Towards a fully synthetic MUC1-based anticancer vaccine: efficient conjugation of glycopeptides with mono-, di-, and tetravalent lipopeptides using click chemistry.

Abstract The membrane-bound tumor-associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor-associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune-stimulating toll-like receptor 2 (TLR 2) lipopeptide ligands. These fully synthetic vaccine candidates were prepared by solid-phase synthesis of the MUC1 glycopeptides. The Pam(3) Cys lipopeptide, also synthesized on solid-phase, was C-terminally coupled to oligovalent lysine…

Global exponential stability of delayed Markovian jump fuzzy cellular neural networks with generally incomplete transition probability

The problem of global exponential stability in mean square of delayed Markovian jump fuzzy cellular neural networks (DMJFCNNs) with generally uncertain transition rates (GUTRs) is investigated in this paper. In this GUTR neural network model, each transition rate can be completely unknown or only its estimate value is known. This new uncertain model is more general than the existing ones. By constructing suitable Lyapunov functionals, several sufficient conditions on the exponential stability in mean square of its equilibrium solution are derived in terms of linear matrix inequalities (LMIs). Finally, a numerical example is presented to illustrate the effectiveness and efficiency of our res…

Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis.

Familial idiopathic basal ganglia calcification (IBGC) is a genetic condition with a wide spectrum of neuropsychiatric symptoms, including parkinsonism and dementia. Here, we identified mutations in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT2), in IBGC-affected families of varied ancestry, and we observed significantly impaired phosphate transport activity for all assayed PiT2 mutants in Xenopus laevis oocytes. Our results implicate altered phosphate homeostasis in the etiology of IBGC.

Synthetic MUC1 Antitumor Vaccine Candidates with Varied Glycosylation Pattern Bearing R/S-configured Pam3 CysSerLys4.

The Toll-like receptor 2 ligand Pam3 CysSer is of particular interest for the construction synthetic vaccines because of its ability to stimulate of the innate immune system. Such vaccines usually comprise Pam3 CysSer with the natural R-configuration at the glycerol 2-position. Pam3 CysSer peptide vaccines with natural configuration have been shown to be more efficient than the corresponding R/S diastereomers. In order to clarify whether the effect of the configuration of Pam3 Cys on the immune response also applies to glycopeptide vaccines, MUC1 glycopeptide-lipopeptide vaccines bearing either R- or R/S-configured Pam3 CysSerLys4 were compared for their immunological effects. In order to f…

Variation of the glycosylation pattern in MUC1 glycopeptide BSA vaccines and its influence on the immune response.

Treatment with human umbilical cord-derived mesenchymal stem cells for COVID-19 patients with lung damage: a randomised, double-blind, placebo-controlled phase 2 trial

AbstractBACKGROUNDTreatment of severe Corona Virus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data.METHODSIn this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test, maximum vital capaci…

Ligand-Stabilized Au13Cux (x = 2, 4, 8) Bimetallic Nanoclusters: Ligand Engineering to Control the Exposure of Metal Sites

Three novel bimetallic Au-Cu nanoclusters stabilized by a mixed layer of thiolate and phosphine ligands bearing pyridyl groups are synthesized and fully characterized by X-ray single crystal analysis and density functional theory computations. The three clusters have an icosahedral Au13 core face-capped by two, four, and eight Cu atoms, respectively. All face-capping Cu atoms in the clusters are triply coordinated by thiolate or pyridyl groups. The surface ligands control the exposure of Au sites in the clusters. In the case of the Au13Cu8 cluster, the presence of 12 2-pyridylthiolate ligands still leaves open space for catalysis. All the 3 clusters are 8-electron superatoms displaying opti…

Fully synthetic self-adjuvanting thioether-conjugated glycopeptide-lipopeptide antitumor vaccines for the induction of complement-dependent cytotoxicity against tumor cells.

Glycopeptides of tumor-associated mucin MUC1 are promising target structures for the development of antitumor vaccines. Because these endogenous structures were weakly immunogenic, they were coupled to immune-response-stimulating T-cell epitopes and the Pam(3)Cys lipopeptide to induce strong immune responses in mice. A new thioether-ligation method for the synthesis of two- and three-component vaccines that contain MUC1 glycopeptides as the B-cell epitopes, a T-cell epitope peptide, and the Pam(3)CSK(4) lipopeptide is described. The resulting fully synthetic vaccines were used for the vaccination of mice, either in a liposome with Freund's adjuvant or in aqueous PBS buffer. The three-compon…

Variation des Glycosylierungsmusters von Vakzinen aus MUC1- Glycopeptiden und Rinderserumalbumin und der Einfluss auf die Immunreaktion

Synthesis of Tn/T Antigen MUC1 Glycopeptide BSA Conjugates and Their Evaluation as Vaccines

The tumor-associated mucin MUC1 over-expressed in most epithelial tumor tissues is considered a promising target for immunotherapy. The extracellular part of MUC1 contains a domain of numerous tandem repeats of the amino acid sequence HGVTSAPDTRPAPGSTAPPA, including five potential O-glycosylation sites. In this study, T9 and S15 have been chosen as the positions of glycosylation. The glycopeptides N-terminally equipped with a triethylene glycol spacer were synthesized by microwave-assisted Fmoc solid-phase peptide synthesis. After detachment from the resin and deprotection, the MUC1 glycopeptides were conjugated to bovine serum albumin (BSA). To evaluate the immunological properties, balb/c…

CCDC 954905: Experimental Crystal Structure Determination

Related Article: Huayan Yang , Yu Wang , Jing Lei , Lei Shi , Xiaohu Wu , Ville Mäkinen , Shuichao Lin , Zichao Tang , Jian He , Hannu Häkkinen , Lansun Zheng , and Nanfeng Zheng|2013|J.Am.Chem.Soc.|135|9568|doi:10.1021/ja402249s

CCDC 954903: Experimental Crystal Structure Determination

Related Article: Huayan Yang , Yu Wang , Jing Lei , Lei Shi , Xiaohu Wu , Ville Mäkinen , Shuichao Lin , Zichao Tang , Jian He , Hannu Häkkinen , Lansun Zheng , and Nanfeng Zheng|2013|J.Am.Chem.Soc.|135|9568|doi:10.1021/ja402249s

CCDC 954904: Experimental Crystal Structure Determination

Related Article: Huayan Yang , Yu Wang , Jing Lei , Lei Shi , Xiaohu Wu , Ville Mäkinen , Shuichao Lin , Zichao Tang , Jian He , Hannu Häkkinen , Lansun Zheng , and Nanfeng Zheng|2013|J.Am.Chem.Soc.|135|9568|doi:10.1021/ja402249s