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- Boerma, M, et al.
(författare)
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A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development
- 1999
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 246:2, s. 211-218
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Atherosclerosis is a multifactorial disease, in part characterized by chronic inflammatory changes in the vessel wall and loss of normal physical and biochemical interactions between endothelial cells and smooth muscle cells. Previous studies [Hu J., Cotgreave IA. J Clin Invest; 99: 1-5] have provided molecular links between inflammation and myoendothelial communication via gap junctions, suggesting that these structures may be important in the development of the atherosclerotic vessel phenotype. In order to strengthen this premise, the aim of the present work was to probe for structural polymorphisms in connexin 37, a gap junctional protein uniquely expressed in endothelial cells, and to assess for potential genotypic segregation in individuals displaying atherosclerotic plaque. METHODS AND RESULTS: Computer-based comparisons of Expressed Sequence Tags (ESTs) predicted a polymorphism in the human gap junctional protein connexin 37 (cx37). The C1019-T mutation results in a proline to serine shift at codon 319 (cx37*1-cx37*2). A Restriction Fragment Length Polymorphism (RFLP) assay, involving the insertion of a novel Drd I cleavage site in the proline variant revealed a statistically significant over-representation of the cx37*1 allele in association with atherosclerotic plaque-bearing individuals (Odds-ratio for the homozygote = 2.38, Chi2 = 7.693, P = 0.006), in comparison to individuals lacking plaque, irrespective of a history of hypertension. CONCLUSIONS: These data suggest that the C1019-T polymorphism in cx37 may provide 'single gene marker', which could be useful in assessing atherosclerotic plaque development, particularly in cardiovascular risk groups such as those with borderline hypertension.
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- Huhtaniemi, R., et al.
(författare)
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High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:5
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Tidskriftsartikel (refereegranskat)abstract
- Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
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- Söderquist, Pär, et al.
(författare)
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Admixture between released and wild game birds: a changing genetic landscape in European mallards (Anas platyrhynchos)
- 2017
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Ingår i: European Biophysics Journal. - : Springer Verlag (Germany). - 0175-7571 .- 1432-1017. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- Disruption of naturally evolved spatial patterns of genetic variation and local adaptations is a growing concern in wildlife management and conservation. During the last decade, releases of native taxa with potentially non-native genotypes have received increased attention. This has mostly concerned conservation programs, but releases are also widely carried out to boost harvest opportunities. The mallard, Anas platyrhynchos, is one of few terrestrial migratory vertebrates subjected to large-scale releases for hunting purposes. It is the most numerous and widespread duck in the world, yet each year more than three million farmed mallard ducklings are released into the wild in the European Union alone to increase the harvestable population. This study aimed to determine the genetic effects of such large-scale releases of a native species, specifically if wild and released farmed mallards differ genetically among subpopulations in Europe, if there are signs of admixture between the two groups, if the genetic structure of the wild mallard population has changed since large-scale releases began in the 1970s, and if the current data matches global patterns across the Northern hemisphere. We used Bayesian clustering (Structure software) and Discriminant Analysis of Principal Components (DAPC) to analyze the genetic structure of historical and present-day wild (n = 171 and n = 209, respectively) as well as farmed (n = 211) mallards from six European countries as inferred by 360 single-nucleotide polymorphisms (SNPs). Both methods showed a clear genetic differentiation between wild and farmed mallards. Admixed individuals were found in the present-day wild population, implicating introgression of farmed genotypes into wild mallards despite low survival among released farmed mallards. Such cryptic introgression would alter the genetic composition of wild populations and may have unknown long-term consequences for conservation.
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| 8. |
- Bäck, Tom, 1964, et al.
(författare)
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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors
- 2020
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Ingår i: Ejnmmi Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic alpha-radioimmunotherapy (alpha-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the alpha-particle emitter At-211-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. Methods PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of alpha-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (100-200 mu m; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. Results Tumor targeting of At-211-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 +/- 0.003 mm(3) versus 3.79 +/- 1.24 mm(3) (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). Conclusion Evaluating fractionated alpha-RIT with At-211-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of At-211-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of alpha-RIT or by altering the size of the targeting vector.
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| 9. |
- Elmberg, Johan, et al.
(författare)
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Farmed European mallards are genetically different and cause introgression in the wild population following releases
- 2016
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Konferensbidrag (refereegranskat)abstract
- The practice of restocking already viable populations to increase harvest potential has since long been common in forestry, fisheries and wildlife management. The potential risks of restocking native species have long been overshadowed by the related issue of invasive alien species. However, during the last decade releases of native species with potentially non-native genome have received more attention. A suitable model to study genetic effects of large-scale releases of native species is the Mallard Anas platyrhynchos, being the most widespread duck in the world, largely migratory, and an important quarry species. More than 3 million unfledged hatchlings are released each year around Europe to increase local harvest. The aims of this study were to determine if wild and released farmed Mallards differ genetically, if there are signs of previous or ongoing introgression between wild and farmed birds, and if the genetic structure of the wild Mallard population has changed since large-scale releases started in Europe in the 1970s. Using 360 Single Nucleotide Polymorphisms (SNPs) we found that the genetic structure differed among historical wild, present-day wild, and farmed Mallards in Europe. We also found signs of introgression in the wild Mallard population, that is, individuals with a genetic background of farmed stock are part of the present free-living population. Although only a small proportion of the released Mallards appears to survive to merge with the free-living breeding population, their numbers are still so large that the genetic impact may have significance for the wild population in terms of individual survival and longterm fitness.
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| 10. |
- Elmberg, Johan, et al.
(författare)
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Farmed European mallards are genetically different and cause introgression in the wild population following releases
- 2016
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The practice of restocking already viable populations to increase harvest potential has since long been common in forestry, fisheries and wildlife management. The potential risks of restocking native species have long been overshadowed by the related issue of invasive alien species. However, during the last decade releases of native species with potentially non-native genome have received more attention. A suitable model to study genetic effects of large-scale releases of native species is the Mallard Anas platyrhynchos, being the most widespread duck in the world, largely migratory, and an important quarry species. More than 3 million unfledged hatchlings are released each year around Europe to increase local harvest. The aims of this study were to determine if wild and released farmed Mallards differ genetically, if there are signs of previous or ongoing introgression between wild and farmed birds, and if the genetic structure of the wild Mallard population has changed since large-scale releases started in Europe in the 1970s. Using 360 Single Nucleotide Polymorphisms (SNPs) we found that the genetic structure differed among historical wild, present-day wild, and farmed Mallards in Europe. We also found signs of introgression in the wild Mallard population, that is, individuals with a genetic background of farmed stock are part of the present free-living population. Although only a small proportion of the released Mallards appears to survive to merge with the free-living breeding population, their numbers are still so large that the genetic impact may have significance for the wild population in terms of individual survival and longterm fitness.
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