| 1. |
- Bränn, Emma, 1988-, et al.
(författare)
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Metabolic Profiling Indicates Diversity in the Metabolic Physiologies Associated With Maternal Postpartum Depressive Symptoms
- 2021
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Ingår i: Frontiers in Psychiatry. - : Frontiers Media S.A.. - 1664-0640. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postpartum depression (PPD) is a devastating disease requiring improvements in diagnosis and prevention. Blood metabolomics identifies biological markers discriminatory between women with and those without antenatal depressive symptoms. Whether this cutting-edge method can be applied to postpartum depressive symptoms merits further investigation. Methods: As a substudy within the Biology, Affect, Stress, Imagine and Cognition Study, 24 women with PPD symptom (PPDS) assessment at 6 weeks postpartum were included. Controls were selected as having a score of ≤ 6 and PPDS cases as ≥12 on the Edinburgh Postnatal Depression Scale. Blood plasma was collected at 10 weeks postpartum and analyzed with gas chromatography-mass spectrometry metabolomics. Results: Variations of metabolomic profiles within the PPDS samples were identified. One cluster showed altered kidney function, whereas the other, a metabolic syndrome profile, both previously associated with depression. Five metabolites (glycerol, threonine, 2-hydroxybutanoic acid, erythritol, and phenylalanine) showed higher abundance among women with PPDSs, indicating perturbations in the serine/threonine and glycerol lipid metabolism, suggesting oxidative stress conditions. Conclusions: Alterations in certain metabolites were associated with depressive pathophysiology postpartum, whereas diversity in PPDS physiologies was revealed. Hence, plasma metabolic profiling could be considered in diagnosis and pathophysiological investigation of PPD toward providing clues for treatment. Future studies require standardization of various subgroups with respect to symptom onset, lifestyle, and comorbidities.
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| 2. |
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| 3. |
- 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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| 4. |
- Brulin, Emma, et al.
(författare)
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An impaired learning environment : Resident physicians’ experience of the transition to pandemic care during the first wave of the COVID-19 pandemic in Sweden
- 2023
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Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Extensive studies regarding the COVID-19 pandemic have shown negative effects on physicians-in-training. Besides a high workload, their learning environment has been affected. A quality learning environment is vital for residents’ physician’s clinical development and also their health. Nevertheless, few studies have explored this. The aim of this study was to explore resident physicians’ experiences of transition to pandemic care during the first wave of the COVID-19 pandemic in Sweden. Method: In this qualitative study, 12 Swedish resident physicians were interviewed using a semi-structured interview guide. They were interviewed between June and October of 2020 and asked to reflect on the pandemic and, more specifically, the first wave. The empirical material was analysed using qualitative content analysis. The analysis resulted in one theme and four categories. Results: The theme identified was An impaired learning environment which signifies the disruptions the resident physicians experienced during the first wave of the pandemic. The four categories, Professional role insecurity, High expectations but little influence, Stagnant clinical development, and Professional growth through experience, describe in what way the learning environment was impacted.
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| 5. |
- Chotiwan, Nunya, et al.
(författare)
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Type I interferon shapes brain distribution and tropism of tick-borne flavivirus
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.
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| 6. |
- Johansson, Birgitta, 1959-, et al.
(författare)
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The effect of internet-administered support (carer eSupport) on preparedness for caregiving in informal caregivers of patients with head and neck cancer compared with support as usual: a study protocol for a randomized controlled trial.
- 2024
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Ingår i: BMC cancer. - 1471-2407. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Informal caregivers (ICs) of patients with cancer provide essential and mainly uncompensated care. A self-perceived preparedness to care for the patient is associated with a lower caregiver burden, described as the extent to which caregiving is perceived as having adverse effects on IC functioning and well-being. ICs' well-being is associated with patient-perceived quality of care, suggesting that interventions to optimize ICs' health are essential in order to improve patient care. Head and neck cancer (HNC) is the seventh most common malignant disease in the world. The disease and its treatment have a significant negative impact on the patient's health and quality of life. Symptoms usually interfere with swallowing, food and fluid intake, breathing, speaking, and communication. ICs frequently manage patients' symptoms and side effects, especially problems related to nutrition and oral pain, without being properly prepared. Carer eSupport is an Internet-administered intervention, based on focus group discussions with ICs, developed in collaboration with ICs and healthcare professionals, tested for feasibility, and deemed feasible. This study protocol outlines the methods of investigating the effects of Carer eSupport plus support as usual (SAU) on self-reported preparedness for caregiving, caregiver burden, and well-being in the ICs of patients with HNC, compared with ICs receiving SAU only.In this randomized controlled trial, 110 ICs of patients with HNC, undergoing radiotherapy combined with surgery and/or medical oncological treatment, will be randomized (1:1) to Carer eSupport plus SAU or SAU only. Data will be collected at baseline (before randomization), post-intervention (after 18 weeks), and 3 months after post-intervention. The primary outcome is self-reported preparedness for caregiving. Secondary outcomes are self-reported caregiver burden, anxiety, depression, and health-related quality of life. The effect of Carer eSupport plus SAU on preparedness for caregiving and secondary outcomes, compared with SAU only, will be evaluated by intention to treat analyses using linear regression models, mixed-model regression, or analysis of covariance.If proven effective, Carer eSupport has the potential to significantly improve ICs' preparedness for caregiving and their wellbeing, thereby improving patient-perceived quality of care and patient wellbeing.ClinicalTrials.gov; NCT06307418, registered 12.03.2024 (https://clinicaltrials.gov/search? term=NCT06307418).
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| 7. |
- Michel, M., et al.
(författare)
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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
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Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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| 8. |
- Michelsen, Halldora Ögmundsdottir, et al.
(författare)
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Organizational and patient-level predictors for attaining key risk factor targets in cardiac rehabilitation after myocardial infarction: The Perfect-CR study.
- 2023
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 371, s. 40-48
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Tidskriftsartikel (refereegranskat)abstract
- Benefits of cardiac rehabilitation (CR) programme components on attaining risk factor targets post-myocardial infarction (MI) and their predictive strength relative to patient characteristics remain unclear. We aimed to identify organizational and patient-level predictors of risk factor target attainment at one-year post-MI.In this observational study data on CR organization at 78 Swedish CR centres was collected and merged with patient-level registry data (n=7549). Orthogonal partial least squares discriminant analysis identified predictors (Variables of Importance for the Projection (VIP) values >0.8) of attaining low-density lipoprotein-cholesterol (LDL-C) <1.8mmol/L, blood pressure (BP) <140/90mmHg and smoking abstinence.The strongest predictors (VIP [95% CI]) for attaining LDL-C and BP targets were offering psychosocial management (2.14 [1.78-2.50]; 2.45 [1.91-2.99]), having a psychologist in the CR team (1.62 [1.36-1.87]; 2.05 [1.67-2.44]), extended opening hours (2.13 [2.00-2.27]; 1.50 [0.91-2.10]), adequate facilities (1.54 [0.91-2.18]; 1.89 [1.38-2.40]), and having a medical director (1.70 [0.91-2.48]; 1.46 [1.04-1.88]). The strongest patient-level predictors of attaining LDL-C and/or BP targets were low baseline LDL-C (3.95 [3.39-4.51]) and having no history of hypertension (2.93 [2.60-3.26]), respectively, followed by exercise-based CR participation (1.38 [0.66-2.10]; 1.46 [1.14-1.78]). For smoking abstinence, the strongest organizational predictor was varenicline being prescribed by CR physicians (1.88 [0.95-2.80]) and patient-level predictors were participation in exercise-based CR (2.47 [2.07-2.88]) and group education (1.92 [1.43-2-42]), and no cardiovascular disease history (2.13 [1.78-2.48]).We identified multiple CR organizational and patient-level predictors of attaining risk factor targets post-MI. These results may influence the future design of comprehensive CR programmes.
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| 9. |
- Planting-Bergloo, Sara, 1978-, et al.
(författare)
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Att utveckla elevers förmåga att formulera undersökningsbara frågor i naturvetenskap : Mangling av en didaktisk modell
- 2021
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Ingår i: LUMAT. - : LUMA Centre Finland. - 2323-7112. ; 9:1, s. 774-803
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Tidskriftsartikel (refereegranskat)abstract
- En viktig målsättning för naturvetenskaplig undervisning är att utveckla förmågan att formulera undersökningsbara frågor. Syftet med den här studien är att undersöka hur undervisning som utformats med hjälp av metoden Question Formulation Technique (QFT) kan stödja utveckling av elevers förmåga att formulera naturvetenskapligt undersökningsbara frågor. QFT är en modell för att utveckla elevers förmåga att formulera och värdera sina egna frågor i allmänhet. I studien prövas QFT i en svensk skolkontext och inom ramen för naturvetenskaplig undervisning. Studien genomfördes som en interventionsstudie i gymnasieskolan och inom ramen för kursen Gymnasiearbete. I kursen ska eleverna genomföra en egen naturvetenskaplig undersökning. QFT användes för att utforma undervisning som del av introduktionen till kursen. Data består av videoinspelningar av elevsamtal från undervisning som har analyserats utifrån ett pragmatiskt ramverk med organiserande syften och praktisk epistemologisk analys. Resultaten visar vilka närliggande syften som etableras i elevernas samtal om undersökningsbara frågor i undervisningen: (A) att producera så många frågor som möjligt, (B) att bedöma vilka frågor som är mest relevanta, (C) att kategorisera frågor, (D) att hitta och specificera ett undersökningsobjekt och (E) att planera för att genomföra en undersökning. Slutsatsen är att QFT kan fungera som stöd för lärares planering av undervisning om naturvetenskapligt undersökningsbara frågor under förutsättning att läraren aktivt stödjer eleverna i att uppmärksamma centrala kvaliteter avseende undersökningsbarhet och genom att binda samman närliggande syften med det övergripande syftet.
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| 10. |
- Scaletti, Emma Rose, et al.
(författare)
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The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors
- 2022
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:18
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Tidskriftsartikel (refereegranskat)abstract
- Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors.
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| 11. |
- Ögmundsdottir Michelsen, Halldora, et al.
(författare)
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Cardiac rehabilitation after acute myocardial infarction in Sweden : evaluation of programme characteristics and adherence to European guidelines: The Perfect Cardiac Rehabilitation (Perfect-CR) study
- 2020
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 27:1, s. 18-27
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: While patient performance after participating in cardiac rehabilitation programmes after acute myocardial infarction is regularly reported through registry and survey data, information on cardiac rehabilitation programme characteristics is less well described.AIM: The aim of this study was to evaluate Swedish cardiac rehabilitation programme characteristics and adherence to European Guidelines on Cardiovascular Disease Prevention.METHOD: Cardiac rehabilitation programme characteristics at all 78 cardiac rehabilitation centres in Sweden in 2016 were surveyed using a web-based questionnaire (100% response rate). The questions were based on core components of cardiac rehabilitation as recommended by European Guidelines.RESULTS: There was a wide variation in programme duration (2-14 months). All programmes reported offering an individual post-discharge visit with a nurse, and 90% (n = 70) did so within three weeks from discharge. Most programmes offered centre-based exercise training (n = 76, 97%) and group educational sessions (n = 61, 78%). All programmes reported to the national audit, SWEDEHEART, and 60% (n = 47) reported that performance was regularly assessed using audit data, to improve quality of care. Ninety-six per cent (n = 75) had a core team consisting of a cardiologist, a physiotherapist and a nurse and 76% (n = 59) reported having a medical director. Having other allied healthcare professionals included in the cardiac rehabilitation team varied. Forty per cent (n = 31) reported having regular team meetings where nurses, physiotherapists and cardiologist could discuss patient cases.CONCLUSION: The overall quality of cardiac rehabilitation programmes provided in Sweden is high. Still, there are several areas of potential improvement. Monitoring programme characteristics as well as patient outcomes might improve programme quality and patient outcomes both at a local and a national level.
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