MMP11 is associated with the immune response and immune microenvironment in EGFR-mutant lung adenocarcinoma

BackgroundHigh expression of matrix metalloproteinase-11 (MMP11) is associated with various tumors and immune microenvironments. Conversely, poor response to immunotherapy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients is closely related to the characteristics of immune microenvironment.MethodsThe Cancer Genome Atlas (TCGA)-LUAD database and our gathered clinical LUAD samples were used to examine the relationship between MMP11 expression and EGFR mutation. Then the correlation between MMP11 and immune response and the difference of immune cell infiltration in different groups were analyzed. Compared the differences in the immune microenvironment between the MMP11-positive and MMP11-negative expression groups using immunohistochemistry (IHC) and multiplex immunohistochemistry.ResultsThe expression of MMP11 in samples with exon 19 deletions, exon 21 L858R or de novo exon 20 T790M mutations was higher than wild type, but there was no difference between the samples with uncommon mutation and the wild-type. The high MMP11 expression group had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. Pathways associated with enrichment in the extracellular matrix (ECM) were the main biological functions of differential genes between the high and low MMP11 groups. The IHC score of MMP11 in the EGFR-mutant group was higher than in the EGFR-wild group. In TCGA-LUAD, the high MMP11 group had a lower proportion of T cell CD8+ and NK cells activated. In the clinical samples, the infiltration levels of T cell CD8+ and NK cells in the tumor parenchyma of EGFR-mutant LUAD was lower in the MMP11-positive than in the MMP11-negative group. The expression levels of tumor cell PD-L1 were higher in the MMP11-positive expression group than in the MMP11-negative expression group, and the proportion of PD1+CD8+ T cells infiltrated was reduced in the MMP11-positive group compared to the MMP11-negative group.ConclusionsHigh expression of MMP11 was associated with EGFR mutations. Patients with EGFR-mutant LUAD with high expression of MMP11 responded poorly to immunotherapy, and the percentage of T cell CD8+ and NK cells in immune cell infiltration was lower in MMP11. Consequently, MMP11 is related to the immunological microenvironment of EGFR-mutant lung adenocarcinoma, which may be a predictor of possible immunotherapeutic response

Investigation of the prevalence and clinical implications of ERBB2 exon 16 skipping mutations in Chinese pan-cancer patients

BackgroundAlthough rare, ERBB2 exon 16 skipping mutations (ERBB2ΔEx16) have been implicated in resistance to anti-HER2 and anti-EGFR targeted agents. Our study investigated the prevalence and clinical significance of ERBB2ΔEx16 in Chinese pan-cancer patients.MethodsWe retrospectively screened 40996 patients, spanning 19 cancer types, who had available genomic profiles acquired with DNA-based next-generation sequencing (NGS). We characterized the clinical and molecular features of the ERBB2ΔEx16-positive patients. Furthermore, we also analyzed a pan-cancer dataset from the Cancer Genome Atlas (TCGA; n=8705).ResultsA total of 22 patients were detected with ERBB2ΔEx16, resulting in an overall prevalence rate of 0.054% (22/40996). Of them, 16 patients had lung cancer (LC; 0.05%, 16/30890), five patients had gastric cancer (GC; 0.35%, 5/1448), and one patient had ovarian cancer (0.12%, 1/826). Among the 16 LC patients, ERBB2ΔEx16 was detected in four treatment-naïve EGFR/ALK-negative patients and 12 EGFR-positive patients after the onset of resistance to EGFR tyrosine kinase inhibitors (TKIs). The treatment-naïve patients harbored no LC-associated oncogenic drivers except ERBB2 amplification, suggesting a potential oncogenic role for ERBB2ΔEx16. Consistently, ERBB2ΔEx16+ patients from TCGA data also carried no known drivers despite various concurrent alterations. In the 12 EGFR TKI-resistant LC patients, relative variant frequencies for ERBB2ΔEx16 were lower than in untreated patients, suggesting ERBB2ΔEx16 as secondary alterations following TKI treatment and thereby implicating ERBB2ΔEx16 in mediating therapeutic resistance.ConclusionsOur study identified an overall ERBB2ΔEx16 prevalence rate of 0.054% and provided insights into the clinical implications of ERBB2ΔEx16 in Chinese pan-cancer patients

Numerical Simulation and Experimental Investigation of Rotating Blade Centrifugal Jet in Slurry Blast Device Used for Steel Strip Descaling

Under the requirement of clean production, a new type of slurry blast device for mechanically removing oxide scale on the surface of steel strips is presented, which can avoid the serious problems of rapid wear, low service life, and low efficiency of the traditional abrasive water jet with a nozzle. In this paper, the numerical simulation of the rotating blade centrifugal jet in the slurry blast device is conducted based on CFD, where the DPM and the erosion model are innovatively employed to simulate the movement characteristics of abrasive particles and the erosion rate of mixed slurry on the surface of the steel strip. Simulation results show that the erosion rate and particle motion velocity are proportional to the blade rotation speed and inlet pressure. Reasonable inlet pressure and rotation speed are helpful for improving the rust removal efficiency of slurry blast devices. An experimental system is established to validate the simulation results. The experimental results are consistent with the simulation trend, which exhibits that the developed slurry blast device is feasible for steel strip descaling. This work will play substantial guiding roles in the engineering optimization of slurry blast devices for steel strip descaling

Numerical Simulation and Experimental Investigation of Rotating Blade Centrifugal Jet in Slurry Blast Device Used for Steel Strip Descaling

Under the requirement of clean production, a new type of slurry blast device for mechanically removing oxide scale on the surface of steel strips is presented, which can avoid the serious problems of rapid wear, low service life, and low efficiency of the traditional abrasive water jet with a nozzle. In this paper, the numerical simulation of the rotating blade centrifugal jet in the slurry blast device is conducted based on CFD, where the DPM and the erosion model are innovatively employed to simulate the movement characteristics of abrasive particles and the erosion rate of mixed slurry on the surface of the steel strip. Simulation results show that the erosion rate and particle motion velocity are proportional to the blade rotation speed and inlet pressure. Reasonable inlet pressure and rotation speed are helpful for improving the rust removal efficiency of slurry blast devices. An experimental system is established to validate the simulation results. The experimental results are consistent with the simulation trend, which exhibits that the developed slurry blast device is feasible for steel strip descaling. This work will play substantial guiding roles in the engineering optimization of slurry blast devices for steel strip descaling

Effects of Hyporheic Water Fluxes and Sediment Grain Size on the Concentration and Diffusive Flux of Heavy Metals in the Streambed

The hyporheic zone regulates physicochemical processes in surface-groundwater systems and can be an important source of heavy metals in fluvial systems. This study assesses the pore water concentrations and diffusive fluxes of heavy metals with respect to the vertical water exchange flux (VWEF) and sediment grain size. Water and sediment samples were collected on August 2016 from upstream Site 1 and downstream Site 2 along the Juehe River in Shaanxi Province, China. Streambed vertical hydraulic conductivity (Kv) and the VWEF were estimated via the standpipe permeameter test method and Darcy’s law. The heavy metal concentrations in the pore water were measured and the diffusive fluxes were calculated using Fick’s first law. The VWEF patterns were dominated by upward flow, and Site 1 featured higher values of Kv and VWEF. Higher Cu and Zn concentrations occurred near the channel centre with coarse sand and gravel and greater upward VWEFs because coarser sediment and greater upward VWEFs cause stronger metal desorption capacity. Additionally, Cu and Zn at the two sites generally diffused from pore water to surface water, potentially due to the upward VWEF. The VWEF and sediment grain size are likely crucial factors influencing the heavy metal concentrations and diffusive fluxes

Distinct Metabolome Changes during Seed Germination of Lettuce (Lactuca sativa L.) in Response to Thermal Stress as Revealed by Untargeted Metabolomics Analysis

Temperature strongly influences lettuce (Lactuca sativa L.) seed germination. Different lettuce genotypes respond differently to higher temperatures or thermal stress. In this study, we evaluated the germination performance of 304 lettuce accessions incubated at three temperature settings, 21 °C, 28 °C and 35 °C, respectively, for 40 h. At 21 °C, seeds of all 304 accessions germinated with very well an average germination percentage of 87.72%; at 28 °C, the average germination percentage dropped to 42.84% and at 35 °C, the germination decreased to 1.01%. Then, we investigated changes in metabolic profiles of lettuce seed response to thermal stress using an untargeted metabolomics approach. Results suggested that seeds of thermal-sensitive and thermal-tolerant cultivars employed different metabolic strategies in response to thermal stress during germination. Thermal-sensitive buds accumulated more significant amounts of organic acids, amino acids, sugars, sterols, phenolic compounds and terpenoids compared to thermal-tolerant buds at 21 °C. Thermal-tolerant lettuce cultivar accumulated higher concentrations of amino acids, organic acids, sugars, sesquiterpene lactones, sterols, and fatty acids derivatives during the germination at 35 °C compared to germinated at 21 °C. This investigation paves the way to link the metabolomics to other external and internal factors affecting lettuce seed germination under thermal stress