Extracellular vesicles (EVs) are excellent potential vectors for the delivery of therapeutic drugs. However, issues with biological safety and disease targeting substantially limit their clinical application. EVs from red blood cells (RBC‐EVs) are potential drug delivery vehicles because of their unique biological safety. Here, we demonstrated that EVs, including RBC‐EVs, show natural liver accumulation. Mechanistically, the liver environment induces macrophages to phagocytize RBC‐EVs in a C1q‐dependent manner. RBC‐EVs loaded with antisense oligonucleotides of microRNA‐155 showed macrophage‐dependent protective effects against acute liver failure (ALF) in a mouse model. These RBC‐EVs were also effective in treatment of ALF. Furthermore, compared to routine doses of doxorubicin and sorafenib (SRF), RBC‐EVs loaded with doxorubicin or SRF showed enhanced therapeutic effects on a murine model of orthotopic liver cancer through a mechanism dependent on macrophages. Importantly, drug‐loaded RBC‐EVs showed no systemic toxicity at therapeutically effective doses, whereas routine doses of doxorubicin and SRF showed obvious toxicity. Thus, drug‐loaded RBC‐EVs hold high potential for clinical applications in the treatment of liver disease therapy.

Background Apatinib, a competitive inhibitor of VEGFR2, has anti-angiogenesis and anticancer activities through different mechanisms, but it still cannot fully explain the drug efficacy of apatinib. Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in cancer biology, however, the exact role of ferroptosis in apatinib-mediating anticancer treatment are still not clear. Methods The effects of (1S, 3R)-RSL3 and apatinib were evaluated in different GC cell lines and in normal human gastric epithelial cells. Further, the effects of apatinib and inhibition of antioxidant defense enzyme glutathione peroxidase (GPX4) on cell viability, cell death, glutathione (GSH) levels, lipid ROS production, cellular malondialdehyde (MDA) levels and protein expression were evaluated in vitro as well as in a mouse tumor xenograft model. The expression level of GPX4 in GC tissues and paracancerous tissues was measured by immunohistochemistry. Results (1S, 3R)-RSL3 selectively killed GC cells, but not normal cells. Apatinib induced ferroptosis in GC cells by decreasing cellular GSH levels and increasing lipid peroxidation levels. This effect was blocked by co-incubation with ferrostatin-1, liproxstatin-1, GSH, or vitamin E. Further investigation revealed that apatinib down-regulated GPX4 expression via inhibition of the transcription factors Sterol regulatory element-binding protein-1a (SREBP-1a). Besides, we found that multi-drug resistant GC cells were vulnerable to apatinib-induced GPX4 inhibition. Conclusions In summary, we show that apatinib could induce the lipid peroxidation through GPX4 mediated by SREBP-1a, then negatively regulate the GC cell, even the multi-drug-resistant GC cell, ferroptosis.

IntroductionThe pathways underlying chronic rhinosinusitis with nasal polyps (CRSwNP) are unclear. We conducted genome-wide gene expression analysis to determine pathways and candidate gene sets associated with CRSwNP.MethodsWe performed whole-transcriptome RNA sequencing on 42 polyp (CRSwNP-NP) and 33 paired nonpolyp inferior turbinate (CRSwNP-IT) tissues from patients with CRSwNP and 28 inferior turbinate samples from non-CRS controls (CS-IT). We analysed the differentially expressed genes (DEGs) and the gene sets that were enriched in functional pathways.ResultsPrincipal component-informed analysis revealed cilium function and immune regulation as the two main Gene Ontology (GO) categories differentiating CRSwNP patients from controls. We detected 6182 and 1592 DEGs between CRSwNP-NP versus CS-IT and between CRSwNP-NP versus CRSwNP-IT tissues, respectively. Atopy status did not have a major impact on gene expression in various tissues. GO analysis on these DEGs implicated extracellular matrix (ECM) disassembly, O-glycan processing, angiogenesis and host viral response in CRSwNP pathogenesis. Ingenuity Pathway Analysis identified significant enrichment of type 1 interferon signalling and axonal guidance canonical pathways, angiogenesis, and collagen and fibrotic changes in CRSwNP (CRSwNP-NP and CRSwNP-IT) tissues compared with CS-IT. Finally, gene set enrichment analysis implicated sets of genes co-regulated in processes associated with inflammatory response and aberrant cell differentiation in polyp formation.ConclusionsGene signatures involved in defective host defences (including cilia dysfunction and immune dysregulation), inflammation and abnormal metabolism of ECM are implicated in CRSwNP. Functional validation of these gene expression patterns will open opportunities for CRSwNP therapeutic interventions such as biologics and immunomodulators.

PurposeTo assess the predictive role of pretreatment ki67 and Ki67 changes in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) in various molecular subtypes.Methods1010 BC patients who had undergone anthracycline and taxane-based NAC from January 2012 to July 2017 were retrospectively analyzed. Clinical and pathological parameters of the patients were retrieved and the predictive factors for NAC response were evaluated.Results705 patients showed clinical response (cRes), and 131 patients acquired pathologic complete response (pCR). Patients with higher pretreatment Ki67 (≥ 14%), tumor size ≥ 4 cm, and positive clinical nodal had better clinical therapy response, while patients with negative ER and PR, higher pretreatment Ki67 (≥ 14%), and tumor size < 4 cm were more probable to attain pCR. The pretreatment Ki67 could be used as a predictor of NAC only in luminal subtypes, and 25.5% were identified as an ideal cut-off point to differentiate the cRes from non-cRes cases. Although a decrease in Ki67 had been found in almost all molecular subtypes after NAC, no statistically significant differences were found in the decrease of Ki67 were validated between the cRes and non-cRes group in HER2-rich and triple-negative subtypes (P = 0.488 and P = 0.111, respectively).ConclusionsThe best cut-off for pretreatment Ki67 in predicting the connection with the tumor size lessening was 25.5% in luminal subtype. Aggressive adjuvant systemic treatments should be considered for patients with HER2-rich and triple-negative subtype who exhibit tumor shrinkage in NAC but still have high levels of Ki67.Electronic supplementary materialThe online version of this article (10.1007/s10549-018-4730-1) contains supplementary material, which is available to authorized users.