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Glioblastoma (GBM) is the most devastating brain tumor and highly resistant to conventional chemotherapy. Herein, we introduce biomimetic nanosonosensitizer systems (MDNPs) combined with noninvasive ultrasound (US) actuation for orthotopic GBM-targeted delivery and sonodynamic-enhanced chemotherapy. MDNPs were fabricated with biodegradable and pH-sensitive polyglutamic acid (PGA) and the chemotherapeutic agent and sonosensitizer doxorubicin (DOX), camouflaged with human GBM U87 cell membranes. MDNPs presented homologous targeting accumulation and in vivo long-term circulation ability. They effectively passed through the blood-brain barrier (BBB) under US assistance and reached the orthotopic GBM site. MDNPs exhibited controllable US-elicited sonodynamic effect by generation of reactive oxygen species (ROS). ROS not only induced cancer cell apoptosis but also downregulated drug-resistance-related factors to disrupt chemoresistance and increase sensitivity to chemotherapy. The in vivo study of orthotopic GBM treatments further proved that MDNPs exhibited US-augmented synergistic antitumor efficacy and strongly prolonged the survival rate of mice. The use of low-dose DOX and the safety of US enabled repeated treatment (4 times) without obvious cardiotoxicity. This effective and safe US-enhanced chemotherapy strategy with the advantages of noninvasive brain delivery and high drug sensitivity holds great promise for deep-seated and drug-resistant tumors.

Cucumber is one of the most widely consumed vegetables worldwide, and the fruit spine is an important fruit quality trait. Expansins play critical roles in fruit development; however, the regulation of expansins in cucumber fruit spine development has not been reported. In this study, 33 expansin genes were identified in the cucumber genome V3; additionally, expansin genes in Citrullus lanatus, Cucumis melo, Cucurbita maxima, Lagenaria siceraria, and Benincasa hispida were also identified. Phylogenetic analysis of expansin proteins in Cucurbitaceae and Arabidopsis showed that they evolved separately in each plant species. Phylogenetic analysis showed that C. maxima was derived earlier than the other five Cucurbitaceae species. The expression of CsEXPA2, CsEXPA14, and CsEXLA3 varied in cucumber lines with different fruit spine densities. A yeast two-hybrid assay showed that a putative auxin transporter encoded by numerous spine gene (ns) interacts with CsEXLA2, which may be involved in the development of the numerous spines in cucumber. These results provide novel insights into the expansins related to plant development and fruit spine development in cucumber.

Purpose:Tumor repopulation is known as a major cause of treatment failure and/or tumor recurrence after radiotherapy. The underlying mechanism remains unclear. Our previous study demonstrated that irradiated apoptotic cells mediated tumor repopulation, in which caspase-3 played an important role. Herein, we investigated downstream effectors of caspase-3 involved in this process.Experimental Design:A dominant-negative protein kinase Cδ (DN_PKCδ) mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. DN_PKCδ stably transduced tumor cells were compared with wild-type tumor cells for their growth stimulation effects in in vitro and in vivo tumor repopulation models. Downstream effectors of caspase-3 and PKCδ were investigated. The role of PKCδ was further verified in human colorectal tumor specimens.Results:Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened PKCδ cleavage. Both DN_PKCδ and PKCδ inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3–, caspase-7–, or PKCδ-inactivated tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1α (HIF1α) was decreased in PKCδ- or Akt-inactivated tumor cells. In addition, inhibition of p-Akt, HIF1α, VEGF-A, or VEGF-A receptor reduced tumor repopulation significantly. Finally, increased nuclear translocation of PKCδ in colorectal tumor specimens was associated with worse patient prognosis.Conclusions:The caspase-3/PKCδ/Akt/VEGF-A axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy.

Supplementary Figures and Tables. // Figure S1, Survival fractions. Figure S2, Linearity of bioluminescence signals vs. Fluc-GFP-labeled tumor cell numbers. Figure S3, Cisplatin-induced dying tumor cells stimulated living tumor cell growth. Figure S4, DN_PKCÎ' (K378A) stably transduced HT-29 cells showed less growth stimulation effect when compared with wild-type HT-29 cells. Figure S5, A specific HIF1α inhibitor PX-478 2HCl remarkably suppressed the reporter cell growth on irradiated feeder cells. // Table S1, Summary of clinical characteristics in 68 patients of colorectal cancer.