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Normal Organs (normal + organ)
Selected AbstractsRetroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapyTHE JOURNAL OF GENE MEDICINE, Issue 5 2009Ryosuke Uchibori Abstract Background Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector-producing MSCs that enhance tumor transduction via progeny vector production. Methods Rat bone marrow-derived MSCs were nucleofected with the proviral plasmids (vesicular stomatitis virus-G protein-pseudotyped retroviral vector components) (VP-MSCs) or pLTR plasmid alone (non-VP-MSCs). The luciferase-based in vivo imaging system was used to assess gene expression periodically. To evaluate the anticancer effects, we administered MSCs expressing herpes simplex virus-thymidine kinase (HSV- tk) into the left ventricular cavity of nude mice engrafted with 9L glioma cells subcutaneously. Results In vivo imaging revealed that administration of luciferase-expressing non-VP-MSCs enhanced the bioluminescence signal at the inoculation sites of 9L cells, whereas no accumulation was observed in mice at the site of the control Rat-1 fibroblasts. Compared to non-VP-MSCs, the administration of VP-MSCs resulted in significant augmentation of the signal with an increase in transgene copy number. Immunohistochemical analysis showed marked luciferase expression at the tumor periphery in mice injected with VP-MSCs, whereas little expression was detected in those injected with non-VP-MSCs. Under the continuous infusion of ganciclovir, systemic administration of VP-MSCs expressing HSV- tk suppressed tumor growth more effectively than non-VP-MSC administration, whereas no anticancer effect was observed without ganciclovir treatment. Furthermore, VP-MSC administration caused no transgene transduction in the normal tissues and organs. Conclusions VP-MSCs accumulated at the site of tumors after intravascular injection in tumor-bearing mice, followed by in situ gene transfer to tumors without transduction of normal organs. When applied to the HSV- tk/ganciclovir suicide gene therapy, more efficient tumor growth suppression was observed using VP-MSCs compared to non-VP-MSCs. This VP-MSC-based system has great potential for improved cancer gene therapy. Copyright © 2009 John Wiley & Sons, Ltd. [source] Chimerism in Kidneys, Livers and Hearts of Normal Women: Implications for Transplantation StudiesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005Marije Koopmans Tissue chimerism was recently described in transplanted organs from female donors into male recipients, by demonstration of the Y-chromosome in tissue-derived cells. It was claimed that these Y-chromosome positive cells were recipient derived. To find out whether the chimeric cells, derived from pregnancies of sons or blood transfusions, could have been present in the solid organs before transplantation, we performed the following study. In situ hybridization for the Y-chromosome was performed on the normal organs (51 kidneys, 51 livers, 69 hearts) from 75 women of the normal population, whose child and blood transfusion status were known. Chimeric cells were found in 13 kidneys, 10 livers and 4 hearts, of 23 women. There was no relation between the child status or the blood transfusion history with the presence of Y-chromosome positive cells. We have for the first time demonstrated that male cells are present in normal kidneys, livers and hearts. Theoretically, these organs could have been used for the transplantation. Therefore, our findings demonstrate that the chimeric cells thus far described in transplantation studies, are not necessarily donor derived, and could have been present in the organs before the transplantation. [source] A Nonsurgical Technique for Blood Access in Extracorporeal Affinity Adsorption of Antibodies in RatsARTIFICIAL ORGANS, Issue 4 2007Linda Mårtensson Abstract:, Monoclonal antibodies for targeting cytotoxic conjugates to tumor cells are currently being evaluated together with extracorporeal affinity adsorption. The aim of the adsorption was to reduce undesired side effects in normal organs and to increase the tumor-to-normal tissue ratios. This technique is also applicable to several other therapeutic areas such as immune-mediated disorders, that is, autoimmunity, allergy, and transplantation rejection. We describe an improved technique for extracorporeal affinity adsorption of radiolabeled biotinylated antibodies in rats. Blood access is established through the tail artery and tail vein, without surgical insertion of permanent catheters. This technique is simple, does not require surgery, and causes only minimal stress to the animals. In addition, experiments can be carried out on several animals simultaneously. This new technique is of considerable benefit for studying extracorporeal affinity adsorption in rats, as experiments can be carried out with negligible anatomical and physiological interventions, compared to previously used techniques. [source] Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by ,-catenin/TCFCANCER SCIENCE, Issue 6 2008Yuichi Torisu The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of ,-catenin protein: all 10 HCC with high intracellular ,-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular ,-catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant-negative mutant of TCF4, a ,-catenin partner. In vivo binding of the ,-catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of ,-catenin/TCF4 and is upregulated in Wnt/,-catenin signaling-activated HCC. (Cancer Sci 2008; 99: 1139,1146) [source] Identification of oligopeptides binding to peritoneal tumors of gastric cancerCANCER SCIENCE, Issue 10 2006Noriyuki Akita This is a report of in vivo intraperitoneal biopanning, and we successfully identified a novel peptide to target the multiple peritoneal tumors of gastric cancer. A phage display library was injected directly into the abdominal cavity of mice bearing peritoneal tumors of human gastric cancer, and phages associated with the tumors were subsequently reclaimed from isolated samples. The tumor-associated phages were amplified and the biopanning cycle was repeated five times to enrich for high affinity tumor-selective binding peptides. Finally, a tri-peptide motif, KLP, which showed homology with laminin 5 (a ligand for ,3,1 integrin), was identified as a binding peptide for peritoneal tumors of gastric cancer. Phage clones displaying the sequence KLP showed 64-fold higher binding to peritoneal tumors than control phage and were preferentially distributed in tumors rather than in normal organs after intraperitoneal injection into mice. In addition, the KLP phages were more likely to bind to cancer cells in malignant ascites derived from a patient with recurrent gastric cancer. Synthesized peptide containing the motif KLP (SWKLPPS) also showed a strong binding activity to peritoneal tumors without cancer growth effect. Liposomes conjugated with SWKLPPS peptide appeared significantly more often in tumors than control liposomes after intraperitoneal injection into mice. Furthermore, modification of liposomes with SWKLPPS peptide enhanced the antitumor activity of adriamycin on gastric cancer cells. The peptide motif KLP seems a potential targeting ligand for the treatment of peritoneal metastasis of gastric cancer. (Cancer Sci 2006; 97: 1075,1081) [source] | ||||||||||