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      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 :
        Shan, Liang; Wang, Songping; Korotcov, Alexandru; Sridhar, Rajagopalan; Wang, Paul C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Ethnicity & disease
      6. Products :
      7. Volume :
        18
      8. Issue :
        2 Suppl 2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Breast Neoplasms; Disease Models, Animal; Humans; Luciferases; Luminescent Measurements; Lung Neoplasms; Mammary Neoplasms, Animal; MDA-MB-231-D3H1 cells; Mice; Mice, Nude; Tumor Cells, Cultured
      12. Abstract :
        INTRODUCTION Convenient animal models are needed to study the progression and treatment of human tumors in vivo. Luciferase-based bioluminescent imaging (BLI) enables researchers to monitor tumors noninvasively and is sensitive to subtle changes in tumors. METHODS Three human breast cancer models in nude mice were established by using luciferase-expressing MDA-MB-231-luc cells. They were subcutaneous xenografts (n = 8), mammary gland xenografts (n = 5), and lung metastases (n = 3). The tumors were imaged in live mice by using a highly sensitive BLI system. The relationship between the intensity of bioluminescence from the tumor was analyzed with respect to tumor volume. Bioluminescent signals from lung metastases were studied to determine the threshold of detectability. RESULTS Tumors growing in the mice's backs and mammary gland fat pads were imaged dynamically after administration of D-luciferin. The bioluminescent intensity from the tumors gradually increased and then decreased in a one-hour span. The time to reach maximum signal intensity differed significantly among tumors and was independent of tumor volume and unrelated to maximum signal intensity. A significant correlation was observed between tumor volume and maximum signal intensity in tumors from both sites. Lung metastatic lesions of .3-.5 mm in diameter were clearly detectable through the entire animal imaging process. CONCLUSION The animal models established with luciferase-expressing cancer cells in combination with BLI provide a system for rapid, noninvasive, and quantitative analysis of tumor biomass and metastasis. This biosystem simplifies in vivo monitoring of tumors and will be useful for noninvasive investigation of tumor growth and response to therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18646323
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8991
      1. Author :
        Shan, Liang; Wang, Songping; Sridhar, Rajagopalan; Bhujwalla, Zaver M; Wang, Paul C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Molecular imaging
      6. Products :
      7. Volume :
        6
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Breast Neoplasms; Cell Line, Tumor; Fluorescence; Fluorescent Dyes; Humans; Liposomes; Magnetic Resonance Imaging; Magnetics; MDA-MB-231-D3H1 cells; Mice; Mice, Inbred Strains; Microscopy, Confocal; Molecular Probes; Optics and Photonics; Transferrin; Xenograft Model Antitumor Assays
      12. Abstract :
        A dual probe with fluorescent and magnetic reporter groups was constructed by linkage of the near-infrared (NIR) fluorescent transferrin conjugate (Tf(NIR)) on the surface of contrast agent-encapsulated cationic liposome (Lip-CA). This probe was used for magnetic resonance imaging (MRI) and optical imaging of MDA-MB-231-luc breast cancer cells grown as a monolayer in vitro and as solid tumor xenografts in nude mice. Confocal microscopy, optical imaging, and MRI showed a dramatic increase of in vitro cellular uptake of the fluorescent and magnetic reporter groups from the probe compared with the uptake of contrast agent or Lip-CA alone. Pretreatment with transferrin (Tf) blocked uptake of the probe reporters, indicating the importance and specificity of the Tf moiety for targeting. Intravenous administration of the dual probe to nude mice significantly enhanced the tumor contrast in MRI, and preferential accumulation of the fluorescent signal was clearly seen in NIR-based optical images. More interestingly, the contrast enhancement in MRI showed a heterogeneous pattern within tumors, which reflected the tumor's morphologic heterogeneity. These results indicate that the newly developed dual probe enhances the tumor image contrast and is superior to contrast agent alone for identifying the tumor pathologic features on the basis of MRI but also is suitable for NIR-based optical imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17445503
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8992
      1. Author :
        Sharma, P. K.; Engels, E.; Van Oeveren, W.; Ploeg, R. J.; van Henny der Mei, C.; Busscher, H. J.; Van Dam, G. M.; Rakhorst, G.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Surgery
      6. Products :
      7. Volume :
        147
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen14, Xen 14, E. coli Xen14, IVIS, Animals; Bacteroides fragilis/*isolation & purification; Diagnostic Imaging/methods; Disease Progression; Escherichia coli/*isolation & purification; Luciferases, Bacterial/*diagnostic use; Luminescent Agents/*diagnostic use; Male; Peritoneal Lavage; Peritonitis/*microbiology/pathology/therapy; Rats; Rats, Wistar
      12. Abstract :
        BACKGROUND: Bacterial peritonitis is a life-threatening abdominal infection associated with high morbidity and mortality. The rat is a popular animal model for studying peritonitis and its treatment, but longitudinal monitoring of the progression of peritonitis in live animals has been impossible until now and thus required a large number of animals. Our objective was to develop a noninvasive in vivo imaging technique to monitor the spatiotemporal spread of bacterial peritonitis. METHODS: Peritonitis was induced in 8 immunocompetent male Wistar rats by placing fibrin clots containing 5x10(8) cells of both Bacteroides fragilis (American Type Tissue Culture [ATCC)] 25,285 and bioluminescent Escherichia coli Xen14. After 1 or 2 days, infected clots were removed and open abdomen lavage was performed. In vivo bioluminescent imaging was used to monitor the spread of peritonitis. RESULTS: Bioluminescent in vivo imaging showed an increase in the area of spread, and the number of E. coli tripled into the rat's abdominal cavity on day 1 after clot insertion; however, on day 2, encapsulation of the clot confined bacterial spread. Bioluminescent E. coli respread over the peritoneal cavity after lavage; within 10 days, however, in vivo imaging showed a decrease of 3-4 orders of magnitude in bacterial load. CONCLUSION: Bioluminescent in vivo imaging can be effectively used to monitor the spatiotemporal behavior of the peritonitis during 3 different stages of the disease process: initiation, treatment, and follow-up. Imaging allows researchers to repeatedly image the same animal, thereby reducing variability and providing greater confidence in determining treatment efficacies for therapeutic interventions using a small number of animals.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19733882
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10396
      1. Author :
        Sharma, Prashant K; Engels, Eefje; Van Oeveren, Wim; Ploeg, Rutger J; van Henny der Mei, C; Busscher, Henk J; Van Dam, Gooitzen M; Rakhorst, Gerhard
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Surgery
      6. Products :
      7. Volume :
        147
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bacteroides fragilis; Diagnostic Imaging; Disease Progression; Escherichia coli; Luciferases, Bacterial; Luminescent Agents; Male; Peritoneal Lavage; Peritonitis; Rats; Rats, Wistar; Xen14
      12. Abstract :
        BACKGROUND Bacterial peritonitis is a life-threatening abdominal infection associated with high morbidity and mortality. The rat is a popular animal model for studying peritonitis and its treatment, but longitudinal monitoring of the progression of peritonitis in live animals has been impossible until now and thus required a large number of animals. Our objective was to develop a noninvasive in vivo imaging technique to monitor the spatiotemporal spread of bacterial peritonitis. METHODS Peritonitis was induced in 8 immunocompetent male Wistar rats by placing fibrin clots containing 5x10(8) cells of both Bacteroides fragilis (American Type Tissue Culture [ATCC)] 25,285 and bioluminescent Escherichia coli Xen14. After 1 or 2 days, infected clots were removed and open abdomen lavage was performed. In vivo bioluminescent imaging was used to monitor the spread of peritonitis. RESULTS Bioluminescent in vivo imaging showed an increase in the area of spread, and the number of E. coli tripled into the rat's abdominal cavity on day 1 after clot insertion; however, on day 2, encapsulation of the clot confined bacterial spread. Bioluminescent E. coli respread over the peritoneal cavity after lavage; within 10 days, however, in vivo imaging showed a decrease of 3-4 orders of magnitude in bacterial load. CONCLUSION Bioluminescent in vivo imaging can be effectively used to monitor the spatiotemporal behavior of the peritonitis during 3 different stages of the disease process: initiation, treatment, and follow-up. Imaging allows researchers to repeatedly image the same animal, thereby reducing variability and providing greater confidence in determining treatment efficacies for therapeutic interventions using a small number of animals.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19733882
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        10005
      1. Author :
        Sharma, Praveen K; Singh, Rajesh; Novakovic, Kristian R; Eaton, John W; Grizzle, William E; Singh, Shailesh
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        International journal of cancer. Journal international du cancer
      6. Products :
      7. Volume :
        127
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents; Apoptosis; Bioware; Caspase 3; Cell Line, Tumor; Chemokines, CC; Disease Progression; Enzyme Activation; Etoposide; Humans; Male; Mice; Mice, Nude; PC-3M-luc; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptors, CCR; Signal Transduction
      12. Abstract :
        Despite recent advances in treatment and management of prostate cancer (PCa), it remains the second leading cause of cancer-related deaths among men in the US. Chemotherapy is one of the treatment alternatives for hormone refractory metastatic PCa. However, current chemotherapeutic regimens provide palliative benefit but relatively modest survival advantage primarily due to chemo-resistance and upregulated antiapoptotic machineries in PCa cells. Therefore, blocking the mechanisms responsible for suppression of apoptosis might improve current chemotherapeutic regimens. In this study, we show that CC chemokine receptor-9 (CCR9) and its natural ligand CCL25 interaction upregulates antiapoptotic proteins (i.e., PI3K, AKT, ERK1/2 and GSK-3beta) and downregulate activation of caspase-3 in PCa cells. Significant downregulation of these CCR9-mediated antiapoptotic proteins in the presence of a PI3K inhibitor (wortmannin), further suggests that the antiapoptotic action of CCR9 is primarily regulated through PI3K. Furthermore, the cytotoxic effect of etoposide was significantly inhibited in the presence of CCL25, and this inhibitory effect of CCL25 was abrogated when CCR9-CCL25 interaction was blocked using anti-CCR9 monoclonal antibodies. In conformation to these in vitro studies, significant reduction in tumor burden was found in mice receiving CCL25 neutralizing antibodies and etoposide together as compared to both as a single agent. These results suggest that the CCR9-CCL25 axis mediates PI3K/AKT-dependent antiapoptotic signals in PCa cells and could be a possible reason for low apoptosis and modest chemotherapeutic response. Therefore, targeting CCR9-CCL25 axis with cytotoxic agents may provide better therapeutic outcomes than using cytotoxic agents alone.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20127861
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8945
      1. Author :
        Shi, Lei; Takahashi, Kazue; Dundee, Joseph; Shahroor-Karni, Sarit; Thiel, Steffen; Jensenius, Jens Christian; Gad, Faten; Hamblin, Michael R; Sastry, Kedarnath N; Ezekowitz, R Alan B
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        The Journal of experimental medicine
      6. Products :
      7. Volume :
        199
      8. Issue :
        10
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Disease Susceptibility; DNA, Bacterial; Lung; Mannose-Binding Lectin; Mice; Mice, Knockout; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Spleen; Staphylococcal Infections; Xen8.1
      12. Abstract :
        Gram-positive organisms like Staphylococcus aureus are a major cause of morbidity and mortality worldwide. Humoral response molecules together with phagocytes play a role in host responses to S. aureus. The mannose-binding lectin (MBL, also known as mannose-binding protein) is an oligomeric serum molecule that recognizes carbohydrates decorating a broad range of infectious agents including S. aureus. Circumstantial evidence in vitro and in vivo suggests that MBL plays a key role in first line host defense. We tested this contention directly in vivo by generating mice that were devoid of all MBL activity. We found that 100% of MBL-null mice died 48 h after exposure to an intravenous inoculation of S. aureus compared with 45% mortality in wild-type mice. Furthermore, we demonstrated that neutrophils and MBL are required to limit intraperitoneal infection with S. aureus. Our study provides direct evidence that MBL plays a key role in restricting the complications associated with S. aureus infection in mice and raises the idea that the MBL gene may act as a disease susceptibility gene against staphylococci infections in humans.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15148336
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9994
      1. Author :
        Shimomura, Toshiyasu; Hasako, Shinichi; Nakatsuru, Yoko; Mita, Takashi; Ichikawa, Koji; Kodera, Tsutomu; Sakai, Takumi; Nambu, Tadahiro; Miyamoto, Mayu; Takahashi, Ikuko; Miki, Satomi; Kawanishi, Nobuhiko; Ohkubo, Mitsuru; Kotani, Hidehito; Iwasawa, Yoshikazu
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Molecular cancer therapeutics
      6. Products :
      7. Volume :
        9
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bioware; Cell Death; Cell Line, Tumor; Cell Proliferation; Cyclohexanecarboxylic Acids; HeLa-luc; Humans; Inhibitory Concentration 50; Mice; Mitosis; Protein kinase inhibitors; Protein-Serine-Threonine Kinases; Rats; Taxoids; Thiazoles; Xenograft Model Antitumor Assays
      12. Abstract :
        Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G(2)-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone-treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20053775
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9006
      1. Author :
        Shiota, M.; Zardan, A.; Takeuchi, A.; Kumano, M.; Beraldi, E.; Naito, S.; Zoubeidi, A.; Gleave, M. E.
      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 :
        PC-3M-luc-C6, PC-3M-luc, IVIS, Bioware, Prostate cancer, Bioluminescence, Animals; Base Sequence; Blotting, Western; Chromatin Immunoprecipitation; Clusterin/genetics/*physiology; DNA Primers; Epithelial-Mesenchymal Transition/*physiology; Humans; Male; Mice; *Neoplasm Metastasis; Nuclear Proteins/*physiology; Promoter Regions, Genetic; Prostatic Neoplasms/*pathology; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta/*physiology; Twist Transcription Factor/*physiology
      12. Abstract :
        TGF-beta promotes epithelial-mesenchymal transition (EMT) and induces clusterin (CLU) expression, linking these genes to cancer metastasis. CLU is a pleiotropic molecular chaperone that confers survival and proliferative advantage to cancer cells. However, the molecular mechanisms by which TGF-beta regulates CLU expression and CLU affects metastasis remain unknown. In this study, we report that the transcription factor Twist1 mediates TGF-beta-induced CLU expression. By binding to E-boxes in the distal promoter region of CLU gene, Twist1 regulated basal and TGF-beta-induced CLU transcription. In addition, CLU reduction reduced TGF-beta induction of the mesenchymal markers, N-cadherin and fibronectin, thereby inhibiting the migratory and invasive properties induced by TGF-beta. Targeted inhibition of CLU also suppressed metastasis in an in vivo model. Taken together, our findings indicate that CLU is an important mediator of TGF-beta-induced EMT, and suggest that CLU suppression may represent a promising therapeutic option for suppressing prostate cancer metastatic progression.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22896337
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10540
      1. Author :
        Singh, Abhinav; Massoud, Tarik F; Deroose, Christophe; Gambhir, Sanjiv S
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Seminars in nuclear medicine
      6. Products :
      7. Volume :
        38
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Bioware; Diagnostic Imaging; Genes, Reporter; Humans; Male; Molecular Probe Techniques; Neoplasm Proteins; PC-3M-luc; Prostatic Neoplasms; Tumor Markers, Biological
      12. Abstract :
        Prostate cancer remains an important and growing health problem. Advances in imaging of prostate cancer may help to achieve earlier and more accurate diagnosis and treatment. We review the various strategies using reporter genes for molecular imaging of prostate cancer. These approaches are emerging as valuable tools for monitoring gene expression in laboratory animals and humans. Further development of more sensitive and selective reporters, combined with improvements in detection technology, will consolidate the position of reporter gene imaging as a versatile method for understanding of intracellular biological processes and the underlying molecular basis of prostate cancer, as well as potentially establishing a future role in the clinical management of patients afflicted with this disease.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18096460
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8966
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