IL-6 contributes to the suppression of T and NK cell anti-tumor activity in EGFR-mutant NSCLC

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Spatially Explicit Mapping of Historical Population Density with Random Forest Regression: A Case Study of Gansu Province, China, in 1820 and 2000

This study established a random forest regression model (RFRM) using terrain factors, climatic and river factors, distances to the capitals of provinces, prefectures (Fu, in Chinese Pinyin), and counties as independent variables to predict the population density. Then, using the RFRM, we explicitly reconstructed the spatial distribution of the population density of Gansu Province, China, in 1820 and 2000, at a resolution of 10 by 10 km. By comparing the explicit reconstruction with census data at the township level from 2000, we found that the RFRM-based approach mostly reproduced the spatial variability in the population density, with a determination coefficient (R2) of 0.82, a positive reduction of error (RE, 0.72) and a coefficient of efficiency (CE) of 0.65. The RFRM-based reconstructions show that the population of Gansu Province in 1820 was mostly distributed in the Lanzhou, Gongchang, Pingliang, Qinzhou, Qingyang, and Ningxia prefecture. The macro-spatial pattern of the population density in 2000 kept approximately similar with that in 1820. However, fine differences could be found. The 79.92% of the population growth of Gansu Province from 1820 to 2000 occurred in areas lower than 2500 m. As a result, the population weighting in the areas above 2500 m was ~9% in 1820 while it was greater than 14% in 2000. Moreover, in comparison to 1820, the population density intensified in Lanzhou, Xining, Yinchuan, Baiyin, Linxia, and Tianshui, while it weakened in Gongchang, Qingyang, Ganzhou, and Suzhou

Evaluation of the Performance of a Composite Water Control Process for Offshore Bottom Water Fractured Gas Reservoirs

Natural gas, as one of the main energy sources of the modern clean energy system, is also an important raw material for the chemical industry, and the stable extraction of natural gas reservoirs is often affected by bottom water. It is difficult to control water in natural gas reservoirs, while fractured gas reservoirs are even more demanding. This is due to the complexity of the seepage laws of gas and water in fractures, resulting in the poor applicability of conventional processes for water control. Continuous research is needed to propose a process with effective control capabilities for bottom-water fractured gas reservoirs. Aiming at the above difficulties, this paper is based on a large-scale three-dimensional physical simulation device to carry out physical model design and simulation results testing and analysis. The water control ability of the combination of density-segmented sieve tubes and continuous packers in fractured gas reservoirs is explored. The physical simulation results show that the fracture distribution characteristics control the upward transportation path of bottom water. According to the segmentation characteristics of the fractures at the horizontal section location, optimizing the number of horizontal well screen tube segments and the density of boreholes reduces the cone-in velocity of bottom water before connecting the fractures to a certain extent. And the combined process has different degrees of water control ability for the three stages of bottom water transportation from the fractured gas reservoir to the production well. As the degree of water in the production well increases, the water control ability of the process gradually decreases. After the implementation of the water control process, the water-free gas production period was extended by about 6.84%, and the total production time was extended by about 6.46%. After the shutdown of the horizontal wells, the reduction in daily water production can still reach 21% compared to the natural extraction. The results of this research can provide process suggestions for water control in offshore fractured reservoirs and further ensure stable production in offshore fractured gas reservoirs

Characterization of Rabbit Nucleotide-Binding Oligomerization Domain 1 (NOD1) and the Role of NOD1 Signaling Pathway during Bacterial Infection

Nucleotide-binding oligomerization domain 1 (NOD1) is the most prominent of all NOD-like receptors, which in the mammalian innate immune system, serve as intracellular receptors for pathogens and endogenous molecules during tissue injury. From rabbit kidney cells, we cloned rabbit NOD1 (rNOD1) and identified an N-terminal caspase activation and recruitment domain, a central NACHT domain, and C-terminal leucine-rich repeat domains. rNOD1 was expressed in all tested tissues; infection with Escherichia coli induced significantly higher expression in the spleen, liver, and kidney compared to other tissues. The overexpression of rNOD1 induced the expression of proinflammatory cytokines Il1b, Il6, Il8, Ifn-γ, and Tnf and defensins, including Defb124, Defb125, Defb128, Defb135, and Np5 via activation of the nuclear factor (NF)-κB pathway. Overexpression of rNOD1 inhibited the growth of E. coli, whereas knockdown of rNOD1 or inhibition of the NF-κB pathway promoted the growth of E. coli. rNOD1 colocalized with LC3, upregulated autophagy pathway protein LC3-II, and increased autolysosome formation in RK-13 cells infected with E. coli. In summary, our results explain the primary signaling pathway and antibacterial ability of rNOD1, as well as the induction of autophagy that it mediates. Such findings suggest that NOD1 could contribute to therapeutic strategies such as targets of new vaccine adjuvants or drugs

Macitentan (ACT-064992), a Tissue-Targeting Endothelin Receptor Antagonist, Enhances Therapeutic Efficacy of Paclitaxel by Modulating Survival Pathways in Orthotopic Models of Metastatic Human Ovarian Cancer

Potential treatments for ovarian cancers that have become resistant to standard chemotherapies include modulators of tumor cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice. Mice with established disease were treated with vehicle (control), paclitaxel (weekly, intraperitoneal injections), macitentan (daily oral administrations), or a combination of paclitaxel and macitentan. Treatment with paclitaxel decreased tumor weight and volume of ascites. Combination therapy with macitentan and paclitaxel reduced tumor incidence and further reduced tumor weight and volume of ascites when compared with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but alone had no effect on tumor incidence or ascites. Immunohistochemical analyses revealed that treatment with macitentan and macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of paclitaxel. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. Collectively, these results show that administration of macitentan in combination with paclitaxel prevents the progression of ovarian cancer in the peritoneal cavity of nude mice in part by inhibiting survival pathways of both tumor cells and tumor-associated endothelial cells