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      1. Author :
        Beckers, Annelies; Organe, Sophie; Timmermans, Leen; Vanderhoydonc, Frank; Deboel, Ludo; Derua, Rita; Waelkens, Etienne; Brusselmans, Koen; Verhoeven, Guido; Swinnen, Johannes V
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Molecular cancer therapeutics
      6. Products :
      7. Volume :
        5
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Adenosine Triphosphate; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Bioware; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Line, Tumor; DNA, Neoplasm; Drug Synergism; Enzyme Activation; Humans; Lipids; Methotrexate; Multienzyme Complexes; Nucleotide Deaminases; PC-3M-luc; Phosphoribosylaminoimidazolecarboxamide Formyltransferase; Phosphoribosylglycinamide Formyltransferase; Protein-Serine-Threonine Kinases; Purines; Ribonucleosides; Ribonucleotides; RNA Interference
      12. Abstract :
        Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA riboside-induced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16985054
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8978
      1. Author :
        Beckers, Annelies; Organe, Sophie; Timmermans, Leen; Scheys, Katryn; Peeters, Annelies; Brusselmans, Koen; Verhoeven, Guido; Swinnen, Johannes V
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        67
      8. Issue :
        17
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Acetyl-CoA Carboxylase; Apoptosis; Autophagy; Bioware; Cell Death; Cell Proliferation; Drug Evaluation, Preclinical; Fatty Acids; Humans; Macrolides; Male; Neoplasms; Palmitic Acid; PC-3M-luc; Phospholipids; Prostatic Neoplasms; Tumor Cells, Cultured
      12. Abstract :
        Development and progression of cancer is accompanied by marked changes in the expression and activity of enzymes involved in the cellular homeostasis of fatty acids. One class of enzymes that play a particularly important role in this process are the acetyl-CoA carboxylases (ACC). ACCs produce malonyl-CoA, an intermediate metabolite that functions as substrate for fatty acid synthesis and as negative regulator of fatty acid oxidation. Here, using the potent ACC inhibitor soraphen A, a macrocyclic polyketide from myxobacteria, we show that ACC activity in cancer cells is essential for proliferation and survival. Even at nanomolar concentrations, soraphen A can block fatty acid synthesis and stimulate fatty acid oxidation in LNCaP and PC-3M prostate cancer cells. As a result, the phospholipid content of cancer cells decreased, and cells stopped proliferating and ultimately died. LNCaP cells predominantly died through apoptosis, whereas PC-3M cells showed signs of autophagy. Supplementation of the culture medium with exogenous palmitic acid completely abolished the effects of soraphen A and rescued the cells from cell death. Interestingly, when added to cultures of premalignant BPH-1 cells, soraphen A only slightly affected cell proliferation and did not induce cell death. Together, these findings indicate that cancer cells have become dependent on ACC activity to provide the cell with a sufficient supply of fatty acids to permit proliferation and survival, introducing the concept of using small-molecule ACC inhibitors as therapeutic agents for cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17804731
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8974
      1. Author :
        Beck, Benjamin H; Kim, Hyung-Gyoon; Kim, Hyunki; Samuel, Sharon; Liu, Zhiyong; Shrestha, Robin; Haines, Hilary; Zinn, Kurt; Lopez, Richard D
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Breast cancer research and treatment
      6. Products :
      7. Volume :
        122
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        4T1-luc2; Adenocarcinoma; Animals; Bioware; Breast Neoplasms; Cell Line, Tumor; Chemotaxis, Leukocyte; Cytotoxicity, Immunologic; Female; Humans; Immunotherapy, Adoptive; Indium Radioisotopes; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Transplantation; Radiopharmaceuticals; Receptors, Antigen, T-Cell, gamma-delta; Spleen; Tissue Distribution; T-Lymphocyte Subsets; Tomography, Emission-Computed, Single-Photon; Transplantation, Heterologous; Transplantation, Isogeneic
      12. Abstract :
        In contrast to antigen-specific alphabeta-T cells (adaptive immune system), gammadelta-T cells can recognize and lyse malignantly transformed cells almost immediately upon encounter in a manner that does not require the recognition of tumor-specific antigens (innate immune system). Given the well-documented capacity of gammadelta-T cells to innately kill a variety of malignant cells, efforts are now actively underway to exploit the antitumor properties of gammadelta-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of gammadelta-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively transferred gammadelta-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled gammadelta-T cells, we first show that adoptively transferred gammadelta-T cells localize to breast tumors in a mouse model (4T1 mammary adenocarcinoma) of human breast cancer. Moreover, by using an antibody directed against the gammadelta-T cell receptor (TCR), we determined that localization of adoptively transferred gammadelta-T cells to tumor is a TCR-dependant process. Additionally, biodistribution studies revealed that adoptively transferred gammadelta-T cells traffic differently in tumor-bearing mice compared to healthy mice with fewer gammadelta-T cells localizing into the spleens of tumor-bearing mice. Finally, in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, we demonstrate that adoptively transferred gammadelta-T cells are both effective against breast cancer and are otherwise well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively transferred gammadelta-T cells as a form of cell-based immunotherapy for the treatment of breast cancer. Additionally, these studies establish that clinically applicable methods for radiolabeling gammadelta-T cells allows for the tracking of adoptively transferred gammadelta-T cells in tumor-bearing hosts.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19763820
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8939
      1. Author :
        Batra, J.; Robinson, J.; Mehner, C.; Hockla, A.; Miller, E.; Radisky, D. C.; Radisky, E. S.
      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-luc2, IVIS, Breast Cancer, Bioware
      12. Abstract :
        Excess proteolytic activity of matrix metalloproteinases (MMPs) contributes to the development of arthritis, cardiovascular diseases and cancer progression, implicating these enzymes as therapeutic targets. While many small molecule inhibitors of MMPs have been developed, clinical uses have been limited, in part by toxicity and off-target effects. Development of the endogenous tissue inhibitors of metalloproteinases (TIMPs) as recombinant biopharmaceuticals represents an alternative therapeutic approach; however, the short plasma half-life of recombinant TIMPs has restricted their potential in this arena. To overcome this limitation, we have modified recombinant human TIMP-1 (rhTIMP-1) by PEGylation on lysine residues. We analyzed a mixture of mono- and di-PEGylated rhTIMP-1 species modified by attachment of 20 kDa mPEG chains (PEG(20K)-TIMP-1), as confirmed by SELDI-TOF mass spectrometry. This preparation retained complete inhibitory activity toward the MMP-3 catalytic domain and partial inhibitory activity toward full length MMP-9. Pharmacokinetic evaluation showed that PEGylation extended the plasma half-life of rhTIMP-1 in mice from 1.1 h to 28 h. In biological assays, PEG(20K)-TIMP-1 inhibited both MMP-dependent cancer cell invasion and tumor cell associated gelatinase activity. Overall these results suggest that PEGylated TIMP-1 exhibits improved potential for development as an anti-cancer recombinant protein therapeutic, and additionally may offer potential for clinical applications in the treatment of other diseases.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23185522
      14. Call Number :
        PKI @ kd.modi @ 9
      15. Serial :
        10491
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Circulation
      6. Products :
      7. Volume :
        119
      8. Issue :
        20
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        In vivo imaging; MMPSense
      12. Abstract :
        An extract of the first 250 words of the full text is provided, because this article has no abstract:

        Formation of unstable atherosclerotic plaque in the internal carotid artery carries a high risk for emboli and subsequent cerebral ischemic events. The fibrous cap of such a plaque may become thin and rupture as a result of the depletion of matrix components through the activation of proteolytic enzymes such as matrix-degrading proteinases. Enhanced matrix breakdown has been attributed primarily to a family of matrix-degrading metalloproteinases (MMPs) that are highly concentrated in atherosclerotic plaques by inflammatory cells (eg, macrophages, foam cells), smooth muscle cells and endothelial cells.

        Elevated serum MMP-9 concentration is associated with carotid plaque instability and the presence of infiltrated macrophages. Furthermore, analysis of the presence of MMP-9 protein by ELISA within excised carotid plaques revealed high MMP-9 protein mass in calcified segments at or near the carotid bifurcation and in segments with intraplaque hemorrhage. Gelatin zymography showed an increased gelatinase activity of MMP-9 in these segments. These data favor the important role of MMP-9 in the pathogenesis of plaque instability. We analyzed the topographic distribution of MMPs within an excised human carotid plaque by applying multispectral near-infrared fluorescence (NIRF) imaging (IVIS Spectrum, Caliper Life Sciences, Hopkinton, Mass).

        A surgical endarterectomy was performed on a 74-year-old women with a left-sided, symptomatic, >70% carotid stenosis. Immediately after endarterectomy, the plaque was placed in PBS and transported to the NIRF system. The plaque was then stretched out and fixed on a silicon plate with 25G needles. A PBS NIRF image was generated from both the intraluminal and extraluminal side of the . . .
      13. URL :
        http://circ.ahajournals.org/cgi/content/extract/119/20/e534
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4644
      1. Author :
        Barman, T. K.; Rao, M.; Bhati, A.; Kishore, K.; Shukla, G.; Kumar, M.; Mathur, T.; Pandya, M.; Upadhyay, D. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Indian J Med Res
      6. Products :
      7. Volume :
        134
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen10, Xen 10, Streptococcus pnuemoniae Xen10, IVIS,
      12. Abstract :
        Background & objectives: In vivo imaging system has contributed significantly to the understanding of bacterial infection and efficacy of drugs in animal model. We report five rapid, reproducible, and non invasive murine pulmonary infection, skin and soft tissue infection, sepsis, and meningitis models using Xenogen bioluminescent strains and specialized in vivo imaging system (IVIS). Methods: The progression of bacterial infection in different target organs was evaluated by the photon intensity and target organ bacterial counts. Genetically engineered bioluminescent bacterial strains viz. Staphylococcus aureus Xen 8.1, 29 and 31; Streptococcus pneumoniae Xen 9 and 10 and Pseudomonas aeruginosa Xen-5 were used to induce different target organs infection and were validated with commercially available antibiotics. Results: The lower limit of detection of colony forming unit (cfu) was 1.7-log10 whereas the lower limit of detection of relative light unit (RLU) was 4.2-log10 . Recovery of live bacteria from different target organs showed that the bioluminescent signal correlated to the live bacterial count. Interpretation & conclusions: This study demonstrated the real time monitoring and non-invasive analysis of progression of infection and pharmacological efficacy of drugs. These models may be useful for pre-clinical discovery of new antibiotics.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22199109
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10399
      1. Author :
        Baoum, A.; Ovcharenko, D.; Berkland, C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Int J Pharm
      6. Products :
      7. Volume :
        427
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        A549-luc-C8, A549-luc, IVIS, Bioware, Calcium/chemistry; Cell Line; Cell-Penetrating Peptides/administration & dosage/*chemistry; Drug Carriers/administration & dosage/adverse effects/*chemistry; *Gene Silencing; Genetic Therapy/*methods; Humans; Luciferases; Nanoparticles/administration & dosage/chemistry; RNA, Small Interfering/*administration & dosage/chemistry; Tissue Distribution
      12. Abstract :
        The development of short-interfering RNA (siRNA) offers new strategies for manipulating specific genes responsible for pathological disorders. Myriad cationic polymer and lipid formulations have been explored, but an effective, non-toxic carrier remains a major barrier to clinical translation. Among the emerging candidates for siRNA carriers are cell penetrating peptides (CPPs), which can traverse the plasma membrane and facilitate the intracellular delivery of siRNA. Previously, a highly efficient and non-cytotoxic means of gene delivery was designed by complexing plasmid DNA with CPPs, then condensing with calcium. Here, the CPP TAT and a longer, 'double' TAT (dTAT) were investigated as potential carriers for siRNA. Various N/P ratios and calcium concentrations were used to optimize siRNA complexes in vitro. Upon addition of calcium, 'loose' siRNA/CPP complexes were condensed into small nanoparticles. Knockdown of luciferase expression in the human epithelial lung cell line A549-luc-C8 was high (up to 93%) with no evidence of cytotoxicity. Selected formulations of the dTAT complexes were dosed intravenously up to 1000 mg/kg with minimal toxicity. Biodistribution studies revealed high levels of gene knockdown in the lung and muscle tissue suggesting these simple vectors may offer a translatable approach to siRNA delivery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21856394
      14. Call Number :
        PKI @ kd.modi @ 9
      15. Serial :
        10519
      1. Author :
        Balibar, Carl J; Shen, Xiaoyu; McGuire, Dorothy; Yu, Donghui; McKenney, David; Tao, Jianshi
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Microbiology (Reading, England)
      6. Products :
      7. Volume :
        156
      8. Issue :
        Pt 5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bacterial Proteins; Bacteriolysis; Bioware; Cell Wall; Gene Expression Profiling; Gene Knockout Techniques; Genes, Reporter; Lysostaphin; Mice; Microbial Sensitivity Tests; Sepsis; Staphylococcus aureus; Virulence; Xen29
      12. Abstract :
        Transcriptional profiling data accumulated in recent years for the clinically relevant pathogen Staphylococcus aureus have established a cell wall stress stimulon, which comprises a coordinately regulated set of genes that are upregulated in response to blockage of cell wall biogenesis. In particular, the expression of cwrA (SA2343, N315 notation), which encodes a putative 63 amino acid polypeptide of unknown biological function, increases over 100-fold in response to cell wall inhibition. Herein, we seek to understand the biological role that this gene plays in S. aureus. cwrA was found to be robustly induced by all cell wall-targeting antibiotics tested – vancomycin, oxacillin, penicillin G, phosphomycin, imipenem, hymeglusin and bacitracin – but not by antibiotics with other mechanisms of action, including ciprofloxacin, erythromycin, chloramphenicol, triclosan, rifampicin, novobiocin and carbonyl cyanide 3-chlorophenylhydrazone. Although a DeltacwrA S. aureus strain had no appreciable shift in MICs for cell wall-targeting antibiotics, the knockout was shown to have reduced cell wall integrity in a variety of other assays. Additionally, the gene was shown to be important for virulence in a mouse sepsis model of infection.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20167623
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9037
      1. Author :
        Baddour, Ralph E; Dadani, Farhan N; Kolios, Michael C; Bisland, Stuart K
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Journal of biological physics
      6. Products :
      7. Volume :
        33
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Bioware; Xen29
      12. Abstract :
        Ultrasound imaging is proving to be an important tool for medical diagnosis of dermatological disease. Backscatter spectral profiles using high-frequency ultrasound (HFUS, 10-100 MHz) are sensitive to subtle changes in eukaryotic cellular morphology and mechanical properties that are indicative of early apoptosis, the main type of cell death induced following photodynamic therapy (PDT). We performed experiments to study whether HFUS could also be used to discern changes in bacteria following PDT treatment. Pellets of planktonic Staphylococcus aureus were treated with different PDT protocols and subsequently interrogated with HFUS. Changes in ultrasound backscatter response were found to correlate with antimicrobial effect. Despite their small size, distinct changes in bacterial morphology that are indicative of cell damage or death are detectable by altered backscatter spectra from bacterial ensembles using HFUS. This highlights the potential for HFUS in rapidly and non-invasively assessing the structural changes related to antimicrobial response.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19669553
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9052
      1. Author :
        Asai, T.; Matsushita, S.; Kenjo, E.; Tsuzuku, T.; Yonenaga, N.; Koide, H.; Hatanaka, K.; Dewa, T.; Nango, M.; Maeda, N.; Kikuchi, H.; Oku, N.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Bioconjug Chem
      6. Products :
      7. Volume :
        22
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2; Base Sequence; Cell Line, Tumor; Cholesterol/metabolism; Ethylenediamines/*chemistry; Fibrosarcoma/metabolism/pathology; Gene Silencing; Humans; Injections, Intravenous; Liposomes/administration & dosage/chemical; synthesis/*chemistry/pharmacokinetics; Male; Mice; Mice, Inbred BALB C; Molecular Imaging; Phosphoric Acid Esters/*chemistry; Polyethylene Glycols/chemistry; RNA, Small Interfering/genetics/*metabolism; Spectrophotometry, Infrared
      12. Abstract :
        Dicetyl phosphate-tetraethylenepentamine (DCP-TEPA) conjugate was newly synthesized and formed into liposomes for efficient siRNA delivery. Formulation of DCP-TEPA-based polycation liposomes (TEPA-PCL) complexed with siRNA was examined by performing knockdown experiments using stable EGFP-transfected HT1080 human fibrosarcoma cells and siRNA for GFP. An adequate amount of DCP-TEPA in TEPA-PCL and N/P ratio of TEPA-PCL/siRNA complexes were determined based on the knockdown efficiency. Then, the biodistribution of TEPA-PCL modified with poly(ethylene glycol) (PEG) was examined in BALB/c mice. As a result, TEPA-PCL modified with PEG6000 avoided reticuloendothelial system uptake and showed long circulation in the bloodstream. On the other hand, PEGylation of TEPA-PCL/siRNA complexes caused dissociation of a portion of the siRNA from the liposomes. However, we found that the use of cholesterol-conjugated siRNA improved the interaction between TEPA-PCL and siRNA, which allowed PEGylation of TEPA-PCL/siRNA complexes without siRNA dissociation. In addition, TEPA-PCL complexed with cholesterol-conjugated siRNA showed potent knockdown efficiency in stable luciferase-transfected B16-F10 murine melanoma cells. Finally, the biodistribution of cholesterol-conjugated siRNA formulated in PEGylated TEPA-PCL was examined by performing near-infrared fluorescence imaging in Colon26 NL-17 murine carcinoma-bearing mice. Our results showed that tumor targeting with siRNA via systemic administration was achieved by using PEGylated TEPA-PCL combined with active targeting with Ala-Pro-Arg-Pro-Gly, a peptide used for targeting angiogenic endothelium.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21361311
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10347
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