Role of vascular endothelial growth factor D in lung adenocarcinoma immunotherapy response.

OBJECTIVE: To identify key genes associated with tumor-associated macrophages (TAMs), tumor immunotherapy, in the prognosis of lung adenocarcinoma (LUAD). METHODS: The mRNA expression profiles of LUAD samples were obtained from The Cancer Genome Atlas (TCGA) database. The "CIBERSORT" R package was employed to calculate the proportion of innate immune cell infiltration in both tumor and adjacent normal tissues. TAM-associated genes in LUAD were identified to construct a prognostic risk model using weighted gene correlation network analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses (COX). The IMvigor210 cohort was utilized to validate the roles of these genes as predictors of immunotherapy response. Tissue microarrays, immunofluorescence staining, and mRNA level detection methods were used to determine the correlation of risk factors in LUAD tissues. RESULTS: CIBERSORT analysis revealed significant differences in innate immune cells between tumor and adjacent tissues. Seventy-four differential genes linked to these cells were identified from WGCNA. Four hub genes (endothelin receptor type B, vascular endothelial growth factor D (VEGFD), latent transforming growth factor beta binding protein 4 (LTBP4), and fibroblast growth factor receptor 4 (FGFR4)) in the TAM prognostic model were identified as independent prognostic risk factors (P < 0.05). VEGFD expression was identified as a low-risk factor for LUAD prognosis prediction (P < 0.05). Moreover, low-risk patients exhibited higher sensitivity to anti-PD-L1 therapy compared to high-risk patients (P < 0.05). VEGFD levels were negatively correlated with programmed cell death 1 (PD-1) levels (r = -0.363; P < 0.05), suggesting that VEGFD may serve as a predictor for anti-PD-1 treatment. CONCLUSIONS: VEGFD is associated with innate immunity in LUAD, it can predict LUAD prognosis, and therefor may be a potential predictor for anti-PD-1 treatment in patients with LUAD.

Self-assembled albumin nanoparticles induce pyroptosis for photodynamic/photothermal/immuno synergistic therapies in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by a high degree of malignancy, early metastasis, limited treatment, and poor prognosis. Immunotherapy, as a new and most promising treatment for cancer, has limited efficacy in TNBC because of the immunosuppressive tumor microenvironment (TME). Inducing pyroptosis and activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity have become an emerging strategy for enhancing tumor immunotherapy. In this study, albumin nanospheres were constructed with photosensitizer-IR780 encapsulated in the core and cGAS-STING agonists/H2S producer-ZnS loaded on the shell (named IR780-ZnS@HSA). In vitro, IR780-ZnS@HSA produced photothermal therapy (PTT) and photodynamic therapy (PDT) effects. In addition, it stimulated immunogenic cell death (ICD) and activated pyroptosis in tumor cells via the caspase-3-GSDME signaling pathway. IR780-ZnS@HSA also activated the cGAS-STING signaling pathway. The two pathways synergistically boost immune response. In vivo, IR780-ZnS@HSA + laser significantly inhibited tumor growth in 4T1 tumor-bearing mice and triggered an immune response, improving the efficacy of the anti-APD-L1 antibody (aPD-L1). In conclusion, IR780-ZnS@HSA, as a novel inducer of pyroptosis, can significantly inhibit tumor growth and improve the efficacy of aPD-L1.

TNFSF15 and MIA Variant Associated with Immunotherapy and Prognostic Evaluation in Esophageal Cancer.

Background: Esophageal cancer (ESCA) is a common gastrointestinal tumor, and China is one of the regions with a high incidence. Tumor immune-related cells play important roles in the tumorigenesis and development of ESCA. However, the role of tumor immune-related genes in the development of ESCA has not been established. Methods: In this study, weighted gene coexpression network analysis (WGCNA) was used to analyze ESCA gene expression using data from The Cancer Genome Atlas (TCGA) database. Gene expression was associated with clinical traits, and modules related to CD8+T cells, dendritic cells, and regulatory T cells (Tregs) were obtained. Results: The GO analysis showed that inflammatory chemotaxis networks were activated by cell chemotaxis, chemokine activity, and chemokine binding receptor. Three hub genes (IL17C, TNFSF15, and MIA) related to tumor immunity and metastasis were identified by WGCNA, and the abnormal expression of each hub gene in ESCA has a poor prognosis, especially in patients with high expression (P < 0.05). The risk assessment analysis also showed that tumor stage was positively correlated with tumor risk in ESCA (P < 0.05). Therefore, more than 50 pairs of tumor tissues from the T1-T3 stages with different degrees of differentiation and paracancerous tissues were selected to confirm the expression of the three genes using RT-qPCR and immunofluorescence (IF). The infiltration of CD8+ T cells in tumor tissues was lower than that in normal tissues. According to the RT-qPCR, the expressions of IL17 C, TNFSF15, and MIA in moderately and poorly differentiated tissues were significantly higher than those in normal tissues (P < 0.05). In contrast, their expressions were decreased in high differentiated tissues (P < 0.05). Furthermore, IL17C, TNFSF15, and MIA were all positively correlated with immune checkpoint PD-1; TNFSF15 and MIA were also positively correlated with CTLA4, TIGIT, and CD96. Conclusion: In summary, IL17C, TNFSF15, and MIA may act as biomarkers for prognosis in moderately and poorly differentiated ESCAs, and they may be used as predictive genes of immunotherapy associated with CD8+ T cell and Tregs invasion in ESCAs.

Ecosystem services, landscape pattern, and landscape ecological risk zoning in China.

Ecosystem services represent a bridge between natural ecosystems and human well-being and are closely associated with landscape ecological risk (LER). Delimiting reasonable LER areas is important for ecosystem protection, and it is essential to link ecosystem services to LER zoning. However, only a few studies have achieved this, and the zoning accuracy of LER remains poorly understood. Therefore, in this study, we evaluated the ecosystem service value (ESV) and LER index using the equivalent value method and landscape pattern index via the remote sensing of land use data at the county level in China in 2000-2015. We applied bivariate spatial autocorrelation as well as the grey correlation analysis model to analyse the ESV-LER spatial relationships and developed a general framework to improve the accuracy of LER zoning. We found that the average ESV increased from $761.42 thousand/km2 in 2000 to $766.16 thousand/km2 in 2015, while the LER index continuously decreased in China. We also discerned a significant negative correlation between ESV and LER (p < 0.001), whereas approximately 750 counties in China exhibited high ESV and low LER indices during the study period. The final LER zoning revealed that the high-LER areas in China were mainly located in the plain areas, and the proportion of counties with high LER levels increased from 17.97% in 2000 to 26.56% in 2015. Overall, our results have important implications for ecological security, future landscape planning and design, and ecologically sustainable development in China.

Impact of Urbanization on Ecosystem Services Balance in the Han River Ecological Economic Belt, China: A Multi-Scale Perspective.

Urbanization intensification seriously interferes with the supply capacity and demand level of ecosystem services (ESs); therefore, it affects the balance state of ESs. Coordination of urbanization development and ecosystem protection in the ecological economic belt is vital for ecological protection and high-quality development of the ecological economic belt. However, previous studies lacked multi-scale analysis of the impact of urbanization elements on the ESs balance index (ESBI) in the ecological economic belt. In this study, a geographically weighted regression model was employed to measure the spatial non-stationary patterns associated with the impact of urbanization elements on the ESBI at 5 km and 10 km in the Han River Ecological Economic Belt (HREEB) in China based on land use data. The main findings were shown as follows. The supply capacity and demand level of ESs in the HREEB increased from 2000 to 2020 simultaneously, while the ESBI showed a decreasing trend. In mountainous areas, the ESBIs were evidently higher than those in the plain areas. During the study period, the urbanization level in the HREEB improved evidently, and the urbanization levels of the middle and lower reaches of the Hanjiang River were relatively high. Significant spatial dependence between urbanization elements and the ESBI was identified. Urbanization had significant positive and negative impacts on ESBI, and there were significant differences among different scales. The findings of this study can act as a decision-making reference for ecological protection and high-quality development of the HREEB and can also provide a perspective for exploring the impact of urbanization on the ESBI of the ecological economic belt in other similar regions.

Evolution Characteristics and Formation Mechanism of Production-Living-Ecological Space in China: Perspective of Main Function Zones.

The main function zone (MFZ) is the major strategy of China's economic development and ecological environment protection. Clarifying the logical relationship between "MFZ strategy" and "territorial spatial layout" is vital to construct regional economic layout and territorial spatial supporting system of high-quality development. However, few studies have revealed the evolution process and formation mechanism of the production-living-ecological space (PLES) structure of China's MFZ over a long period of time. To bridge the gap, based on the land use dataset in China from 1980 to 2020, this study analyzed the evolution patterns of PLES in China's MFZs using multiple methods and measured the formation mechanism of PLES in different types of MFZs with the GeoDetector model. Results showed that the spatial structure of China's national territory has evolved drastically in the past 40 years, showing significant horizontal regional differentiation and vertical gradient differentiation. Ecological space has been continuously decreasing, while production space and living space have been continuously increasing, and the evolution of PLES varied significantly in different MFZs. During the study period, the gravity center of PLES in China all moved westward. The spatial distribution pattern of production space and living space was from northeast to southwest, and the ecological space was from east to west. The evolution of China's territorial spatial structure was subject to the combined effects of natural and socio-economic factors, exhibiting significant differences in different MFZs. Land use intensity had the most prominent influence on the formation of PLES, followed by elevation. The influences of different factors on PLES structure were strengthened mainly through two types of nonlinear enhancement and dual-factor enhancement. This study can provide scientific support for the optimal management and high-quality development of territorial space in China.

Spatial Distribution Characteristics and Influencing Factors of Traditional Villages in China.

Traditional villages carry the essence of traditional culture, which is necessary for rural revitalisation. However, continuous urban expansion has resulted in the rapid decline and even disappearance of these villages in recent decades. It is necessary to analyse the spatial pattern and influencing factors for the protection and development of traditional villages. Previous studies focused on the value and theoretical protection mechanism of traditional villages in China, disregarding their spatial distribution characteristics and influencing factors. Thus, we employed a Geographic Information System and spatial analysis with mathematical statistics to analyse the characteristics of these villages. Moreover, we analysed the associated influencing factors both qualitatively and quantitatively. The results show that traditional villages were mainly distributed in the southeast of the Hu Line in China, with an unbalanced spatial distribution pattern and an agglomeration distribution tendency. In general, four major agglomeration areas of traditional villages formed at the junction of Hebei, Shandong, and Henan provinces; the border between the Guizhou, Guangxi, and Hunan provinces; the border between the Anhui, Zhejiang, and Jiangxi provinces; and northwestern and southeastern Yunnan provinces. Traditional villages also existed in areas with relief lower than 300 m, altitudes of less than 1000 m, and slopes of less than 10°. They were mostly distributed in subtropical and temperate zones. A positive correlation was found between traditional villages and the level of economic development, population, and human history; conversely, the transportation network was negatively correlated. This study reveals the complex and diverse characteristics of traditional villages and provides scientific suggestions for their future protection, development, and utilisation.