Remodeling the tumor immune microenvironment via siRNA therapy for precision cancer treatment

How to effectively transform the pro-oncogenic tumor microenvironments(TME)surrounding a tumor into an anti-tumoral never fails to attract people to study.Small interfering RNA(siRNA)is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference(RNAi).The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years.Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions.However,the manufacture of a siRNA delivery system faces three major obstacles,i.e.,appropriate cargo protection,accurately targeted delivery,and site-specific cargo release.In the following review,we summarized the pharmacological actions of siRNA drugs in remolding TME.In addition,the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed.In the meanwhile,the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented.Ultimately,we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy.This summary offers a thorough analysis and roadmap for general readers working in the field.

Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/ BRAF/TAK1/ERK/ETV4 signaling

Objective:PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade.The factors that drive inducible PD-L1 expression have been extensively studied,but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown.Methods:DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout.Protein function was inhibited by chemical inhibitors.Protein levels were examined by Western blot,mRNA levels were examined by real-time RT-PCR,and surface protein expression was determined by cellular immunofluorescence and flow cytometry.Immune evasion was examined by in vitro T cell-mediated killing.Results:We determined the core regions(chr9:5,496,378–5,499,663)of a previously identified PD-L1L2-super-enhancer(SE).Through systematic analysis,we found that the E26 transformation-specific(ETS)variant transcription factor(ETV4)bound to this core DNA region but not to DNA surrounding PD-L1L2SE.Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2.ETV4 transcription was dependent on ERK activation,and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling fromαvβ3 integrin,which profoundly affected ETV4 transcription and PD-L1/L2 expression.Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing.Conclusions:We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion.These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.

Influencing Factors of Rural Land Internal Circulation Market in Guangdong Province

The circulation of rural land is helpful to improving the allocation efficiency of land resources,increasing farmers'income and promoting the development of modern agriculture.In this paper,we used the social economy,the main participants and the market environment of rural land circulation to make a qualitative analysis for the factor of rural land internal circulation.With the aid of principal component analysis,grey correlation model,and other methods to make a quantitative analysis for the factor of rural land internal circulation.The results show that the grey correlation degrees of the output value of secondary and tertiary industries as a proportion of GDP,the expenditure on science and education per capita,the expenditure on financial support for agriculture,the proportion of non-agricultural population and the standardization of rural land circulation contracts are 0.8988,0.8382,0.7632 and 0.7576 respectively,indicating that these factors are significantly related to the rural internal land circulation market.

中国互联网巨头面临更监管

中国监管机构根据《反垄断法》规定,对阿里巴巴以及腾讯控股旗下一公司分别处以50万元人民币罚款,原因是它们进行特定收购时未依法申报经营者集中。根据2020年12月14日的声明,阿里巴巴在2017年把其在连锁百货店银泰的持股比例提高到73.79%之前,应该寻求国家市场监督管理总局批准。腾讯拆分出来的电子书业务阅文集团也因2018年收购新丽传媒股权而被处以相同数额的罚款。不过该局表示,这些交易均不具有排除、限制竞争效果。