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Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system 1 . We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells 2 , providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10 6 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly 3 . Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG. A phase I dose-escalation trial of GD2-CAR T cells in children and young adults with diffuse midline gliomas to assess the feasibility of manufacturing, safety and tolerability, and to preliminarily assess efficacy.

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders 1 , 2 . Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour 3 – 7 . Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward. Oligodendrogenesis is shown to be involved in reward learning, with dopaminergic neuronal activity-regulated myelin plasticity being an important reward circuit modification.

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward. Activity-dependent myelin plasticity in the ventral tegmental area modulates dopaminergic circuit function and opioid reward

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor 1 – 3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors 4 , 5 . The consequent glioma cell membrane depolarization drives tumour proliferation 4 , 6 . In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity 7 , 8 and strength 9 – 15 . Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B 16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity 17 – 22 that contributes to memory and learning in the healthy brain 23 – 26 . BDNF–TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF–TrkB signalling promotes malignant synaptic plasticity and augments tumour progression. In glioma, malignant synapses hijack mechanisms of synaptic plasticity to increase glutamate-dependent currents in tumour cells and the formation of neuron–glioma synapses, thereby promoting tumour proliferation and progression.

The Developing Belief Network is a consortium of researchers studying human development in diverse social-cultural settings, with a focus on the interplay between general cognitive development and culturally specific processes of socialization and cultural transmission in early and middle childhood. The current manuscript describes the study protocol for the network’s first wave of data collection, which aims to explore the development and diversity of religious cognition and behavior. This work is guided by three key research questions: (1) How do children represent and reason about religious and supernatural agents? (2) How do children represent and reason about religion as an aspect of social identity? (3) How are religious and supernatural beliefs transmitted within and between generations? The protocol is designed to address these questions via a set of nine tasks for children between the ages of 4 and 10 years, a comprehensive survey completed by their parents/caregivers, and a task designed to elicit conversations between children and caregivers. This study is being conducted in 39 distinct cultural-religious groups (to date), spanning 17 countries and 13 languages. In this manuscript, we provide detailed descriptions of all elements of this study protocol, give a brief overview of the ways in which this protocol has been adapted for use in diverse religious communities, and present the final, English-language study materials for 6 of the 39 cultural-religious groups who are currently being recruited for this study: Protestant Americans, Catholic Americans, American members of the Church of Jesus Christ of Latter-day Saints, Jewish Americans, Muslim Americans, and religiously unaffiliated Americans.

Abstract Background After antiretroviral therapy (ART) initiation, people with HIV (PWH) treated for tuberculosis (TB) may develop TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Integrase inhibitors, by providing a faster HIV-RNA decline than efavirenz, might increase the risk for this complication. We sought to assess incidence and determinants of TB-IRIS in PWH with TB on raltegravir- or efavirenz-based ART. Methods We conducted a secondary analysis of the Reflate TB 2 trial, which randomized ART-naive PWH on standard TB treatment, to receive raltegravir- or efavirenz-based ART. The primary objective was to evaluate the incidence of TB-IRIS. Incidence rate ratio comparing TB-IRIS incidence in each arm was calculated. Kaplan-Meier curves were used to compare TB-IRIS–free survival probabilities by ART arm. Cox regression models were fitted to analyze baseline characteristics associated with TB-IRIS. Results Of 460 trial participants, 453 from Brazil, Côte d’Ivoire, Mozambique, and Vietnam were included in this analysis. Baseline characteristics were median age 35 years (interquartile range [IQR], 29–43), 40% female, 69% pulmonary TB only, median CD4, 102 (IQR, 38–239) cells/mm³, and median HIV RNA, 5.5 (IQR, 5.0–5.8) log copies/mL. Forty-eight participants developed TB-IRIS (incidence rate, 24.7/100 PY), 19 cases in the raltegravir arm and 29 in the efavirenz arm (incidence rate ratio 0.62, 95% confidence interval .35–1.10). Factors associated with TB-IRIS were: CD4 ≤ 100 cells/μL, HIV RNA ≥500 000 copies/mL, and extrapulmonary/disseminated TB. Conclusions We did not demonstrate that raltegravir-based ART increased the incidence of TB-IRIS compared with efavirenz-based ART. Low CD4 counts, high HIV RNA, and extrapulmonary/disseminated TB at ART initiation were associated with TB-IRIS. Integrase strand transfer inhibitor–based antiretroviral therapy (ART) did not increase the risk of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the Reflate TB2 randomized controlled trial. Low CD4 counts and high HIV-RNA at ART initiation and extrapulmonary/disseminated TB were risk factors for TB-IRIS.

A retrospective study of 261 Vietnamese adults with severe malaria was conducted to determine the relationship between cerebrospinal fluid (CSF) levels of metabolites of the kynurenine pathway, the incidence of neurologic complications, and the disease outcome. Three metabolites were measured: the excitotoxin quinolinic acid (QA); the protective receptor antagonist kynurenic acid (KA); and the proinflammatory mediator picolinic acid (PA). These measurements were related prospectively to CSF lactate levels. QA and PA levels were elevated, compared with those of controls. There was no difference in the levels of KA between these groups. Although >40%of malaria patients had QA CSF concentrations in the micromolar range, there was no association with convulsions or depth of coma. Levels of QA and PA were associated significantly with death, but a multivariate analysis suggested that these elevations were a consequence of impaired renal function. CSF lactate remained an independent and significant predictor of poor outcome.

Hepatitis C Virus (HCV) infection is associated with the B-cell non-Hodgkin lymphomas (NHL), preferentially marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL). While chronic antigenic stimulation is a main determinant of lymphomagenesis in marginal zone lymphomas (MZL), a putative role of HCV infection of B-cells is supported by in vitro studies. We performed a pathological study within the \"ANRS HC-13 LymphoC\" observational study focusing on in situ expression of the oncogenic HCV non structural 3 (NS3) protein. Lympho-C study enrolled 116 HCV-positive patients with B-NHL of which 86 histological samples were collected for centralized review. Main histological subtypes were DLBCL (36%) and MZL (34%). Almost half of DLBCL (12/26) were transformed from underlying small B-cell lymphomas. NS3 immunostaining was found positive in 17 of 37 tested samples (46%). There was a striking association between NS3 detection and presence of high grade lymphoma features: 12 out of 14 DLBCL were NS3+ compared to only 4 out of 14 MZL (p = 0.006). Moreover, 2 among the 4 NS3+ MZL were enriched in large cells. Remarkably, this study supports a new mechanism of transformation with a direct oncogenic role of HCV proteins in the occurrence of high-grade B lymphomas.