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      1. Author :
        McCann CM, Waterman P, Figueiredo JL, Aikawa E, Weissleder R and Chen JW
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Neuroimage
      6. Products :
      7. Volume :
        45
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        Neuroscience
      11. Keywords :
        FMT; in vivo imaging; ProSense
      12. Abstract :
        Fluorescent molecular tomographic (FMT) imaging can noninvasively monitor molecular function in living animals using specific fluorescent probes. However, macroscopic imaging methods such as FMT generally exhibit low anatomical details. To overcome this, we report a quantitative technique to image both structure and function by combining FMT and magnetic resonance (MR) imaging. We show that FMT-MR imaging can produce three-dimensional, multimodal images of living mouse brains allowing for serial monitoring of tumor morphology and protease activity. Combined FMT-MR tumor imaging provides a unique in vivo diagnostic parameter, protease activity concentration (PAC), which reflects histological changes in tumors and is significantly altered by systemic chemotherapy. Alterations in this diagnostic parameter are detectable early after chemotherapy and correlate with subsequent tumor growth, predicting tumor response to chemotherapy. Our results reveal that combined FMT-MR imaging of fluorescent molecular probes could be valuable for brain tumor drug development and other neurological and somatic imaging applications.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19154791
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4544
      1. Author :
        Virna Cortez-Retamozo, Filip K. Swirski, Peter Waterman, Hushan Yuan, Jose Luiz Figueiredo, Andita P. Newton, Rabi Upadhyay, Claudio Vinegoni, Rainer Kohler, Joseph Blois, Adam Smith, Matthias Nahrendorf, Lee Josephson, Ralph Weissleder and Mikael J. Pittet
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Journal of Clinical Investigation
      6. Products :
      7. Volume :
        118
      8. Issue :
        12
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        FMT; in vivo imaging; ProSense; MMPSense
      12. Abstract :
        Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579705/?tool=pubmed
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4536
      1. Author :
        Kenneth M Kozloff, Ralph Weissleder and Umar Mahmood
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Journal of Bone and Mineral Research
      6. Products :
      7. Volume :
        22
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        FMT; OsteoSense; ProSense bone mineralization; bone turnover markers; molecular imaging; bisphosphonates; in vivo imaging
      12. Abstract :
        Abstract: FRFP binds to mineral at osteoblastic, osteoclastic, and quiescent surfaces, with accumulation likely modulated by vascular delivery. In vivo visualization and quantification of binding can be accomplished noninvasively in animal models through optical tomographic imaging.

        Introduction: The development of near-infrared optical markers as reporters of bone metabolism will be useful for early diagnosis of disease. Bisphosphonates bind differentially to osteoblastic and osteoclastic surfaces depending on choice of side-chain and dose, and fluorescently tagged bisphosphonates provide a convenient way to visualize these sites. This study examines the ability of a fluorescently labeled pamidronate imaging probe to bind to regions of bone formation and resorption in vivo.

        Materials and Methods: In vitro binding of a far-red fluorescent pamidronate (FRFP) to mineral was assessed using intact and demineralized dentine slices. In vivo, FRFP binding was studied in three models: developing neonatal mouse, bone healing after injury, and metastasis-induced osteolysis and fracture. 3D fluorescence molecular tomographic (FMT) imaging was used to visualize signal deep within the body.

        Results: FRFP binding to bone depends on the quantity of mineral present and can be liberated from the bone during decalcification. In vivo, FRFP binds to surfaces of actively forming bone, as assessed by alkaline phosphatase staining, surfaces undergoing active resorption, as noted by scalloped bone border and presence of osteoclasts, and to quiescent surfaces not involved in formation or resorption. Binding is likely modulated by vascular delivery of the imaging agent to the exposed mineral surface and total quantity of surface exposed.FMT imaging is capable of visualizing regions of bone formation because of a large volume of labeled surface, but like radiolabeled bone scans, cannot discriminate pure osteolysis caused by metastasis.

        Conclusions: FRFP may function as a local biomarker of bisphosphonate deposition to assess interplay between drug and cellular environment or may be combined with other imaging agents or fluorescent cells for the noninvasive assessment of local bone metabolism in vivo.
      13. URL :
        http://onlinelibrary.wiley.com/doi/10.1359/jbmr.070504/references?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Nat%20Med&rft.atitle=Shedding%20light%20onto%20live%20molecular%20targets&rft.volume=9&rf
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4530
      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 :
        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 :
        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 :
        Abdelwahab, M. G.; Fenton, K. E.; Preul, M. C.; Rho, J. M.; Lynch, A.; Stafford, P.; Scheck, A. C.
      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 :
        GL261-luc2, IVIS, 3-Hydroxybutyric Acid/metabolism; Animals; Blood Glucose/metabolism; Brain/metabolism/pathology; Combined Modality Therapy; Disease Models, Animal; Glioma/*diet therapy/*radiotherapy; Humans; Kaplan-Meier Estimate; *Ketogenic Diet; Ketones/blood; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Time Factors
      12. Abstract :
        INTRODUCTION: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal(R) (KC) is a nutritionally complete, commercially available 4:1 (fat:carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas. METHODS: We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2x4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging. RESULTS: Animals fed KC had elevated levels of beta-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days. CONCLUSIONS: KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22563484
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10485
      1. Author :
        Abdelwahab, M. G.; Sankar, T.; Preul, M. C.; Scheck, A. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Vis Exp
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        GL261-luc2, IVIS, Glioma, Biolumninescence imaging
      12. Abstract :
        The mouse glioma 261 (GL261) is recognized as an in vivo model system that recapitulates many of the features of human glioblastoma multiforme (GBM). The cell line was originally induced by intracranial injection of 3-methyl-cholantrene into a C57BL/6 syngeneic mouse strain (1); therefore, immunologically competent C57BL/6 mice can be used. While we use GL261, the following protocol can be used for the implantation and monitoring of any intracranial mouse tumor model. GL261 cells were engineered to stably express firefly luciferase (GL261-luc). We also created the brighter GL261-luc2 cell line by stable transfection of the luc2 gene expressed from the CMV promoter. C57BL/6-cBrd/cBrd/Cr mice (albino variant of C57BL/6) from the National Cancer Institute, Frederick, MD were used to eliminate the light attenuation caused by black skin and fur. With the use of albino C57BL/6 mice; in vivo imaging using the IVIS Spectrum in vivo imaging system is possible from the day of implantation (Caliper Life Sciences, Hopkinton, MA). The GL261-luc and GL261-luc2 cell lines showed the same in vivo behavior as the parental GL261 cells. Some of the shared histological features present in human GBMs and this mouse model include: tumor necrosis, pseudopalisades, neovascularization, invasion, hypercellularity, and inflammation (1). Prior to implantation animals were anesthetized by an intraperitoneal injection of ketamine (50 mg/kg), xylazine (5 mg/kg) and buprenorphine (0.05 mg/kg), placed in a stereotactic apparatus and an incision was made with a scalpel over the cranial midline. A burrhole was made 0.1mm posterior to the bregma and 2.3mm to the right of the midline. A needle was inserted to a depth of 3mm and withdrawn 0.4mm to a depth of 2.6mm. Two mul of GL261-luc or GL261-luc2 cells (10(7) cells/ml) were infused over the course of 3 minutes. The burrhole was closed with bonewax and the incision was sutured. Following stereotactic implantation the bioluminescent cells are detectable from the day of implantation and the tumor can be analyzed using the 3D image reconstruction feature of the IVIS Spectrum instrument. Animals receive a subcutaneous injection of 150mug luciferin /kg body weight 20 min prior to imaging. Tumor burden is quantified using mean tumor bioluminescence over time. Tumor-bearing mice were observed daily to assess morbidity and were euthanized when one or more of the following symptoms are present: lethargy, failure to ambulate, hunched posture, failure to groom, anorexia resulting in >10% loss of weight. Tumors were evident in all of the animals on necropsy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22158303
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10486