Glioblastoma (GBM) is highly invasive and the deadliest brain tumor in adults. It is characterized by inter-tumor and intra-tumor heterogeneity, short patient survival, and lack of effective treatment. Prognosis and therapy selection is driven by molecular data from gene transcription, genetic alterations and DNA methylation. The four GBM molecular subtypes are proneural, neural, classical, and mesenchymal. More effective personalized therapy heavily depends on higher resolution molecular subtype signatures, combined with gene therapy, immunotherapy and organoid technology. In this review, we summarize the principal GBM molecular classifications that guide diagnosis, prognosis, and therapeutic recommendations.

Inflammation is a common characteristic of chronic liver disease (CLD). Inflammasomes are multiprotein complexes that can sense and recognize various exogenous and endogenous danger signals, eventually activating interleukin (IL)-1β and IL-18. The sensor component of the inflammasome system is a nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). The NLRs family pyrin domain containing 3 (NLRP3) inflammasome has been involved in the initiation and progression of CLD. However, the molecular mechanisms by which it triggers liver inflammation and damage remain unclear. Here, we focus on recent advances on the potential role of NLRP3 inflammasome activation in the progression of CLD, including viral hepatitis, non-alcoholic steatohepatitis and alcoholic liver disease, and in particular, its ability to alleviate liver inflammation in animal models. Additionally, we also discuss various pharmacological inhibitors identifying the NLRP3 inflammasome signaling cascade as novel therapeutic targets in the treatment of CLD. In summary, this review summarizes the relevance of the NLRP3 inflammasome in the initiation and progression of CLD, and provides critical targets to suppress the development of CLD in clinical management.

The mitochondrial GTPase mitofusin-2 (MFN2) has previously been reported to play a role in regulating cell proliferation, apoptosis and differentiation in a number of cell types. Here, we report that breast cancer patients with low MFN2 expression are associated with poor prognosis as compared to patients with high MFN2 expression. We find that MFN2 knockout from MCF7 and A549 cells via Crispr/Cas9 greatly promotes cell viability, colony formation, and invasion of cancer cells in vitro and in vivo, which were confirmed by colony formation assay, transwell invasion assay, and tumor xenograft model. Signaling analyses suggest the mammalian target of rapamycin complex 2 (mTORC2)/Akt signaling pathway is highly elevated in MFN2 knockout cancer cells. The elevated mTORC2 promotes cancer cell growth and metastasis via Akt^S437 phosphorylation mediated signaling pathway. Mechanistic studies reveal that MFN2 suppresses mTORC2 through direct interaction by binding its domain HR1. Inhibition of mTORC2 significantly suppresses MFN2 deficient tumor growth. Collectively, this study provides novel insights into the tumor progression associated with MFN2 deficiency and suggests that the importance of mTORC2 inhibitor in the treatment of MFN2 downregulated cancer patients.

AMD3100, also known as plerixafor, was originally developed as an anti-human immunodeficiency virus (HIV) drug, and later characterized as a C-X-C chemokine receptor type 4 (CXCR4) antagonist. Previous reviews have focused on the application of AMD3100 in the treatment of HIV, but a comprehensive evaluation of AMD3100 in the treatment of leukemia, solid tumor, and diagnosis is lacking. In this review, we broadly describe AMD3100, including the background, functional mechanism and clinical applications. Until the late 1990s, CXCR4 was known as a crucial factor for hematopoietic stem and progenitor cell (HSPC) retention in bone marrow. Subsequently, the action and synergy of plerixafor with Granulocyte-colony stimulating factor (G-CSF) led to the clinical approval of plerixafor as the first compound for mobilization of HSPCs. The amount of HSPC mobilization and the rapid kinetics promoted additional clinical uses. Recently, CXCR4/CXCL12 (C-X-C motif chemokine 12) axis was found to be involved in a variety of roles in tumors, including leukemic stem cell (LSC) homing and signaling transduction. Thus, CXCR4 targeting has been a treatment strategy against leukemia and solid tumors. Understanding this mechanism will help shed light on therapeutic potential for HIV infection, inflammatory diseases, stem-cell mobilization, leukemia, and solid tumors. Clarifying the CXCR4/CXCL12 axis and role of AMD3100 will help remove malignant cells from the bone marrow niche, rendering them more accessible to targeted therapeutic agents.

Purpose: Uveal melanoma (UM) is the most prevalent and lethal intraocularmalignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the anti-tumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. Experimental Design: UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal-epithelial transition factor (c-Met)were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex. Results: Systemic administration of 64B had potent anti-tumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (~70% reduction) and spontaneous liver metastasis (~50% reduction), and extending mice survival (p< 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met,two key drivers of tumor invasion and metastasis. 64B disrupted HIF-1 complex by interfering with HIF-1α binding to p300/CBP co-factors, reducing p300 recruitment to the METand CXCR4gene promoters. 64B could thermo-stabilize p300, supporting direct 64B binding to p300. Conclusions: Our pre-clinical efficacy studies support the further optimization of the 64B chemical scaffold towards a clinical candidate for the treatment of UM.