The incorporation of new modalities into chemotherapy greatly enhances the anticancer efficacy combining the merits of each treatment, showing promising potentials in clinical translations. Herein, a hybrid nanomedicine (Au/FeMOF@CPT NPs) is fabricated using metal–organic framework (MOF) nanoparticles and gold nanoparticles (Au NPs) as building blocks for cancer chemo/chemodynamic therapy. MOF NPs are used as vehicles to encapsulate camptothecin (CPT), and the hybridization by Au NPs greatly improves the stability of the nanomedicine in a physiological environment. Triggered by the high concentration of phosphate inside the cancer cells, Au/FeMOF@CPT NPs effectively collapse after internalization, resulting in the complete drug release and activation of the cascade catalytic reactions. The intracellular glucose can be oxidized by Au NPs to produce hydrogen dioxide, which is further utilized as chemical fuel for the Fenton reaction, thus realizing the synergistic anticancer efficacy. Benefitting from the enhanced permeability and retention effect and sophisticated fabrications, the blood circulation time and tumor accumulation of Au/FeMOF@CPT NPs are significantly increased. In vivo results demonstrate that the combination of chemotherapy and chemodynamic therapy effectively suppresses the tumor growth, meantime the systemic toxicity of this nanomedicine is greatly avoided.

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Background. Ferroptosis is a newly identified form of programmed cell death caused by iron-dependent lipid peroxidation. Our study was designed to determine the expression patterns and role of 15-lipoxygenase-1 (ALOX15) in subarachnoid hemorrhage (SAH) and to investigate whether cepharanthine (CEP) can inhibit ferroptosis by inhibiting ALOX15 in specific cell types. Methods. A mouse model of SAH was developed by the endovascular perforation method. bEend.3 endothelial cells and BV2 microglial cells as well as RSL3 and hemin were used to simulate SAH in vitro. Mice and cell lines were treated with CEP and a group of specific oxygenase inhibitors to explore the protection effect from ferroptosis. Lipid peroxidation staining with BODIPY 581/591 C11 and transmission electron microscopy were used to identify ferroptosis in vitro and in vivo. Results. In the present study, the accumulation of lipid peroxide, a defect in the glutathione peroxidase 4 (GPx4)/glutathione (GSH) antioxidant system, highly expressed ALOX15 in microglia and endothelium, and ferroptotic changes in microglial mitochondria confirmed the occurrence of ferroptosis after SAH in vivo. Further, CEP was shown to inhibit ferroptosis and improve neurological function by downregulating the expression of ALOX15. During in vitro experiments, we investigated the important role ALOX15 in RSL3-induced endothelial ferroptosis. In addition, we found that M2-type microglia are more sensitive to RSL3-induced ferroptosis than M1-type microglia and that hemin probably induced ferroptosis in M2-type microglia by increasing ALOX15 levels and decreasing GPx4 levels. The effect of CEP treatment was also demonstrated in vitro. Conclusions. In summary, to the best of our knowledge, this is the first study demonstrating that ferroptosis occurred in the microglia and endothelium after SAH, and this process was facilitated by increased ALOX15 levels. More importantly, treatment with CEP could inhibit ferroptosis through downregulating the expression of ALOX15.

We aimed to explore the tumor mutational burden (TMB) and immune infiltration in HCC and investigate new biomarkers for immunotherapy. Transcriptome and gene mutation data were downloaded from the GDC portal, including 374 HCC samples and 50 matched normal samples. Furthermore, we divided the samples into high and low TMB groups, and analyzed the differential genes between them with GO, KEGG, and GSEA. Cibersort was used to assess the immune cell infiltration in the samples. Finally, univariate and multivariate Cox regression analyses were performed to identify differential genes related to TMB and immune infiltration, and a risk prediction model was constructed. We found 10 frequently mutated genes, including TP53, TTN, CTNNB1, MUC16, ALB, PCLO, MUC, APOB, RYR2, and ABCA. Pathway analysis indicated that these TMB-related differential genes were mainly enriched in PI3K-AKT. Cibersort analysis showed that memory B cells (p = 0.02), CD8+ T cells (p = 0.09), CD4+ memory activated T cells (p = 0.07), and neutrophils (p = 0.06) demonstrated a difference in immune infiltration between high and low TMB groups. On multivariate analysis, GABRA3 (p = 0.05), CECR7 (p < 0.001), TRIM16 (p = 0.003), and IL7R (p = 0.04) were associated with TMB and immune infiltration. The risk prediction model had an area under the curve (AUC) of 0.69, suggesting that patients with low risk had better survival outcomes. Our study demonstrated for the first time that CECR7, GABRA3, IL7R, and TRIM16L were associated with TMB and promoted antitumor immunity in HCC.

HCC is one of the most common types of malignancies worldwide and the fourth-leading cause of cancer deaths. Thus, there is an urgent need to search for novel targeted therapies in HCC. 186 m6a-related lncRNAs were screened for subsequent analysis. Two distinct m6A modification clusters were identified to be associated with the overall prognosis in TCGA-LIHC based on the m6A-related lncRNAs profiling, followed by univariate Cox regression analysis. In addition, four m6A-related lncRNAs prognostic signatures were developed and validated that could predict the OS of HCC patients, followed by univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. Moreover, four m6A-related lncRNAs were identified to be related to HCC prognosis. ESTIMATE was used to evaluate the stromal score, immune score, ESTIMATE score, and tumor purity of each HCC sample. ssGSEA was performed to identify the enrichment levels of 29 immune signatures in each sample. Finally, quantitative real-time polymerase chain reaction shown that KDM4A-AS1, BACE1-AS, and NRAV expressions were upregulated in HCC patients. We proved that our m6A-related lncRNAs signature had powerful and robust ability for predicting OS of different HCC subgroups.