Expression analysis, clinical significance and potential function of PLXNB2 in acute myeloid leukaemia.

BACKGROUND: The overall survival (OS) rate of adult patients suffering from acute myeloid leukaemia (AML) remains unsatisfactory at less than 40%. Current risk stratification systems fail to provide accurate guidelines for precise treatment. Novel biomarkers for predicting prognosis are urgently needed. Plexin B2 (PLXNB2), a functional receptor of angiogenin (ANG), has been found to be aberrantly expressed in multitudinous tumours. We detected overexpression of PLXNB2 mRNA in AML via transcriptome microarray analysis. This study aims to explore the potential role of PLXNB2 as a biomarker of prognosis and a prospective target of AML. METHODS: qRT‒PCR was conducted to verify the expression of PLXNB2 mRNA in bone marrow mononuclear cells from AML patients. Immunohistochemical and immunofluorescence staining were performed and confirmed increased expression of PLXNB2 protein in AML bone marrow tissues. Data on PLXNB2 expression, prognosis and clinical features were accessed from multiple bioinformatic databases, including The Cancer Genome Atlas (TCGA). Genes coexpressed and correlated with PLXNB2 were identified and analysed in the TCGA AML cohort. Metascape was applied for functional and pathway enrichment analysis of genes related to PLXNB2. Small molecular agents and traditional Chinese medicines potentially targeting genes related to PLXNB2 were screened via the Connectivity Map, TCMSP and HIT databases. RESULTS: PLXNB2 mRNA and protein levels are higher in AML samples than in normal controls. Overexpression of PLXNB2 is associated with worse OS in AML. Patients with high PLXNB2 expression might benefit more from haematopoietic stem cell transplantation (HSCT) (indicated by prolonged OS) than those with only chemotherapy treatment. Differentially expressed genes between the high and low PLXNB2 expression groups were overlapped with PLXNB2-coexpressed genes, and genes that overlapped were enriched in immune functions, endothelial cell regulation and cell interaction gene sets, indicating the potential function of PLXNB2 in AML. A total of 36 hub genes were identified from the differentially expressed genes, and MRC1, IL10, CD163 and CCL22 had significant prognostic value for AML. Analysis of the connectivity map and traditional agents revealed that honokiol, morphines, triptolide and paeoniflorin could be potential treatment regimens. CONCLUSIONS: The overexpression of PLXNB2 is an adverse prognostic factor in adult AML patients and could be used as a potential biomarker. PLXNB2 might exert an oncogenic role by modulating immune functions, endothelial cell functions and cell interactions. AML patients with high PLXNB2 expression could benefit more from HSCT.

The armed oncolytic adenovirus ZD55-IL-24 eradicates melanoma by turning the tumor cells from the self-state into the nonself-state besides direct killing.

ZD55-IL-24 is similar but superior to the oncolytic adenovirus ONYX-015, yet the exact mechanism underlying the observed therapeutic effect is still not well understood. Here we sought to elucidate the underlying antitumor mechanism of ZD55-IL-24 in both immunocompetent and immunocompromised mouse model. We find that ZD55-IL-24 eradicates established melanoma in B16-bearing immunocompetent mouse model not through the classic direct killing pathway, but mainly through the indirect pathway of inducing systemic antitumor immunity. Inconsistent with the current prevailing view, our further results suggest that ZD55-IL-24 can induce antitumor immunity in B16-bearing immunocompetent mouse model in fact not due to its ability to lyse tumor cells and release the essential elements, such as tumor-associated antigens (TAAs), but due to its ability to put a "nonself" label in tumor cells and then turn the tumor cells from the "self" state into the "nonself" state without tumor cell death. The observed anti-melanoma efficacy of ZD55-IL-24 in B16-bearing immunocompetent mouse model was practically caused only by the viral vector. In addition, we also notice that ZD55-IL-24 can inhibit tumor growth in B16-bearing immunocompetent mouse model through inhibiting angiogenesis, despite it plays only a minor role. In contrast to B16-bearing immunocompetent mouse model, ZD55-IL-24 eliminates established melanoma in A375-bearing immunocompromised mouse model mainly through the classic direct killing pathway, but not through the antitumor immunity pathway and anti-angiogenesis pathway. These findings let us know ZD55-IL-24 more comprehensive and profound, and provide a sounder theoretical foundation for its future modification and drug development.

Prostate Cancer-Specific of DD3-driven Oncolytic Virus-harboring mK5 Gene.

Prostate cancer (PCa) is the second most diagnosed cancer in Western male population. In this study, we insert mK5 (the mutational kringle5 of human plasminogen) into a DD3-promoted (differential display code 3) oncolytic adenovirus to construct OncoAd.mK5.DD3. E1A.dE1B, briefly, OAd.DD3.mK5. DD3 is one of the most prostate cancer specific promoters which can transcriptionally control adenoviral replication. mK5 has been proved to be able to inhibit the tumor angiogenesis and inhibit cell proliferation. Our results suggested that targeting PCa with OAd.DD3.mK5 elicited strong antitumor effect.

Adenovirus armed with VGLL4 selectively kills hepatocellular carcinoma with G2/M phase arrest and apoptosis promotion.

The Vestigial-Like Family Member 4 (VGLL4) functions as a native inhibitor of cell proliferation and tumor growth through multiple signaling pathways. We first discovered that VGLL4 causes G2/M phase arrest in hepatocellular carcinoma (HCC) cells. Then, we designed a novel survivin-regulated oncolytic adenovirus Ad-sp-VGLL4 carrying the VGLL4 gene. Ad-sp-VGLL4 exerted high HCC-targeting-selectivity but is less harmful to normal cells. This adenovirus construction enhanced antitumor activity due to G2/M phase arrest and enhanced apoptosis. It's also indicated that Ad-sp-VGLL4 could suppress the growth of transplanted tumor of HCC in vivo experiment. Taken together, our results suggest that Ad-sp-VGLL4 possesses strong antitumor capacity and has great potential use for HCC therapy.

Fabrication of porous covalent organic frameworks as selective and advanced adsorbents for the on-line preconcentration of trace elements against the complex sample matrix.

Herein, for the first time, the typical porous Covalent Organic Frameworks (COFs) CTpBD with superior chemical stability and large surface area were applied as sorbents for solid phase extraction of trace ions via flow injection followed by inductively coupled plasma mass spectrometry (ICP-MS) detection. The well-prepared and fully-characterized CTpBD COFs were filled in solid phase extraction cartridge as novel and robust adsorbents for element analysis. Separation and enrichment of Cr (III), Mn (II), Co (II), Ni (II), Cd (II), V (V), Cu (II), As (III), Se (IV), and Mo (VI) was then carried out, and the contents were measured by ICP-MS. Owing to the large surface area and instinctive porous structure of CTpBD, preconcentration of the target trace elements via COF-filled on-line SPE column has achieved low detection limits of 2.1-21.6ngL-1 along with a wide linearity range at 0.05-25µgL-1 for all target ions. The relative standard deviations (RSD) of 1.2%-4.3% obtained via 11 parallel determinations at the sample concentration of 100ngL-1 revealed excellent repeatability of the developed methods Our proposed methods have been successfully utilized for trace element analysis in environmental and food samples.

Spherical covalent organic frameworks as advanced adsorbents for preconcentration and separation of phenolic endocrine disruptors, followed by high performance liquid chromatography.

As a promising generation of porous micro-materials, covalent organic frameworks (COFs) have great potentials for applications in separation and adsorption. In the present study, an advanced food-safety inspection method involving COFs as the adsorbents of solid phase extraction (SPE) is proposed for sensitive and accurate determination of target hazardous substances. Typical spherical TpBD COFs with large surface area and superior chemical stability were utilized as adsorbents for the preconcentration of phenolic endocrine disruptors (PEDs), followed by high performance liquid chromatography (HPLC) analysis. The well-prepared TpBD COFs were encapsulated in SPE cartridges and applied in food research, namely, for the separation and enrichment of four target endocrine disruptors in food samples. The possible factors influencing the SPE performance including the composition of the sample solvent, sample solution pH, sample flow rate, composition of the eluent, and the volume of the eluent were investigated and optimized. Due to the porous architecture and superior surface area of spherical TpBD, the enrichment of analytes via a COF-filled SPE column gave extremely low detection limits of 0.056-0.123 µg L-1 along with a wide linear range of 0.5-100 µg L-1 for all the analytes. Nine parallel determinations of the mixed standard with a concentration of 10 µg L-1 produced the relative standard deviations of 2.23-3.08%, indicating the excellent repeatability of the COF-SPE assay. This study can open up a new route for the employment of COFs as efficient SPE adsorbents for the enrichment and quantification of trace/ultra-trace hazardous materials in complex food samples.

In Vivo Long-Term Biodistribution, Excretion, and Toxicology of PEGylated Transition-Metal Dichalcogenides MS2 (M = Mo, W, Ti) Nanosheets.

With unique 2D structures and intriguing physicochemical properties, various types of transition metal dichalcogenides (TMDCs) have attracted much attention in many fields including nanomedicine. Hence, it is of great importance to carefully study the in vivo biodistribution, excretion, and toxicology profiles of different TMDCs, and hopefully to identify the most promising type of TMDCs with low toxicity and fast excretion for further biomedical applications. Herein, the in vivo behaviors of three representative TMDCs including molybdenum dichalcogenides (MoS2), tungsten dichalcogenides (WS2), and titanium dichalcogenides (TiS2) nanosheets are systematically investigated. Without showing significant in vitro cytotoxicity, all the three types of polyethylene glycol (PEG) functionalized TMDCs show dominate accumulation in reticuloendothelial systems (RES) such as liver and spleen after intravenous injection. In marked contrast to WS2-PEG and TiS2-PEG, which show high levels in the organs for months, MoS2-PEG can be degraded and then excreted almost completely within one month. Further degradation experiments indicate that the distinctive in vivo excretion behaviors of TDMCs can be attributed to their different chemical properties. This work suggests that MoS2, among various TMDCs, may be particularly interesting for further biomedical applications owning to its low toxicity, capability of biodegradation, and rapid excretion.

Degradable Molybdenum Oxide Nanosheets with Rapid Clearance and Efficient Tumor Homing Capabilities as a Therapeutic Nanoplatform.

Molybdenum oxide (MoOx) nanosheets with high near-infrared (NIR) absorbance and pH-dependent oxidative degradation properties were synthesized, functionalized with polyethylene glycol (PEG), and then used as a degradable photothermal agent and drug carrier. The nanosheets, which are relatively stable under acidic pH, could be degraded at physiological pH. Therefore, MoOx-PEG distributed in organs upon intravenous injection would be rapidly degraded and excreted without apparent in vivo toxicity. MoOx-PEG shows efficient accumulation in tumors, the acidic pH of which then leads to longer tumor retention of those nanosheets. Along with the capability of acting as a photothermal agent for effective tumor ablation, MoOx-PEG can load therapeutic molecules with high efficiencies. This concept of inorganic theranostic nanoagent should be relatively stable in tumors to allow imaging and treatment, while being readily degradable in normal organs to enable rapid excretion and avoid long-term retention/toxicity.

Facile preparation of uniform FeSe2 nanoparticles for PA/MR dual-modal imaging and photothermal cancer therapy.

Recently, magnetic photothermal nanomaterials have emerged as a new class of bio-nanomaterials for application in cancer diagnosis and therapy. Hence, we developed a new kind of magnetic nanomaterials, iron diselenide (FeSe(2)) nanoparticles, for multimodal imaging-guided photothermal therapy (PTT) to improve the efficacy of cancer treatment. By controlling the reaction time and temperature, FeSe(2) nanoparticles were synthesized by a simple solution-phase method. After modification with polyethylene glycol (PEG), the obtained FeSe(2)-PEG nanoparticles showed high stability under various physiological conditions. FeSe(2)-PEG could serve as a T2-weighted magnetic resonance (MR) imaging contrast agent because of its strong superparamagnetic properties, with its r(2) relaxivity determined to be 133.38 mM(-1) S(-1), a value higher than that of the clinically used Feridex. On the other hand, with high absorbance in the near-infrared (NIR) region, FeSe(2)-PEG also appeared to be a useful contrast agent for photoacoustic imaging (PA) as well as an effective photothermal agent for PTT cancer treatment, as demonstrated in our animal tumor model experiments. Moreover, long-term toxicity tests have proven that FeSe(2)-PEG nanoparticles after systematic administration rendered no appreciable toxicity to the treated animals, and could be gradually excreted from the major organs of mice. Our work indicates that FeSe(2)-PEG nanoparticles would be a new class of theranostic agents promising for application in bioimaging and cancer therapy.