| 1. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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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.
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| 2. |
- Arvidsson, Anna, 1973, et al.
(författare)
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Early interactions between leukocytes and three different potentially bioactive titanium surface modifications
- 2011
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Ingår i: Journal of Biomedical Materials Research. Part B - Applied biomaterials. - : Wiley. - 1552-4973 .- 1552-4981. ; 97:2, s. 364-72
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to compare the early interactions between leukocytes and three different surface modifications, suggested as bioactive. Blasted titanium discs were modified by alkali and heat treatment, sodium fluoride treatment, or hydroxyapatite coating. A number of these discs were also immersed in simulated body fluid (SBF) for a week, a treatment which yielded high levels of calcium and phosphate on each surface type. The specimens were exposed for human venous blood for 32 minutes and the respiratory burst response was measured in terms of reactive oxygen species with a luminometer, and coverage of viable cells with a fluorescence microscope after staining steps. The topography, morphology, and chemistry of the surfaces were evaluated with optical interferometry and scanning electron microscopy/energy dispersive X-ray analysis (SEM/EDX). A high respiratory burst response was found for HA coated titanium in comparison with the other surface groups (p < 0.0005). The SBF immersion resulted in an increased respiratory burst response (p < 0.0005) and removed statistically significant differences between the surface groups. Thus, the results in the present study indicate that different titanium surface modifications influence the early inflammatory response differently, and that calcium phosphate compounds increase the inflammatory response.
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| 3. |
- Arvidsson, Per Martin, et al.
(författare)
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Kinetic energy of left ventricular blood flow across heart failure phenotypes and in subclinical diastolic dysfunction
- 2022
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Ingår i: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 133:3, s. 697-709
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Kinetic energy (KE) of intracardiac blood flow reflects myocardial work spent on accelerating blood and provides a mechanistic window into diastolic filling dynamics. Diastolic dysfunction may represent an early stage in the development of heart failure (HF). Here we evaluated the hemodynamic effects of impaired diastolic function in subjects with and without HF, testing the hypothesis that left ventricular KE differs between controls, subjects with subclinical diastolic dysfunction (SDD), and HF patients.METHODS: We studied 77 subjects (16 controls, 20 subjects with SDD, 16 HFpEF, 9 HFmrEF, and 16 HFrEF patients, age- and sex-matched at the group level). Cardiac magnetic resonance at 1.5T included intracardiac 4D flow and cine imaging. Left ventricular KE was calculated as 0.5*m*v 2. RESULTS: Systolic KE was similar between groups (p>0.4), also after indexing to stroke volume (p=0.25), and was primarily driven by ventricular emptying rate (p<0.0001, R 2=0.52). Diastolic KE was higher in heart failure patients than controls (p<0.05) but similar between SDD and HFpEF (p>0.18), correlating with inflow conditions (E-wave velocity, p<0.0001, R 2=0.24) and end-diastolic volume (p=0.0003, R 2=0.17) but not with average e' (p=0.07). CONCLUSIONS: Diastolic KE differs between controls and heart failure, suggesting more work is spent filling the failing ventricle, while systolic KE does not differentiate between well-matched groups with normal ejection fraction even in the presence of relaxation abnormalities and heart failure. Mechanistically, KE reflects the acceleration imparted on the blood and is driven by variations in ventricular emptying and filling rates, volumes, and heart rate, regardless of underlying pathology.
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| 4. |
- Arvidsson, Per Martin, et al.
(författare)
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Kinetic energy of left ventricular blood flow across heart failure phenotypes and in subclinical diastolic dysfunction.
- 2022
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601.
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Tidskriftsartikel (refereegranskat)abstract
- Kinetic energy (KE) of intracardiac blood flow reflects myocardial work spent on accelerating blood and provides a mechanistic window into diastolic filling dynamics. Diastolic dysfunction may represent an early stage in the development of heart failure (HF). Here we evaluated the hemodynamic effects of impaired diastolic function in subjects with and without HF, testing the hypothesis that left ventricular KE differs between controls, subjects with subclinical diastolic dysfunction (SDD), and HF patients.We studied 77 subjects (16 controls, 20 subjects with SDD, 16 HFpEF, 9 HFmrEF, and 16 HFrEF patients, age- and sex-matched at the group level). Cardiac magnetic resonance at 1.5T included intracardiac 4D flow and cine imaging. Left ventricular KE was calculated as 0.5*m*v2.Systolic KE was similar between groups (p>0.4), also after indexing to stroke volume (p=0.25), and was primarily driven by ventricular emptying rate (p<0.0001, R2=0.52). Diastolic KE was higher in heart failure patients than controls (p<0.05) but similar between SDD and HFpEF (p>0.18), correlating with inflow conditions (E-wave velocity, p<0.0001, R2=0.24) and end-diastolic volume (p=0.0003, R2=0.17) but not with average e' (p=0.07).Diastolic KE differs between controls and heart failure, suggesting more work is spent filling the failing ventricle, while systolic KE does not differentiate between well-matched groups with normal ejection fraction even in the presence of relaxation abnormalities and heart failure. Mechanistically, KE reflects the acceleration imparted on the blood and is driven by variations in ventricular emptying and filling rates, volumes, and heart rate, regardless of underlying pathology.
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| 5. |
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| 6. |
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| 7. |
- Almobarak, Bilal, et al.
(författare)
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Exposure to nonanoic acid alters small intestinal neuroendocrine tumor phenotype
- 2023
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSmall intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location.MethodsClinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology.ResultsTumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology.ConclusionOur results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.
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| 8. |
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Aquatic Conservation with Focus on Margaritifera margaritifera : Proceedings of the International Conference in Sundsvall, Sweden, 12-14 August, 2009
- 2012
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Proceedings (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- The freshwater pearl mussel Margaritifera margaritifera (L.) has attracted a large human interest, since the mussel is fascinating from biological, cultural andenvironmental perspectives. The mussel has a complicated life cycle dependingon host fish, and has great demands on its habitat. Furthermore, the mussel is anenvironmental indicator, and is used as an umbrella and flagship species. Pearl fishing has been described in Sweden as early as in the 16th century and by Carl Linnaeus in the 18th century.Many freshwater pearl mussel populations have insufficient recruitment and therefore decrease in numbers, and many populations are even extinct. Therefore, conservation work on the freshwater pearl mussel is going on all over Europe. Actions to preserve the freshwater pearl mussel will also favour other aquatic species – freshwater pearl mussel conservation is aquatic biodiversity conservation! WWF (World Wide Fund for Nature) Sweden implemented the project “The Freshwater Pearl Mussel and its habitats in Sweden” during 2004-2009 (LIFE04NAT/SE/000231). The overall objective was to improve the habitats of juvenile freshwater pearl mussels and the host fish brown trout Salmo trutta in21 streams. The actions were improvements of the biotopes, re-introduction of mussels, information to the stakeholders, and development of planning methods. An international conference “Aquatic Conservation with Focus on the Freshwater Pearl Mussel Margaritifera margaritifera” was held in Sundsvall 12–14 August, 2009. In these proceedings, presentations from the conference are published.
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| 9. |
- Arup, Ulf, et al.
(författare)
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Lavar Lichenes
- 2015
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Ingår i: Rödlistade arter i Sverige 2015. - 9789187853104 ; , s. 72-79
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Arvidsson, Anna, 1973, et al.
(författare)
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Formation of calcium phosphates on titanium implants with four different bioactive surface preparations. An in vitro study
- 2007
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Ingår i: Journal of Materials Science-Materials in Medicine. - : Springer Science and Business Media LLC. - 0957-4530 .- 1573-4838. ; 18:10, s. 1945-1954
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to compare the nucleating and growing behaviour on four types of bioactive surfaces by using the simulated body fluid (SBF) model. Titanium discs were blasted and then prepared by alkali and heat treatment, anodic oxidation, fluoridation, or hydroxyapatite coating. The discs were immersed in SBF for 1, 2, 4 and 6 weeks. Calcium phosphates were found on all specimens, as analysed with scanning electron microscopy/energy dispersive X-ray analysis (SEM/EDX). After 1 and 2 weeks of SBF immersion more titanium was accessible with SEM/EDX on the blasted surfaces than the four bioactive surface types, indicating a difference in coverage by calcium phosphates. The Ca/P mean ratio of the surfaces was approximately 1.5 after 1 week, in contrast to the fluoridated specimens which displayed a Ca/P mean ratio of approximately 2. Powder X-ray diffraction (P-XRD) analyses showed the presence of hydroxyapatite on all types of surfaces after 4 and 6 weeks of immersion. The samples immersed for 6 weeks showed a higher degree of crystallinity than the samples immersed for 4 weeks. In conclusion, differences appeared at the early SBF immersion times of 1 and 2 weeks between controls and bioactive surface types, as well as between different bioactive surface types.
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