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      1. Author :
        Fogal, Valentina; Richardson, Adam D; Karmali, Priya P; Scheffler, Immo E; Smith, Jeffrey W; Ruoslahti, Erkki
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Molecular and cellular biology
      6. Products :
      7. Volume :
        30
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Carbon; Carrier Proteins; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Electron Transport Complex I; Gene Knockdown Techniques; Humans; Mass Spectrometry; MDA-MB-231-D3H2LN cells; Mice; Mitochondria; Mitochondrial Proteins; Neoplasm Metastasis; Neoplasms; Oxidative Phosphorylation; Protein Biosynthesis; Protein Stability; Rotenone
      12. Abstract :
        p32/gC1qR/C1QBP/HABP1 is a mitochondrial/cell surface protein overexpressed in certain cancer cells. Here we show that knocking down p32 expression in human cancer cells strongly shifts their metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. The p32 knockdown cells exhibited reduced synthesis of the mitochondrial-DNA-encoded OXPHOS polypeptides and were less tumorigenic in vivo. Expression of exogenous p32 in the knockdown cells restored the wild-type cellular phenotype and tumorigenicity. Increased glucose consumption and lactate production, known as the Warburg effect, are almost universal hallmarks of solid tumors and are thought to favor tumor growth. However, here we show that a protein regularly overexpressed in some cancers is capable of promoting OXPHOS. Our results indicate that high levels of glycolysis, in the absence of adequate OXPHOS, may not be as beneficial for tumor growth as generally thought and suggest that tumor cells use p32 to regulate the balance between OXPHOS and glycolysis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20100866
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8952
      1. Author :
        Hickson, J; Ackler, S; Klaubert, D; Bouska, J; Ellis, P; Foster, K; Oleksijew, A; Rodriguez, L; Schlessinger, S; Wang, B; Frost, D
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cell death and differentiation
      6. Products :
      7. Volume :
        17
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents; Apoptosis; Bioware; Caspase 3; Cell Line, Tumor; Female; Firefly Luciferin; Humans; Luminescent Agents; MDA-MB-231-D3H2LN cells; Mice; Mice, SCID; SKOV3-luc-D3 cells; Molecular Imaging; Neoplasms; Oligopeptides; Taxoids
      12. Abstract :
        Apoptosis is a highly regulated process of programmed cell death essential for normal physiology. Dysregulation of apoptosis contributes to the development and progression of various diseases, including cancer, neurodegenerative disorders, and chronic heart failure. Quantitative noninvasive imaging of apoptosis in preclinical models would allow for dynamic longitudinal screening of compounds and facilitates a more rapid determination of therapeutic efficacy. In this study, we report the in vivo characterization of Z-DEVD-aminoluciferin, a modified firefly luciferase substrate that in apoptotic cells is cleaved by caspase-3 to liberate aminoluciferin, which can be consumed by luciferase to generate a luminescent signal. In two oncology models, namely SKOV3-luc and MDA-MB-231-luc-LN, at 24, 48, and 72 h after treatment with docetaxel, animals were injected with Z-DEVD-aminoluciferin and bioluminescent images were acquired. Significantly more light was detected at 24 (P<0.05), 48 (P<0.01), and 72 h (P<0.01) in the docetaxel-treated group compared with the vehicle-treated group, with caspase-3 activation at these time points confirmed using immunohistochemistry. Importantly, whereas significant differences between groups were detected as early as 24 h after treatment by molecular imaging, caliper measurements were unable to detect a difference for 4-5 additional days. Taken together, these data show that in vivo imaging of apoptosis using Z-DEVD-aminoluciferin could provide a sensitive and rapid method for early detection of drug efficacy, which could potentially be used by numerous therapeutic programs.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20057500
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8950
      1. Author :
        Quintela-Fandino, Miguel; Arpaia, Enrico; Brenner, Dirk; Goh, Theo; Yeung, Faith Au; Blaser, Heiko; Alexandrova, Roumiana; Lind, Evan F; Tusche, Mike W; Wakeham, Andrew; Ohashi, Pamela S; Mak, Tak W
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Proceedings of the National Academy of Sciences of the United States of America
      6. Products :
      7. Volume :
        107
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Actins; Animals; B16-F10-luc-G5; Bioware; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cofilin 1; Cytoskeleton; Female; Humans; Immunoblotting; Immunoprecipitation; Male; Mammary Neoplasms, Experimental; MDA-MB-231-D3H2LN cells; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Protein Binding; Protein Kinases; Protein Phosphatase 2; Protein-Serine-Threonine Kinases; RNA Interference; Transplantation, Heterologous
      12. Abstract :
        Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Up-regulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20133759
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8951
      1. Author :
        Hokaiwado, Naomi; Takeshita, Fumitaka; Naiki-Ito, Aya; Asamoto, Makoto; Ochiya, Takahiro; Shirai, Tomoyuki
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Carcinogenesis
      6. Products :
      7. Volume :
        29
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Androgens; Animals; Animals, Genetically Modified; Apoptosis; Bioware; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Glutathione S-Transferase pi; Humans; In Situ Nick-End Labeling; Male; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; PC-3M-luc; Prostatic Neoplasms; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering
      12. Abstract :
        Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the 'transgenic rat adenocarcinoma in prostate' (TRAP) model, to analyze their gene expression using microarrays. Among the overexpressed genes in androgen-independent prostate cancers compared with the androgen-dependent tumors, glutathione S-transferase pi (GST-pi) was included. In line with this, human prostate cancer cell lines PC3 and DU145 (androgen independent) had higher expression of GST-pi compared with LNCaP (androgen dependent) as determined by semiquantitative reverse transcription-polymerase chain reaction analysis. To investigate the roles of GST-pi expression in androgen-independent human prostate cancers, GST-pi was knocked down by a small interfering RNA (siRNA), resulting in significant decrease of the proliferation rate in the androgen-independent PC3 cell line. In vivo, administration of GST-pi siRNA-atelocollagen complex decreased GST-pi protein expression, resulting in enhanced numbers of TdT mediated dUTP-biotin nick-end labering (TUNEL)-positive apoptotic cells. These findings suggest that GST-pi might play important roles in proliferation of androgen-independent human prostate cancer cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18413363
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8967
      1. Author :
        Marttila-Ichihara, Fumiko; Castermans, Karolien; Auvinen, Kaisa; Oude Egbrink, Mirjam G A; Jalkanen, Sirpa; Griffioen, Arjan W; Salmi, Marko
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        184
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Adjuvants, Immunologic; Allylamine; Amine Oxidase (Copper-Containing); Animals; Antibodies, Blocking; Antibodies, Monoclonal; B16-F10-luc-G5 cells; Bioware; Cell Adhesion Molecules; Cell Line, Tumor; Cell Migration Inhibition; Enzyme Inhibitors; Female; Growth Inhibitors; Lymphoma, T-Cell; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Myeloid Cells; Semicarbazides
      12. Abstract :
        Vascular adhesion protein-1 (VAP-1) is an endothelial, cell surface-expressed oxidase involved in leukocyte traffic. The adhesive function of VAP-1 can be blocked by anti-VAP-1 Abs and small-molecule inhibitors. However, the effects of VAP-1 blockade on antitumor immunity and tumor progression are unknown. In this paper, we used anti-VAP-1 mAbs and small-molecule inhibitors of VAP-1 in B16 melanoma and EL-4 lymphoma tumor models in C57BL/6 mice. Leukocyte accumulation into tumors and neoangiogenesis were evaluated by immunohistochemistry, flow cytometry, and intravital videomicroscopy. We found that both anti-VAP-1 Abs and VAP-1 inhibitors reduced the number of leukocytes in the tumors, but they targeted partially different leukocyte subpopulations. Anti-VAP-1 Abs selectively inhibited infiltration of CD8-positive lymphocytes into tumors and had no effect on accumulation of myeloid cells into tumors. In contrast, the VAP-1 inhibitors significantly reduced only the number of proangiogenic Gr-1(+)CD11b(+) myeloid cells in melanomas and lymphomas. Blocking of VAP-1 by either means left tumor homing of regulatory T cells and type 2 immune-suppressing monocytes/macrophages intact. Notably, VAP-1 inhibitors, but not anti-VAP-1 Abs, retarded the growth of melanomas and lymphomas and reduced tumor neoangiogenesis. The VAP-1 inhibitors also reduced the binding of Gr-1(+) myeloid cells to the tumor vasculature. We conclude that tumors use the catalytic activity of VAP-1 to recruit myeloid cells into tumors and to support tumor progression. Small-molecule VAP-1 inhibitors therefore might be a potential new tool for immunotherapy of tumors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20154208
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8996
      1. Author :
        Peter, Christoph; Kielstein, Jan T; Clarke-Katzenberg, Regina; Adams, M Christopher; Pitsiouni, Maria; Kambham, Neeraja; Karimi, Mobin A; Kengatharan, Ken M; Cooke, John P
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        The Journal of urology
      6. Products :
      7. Volume :
        177
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; carcinoma, renal cell; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Firefly Luciferin; HT-29-luc-D6 cells; Humans; Kidney Neoplasms; Luminescence; Luminescent Agents; Male; Mice; Mice, SCID; Models, Biological; Tumor Burden
      12. Abstract :
        PURPOSE Bioluminescent imaging permits sensitive in vivo detection and quantification of cells engineered to emit light. We developed a bioluminescent human renal cancer cell line for in vitro and in vivo studies. MATERIAL AND METHODS The 2 human renal cell carcinoma cell lines SN12-C and SN12-L1 were stably transfected to constitutively express luciferase using a retroviral shuttle. The bioluminescent signal was correlated with tumor cell numbers in vitro. Parental and transfected cells were compared by growth kinetics and histology. Tumor burden after heterotopic injection in immune deficient mice was monitored up to 39 days. The kinetics of the bioluminescent signal was evaluated for 1 to 60 minutes following luciferin injection. RESULTS Bioengineered renal cancer cell lines stably expressed luciferase. The growth kinetics of the cells in vitro and the histology of tumors resulting from implantation of these cells were unaffected by retroviral transfection with the luciferase gene. As few as 1,000 cells could be reliably detected. The intensity of the bioluminescent signal correlated with the number of tumor cells in vitro. Photon emission in vivo and ex vivo correlated significantly with tumor weight at sacrifice. After intraperitoneal injection of luciferin there was a time dependent change in the intensity of the bioluminescent signal with maximum photon emission at 20 minutes (optimal 17 to 25). CONCLUSIONS Luciferase transfected human renal cancer lines allow reliable, rapid, noninvasive and longitudinal monitoring of tumor growth in vivo. The ability to assess tumor development in vivo with time is economical and effective compared to end point data experiments.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17509355
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9009
      1. Author :
        Engelsman, Anton F; Krom, Bastiaan P; Busscher, Henk J; van Dam, Gooitzen M; Ploeg, Rutger J; van der Mei, Henny C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Acta biomaterialia
      6. Products :
      7. Volume :
        5
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bioware; Connective Tissue; Diffusion; Drug Implants; Female; Mice; Mice, Inbred BALB C; Nitric Oxide; Polyvinyls; Prostheses and Implants; pXen-5; Staphylococcal Infections; Xen29
      12. Abstract :
        Infection of surgical meshes used in abdominal wall reconstructions often leads to removal of the implant and increases patient morbidity due to repetitive operations and hospital administrations. Treatment with antibiotics is ineffective due to the biofilm mode of growth of the infecting bacteria and bears the risk of inducing antibiotic resistance. Hence there is a need for alternative methods to prevent and treat mesh infection. Nitric oxide (NO)-releasing coatings have been demonstrated to possess bactericidal properties in vitro. It is the aim of this study to assess possible benefits of a low concentration NO-releasing carbon-based coating on monofilament polypropylene meshes with respect to infection control in vitro and in vivo. When applied on surgical meshes, NO-releasing coatings showed significant bactericidal effect on in vitro biofilms of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and CNS. However, using bioluminescent in vivo imaging, no beneficial effects of this NO-releasing coating on subcutaneously implanted surgical meshes in mice could be observed.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19251498
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9019
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        PLoS pathogens
      6. Products :
      7. Volume :
        3
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anthrax; Bacillus anthracis; Bioware; Disease Models, Animal; Gastrointestinal Diseases; Inhalation Exposure; Luciferases; Luminescence; Luminescent Measurements; Lymph Nodes; Mice; Mice, Inbred BALB C; Nasal Cavity; Organisms, Genetically Modified; Peyer's Patches; Pharynx; pXen-5; Skin; Spores, Bacterial
      12. Abstract :
        Bacillus anthracis causes three forms of anthrax: inhalational, gastrointestinal, and cutaneous. Anthrax is characterized by both toxemia, which is caused by secretion of immunomodulating toxins (lethal toxin and edema toxin), and septicemia, which is associated with bacterial encapsulation. Here we report that, contrary to the current view of B. anthracis pathogenesis, B. anthracis spores germinate and establish infections at the initial site of inoculation in both inhalational and cutaneous infections without needing to be transported to draining lymph nodes, and that inhaled spores establish initial infection in nasal-associated lymphoid tissues. Furthermore, we found that Peyer's patches in the mouse intestine are the primary site of bacterial growth after intragastric inoculation, thus establishing an animal model of gastrointestinal anthrax. All routes of infection progressed to the draining lymph nodes, spleen, lungs, and ultimately the blood. These discoveries were made possible through the development of a novel dynamic mouse model of B. anthracis infection using bioluminescent non-toxinogenic capsulated bacteria that can be visualized within the mouse in real-time, and demonstrate the value of in vivo imaging in the analysis of B. anthracis infection. Our data imply that previously unrecognized portals of bacterial entry demand more intensive investigation, and will significantly transform the current perception of inhalational, gastrointestinal, and cutaneous B. anthracis pathogenesis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17542645
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9022
      1. Author :
        Gillrie, Mark R; Zbytnuik, Lori; McAvoy, Erin; Kapadia, Roxna; Lee, Kristine; Waterhouse, Christopher C M; Davis, Shevaun P; Muruve, Daniel A; Kubes, Paul; Ho, May
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        European journal of immunology
      6. Products :
      7. Volume :
        40
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Chemotaxis, Leukocyte; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Humans; Interferon-gamma; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Staphylococcal Infections; Staphylococcus aureus; Teichoic Acids; Toll-Like Receptor 2; Transplantation Chimera; Xen29
      12. Abstract :
        The response of leukocytes to lipoteichoic acid (LTA), a TLR2-dependent major cell wall component of Staphylococcus aureus, is linked to the outcome of an infection. In this study we investigated the role of nonhematopoietic TLR2 in response to LTA and S. aureus by creating bone marrow chimeras. Significant leukocyte recruitment in response to LTA required IFN-gamma priming in WT C57BL/6 and TLR2(-/-)-->WT mice, but was not observed in TLR2(-/-) or WT-->TLR2(-/-) animals. LTA also induced a proinflammatory response in IFN-gamma primed primary human microvascular endothelial cells leading to leukocyte recruitment in vitro. When mice were infected with S. aureus, the most profound elevation of TNF-alpha and IL-6 was seen in TLR2(-/-) and TLR2(-/-)-->WT mice. TLR2(-/-), but not chimeric mice, demonstrated increased IL-17, blood leukocytosis and pulmonary neutrophilia compared to WT mice. Collectively, the results suggest an essential role for IFN-gamma and nonhematopoietic TLR2 for leukocyte recruitment in response to LTA. In contrast, TLR2 on both hematopoietic and nonhematopoietic cells appears to orchestrate an inhibitory response to S. aureus such that in complete TLR2 deficiency, there is an exaggerated proinflammatory response and/or skewing of the immune response towards a Th17 phenotype that may contribute to the decreased survival of TLR2(-/-) mice.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20306471
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9036
      1. Author :
        Kadurugamuwa, Jagath L; Sin, Lin V; Yu, Jun; Francis, Kevin P; Purchio, Tony F; Contag, Pamela R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        Antimicrobial agents and chemotherapy
      6. Products :
      7. Volume :
        48
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antibiotics, Antitubercular; Biofilms; Bioware; Colony Count, Microbial; Diagnostic Imaging; DNA-Directed RNA Polymerases; Luminescent Measurements; Mice; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Xen29
      12. Abstract :
        Eradication of Staphylococcus aureus biofilms after rifampin treatment was tested in a mouse model of device-related infection by using biophotonic imaging. Following treatment, the bioluminescent signals decreased to undetectable levels, irrespective of the age of the biofilm. After the final treatment, the signals rebounded in a time-dependent manner and reached those for the untreated mice. Readministration of rifampin was unsuccessful in eradicating reestablished infections, with the rifampin MICs for such bacteria being increased and with the bacteria having point mutations in the rpoB gene.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15155235
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9056