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      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 :
        Kenneth M. Kozloff, Luisa Quinti, Somying Patntirapong, Peter V. Hauschka, Ching-Hsuan Tung, Ralph Weissleder and Umar Mahmood
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Bone
      6. Products :
      7. Volume :
        44
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        FMT; ProSense; OsteoSense; bone; osteoclast; cathepsin K; non-invasive imaging; molecular imaging; fluorescence; in vivo imaging
      12. Abstract :
        Osteoclasts degrade bone matrix by demineralization followed by degradation of type I collagen through secretion of the cysteine protease, cathepsin K. Current imaging modalities are insufficient for sensitive observation of osteoclast activity, and in vivo live imaging of osteoclast resorption of bone has yet to be demonstrated. Here, we describe a near-infrared fluorescence reporter probe whose activation by cathepsin K is shown in live osteoclast cells and in mouse models of development and osteoclast upregulation. Cathepsin K probe activity was monitored in live osteoclast cultures and correlates with cathepsin K gene expression. In ovariectomized mice, cathepsin K probe upregulation precedes detection of bone loss by micro-computed tomography. These results are the first to demonstrate non-invasive visualization of bone degrading enzymes in models of accelerated bone loss, and may provide a means for early diagnosis of upregulated resorption and rapid feedback on efficacy of treatment protocols prior to significant loss of bone in the patient.
      13. URL :
        http://www.thebonejournal.com/article/S8756-3282(08)00816-8/abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4526
      1. Author :
        Kozloff KM, Volakis LI, Marini JC and Caird MS
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of Bone and Mineral Research
      6. Products :
      7. Volume :
        25
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        FMT; bone; OsteoSense; FRFP; in vivo imaging
      12. Abstract :
        Bisphosphonate use has expanded beyond traditional applications to include treatment of a variety of low-bone-mass conditions. Complications associated with long-term bisphosphonate treatment have been noted, generating a critical need for information describing the local bisphosphonate-cell interactions responsible for these observations. This study demonstrates that a fluorescent bisphosphonate analogue, far-red fluorescent pamidronate (FRFP), is an accurate biomarker of bisphosphonate deposition and retention in vivo and can be used to monitor site-specific local drug concentration. In vitro, FRFP is competitively inhibited from the surface of homogenized rat cortical bone by traditional bisphosphonates. In vivo, FRFP delivery to the skeleton is rapid, with fluorescence linearly correlated with bone surface area. Limb fluorescence increases linearly with injected dose of FRFP; injected FRFP does not interfere with binding of standard bisphosphonates at the doses used in this study. Long-term FRFP retention studies demonstrated that FRFP fluorescence decreases in conditions of normal bone turnover, whereas fluorescence was retained in conditions of reduced bone turnover, demonstrating preservation of local FRFP concentration. In the mandible, FRFP localized to the alveolar bone and bone surrounding the periodontal ligament and molar roots, consistent with findings of osteonecrosis of the jaw. These findings support a role for FRFP as an effective in vivo marker for bisphosphonate site-specific deposition, turnover, and long-term retention in the skeleton.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20200982
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4527
      1. Author :
        Stangenberg L, Ellson C, Cortez-Retamozo V, Ortiz-Lopez A, Yuan H, Blois J, Smith RA, Yaffe MB, Weissleder R, Benoist C, Mathis D, Josephson L and Mahmood U
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Arthritis and Rheumatism
      6. Products :
      7. Volume :
        60
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        ProSense; AngioSense; arthritis; in vivo imaging
      12. Abstract :
        OBJECTIVE: To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis.

        METHODS: The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin-selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil-endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay.

        RESULTS: SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor alpha was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration.

        CONCLUSION: A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions.
      13. URL :
        http://onlinelibrary.wiley.com/doi/10.1002/art.24704/abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4528