| 1. |
- Bellamkonda, Kishan, et al.
(författare)
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Montelukast, a CysLT1 receptor antagonist, reduces colon cancer stemness and tumor burden in a mouse xenograft model of human colon cancer
- 2018
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 437, s. 13-24
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is implicated in the etiology of sporadic colon cancer (CC), which is one of the leading causes of cancer-related deaths worldwide. Here, we report that inhibition of the inflammatory receptor CysLT1 through its antagonist, montelukast, is beneficial in minimizing stemness in CC and thereby minimizing tumor growth in a mouse xenograft model of human colon cancer. Upon treatment with montelukast, colonospheres derived from HT-29 and SW-480 human colon cancer cells exhibited a significant phenotypic change coupled with the downregulation of mRNA and protein expression of cancer stem cell (CSC) markers ALDH1 and DCLK1. Moreover, montelukast reduced the size of HT-29 cell-derived tumors in mice. The reduction in tumor size was associated with decreased levels of ALDH1A1, DCLK1, BCL2 mRNA and macrophage infiltration into the tumor tissue. Interestingly, this treatment elevated levels of the tumor suppressor 15-PGDH while reducing COX-2 expression. Our data highlight the association of CysLT1R with CSCs and demonstrate that inhibition of CysLT1R could prove beneficial in minimizing CSC-induced tumor growth. This work advances the notion that targeting CSCs is a promising approach to improve outcomes in those afflicted with colon cancer.
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| 2. |
- Blechert, Oliver, et al.
(författare)
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Conserved function of the Krüppel gap gene in the blowfly Lucilia sericata, despite anterior shift of expression.
- 2011
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Ingår i: Insect Molecular Biology. - : Wiley. - 1365-2583 .- 0962-1075. ; 20, s. 257-265
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Tidskriftsartikel (refereegranskat)abstract
- To determine whether expression patterns of segmentation genes found in Drosophila melanogaster can be scaled to pattern larger insects, we studied the expression of the Krüppel (Kr) gene in the blowfly Lucilia sericata. Compared with Drosophila Kr, L. sericata Kr showed an unexpected 10% shift of expression towards the anterior pole. Furthermore, expression domains not found in D. melanogaster were present at the blastoderm stage of L. sericata. To compare Kr activity and function, we employed RNA interference-mediated gene silencing. We found Kr phenotypes in L. sericata comparable with those observed in D. melanogaster, demonstrating that L. sericata Kr functions as a gap gene as it does in Drosophila. Our results show that, despite an anterior shift in expression, Kr function has remained conserved during the evolution of the blowflies.
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| 3. |
- Douglas, Desiree, et al.
(författare)
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A mitogenomic study on the phylogenetic position of snakes
- 2006
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Ingår i: Zoologica Scripta. - : Wiley. - 0300-3256 .- 1463-6409. ; 35:6, s. 545-558
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Tidskriftsartikel (refereegranskat)abstract
- Phylogenetic relationships of squamates (lizards, amphisbaenians and snakes) have received considerable attention, although no consensus has been reached concerning some basal divergences. This paper focuses on the Serpentes (snakes), whose phylogenetic position within the Squamata remains uncertain despite a number of morphological and molecular studies. Some mitogenomic studies have suggested a sister-group relationship between snakes and varanid lizards, while other studies have identified snakes and lizards as sister groups. However, recent studies using nuclear data have presented a different scenario, with snakes being more closely related to anguimorph and iguanian lizards. In this mitogenomic study we have examined the above hypotheses with the inclusion of amphisbaenians, one gekkotan and one acrodont lizard, taxa not represented in previous mitogenomic studies. To this end we have also extended the representation of snakes by sequencing five additional snake genomes: two scolecophidians (Ramphotyphlops australis and Typhlops mirus) two henophidians (Eunectes notaeus and Boa constrictor) and one caenophidian (Elaphe guttata). The phylogenetic analysis recovered snakes and amphisbaenians as sister groups, thereby differing from previous hypotheses. In addition to a discussion on previous morphological and molecular studies in light of the results presented here, the current study also provides some details regarding features of the new snake mitochondrial genomes described.
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| 4. |
- Douglas, Desiree, et al.
(författare)
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Examining the utility of categorical models and alleviating artifacts in phylogenetic reconstruction of the Squamata (Reptilia).
- 2009
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Ingår i: Molecular Phylogenetics and Evolution. - : Elsevier BV. - 1095-9513 .- 1055-7903. ; 52, s. 784-796
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Tidskriftsartikel (refereegranskat)abstract
- Reconstruction artifacts are a serious hindrance to the elucidation of phylogenetic relationships and a number of methods have been devised to alleviate them. Previous studies have demonstrated a striking disparity in the evolutionary rates of the mitochondrial (mt) genomes of squamate reptiles (lizards, worm lizards and snakes) and the reconstruction artifacts that may arise from this. Here, to examine basal squamate relationships, we have added the mt genome of the blind skink Dibamus novaeguineae to the mitogenomic dataset and applied different models for resolving the squamate tree. Categorical models were found to be less susceptible to artifacts than were the commonly used noncategorical phylogenetic models GTR and mtREV. The application of different treatments to the data showed that the removal of the fastest evolving sites in snakes improved phylogenetic signal in the dataset. Basal divergences remained, nevertheless, poorly resolved. The proportion of both fast-evolving and conserved sites in the squamate mt genomes relative to sites with intermediate rates of evolution suggests rapid early divergences among squamate taxa and at least partly explains the short internal relative to external branches in the squamate tree. Thus, mt and nuclear trees may never reach full agreement because of the short branches characterizing these divergences.
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| 5. |
- Douglas, Desiree, et al.
(författare)
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Snake mitochondrial genomes: phylogenetic relationships and implications of extended taxon sampling for interpretations of mitogenomic evolution
- 2010
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Snake mitochondrial genomes are of great interest in understanding mitogenomic evolution because of gene duplications and rearrangements and the fast evolutionary rate of their genes compared to other vertebrates. Mitochondrial gene sequences have also played an important role in attempts to resolve the contentious phylogenetic relationships of especially the early divergences among alethinophidian snakes. Two recent innovative studies found dramatic gene-and branch-specific relative acceleration in snake protein-coding gene evolution, particularly along internal branches leading to Serpentes and Alethinophidia. It has been hypothesized that some of these rate shifts are temporally (and possibly causally) associated with control region duplication and/or major changes in ecology and anatomy. Results: The near-complete mitochondrial (mt) genomes of three henophidian snakes were sequenced: Anilius scytale, Rhinophis philippinus, and Charina trivirgata. All three genomes share a duplicated control region and translocated tRNA(LEU), derived features found in all alethinophidian snakes studied to date. The new sequence data were aligned with mt genome data for 21 other species of snakes and used in phylogenetic analyses. Phylogenetic results agreed with many other studies in recovering several robust clades, including Colubroidea, Caenophidia, and Cylindrophiidae+Uropeltidae. Nodes within Henophidia that have been difficult to resolve robustly in previous analyses remained uncompellingly resolved here. Comparisons of relative rates of evolution of rRNA vs. protein-coding genes were conducted by estimating branch lengths across the tree. Our expanded sampling revealed dramatic acceleration along the branch leading to Typhlopidae, particularly long rRNA terminal branches within Scolecophidia, and that most of the dramatic acceleration in protein-coding gene rate along Serpentes and Alethinophidia branches occurred before Anilius diverged from other alethinophidians. Conclusions: Mitochondrial gene sequence data alone may not be able to robustly resolve basal divergences among alethinophidian snakes. Taxon sampling plays an important role in identifying mitogenomic evolutionary events within snakes, and in testing hypotheses explaining their origin. Dramatic rate shifts in mitogenomic evolution occur within Scolecophidia as well as Alethinophidia, thus falsifying the hypothesis that these shifts in snakes are associated exclusively with evolution of a non-burrowing lifestyle, macrostomatan feeding ecology and/or duplication of the control region, both restricted to alethinophidians among living snakes.
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| 6. |
- Douglas, Desiree
(författare)
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The Molecular Evolution of Snakes as revealed by Mitogenomic Data
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Snakes (Serpentes) are a diverse suborder of reptiles that, along with lizards and amphisbaenians, belong to the reptilian order Squamata. The phylogenetic position of snakes relative to lizards and amphisbaenians has been debated for about 140 years. Despite the many morphological and molecular studies that had been done, no consensus had been reached as to the phylogenetic position of snakes or on the relationships of families within Serpentes. In addition, previous molecular studies were based on only one or two genes. For my PhD I attempted to elucidate the affinities of snakes using mitogenomic data. Complete or nearly complete mitochondrial (mt) genomes were sequenced from eight snakes and two lizards. This provided a substantial amount of data for phylogenetic analysis to infer the position of snakes and to resolve the interrelationships of snake families. In addition, mitogenomic features and composition bias of mt genomes from different snake lineages were examined. The first and third papers deal with the affinities of snakes, squamate phylogeny, and the root of the squamate tree. The results support a close relationship between snakes, amphisbaenians and lacertiform lizards. The second paper is a comparative study of strand bias and base composition in the mt genomes of different snake lineages. Different snake lineages showed different trends for strand bias, suggesting that there maybe other modes of replication prevalent in the mt genomes of some snakes. The results also revealed that snakes have highly divergent composition that may explain the fast evolutionary rates of snake mt genes compared to other squamates. A phylogenetic analysis on the relationships of basal alethinophidians was performed. The results do not support some classical higher-level groupings. There is also evidence that macrostomy, the ability of snakes to increase the gape of the jaws, may be more primitive than many previous studies had suggested.
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| 7. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 8. |
- Lindgren, Johan, et al.
(författare)
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Microspectroscopic evidence of cretaceous bone proteins.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Low concentrations of the structural protein collagen have recently been reported in dinosaur fossils based primarily on mass spectrometric analyses of whole bone extracts. However, direct spectroscopic characterization of isolated fibrous bone tissues, a crucial test of hypotheses of biomolecular preservation over deep time, has not been performed. Here, we demonstrate that endogenous proteinaceous molecules are retained in a humerus from a Late Cretaceous mosasaur (an extinct giant marine lizard). In situ immunofluorescence of demineralized bone extracts shows reactivity to antibodies raised against type I collagen, and amino acid analyses of soluble proteins extracted from the bone exhibit a composition indicative of structural proteins or their breakdown products. These data are corroborated by synchrotron radiation-based infrared microspectroscopic studies demonstrating that amino acid containing matter is located in bone matrix fibrils that express imprints of the characteristic 67 nm D-periodicity typical of collagen. Moreover, the fibrils differ significantly in spectral signature from those of potential modern bacterial contaminants, such as biofilms and collagen-like proteins. Thus, the preservation of primary soft tissues and biomolecules is not limited to large-sized bones buried in fluvial sandstone environments, but also occurs in relatively small-sized skeletal elements deposited in marine sediments.
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| 9. |
- Osman, Janina, et al.
(författare)
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Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitis-associated colon cancer
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:21, s. 34773-34786
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Tidskriftsartikel (refereegranskat)abstract
- Cysteinyl leukotriene receptor 1 (CysLT1R) has been shown to be up-regulated in the adenocarcinomas of colorectal cancer patients, which is associated with a poor prognosis. In a spontaneous model of colon cancer, CysLT1R disruption was associated with a reduced tumor burden in double-mutant female mice (ApcMin/+/Cysltr1-/-) compared to ApcMin/+ littermates. In the current study, we utilized a genetic approach to investigate the effect of CysLT1R in the induced azoxymethane/dextran sulfate sodium (AOM/DSS) model of colitis-associated colon cancer. We found that AOM/DSS female mice with a global disruption of the Cysltr1 gene (Cysltr1-/-) had a higher relative body weight, a more normal weight/length colon ratio and smaller-sized colonic polyps compared to AOM/DSS wild-type counterparts. The Cysltr1-/- colonic polyps exhibited low-grade dysplasia, while wild-type polyps had an adenoma-like phenotype. The Cysltr1-/- colonic polyps exhibited significant decreases in nuclear β-catenin and COX-2 protein expression, while the normal crypts surrounding the polyps exhibited increased Mucin 2 expression. Furthermore, Cysltr1-/- mice exhibited an overall reduction in inflammation, with a significant decrease in proinflammatory cytokines, polyp 5-LOX expression and infiltration of CD45 leukocytes and F4/80 macrophages. In conclusion, the present genetic approach in an AOM/DSS model further supports an important role for CysLT1R in colon tumorigenesis.
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| 10. |
- Savari, Sayeh, et al.
(författare)
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Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 37:5, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- There is emerging literature emphasizing the role of inflammatory eicosanoids, including prostaglandins and leukotrienes, in cancer development. Increased expression of both the cysteinyl leukotriene receptor 1 (CysLTR1) and the enzyme responsible for the production of leukotrienes, 5-lipoxygenase (5-LOX), is associated with poor prognosis in patients with colorectal adenocarcinomas. Apc mutation is an early event in the development of sporadic and hereditary (FAP) colorectal cancer. We utilized the Apc(Min/+) mouse model of FAP/sporadic colorectal cancer to investigate the role of CysLTR1 in intestinal tumorigenesis by crossing Apc(Min/+) mice with mice lacking the Cysltr1 gene. We could observe a reduced tumor burden in the small intestine of double-mutant female (Cysltr1(-/-) Apc(Min/+)) but not double-mutant male mice, compared to gender-matched single-mutant (Cysltr1(+/+) Apc(Min/+)) mice. This reduction was in a Cysltr1 dependent manner, female double mutant mice having significantly reduced tumor formation compared to control littermates. The female double-mutant phenotype was accompanied with decreased systemic inflammation, as evidenced by significantly reduced serum levels of PGE2 and CysLTs, as well as increased CD3(+)CD8(+) T cell tumor infiltration. Furthermore, the reduced formation of polyps in double-mutant (Cysltr1(-/-) Apc(Min/+)) female mice could in part be explained by the cytotoxic action of CD3(+)CD8(+) T cells in the polyp and reduced nuclear accumulation of β-catenin in the epithelium of small intestinal polyps. Our results stress the important role that CysLTR1 plays in colorectal cancer and its potential as a therapeutic target in cancer therapy.
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