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Chimeric antigen receptor (CAR)-modified T-cells (CAR-T) have demonstrated promising clinical benefits against B-cell malignancies. Yet, its application for solid tumors is still facing challenges. Unlike haematological cancers, solid tumors often lack good targets, which are ideally expressed on the tumor cells, but not by the normal healthy cells. Fortunately, receptor tyrosine kinase-like orphan receptor 1 (ROR1) is among a few good cancer targets that is aberrantly expressed on various tumors but has a low expression on normal tissue, suggesting it as a good candidate for CAR-T therapy. Here, we constructed two ROR1 CARs with the same antigen recognition domain that was derived from Zilovertamab but differing in hinge regions. Both CARs target ROR1+ cancer cells specifically, but CAR with a shorter IgG4 hinge exhibits a higher surface expression and better in vitro functionality. We further tested the ROR1 CAR-T in three human solid tumor xenografted mouse models. Our ROR1 CAR-T cells controlled the solid tumor growth without causing any severe toxicity. Our results demonstrated that ROR1 CAR-T derived from Zilovertamab is efficacious and safe to suppress ROR1+ solid tumors in vitro and in vivo, providing a promising therapeutic option for future clinical application.

BiFeO3 (BFO) and Bi1−x La x Fe0.9Cr0.1O3 (x = 0.1–0.2, BLFC x=0.1–0.2) ceramics were prepared by modified solid-state reaction. The influence of La/Cr codoping on the microstructure, leakage, dielectric and magnetic properties of BFO was studied. It is found that the La/Cr codoping can induce a structural transformation from a rhombohedral (R3c) phase to a triclinic (P1) phase, suppress the formation of oxygen vacancies and modulate the spiral spin structure. With the increasing La concentration, the leakage current density can be diminished by over two orders of magnitude compared with undoped BFO, in a reasonable range for device applications. The dielectric loss follows almost the same trend as the leakage current, while the dielectric constant is raised to 400.8 at 100 kHz for x = 0.2, over eight times larger than that of undoped BFO. The substantially enhanced magnetization can be mainly attributed to the suppression of the spiral spin structure and a new ferromagnetic Fe3+–O2−–Cr3+ super-exchange interaction. More interestingly, abrupt changes are observed around x = 0.15, not only in microstructure but also in electrical and magnetic properties, which may indirectly reflect the coupling effect among them. The BLFC x=0.2 ceramic shows the highest magnetization and dielectric constant together with the lowest leakage current and dielectric loss. The results indicate that the La/Cr codoping can effectively improve the magnetic and electrical properties of BFO ceramic for potential applications in magnetoelectric devices.

Cu(Cr0.96−xMg0.04Mnx)O2−δ ceramics (0 ≤ x ≤ 15 at.%) were prepared by solid-state reaction. The influence of Mg acceptor codoping on microstructure, magnetic, and optical properties was studied. The codoping with Mg acceptors and the resulting lattice expansion are both favorable for the enhancement of hole density. Furthermore, the lower valence of Mg2+ compared with Cr3+ enables the mixed valence state of Mn ions: Mn3+ and Mn4+, and hence induces the hole-mediated double-exchange mechanism not only between Mn3+ and Cr3+ but also between Mn3+ and Mn4+. The coexistence of two ferromagnetic interactions and the high hole density are responsible for the improved saturation magnetization and Curie temperature. For photoluminescence, an unusual near-infrared emission at 1.5 eV is observed in the Mn-contained samples and can be attributed to the internal transition between the e and t2 states of the Mn3+ impurity band. The emission intensity is primarily affected by two factors: the Mn3+ concentration and the position of the Fermi level. The results show that codoping with Mg acceptors is an effective way to strengthen the hole-mediated ferromagnetic interactions in CuCrO2 delafossite.

Temperature is a physiological factor that affects neuronal growth and synaptic homeostasis at the invertebrate neuromuscular junctions (NMJs); however, whether temperature stress could also regulate the structure and function of the vertebrate NMJs remains unclear. In this study, we useXenopus laevisprimary cultures as a vertebrate model system for investigating the involvement of heat shock protein 90 (HSP90) family of stress proteins in NMJ development. First, cold temperature treatment or HSP90 inhibition attenuates the formation of aneural acetylcholine receptor (AChR) clusters, but increases their stability after they are formed, in cultured muscles. HSP90 inhibition specifically affects the stability of aneural AChR clusters and their associated intracellular scaffolding protein rapsyn, instead of causing a global change in cell metabolism and protein expression inXenopusmuscle cultures. Upon synaptogenic stimulation, a specific HSP90 family member, glucose-regulated protein 94 (Grp94), modulates the phosphorylation and dynamic turnover of actin depolymerizing factor (ADF)/cofilin at aneural AChR clusters, leading to the recruitment of AChR molecules from aneural clusters to the assembly of agrin-induced postsynaptic specializations. Finally, postsynaptic Grp94 knock-down significantly inhibits nerve-induced AChR clustering and postsynaptic activity in nerve-muscle co-cultures as demonstrated by live-cell imaging and electrophysiological recording, respectively. Collectively, this study suggests that temperature-dependent alteration in Grp94 expression and activity inhibits the assembly of postsynaptic specializations through modulating ADF/cofilin phosphorylation and activity at aneural AChR clusters, which prevents AChR molecules from being recruited to the postsynaptic sites via actin-dependent vesicular trafficking, at developing vertebrate NMJs.