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- Schuster, C, et al.
(författare)
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The cooperating mutation or "second hit" determines the immunologic visibility toward MYC-induced murine lymphomas
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:17, s. 4635-4645
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Tidskriftsartikel (refereegranskat)abstract
- In Eμ-myc transgenic animals lymphoma formation requires additional genetic alterations, which frequently comprise loss of p53 or overexpression of BCL-2. We describe that the nature of the “second hit” affects the ability of the immune system to contain lymphoma development. Tumors with disrupted p53 signaling killed the host more rapidly than BCL-2 overexpressing ones. Relaxing immunologic control, using Tyk2−/− mice or by Ab-mediated depletion of CD8+ T or natural killer (NK) cells accelerated formation of BCL-2–overexpressing lymphomas but not of those lacking p53. Most strikingly, enforced expression of BCL-2 prolonged disease latency in the absence of p53, whereas blocking p53 function in BCL-2–overexpressing tumors failed to accelerate disease. This shows that blocking apoptosis in p53-deficient cells by enforcing BCL-2 expression can mitigate disease progression increasing the “immunologic visibility.” In vitro cytotoxicity assays confirmed that high expression of BCL-2 protein facilitates NK and T cell–mediated killing. Moreover, we found that high BCL-2 expression is accompanied by significantly increased levels of the NKG2D ligand MULT1, which may account for the enhanced killing. Our findings provide first evidence that the nature of the second hit affects tumor immunosurveillance in c-MYC–driven lymphomas and define a potential shortcoming of antitumor therapies targeting BCL-2.
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| 3. |
- Müllauer, Julia, et al.
(författare)
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Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood--brain barriers studied with (R)-[11C]verapamil positron emission tomography.
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET). METHODS: Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood--brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated. RESULTS: Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment. CONCLUSIONS: Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
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| 4. |
- Stefan, M., et al.
(författare)
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Ethnical discrimination in Europe: Field evidence from the finance industry
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The integration of ethnical minorities has been a hotly discussed topic in the political, societal, and economic debate. Persistent discrimination of ethnical minorities can hinder successful integration. Given that unequal access to investment and financing opportunities can cause social and economic disparities due to inferior economic prospects, we conducted a field experiment on ethnical discrimination in the finance sector with 1,218 banks in seven European countries. We contacted banks via e-mail, either with domestic or Arabic sounding names, asking for contact details only. We find pronounced discrimination in terms of a substantially lower response rate to e-mails from Arabic senders. Remarkably, the observed discrimination effect is robust for loan- and investment-related requests, across rural and urban locations of banks, and across countries. © 2018 Stefan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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