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Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment.

The enzyme‐resistant thioglycosides are highly valuable immunogens because of their enhanced metabolic stability. We report the first synthesis of a family of thiooligosaccharides related to the capsular polysaccharides (CPS) of Campylobacter jejuni HS:4 for potential use in conjugate vaccines. The native CPS structures of the pathogen consist of a challenging repeating disaccharide formed with β(1→4)‐linked 6‐deoxy‐β‐D‐ido‐heptopyranoside and N‐acetyl‐D‐glucosamine; the rare 6‐deoxy‐ido‐heptopyranosyl backbone and β‐anomeric configuration of the former monosaccharide makes the synthesis of this family of antigens very challenging. So far, no synthesis of the thioanalogs of the CPS antigens have been reported. The unprecedented synthesis presented in this work is built on an elegant approach by using β‐glycosylthiolate as a glycosyl donor to open the 2,3‐epoxide functionality of pre‐designed 6‐deoxy‐β‐D‐talo‐heptopyranosides. Our results illustrated that this key trans‐thioglycosylation can be designed in a modular and regio and stereo‐selective manner. Built on the success of this novel approach, we succeeded the synthesis of a family of thiooligosaccharides including a thiohexasaccharide which is considered to be the desired antigen length and complexity for immunizations. We also report the first direct conversion of base‐stable but acid‐labile 2‐trimethylsilylethyl glycosides to glycosyl‐1‐thioacetates in a one‐pot manner. [ABSTRACT FROM AUTHOR]

Abstract: A β-GlcNAc-[Le.sup.X] tetrasaccharides and another α-Gal-[Le.sup.X] analog have been synthesized for studying interaction with toxins produced by the human pathogen Clostridium difficile. [Le.sup.X]-based trisaccharides bearing either a 2-azidoethyl or [...]

The synthesis of novel cyanoethylated cyclodextrin derivatives from previously prepared intermediates is described. It was found the alcohols at the primary face of cyclodextrins readily react to add to acrylonitrile, but similar additions from hydroxyl groups of the secondary face appear to be more difficult. The obtained cyanides could be reduced to form the corresponding amines. Key words: cyclodextrin, cyanoethylation, acrylonitrile, polyacrylate, Michael addition. Nous decrivons la synthese de nouveaux derives de cyclodextrine cyanoethylee formes a partir d'intermediaires prepares anterieurement. Nous avons observe que les alcools sur la face primaire des cyclodextrines reagissent facilement avec l'acrylonitrile pour former des produits d'addition, alors que des groupes hydroxyles de la face secondaire semblent reagir plus difficilement face a de telles additions. En outre, les cyanures obtenus peuvent subir une reduction pour former les amines correspondantes. [Traduit par la Redaction] Mots-cles : cyclodextrine, cyanoethylation, acrylonitrile, polyacrylate, addition de Michael., Introduction Cyanoethylations involve the conjugate addition of nucleophiles possessing a labile proton such as alcohols, amines, or thiols to the reactive acrylonitrile. (1) The formed 3-substituted proprionitriles are very useful [...]

As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with [CD4.sup.+] T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures., Alum, loosely defined as any trivalent aluminum-containing salt, was first tested as an adjuvant by A.T. Glenny in a tetanus toxin vaccine (1). Subsequently, alum was vital to the success [...]