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- Semb, G, et al.
(author)
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Erratum
- 2017
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In: Journal of plastic surgery and hand surgery. - 2000-6764. ; 51:2, s. 158-158
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Journal article (peer-reviewed)
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- Herold, Nikolas, et al.
(author)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
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Journal article (peer-reviewed)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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- Platon, B., et al.
(author)
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High-frequency, high-intensity transcutaneous electrical nerve stimulation as treatment of pain after surgical abortion
- 2010
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In: Pain. - 0304-3959. ; 148:1, s. 114-119
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Journal article (peer-reviewed)abstract
- The aim of the study was to compare the pain-relieving effect and the time spent in the recovery ward after treatment with high-frequency, high-intensity transcutaneous electrical nerve stimulation (TENS) or intravenous (IV) conventional pharmacological treatment after surgical abortion. Two-hundred women who underwent surgical abortion and postoperatively reported a visual analogue scale (VAS) pain score3 were included. The patients were randomised to TENS or conventional pharmacological treatment for their postoperative pain. The TENS treatment was given with a stimulus intensity between 20 and 60 mA during 1 min and repeated once if insufficient pain relief (VAS3). In the conventional pharmacological treatment group, a maximum dose of 100 microg fentanyl was given IV. There was no difference between the groups with regard to pain relief according to the VAS pain score (TENS=VAS 1.3 vs. IV opioids=VAS 1.6; p=0.09) upon discharge from the recovery ward. However, the patients in the TENS group spent shorter time (44 min) in the recovery ward than the conventional pharmacological treatment group (62 min; p<0.0001). The number of patients who needed additional analgesics in the recovery ward was comparable in both groups, as was the reported VAS pain score upon leaving the hospital (TENS=2.0 vs. conventional pharmacological treatment=1.8, NS). These results suggest that the pain-relieving effect of TENS seems to be comparable to conventional pharmacological treatment with IV opioids. Hence, TENS may be a suitable alternative to conventional pain management with IV opioids after surgical abortion.
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