Search

Central nervous system (CNS) infections, which can be caused by a number of different viruses, bacteria, fungi, and parasites, cause substantial disease and death in Southeast Asia (1). The etiologies [...]

Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival.sup.1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later. Neoadjuvant nivolumab treatment in patients with glioblastoma induces intratumoral immune activation and underscores the need for rationale-based combination approaches for improving clinical responses., Author(s): Kurt A. Schalper [sup.1] , Maria E. Rodriguez-Ruiz [sup.2] [sup.3] [sup.4] , Ricardo Diez-Valle [sup.5] [sup.6] , Alvaro López-Janeiro [sup.7] , Angelo Porciuncula [sup.1] , Miguel A. Idoate [sup.7] [...]

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein [beta]-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of [beta]-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, [beta]-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of [beta]-synuclein in provoking T-cell-mediated pathology of the central nervous system. In a rat model of multiple sclerosis, [beta]-synuclein-specific T cells induce inflammation and pathological changes in the grey matter of the central nervous system; these cells were also found in higher numbers in patients with multiple sclerosis, particularly those with a chronic progressive course., Author(s): Dmitri Lodygin [sup.1] , Moritz Hermann [sup.1] , Nils Schweingruber [sup.1] , Cassandra Flügel-Koch [sup.2] , Takashi Watanabe [sup.3] , Corinna Schlosser [sup.1] , Arianna Merlini [sup.1] , Henrike [...]

Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination.sup.1, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same--those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex.sup.2, and single-cell analysis of the mouse central nervous system identified further differences.sup.3,4. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches. Single-nucleus RNA sequencing analysis identifies different subclusters of oligodendroglia in white matter from individuals with multiple sclerosis compared with controls, and these differences may be important for understanding disease progression., Author(s): Sarah Jäkel [sup.1] , Eneritz Agirre [sup.2] , Ana Mendanha Falcão [sup.2] , David van Bruggen [sup.2] , Ka Wai Lee [sup.2] , Irene Knuesel [sup.3] , Dheeraj Malhotra [...]

Current methods for bioprinting functional tissue lack appropriate biofabrication techniques to build complex 3D microarchitectures essential for guiding cell growth and promoting tissue maturation.sup.1. 3D printing of central nervous system (CNS) structures has not been accomplished, possibly owing to the complexity of CNS architecture. Here, we report the use of a microscale continuous projection printing method ([mu]CPP) to create a complex CNS structure for regenerative medicine applications in the spinal cord. [mu]CPP can print 3D biomimetic hydrogel scaffolds tailored to the dimensions of the rodent spinal cord in 1.6 s and is scalable to human spinal cord sizes and lesion geometries. We tested the ability of [micro]CPP 3D-printed scaffolds loaded with neural progenitor cells (NPCs) to support axon regeneration and form new 'neural relays' across sites of complete spinal cord injury in vivo in rodents.sup.1,2. We find that injured host axons regenerate into 3D biomimetic scaffolds and synapse onto NPCs implanted into the device and that implanted NPCs in turn extend axons out of the scaffold and into the host spinal cord below the injury to restore synaptic transmission and significantly improve functional outcomes. Thus, 3D biomimetic scaffolds offer a means of enhancing CNS regeneration through precision medicine. Fast scalable 3D bioprinting generates biocompatible and biomimetic scaffolds to precisely fit the geometries of spinal cord lesions, promote axonal regeneration, and support stem cell grafts to promote recovery from spinal cord injury in rodents., Author(s): Jacob Koffler [sup.1] , Wei Zhu [sup.2] , Xin Qu [sup.2] , Oleksandr Platoshyn [sup.3] , Jennifer N. Dulin [sup.1] , John Brock [sup.1] , Lori Graham [sup.1] , [...]

While research into the biology of animal behaviour has primarily focused on the central nervous system, cues from peripheral tissues and the environment have been implicated in brain development and function.sup.1. There is emerging evidence that bidirectional communication between the gut and the brain affects behaviours including anxiety, cognition, nociception and social interaction.sup.1-9. Coordinated locomotor behaviour is critical for the survival and propagation of animals, and is regulated by internal and external sensory inputs.sup.10,11. However, little is known about how the gut microbiome influences host locomotion, or the molecular and cellular mechanisms involved. Here we report that germ-free status or antibiotic treatment results in hyperactive locomotor behaviour in the fruit fly Drosophila melanogaster. Increased walking speed and daily activity in the absence of a gut microbiome are rescued by mono-colonization with specific bacteria, including the fly commensal Lactobacillus brevis. The bacterial enzyme xylose isomerase from L. brevis recapitulates the locomotor effects of microbial colonization by modulating sugar metabolism in flies. Notably, thermogenetic activation of octopaminergic neurons or exogenous administration of octopamine, the invertebrate counterpart of noradrenaline, abrogates the effects of xylose isomerase on Drosophila locomotion. These findings reveal a previously unappreciated role for the gut microbiome in modulating locomotion, and identify octopaminergic neurons as mediators of peripheral microbial cues that regulate motor behaviour in animals.Female Drosophila that lack a microbiota are hyperactive, and xylose isomerase from Lactobacillus brevis is sufficient to reverse this effect., Author(s): Catherine E. Schretter [sup.1] , Jost Vielmetter [sup.2] , Imre Bartos [sup.3] , Zsuzsa Marka [sup.3] , Szabolcs Marka [sup.3] , Sulabha Argade [sup.4] , Sarkis K. Mazmanian [sup.1] [...]

Regeneration of myelin is mediated by oligodendrocyte progenitor cells--an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases.sup.1-3. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo.sup.4-10. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.Many small molecules that stimulate oligodendrocyte formation act not through their canonical pathways but by inhibiting enzymes within the cholesterol biosynthesis pathway and thereby inducing the accumulation of 8,9-unsaturated sterols., Author(s): Zita Hubler [sup.1] , Dharmaraja Allimuthu [sup.1] , Ilya Bederman [sup.2] , Matthew S. Elitt [sup.1] , Mayur Madhavan [sup.1] , Kevin C. Allan [sup.1] , H. Elizabeth Shick [...]

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS).sup.1-3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood.sup.4,5. Here we report that TGF[alpha] and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGF[alpha] acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGF[alpha] also participate in the microglial control of human astrocytes. Furthermore, expression of TGF[alpha] and VEGF-B in CD14.sup.+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGF[alpha] and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.TGF[alpha] and VEGF-B produced by microglia regulate astrocyte function in the experimental autoimmune encephalomyelitis model of multiple sclerosis., Author(s): Veit Rothhammer [sup.1] , Davis M. Borucki [sup.1] , Emily C. Tjon [sup.1] , Maisa C. Takenaka [sup.1] , Chun-Cheih Chao [sup.1] , Alberto Ardura-Fabregat [sup.2] , Kalil Alves [...]

The analysis of autopsy material from individuals with multiple sclerosis with single-cell transcriptomics and .sup.14C carbon dating calls for a reevaluation of mature oligodendrocytes in myelin repair., Author(s): Klaus-Armin Nave [sup.1] , Hannelore Ehrenreich [sup.1] Author Affiliations: (1) Max Planck Institute of Experimental Medicine, Göttingen, Germany Multiple sclerosis (MS) is clinically the most important disease affecting myelin, [...]

Byline: Lidiia. Prakhova, Aleksandr. Ilves, Svetlana. Kizhlo, Zhanna. Savintseva For the first time, human immunodeficiency virus (HIV)-associated vacuolar myelopathy (VM) was detailed in an autopsy-based study of 89 cases in [...]

Background As more animal studies start to disentangle pathways linking the gut microbial ecosystem and neurobehavioral traits, human studies have grown rapidly. Many have since investigated the bidirectional communication between the gastrointestinal tract and the central nervous system, specifically on the effects of microbial composition on the brain and development. Methods Our review at the initial stage aimed to evaluate literature on gut microbial alterations in pediatric neurobehavioral conditions. We searched five literature databases (Embase, PubMed, PsychInfo, Scopus, and Medline) and found 4489 published work. As the mechanisms linking gut microbiota to these conditions are divergent, the scope of this review was narrowed to focus on describing gut dysbiosis in children with autism spectrum disorder (ASD). Results Among the final 26 articles, there was a lack of consistency in the reported gut microbiome changes across ASD studies, except for distinguishable patterns, within limits, for Prevotella, Firmicutes at the phylum level, Clostridiales clusters including Clostridium perfringens, and Bifidobacterium species. Conclusions These results were inadequate to confirm a global microbiome change in children with ASD and causality could not be inferred to explain the etiology of the behaviors associated with ASD. Mechanistic studies are needed to elucidate the specific role of the gut microbiome in the pathogenesis of ASD. Keywords: Microbiome, Microbiota, Dysbiosis, Systematic review, Autism spectrum disorder, Author(s): Lucius Kang Hua Ho[sup.1], Valerie Jia Wei Tong[sup.1], Nicholas Syn[sup.1], Niranjan Nagarajan[sup.1,2], Elizabeth Huiwen Tham[sup.4,5], Stacey K. Tay[sup.4,5], Shefaly Shorey[sup.6], Paul Anantharajah Tambyah[sup.7,8] and Evelyn Chung Ning Law[sup.3,4,5] Background [...]

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of [alpha]2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-[beta] oligomers and [alpha]-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain. CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice., Author(s): John V. Pluvinage [sup.1] [sup.2] [sup.3] , Michael S. Haney [sup.3] , Benjamin A. H. Smith [sup.1] [sup.4] [sup.5] , Jerry Sun [sup.3] , Tal Iram [sup.3] , Liana [...]

Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths.sup.1. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process.sup.2-4. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans.sup.5-9, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of .sup.14C derived from nuclear testing in genomic DNA.sup.10, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques--thinly myelinated lesions that are thought to represent remyelinated areas--were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies. There are no new oligodendrocytes in potentially remyelinated multiple sclerosis shadow plaques, although oligodendrocyte generation is increased in the normal appearing white matter of patients with aggressive disease, informing the development of new therapies., Author(s): Maggie S. Y. Yeung [sup.1] , Mehdi Djelloul [sup.1] , Embla Steiner [sup.1] , Samuel Bernard [sup.2] , Mehran Salehpour [sup.3] , Göran Possnert [sup.3] , Lou Brundin [sup.4] [...]

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system.sup.1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies. Analyses at single-cell resolution show that diverse subtypes of microglia exist during development and homeostasis of the central nervous system, and identify specific subsets of microglia associated with demyelination and neurodegenerative disease in mice and humans., Author(s): Takahiro Masuda [sup.1] , Roman Sankowski [sup.1] [sup.2] , Ori Staszewski [sup.1] , Chotima Böttcher [sup.3] , Lukas Amann [sup.1] [sup.4] , Christian Scheiwe [sup.5] , Stefan Nessler [sup.6] [...]

Byline: Vani. Santosh, Palavalasa. Sravya, Tejpal. Gupta, Dattatraya. Muzumdar, Geeta. Chacko, Vaishali. Suri, Sridhar. Epari, Anandh. Balasubramaniam, Bishan. Radotra, Sandip. Chatterjee, Chitra. Sarkar, Rakesh. Jalali Introduction: Recent advances in the [...]

Dysfunctional breathing is the main cause of morbidity and mortality after traumatic injury of the cervical spinal cord.sup.1,2 and often necessitates assisted ventilation, thus stressing the need to develop strategies to restore breathing. Cervical interneurons that form synapses on phrenic motor neurons, which control the main inspiratory muscle, can modulate phrenic motor output and diaphragmatic function.sup.3-5. Here, using a combination of pharmacogenetics and respiratory physiology assays in different models of spinal cord injury, we show that mid-cervical excitatory interneurons are essential for the maintenance of breathing in mice with non-traumatic cervical spinal cord injury, and are also crucial for promoting respiratory recovery after traumatic spinal cord injury. Although these interneurons are not necessary for breathing under normal conditions, their stimulation in non-injured animals enhances inspiratory amplitude. Immediately after spinal cord injury, pharmacogenetic stimulation of cervical excitatory interneurons restores respiratory motor function. Overall, our results demonstrate a strategy to restore breathing after central nervous system trauma by targeting a neuronal subpopulation.A population of cervical interneurons is identified that can regulate diaphragm function by modulating phrenic motor neurons; targeting this small population of neurons may be a functional strategy to restore breathing after traumatic spinal cord injury., Author(s): Kajana Satkunendrarajah [sup.1] , Spyridon K. Karadimas [sup.2] , Alex M. Laliberte [sup.1] , Gaspard Montandon [sup.3] [sup.4] , Michael G. Fehlings [sup.1] [sup.2] Author Affiliations:(1) Krembil Research Institute, [...]

Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease.sup.1-4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers.sup.1-4. Here we use the developing liver as a model organ to study angiocrine signals.sup.5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates [beta]1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both [beta]1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.In mouse and human liver models, blood vessel perfusion and mechanical stretching release angiocrine signals from endothelial cells that lead to hepatocyte survival and liver growth., Author(s): Linda Lorenz [sup.1] [sup.2] [sup.3] , Jennifer Axnick [sup.1] , Tobias Buschmann [sup.1] [sup.4] , Carina Henning [sup.1] , Sofia Urner [sup.1] , Shentong Fang [sup.5] , Harri Nurmi [...]

Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-[beta] deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-[beta] accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.Meningeal lymphatic dysfunction promotes amyloid-[beta] deposition in the meninges and worsens brain amyloid-[beta] pathology, acting as an aggravating factor in Alzheimer's disease and in age-associated cognitive decline; improving meningeal lymphatic function could help to prevent or delay age-associated neurological diseases., Author(s): Sandro Da Mesquita [sup.1] [sup.2] , Antoine Louveau [sup.1] [sup.2] , Andrea Vaccari [sup.3] [sup.4] , Igor Smirnov [sup.1] [sup.2] , R. Chase Cornelison [sup.4] , Kathryn M. Kingsmore [...]

A new technique, in which forebrain-precursor cells are ablated from early-stage mouse embryos and replaced with embryonic stem cells, promises to facilitate our ability to study the central nervous system. A blastocyst complementation strategy for the brain., Author(s): Jimena Andersen, Sergiu P. PaòcaAuthor Affiliations:Absent forebrain replaced by embryonic stem cells For the past few decades, it has been possible to directly manipulate an organism's genes early in [...]

Byline: D. Menon, P. Chelakkot BACKGROUND: Radiation therapy is a major treatment option in the management of primary central nervous system (CNS) tumors, though recurrences after primary treatment, especially in [...]

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors. Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors., Author(s): Neibla Priego [sup.1] , Lucía Zhu [sup.1] , Cátia Monteiro [sup.1] , Manon Mulders [sup.1] , David Wasilewski [sup.1] [sup.18] , Wendy Bindeman [sup.1] , Laura Doglio [sup.1] [sup.19] [...]

Introduced by Quincke in 1891 to diagnose and treat tuberculous meningitis, lumbar puncture (LP), has since been used extensively in the investigation of many neurological conditions. (1) Cerebrospinal fluid (CSF) [...]

Abstract Aim--To establish the prevalence of central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) in a population of children with congenital melanocytic naevi (CMN) over the head and/or […]