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      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 :
        von Schwarzenberg, K.; Wiedmann, R. M.; Oak, P.; Schulz, S.; Zischka, H.; Wanner, G.; Efferth, T.; Trauner, D.; Vollmar, A. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Biol Chem
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        4T1-luc2, IVIS, Bioluminescence
      12. Abstract :
        The vacuolar H+-ATPase (V-ATPase), a multisubunit proton pump, has come into focus as an attractive target in cancer invasion. However little is known about the role of V-ATPase in cell death and especially the underlying mechanisms remain mostly unknown. We used the myxobacterial macrolide archazolid B, a potent inhibitor of the V-ATPase, as an experimental drug as well as a chemical tool to decipher V-ATPase related cell death signaling. We found that archazolid induced apoptosis in highly invasive tumor cells at nanomolar concentrations which was executed by the mitochondrial pathway. Prior to apoptosis induction archazolid lead to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1 alpha (HIF1alpha) and autophagy. Autophagy was induced at low concentrations of archazolid that do not alter pH in lysosomes and was shown by degradation of p62 or fusion of autophagosomes with lysosomes. HIF1alpha was induced due to energy stress shown by a decline of the ATP level and followed by a shut down of energy consuming processes. As silencing HIF1alpha increases apoptosis, the cellular stress response was suggested to be a survival mechanism. We conclude that archazolid leads to energy stress which activates adaptive mechanisms like autophagy mediated by HIF1alpha and finally leads to apoptosis. We propose V-ATPase as a promising drugable target in cancer therapy caught up at the interplay of apoptosis, autophagy and cellular/metabolic stress.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23168408
      14. Call Number :
        PKI @ kd.modi @ 9
      15. Serial :
        10480
      1. Author :
        Wang, S.; Noberini, R.; Stebbins, J. L.; Das, S.; Zhang, Z.; Wu, B.; Mitra, S.; Billet, S.; Fernandez, A.; Bhowmick, N. A.; Kitada, S.; Pasquale, E. B.; Fisher, P. B.; Pellecchia, M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2013
      5. Publication :
        Clin Cancer Res
      6. Products :
      7. Volume :
        19
      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
      12. Abstract :
        PURPOSE: YSA is an EphA2-targeting peptide that effectively delivers anticancer agents to prostate cancer tumors. Here, we report on how we increased the drug-like properties of this delivery system. EXPERIMENTAL DESIGN: By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo. RESULTS: dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared with vehicle or paclitaxel treatments. CONCLUSION: This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anticancer agents to a variety of tumor types. Clin Cancer Res; 19(1); 128-37. (c)2012 AACR.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23155185
      14. Call Number :
        PKI @ kd.modi @ 6
      15. Serial :
        10541
      1. Author :
        Liu, W.; McDaniel, J.; Li, X.; Asai, D.; Quiroz, F. G.; Schaal, J.; Park, J. S.; Zalutsky, M.; Chilkoti, A.
      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-luc2, PC3M-luc2, IVIS, Prostate Cancer, Bioware
      12. Abstract :
        Brachytherapy is a common clinical technique involving implantation of sealed radioactive “seeds” within a tumor to selectively irradiate the tumor mass while minimizing systemic toxicity. To mitigate the disadvantages associated with complex surgical implantation and subsequent device removal procedures, we have developed an alternative approach using a genetically encoded peptide polymer solution composed of a thermally responsive elastin-like polypeptide (ELP) radiolabeled with (131)I that self-assembles into radionuclide seeds upon intratumoral injection. The formation of these nontoxic and biodegradable polymer seeds led to prolonged intratumoral retention (~85% ID/tumor 7 days postinjection) of the radionuclide, elicited a tumor growth delay in 100% of the tumors in two human xenografts (FaDu and PC-3), and cured more than 67% of tumor-bearing animals after a single administration of labeled ELP. These results suggest that in situ self-assembly of biodegradable and injectable radionuclide-containing polypeptide seeds could be a promising therapeutic alternative to conventional brachytherapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23155121
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10487
      1. Author :
        Albanesi, M.; Mancardi, D. A.; Macdonald, L. E.; Iannascoli, B.; Zitvogel, L.; Murphy, A. J.; Leusen, J. H.; Bruhns, P.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Immunol
      6. Products :
      7. Volume :
        189
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        B16-F10-luc2, B16F10-luc2, IVIS
      12. Abstract :
        mAb therapy for experimental metastatic melanoma relies on activating receptors for the Fc portion of IgG (FcgammaR). Opposing results on the respective contribution of mouse FcgammaRI, FcgammaRIII, and FcgammaRIV have been reported using the gp75-expressing B16 melanoma and the protective anti-gp75 mAb TA99. We analyzed the contribution of FcgammaRs to this therapy model using bioluminescent measurement of lung metastases loads, novel mouse strains, and anti-FcgammaR blocking mAbs. We found that the TA99 mAb-mediated effects in a combination therapy using cyclophosphamide relied on activating FcgammaRs. The combination therapy, however, was not more efficient than mAb therapy alone. We demonstrate that FcgammaRI and, unexpectedly, FcgammaRIII contributed to TA99 mAb therapeutic effects, whereas FcgammaRIV did not. Therefore, FcgammaRIII and FcgammaRI are, together, responsible for anti-gp75 mAb therapy of B16 lung metastases. Our finding that mouse FcgammaRIII contributes to Ab-induced tumor reduction correlates with clinical data on its human functional equivalent human FcgammaRIIIA (CD16A).
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23150715
      14. Call Number :
        PKI @ kd.modi @ 8
      15. Serial :
        10482
      1. Author :
        Leszczynska, K.; Namiot, D.; Byfield, F. J.; Cruz, K.; Zendzian-Piotrowska, M.; Fein, D. E.; Savage, P. B.; Diamond, S.; McCulloch, C. A.; Janmey, P. A.; Bucki, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Antimicrob Chemother
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen5, Xen 5, Pseudomonas aeruginosa
      12. Abstract :
        OBJECTIVES: We aim to develop antibacterial peptide mimics resistant to protease degradation, with broad-spectrum activity at sites of infection. METHODS: The bactericidal activities of LL-37, ceragenins CSA-13, CSA-90 and CSA-92 and the spermine-conjugated dexamethasone derivative D2S were evaluated using MIC and MBC measurements. Gingival fibroblast counting, interleukin-8 (IL-8) and lactate dehydrogenase (LDH) release from keratinocytes (HaCat) were used to determine effects on cell growth, pro-inflammatory response and toxicity. RESULTS: All tested cationic lipids showed stronger bactericidal activity than LL-37. Incubation of Staphylococcus aureus with half the MIC of LL-37 led to the appearance of bacteria resistant to its bactericidal effects, but identical incubations with CSA-13 or D2S did not produce resistant bacteria. Cathelicidin LL-37 significantly increased the total number of gingival fibroblasts, but ceragenins and D2S did not alter gingival fibroblast growth. Cationic lipids showed no toxicity to HaCat cells at concentrations resulting in bacterial killing. CONCLUSIONS: These data suggest that cationic lipids such as ceragenins warrant further testing as potential novel antibacterial agents.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23134677
      14. Call Number :
        PKI @ kd.modi @ 6
      15. Serial :
        10551
      1. Author :
        Lin, S. A.; Patel, M.; Suresch, D.; Connolly, B.; Bao, B.; Groves, K.; Rajopadhye, M.; Peterson, J. D.; Klimas, M.; Sur, C.; Bednar, B.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Int J Mol Imaging
      6. Products :
      7. Volume :
        2012
      8. Issue :
        N/A
      9. Page Numbers :
        189254
      10. Research Area :
        N/A
      11. Keywords :
        FMT, Prosense, CatB, Cathepsin B, fluorescence imaing, tomography, microCT
      12. Abstract :
        Inflammation as a core pathological event of atherosclerotic lesions is associated with the secretion of cathepsin proteases and the expression of alpha(v)beta(3) integrin. We employed fluorescence molecular tomographic (FMT) noninvasive imaging of these molecular activities using cathepsin sensing (ProSense, CatB FAST) and alpha(v)beta(3) integrin (IntegriSense) near-infrared fluorescence (NIRF) agents. A statistically significant increase in the ProSense and IntegriSense signal was observed within the chest region of apoE(-/-) mice (P < 0.05) versus C57BL/6 mice starting 25 and 22 weeks on high cholesterol diet, respectively. In a treatment study using ezetimibe (7 mg/kg), there was a statistically significant reduction in the ProSense and CatB FAST chest signal of treated (P < 0.05) versus untreated apoE(-/-) mice at 31 and 21 weeks on high cholesterol diet, respectively. The signal of ProSense and CatB FAST correlated with macrophage counts and was found associated with inflammatory cells by fluorescence microscopy and flow cytometry of cells dissociated from aortas. This report demonstrates that cathepsin and alpha(v)beta(3) integrin NIRF agents can be used as molecular imaging biomarkers for longitudinal detection of atherosclerosis, and cathepsin agents can monitor anti-inflammatory effects of ezetimibe with applications in preclinical testing of therapeutics and potentially for early diagnosis of atherosclerosis in patients.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23119157
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10571
      1. Author :
        Tafreshi, N. K.; Huang, X.; Moberg, V. E.; Barkey, N. M.; Sondak, V. K.; Tian, H.; Morse, D. L.; Vagner, J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Bioconjug Chem
      6. Products :
      7. Volume :
        23
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, B16-F10-luc-G5, B16F10-luc-G5, B16-F10-luc, B16F10-luc
      12. Abstract :
        The incidence of malignant melanoma is rising more rapidly than that of any other cancer in the United States. The melanocortin 1 receptor (MC1R) is overexpressed in most human melanoma metastases, thus making it a promising target for imaging and therapy of melanomas. We have previously reported the development of a peptidomimetic ligand with high specificity and affinity for MC1R. Here, we have conjugated near-infrared fluorescent dyes to the C-terminus of this ligand via lysine-mercaptopropionic acid linkers to generate MC1R specific optical probes (MC1RL-800, 0.4 nM K(i); and MC1RL-Cy5, 0.3 nM K(i)). Internalization of the imaging probe was studied in vitro by fluorescence microscopy using engineered A375/MC1R cells and B16F10 cells with endogenous MC1R expression. The in vivo tumor targeting of MC1RL-800 was evaluated by intravenous injection of probe into nude mice bearing bilateral subcutaneous A375 xenograft tumors with low MC1R expression and engineered A375/MC1R tumors with high receptor expression. Melanotic B16F10 xenografts were also studied. Fluorescence imaging showed that the agent has higher uptake values in tumors with high expression compared to low (p < 0.05), demonstrating the effect of expression levels on image contrast-to-noise. In addition, tumor uptake was significantly blocked by coinjection of excess NDP-alpha-MSH peptide (p < 0.05). In conclusion, the MC1R-specific imaging probe developed in this study displays excellent potential for the intraoperative detection of regional node involvement and for margin detection during melanoma metastasis resection.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23116461
      14. Call Number :
        PKI @ kd.modi @ 18
      15. Serial :
        10535
      1. Author :
        Comenge, J.; Sotelo, C.; Romero, F.; Gallego, O.; Barnadas, A.; Parada, T. G.; Dominguez, F.; Puntes, V. F.
      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 :
        A549-luc-C8, A549-luc, IVIS, Bioware
      12. Abstract :
        Nanoparticles (NPs) have emerged as a potential tool to improve cancer treatment. Among the proposed uses in imaging and therapy, their use as a drug delivery scaffold has been extensively highlighted. However, there are still some controversial points which need a deeper understanding before clinical application can occur. Here the use of gold nanoparticles (AuNPs) to detoxify the antitumoral agent cisplatin, linked to a nanoparticle via a pH-sensitive coordination bond for endosomal release, is presented. The NP conjugate design has important effects on pharmacokinetics, conjugate evolution and biodistribution and results in an absence of observed toxicity. Besides, AuNPs present unique opportunities as drug delivery scaffolds due to their size and surface tunability. Here we show that cisplatin-induced toxicity is clearly reduced without affecting the therapeutic benefits in mice models. The NPs not only act as carriers, but also protect the drug from deactivation by plasma proteins until conjugates are internalized in cells and cisplatin is released. Additionally, the possibility to track the drug (Pt) and vehicle (Au) separately as a function of organ and time enables a better understanding of how nanocarriers are processed by the organism.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23082177
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10522
      1. Author :
        Sehrawat, A.; Arlotti, J. A.; Murakami, A.; Singh, S. V.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Breast Cancer Res Treat
      6. Products :
      7. Volume :
        136
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-D3H1, MDA-MB-231-luc-D3H1, IVIS, Bioware, Breast Cancer
      12. Abstract :
        The present study was undertaken to determine the anticancer efficacy of zerumbone (ZER), a sesquiterpene from subtropical ginger, against human breast cancer cells in vitro and in vivo. ZER treatment caused a dose-dependent decrease in viability of MCF-7 and MDA-MB-231 human breast cancer cells in association with G(2)/M phase cell cycle arrest and apoptosis induction. ZER-mediated cell cycle arrest was associated with downregulation of cyclin B1, cyclin-dependent kinase 1, Cdc25C, and Cdc25B. Even though ZER treatment caused stabilization of p53 and induction of PUMA, these proteins were dispensable for ZER-induced cell cycle arrest and/or apoptosis. Exposure of MDA-MB-231 and MCF-7 cells to ZER resulted in downregulation of Bcl-2 but its ectopic expression failed to confer protection against ZER-induced apoptosis. On the other hand, the SV40 immortalized mouse embryonic fibroblasts derived from Bax and Bak double knockout mice were significantly more resistant to ZER-induced apoptosis. ZER-treated MDA-MB-231 and MCF-7 cells exhibited a robust activation of both Bax and Bak. In vivo growth of orthotopic MDA-MB-231 xenografts was significantly retarded by ZER administration in association with apoptosis induction and suppression of cell proliferation (Ki-67 expression). These results indicate that ZER causes G(2)/M phase cell cycle arrest and Bax/Bak-mediated apoptosis in human breast cancer cells, and retards growth of MDA-MB-231 xenografts in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23053663
      14. Call Number :
        PKI @ kd.modi @ 5
      15. Serial :
        10518
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