The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing ...how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors—gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas—highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options—including clinical trials and targeted therapies—and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review.
The 2021 World Health Organization classification of tumors of the central nervous system increasingly relies on molecular alterations for central nervous system tumor categorization. The new classification will help improve diagnosis, prognosis, and treatment selection (including enrollment into relevant clinical trials) for patients with brain tumors.
Mechanisms underlying central neuropathic pain are poorly understood. Although glial dysfunction has been functionally linked with neuropathic pain, very little is known about modulation of pain by ...oligodendrocytes. Here we report that genetic ablation of oligodendrocytes rapidly triggers a pattern of sensory changes that closely resemble central neuropathic pain, which are manifest before overt demyelination. Primary oligodendrocyte loss is not associated with autoreactive T- and B-cell infiltration in the spinal cord and neither activation of microglia nor reactive astrogliosis contribute functionally to central pain evoked by ablation of oligodendrocytes. Instead, light and electron microscopic analyses reveal axonal pathology in the spinal dorsal horn and spinothalamic tract concurrent with the induction and maintenance of nociceptive hypersensitivity. These data reveal a role for oligodendrocytes in modulating pain and suggest that perturbation of oligodendrocyte functions that maintain axonal integrity can lead to central neuropathic pain independent of immune contributions.
Background
Stroke patients often suffer from a central neuropathic pain syndrome called central post-stroke pain. This syndrome is characterized by evoked pain hypersensitivity as well as ...spontaneous, on-going pain in the body area affected by the stroke. Clinical evidence strongly suggests a dysfunction in central pain pathways as an important pathophysiological factor in the development of central post-stroke pain, but the exact underlying mechanisms remain poorly understood. To elucidate the underlying pathophysiology of central post-stroke pain, we generated a mouse model that is based on a unilateral stereotactic lesion of the thalamic ventral posterolateral nucleus, which typically causes central post-stroke pain in humans.
Results
Behavioral analysis showed that the sensory changes in our model are comparable to the sensory abnormalities observed in patients suffering from central post-stroke pain. Surprisingly, pharmacological inhibition of spinal and peripheral key components of the pain system had no effect on the induction or maintenance of the evoked hypersensitivity observed in our model. In contrast, microinjection of lidocaine into the thalamic lesion completely reversed injury-induced hypersensitivity.
Conclusions
These results suggest that the evoked hypersensitivity observed in central post-stroke pain is causally linked to on-going neuronal activity in the lateral thalamus.
BackgroundRecurrent high-grade glioma (HGG) represents a significant clinical unmet need with expected survival between 6 to 9 months. Oncolytic viruses are a new therapeutic approach for solid ...tumors that deploy oncolytic activity combined with local and systemic immune activation. CAN-3110 (rQNestin34.5v2) is an oncolytic herpes simplex virus (HSV), modified to encode the HSV1 ICP34.5 protein under control of the nestin promoter. Selective expression of nestin in brain tumors confers tumor-restricted replication of CAN-3110. We conducted an open-label dose-escalation phase 1 clinical trial in patients with recurrent HGG to evaluate safety, tolerability, and immunological changes after CAN-3110 treatment.MethodsThirty patients with biopsy-confirmed recurrent HGG were enrolled from September 2017 to February 2020. CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose-escalated by half log to 1x1010 pfu. Patients also received standard of care. Peripheral blood mononuclear cells (PBMCs), plasma and tumor samples were collected for analysis at different time-points post treatment. We evaluated HSV antigen expression in tumor tissue. RNA sequencing and T cell receptor (TCR) rearrangement analysis was performed in matched tissue and PBMCs. Cytokine profiling was completed in 29 patients at baseline, day 2, and day 28 post treatment.ResultsEighteen patients were recruited at their first recurrence and 12 at the second recurrence. Three patients presented with multifocal disease. Tumor volume ranged from 357.4 to and 54,036.1mm3 (median 7,733.9mm3, SDV 15,610.2). CAN-3110 was well-tolerated with no dose-limiting toxicity. Median overall survival was 11.7 months. We demonstrated persistence of HSV antigen and CD8+ T cell infiltrates at the site of injected tumor. Preliminary analysis revealed expansion of shared TCR clonotypes and upregulation of pro-inflammatory genes in post-treatment tumors and peripheral blood samples. Longitudinal modeling of cytokine profiling demonstrated increased levels of IL-6, VEGF alpha, CCL2 and IL1-RA and a decrease in GCP-2 levels at day 2 post-treatment (p <0.05). Significant correlations were observed between CXCL2 and CXCL6 (r=0.89 and r=0.95, respectively, at day 2 and day 28 post treatment; p<0.05), CCL2 and CXCL6 (r=0.73 and r=0.61 at days 2 and 28 post treatment; p<0.05) and between CCL2 and CXCL2 (r=0.68, p<0.05 at day 2 post treatment) in patients surviving more than 12 months.ConclusionsIntratumoral administration of CAN-3110 appears well-tolerated in recurrent HGG. Histologic, molecular, and cytokine analyses demonstrate persistence of viral antigen as well as local and systemic immune activation after treatment.Ethics ApprovalThe study was approved by the Office for Human Research Studies at Dana-Farber Cancer Institute, Protocol Number 16–557.
T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart ...the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.
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•Single-cell analysis charts expression, clonal landscape of glioma-infiltrating T cells•T cells with a cytotoxicity program express multiple NK cell receptors•The NK cell receptor CD161 inhibits killing of glioma cells by T cells•Tumor cells and immunosuppressive myeloid cells express the CLEC2D ligand
Single-cell analysis of tumor-infiltrating T cells in glioma patients identifies a T cell population co-expressing a cytotoxicity program and NK cell receptors. Mathewson et al. reveal the functional significance of NK cell receptors such as CD161 in inhibiting the anti-tumor function of T cells, highlighting their potential as targets for immunotherapy.
Im vorliegenden Beitrag wird der Einfluss der Modellierung des Kellergeschosses auf die Querkraft und die Verformungen von im Kellergeschoss eingespannten Stahlbeton‐Aussteifungswänden untersucht. ...Der Querkraftverlauf der Wand und die Verschiebung am Kopf der Wand werden mit den entsprechenden, am vereinfachten Kragwandmodell ermittelten Werten verglichen, bei dem die Wand auf Höhe der Kellerdecke voll eingespannt ist und die Weiterleitung der Schnittkräfte im Kellergeschoss nicht näher betrachtet wird. Für die Berücksichtigung des Kellergeschosses wird zunächst eine gelenkige Festhaltung durch die Kellerdecke und die Bodenplatte betrachtet, wodurch sich eine unrealistisch große Wandquerkraft im Kellergeschoss ergibt. Danach wird ein verfeinertes Modell mit Teileinspannung in der Bodenplatte und nachgiebiger Halterung durch die Kellerdecke untersucht. Es werden Empfehlungswerte für die Federkonstante der Drehfeder auf Höhe der Bodenplatte und der horizontalen Translationsfeder auf Höhe der Kellerdecke angegeben, die in der Praxis Anwendung finden können. Es wird besonders der Frage nachgegangen, welche Einflüsse die Berücksichtigung des Kellergeschosses bei der Erdbebenbemessung der Aussteifungswände hat. Dabei wird einerseits die Systemsteifigkeit, von der die Erdbebenersatzlasten abhängen, und andererseits die mögliche Verschiebungsduktilität, von der der mögliche Verhaltensbeiwert q abhängt, betrachtet.
Lateral Bracing of Buildings with a Basement – Influence on the Stress Resultants and Deformations of Reinforced Concrete Bracing Walls when including the Basement in the Mechanical Model
This paper presents an investigation of the influence on the shear force distribution and on the displacements of reinforced concrete bracing walls continuous through a basement, when modelling these walls. The shear forces and displacements are compared with those obtained when simplifying the wall by a cantilever with full fixity at the top of the basement, ignoring the transfer of shear force and bending moment into the basement. First, the influence of the basement is modelled by hinged connections between the wall and the base slab and the floor diaphragm above the basement, respectively. This will result in an unrealistically large wall shear force in the basement. Then, the flexural restraint of the wall by the base plate, and the lateral compliance of the floor diaphragm are modelled by a rotational spring and a lateral spring at those levels. Recommendations are given for reasonable values of the spring constants for practical design purposes. Special attention is given to the way in which including the basement in the mechanical model of such walls will influence aspects of their seismic design. Such aspects are the rigidity of the bracing system which influences the lateral earthquake loads, and the displacement ductility factor which influences the maximum admissible behaviour factor q.
Abstract
Im vorliegenden Beitrag wird der Einfluss der Modellierung des Kellergeschosses auf die Querkraft und die Verformungen von im Kellergeschoss eingespannten Stahlbeton‐Aussteifungswänden ...untersucht. Der Querkraftverlauf der Wand und die Verschiebung am Kopf der Wand werden mit den entsprechenden, am vereinfachten Kragwandmodell ermittelten Werten verglichen, bei dem die Wand auf Höhe der Kellerdecke voll eingespannt ist und die Weiterleitung der Schnittkräfte im Kellergeschoss nicht näher betrachtet wird. Für die Berücksichtigung des Kellergeschosses wird zunächst eine gelenkige Festhaltung durch die Kellerdecke und die Bodenplatte betrachtet, wodurch sich eine unrealistisch große Wandquerkraft im Kellergeschoss ergibt. Danach wird ein verfeinertes Modell mit Teileinspannung in der Bodenplatte und nachgiebiger Halterung durch die Kellerdecke untersucht. Es werden Empfehlungswerte für die Federkonstante der Drehfeder auf Höhe der Bodenplatte und der horizontalen Translationsfeder auf Höhe der Kellerdecke angegeben, die in der Praxis Anwendung finden können. Es wird besonders der Frage nachgegangen, welche Einflüsse die Berücksichtigung des Kellergeschosses bei der Erdbebenbemessung der Aussteifungswände hat. Dabei wird einerseits die Systemsteifigkeit, von der die Erdbebenersatzlasten abhängen, und andererseits die mögliche Verschiebungsduktilität, von der der mögliche Verhaltensbeiwert
q
abhängt, betrachtet.
Abstract
Lateral Bracing of Buildings with a Basement – Influence on the Stress Resultants and Deformations of Reinforced Concrete Bracing Walls when including the Basement in the Mechanical Model
This paper presents an investigation of the influence on the shear force distribution and on the displacements of reinforced concrete bracing walls continuous through a basement, when modelling these walls. The shear forces and displacements are compared with those obtained when simplifying the wall by a cantilever with full fixity at the top of the basement, ignoring the transfer of shear force and bending moment into the basement. First, the influence of the basement is modelled by hinged connections between the wall and the base slab and the floor diaphragm above the basement, respectively. This will result in an unrealistically large wall shear force in the basement. Then, the flexural restraint of the wall by the base plate, and the lateral compliance of the floor diaphragm are modelled by a rotational spring and a lateral spring at those levels. Recommendations are given for reasonable values of the spring constants for practical design purposes. Special attention is given to the way in which including the basement in the mechanical model of such walls will influence aspects of their seismic design. Such aspects are the rigidity of the bracing system which influences the lateral earthquake loads, and the displacement ductility factor which influences the maximum admissible behaviour factor
q
.
T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and ...T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.
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•Dual expressers (DEs) are new lymphocytes that coexpress functional BCR and TCR•A single BCR clonotype (x-clonotype) predominates DEs in T1D subjects•x-clonotype encodes a potent autoantigen with an optimal register for HLA-DQ8•x-mAb secreted by DEs is a potent stimulator of insulin-specific CD4 T cells
Type I diabetes patients have unique TCR- and BCR-positive lymphocytes, in which a public BCR encodes a potent autoantigen that stimulates autologous CD4 T cells and may contribute to autoimmunity.
Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant ...cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling-integrating DNA methylation, transcriptome and genotype within the same cells-of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.
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