| 11. |
- 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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| 12. |
- 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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| 15. |
- Hayden, Jane M., et al.
(författare)
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Does intraperitoneal ropivacaine reduce postoperative inflammation? A prospective, double-blind, placebo-controlled pilot study
- 2019
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 63:8, s. 1048-1054
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postoperative inflammation is a common consequence of surgery and the ensuing stress response. Local anesthetics have anti-inflammatory properties. The primary aim of this study was to evaluate if LA administrated intraperitoneally perioperatively might inhibit expression of inflammatory cytokines. Methods: This was a, randomized, double blind, placebo-controlled study (ClinicalTrial.gov reg no: NCT02256228) in patients undergoing surgery for ovarian cancer. Patients were randomized to receive: intraperitoneal ropivacaine (Group IPLA) or saline (Group P) perioperatively. Except for study drug, patients were treated similarly. At the end of surgery, a multi-port catheter was inserted intraperitoneally, and ropivacaine 2mg/mL or 0.9% saline, 10mL was injected intermittently every other hour during 72hours postoperatively. Systemic expression of cytokines and plasma ropivacaine were determined before and 6, 24, and 48hours after surgery. Stress response was measured by serum glucose, cortisol, and insulin. Results: Forty patients were recruited, 20 in each group. There was no statistical significant difference in systemic cytokine between the groups at any time point. Serum cortisol was significantly lower in the IPLA group at 6hours, median 103nmol/L (IQR 53-250) compared to placebo, median 440nmol/L (IQR 115-885), P=0.023. Serum glucose and insulin were similar between the groups. Total and free serum concentrations of ropivacaine were well below toxic concentrations. Conclusion: In this small study, perioperative intraperitoneal ropivacaine did not reduce the systemic inflammatory response associated with major abdominal surgery. Total and free ropivacaine concentrations were below known toxic concentrations in humans. © 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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| 16. |
- Hendriks, Kasper P., et al.
(författare)
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Global Brassicaceae phylogeny based on filtering of 1,000-gene dataset
- 2023
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Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 33:19, s. 4052-4068
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Tidskriftsartikel (refereegranskat)abstract
- The mustard family (Brassicaceae) is a scientifically and economically important family, containing the model plant Arabidopsis thaliana and numerous crop species that feed billions worldwide. Despite its relevance, most phylogenetic trees of the family are incompletely sampled and often contain poorly supported branches. Here, we present the most complete Brassicaceae genus-level family phylogenies to date (Bras-sicaceae Tree of Life or BrassiToL) based on nuclear (1,081 genes, 319 of the 349 genera; 57 of the 58 tribes) and plastome (60 genes, 265 genera; all tribes) data. We found cytonuclear discordance between the two, which is likely a result of rampant hybridization among closely and more distantly related lineages. To eval-uate the impact of such hybridization on the nuclear phylogeny reconstruction, we performed five different gene sampling routines, which increasingly removed putatively paralog genes. Our cleaned subset of 297 genes revealed high support for the tribes, whereas support for the main lineages (supertribes) was moder-ate. Calibration based on the 20 most clock-like nuclear genes suggests a late Eocene to late Oligocene origin of the family. Finally, our results strongly support a recently published new family classification, dividing the family into two subfamilies (one with five supertribes), together representing 58 tribes. This includes five recently described or re-established tribes, including Arabidopsideae, a monogeneric tribe accommodating Arabidopsis without any close relatives. With a worldwide community of thousands of researchers working on Brassicaceae and its diverse members, our new genus-level family phylogeny will be an indispensable tool for studies on biodiversity and plant biology.
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| 20. |
- Larsson, Johan P., et al.
(författare)
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Independent by necessity? The life satisfaction of necessity and opportunity entrepreneurs in 70 countries
- 2019
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Ingår i: Small Business Economics. - : Springer. - 0921-898X .- 1573-0913. ; 53:4, s. 921-934
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Tidskriftsartikel (refereegranskat)abstract
- The relationship between self-employment and subjective well-being (SWB) is contingent on the heterogeneity observed among entrepreneurs. We argue that independence and job control, two commonly suggested sources of entrepreneurs’ higher SWB, are likely to disproportionately benefit opportunity entrepreneurs who were pulled into their occupation choice. A review of the psychological literature on the determinants of well-being further supports the view that more dynamic and impactful entrepreneurship should lead to higher SWB. Analysis of Global Entrepreneurship Monitor data from 70 countries (N = 111,589) confirm this proposition. We show that entrepreneurs, all else equal, rate their life satisfaction substantially higher than employees and, further, that this effect is entirely driven by opportunity entrepreneurs.
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