Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells

Brain malignancies encompass a range of primary and metastatic cancers, including low-grade and high-grade gliomas and brain metastases (BrMs) originating from diverse extracranial tumors. Our understanding of the brain tumor microenvironment (TME) remains limited, and it is unknown whether it is sculpted differentially by primary versus metastatic disease. We therefore comprehensively analyzed the brain TME landscape via flow cytometry, RNA sequencing, protein arrays, culture assays, and spatial tissue characterization. This revealed disease-specific enrichment of immune cells with pronounced differences in proportional abundance of tissue-resident microglia, infiltrating monocyte-derived macrophages, neutrophils, and T cells. These integrated analyses also uncovered multifaceted immune cell activation within brain malignancies entailing converging transcriptional trajectories while maintaining disease- and cell-type-specific programs. Given the interest in developing TME-targeted therapies for brain malignancies, this comprehensive resource of the immune landscape offers insights into possible strategies to overcome tumor-supporting TME properties and instead harness the TME to fight cancer

A new approach to evidence synthesis in traumatic brain injury: a living systematic review

Living systematic reviews (LSRs) are online summaries of health care research that are updated as new research becomes available. This new development in evidence synthesis is being trialled as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) project. We will develop and sustain an international TBI knowledge community that maintains up-to-date, high quality LSRs of the current state of knowledge in the most important questions in TBI. Automatic search updates will be run three-monthly, and newly identified studies incorporated into the review. Review teams will seek to publish journal updates at regular intervals, with abridged updates available more frequently online. Future project stages include the integration of LSR and other study findings into "living" clinical practice guidance. It is hoped these efforts will go some way to bridging current temporal disconnects between evidence, guidelines, and practice in TBI.Development and application of statistical models for medical scientific researc

Today's View on Strangeness

There are several different experimental indications, such as the pion-nucleon sigma term and polarized deep-inelastic scattering, which suggest that the nucleon wave function contains a hidden s bar s component. This is expected in chiral soliton models, which also predicted the existence of new exotic baryons that may recently have been observed. Another hint of hidden strangeness in the nucleon is provided by copious phi production in various N bar N annihilation channels, which may be due to evasions of the Okubo-Zweig-Iizuka rule. One way to probe the possible polarization of hidden s bar s pairs in the nucleon may be via Lambda polarization in deep-inelastic scattering.Comment: 8 pages LaTeX, 10 figures, to appear in the Proceedings of the International Conference on Parity Violation and Hadronic Structure, Grenoble, June 200

Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms.We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non–apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood–brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6–12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitiv

The structure of the Yang-Mills spectrum for arbitrary simple gauge algebras

The mass spectrum of pure Yang-Mills theory in 3+1 dimensions is discussed for an arbitrary simple gauge algebra within a quasigluon picture. The general structure of the low-lying gluelump and two-quasigluon glueball spectrum is shown to be common to all algebras, while the lightest $C=-$ three-quasigluon glueballs only exist when the gauge algebra is A$_{r\geq 2}$, that is in particular $\mathfrak{su}(N\geq3)$. Higher-lying $C=-$ glueballs are shown to exist only for the A$_{r\geq2}$, D$_{{\rm odd}-r\geq 4}$ and E$_6$ gauge algebras. The shape of the static energy between adjoint sources is also discussed assuming the Casimir scaling hypothesis and a funnel form; it appears to be gauge-algebra dependent when at least three sources are considered. As a main result, the present framework's predictions are shown to be consistent with available lattice data in the particular case of an $\mathfrak{su}(N)$ gauge algebra within 't Hooft's large-$N$ limit.Comment: 21 pages, 4 figures; remarks added, typos corrected in v2. v3 to appear in EPJ

Strong evidences of hadron acceleration in Tycho's Supernova Remnant

Very recent gamma-ray observations of G120.1+1.4 (Tycho's) supernova remnant (SNR) by Fermi-LAT and VERITAS provided new fundamental pieces of information for understanding particle acceleration and non-thermal emission in SNRs. We want to outline a coherent description of Tycho's properties in terms of SNR evolution, shock hydrodynamics and multi-wavelength emission by accounting for particle acceleration at the forward shock via first order Fermi mechanism. We adopt here a quick and reliable semi-analytical approach to non-linear diffusive shock acceleration which includes magnetic field amplification due to resonant streaming instability and the dynamical backreaction on the shock of both cosmic rays (CRs) and self-generated magnetic turbulence. We find that Tycho's forward shock is accelerating protons up to at least 500 TeV, channelling into CRs about the 10 per cent of its kinetic energy. Moreover, the CR-induced streaming instability is consistent with all the observational evidences indicating a very efficient magnetic field amplification (up to ~300 micro Gauss). In such a strong magnetic field the velocity of the Alfv\'en waves scattering CRs in the upstream is expected to be enhanced and to make accelerated particles feel an effective compression factor lower than 4, in turn leading to an energy spectrum steeper than the standard prediction {\propto} E^-2. This latter effect is crucial to explain the GeV-to-TeV gamma-ray spectrum as due to the decay of neutral pions produced in nuclear collisions between accelerated nuclei and the background gas. The self-consistency of such an hadronic scenario, along with the fact that the concurrent leptonic mechanism cannot reproduce both the shape and the normalization of the detected the gamma-ray emission, represents the first clear and direct radiative evidence that hadron acceleration occurs efficiently in young Galactic SNRs.Comment: Minor changes. Accepted for publication in Astronomy & Astrophysic

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations