Single-ion magnets 1 and 2 and their diamagnetic analogues 3 and 4 for magnetic-site dilution were obtained through substitution of the coordinated water molecules of [Ln(TTA)(3)(H(2)O)(2)] (Ln=Dy (1, 2), Y (3, 4); TTA=4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedionate) by 2,2'-bipyridine (1, 3) and 1,10-phenanthroline (2, 4) capping ligands. Their structures and magnetic properties were investigated with the goal of identifying features relevant to modulating relaxation dynamics of single-ion magnets. The metal ions in all complexes adopt an approximately square-antiprismatic (SAP) O(6)N(2) coordination environment. The SAP polyhedrons for both 1 and 2 show slight longitudinal compression, while the coordination sphere of 1 deviates more from an ideal SAP than that of 2, as indicated by the skew angles of the SAP environment. The similar values of U(eff) for the two magnetically diluted samples imply nearly the same distribution of low-lying states for their Dy(III) centers, which is consistent with the slight axial contraction observed for 1 and 2 and further corroborated by ligand-field analysis. The fast quantum tunneling rate τ(QTM) of 1, which is about ten times faster than that of 2, can presumably be associated with the larger rotation of the SAP surroundings. This distortion may result in a significant transverse anisotropy terms, and thus strongly affect the dynamic behavior of the system.

A series of promising multifunctional lanthanide single-molecule magnets (SMMs). Lanthanide luminescence under a pulsed magnetic field for SMMs is examined for the first time.

Adoptive immunotherapy leveraging chimeric antigen receptor-modified T (CAR-T) cells holds great promise for the treatment of cancer. However, tumor-associated antigens often have low expression levels in normal tissues, which can cause on-target, off-tumor toxicity. Recently, we reported that GPC3-targeted CAR-T cells could eradicate hepatocellular carcinoma (HCC) xenografts in mice. However, it remains unknown whether on-target, off-tumor toxicity can occur. Therefore, we proposed that dual-targeted CAR-T cells co-expressing glypican-3 (GPC3) and asialoglycoprotein receptor 1 (ASGR1) (a liver tissue-specific protein)-targeted CARs featuring CD3ζ and 28BB (containing both CD28 and 4-1BB signaling domains), respectively, may have reduced on-target, off-tumor toxicity. Our results demonstrated that dual-targeted CAR-T cells caused no cytotoxicity to ASGR1GPC3 tumor cells, but they exhibited a similar cytotoxicity against GPC3ASGR1 and GPC3ASGR1 HCC cells in vitro. We found that dual-targeted CAR-T cells showed significantly higher cytokine secretion, proliferation and antiapoptosis ability against tumor cells bearing both antigens than single-targeted CAR-T cells in vitro. Furthermore, the dual-targeted CAR-T cells displayed potent growth suppression activity on GPC3ASGR1 HCC tumor xenografts, while no obvious growth suppression was seen with single or double antigen-negative tumor xenografts. Additionally, the dual-targeted T cells exerted superior anticancer activity and persistence against single-targeted T cells in two GPC3ASGR1 HCC xenograft models. Together, T cells carrying two complementary CARs against GPC3 and ASGR1 may reduce the risk of on-target, off-tumor toxicity while maintaining relatively potent antitumor activities on GPC3ASGR1 HCC.

There are limited strategies for the treatment of hepatocellular carcinoma (HCC). In this study, we prepared a Bispecific T cell engager (BiTE) targeting Glypican 3 (GPC3) and CD3. The GPC3/CD3 BiTE was prepared by fusing the single-chain variable fragment (scFv) of the humanized anti-GPC3 antibody (9F2) with the scFv of the anti-CD3 antibody (OKT3). The in vitro and in vivo cytotoxic activities of the GPC3/CD3 BiTE were evaluated against various HCC cell lines. The GPC3/CD3 BiTE could efficiently mediate the T cell killing of GPC3-positive HCC in vitro, which was dependent on GPC3 expression on the surface of HCC cells. Moreover, our study indicates that, in the presence of the GPC3/CD3 BiTE, T cells could efficiently destroy GPC3-positive human HCC cells in vitro and in vivo. Additionally, our study further proved that GPC3 is not expressed in normal tissues. Thus, GPC3 may be a cancer-specific antigen. Collectively, these findings suggest that this anti-GPC3 BiTE might be a promising anti-tumor reagent for patients with GPC3-positive HCC.

ABSTRACT

No abstract

Background: In recent years, B-cell dysfunction has been found to play an important role in the pathogenesis of primary nephrotic syndrome (PNS). B cells play a pathogenic role by secreting antibodies against their target antigens after transforming into plasma cells. Therefore, this study aimed to screen the autoantibodies that cause PNS and explore their pathogenic mechanisms.Methods: Western blotting and mass spectrometry were employed to screen and identify autoantibodies against podocytes in children with PNS. Both in vivo and in vitro experiments were used to study the pathogenic mechanism of PNS. The results were confirmed in a large multicenter clinical study in children.Results: Annexin A 2 autoantibody was highly expressed in children with PNS with a pathological type of minimal change disease (MCD) or focal segmental glomerulosclerosis without genetic factors. The mouse model showed that anti-Annexin A 2 antibody could induce proteinuria in vivo. Mechanistically, the effect of Annexin A 2 antibody on the Rho signaling pathway was realized through promoting the phosphorylation of Annexin A 2 at Tyr24 on podocytes by reducing its binding to PTP1B, which led to the cytoskeletal rearrangement and damage of podocytes, eventually causing proteinuria and PNS.Conclusions: Annexin A 2 autoantibody may be responsible for some cases of PNS with MCD/FSGS in children.

Background Increasing studies have reported the therapeutic effect of mesenchymal stem cell (MSC)-derived exosomes by which protein and miRNA are clearly characterized. However, the proteomics and miRNA profiles of exosomes derived from human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) remain unclear. Methods In this study, we isolated exosomes from hESCs, hiPSCs, and human umbilical cord mesenchymal stem cells (hUC-MSCs) via classic ultracentrifugation and a 0.22-μm filter, followed by the conservative identification. Tandem mass tag labeling and label-free relative peptide quantification together defined their proteomics. High-throughput sequencing was performed to determine miRNA profiles. Then, we conducted a bioinformatics analysis to identify the dominant biological processes and pathways modulated by exosome cargos. Finally, the western blot and RT-qPCR were performed to detect the actual loads of proteins and miRNAs in three types of exosomes. Results Based on our study, the cargos from three types of exosomes contribute to sophisticated biological processes. In comparison, hESC exosomes (hESC-Exos) were superior in regulating development, metabolism, and anti-aging, and hiPSC exosomes (hiPSC-Exos) had similar biological functions as hESC-Exos, whereas hUC-MSCs exosomes (hUC-MSC-Exos) contributed more to immune regulation. Conclusions The data presented in our study help define the protein and miRNA landscapes of three exosomes, predict their biological functions via systematic and comprehensive network analysis at the system level, and reveal their respective potential applications in different fields so as to optimize exosome selection in preclinical and clinical trials.