No abstract

Chronic myelogenous leukemia (CML) stem cells (LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here, we show that although miR-126 supports the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels are lower in CML LSCs as compared to normal long-term hematopoietic stem cells (LT-HSCs). Down-regulation of miR-126 levels in CML LSCs is due to phosphorylation of SPRED1 by BCR-ABL, leading to inhibition of the RAN/EXP-5/RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using CML mouse models with conditional miR-126 knock-out (KO) in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment causes an undesired increase in endogenous miR-126 levels, thereby enhancing LSC quiescence and persistence. miR-126 KO in LSCs and/or ECs, or treatment with a CpG-miR-126 inhibitor targeting miR-126 in both LSCs and ECs, enhances the in vivo anti-leukemic effects of TKI treatment and strongly diminishes LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in CML.

Purpose: Prostate cancers show remarkable resistance to emerging immunotherapies, partly due to tolerogenic STAT3 signaling in tumor-associated myeloid cells. Here, we describe a novel strategy combining STAT3 inhibition with Toll-like Receptor-9 (TLR9) stimulation to unleash immune response against prostate cancers regardless of the genetic background. Experimental Design: We developed and validated a conjugate of the STAT3 antisense oligonucleotide (ASO) tethered to immunostimulatory TLR9 agonist (CpG oligonucleotide) to improve targeting of human and mouse prostate cancer and myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs). Results: CpG-STAT3ASO conjugates showed improved biodistribution and potency of STAT3 knockdown in target cells in vitro and in vivo. Systemic administration of CpG-STAT3ASO (5mg/kg) eradicated bone-localized, Ras-/Myc-driven and Ptenpc−/−Smad4pc−/−Trp53c−/− prostate tumors in the majority of treated mice. These antitumor effects were primarily immune-mediated and correlated with an increased ratio of CD8+ to regulatory T-cells and reduced pSTAT3+/PD-L1+ MDSCs. Both innate and adaptive immunity contributed to systemic antitumor responses as verified by the depletion of Gr1+ myeloid cells and CD8+, CD4+ T-cells, respectively. Importantly, only the bi-functional CpG-STAT3ASO, but not control CpG oligonucleotides, STAT3ASO alone nor the co-injection of both oligonucleotides, succeeded in recruiting neutrophils and CD8+ T-cells into tumors. Thus, the concurrence of TLR9 activation with STAT3 inhibition in the same cellular compartment is indispensable for overcoming tumor immune tolerance and effective antitumor immunity against prostate cancer. Conclusions: The bi-functional, immunostimulatory and tolerance-breaking design of CpG-STAT3ASO offers a blueprint for the development of effective and safer oligonucleotide strategies for treatment of immunologically “cold” human cancers.

No abstract

Metal nanoclusters (NCs) have recently attracted great interest in biomedical applications due to their ultrasmall size, good biocompatibility, and unique molecule-like physical and chemical properties. Metal NCs can be rationally designed and integrated with various targeting moieties to achieve unique physicochemical properties and functions. For therapeutic applications, these multifunctional surface-modified NCs can provide distinctive advantages over native metal NCs, such as improved therapeutic effects and reduced side effects. In this review, the design principles of targeting strategies for metal NCs and their composites, including passive and active targeting, and physical and chemical targeting are first discussed. The authors then focus on the recent achievements in the application of metal NCs in targeted therapeutics, including chemotherapy, phototherapy, and radiotherapy. Finally, the authors' perspectives on the challenges and opportunities of developing metal NCs in targeted therapeutics, further paving their way for potential clinical applications are provided.

A new type of magnetic nanoparticles (MNPs), as the absorbents of bisphenol A (BPA), was prepared by functionalization of FeO@SiO with BPA-specific aptamer in this work. ssDNA aptamer was immobilized on the FeO@SiO surface through biotin-avidin interactions, playing a role of the specific probe for BPA. The resultant materials (Apt-MNPs) exhibited outstanding magnetic responsibility and can be separated efficiently by the magnetic field. Experimental results also showed that Apt-MNPs had large adsorption capacity and high competitive selectivity for the targeted compound BPA. Furthermore, Apt-MNPs were adopted as the specific absorbents to extract and enrich BPA from human serum and urine samples. Therefore, an efficient detection method of BPA was developed in combination with high-performance liquid chromatography (HPLC). The linearity of the method was over a range of 5-10,000 ng mL with a correlation coefficient of 0.99997, and the limit of detections (LODs) for serum and urine were 2.0 and 1.0 ng mL, respectively. The recoveries of BPA in the spiked human serum and urine samples were 90.8 ± 7.3% (RSD) and 92.3 ± 1.5%, respectively. Our results demonstrated that Apt-MNPs were high-performance adsorbents for extracting and enriching BPA, resulting in fast and efficient detection of BPA in serum and urine samples. Graphical abstract Aptamer-MNPs were effective for BPA separation from serum and urine.

Helicobacter pylori (H. pylori ) infection is a major cause of chronic gastritis and is highly related to duodenal ulcer (DU) and gastric cancer (GC). To identify H. pylori-related GC biomarkers with high seropositivity in GC patients, differences in levels of protein expression between H. pylori from GC and DU patients were analyzed by isobaric tag for relative and absolute quantitation (iTRAQ). In total, 99 proteins showed increased expression (>1.5-fold) in GC patients compared to DU patients, and 40 of these proteins were categorized by KEGG pathway. The four human disease-related adhesin identified, AlpA, OipA, BabA, and SabA, were potential GC-related antigens, with a higher seropositivity in GC patients (n = 76) than in non-GC patients (n = 100). Discrimination between GC and non-GC patients was improved using multiple antigens, with an odds ratio of 9.16 (95% CI, 2.99–28.07; p < 0.0001) for three antigens recognized. The optimized combination of OipA, BabA, and SabA gave a 77.3% correct prediction rate. A GC-related protein microarray was further developed using these antigens. The combination of OipA, BabA, and SabA showed significant improvement in the diagnostic accuracy and the protein microarray containing above antigens should provide a rapid and convenient diagnosis of H. pylori-associated GC.

Melittin (MEL), the primary active component of bee venom, has recently emerged as a promising cancer chemotherapeutic agent. However, the instability and rapid degradation of MEL is a significant challenge in practical therapeutic applications. In the present study, graphene oxide (GO)-based magnetic nanocomposites (PEG-GO-Fe3O4) were prepared and adopted as the drug delivery vehicles of MEL, and the anticancer effects of PEG-GO-Fe3O4/MEL complexes on human cervical cancer HeLa cells were studied. PEG-GO-Fe3O4 exhibited a series of unique physical and chemical properties resulting in multiple interactions with MEL, and ultimately the release of MEL. In vitro experiments showed that PEG-GO-Fe3O4/MEL not only distinctly enhanced the inhibition effect on HeLa cells, but also induced pore formation in the cell membrane that ultimately led to cell lysis. In this newly developed drug delivery system, PEGylated GO plays the role of a MEL protector while Fe3O4 nanoparticles act as magnetic responders; therefore active MEL can be released over a long period of time (up to 72 h) and maintain its inhibition effect on HeLa cells.