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      1. Author :
        G. Blum
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Current Opinion in Drug Discovery Development
      6. Products :
      7. Volume :
        10
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        Biology; Cancer
      11. Keywords :
        Proteases; pathology; biological markers; fluorescence imaging reagents; in vivo imaging; fluorescence molecular tomography; FMT
      12. Abstract :
        Proteases play pivotal roles in the normal function of cells. In addition, the expression and activity of proteases are significantly upregulated in several pathologies, including cancer, arthritis and atherosclerosis, and hence they can be considered to be biological markers for these pathologies. The hydrolyzing activity of proteases has been used to generate a variety of fluorescent imaging reagents, the design and utility of which are reviewed here. The use of imaging reagents to visualize protease activity allows for improved detection of various pathologies as well as the ability to monitor the efficacy of therapies in vivo and provide molecular information regarding the nature of the pathology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18729022
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4475
      1. Author :
        Jan Grimm; David G. Kirsch; Stephen D. Windsor; Carla F. Bender Kim; Philip M. Santiago; Vasilis Ntziachristos; Tyler Jacks; Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        PNAS
      6. Products :
      7. Volume :
        102
      8. Issue :
        40
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        gene expression profiling; lung cancer; immunohistochemistry; Western blotting; in vivo imaging; moleuclar imaging; fluorescence molecular tomography
      12. Abstract :
        Using gene expression profiling, we identified cathepsin cysteine proteases as highly up-regulated genes in a mouse model of human lung adenocarcinoma. Overexpression of cathepsin proteases in these lung tumors was confirmed by immunohistochemistry and Western blotting. Therefore, an optical probe activated by cathepsin proteases was selected to detect murine lung tumors in vivo as small as 1 mm in diameter and spatially separated. We generated 3D maps of the fluorescence signal and fused them with anatomical computed tomography images to show a close correlation between fluorescence signal and tumor burden. By serially imaging the same mouse, optical imaging was used to follow tumor progression. This study demonstrates the capability for molecular imaging of a primary lung tumor by using endogenous proteases expressed by a tumor. It also highlights the feasibility of using gene expression profiling to identify molecular targets for imaging lung cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242291/
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4524
      1. Author :
        Luo, Z R; Huang, T; Li, W; Shen, B Z
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Panminerva medica
      6. Products :
      7. Volume :
        52
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; B16-F10-luc-G5 cells; Bioware; Diagnostic Imaging; Luminescence; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation
      12. Abstract :
        AIM The aim of this study was to evaluate the veracity and sensitivity of in-vivo imaging system (IVIS) for inspection of tumor dynamic morphology. METHODS Mouse melanoma cells (B16-F10-luc-G5) in 100 mL media were seeded into a 96-well plate by 1:2 serial dilution from 10000 cells (well #1) to 78 cells (well #8). The plate was imaged using IVIS system to evaluate its sensitivity for luminescence. Ten Bablc mice with tumor cells were injected subcutaneously (1 x 10(5) in 100 mL) and tumor luminescence was detected by IVIS at Day 0, Day 3, Day 5, Day 7 and Day 9. RESULTS As few as 78 tumor cells were detectable by IVIS. A strong correlation between number of tumor cells and bioluminescence (R2=0.99) was also demonstrated. Tumor luminescence were observed in all mice by IVIS at all days, and there was significant difference (P<0.01) between each two days from Day 0 to Day 9. Moreover, tumor dynamic morphology could be monitored by IVIS when it is invisible. CONCLUSION Compared with conventional methods, with high veracity and sensitivity, IVIS system should be recommended as an effective method for inspection of tumor dynamic morphology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20228722
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8995
      1. Author :
        Elena S. Izmailova; Nancy Paz; Herlen Alencar; Miyoung Chun; Lisa Schopf; Michael Hepperle; Joan H. Lane; Geraldine Harriman; Yajun Xu; Timothy Ocain; Ralph Weissleder; Umar Mahmood; Aileen M. Healy; Bruce Jaffee
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Arthritis and Rheumatism
      6. Products :
      7. Volume :
        56
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        inflammation; immune response; rheumatoid arthritis; arthritis; in vivo imaging
      12. Abstract :
        OBJECTIVE: The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis.

        METHODS: ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-kappaB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.

        RESULTS: Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-kappaB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-kappaB pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor alpha, interleukin-1beta, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.

        CONCLUSION: Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.
      13. URL :
        http://onlinelibrary.wiley.com/doi/10.1002/art.22303/abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4511
      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 :
        Katharina Jannasch, Jeannine Missbach-Guentner and Frauke Alves
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        N/A
      5. Publication :
        Drug Discovery Today: Disease Models
      6. Products :
      7. Volume :
        6
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        Drug Discovery
      11. Keywords :
        FMT; ProSense; in vivo imaging
      12. Abstract :
        The incidence of asthma is increasing throughout the world. Animal models are crucial for understanding the pathophysiology of asthma and for developing new therapies. Novel imaging approaches will be a powerful tool for studying asthma in animal models. This review will give a short overview of different imaging techniques that are currently used and will focus on new developments in visualization of asthma that might be used in animals as well as being translated to humans.
      13. URL :
        http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B75D8-4Y5GVHG-1&_user=10&_coverDate=02%2F28%2F2010&_rdoc=1&_fmt=high&_orig=browse&_origin=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=58c3195065086c72b7aa74f13df11
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4533
      1. Author :
        Ketonis, C.; Barr, S.; Adams, C. S.; Shapiro, I. M.; Parvizi, J.; Hickok, N. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Antimicrob Agents Chemother
      6. Products :
      7. Volume :
        55
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Anti-Bacterial Agents/chemistry/*pharmacology; Bacterial Adhesion/drug effects; Biofilms/drug effects/growth & development; *Bone Transplantation; Bone and Bones/*chemistry/*microbiology; Cell Adhesion/drug effects; Cell Line; Colony Count, Microbial; Humans; Microscopy, Confocal; Osteoblasts/cytology; Staphylococcus aureus/drug effects/*growth & development/physiology; Vancomycin/chemistry/*pharmacology
      12. Abstract :
        Infection is an important medical problem associated with the use of bone allografts. To retard bacterial colonization, we have recently reported on the modification of bone allografts with the antibiotic vancomycin (VAN). In this report, we examine the ability of this antibiotic-modified allograft to resist bacterial colonization and biofilm formation. When antibiotic was coupled to the allograft, a uniform distribution of the antibiotic was apparent. Following challenges with Staphylococcus aureus for 6 h, the covalently bonded VAN decreased colonization as a function of inoculum, ranging from 0.8 to 2.0 log(10) CFU. Furthermore, the VAN-modified surface resisted biofilm formation, even in topographical niches that provide a protected environment for bacterial adhesion. Attachment of the antibiotic to the allograft surface was robust, and the bonded VAN was stable whether incubated in aqueous media or in air, maintaining levels of 75 to 100% of initial levels over 60 days. While the VAN-modified allograft inhibited the Gram-positive S. aureus colonization, in keeping with VAN's spectrum of activity, the VAN-modified allograft was readily colonized by the Gram-negative Escherichia coli. Finally, initial toxicity measures indicated that the VAN-modified allograft did not influence osteoblast colonization or viability. Since the covalently tethered antibiotic is stable, is active, retains its specificity, and does not exhibit toxicity, it is concluded that this modified allograft holds great promise for decreasing bone graft-associated infections.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21098245
      14. Call Number :
        PKI @ kd.modi @ 8
      15. Serial :
        10408
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Journal of immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        179
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amine Oxidase (Copper-Containing); Animals; Bacterial Adhesion; Bioware; Cell Adhesion Molecules; Coxsackievirus Infections; Immunity, Mucosal; Immunoglobulin A; Lymphocyte Count; Lymphocytes; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Knockout; Peyer's Patches; Receptors, Lymphocyte Homing; Staphylococcal Vaccines; Staphylococcus aureus; Xen36
      12. Abstract :
        VAP-1, an ecto-enzyme expressed on the surface of endothelial cells, is involved in leukocyte trafficking between the blood and tissues under physiological and pathological conditions. In this study, we used VAP-1-deficient mice to elucidate whether absence of VAP-1 alters the immune system under normal conditions and upon immunization and microbial challenge. We found that VAP-1-deficient mice display age-dependent paucity of lymphocytes, in the Peyer's patches of the gut. IgA concentration in serum was also found to be lower in VAP-1(-/-) animals than in wild-type mice. Although there were slightly less CD11a on B and T cells isolated from VAP-1-deficient mice than on those from wild-type mice, there were no differences in the expression of gut-homing-associated adhesion molecules or chemokine receptors. Because anti-VAP-1 therapies are being developed for clinical use to treat inflammation, we determined the effect of VAP-1 deletion on useful immune responses. Oral immunization with OVA showed defective T and B cell responses in VAP-1-deficient mice. Antimicrobial immune responses against Staphylococcus aureus and coxsackie B4 virus were also affected by the absence of VAP-1. Importantly, when the function of VAP-1 was acutely neutralized using small molecule enzyme inhibitors and anti-VAP-1 Abs rather than by gene deletion, no significant impairment in antimicrobial control was detected. In conclusion, VAP-1-deficient mice have mild deviations in the mucosal immune system and therapeutic targeting of VAP-1 does not appear to cause a generalized increase in the risk of infection.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17947691
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9984
      1. Author :
        Marttila-Ichihara, Fumiko; Auvinen, Kaisa; Elima, Kati; Jalkanen, Sirpa; Salmi, Marko
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        69
      8. Issue :
        19
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amine Oxidase (Copper-Containing); Animals; Antigens, CD11b; B16-F10-luc-G5 cells; Bioware; Cell Adhesion Molecules; Cell Growth Processes; Female; Lymphoma; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Neovascularization, Pathologic; Oxidoreductases; Receptors, Chemokine
      12. Abstract :
        Cancer growth is regulated by several nonmalignant cell types, such as leukocytes and endothelial cells, which reside in the stroma of the tumor. Vascular adhesion protein-1 (VAP-1) is an amine oxidase enzyme that is expressed on the surface of endothelial cells. It supports leukocyte traffic into inflamed tissues, but nothing is known about its possible role in cancer biology in vivo. Here, we report that B16 melanoma and EL-4 lymphoma remain smaller in VAP-1-deficient mice than in wild-type controls. We found an unexpected defect in tumor angiogenesis in the absence of VAP-1. VAP-1 also selectively enhanced the recruitment of Gr-1+CD11b+ myeloid cells into the tumors. Generation of mice expressing enzymatically inactive VAP-1 showed that the oxidase activity of VAP-1 was necessary to support neoangiogenesis, myeloid cell recruitment, and tumor growth in vivo. These data describe VAP-1 as the first adhesion molecule known to be involved in the recruitment of Gr-1+CD11b+ myeloid cells into tumors. They also suggest that VAP-1 is a potential new tool for immunotherapy of tumors that could be exploited to reduce tumor burden by controlling the traffic of Gr-1+CD11b+ myeloid cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19789345
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8997
      1. Author :
        Cheung, Alison M.; Brown, Allison S.; Shaked, Yuval; Franco, Marcela; Kerbel, Robert S.; Foster, F. S.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        AACR Meeting Abstracts
      6. Products :
      7. Volume :
        2006
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Bioware; PC-3M-luc; hVEGF-luc-PC3M
      12. Abstract :
        Background: Preclinical cancer studies increasingly utilize non-invasive imaging modalities. In the current study we have monitored tumor growth and vascular changes using two in vivo imaging tools: surface bioluminescence (BLI) and ultrasound biomicroscopy (UBM). BLI permits visualization of tumor location in the context of the whole body, including metastases localization. UBM imaging then permits high resolution 3D volumetric tumor measurements as well as blood flow estimates down to 200 microns/s. Measurements obtained from these complementary modalities were analyzed and compared to conventional, biochemical markers. Methods: Human prostate cancer cells expressing Firefly Luciferase constitutively (PC-3M-luc-C6) or under the control of hVEGF promoter (hVEGF-luc/PC3M) were implanted into male nude mice via an intradermal or subcutaneous injection. Tumor-bearing mice were subsequently imaged every week for nine weeks starting at week 2, by UBM to measure tumor burden using 3D volumetric analysis, or to estimate blood flow using speckle-variance flow processing. Surface bioluminescence was also acquired 10 minutes post i.p. injection of D-luciferin. In a longitudinal drug intervention study anti-hVEGF antibody (Bevacizumab, 200 ug) was injected i.p. into nude mice with subcutaneous xenografts of PC-3M-luc-C6 or hVEGF-luc/PC-3M twice per week for three weeks, starting at 14 days post-xenograft. UBM and surface BLI imaging were conducted every week. In order to study the correlation between VEGF expression in hVEGF-luc/PC3M xenografts (estimated by BLI) to tumor hypoxia level, mice were injected with pimonidazole hydrochloride (60 mg/kg i.v.) after three weeks of treatment and tumors were harvested for immunostaining analysis. Results: Surface BLI outputs (photons/s) from subcutaneous PC-3M-luc-C6 xenografts were highly correlated to tumor volumes measured using 3D UBM for small tumors (<100 mm3, r=0.92, n=8), yet poorly correlated to tumors of large size (>100 mm3, r=0.079, n=8). BLI signals in subcutaneous hVEGF-luc/PC3M xenografts showed an inverse trend to tumor blood flow. PC-3M-luc-C6 tumors treated with Bevacizumab showed growth inhibition by day 28 as demonstrated by 3D UBM (control vs treated = 67.27 vs 48.54 mm3). Moreover, control xenografts showed increased average BLI output over time, whereas treated tumors showed variation in BLI output. Necrosis, hypoxia and blood flow estimates were also investigated. Conclusions: Surface bioluminescence imaging demonstrated high correlations to accurate 3D UBM volumetric measurements of small tumor volumes, suggesting its usefulness in tracking early tumor growth quantitatively in drug intervention studies. A complementary imaging modality, like ultrasound biomicroscopy, is recommended to monitor tumor burden in advanced stages.
      13. URL :
        http://www.aacrmeetingabstracts.org/cgi/content/abstract/2006/1/646-a
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8977