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  • 1
    Publication Date: 2018-10-02
    Description: Therapeutic strategies to target RAS -mutant cancers Therapeutic strategies to target 〈i〉RAS〈/i〉-mutant cancers, Published online: 01 October 2018; doi:10.1038/s41571-018-0105-0 Effective therapeutic strategies to target RAS-mutant cancers have proved elusive, but in the past few years, several promising strategies have been tested in clinical trials. The authors describe historical and ongoing therapeutic approaches based on the direct or indirect targeting of RAS.
    Print ISSN: 1759-4774
    Electronic ISSN: 1759-4782
    Topics: Medicine
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  • 2
    Publication Date: 2018-02-06
    Description: Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes, Published online: 05 February 2018; doi:10.1038/s41467-017-02383-6 Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-01-28
    Description: Since the invention of the laser more than 50 years ago, scientists have striven to achieve amplification on atomic transitions of increasingly shorter wavelength. The introduction of X-ray free-electron lasers makes it possible to pump new atomic X-ray lasers with ultrashort pulse duration, extreme spectral brightness and full temporal coherence. Here we describe the implementation of an X-ray laser in the kiloelectronvolt energy regime, based on atomic population inversion and driven by rapid K-shell photo-ionization using pulses from an X-ray free-electron laser. We established a population inversion of the Kalpha transition in singly ionized neon at 1.46 nanometres (corresponding to a photon energy of 849 electronvolts) in an elongated plasma column created by irradiation of a gas medium. We observed strong amplified spontaneous emission from the end of the excited plasma. This resulted in femtosecond-duration, high-intensity X-ray pulses of much shorter wavelength and greater brilliance than achieved with previous atomic X-ray lasers. Moreover, this scheme provides greatly increased wavelength stability, monochromaticity and improved temporal coherence by comparison with present-day X-ray free-electron lasers. The atomic X-ray lasers realized here may be useful for high-resolution spectroscopy and nonlinear X-ray studies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rohringer, Nina -- Ryan, Duncan -- London, Richard A -- Purvis, Michael -- Albert, Felicie -- Dunn, James -- Bozek, John D -- Bostedt, Christoph -- Graf, Alexander -- Hill, Randal -- Hau-Riege, Stefan P -- Rocca, Jorge J -- England -- Nature. 2012 Jan 25;481(7382):488-91. doi: 10.1038/nature10721.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94551, USA. nina.rohringer@asg.mpg.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22281598" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2016-04-21
    Description: Gauss's law dictates that the net electric field inside a conductor in electrostatic equilibrium is zero by effective charge screening; free carriers within a metal eliminate internal dipoles that may arise owing to asymmetric charge distributions. Quantum physics supports this view, demonstrating that delocalized electrons make a static macroscopic polarization, an ill-defined quantity in metals--it is exceedingly unusual to find a polar metal that exhibits long-range ordered dipoles owing to cooperative atomic displacements aligned from dipolar interactions as in insulating phases. Here we describe the quantum mechanical design and experimental realization of room-temperature polar metals in thin-film ANiO3 perovskite nickelates using a strategy based on atomic-scale control of inversion-preserving (centric) displacements. We predict with ab initio calculations that cooperative polar A cation displacements are geometrically stabilized with a non-equilibrium amplitude and tilt pattern of the corner-connected NiO6 octahedral--the structural signatures of perovskites--owing to geometric constraints imposed by the underlying substrate. Heteroepitaxial thin-films grown on LaAlO3 (111) substrates fulfil the design principles. We achieve both a conducting polar monoclinic oxide that is inaccessible in compositionally identical films grown on (001) substrates, and observe a hidden, previously unreported, non-equilibrium structure in thin-film geometries. We expect that the geometric stabilization approach will provide novel avenues for realizing new multifunctional materials with unusual coexisting properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, T H -- Puggioni, D -- Yuan, Y -- Xie, L -- Zhou, H -- Campbell, N -- Ryan, P J -- Choi, Y -- Kim, J-W -- Patzner, J R -- Ryu, S -- Podkaminer, J P -- Irwin, J -- Ma, Y -- Fennie, C J -- Rzchowski, M S -- Pan, X Q -- Gopalan, V -- Rondinelli, J M -- Eom, C B -- England -- Nature. 2016 May 5;533(7601):68-72. doi: 10.1038/nature17628. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. ; Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208, USA. ; Department of Materials Science and Engineering and Materials Research Institute, Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Chemical Engineering and Materials Science and Department of Physics and Astronomy, University of California-Irvine, Irvine, California 92697, USA. ; National Laboratory of Solid State Microstructures and College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu 210093, China. ; Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois 60439, USA. ; Department of Physics, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. ; School of Applied and Engineering Physics, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096369" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-01-07
    Description: Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shu, Shaokun -- Lin, Charles Y -- He, Housheng Hansen -- Witwicki, Robert M -- Tabassum, Doris P -- Roberts, Justin M -- Janiszewska, Michalina -- Huh, Sung Jin -- Liang, Yi -- Ryan, Jeremy -- Doherty, Ernest -- Mohammed, Hisham -- Guo, Hao -- Stover, Daniel G -- Ekram, Muhammad B -- Peluffo, Guillermo -- Brown, Jonathan -- D'Santos, Clive -- Krop, Ian E -- Dillon, Deborah -- McKeown, Michael -- Ott, Christopher -- Qi, Jun -- Ni, Min -- Rao, Prakash K -- Duarte, Melissa -- Wu, Shwu-Yuan -- Chiang, Cheng-Ming -- Anders, Lars -- Young, Richard A -- Winer, Eric P -- Letai, Antony -- Barry, William T -- Carroll, Jason S -- Long, Henry W -- Brown, Myles -- Liu, X Shirley -- Meyer, Clifford A -- Bradner, James E -- Polyak, Kornelia -- CA080111/CA/NCI NIH HHS/ -- CA103867/CA/NCI NIH HHS/ -- CA120184/CA/NCI NIH HHS/ -- CA168504/CA/NCI NIH HHS/ -- P50 CA168504/CA/NCI NIH HHS/ -- R01 CA103867/CA/NCI NIH HHS/ -- England -- Nature. 2016 Jan 21;529(7586):413-7. doi: 10.1038/nature16508. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; Princess Margaret Cancer Center/University Health Network, Toronto, Ontario M5G1L7, Canada. ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G2M9, Canada. ; Harvard University, Cambridge, Massachusetts 02138, USA. ; Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK. ; Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. ; Broad Institute, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735014" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2018-11-03
    Description: Publisher Correction: Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma Publisher Correction: Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma, Published online: 02 November 2018; doi:10.1038/s41467-018-07182-1 Publisher Correction: Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2018-11-06
    Description: Radiotherapy induces responses of lung cancer to CTLA-4 blockade Radiotherapy induces responses of lung cancer to CTLA-4 blockade, Published online: 05 November 2018; doi:10.1038/s41591-018-0232-2 Radiotherapy-induced abscopal responses enhance the efficacy of anti-CTLA-4 in patients with non-small-cell lung cancer.
    Print ISSN: 1078-8956
    Electronic ISSN: 1546-170X
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2018-12-11
    Description: Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis, Published online: 10 December 2018; doi:10.1038/s41590-018-0273-1 Germinal center B cells undergo reiterative rounds of proliferation and selection. Melnick and colleagues show that the histone demethylase LSD1 is necessary for this reiterative process via its interactions with the transcription factor BCL6.
    Print ISSN: 1529-2908
    Electronic ISSN: 1529-2916
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2011-03-29
    Description: CD4(+) T helper lymphocytes that express interleukin-17 (T(H)17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in T(H)17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of T(H)17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human T(H)17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORgammat, which is required for induction of IL-17 transcription and for the manifestation of T(H)17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORgammat transcriptional activity. Digoxin inhibited murine T(H)17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4(+) T cells. Using these small-molecule compounds, we demonstrate that RORgammat is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORgammat-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172133/" 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/PMC3172133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huh, Jun R -- Leung, Monica W L -- Huang, Pengxiang -- Ryan, Daniel A -- Krout, Michael R -- Malapaka, Raghu R V -- Chow, Jonathan -- Manel, Nicolas -- Ciofani, Maria -- Kim, Sangwon V -- Cuesta, Adolfo -- Santori, Fabio R -- Lafaille, Juan J -- Xu, H Eric -- Gin, David Y -- Rastinejad, Fraydoon -- Littman, Dan R -- 2R01GM55217/GM/NIGMS NIH HHS/ -- F32GM0860552/GM/NIGMS NIH HHS/ -- R01 AI080885/AI/NIAID NIH HHS/ -- R01AI080885/AI/NIAID NIH HHS/ -- R01GM058833/GM/NIGMS NIH HHS/ -- R01GM067659/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Apr 28;472(7344):486-90. doi: 10.1038/nature09978. Epub 2011 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21441909" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmune Diseases/drug therapy/immunology/pathology ; Autoimmunity/drug effects/immunology ; Cell Differentiation/*drug effects ; Cell Line ; Digoxin/*analogs & derivatives/chemistry/metabolism/*pharmacology/therapeutic use ; Drosophila/cytology ; Humans ; Interleukin-17/biosynthesis/immunology ; Mice ; Nuclear Receptor Subfamily 1, Group F, Member 3/*antagonists & ; inhibitors/metabolism ; Th17 Cells/*cytology/*drug effects/immunology ; Transcription, Genetic/drug effects/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2011-08-26
    Description: Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency 〈30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoffmann, A A -- Montgomery, B L -- Popovici, J -- Iturbe-Ormaetxe, I -- Johnson, P H -- Muzzi, F -- Greenfield, M -- Durkan, M -- Leong, Y S -- Dong, Y -- Cook, H -- Axford, J -- Callahan, A G -- Kenny, N -- Omodei, C -- McGraw, E A -- Ryan, P A -- Ritchie, S A -- Turelli, M -- O'Neill, S L -- England -- Nature. 2011 Aug 24;476(7361):454-7. doi: 10.1038/nature10356.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Bio21 Institute, Department of Genetics, The University of Melbourne, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21866160" target="_blank"〉PubMed〈/a〉
    Keywords: Aedes/*microbiology/physiology/*virology ; Animals ; Dengue/microbiology/*prevention & control/*transmission/virology ; Dengue Virus/isolation & purification/*physiology ; Drosophila melanogaster/microbiology ; Female ; Humans ; Insect Vectors/microbiology/physiology/virology ; Male ; Pest Control, Biological/*methods ; Queensland ; Time Factors ; Wolbachia/isolation & purification/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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