Familial and lifestyle factors related to physical activity in elementary school students: a cross-sectional study based on a nationally representative survey in Japan.

PURPOSE: The decrease in physical activity (PA) among children has become a global concern. Since the analysis of sociodemographic factors as determinants of exercise habits has been inconclusive, this study investigated the factors related to participation in organized sports and moderate-to-vigorous PA (MVPA) levels. METHODS: Cross-sectional data from the Sports-Life Survey conducted in 2019 by the Sasagawa Sports Foundation were used. Data on the gender, age, grade, annual household income, family members, and lifestyle habits of elementary school children as well as information on participation in organized sports and MVPA were collected by written questionnaires. Multiple logistic regression models were applied to calculate the adjusted odds ratio and 95% confidence interval for the association of each variable with participation in organized sports and frequent MVPA (≥ 60 min/day for ≥ 5 days/week). RESULTS: A total of 1,197 participants were included in the analysis. Whereas 1,053 (88.2%) students expressed a like for PA, only 725 students (60.8%) actually took part in organized sports. Organized sports participation was significantly associated with gender, grade, population density, household income, daily breakfast, lower screen time, and frequent exercise with parents (all P < 0.05). We observed that 12.3% of participants met the frequent MVPA level, which was significantly related to lower screen time and exercise habits with parents (both P < 0.05). CONCLUSIONS: Social and family factors may be strong determinants of engagement in PA among Japanese elementary school-aged children. Parental involvement appears particularly important for promoting PA among youths.

A lymphodepleted non-human primate model for the assessment of acute on-target and off-tumor toxicity of human chimeric antigen receptor-T cells.

OBJECTIVES: Chimeric antigen receptor (CAR)-T cell therapy possesses the potential to cause unexpected on-target toxicities that may be life-threatening. Non-human primates (NHPs) share considerable structural homology and expression profiles of most proteins with humans and are therefore utilised as an animal model for non-clinical safety studies. We have developed a lymphodepleted NHP model by conditioning the animals with immunosuppressive chemotherapy designed to simulate clinical practice conditions, to induce transient mixed chimerism before the administration of human CAR-T cells redirected to target Ephrin type-B receptor 4 (EPHB4-CAR-T cells) to evaluate the toxicity of these cells. METHODS: We administered 60 mg m-2 day-1 of fludarabine for 4 days and 30 mg kg-1 day-1 of cyclophosphamide for 2 days intravenously to cynomolgus macaques for lymphodepletion; then, 3.3 × 106 kg-1 of non-transduced or EPHB4-CAR-T cells was infused into the macaques, respectively. All macaques were closely monitored and evaluated for potential toxicity for 7 days. RESULTS: Lymphodepletion was successfully achieved on day -1 before T-cell infusion and persisted over 7 days without severe organ toxicities. A single administration of human EPHB4-CAR-T cells did not induce overt organ toxicities, although EPHB4-CAR-T cells were activated in vivo as evidenced by the elevation in copy numbers of the CAR transgene 24 h after infusion. CONCLUSION: Although this NHP model is limited for the full evaluation of toxicity of human CAR-T cells and the conditioning protocol should be further optimised, this lymphodepleted NHP model could be used to assess acute on-target/off-tumor toxicities of CAR-T cells.

Autologous non-human primate model for safety assessment of piggyBac transposon-mediated chimeric antigen receptor T cells on granulocyte-macrophage colony-stimulating factor receptor.

OBJECTIVES: Chimeric antigen receptor (CAR)-T cell therapy redirected to specific antigens on tumor cells is a promising immunotherapy strategy for various cancers. Most target antigens are also expressed on normal tissues at varying levels, and therefore, a considerable challenge in the field is determining safety profiles, including life-threatening off-tumor and off-target toxicities. The granulocyte-macrophage colony-stimulating factor receptor (hGMR) is a promising target for CAR T-cell therapy for a subset of acute myelocytic leukaemia, although it is also expressed on normal cells including monocytes, macrophages, CD34-positive haematopoietic cells and vascular endothelial cells. hGMR and other immune-related proteins are highly conserved between humans and cynomolgus macaques (Macaca fascicularis). Therefore, in this study, we engineered cynomolgus T cells to express CAR molecules redirected to hGMR by piggyBac (PB) transposon-based gene transfer and adoptively transferred autologous hGMR-CAR T cells into cynomolgus macaques. METHODS: We established PB-mediated human GMR (hGMR)-specific CAR T cells using cynomolgus peripheral blood mononuclear cells and transferred them into autologous individuals, and evaluated the potential toxicity related to hGMR-CAR T cells. RESULTS: hGMR-CAR T cells did not exert overt organ toxicities such as bone marrow suppression, monocytopenia and vasculitis, although they recognised and killed cynomolgus monocytes and macrophages in vitro. CONCLUSION: Although our model did not simulate a tumor-bearing model, it supports the safety of hGMR-CAR T cells and demonstrates the usefulness of a non-human primate model to evaluate the safety of T-cell products by assessing off-tumor/off-target toxicity before clinical trials.

Assessment of kidney function using inulin-based and estimated glomerular filtration rates before and after allogeneic hematopoietic stem cell transplantation in pediatric patients.

BACKGROUND: Accurate evaluation of kidney function before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is important for both informed decision making and detection of chronic kidney disease. However, to the best of our knowledge, no report has evaluated the glomerular filtration rate (GFR) in pediatric patients who underwent HSCT using the gold standard GFR measurement, as well as inulin-based GFR (iGFR). METHODS: We assessed iGFR before and after allo-HSCT to evaluate the impact of allo-HSCT on GFR in a prospective cohort study of 17 pediatric patients. We also assessed the accuracy and bias of the values of estimated GFR (eGFR) calculated using serum creatinine (Cr), cystatin C (CysC), beta-2 microglobulin (ß2 MG), 24-h creatinine clearance (24hCcr), and the full chronic kidney disease in children (CKiD) index that combines Cr, CysC, and blood urea nitrogen-based equations with iGFR as a reference to identify the most reliable equation for GFR. RESULTS: There was no significant difference between the values before and after allo-HSCT. CKiD CysC-, 24hCcr-, and full CKiD-based values showed good within 30% (P30) accuracy (80.6%, 79.3%, and 80.6%, respectively), but only 24hCcr and full CKiD had good mean bias (8.5% and 8.9%, respectively) and narrow 95% limits of agreement (-32.2 to 52.7 mL/min/1.73 m2 and -29.3 to 47.4 mL/min/1.73 m2 , respectively) compared with the corresponding iGFR. CONCLUSION: There was no significant impact of allo-HSCT on GFR in our cohort. The most reliable equations for pediatric patients with allo-HSCT were eGFR-24hCcr and eGFR-full CKiD.

Regulation of adoptive immunotherapy.

Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells has provided a major breakthrough in the treatment of hematological malignancies. In Japan, it is expected that CD19 CAR-T cell therapy will be introduced earlier in clinical B cell malignancy settings and/or that a novel CAR-T cell therapy will be developed for non-B cell malignancies. The "Act on the Safety of Regenerative Medicine" and the "Revised Pharmaceutical Affairs Act" were promulgated in 2014. Both Acts were very important to the introduction and development of CAR-T therapy in Japan. "Specified cell products" produced according to the former Act can be used in clinical research projects, while "regenerated medical products" produced according to the latter Act can be used in clinical trials, having been launched on the market. In this chapter, we will summarize the regulations pertaining to adoptive immunotherapy on the basis of these two essential Acts.