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      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 :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Journal of immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        179
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amine Oxidase (Copper-Containing); Animals; Bacterial Adhesion; Bioware; Cell Adhesion Molecules; Coxsackievirus Infections; Immunity, Mucosal; Immunoglobulin A; Lymphocyte Count; Lymphocytes; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Knockout; Peyer's Patches; Receptors, Lymphocyte Homing; Staphylococcal Vaccines; Staphylococcus aureus; Xen36
      12. Abstract :
        VAP-1, an ecto-enzyme expressed on the surface of endothelial cells, is involved in leukocyte trafficking between the blood and tissues under physiological and pathological conditions. In this study, we used VAP-1-deficient mice to elucidate whether absence of VAP-1 alters the immune system under normal conditions and upon immunization and microbial challenge. We found that VAP-1-deficient mice display age-dependent paucity of lymphocytes, in the Peyer's patches of the gut. IgA concentration in serum was also found to be lower in VAP-1(-/-) animals than in wild-type mice. Although there were slightly less CD11a on B and T cells isolated from VAP-1-deficient mice than on those from wild-type mice, there were no differences in the expression of gut-homing-associated adhesion molecules or chemokine receptors. Because anti-VAP-1 therapies are being developed for clinical use to treat inflammation, we determined the effect of VAP-1 deletion on useful immune responses. Oral immunization with OVA showed defective T and B cell responses in VAP-1-deficient mice. Antimicrobial immune responses against Staphylococcus aureus and coxsackie B4 virus were also affected by the absence of VAP-1. Importantly, when the function of VAP-1 was acutely neutralized using small molecule enzyme inhibitors and anti-VAP-1 Abs rather than by gene deletion, no significant impairment in antimicrobial control was detected. In conclusion, VAP-1-deficient mice have mild deviations in the mucosal immune system and therapeutic targeting of VAP-1 does not appear to cause a generalized increase in the risk of infection.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17947691
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9984
      1. Author :
        Kosaka, Nobuyoshi; Iguchi, Haruhisa; Yoshioka, Yusuke; Takeshita, Fumitaka; Matsuki, Yasushi; Ochiya, Takahiro
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        The Journal of biological chemistry
      6. Products :
      7. Volume :
        285
      8. Issue :
        23
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Aniline Compounds; Animals; Benzylidene Compounds; Biological Transport; Bioware; Cercopithecus aethiops; COS Cells; Culture Media, Conditioned; Exosomes; Gene Silencing; Humans; MicroRNAs; Neoplasms; PC-3M-luc; RNA Interference; RNA, Small Interfering; Sphingomyelin Phosphodiesterase; Tumor Markers, Biological
      12. Abstract :
        The existence of circulating microRNAs (miRNAs) in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function of extracellular miRNAs remain unclear. Here, we show that miRNAs are released through a ceramide-dependent secretory machinery and that the secretory miRNAs are transferable and functional in the recipient cells. Ceramide, whose biosynthesis is regulated by neutral sphingomyelinase 2 (nSMase2), triggers secretion of small membrane vesicles called exosomes. The decreased activity of nSMase2 with a chemical inhibitor, GW4869, and a specific small interfering RNA resulted in the reduced secretion of miRNAs. Complementarily, overexpression of nSMase2 increased extracellular amounts of miRNAs. We also revealed that the endosomal sorting complex required for transport system is unnecessary for the release of miRNAs. Furthermore, a tumor-suppressive miRNA secreted via this pathway was transported between cells and exerted gene silencing in the recipient cells, thereby leading to cell growth inhibition. Our findings shed a ray of light on the physiological relevance of secretory miRNAs.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20353945
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8946
      1. Author :
        Kosaka, N.; Iguchi, H.; Yoshioka, Y.; Hagiwara, K.; Takeshita, F.; Ochiya, T.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Biol Chem
      6. Products :
      7. Volume :
        287
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        PC-3M-luc-C6, PC-3M-luc, IVIS, Bioware, Prostate cancer, Bioluminescence
      12. Abstract :
        Normal epithelial cells regulate the secretion of autocrine and paracrine factors that prevent aberrant growth of neighboring cells, leading to healthy development and normal metabolism. One reason for tumor initiation is considered to be a failure of this homeostatic cell competitive system. Here we identify tumor-suppressive microRNAs (miRNAs) secreted by normal cells as anti-proliferative signal entities. Culture supernatant of normal epithelial prostate PNT-2 cells attenuated proliferation of PC-3M-luc cells, prostate cancer cells. Global analysis of miRNA expression signature revealed that a variety of tumor-suppressive miRNAs are released from PNT-2 cells. Of these miRNAs, secretory miR-143 could induce growth inhibition exclusively in cancer cells in vitro and in vivo. These results suggest that secretory tumor-suppressive miRNAs can act as a death signal in a cell competitive process. This study provides a novel insight into a tumor initiation mechanism.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22123823
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10537
      1. Author :
        Korotcov, Alexandru; Shan, Liang; Meng, Huan; Wang, Tongxin; Sridhar, Rajagopalan; Zhao, Yuliang; Liang, Xing-Jie; Wang, Paul C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of nanoscience and nanotechnology
      6. Products :
      7. Volume :
        10
      8. Issue :
        11
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Contrast Media; Magnetic Resonance Imaging; Mice; Nanotechnology; PC-3M-luc
      12. Abstract :
        We have developed and tested a liposomal nanocomplex system, which contains Gd-DTPA as a payload and transferrin on the surface, as a tumor specific targeting MRI contrast agent for studying prostate cancer tumors in mice. In vivo, the probe significantly enhanced the MRI signal. The image contrast between the peripheral region of the tumor and the non-involved muscle was nearly 50% higher two hours after administration of the nanocomplex. The liposomal nanocomplex increased the amount of Gd accumulated in tumors by factor 2.8 compared to that accumulated by using Magnevist alone. Moreover, the heterogeneous MRI image features correlate well with the tumor pathology. The image enhancement patterns can be used for cancer prognosis and non-invasive monitoring of the response to therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21137979
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8963
      1. Author :
        Korotcov, A. V.; Ye, Y.; Chen, Y.; Zhang, F.; Huang, S.; Lin, S.; Sridhar, R.; Achilefu, S.; Wang, P. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Mol Imaging Biol
      6. Products :
      7. Volume :
        14
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        PC-3M-luc-C6, PC-3M-luc, IVIS, Bioware, Prostate cancer, Bioluminescence, Animals; Cell Line, Tumor; Endocytosis; Fluorescent Dyes/chemistry/*diagnostic use; Glucosamine/chemistry/*diagnostic use; Humans; Kinetics; Male; Mice; Mice, Nude; Molecular Imaging/*methods; Neoplasms/*diagnosis/pathology; Optical Devices; Prostatic Neoplasms/diagnosis/pathology; Spectroscopy, Near-Infrared; Tissue Distribution; *Xenograft Model Antitumor Assays
      12. Abstract :
        PURPOSE: Near-infrared fluorescence (NIRF) imaging is an attractive technique for studying diseases at the molecular level in vivo. Glucose transporters are often used as targets for in vivo imaging of tumors. The efficiency of a tumor-seeking fluorescent probe can be enhanced by attaching one or more glucosamine (GlcN) moieties. This study was designed to evaluate the use of previously developed GlcN-linked NIRF probes for in vitro and in vivo optical imaging of cancer. PROCEDURES: Cellular uptake of the probes (1 muM) was investigated in monolayer cultures of luciferase-expressing PC3 (PC3-luc) cells. The prostate tumors were established as subcutaneous xenografts using PC3-luc cells in nude mice. The biodistributions and tumor-targeting specificities of cypate (cyp), cypate-D: -(+)-glucosamine (cyp-GlcN), and D: -(+)-gluosamine-cypate-D: -(+)-gluosamine (cyp-2GlcN) were studied. The tumor, muscle, and major organs were collected for ex vivo optical imaging. RESULTS: The tumor cell uptake of the probe containing two glucosamine residues, cyp-2GlcN, was significantly higher than the uptake of both the probe with one glucosamine residue, cyp-GlcN, and the probe without glucosamine, cyp only. Similarly, in in vivo experiments, cyp-2GlcN demonstrated higher maximum fluorescence intensity and longer residence lifetime in tumors than cyp-GlcN or cyp. The ex vivo biodistribution analysis revealed that tumor uptake of cyp-2GlcN and cyp-GlcN was four- and twofold higher than that of cyp at 24 h post-injection, respectively. CONCLUSION: Both cyp-GlcN and cyp-2GlcN NIRF probes exhibited good tumor-targeting properties in prostate cancer cell cultures and live mice. The cyp-2GlcN probe showed the highest uptake with good retention characteristics in vivo. The uptake of cyp-2GlcN and cyp-GlcN is likely mediated by glucosamine-recognizing transporters. The uptake mechanism is being explored further for developing cypate-glucosamine-based probes for in vivo imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21971932
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10536
      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 :
        Kirby, A. C.; Beattie, L.; Maroof, A.; Rooijen, N. van; Kaye, P. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        American Journal of Pathology
      6. Products :
      7. Volume :
        175
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen10
      12. Abstract :
        Marginal zone macrophages in the murine spleen play an important role in the capture of blood-borne pathogens and are viewed as an essential component of host defense against the development of pneumococcal sepsis. However, we and others have previously described the loss of marginal zone macrophages associated with the splenomegaly that follows a variety of viral and protozoal infections; this finding raises the question of whether these infected mice would become more susceptible to secondary pneumococcal infection. Contrary to expectations, we found that mice lacking marginal zone macrophages resulting from Leishmania donovani infection have increased resistance to Streptococcus pneumoniae type 3 and do not develop sepsis. Using biophotonic imaging, we observed that pneumococci are rapidly trapped in the spleens of L. donovani-infected mice. By selective depletion studies using clodronate liposomes, depleting monoclonal antibodies specific for Ly6C/G and Ly6G, and CD11c-DTR mice, we show that the enhanced early resistance in L. donovani-infected mice is entirely due to the activity of SIGNR1? red pulp macrophages. Our data demonstrate, therefore, that the normal requirement for SIGNR1+ marginal zone macrophages to protect against a primary pneumococcal infection can, under conditions of splenomegaly, be readily compensated for by activated red pulp macrophages.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19644016
      14. Call Number :
        139699
      15. Serial :
        7610
      1. Author :
        Kimberly A. Kelly; Nabeel Bardeesy; Rajesh Anbazhagan; Sushma Gurumurthy; Justin Berger; Herlen Alencar; Ronald A. DePinho; Umar Mahmood; Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        PLoS Medicine
      6. Products :
      7. Volume :
        15
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer; Biology
      11. Keywords :
        in vivo imaging; cancer
      12. Abstract :
        Background: Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.

        Methods and Findings: Here, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models.

        Conclusions: Our approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans.
      13. URL :
        http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050085
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4478
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