Markedly enhanced intratumoral spread and antitumor effect of oncolytic adenovirus expressing decorin

With the aim of improving viral distribution and tumor penetration, we have engineered decorin expressing replication-incompetent (dl-LacZ-DCNG) and -competent (Ad-[DELTA]E1B-DCNG) adenoviruses. In both tumor spheroids and established solid tumors in vivo, administration of dl-LacZ-DCNG resulted in greater transduction efficiency and viral spread throughout the tumor mass. Ad-[DELTA]E1B-DCNG also enhanced viral distribution and tumor spread, leading to an increased anti-tumor effect and survival advantage. Upon histological analysis, Ad-[DELTA]E1B-DCNG also elicited greater percentage of apoptotic cells and extensive necrosis compared to those from untreated or control virus-treated tumors. Furthermore, Ad-[DELTA]E1B-DCNG substantially decreased extracellular matrix components within the tumor tissue, while normal tissue adjacent to the tumor was not affected. Finally, intratumoral administration of Ad-[DELTA]E1B-DCNG did not enhance but inhibited the formation of pulmonary metastases of B16BL6 melanoma cells in mice. Taken together, these data demonstrate the utility of decorin as a dispersion agent and suggest its utility and potential in improving the efficacy of replicating adenovirus-mediated cancer gene therapy

A Synergistic Anti-Diabetic Effect by Ginsenosides Rb1 and Rg3 through Adipogenic and Insulin Signaling Pathways in 3T3-L1 Cells

Although ginsenosides Rb1 and Rg3 have been identified as the significant ginsenosides found in red ginseng that confer anti-diabetic actions, it is unclear whether insulin-sensitizing effects are mediated by the individual compounds or by their combination. To determine the effect of ginsenosides Rb1 and Rg3 on adipocyte differentiation, 3T3-L1 preadipocytes were induced to differentiate the standard hormonal inducers in the absence or presence of ginsenosides Rb1 or Rg3. Additionally, we determined the effects of Rb1, Rg3, or their combination on the expression of genes related to adipocyte differentiation, adipogenic transcription factors, and the insulin signaling pathway in 3T3-L1 cells using semi-quantitative RT-PCR. Rb1 significantly increased the expression of CEBP alpha, PPAR gamma, and aP2 mRNAs. However, Rg3 exerted its maximal stimulatory effect on these genes at 1 mu M concentration, while a high concentration (50 mu M) showed inhibitory effects. Similarly, treatment with Rb1 and Rg3 (1 mu M) increased the expression of IRS-1, Akt, PI3K, GLUT4, and adiponectin. Importantly, co-treatment of Rb1 and Rg3 (9:1) induced the maximal expression levels of these mRNAs. Our data indicate that the anti-diabetic activity of red ginseng is, in part, mediated by synergistic actions of Rb1 and Rg3, further supporting the significance of minor Rg3

Characterization of Fabry mice treated with recombinant adeno-associated virus 2/8-mediated gene transfer

<p>Abstract</p> <p>Background</p> <p>Enzyme replacement therapy (ERT) with α-galactosidase A (α-Gal A) is currently the most effective therapeutic strategy for patients with Fabry disease, a lysosomal storage disease. However, ERT has limitations of a short half-life, requirement for frequent administration, and limited efficacy for patients with renal failure. Therefore, we investigated the efficacy of recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for a Fabry disease mouse model and compared it with that of ERT.</p> <p>Methods</p> <p>A pseudotyped rAAV2/8 vector encoding α-Gal A cDNA (rAAV2/8-hAGA) was prepared and injected into 18-week-old male Fabry mice through the tail vein. The α-Gal A expression level and globotriaosylceramide (Gb3) levels in the Fabry mice were examined and compared with Fabry mice with ERT. Immunohistochemical and ultrastructural studies were conducted.</p> <p>Results</p> <p>Treatment of Fabry mice with rAAV2/8-hAGA resulted in the clearance of accumulated Gb3 in tissues such as liver, spleen, kidney, heart, and brain with concomitant elevation of α-Gal A enzyme activity. Enzyme activity was elevated for up to 60 weeks. In addition, expression of the α-Gal A protein was identified in the presence of rAAV2/8-hAGA at 6, 12, and 24 weeks after treatment. α-Gal A activity was significantly higher in the mice treated with rAAV2/8-hAGA than in Fabry mice that received ERT. Along with higher α-Gal A activity in the kidney of the Fabry mice treated with gene therapy, immunohistochemical studies showed more α-Gal A expression in the proximal tubules and glomerulus, and less Gb3 deposition in Fabry mice treated with this gene therapy than in mice given ERT. The α-gal A gene transfer significantly reduced the accumulation of Gb3 in the tubules and podocytes of the kidney. Electron microscopic analysis of the kidneys of Fabry mice also showed that gene therapy was more effective than ERT.</p> <p>Conclusions</p> <p>The rAAV2/8-hAGA mediated α-Gal A gene therapy provided improved efficiency over ERT in the Fabry disease mouse model. Furthermore, rAAV2/8-hAGA-mediated expression showed a greater effect in the kidney than ERT.</p

Antinociceptive and Anti-Inflammatory Effects of Ethanolic Extracts of Glycine max (L.) Merr and Rhynchosia nulubilis Seeds

The aim of this study was to assess the in vivo potential of ethanolic extracts of Glycine max (L.) Merr. (SoRiTae) and Rhynchosia nulubilis (Yak-Kong) seeds as natural anti-nociceptive and anti-inflammatory agents. To assess the anti-nociceptive and anti-inflammatory potential, the ethanolic extracts of SoRiTae and Yak-Kong seeds were tested in arachidonic acid-induced ear edema, carrageenan induced paw edema, formalin-induced licking time, acetic acid induced writhing and hot plate-induced thermal stimulation in mice. The administration of ethanolic extracts of SoRiTae and Yak-Kong seeds evoked a significant effect of anti-nociceptive and anti-inflammatory activities as compared to standards aminopyrine and indomethacin. The ear edema, paw edema, paw licking time, pain and writhes in mice were significantly reduced (p < 0.05) as compared to the control. The results obtained in this study indicate that both SoRiTae and Yak-Kong soybeans possesses potential anti-nociceptive and anti-inflammatory activities

Optimizing DC Vaccination by Combination With Oncolytic Adenovirus Coexpressing IL-12 and GM-CSF

Dendritic cell (DC)-based vaccination is a promising strategy for cancer immunotherapy. However, clinical trials have indicated that immunosuppressive microenvironments induced by tumors profoundly suppress antitumor immunity and inhibit vaccine efficacy, resulting in insufficient reduction of tumor burdens. To overcome these obstacles and enhance the efficiency of DC vaccination, we generated interleukin (IL)-12- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-coexpressing oncolytic adenovirus (Ad-ΔB7/IL12/GMCSF) as suitable therapeutic adjuvant to eliminate immune suppression and promote DC function. By treating tumors with Ad-ΔB7/IL12/GMCSF prior to DC vaccination, DCs elicited greater antitumor effects than in response to either treatment alone. DC migration to draining lymph nodes (DLNs) dramatically increased in mice treated with the combination therapy. This result was associated with upregulation of CC-chemokine ligand 21 (CCL21+) lymphatics in tumors treated with Ad-ΔB7/IL12/GMCSF. Moreover, the proportion of CD4+CD25+ T-cells and vascular endothelial growth factor (VEGF) expression was decreased in mice treated with the combination therapy. Furthermore, combination therapy using immature DCs also showed effective antitumor effects when combined with Ad-ΔB7/IL12/GMCSF. The combination therapy had a remarkable therapeutic efficacy on large tumors. Taken together, oncolytic adenovirus coexpressing IL-12 and GM-CSF in combination with DC vaccination has synergistic antitumor effects and can act as a potent adjuvant for promoting and optimizing DC vaccination

PREFACE

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Size distributions of atmospheric particulate matter and associated trace metals in the multi-industrial city of Ulsan, Korea

Particulate matter (PM) was collected using micro-orifice uniform deposit impactors from a residential (RES) site and an industrial (IND) site in Ulsan, South Korea, in September-October 2014. The PM samples were measured based on their size distributions (11 stages), ranging from 0.06 ??m to over 18.0 ??m. Nine trace metals (As, Se, Cr, V, Cd, Pb, Ba, Sb, and Zn) associated with PM were analyzed. The PM samples exhibited weak bimodal distributions irrespective of sampling sites and events, and the mean concentrations of total PM (TPM) measured at the IND site (56.7 ??g/m3) was higher than that measured at the RES site (38.2 ??g/m3). The IND site also showed higher levels of nine trace metals, reflecting the influence of industrial activities and traffic emissions. At both sites, four trace metals (Ba, Zn, V, and Cr) contributed to over 80% of the total concentrations in TPM. The modality of individual trace metals was not strong except for Zn; however, the nine trace metals in PM2.5 and PM10 accounted for approximately 50% and 90% of the total concentrations in TPM, respectively. This result indicates that the size distributions of PM and trace metals are important to understand how respirable PM affects public health

Switching Magnetism and Superconductivity with Spin-Polarized Current in Iron-Based Superconductor

We have explored a new mechanism for switching magnetism and superconductivity in a magnetically frustrated iron-based superconductor using spin-polarized scanning tunneling microscopy (SPSTM). Our SPSTM study on single crystal Sr$_2$VO$_3$FeAs shows that a spin-polarized tunneling current can switch the Fe-layer magnetism into a non-trivial $C_4$ (2$\times$2) order, not achievable by thermal excitation with unpolarized current. Our tunneling spectroscopy study shows that the induced $C_4$ (2$\times$2) order has characteristics of plaquette antiferromagnetic order in Fe layer and strongly suppressed superconductivity. Also, thermal agitation beyond the bulk Fe spin ordering temperature erases the $C_4$ state. These results suggest a new possibility of switching local superconductivity by changing the symmetry of magnetic order with spin-polarized and unpolarized tunneling currents in iron-based superconductors.Comment: 33 pages, 16 figure