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Tumor-associated macrophages: from mechanisms to therapy.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

A complex network of chemokines and their receptors influences the development of primary tumours and metastases. New information about the biological role of chemokines in these processes is providing insights into host–tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Could manipulating the local chemokine network have therapeutic benefits in malignant disease?

Cancer and the chemokine network

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(09)00153-2.pdf

Molecular dissection of reactive astrogliosis and glial scar formation.

Purpose: The objective of this study is to review the role of matrix metalloproteinases in intracerebral hemorrhage, which is associated with hypertension, head trauma and premature birth. Materials and methods: A PubMed search of literature pertaining to this study was conducted in April 2008 using specific keyword search terms pertaining to intracerebral hemorrhage and matrix metalloproteinases. Some papers are not cited here as it is not possible to be all inclusive or due to the space limit from the journal. Discussion: The prognosis following ICH is more detrimental than that of ischemic strokes. Matrix metalloproteases have been implicated in the pathogenesis of brain damage following ICH. The goal of this review is to bring together recent diverse data concerning the roles of matrix metalloproteinases after intracerebral hemorrhage, which includes the role of matrix metalloproteinases in central nervous system, matrix metalloproteinases in animal models and humans of intracerebral hemorrha...

Matrix metalloproteinases in intracerebral hemorrhage

Following myocardial infarction (MI), cardiac myofibroblasts remodel the extracellular matrix (ECM), preventing mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis, and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity; however, the mechanisms are unclear. We assessed the influence of peripheral blood monocytes on human cardiac myofibroblast activity in a three-dimensional (3D) ECM microenvironment. Human cardiac myofibroblasts isolated from surgical biopsies of the right atrium and left ventricle were seeded into 3D collagen matrices. Peripheral blood monocytes were isolated from healthy human donors and cocultured with myofibroblasts. Monocytes increased myofibroblast activity measured by collagen gel contraction (baseline: 57.6 ± 5.9% vs. coculture: 65.2 ± 7.1% contraction; P < 0.01) and increased local ECM remodeling quantified by confocal microscopy. Under coculture conditions that allow indirect cellular interaction via paracrine factors but prevent direct cell-cell contact, monocytes had minimal effects on myofibroblast activity (17.9 ± 11.1% vs. 6.4 ± 7.0% increase, respectively; P < 0.01). When cells were cultured under direct contact conditions, multiplex analysis of the coculture media revealed an increase in the paracrine factors TGF-β1 and matrix metalloproteinase 9 compared with baseline (122.9 ± 10.1 pg/ml and 3,496.0 ± 190.4 pg/ml, respectively, vs. 21.5 ± 16.3 pg/ml and 183.3 ± 43.9 pg/ml; P < 0.001). TGF-β blockade abolished the monocyte-induced increase in cardiac myofibroblast activity. These data suggest that direct cell-cell interaction between monocytes and cardiac myofibroblasts stimulates TGF-β-mediated myofibroblast activity and increases remodeling of local matrix. Peripheral blood monocyte interaction with human cardiac myofibroblasts stimulates myofibroblast activity through release of TGF-β1. These data implicate inflammation as a potential driver of cardiac fibrosis.

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00309.2015

Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-β1

Contexte: La sclerose en plaques (SP) est une maladie consideree comme ayant des causes environnementales. Des correlations concordantes ont ete etablies dans differents contextes pour la latitude, l'exposition au tabagisme, la lumiere du soleil et le deficit en vitamine D. Nous avons analyse la contribution de differents facteurs environnementaux au risque de developper la SP a partir d'une perspective populationnelle. Methodes: Nous avons collige les donnees globales de 54 etudes sur la prevalence de la SP au cours des 10 annees anterieures et nous avons calcule le degre de risque attribuable a la latitude, la longitude, la radiation ultraviolette (UV) (donnees obtenues par satellite de la NASA et adaptees selon les heures d'ensoleillement) les taux de tabagisme des populations (donnees de l'OMS), le sexe, la date de l'etude, les donnees demographiques de l'etude ainsi que plusieurs facteurs socioeconomiques. Nous rapportons une correlation negative tres significative entre la prevalence de la SP et la radiation UV. Resultats: Le manque de radiation UV a plus d'influence que les autres facteurs dans une proportion d'au moins 20 fois (p < 10^-8) a l'analyse de regression univariee. L'analyse de regression multiple a montre que la latitude et la longitude sont egalement des facteurs significatifs et que le tabagisme peut jouer un role minime. Les huit etudes de prevalence scandinaves ont revele des prevalences plus faibles que prevu etant donne la position geographique. Conclusions: La radiation UV disponible est un facteur environnemental significatif qui est plus important que tous les autres facteurs examines.

/pdf/a-quantitative-analysis-of-suspected-environmental-causes-of-14vnkqrcne.pdf

A quantitative analysis of suspected environmental causes of MS.

White matter injury, consisting of loss of axons, myelin and oligodendrocytes, is common in many neurological disorders and is believed to underlie several motor and sensory deficits. Remyelination is the process in which the insulative myelin sheath is restored to axons, thereby facilitating recovery from functional loss. Remyelination proceeds with oligodendrocyte precursor cells that differentiate into oligodendrocytes to synthesize the new myelin sheath after demyelination. This process is influenced by several factors, including trophic factors, inhibitory molecules in the lesion microenvironment, age of the subject, as well as the inflammatory response. Currently studied strategies that enhance remyelination consist of pharmacological approaches that directly induce oligodendrocyte precursor cell differentiation or using agents to neutralize the inhibitory microenvironment. Another strategy is to harness a reparative inflammatory response. This response, coordinated by central nervous system resident microglia and peripherally-derived infiltrating macrophages, has been shown to be important in the remyelination process. These innate immune cells perform important functions in remyelination, including the proteolysis and phagocytosis of inhibitory molecules present in the lesion microenvironment, the provision of trophic and metabolic factors to oligodendrocyte precursor cells, in addition to iron handling capacity. Additionally, an initial pro-inflammatory phase followed by a regulatory/anti-inflammatory phase has been shown to be important for oligodendrocyte precursor cell proliferation and differentiation, respectively. This review will discuss the beneficial roles of macrophages/microglia in remyelination and discuss therapeutic strategies to obtain the optimal regenerative macrophage phenotype for enhanced remyelination.

/pdf/regenerative-capacity-of-macrophages-for-remyelination-5ertzpz9p7.pdf

Regenerative Capacity of Macrophages for Remyelination

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.

V. Wee Yong

Papers

Matrix metalloproteinases in intracerebral hemorrhage

Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-β1

A quantitative analysis of suspected environmental causes of MS.

Regenerative Capacity of Macrophages for Remyelination

Focus on the gut-brain axis: Multiple sclerosis, the intestinal barrier and the microbiome.