Immune checkpoint blockade has been proven to have great therapeutic potential and has revolutionized the treatment of tumors. However, various limitations remain, including the low response rate of exhausted T cells and mutual regulation of multiple immunosuppressive cell types that compromise the effect of single-target therapy. Nano-delivery systems can be used to regulate the tumor immune microenvironment in favor of immunotherapy. In this study, we constructed a polypeptide-based micellar system that encapsulates an aryl hydrocarbon receptor (AhR) inhibitor (CH223191) conjugated to T cell activator anti-CD28. The inhibition of AhR activation downregulates the fraction of immunosuppressive cells and effectively inhibits tumor cell metastasis. In addition, the combination with co-stimulatory antibodies improves T-cell activation and synergistically enhances the antitumor effect of AhR inhibitors. The micellar system developed in this study represents a novel and effective tumor immunotherapy approach.

UNASSIGNED: Gliomas are one of the most common types of primary tumors in central nervous system. Previous studies have found that macrophages actively participate in tumor growth.
UNASSIGNED: Weighted gene co-expression network analysis was used to identify meaningful macrophage-related gene genes for clustering. Pamr, SVM, and neural network were applied for validating clustering results. Somatic mutation and methylation were used for defining the features of identified clusters. Differentially expressed genes (DEGs) between the stratified groups after performing elastic regression and principal component analyses were used for the construction of MScores. The expression of macrophage-specific genes were evaluated in tumor microenvironment based on single cell sequencing analysis. A total of 2365 samples from 15 glioma datasets and 5842 pan-cancer samples were used for external validation of MScore.
UNASSIGNED: Macrophages were identified to be negatively associated with the survival of glioma patients. Twenty-six macrophage-specific DEGs obtained by elastic regression and PCA were highly expressed in macrophages at single-cell level. The prognostic value of MScores in glioma was validated by the active proinflammatory and metabolic profile of infiltrating microenvironment and response to immunotherapies of samples with this signature. MScores managed to stratify patient survival probabilities in 15 external glioma datasets and pan-cancer datasets, which predicted worse survival outcome. Sequencing data and immunohistochemistry of Xiangya glioma cohort confirmed the prognostic value of MScores. A prognostic model based on MScores demonstrated high accuracy rate.
UNASSIGNED: Our findings strongly support a modulatory role of macrophages, especially M2 macrophages in glioma progression and warrants further experimental studies.

UNASSIGNED: The objective of this study is to evaluate the effect of basic fibroblast growth factor (bFGF) on the proliferation and secretion activity of feline adipose-derived mesenchymal stem cells (MSC).
UNASSIGNED: Feline MSC isolated from the subcutaneous adipose tissue of cats were cultured with or without bFGF.
UNASSIGNED: The bFGF addition enhanced the proliferation of feline MSC to a significant great extent compared with that without bFGF, although the cell proliferation tended to increase with the bFGF concentration. In addition, adipogenic and osteogenic staining assay demonstrated that the bFGF addition allowed MSC to maintain the differentiation ability even after the proliferation. Moreover, no change in the surface markers of MSC was observed between the cultures with or without bFGF. A quantitative RT-PCR assay revealed that the HGF and TSG-6 expression significantly increased by the bFGF addition. The highest mRNA expression of MMP-2 was observed for cells cultured in 1000 ng/ml bFGF concentration.
UNASSIGNED: The culture with bFGF is a promising way to enhance the proliferation, and HGF secretion ability of MSC as well as maintain their differentiation ability and immunophenotype nature.

Over the past few decades, there has been growing interest in understanding the molecular mechanisms of cancer pathogenesis and progression, as it is still associated with high morbidity and mortality. Current management of large bone sarcomas typically includes the complex therapeutic approach of limb salvage or sacrifice combined with pre- and postoperative multidrug chemotherapy and/or radiotherapy, and is still associated with high recurrence rates. The development of cellular strategies against specific characteristics of tumour cells appears to be promising, as they can target cancer cells selectively. Recently, Mesenchymal Stromal Cells (MSCs) have been the subject of significant research in orthopaedic clinical practice through their use in regenerative medicine. Further research has been directed at the use of MSCs for more personalized bone sarcoma treatments, taking advantage of their wide range of potential biological functions, which can be augmented by using tissue engineering approaches to promote healing of large defects. In this review, we explore the use of MSCs in bone sarcoma treatment, by analyzing MSCs and tumour cell interactions, transduction of MSCs to target sarcoma, and their clinical applications on humans concerning bone regeneration after bone sarcoma extraction.

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE)-mediated expression of extracellular matrix genes. For this purpose, human retinal pigment epithelial cells (ARPE-19) were treated with different concentrations of transforming growth factor-β (TGFβ), connective tissue growth factor (CTGF), interferon-γ (IFNγ) and the irreversible proteasome inhibitor epoxomicin. First, cytotoxicity and proliferation assays were carried out. The expression of proteasome-related genes and proteins was assessed and proteasome activity was determined. Then, expression of fibrosis-associated factors fibronectin (FN), fibronectin EDA domain (FN EDA), metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-1 (TIMP-1) and peroxisome proliferator-associated receptor-γ (PPARγ) was assessed. The proteasome inhibitor epoxomicin strongly arrested cell cycle progression and down-regulated TGFβ gene expression, which in turn was shown to induce expression of pro-fibrogenic genes in ARPE-19 cells. Furthermore, epoxomicin induced a directional shift in the balance between MMP-2 and TIMP-1 and was associated with down-regulation of transcription of extracellular matrix genes FN and FN-EDA and up-regulation of the anti-fibrogenic factor PPARγ. In addition, both CTGF and TGFβ were shown to affect expression of proteasome-associated mRNA and protein levels. Our results suggest a link between proteasome activity and pro-fibrogenic mechanisms in the RPE, which could imply a role for proteasome-modulating agents in the treatment of retinal disorders characterized by RPE-mediated fibrogenic responses.