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      1. Author :
        Guo, K.; Tang, J. P.; Jie, L.; Al-Aidaroos, A. Q.; Hong, C. W.; Tan, C. P.; Park, J. E.; Varghese, L.; Feng, Z.; Zhou, J.; Chng, W. J.; Zeng, Q.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Oncotarget
      6. Products :
      7. Volume :
        3
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        HCT-116-luc2, IVIS, Bioware, HCT116-luc2, Animals; Antibodies, Monoclonal/*immunology; Antibody-Dependent Cell Cytotoxicity/immunology; Carcinoma, Non-Small-Cell Lung/drug therapy; Carcinoma, Squamous Cell/drug therapy; Cell Line, Tumor; Colorectal Neoplasms/drug therapy; Humans; Immediate-Early Proteins/*immunology; Killer Cells, Natural/*immunology; Lymphocyte Activation/immunology; Melanoma/drug therapy; Mice; Mice, Nude; Mice, SCID; Molecular Targeted Therapy/*methods; Protein Tyrosine Phosphatases/*immunology; Recombinant Fusion Proteins/immunology/pharmacology/therapeutic use
      12. Abstract :
        Antibodies are considered as 'magic bullets' because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency' (scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22374986
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10497
      1. Author :
        Hamrahi, V.; Hamblin, M. R.; Jung, W.; Benjamin, J. B.; Paul, K. W.; Fischman, A. J.; Tompkins, R. G.; Carter, E. A.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Interdiscip Perspect Infect Dis
      6. Products :
      7. Volume :
        2012
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen44, Xen 44, Proteus mirabilis, bioluminescence imaging
      12. Abstract :
        Sepsis remains the major cause of death in patients with major burn injuries. In the present investigation we evaluated the interaction between burn injuries of varying severity and preexisting distant infection. We used Gram-negative bacteria (Pseudomonas aeruginosa and Proteus mirabilis) that were genetically engineered to be bioluminescent, which allowed for noninvasive, sequential optical imaging of the extent and severity of the infection. The bioluminescent bacteria migrated from subcutaneous abscesses in the leg to distant burn wounds on the back depending on the severity of the burn injury, and this migration led to increased mortality of the mice. Treatment with ciprofloxacin, injected either in the leg with the bacterial infection or into the burn eschar, prevented this colonization of the wound and decreased mortality. The present data suggest that burn wounds can readily become colonized by infections distant from the wound itself.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22899912
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10562
      1. Author :
        Hanai, J.; Doro, N.; Sasaki, A. T.; Kobayashi, S.; Cantley, L. C.; Seth, P.; Sukhatme, V. P.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Cell Physiol
      6. Products :
      7. Volume :
        227
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        A549-luc-C8, A549-luc, IVIS, Bioware, ATP Citrate (pro-S)-Lyase/*antagonists & inhibitors/genetics; Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Epithelial-Mesenchymal Transition; Female; Gene Knockdown Techniques; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use; Lung Neoplasms/*drug therapy/enzymology/pathology/*therapy; MAP Kinase Signaling System/drug effects; Mice; Mutation; Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Proto-Oncogene Proteins c-akt/antagonists & inhibitors; Receptor, Epidermal Growth Factor/genetics; Signal Transduction/drug effects; Xenograft Model Antitumor Assays
      12. Abstract :
        ATP citrate lyase (ACL) catalyzes the conversion of cytosolic citrate to acetyl-CoA and oxaloacetate. A definitive role for ACL in tumorigenesis has emerged from ACL RNAi and chemical inhibitor studies, showing that ACL inhibition limits tumor cell proliferation and survival and induces differentiation in vitro. In vivo, it reduces tumor growth leading to a cytostatic effect and induces differentiation. However, the underlying molecular mechanisms are poorly understood and agents that could enhance the efficacy of ACL inhibition have not been identified. Our studies focus on non-small cell lung cancer (NSCLC) lines, which show phosphatidylinositol 3-kinase (PI3K)/AKT activation secondary to a mutation in the K-Ras gene or the EGFR gene. Here we show that ACL knockdown promotes apoptosis and differentiation, leading to the inhibition of tumor growth in vivo. Moreover, in contrast to most studies, which elucidate how activation/suppression of signaling pathways can modify metabolism, we show that inhibition of a metabolic pathway “reverse signals” and attenuates PI3K/AKT signaling. Additionally, we find that statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which act downstream of ACL in the cholesterol synthesis pathway, dramatically enhance the anti-tumor effects of ACL inhibition, even regressing established tumors. With statin treatment, both PI3K/AKT and the MAPK pathways are affected. Moreover, this combined treatment is able to reduce the growth of EGF receptor resistant tumor cell types. Given the essential role of lipid synthesis in numerous cancers, this work may impact therapy in a broad range of tumors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21688263
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10523
      1. Author :
        Hanai, Koji; Takeshita, Fumitaka; Honma, Kimi; Nagahara, Shunji; Maeda, Miho; Minakuchi, Yoshiko; Sano, Akihiko; Ochiya, Takahiro
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Annals of the New York Academy of Sciences
      6. Products :
      7. Volume :
        1082
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Bone Neoplasms; Collagen; Dermatitis; Disease Models, Animal; Drug Carriers; Gene Therapy; Humans; Hypersensitivity; Mice; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Oligonucleotides; PC-3M-luc; RNA, Small Interfering; Tissue Distribution
      12. Abstract :
        The goal of our research is to provide a practical platform for drug delivery in oligonucleotide therapy. We report here the efficacy of an atelocollagen-mediated oligonucleotide delivery system applied to systemic siRNA and antisense oligonucleotide treatments in animal disease models. Atelocollagen and oligonucleotides formed a complex of nanosized particles, which was highly stable against nucleases. The complex allowed oligonucleotides to be delivered efficiently into several organs and tissues via intravenous administration. In a tumor metastasis model, the complex successfully delivered siRNA to metastasized tumors in bone tissue and inhibited their growth. We also demonstrated that a single intravenous treatment of the antisense oligodeoxynucleotide complex suppressed ear dermatitis in a contact hypersensitivity model. These results indicate the strong potential of the atelocollagen-mediated drug delivery system for practical therapeutic technology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17145919
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8976
      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 :
        Hardy, Jonathan; Chu, Pauline; Contag, Christopher H
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Disease models & mechanisms
      6. Products :
      7. Volume :
        2
      8. Issue :
        1-2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Female; Host-Pathogen Interactions; Humans; Knee Joint; Listeria monocytogenes; Listeriosis; Mice; Mice, Inbred BALB C; Mutation; pXen-5; Tibia
      12. Abstract :
        Murine listeriosis is one of the most comprehensive and well-studied models of infection, and Listeria monocytogenes has provided seminal information regarding bacterial pathogenesis. However, many aspects of the mouse model remain poorly understood, including carrier states and chronic colonization which represent important features of the spectrum of host-pathogen interaction. Bone marrow has recently been shown to harbor L. monocytogenes, which spreads from this location to the central nervous system. Bone could, therefore, be an important chronic reservoir, but this infection is difficult to study because it involves only a few bacteria and the extent of infection cannot be assessed until after the animal is sacrificed. We employed in vivo bioluminescence imaging to localize L. monocytogenes bone infections over time in live mice, revealing that the bacteria grow in discrete foci. These lesions can persist in many locations in the legs of mice and are not accompanied by a histological indication such as granuloma or a neutrophil infiltratate. We demonstrate that highly attenuated hly mutants, which have defective intracellular replication, are capable of prolonged focal infection of the bone marrow for periods of up to several weeks. These results support the recently proposed hypothesis that the bone marrow is a unique niche for L. monocytogenes.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19132117
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9018
      1. Author :
        Hardy, Jonathan; Margolis, Jeffrey J; Contag, Christopher H
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        74
      8. Issue :
        3
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bacterial Toxins; Biliary Tract; Bioware; Feces; Food Contamination; Intestines; Listeria monocytogenes; Listeriosis; Mice; Mice, Inbred BALB C; pXen-5
      12. Abstract :
        Listeria monocytogenes is a ubiquitous gram-positive bacterium that can cause systemic and often life-threatening disease in immunocompromised hosts. This organism is largely an intracellular pathogen; however, we have determined that it can also grow extracellularly in animals, in the lumen of the gallbladder. The significance of growth in the gallbladder with respect to the pathogenesis and spread of listeriosis depends on the ability of the bacterium to leave this organ and be disseminated to other tissues and into the environment. Should this process be highly inefficient, growth in the gallbladder would have no impact on pathogenesis or spread, but if it occurs efficiently, bacterial growth in this organ may contribute to listeriosis and dissemination of this organism. Here, we use whole-body imaging to determine the efficacy and kinetics of food- and hormone-induced biliary excretion of L. monocytogenes from the murine gallbladder, demonstrating that transit through the bile duct into the intestine can occur within 5 min of induction of gallbladder contraction by food or cholecystokinin and that movement of bacteria through the intestinal lumen can occur very rapidly in the absence of fecal material. These studies demonstrate that L. monocytogenes bacteria replicating in the gallbladder can be expelled from the organ efficiently and that the released bacteria move into the intestinal tract, where they pass into the environment and may possibly reinfect the animal.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16495556
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9024
      1. Author :
        Harms, Jerome S; Durward, Marina A; Magnani, Diogo M; Splitter, Gary A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Journal of immune based therapies and vaccines
      6. Products :
      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Bioware; pXen-13
      12. Abstract :
        BACKGROUND There is no safe, effective human vaccine against brucellosis. Live attenuated Brucella strains are widely used to vaccinate animals. However these live Brucella vaccines can cause disease and are unsafe for humans. Killed Brucella or subunit vaccines are not effective in eliciting long term protection. In this study, we evaluate an approach using a live, non-pathogenic bacteria (E. coli) genetically engineered to mimic the brucellae pathway of infection and present antigens for an appropriate cytolitic T cell response. METHODS E. coli was modified to express invasin of Yersinia and listerialysin O (LLO) of Listeria to impart the necessary infectivity and antigen releasing traits of the intracellular pathogen, Brucella. This modified E. coli was considered our vaccine delivery system and was engineered to express Green Fluorescent Protein (GFP) or Brucella antigens for in vitro and in vivo immunological studies including cytokine profiling and cytotoxicity assays. RESULTS The E. coli vaccine vector was able to infect all cells tested and efficiently deliver therapeutics to the host cell. Using GFP as antigen, we demonstrate that the E. coli vaccine vector elicits a Th1 cytokine profile in both primary and secondary immune responses. Additionally, using this vector to deliver a Brucella antigen, we demonstrate the ability of the E. coli vaccine vector to induce specific Cytotoxic T Lymphocytes (CTLs). CONCLUSION Protection against most intracellular bacterial pathogens can be obtained mostly through cell mediated immunity. Data presented here suggest modified E. coli can be used as a vaccine vector for delivery of antigens and therapeutics mimicking the infection of the pathogen and inducing cell mediated immunity to that pathogen.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19126207
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9029
      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
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