Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma.

Chimeric antigen receptor (CAR) T cells targeting CD19 have emerged as a leading engineered T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. The phase 1/2 clinical trials that led to US Food and Drug Administration approval excluded patients with central nervous system (CNS) involvement, due to strict eligibility criteria. Here, we report on our institutional experience with 8 secondary CNS lymphoma patients treated with commercial tisagenlecleucel. No patient experienced greater than grade 1 neurotoxicity, and no patient required tocilizumab or steroids for CAR T-cell-mediated toxicities. Biomarker analysis suggested CAR T-cell expansion, despite the absence of systemic disease, and early response assessments demonstrated activity of IV infused CAR T cells within the CNS space.

Vision fine-tunes preparation for landing in the cane toad, Rhinella marina.

In toad hopping, the hindlimbs generate the propulsive force for take-off while the forelimbs resist the impact forces associated with landing. Preparing to perform a safe landing, in which impact forces are managed appropriately, likely involves the integration of multiple types of sensory feedback. In toads, vestibular and/or proprioceptive feedback is critical for coordinated landing; however, the role of vision remains unclear. To clarify this, we compare pre-landing forelimb muscle activation patterns before and after removing vision. Specifically, we recorded EMG activity from two antagonistic forelimb muscles, the anconeus and coracoradialis, which demonstrate distance-dependent onset timing and recruitment intensity, respectively. Toads were first recorded hopping normally and then again after their optic nerves were severed to remove visual feedback. When blind, toads exhibited hop kinematics and pre-landing muscle activity similar to when sighted. However, distance-dependent relationships for muscle activity patterns were more variable, if present at all. This study demonstrates that blind toads are still able to perform coordinated landings, reinforcing the importance of proprioceptive and/or vestibular feedback during hopping. But the increased variability in distance-dependent activity patterns indicates that vision is more responsible for fine-tuning the motor control strategy for landing.

16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors.

In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). As ASD is frequently associated with altered response to acute stress and stress may exacerbate repetitive behavior in ASD, we studied the Del mouse behavior in the context of an acute stress using the forced swim test, a paradigm well characterized with respect to serotonin. Del mice perseverated with active coping (swimming) in the forced swim test and failed to adopt passive coping strategies with time as did their wild-type littermates. Analysis of monoamine content by HPLC provided evidence for altered endogenous serotonin neurotransmission in Del mice while there was no effect of genotype on any other monoamine. Moreover, we found that Del mice were highly sensitive to the 5-HT2A antagonists M100907, which at a dose of 0.1 mg/kg normalized their level of active coping and restored the gradual shift to passive coping in the forced swim test. Supporting evidence for altered endogenous serotonin signaling was provided by observations of additional ligand effects including altered forebrain Fos expression. Taken together, these observations indicate notable changes in endogenous serotonin signaling in 16p11.2 deletion mice and support the therapeutic utility of 5-HT2A receptor antagonists.

Prenatal intermittent hypoxia sensitizes the laryngeal chemoreflex, blocks serotoninergic shortening of the reflex, and reduces 5-HT3 receptor binding in the NTS in anesthetized rat pups.

We tested the hypothesis that exposure to intermittent hypoxia (IH) during pregnancy would prolong the laryngeal chemoreflex (LCR) and diminish the capacity of serotonin (5-hydroxytryptamine; 5-HT) to terminate the LCR. Prenatal exposure to IH was associated with significant prolongation of the LCR in younger, anesthetized, postnatal day (P) rat pups age P8 to P16 compared to control, room air (RA)-exposed rat pups of the same age. Serotonin microinjected into the NTS shortened the LCR in rat pups exposed to RA during gestation, but 5-HT failed to shorten the LCR in rat pups exposed to prenatal IH. Given these observations, we tested the hypothesis that prenatal hypoxia would decrease binding to 5-HT3 receptors in the nucleus of the solitary tract (NTS) where 5-HT acts to shorten the LCR. Serotonin 3 receptor binding was reduced in younger rat pups exposed to IH compared to control, RA-exposed rat pups in the age range P8 to P12. Serotonin 3 receptor binding was similar in older animals (P18-P24) regardless of gas exposure during gestation. The failure of the 5-HT injected into the NTS to shorten the LCR was correlated with a developmental decrease in 5-HT3 receptor binding in the NTS associated with exposure to prenatal IH. In summary, prenatal IH sensitized reflex apnea and blunted processes that terminate reflex apneas in neonatal rat pups, processes that are essential to prevent death following apneas such as those seen in babies who died of SIDS.