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      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 :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Clinical & experimental metastasis
      6. Products :
      7. Volume :
        26
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        4T1-luc2; Animals; Bioware; Cell Line, Tumor; Disease Models, Animal; DNA-Binding Proteins; Female; Flow Cytometry; Killer Cells, Natural; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; Neoplasm Metastasis; Rats
      12. Abstract :
        The occurrence of metastases is a critical determinant of the prognosis for breast cancer patients. Effective treatment of breast cancer metastases is hampered by a poor understanding of the mechanisms involved in the formation of these secondary tumor deposits. To study the processes of metastasis, valid in vivo tumor metastasis models are required. Here, we show that increased expression of the EGF receptor in the MTLn3 rat mammary tumor cell-line is essential for efficient lung metastasis formation in the Rag mouse model. EGFR expression resulted in delayed orthotopic tumor growth but at the same time strongly enhanced intravasation and lung metastasis. Previously, we demonstrated the critical role of NK cells in a lung metastasis model using MTLn3 cells in syngenic F344 rats. However, this model is incompatible with human EGFR. Using the highly metastatic EGFR-overexpressing MTLn3 cell-line, we report that only Rag2(-/-)gammac(-/-) mice, which lack NK cells, allow efficient lung metastasis from primary tumors in the mammary gland. In contrast, in nude and SCID mice, the remaining innate immune cells reduce MTLn3 lung metastasis formation. Furthermore, we confirm this finding with the orthotopic transplantation of the 4T1 mouse mammary tumor cell-line. Thus, we have established an improved in vivo model using a Rag2(-/-) gammac(-/-) mouse strain together with MTLn3 cells that have increased levels of the EGF receptor, which enables us to study EGFR-dependent tumor cell autonomous mechanisms underlying lung metastasis formation. This improved model can be used for drug target validation and development of new therapeutic strategies against breast cancer metastasis formation.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19466569
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8940
      1. Author :
        Lee, H. L.; Chen, C. C.; Baasov, T.; Ron, Y.; Dougherty, J. P.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Mol Ther
      6. Products :
      7. Volume :
        19
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        RediJect Coelenterazine h, XenoLight
      12. Abstract :
        Cells have developed a mechanism to discriminate between premature termination codons (PTCs) and normal stop codons during translation, sparking vigorous research to develop drugs promoting readthrough at PTCs to treat genetic disorders caused by PTCs. It was posed that this concept could also be applied to regulated gene therapy protocols by incorporating a PTC into a therapeutic gene, so active protein would only be made after administration of a readthrough agent. The strengths of the system are highlighted here by results demonstrating: (i) background expression levels were reduced to 0.01% to 0.0005% of wild type in unselected mass populations of cells depending upon the specific stop codon utilized and its position within the gene; (ii) expression levels responded well to multiple “On” and “Off” regulation cycles in vivo in human xenograft systems; (iii) the level of induction approached three logs using aminoglycoside activators including NB54, a newly synthesized aminoglycoside with significantly reduced toxicity; and (iv) expression levels could be appreciably altered when employing different promoters in a variety of cell types. These results strongly support the contention that this system should have important clinical applications when tight control of gene expression is required.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21587212
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10422
      1. Author :
        Lee, S. K.; Han, M. S.; Asokan, S.; Tung, C. H.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Small
      6. Products :
      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        364-70
      10. Research Area :
        N/A
      11. Keywords :
        LnCaP-luc2, Prostate Cancer, IVIS, *Gene Silencing; *Gold; Metal Nanoparticles/*chemistry/ultrastructure; Microscopy, Electron, Transmission; Polylysine/chemistry; RNA, Small Interfering/*genetics
      12. Abstract :
        Small interfering RNA (siRNA) has been widely proposed to treat various diseases by silencing genes, but its delivery remains a challenge. A well controlled assembly approach is applied to prepare a protease-assisted nanodelivery system. Protease-degradable poly-L-lysine (PLL) and siRNA are fabricated onto gold nanoparticles (AuNPs), by alternating the charged polyelectrolytes. In this study, up to 4 layers of PLL and 3 layers of siRNA (sR3P) are coated. Due to the slow degradation of PLL, the incorporated siRNA is released gradually and shows extended gene-silencing effects. Importantly, the inhibition effect in cells is found to correlate with the number of siRNA layers.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21294265
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10547
      1. Author :
        Lee, S.; Vinegoni, C.; Feruglio, P. F.; Fexon, L.; Gorbatov, R.; Pivoravov, M.; Sbarbati, A.; Nahrendorf, M.; Weissleder, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Nat Commun
      6. Products :
      7. Volume :
        3
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        AngioSense
      12. Abstract :
        Real-time imaging of moving organs and tissues at microscopic resolutions represents a major challenge in studying the complex biology of live animals. Here we present a technique based on a novel stabilizer setup combined with a gating acquisition algorithm for the imaging of a beating murine heart at the single-cell level. The method allows serial in vivo fluorescence imaging of the beating heart in live mice in both confocal and nonlinear modes over the course of several hours. We demonstrate the utility of this technique for in vivo optical sectioning and dual-channel time-lapse fluorescence imaging of cardiac ischaemia. The generic method could be adapted to other moving organs and thus broadly facilitate in vivo microscopic investigations.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22968700
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10436
      1. Author :
        Lemarie, F.; Chang, C. W.; Blatchford, D. R.; Amor, R.; Norris, G.; Tetley, L.; McConnell, G.; Dufes, C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Nanomedicine (Lond)
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, B16-F10-luc-G5, B16F10-luc-G5, B16-F10-luc, B16F10-luc
      12. Abstract :
        Aim: The therapeutic potential of epigallocatechin-3-gallate (EGCG), a green tea polyphenol with anticancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study was to determine whether a tumor-targeted vesicular formulation of EGCG would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo. Materials & methods: Transferrin-bearing vesicles encapsulating EGCG were administered intravenously to mice bearing subcutaneous A431 and B16-F10 tumors. Results: The intravenous administration of EGCG encapsulated in transferrin-bearing vesicles resulted in tumor suppression in 40% of A431 and B16-F10 tumors. Animal survival was improved by more than 20 days compared with controls. Conclusion: Encapsulation of EGCG in transferrin-bearing vesicles is a promising therapeutic strategy. Original submitted 28 November 2011; Revised submitted 11 May 2012.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22891867
      14. Call Number :
        PKI @ kd.modi @ 14
      15. Serial :
        10532
      1. Author :
        Leong, H. S.; Lizardo, M. M.; Ablack, A.; McPherson, V. A.; Wandless, T. J.; Chambers, A. F.; Lewis, J. D.
      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 :
        MDA-MB-231-luc-D3H2Ln, D3H2Ln, IVIS, Breast cancer, Bioware, Animals; Birds/embryology; Breast Neoplasms/*metabolism; Cadherins/*metabolism; Cell Line, Tumor; Diagnostic Imaging; Epithelial-Mesenchymal Transition/drug effects; Female; Humans; Microscopy, Confocal; Microscopy, Fluorescence; Morpholines/pharmacokinetics/pharmacology; Transplantation, Heterologous; Vimentin/metabolism
      12. Abstract :
        The analysis of dynamic events in the tumor microenvironment during cancer progression is limited by the complexity of current in vivo imaging models. This is coupled with an inability to rapidly modulate and visualize protein activity in real time and to understand the consequence of these perturbations in vivo. We developed an intravital imaging approach that allows the rapid induction and subsequent depletion of target protein levels within human cancer xenografts while assessing the impact on cell behavior and morphology in real time. A conditionally stabilized fluorescent E-cadherin chimera was expressed in metastatic breast cancer cells, and the impact of E-cadherin induction and depletion was visualized using real-time confocal microscopy in a xenograft avian embryo model. We demonstrate the assessment of protein localization, cell morphology and migration in cells undergoing epithelial-mesenchymal and mesenchymal-epithelial transitions in breast tumors. This technique allows for precise control over protein activity in vivo while permitting the temporal analysis of dynamic biophysical parameters.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22276156
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10508
      1. Author :
        Leszczynska, K.; Namiot, A.; Cruz, K.; Byfield, F. J.; Won, E.; Mendez, G.; Sokolowski, W.; Savage, P. B.; Bucki, R.; Janmey, P. A.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Appl Microbiol
      6. Products :
      7. Volume :
        110
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen5, Xen 5, Pseudomonas aeruginosa Xen 5, Anti-Bacterial Agents/administration & dosage/*pharmacology/therapeutic; use; Antimicrobial Cationic Peptides/chemistry; Biofilms/drug effects; Cholic Acid/chemistry; Cystic Fibrosis/microbiology; Hemolysis/drug effects; Humans; *Poloxamer; Pseudomonas Infections/drug therapy; Pseudomonas aeruginosa/drug effects/growth & development; Skin Diseases, Bacterial/drug therapy; Staphylococcus aureus/drug effects; Steroids/administration & dosage/*pharmacology/therapeutic use; *Surface-Active Agents
      12. Abstract :
        AIMS: Ceragenin CSA-13 is a synthetic mimic of cationic antibacterial peptides, with facial amphiphilic morphology reproduced using a cholic acid scaffold. Previous data have shown that this molecule displays broad-spectrum antibacterial activity, which decreases in the presence of blood plasma. However, at higher concentrations, CSA-13 can cause lysis of erythrocytes. This study was designed to assess in vitro antibacterial and haemolytic activity of CSA-13 in the presence of pluronic F-127. METHODS AND RESULTS: CSA-13 bactericidal activity against clinical strains of bacteria associated with topical infections and in an experimental setting relevant to their pathophysiological environment, such as various epithelial tissue fluids and the airway sputum of patients suffering from cystic fibrosis (CF), was evaluated using minimum inhibitory and minimum bactericidal concentration (MIC/MBC) measurements and bacterial killing assays. We found that in the presence of pluronic F-127, CSA-13 antibacterial activity was only slightly decreased, but CSA-13 haemolytic activity was significantly inhibited. CSA-13 exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa present in CF sputa, and biofilms formed by different Gram (+) and Gram (-) bacteria. CSA-13 bactericidal action is partially compromised in the presence of plasma, but is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid. The synergistic action of CSA-13, determined by the use of a standard checkerboard assay, reveals an increase in CSA-13 antibacterial activity in the presence of host defence molecules such as the cathelicidin LL-37 peptide, lysozyme, lactoferrin and secretory phospholipase A (sPLA). CONCLUSION: These results suggest that CSA-13 may be useful to prevent and treat topical infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Combined application of CSA-13 with pluronic F-127 may be beneficial by reducing CSA-13 toxicity.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20961363
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10389
      1. Author :
        Leszczynska, K.; Namiot, D.; Byfield, F. J.; Cruz, K.; Zendzian-Piotrowska, M.; Fein, D. E.; Savage, P. B.; Diamond, S.; McCulloch, C. A.; Janmey, P. A.; Bucki, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Antimicrob Chemother
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen5, Xen 5, Pseudomonas aeruginosa
      12. Abstract :
        OBJECTIVES: We aim to develop antibacterial peptide mimics resistant to protease degradation, with broad-spectrum activity at sites of infection. METHODS: The bactericidal activities of LL-37, ceragenins CSA-13, CSA-90 and CSA-92 and the spermine-conjugated dexamethasone derivative D2S were evaluated using MIC and MBC measurements. Gingival fibroblast counting, interleukin-8 (IL-8) and lactate dehydrogenase (LDH) release from keratinocytes (HaCat) were used to determine effects on cell growth, pro-inflammatory response and toxicity. RESULTS: All tested cationic lipids showed stronger bactericidal activity than LL-37. Incubation of Staphylococcus aureus with half the MIC of LL-37 led to the appearance of bacteria resistant to its bactericidal effects, but identical incubations with CSA-13 or D2S did not produce resistant bacteria. Cathelicidin LL-37 significantly increased the total number of gingival fibroblasts, but ceragenins and D2S did not alter gingival fibroblast growth. Cationic lipids showed no toxicity to HaCat cells at concentrations resulting in bacterial killing. CONCLUSIONS: These data suggest that cationic lipids such as ceragenins warrant further testing as potential novel antibacterial agents.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23134677
      14. Call Number :
        PKI @ kd.modi @ 6
      15. Serial :
        10551
      1. Author :
        Leuschner, F.; Rauch, P. J.; Ueno, T.; Gorbatov, R.; Marinelli, B.; Lee, W. W.; Dutta, P.; Wei, Y.; Robbins, C.; Iwamoto, Y.; Sena, B.; Chudnovskiy, A.; Panizzi, P.; Keliher, E.; Higgins, J. M.; Libby, P.; Moskowitz, M. A.; Pittet, M. J.; Swirski, F. K.; Weissleder, R.; Nahrendorf, M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Exp Med
      6. Products :
      7. Volume :
        209
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Adoptive Transfer; Animals; Biological Markers/metabolism; Cell Death/genetics; Disease Models, Animal; Female; *Hematopoiesis, Extramedullary; Inflammation/immunology/metabolism; Interleukin-1beta/genetics/metabolism; Kinetics; Macrophages/cytology/*physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Monocytes/*cytology/*physiology; Myeloid Cells/metabolism; Myocardial Infarction/immunology/pathology/*physiopathology; Signal Transduction; Spleen/physiology; Stroke/immunology/metabolism; Wound Healing/physiology
      12. Abstract :
        Monocytes (Mo) and macrophages (MPhi) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MPhi and their effector functions without compromising innate immunity's critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MPhi in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1beta; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MPhi exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MPhi flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22213805
      14. Call Number :
        PKI @ kd.modi @ 27
      15. Serial :
        10370
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