Background: Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome. Methods: We redesigned the hGPC3-specific CAR by splitting the traditional CAR into two parts. By using coculturing assays and a xenograft mouse model, the in vitro and in vivo cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells. Results: In vitro data demonstrated that split anti-hGPC3 CAR-T cells could recognize and lyse hGPC3+ HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells. Conclusions: We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment.
ObjectiveThe causes of low back pain in China and Western countries are extremely different. We attempted to analyze the risk factors of low back pain in urban and rural patients under the dual economy with the simplified Chinese version of Roland-Morris disability questionnaire (SC-RMDQ) to demonstrate that SC-RMDQ could evaluate patients with low back pain arising from different causes.MethodsRoland-Morris disability questionnaire was translated into SCRMDQ according to international guidelines for questionnaire adaptation. In this study, causes of low back pain of 187 outpatients and inpatients (99 urban patients and 88 rural patients) were analyzed. All patients underwent simplified Chinese version of Roland-Morris disability questionnaire (SC-RMDQ), simplified Chinese Oswestry disability index (SCODI) and visual analogue scale (VAS). Reliability was tested using reproducibility (intraclass coefficient of correlation – ICC) and internal consistency (Cronbach's alpha). Validity was tested using Pearson correlation analysis.ResultsThe leading causes for low back pain were sedentariness (38.4%) and vibration (18.1%) in urban patients and waist bending (48.9%) and spraining (25%) in rural patients. Although causes of low back pain in the two groups of population were completely different, SCRMDQ had high internal consistency (Cronbach's α value of 0.874 in urban patients and 0.883 in rural patients) and good reproducibility (ICC value of .952 in urban patients and 0.949 in rural patients, P<0.01). SCRMDQ also showed significant correlation with Simplified Chinese version of Oswestry disability index (SCODI) and visual analogue scale (VAS) in rural areas (SCRMDQ-SCODI r = 0.841; SCRMDQ -VAS: r = 0.685, P<0.01) and in urban areas (SCRMDQ-SCODI: r = 0.818, P<0.01; SCRMDQ –VAS: r = 0.666, P<0.01).ConclusionsAlthough causes of low back pain are completely different in rural and urban patients, SCRMDQ has a good reliability and validity, which is a reliable clinical method to evaluate disability of rural and urban patients.
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