| 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. |
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| 3. |
- Stenmark, Bianca, 1987-, et al.
(författare)
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Complete genome and methylome analysis of Neisseria meningitidis associated with increased serogroup Y disease
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Invasive meningococcal disease (IMD) due to serogroup Y Neisseria meningitidis emerged in Europe during the 2000s. Draft genomes of serogroup Y isolates in Sweden revealed that although the population structure of these isolates was similar to other serogroup Y isolates internationally, a distinct strain (YI) and more specifically a sublineage (1) of this strain was responsible for the increase of serogroup Y IMD in Sweden. We performed single molecule real-time (SMRT) sequencing on eight serogroup Y isolates from different sublineages to unravel the genetic and epigenetic factors delineating them, in order to understand the serogroup Y emergence. Extensive comparisons between the serogroup Y sublineages of all coding sequences, complex genomic regions, intergenic regions, and methylation motifs revealed small point mutations in genes mainly encoding hypothetical and metabolic proteins, and non-synonymous variants in genes involved in adhesion, iron acquisition, and endotoxin production. The methylation motif CACNNNNNTAC was only found in isolates of sublineage 2. Only seven genes were putatively differentially expressed, and another two genes encoding hypothetical proteins were only present in sublineage 2. These data suggest that the serogroup Y IMD increase in Sweden was most probably due to small changes in genes important for colonization and transmission.
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| 4. |
- Stenmark, Bianca, 1987-, et al.
(författare)
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Genome-wide methylome analysis of two strains belonging to the hypervirulent Neisseria meningitidis serogroup W ST-11 clonal complex
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- A rising incidence of meningococcal serogroup W disease has been evident in many countries worldwide. Serogroup W isolates belonging to the sequence type (ST)-11 clonal complex have been associated with atypical symptoms and increased case fatality rates. The continued expansion of this clonal complex in the later part of the 2010s has been largely due to a shift from the so-called original UK strain to the 2013 strain. Here we used single-molecule real-time (SMRT) sequencing to determine the methylomes of the two major serogroup W strains belonging to ST-11 clonal complex. Five methylated motifs were identified in this study, and three of the motifs, namely 5'-GATC-3', 5'-GAAGG-3', 5'-GCGCGC-3', were found in all 13 isolates investigated. The results showed no strain-specific motifs or difference in active restriction modification systems between the two strains. Two phase variable methylases were identified and the enrichment or depletion of the methylation motifs generated by these methylases varied between the two strains. Results from this work give further insight into the low diversity of methylomes in highly related strains and encourage further research to decipher the role of regions with under- or overrepresented methylation motifs.
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| 5. |
- Stenmark, Richard, et al.
(författare)
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Resource utilization in mental illness–evaluation of an instrument for measuring direct costs of treatment for patients with severe mental illness (SMI)
- 2023
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Ingår i: Nordic Journal of Psychiatry. - : Informa UK Limited. - 0803-9488 .- 1502-4725. ; 77:2, s. 172-178
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Serious mental illnesses (SMIs) exert a considerable financial burden on health-care systems. In this study, the resource utilization in mental illness (RUMI) tool was developed and employed to evaluate resource utilization in patients with SMI. Materials and methods: Data from 107 patients with SMI treated in four psychiatric outpatient clinics in Sweden were collected. The relationships between costs for physical and psychiatric care, social services, and the justice system, to self-reported health and quality of life, educational level, Global Assessment of Functioning (GAF), the Clinical Global Impressions scale score (CGI), and body mass index (BMI) were studied. Results: Sixteen out of 107 patients accounted for 74% of the total costs. The mean and median cost for 6 months included in the survey for social services, family and social welfare and healthcare, psychiatric and physical treatment interventions, mean 8349 EUR, median 2599 EUR per patient (currency value for 2021). Education and psychosocial function (GAF) were both negatively correlated with costs for the social services (education, r=–0.207, p < 0.014; GAF, r=–0.258, p < 0.001). CGI was correlated with costs for physical and psychiatric healthcare (r = 0.161, p < 0.027), social services support (r = 0.245, p = 0.002) and total cost (r = 0.198, p = 0.007). BMI correlated with costs for psychiatric and physical health settings interventions (r = 0.155, p < 0.019) and for somatic and psychiatric medicines (r = 0.154, p < 0.019). Conclusion: The RUMI scale was acceptable and enabled estimation of resource utilization in a comparable manner across different care settings. Such comparable data have potential to provide a basis for budgeting and resource allocation.
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