Balancing activation and co-stimulation of CAR tunes signaling dynamics and enhances therapeutic potency.

CD19-targeting chimeric antigen receptors (CARs) with CD28 and CD3ζ signaling domains have been approved by the US FDA for treating B cell malignancies. Mutation of immunoreceptor tyrosine-based activation motifs (ITAMs) in CD3ζ generated a single-ITAM containing 1XX CAR, which displayed superior antitumor activity in a leukemia mouse model. Here, we investigated whether the 1XX design could enhance therapeutic potency against solid tumors. We constructed both CD19- and AXL-specific 1XX CARs and compared their in vitro and in vivo functions with their wild-type (WT) counterparts. 1XX CARs showed better antitumor efficacy in both pancreatic and melanoma mouse models. Detailed analysis revealed that 1XX CAR-T cells persisted longer in vivo and had a higher percentage of central memory cells. With fluorescence resonance energy transfer (FRET)-based biosensors, we found that decreased ITAM numbers in 1XX resulted in similar 70-kDa zeta chain-associated protein (ZAP70) activation, while 1XX induced higher Ca2+ elevation and faster extracellular signal-regulated kinase (Erk) activation than WT CAR. Thus, our results confirmed the superiority of 1XX against two targets in different solid tumor models and shed light on the underlying molecular mechanism of CAR signaling, paving the way for the clinical applications of 1XX CARs against solid tumors.

Effects of immersive and non-immersive virtual reality-based rehabilitation training on cognition, motor function, and daily functioning in patients with mild cognitive impairment or dementia: A systematic review and meta-analysis.

OBJECTIVE: To examine the effectiveness of virtual reality (VR)-based rehabilitation training in improving cognition, motor function, and daily functioning in patients with mild cognitive impairment and dementia. DATA SOURCES: A systematic review of published literature was conducted using PubMed, Web of Science, Elsevier, Embase, Cochrane, CNKI, Networked Digital Library of Theses and Dissertations. METHODS: The search period was from inception to 7 October 2023. Eligible studies were randomized controlled trials evaluating the efficacy of VR-based rehabilitation training in patients with mild cognitive impairment or dementia versus control subjects. Methodologic quality was assessed with the Cochrane risk of bias tool, and outcomes were calculated as the standard mean difference between participant groups with 95% confidence interval. RESULTS: A total of 21 randomized controlled trials with 1138 patients were included. The meta-analysis showed that VR-based rehabilitation training had significant effects on Montreal Cognitive Assessment (SMD: 0.50; 95%CI: 0.05 to 0.95; P = 0.030), Trail-making test A (SMD: -0.38; 95%CI: -0.61 to -0.14; P = 0.002), and Berg Balance Scale scores (SMD: 0.79; 95%CI: 0.13 to 1.45; P = 0.020). A subgroup analysis revealed that the type of VR, and duration and frequency of interventions had statistically significant effects on cognition and motor function. CONCLUSION: VR-based rehabilitation training is a beneficial nonpharmacologic approach for managing mild cognitive impairment or dementia. Immersive VR-based training had greater effects on cognition and motor function than non-immersive VR-based training, but non-immersive VR-based training was more convenient for patients with limitations imposed by their disease. Also, an intervention lasting 5-8 weeks and for >30 min at a frequency of ≥3 times/week achieved the best results. It indicated that a longer intervention cycle may not achieve the best intervention effect and training duration and schedule should be carefully considered when managing patients.