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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Madsen, C. L., et al.
(författare)
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The left atrial appendage closure by surgery-2 (LAACS-2) trial protocol rationale and design of a randomized multicenter trial investigating if left atrial appendage closure prevents stroke in patients undergoing open-heart surgery irrespective of preoperative atrial fibrillation status and stroke risk
- 2023
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Ingår i: American Heart Journal. - 0002-8703. ; 264, s. 133-142
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Tidskriftsartikel (refereegranskat)abstract
- Background Current recommendations regarding the use of surgical left atrial appendage (IAA) closure to prevent thromboembolisms lack high-level evidence. Patients undergoing open-heart surgery often have several cardiovascular risk factors and a high occurrence of postoperative atrial fibrillation (AF)-with a high recurrence rate-and are thus at a high risk of stroke. Therefore, we hypothesized that concomitant IAA closure during open-heart surgery will reduce mid-term risk of stroke independently of preoperative AF status and CHA 2 DS 2 -VASc score. Methods This protocol describes a randomized multicenter trial. Consecutive participants & GE;18 years scheduled for first-time planned open-heart surgery from cardiac surgery centers in Denmark, Spain, and Sweden are included. Both patients with a previous diagnosis of paroxysmal or chronic AF, as well as those without AF, are eligible to participate, irrespective of their CHA 2 DS 2 -VASc score. Patients already planned for ablation or IAA closure during surgery, with current endocarditis, or where follow-up is not possible are considered noneligible. Patients are stratified by site, surgery type, and preoperative or planned oral anticoagulation treatment. Subsequently, patients are randomized 1:1 to either concomitant IAA closure or standard care (ie, open IAA). The primary outcome is stroke, including transient ischemic attack, as assigned by 2 independent neurologists blinded to the treatment allocation. To recognize a 60% relative risk reduction of the primary outcome with LAA closure, 1,500 patients are randomized and followed for 2 years (significance level of 0.05 and power of 90%). Conclusions The LAACS-2 trial is likely to impact the LAA closure approach in most patients undergoing open-heart surgery. Trial registration: NCT03724318. (Am HeartJ 2023;264:133-142.)
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- Anttila, V., et al.
(författare)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool. © 2022
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- Brynjarsdottir, H. B., et al.
(författare)
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Long-term outcome of surgical revascularization in patients with reduced left ventricular ejection fraction-a population-based cohort study
- 2022
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Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9285 .- 1569-9293. ; 35:3
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Surgical revascularization is an established indication for patients with advanced coronary artery disease and reduced left ventricular ejection fraction (LVEF). Long-term outcomes for these patients are not well-defined. We studied the long-term outcomes of patients with ischaemic cardiomyopathy who underwent surgical revascularization in a well-defined nationwide cohort. MATERIALS AND METHODS: A retrospective study on 2005 patients that underwent isolated coronary artery bypass grafting in Iceland between 2000 and 2016. Patients were categorized into two groups based on their preoperative LVEF; LVEF ≤35% (n=146, median LVEF 30%) and LVEF >35% (n=1859, median LVEF 60%). Demographics and major adverse cardiac and cerebrovascular events were compared between groups along with cardiac-specific and overall survival. The median follow-up was 7.6years. RESULTS: Demographics were similar in both groups regarding age, gender and most cardiovascular risk factors. However, patients with LVEF ≤35% more often had diabetes, renal insufficiency, chronic obstructive pulmonary disease and a previous history of myocardial infarction. Thirty-day mortality was 4 times higher (8% vs 2%, P<0.001) in the LVEF ≤35%-group compared to controls. Overall survival was significantly lower in the LVEF ≤35%-group compared to controls, at 1 year (87% vs. 98%, P < 0.001) and 5 years (69% vs. 91%, P < 0.001). In multivariable analysis LVEF ≤35% was linked to inferior survival with an adjusted hazard ratio of 2.0 (95%-CI 1.5 - 2.6, p<0.001). CONCLUSIONS: A good long-term outcome after coronary artery bypass grafting can be expected for patients with reduced LVEF, however, their survival is still significantly inferior to patients with normal ventricular function. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.
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- Khuyagbaatar, J., et al.
(författare)
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New Short-Lived Isotope 221U and the Mass Surface Near N=126
- 2015
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Ingår i: Physical Review Letters. - 1079-7114. ; 115:24
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Tidskriftsartikel (refereegranskat)abstract
- Two short-lived isotopes 221U and 222U were produced as evaporation residues in the fusion reaction 50Ti+176Yb at the gas-filled recoil separator TASCA. An α decay with an energy of Eα=9.31(5) MeV and half-life T1/2=4.7(7) μs was attributed to 222U. The new isotope 221U was identified in α-decay chains starting with Eα=9.71(5) MeV and T1/2=0.66(14) μs leading to known daughters. Synthesis and detection of these unstable heavy nuclei and their descendants were achieved thanks to a fast data readout system. The evolution of the N=126 shell closure and its influence on the stability of uranium isotopes are discussed within the framework of α-decay reduced width.
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- Mennander, A., et al.
(författare)
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The significance of bicuspid aortic valve after surgery for acute type A aortic dissection
- 2020
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223 .- 1097-685X. ; 159:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Decision-making concerning the extent of the repair of acute type A aortic dissection (ATAAD) includes functional and anatomical assessment of the aortic valve. We hypothesized that bicuspid aortic valve (BAV) does not impact outcome after surgery for ATAAD. We therefore evaluated the outcome after ATAAD surgery in relation to the presence of BAV, acute aortic regurgitation (AR), and surgical approach, using the Nordic Consortium for Acute Type A Aortic Dissection database. Methods: Eight participating Nordic centers collected data from 1122 patients undergoing ATAAD surgery during the years 2005 to 2014. Early complications, reoperations and survival were compared between patients with BAV and tricuspid aortic valves (TAV) before and after propensity score matching for sex, age, AR, organ malperfusion, hemodynamic instability, and site of the tear. Mean follow-up (range) for patients with TAV and BAV was 3.1 years (0-10.4 years) and 3.2 years (0-9.0 years), respectively. Results: Altogether, 65 (5.8%) of the patients had BAV. Root replacement was more frequently performed in the BAV as compared with the TAV group (60% vs 23%, P <.001). Survival, however, did not differ significantly between patients with BAV or TAV, either before (P =.230) or after propensity score-matching (P =.812). Even so, in cohort as a whole, patients presenting with AR had less favorable survival. Conclusions: Early and mid-term survival did not differ significantly between patients with BAV and TAV. © 2019 The American Association for Thoracic Surgery
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