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      1. Author :
        Francis, K P; Yu, J; Bellinger-Kawahara, C; Joh, D; Hawkinson, M J; Xiao, G; Purchio, T F; Caparon, M G; Lipsitch, M; Contag, P R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2001
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        69
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amoxicillin; Animals; Bioware; DNA Transposable Elements; Female; Luminescent Measurements; Lung; Mice; Mice, Inbred BALB C; Nasopharynx; Operon; Promoter Regions, Genetic; pXen-5; Streptococcus pneumoniae; Transformation, Bacterial, Xen10, Xen7
      12. Abstract :
        Animal studies with Streptococcus pneumoniae have provided valuable models for drug development. In order to monitor long-term pneumococcal infections noninvasively in living mice, a novel gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r), that allows random integration of lux genes onto the bacterial chromosome was constructed. The cassette was designed so that the luxABCDE and kanamycin resistance genes were linked to form a single promoterless operon. Bioluminescence and kanamycin resistance only occur in a bacterial cell if this operon has transposed downstream of a promoter on the bacterium's chromosome. S. pneumoniae D39 was transformed with plasmid pAUL-A Tn4001 luxABCDE Km(r), and a number of highly bioluminescent colonies were recovered. Genomic DNA from the brightest D39 strain was used to transform a number of clinical S. pneumoniae isolates, and several of these strains were tested in animal models, including a pneumococcal lung infection model. Strong bioluminescent signals were seen in the lungs of the animals containing these pneumococci, allowing the course and antibiotic treatment of the infections to be readily monitored in real time in the living animals. Recovery of the bacteria from the animals showed that the bioluminescent signal corresponded to the number of CFU and that the lux construct was highly stable even after several days in vivo. We believe that this lux transposon will greatly expand the ability to evaluate drug efficacy against gram-positive bacteria in living animals using bioluminescence.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/11292758
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9027
      1. Author :
        Park, Hae-Sun; Francis, Kevin P; Yu, Jun; Cleary, P Patrick
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2003
      5. Publication :
        Journal of immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        171
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Administration, Intranasal; Animals; Bioware; Disease Models, Animal; Female; Humans; Immunohistochemistry; Intracellular Fluid; Lymphoid Tissue; Mice; Mice, Inbred BALB C; Nasal Mucosa; Nasopharynx; Palatine Tonsil; pXen-5; Streptococcal Infections; Streptococcus pyogenes
      12. Abstract :
        Human tonsils are suspected to be an antibiotic-impervious human reservoir for group A streptococcus. An intranasal infection model in mice and a bioluminescent-tagged strain were used to investigate this possibility. Viable streptococci were predominantly found both intra- and extracellularly in nasal-associated lymphoid tissue (NALT), a human tonsil homologue. Ulex europaeus-1, a membranous (M) cell-specific lectin, identified cells harboring streptococci at the epithelial surface of NALT and blocked bacterial colonization of this tissue. These results suggest that M cells in NALT transport this Gram-positive pathogen across the epithelial layers in a manner similar to those in Peyer's patches, which permit enteric pathogens to invade deeper tissues from the gastrointestinal tract.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/12928403
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9025
      1. Author :
        Hart, Emily; Azzopardi, Kristy; Taing, Heng; Graichen, Florian; Jeffery, Justine; Mayadunne, Roshan; Wickramaratna, Malsha; O'Shea, Mike; Nijagal, Brunda; Watkinson, Rebecca; O'Leary, Stephen; Finnin, Barrie; Tait, Russell; Robins-Browne, Roy
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        The Journal of antimicrobial chemotherapy
      6. Products :
      7. Volume :
        65
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bioware; Colony Count, Microbial; Disease Models, Animal; Female; Foreign Bodies; Humans; Mice; Mice, Inbred BALB C; Ofloxacin; Polymers; Prosthesis-Related Infections; Staphylococcal Infections; Staphylococcus aureus; Xen29
      12. Abstract :
        OBJECTIVES To assess support discs, comprising polyethylene terephthalate (PET), coated with different polymer/levofloxacin combinations for antimicrobial activity in an animal model of infection, in order to explore the use of specific polymer coatings incorporating levofloxacin as a means of reducing device-related infections. METHODS Aliphatic polyester-polyurethanes containing different ratios of poly(lactic acid) diol and poly(caprolactone) diol were prepared, blended with levofloxacin and then used to coat support discs. The in vitro levofloxacin release profiles from these discs were measured in aqueous solution. Mice were surgically implanted with the coated discs placed subcutaneously and infection was initiated by injection of 10(6) cfu of Staphylococcus aureus into the subcutaneous pocket containing the implant. After 5, 10, 20 and 30 days, the discs were removed, and the number of bacteria adhering to the implant and the residual antimicrobial activity of the discs were determined. RESULTS In vitro, the release of levofloxacin from the coated discs occurred at a constant rate and then reached a plateau at different timepoints, depending on the polymer preparation used. In vivo, none of the discs coated with polymer blends containing levofloxacin was colonized by S. aureus, whereas 94% of the discs coated with polymer alone were infected. All discs coated with levofloxacin-blended polymers displayed residual antimicrobial activity for at least 20 days post-implantation. CONCLUSIONS Bioerodable polyester-polyurethane polymer coatings containing levofloxacin can prevent bacterial colonization of implants in an intra-operative model of device-related infections.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20233779
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9035
      1. Author :
        Mortin, Lawrence I; Li, Tongchuan; Van Praagh, Andrew D G; Zhang, Shuxin; Zhang, Xi-Xian; Alder, Jeff D
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Antimicrobial agents and chemotherapy
      6. Products :
      7. Volume :
        51
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Acetamides; Animals; Anti-Bacterial Agents; Bioware; Colony Count, Microbial; Daptomycin; Female; Luminescent Measurements; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Neutropenia; Oxazolidinones; Peritonitis; Staphylococcus aureus; Xen29
      12. Abstract :
        The rising rates of antibiotic resistance accentuate the critical need for new antibiotics. Daptomycin is a new antibiotic with a unique mode of action and a rapid in vitro bactericidal effect against gram-positive organisms. This study examined the kinetics of daptomycin's bactericidal action against peritonitis caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in healthy and neutropenic mice and compared this activity with those of other commonly used antibiotics. CD-1 mice were inoculated intraperitoneally with lethal doses of MSSA (Xen-29) or MRSA (Xen-1), laboratory strains transformed with a plasmid containing the lux operon, which confers bioluminescence. One hour later, the animals were given a single dose of daptomycin at 50 mg/kg of body weight subcutaneously (s.c.), nafcillin at 100 mg/kg s.c., vancomycin at 100 mg/kg s.c., linezolid at 100 mg/kg via gavage (orally), or saline (10 ml/kg s.c.). The mice were anesthetized hourly, and photon emissions from living bioluminescent bacteria were imaged and quantified. The luminescence in saline-treated control mice either increased (neutropenic mice) or remained relatively unchanged (healthy mice). In contrast, by 2 to 3 h postdosing, daptomycin effected a 90% reduction of luminescence of MSSA or MRSA in both healthy and neutropenic mice. The activity of daptomycin against both MSSA and MRSA strains was superior to those of nafcillin, vancomycin, and linezolid. Against MSSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than nafcillin or linezolid. Against MRSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than vancomycin or linezolid. The rapid decrease in the luminescent signal in the daptomycin-treated neutropenic mice underscores the potency of this antibiotic against S. aureus in the immune-suppressed host.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17307984
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9050
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        184
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides; Bacterial Infections; Bioware; Cell Line; Cells, Cultured; Chemokine CCL2; Chemokine CCL7; Chemokine CXCL1; Chemokines; Female; Humans; Interleukin-8; Leukocytes; Leukocytes, Mononuclear; Macrophages; Mice; Mice, Inbred C57BL; Molecular Sequence Data; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Staphylococcal Infections; Staphylococcus aureus; Xen29, Xen14
      12. Abstract :
        With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-kappaB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20107187
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9033
      1. Author :
        Filip K. Swirski, Matthias Nahrendorf, Martin Etzrodt, Moritz Wildgruber, Virna Cortez-Retamozo, Peter Panizzi, Jose-Luiz Figueiredo, Rainer H. Kohler, Aleksey Chudnovskiy, Peter Waterman, Elena Aikawa, Thorsten R. Mempel, Peter Libby, Ralph Weissleder and Mikael J. Pittet
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Science
      6. Products :
      7. Volume :
        325
      8. Issue :
        5940
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research; Immunology
      11. Keywords :
        splenic monocytes; in vivo imaging; ProSense; FMT; fluorescence molecular tomography
      12. Abstract :
        A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a resource that the body exploits to regulate inflammation.
      13. URL :
        http://www.sciencemag.org/content/325/5940/612.abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4567
      1. Author :
        Laurie E. Littlepage; Mark D. Sternlicht; Nathalie Rougier; Joanna Phillips; Eugenio Gallo; Ying Yu; Kurt Williams; Audrey Brenot; Jeffrey I. Gordon; Zena Werb
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Research
      6. Products :
      7. Volume :
        70
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        matrix metalloproteinase; neuroendocrine; prostate cancer; metatasis
      12. Abstract :
        Prostate cancer is the leading form of cancer in men. Prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Matrix metalloproteinases (MMP), a family of enzymes that remodel the microenvironment, are associated with tumorigenesis and metastasis. To evaluate MMPs during metastatic prostatic neuroendocrine cancer development, we used transgenic mice expressing SV40 large T antigen in their prostatic neuroendocrine cells, under the control of transcriptional regulatory elements from the mouse cryptdin-2 gene (CR2-TAg). These mice have a stereotypical pattern of tumorigenesis and metastasis. MMP-2, MMP-7, and MMP-9 activities increased concurrently with the transition to invasive metastatic carcinoma, but they were expressed in different prostatic cell types: stromal, luminal epithelium, and macrophages, respectively. CR2-TAg mice treated with AG3340/Prinomastat, an MMP inhibitor that blocks activity of MMP-2, MMP-9, MMP-13, and MMP-14, had reduced tumor burden. CR2-TAg animals were crossed to mice homozygous for null alleles of MMP-2, MMP-7, or MMP-9 genes. At 24 weeks CR2-TAg; MMP-2-/- mice showed reduced tumor burden, prolonged survival, decreased lung metastasis, and decreased blood vessel density, whereas deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival. Mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size, and mice lacking MMP-9 had increased numbers of invasive foci and increased perivascular invasion, as well as decreased tumor blood vessel size. Together, these results suggest distinct contributions by MMPs to the progression of aggressive prostate tumor and to helping tumors cleverly find alternative routes to malignant progression.
      13. URL :
        http://cancerres.aacrjournals.org/content/70/6/2224.abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4490
      1. Author :
        Christoph Bremer; Ching-Hsuan Tung; Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2001
      5. Publication :
        Nature Medicine
      6. Products :
      7. Volume :
        7
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        near-infrared; near infrared; matrix metalloproteinase; MMP; in vivo imaging; near-infrared fluorescence imaging
      12. Abstract :
        A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.
      13. URL :
        http://www.nature.com/nm/journal/v7/n6/abs/nm0601_743.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4509
      1. Author :
        Wallis de Vries BM, van Dam GM, Tio RA, Hillebrands JL, Slart RH and Zeebregts CJ
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Journal of Vascular Surgery
      6. Products :
      7. Volume :
        48
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        In vivo imaging; MMPSense; atherosclerotic carotid plaque
      12. Abstract :
        BACKGROUND: There is increasing evidence that plaque vulnerability, rather than the degree of stenosis, is important in predicting the occurrence of subsequent cerebral ischemic events in patients with carotid artery stenosis. The many imaging modalities currently available have different properties with regard to the visualization of the extent of vulnerability in carotid plaque formation.

        METHODS: Original published studies were identified using the MEDLINE database (January 1966 to March 2008). Manual cross-referencing was also performed.

        RESULTS: There is no single imaging modality that can produce definitive information about the state of vulnerability of an atherosclerotic plaque. Each has its own specific drawbacks, which may be the use of ionizing radiation or nephrotoxic contrast agents, an invasive character, low patient tolerability, or simply the paucity of information obtained on plaque vulnerability. Functional molecular imaging techniques such as positron emission tomography (PET), single photon emission-computed tomography (SPECT) and near infra-red spectroscopy (NIRS) do seem able accurately to visualize and even quantify features of plaque vulnerability and its pathophysiologic processes. Promising new techniques like near infra-red fluorescence imaging are being developed and may be beneficial in this field.

        CONCLUSION: There is a promising role for functional molecular imaging modalities like PET, SPECT, or NIRS related to improvement of selection criteria for carotid intervention, especially when combined with CT or MRI to add further anatomical details to molecular information. Further information will be needed to define whether and where this functional molecular imaging will fit into a clinical strategy.
      13. URL :
        http://www.jvascsurg.org/article/S0741-5214(08)01146-4/abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4643
      1. Author :
        Jason R. McCarthy, Purvish Patel, Ion Botnaru, Pouneh Haghayeghi, Ralph Weissleder and Farouc A. Jaffer
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Bioconjugate Chemistry
      6. Products :
      7. Volume :
        20
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        In vivo imaging; thrombi; VivoTag
      12. Abstract :
        Thrombosis underlies numerous life-threatening cardiovascular syndromes. Development of thrombosis-specific molecular imaging agents to detect and monitor thrombogenesis and fibrinolysis in vivo could improve the diagnosis, risk stratification, and treatment of thrombosis syndromes. To this end, we have synthesized efficient multimodal nanoagents targeted to two different constituents of thrombi, namely, fibrin and activated factor XIII. These agents are targeted via the conjugation of peptide-targeting ligands to the surface of fluorescently labeled magnetic nanoparticles. As demonstrated by in vitro and in vivo studies, both nanoagents possess high affinities for thrombi, and enable mutimodal fluorescence and magnetic resonance imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19456115
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4647
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