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      1. Author :
        Zhang, J.; Wang, C.; Ke, N.; Bliesath, J.; Chionis, J.; He, Q. S.; Li, Qx; Chatterton, J. E.; Wong-staal, F.; Zhou, D.
      2. Title :
        A more efficient RNAi inducible system for tight regulation of gene expression in mammalian cells and xenograft animals
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        RNA
      6. Products :
      7. Volume :
        13
      8. Issue :
        N/A
      9. Page Numbers :
        1375
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Two types of tetracycline-controlled inducible RNAi expression systems have been developed that generally utilize multiple tetracycline operators (TetOs) or repressor fusion proteins to overcome the siRNA leakiness. Here, we report a novel system that overexpresses the tetracycline repressor (TetR) via a bicistronic construct to control siRNA expression. The high level of TetR expression ensures that the inducible promoter is tightly bound, with minimal basal transcription, allowing for regulation solely dependent on TetR rather than a TetR fusion protein via a more complicated mechanism. At the same time, this system contains only a single TetO, thus minimizing the promoter impairment occurring in existing systems due to the incorporation of multiple TetOs, and maximizing the siRNA expression upon induction. In addition, this system combines all the components required for regulation of siRNA expression into a single lentiviral vector, so that stable cell lines can be generated by a single transduction and selection, with significant reduction in time and cost. Taken together, this all-in-one lentiviral vector with the feature of TetR overexpression provides a unique and more efficient tool for conditional gene knockdown that has wide applications. We have demonstrated the high degree of robustness and versatility of this system as applied to several mammalian cells and xenograft animals.
      13. URL :
        N/A
      14. Call Number :
        144976
      15. Serial :
        5225
      1. Author :
        Miretti, S.; Roato, I.; Taulli, R.; Ponzetto, C.; Cilli, M.; Olivero, M.; Renzo, M. F. Di; Godio, L.; Albini, A.; Buracco, P.; Ferracini, R.
      2. Title :
        A Mouse Model of Pulmonary Metastasis from Spontaneous Osteosarcoma Monitored In Vivo by Luciferase Imaging
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        3
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Background: Osteosarcoma (OSA) is lethal when metastatic after chemotherapy and/or surgical treatment. Thus animal models are necessary to study the OSA metastatic spread and to validate novel therapies able to control the systemic disease. We report the development of a syngeneic (Balb/c) murine OSA model, using a cell line derived from a spontaneous murine tumor. Methodology: The tumorigenic and metastatic ability of OSA cell lines were assayed after orthotopic injection in mice distal femur. Expression profiling was carried out to characterize the parental and metastatic cell lines. Cells from metastases were propagated and engineered to express Luciferase, in order to follow metastases in vivo. Principal Findings: Luciferase bioluminescence allowed to monitor the primary tumor growth and revealed the appearance of spontaneous pulmonary metastases. In vivo assays showed that metastasis is a stable property of metastatic OSA cell lines after both propagation in culture and luciferase trasduction. When compared to parental cell line, both unmodified and genetically marked metastatic cells, showed comparable and stable differential expression of the enpp4, pfn2 and prkcd genes, already associated to the metastatic phenotype in human cancer. Conclusions: This OSA animal model faithfully recapitulates some of the most important features of the human malignancy, such as lung metastatization. Moreover, the non-invasive imaging allows monitoring the tumor progression in living mice. A great asset of this model is the metastatic phenotype, which is a stable property, not modifiable after genetic manipulation.
      13. URL :
        N/A
      14. Call Number :
        141238
      15. Serial :
        5227
      1. Author :
        Fujita, M; Khazenzon, NM; Lee, BS; Holler, E; Black, KL; Ljubimova, JY
      2. Title :
        A multi-drug delivery system based on poly (malic Acid) for tumor targeting
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Proceedings of the American Association for Cancer Research
      6. Products :
      7. Volume :
        2006
      8. Issue :
        N/A
      9. Page Numbers :
        720
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Genomics and proteomics are blossoming fields that are identifying functional markers on an accelerated basis. Our technology provides a potent drug delivery vehicle for inhibiting several tumor targets at the same time resulting in a synergistic effect. A prototype of drug delivery system, the nanoconjugate Polycefin, was synthesized for targeted delivery of antisense oligonucleotides and monoclonal antibodies into certain tumors. Polycefin consists of modules active in endosomal uptake, disruption of endosomal membranes, oligonucleotide release in the cytoplasm, monoclonal antibodies for tumor targeting and protection against enzymatic degradation in the vascular system. These are covalently conjugated with highly purified poly(malic acid) (Mw 50000, Mw/Mn 1.3) from cultures of myxomycete Physarum polycephalum. Methods. Using Polycefin two antisense oligonucleotides to chains of laminin-8, a vascular basement membrane protein and an invasive glioma marker (Ljubimova et, al., Cancer 2004), and one oligonucleotide to epidermal growth factor receptor (EGFR), were delivered simultaneously to brain tumor cells through receptor-mediated endocytosis using an antibody to transferrin receptor attached to the poly(malic acid)-based drug delivery molecule. Nude rats and mice with inoculated human glioma cells U87MG were used. Xenogen IVISTM 200 imaging system (USA) was used on whole body and isolated organs of glioma-bearing mice 6-24 hours following Polycefin injection to detect the drug distribution. Results. Evidence from imaging analysis demonstrates that the delivery system passes through the blood-brain and blood-tumor barriers. The experimental data demonstrate that Polycefin accumulates in tumor by enhanced permeability and retention (EPR) effect and in addition by an effective mechanism of transferrin receptor antibody targeting. Polycefin-delivered antisense oligonucleotides to alpha4 and beta1 chains of laminin-8 and EGFR suppressed the synthesis of corresponding proteins in vitro and in vivo. Treatment of glioma-bearing rats significantly diminished tumor vascularity and significantly increased animal survival time (p<0.004). Conclusion Efficient blocking of the expression of multimeric proteins such as laminin-8, is possible with the new vehicle, which can simultaneously carry several attached inhibitors with different specificities. A significant feature of our novel agent is its ability to target multiple tumor-associated proteins attached to one drug. The drug has dual effect: as a high molecular mass biopolymer it accumulates in tumor tissues and using the specific targeting antibody it is selectively delivered to the tumor to increase the drug concentration in tumor tissue. The drug has the ability to pass blood-tumor barrier.x000Dx000D... Nude rats and mice with inoculated human glioma cells U87MG were used. Xenogen IVIS TMx000D200 imaging system (USA) was used on whole body and isolated organs of glioma-bearing micex000D6-24 hours following Polycefin injection to detect the drug distribution...
      13. URL :
        N/A
      14. Call Number :
        137890
      15. Serial :
        5228
      1. Author :
        Mason, K. M.; Munson, R. S.; Bakaletz, L. O.
      2. Title :
        A Mutation in the sap Operon Attenuates Survival of Nontypeable Haemophilus influenzae in a Chinchilla Model of Otitis Media
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and Immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        N/A
      9. Page Numbers :
        599
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Bacteria have evolved strategies to resist killing by antimicrobial peptides (APs), important effectors of innate immunity. The sap (sensitivity to antimicrobial peptides) operon confers resistance to AP-mediated killing of Salmonella. We have recently shown that sapA gene expression is upregulated in the middle ear in a chinchilla model of nontypeable Haemophilus influenzae (NTHI)-induced otitis media. Based on these findings, we constructed an NTHI strain containing a Lux reporter plasmid driven by the sapA promoter and demonstrated early yet transient expression of the sap operon within sites of the chinchilla upper airway upon infection. We hypothesized that the sap operon products mediate NTHI resistance to APs. In order to test this hypothesis, we constructed a nonpolar mutation in the sapA gene of NTHI strain 86-028NP, a low-passage-number clinical isolate. The sapA mutant was approximately eightfold more sensitive than the parent strain to killing by recombinant chinchilla ?-defensin 1. We then assessed the ability of this mutant to both colonize and cause otitis media in chinchillas. The sapA mutant was significantly attenuated compared to the parent strain in its ability to survive in both the nasopharynx and the middle ear of the chinchilla. In addition, the mutant was impaired in its ability to compete with the parent strain in a dual-strain challenge model of infection. Our results indicate that the products of the sap operon are important for resisting the activity of APs and may regulate, in part, the balance between normal carriage and disease caused by NTHI.
      13. URL :
        N/A
      14. Call Number :
        140977
      15. Serial :
        5230
      1. Author :
        Siggs, O. M.; Berger, M.; Krebs, P.; Arnold, C. N.; Eidenschenk, C.; Huber, C.; Pirie, E.; Smart, N. G.; Khovananth, K.; Xia, Y.; McInerney, G.; Hedestam, G. B. Karlsson; Nemazee, D.; Beutler, B.
      2. Title :
        A mutation of Ikbkg causes immune deficiency without impairing degradation of I?B?
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Proceedings of the National Academy of Sciences of the United States of America
      6. Products :
      7. Volume :
        107
      8. Issue :
        N/A
      9. Page Numbers :
        3046
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Null alleles of the gene encoding NEMO (NF-?B essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of I?B?, which is considered a primary requirement for NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and NF-?B p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond I?B? degradation, and offers a biochemical explanation for rare immune deficiencies in man.
      13. URL :
        N/A
      14. Call Number :
        143089
      15. Serial :
        5231
      1. Author :
        Gu, L.; Tsark, W. M.; Brown, D. A.; Blanchard, S.; Synold, T. W.; Kane, S. E.
      2. Title :
        A new model for studying tissue-specific mdr1a gene expression in vivo by live imaging
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Proceedings of the National Academy of Sciences of the United States of America
      6. Products :
      7. Volume :
        106
      8. Issue :
        N/A
      9. Page Numbers :
        5394
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Multidrug resistance continues to be a major impediment to successful chemotherapy in cancer patients. One cause of multidrug resistance is enhanced expression of the mdr1 gene, but the precise factors and physiological conditions controlling mdr1 expression are not entirely known. To gain a better understanding of mdr1 transcriptional regulation, we created a unique mouse model that allows noninvasive bioimaging of mdr1 gene expression in vivo and in real time. The model uses a firefly luciferase (fLUC) gene inserted by homologous recombination into the murine mdr1a genetic locus. The inserted fLUC gene is preceded by a neo expression cassette flanked by loxP sites, so that Cre-mediated recombination is required to configure the fLUC gene directly under the control of the endogenous mdr1a promoter. We now demonstrate that the mdr1a.fLUC knock-in is a faithful reporter for mdr1a expression in naive animals, in which fLUC mRNA levels and luminescence intensities accurately parallel endogenous mdr1a mRNA expression. We also demonstrate xenobiotic-inducible regulation of mdr1a.fLUC expression in real time, in parallel with endogenous mdr1a expression, resulting in a more detailed understanding of the kinetics of mdr1a gene induction. This mouse model demonstrates the feasibility of using bioimaging coupled with Cre/loxP conditional knock-in to monitor regulated gene expression in vivo. It represents a unique tool with which to study the magnitude and kinetics of mdr1a induction under a variety of physiologic, pharmacologic, genetic, and environmental conditions.
      13. URL :
        N/A
      14. Call Number :
        138244
      15. Serial :
        5233
      1. Author :
        Danussi, C.; Coslovi, A.; Campa, C.; Mucignat, M. T.; Spessotto, P.; Uggeri, F.; Paoletti, S.; Colombatti, A.
      2. Title :
        A newly generated functional antibody identifies Tn antigen as a novel determinant in the cancer cell-lymphatic endothelium interaction
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Glycobiology
      6. Products :
      7. Volume :
        19
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Malignant transformation of epithelial cells is frequently associated with the alteration of glycosylation pathways. Tn is a common tumor-associated carbohydrate antigen present in 90% of human carcinomas and its expression correlates with metastatic potential and poor prognosis. Despite its relevance, the functional role of Tn in tumor biology has not been firmly established probably for the lack of appropriate experimental tools. Our aims were to produce highly reactive monoclonal antibodies against Tn making use of synthetically produced Tn and to test their usefulness for in vivo imaging as well as to define their potential functional activity in tumor cell spread. We immunized mice with Tn clustered on cationized BSA and screened the positive hybridomas with Tn-biotinylated alginate. Enzyme-linked immuno sorbent assay and immunofluorescence assays revealed that the most reactive anti-Tn IgM mAb (2154F12A4) selectively recognized Tn on the MCF7 breast cancer cell line since its binding to the cell membrane was completely abolished by preincubation with purified Tn. Importantly, QDot 800-conjugated mAb injected in MCF7-tumor bearing mice specifically bound to primary tumor lesions as well as to metastases in lymph nodes. In addition, this mAb was able to inhibit cancer cell adhesion to lymphatic endothelium suggesting a novel involvement of Tn in the lymphatic dissemination of cancer cells and hypothesizing future applications in inhibiting lymphatic metastases.
      13. URL :
        N/A
      14. Call Number :
        137245
      15. Serial :
        5236
      1. Author :
        Oh, S.; Stish, B. J.; Sachdev, D.; Chen, H.; Dudek, A. Z.; Vallera, D. A.
      2. Title :
        A novel reduced immunogenicity bispecific targeted toxin simultaneously recognizing human epidermal growth factor and interleukin-4 receptors in a mouse model of metastatic breast carcinoma.
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Clinical Cancer Research
      6. Products :
      7. Volume :
        15
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        PURPOSE: To develop a targeted biological drug that when systemically injected can penetrate to metastatic breast cancer tumors, one needs a drug of high potency and reduced immunogenicity. Thus, we bioengineered a novel bispecific ligand-directed toxin (BLT) targeted by dual high-affinity cytokines with a PE(38)KDEL COOH terminus. Our purpose was to reduce toxin immunogenicity using mutagenesis, measure the ability of mutated drug to elicit B-cell antitoxin antibody responses, and show that mutated drug was effective against systemic breast cancer in vivo.
        EXPERIMENTAL DESIGN:
        A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin (PE(38)). Site-specific mutagenesis was used to mutate amino acids in seven key epitopic toxin regions that dictate B-cell generation of neutralizing antitoxin antibodies. Bioassays were used to determine whether mutation reduced potency, and ELISA studies were done to determine whether antitoxin antibodies were reduced. Finally, a genetically altered luciferase xenograft model was used; this model could be imaged in real time to determine the effect on the systemic malignant human breast cancer MDA-MB-231.
        RESULTS: EGF4KDEL 7mut was significantly effective against established systemic human breast cancer and prevented metastatic spread. Mutagenesis reduced immunogenicity by approximately 90% with no apparent loss in in vitro or in vivo activity.
        CONCLUSIONS: Because EGF4KDEL 7mut was highly effective even when we waited 26 days to begin therapy and because immunogenicity was significantly reduced, we can now give multiple drug treatments for chemotherapy-refractory breast cancer in clinical trials.
      13. URL :
        N/A
      14. Call Number :
        141778
      15. Serial :
        5237
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