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      1. Author :
        Izukuri, K.; Suzuki, K.; Yajima, N.; Ozawa, S.; Ito, S.; Kubota, E.; Hata, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Transgenic Res
      6. Products :
      7. Volume :
        19
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2; Base Sequence; Carcinoma, Lewis Lung/blood supply/genetics/immunology/therapy; Cell Line, Tumor; Chemokines, CXC/*genetics/*immunology; DNA Primers/genetics; Female; Gene Expression; Humans; Kidney/immunology; Male; Melanoma, Experimental/blood supply/genetics/immunology/therapy; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Transplantation; Neoplasms, Experimental/blood supply/genetics/*immunology/*therapy; RNA, Messenger/genetics; Recombinant Proteins/genetics/immunology; Transplantation, Heterologous
      12. Abstract :
        We reported previously that the forced expression of the chemokine BRAK, also called CXCL14 in head and neck squamous cell carcinoma (HNSCC) cells decreased the rate of tumor formation and size of tumor xenografts compared with mock-vector treated cells in athymic nude mice or in severe combined immunodeficiency mice. This suppression occurred even though the growth rates of these cells were the same under in vitro culture conditions, suggesting that a high expression level of the gene in tumor cells is important for the suppression of tumor establishment in vivo. The aim of this study was to determine whether CXCL14/BRAK transgenic mice show resistance to tumor cell xenografts or not. CXCL14/BRAK cDNA was introduced into male C57BL/6 J pronuclei, and 10 founder transgenic mice (Tg) were obtained. Two lines of mice expressed over 10 times higher CXCL14/BRAK protein levels (14 and 11 ng/ml plasma, respectively) than normal blood level (0.9 ng/ml plasma), without apparent abnormality. The sizes of Lewis lung carcinoma and B16 melanoma cell xenografts in Tg mice were significantly smaller than those in control wild-type mice, indicating that CXCL14/BRAK, first found as a suppressor of tumor progression of HNSCC, also suppresses the progression of a carcinoma of other tissue origin. Immunohistochemical studies showed that invasion of blood vessels into tumors was suppressed in tumor xenografts of CXCL14/BRAK Tg mice. These results indicate that CXCL14/BRAK suppressed tumor cell xenografts by functioning paracrine or endocrine fashion and that CXCL14/BRAK is a very promising molecular target for tumor suppression without side effects.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20333465
      14. Call Number :
        PKI @ kd.modi @ 5
      15. Serial :
        10348
      1. Author :
        Mumprecht, V.; Honer, M.; Vigl, B.; Proulx, S. T.; Trachsel, E.; Kaspar, M.; Banziger-Tobler, N. E.; Schibli, R.; Neri, D.; Detmar, M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Res
      6. Products :
      7. Volume :
        70
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2; Antibodies, Monoclonal/diagnostic use/immunology; *Diagnostic Imaging; Female; Fluorodeoxyglucose F18/diagnostic use; Glycoproteins/*immunology; Humans; Inflammation/*complications/immunology/pathology; Iodine Radioisotopes/diagnostic use/pharmacokinetics; Luminescent Measurements; Lymph Nodes/immunology/pathology/*radionuclide imaging; *Lymphangiogenesis; Lymphatic Metastasis; Melanoma, Experimental/*complications/immunology/pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; *Positron-Emission Tomography; Prognosis; Radiopharmaceuticals/diagnostic use; Skin/metabolism; Tissue Distribution; Vascular Endothelial Growth Factor C/metabolism; Vascular Endothelial Growth Factor Receptor-3/immunology
      12. Abstract :
        Metastasis to regional lymph nodes (LN) is a prognostic indicator for cancer progression. There is a great demand for sensitive and noninvasive methods to detect metastasis to LNs. Whereas conventional in vivo imaging approaches have focused on the detection of cancer cells, lymphangiogenesis within tumor-draining LNs might be the earliest sign of metastasis. In mouse models of LN lymphangiogenesis, we found that systemically injected antibodies to lymphatic epitopes accumulated in the lymphatic vasculature in tissues and LNs. Using a (124)I-labeled antibody against the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), we imaged, for the first time, inflammation- and tumor-draining LNs with expanded lymphatic networks in vivo by positron emission tomography (PET). Anti-LYVE-1 immuno-PET enabled visualization of lymphatic vessel expansion in LNs bearing metastases that were not detected by [(18)F]fluorodeoxyglucose-PET, which is clinically applied to detect cancer metastases. Immuno-PET with lymphatic-specific antibodies may open up new avenues for the early detection of metastasis, and the images obtained might be used as biomarkers for the progression of diseases associated with lymphangiogenesis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20978206
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10349
      1. Author :
        Seo, G. M.; Rachakatla, R. S.; Balivada, S.; Pyle, M.; Shrestha, T. B.; Basel, M. T.; Myers, C.; Wang, H.; Tamura, M.; Bossmann, S. H.; Troyer, D. L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Mol Biol Rep
      6. Products :
      7. Volume :
        39
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2
      12. Abstract :
        Gene-directed enzyme prodrug therapy (GDEPT) has been investigated as a means of cancer treatment without affecting normal tissues. This system is based on the delivery of a suicide gene, a gene encoding an enzyme which is able to convert its substrate from non-toxic prodrug to cytotoxin. In this experiment, we have developed a targeted suicide gene therapeutic system that is completely contained within tumor-tropic cells and have tested this system for melanoma therapy in a preclinical model. First, we established double stable RAW264.7 monocyte/macrophage-like cells (Mo/Ma) containing a Tet-On(R) Advanced system for intracellular carboxylesterase (InCE) expression. Second, we loaded a prodrug into the delivery cells, double stable Mo/Ma. Third, we activated the enzyme system to convert the prodrug, irinotecan, to the cytotoxin, SN-38. Our double stable Mo/Ma homed to the lung melanomas after 1 day and successfully delivered the prodrug-activating enzyme/prodrug package to the tumors. We observed that our system significantly reduced tumor weights and numbers as targeted tumor therapy after activation of the InCE. Therefore, we propose that this system may be a useful targeted melanoma therapy system for pulmonary metastatic tumors with minimal side effects, particularly if it is combined with other treatments.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21567204
      14. Call Number :
        PKI @ kd.modi @ 6
      15. Serial :
        10351
      1. Author :
        Kadurugamuwa, J. L.; Sin, L. V.; Yu, J.; Francis, K. P.; Kimura, R.; Purchio, T.; Contag, P. R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2003
      5. Publication :
        Antimicrobial Agents and Chemotherapy
      6. Products :
      7. Volume :
        47
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, Anti-Bacterial Agents/ pharmacology, Bacterial Infections/drug therapy/microbiology, Biofilms/ drug effects/growth & development, Bioware; Catheterization/adverse effects, Chemiluminescent Measurements, Ciprofloxacin/pharmacology, Colony Count, Microbial, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Monitoring/methods, Mice, Rifampin/pharmacology, Staphylococcus aureus/drug effects/genetics/growth & development, Tobramycin/pharmacology IVIS, Xenogen; Xen29
      12. Abstract :
        We have developed a rapid, continuous method for monitoring the effectiveness of several antibacterial agents in real time, noninvasively, by using a recently described mouse model of chronic biofilm infection (J. L. Kadurugamuwa et al., Infect. Immun. 71:882-890, 2003), which relies on biophotonic imaging of bioluminescent bacteria. To facilitate real-time monitoring of infection, we used a Staphylococcus aureus isolate that was made bioluminescent by inserting a modified lux operon into the bacterial chromosome. This bioluminescent reporter bacterium was used to study the antimicrobial effects of several antibiotics belonging to different molecular families. Treatment with rifampin, tobramycin, and ciprofloxacin was started 7 days after subcutaneous implantation of catheters precolonized with 10(4) CFU of S. aureus. Three different doses of antibiotics were administered twice a day for 4 consecutive days. The number of metabolically active bacteria in untreated mice and the tobramycin- and ciprofloxacin-treated groups remained relatively unchanged over the 4-week observation period, indicating poor efficacies for tobramycin and ciprofloxacin. A rapid dose-dependent decline in metabolic activity in rifampin-treated groups was observed, with almost a 90% reduction after two doses and nearly undetectable levels after three doses. The disappearance of light emission correlated with colony counts. After the final treatment, cell numbers rebounded as a function of concentration in a time-dependent manner. The staphylococci isolated from the catheters of mice treated with rifampin were uniformly resistant to rifampin but retained their in vitro susceptibilities to tobramycin and ciprofloxacin. Since the metabolic activities of viable cells and a postantibiotic effect could be detected directly on the support matrix nondestructively and noninvasively, the methodology is specifically appealing for investigating the effects of antibiotics on biofilms in vivo. Moreover, our study points to the possible use of biophotonic imaging for the detection of the development of resistance to therapeutic agents during treatment of chronic infections in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/14506020
      14. Call Number :
        139345
      15. Serial :
        7448
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        77
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animal Structures; Animals; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Bioware; Cell Wall; Colony Count, Microbial; Female; Humans; Mice; Mice, Inbred BALB C; Neutrophils; Opsonin Proteins; Proteome; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staphylococcal Infections; Staphylococcal Vaccines; Staphylococcus aureus; Vaccines, Subunit; Vaccines, Synthetic; Whole Body Imaging; Xen29
      12. Abstract :
        Staphylococcus aureus is an important human pathogen with increasing clinical impact due to the extensive spread of antibiotic-resistant strains. Therefore, development of a protective polyvalent vaccine is of great clinical interest. We employed an intravenous immunoglobulin (IVIG) preparation as a source of antibodies directed against anchorless S. aureus surface proteins for identification of novel vaccine candidates. In order to identify such proteins, subtractive proteome analysis (SUPRA) of S. aureus anchorless cell wall proteins was performed. Proteins reacting with IVIG but not with IVIG depleted of S. aureus-specific opsonizing antibodies were considered vaccine candidates. Nearly 40 proteins were identified by this preselection method using matrix-assisted laser desorption ionization--time of flight analysis. Three of these candidate proteins, enolase (Eno), oxoacyl reductase (Oxo), and hypothetical protein hp2160, were expressed as glutathione S-transferase fusion proteins, purified, and used for enrichment of corresponding immunoglobulin Gs from IVIG by affinity chromatography. Use of affinity-purified anti-Eno, anti-Oxo, and anti-hp2160 antibodies resulted in opsonization, phagocytosis, and killing of S. aureus by human neutrophils. High specific antibody titers were detected in mice immunized with recombinant antigens. In mice challenged with bioluminescent S. aureus, reduced staphylococcal spread was measured by in vivo imaging. The recovery of S. aureus CFU from organs of immunized mice was diminished 10- to 100-fold. Finally, mice immunized with hp2160 displayed statistically significant higher survival rates after lethal challenge with clinically relevant S. aureus strains. Taken together, our data suggest that anchorless cell wall proteins might be promising vaccine candidates and that SUPRA is a valuable tool for their identification.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19364833
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9039
      1. Author :
        Hardy, J.; Francis, K. P.; DeBoer, M.; Chu, P.; Gibbs, K.; Contag, C. H.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        Science
      6. Products :
      7. Volume :
        303
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        animal cell, animal model, article, bacterial colonization, bacterial growth, bacterial virulence, bioluminescence, cell culture, controlled study, extracellular space, gallbladder, in vivo study, Listeria monocytogenes, mouse, nonhuman, priority journal IVIS, Xenogen, Xen32
      12. Abstract :
        The bacterium Listeria monocytogenes can cause a life-threatening systemic illness in humans. Despite decades of progress in animal models of listeriosis, much remains unknown about the processes of infection and colonization. Here, we report that L. monocytogenes can replicate in the murine gall bladder and provide evidence that its replication there is extracellular and intraluminal. In vivo bioluminescence imaging was employed to determine the location of the infection over time in live animals, revealing strong signals from the gall bladder over a period of several days, in diseased as well as asymptomatic animals. The data suggest that L. monocytogenes may be carried in the human gall bladder.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/14764883
      14. Call Number :
        138442
      15. Serial :
        6154
      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 :
        Tseng, J. C.; Granot, T.; DiGiacomo, V.; Levin, B.; Meruelo, D.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Gene Ther
      6. Products :
      7. Volume :
        17
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        AngioSense, IVIS, Alphavirus Infections/pathology/*therapy/virology; Animals; Antineoplastic Agents, Phytogenic/therapeutic use; Blotting, Western; Cell Membrane Permeability; Combined Modality Therapy; Cricetinae; Drug Delivery Systems; Female; *Genetic Vectors; Humans; Mice; Mice, SCID; Neovascularization, Pathologic/*prevention & control; Neuroblastoma/blood supply/therapy/virology; *Oncolytic Virotherapy; Ovarian Neoplasms/*blood supply/*therapy/virology; Paclitaxel/therapeutic use; Sindbis Virus/*physiology; Vascular Endothelial Growth Factor A/metabolism; Xenograft Model Antitumor Assays
      12. Abstract :
        Genetic instability of cancer cells generates resistance after initial responses to chemotherapeutic agents. Several oncolytic viruses have been designed to exploit specific signatures of cancer cells, such as important surface markers or pivotal signaling pathways for selective replication. It is less likely for cancer cells to develop resistance given that mutations in these cancer signatures would negatively impact tumor growth and survival. However, as oncolytic viral vectors are large particles, they suffer from inefficient extravasation from tumor blood vessels. Their ability to reach cancer cells is an important consideration in achieving specific oncolytic targeting and potential vector replication. Our previous studies indicated that the Sindbis viral vectors target tumor cells by the laminin receptor. Here, we present evidence that modulating tumor vascular leakiness, using VEGF and/or metronomic chemotherapy regimens, significantly enhances tumor vascular permeability and directly enhances oncolytic Sindbis vector targeting in tumor models. Because host-derived vascular endothelium cells are genetically stable and less likely to develop resistance to chemotherapeutics, a combined metronomic chemotherapeutics and oncolytic vector regimen should provide a new approach for cancer therapy. This mechanism could explain the synergistic treatment outcomes observed in clinical trials of combined therapies.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19798121
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10442
      1. Author :
        Stelter, L.; Tseng, J. C.; Torosjan, A.; Levin, B.; Longo, V. A.; Pillarsetty, N.; Zanzonico, P.; Meruelo, D.; Larson, S. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Mol Imaging Biol
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        AngioSense, FMT, IVIS, Biolumninescence
      12. Abstract :
        PURPOSE: Sindbis virus (SINV) infect tumor cells specifically and systemically throughout the body. Sindbis vectors are capable of expressing high levels of transduced suicide genes and thus efficiently produce enzymes for prodrug conversion in infected tumor cells. The ability to monitor suicide gene expression levels and viral load in patients, after administration of the vectors, would significantly enhance this tumor-specific therapeutic option. PROCEDURES: The tumor specificity of SINV is mediated by the 67-kDa laminin receptor (LR). We probed different cancer cell lines for their LR expression and, to determine the specific role of LR-expression in the infection cycle, used different molecular imaging strategies, such as bioluminescence, fluorescence molecular tomography, and positron emission tomography, to evaluate SINV-mediated infection in vitro and in vivo. RESULTS: All cancer cell lines showed a marked expression of LR. The infection rates of the SINV particles, however, differed significantly among the cell lines. CONCLUSION: We used novel molecular imaging techniques to visualize vector delivery to different neoplatic cells. SINV infection rates proofed to be not solely dependent on cellular LR expression. Further studies need to evaluate the herein discussed ways of cellular infection and viral replication.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22847302
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10440
      1. Author :
        Earley, S.; Vinegoni, C.; Dunham, J.; Gorbatov, R.; Feruglio, P. F.; Weissleder, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Cancer Res
      6. Products :
      7. Volume :
        72
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        AngioSense, Annexin Vivo, Annexin-Vivo, Aniline Compounds/*pharmacology; Animals; Antineoplastic Agents/*pharmacology; *Apoptosis; Breast Neoplasms/drug therapy/*physiopathology; Cell Line, Tumor; Female; Green Fluorescent Proteins; Humans; Image Processing, Computer-Assisted; Mice; Mice, Nude; Mitochondrial Membranes/drug effects/*physiology; Mitochondrial Proteins/metabolism; Molecular Imaging/*methods; Pancreatic Neoplasms/drug therapy/*physiopathology; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors; Recombinant Fusion Proteins/metabolism; Single-Cell Analysis; Sulfonamides/*pharmacology; Tumor Microenvironment
      12. Abstract :
        Observing drug responses in the tumor microenvironment in vivo can be technically challenging. As a result, cellular responses to molecularly targeted cancer drugs are often studied in cell culture, which does not accurately represent the behavior of cancer cells growing in vivo. Using high-resolution microscopy and fluorescently labeled genetic reporters for apoptosis, we developed an approach to visualize drug-induced cell death at single-cell resolution in vivo. Stable expression of the mitochondrial intermembrane protein IMS-RP was established in human breast and pancreatic cancer cells. Image analysis was then used to quantify release of IMS-RP into the cytoplasm upon apoptosis and irreversible mitochondrial permeabilization. Both breast and pancreatic cancer cells showed higher basal apoptotic rates in vivo than in culture. To study drug-induced apoptosis, we exposed tumor cells to navitoclax (ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w, both in vitro and in vivo. Although the tumors responded to Bcl-2 inhibition in vivo, inducing apoptosis in around 20% of cancer cells, the observed response was much higher in cell culture. Together, our findings show an imaging technique that can be used to directly visualize cell death within the tumor microenvironment in response to drug treatment.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22505651
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10433
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