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      1. Author :
        Bratlie, K. M.; Dang, T. T.; Lyle, S.; Nahrendorf, M.; Weissleder, R.; Langer, R.; Anderson, D. G.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        5
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Prosense, IVIS, Animals; Biocompatible Materials/*diagnostic use; Diagnostic Imaging/*methods; *Fluorescence; Macrophage Activation; Materials Testing/*methods; Mice; Models, Animal; Peptide Hydrolases/metabolism; Phagocytes
      12. Abstract :
        BACKGROUND: Many materials are unsuitable for medical use because of poor biocompatibility. Recently, advances in the high throughput synthesis of biomaterials has significantly increased the number of potential biomaterials, however current biocompatibility analysis methods are slow and require histological analysis. METHODOLOGY/PRINCIPAL FINDINGS: Here we develop rapid, non-invasive methods for in vivo quantification of the inflammatory response to implanted biomaterials. Materials were placed subcutaneously in an array format and monitored for host responses as per ISO 10993-6: 2001. Host cell activity in response to these materials was imaged kinetically, in vivo using fluorescent whole animal imaging. Data captured using whole animal imaging displayed similar temporal trends in cellular recruitment of phagocytes to the biomaterials compared to histological analysis. CONCLUSIONS/SIGNIFICANCE: Histological analysis similarity validates this technique as a novel, rapid approach for screening biocompatibility of implanted materials. Through this technique there exists the possibility to rapidly screen large libraries of polymers in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20386609
      14. Call Number :
        PKI @ kd.modi @ 5
      15. Serial :
        10427
      1. Author :
        Mieog, J. S.; Hutteman, M.; van der Vorst, J. R.; Kuppen, P. J.; Que, I.; Dijkstra, J.; Kaijzel, E. L.; Prins, F.; Lowik, C. W.; Smit, V. T.; van de Velde, C. J.; Vahrmeijer, A. L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Breast Cancer Res Treat
      6. Products :
      7. Volume :
        128
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        ProSense, IVIS, Animals; Breast Neoplasms/pathology/*surgery; Cell Line, Tumor; Disease Models, Animal; Female; *Microscopy, Fluorescence; Rats; *Surgery, Computer-Assisted; Transplantation, Isogeneic; Xenograft Model Antitumor Assays
      12. Abstract :
        Tumor involvement of resection margins is found in a large proportion of patients who undergo breast-conserving surgery. Near-infrared (NIR) fluorescence imaging is an experimental technique to visualize cancer cells during surgery. To determine the accuracy of real-time NIR fluorescence imaging in obtaining tumor-free resection margins, a protease-activatable NIR fluorescence probe and an intraoperative camera system were used in the EMR86 orthotopic syngeneic breast cancer rat model. Influence of concentration, timing and number of tumor cells were tested in the MCR86 rat breast cancer cell line. These variables were significantly associated with NIR fluorescence probe activation. Dosing and tumor size were also significantly associated with fluorescence intensity in the EMR86 rat model, whereas time of imaging was not. Real-time NIR fluorescence guidance of tumor resection resulted in a complete resection of 17 out of 17 tumors with minimal excision of normal healthy tissue (mean minimum and a mean maximum tumor-free margin of 0.2 +/- 0.2 mm and 1.3 +/- 0.6 mm, respectively). Moreover, the technique enabled identification of remnant tumor tissue in the surgical cavity. Histological analysis revealed that the NIR fluorescence signal was highest at the invasive tumor border and in the stromal compartment of the tumor. In conclusion, NIR fluorescence detection of breast tumor margins was successful in a rat model. This study suggests that clinical introduction of intraoperative NIR fluorescence imaging has the potential to increase the number of complete tumor resections in breast cancer patients undergoing breast-conserving surgery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20821347
      14. Call Number :
        PKI @ kd.modi @ 4
      15. Serial :
        10429
      1. Author :
        Ignat M, Aprahamian M, Lindner V, Altmeyer A, Perretta S, Dallemagne B, Mutter D and Marescaux J
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Gastroenterology
      6. Products :
      7. Volume :
        137
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        ProSense; AngioSense; AngioSpark; in vivo imaging; pancreatic cancer
      12. Abstract :
        BACKGROUND & AIMS: Surgical management of pancreatic cancer depends on tumor resectability and staging. This study evaluated a new in vivo technique, fiberoptic confocal fluorescence microscopy (FCFM), for detection and staging of pancreatic tumors in rats.

        METHODS: FCFM was used with a protease-activated fluorescent marker (ProSense; VisEn Medical Inc, Woburn, MA) for in vivo imaging of solid organs (1.8-microm resolution) in a rat model of pancreatic ductal adenocarcinoma. A preliminary study described the FCFM rendering of normal and pathologic tissues. Subsequently, 2 double-blind studies compared FCFM to standard histology in (1) detection of tumors in rat models of cancer and controls and (2) detection of nodal involvement (splenic, celiac, mesenteric, and colic) 4, 5, and 6 weeks after tumor induction vs controls.

        RESULTS: Tumor cells displayed a fluorescent ductal pattern compared with non-fluorescent normal pancreas or normal follicular pattern of lymph nodes (LNs). FCFM detected all the pancreatic tumors (1.7-mm mean diameter) and identified 23 LNs that contained metastases of 99 LNs examined. Standard histologic analyses resulted in 1 false-negative result in tumor detection and 2 false negatives in LN detection, whereas FCFM produced no false-negative results. Additional serial sectioning confirmed all tumors and 16 metastatic LNs; FCFM had a negative predictive value of 100% and a positive predictive value of 69.6%.

        CONCLUSIONS: Real-time “virtual biopsy” using FCFM detects tumors and LN metastases with 100% sensitivity and 92.2% specificity in rats, making it a reliable technique for detection and staging of pancreatic cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19632230
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4540
      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
      1. Author :
        Vasilis Ntziachristos
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        The Proceedings of the American Thoracic Society
      6. Products :
      7. Volume :
        6
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        ProSense; FMT; fluorescence; tomography; proteases; lung; inflammation; in vivo imaging
      12. Abstract :
        Biomedical imaging has become an important tool in the study of “-omics” fields by allowing the noninvasive visualization of functional and molecular events using in vivo staining and reporter gene approaches. This capacity can go beyond the understanding of the genetic basis and phenotype of such respiratory conditions as acute bronchitis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and asthma and investigate the development of disease and of therapeutic events longitudinally and in unperturbed environments. Herein, we show how the application of novel quantitative optical imaging methods, using transillumination and fluorescence molecular tomography (FMT), can allow visualization of pulmonary inflammation in small animals in vivo. The results confirm prior observations using a protease-sensitive probe. We discuss how this approach enables in vivo insights at the system level as to the dynamic role of proteases in respiratory pathophysiology and their potential as therapeutic targets. Overall, the proposed imaging method can be used with a significantly wider range of possible targets and applications in lung imaging.
      13. URL :
        http://pats.atsjournals.org/cgi/content/full/6/5/416
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4534
      1. Author :
        Kim DE, Kim JY, Schellingerhout D, Shon SM, Jeong SW, Kim EJ and Kim WK
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Molecular Imaging
      6. Products :
      7. Volume :
        8
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        ProSense; in vivo imaging
      12. Abstract :
        Inflammation in atherosclerotic plaques causes plaque vulnerability and rupture, leading to thromboembolic complications. Cathepsin B (CatB) proteases secreted by macrophages play a major role in plaque inflammation. We used a CatB-activatable near-infrared fluorescence (NIRF) imaging agent to demonstrate the inflammatory component in mice atheromata and the atherosclerosis- modulating effects of atorvastatin or glucosamine treatments. Apolipoprotein E knockout mice (n = 35) were fed normal chow, a Western diet, a Western diet + atorvastatin, a Western diet + glucosamine, or a Western diet + atorvastatin + glucosamine for 14 weeks. Twenty-four hours after the intravenous injection of a CatB-activatable probe, ex vivo NIRF imaging of the aortas and brains was performed, followed by histology. The CatB-related signal, observed in the aortas but not in the cerebral arteries, correlated very well with protease activity and the presence of macrophages on histology. Animals on Western diets could be distinguished from animals on a normal diet. The antiatherosclerotic effects of atorvastatin and glucosamine could be demonstrated, with reduced CatB-related signal compared with untreated animals. Plaque populations were heterogeneous within individuals, with some plaques showing a high and others a lower CatB-related signal. These differences in signal intensity could not be predicted by visual inspection of the plaques but did correlate with histologic evidence of inflammation in every case. This suggests that vulnerable inflamed plaques can be identified by optical molecular imaging.
      13. URL :
        http://www.bcdecker.com/pubMedLinkOut.aspx?pub=MIO&vol=8&iss=5&page=291
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4558
      1. Author :
        Rosenzweig HL, Jann MM, Glant TT, Martin TM, Planck SR, van Eden W, van Kooten PJ, Flavell RA, Kobayashi KS, Rosenbaum JT and Davey MP
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Journal of Leukocyte Biology
      6. Products :
      7. Volume :
        85
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        ProSense; in vivo imaging; NOD2; mice; inflammatory arthritis; TCR transgenic; knockout
      12. Abstract :
        In addition to its role in innate immunity, nucleotide oligomerization domain 2 (NOD2) has been shown to play a suppressive role in models of colitis. Notably, mutations in NOD2 cause the inherited granulomatous disease of the joints called Blau syndrome, thereby linking NOD2 with joint disease as well. However, the role of NOD2 in joint inflammation has not been clarified. We demonstrate here that NOD2 is functional within the mouse joint and promotes inflammation, as locally or systemically administered muramyl dipeptide (MDP; the NOD2 agonist) resulted in significant joint inflammation that was abolished in NOD2-deficient mice. We then sought to investigate the role of NOD2 in a mouse model of inflammatory arthritis dependent on adaptive immunity using TCR-transgenic mice whose T cells recognized the dominant epitope of proteoglycan (PG). Mice immunized with PG in the presence of MDP developed a more severe inflammatory arthritis and histopathology within the joints. Antigen-specific activation of splenocytes was enhanced by MDP with respect to IFN-gamma production, which would be consistent with the Th1-mediated disease in vivo. Intriguingly, NOD2 deficiency did not alter the PG-induced arthritis, indicating that NOD2 does not play an essential role in this model of joint disease when it is not activated by MDP. In conclusion, we demonstrate that in a model of inflammatory arthritis dependent on T and B cell priming, NOD2 activation potentiates disease. However, the absence of NOD2 does not alter the course of inflammatory arthritis, in contrast to models of intestinal inflammation.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718807/?tool=pubmed
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4535
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