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      1. Author :
        Correa de Sampaio, P.; Auslaender, D.; Krubasik, D.; Failla, A. V.; Skepper, J. N.; Murphy, G.; English, W. R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-luc2, IVIS, Breast Cancer, Bioware, Angiogenesis Inhibitors/pharmacology; *Cell Communication/drug effects; Cell Proliferation/drug effects; Extracellular Matrix/drug effects/metabolism; Fibroblasts/drug effects/metabolism/pathology; Gene Silencing/drug effects; Human Umbilical Vein Endothelial Cells/drug effects/metabolism; Humans; Intercellular Signaling Peptides and Proteins/pharmacology; Luminescent Measurements; Matrix Metalloproteinase 14/metabolism; Microscopy, Fluorescence, Multiphoton; *Models, Biological; Neoplasms/*blood supply/enzymology/*pathology; Neovascularization, Pathologic/*pathology; Signal Transduction/drug effects; Spheroids, Cellular/drug effects/enzymology/pathology; Stromal Cells/drug effects/pathology; Tumor Cells, Cultured
      12. Abstract :
        Angiogenesis, the formation of new blood vessels, is an essential process for tumour progression and is an area of significant therapeutic interest. Different in vitro systems and more complex in vivo systems have been described for the study of tumour angiogenesis. However, there are few human 3D in vitro systems described to date which mimic the cellular heterogeneity and complexity of angiogenesis within the tumour microenvironment. In this study we describe the Minitumour model--a 3 dimensional human spheroid-based system consisting of endothelial cells and fibroblasts in co-culture with the breast cancer cell line MDA-MB-231, for the study of tumour angiogenesis in vitro. After implantation in collagen-I gels, Minitumour spheroids form quantifiable endothelial capillary-like structures. The endothelial cell pre-capillary sprouts are supported by the fibroblasts, which act as mural cells, and their growth is increased by the presence of cancer cells. Characterisation of the Minitumour model using small molecule inhibitors and inhibitory antibodies show that endothelial sprout formation is dependent on growth factors and cytokines known to be important for tumour angiogenesis. The model also shows a response to anti-angiogenic agents similar to previously described in vivo data. We demonstrate that independent manipulation of the different cell types is possible, using common molecular techniques, before incorporation into the model. This aspect of Minitumour spheroid analysis makes this model ideal for high content studies of gene function in individual cell types, allowing for the dissection of their roles in cell-cell interactions. Finally, using this technique, we were able to show the requirement of the metalloproteinase MT1-MMP in endothelial cells and fibroblasts, but not cancer cells, for sprouting angiogenesis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22363483
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10492
      1. Author :
        Contag, C H; Jenkins, D; Contag, P R; Negrin, R S
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2000
      5. Publication :
        Neoplasia (New York, N.Y.)
      6. Products :
      7. Volume :
        2
      8. Issue :
        1-2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Diagnostic Imaging; Genes, Reporter; Green Fluorescent Proteins; Humans; Luciferases; Luminescent Proteins; Neoplasms; PC-3M-luc; Time Factors; Tumor Cells, Cultured
      12. Abstract :
        Revealing the cellular and molecular changes associated with cancer, as they occur in intact living animal models of human neoplastic disease, holds tremendous potential for understanding disease mechanisms and elucidating effective therapies. Since light is transmitted through mammalian tissues, at a low level, optical signatures conferred on tumor cells by expression of reporter genes encoding bioluminescent and fluorescent proteins can be detected externally using sensitive photon detection systems. Expression of reporter genes, such as the bioluminescent enzyme firefly luciferase (Luc) or variants of green fluorescent protein (GFP) in transformed cells, can effectively be used to reveal molecular and cellular features of neoplasia in vivo. Tumor cell growth and regression in response to various therapies have been evaluated non-invasively in living experimental animals using these reporter genes. Detection of Luc-labeled cells in vivo was extremely sensitive with signals over background from as few as 1000 human tumor cells distributed throughout the peritoneal cavity of a mouse with linear relationships between cell number and signal intensity over five logs. GFP offers the strength of high-resolution ex vivo analyses following in vivo localization of the tumor. The dynamic range of Luc detection allows the full disease course to be monitored since disease progression from small numbers of cells to extensive disease can be assessed. As such, therapies that target minimal disease as well as those designed for late stage disease can be readily evaluated in animal models. Real time spatiotemporal analyses of tumor cell growth can reveal the dynamics of neoplastic disease, and facilitate rapid optimization of effective treatment regimens. Thus, these methods improve the predictability of animal models of human disease as study groups can be followed over time, and can accelerate the development of therapeutic strategies.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/10933067
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8985
      1. Author :
        Comenge, J.; Sotelo, C.; Romero, F.; Gallego, O.; Barnadas, A.; Parada, T. G.; Dominguez, F.; Puntes, V. F.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        A549-luc-C8, A549-luc, IVIS, Bioware
      12. Abstract :
        Nanoparticles (NPs) have emerged as a potential tool to improve cancer treatment. Among the proposed uses in imaging and therapy, their use as a drug delivery scaffold has been extensively highlighted. However, there are still some controversial points which need a deeper understanding before clinical application can occur. Here the use of gold nanoparticles (AuNPs) to detoxify the antitumoral agent cisplatin, linked to a nanoparticle via a pH-sensitive coordination bond for endosomal release, is presented. The NP conjugate design has important effects on pharmacokinetics, conjugate evolution and biodistribution and results in an absence of observed toxicity. Besides, AuNPs present unique opportunities as drug delivery scaffolds due to their size and surface tunability. Here we show that cisplatin-induced toxicity is clearly reduced without affecting the therapeutic benefits in mice models. The NPs not only act as carriers, but also protect the drug from deactivation by plasma proteins until conjugates are internalized in cells and cisplatin is released. Additionally, the possibility to track the drug (Pt) and vehicle (Au) separately as a function of organ and time enables a better understanding of how nanocarriers are processed by the organism.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23082177
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10522
      1. Author :
        Close, P.; Gillard, M.; Ladang, A.; Jiang, Z.; Papuga, J.; Hawkes, N.; Nguyen, L.; Chapelle, J. P.; Bouillenne, F.; Svejstrup, J.; Fillet, M.; Chariot, A.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Biol Chem
      6. Products :
      7. Volume :
        287
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, B16-F10-luc-G5, B16F10-luc-G5, B16-F10-luc, B16F10-luc, Carrier Proteins/genetics/*metabolism; Cell Line, Tumor; *Cell Movement; Gene Deletion; HEK293 Cells; Humans; Melanoma/genetics/*metabolism/pathology; Multiprotein Complexes/genetics/*metabolism; Neoplasm Invasiveness; Neoplasm Proteins/genetics/*metabolism; Proteins/genetics/*metabolism; RNA Polymerase II/genetics/metabolism
      12. Abstract :
        The Elongator complex is composed of 6 subunits (Elp1-Elp6) and promotes RNAPII transcript elongation through histone acetylation in the nucleus as well as tRNA modification in the cytoplasm. This acetyltransferase complex directly or indirectly regulates numerous biological processes ranging from exocytosis and resistance to heat shock in yeast to cell migration and neuronal differentiation in higher eukaryotes. The identity of human ELP1 through ELP4 has been reported but human ELP5 and ELP6 have remained uncharacterized. Here, we report that DERP6 (ELP5) and C3ORF75 (ELP6) encode these subunits of human Elongator. We further investigated the importance and function of these two subunits by a combination of biochemical analysis and cellular assays. Our results show that DERP6/ELP5 is required for the integrity of Elongator and directly connects ELP3 to ELP4. Importantly, the migration and tumorigenicity of melanoma-derived cells are significantly decreased upon Elongator depletion through ELP1 or ELP3. Strikingly, DERP6/ELP5 and C3ORF75/ELP6-depleted melanoma cells have similar defects, further supporting the idea that DERP6/ELP5 and C3ORF75/ELP6 are essential for Elongator function. Together, our data identify DERP6/ELP5 and C3ORF75/ELP6 as key players for migration, invasion and tumorigenicity of melanoma cells, as integral subunits of Elongator.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22854966
      14. Call Number :
        PKI @ kd.modi @ 20
      15. Serial :
        10530
      1. Author :
        Clapper, M. L.; Hensley, H. H.; Chang, W. C.; Devarajan, K.; Nguyen, M. T.; Cooper, H. S.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Neoplasia
      6. Products :
      7. Volume :
        13
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MMPSense, IVIS, Adenoma/diagnosis/*enzymology/pathology; Animals; Colorectal Neoplasms/diagnosis/*enzymology/pathology; Disease Models, Animal; Female; *Fluorescent Dyes/administration & dosage/diagnostic use; Male; Matrix Metalloproteinases/*metabolism; Mice; Mice, Inbred C57BL; Molecular Imaging
      12. Abstract :
        A significant proportion of colorectal adenomas, in particular those that lack an elevated growth component, continue to escape detection during endoscopic surveillance. Elevation of the activity of matrix metalloproteinases (MMPs), a large family of zinc endopeptidases, in adenomas serves as a biomarker of early tumorigenesis. The goal of this study was to assess the feasibility of using a newly developed near-infrared bioactivatable probe (MMPSense 680) that reports the activity of a broad array of MMP isoforms to detect early colorectal adenomas. Adenomatous polyposis coli (Apc)(+/Min-FCCC) mice that spontaneously develop multiple colorectal adenomas were injected with MMPSense 680, and the colons were imaged in an IVIS Spectrum system ex vivo. Image analyses were correlated with histopathologic findings for all regions of interest (ROIs). The biochemical basis of fluorescent signal was investigated by immunohistochemical staining of MMP-7 and -9. A strong correlation (Kendall = 0.80) was observed between a positive signal and the presence of pathologically confirmed colonic adenomas; 92.9% of the 350 ROIs evaluated were classified correctly. The correlation between two independent observers was 0.87. MMP-7 expression was localized to epithelial cells of adenomas and microadenomas, whereas staining of MMP-9 was found in infiltrating polymorphonuclear leukocytes within the adenomas. MMPSense 680 identifies colorectal adenomas, both polypoid and nonpolypoid, in Apc(+/Min-FCCC) mice with high specificity. Use of this fluorescent probe in combination with colonoscopy could aid in preventing colorectal neoplasias by providing new opportunities for early detection and therapeutic intervention.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21847360
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10459
      1. Author :
        Cirstoiu-Hapca, A; Buchegger, F; Lange, N; Bossy, L; Gurny, R; Delie, F
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of controlled release: official journal of the Controlled Release Society
      6. Products :
      7. Volume :
        144
      8. Issue :
        3
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bioware; Cell Line, Tumor; Drug Carriers; Female; Humans; Mice; Nanoparticles; Ovarian Neoplasms; Paclitaxel; Receptor, erbB-2; SKOV3-luc-D3 cells; Tissue Distribution; Xenograft Model Antitumor Assays
      12. Abstract :
        The benefit of polymeric immuno-nanoparticles (NPs-Tx-HER), consisting of paclitaxel (Tx)-loaded nanoparticles coated with anti-HER2 monoclonal antibodies (Herceptin, trastuzumab), in cancer treatment was assessed in a disseminated xenograft ovarian cancer model induced by intraperitoneal inoculation of SKOV-3 cells overexpressing HER2 antigens. The study was focused on the evaluation of therapeutic efficacy and biodistribution of NPs-Tx-HER compared to other Tx formulations. The therapeutic efficacy was determined by two methods: bioluminescence imaging and survival rate. The treatment regimen consisted in an initial dose of 20mg/kg Tx administered as 10mg/kg intravenously (IV) and 10mg/kg intraperitonealy (IP), followed by five alternative IP and IV injections of 10mg/kg Tx every 3 days. The bioluminescence study has clearly shown the superior anti-tumor activity of NPs-Tx-HER compared to free Tx. As a confirmation of these results, a significantly longer survival of mice was observed for NPs-Tx-HER treatment compared to free Tx, Tx-loaded nanoparticles coated with an irrelevant mAb (Mabthera, rituximab) or Herceptin alone, indicating the potential of immuno-nanoparticles in cancer treatment. The biodistribution pattern of Tx was assessed on healthy and tumor bearing mice after IV or IP administration. An equivalent biodistribution profile was observed in healthy mice for Tx encapsulated either in uncoated nanoparticles (NPs-Tx) or in NPs-Tx-HER. No significant difference in Tx biodistribution was observed after IV or IP injection, except for a lower accumulation in the lungs when NPs were administered by IP. Encapsulated Tx accumulated in the organs of the reticulo-endothelial system (RES) such as the liver and spleen, whereas free Tx had a non-specific distribution in all tested organs. Compared to free Tx, the single dose injection (IV or IP) of encapsulated Tx in mice bearing tumors induced a higher tumor accumulation. However, no difference in overall tumor accumulation between NPs-Tx-HER and NPs-Tx was observed. In conclusion, the encapsulation of Tx into NPs-Tx-HER immuno-nanoparticles resulted in an improved efficacy of drug in the treatment of disseminated ovarian cancer overexpressing HER2 receptors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20219607
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9012
      1. Author :
        Chung, HM; Cartwright, MM; Bortz, DM; Jackson, TL; Younger, JG
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Shock
      6. Products :
      7. Volume :
        30
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen39
      12. Abstract :
        Unlike many localized infections, the development and resolution of bacteremia involves physical and immunological interactions between many anatomic sites. In an effort to better understand these interactions, we developed a computational model of bacteremia as a dynamical system fashioned after multicompartmental pharmacodynamic models, incorporating bacterial proliferation and clearance in the blood, liver, spleen, and lungs, and the transport of pathogens between these sites. A system of four first-order homogeneous ODEs was developed. Blood and organ bacterial burdens were measured at various time points from 3 to 48 h postinoculation using an LD25 murine model of Staphylococcus epidermidis bacteremia. Using these empiric data, solutions to the mathematical model were recovered. A bootstrap resampling method was used to generate 95% confidence intervals around the solved parameters. The validity of the model was examined in parallel experiments using animals acutely immunocompromised with cyclophosphamide; the model captured abnormalities in bacterial partitioning previously described with this antineoplastic agent. Lastly, the approach was used to explore possible benefits to clinically observed hyperdynamic blood flow during sepsis: in simulation, normal mice, but not those treated with cyclophosphamide, enjoyed significantly more rapid bacterial clearance from the bloodstream under hyperdynamic conditions.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18317411
      14. Call Number :
        136975
      15. Serial :
        5976
      1. Author :
        Christoph Bremer; Ching-Hsuan Tung; Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2001
      5. Publication :
        Nature Medicine
      6. Products :
      7. Volume :
        7
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        near-infrared; near infrared; matrix metalloproteinase; MMP; in vivo imaging; near-infrared fluorescence imaging
      12. Abstract :
        A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.
      13. URL :
        http://www.nature.com/nm/journal/v7/n6/abs/nm0601_743.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4509
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