Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

The concept of epigenetics was first proposed by Waddington in 1942,referring to phenotypic changes that are not related to the underlying DNA sequence,yet alterations in the level and function of gene expression can be heritable,such as DNA methylation,histone modifications,microRNA interference,etc.Phenotype changes while genotype remains unchanged,this controlled mechanism can be kept stable throughout cell division,proliferation,and subsequent process of development.This process thus may cause corresponding changes in the pathophysiology,which are correlated with the occurrence of cancer,immune disorder,cardiovascular disease,metabolic syndrome and so on.Diabetes mellitus is the third heaviest chronic diseases in the world,and does serious harm to human health,especially the diabetic vascular diseases.Even if the blood glucose level is controlled in an ideal state,vascular inflammation still persists,indicating the existence of metabolic memory.Studies have suggested that the pathogenesis can be elucidated at the level of epigenetics.This paper mainly focuses on DNA methylation,histone modifications,and is an overview of epigenetics research progress in diabetic vascular diseases.

Objective To study the expression of interleukin-17 (IL-17) in diabetic rat aorta and the effect of intervention with resveratrol,meanwhile,to explore the potential mechanisms of IL-17 induced diabetic vascular diseases and the protective role played by resveratrol in the epigenetic field.Methods The experiment was carried out in 4 groups:normal control group(NC),normal interventional group(NB),diabetic group(DM),and diabetic interventional group(DB),NB and DB groups were intervened with resveratrol.Immunohistochemistry was used to observe the histological localization of IL-17 and to measure the thickness of rat abdominal aorta.Western blotting,real-time PCR,and methylation-specific PCR were used respectively to compare the expression of IL-17 protein and mRNA,as well as DNA methylation in 4 groups.Results IL-17 mainly expressed in arterial intima of diabetic rats,the abdominal aorta in DM group was obviously thicker than that in NC and DB groups(P＜0.05).IL-17 protein and mRNA expressions in DM group were significantly higher than NC group(P＜0.05),and were reduced in NB and DB groups compared with NC and DM groups respectively.While DNA methylation levels of IL-17 in DM group were significantly lower than NC group(P＜0.01),however,the levels in NB and DB groups were elevated accordingly as compared with corresponding groups.Conclusions The increased levels of IL-17 in aorta of diabetic rats suggests that IL-17 is involved in the process of inflammatory responses to diabetic macrovascular diseases,while resveratrol could inhibit the expression,it may play a role in protecting aorta,and the regulation of IL-17 gene promoter DNA methylation levels may be the potential mechanism underlying these two phenomena.

Objective　To evaluate the value of CT virtual gastroscopy (CTVE) in clinical applications. Methods　52 patients (65 foci of stomach) were examined by CTVE combined with 2D CT, gastrointestinal series (GI) and fibric gastroscopy (FG). The accurate ratio in quantitative, locating, qualitative and staging diagnoses was compared. Results　CTVE demonstrated the diameter of 0.3 cm foci in stomach. The accurate ratio in quantitative, locating and qualitative diagnoses with combination of CT and CTVE was higher than that of GI (P<0.001 ) but lower that of FG (P>0.05); In staging, CTVE was better than GI and FG. Conclusion　CTVE is a complementary gastric examination, which can replace GI in the diagnosis of common physical gastrical diseases.