to assess GC cell proliferation ability. “*” represented comparing with Con group, and “#” represented comparing with siIDO1 or IDO1 group. *P

Table S1. SiRNA sequences used in this study. (DOCX 12 kb)

Figure S2. IDO1 metabolite kynurenine promotes GC cell migration. SGC-7901 and HGC-27 cells were treated with different concentrations of L-kynurenine (0-100 μM), and transwell assay was performed to assess migration ability. *P

Figure S1. IDO1 metabolite kynurenine promotes GC cell proliferation. L-kynurenine (0-100 μM) was used to treat GC cells at different concentrations for 48 h, and CCK8 assay was performed to assess GC cell proliferation ability. **P

Table S3. Antibodies used in this study. (DOCX 16 kb)

Table S2. Primer sequences used in this study. (DOCX 13 kb)

Coal dust explosion is easy to happen in the process of coal pulverization. In order to reduce the risk of coal dust explosion and promote the safety of coal chemical industry, surface modification of the ammonium dihydrogen phosphate (ADP) explosion suppressant was performed with methyl hydrogen-containing silicone oil to obtain modified ammonium dihydrogen phosphate (MADP) powder. The explosion suppression and hydrophobic properties of MADP were tested. The experimental results show that after surface modification, MADP overcomes the defect that the traditional ammonium dihydrogen phosphate explosion suppressant is easily affected by moisture, which results in agglomeration; further, MADP has little or no solubility in water and has excellent hydrophobic properties. After surface modification, MADP has better thermal stability and can withstand higher ambient temperatures. MADP can significantly increase the minimum ignition energy, thus reducing the possibility of combustion and explosion. With the increase in the mass concentration of the explosion suppressant, the maximum explosion pressure gradually decreases and delays. Compared with ADP, MADP has better explosion suppression characteristics and can quickly and efficiently suppress explosion.

Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out predictive biomarkers related to anti-cy...

Metadherin (MTDH) can be recruited to mature tight junction complexes, and it regulates mesenchymal marker protein expression in many tumors and promote cancer metastasis. This study investigated the influence of MTDH expression on gastric cancer and to elucidate the potential mechanisms by which MTDH regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition (EMT). Relative MTDH mRNA expression levels were assessed by quantitative real-time PCR (Q-PCR), and MTDH protein expression levels and localization were evaluated via immunohistochemical (ICH) staining. We studied the role of MTDH in cancer cell migration and invasion by modulating MTDH expression in the gastric cancer cell lines MKN45 and AGS. We also confirmed the functions of MTDH through in vivo experiments. We found that MTDH expression levels were correlated with lymph node metastasis, TNM stages and decreased OS (P=0.002

To investigate the regulatory mechanism of bone marrow mesenchymal stem cells(BMSC) on the biological profiles of KATO-III( cell lines of gastric cancer.Transwell cubicle was applied to build the co-cultured model in non-contact style. The differences of cell proliferation and the resistance of anti-tumour drug (5-fluoropyrimidinedione, 5-FU and Cisplatin, CDDP) between co-cultured group and single cultured group were evaluated by Cell Counting Kit 8-assay(CCK-8). The invasion ability was detected by Transwell assay. The expressions of stem cell makers, apoptosis-related factors and epithelium-mesenchymal transition (EMT)-related factors were detected by RT-PCR.The proliferation ability of KATO-III( cells in co-cultured group was significantly stronger than that in single cultured group. The growth rate of KATO-III( cells in co-cultured group was significantly higher than that in single cultured group after treatment of 5-FU and CDDP(P0.05). The mRNA expression level of Bcl-2 was significantly higher in co-cultured group KATO-III( cells(P0.05), while the mRNA expression level of Bax was significantly lower in co-cultured group KATO-III( cells(P0.05) in comparison with those in single cultured group. As compared to KATO-III( cells in single cultured group, the number of infiltrating-membrane cells was significantly higher (37.33±5.22 vs 14.56±2.54, P0.01) in co-cultured group, and the mRNA expression levels of Snail and N-cadherin were significantly higher in co-cultured group KATO-III( cells (P0.05), while the mRNA expression level of E-cadherin was significantly lower in co-cultured group KATO-III( cells (P0.05). The expressions of CD133, Nanog and Sox-2 mRNA in co-cultured group KATO-III( cells were significantly higher than those in single cultured group(P0.05).In co-cultured model sharing non-contact style, BMSC can enhance such properties of KATO-III( gastric cancer cells as the proliferation, the invasion and the chemoresistance. Furthermore, the regulatory mechanisms may be related to the increase of the expressions of some stem cell markers in gastric cancer cells.

In this paper, the storage-measurement method of missile data is described. The serial DD intelligent missile black-boxes, their design idea, performance features, and working principle are given. Their applications are also briefly presented with examples. >

An electronic manometer is presented to study the formation fracturing process by high pressure gas in an oil-well and develop a kind of torpedo used for this process. It can record the pressure-time relation over the whole process. The measurement error is less than 1.5% under a temperature up to 150/spl deg/C and a pressure of 200 MPa. In this paper, a new type of self-compensating charge amplifier, an ASIC and a calibration system are discussed in detail. Other units of the manometer are described briefly. The field test results are also presented. >

The article presents an integrated micro self-adaptive sampling acceleration measurement system (IMSAMS) that consists of silicon micromachined or quartz accelerometer, TH9601-ASIC of self-adaptive sampling and encoding, as well as data storage and readout controlling, ADC, RAM, etc. The IMSAMS has been successfully used to measure acceleration information of weapon systems, transportation, health-care, and so on. The main performance parameters include: measurement scale for silicon accelerometer: /spl plusmn/10 g, /spl plusmn/200 g, /spl plusmn/500 g, quartz accelerometer: /spl plusmn/50000 g; real-time self-adaptive sampling frequency f=f/sub 0//spl sim/f/sub 0//n, where f/sub 0//spl les/10 MHz n=1, 2,...,2/sup 14/; memory capacity 512 k bytes; and high g shock in the excess of 60000 g. The composition, operation principle and structure of the IMSAMS are detailed. The test results of the IMSAMS in measuring acceleration waveforms of a separating process of a rocket from a missile by a detonating bolt and a projectile penetrating a concrete target plate are reported.