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- Gad, Helge, et al.
(author)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Journal article (peer-reviewed)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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- Jeppsson, Lennart, et al.
(author)
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High-resolution Late Silurian correlations between Gotland, Sweden and the Broken River region, NE Australia: Lithologies, conodonts and isotopes
- 2007
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In: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 0031-0182 .- 1872-616X. ; 245:1-2, s. 115-137
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Conference paper (peer-reviewed)abstract
- High-resolution correlations, partly with a precision better than 10 ka, are achieved between late Ludfordian sequences on Gotland, Sweden (on Baltica), and a section (COG) through the Coral Gardens Formation along the Broken River, northeastern Australia (on Gondwana), despite these sections having been on different palaeocontinents facing different oceans. The interval is characterised by rapid, very large faunal, isotopic, and lithologic changes. Lithologies are remarkably similar in the two areas, consisting of, in order from below: marls with thin limestone beds, flaggy limestones, oncoidal crinoidal limestone, oncoidal marls, terrigenous clastics (silty clay, mudstone, sandstone), oolite, and cliff-/gorge-forming limestones. Further, independent correlation dates several of the lithological changes as coeval. The 813 C excursion in whole rock carbonates is one of the three largest ones known during the Phanerozoic. The increase in delta C-13 is very similar in the two areas, from below + 1 parts per thousand to c. + 9 parts per thousand VPDB though two Gotland samples yielded + 9.71 parts per thousand and + 10.54 parts per thousand (the corresponding COG interval included fewer carbonate layers than needed to definitely exclude that this difference is due to a lack of suitable rocks for sampling). Compared with the lithologies and the delta C-13 curves, the conodont faunas display some divergence, but key taxa permit precise correlations for much of the studied interval. The conodont assemblages change stepwise from very diverse in the Polygnathoides siluricus Zone to a low diversity fauna dominated markedly by a single taxon (Upper Icriodontid Subzone), returning abruptly to a comparatively diverse Ozarkodina snajdri Zone fauna. A method resembling graphic correlation in some respects is used to propose a similarly high-resolution correlation through a longer interval for future testing. (c) 2006 Elsevier B.V. All rights reserved.
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- Madsen, C. L., et al.
(author)
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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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In: American Heart Journal. - 0002-8703. ; 264, s. 133-142
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Journal article (peer-reviewed)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.
(author)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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In: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Journal article (peer-reviewed)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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