Sunitinib, a multitargeted tyrosine kinase inhibitor, is the frontline therapy for renal and gastrointestinal cancers. In view of its well-documented proapoptotic and immunoadjuvant properties, we speculate that combination of Sunitinib and immunotherapy would provide a synergistic antitumor effect. Here, we report that a remarkably synergistic antitumor responses elicited by the combined treatment of Sunitinib and an agonistic antibody against glucocorticoid-induced TNFR related protein (GITR) in a model of metastatic renal cell carcinoma. Sunitinib significantly increased the infiltration, activation, and proliferation and/or cytotoxicity of CD81 T cells and NK cells in liver metastatic foci when combined with the anti (a)-GITR agonist, which was associated with treatment-induced prominent upregulation of Th1-biased immune genes in the livers from mice receiving combined therapy versus single treatment. Sunitinib/a-GITR treatment also markedly promoted the maturation, activation and cytokine production of liver-resident macrophages and DCs compared with that achieved by a-GITR or Sunitinib treatment alone in mice. Cell depletion experiments demonstrated that CD8 1 T cells, NK cells and macrophage infiltrating liver metastatic foci all contribute to the antitumor effect induced by combined treatment. Furthermore, mechanistic investigation revealed that Sunitinib treatment reprograms tumor-associated macrophages toward classically activated or "M1" polarization upon GITR stimulation and consequently mounts an antitumor CD8 1 T and NK cell response via inhibiting STAT3 activity.Thus, our findings provide a proof of concept that Sunitinib can synergize with a-GITR treatment to remodel the tumor immune microenvironment to trigger regressions of an established metastatic cancer.Renal cell carcinoma (RCC) is the most common form of kidney cancer, of which most patients present with localized RCC and can be cured with radical nephrectomy. 1,2 However, approximately 25 to 30% of patients will have metastatic RCC (mRCC) at diagnosis, and their long-term outcomes are generally dismal with an estimated 10% of 5-year survival rate.

BackgroundThe present study examined the role of microRNA (miR)-96 in renal cell carcinoma (RCC) invasion.MethodsThe expression of miR-96 was detected by quantitative reverse transcription-polymerase chain reaction in human RCC cell lines with high (Caki-1) and low (786-O) metastatic potential. Invasive ability and Ezrin expression were assessed in Caki-1 and 786-O cells transfected with a miR-96 mimic or inhibitor using wound healing assays, Transwell assays and western blotting. Expression of miR-96 and Ezrin was also examined in primary RCC samples from 17 patients with metastatic disease and 46 patients who maintained remission during a follow-up period of 37 months.ResultsmiR-96 expression was significantly lower in Caki-1compared to786-O cells. The invasive ability of Caki-1 and 786-O cells increased following transfection of cells with miR-96 inhibitor, whereas it decreased following transfection with miR-96 mimic. Ezrin levels were negatively correlated with miR-96 in RCC, and inhibition of Ezrin expression suppressed the miR-96-induced change in invasive ability. The negative correlation between miR-96 and metastasis/Ezrin expression was also observed in human RCC specimens.ConclusionsThese results suggest that miR-96 suppresses RCC invasion by modulating Ezrin expression.

Background: Breast cancer (BC) is the most commonly diagnosed cancer in women. Tumor recurrence and metastasis are the key causes of death in BC patients. Long noncoding RNA (lncRNA) is closely associated with BC progression. lncRNA nuclear-enriched abundant transcript (NEAT)1 has been reported to regulate the proliferation and mobility of several types of cancer cells. However, how lncRNA NEAT1 affects the proliferation and invasion of BC cells is not known. Methods: Quantitative real time-polymerase chain reaction (qRT-PCR) was used to measure expression of lncRNA NEAT1 and microRNA (miR)-146b-5p in BC tissues and cell lines. Cell Counting Kit (CCK)-8, cell colony-formation, wound-healing, and Transwell™ assays were undertaken to determine the effects of lncRNA NEAT1 and miR-146b-5p on progression of BC cells. The interaction between lncRNA NEAT1 and miR-146b-5p was examined by luciferase reporter, RNA-binding protein immunoprecipitation (RIP), and RNA-pulldown assays. Results: Expression of lncRNA NEAT1 was upregulated in BC tissues and cell lines. High expression of lncRNA NEAT1 predicted poor overall survival in BC patients. Silencing of expression of lncRNA NEAT1 inhibited epithelial-mesenchymal transition (EMT) and suppressed the proliferation, migration and invasion of BC cells. Ectopic expression of lncRNA NEAT1 induced EMT and promoted BC progression. Mechanistic investigations revealed that miR-146b-5p was a direct target of lncRNA NEAT1, and its expression was correlated negatively with expression of lncRNA NEAT1 in BC tissues. Conclusion: lncRNA NEAT1 could (i) serve as a novel prognostic marker for BC and (ii) be a potential therapeutic target for BC.

Fluoroquinolones are antimicrobial agents that are widely used clinically, but the increasing resistance of Acinetobacter baumannii (A. baumannii) to these agents is a matter of concern. We investigated mutant prevention concentrations (MPCs) of three fluoroquinolones, levofloxacin (LVX), pazufloxacin (PAZ) and ciprofloxacin (CIP). We analyzed an A. baumannii standard strain (ATCC19606) for mutation prevention indices (MPIs), MPCs and mutant selection windows as well as MICs of CIP, PAZ and LVX and compared the derived values with 34 A. baumannii strains collected in hospitals. In addition, A. baumannii standard strain (ATCC19606) fluoroquinolone-resistant mutants were investigated for gyrA and parC gene mutations. MPCs of CIP, prevention antibiotics concentration and LVX for A. baumannii ATCC19606 were 12.8, 5.6 and 2.8 μg ml(-1) and their MPIs were 16, 8 and 4, respectively. Clinically isolated A. baumannii strains had CIP, PAZ and LVX MPC value ranges of 1-8, 1-16 and 0.5-2 μg ml(-1) and their MPIs were 8, 8 and 4 μg ml(-1). Single gyrA mutations (Ser(83)-Leu(83)) occurred in 18 resistant strains (48.7%) and single parC mutations (Ala(79)-Asp(79) or (Ser(80)-Leu(80)) occurred in 8 resistant strains (21.6%), whereas gyrA and parC double mutations occurred in 2 (5.4%) of the resistant strains. MPC and MPI values of LVX were lower than that of CIP and PAZ. Single gyrA and parC mutations accounted for the majority of mutations (n=24), whereas double mutations occurred only in two strains.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited effective treatment options. New therapeutic approaches are urgently needed to improve the prognosis of TNBC. Here we demonstrated that a redox modulator, selenocystine (SeC), significantly inhibits TNBC cell proliferation in a dose- and time-dependent manner. Through cell apoptosis assays and cell cycle distribution analyses, we have shown that the in vitro inhibitory effect of SeC on TNBC cells can be attributed to the induction of apoptosis and the S-phase arrest in a dose-dependent manner. Therefore, this finding implies that SeC potentially is a novel therapeutic agent for TNBC.