| 1. |
- 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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| 2. |
- Abrahamsson, L., et al.
(författare)
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Behöver arbetslinjen inte forskning?
- 2007
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Ingår i: Svenska Dagbladet Brännpunkt (debattinlägg). ; :2007-11-28
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
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| 4. |
- Axelsson, Birger, 1957-, et al.
(författare)
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Effects of Combined Milrinone and Levosimendan Treatment on Systolic and Diastolic Function During Postischemic Myocardial Dysfunction in a Porcine Model
- 2016
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Ingår i: Journal of Cardiovascular Pharmacology and Therapeutics. - Thousand Oaks, USA : Sage Publications. - 1074-2484 .- 1940-4034. ; 21:5, s. 495-503
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Tidskriftsartikel (refereegranskat)abstract
- It is not known whether there are positive or negative interactions on ventricular function when a calcium-sensitizing inotrope is added to a phosphodiesterase inhibitor in the clinical setting of acute left ventricular (LV) dysfunction. We hypothesized that when levosimendan is added to milrinone treatment, there will be synergetic inotropic and lusitropic effects. This was tested in an anesthetized porcine postischemic global LV injury model, where ventricular pressures and volumes (conductance volumetry) were measured. A global ischemic injury was induced by repetitive left main stem coronary artery occlusions. Load-independent indices of LV function were assessed before and after ventricular injury, after milrinone treatment, and finally after addition of levosimendan to the milrinone treatment. Nonparametric, within-group comparisons were made. The protocol was completed in 12 pigs, 7 of which received the inotrope treatment and 5 of which served as controls. Milrinone led to positive lusitropic effects seen by improvement in tau after myocardial stunning. The addition of levosimendan to milrinone further increased lusitropic state. The latter effect could however not be attributed solely to levosimendan, since lusitropic state also improved spontaneously in time-matched controls at the same rate during the corresponding period. When levosimendan was added to milrinone infusion, there was no increase in systolic function (preload recruitable stroke work) compared to milrinone treatment alone. We conclude that in this model of postischemic LV dysfunction, there appears to be no clear improvement in systolic or diastolic function after addition of levosimendan to established milrinone treatment but also no negative effects of levosimendan in this context.
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| 5. |
- Axelsson, Birger, 1957-, et al.
(författare)
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Milrinone and levosimendan during porcine myocardial ischemia : no effects on calcium overload and metabolism
- 2013
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Ingår i: Acta Anaesthesiologica Scandinavica. - : John Wiley & Sons. - 0001-5172 .- 1399-6576. ; 57:6, s. 719-728
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although inotropic stimulation is considered harmful in the presence of myocardial ischaemia, both calcium sensitisers and phosphodiesterase inhibitors may offer cardioprotection. We hypothesise that these cardioprotective effects are related to an acute alteration of myocardial metabolism. We studied in vivo effects of milrinone and levosimendan on calcium overload and ischaemic markers using left ventricular microdialysis in pigs with acute myocardial ischaemia.Methods: Anaesthetised juvenile pigs, average weight 36kg, were randomised to one of three intravenous treatment groups: milrinone 50g/kg bolus plus infusion 0.5g/kg/min (n=7), levosimendan 24g/kg plus infusion 0.2g/kg/min (n=7), or placebo (n=6) for 60min prior to and during a 45min acute regional coronary occlusion. Systemic and myocardial haemodynamics were assessed, and microdialysis was performed with catheters positioned in the left ventricular wall. 45Ca2+ was included in the microperfusate in order to assess local calcium uptake into myocardial cells. The microdialysate was analysed for glucose, lactate, pyruvate, glycerol, and for 45Ca2+ recovery.Results: During ischaemia, there were no differences in microdialysate-measured parameters between control animals and milrinone- or levosimendan-treated groups. In the pre-ischaemic period, arterial blood pressure decreased in all groups while myocardial oxygen consumption remained stable.Conclusions: These findings reject the hypothesis of an immediate energy-conserving effect of milrinone and levosimendan during acute myocardial ischaemia. On the other hand, the data show that inotropic support with milrinone and levosimendan does not worsen the metabolic parameters that were measured in the ischaemic myocardium.
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| 6. |
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| 7. |
- Azawi, Nessn, et al.
(författare)
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suPARnostic : an advanced predictive tool for detecting recurrence in renal cell carcinoma
- 2023
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Ingår i: BMC Urology. - 1471-2490. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Plasma soluble urokinase-type Plasminogen Activator Receptor (suPAR) predicts disease aggressiveness in renal cell carcinoma (ccRCC), but its prognostic accuracy has not been investigated. To investigate the prognostic accuracy of preoperative plasma suPAR in patients who received curative treatment for initially localized ccRCC. Methods: We retrospectively analyzed plasma samples stored in the Danish National Biobank between 2010 and 2015 from 235 patients with ccRCC at any stage. Relationships with outcome analyzed using univariate and multiple logistic Cox regression analysis. Results: There were 235 patients with ccRCC. The median follow-up period was 7.7 years. In univariate analysis suPAR ≥ 6 ng/mL was significantly associated with overall survival (OS) and recurrence-free survival (RFS). Patients with elevated suPAR were more likely to recur, with a Hazard Ratio (HR) of 2.3 for RFS. In multiple logistic regression, suPAR ≥ 6 ng/mL remained a negative predictor of OS and RFS. Limitations include retrospective study design, wide confidence intervals, and tumor subtype heterogeneity bias. Conclusions: ccRCC patients with high plasma suPAR concentrations are at an elevated risk of disease recurrence and see lower OS. suPAR is a promising surveillance tool to more precisely follow up with ccRCC patients and detect future recurrences. Patient Summary: In this study, we showed that new type of liquid marker in blood plasma, called suPAR, is associated to a higher risk of kidney cancer recurrence when elevated above 6ng/mL. We also showed suPAR to independently be able to predict patients overall and recurrence free survival in patient with any stage of kidney cancer.
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| 8. |
- Backhaus, Erik, et al.
(författare)
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Antimicrobial susceptibility of invasive pneumococcal isolates from a region in south-west Sweden 1998-2001.
- 2007
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Ingår i: Scandinavian journal of infectious diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 39:1, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Invasive disease caused by antibiotic resistant pneumococci is a worldwide problem. All invasive pneumococcal strains in an area of south-west Sweden with 1.7 million inhabitants were collected prospectively during 1998-2001. Minimum inhibitory concentrations (MICs) were determined by E-test and correlated to serotypes and clinical characteristics. Of 827 strains, 744 (90%) were susceptible (S) to all agents tested and 83 (10%) were indeterminate (I) or resistant (R) to at least 1 agent. 22 isolates (2.7%) were I to penicillin (MIC >0.06 to < or = 1.0 mg/l), but none were R (MIC >1.0 mg/l). Numbers and proportions of decreased susceptibility against other agents tested were as follows: erythromycin R: 30 (3.6%), clindamycin R: 6 (0.7%), tetracycline R: 16 (1.9%), moxifloxacin R: 1 (0.1%), cotrimoxazole I: 17 (2%) and R: 31(4%). Non-susceptibility to at least 1 agent was not correlated with age, clinical manifestation, underlying diseases and outcome. The serotype distribution differed between non-susceptible and susceptible strains. The serotypes in the 7-valent pneumococcal conjugate vaccine covered 42% of all infections and 73% of those caused by non-susceptible strains. In conclusion, the impact of antibiotic resistance in invasive pneumococcal disease remains limited in south-west Sweden.
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| 10. |
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