Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer.

BACKGROUND: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. METHODS: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. RESULTS: In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. CONCLUSIONS: Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.

ADORA2B, transcriptionally suppressing by MYC, promotes ferroptosis of chondrocytes via inhibition of the PI3K/Akt pathway in mice with osteoarthritis.

Recent studies have shown that chondrocyte ferroptosis contributes importantly to the pathogenesis of osteoarthritis (OA). However, it is largely unknown how it is regulated. In this study, the data sets GSE167852 and GSE190184 were downloaded from the Gene Expression Omnibus (GEO) database, and 161 differentially expressed genes (DEGs) related to ferroptosis were screened by bioinformatics analysis. Subsequently, ADORA2B was screened as a candidate gene from DEGs, which was significantly upregulated in palmitic acid (PA) treated chondrocytes. CCK-8, EdU, Western blotting, and ferroptosis-related kits assays demonstrated that knockdown of ADORA2B constrained ferroptosis and promoted viability of chondrocytes. Overexpression of ADORA2B promoted ferroptosis, while the PI3K/Akt pathway inhibitor LY294002 reversed the promotion of ADORA2B on ferroptosis. Dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assays indicated MYC was a transcription suppressor of ADORA2B, and overexpression of MYC promoted the viability, and inhibited the ferroptosis of chondrocytes, while ADORA2B overexpression abated the promotion of MYC on chondrocyte viability and the inhibition on ferroptosis. In vivo experiments showed that MYC overexpression alleviated cartilage tissue damage in OA mice, which was able to reversed by ADORA2B overexpression. In summary, ADORA2B, transcriptionally suppressing by MYC, promotes ferroptosis of chondrocytes via inhibition of the PI3K/Akt pathway. Thus, ADORA2B can be used as a potential treatment target for ferroptosis-related diseases.

SLC9A2, suppressing by the transcription suppressor ETS1, restrains growth and invasion of osteosarcoma via inhibition of aerobic glycolysis.

Recent studies have shown that Solute Carrier Family 9 Member A2 (SLC9A2) could serve as a biomarker for cancer. However, its mechanism of action in osteosarcoma (OS) was still unclear. In this study, the data sets GSE154530 and GSE99671 were downloaded from the Gene Expression Omnibus (GEO) database, and 31 differentially expressed genes (DEGs) related to methylation were screened by bioinformatics analysis tools. Subsequently, SLC9A2 was screened as a candidate gene from DEGs, which was significantly downregulated in OS. CCK-8, transwell, western blotting and Seahorse XFe24 Cell Metabolic Analyzer assays demonstrated that overexpression of SLC9A2 could constrain OS cell proliferation, invasion, and aerobic glycolysis. Dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assays indicated ETS proto-oncogene 1 (ETS1) was a transcription suppressor of SLC9A2, and overexpression of ETS1 could promote methylation levels in specific regions of the SLC9A2 promoter. ETS1 could promote the proliferation, invasion, and aerobic glycolysis ability of OS cells, as well as tumor growth in vivo by inhibiting the expression of SLC9A2. In addition, SLC9A2, suppressing by ETS1, restrains growth and invasion of OS via inhibition of aerobic glycolysis. Thus, SLC9A2 can function as a key inhibitory factor in the aerobic glycolysis to inhibit proliferation and invasion of OS. This indicated that SLC9A2 has a potential targeted therapeutic effect on OS.

Identification of surface water - groundwater nitrate governing factors in Jianghuai hilly area based on coupled SWAT-MODFLOW-RT3D modeling approach.

A comprehensive understanding of the key controlling factors on NO3-N spatiotemporal distribution in surface and groundwater is of great significance to nitrogen pollution control and water resources management in watershed. Hence, the coupled SWAT-MODFLOW-RT3D model was employed to simulate nitrate (NO3-) fate and transport in Huashan watershed system. The model was calibrated using a combination of stream discharge, groundwater levels, NO3-N in-stream loading and groundwater NO3-N concentrations. The simulation revealed the significant spatiotemporal variations in surface water-groundwater nitrate interactions. The annual average percolation of NO3- from rivers to groundwater was 171.5 kg/km2 and the annual average discharge NO3- content from groundwater into rivers was 451.9 kg/km2 over the simulation period. The highest percolation of NO3- from rivers to groundwater occurred in April and the highest discharge NO3- content from groundwater into rivers occurred in July. Grassland and agriculture land contributed more nitrate contents in river water and groundwater compared to bare land and forest in the study area and the water exchange was the primary driving force for nitrate interactions in the surface water-groundwater system. Sensitivity analysis indicated that river runoff and groundwater levels were most influenced by the SCS runoff curve number f (CN2) and aquifer hydraulic conductivity (K), which, in turn, significantly affected nitrate transport. Regarding water quality parameters, the denitrification exponential rate coefficient (CDN) had the most pronounced impact on NO3-N in-stream loading and groundwater NO3-N concentrations. This study underscores the central role of surface-groundwater (SW-GW) interactions in watershed-scale nitrate research and suggests that parameters with higher sensitivity should be prioritized in analogous watershed modeling.

Assessment of Mechanical Properties for Three-Dimensional Needled Composites: A Geometric Partitioning Strategy Dealing with Mesoscopic Needling Damage.

A geometric partitioning strategy was proposed to evaluate the mechanical properties of three-dimensional needled composites. The microstructure of the composite was divided to accurately characterize the mesoscopic damage in the needling regions and the macroscopic damage in the un-needling regions, to balance the computational accuracy and efficiency. The general method of cells (GMC) models along with the damage criteria were established for different material phases in the needling regions, while the continuum damage mechanics (CDM) model was adopted to portray the damage evolution in the un-needling regions. Through conducting the multi-scale simulation, the mechanical properties of the needled composites were predicted, based upon which the effect of repeated needling on the mesoscale damage process was further investigated. Results showed that the predictions are in good agreement with the experiments, with a relative error of 2.6% for strength and 4.4% for failure strain. The proposed approach can provide guidance for the process optimization and design of needled composites.

Development of a human rotavirus induced diarrhea model in Chinese mini-pigs.

AIM: To establish a new animal model for the research of human rotavirus (HRV) infection, its pathogenesis and immunity and evaluation of potential vaccines. METHODS: 5-d, 30-d and 60-d-old Chinese mini-pigs, Guizhou and Bamma, were inoculated with a single oral dose of attenuated strain Wa, G1, G3 of HRV, and PBS (control), respectively, and fecal samples of pigs from 0 to 7 d post infection (DPI) were collected individually. Enzyme linked immunosorbent assay was used to detect HRV antigen in feces. The HRV was tested by real-time PCR (RT-PCR). The sections of the intestinal tissue were stained with hematoxylin and eosin to observe the morphologic variation by microscopy. Immunofluorescence was used to determine the HRV in intestinal tissue. HRV particles in cells of the ileum were observed by electron micrography. RESULTS: When inoculated with HRV, mini-pigs younger than 30 d developed diarrhea in an age-dependent manner and shed HRV antigen of the same inoculum, as demonstrated by RT-PCR. Histopathological changes were observed in HRV inoculated mini-pigs including small intestinal cell tumefaction and necrosis. HRV that was distributed in the small intestine was restricted to the top part of the villi on the internal wall of the ileum, which was observed by immunofluorescence and transmission electron microscopy. Virus particles were observed in Golgi like follicles in HRV-infected neonatal mini-pigs. Guizhou mini-pigs were more sensitive to HRV than Bamma with respect to RV antigen shedding and clinical diarrhea. CONCLUSION: These results indicate that we have established a mini-pig model of HRV induced diarrhea. Our findings are useful for the understanding of the pathogenic mechanisms of HRV infection.

Photodynamic therapy versus surgical excision to basal cell carcinoma: meta-analysis.

BACKGROUND: Surgical excision (SE) is a first-line treatment for basal cell carcinoma (BCC). Topical photodynamic therapy (PDT) has also been used and has cosmetic advantages over surgery. The latest European guidelines for topical PDT recommended that it be used to treat nodular basal cell carcinoma (nBCC) but a consensus has not been reached. Our study was to evaluate the efficacy of PDT versus SE for the treatment for nBCC by a meta-analysis. MATERIALS AND METHODS: We searched PubMed, EMBASE, the Cochrane Library, CKNI, VIP, and relevant references up to October 2014 including randomized controlled trials (RCTs) that compared PDT with SE for treatment of nBCC patients. A meta-analysis was conducted by using the Cochrane Collaboration's revman 5.0 software. RESULTS: We selected five studies that covered 596 of pathologically confirmed nBCC. We compared complete response rate (RR) of PDT and SE at 3 months and 1, 2, 3, 4, and 5 years. We found that the RR was 0.95 (0.90, 1.00), 0.89 (0.80, 0.99), 0.83 (0.69, 1.00), 0.73 (0.63, 0.85), 0.84 (0.65, 1.08), and 0.79 (0.61, 1.03), respectively, for those time points, the cumulative probability of recurrence for the time points post-treatment, with an estimate at RR 5.28 (1.85, 15.12), 6.48 (2.46, 17.09), 9.67 (3.02, 30.99), 7.73 (2.81, 21.28), and 8.25 (3.01-22.62), respectively. CONCLUSION: We observed no significant differences between PDT and SE for the complete RR, but there was an increased cumulative probability of recurrence. More large-scale RCTs are required to verify our findings.

Dynamics of soil water evaporation during soil drying: laboratory experiment and numerical analysis.

Laboratory and numerical experiments were conducted to investigate the evolution of soil water evaporation during a continuous drying event. Simulated soil water contents and temperatures by the calibrated model well reproduced measured values at different depths. Results show that the evaporative drying process could be divided into three stages, beginning with a relatively high evaporation rate during stage 1, followed by a lower rate during transient stage and stage 2, and finally maintaining a very low and constant rate during stage 3. The condensation zone was located immediately below the evaporation zone in the profile. Both peaks of evaporation and condensation rate increased rapidly during stage 1 and transition stage, decreased during stage 2, and maintained constant during stage 3. The width of evaporation zone kept a continuous increase during stages 1 and 2 and maintained a nearly constant value of 0.68 cm during stage 3. When the evaporation zone totally moved into the subsurface, a dry surface layer (DSL) formed above the evaporation zone at the end of stage 2. The width of DSL also presented a continuous increase during stage 2 and kept a constant value of 0.71 cm during stage 3.