2’-Fucosyllactose alleviate immune checkpoint blockade-associated colitis by reshaping gut microbiota and activating AHR pathway

Immune checkpoint blockade(ICB)therapeutics are highly effective in cancer immunotherapy,but gastrointestinal toxicity limited the application.Intestinal microbiota plays a crucial role in ICB-associated colitis.2’-Fucosyllactose(2’FL)is most abundance prebiotic in human milk that can reshape gut microbiota and exert immune regulatory effect.The study aimed to determine the effects of 2’FL on ICB-associated colitis and to uncover the mediating mechanism.ICB-associated colitis was induced by the ipilimumab and dextran sulfate sodium.Oral administration of 2’FL(0.6 g/(kg∙day))ameliorated ICB-induced colitis by enhancing regulatory T cells(Treg)and the M2/M1 ratio of macrophages in colon.2’FL treatment also increased the expression of tight junction proteins(zonula occludens-1(ZO-1)and mucin 2(MUC2))and antioxidant stress indicators(superoxide dismutase(SOD)and catalase(CAT)).In addition,administration of 2’FL increased the abundance of Bifidobacterium and Lactobacillus,and elevated the levels of microbial metabolites,such as indole-3-lactic acid(ILA),which activated the aryl hydrocarbon receptor ligands(AHR)pathway.The protective effect of 2’FL was abolished upon depletion of gut microbiota,and ILA treatment partially simulated the protective effect of 2’FL.Notably,2’FL did not exhibit inhibition of antitumor immunity.These findings suggest that 2’FL could serve as a potential protective strategy for ICB-associated colitis by modulating the intestinal microbiota and bacterial metabolites.

Efficient production of 2′-fucosyllactose in unconventional yeast Yarrowia lipolytica

2′-Fucosyllactose(2′-FL)has great application value as a nutritional component and the whole cell biosynthesis of 2′-FL has become the focus of current research.Yarrowia lipolytica has great potential in oligosaccharide synthesis and large-scale fermentation.In this study,systematic engineering of Y.lipolytica for efficient 2′-FL production was performed.By fusing different protein tags,the synthesis of 2′-FL was optimized and the ubiquitin tag was demonstrated to be the best choice to increase the 2′-FL production.By iterative integration of the related genes,increasing the precursor supply,and promoting NADPH regeneration,the 2′-FL synthesis was further improved.The final 2′-FL titer,41.10 g/L,was obtained in the strain F5-1.Our work reports the highest 2′-FL production in Y.lipolytica,and demonstrates that Y.lipolytica is an efficient microbial chassis for the synthesis of oligosaccharides.

92例胸段食管癌手术治疗分析

目的探讨胸段食管癌手术治疗的方法。方法92例胸段食管癌患者全部行右侧开胸全胸段食管切除、三野淋巴结清扫(3-FL)。结果食管癌沿食管壁内上行播散与下行播散差异有显著性,胸上、中、下段食管癌下颈野淋巴结转移率差异有显著性。结论胸下段食管癌,全胸段食管切除、二野淋巴结清扫(2-FL)可列为首选术式;胸中、上段食管癌,特别是胸上段食管癌,全胸段食管切除、三野淋巴结清扫(3-FL)应列为首选术式。

Recent advances and challenges in microbial production of human milk oligosaccharides

Human milk oligosaccharides(HMOs)are one of the major differences between livestock milk and human milk,and the prebiotic functions of HMOs have been verified through in vitro and clinical trials.The most abundant HMOs include 2′-fucysollactose(2′-FL),3-fucosyllactose(3-FL),lacto-N-neotetraose(LNnT)and lacto-N-tetraose(LNT);their application and synthesis have attracted wide attentions.In recent years,the biotechnological production of 2′-FL,3-FL,LNnT and LNT have emerged based on techniques such as whole-cell catalysis and fermentation.In particular,the development of metabolic engineering and synthetic biology methods and strategies have facilitated efficient biosynthesis of these HMOs.However,these advantages have not been systematically reviewed yet.In this review,we first discuss the structures and applications of HMOs;secondly,strategies of microbial synthesis of the most abundant 2′-FL,3-FL,LNnT and LNT are summarized and compared.Finally,challenges and perspectives of efficient microbial production of HMOs as well as strategies for overcoming the challenges are discussed.This review reveals the whole picture of recent development in HMOs microbial synthesis and can further facilitate the understanding of limiting factors,and further propose a few directions to promote the development of efficient production hosts.

The long and the short of it:the MDM4 tail so far

The mouse double minute 4(MDM4)is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight,largely due to its therapeutic possibilities.MDM4 is a vital regulator of the tumor suppressor p53?It restricts p53 transcriptional activity and also,at least in development,facilitates MDM2's E3 ligase activity toward p53.These functions of MDM4 are critical for normal cell function and a proper response to stress.Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer.MDM4 tails are vital for its function,where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2.In this review,we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dys regulation in disease.