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| 2. |
- 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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| 3. |
- 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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| 4. |
- Oudin Åström, Daniel, et al.
(författare)
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Temperature effects on incidence of surgery for acute type A aortic dissection in the Nordics
- 2022
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Ingår i: Global health action. - : Informa UK Limited. - 1654-9880 .- 1654-9880 .- 1654-9716. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to investigate a hypothesised association between daily mean temperature and the risk of surgery for acute type A aortic dissection (ATAAD). For the period of 1 January 2005 until 31 December 2019, we collected daily data on mean temperatures and date of 2995 operations for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Using a two-stage time-series approach, we investigated the association between hot and cold temperatures relative to the optimal temperature and the rate of ATAAD repair in the selected cities. The relative risks (RRs) of cold temperatures (<=-5 degrees C) and hot temperatures (>= 21 degrees C) compared to optimal temperature were 1.47 (95% CI: 0.72-2.99) and 1.43 (95% CI: 0.67-3.08), respectively. In line with previous studies, we observed increased risk at cold and hot temperatures. However, the observed associations were not statistically significant, thus only providing weak evidence of an association.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- Pan, E., et al.
(författare)
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Low rate of reoperations after acute type A aortic dissection repair from The Nordic Consortium Registry
- 2018
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223 .- 1097-685X. ; 156:3, s. 939-948
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To describe the relationship between the extent of primary aortic repair and the incidence of reoperations after surgery for type A aortic dissection. Methods: A retrospective cohort of 1159 patients treated for type A aortic dissection at eight Nordic low-to medium-sized cardiothoracic centers from 2005 to 2014. Data were gathered from patient records and national registries. Patients were separately divided into 3 groups according to the distal anastomoses technique (ascending aorta [n = 791], hemiarch [n = 247], and total arch [n = 66]), and into 2 groups for proximal repair (aortic root replacement [n = 285] and supracoronary repair [n = 832]). Freedom from reoperation was estimated with cumulative incidence survival and Fine-Gray competing risk regression model was used to identify independent risk factors for reoperation. Results: The median follow-up was 2.7 years (range, 0-10 years). Altogether 51 out of 911 patients underwent reoperation. Freedom from distal reoperation at 5 years was 96.9%, with no significant difference between the groups (P = .22). Freedom from proximal reoperation at 5 years was 97.8%, with no difference between the groups (P = .84). Neither DeBakey classification nor the extent of proximal or distal repair predicted freedom from a later reoperation. The only independent risk factor associated with a later proximal reoperation was a history of connective tissue disease. Conclusions: Type A aortic dissection repair in low-to medium-volume centers was associated with a low reoperation rate and satisfactory midterm survival. The extent of the primary repair had no significant influence on reoperation rate or midterm survival.
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| 9. |
- Deb, S., et al.
(författare)
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SUPERIOR SVG: no touch saphenous harvesting to improve patency following coronary bypass grafting (a multi-Centre randomized control trial, NCT01047449)
- 2019
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Ingår i: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSingle centre studies support No Touch (NT) saphenous vein graft (SVG) harvesting technique. The primary objective of the SUPERIOR SVG study was to determine whether NT versus conventional (CON) SVG harvesting was associated with improved SVG patency 1year after coronary artery bypass grafting surgery (CABG).MethodsAdults undergoing isolated CABG with at least 1 SVG were eligible. CT angiography was performed 1-year post CABG. Leg adverse events were assessed with a questionnaire. A systematic review was performed for published NT graft patency studies and results aggregated including the SUPERIOR study results.ResultsTwo hundred and-fifty patients were randomized across 12-centres (NT 127 versus CON 123 patients). The primary outcome (study SVG occlusion or cardiovascular (CV) death) was not significantly different in NT versus CON (NT: 7/127 (5.5%), CON 13/123 (10.6%), p=0.15). Similarly, the proportion of study SVGs with significant stenosis or total occlusion was not significantly different between groups (NT: 8/102 (7.8%), CON: 16/107 (15.0%), p=0.11). Vein harvest site infection was more common in the NT patients 1month postoperatively (23.3% vs 9.5%, p<0.01). Including this study's results, in a meta-analysis, NT was associated with a significant reduction in SVG occlusion, Odds Ratio 0.49, 95% Confidence Interval 0.29-0.82, p=0.007 in 3 randomized and 1 observational study at 1year postoperatively.ConclusionsThe NT technique was not associated with improved patency of SVGs at 1-year following CABG while early vein harvest infection was increased. The aggregated data is supportive of an important reduction of SVG occlusion at 1year with NT harvesting.Trial registrationNCT01047449.
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