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  • Chemical Engineering  (23)
  • Physics  (17)
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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
    The effect of processing on rheological and molecular characteristics of a low density polyethylene (1993)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 33 (1993), S. 377-382 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: The viscoelastic responses of some molten polymers, and particularly of low density polyethylene (LDPE), are known to vary with processing history. Reasons for the variations include the effects of shear history on morphological states of the polymer, or on its molecular weight parameters. A typical low density polyethylene has been used to test the shear-history dependence concept following a variety of processing steps. The polymer was sheared in single-screw and twin-screw extruders, and in a high speed melter / mixer (Gelimat). Samples also were precipitated from very dilute solutions in trichlorobenzene and in p-xylene. GPC analyses showed that, in general, these procedures did not affect the various moments of molecular weight. An exception was the Gelimat-mixed sample, for which mild reductions in Mn and Mw were noted. In contrast, melt viscosity and elasticity readings, the former from low shear evaluations and the latter from extrudate swelling, were affected by the various procedures. A drop in melt viscosity and in elasticity was observed, being most pronounced for precipitated and twin-screw extruded versions of the LDPE. Reductions also were observed in the specimen sheared in the Gelimat instrument. Following conditioning at the test extrusion temperature (170°C), viscous and elastic responses tended to revert to those of the unsheared control sample, the exception again being the sample sheared in the Gelimat melter / mixer. Of the various mechanisms proposed in the literature to account for transient property changes such as those reported, temporary changes in the degree of chain entanglement appear the most satisfactory explanation. Irreversible alterations in viscoelastic properties may be associated with changes in molecular weights due to processing at high shear.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760330702
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  • 5
    Electronic Resource
    Electronic Resource
    A note on the effect of comonomer sequence distribution on TREF branching distributions (1993)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 33 (1993), S. 1370-1371 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760332011
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  • 6
    Electronic Resource
    Electronic Resource
    Mechanism of shear modification of low density polyethylene (1994)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 34 (1994), S. 570-579 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: In this paper we address the aspects associated with shear modification of low density polyethylene by extrusion. By successive passes of the polymer through an extruder it can be shown that both the melt viscosity and melt elasticity are reduced by shear modification. These reversible variations are not accompanied by significant changes in molecular weight distribution. The major effects of extrusion are to decrease the amount of elastically effecitve material. Study of proton relaxation times at 150°C shows that the melt comprises regions of relatively ordered, entangled, and unentangled polymer. Shearing reduces the proportion of more ordered material. The elastically effective anchors that are reduced by shearing are regions with restricted segmental mobility rather than conventional entanglements or intermolecular knots. Successive extrusions produce a relatively small decrease in the number of such constraints to molecular motion. Repeated shearing has a diminishing effect on the proportion of more ordered material in the polyethlene melt. This parallels observations of the effects of repeated shear modification on the properties of polyethylene films and other extrudates.
    Additional Material: 14 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760340705
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  • 7
    Electronic Resource
    Electronic Resource
    Fracture mechanics parameters for polystyrene under high speed impact (1990)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 30 (1990), S. 596-602 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: A series of commercial polystyrenes was tested using an instrumented impact tester to determine the fracture toughness Kc and critical strain energy release rate Gc. Over the range of Mw, 201,000 to 336,000, Kc increased from 1.38 MN/m3/2 to 1.76 MN/m3/2and Gc from 0.92 kJ/m2 to 1.60 kJ/m2. A linear correlation for Kc and Gc was seen with melt index, and an inverse relationship was obtained against molecular weight. Examination of the fracture surfaces revealed the presence of crack growth bands corresponding to the crack tip plastic zone size. It is suggested that these bands are the consequence of variations in crack growth along crazes that form in the crack tip stress field. As the crack propagates, the stress is relaxed locally, decreasing the growth rate allowing a new bundle of crazes to nucleate along which the crack advances. The spacing of these bands corresponds to the craze length formed in the plastic zone, and the band spacing increases with molecular weight.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760301006
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  • 8
    Electronic Resource
    Electronic Resource
    Properties and morphology of polystyrene and linear low density polyethylene polyblend and polyalloy (1991)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 31 (1991), S. 1033-1042 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: A co-rotating twin screw extruder was employed in melt mixing and reactive extrusion of polystyrene/linear low density polyethylene (PS/PE) blends. Blends of PS/PE in the ratio of 9: 1 were prepared under different conditions of shear mixing and with different concentrations of dicurnlyl peroxide (DP) and triallyl isocyanurate (TALC) coupling agent. The Charpy impact strength of unnotched samples of melt blends was found to be lower than that of the polystyrene and was not affected much by the different conditions of melt mixing at different rates of extrusion, screw speeds, and screw configurations. In the case of reaction-extruded blends, the impact strength initially deteriorated with small addition of TAIC/DP, but improved with further increase in the level of TAIC/DP, exceeding that of polystyrene at an optimum concentration. With even further increase in TAIC/DP concentration, the impact strength again decreased. This was attributed to the different extents of coupling reactions of PE-TAIC-PE, PE-TAIC-PS, and PS-TAIC-PS with different levels of TAIC/DP. The interfacial adhesion of the incompatible PS-PE was postulated to be improved by the graft copolymers formed during reactive extrusion. This observation was supported by melt rheology, thermal characterization, molecular weight, and fracture surface morphology studies.
    Additional Material: 11 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760311407
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  • 9
    Electronic Resource
    Electronic Resource
    Effects of polyethylene molecular structure on peroxide crosslinking of low density polyethylene (1992)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 32 (1992), S. 939-943 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: The effects of molecular structure on the dicumyl peroxide crosslinking of two low density polyethylenes have been studied. Peroxide efficiency was determined largely by the content of terminal vinyls in the two polymers. Differences in molecular weight distribution and branch content had comparatively little influence on the gel content but hot creep resistance of the vulcanized materials was affected. Scorching was affected, also, by the presence of vinyl unsaturations in the polymer.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760321405
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  • 10
    Electronic Resource
    Electronic Resource
    Reactive extrusion of polystyrene/polyethylene blends (1988)
    Stamford, Conn. [u.a.] : Wiley-Blackwell
    Polymer Engineering and Science 28 (1988), S. 1434-1442 
    Details
    ISSN: 0032-3888
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: The feasibility of inducing beneficial changes to polystyrene/polyethylene (PS/PE) blends via reactive extrusion processes is considered. Experiments have been conducted on 50:50 wt.% PS/PE blends that were treated with different levels of dicumyl peroxide and triallyl isocyanurate coupling agent. Both a low molecular weight and a high molecular weight blend series have been investigated. A “more reactive” polystyrene was synthesized by incorporation of a minor amount of ortho-vinylbenzaldehyde. Blends containing this modified polystyrene were subjected to identical processing' conditions on a counter-rotating twin screw extruder. Examination of the tensile properties of the extrusion products suggested that a judicious level of peroxide and coupling agent additives would be beneficial to the ultimate physical properties. The quantity of styrenic phase becoming chemically grafted to the polyethylene matrix was influenced most strongly by the level of the chosen coupling agent. As determined by scanning electron microscopy, the phase morphologies of the tensile test fracture surfaces were strongly dependent upon the reaction extrusion process; those extruded blends that had been exposed to the additive pre-treatment displayed substantially finer microstructure. The enthalpy of fusion of the polyethylene melting endotherm was likewise influenced by both the presence or absence of the additives as well as the molecular weight nature of the blend series.
    Additional Material: 13 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/pen.760282113
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