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- Asim, M, et al.
(författare)
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Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 374-
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Tidskriftsartikel (refereegranskat)abstract
- Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.
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| 3. |
- Joshi, Jayant, et al.
(författare)
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Vertical magnetic field gradient in the photospheric layers of sunspots
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 599
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We investigate the vertical gradient of the magnetic field of sunspots in the photospheric layer. Methods. Independent observations were obtained with the Solar Optical Telescope/Spectropolarimeter (SOT/SP) on board the Hinode spacecraft and with the Tenrife Infrared Polarimeter-2 (TIP-2) mounted at the German Vacuum Tower Telescope (VTT). We apply state-of-the-art inversion techniques to both data sets to retrieve the magnetic field and the corresponding vertical gradient along with other atmospheric parameters in the solar photosphere. Results. In the sunspot penumbrae we detected patches of negative vertical gradients of the magnetic field strength, i.e., the magnetic field strength decreases with optical depth in the photosphere. The negative gradient patches are located in the inner and partly in the middle penumbrae in both data sets. From the SOT/SP observations we found that the negative gradient patches are restricted mainly to the deep photospheric layers and are concentrated near the edges of the penumbral filaments. Magnetohydrodynamic (MHD) simulations also show negative gradients in the inner penumbrae, also at the locations of filaments. In the observations and the simulation negative gradients of the magnetic field vs. optical depth dominate at some radial distances in the penumbra. The negative gradient with respect to optical depth in the inner penumbrae persists even after averaging in the azimuthal direction in the observations and, to a lesser extent, in the MHD simulations. If the gradients in the MHD simulations are determined with respect to geometrical height, then the azimuthal averages are always positive within the sunspot (above log tau = 0), corresponding to magnetic field increasing with depth, as generally expected. Conclusions. We interpret the observed localized presence of negative vertical gradient of the magnetic field strength in the observations as a consequence of stronger field from spines expanding with height and closing above the weaker field inter-spines. The presence of the negative gradients with respect to optical depth after azimuthal averaging can be explained by two different mechanisms: the high corrugation of equal optical depth surfaces and the cancellation of polarized signal due to the presence of unresolved opposite polarity patches in the deeper layers of the penumbra.
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| 8. |
- Herold, Nikolas, et al.
(författare)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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