EGFR-ERK pathway regulates CSN6 to contribute to PD-L1 expression in glioblastoma.

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD-L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR-ERK pathway regulates CSN6 for PD-L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD-L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD-L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD-L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF-upregulated p-EGFR, p-ERK, CSN6, and PD-L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD-L1 in EGF-treated cells. Inhibition of CSN6 by small interfering RNA decreased PD-L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF-reduced CHX-induced CSN6 and PD-L1 turnover in GBM cells. Furthermore, CSN6-mediated downregulation of PD-L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR-ERK pathway may upregulate CSN6, which may inhibit PD-L1 degradation and subsequently maintain PD-L1 stability in GBM.

Distribution of per- and poly-fluoroalkyl substances and their precursors in human blood.

Many studies have examined per- and poly-fluoroalkyl substances (PFASs) in human blood. However, the distribution of PFASs in human blood remains not well known, especially for perfluorooctane sulfonate (PFOS) precursors. In this study, human blood samples (n = 162) were collected from general Chinese population, and then the isomer-specific partitioning of PFASs between human plasma and red blood cells (RBCs) were investigated. Perfluorooctanoate (PFOA) and PFOS were consistently the predominant PFASs in both human plasma and RBCs. In human blood, among C4-C7 perfluoroalkyl carboxylates (PFCAs), the calculated mean mass fraction in plasma (Fp) values increased from 0.76 to 0.82 with the increasing chain length. C7-C13 PFCAs exhibited a trend of gradually decreasing mean Fp with chain length. Among PFAS precursors, 6:2 fluorotelomer phosphate diester had the highest mean Fp value (0.87 ± 0.11). Calculated Fp values of N-methyl perfluorooctanesulfonamide (N-MeFOSA) and N-ethyl perfluorooctanesulfonamide (N-EtFOSA) were 0.66 ± 0.13 and 0.70 ± 0.12, respectively. Individual branched isomers consistently had greater Fp values than their corresponding linear isomers for PFOA, PFHxS, and perfluoroctane sulfonamide. To our knowledge, this study first reports the distribution of N-MeFOSA and N-EtFOSA in human blood, contributing to the better understanding of the occurrence and fate of PFASs in humans.

[Pollution Characteristics and Transport contributions of Ambient Ozone and Volatile Organic Compounds in Southern Hebei Cities].

The "14th Five-Year Plan" period is the key stage for southern Hebei cities (Shijiazhuang, Xingtai, and Handan) to be removed from the bottom ten of the Air Quality Composite Index. The hourly ozone (O3) data of 15 country-controlled monitoring stations in the southern cities of Hebei Province from April to October 2020, hourly data of three volatile organic compound (VOCs) supersites, and the meteorological data of the same period were used for analysis, combined with the spatiotemporal succession, O3 formation potential (OFP), backward trajectory modeling, and spatial statistical modeling. The results showed the following:firstly, the temporal variations in O3 in southern cities of Hebei Province from April to October presented an inverted "U" shape, and the spatial distribution was high in the south and low in the north. O3 pollution was the most serious in June, with Xingtai (233.8 µg·m-3)>Handan (225.2 µg·m-3)>Shijiazhuang (224.8 µg·m-3). O3 was positively correlated with temperature and wind speed and negatively correlated with humidity and VOCs; furthermore, the ρ(TVOC) from April to October followed the order of Xingtai (274 µg·m-3)>Shijiazhuang (266 µg·m-3)>Handan (218 µg·m-3). The total OFP of alkenes and aromatics accounted for more than half; moreover, the trajectory of O3 pollution in southern cities of Hebei Province showed spatial directionality and relevance. The highest mass concentration of O3 (198.92 µg·m-3) was in the trajectory from Shijiazhuang to Xingtai, and the highest frequency of O3 pollution was in the trajectory from Handan to Xingtai. Moreover, the transmission contributions of O3from Xingtai to Shijiazhuang agglomerations were high (27.39%), and Handan played a significant role in the transmission contribution of O3 to Xingtai (32.76%).

Differences of bisphenol analogue concentrations in indoor dust between rural and urban areas.

Bisphenol analogues (BPs) are widely applied in varying consumer products. Many studies have reported their presence in indoor dust samples from China. However, the differences in occurrence and concentration profiles of BPs in indoor dust between rural and urban areas are still not well characterized. In this study, eight BPs were measured in 60 indoor dust samples collected from rural and urban districts of Hangzhou, China. Bisphenol A (BPA; mean 1.8 µg/g, range 0.20-7.2 µg/g) was the predominant BP in indoor dust samples, accounting for mean 57% of the total BP (∑BP) concentration, followed by bisphenol S (BPS; 0.58 µg/g,

[Spatio-Temporal Characteristics and Potential Source Areas of Seasonal Atmospheric Pollution in Shijiazhuang].

In order to systematically study the transmission characteristics of seasonal and typical pollutants in Shijiazhuang, hourly data of ground-level pollutants(PM2.5, PM10, O3, NO2, SO2, and CO) from 46 state-and provincial-controlled stations, and meteorological(temperature, humidity, and wind speed) data from 17 counties in Shijiazhuang City from December 2018 to November 2019 was analyzed. The interpolation(IDW) and correlation analysis were applied to seasonal and temporal spatial patterns of pollutant concentration. The backward trajectories analysis was performed to explore the seasonal transmission pattern and potential source areas of pollution in Shijiazhuang by combining with the global data assimilation system(GDAS). The results indicate that the different seasons have characteristic pollutants, as follows:spring(PM10, 48.91%), summer(O3, 81.97%), autumn(PM10 and PM2.5, 47.54% and 32.79%), and winter(PM2.5, 74.44%), which are related to the variation of meteorological conditions. Furthermore, the PM10(spring) concentration correlated negatively with the wind speed, presenting a high distribution in the northwest and low in the southeast, with a southerly transmission direction(53.32%). Central and southern Hebei, central and northern Henan, and central Shanxi are the potential sources of pollution(WPCWTij ≥ 160 µg·m-3), impacting western Shandong and northwest Shanxi(WPSCFij ≥ 0.3) with PM10. Moreover, the O3(summer) concentration correlated positively with temperature, and negatively with humidity. The southeast-south(54.24%) is the source direction of the transmission, and the potential source of O3 pollution is an arc area with Shijiazhuang in the center and Cangzhou and Heze as the double wings. Lastly, the PM2.5(autumn and winter) concentration correlated positively with humidity, and the winter concentration shows an increasing gradient from west to east. The trajectories of PM2.5 clustered the source directions:autumn(northeast-southeast, 74.75%), winter(northwest, 55.47%); central and southern Hebei, central and western Shanxi and northern Henan are the concentrated sources of potential pollution(WPCWTij ≥ 180 µg·m-3).

[Seasonal Variation and Source Apportionment of Carbonaceous Species in PM2.5 in Chengde].

In order to study the seasonal variations and pollution sources of carbonaceous species in PM2.5 in Chengde, the concentration of these components was determined in atmospheric PM2.5 samples collected in January, April, July, and October 2019. The change in carbonaceous species were analyzed based on the estimation of the ratio of organic carbon(OC) to elemental carbon(EC), total carbonaceous aerosol(TCA), and secondary organic carbon(SOC). The source of these pollutants was determined by means of the backward trajectory and principal component analysis(PCA). The results showed that the mean mass concentrations of PM2.5, OC, and EC during the sampling period were(31.26±21.39) µg·m-3,(13.27±8.68) µg·m-3, and(2.80±1.95) µg·m-3, respectively. The seasonal variations of PM2.5 were:winter[(47.68±30.37) µg·m-3]>autumn[(28.72±17.12) µg·m-3]>spring[(26.59±15.32) µg·m-3]>summer[(23.17±8.38) µg·m-3], consistent with the trend of total carbon(TC), OC, and EC. The source of OC and EC during winter(R2=0.85) was similar. Based on the ratio of OC/EC, all four seasons were affected by traffic and coal-burning source emissions, and the most affected season by bituminous coal emissions was winter. The average concentration of TCA was(21.38±13.68) µg·m-3, which accounted for 68.39% of PM2.5. The order of secondary conversion rate(SOC/OC) was:spring(54.09%) >autumn(37.64%) >summer(32.91%) >winter(25.43%). The results of the backward trajectory simulation show that the pollutant concentrations carried by air masses are relatively low in spring and summer, and the transport channels of pollutants are southwest in autumn and northwest in winter. The results of the PCA showed that the key to reducing PM2.5 in Chengde is to control emissions from vehicle exhausts, and coal and biomass combustion sources.

[Spatio-Temporal Evolution Characteristics and Source Apportionment of O3 and NO2 in Shijiazhuang].

Ground-level O3, NO2, and meteorological (temperature, humidity, wind speed, precipitation, and sunshine duration) data from 18 counties in Shijiazhuang City from 2014 to 2017, and volatile organic compounds (VOCs) data for Summer 2017, were analyzed to explore the spatial patterns, evolution, influencing factors, and source apportionment of O3 and NO2 in Shijiazhuang City. Network analysis and inverse distance weighted (IDW) spatial autocorrelation and backward trajectories analyses were performed. The results indicate that O3 concentrations increased between 2014 and 2017, and monthly variations showed a unimodal trend. The typical period of peak O3 pollution (O3 ≥ 160 µg·m-3) was from May to September, characterized by high temperatures, low humidity, weak winds, and strong solar radiation. The O3 concentrations were negatively correlated with the NO2. Furthermore, O3 concentrations increased year-on-year since 2015 in main urban area, and the dominant pollutant type had changed from NO2 (2014 to 2016) to VOCs (2016 and 2017). However, the O3 concentration of county-areas limited by the VOCs. The main factors affecting O3 concentrations were industry, agriculture, economy, and population, and centers of O3 pollution associated with secondary industry appeared in the main urban areas of Shijiazhuang and Luancheng. Moreover, VOCs trajectories during the summer monitoring period were clustered in three source directions:(A) East-northeast, 26.67%; (B) Northwest-west, 43.33%; and (C) Southeast-south, 30%). Trajectories (A) and (C) were the dominant directions of VOC transmission (east-southeast).

Expression, association with clinicopathological features and prognostic potential of CEP55, p-Akt, FoxM1 and MMP-2 in astrocytoma.

Centrosomal protein 55 (CEP55) is a member of the centrosomal-associated protein family and participates in the regulation of cytokinesis during cell mitosis. However, aberrant CEP55 protein expression has been observed in human tumors. In addition, CEP55 regulates the biological functions of tumors by inducing the Akt pathway and upregulating forkhead box protein M1 (FoxM1) and matrix metalloproteinase-2 (MMP-2). In the present study, the levels, clinicopathological features and prognostic potential of CEP55, phosphorylated Akt (p-Akt), FoxM1 and MMP-2 in astrocytoma were evaluated. CEP55, p-Akt, FoxM1 and MMP-2 levels were examined in 27 normal brain tissues and 262 astrocytoma tissues by using immunohistochemistry. Furthermore, Kaplan-Meier analysis and Cox proportional hazards models were applied to predict the prognosis of patients with astrocytoma. The results indicated that expression levels of CEP55 and other proteins were elevated in human astrocytoma compared with those in normal brain tissue. The levels of the selected proteins were increased as the tumor grade increased. Furthermore, CEP55 expression was positively correlated with p-Akt, FoxM1 and MMP-2 levels in astrocytoma. Overall survival analysis revealed that patient prognosis was associated with CEP55, p-Akt, FoxM1 and MMP-2 levels, as well as with the tumor grade and patient age. Furthermore, CEP55, FoxM1, tumor grade and patient age were independent prognostic factors in astrocytoma according to multivariate analysis. Taken together, the present results suggested that CEP55, p-Akt, FoxM1 and MMP-2 have crucial roles in the progression and prognosis of human astrocytoma and that CEP55 and FoxM1 may be potential therapeutic targets.

Clinical significance of AJUBA, YAP1, and MMP14 expression in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is generally known to be a highly fatal cancer, and thus novel molecular targets are needed to improve its diagnosis and treatment. AJUBA has been shown to regulate cell cycle, adhesion, proliferation, apoptosis, and migration in many malignant tumors. However, the clinical significance of AJUBA in ESCC tumor metastasis remains unclear. In this study, we explored the role of AJUBA, Yes-associated protein 1 (YAP1), and matrix metalloproteinase 14 (MMP14) in the clinical presentation and survival of ESCC. Immunohistochemical staining showed higher expression of these proteins in cancer tissues than in paired adjacent tissues, and this upregulation was differently related to lymph node metastasis and TNM stage. AJUBA expression was positively correlated with that of YAP1. High expression of MMP14 was associated with reduced survival. In general, our findings reveal that AJUBA, YAP1, and MMP14 might function as oncoproteins and contribute to novel targeted therapy in ESCC.