Search

Abstract Background Skin cutaneous melanoma (SKCM) poses a significant public health challenge due to its aggressive nature and limited treatment options. To address this, the study introduces the Tumor Mutational Burden-Derived Immune lncRNA Prognostic Index (TILPI) as a potential prognostic tool for SKCM. Methods TILPI was developed using a combination of gene set variation analysis, differential expression analysis, and COX regression analysis. Additionally, functional experiments were conducted to validate the findings, focusing on the effects of STARD4-AS1 knockdown on SKCM tumor cell behavior. These experiments encompassed assessments of tumor cell proliferation, gene and protein expression, migration, invasion, and in vivo tumor growth. Results The results demonstrated that knockdown of STARD4-AS1 led to a significant reduction in tumor cell proliferation and impaired migration and invasion abilities. Moreover, it resulted in the downregulation of ADCY4, PRKACA, and SOX10 gene expression, as well as decreased protein expression of ADCY4, PRKACA, and SOX10. In vivo experiments further confirmed the efficacy of STARD4-AS1 knockdown in reducing tumor growth. Conclusions This study elucidates the mechanistic role of STARD4-AS1 and its downstream targets in SKCM progression, highlighting the importance of the ADCY4/PRKACA/SOX10 pathway. The integration of computational analysis with experimental validation enhances the understanding of TILPI and its clinical implications. Overall, the findings underscore the potential of novel computational frameworks like TILPI in predicting and managing SKCM, particularly through targeting the ADCY4/PRKACA/SOX10 pathway.

Based on the oil and gas exploration in western depression of the Qaidam Basin, NW China, combined with the geochemical, seismic, logging and drilling data, the basic geological conditions, oil and gas distribution characteristics, reservoir-forming dynamics, and hydrocarbon accumulation model of the Paleogene whole petroleum system (WPS) in the western depression of the Qaidam Basin are systematically studied. A globally unique ultra-thick mountain-style WPS is found in the western depression of the Qaidam Basin. Around the source rocks of the upper member of the Paleogene Lower Ganchaigou Formation, the structural reservoir, lithological reservoir, shale oil and shale gas are laterally distributed in an orderly manner and vertically overlapped from the edge to the central part of the lake basin. The Paleogene WPS in the western depression of the Qaidam Basin is believed unique in three aspects. First, the source rocks with low organic matter abundance are characterized by low carbon and rich hydrogen, showing a strong hydrocarbon generating capacity per unit mass of organic carbon. Second, the saline lake basinal deposits are ultra-thick, with mixed deposits dominating the center of the depression, and strong vertical and lateral heterogeneity of lithofacies and storage spaces. Third, the strong transformation induced by strike-slip compression during the Himalayan resulted in the heterogeneous enrichment of oil and gas in the mountain-style WPS. As a result of the coordinated evolution of source-reservoir-caprock assemblage and conducting system, the Paleogene WPS has the characteristics of “whole process” hydrocarbon generation of source rocks which are low-carbon and hydrogen-rich, “whole depression” ultra-thick reservoir sedimentation, “all direction” hydrocarbon adjustment by strike-slip compressional fault, and “whole succession” distribution of conventional and unconventional oil and gas. Due to the severe Himalayan tectonic movement, the western depression of the Qaidam Basin evolved from depression to uplift. Shale oil is widely distributed in the central lacustrine basin. In the sedimentary system deeper than 2 000 m, oil and gas are continuous in the laminated limy-dolomites within the source rocks and the alga limestones neighboring the source kitchen, with intercrystalline pores, lamina fractures in dolomites and fault-dissolution bodies serving as the effective storage space. All these findings are helpful to supplement and expand the WPS theory in the continental lake basins in China, and provide theoretical guidance and technical support for oil and gas exploration in the Qaidam Basin.

Abstract The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P

In recent years, great breakthroughs have been made in the exploration and development of natural gas in deep coal-rock reservoirs in Junggar, Ordos and other basins in China. In view of the inconsistency between the industrial and academic circles on this new type of unconventional natural gas, this paper defines the concept of “coal-rock gas” on the basis of previous studies, and systematically analyzes its characteristics of occurrence state, transport and storage form, differential accumulation, and development law. Coal-rock gas, geologically unlike coalbed methane in the traditional sense, occurs in both free and adsorbed states, with free state in abundance. It is generated and stored in the same set of rocks through short distance migration, occasionally with the accumulation from other sources. Moreover, coal rock develops cleat fractures, and the free gas accumulates differentially. The coal-rock gas reservoirs deeper than 2000 m are high in pressure, temperature, gas content, gas saturation, and free-gas content. In terms of development, similar to shale gas and tight gas, coal-rock gas can be exploited by natural formation energy after the reservoirs connectivity is improved artificially, that is, the adsorbed gas is desorbed due to pressure drop after the high-potential free gas is recovered, so that the free gas and adsorbed gas are produced in succession for a long term without water drainage for pressure drop. According to buried depth, coal rank, pressure coefficient, reserves scale, reserves abundance and gas well production, the classification criteria and reserves/resources estimation method of coal-rock gas are presented. It is preliminarily estimated that the coal-rock gas in place deeper than 2 000 m in China exceeds 30×1012 m3, indicating an important strategic resource for the country. The Ordos, Sichuan, Junggar and Bohai Bay basins are favorable areas for large-scale enrichment of coal-rock gas. The paper summarizes the technical and management challenges and points out the research directions, laying a foundation for the management, exploration, and development of coal-rock gas in China.

Summary: Background: Multiplexed immunofluorescence (mIF) staining, such as CODEX and MIBI, holds significant clinical value for various fields, such as disease diagnosis, biological research, and drug development. However, these techniques are often hindered by high time and cost requirements. Methods: Here we present a Multimodal-Attention-based virtual mIF Staining (MAS) system that utilises a deep learning model to extract potential antibody-related features from dual-modal non-antibody-stained fluorescence imaging, specifically autofluorescence (AF) and DAPI imaging. The MAS system simultaneously generates predictions of mIF with multiple survival-associated biomarkers in gastric cancer using self- and multi-attention learning mechanisms. Findings: Experimental results with 180 pathological slides from 94 patients with gastric cancer demonstrate the efficiency and consistent performance of the MAS system in both cancer and noncancer gastric tissues. Furthermore, we showcase the prognostic accuracy of the virtual mIF images of seven gastric cancer related biomarkers, including CD3, CD20, FOXP3, PD1, CD8, CD163, and PD-L1, which is comparable to those obtained from the standard mIF staining. Interpretation: The MAS system rapidly generates reliable multiplexed staining, greatly reducing the cost of mIF and improving clinical workflow. Funding: Stanford 2022 HAI Seed Grant; National Institutes of Health 1R01CA256890.

Abstract Gastric cancer (GC) contains subpopulations of cancer stem cells (CSCs), which are described as the main contributors in tumor initiation and metastasis. It is necessary to clarify the molecular mechanism underlying CSCs phenotype and develop novel biomarkers and therapeutic targets for gastric cancer. Here, we show that POLQ positively regulates stem cell-like characteristics of gastric cancer cells, knockdown of POLQ suppressed the stemness of GC cells in vitro and in vivo. Further mechanistic studies revealed that POLQ knockdown could downregulate the expression of dihydroorotate dehydrogenase (DHODH). DHODH overexpression rescued the reduced stemness resulted by POLQ knockdown. Furthermore, we found that POLQ expression correlated with resistance to ferroptosis, and POLQ inhibition renders gastric cancer cells more vulnerable to ferroptosis. Further investigation revealed that POLQ regulated DHODH expression via the transcription factors E2F4, thereby regulating ferroptosis resistance and stemness of gastric cancer cells. Given the importance of POLQ in stemness and ferroptosis resistance of GC, we further evaluated the therapeutic potential of POLQ inhibitor novobiocin, the results show that novobiocin attenuates the stemness of GC cells and increased ferroptosis sensitivity. Moreover, the combination of POLQ inhibitor and ferroptosis inducer synergistically suppressed MGC-803 xenograft tumor growth and diminished metastasis. Our results identify a POLQ-mediated stemness and ferroptosis defense mechanism and provide a new therapeutic strategy for gastric cancer.

ABSTRACTLactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

ABSTRACTThe gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A−/−mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.

Abstract Phosphodiesterase‐5 (PDE5) inhibitors are used clinically for the treatment of erectile dysfunction, pulmonary arterial hypertension, and other urological diseases. Emerging evidences have suggested the therapeutic capacity of PDE5 inhibitors as the repurposed drugs in oncology. However, the essential immune function of PDE5 inhibitors against cancer in tumor microenvironment (TME) remains unclear. This review aimed to summarize the recent advances regarding the repurposing of PDE5 inhibitors as anti‐cancer agents for cancer management to enhance the anti‐tumor immune response by mediating various immune cells, which included the myeloid‐derived suppressor cells, macrophages, T cells, fibroblasts, and natural killer cells in TME. Moreover, artificial intelligence (AI), as a new approach, is composed of traditional machine learning and deep learning methods and could be potentially used to identify the targets of immune cells in TME and predict the efficacy for repurposed drug toward malignancies. In summary, these endeavors provide novel insights into the comprehensive strategies for PDE5 inhibitors mediating immune cells against cancer and AI‐based approach for future drug repurposing exploration.

The investigate of novel cementitious system suitable for negative temperature concreting was the key way to solve the high energy consumption of traditional winter construction. In this study, the matching effects of anti-freezing agents (CaCl2, NaNO2 and Li2CO3) on the Portland cement-calcium sulphoaluminate cement blended system (PC-CSA system) based on Taguchi-Grey Relational Analysis (Taguchi-GRA method) were studied. The setting time, compressive strength and freezing point were tested, and the hydration products, pore structure and morphology were also analyzed to reveal the mechanism. The results showed that CaCl2 was the main parameter influencing the initial and final setting time. Whether at the early stage of continuous negative temperature curing, or from negative to positive temperature curing, CaCl2 had a dominant influence on the compressive strength of PC-CSA system, which promoted the increase of the early hydration products, resulting in the rapid formation of a network structure. At the later stage of continuous negative temperature curing, the influential parameter changed to NaNO2. The basic condition for hydration was provided due to the lowering of the freezing point of the liquid phase by NaNO2. The presence of Li2CO3 enhanced the promoting effect of CaCl2 on early strength. The optimal parameter combination for PC-CSA system was 1.0 % CaCl2, 2.0 % NaNO2 and 0.4 % Li2CO3 based on Taguchi-GRA method.

Abstract Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.

This paper considers a full-duplex relay-assisted system for covert communication, in which both the transmitter and the relay are the sender of covert messages. Different from current works that only consider the transmitter power optimization or relay power optimization individually, we propose a joint optimization approach for the transmitter and relay power, which is expected to enhance the system’s covert performance. We establish the minimum error detection probability using the Kullback-Leibler (KL) divergence, which serves as the foundation for formulating our joint optimization problem. The objective is to achieve the highest covert transmission rate within the constraints of covertness requirement and total power limitation. Employing a graphical method, we effectively transform inequality constraints into equality constraints, leading to the derivation of an optimal closed-form solution. The simulation results confirm the accuracy of the theoretical derivation and demonstrate that the proposed power allocation method is effective in determining the optimal power for both the transmitter and the full-duplex relay within a two-hop covert communication system.

In recent years, deep-learning methods have significantly improved the classification results in the field of plant-leaf recognition. However, limited by the model input, the original image needs to be compressed to a certain size before it can be input into the convolutional neural network. This results in great changes in the shape and texture information of some samples, thus affecting the classification accuracy of the model to a certain extent. Therefore, a minimum enclosing quadrate (MEQ) method is proposed to standardize the sample datasets. First, the minimum enclosing rectangle (MER) of the leaf is obtained in the original image, and the target area is clipped. Then, the minimum enclosing quadrate of the leaf is obtained by extending the short side of the rectangle. Finally, the sample is compressed to fit the input requirements of the model. In addition, in order to further improve the classification accuracy of plant-leaf recognition, an EC-ResNet50 model based on transfer-learning strategy is proposed and further combined with the MEQ method. The Swedish leaf, Flavia leaf, and MEW2012 leaf datasets are used to test the performance of the proposed methods, respectively. The experimental results show that using the MEQ method to standardize datasets can significantly improve the classification accuracy of neural networks. The Grad-CAM visual analysis reveals that the convolutional neural network exhibits a higher degree of attention towards the leaf surface features and utilizes more comprehensive feature regions during recognition of the leaf samples processed by MEQ method. In addition, the proposed MEQ + EC-ResNet50 method also achieved the best classification results among all the compared methods. This experiment provides a widely applicable sample standardization method for leaf recognition research, which can avoid the problem of sample deformation caused by compression processing and reduce the interference of redundant information in the image to the classification results to a certain degree.

Background Only a subset of patients with gastric cancer experience long-term benefits from immune checkpoint inhibitors (ICIs). Currently, there is a deficiency in precise predictive biomarkers for ICI efficacy. The aim of this study was to develop and validate a pathomics-driven ensemble model for predicting the response to ICIs in gastric cancer, using H&E-stained whole slide images (WSI).Methods This multicenter study retrospectively collected and analyzed H&E-stained WSIs and clinical data from 584 patients with gastric cancer. An ensemble model, integrating four classifiers: least absolute shrinkage and selection operator, k-nearest neighbors, decision trees, and random forests, was developed and validated using pathomics features, with the objective of predicting the therapeutic efficacy of immune checkpoint inhibition. Model performance was evaluated using metrics including the area under the curve (AUC), sensitivity, and specificity. Additionally, SHAP (SHapley Additive exPlanations) analysis was used to explain the model’s predicted values as the sum of the attribution values for each input feature. Pathogenomics analysis was employed to explain the molecular mechanisms underlying the model’s predictions.Results Our pathomics-driven ensemble model effectively stratified the response to ICIs in training cohort (AUC 0.985 (95% CI 0.971 to 0.999)), which was further validated in internal validation cohort (AUC 0.921 (95% CI 0.839 to 0.999)), as well as in external validation cohort 1 (AUC 0.914 (95% CI 0.837 to 0.990)), and external validation cohort 2 (0.927 (95% CI 0.802 to 0.999)). The univariate Cox regression analysis revealed that the prediction signature of pathomics-driven ensemble model was a prognostic factor for progression-free survival in patients with gastric cancer who underwent immunotherapy (p

RationaleWith the accelerating process of population aging, the comorbidity of chronic disease (CCD) has become a major public health problem that threatens the health of older adults.ObjectiveThis study aimed to assess whether CCD is associated with basic activities of daily living (BADL) and explore the factors influencing BADL in older adults.MethodA cross-sectional community health survey with stratified random sampling among older residents (≥60 years old) was conducted in 2022. A questionnaire was used to collect information on BADL, chronic diseases, and other relevant aspects. Propensity score matching (PSM) was used to match the older adults with and without CCD. Univariate and multivariate logistic regression analyses were used to explore the factors influencing BADL. PSM was used to match participants with single-chronic disease (SCD) and CCD.ResultsAmong the 47,720 participants, those with CCD showed a higher prevalence of BADL disability (13.07%) than those with no CCD (6.33%) and SCD (7.39%). After adjusting for potential confounders with PSM, 6,513 pairs of cases with and without CCD were matched. The univariate analysis found that the older adults with CCD had a significantly higher prevalence of BADL disability (13.07%, 851 of 6,513) than those without CCD (9.83%, 640 of 6,513, P < 0.05). The multivariate logistic regression analysis revealed that CCD was a risk factor for BADL in older adults [OR = 1.496, 95% CI: 1.393–1.750, P < 0.001]. In addition, age, educational level, alcohol intake, social interaction, annual physical examination, retirement benefits, depression, weekly amount of exercise, and years of exercise were related to BADL disability (P < 0.05). PSM matching was performed on participants with CCD and SCD and showed that the older adults with CCD had a significantly higher prevalence of BADL disability (13.07%, 851 of 6,513) than those with SCD (11.39%, 742 of 6,513, P < 0.05).ConclusionThe older adults with CCD are at a higher risk of BADL disability than their counterparts with no CCD or SCD. Therefore, we advocate paying attention to and taking measures to improve the health and quality of life of these individuals.

BackgroundPorcine deltacoronavirus (PDCoV), a novel swine enteropathogenic coronavirus, challenges the global swine industry. Currently, there are no approaches preventing swine from PDCoV infection.MethodsA new PDCoV strain named JS2211 was isolated. Next, the dimer receptor binding domain of PDCoV spike protein (RBD-dimer) was expressed using the prokaryotic expression system, and a novel nanoparticle containing RBD-dimer and ferritin (SC-Fe) was constructed using the SpyTag/SpyCatcher system. Finally, the immunoprotection of RBD-Fe nanoparticles was evaluated in mice.ResultsThe novel PDCoV strain was located in the clade of the late Chinese isolate strains and close to the United States strains. The RBD-Fe nanoparticles were successfully established. Immune responses of the homologous prime-boost regime showed that RBD-Fe nanoparticles efficiently elicited specific humoral and cellular immune responses in mice. Notably, high level PDCoV RBD-specific IgG and neutralizing antibody (NA) could be detected, and the histopathological results showed that PDCoV infection was dramatically reduced in mice immunized with RBD-Fe nanoparticles.ConclusionThis study effectively developed a candidate nanoparticle with receptor binding domain of PDCoV spike protein that offers protection against PDCoV infection in mice.

Abstract African swine fever virus (ASFV) is a highly contagious and deadly virus that leads to high mortality rates in domestic swine populations. Although the envelope protein CD2v of ASFV has been implicated in immunomodulation, the molecular mechanisms underlying CD2v-mediated immunoregulation remain unclear. In this study, we generated a stable CD2v-expressing porcine macrophage (PAM-CD2v) line and investigated the CD2v-dependent transcriptomic landscape using RNA-seq. GO terms enrichment analysis and gene set enrichment analysis revealed that CD2v predominantly affected the organization and assembly process of the extracellular matrix. Wound healing and Transwell assays showed that CD2v inhibited swine macrophage migration. Further investigation revealed a significant decrease in the expression of transcription factor early growth response 1 (EGR1) through inhibiting the activity of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Notably, EGR1 knockout in swine macrophages restricted cell migration, whereas EGR1 overexpression in PAM-CD2v restored the ability of macrophage migration, suggesting that CD2v inhibits swine macrophage motility by downregulating EGR1 expression. Furthermore, we performed chromatin immunoprecipitation and sequencing for EGR1 and the histone mark H3K27 acetylation (H3K27ac), and we found that EGR1 co-localized with the activated histone modification H3K27ac neighboring the transcriptional start sites. Further analysis indicated that EGR1 and H3K27ac co-occupy the promoter regions of cell locomotion-related genes. Finally, by treating various derivatives of swine macrophages with lipopolysaccharides, we showed that depletion of EGR1 decreased the expression of inflammatory cytokines including TNFα, IL1α, IL1β, IL6, and IL8, which play essential roles in inflammation and host immune response. Collectively, our results provide new insights into the immunomodulatory mechanism of ASFV CD2v.

The geochemical analysis and experimental simulation are comprehensively used to systematically study the hydrocarbon generation material, organic matter enrichment and hydrocarbon generation model of Paleogene source rock in the Western Qaidam Depression, Qaidam Basin, NW China. Three main factors result in low TOC values of saline lacustrine source rock of the Qaidam Basin: relatively poor nutrient supply inhibits the algal bloom, too fast deposition rate causes the dilution of organic matter, and high organic matter conversion efficiency causes the low residual organic carbon. For this type of hydrogen-rich organic matter, due to the reduction of organic carbon during hydrocarbon generation, TOC needs to be restored based on maturity before evaluating organic matter abundance. The hydrocarbon generation of saline lacustrine source rocks of the Qaidam Basin is from two parts: soluble organic matter and insoluble organic matter. The soluble organic matter is inherited from organisms and preserved in saline lacustrine basins. It generates hydrocarbons during low-maturity stage, and the formed hydrocarbons are rich in complex compounds such as NOS, and undergo secondary cracking to form light components in the later stage; the hydrocarbon generation model of insoluble organic matter conforms to the traditional “Tissot” model, with an oil generation peak corresponding to Ro of 1.0%.

Abstract Transcription factors (TFs) and long noncoding RNAs (lncRNAs) contribute to gastric cancer (GC). However, the roles of TFs and lncRNAs in the invasion and metastasis of GC remain largely unknown. Here, we observed that the transcription factor VAX2 is significantly upregulated in GC cells and tissues and acts as an oncogene. Moreover, high VAX2 expression is associated with the advancement of tumors in GC. In terms of functionality, the enforced expression of VAX2 promotes the proliferation and metastasis of GC cells. Mechanistically, VAX2 specifically interacts with the LINC01189 promoter and represses LINC01189 transcription. Furthermore, LINC01189 exhibits significant downregulation in GC and functions as a suppressor gene. Functionally, it inhibits migratory and invasive abilities in GC cells. In the context of GC metastasis, VAX2 plays a role in modulating it by trans-repressing the expression of LINC01189. Additionally, LINC01189 binds to hnRNPF to enhance hnRNPF degradation through ubiquitination. The cooperation between LINC01189 and hnRNPF regulates GC cell invasion and migration. In addition, both VAX2 and hnRNPF are highly expressed, while LINC01189 is expressed in at low levels in GC tissues compared to normal gastric tissues. Our study suggests that VAX2 expression facilitates, while LINC01189 expression suppresses, metastasis and that the VAX2-LINC01189-hnRNPF axis plays a contributory role in GC development.

The majority of the energy required for human survival is derived either directly or indirectly from solar radiation, thus it is important to investigate the periodic fluctuations in global solar radiation over time. In this study, six cities—Harbin, Shenyang, Beijing, Shanghai, Wuhan, and Guangzhou—located in the utilizable areas of solar energy in China, were selected, and the periodicity of the daily global solar radiation of these six cities with time were investigated by means of wavelet power spectrum analysis. Furthermore, Harbin, which has the lowest monthly average of global solar radiation in the cold of winter, was selected to explore the temporal evolution relationship between global solar radiation and other meteorological factors, and air quality factors by wavelet coherence analysis. Among the meteorological factors, the correlation between global solar radiation and sunshine duration exhibits the highest level of consistency. Global solar radiation demonstrates a positive association with atmospheric temperature/wind speed/precipitation over the annual cycle. Conversely, it displays a negative correlation with atmospheric pressure during this time frame. Additionally, on shorter timescales, global solar radiation is negatively correlated with air humidity and precipitation. Among air quality factors, the relationship between global solar radiation and CO/NO2/O3/PM2.5/PM10/SO2 primarily manifests in the broader annual cycle time scale. Within this context, global solar radiation shows a positive correlation with O3, while displaying negative associations with the other five air quality indicators. These findings contribute to urban environmental planning and the effective management and utilization of solar radiation, thereby providing valuable insights to guide the future development of cross-regional comprehensive energy utilization projects under diverse climatic and geographical conditions. Additionally, they serve as a reference for subsequent research aimed at enhancing the accuracy of global solar radiation prediction models.

Unmanned aerial vehicle (UAV) communication network is an important part of the future integrated space-aerial-ground network, and an effective support to achieve the global three-dimensional coverage of the communication network.The open characteristics of wireless channels make UAV communication vulnerable to malicious attacks by illegal users.Covert communication provides a promising solution for improving the security defense and privacy protection capabilities of UAV communication.However, the overlapping characteristics of the mobility of UAV systems and the requirements of covert communication scenarios bring severe challenges to the collaborative optimization of network resources.The UAV covert communication network was investigated from requirements, challenges, framework and main technologies perspectives.The architecture and model, performance characteristic, as well as potential candidate technologies were analyzed and discussed, in an attempt to outline the overall framework of UAV covert communication, and provide guidance for the subsequent research on UAV covert communication.

Abstract Substantial progress has been made in using deep learning for cancer detection and diagnosis in medical images. Yet, there is limited success on prediction of treatment response and outcomes, which has important implications for personalized treatment strategies. A significant hurdle for clinical translation of current data-driven deep learning models is lack of interpretability, often attributable to a disconnect from the underlying pathobiology. Here, we present a biology-guided deep learning approach that enables simultaneous prediction of the tumor immune and stromal microenvironment status as well as treatment outcomes from medical images. We validate the model for predicting prognosis of gastric cancer and the benefit from adjuvant chemotherapy in a multi-center international study. Further, the model predicts response to immune checkpoint inhibitors and complements clinically approved biomarkers. Importantly, our model identifies a subset of mismatch repair-deficient tumors that are non-responsive to immunotherapy and may inform the selection of patients for combination treatments.

Abstract Background The perineural invasion (PNI)-mediated inflammation of the tumor microenvironment (TME) varies among gastric cancer (GC) patients and exhibits a close relationship with prognosis and immunotherapy. Assessing the neuroinflammation of TME is important in predicting the response to immunotherapy in GC patients. Methods Fifteen independent cohorts were enrolled in this study. An inflammatory score was developed and validated in GC. Based on PNI-related prognostic inflammatory signatures, patients were divided into Clusters A and B using unsupervised clustering. The characteristics of clusters and the potential regulatory mechanism of key genes were verified by RT-PCR, western-blot, immunohistochemistry and immunofluorescence in cell and tumor tissue samples.The neuroinflammation infiltration (NII) scoring system was developed based on principal component analysis (PCA) and visualized in a nomogram together with other clinical characteristics. Results Inflammatory scores were higher in GC patients with PNI compared with those without PNI (P

Abstract Long non-coding RNAs (lncRNAs) have been functionally characterised in various diseases. LncRNA PAX-interacting protein 1-antisense RNA 1 (PAXIP1-AS1) has reportedly been associated with cancer development. However, its role in gastric cancer (GC) remains poorly understood. Here, we showed that PAXIP1-AS1 was transcriptionally repressed by homeobox D9 (HOXD9) and was significantly downregulated in GC tissues and cells. Decreased expression of PAXIP1-AS1 was positively correlated with tumour progression, while PAXIP1-AS1 overexpression inhibited cell growth and metastasis both in vitro and in vivo. PAXIP1-AS1 overexpression significantly attenuated HOXD9-enhanced epithelial-to-mesenchymal transition (EMT), invasion and metastasis in GC cells. Poly(A)-binding protein cytoplasmic 1 (PABPC1), an RNA-binding protein, was found to enhance the stability of PAK1 mRNA, leading to EMT progress and GC metastasis. PAXIP1-AS1 was found to directly bind to and destabilise PABPC1, thereby regulating EMT and metastasis of GC cells. In summary, PAXIP1-AS1 suppressed metastasis, and the HOXD9/PAXIP1-AS1/PABPC1/PAK1 signalling axis may be involved in the progression of GC.

Background Despite remarkable benefits have been provided by immune checkpoint inhibitors in gastric cancer (GC), predictions of treatment response and prognosis remain unsatisfactory, making identifying biomarkers desirable. The aim of this study was to develop and validate a CT imaging biomarker to predict the immunotherapy response in patients with GC and investigate the associated immune infiltration patterns.Methods This retrospective study included 294 GC patients who received anti-PD-1/PD-L1 immunotherapy from three independent medical centers between January 2017 and April 2022. A radiomics score (RS) was developed from the intratumoral and peritumoral features on pretreatment CT images to predict immunotherapy-related progression-free survival (irPFS). The performance of the RS was evaluated by the area under the time-dependent receiver operating characteristic curve (AUC). Multivariable Cox regression analysis was performed to construct predictive nomogram of irPFS. The C-index was used to determine the performance of the nomogram. Bulk RNA sequencing of tumors from 42 patients in The Cancer Genome Atlas was used to investigate the RS-associated immune infiltration patterns.Results Overall, 89 of 294 patients (median age, 57 years (IQR 48–66 years); 171 males) had an objective response to immunotherapy. The RS included 13 CT features that yielded AUCs of 12-month irPFS of 0.787, 0.810 and 0.785 in the training, internal validation, and external validation 1 cohorts, respectively, and an AUC of 24-month irPFS of 0.805 in the external validation 2 cohort. Patients with low RS had longer irPFS in each cohort (p

The characterization of epigenetic changes during cancer development and progression led to notable insights regarding the roles of cancer-specific epigenetic reprogramming. Recent studies showed that transcription factors (TFs) are capable to regulate epigenetic reprogramming at specific loci in different cancer types through their DNA-binding activities. However, the causal association of dynamic histone modification change mediated by TFs is still not well elucidated. Here we evaluated the impacts of 636 transcription factor binding activities on histone modification in 24 cancer types. We performed Instrumental Variables analysis by using genetic lesions of TFs as our instrumental proxies, which previously discovered to be associated with histone mark activities. As a result, we showed a total of 6 EpiTFs as strong directors of epigenetic reprogramming of histone modification in cancers, which alters the molecular and clinical phenotypes of cancer. Together our findings highlight a causal mechanism driven by the TFs and genome-wide histone modification, which is relevant to multiple status of oncogenesis.

As a highly pathogenic large DNA virus, African swine fever virus (ASFV) has huge particles and numerous encoded proteins. At present, few of the existing studies on ASFV proteins have investigated the function of p17. Specific antibodies against p17 to promote the development of prevention techniques against African swine fever (ASF) are urgently needed. Herein, we successfully expressed ASFV p17 in CHO cells using a suspension culture system and generated a monoclonal antibody (mAb) against p17. The mAb recognized a novel linear epitope (8LLSHNLSTREGIK20) and exhibited specific reactivity, which was conducive to the identification of ectopically expressed p17, the recombinant porcine reproductive and respiratory syndrome virus expressing p17, and the ASFV-SY18. The epitope was conservative among genotype I and genotype II ASFV strains. Overall, the mAb against p17 revealed efficient detection and promising application prospects, making it a useful tool for future vaccine research on ASF. Determination of the conserved linear epitope of p17 would contribute to the in-depth exploration of the biological function of ASFV antigen protein.

Abstract Background Peritoneal metastasis (PM) is not uncommon in patients with gastric cancer(GC), which affects clinical treatment decisions, but the relevant examination measures are not efficiently detected. Our goal was to develop a clinical radiomics nomogram to better predict peritoneal metastases. Methods A total of 3480 patients from 2 centers were divided into 1 training, 1 internal validation, and 1 external validation cohort(1949 in the internal training set, 704 in the validation set, and 827 in the external validation cohort) with clinicopathologically confirmed GC. We recruited 11 clinical factors, including age, sex, smoking status, tumor size, differentiation, Borrmann type, location, clinical T stage, and serum tumor markers (STMs) comprising carbohydrate antigen 19–9 (CA19-9), carbohydrate antigen 72–4 (CA72-4), and carcinoembryonic antigen (CEA), to develop the radiomics nomogram. For clinical predictive feature selection and the establishment of clinical models, statistical methods of analysis of variance (ANOVA), relief and recursive feature elimination (RFE) and logistic regression analysis were used. To develop combined predictive models, tumor diameter, type, and location, clinical T stage and STMs were finally selected. The discriminatory ability of the nomogram to predict PM was evaluated by the area under the receiver operating characteristic curve(AUC), and decision curve analysis (DCA) was conducted to evaluate the clinical usefulness of the nomogram. Results The AUC of the clinical models was 0.762 in the training cohorts, 0.772 in the internal validation cohort, and 0.758 in the external validation cohort. However, when combined with STMs, the AUC was improved to 0.806, 0.839 and 0.801, respectively. DCA showed that the combined nomogram was of good clinical evaluation value to predict PM in GC. Conclusions The present study proposed a clinical nomogram with a combination of clinical risk factors and radiomics features that can potentially be applied in the individualized preoperative prediction of PM in GC patients.

Unconventional oil and gas resources have become the most important and realistic field for increasing China’s domestic oil and gas reserves and production. At present, the production scale does not match the massive amount of resources and the rapid growth of proven geological reserves. The challenges of technology, cost, management, and methodology restrict large-scale and economic development. Based on successful practices, a “one engine with six gears” system engineering methodology is put forward, which includes life-cycle management, overall synergy, interdisciplinary cross-service integration, market-oriented operation, socialized support, digitalized management, and low-carbon and green development. The methodology has been proved to be effective in multiple unconventional oil and gas national demonstration areas, including the Jimusar continental shale oil demonstration area. Disruptive views are introduced—namely, that unconventional oil and gas do not necessarily yield a low return, nor do they necessarily have a low recovery factor. A determination to achieve economic benefit must be a pervasive underlying goal for managers and experts. Return and recovery factors, as primary focuses, must be adhered to during China’s development of unconventional oil and gas. The required methodology transformation includes a revolution in management systems to significantly decrease cost and increase production, resulting in technological innovation.

Abstract Background Transaxillary endoscopic thyroidectomy has been introduced to achieve better cosmetic outcomes. However, the benefits of this technology on the patients’ health‐related quality of life (HRQoL) remain unclear. We aimed to investigate whether transaxillary endoscopic lobectomy is comparable to conventional open lobectomy in terms of QOL and cosmetic results in order to provide more evidence for establishing appropriate clinical decisions. Methods Between August 2019 and May 2020, transaxillary endoscopic lobectomy and conventional open lobectomy were performed in 73 and 99 patients with papillary thyroid microcarcinoma, respectively. HRQoL was assessed at 1, 3, 6, and 12 months after surgery using the Thyroid Cancer‐Specific Quality of Life Questionnaire. The cosmetic outcomes were assessed 12 months after surgery using the Patient and Observer Scar Assessment Scale (POSAS). Results No significant difference was observed in the surgical results between the two groups. However, the data showed that the average operative time and postoperative hospital stay of the transaxillary group were longer than those of the open group (p

The current tumour-node-metastasis staging system alone cannot provide adequate information for prognosis and adjuvant chemotherapy benefits in patients with gastric cancer. Herein, the authors propose a pathomics signature that was derived from multiple features of haematoxylin and eosin-stained slides.

Abstract Background Radiotherapy (RT) is one of the major therapeutic approaches to hepatocellular carcinoma (HCC). Ionizing radiation (IR) inducing the generation of reactive oxygen species (ROS) leads to a promising antitumor effect. However, the dysregulation of the redox system often causes radioresistance and impairs the efficacy of RT. Increasing evidence indicates that nuclear protein 1 (NUPR1) plays a critical role in redox reactions. In this study, we aim to explore the role of NUPR1 in maintaining ROS homeostasis and radioresistance in HCC. Methods The radioresistant role of NUPR1 was determined by colony formation assay, comet assay in vitro, and xenograft tumor models in vivo. Probes for ROS, apoptosis assay, and lipid peroxidation assay were used to investigate the functional effect of NUPR1 on ROS homeostasis and oxidative stress. RNA sequencing and co-immunoprecipitation assay were performed to clarify the mechanism of NUPR1 inhibiting the AhR/CYP signal axis. Finally, we analyzed clinical specimens to assess the predictive value of NUPR1 and AhR in the radiotherapeutic efficacy of HCC. Results We demonstrated that NUPR1 was upregulated in HCC tissues and verified that NUPR1 increased the radioresistance of HCC in vitro and in vivo. NUPR1 alleviated the generation of ROS and suppressed oxidative stress, including apoptosis and lipid peroxidation by downregulating cytochrome P450 (CYP) upon IR. ROS scavenger N-acetyl-L-cysteine (NAC) and CYP inhibitor alizarin restored the viability of NUPR1-knockdown cells during IR. Mechanistically, the interaction between NUPR1 and aryl hydrocarbon receptor (AhR) promoted the degradation and decreased nuclear translation of AhR via the autophagy-lysosome pathway, followed by being incapable of CYP’s transcription. Furthermore, genetically and pharmacologically activating AhR abrogated the radioresistant role of NUPR1. Clinical data suggested that NUPR1 and AhR could serve as novel biomarkers for predicting the radiation response of HCC. Conclusions Our findings revealed the role of NUPR1 in regulating ROS homeostasis and oxidative stress via the AhR/CYP signal axis upon IR. Strategies targeting the NUPR1/AhR/CYP pathway may have important clinical applications for improving the radiotherapeutic efficacy of HCC.

Abstract Background Although the anti-programmed death-1 (PD-1) inhibitor plus chemotherapy combination has been approved as the standard first-line treatment for advanced gastric cancer, a proportion of patients do not significantly benefit from this therapy. Who would respond poorly to this treatment and the underlying mechanisms of treatment failure are far from clear. Methods We retrospectively analyzed the associations between the peripheral basophils at baseline and clinical outcomes in 63 advanced gastric cancer patients treated with anti-PD-1 plus chemotherapy and 54 patients treated with chemotherapy alone. Immunohistochemistry and immunofluorescence staining in gastric cancer samples were utilized to investigate the basophil-related immunophenotype. Results The optimal cutoff of basophil count to distinguish responders to anti-PD-1 plus chemotherapy from non-responders was 20.0/μL. Compared with the low basophil group (≤ 20.0/μL, n = 40), the high basophil group (> 20.0/μL, n = 23) had a significantly lower objective response rate (ORR 17.4% vs. 67.5%, p = 0.0001), worse progression-free survival (median PFS 4.0 vs. 15.0 months, p = 0.0003), and worse overall survival (median OS not reached, p = 0.027). Multivariate analyses identified a basophil count of > 20.0/μL as an independent risk factor for a worse ORR (OR 0.040, 95% CI 0.007–0.241, p = 0.0004), worse PFS (HR 3.720, 95% CI 1.823–7.594, p = 0.0003) and worse OS (HR 3.427, 95% CI 1.698–6.917, p = 0.001). In contrast, there was no significant association between peripheral basophil counts and tumor response or survival in the chemotherapy-alone group (p > 0.05). In primary gastric cancer samples, we observed a correlation between higher peripheral basophil counts and the accumulation of tumor-infiltrating basophils (r = 0.6833, p = 0.005). Tumor-infiltrating basophils were found to be spatially proximate to M2 macrophages within TME and positively correlated with tumor M2 macrophage infiltration (r = 0.7234, p = 0.0023). The peripheral basophil counts also had a significant positive correlation with tumor-infiltrating M2 macrophage counts (r = 0.6584, p = 0.003). Further validation in tumor samples treated with the neoadjuvant anti-PD-1 inhibitor plus chemotherapy combination suggests that the peripheral basophils, tumor infiltration of basophils, and M2 macrophages were significantly more abundant in non-responders than in responders (p = 0.0333, p = 0.0007, and p = 0.0066, respectively). Conclusions The peripheral basophil count was observed to be a potential biomarker of anti-PD-1 efficacy for advanced gastric cancer. Moreover, basophils may induce an immune-evasive tumor microenvironment by increasing M2 macrophage infiltration, which could be a potential immunotherapeutic target for advanced gastric cancer.

Abstract Anti‐angiogenic therapy has long been considered a promising strategy for solid cancers. Intrinsic resistance to hypoxia is a major cause for the failure of anti‐angiogenic therapy, but the underlying mechanism remains unclear. Here, it is revealed that N4‐acetylcytidine (ac4C), a newly identified mRNA modification, enhances hypoxia tolerance in gastric cancer (GC) cells by promoting glycolysis addiction. Specifically, acetyltransferase NAT10 transcription is regulated by HIF‐1α, a key transcription factor of the cellular response to hypoxia. Further, acRIP‐sequencing, Ribosome profiling sequencing, RNA‐sequencing, and functional studies confirm that NAT10 in turn activates the HIF‐1 pathway and subsequent glucose metabolism reprogramming by mediating SEPT9 mRNA ac4C modification. The formation of the NAT10/SEPT9/HIF‐1α positive feedback loop leads to excessive activation of the HIF‐1 pathway and induces glycolysis addiction. Combined anti‐angiogenesis and ac4C inhibition attenuate hypoxia tolerance and inhibit tumor progression in vivo. This study highlights the critical roles of ac4C in the regulation of glycolysis addiction and proposes a promising strategy to overcome resistance to anti‐angiogenic therapy by combining apatinib with ac4C inhibition.

The combination of superabsorbent polymer (SAP) and expansive agent can effectively reduce the shrinkage deformation of ultra-high strength cement-based grouting materials (UHS-CGM) in dry environment. However, there are differences in the compensation shrinkage mechanism of SAP and expansive agent, and the presence of SAP may have adverse effects on the working and mechanical properties of grouting materials. In order to evaluate the synergistic effect of SAP with different water adsorption and release characteristics and MgO expansion agent (MEA), the influence of different SAP size and dosage on the compressive strength, restrained expansion rate, internal relative humidity (IRH) and hydration characteristics of UHS-CGM containing MEA were investigated, and then the composition and content of hydration products were analyzed by TG and XRD, the microstructures were observed by SEM in this paper. The results show that SAP improved the hydration degree of UHS-CGM and the expansion efficiency of MEA, and significantly increased the restrained expansion rate of UHS-CGM under standard curing and sealed curing, while reduced the compressive strength of UHS-CGM, and the decreasing degree was aggravated with increasing size and dosage of SAP. Overall, small size SAP has better inner curing efficiency and compensates shrinkage effect.

Tumour microenvironment has been linked with immunotherapy response in gastric cancer. Here, the authors use CT-based radiomics to predict neutrophils-to-lymphocyte ratio and response to immunotherapy.

Abstract Chemoresistance remains the primary challenge of clinical treatment of gastric cancer (GC), making the biomarkers of chemoresistance crucial for treatment decision. Our previous study has reported that p21-actived kinase 6 (PAK6) is a prognostic factor for selecting which patients with GC are resistant to 5-fluorouracil/oxaliplatin chemotherapy. However, the mechanistic role of PAK6 in chemosensitivity remains unknown. The present study identified PAK6 as an important modulator of the DNA damage response (DDR) and chemosensitivity in GC. Analysis of specimens from patients revealed significant associations between the expression of PAK6 and poorer stages, deeper invasion, more lymph node metastases, higher recurrence rates, and resistance to oxaliplatin. Cells exhibited chemosensitivity to oxaliplatin after knockdown of PAK6, but showed more resistant to oxaliplatin when overexpressing PAK6. Functionally, PAK6 mediates cancer chemoresistance by enhancing homologous recombination (HR) to facilitate the DNA double-strand break repair. Mechanistically, PAK6 moves into nucleus to promote the activation of ATR, thereby further activating downstream repair protein CHK1 and recruiting RAD51 from cytoplasm to the DNA damaged site to repair the broken DNA in GC. Activation of ATR is the necessary step for PAK6 mediated HR repair to protect GC cells from oxaliplatin-induced apoptosis, and ATR inhibitor (AZD6738) could block the PAK6-mediated HR repair, thereby reversing the resistance to oxaliplatin and even promoting the sensitivity to oxaliplatin regardless of high expression of PAK6. In conclusion, these findings indicate a novel regulatory mechanism of PAK6 in modulating the DDR and chemoresistance in GC and provide a reversal suggestion in clinical decision.

Radiotherapy (RT) incorporated multidisciplinary treatment is producing excellent clinical results, but its efficacy in treating late-stage gastric cancer is constrained by radioresistance and RT-related toxicity. Especially, since reactive oxygen species are the pivotal effectual molecules of ionizing radiation, improving ROS production by nanoparticles and other pharmacological modulation to amplify oxidation of polyunsaturated fatty acids and subsequent ferroptotic cell death is shown to enhance cancer cell radioresponse. Herein, we constructed a nanosystem by loading Pyrogallol (PG), a polyphenol compound and ROS generator, into mesoporous organosilica nanoparticles named as MON@pG. The nanoparticles exhibit proper size distribution with amplified ROS production and substantial glutathione depletion under X-ray radiation in gastric cancer cell line. Meanwhile, MON@PG enhanced radiosensitivity of gastric cancer in xenograft tumor model by ROS-mediated accumulation of DNA damage and apoptosis. Furthermore, this augmented oxidative process induced mitochondrial dysfunction and ferroptosis. In summary, MON@PG nanoparticles show the capacity to improve RT potency in gastric cancer by disrupting redox balance and augmenting ferroptosis.

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) and Classical Swine Fever Virus (CSFV) are two important pathogens, which cause serious impact on swine industry worldwide. In our previous research, rPRRSV-E2, the recombinant PRRSV expressing CSFV E2 protein, could provide sufficient protection against the lethal challenge of highly pathogenic PRRSV and CSFV, and could maintained genetically stable in vitro. Here, to evaluate the virulence reversion potential risk, rPRRSV-E2 had been continuously passaged in vivo, the stability of E2 expression and virulence of the passage viruses were analyzed. The results showed that no clinical symptoms or pathological changes could be found in the inoculated groups, and there were no significant differences of viraemia among the test groups. Sequencing and IFA analysis showed that the coding gene of exogenous CSFV E2 protein existed in the passaged viruses without any sequence mutations, deletions or insertions, and could expressed steadily. It could be concluded that the foreign CSFV E2 gene in the genome of rPRRSV-E2 could be maintained genetically stable in vivo, and rPRRSV-E2 strain had relatively low level of potential risk for virulence reversion.

Abstract. Background:. Previous studies have revealed that diabetes mellitus (DM) promotes disease progress of gastric cancer (GC). This study aimed to further investigating whether DM advanced lymph nodes (LNs) metastasis in GC. Methods:. The clinicopathologic data of GC patients with >15 examined LN (ELN) between October 2004 and December 2019 from a prospectively maintained database were included. The observational outcomes included the number (N3b status) and anatomical distribution (N3 stations) of metastatic LN (MLN). Results:. A total of 2142 eligible patients were included in the study between October 2004 and December 2019. N3 stations metastasis (26.8% in DM vs. 19.3% in non-DM, P = 0.026) and N3b status (18.8% in DM vs. 12.8% in non-DM, P = 0.039) were more advanced in the DM group, and multivariate logistic regression analyses confirmed that DM was an independent factor of developing N3 stations metastasis (odds ratio [OR] = 1.771, P = 0.011) and N3b status (OR = 1.752, P = 0.028). Also, multivariate analyses determined DM was independently associated with more MLN (β = 1.424, P = 0.047). The preponderance of N3 stations metastasis (DM vs. non-DM, T1–2: 2.2% vs. 4.9%, T3: 29.0% vs. 20.3%, T4a: 38.9% vs. 25.8%, T4b: 50.0% vs. 36.6%; ELN16–29: 8.6% vs. 10.4%, ELN30–44: 27.9% vs. 20.5%, ELN ≥ 45: 37.7% vs. 25.3%), N3b status (DM vs. non-DM, T1–2: 0% vs. 1.7%, T3: 16.1% vs. 5.1%, T4a: 27.8% vs. 19.1%, T4b: 44.0% vs. 28.0%; ELN16–29: 8.6% vs. 7.9%, ELN30–44: 18.0% vs. 11.8%, ELN ≥ 45: 26.4% vs. 17.3%), and the number of MLN (DM vs. non-DM, T1–2: 0.4 vs. 1.1, T3: 8.6 vs. 5.2, T4a: 9.7 vs. 8.6, T4b: 17.0 vs. 12.8; ELN16–29: 3.6 vs. 4.6, ELN30–44: 5.8 vs. 5.5, ELN ≥ 45: 12.0 vs. 7.7) of DM group increased with the advancement of primary tumor depth stage and raising of ELN. Conclusions:. DM was an independent risk factor for promoting LN metastasis. The preponderance of LN involvement in the DM group was aggravated with the advancement of tumor depth.

Association of tumor microenvironment and immune checkpoint (e.g., PD-L1) is important for immune escape, impacting chemotherapy and immunotherapy efficacy. We aimed to investigate biomarkers and therapeutic targets against treatment resistance in gastric cancer. Abundances of tumor-infiltrating immune cells were estimated in multiple datasets. Three patient subgroups (A, B, and C) were identified based on seven types of PD-L1- and IFN-γ-associated immune cells. Patients yielded increased prognosis from subgroup A to C (p = 0.027). Subgroup A was characterized by high activated CD4+ memory T cell infiltration, while more resting CD4+ memory T cells were in subgroup C. Further, a risk score was developed for prognostication. Lipoma preferred partner (LPP), as the hub gene in subgroup-related regulatory network, was upregulated (p < 0.01) and was associated with high risk score (p < 0.001) and poor survival (p < 0.05). Bioinformatics analyses and experiments found that LPP expressed restrictively in fibroblasts and associated with activated CD4+ memory T cell infiltration and tumor growth. High-LPP patients yielded fewer benefits from chemotherapy or immunotherapy, compared with the low-LPP group. We finally identified 28 compounds as sensitive drugs for high-LPP patients. Our findings suggested LPP might be a biomarker for treatment response and therapeutic target in gastric cancer.

Abstract Aim Much attention has been paid to conversion therapy for stage IV gastric cancer, however, its operative comorbidities and survival benefit have not yet been clarified. CONVO‐GC‐1, an international retrospective cohort study, was designed to investigate the role of conversion surgery in Japan, Korea, and China. Methods The rate of operative complications was the primary endpoint and the overall survival (OS), according to the four‐category criteria previously published (Gastric Cancer:19; 2016), was analyzed as the secondary endpoint. Results A total of 1206 patients underwent surgery after chemotherapy with curative intent. Operative complications were observed in 290 (24.0%) patients in all grades, including pancreatic fistula and surgical site infection. The median survival time (MST) of all resected patients was 36.7 mo (M) and those of R0, R1, and R2 resection were 56.6 M, 25.8 M, and 21.7 M, respectively. Moreover, the MST of R0 patients were 47.8 M, 116.7 M, 44.8 M in categories 1, 2, and 3, respectively, and not reached in category 4. Interestingly, the MST of P1 patients was as favorable as that of P0CY1 patients if R0 resection was achieved. The MST of patients with liver metastasis was also favorable regardless of the number of lesions, and the MST of patients with para‐aortic lymph node (LN) No 16a1/b2 metastasis was not inferior to that of patients with para‐aortic LN No 16a2/b1 metastasis. Conclusion Conversion therapy for stage IV gastric cancer is safe and could be a new therapeutic strategy to improve the survival of patients, especially those with R0 resection.

Porcine reproductive and respiratory syndrome virus (PRRSV) is globally prevalent and seriously harms the economic efficiency of pig farming. Because of its immunosuppression and high incidence of mutant recombination, PRRSV poses a great challenge for disease prevention and control. Nonstructural protein 2 (NSP2) is the most variable functional protein in the PRRSV genome and can generate NSP2N and NSP2TF variants due to programmed ribosomal frameshifts. These variants are broad and complex in function and play key roles in numerous aspects of viral protein maturation, viral particle assembly, regulation of immunity, autophagy, apoptosis, cell cycle and cell morphology. In this paper, we review the structural composition, programmed ribosomal frameshift and biological properties of NSP2 to facilitate basic research on PRRSV and to provide theoretical support for disease prevention and control and therapeutic drug development.

Major breakthroughs of shale oil exploration have been made recently in the upper member of Paleogene Lower Ganchaigou Formation of Yingxiongling area, Qaidam Basin. However, the low total organic carbon content of saline-lacustrine source rock, and unclear genetic mechanism, evaluation criteria and resources potential of the shale oil have restricted the exploration and evaluation of Yingxiongling shale oil. Through analysis of large amounts of cores, well drilling, seismic, laboratory test data and integrated study, focusing on the shale and mixed types of shale oil reservoirs characterized by high-frequency interbedded organic-rich laminated shale and limy dolomite, it is concluded that the shale oil in the upper member of Lower Ganchaigou Formation in the Yingxiongling area have six geological characteristics: (1) two-stage hydrocarbon generation of hydrogen-rich source rock and large amount of retained oil; (2) multiple types of reservoir space and good reservoir properties; (3) source-reservoir integration, thick “sweet spot” and high oil-bearing grade; (4) high pressure coefficient between and under salt layers, and sufficient formation energy; (5) high content of light components, high gas-oil ratio, and good quality of the crude oil; (6) high content of brittle minerals and good fracability. The evaluation criterion of shale oil is preliminarily established based on the eight parameters: total organic carbon content, maturity, effective porosity, oil saturation, brittle mineral content, pressure coefficient, lamellation density, and burial depth. Combined with parameters of E32 source rock thickness, area, vertical distribution of oil layers, and free hydrocarbon content, the shale oil resources have been preliminarily estimated as 21×108 t. The structurally stable area is the predominant objective of shale oil exploration and the favorable exploration area for Yingxiongling shale oil is nearly 800 km2.

Abstract Background The tumor microenvironment (TME) plays an important role in the occurrence and development of gastric cancer (GC) and is widely used to assess the treatment outcomes of GC patients. Immunohistochemistry (IHC) and gene sequencing are the main analysis methods for the TME but are limited due to the subjectivity of observers, the high cost of equipment and the need for professional analysts. Methods The ImmunoScore (IS) was developed in the TCGA cohort and validated in GEO cohorts. The Radiomic ImmunoScore (RIS) was developed in the TCGA cohort and validated in the Nanfang cohort. A nomogram was developed and validated in the Nanfang cohort based on RIS and clinical features. Results For IS, the area under the curves (AUCs) were 0.798 for 2-year overall survival (OS) and 0.873 for 4-year overall survival. For RIS, in the TCGA cohort, the AUCs distinguishing High-IS or Low-IS and predicting prognosis were 0.85 and 0.81, respectively; in the Nanfang cohort, the AUC predicting prognosis was 0.72. The nomogram performed better than the TNM staging system according to the ROC curve (all P

Abstract Background The prevalence of diffuse-type gastric cancer (GC), especially signet ring cell carcinoma (SRCC), has shown an upward trend in the past decades. This study aimed to develop computed tomography (CT) based radiomics nomograms to distinguish diffuse-type and SRCC GC preoperatively. Methods A total of 693 GC patients from two centers were retrospectively analyzed and divided into training, internal validation and external validation cohorts. Radiomics features were extracted from CT images, and the Lauren radiomics model was established with a support vector machine (SVM) classifier to identify diffuse-type GC. The Lauren radiomics nomogram integrating radiomics features score (Rad-score) and clinicopathological characteristics were developed and evaluated regarding prediction ability. Further, the SRCC radiomics nomogram designed to identify SRCC from diffuse-type GC was developed and evaluated following the same procedures. Results Multivariate analysis revealed that Rad-scores was significantly associated with diffuse-type GC and SRCC (p

African swine fever (ASF) is a contagious infectious disease with high lethality which continuously threatens the global pig industry causing huge economic losses. Currently, there are no commercially available vaccines or antiviral drugs that can effectively control ASF. The pathogen of ASF, ASF virus (ASFV) is a double-stranded DNA virus with a genome ranging from 170 to 193 kb and 151 to 167 open reading frames in various strains, which encodes 150–200 proteins. An effective method of monitoring ASFV antibodies, and specific antibodies against ASFV to promote the development of prevention techniques are urgently needed. In the present study, pK205R of ASFV was successfully expressed in mammalian cells using a suspension culture system. An indirect enzyme-linked immunosorbent assay (ELISA) based on the purified pK205R was established and optimized. The monoclonal antibody (mAb) against pK205R recognized a conservative linear epitope (2VEPREQFFQDLLSAV16) and exhibited specific reactivity, which was conducive to the identification of the recombinant porcine reproductive and respiratory syndrome virus (PRRSV) expressing pK205R. The ELISA method efficiently detected clinical ASFV infection and revealed good application prospects in monitoring the antibody level in vivo for recombinant PRRSV live vector virus expressing the ASFV antigen protein. The determination of the conserved linear epitope of pK205R would contribute to further research on the structural biology and function of pK205R. The indirect ELISA method and mAb against ASFV pK205R revealed efficient detection and promising application prospects, making them ideal for epidemiological surveillance and vaccine research on ASF.