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Objective To investigate the effect of cinobufacini on inhibiting colorectal cancer metastasis by regula-ting the polarization of M2 macrophages.Methods THP-1 was induced into M0 type macrophages.The condi-tioned medium of HCT116 cells was collected to stimulate M0 type macrophages.The polarization of M2 type mac-rophages was observed by flow cytometry,real-time quantitative PCR and ELISA experiments.The conditioned me-dium of M0 type macrophages and HCT116-Mφ cells was collected to stimulate HCT116 cells.The ability of migra-tion and invasion was observed by wound healing assay and Transwell assay.The effect of cinobufacini on the via-bility of HCT116 cells was detected by CCK-8 assay.The conditioned medium of HCT116 and HCT116+cinobufa-cini was collected to stimulate M0 type macrophages.The polarization of M2 type macrophages was observed by flow cytometry,real-time quantitative PCR and ELISA experiments.The conditioned media of HCT116-Mφ cells and(HCT116+cinobufacini)-Mφ cells were collected to stimulate HCT116 cells.The changes of migration and inva-sion ability were observed by wound healing assay and Transwell assay.Results After stimulation of M0 type mac-rophages in HCT116 cell conditioned medium,the morphology of M0 macrophages turned into fusiform cells,the proportion of CD11b+CD206+cells increased,and the expression of M2 macrophage markers IL-10 and TGF-β in-creased.The migration and invasion ability of HCT116 cells were significantly enhanced after stimulation in the conditioned medium of HCT1 16-Mφ cells.After the addition of cinobufacini,not only the polarization proportion of M2 macrophages decreased,but also the metastatic effect mediated by M2 macrophages was inhibited.Conclusion HCT116 cells can induce the polarization of M2 macrophages,while cinobufacini can inhibit the tumor metastasis mediated by M2 macrophages by inhibiting the polarization of M2 macrophages.
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Objective To investigate the role of bufalin(BU)in inhibiting M2-type macrophage-mediated colorec-tal cancer metastasis.Methods Human acute leukemia mononuclear cells(THP-1)were differentiated into M0 macrophages using phorbol ester induction(PMA)for 48 hours.The M0 macrophages were then treated with IL-4 and IL-13 medium.Surface markers and morphological changes were observed through ELISA,morphology,and RT-qPCR experiments.RT-PCR and ELISA experiments were conducted to detect the surface markers TGF-β and IL-10 of M2 macrophages.The secretion level of IL-6 in the supernatant of M2 macrophages and colorectal cancer cells HCT116 was compared using ELISA.Additionally,the effect of conditioned medium on colorectal cancer cell HCT116 was assessed through Transwell,Wound healing,RT-qPCR,and Western blot experiments.Subsequent-ly,bufalin was added to the conditioned medium and the changes in AKT/PI3K protein,migration,and epithelial-mesenchymal transition ability in HCT116 were observed using Western blot,Transwell,Wound healing and RT-qPCR experiments.Results THP-1 were successfully differentiated into M2 macrophages.The activation of AKT/PI3K protein in HCT116 cells was induced by the secretion of IL-6 from M2 macrophages,which in turn promoted the migration and epithelial-mesenchymal transition ability of the HCT116 cells.The migration and epithelial-mes-enchymal transition mediated by M2 macrophages in HCT116 cells were effectively inhibited by Bufalin.Conclu-sion The release of IL-6 from M2 macrophages activates the AKT/PI3K signaling pathway in colorectal cancer cells,thereby promoting their migration and epithelial-mesenchymal transition capacity.Moreover,bufalin exhibits inhibitory effects on this effect.
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Colorectal cancer(CRC)is a common malignant tumor of the digestive system.The main treatments for CRC currently include surgical resection,chemotherapy,radiotherapy,and immunotherapy.Immunogenic cell death(ICD)is an important method ofanti-tumortherapy.ICD is a specific type of cell death that involves the release of damage-associated molecular patterns(DAMPs).These DAMPs can be effectively taken up by dendritic cells(DCs),neutrophils,and macrophages,thereby stimulating adaptive immune responses in the body.However,colorectal cancer is considered a"cold tumor"with relatively low immunogenicity,resulting in a low response rate to immunotherapy.Inducing ICD can potentially enhance the immunogenicity of colorectal cancer,leading to long-term tumor control.This review aims to explore the impact of ICD development in colorectal cancer treatment and investigate the potential of ICD inducers in colorectal cancer immunotherapy.
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Objective To investigate the effect of Liu-Shen-Wan on transplanted tumors in mice with colon cancer based on the polarization of M2 macrophages in the tumor microenvironment. Methods We established a subcutaneous transplantation tumor model of mice with CT26 colon cancer. Mice were randomly divided into vehicle, oxaliplatin, and oxaliplatin combined with Liu-Shen-Wan groups. Treatment was administered for three weeks, and tumor volume was measured. All mice were weighed during the administration. After the end of the treatment, the mice were dissected and tumors were photographed and weighed. Spleen index was calculated. The expression levels of IFN-γ and IL-12P40 in serum and related blood biochemical indices were measured. The expression levels of M2 macrophage polarization indices, namely, IL-10 and TGF-β, in serum and tumor tissues were detected. The infiltration degree of M2 macrophages in each group was observed by immunohistochemical experiments. Results The tumor volume and mouse weight in the oxaliplatin combined with Liu-Shen-Wan group significantly decreased compared with those in the vehicle group. The spleen index increased, and the expression levels of IFN-γ and IL-12P40 in serum also significantly increased. The mice had no obvious side effects after the drug treatment. In addition, the expression levels of IL-10 and TGF-β in the serum and tissues of mice in the oxaliplatin combined with Liu-Shen-Wan group significantly decreased. The expression levels of CD68 and CD206 in tumor tissues also decreased. Conclusion The anti-tumor effect of Liu-Shen-Wan on the transplanted tumors of mice with colon cancer is related to the inhibition of M2 macrophage polarization in the tumor microenvironment.
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Objective The cumulative incidence function (CIF) is an important descriptive indicator for competing risk data in medical follow-up study.However,the upper and lower limits of the classic confidence interval (CI) of CIF may be exclusive the boundaries.In this paper,the CI estimators based on five different transformations and their performances are studied.Methods The CIs of CIF are constructed based on the linear (classical),log,log (-log),arcsine and logit transformation,respectively.Through the simulation study,the average deviations of the false coverage probabilities for all CIs are comprehensively investigated by the ANOVA technology.Results The simulation results show that the CIs based on linear and arcsine transformation have a large positive deviation.Log transformation is prone to fluctuations and has a minimum negative deviation,only log (-log) transformation is closest to the expected constant 0,and most robust and reliable.Conclusion Combined with the simulation results and example,CIs base on linear and log transformation are easy to have wide range and unstable performance,and can not overcome the bounds being negative or above 1;the arcsine and logit is slightly fluctuated,but their performances are relatively balanced;only performance of log(-log) is the most robust and reliable.
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Objective Nonparametric maximum likelihood estimate(NPMLE)and Breslow-Fleming-Harrington estimate(BFH)are extremely sensitive to small risk set for left truncated and right censored data,this study aims to develop estimation methods to improve the estimation accuracy and compare the existing methods.Methods We introduced the NPMLE,weighted NPMLE,conditional NPMLE,BFH and a new weighted BFH estimate.Simulation studies were carried out to compare five methods via the integrated absolute error(IAE) and integrated average width(IAW).Results The IAE of NPMLE,BFH,weighted NPMLE,weighted BFH and conditional NPMLE is ascending in turn;The IAW of weighted BFH is the lowest and NPMLE is the largest,BFH,conditional NPMLE and weighted NPMLE is reversed under different censored rate.Conclusion According to the results of simulation and example,weighted BFH and weighted NPMLE is recommended in turn when the risk set is small.Otherwise,the results of five methods would be consistent.
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Comparison of survival curves between two groups is an important part of disease prognosis study.Log-rank test is commonly used,but when the two curves' later intersecting opening is too large,the proportion of assumptions is not established,thus the Log-rank test is ineffective.We introduces five statistical tests to compare two survival curves at a fixed time points:classic method,logarithmic transformation,cloglog transformation,arcsine transformation and logit transformation.Through the study we found that if the overall survival curves are difficult to compare between groups tested with Log-rank test method or Two-stage test method,the fixed time point test can effectively determine whether there was significant difference in survival rate at a fixed time point.Among the five fixed time point tests,cloglog transformation could give more precise result.