Developing ROR1 Targeting CAR-T Cells against Solid Tumors in Preclinical Studies.

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.

Obesity is associated with severe COVID-19 but not death: a dose-response meta-analysis.

The coronavirus disease 2019 (COVID-19) epidemic is spreading globally. Studies revealed that obesity may affect the progression and prognosis of COVID-19 patients. The aim of the meta-analysis is to identify the prevalence and impact of obesity on COVID-19. Studies on obese COVID-19 patients were obtained by searching PubMed, Cochrane Library databases and Web of Science databases, up to date to 5 June 2020. And the prevalence rate and the odds ratio (OR) of obesity with 95% confidence interval (CI) were used as comprehensive indicators for analysis using a random-effects model. A total of 6081 patients in 11 studies were included. The prevalence of obesity in patients with COVID-19 was 30% (95% CI 21-39%). Obese patients were 1.79 times more likely to develop severe COVID-19 than non-obese patients (OR 1.79, 95% CI 1.52-2.11, P < 0.0001, I2 = 0%). However obesity was not associated with death in COVID-19 patients (OR 1.05, 95% CI 0.65-1.71, P = 0.84, I2 = 66.6%). In dose-response analysis, it was estimated that COVID-19 patients had a 16% increased risk of invasive mechanical ventilation (OR 1.16, 95% CI 1.10-1.23, P < 0.0001) and a 20% increased risk of admission to ICU (OR 1.20, 95% CI 1.11-1.30, P < 0.0001) per 5 kg/m2 increase in BMI. In conclusion, obesity in COVID-19 patients is associated with severity, but not mortality.

Grp94 Regulates the Recruitment of Aneural AChR Clusters for the Assembly of Postsynaptic Specializations by Modulating ADF/Cofilin Activity and Turnover.

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 use Xenopus laevis primary 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 in Xenopus muscle 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.