| 11. |
- Wilcox, K. S., et al.
(författare)
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Issues related to development of new antiseizure treatments
- 2013
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Ingår i: Epilepsia. - : Wiley. - 0013-9580. ; 54, s. 24-34
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Tidskriftsartikel (refereegranskat)abstract
- This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). Wereview here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. Wealso briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.
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| 12. |
- Bundred, Nigel J, et al.
(författare)
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Cyclooxygenase-2 inhibition does not improve the reduction in ductal carcinoma in situ proliferation with aromatase inhibitor therapy: results of the ERISAC randomized placebo-controlled trial.
- 2010
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 16:5, s. 1605-12
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Tidskriftsartikel (refereegranskat)abstract
- Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)-positive DCIS. Methods: Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 x 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision.
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| 13. |
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| 14. |
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| 15. |
- Geenes, V., et al.
(författare)
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The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy Is Corrected by Ursodeoxycholic Acid
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.
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| 16. |
- Nestor, Colm, 1977-, et al.
(författare)
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Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes
- 2012
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory Press (CSHL). - 1088-9051 .- 1549-5469. ; 22:3, s. 467-477
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of substantial amounts of 5-hydroxymethylcytosine (5hmC), formed by the oxidation of 5-methylcytosine (5mC), in various mouse tissues and human embryonic stem (ES) cells has necessitated a reevaluation of our knowledge of 5mC/5hmC patterns and functions in mammalian cells. Here, we investigate the tissue specificity of both the global levels and locus-specific distribution of 5hmC in several human tissues and cell lines. We find that global 5hmC content of normal human tissues is highly variable, does not correlate with global 5mC content, and decreases rapidly as cells from normal tissue adapt to cell culture. Using tiling microarrays to map 5hmC levels in DNA from normal human tissues, we find that 5hmC patterns are tissue specific; unsupervised hierarchical clustering based solely on 5hmC patterns groups independent biological samples by tissue type. Moreover, in agreement with previous studies, we find 5hmC associated primarily, but not exclusively, with the body of transcribed genes, and that within these genes 5hmC levels are positively correlated with transcription levels. However, using quantitative 5hmC-qPCR, we find that the absolute levels of 5hmC for any given gene are primarily determined by tissue type, gene expression having a secondary influence on 5hmC levels. That is, a gene transcribed at a similar level in several different tissues may have vastly different levels of 5hmC (>20-fold) dependent on tissue type. Our findings highlight tissue type as a major modifier of 5hmC levels in expressed genes and emphasize the importance of using quantitative analyses in the study of 5hmC levels.
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| 17. |
- Sproul, Duncan, et al.
(författare)
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Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns
- 2012
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Ingår i: Genome Biology. - : BioMed Central. - 1465-6906 .- 1474-760X. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer and is believed to contribute to tumor progression by silencing the expression of tumor suppressor genes. Previously, we observed that promoter hypermethylation in breast cancer reflects cell lineage rather than tumor progression and occurs at genes that are already repressed in a lineage-specific manner. To investigate the generality of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different tissue types.RESULTS:We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer. Nearly half of these genes varied in their susceptibility to hypermethylation between different cancer types. We show that the expression status of hypermethylation prone genes in the originator tissue determines their propensity to become hypermethylated in cancer; specifically, genes that are normally repressed in a tissue are prone to hypermethylation in cancers derived from that tissue. We also show that the promoter regions of hypermethylation-prone genes are depleted of repetitive elements and that DNA sequence around the same promoters is evolutionarily conserved. We propose that these two characteristics reflect tissue-specific gene promoter architecture regulating the expression of these hypermethylation prone genes in normal tissues.CONCLUSIONS:As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue, we suggest that their hypermethylation does not directly contribute to cancer development via silencing. Instead aberrant hypermethylation reflects developmental history and the perturbation of epigenetic mechanisms maintaining these repressed promoters in a hypomethylated state in normal cells.
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| 18. |
- Sproul, Duncan, et al.
(författare)
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Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:11, s. 4364-4369
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM-ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and >90% could not be derepressed by treatment with 5-aza-2'-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.
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| 19. |
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| 20. |
- Zhang, Guojie, et al.
(författare)
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Comparative genomics reveals insights into avian genome evolution and adaptation
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1311-1320
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Tidskriftsartikel (refereegranskat)abstract
- Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
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