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  • 1
    Publication Date: 2012-03-20
    Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Combined Chemotherapy Protocols ; Benzimidazoles/*pharmacology/therapeutic use ; Biomarkers, Tumor/genetics/metabolism ; *Clinical Trials, Phase II as Topic ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Fluorodeoxyglucose F18 ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*drug therapy/enzymology/*genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mutation/genetics ; Pharmacogenetics/*methods ; Positron-Emission Tomography ; Protein-Serine-Threonine Kinases/deficiency/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Randomized Controlled Trials as Topic ; Reproducibility of Results ; Taxoids/*therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome ; ras Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 0168-9452
    Keywords: Anther culture ; Chromosome doubling ; Pollen plant ; Wheat
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2242
    Keywords: Anther culture ; Culture temperature ; Induction frequency ; Pollen callus (plantlet) ; Triticum aestivum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The response of anther culture to culture temperature was studied in detail using many varieties, F1 hybrids and pollen-derived lines of wheat (Triticum aestivum) as materials. The suitable culture temperature for inducing pollen callus (or embryoids) in wheat anther culture ranged from 26 °C to 30 °C, varying with genotypes. But for the great majority of wheat genotypes the suitable culture temperatures lay between 28 °C and 30°C. The most significant genotypic variation in the response to culture temperature was observed in the comparison between the culture at 33 °C for eight days followed by culture at 25 °C (or 26 °C) and the continuous culture at 25 °C (or 26 °C). This genotypic variation in the response to culture temperature is a heritable character which may be controlled by multiple genes. The effect of culture at 30 °C for eight days followed by culture at 26 °C was similar to, or in some cases, better than that of continuous culture at 28 °C, and the effect of culture at 32 °C for eight days followed by culture at 28 °C was similar to that of continuous culture at 30 °C. In the range from 26 °C to 32 °C, the overwhelming majority of pollen calli emerged before the 40th day after anther inoculation, and the higher the culture temperature, the earlier and more concentrated the emerging period of the pollen callus. The pollen callus obtained at high temperatures above 28 °C should be transferred in time onto the regeneration medium at 25°–27°C to induce shoots.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 54 (1998), S. 728-732 
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of food science 45 (1980), S. 0 
    ISSN: 1750-3841
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Decomposition products of β-carotene formed during a simulated commercial deodorization of palm oil were separated from unsaponifiable portion into six fractions by liquid chromatography. Fraction two containing slightly polar substances was further separated using thin-layer chromatography and high performance liquid chromatography. In this fraction, β-13-apo-carotenone, β-15-apo-caro-tenal, and β-14′-apo-carotenal were identified by infrared spectrometry and mass spectroscopy.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 53 (1997), S. 1226-1228 
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Measurements of infrared and visible emission in a macroscopic discharge cell similar to a plasma display panel (PDP) cell are analyzed using a two-dimensional fluid model of the discharge. The comparisons between experiments and models show a good qualitative agreement but the plasma spreading velocity above the cathode surface is much faster in the experiments. We find that including photoemission (in a simplified way) in the model considerably increases the agreement between experiments and models. With a well-chosen photoemission coefficient, the model reproduces the trends observed in the experiments when the gas mixture (between 2% and 10% of xenon in neon) or the applied voltage is changed. The influence of photoemission on the current rise time and on the velocity of plasma spreading above the dielectric surfaces is more important in the macrocell than in a similar (same dimension × pressure) PDP cell because resonant photon transport does not follow the similarity laws. © 2002 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The space and time variations of the light emission in a macroscopic plasma display panel (PDP) discharge cell have been studied with an image-intensified charge-coupled device. The discharge cell is similar to a real PDP cell with a coplanar electrode configuration. The cell dimensions are on the order of 100 times larger than those of a real PDP cell and the operating pressure is about 100 times smaller. Different xenon–neon gas mixtures have been investigated. Optical filters have been used to measure infrared emission from xenon excited states 823.1 and 828.0 nm, and visible emission from neon at 640.2 nm. The measurements show that the neon visible emission occurs only above the cathode while xenon infrared emission occurs above both cathode and anode. Standing striations can be observed above the anode. The strong xenon emission above anode indicates that this region is more efficient than the cathode region in terms of ultraviolet production. The measurements are in excellent qualitative agreement with similar measurements performed in real PDP cells. However the velocity of plasma spreading above the cathode in the macrocell is significantly larger than in a real PDP cell. The interpretation of this discrepancy is given in a companion paper (part II) [J. Appl. Phys. 91, 1000 (2002)] where the experimental results are compared with results from a fluid model of the plasma. © 2002 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Electroanalytical Chemistry 271 (1989), S. 331-338 
    ISSN: 0022-0728
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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