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  • 1
    Publication Date: 2018-06-16
    Description: Purpose: We investigated the mechanisms of how TGFβ pathway is activated by chemotherapeutics and whether a novel TGFβ trap called RER can block chemotherapeutics-induced TGFβ pathway activation and enhance their antitumor activity in gynecologic cancer. Patients and Methods: An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cervical cancer using IHC. Furthermore, the effects of chemotherapeutics on TGFβ signaling and function, and the effects of RER on chemotherapy-induced TGFβ signaling were determined in gynecologic cancer cells. Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGFβ signaling activation. Chemotherapy was found to activate TGFβ signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGFβ1, chemotherapeutics were found to stimulate Smad2/3 phosphorylation, cell migration, and markers related to epithelial–mesenchymal transition (EMT) and cancer stem cells (CSC). These TGFβ-like effects were due to the stimulation of TGFβ1 expression and secretion, and could all be abrogated by TGFβ inhibitors including a novel TGFβ trap protein called RER both in vitro and in vivo . Importantly, combination treatment with RER and cisplatin showed a higher tumor inhibitory activity than either agent alone in a xenograft model of ovarian cancer. Conclusions: Chemotherapeutics can stimulate TGFβ1 production and consequently enhance TGFβ signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGFβ inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy. Clin Cancer Res; 24(12); 2780–93. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2012-03-30
    Description: DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of 5-methylcytosine at fertilization, followed by passive loss that reaches a minimum at the blastocyst stage. However, this model is based on limited data, and so far no base-resolution maps exist to support and refine it. Here we generate genome-scale DNA methylation maps in mouse gametes and from the zygote through post-implantation. We find that the oocyte already exhibits global hypomethylation, particularly at specific families of long interspersed element 1 and long terminal repeat retroelements, which are disparately methylated between gametes and have lower methylation values in the zygote than in sperm. Surprisingly, the oocyte contributes a unique set of differentially methylated regions (DMRs)--including many CpG island promoters--that are maintained in the early embryo but are lost upon specification and absent from somatic cells. In contrast, sperm-contributed DMRs are largely intergenic and become hypermethylated after the blastocyst stage. Our data provide a genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic, before returning to the canonical somatic pattern.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331945/" 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/PMC3331945/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smith, Zachary D -- Chan, Michelle M -- Mikkelsen, Tarjei S -- Gu, Hongcang -- Gnirke, Andreas -- Regev, Aviv -- Meissner, Alexander -- 1P50HG006193-01/HG/NHGRI NIH HHS/ -- 5DP1OD003958/OD/NIH HHS/ -- 5RC1AA019317/AA/NIAAA NIH HHS/ -- DP1 CA174427/CA/NCI NIH HHS/ -- DP1 OD003958/OD/NIH HHS/ -- DP1 OD003958-04/OD/NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- P50 HG006193-01/HG/NHGRI NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 28;484(7394):339-44. doi: 10.1038/nature10960.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22456710" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CpG Islands/genetics ; *DNA Methylation/genetics ; Embryo, Mammalian/*embryology/*metabolism ; Embryonic Development/*genetics ; Female ; Fertilization/genetics ; Genome/genetics ; Long Interspersed Nucleotide Elements/genetics ; Male ; Mice ; Oocytes/metabolism ; Spermatozoa/metabolism ; Terminal Repeat Sequences/genetics ; Zygote/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-08-09
    Description: DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively stable DNA methylation patterns, with 70-80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821869/" 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/PMC3821869/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ziller, Michael J -- Gu, Hongcang -- Muller, Fabian -- Donaghey, Julie -- Tsai, Linus T-Y -- Kohlbacher, Oliver -- De Jager, Philip L -- Rosen, Evan D -- Bennett, David A -- Bernstein, Bradley E -- Gnirke, Andreas -- Meissner, Alexander -- ES017690/ES/NIEHS NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- P30AG10161/AG/NIA NIH HHS/ -- R01 AG017917/AG/NIA NIH HHS/ -- R01AG15819/AG/NIA NIH HHS/ -- R01AG17917/AG/NIA NIH HHS/ -- R01AG36042/AG/NIA NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- England -- Nature. 2013 Aug 22;500(7463):477-81. doi: 10.1038/nature12433. Epub 2013 Aug 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23925113" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; CpG Islands/genetics ; *DNA Methylation ; Enhancer Elements, Genetic/genetics ; Genome, Human/*genetics ; Genome-Wide Association Study ; Humans ; Organ Specificity ; Polymorphism, Single Nucleotide/genetics ; Sequence Analysis, DNA ; Sulfites/metabolism ; Transcription Factors/metabolism
    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: 2014-03-29
    Description: Hitherto, rings have been found exclusively around the four giant planets in the Solar System. Rings are natural laboratories in which to study dynamical processes analogous to those that take place during the formation of planetary systems and galaxies. Their presence also tells us about the origin and evolution of the body they encircle. Here we report observations of a multichord stellar occultation that revealed the presence of a ring system around (10199) Chariklo, which is a Centaur--that is, one of a class of small objects orbiting primarily between Jupiter and Neptune--with an equivalent radius of 124 +/- 9 kilometres (ref. 2). There are two dense rings, with respective widths of about 7 and 3 kilometres, optical depths of 0.4 and 0.06, and orbital radii of 391 and 405 kilometres. The present orientation of the ring is consistent with an edge-on geometry in 2008, which provides a simple explanation for the dimming of the Chariklo system between 1997 and 2008, and for the gradual disappearance of ice and other absorption features in its spectrum over the same period. This implies that the rings are partly composed of water ice. They may be the remnants of a debris disk, possibly confined by embedded, kilometre-sized satellites.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Braga-Ribas, F -- Sicardy, B -- Ortiz, J L -- Snodgrass, C -- Roques, F -- Vieira-Martins, R -- Camargo, J I B -- Assafin, M -- Duffard, R -- Jehin, E -- Pollock, J -- Leiva, R -- Emilio, M -- Machado, D I -- Colazo, C -- Lellouch, E -- Skottfelt, J -- Gillon, M -- Ligier, N -- Maquet, L -- Benedetti-Rossi, G -- Ramos Gomes, A Jr -- Kervella, P -- Monteiro, H -- Sfair, R -- El Moutamid, M -- Tancredi, G -- Spagnotto, J -- Maury, A -- Morales, N -- Gil-Hutton, R -- Roland, S -- Ceretta, A -- Gu, S-h -- Wang, X-b -- Harpsoe, K -- Rabus, M -- Manfroid, J -- Opitom, C -- Vanzi, L -- Mehret, L -- Lorenzini, L -- Schneiter, E M -- Melia, R -- Lecacheux, J -- Colas, F -- Vachier, F -- Widemann, T -- Almenares, L -- Sandness, R G -- Char, F -- Perez, V -- Lemos, P -- Martinez, N -- Jorgensen, U G -- Dominik, M -- Roig, F -- Reichart, D E -- LaCluyze, A P -- Haislip, J B -- Ivarsen, K M -- Moore, J P -- Frank, N R -- Lambas, D G -- England -- Nature. 2014 Apr 3;508(7494):72-5. doi: 10.1038/nature13155. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Observatorio Nacional/MCTI, Rua General Jose Cristino 77, CEP 20921-400 Rio de Janeiro, RJ, Brazil. ; LESIA, Observatoire de Paris, CNRS UMR 8109, Universite Pierre et Marie Curie, Universite Paris-Diderot, 5 place Jules Janssen, F-92195 Meudon Cedex, France. ; Instituto de Astrofisica de Andalucia, CSIC, Apartado 3004, 18080 Granada, Spain. ; Max Planck Institute for Solar System Research, Justus-von-Liebig-Weg 3, 37077 Gottingen, Germany. ; 1] Observatorio Nacional/MCTI, Rua General Jose Cristino 77, CEP 20921-400 Rio de Janeiro, RJ, Brazil [2] Observatorio do Valongo/UFRJ, Ladeira Pedro Antonio 43, CEP 20.080-090 Rio de Janeiro, RJ, Brazil [3] Observatoire de Paris, IMCCE, UPMC, CNRS, 77 Avenue Denfert-Rochereau, 75014 Paris, France. ; Observatorio do Valongo/UFRJ, Ladeira Pedro Antonio 43, CEP 20.080-090 Rio de Janeiro, RJ, Brazil. ; Institut d'Astrophysique de l'Universite de Liege, Allee du 6 Aout 17, B-4000 Liege, Belgium. ; Physics and Astronomy Department, Appalachian State University, Boone, North Carolina 28608, USA. ; Instituto de Astrofisica, Facultad de Fisica, Pontificia Universidad Catolica de Chile, Avenida Vicuna Mackenna 4860, Santiago 7820436, Chile. ; Universidade Estadual de Ponta Grossa, O.A. - DEGEO, Avenida Carlos Cavalcanti 4748, Ponta Grossa 84030-900, PR, Brazil. ; 1] Polo Astronomico Casimiro Montenegro Filho/FPTI-BR, Avenida Tancredo Neves 6731, CEP 85867-900, Foz do Iguacu, PR, Brazil [2] Universidade Estadual do Oeste do Parana (Unioeste), Avenda Tarquinio Joslin dos Santos, 1300, CEP 85870-650, Foz do Iguacu, PR, Brazil. ; 1] Ministerio de Educacion de la Provincia de Cordoba, Santa Rosa 751, Cordoba 5000, Argentina [2] Observatorio Astronomico, Universidad Nacional de Cordoba, Laprida 854, Cordoba 5000, Argentina. ; 1] Niels Bohr Institute, University of Copenhagen, Juliane Maries vej 30, 2100 Copenhagen, Denmark [2] Centre for Star and Planet Formation, Geological Museum, Oster Voldgade 5, 1350 Copenhagen, Denmark. ; Instituto de Fisica e Quimica, Avenida BPS 1303, CEP 37500-903, Itajuba, MG, Brazil. ; UNESP - Universidade Estadual Paulista, Avenida Ariberto Pereira da Cunha, 333, CEP 12516-410 Guaratingueta, SP, Brazil. ; 1] LESIA, Observatoire de Paris, CNRS UMR 8109, Universite Pierre et Marie Curie, Universite Paris-Diderot, 5 place Jules Janssen, F-92195 Meudon Cedex, France [2] Observatoire de Paris, IMCCE, UPMC, CNRS, 77 Avenue Denfert-Rochereau, 75014 Paris, France. ; 1] Observatorio Astronomico Los Molinos, DICYT, MEC, 12400 Montevideo, Uruguay [2] Departamento de Astronomia, Facultad Ciencias, Universidad de la Republica, 11300 Montevideo, Uruguay. ; Observatorio El Catalejo, Mussio 255, Santa Rosa, La Pampa 6300, Argentina. ; San Pedro de Atacama Celestial Explorations, Casilla 21, San Pedro de Atacama 1410000, Chile. ; Complejo Astronomico El Leoncito (CASLEO) and San Juan National University, Avenida Espana 1512 sur, J5402DSP, San Juan, Argentina. ; Observatorio Astronomico Los Molinos, DICYT, MEC, 12400 Montevideo, Uruguay. ; 1] Departamento de Astronomia, Facultad Ciencias, Universidad de la Republica, 11300 Montevideo, Uruguay [2] Observatorio del IPA, Consejo de Formacion en Educacion, 11800 Montevideo, Uruguay. ; 1] Yunnan Observatories, Chinese Academy of Sciences, Kunming 650011, China [2] Key Laboratory for the Structure and Evolution of Celestial Objects, Chinese Academy of Sciences, Kunming 650011, China. ; 1] Instituto de Astrofisica, Facultad de Fisica, Pontificia Universidad Catolica de Chile, Avenida Vicuna Mackenna 4860, Santiago 7820436, Chile [2] Max Planck Institute for Astronomy, Konigstuhl 17, 69117 Heidelberg, Germany. ; Department of Electrical Engineering and Center of Astro-Engineering, Pontificia Universidad Catolica de Chile, Avenida Vicuna Mackenna 4860, Santiago 7820436, Chile. ; Polo Astronomico Casimiro Montenegro Filho/FPTI-BR, Avenida Tancredo Neves 6731, CEP 85867-900, Foz do Iguacu, PR, Brazil. ; 1] Observatorio Astronomico, Universidad Nacional de Cordoba, Laprida 854, Cordoba 5000, Argentina [2] Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Cordoba 5000, Argentina [3] Instituto de Astronomia Teorica y Experimental IATE-CONICET, Cordoba 5000, Argentina [4] Facultad de Ciencias Exactas, Fisicas y Naturales, Universidad Nacional de Cordoba (UNC), Cordoba 5000, Argentina. ; Observatorio Astronomico, Universidad Nacional de Cordoba, Laprida 854, Cordoba 5000, Argentina. ; Observatoire de Paris, IMCCE, UPMC, CNRS, 77 Avenue Denfert-Rochereau, 75014 Paris, France. ; Unidad de Astronomia, Facultad de Ciencias Basicas, Universidad de Antofagasta, Avenida Angamos 601, Antofagasta, Region II, Chile. ; Departamento de Astronomia, Facultad Ciencias, Universidad de la Republica, 11300 Montevideo, Uruguay. ; Scottish Universities Physics Alliance, University of St Andrews, School of Physics and Astronomy, North Haugh, St Andrews KY16 9SS, UK. ; Department of Physics and Astronomy, University of North Carolina - Chapel Hill, North Carolina 27599, USA. ; 1] Observatorio Astronomico, Universidad Nacional de Cordoba, Laprida 854, Cordoba 5000, Argentina [2] Instituto de Astronomia Teorica y Experimental IATE-CONICET, Cordoba 5000, Argentina.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670644" 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: 2015-02-20
    Description: Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499331/" 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/PMC4499331/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsankov, Alexander M -- Gu, Hongcang -- Akopian, Veronika -- Ziller, Michael J -- Donaghey, Julie -- Amit, Ido -- Gnirke, Andreas -- Meissner, Alexander -- 5F32DK095537/DK/NIDDK NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- P50HG006193/HG/NHGRI NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):344-9. doi: 10.1038/nature14233.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Immunology, Weizmann Institute, Rehovot, 76100 Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693565" target="_blank"〉PubMed〈/a〉
    Keywords: *Cell Differentiation/genetics ; Cell Lineage ; Chromatin/chemistry/genetics/metabolism ; Chromatin Assembly and Disassembly/genetics ; DNA Methylation ; Embryonic Stem Cells/*cytology/*metabolism ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/genetics ; Epigenomics ; Genome, Human/genetics ; Germ Layers/cytology/metabolism ; Histones/chemistry/metabolism ; Humans ; Protein Binding ; Signal Transduction ; Transcription Factors/*metabolism ; Transcription, Genetic/genetics
    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: 2018-08-02
    Description: Telomerase is the ribonucleoprotein reverse transcriptase that catalyzes the synthesis of telomeres at the ends of linear chromosomes and contributes to proper telomere-loop (T-loop) formation. Formation of the T-loop, an obligate step before cell division can proceed, requires the generation of a 3'-overhang on the G-rich strand of telomeric DNA via telomerase or C-strand specific nucleases. Here, it is discovered that telomerase activity is critical for efficient cell-cycle progression using transient chemical inhibition by the telomerase inhibitor, imetelstat. Telomerase inhibition changed cell cycle kinetics and increased the proportion of cells in G 2 -phase, suggesting delayed clearance through this checkpoint. Investigating the possible contribution of unstructured telomere ends to these cell-cycle distribution changes, it was observed that imetelstat treatment induced H2AX DNA damage foci in a subset of telomerase-positive cells but not telomerase-negative primary human fibroblasts. Chromatin-immunoprecipitation with H2AX antibodies demonstrated imetelstat treatment-dependent enrichment of this DNA damage marker at telomeres. Notably, the effects of telomerase inhibition on cell cycle profile alterations were abrogated by pharmacological inhibition of the DNA-damage-repair transducer, ATM. Also, imetelstat potentiation of etoposide, a DNA-damaging drug that acts preferentially during S–G 2 phases of the cell cycle, depends on functional ATM signaling. Thus, telomerase inhibition delays the removal of ATM-dependent DNA damage signals from telomeres in telomerase-positive cancer cells and interferes with cell cycle progression through G 2 . Implications: This study demonstrates that telomerase activity directly facilitates the progression of the cell cycle through modulation of transient telomere dysfunction signals. Mol Cancer Res; 16(8); 1215–25. ©2018 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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  • 7
    Publication Date: 2014-12-24
    Description: Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system. Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line. Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336237/" 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/PMC4336237/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ziller, Michael J -- Edri, Reuven -- Yaffe, Yakey -- Donaghey, Julie -- Pop, Ramona -- Mallard, William -- Issner, Robbyn -- Gifford, Casey A -- Goren, Alon -- Xing, Jeffrey -- Gu, Hongcang -- Cacchiarelli, Davide -- Tsankov, Alexander M -- Epstein, Charles -- Rinn, John L -- Mikkelsen, Tarjei S -- Kohlbacher, Oliver -- Gnirke, Andreas -- Bernstein, Bradley E -- Elkabetz, Yechiel -- Meissner, Alexander -- F32 DK095537/DK/NIDDK NIH HHS/ -- HG006911/HG/NHGRI NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- U54 HG006991/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):355-9. doi: 10.1038/nature13990. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 6997801, Israel. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [3] Center for Systems Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Applied Bioinformatics, Center for Bioinformatics and Quantitative Biology Center, University of Tubingen, Tubingen 72076, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533951" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Differentiation/*genetics ; Cell Lineage/genetics ; Embryonic Stem Cells/*cytology/metabolism ; Epigenesis, Genetic/*genetics ; Epigenomics/*methods ; Humans ; Neural Stem Cells/*cytology/*metabolism ; RNA, Small Interfering/analysis/genetics ; Reproducibility of Results ; Transcription Factors/metabolism ; Transcription, Genetic/genetics
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2018-01-04
    Description: We investigated the effect of daily dietary curcumin intake on the development and progression of spontaneous ovarian cancer in a galline (hen) model, as the chicken is the only nonhuman animal in which ovarian cancer spontaneously develops with a high prevalence. At the end of 12 months, ovarian cancer had spontaneously developed in 39% (35/90) of control hens not fed curcumin ( n = 90). In comparison, it spontaneously developed in 27% (24/90) and 17% (15/90) of hens given curcumin at 25.8 ( n = 90) and 53.0 mg/day ( n = 90), respectively ( P = 0.004). This represented significant dose-dependent reductions in overall ovarian cancer incidence in the 25.8 and 53.0 mg/day curcumin-fed groups (31% and 57%, respectively). Daily curcumin intake also reduced ovarian tumor sizes ( P = 0.04) and number of tumors ( P = 0.006). Evaluation of the molecular mechanisms underlying the chemopreventive and antitumor effects of curcumin revealed that NF-B and STAT3 signaling pathways were significantly inhibited but that the nuclear factor erythroid 2/heme oxygenase 1 antioxidant pathway was induced by curcumin intake in a dose-dependent manner in ovarian tissues ( P 〈 0.05). Sequencing of the Ras family genes ( KRAS, NRAS , and HRAS) revealed less frequent KRAS and HRAS mutations in ovarian tumors in the curcumin-fed animals. In conclusion, our results demonstrated for the first time that daily curcumin intake leads to a significant and dose-dependent reduction in spontaneous ovarian cancer incidence and tumor growth, indicating a tremendous role for curcumin as a chemopreventive strategy for ovarian cancer. Cancer Prev Res; 11(1); 59–67. ©2017 AACR .
    Print ISSN: 1940-6207
    Electronic ISSN: 1940-6215
    Topics: Medicine
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Hydrobiologia 377 (1998), S. 73-83 
    ISSN: 1573-5117
    Keywords: diet ; early life ; clupeid ; zooplankton ; reservoir
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We studied dietary shifts in the early life stages of gizzard shad Dorosoma cepedianum, a dominant forage species in North American reservoirs. Larval fish and zooplankton samples were collected weekly during spring in Sardis Reservoir, Mississippi, USA. Diet and prey electivity data suggested the existence of three dietary niches during early life stages: microzooplankton (larvae ≤10 mm total length) in which microzooplankters comprised over 90% by number; crustacean zooplankton (larvae 11–25 mm) in which larval gizzard shad consumed substantial numbers of crustacean zooplankton; and microplankton (larvae 〉25 mm) in which gizzard shad shifted to filtering protozoans, rotifers, and phytoplankton. There was a high overlap (84%) between the diet of larval gizzard shad and crappies Pomoxis spp. during early May. Larval gizzard shad can potentially reduce microzooplankton density through predation, then shift to crustacean zooplankton and drive their density to decline, then revert to filtration of microzooplankton and exploit phytoplankton. Although, gizzard shad have the ability to influence trophic interactions in reservoir ecosystems, their influence may sometimes be masked by the intensity of bottom-up and top-down effects, as well as population and community interactions.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1570-7458
    Keywords: dispersal ; flight duration ; cactophilic ; Drosophila ; age effects ; body size
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The flight ability ofDrosophila aldrichi (Patterson & Crow) andD. buzzatii (Patterson & Wheeler) using tethered flights, was measured with respect to age-related changes, genetic variation and adult body size variation induced by rearing at different larval densities.Drosophila buzzatii flew for much longer thanD. aldrichi, especially females, but age-related changes in flight duration were significant only forD. aldrichi. Effects of body size on flight ability were significant inD. buzzatii, but not inD. aldrichi. InD. buzzatii, there was a significant genotype-environment interaction (larval density × line) for flight duration, with short and average flight duration isofemale lines showing longer flights, but a long flight duration line shorter flights as body size decreased (i.e., as larval density increased). Heritability estimates for flight duration were similar in the two species, but flight duration showed no significant genetic correlations with developmental time, body size or wing dimensions (except for one wing dimension inD. buzzatii). Although not significantly different between the species, heritabilities for life-history traits (adult size and developmental time) showed contrasting patterns — with higher heritability for body size (body weight and thorax length) inD. buzzatii, and higher for developmental time inD. aldrichi. In agreement with limited previous field evidence,D. buzzatii is better adapted for colonization than isD. aldrichi.
    Type of Medium: Electronic Resource
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