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      1. Author :
        Hickson, Jonathan
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Urologic oncology
      6. Products :
      7. Volume :
        27
      8. Issue :
        3
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Biological Markers; Bioware; Diagnostic Imaging; Image Processing, Computer-Assisted; Luminescent Measurements; Luminescent Proteins; Molecular Probes; Optical Devices; Optical Phenomena; PC-3M-luc; Reproducibility of Results
      12. Abstract :
        There has recently been an explosion in the availability of new technologies to noninvasively detect biological processes in preclinical models. One such modality, optical imaging, comprises using bioluminescent and fluorescent reporters and probes to repetitively interrogate molecular events and monitor disease progression in animal models. This review includes an overview of optical imaging technologies (e.g., hardware, reporters, probes) available for small animal imaging and their application in monitoring disease progression, therapeutic efficacy, and molecular processes such as proliferation, apoptosis, and angiogenesis. Also discussed are some of the challenges associated with in vivo optical imaging and the necessary controls and biological correlates one must include in experimental design and interpretation for successful preclinical studies.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19414115
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8964
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Journal of orthopaedic research: official publication of the Orthopaedic Research Society
      6. Products :
      7. Volume :
        27
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bioware; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Female; Fractures, Bone; Mice; Mice, Inbred C57BL; Osteomyelitis; Xen29
      12. Abstract :
        Osteomyelitis (OM) from multidrug-resistant (MDR) Acinetobacter has emerged in >30% of combat-related injuries in Iraq and Afghanistan. While most of these strains are sensitive to colistin, the drug is not available in bone void fillers for local high-dose delivery. To address this, we developed a mouse model with MDR strains isolated from wounded military personnel. In contrast to S. aureus OM, which is osteolytic and characterized by biofilm in necrotic bone, A. baumannii OM results in blastic lesions that do not contain apparent biofilm. We also found that mice mount a specific IgG response against three proteins (40, 47, and 56 kDa) regardless of the strain used, suggesting that these may be immuno-dominant antigens. PCR for the A. baumannii-specific parC gene confirmed a 100% infection rate with 75% of the MDR strains, and in vitro testing confirmed that all strains were sensitive to colistin. We also developed a real-time quantitative PCR (RTQ-PCR) assay that could detect as few as 10 copies of parC in a sample. To demonstrate the efficacy of colistin prophylaxis in this model, mice were treated with either parenteral colistin (0.2 mg colistinmethate i.m. for 7 days), local colistin (PMMA bead impregnated with 1.0 mg colistin sulfate), or an unloaded PMMA bead control. While the parenteral colistin failed to demonstrate any significant effects versus the placebo, the colistin PMMA bead significantly reduced the infection rate such that only 29.2% of the mice had detectable levels of parC at 19 days (p < 0.05 vs. i.m. colistin and placebo).
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19173261
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9043
      1. Author :
        Burkatovskaya, Marina; Tegos, George P; Swietlik, Emilia; Demidova, Tatiana N; P Castano, Ana; Hamblin, Michael R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Biomaterials
      6. Products :
      7. Volume :
        27
      8. Issue :
        22
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Acetates; Alginates; Animals; Anti-Infective Agents; Bandages; Bioware; Chitosan; Glucuronic Acid; Hexuronic Acids; Male; Mice; Mice, Inbred BALB C; Occlusive Dressings; Proteus mirabilis; Pseudomonas aeruginosa; Silver Sulfadiazine; Staphylococcus aureus; Wound Healing; Wound Infection; Xen8.1, Xen5, Xen44
      12. Abstract :
        HemCon bandage is an engineered chitosan acetate preparation used as a hemostatic control dressing, and its chemical structure suggests that it should also be antimicrobial. We tested its ability to rapidly kill bacteria in vitro and in mouse models of infected wounds. We used the Gram-negative species Pseudomonas aeruginosa and Proteus mirabilis and the Gram-positive Staphylococcus aureus that had all been stably transduced with the entire bacterial lux operon to allow in vivo bioluminescence imaging. An excisional wound in Balb/c mice was inoculated with 50-250 million cells followed after 30 min by application of HemCon bandage, alginate sponge bandage, silver sulfadiazine cream or no treatment. HemCon was more adhesive to the wound and conformed well to the injury compared to alginate. Animal survival was followed over 15 days with observations of bioluminescence emission and animal activity daily. Chitosan acetate treated mice infected with P. aeruginosa and P. mirabilis all survived while those receiving no treatment, alginate and silver sulfadiazine demonstrated 25-100% mortality. Chitosan acetate was much more effective than other treatments in rapidly reducing bioluminescence in the wound consistent with its rapid bactericidal activity in vitro as well as its light-scattering properties. S. aureus formed only non-lethal localized infections after temporary immunosuppression of the mice but HemCon was again more effective in reducing bioluminescence. The data suggest that chitosan acetate rapidly kills bacteria in the wound before systemic invasion can take place, and is superior to alginate bandage and silver sulfadiazine that may both encourage bacterial growth in the short term.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16616364
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9987
      1. Author :
        Sabbagh, Y.; Graciolli, F. G.; O'Brien, S.; Tang, W.; dos Reis, L. M.; Ryan, S.; Phillips, L.; Boulanger, J.; Song, W.; Bracken, C.; Liu, S.; Ledbetter, S.; Dechow, P.; Canziani, M. E.; Carvalho, A. B.; Jorgetti, V.; Moyses, R. M.; Schiavi, S. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Bone Miner Res
      6. Products :
      7. Volume :
        27
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        OsteoSense, Animals; Biopsy; Bone Remodeling; Bone and Bones/metabolism/pathology; Calcification, Physiologic; Cardiovascular Abnormalities/blood/complications/pathology/physiopathology; *Disease Progression; Female; Gene Expression Profiling; Gene Expression Regulation; Glycoproteins/metabolism; Humans; Kidney Failure, Chronic/blood/complications/pathology/physiopathology; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mutation/genetics; Osteoclasts/metabolism/pathology; Osteocytes/*metabolism/*pathology; Protein-Serine-Threonine Kinases/genetics; Renal Osteodystrophy/blood/*metabolism/*pathology/physiopathology; Vascular Calcification; *Wnt Signaling Pathway/genetics
      12. Abstract :
        Chronic kidney disease-mineral bone disorder (CKD-MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft-tissue calcification. Emerging evidence suggests that features of CKD-MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild-type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD-MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild-type mice. To capture the early molecular and cellular events in the progression of CKD-MBD we examined cell-specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor-Ser33/37-beta-catenin was observed both in mouse and human bones. Overall repression of Wnt/beta-catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF-kappaB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late-stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD-MBD and suggest that repression of the Wnt/beta-catenin pathway is involved in the pathogenesis of renal osteodystrophy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22492547
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10475
      1. Author :
        Galina Gabriely, Thomas Wurdinger, Santosh Kesari, Christine C. Esau, Julja Burchard, Peter S. Linsley and Anna M. Krichevsky
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Molecular and Cellular Biology
      6. Products :
      7. Volume :
        28
      8. Issue :
        17
      9. Page Numbers :
        N/A
      10. Research Area :
        Neuroscience
      11. Keywords :
        in vivo imaging; MMPSense; microRNA 21; glioma
      12. Abstract :
        Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for “physiological” modulation of multiple proteins whose expression is deregulated in cancer.
      13. URL :
        http://mcb.asm.org/cgi/content/abstract/28/17/5369
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4546
      1. Author :
        Inglefield, Jon R; Dumitru, Calin Dan; Alkan, Sefik S; Gibson, Sheila J; Lipson, Kenneth E; Tomai, Mark A; Larson, Chris J; Vasilakos, John P
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research
      6. Products :
      7. Volume :
        28
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Aminoquinolines; Animals; B16-F10-luc-G5 cells; Bioware; Cell Line, Tumor; Cell Proliferation; Cell Survival; Culture Media, Conditioned; dendritic cells; Humans; Interferon Type I; Leukocytes, Mononuclear; Lung; Melanoma; Mice; Neoplasms; Oligodeoxyribonucleotides; Quinolines; Subcellular Fractions; Sulfonamides; Toll-Like Receptor 7
      12. Abstract :
        Antitumor effects of the toll-like receptor 7 (TLR7) agonist, 852A, were evaluated. Supernatants from human peripheral blood mononuclear cells (PBMC) stimulated with 852A inhibited the proliferation of tumor cell lines Hs294T and 769-P but had no effect on others (786-O and Caki-1). Because addition of 852A directly to the Hs294T cells did not inhibit their proliferation, the mechanism(s) of inhibition of tumor cell proliferation was investigated. Low nanomolar concentrations of 852A stimulated the production of interferon-alpha (IFN-alpha), IFN-inducible protein-10 (IP-10), interleukin-1 receptor antagonist (IL-1Ra), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from human PBMCs. Cytokines stimulated by submicromolar concentrations of 852A were sufficient to inhibit Hs294T proliferation. At higher concentrations (3-30 microM), 852A induced the production of IL-12p70, IL-18, and IFN-gamma. PBMC cultures depleted of plasmacytoid dendritic cells (pDC) did not produce IFN-alpha, and their conditioned medium did not inhibit Hs294T proliferation. Anti-IFN-alpha/beta receptor (IFNAR) and anti-IFN-alpha antibodies partially abrogated Hs294T proliferation inhibition by 852A-stimulated PBMC supernatants, whereas separate neutralization of TRAIL, tumor necrosis factor-alpha (TNF-alpha, IFN-gamma, IFN-beta, or IFN-omega had no effect. In vivo, six doses of 852A administration significantly delayed the onset of lung colonies in a B16 melanoma model. Thus, the results demonstrate that the TLR7 agonist 852A inhibits in vitro proliferation of some tumor cells in a pDC-dependent and IFN-alpha-dependent manner and can delay tumor growth in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18439103
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9001
      1. Author :
        Meincke, M.; Tiwari, S.; Hattermann, K.; Kalthoff, H.; Mentlein, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Clin Exp Metastasis
      6. Products :
      7. Volume :
        28
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Breast Neoplasms/metabolism/*pathology; Cattle; Chemokine CXCL12/metabolism; Female; Fluorescent Dyes/diagnostic use; Glioma/metabolism/*pathology; Humans; Image Processing, Computer-Assisted; Mice; Mice, Nude; Receptors, CXCR/*metabolism; Receptors, CXCR4/*metabolism; Serum Albumin, Bovine/metabolism; Spectroscopy, Near-Infrared; Tumor Cells, Cultured
      12. Abstract :
        The chemokine CXCL12/SDF-1 and its receptors CXCR4 and CXCR7 play a major role in tumor invasion, proliferation and metastasis. Since both receptors are overexpressed on distinct tumor cells and on the tumor vasculature, we evaluated their potential as targets for detection of cancers by molecular imaging. We synthesized conjugates of CXCL12 and the near-infrared (NIR) fluorescent dye IRDye((R))800CW, tested their selectivity, sensitivity and biological activity in vitro and their feasibility to visualize tumors in vivo. Purified CXCL12-conjugates detected in vitro as low as 500 A764 human glioma cells or MCF-7 breast cancer cells that express CXCR7 alone or together with CXCR4. Binding was time- and concentration-dependent, and the label could be competitively displaced by the native peptide. Control conjugates with bovine serum albumin or lactalbumin failed to label the cells. In mice, the conjugate distributed rapidly. After 1-92 h, subcutaneous tumors of human MCF-7 and A764 cells in immunodeficient mice were detected with high sensitivity. Background was observed in particular in liver within the first 24 h, but also skull and hind limbs yielded some background. Overall, fluorescent CXCL12-conjugates are sensitive and selective probes to detect solid and metastatic tumors by targeting tumor cells and tumor vasculature.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21735100
      14. Call Number :
        PKI @ kd.modi @ 13
      15. Serial :
        10372
      1. Author :
        M van Eekelen; LS Sasportas; R Kasmieh; S Yip; J-L Figueiredo; DN Louis; R Weissleder; K Shah
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        29
      8. Issue :
        22
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        brain tumor; glioma; human neural stem cells; TSP-1; endothelial cells; angiogenesis; in vivo imaging
      12. Abstract :
        Novel therapeutic agents combined with innovative modes of delivery and non-invasive imaging of drug delivery, pharmacokinetics and efficacy are crucial in developing effective clinical anticancer therapies. In this study, we have created and characterized multiple novel variants of anti-angiogenic protein thrombospondin (aaTSP-1) that comprises unique regions of three type-I-repeats of TSP-1 and used engineered human neural stem cells (hNSC) to provide sustained on-site delivery of secretable aaTSP-1 to tumor-vasculature. We show that hNSC-aaTSP-1 has anti-angiogenic effect on human brain and dermal microvascular endothelial cells co-cultured with established glioma cells and CD133+ glioma-initiating cells. Using human glioma cells and hNSC engineered with different combinations of fluorescent and bioluminescent marker proteins and employing multi-modality imaging techniques, we show that aaTSP-1 targets the vascular-component of gliomas and a single administration of hNSC-aaTSP-1 markedly reduces tumor vessel-density that results in inhibition of tumor-progression and increased survival in mice bearing highly malignant human gliomas. We also show that therapeutic hNSC do not proliferate and remain in an un-differentiated state in the brains of glioma-bearing mice. This study provides a platform for accelerated development of future cell-based therapies for cancer.
      13. URL :
        http://www.nature.com/onc/journal/v29/n22/abs/onc201075a.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4492
      1. Author :
        Klohs J, Baeva N, Steinbrink J, Bourayou R, Boettcher C, Royl G, Megow D, Dirnagl U, Priller J and Wunder A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Journal of Cerebral Blood Flow and Metabolism
      6. Products :
      7. Volume :
        29
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        Neuroscience
      11. Keywords :
        MMPSense; in vivo imaging; matrix metalloproteinases; stroke
      12. Abstract :
        Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of cerebral ischemia. In this study, we explored whether MMP activity can be visualized by noninvasive near-infrared fluorescence (NIRF) imaging using an MMP-activatable probe in a mouse model of stroke. C57Bl6 mice were subjected to transient middle cerebral artery occlusion (MCAO) or sham operation. Noninvasive NIRF imaging was performed 24 h after probe injection, and target-to-background ratios (TBRs) between the two hemispheres were determined. TBRs were significantly higher in MCAO mice injected with the MMP-activatable probe than in sham-operated mice and in MCAO mice that were injected with the nonactivatable probe as controls. Treatment with an MMP inhibitor resulted in significantly lower TBRs and lesion volumes compared to injection of vehicle. To test the contribution of MMP-9 to the fluorescence signal, MMP9-deficient (MMP9(-/-)) mice and wild-type controls were subjected to MCAO of different durations to attain comparable lesion volumes. TBRs were significantly lower in MMP9(-/-) mice, suggesting a substantial contribution of MMP-9 activity to the signal. Our study shows that MMP activity after cerebral ischemia can be imaged noninvasively with NIRF using an MMP-activatable probe, which might be a useful tool to study MMP activity in the pathophysiology of the disease.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19417756
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4547
      1. Author :
        Matthias Nahrendorf, Peter Waterman, Greg Thurber, Kevin Groves, Milind Rajopadhye, Peter Panizzi, Brett Marinelli, Elena Aikawa, Mikael J Pittet, Filip K Swirski and Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Arteriosclerosis, Thrombosis, and Vascular Biology
      6. Products :
      7. Volume :
        29
      8. Issue :
        10
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        FMT-CT; molecular imaging; atherosclerosis; protease activity; inflammation; in vivo imaging; fluorescence molecular tomography; ProSense
      12. Abstract :
        Objective: Proteases are emerging biomarkers of inflammatory diseases. In atherosclerosis, these enzymes are often secreted by inflammatory macrophages, digest the extracellular matrix of the fibrous cap and destabilize atheromata. Protease function can be monitored with protease activatable imaging probes and quantitated in vivo by fluorescence molecular tomography (FMT). To address two major constraints currently associated with imaging of murine atherosclerosis (lack of highly sensitive probes and absence of anatomical information), we compared protease sensors (PS) of variable size and pharmacokinetics and co-registered FMT datasets with computed tomography (FMT-CT).

        Methods and results: Co-registration of FMT and CT was achieved with a multimodal imaging cartridge containing fiducial markers detectable by both modalities. A high-resolution CT angiography protocol accurately localized fluorescence to the aortic root of atherosclerotic apoE-/- mice. To identify suitable sensors, we first modeled signal kinetics in-silico and then compared three probes with identical oligo-L-lysine cleavage sequences: PS-5, 5nm in diameter containing 2 fluorochromes , PS-25, a 25nm version with an elongated lysine chain and PS-40, a polymeric nanoparticle. Serial FMT-CT showed fastest kinetics for PS-5 but, surprisingly, highest fluorescence in lesions of the aortic root for PS-40. PS-40 robustly reported therapeutic effects of atorvastatin, corroborated by ex vivo imaging and qPCR for the model protease cathepsin B.

        Conclusions: FMT-CT is a robust and observer-independent tool for non-invasive assessment of inflammatory murine atherosclerosis. Reporter-containing nanomaterials may have unique advantages over small molecule agents for in vivo imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746251/?tool=pubmed
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4568
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