| 1. |
- Western, Elin, et al.
(författare)
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(-)-OSU6162 in the treatment of fatigue and other sequelae after aneurysmal subarachnoid hemorrhage : a double-blind, randomized, placebo-controlled study
- 2022
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Ingår i: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085 .- 1933-0693. ; 136:6, s. 1705-1715
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Fatigue after aneurysmal subarachnoid hemorrhage (aSAH) is common and usually long-lasting, and it has a considerable negative impact on health-related quality of life (HRQOL), social functioning, and the ability to return to work (RTW). No effective treatment exists. The dopaminergic regulator (-)-OSU6162 has shown promising results regarding the mitigation of fatigue in various neurological diseases, and therefore the authors aimed to investigate the efficacy of (-)-OSU6162 in alleviating fatigue and other sequelae after aSAH. METHODS A double-blind, randomized, placebo-controlled, single-center trial was performed in which 96 participants with post-aSAH fatigue were administered 30-60 mg/day of (-)-OSU6162 or placebo over a period of 12 weeks. Efficacy was assessed using the Fatigue Severity Scale (FSS), the Mental Fatigue Scale (MFS), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI-II), the SF-36 questionnaire, and a neuropsychological test battery. Assessments were performed at baseline, after 1, 4, 8, and 12 weeks of treatment, and at follow-up, 8 weeks after treatment. RESULTS The 96 participants with post-aSAH fatigue were randomized to treatment with (-)- OSU6162 (n = 49) or placebo (n = 47). The FSS, MFS, and BDI scores improved significantly in both groups after 12 weeks of treatment, whereas the BAI scores improved in the placebo group only. HRQOL improved significantly in the SF-36 domain "Vitality" in both groups. Neuropsychological test performances were within the normal range at baseline and not affected by treatment. The FSS score was distinctly improved in patients with complete RTW upon treatment with (-)-OSU6162. Concomitant use of antidepressants improved the efficacy of (-)- OSU6162 on the FSS score at week 1 beyond the placebo response, and correspondingly the use of beta- or calcium-channel blockers improved the (-)-OSU6162 efficacy beyond the placebo response in MFS scores at week 4 of treatment. There was a significant correlation between improvement in FSS, BAI, and BDI scores and the plasma concentration of (-)-OSU6162 at the dose of 60 mg/day. No serious adverse events were attributable to the treatment, but dizziness was reported more often in the (-)-OSU6162 group. CONCLUSIONS Fatigue and other sequelae after aSAH were similarly alleviated by treatment with (-)-OSU6162 and placebo. (-)-OSU6162 improved fatigue, as measured with the FSS score, significantly in patients with complete RTW. There seemed to be synergetic effects of (-)-OSU6162 and medications interfering with dopaminergic pathways that should be explored further. The strong placebo response may be exploited in developing nonpharmacological treatment programs for post-aSAH fatigue.
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| 2. |
- Abdelrazak Morsy, Mohammad Hamdy, et al.
(författare)
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SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma
- 2024
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 143:19, s. 1953-1964
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Tidskriftsartikel (refereegranskat)abstract
- Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.
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