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Katerine Aldrige
Gingival bleeding was one of the common clinical features seen in hypertensive patients. Patients showed the Russell's periodontal index score of 0.3-0.9. In a study by Mailboridin et al[4] wherein the Russell's index was show to be 2.0-4.9 with 79.14% of the patients presented with the symptoms of periodontitis, was similar to the results of the this present study. Mailboridin et al studied the Micro lympho hemocirculatory bed and leucocytogram of gingival tissue by the light microscopy in patients with chronic periodontitis having normal and high arterial blood pressure. In most cases of arterial hypertension the gingival mucous was characterized by widening of lymphatic vessels and interstitial spaces. In cases of arterial hypertension combination with inflammatory reaction the tendency for widening of lymphatic vessels and interstitial spaces persisted compared with cases of normal blood pressure. It testifies to high probability of lymphogenic generalization of inflammation. Besides, in cases of inflammatory gingival pathology in arterial hypertension the absolute neutrophil number was significantly higher showing for more acute inflammatory process and greater volume of tissue involvement. Thus, concluding that the increased periodontitis in hypertensive patients could probably attributed as one of the manifestation of hypertension.[4] Similar findings were mentioned by Holmlund et al.[5]
Erythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex (mostly IgM) in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure. It is a common disorder, with peak incidence in the second and third decades of life.
Abstract:Reperfusion injury is a very common complication of various indicated therapies such as the re-opening of vessels in the myocardium or brain as well as reflow in hemodynamic shutdown (cardiac arrest, severe trauma, aortic cross-clamping). The treatment and prevention of reperfusion injury has therefore been a topic of immense interest in terms of mechanistic understanding, the exploration of interventions in animal models and in the clinical setting in major prospective studies. While a wealth of encouraging results has been obtained in the lab, the translation into clinical success has met with mixed outcomes at best. Considering the still very high medical need, progress continues to be urgently needed. Multi-target approaches rationally linking interference with pathophysiological pathways as well as a renewed focus on aspects of microvascular dysfunction, especially on the role of microvascular leakage, are likely to provide new insights.Keywords: reperfusion injury; capillary leak; edema; organ protection; clinical outcome
Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.
Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor [33]. Current standard-of-care, including surgery, radiotherapy, and chemotherapy, offers minimal clinical benefits for GBM patients with median survival of less than 16 months [49]. The basis of therapeutic failure is the significant inter- and intra-tumoral heterogeneity of GBM [34, 38, 48, 55, 56]. One aspect of heterogeneity is reflected by the transcriptional subtypes. GBMs have been stratified by bulk gene expression profiles into at least three subtypes, namely proneural, classical, and mesenchymal subtypes [55, 56]. Among these subtypes, the mesenchymal subtype is associated with the worst prognosis and the presence of tumor-associated macrophages/microglia [39, 56].
The GBM microenvironment consists of heterogeneous cells, namely tumor cells, including GSCs and DGCs, and non-tumor cells including endothelial cells, vascular pericytes, tumor-associated macrophages, and other immune cells [11, 16, 22, 46]. Macrophages are an abundant cellular component of the GBM microenvironment and play multiple roles in GBM progression [15, 22, 46]. Tumor-associated macrophages release several factors, including interleukin (IL)-6 and IL-10, which promote tumor cell growth, facilitate angiogenesis, and suppress the anti-tumor functions of other immune cells [24, 45]. Additionally, GSCs and tumor-associated macrophages interact with each other closely [46]. Tumor-associated macrophages secrete cytokines, such as pleiotrophin and TGF-β1, to maintain the stemness of GSCs and promote invasion of GSCs [24, 46, 47]. GSCs recruit monocyte-derived macrophages from peripheral blood through paracrine periostin and osteopontin signaling [46, 58, 63]. GSCs also promote the survival of M2 tumor-supportive macrophages by secretion of WISP1, which play immune suppressive roles in the tumor microenvironment, [52]. The crosstalk between GSCs and macrophages has been explored actively, but the biological roles of DGCs in GBM progression, especially in the tumor microenvironment, are largely unknown.
Here, using DGC-specific transcriptomic signatures, we investigated the biological roles of DGCs in the tumor microenvironment, and demonstrate that DGCs accelerate GSCs-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration.
Tumor samples from GBM patients and mouse intracranial GBM models were fixed in 4% paraformaldehyde overnight at 4 C, followed by overnight cryoprotection with 30% sucrose in PBS at 4 C. Samples were then sectioned at a thickness of 7 µm. Sections were washed with PBS twice, permeabilized, and then blocked with 0.3% Triton X-100, 5% BSA in PBS for 1 h. Then, the sections were stained with primary antibodies against Iba1 (1 µg/mL, FUJIFILM Wako, #019-19741), CD206/MMR (2 µg/mL, R&D Systems, #AF2535), SOX2 (2 µg/mL, R&D Systems, #AF2018), and CCN1/Cyr61 (10 µg/mL, Novus, #NB100-356) overnight at 4 C, followed by the secondary antibodies against rabbit or goat immunoglobulin G (IgG) labeled with Alexa Fluor dyes (Thermo Fisher Scientific) at room temperature for 1 h. After immunostaining, the samples were mounted with DAPI Fluoromount-G (SouthernBiotech, #0100-20). Images were obtained under an LSM780 confocal laser scanning microscope (Carl Zeiss).
We next investigated the clinical and anatomical relevances of the DGC signature in GBM cohorts. Anatomically, regions of microvascular proliferation and pseudopalisading cells expressed the DGC signature more in GBM tissues, whereas the leading edge and infiltrating tumor regions expressed the GSC signature more (Fig. 2b, f, Additional file 1: S2a). Consistent with the findings shown in Fig. 1g, the DGC signature was associated with the mesenchymal subtype in TCGA GBM and IVY GAP datasets (Fig. 2g, Additional file 1: S2b). Furthermore, patients with higher expression of the DGC signature exhibited poorer survival when grouped by both the clustering shown in Fig. 2a and ssGSEA score (Fig. 2h, Additional file 1: S2c). These results suggest that transcriptomic DGC signatures correlate with the mesenchymal subtype and poor patient prognoses.
To identify specific immune cells linked to DGC signatures, we examined TCGA GBM dataset for various types of immune cells using validated gene set signatures [7, 20]. Analysis of immune cell signatures demonstrated that high DGC-signature expression correlated with significant enrichment of macrophages (total, M1, and M2-macrophages), microglia, and monocytes (Fig. 3e). Therefore, we assessed macrophage-related gene sets (macrophage chemoattractant, migration, and activation) by GSEA and found that the DGC-high GBM group exhibited significant enrichment of these gene sets (Fig. 3f). Taken together, these in silico findings suggest a role of DGCs in macrophage infiltration into GBM.
To investigate the biological role of CCN1 in GBM, we explored transcriptomic data of TCGA GBM cohorts. CCN1-high GBMs exhibited prominent representation of immune response gene sets in GSEA, which included the interferon α/γ response, TNF-α/NF-κB signaling, inflammatory response, interleukin-2 (IL-2)/STAT5 signaling, and IL-6/STAT3 signaling (Fig. 6a). CCN1-high GBMs exhibited higher stromal and immune signatures and lower tumor purity than CCN1-low GBMs (Fig. 6b, c, Additional file 1: S6a). Analysis of immune cell signatures demonstrated that high CCN1 expression correlated to significant enrichment of macrophages (total M1 and M2), microglia, and monocytes (Fig. 6d). Gene ontology enrichment analysis (GOEA) of the subontologies of the Biological Process in TCGA GBM patients, which demonstrated that leukocyte migration and chemotaxis activity were CCN1-regulated processes (Additional file 1: Fig. S6b). Furthermore, the CCN1-high GBM group exhibited significant enrichment of macrophage-related gene sets (macrophage chemoattractant, migration, and activation) in the GSEA (Fig. 6e). Taken together, these in silico findings suggest a role of CCN1 in macrophage infiltration into GBM.
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