| 1. |
- Kehoe, Laura, et al.
(författare)
-
Make EU trade with Brazil sustainable
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 2. |
- Bonagas, Nadilly, et al.
(författare)
-
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
-
Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
-
Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
|
|
| 3. |
- Argyropoulos, Dimitris D. S., et al.
(författare)
-
Kraft Lignin: A Valuable, Sustainable Resource, Opportunities and Challenges
- 2023
-
Ingår i: ChemSusChem. - : John Wiley and Sons Inc. - 1864-5631 .- 1864-564X. ; 16:23
-
Forskningsöversikt (refereegranskat)abstract
- Kraft lignin, a by-product from the production of pulp, is currently incinerated in the recovery boiler during the chemical recovery cycle, generating valuable bioenergy and recycling inorganic chemicals to the pulping process operation. Removing lignin from the black liquor or its gasification lowers the recovery boiler load enabling increased pulp production. During the past ten years, lignin separation technologies have emerged and the interest of the research community to valorize this underutilized resource has been invigorated. The aim of this Review is to give (1) a dedicated overview of the kraft process with a focus on the lignin, (2) an overview of applications that are being developed, and (3) a techno-economic and life cycle asseeements of value chains from black liquor to different products. Overall, it is anticipated that this effort will inspire further work for developing and using kraft lignin as a commodity raw material for new applications undeniably promoting pivotal global sustainability concerns.
|
|
| 4. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
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.
|
|
| 5. |
- Henriksson, Gunnar, et al.
(författare)
-
Lignin-carbohydrate network in wood and pulps : A determinant for reactivity
- 2007
-
Ingår i: Holzforschung. - 0018-3830 .- 1437-434X. ; 61:6, s. 668-674
-
Tidskriftsartikel (refereegranskat)abstract
- Pretreatment of wood or kraft pulp with endoglucanase followed by swelling in urea leaves a non-crystalline residue that can be dissolved in strong aqueous sodium hydroxide-sodium borate solution. A stepwise precipitation process employing acid and barium ions can separate lignin-carbohydrate complexes enriched in individual polysaccharides. This procedure has been applied to eucalypt and birch wood and to the corresponding kraft pulps. Thioacidolysis of the various lignin-carbohydrate complexes was used as the major analytical technique to obtain information about the structure and structural changes in lignin. A combination of thioacidolysis and size exclusion chromatography was used to obtain knowledge on the degree of depolymerisation and repolymerisation of lignin when going from wood to chemical pulp. In contrast to spruce wood and kraft pulp, complete recovery of the lignin-carbohydrate complexes could not be obtained from hardwood samples.
|
|
| 6. |
- Henriksson, Gunnar, 1965-, et al.
(författare)
-
Monocomponent endoglucanases : an excellent tool in wood chemistry and pulp processing
- 2005
-
Ingår i: 13th ISWFPC (International Symposium on Wood, Fibre and Pulping Chemistry), Auckland, New Zealand, 16-19 May 2005: Proceedings. ; , s. 503-508
-
Konferensbidrag (refereegranskat)abstract
- Highly pure cellulases of endoglucanase type produced by genetically modified fungi are commercially available. They are useful tools both for analytical wood chemistry and potentially also as industrial chemicals for novel processes for the pulp and paper industry. Here the functionality of cellulases and some application of endoglucanases are reviewed. The mechanisms behind the effects of the enzyme are discussed.
|
|
| 7. |
|
|
| 8. |
- Henriksson, Martin, et al.
(författare)
-
Assessing the cost effectiveness of using prognostic biomarkers with decision models: case study in prioritising patients waiting for coronary artery surgery
- 2010
-
Ingår i: BRITISH MEDICAL JOURNAL. - : BMJ. - 0959-535X. ; 340
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery. Design Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared. Data sources Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers. Results The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10 000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of 20 pound 000-30 pound 000 ((sic)22 000-(sic)33 000; $32 000-$48 000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was andlt;410 pound compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100 000 patients at an additional cost of 245 pound 000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate. Conclusion Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.
|
|
| 9. |
- Henriksson, Martin, et al.
(författare)
-
The cost-effectiveness of an early interventional strategy in non-ST-elevation acute coronary syndrome based on the RITA 3 trial
- 2008
-
Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 94, s. 717-723
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence suggests that an early interventional strategy for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) can improve health outcomes but also increase costs when compared with a conservative strategy. Objective: The aim of this study was to assess the cost-effectiveness of an early interventional strategy in different risk groups from a UK health-service perspective. Design: Decision-analytic model based on randomised clinical trial data. Main outcome measures: Costs in UK Sterling at 2003/2004 prices and quality-adjusted life years (QALYs) combined into an incremental cost-effectiveness ratio. Methods: Data from the third Randomised Intervention Trial of unstable Angina (RITA 3) was employed to estimate rates of cardiovascular death and myocardial infarction, costs and health-related quality of life. Cost-effectiveness was estimated over patients’ lifetimes within the decision-analytic model. Results: The mean incremental cost per QALY gained for an early interventional strategy was approximately £55 000, £22 000 and £12 000 for patients at low, intermediate and high risk, respectively. The early interventional strategy is approximately 1%, 35% and 95% likely to be cost-effective for patients at low, intermediate and high risk, respectively, at a threshold of £20 000 per QALY. The cost-effectiveness of early intervention in low-risk patients is sensitive to assumptions about the duration of the treatment effect. Conclusion: An early interventional strategy in patients presenting with NSTE-ACS is likely to be considered cost-effective for patients at high and intermediate risk, but this is less likely to be the case for patients at low risk.
|
|
| 10. |
- Henriksson, Martin, et al.
(författare)
-
The transfer of clinical prediction models for early trauma care had uncertain effects on mistriage
- 2020
-
Ingår i: Journal of Clinical Epidemiology. - : Elsevier BV. - 0895-4356 .- 1878-5921. ; 128, s. 66-73
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study aimed to assess how transfers of clinical prediction models for early trauma care between different care contexts within a single health system affected mistriage rates. Study Design and Setting: Patients aged 15 years or older, registered between 2011 and 2016 in the Swedish national trauma registry, SweTrau, were included. Three data set groups were created: high- and low-volume centers, metropolitan and nonmetropolitan centers, and multicenters and single centers. Clinical prediction models were developed using logistic regression in each data set group and transferred between data sets within groups. Model performance was evaluated using mistriage rate, undertriage rate, and overtriage rate. Multiple imputation using chained equations was used to handle missing data. Model performance was reported as medians with 95% confidence intervals (CIs). Results: A total of 26,965 patients were included. Changes in mistriage rates after transfer ranged from −0.25 (95% CI −0.21 to 0.04) to 0.29 (95% CI 0.13–0.39). Both overtriage and undertriage rates were affected. Conclusions: Transferring clinical prediction models for early trauma care is associated with substantial uncertainty in regards to the effect on model performance. Depending on the care context, model transfer led to either increased or decreased mistriage. Overtriage was more affected by model transfer than undertriage.
|
|
