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  • 1
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    Introduction to the Special Issue 'The Anthropocene in the Longue Duree' (2015)
    Sage
    In: Holocene
    Details
    Publication Date: 2015-09-17
    Print ISSN: 0959-6836
    Electronic ISSN: 1477-0911
    Topics: Geography , Geosciences
    Published by Sage
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  • 2
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    RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-02-25
    Description: Tumours with mutant BRAF are dependent on the RAF-MEK-ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" 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/PMC3178447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulikakos, Poulikos I -- Zhang, Chao -- Bollag, Gideon -- Shokat, Kevan M -- Rosen, Neal -- 1P01CA129243-02/CA/NCI NIH HHS/ -- 2R01EB001987/EB/NIBIB NIH HHS/ -- P01 CA129243-010002/CA/NCI NIH HHS/ -- R01 EB001987/EB/NIBIB NIH HHS/ -- U01 CA091178/CA/NCI NIH HHS/ -- U01 CA091178-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):427-30. doi: 10.1038/nature08902.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20179705" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Catalytic Domain ; Cell Line ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Indoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Models, Biological ; Neoplasms/drug therapy/enzymology/genetics/metabolism ; Phosphorylation ; Protein Binding ; Protein Kinase Inhibitors/metabolism/*pharmacology/therapeutic use ; Protein Multimerization ; Proto-Oncogene Proteins B-raf/antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Sulfonamides/pharmacology ; Transcriptional Activation/*drug effects ; raf Kinases/*antagonists & inhibitors/chemistry/genetics/*metabolism ; ras Proteins/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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    RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-11-25
    Description: Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266695/" 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/PMC3266695/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulikakos, Poulikos I -- Persaud, Yogindra -- Janakiraman, Manickam -- Kong, Xiangju -- Ng, Charles -- Moriceau, Gatien -- Shi, Hubing -- Atefi, Mohammad -- Titz, Bjoern -- Gabay, May Tal -- Salton, Maayan -- Dahlman, Kimberly B -- Tadi, Madhavi -- Wargo, Jennifer A -- Flaherty, Keith T -- Kelley, Mark C -- Misteli, Tom -- Chapman, Paul B -- Sosman, Jeffrey A -- Graeber, Thomas G -- Ribas, Antoni -- Lo, Roger S -- Rosen, Neal -- Solit, David B -- K22 CA151638/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA127240/CA/NCI NIH HHS/ -- R01 CA127240-01A1/CA/NCI NIH HHS/ -- T32 CACA062948-15/PHS HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 23;480(7377):387-90. doi: 10.1038/nature10662.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22113612" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Animals ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects/*genetics ; Exons/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Indoles/pharmacology ; MAP Kinase Signaling System/drug effects ; Melanoma/enzymology/metabolism/pathology ; Mice ; Mutant Proteins/chemistry/genetics/metabolism ; Protein Isoforms/chemistry/genetics/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Multimerization/drug effects/*genetics ; Proto-Oncogene Proteins B-raf/antagonists & ; inhibitors/chemistry/*genetics/*metabolism ; Sulfonamides/pharmacology
    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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  • 4
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    Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-04
    Description: It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine 5'-diphosphate-bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRAS(G12C) signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRAS(G12C) is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRAS(G12C) inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRAS(G12C) undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRAS(G12C)-driven cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lito, Piro -- Solomon, Martha -- Li, Lian-Sheng -- Hansen, Rasmus -- Rosen, Neal -- K08CA191082-01A1/CA/NCI NIH HHS/ -- P01CA129243-06/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 5;351(6273):604-8. doi: 10.1126/science.aad6204. Epub 2016 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org litop@mskcc.org. ; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ; Wellspring Biosciences, La Jolla, CA, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org litop@mskcc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26841430" target="_blank"〉PubMed〈/a〉
    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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  • 5
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    Therapy-induced tumour secretomes promote resistance and tumour progression (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-03-26
    Description: Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507807/" 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/PMC4507807/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obenauf, Anna C -- Zou, Yilong -- Ji, Andrew L -- Vanharanta, Sakari -- Shu, Weiping -- Shi, Hubing -- Kong, Xiangju -- Bosenberg, Marcus C -- Wiesner, Thomas -- Rosen, Neal -- Lo, Roger S -- Massague, Joan -- CA129243/CA/NCI NIH HHS/ -- CA163167/CA/NCI NIH HHS/ -- J 3013/Austrian Science Fund FWF/Austria -- MC_UU_12022/7/Medical Research Council/United Kingdom -- P01 CA094060/CA/NCI NIH HHS/ -- P01 CA129243/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA176111/CA/NCI NIH HHS/ -- U54 CA163167/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Apr 16;520(7547):368-72. doi: 10.1038/nature14336. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Gerstner Sloan Kettering School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK. ; Division of Dermatology, Department of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA. ; 1] Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807485" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/metabolism/pathology/secretion ; Animals ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Clone Cells/drug effects/pathology ; *Disease Progression ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm/*drug effects ; Enzyme Activation/drug effects ; Female ; Humans ; Lung Neoplasms/drug therapy/metabolism/pathology/*secretion ; Melanoma/drug therapy/metabolism/pathology/*secretion ; Metabolome/*drug effects ; Mice ; Neoplasm Metastasis/drug therapy/pathology ; Protein Kinase Inhibitors/*pharmacology/*therapeutic use ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-fos/deficiency ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Signal Transduction/drug effects ; Tumor Microenvironment/drug effects
    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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  • 6
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    Precision probes of IFN activity [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-10-24
    Description: Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    Foraminiferal Stratigraphy and Paleoecology of Blufftown Formation (Santonian-Campanian) of Georgia and Eastern Alabama: ABSTRACT (1985)
    American Association of Petroleum Geologists
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    Publication Date: 1985-01-01
    Print ISSN: 0149-1423
    Electronic ISSN: 1943-2674
    Topics: Geosciences
    Published by American Association of Petroleum Geologists
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  • 8
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    Planktonic Zonation of the Paleogene of Texas and Louisiana Gulf Coast and Their Relationship to Relative Changes of Coastal Onlap: ABSTRACT (1995)
    American Association of Petroleum Geologists
    Details
    Publication Date: 1995-01-01
    Print ISSN: 0149-1423
    Electronic ISSN: 1943-2674
    Topics: Geosciences
    Published by American Association of Petroleum Geologists
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  • 9
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    Subsurface Planktonic Zonation of the Paleogene of Texas and Louisiana Gulf Coast and Their Relationship to Relative Changes of Coastal Onlap: ABSTRACT (1994)
    American Association of Petroleum Geologists
    Details
    Publication Date: 1994-01-01
    Print ISSN: 0149-1423
    Electronic ISSN: 1943-2674
    Topics: Geosciences
    Published by American Association of Petroleum Geologists
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  • 10
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    Biostratigraphic Application to Pliocene Sequence Stratigraphy of the Western and Central Gulf of Mexico and Its Integration to Lithostratigraphy: ABSTRACT (1990)
    American Association of Petroleum Geologists
    Details
    Publication Date: 1990-01-01
    Print ISSN: 0149-1423
    Electronic ISSN: 1943-2674
    Topics: Geosciences
    Published by American Association of Petroleum Geologists
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