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  • 1
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    Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-04
    Description: The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yauch, Robert L -- Dijkgraaf, Gerrit J P -- Alicke, Bruno -- Januario, Thomas -- Ahn, Christina P -- Holcomb, Thomas -- Pujara, Kanan -- Stinson, Jeremy -- Callahan, Christopher A -- Tang, Tracy -- Bazan, J Fernando -- Kan, Zhengyan -- Seshagiri, Somasekar -- Hann, Christine L -- Gould, Stephen E -- Low, Jennifer A -- Rudin, Charles M -- de Sauvage, Frederic J -- New York, N.Y. -- Science. 2009 Oct 23;326(5952):572-4. doi: 10.1126/science.1179386. Epub 2009 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genentech, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19726788" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Anilides/metabolism/pharmacology/*therapeutic use ; Animals ; Antineoplastic Agents/metabolism/pharmacology/*therapeutic use ; Brain Neoplasms/*drug therapy/*genetics/pathology ; Cell Line, Tumor ; Cinnamates/pharmacology ; Drug Resistance, Neoplasm ; Hedgehog Proteins/antagonists & inhibitors/genetics/*metabolism ; Humans ; Medulloblastoma/*drug therapy/*genetics/pathology ; Mice ; Molecular Sequence Data ; Mutant Proteins/antagonists & inhibitors/chemistry/metabolism ; Mutation, Missense ; Neoplasm Metastasis ; Protein Conformation ; Pyridines/metabolism/pharmacology/*therapeutic use ; Receptors, Cell Surface/genetics/metabolism ; Receptors, G-Protein-Coupled/antagonists & ; inhibitors/chemistry/*genetics/metabolism ; Signal Transduction ; Veratrum Alkaloids/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-02-08
    Description: Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077055/" 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/PMC3077055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaneko, Hiroki -- Dridi, Sami -- Tarallo, Valeria -- Gelfand, Bradley D -- Fowler, Benjamin J -- Cho, Won Gil -- Kleinman, Mark E -- Ponicsan, Steven L -- Hauswirth, William W -- Chiodo, Vince A -- Kariko, Katalin -- Yoo, Jae Wook -- Lee, Dong-ki -- Hadziahmetovic, Majda -- Song, Ying -- Misra, Smita -- Chaudhuri, Gautam -- Buaas, Frank W -- Braun, Robert E -- Hinton, David R -- Zhang, Qing -- Grossniklaus, Hans E -- Provis, Jan M -- Madigan, Michele C -- Milam, Ann H -- Justice, Nikki L -- Albuquerque, Romulo J C -- Blandford, Alexander D -- Bogdanovich, Sasha -- Hirano, Yoshio -- Witta, Jassir -- Fuchs, Elaine -- Littman, Dan R -- Ambati, Balamurali K -- Rudin, Charles M -- Chong, Mark M W -- Provost, Patrick -- Kugel, Jennifer F -- Goodrich, James A -- Dunaief, Joshua L -- Baffi, Judit Z -- Ambati, Jayakrishna -- NIHU10EY013729/EY/NEI NIH HHS/ -- P30 EY006360/EY/NEI NIH HHS/ -- P30 EY014800/EY/NEI NIH HHS/ -- P30 EY014800-07/EY/NEI NIH HHS/ -- P30 EY021721/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- P30EY008571/EY/NEI NIH HHS/ -- P30EY06360/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-05/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-04/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY020672-02/EY/NEI NIH HHS/ -- R01 GM068414/GM/NIGMS NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY011123/EY/NEI NIH HHS/ -- R01EY015240/EY/NEI NIH HHS/ -- R01EY015422/EY/NEI NIH HHS/ -- R01EY017182/EY/NEI NIH HHS/ -- R01EY017950/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01GM068414/GM/NIGMS NIH HHS/ -- R01HD027215/HD/NICHD NIH HHS/ -- R21 EY019778/EY/NEI NIH HHS/ -- R21 EY019778-02/EY/NEI NIH HHS/ -- R21AI076757/AI/NIAID NIH HHS/ -- R21EY019778/EY/NEI NIH HHS/ -- RC1 EY020442/EY/NEI NIH HHS/ -- RC1 EY020442-02/EY/NEI NIH HHS/ -- RC1EY020442/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):325-30. doi: 10.1038/nature09830. Epub 2011 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21297615" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements/*genetics ; Animals ; Cell Death ; Cell Survival ; Cells, Cultured ; DEAD-box RNA Helicases/*deficiency/genetics/metabolism ; Gene Knockdown Techniques ; Humans ; Macular Degeneration/*genetics/*pathology ; Mice ; MicroRNAs/metabolism ; Molecular Sequence Data ; Oligonucleotides, Antisense ; Phenotype ; RNA/*genetics/*metabolism ; Retinal Pigment Epithelium/enzymology/metabolism/pathology ; Ribonuclease III/*deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA (1993)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1993-01-01
    Description: Rat C6 glioma cells express insulin-like growth factor I (IGF-I) and form rapidly growing tumors in syngeneic animals. When transfected with an episome-based vector encoding antisense IGF-I complementary DNA, these cells lost tumorigenicity. Subcutaneous injection of IGF-I antisense-transfected C6 cells into rats prevented formation of both subcutaneous tumors and brain tumors induced by nontransfected C6 cells. The antisense-transfected cells also caused regression of established brain glioblastomas when injected at a point distal to the tumor. These antitumor effects result from a glioma-specific immune response involving CD8+ lymphocytes. Antisense blocking of IGF-I expression may reverse a phenotype that allows C6 glioma cells to evade the immune system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trojan, J -- Johnson, T R -- Rudin, S D -- Ilan, J -- Tykocinski, M L -- CA-43703/CA/NCI NIH HHS/ -- HD-18271/HD/NICHD NIH HHS/ -- HD-25004/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 1993 Jan 1;259(5091):94-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉INSERM, Paris.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8418502" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD8/*immunology ; Brain Neoplasms/immunology/pathology/*prevention & control/*therapy ; Cytotoxicity, Immunologic ; DNA, Recombinant ; Glioma/immunology/pathology/*prevention & control/*therapy ; Immunohistochemistry ; Insulin-Like Growth Factor I/*genetics ; RNA, Antisense/pharmacology/*therapeutic use ; Rats ; T-Lymphocyte Subsets/*immunology ; *Transfection ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
    Electronic Resource
    Electronic Resource
    Extrusion behavior of starch graft copolymers: Starch-g-polystyrene and starch-g-poly(methyl acrylate) (1992)
    Weinheim : Wiley-Blackwell
    Angewandte Makromolekulare Chemie 194 (1992), S. 23-33 
    Details
    ISSN: 0003-3146
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Description / Table of Contents: Stärke/Styrol- und Stärke/Methylacrylat-Pfropfcopolymere wurden hergestellt und ohne vorherige Abtrennung von homopolymerem Polystyrol (PS) bzw. Poly(methylacrylat) (PMA) extrudiert. Das Extrusionsverhalten ähnelte dem thermoplastischer Schmelzen darin, daß die Copolymeren die Scherung herabsetzen, eine merkliche Strangaufweitung verursachen und Eingangsdruckverluste im Kapillarfließerhalten auftreten. Diese und andere Beobachtungen deuten darauf hin, daß diese Materialien deformierbare, mit dem jeweiligen Polymeren gepfropfte Stärkepartikel in der entsprechenden Homopolymermatrix enthalten. Die Fließeigenschaften können anscheinend eher durch solche „Superpartikel“ als durch das Model1 einer kontinuierlichen, homogenen Schmelze erklärt werden.
    Notes: Starch-g-polystyrene and starch-g-poly(methyl acrylate) copolymers were synthesized and extruded without separating homopolymer PS or PMA. The extrusion behavior resembled that of thermoplastic melts in that these products were shear thinning and exhibited significant extrudate swelling and entrance pressure losses in capillary flow. These and other observations indicate that the materials comprise deformable polymer-grafted starch particles suspended in the corresponding homopolymer melt. Flow is apparently by superparticle, rather than continuum melt mechanisms.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/apmc.1992.051940103
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  • 5
    Electronic Resource
    Electronic Resource
    Stabilization of polystyrene/poly(methyl methacrylate) blends by in situ compatibilization with graft copolymers (1989)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 190 (1989), S. 3153-3166 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Copolymers of styrene and ortho-vinylbenzaldehyde (o-VBA) are useful precursors to multicomponent polymer systems. Graft copolymers of poly(styrene-stat-o-VBA) can be produced by free-radical chain transfer to methyl methacrylate monomer to yield materials that display some potential as interfacial agents with binary blends of polystyrene and poly(methyl methacrylate). Significant improvements in ultimate tensile strengths and energy to rupture values have been witnessed for polystyrene/poly(methyl methacrylate) mixtures that contain various levels of the graft component. Scanning electron microscopy of representative fracture surfaces demonstrate a decrease in the particle size of the dispersed phase; it is suggested that this morphological factor contributes to the superior mechanical properties of these composites. In this regard, both the isolated and the crude graft copolymers are able to compatibilize, and thereby enhance, the material properties of polystyrene/poly(methyl methacrylate) blends.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1989.021901213
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  • 6
    Electronic Resource
    Electronic Resource
    Equivalent hydrodynamic sphere models for viscosity, sedimentation, and diffusion (1978)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 179 (1978), S. 2977-2988 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Available data for intrinsic viscosity, molecular weight and infinite dilution frictional properties of polymer-solvent systems are used to establish the relation between the radius, rf, of a “frictional” equivalent sphere applicable to sedimentation and diffusion phenomena, and the radius, rη, of the “viscosity” hydrodynamic sphere. It is found that the experimental data agree with a common equivalent hydrodynamic sphere model in which rη = rf.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1978.021791218
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  • 7
    Electronic Resource
    Electronic Resource
    Characterization of non-homogeneous polymers with size-exclusion chromatography by implementing an on-line viscometer (1993)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 194 (1993), S. 1953-1963 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The viscosity distribution of a polymer sample can be obtained by using an on-line viscometer as a detector in size-exclusion chromatography. This newly defined viscosity distribution is closely related to the molecular weight distribution and expresses weight fraction times intrinsic viscosity of species i as a function of the corresponding molecular weight times intrinsic viscosity (wi[ηi] vs. Mi[ηi]). The intrinsic viscosity ([η]) and number-average molecular weight (M̄n) can be obtained directly from a viscosity distribution. If the Mark-Houwink exponent a is known (or approximately known) for non-homogeneous polymer the M̄w/M̄n can be estimated from the viscosity distribution when the molecular weight distribution is approximated with a known distribution function. These estimates are independent of any other detector and are valid even for non-homogeneous polymer samples. The relation between the moments of the viscosity distribution and the M̄w/M̄n is presented for two widely used distribution functions, the Log-Normal and the Generalized Exponential Distributions. Polymer characterization based on the viscosity distribution is shown to be a robust technique. It is particularly attractive in characterizing non-homogeneous polymers since it is solely obtained from on-line viscometer.
    Additional Material: 4 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1993.021940709
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  • 8
    Electronic Resource
    Electronic Resource
    Multi-detector size-exclusion chromatography: a novel approach to calibration eliminating lag time estimation (1993)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 194 (1993), S. 1965-1974 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: In order to obtain the correct calibration of molecular-weight sensitive detectors (such as on-line viscometers or light scattering detectors) in size-exclusion chromatography, it is necessary to account for the (molecular) non-uniformity of the calibration standards. This is true even in the case of the narrow molecular weight distribution standards typically commercially available for calibration. Methods of taking this non-uniformity into consideration are presented. For a multi-detector size-exclusion chromatography system calibrated in this way, independent calibration curves can be established for each detector. Thus, at a given hydrodynamic volume, corresponding signals from the different detectors can be obtained. This eliminates the need to estimate additional parameters such as interdetector volumes or lag times for matching signals from different detectors. The practicability of this approach in the analysis of (molecularly) non-uniform polymers is demonstrated by combining on-line viscometer and concentration signals (to obtain intrinsic viscosity versus molecular weight information) for two different polymers, viz. polystyrene and poly(methyl methacrylate). The resultant intrinsic viscosity versus molecular weight data is then compared to that predicted from the literature.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1993.021940710
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  • 9
    Electronic Resource
    Electronic Resource
    Chemical modification of polydienes, 3Part 2: cf.2.. Copolymers with polytetrahydrofuran by grafting-from butadiene polymers (1986)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 187 (1986), S. 2763-2774 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Polybutadienes of various microstructures and some butadiene copolymers were epoxidised to low levels (〈1 mol-%) with m-chloroperbenzoic acid. The epoxide groups functioned as initiation sites for a “grafting-from polymerization” of tetrahydrofuran (THF) catalysed by BF3. By conducting the reaction in dilute THF solution ([Monomeric unit] 〈 0,3 mol · 1-1) with a large excess of BF3 over epoxide groups, gel formation was avoided. The conversion of THF was less than 2% and the copolymers contained from 10 to 50% polytetrahydrofuran (PTHF) comprising graft chains of molar mass up to 43000 g · mol-1. The relative rate of grafting tended to decrease as the content of trans-1,4 units in the backbone polymer increased, and, unusually, there was a small increase in volume during the graft copolymerization. The graft copolymers had a two-phase morphology consisting of amorphous rubber and crystallites of PTHF. The latter function as physical crosslinks which break down above the melting point of PTHF, so that the materials behave as thermoplastic elastomers.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1986.021871203
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  • 10
    Electronic Resource
    Electronic Resource
    Gel permeation chromatography of polymer mixtures (1981)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 182 (1981), S. 2801-2809 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: When mixtures of polymers are analyzed in a common gel permeation chromatographic solvent the peak elution volumes of both components are shifted with respect to their values at their nominal concentrations in the same solvent and column set. In this article a theory which has been applied previously to account for concentration effects of a single polymer in a GPC solvent is modified to predict peak elution volumes in polymer mixtures. The model invokes solvent-solute interactions only and provides quantitative predictions of the behavior of mixtures of anionic polystyrene samples with other polystyrenes and with polybutadienes. There is no indication of polymer-polymer repulsive effects except for polystyrene-poly(methylmethacrylate) mixtures at relatively high concentrations.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1981.021821025
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