TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors.

Chimeric antigen receptor (CAR)-T cell therapy shows impressive efficacy treating hematologic malignancies but requires further optimization in solid tumors. Here, we developed a TMIGD2 optimized potent/persistent (TOP) CAR that incorporated the costimulatory domain of TMIGD2, a T and NK cell costimulator, and monoclonal antibodies targeting the IgV domain of B7-H3, an immune checkpoint expressed on solid tumors and tumor vasculature. Comparing second- and third-generation B7-H3 CARs containing TMIGD2, CD28, and/or 4-1BB costimulatory domains revealed superior antitumor responses in B7-H3.TMIGD2 and B7-H3.CD28.4-1BB CAR-T cells in vitro. Comparing these two constructs using in vivo orthotopic human cancer models demonstrated that B7-H3.TMIGD2 CAR-T cells had equivalent or superior antitumor activity, survival, expansion, and persistence. Mechanistically, B7-H3.TMIGD2 CAR-T cells maintained mitochondrial metabolism; produced less cytokines; and established fewer exhausted cells, more central memory cells, and a larger CD8/CD4 T cell ratio. These studies demonstrate that the TOP CAR with TMIGD2 costimulation offered distinct benefits from CD28.41BB costimulation and is effective against solid tumors.

Exploring the Impact of Maternal and Paternal Acceptance on Adolescent Girls' Emotion Regulation.

Maternal acceptance is associated with youth emotion regulation (a correlate of depression among adolescent girls); however, less is known about the impact of fathers. In this prospective study, we examined effects of maternal and paternal acceptance on youth sadness inhibition (a facet of emotion dysregulation) among adolescent girls (n = 82; Mage = 13.28; 43% from minoritized racial/ethnic groups) over 1 year. Youth varied on depression risk, which was assessed via clinical diagnostic interviews. Bivariate results showed that maternal acceptance was associated with lower youth sadness inhibition at baseline and 1-year follow-up, while paternal acceptance was only associated with lower youth sadness inhibition at 1-year follow-up. Step-wise regressions showed that paternal acceptance was inversely associated with youth sadness inhibition over time, above and beyond effects of youth age, baseline sadness inhibition, depression risk, and maternal acceptance. Findings highlight the importance of examining both mothers' and fathers' impact on adolescent girls' development of emotion regulation.

Early life stress and latent trait cortisol in adolescent girls: a prospective examination.

Early life stress (ELS) may become embedded into an individual's stress physiology, changing their hypothalamic-pituitary-adrenal (HPA)-axis in an enduring, trait-like fashion. Cortisol is often utilized to investigate HPA-axis function. However, for "trait" cortisol to be a useful construct, it needs to be internally consistent within measurement occasions and show temporal stability of this reliability. These estimates of physiometrics are rarely tested with biological variables such as cortisol. Identifying reliable and stable individual differences in cortisol may be particularly important when examining questions related to the long-term impact of ELS on HPA-axis function. Using confirmatory factor analysis (CFA) to model latent trait cortisol (LTC) may be a useful statistical approach to capture trait-like indexes of HPA-axis functioning. CFA identifies commonalities among repeated cortisol samples to differentiate characteristic patterns (i.e. a trait) from day-to-day or state variation and measurement error. It is unclear whether LTC estimates are stable prospectively, or if ELS is prospectively associated with LTC. Therefore, we derived LTC factors for 84 adolescent girls (ages 10-17 years) using two-morning salivary cortisol samples, collected sequentially for three days at baseline and again at a one-year follow-up. LTC was internally consistent at both assessments and stable over one year. Greater exposure to ELS was associated with lower LTC over a one-year follow-up. Findings support LTC modeling as a useful strategy to estimate trait-like HPA-axis functioning and suggest that exposure to ELS is associated with lower trait-like cortisol.