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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.

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.

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 nervous system plays an increasingly appreciated role in the regulation of cancer. In malignant gliomas, neuronal activity drives tumor progression not only through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF)1–3, but also through electrophysiologically functional neuron-to-glioma synapses4–6. Malignant synapses are mediated by calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in both pediatric and adult high-grade gliomas4, 5, and consequent depolarization of the glioma cell membrane drives tumor proliferation4. The nervous system exhibits plasticity of both synaptic connectivity and synaptic strength, contributing to neural circuit form and functions. In health, one factor that promotes plasticity of synaptic connectivity7, 8 and strength9–13 is activity-regulated secretion of the neurotrophin BDNF. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF-TrkB (tropomyosin receptor kinase B) signaling. Signaling through the receptor TrkB14, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with the long-term potentiation (LTP)15–23 that is thought to contribute to memory and learning in the healthy brain22 24–27 28, 29. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells exerts growth inhibitory effects in vivo and in neuron:glioma co-cultures that cannot be explained by classical growth factor signaling alone. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.

Background While emphasized as a key aspect of patient-centered care, little is known about the delivery and documentation of serious illness conversations (SIC) for patients with cancer admitted on general internal medicine (GIM) wards. Objectives To characterize the documentation and experiences of SIC from the perspectives of patients and clinicians on GIM wards. Methods This mixed methods quality improvement project gathered data from GIM wards using a: (1) retrospective review of electronic medical record data of hospitalized patients with cancer, (2) survey of physicians, residents, nurses, and allied health clinicians regarding their clinical practice, and (3) semi-structured interviews with hospitalized patients/caregivers. Results The charts of 101 patients were reviewed: 85.2% had a documented code status, while less than half (46.5%) had documentation of a conversation with a clinician addressing hopes, concerns or values. Ninety-seven clinicians completed the survey and reported variable levels of documentation of SICs. Clinician-identified barriers to serious illness conversations included language barriers, prognostic uncertainty, and lack of time. The 21 patients/caregivers who were interviewed reported a lack of focus on values in their discussions with clinicians, and a desire for their clinician to tailor these discussions to their individual needs. Conclusion In patients with cancer admitted to GIM wards, code status was frequently documented, whereas values-based components of these SICs were less frequently recorded Our results represent an opportunity to improve both the delivery and documentation of more holistic, person-centered aspects of serious illness conversations as a means to drive goal-concordant care through targeted clinical and educational interventions.

The objective of this paper is to study the influence of physiological factors that affect the energy balance, such as lactation stage and parity, on milk yield and composition, milk and blood fatty acid concentrations, blood metabolites and hormones in healthy early lactation cows. Thirty-two Holstein dairy cows from five Belgian commercial farms were followed. The grass silage-based diets fed to cows fell within normal composition ranges typically offered to dairy cows on commercial dairy farms in the region. Milk and blood were sampled at each official milk recording and used for the determination of milk fat and protein, milk and blood fatty acids, blood metabolites and hormones concentrations. The considered period was 7 to 150 days in milk. As lactation progressed, concentrations of milk 18:0 and 18:1c9, as well as blood non-esterified fatty acids and β-hydroxybutyrate, decreased, and those of milk C4–C14, blood cholesterol, triglycerides, insulin and IGF-I increased, agreeing with the extensive mobilization of body reserves in early lactation. Lower concentrations of milk C4–C14 and 16:0 and concomitant higher concentrations of milk 18:0 and 18:1c9 suggest a larger body reserve mobilization in first parity cows compared with greater than or equal to second parity cows. This study confirms that early lactation stage along with parity significantly influence milk fatty acids, such as 18:1, and blood metabolites and hormones, such as NEFA and insulin.

The widespread presence of plasmid-mediated quinolone resistance determinants, particularly qnr genes, has become a current issue. By protecting DNA-gyrase from quinolones, Qnr proteins confer a low level quinolone resistance that is not sufficient to explain their emergence. Since Qnr proteins were hypothesized to act as DNA-binding protein regulators, qnr genes could have emerged by providing a selective advantage other than antibiotic resistance. We investigated host fitness of Escherichia coli isogenic strains after acquisition of the qnrA3 gene, inserted either alone onto a small plasmid (pBR322), or harbored on a large conjugative native plasmid, pHe96(qnrA3) found in a clinical isolate. The isogenic strains were derived from the susceptible E. coli CFT073, a virulent B2 group strain known to infect bladder and kidneys in a mouse model of pyelonephritis. In vitro experiments included growth analysis by automatic spectrophotometry and flow cytometry, and competitions with CFU enumeration. In vivo experiments included infection with each strain and pairwise competitions in absence of antimicrobial exposure. As controls for our experiments we used mutations known to reduce fitness (rpsL K42N mutation) or to enhance fitness (tetA deletion in pBR322). E. coli CFT073 transformed with pBRAM(PBR322-qnrA3) had significantly higher maximal OD than E. coli CFT073 transformed with pBR322 or pBR322ΔtetA, and in vivo competitions were more often won by the qnrA3 carrying strain (24 victories vs. 9 loss among 42 competitions, p = 0.001). In contrast, when pHe96(qnrA3) was introduced by conjugation in E. coli CFT073, it exerted a fitness cost shown by an impaired growth observed in vitro and in vivo and a majority of lost competitions (33/35, p<0.0001). In conclusion, qnrA3 acquisition enhanced bacterial fitness, which may explain qnr emergence and suggests a regulation role of qnr. However, fitness was reduced when qnrA3 was inserted onto multidrug-resistant plasmids and this can slow down its dissemination without antibiotic exposure.

Objectives: to determine modifiable risk factors of exacerbations in chronic respiratory diseases with airways obstruction (i.e., asthma and COPD) in southern Vietnam. Methods: an environmental and health-related behavioural questionnaire was submitted to patients with both chronic respiratory symptoms and airways obstruction. An exacerbation was defined as any acute worsening in clinical symptoms requiring a change in treatment, in a patient receiving prophylactic therapy. Results: 235 patients were evaluated, including 131 (56%) chronic obstructive pulmonary disease (COPD) and 104 (44%) asthmatics. There were 75% males and 69% smokers. Occupational exposure accounted for 66%, mainly among construction and industry workers. Smoking was associated with more severe airways obstruction. Respiratory exacerbations were reported in 56/235 patients (24%). The risk of exacerbation was increased in patients with a lower education level, exposure to occupational pollutants, cumulative smoking ≥ 20 pack year, housing space < 10 m2, and poorly ventilated housing. Based on multivariate analysis, the risk of exacerbation remained significantly higher among patients with occupational exposure and low housing space per person. Conclusions: besides smoking cessation, more supportive policies, including improvement of occupational environment and housing design for better ventilation, are needed to prevent the severity of chronic respiratory diseases in Vietnam.