Academic literature on the topic 'Late stage methylation'
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Journal articles on the topic "Late stage methylation"
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Feng, Kaibo, Raundi E. Quevedo, Jeffrey T. Kohrt, Martins S. Oderinde, Usa Reilly, and M. Christina White. "Late-stage oxidative C(sp3)–H methylation." Nature 580, no. 7805 (March 16, 2020): 621–27. http://dx.doi.org/10.1038/s41586-020-2137-8.
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Deshmukh, R. S., O. Svarcova, J. Li, H. Callesen, G. Vajta, and P. Maddox-Hyttel. "85 DEOXYRIBONUCLEIC ACID METHYLATION IN PORCINE PARTHENOGENETIC PREIMPLANTATION EMBRYOS." Reproduction, Fertility and Development 21, no. 1 (2009): 143. http://dx.doi.org/10.1071/rdv21n1ab85.
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DNA methylation is one of the most important epigenetic mechanisms involved in gene silencing. Waves of DNA de- and re-methylation occur during mammalian preimplantation development. Whether the same happens in porcine parthenogenetic embryos has never been determined, and we set out to investigate this question. Porcine oocytes were aspirated from antral follicles, matured in vitro for 42 h, parthenogenetically activated and fixed in 4% paraformaldehyde at the 1-, 2-, 4-, and 8-cell stage as well as at the early and late blastocyst stage. The degree of DNA methylation was assessed by immunocytochemical staining (Anti-5MetC mouse monoclonal; Abcam, Copenhagen, Denmark) and DNA was counterstained with Hoechst 33258. Porcine fetal fibroblasts were used as standard. The fluorescent signals were detected using an epifluorescence microscope (Leica) and a Leica camera set at fixed exposure times. Signals were quantified using NIH ImageJ sofware. Total means of intensities (methylation and DNA) were calculated and exponential curves were obtained using Microsoft Excel-based statistics. DNA methylation and DNA content were highly correlated in porcine fetal fibroblasts demonstrating the effect of an immediate maintenance methylation taking place during the DNA S-phase of the cell cycle. A similar correlation was observed in the parthenogenetic embryos at all the developmental stages. The level of DNA methylation increased slightly from the early to the late 1-cell stage, and a pronounced increase in DNA methylation level was noted at the 2-cell stage. At the late 1-cell stage, the DNA methylation level of the two pronuclei was similar probably due to the maternal origin of both pronuclei. At the 4-cell stage, DNA methylation had decreased again but was higher compared with other developmental stages, except the 2-cell stage, and at the 8-cell stage, the level of DNA methylation reached a minimum. Subsequently, the level of DNA methylation increased slightly at the blastocyst stages. In conclusion, DNA methylation and DNA content were correlated in porcine fetal fibroblasts and parthenogenetic embryos. Furthermore, the levels of DNA methylation in parthenogenetic embryos exhibited an increase to the 2-cell stage followed by a decrease to the 8-cell stage and a final increase to the blastocyst stage. The initial increase in methylation to the 2-cell stage is different from what has been reported previously for in vivo derived porcine embryos. We are thankful to H. Holm and J. Nielsen for excellent technical assistance. This project was supported by Marie Currie Action project MRTN-CT-2006-35468 (CLONET).
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Yang, Xiaosong, Rui Wu, Weiguang Shan, Liqing Yu, Bingzhong Xue, and Hang Shi. "DNA Methylation Biphasically Regulates 3T3-L1 Preadipocyte Differentiation." Molecular Endocrinology 30, no. 6 (June 1, 2016): 677–87. http://dx.doi.org/10.1210/me.2015-1135.
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Abstract Better understanding the mechanisms underlying adipogenesis may provide novel therapeutic targets in the treatment of obesity. Most studies investigating the mechanisms underlying adipogenesis focus on highly regulated transcriptional pathways; little is known about the epigenetic mechanisms in this process. Here, we determined the role of DNA methylation in regulating 3T3-L1 adipogenesis in early and late stage of differentiation. We found that inhibiting DNA methylation pharmacologically by 5-aza-2′-deoxycytidine (5-aza-dC) at early stage of 3T3-L1 differentiation markedly suppressed adipogenesis. This inhibition of adipogenesis by 5-aza-dC was associated with up-regulation of Wnt10a, an antiadipogenic factor, and down-regulation of Wnt10a promoter methylation. In contrast, inhibiting DNA methylation by 5-aza-dC at late stage of differentiation enhanced the lipogenic program. The differential effects of 5-aza-dC on adipogenesis were confirmed by gain or loss of function of DNA methyltransferase 1 using genetic approaches. We further explored the molecular mechanism underlying the enhanced lipogenesis by inhibition of DNA methylation at late stage of differentiation. The Srebp1c promoter is enriched with CpG sites. Chromatin immunoprecipitation assays showed that DNA methyltransferase 1 bound to the methylation region at the Srebp1c promoter. Pyrosequencing analysis revealed that the DNA methylation at the key cis-elements of the Srebp1c promoter was down-regulated in adipogenesis. Further, luciferase reporter assays showed that the Srebp1c promoter activity was dramatically up-regulated by the unmethylated promoter compared with the fully methylated promoter. Thus DNA methylation appears to exert a biphasic regulatory role in adipogenesis, promoting differentiation at early stage while inhibiting lipogenesis at late stage of 3T3-L1 preadipocyte differentiation.
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Li, Y., H. D. Morgan, L. Ganeshan, and C. O'Neill. "124. DNA METHYLATION IN THE 2-CELL MOUSE EMBRYO IS THE RESULT OF DNMT ACTIVITY DURING DEVELOPMENT FROM THE ZYGOTE TO THE 2-CELL STAGE." Reproduction, Fertility and Development 21, no. 9 (2009): 43. http://dx.doi.org/10.1071/srb09abs124.
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In an accompanying abstract we show for the first time that global demethylation of both paternally- and maternally-derived genomes occurs prior to syngamy. It is commonly considered that new methylation of the genome does not commence until late in the preimplantation stage. Yet embryos during cleavage stage are known to show DNA methylation. This creates a paradox, if global demethylation occurs by the time of syngamy yet remethylation does not occur until the blastocysts stage, how can cleavage stage embryos possess methylated DNA. We examined this paradox. We examined DNA methylation in 2-cell embryos by confocal microscopy of anti-methylcytosine immunofluorescence and propidium iodide co-staining of whole mounts. We confirmed that DNA in late zygotes was substantially demethylated in both the male and female pronuclei. By the 2-cell stage, embryos collected direct from the oviduct showed high levels of cytosine methylation. We assessed whether this accumulation of cytosine methylation during the early 2-cell stage was a consequence of DNA methyltransferase (DNMT) activity. This was achieved by treating late stage zygotes with the DNMT inhibitor RG108 (5 μM) for the period of development spanning pronuclear stage 5 to early 2-cell stage. The embryos that developed in the presence of the DNA methyltransferase inhibitor showed significantly less methylcytosine staining than the embryos in the untreated culture conditions (P<0.001). Treatment of embryos during this period with RG108 significantly reduced their capacity to develop to normal blastocysts, indicating that this early DNA re-methylation reaction was important for the normal development of the embryo. Our results show for the first time that de novo methylation of the genome occurs as early as the 2-cell stage of development and that this is mediated by a RG108-sensitive DNMT activity. The results substantially change our understanding of epigenetic reprogramming in the early embryo.
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Friis, Stig D., Magnus J. Johansson, and Lutz Ackermann. "Cobalt-catalysed C–H methylation for late-stage drug diversification." Nature Chemistry 12, no. 6 (May 29, 2020): 511–19. http://dx.doi.org/10.1038/s41557-020-0475-7.
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Ekwattanakit, Supachai, Suchada Riolueang, and Vip Viprakasit. "Epigenetic Analysis of Beta-Globin Gene Cluster during Hematopoiesis." Blood 112, no. 11 (November 16, 2008): 1863. http://dx.doi.org/10.1182/blood.v112.11.1863.1863.
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Abstract Hemoglobin (Hb) switching is described as temporal, tissue- and stage-specific patterns of globin gene expression; from embryonic to fetal and adult Hb in parallel to developmental stages of erythropoiesis. DNA methylation, one of the epigenetic mechanisms, was associated with inactivated chromatin domain and repressive transcription. To study the role of the DNA methylation on the beta (β)-globin genes, we analyzed CpG dinucleotides in 87 kb regions around β-globin gene cluster, including 5’upstream locus control regions (LCR; DNAse I Hypersensitive site (HS) 1–5), 3’HS1, the promoter regions of the G-and A-gamma (Gγ and Aγ), and β-globin genes, in several representative cells. These cells were primary adult erythroid cells culture (three different stages: early, intermediate, and late), fetal cord blood DNA, and neutrophil cell line (non-erythroid). Using bisulphite modification, followed by nested PCR and in vitro translation, the cleavage products were analysed by MALDI-TOF Mass Spectrometry to quantify the DNA methylation level. The results were consistent with bisulphite sequencing. We found that the promoters of Gγ and Aγ-globin genes were significantly hypomethylated in fetal cells (44% and 47% global methylation), when γ-globin genes were fully expressed, while they were heavily methylated in non-erythroid (86% and 95%). There was also a decreasing trend of the DNA methylation level at Gγ and Aγ-globin genes during adult erythroid differentiation from 80% and 82%, in early stage, to 67% and 66% in late stage (p=0.12 and 0.04). At β-globin promoter, the global methylation level changed from 90% in non-erythroid to 81%, 42%, and 26% in fetal, early and late adult erythroid cells, respectively. Moreover, we found the significant changes at 5’HS4, 3, and 1 as all erythroid cells were hypomethylated compare to non-erythroid. While at the insulators, 5’HS5 and 3’HS1, all tested CpG dinucleotides were heavily methylated in all cells. This is the first report that demonstrates the differences in DNA methylation at β-globin LCR between erythroid and non-erythroid cells. These epigenetic marks were associated with globin genes expression and might be useful to predict clinical severity in patients with β-thalassemia intermedia.
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Buckingham, Lela, Gregory Pelkey, Mary J. Fidler, and Philip D. Bonomi. "DNA repair gene promoter methylation in non-small cell lung cancer (NSCLC) patients treated with DNA damaging agents." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22130-e22130. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22130.
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e22130 Background: Approximately 75% of NSCLC patients are advanced at time of diagnosis. Treatments include regimens of DNA-damaging and alkylating agents. Previous in vitro studies have shown that loss of BRCA1 and BRCA2 function through promoter methylation increases sensitivity to sapacitabine, suggesting that tumor cells may be protected by repair systems including BRCA-RAD50 and MGMT pathways induced by DNA damage. The purpose of this study is to investigate the effect of DNA repair gene promoter methylation on outcome of NSCLC patients treated with DNA damaging agents. DNA repair gene promoter hypermethylation may sensitize tumor cells to DNA damaging agents. Methods: The patient group of 240 patients included 135 early stage and 105 late stage (III/IV) cases. Chemotherapy regimens of late stage patients included carboplatin, cisplatin and gemcitabine, as well as other non-DNA damaging agents. Mean overall survival (OS) was 43.7 months. DNA was extracted from micro-dissected primary tumor, bisulfite converted and assessed by pyrosequencing to quantify methylation of cytosine nucleotides along the MGMT, BRCA1 and BRCA2 promoters. Results: Overall average methylation values were 8.4%, 7.3% and 8.3% for MGMT, BRCA1, BRCA2 respectively (compared to 3.2%, 3.6% and 7.3%, respectively, in nonmalignant lung tissue). Percent promoter methylation levels were not significantly correlated with age, gender, smoking status nor histology, with the exception of higher MGMT promoter methylation in smokers. Hypermethylation (greater than 10%) of BRCA1 and BRCA2 promoter was not significantly associated with survival in late stage patients (6.6 mos vs 6.8 mos; p=0.533) in this patient group, however, superior survival was observed with BRCA2 promoter hypermethylation when early stage patients were included (29.3 mos vs median not reached; p=0.045). Promoter hypermethylation of MGMTwas significantly associated with lower five-year survival rate in early stage patients (p=0.022). Conclusions: These data suggest epigenetic control of DNA repair gene expression can affect response to therapy. Further studies on specific treatment regimens will be required to definitively assess these effects.
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Pimson, Charinya, Tipaya Ekalaksananan, Chamsai Pientong, Supannee Promthet, Nuntiput Putthanachote, Krittika Suwanrungruang, and Surapon Wiangnon. "Aberrant methylation ofPCDH10andRASSF1Agenes in blood samples for non-invasive diagnosis and prognostic assessment of gastric cancer." PeerJ 4 (June 9, 2016): e2112. http://dx.doi.org/10.7717/peerj.2112.
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Background.Assessment of DNA methylation of specific genes is one approach to the diagnosis of cancer worldwide. Early stage detection is necessary to reduce the mortality rate of cancers, including those occurring in the stomach. For this purpose, tumor cells in circulating blood offer promising candidates for non-invasive diagnosis. Transcriptional inactivation of tumor suppressor genes, likePCDH10andRASSF1A, by methylation is associated with progression of gastric cancer, and such methylation can therefore be utilized as a biomarker.Methods.The present research was conducted to evaluate DNA methylation in these two genes using blood samples of gastric cancer cases. Clinicopathological data were also analyzed and cumulative survival rates generated for comparison.Results.High frequencies ofPCDH10andRASSF1Amethylations in the gastric cancer group were noted (94.1% and 83.2%, respectively, as compared to 2.97% and 5.45% in 202 matched controls). Most patients (53.4%) were in severe stage of the disease, with a median survival time of 8.4 months after diagnosis. Likewise, the patients with metastases, orRASSF1AandPCDH10methylations, had median survival times of 7.3, 7.8, and 8.4 months, respectively. A Kaplan–Meier analysis showed that cumulative survival was significantly lower in those cases positive for methylation ofRASSF1Athan in their negative counterparts. Similarly, whereas almost 100% of patients positive forPCDH10methylation had died after five years, none of the negative cases died over this period. Notably, the methylations ofRASSF1AandPCDH10were found to be higher in the late-stage patients and were also significantly correlated with metastasis and histology.Conclusions.PCDH10andRASSF1Amethylations in blood samples can serve as potential non-invasive diagnostic indicators in blood for gastric cancer. In addition toRASSF1Amethylation, tumor stage proved to be a major prognostic factor in terms of survival rates.
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Weis, Erik, Martin A. Hayes, Magnus J. Johansson, and Belén Martín-Matute. "Iridium-catalyzed C−H methylation and d3-methylation of benzoic acids with application to late-stage functionalizations." iScience 24, no. 5 (May 2021): 102467. http://dx.doi.org/10.1016/j.isci.2021.102467.
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Kempster, S., W. A. Phillips, S. Baindur-Hudson, R. J. S. Thomas, C. Dow, and S. P. Rockman. "Methylation of exon 2 of p16 is associated with late stage oesophageal cancer." Cancer Letters 150, no. 1 (March 2000): 57–62. http://dx.doi.org/10.1016/s0304-3835(99)00372-9.
Full textBooks on the topic "Late stage methylation"
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Holroyd, Christopher R., Nicholas C. Harvey, Mark H. Edwards, and Cyrus Cooper. Environment. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0038.
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Musculoskeletal disease covers a broad spectrum of conditions whose aetiology comprises variable genetic and environmental contributions. More recently it has become clear that, particularly early in life, the interaction of gene and environment is critical to the development of later disease. Additionally, only a small proportion of the variation in adult traits such as bone mineral density has been explained by specific genes in genome-wide association studies, suggesting that gene-environment interaction may explain a much larger part of the inheritance of disease risk than previously thought. It is therefore critically important to evaluate the environmental factors which may predispose to diseases such as osteorthritis, osteoporosis, and rheumatoid arthritis both at the individual and at the population level. In this chapter we describe the environmental contributors, across the whole life course, to osteoarthritis, osteoporosis and rheumatoid arthritis, as exemplar conditions. We consider factors such as age, gender, nutrition (including the role of vitamin D), geography, occupation, and the clues that secular changes of disease pattern may yield. We describe the accumulating evidence that conditions such as osteoporosis may be partly determined by the early interplay of environment and genotype, through aetiological mechanisms such as DNA methylation and other epigenetic phenomena. Such studies, and those examining the role of environmental influences across other stages of the life course, suggest that these issues should be addressed at all ages, starting from before conception, in order to optimally reduce the burden of musculoskeletal disorders in future generations.
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Holroyd, Christopher R., Nicholas C. Harvey, Mark H. Edwards, and Cyrus Cooper. Environment. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199642489.003.0038_update_001.
Full textAbstract:
Musculoskeletal disease covers a broad spectrum of conditions whose aetiology comprises variable genetic and environmental contributions. More recently it has become clear that, particularly early in life, the interaction of gene and environment is critical to the development of later disease. Additionally, only a small proportion of the variation in adult traits such as bone mineral density has been explained by specific genes in genome-wide association studies, suggesting that gene-environment interaction may explain a much larger part of the inheritance of disease risk than previously thought. It is therefore critically important to evaluate the environmental factors which may predispose to diseases such as osteorthritis, osteoporosis, and rheumatoid arthritis both at the individual and at the population level. In this chapter we describe the environmental contributors, across the whole life course, to osteoarthritis, osteoporosis and rheumatoid arthritis, as exemplar conditions. We consider factors such as age, gender, nutrition (including the role of vitamin D), geography, occupation, and the clues that secular changes of disease pattern may yield. We describe the accumulating evidence that conditions such as osteoporosis may be partly determined by the early interplay of environment and genotype, through aetiological mechanisms such as DNA methylation and other epigenetic phenomena. Such studies, and those examining the role of environmental influences across other stages of the life course, suggest that these issues should be addressed at all ages, starting from before conception, in order to optimally reduce the burden of musculoskeletal disorders in future generations.
Book chapters on the topic "Late stage methylation"
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Taber, Douglass F. "The Fürstner Synthesis of Amphidinolide F." In Organic Synthesis. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190646165.003.0090.
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The amphidinolides, having zero, one, or (as exemplified by amphidinolide F 3) two tetrahydrofuran rings, have shown interesting antineoplastic activity. It is a tribute to his development of robust Mo catalysts for alkyne metathesis that Alois Fürstner of the Max-Planck-Institut für Kohlenforschung Mülheim could with confidence design (Angew. Chem. Int. Ed. 2013, 52, 9534) a route to 3 that relied on the ring-closing metathesis of 1 to 2 very late in the synthesis. Three components were prepared for the assembly of 1. Julia had already reported (J. Organomet. Chem. 1989, 379, 201) the preparation of the E bromodiene 5 from the sulfone 4. The alcohol 7 was available by the opening of the enantiomerically-pure epoxide 6 with propynyl lithium, followed by oxidation following the Pagenkopf protocol. Amino alcohol-directed addition of the organozinc derived from 5 to the aldehyde from oxidation of 7 completed the assembly of 8. Addition of the enantiomer 10 of the Marshall butynyl reagent to 9 followed by protection, oxidation to 11, and addition of, conveniently, the other Marshall enantiomer 12 led to the protected diol 13. Silylcupration–methylation of the free alkyne set the stage for selective desilylation and methylation of the other alkyne. Iodination then completed the trisubstituted alkene of 14. Methylation of the crystalline lactone 15, readily prepared from D-glutamic acid, led to a mixture of diastereomers. Deprotonation of that product followed by an aqueous quench delivered 16. Reduction followed by reaction with the phosphorane 17 gave the unsaturated ester, that cyclized with TBAF to the crystalline 18. The last stereogenic center of 22 was established by proline-mediated aldol condensation of the aldehyde 19 with the ketone 20. To assemble the three fragments, the ketone of 21 was converted to the enol triflate and thence to the alkenyl stannane. Saponification gave the free acid 22, that was activated, then esterified with the alcohol 18. Coupling of the stannane with the iodide 14 followed by removal of the TES group led to the desired diyne 1. It is noteworthy that the Mo metathesis catalyst is stable enough to tolerate the free alcohol of 1 in the cyclization to 2.
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Taber, Douglass F. "The Ding Synthesis of Steenkrotin A." In Organic Synthesis. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190646165.003.0106.
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Steenkrotin A 3 was isolated from Croton steenkampianus Gerstner, widely used in folk medicine for the treatment of coughs, fever, malaria, and rheumatism. Hanfeng Ding of Zhejiang University envisioned (Angew. Chem. Int. Ed. 2015, 54, 6905) that the intriguingly compact core of 3 could be assembled by reductive cyclization of the aldehyde 1 to 2, followed by intramolecular aldol condensation. The diastereoselective assembly of 1 from the cycloheptenone core 4 depended on the conformational preferences of the seven-membered ring. Enol ether formation followed by Rubottom oxidation led to the silyl ether 5. Oxidative rearrangement of the tertiary alcohol generated by 1,2-addition to 5 of in situ generated allyl lithium established the enone 6. Again taking advantage of the conformational preference of the seven-membered ring, cyclopropanation of the silyl enol ether derived from 6 proceeded across the open face of the electron-rich alkene to give 7. The other oxygenated quaternary center of 1 was constructed by O-alkylation of 7 with diazo malonate followed by methylation and reduction. Acetylation of the diol 8 proceeded with 10:1 diastereoselectivity, to give, after oxidation, the aldehyde 9. In the first of a sequence of three intramolecular bond-forming reactions, HF.py cyclized the aldehyde onto the endocyclic alkene, and also freed the alcohol, that was alkylated with the dibromide 10 to give 11 as a 1.5:1 mixture of diastereomers. On exposure to SmI2, the major diastereomer cyclized to give a intermediate that was carried on to 1. The minor diastereomer was merely reduced, to a product that could be recycled to 11. With 1 in hand, the stage was set for the second intramolecular cyclization. Even though 1 was predominantly in the lactol form, there was enough of an equilibrium concentration of aldehyde present for the SmI2-mediated cyclization to proceed smoothly to 2. With 2 in hand, in addition to the last intramolecular cyclization, the two stereogenic centers (marked by an asterisk) had to be inverted. The methyl group adjacent to the ketone was readily equilibrated. The secondary alcohol could be inverted by late-stage oxidation and reduction, and the authors did do that. However, they also observed a small amount of the desired epimeric alcohol 14 from the intramolecular aldol condensation of 12.
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Lucchesi, John C. "Nuclear reprogramming and induced pluripotency." In Epigenetics, Nuclear Organization & Gene Function, 205–12. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198831204.003.0018.
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Four core transcription factors known to maintain the pluripotent state in embryonic stem cells (ESCs)—Oct4, Sox2, Klf4 and c-Myc—were used to induce pluripotent stem cells in adult-derived fibroblasts. Induced pluripotent stem cells (iPSCs), like ESCs, have less condensed and more transcriptionally active chromatin than differentiated cells. The number of genes with bivalent promoter marks increases during reprogramming, reflecting the switch of differentiation-specific active genes to an inactive, but poised, status. The levels of DNA methyl transferases and demethylases are increased, underlying the changes in the pattern of DNA methylation that occur late during reprogramming. The potential therapeutic applications of iPSCs include reprogramming a patient’s own cells to avoid the problem of rejection following injection to restore tissue or organ function. iPSCs derived from individuals at risk of developing late-onset neurological diseases could be differentiated in culture to predict the future occurrence of the disease. Caveats involve the fact that long-term culturing often results in genomic mutations that may, by chance, involve tumor suppressors or oncogenes.
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Taber, Douglass F. "Alkaloid Synthesis: (–)-α-Kainic Acid (Cohen), Hyacinthacine A2 (Fox), (–)-Agelastatin A (Hamada), (+)-Luciduline (Barbe), (+)-Lunarine (Fan), (–)-Runanine (Herzon)." In Organic Synthesis. Oxford University Press, 2015. http://dx.doi.org/10.1093/oso/9780190200794.003.0058.
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The intramolecular ene cyclization is still little used in organic synthesis. Theodore Cohen of the University of Pittsburgh trapped (J. Org. Chem. 2011, 76, 7912) the cyclization product from 1 with iodine to give 2, setting the stage for an enantiospecific total synthesis of (–)-α-kainic acid 3. Intramolecular alkene hydroamination has been effected with transition metal catalysts. Joseph M. Fox of the University of Delaware isomerized (Chem. Sci. 2011, 2, 2162) 4 to the trans cyclooctene 5 with high diastereocontrol. Deprotection of the amine led to spontaneous cyclization, again with high diastereocontrol to hyacinthacine A2 6. Yasumasa Hamada of Chiba University devised (Org. Lett. 2011, 13, 5744) a catalyst system for the enantioselective aziridination of cyclopentenone 7. The product 8 was carried on to the tricyclic alkaloid (–)-agelastatin A 9. Guillaume Barbe, now at Novartis in Cambridge, MA, effected (J. Org. Chem. 2011, 76, 5354) the enantioselective Diels-Alder cycloaddition of acrolein 11 to the dihydropyridine 10. Ring-opening ring-closing metathesis later formed one of the carbocyclic rings of (+)-luciduline 13, and set the stage for an intramolecular aldol condensation to form the other. Chun-An Fan of Lanzhou University employed (Angew. Chem. Int. Ed. 2011, 50, 8161) a Cinchona-derived catalyst for the enantioselective Michael addition to prepare 14. Although 14 and 15 were only prepared in 77% ee, crystallization to remove the racemic component of a later intermediate led to (+)-lunarine 16 in high ee. Seth B. Herzon of Yale University used (Angew. Chem. Int. Ed. 2011, 50, 8863) the enantioselective Diels-Alder addition with 18 to block one face of the quinone 17. Reduction of 19 followed by methylation delivered an iminium salt, only one face of which was open for the addition of an aryl acetylide. Thermolysis to remove the cyclopentadiene gave an intermediate that was carried on to (+)-runanine 20.
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Holroyd, Christopher R., Nicholas C. Harvey, Mark H. Edwards, and Cyrus Cooper. "Environment." In Oxford Textbook of Rheumatology, 290–95. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0038_update_002.
Full textAbstract:
Musculoskeletal disease covers a broad spectrum of conditions whose aetiology comprises variable genetic and environmental contributions. More recently it has become clear that, particularly early in life, the interaction of gene and environment is critical to the development of later disease. Additionally, only a small proportion of the variation in adult traits such as bone mineral density has been explained by specific genes in genome-wide association studies, suggesting that gene-environment interaction may explain a much larger part of the inheritance of disease risk than previously thought. It is therefore critically important to evaluate the environmental factors which may predispose to diseases such as osteorthritis, osteoporosis, and rheumatoid arthritis both at the individual and at the population level. In this chapter we describe the environmental contributors, across the whole life course, to osteoarthritis, osteoporosis and rheumatoid arthritis, as exemplar conditions. We consider factors such as age, gender, nutrition (including the role of vitamin D), geography, occupation, and the clues that secular changes of disease pattern may yield. We describe the accumulating evidence that conditions such as osteoporosis may be partly determined by the early interplay of environment and genotype, through aetiological mechanisms such as DNA methylation and other epigenetic phenomena. Such studies, and those examining the role of environmental influences across other stages of the life course, suggest that these issues should be addressed at all ages, starting from before conception, in order to optimally reduce the burden of musculoskeletal disorders in future generations.
Conference papers on the topic "Late stage methylation"
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Papaiz, Débora, Flávia E. Rius, Diogo Pessoa, Eduardo M. Reis, Christopher E. Mason, Gangning Liang, and Miriam G. Jasiulionis. "Abstract 140: Deregulated genes by abnormal promoter methylation in early and late stages in a linear model of melanoma progression." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-140.
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Ferreira, Nancy, Darley Ferreira, and Thais Ferreira. "GENETIC EVALUATION OF MICROCALCIFICATIONS AS A PROGNOSTIC FACTOR." In Abstracts from the Brazilian Breast Cancer Symposium - BBCS 2021. Mastology, 2021. http://dx.doi.org/10.29289/259453942021v31s2101.
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Introduction: Breast cancer is the most recurring type of cancer among women, with reduced mortality at an initial stage of lesion. From a radiological perspective, perceived microcalcifications may be associated with histological findings such as proliferative injuries with or without atypical features and ductal carcinoma in situ. Currently, percutaneous and vacuum biopsies allow for the correlation between anatomoradiological and identification of previous lesions and those that offer the risk of cancer. No biomarker has been established to predict the risk of cancer in women diagnosed with benign mammary disease. Doing so could strengthen the possibility of stratifying the individual risk of benign injuries for cancer. The platelet-derived growth factor receptor A (PDGFRA) plays its part in tumor oncogenesis, angiogenesis, and metastasis, and its activation is found in some kinds of cancer. In contrast, DNA methylation standards are initial changes to the development of cancer and may be helpful in its early identification, being regulated by a family of enzymes called DNMTs (DNA methyltransferase). Methods: The aim of this study was to evaluate the profile of BI-RADS® 4 and 5 mammary microcalcification women carriers and determine the level of the gene expression of possible molecular markers in 37 patients with mammary microcalcification (paraffin blocks) and 26 patients with breast cancer (fresh in RNA later tissue) cared for at the Hospital Barão de Lucena’s Mastology Ambulatory. Anatomoradiological aspects along with clinical findings have been evaluated , and percentage rates have been calculated. The PDGFRA and DNMTs (DMNT3a) gene expressions have been established using quantitative polymerase chain reaction (qPCR), with the use of β-actin as reference gene. Discussion: In the patients with mammary microcalcification, the average age was 55.9; predominantly whiteskinned subjects (p<0.014). Most of them were mothers (p<0.001), and the average menarche age was 13. The subgroups that presented greater significance were patients classified BI-RADS® in category IV (67.6%) and histological findings of nonproliferative lesion (p<0.001). Lesions of the ductal carcinoma in situ type (100%) presented positive estrogen and progesterone receptors, and 94.6% have undergone sectorectomy surgery by prior needling (p<0.001). The most damaged breast was the left one (62.2%), and the most affected quadrant was the top lateral one (59.5%) (p<0.001). There was no family history in 83.8% of the cases. In the tested microcalcification samples, it was not possible to observe the expression of PDGFRA. Nevertheless, 15 out of 37 patients with microcalcification showed an increase in the gene expression of DMNT3a, most of them greater than Luminal and triple-negative cancer types. Conclusion: The data presented here highlight the improvement on the description of BI-RADS® 4 subclassification in order to better conduct the clinical decision and also demonstrated the potential of DNMTs evaluation in microcalcification samples as a strategy to access the understanding about the role of these molecules in the breast cancer development.