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      1. Author :
        David G Kirsch; Daniela M Dinulescu; John B Miller; Jan Grimm; Philip M Santiago1; Nathan P Young; G Petur Nielsen; Bradley J Quade; Christopher J Chaber; Christian P Schultz; Osamu Takeuchi; Roderick T Bronson; Denise Crowley; Stanley J Korsmeyer; Sam S Yoon; Francis J Hornicek; Ralph Weissleder; Tyler Jacks
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Nature Medicine
      6. Products :
      7. Volume :
        13
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        sarcoma; imaging; apoptosis; metatasis; FMT
      12. Abstract :
        Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.
      13. URL :
        http://www.nature.com/nm/journal/v13/n8/abs/nm1602.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4506
      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
      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 :
        Jeffrey D Peterson; Timothy P LaBranche; Kristine O Vasquez; Sylvie Kossodo; Michele Melton; Randall Rader; John T Listello; Mark A Abrams; Thomas P Misko
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Arthritis Research & Therapy
      6. Products :
      7. Volume :
        12
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        optical tomography; in vivo imaging; inflammation; Fluorescence molecular tomographic; FMT
      12. Abstract :
        Introduction: Standard measurements used to assess murine models of rheumatoid arthritis, notably paw thickness and clinical score, do not align well with certain aspects of disease severity as assessed by histopathology. We tested the hypothesis that non-invasive optical tomographic imaging of molecular biomarkers of inflammation and bone turnover would provide a superior quantitative readout and would discriminate between a disease-modifying anti-rheumatic drug (DMARD) and a non-DMARD treatment.

        Methods: Using two protease-activated near-infrared fluorescence imaging agents to detect inflammation-associated cathepsin and matrix metalloprotease activity, and a third agent to detect bone turnover, we quantified fluorescence in paws of mice with collagen antibody-induced arthritis. Fluorescence molecular tomographic (FMT) imaging results, which provided deep tissue detection and quantitative readouts in absolute picomoles of agent fluorescence per paw, were compared with paw swelling, clinical scores, a panel of plasma biomarkers, and histopathology to discriminate between steroid (prednisolone), DMARD (p38 mitogen-activated protein kinase (MAPK) inhibitor) and non-DMARD (celecoxib, cyclooxygenase-2 (COX-2) inhibitor) treatments.

        Results: Paw thickness, clinical score, and plasma biomarkers failed to discriminate well between a p38 MAPK inhibitor and a COX-2 inhibitor. In contrast, FMT quantification using near-infrared agents to detect protease activity or bone resorption yielded a clear discrimination between the different classes of therapeutics. FMT results agreed well with inflammation scores, and both imaging and histopathology provided clearer discrimination between treatments as compared with paw swelling, clinical score, and serum biomarker readouts.

        Conclusions: Non-invasive optical tomographic imaging offers a unique approach to monitoring disease pathogenesis and correlates with histopathology assessment of joint inflammation and bone resorption. The specific use of optical tomography allowed accurate three-dimensional imaging, quantitation in picomoles rather than intensity or relative fluorescence, and, for the first time, showed that non-invasive imaging assessment can predict the pathologist's histology inflammation scoring and discriminate DMARD from non-DMARD activity.
      13. URL :
        http://arthritis-research.com/content/12/3/R105
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4513
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