Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma.

Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. We sought to determine whether the addition of the blood-brain barrier penetrant PARP inhibitor niraparib to the standard of care DNA alkylator temozolomide (TMZ) could upregulate NKG2DL, thereby improving immune cell recognition. Changes in viability were consistent with prior publications as there was a growth inhibitory effect of the combination of TMZ and niraparib. However, decreases in viability did not always correlate with changes in NKG2DL mRNA. ULBP1/Mult-1 mRNA was increased with the combination therapy in comparison to either drug alone in two of the three cell types tested, even though viability was consistently decreased. mRNA expression correlated with protein levels and ULBP1/MULT-1 cell surface protein was significantly increased with TMZ and niraparib treatment in four of the five cell types tested. Gamma delta T cell-mediated cytotoxicity at a 10:1 effector-to-target ratio was significantly increased upon pretreatment of cells derived from a GBM PDX with TMZ and niraparib in comparison to the control or either drug alone. Together, these data demonstrate that the combination of PARP inhibition, DNA alkylation, and gamma delta T cell therapy has the potential for the treatment of GBM.

Cross-Sectional Study on the Effect of Bilingualism, Age, Gender, and Family Income on Executive Function Development in a Sample of Lebanese School-Aged Children.

This study investigates executive functions (EFs) and selected developmental factors in 120 children aged 6-11 years. By examining inhibition, working memory, and cognitive flexibility, the research evaluates the potential influences of age, gender, bilingualism, and family income on these EF skills. Tests adapted to Lebanese Arabic were used to assess EFs. Results indicate a linear development of inhibition, working memory, and flexibility with age. Gender differences were observed, affecting verbal and visuospatial working memory as well as flexibility. Bilingualism positively impacts EFs, with early bilinguals outperforming late bilinguals. Family income, however, shows no significant effect on EFs.

Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall.

Exercise promotes learning and memory recall as well as rescues cognitive decline associated with aging. The positive effects of exercise are mediated by circulatory factors that predominantly increase Brain Derived Neurotrophic Factor (BDNF) signaling in the hippocampus. Identifying the pathways that regulate the release of the circulatory factors by various tissues during exercise and that mediate hippocampal Mus musculus Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that two weeks of voluntary exercise in male mice activates autophagy in the hippocampus by increasing LC3B protein levels (p = 0.0425) and that autophagy is necessary for exercise-induced spatial learning and memory retention (p < 0.001; exercise + autophagy inhibitor chloroquine CQ versus exercise). We place autophagy downstream of hippocampal BDNF signaling and identify a positive feedback activation between the pathways. We also assess whether the modulation of autophagy outside the nervous system is involved in mediating exercise's effect on learning and memory recall. Indeed, plasma collected from young exercise mice promote spatial learning (p = 0.0446; exercise versus sedentary plasma) and memory retention in aged inactive mice (p = 0.0303; exercise versus sedentary plasma), whereas plasma collected from young exercise mice that received the autophagy inhibitor chloroquine diphosphate failed to do so. We show that the release of exercise factors that reverse the symptoms of aging into the circulation is dependent on the activation of autophagy in young animals. Indeed, we show that the release of the exercise factor, beta-hydroxybutyrate (DBHB), into the circulation, is autophagy-dependent and that DBHB promotes spatial learning and memory formation (p = 0.0005) by inducing hippocampal autophagy (p = 0.0479). These results implicate autophagy in peripheral tissues and in the hippocampus in mediating the effects of exercise on learning and memory recall and identify DBHB as a candidate endogenous exercise factor whose release and positive effects are autophagy-dependent.

Nicotine induces resilience to chronic social defeat stress in a mouse model of water pipe tobacco exposure by activating BDNF signaling.

The purpose of this study was to investigate how nicotine in the context of water pipe tobacco smoking (WTS) affects depression and anxiety-like behaviors associated with chronic social defeat stress (CSDS). Male C57BL/6 J mice were exposed to WTS or received intraperitoneal injections of nicotine for thirty days then subjected to CSDS for ten days. During CSDS, mice were exposed to WTS or received nicotine injections. The social interaction and open-field tests were used to classify animals as resilient or susceptible to stress and to evaluate their anxiety-like behavior. After behavioral testing, mice continued to be exposed to WTS/nicotine for ten days and their behavior was reexamined. The involvement of brain derived neurotrophic factor signaling in the nicotine-mediated effects was assessed with the tropomyosin receptor kinase B (TRKB) inhibitor, ANA-12. We found that WTS promotes resilience to stress and rescues social avoidance. Even though WTS initially decreased anxiety-like behaviors, prolonged exposure after the completion of CSDS significantly induced anxiety-like behaviors. Finally, we showed that nicotine mediates the effects of WTS only on resilience to stress by increasing BDNF and TRKB levels and signaling. Our results suggest that the pathways mediating resilience to stress and anxiety are distinct and that nicotine mediates the effects of WTS on social behavior, but not anxiety, by activating BDNF signaling. Significance statement: This study reports the positive effect of WTS and nicotine on social behavior. Furthermore, it shows the negative effects of prolonged WTS on anxiety-like behaviors and suggests that these effects are not necessarily mediated by nicotine. Finally, it identifies BDNF/TRKB signaling pathway as a major mediator of the positive effects of nicotine on social interaction. As a result, this work emphasizes the importance of considering the activation status of this signaling pathway when developing smoking cessation strategies.