<div>Abstract<p>Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. Here, we show that in clinical samples bladder tumors with intense expression of stem cell marker Oct-3/4 (also known as POU5F1) are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. Expression of Oct-3/4 is detected in human bladder transitional cell carcinoma samples and cell lines. Overexpression of Oct-3/4 enhances, whereas knockdown of Oct-3/4 expression by RNA interference reduces, migration and invasion of bladder cancer cells. Oct-3/4 can up-regulate fibroblast growth factor-4 and matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-13 production, which may contribute to tumor metastasis. Finally, we show that Ad5WS4, an E1B-55 kD–deleted adenovirus driven by the <i>Oct-3/4</i> promoter, exerts potent antitumor activity against bladder cancer in a syngeneic murine tumor model. Therefore, our results implicate that Oct-3/4 may be useful as a novel tumor biological and prognostic marker and probably as a potential therapeutic target for bladder cancer. [Cancer Res 2008;68(15):6281–91]</p></div>
Abstract Objective Because thrombospondin 1 (TSP‐1) inhibits angiogenesis and activates latent transforming growth factor β (TGFβ), a potent immunosuppressive and antiinflammatory cytokine, we investigated the prophylactic and therapeutic effects of TSP‐1 gene transfer in the collagen‐induced arthritis (CIA) model in rats. Methods Adenoviral vectors encoding mouse TSP‐1 (AdTSP‐1) or β‐galactosidase (AdLacZ) as the control were administered by intraarticular injection into CIA rats. The treated ankles were assessed clinically, radiographically, and histologically. Furthermore, expression levels of TSP‐1, TGFβ, vascular endothelial growth factor (VEGF), and interleukin‐1β (IL‐1β) were examined in the synovial tissue. Results Intraarticular administration of AdTSP‐1 reduced the severity of CIA as revealed by examination of the clinical, radiographic, and histologic aspects. Rats treated with AdTSP‐1, as compared with AdLacZ‐treated controls, were found to have fewer blood vessels (mean ± SEM 21.0 ± 0.6 versus 45.3 ± 2.3/mm 2 ; P < 0.001) and lower production of VEGF (17 ± 4 versus 45 ± 10 pg/mg of total protein; P < 0.05) and IL‐1β (374 ± 41 versus 526 ± 39 pg/mg of total protein; P < 0.05), as well as higher levels of TSP‐1 and TGFβ in the synovial tissue. Conclusion Direct intraarticular administration of adenoviral vectors encoding TSP‐1 significantly ameliorated the clinical course of CIA, accompanied by reduction of synovial hypertrophy and fewer blood vessels. These results suggest that TSP‐1 gene therapy may have therapeutic potential for the management of rheumatoid arthritis.
Abstract Background: Cerebral palsy (CP) is a spectrum of non-progressive motor disorders caused by brain injury during fetal or postnatal periods. Current diagnosis of CP mainly relies on neuroimaging and motor assessment. Here, we aimed to explore novel biomarkers for early diagnosis of CP. Methods: Blood plasma from five CP children and their healthy twin brothers/sisters was analyzed by gene microarray to screen out differentially expressed RNAs. Selected differentially expressed circular RNAs (circRNAs) were further validated using quantitative real-time PCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the value of using hsa_circ_0086354 as a biomarker of CP. Results: 43 up-regulated circRNAs and 2 down-regulated circRNAs were obtained by difference analysis (fold change>2, p<0.05), among which five circRNAs related to neuron differentiation and neurogenesis were chosen for further validation. Additional 30 pairs of CP children and healthy controls were recruited and five selected circRNAs were further detected, showing that hsa_circ_0086354 was significantly down-regulated in CP plasma compared with control, which was highly in accord with microarray analysis. ROC curve analysis showed that the area under curve (AUC) to discriminate CP children and healthy controls using hsa_circ_0086354 was 0.967, the sensitivity was 0.833 and the specificity was 0.966. Moreover, hsa_circ_0086354 was predicted as a competitive endogenous RNA for miR-181a, miR-4741 and miR-4656, and much literature evidence suggested that miR-181a may be a key target of hsa_circ_0086354 to regulate neuronal survival and neuronal differentiation. Conclusion: Hsa_circ_0086354 was significantly down-regulated in blood plasma of CP children, which may be a novel competent biomarker for early diagnosis of CP.
The specificity, toxicity and efficacy of lead (212Pb) radioimmunotherapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tumor cell line expressing the HER2/neu proto-oncogene.The therapeutic agent used was the tumor-specific anti-HER2/neu monoclonal antibody AE1 conjugated to 212Pb, 212Bi being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional derivative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was used to couple 212Pb to the anti-HER2/neu monoclonal antibody AE1. The chelating agent did not alter the binding affinity to its antigenic target or the pharmacokinetics and tissue distribution of the AE1 antibody. Toxicity and therapeutic efficacy of 212Pb-AE1 were evaluated in nude mouse ascites or solid tumor models, wherein SK-OV-3 cells were administered i.p. or s.c., respectively.The dose-limiting acute toxicity after i.v. administration of 212Pb-AE1 was bone marrow suppression, which was observed at doses above 25 microCi. Therefore, doses of 10 and 20 microCi were used in efficacy trials. The i.p. administration of 212Pb-AE1 3 days after i.p. tumor inoculation led to a significant (P2 = 0.015) prolongation of tumor-free survival. In a second model, i.v. treatment with 212Pb-AE1 3 days after s.c. tumor inoculation prevented subsequent tumor development in all animals treated with 10 or 20 microCi of 212Pb-AE1 (P2 = 0.002 compared to control groups). This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of small (mean tumor volume, 15 mm3) SK-OV-3 tumors was modestly inhibited. However, tumor growth was not inhibited in mice bearing larger (mean tumor volume, 146 mm3) SK-OV-3 tumors by the administration of a single dose of 10 or 20 microCi of 212Pb-AE1.Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest value in the therapy of bulky solid tumors due to the short physical half-life of 212Pb and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radiolabeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, 212Pb may be of value in select situations, including treatment of leukemia, intercavitary therapy or strategies that target vascular endothelial cells of tumors.
Objective Synovial fibroblasts (SFs) with aberrant expression of microRNAs (miRNAs) are critical pathogenic regulators in rheumatoid arthritis (RA), and studies analyzing the effect of overexpressing or silencing miRNA expression in arthritis models can contribute to the development of miRNA‐based therapeutic strategies. This study was undertaken to examine the hypothesis that miRNAs 140‐3p and 140‐5p are involved in the pathogenesis of RA, and to determine whether targeting SFs through the intraarticular (IA) delivery of these molecules could ameliorate autoimmune arthritis in mice. Methods Synovial tissue samples were obtained from patients with RA. In addition, 2 experimental models in mice were used, collagen‐induced arthritis (CIA) and collagen antibody–induced arthritis (CAIA). Overexpression of miRNAs 140‐3p and 140‐5p in SFs and synovial tissue was induced using lentivirus (LV)–mediated transfer of pre‐miR‐140 precursor molecules. Results Lower expression levels of miR‐140‐3p and miR‐140‐5p were detected in synovial tissue and SFs from patients with RA and from mice in both arthritis models. In mice with CIA and mice with CAIA, the LV‐mediated IA transfer of miR‐140‐3p and miR‐140‐5p ameliorated arthritis, as determined by clinical examination and histopathologic evaluations showing a decrease in SF densities. Overexpression of miRNAs 140‐3p and 140‐5p caused a reduction in expression, with correlated kinetic patterns, of their corresponding target molecules sirtuin 1 and stromal cell–derived factor 1 in the SFs and joints of mice. Transfection of miR‐140‐3p and miR‐140‐5p into SFs increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the concept that miR‐140 expression is regulated by proinflammatory cytokines. Conclusion These results demonstrate that targeting SFs by IA delivery of miRNAs 140‐3p and 140‐5p can ameliorate autoimmune arthritis. These findings might facilitate the pharmacologic development of molecular‐based therapies in RA.
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