| 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. |
- Bossart, Martin, et al.
(författare)
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Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
- 2022
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Ingår i: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
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Tidskriftsartikel (refereegranskat)abstract
- Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
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| 3. |
- Cecconello, Marco, et al.
(författare)
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Conceptual design of a collimated neutron flux monitor and spectrometer for DTT
- 2021
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Ingår i: Fusion engineering and design. - : Elsevier. - 0920-3796 .- 1873-7196. ; 167
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Tidskriftsartikel (refereegranskat)abstract
- A conceptual design and performance studies for a collimated neutron flux monitor and neutron spectrometer for the Divertor Tokamak Test (DTT) facility are presented. This study is based on the single-null divertor configuration and for “Half Power” and “Full power” scenarios with 15 MW of negative-ion NBI, 29 MW of ECH and 3 MW of ICRF heating with a maximum neutron yield of 1.5 × 1017 s−1. Fast ion distributions (both from auxiliary heating systems and fusion born) have been simulated in TRANSP/NUBEAM and the corresponding neutron energy spectra have been calculated using DRESS. Synthetic diagnostics have been implemented to determine the neutron fluxes and spectra at the detector location. Neutron emissivity profiles, plasma position, core ion temperature and the ratio of thermal and non-thermal D ion populations can be obtained with good accuracy and time resolution.
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| 4. |
- Danielsson, Ravi, et al.
(författare)
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Metabolic Reprogramming of Macrophages upon In Vitro Incubation with Aluminum-Based Adjuvant
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:5
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Tidskriftsartikel (refereegranskat)abstract
- Aluminum-based adjuvants have been extensively used in vaccines. Despite their widespread use, the mechanism behind the immune stimulation properties of these adjuvants is not fully understood. Needless to say, extending the knowledge of the immune-stimulating properties of aluminum-based adjuvants is of utmost importance in the development of new, safer, and efficient vaccines. To further our knowledge of the mode of action of aluminum-based adjuvants, the prospect of metabolic reprogramming of macrophages upon phagocytosis of aluminum-based adjuvants was investigated. Macrophages were differentiated and polarized in vitro from human peripheral monocytes and incubated with the aluminum-based adjuvant Alhydrogel((R)). Polarization was verified by the expression of CD markers and cytokine production. In order to recognize adjuvant-derived reprogramming, macrophages were incubated with Alhydrogel((R)) or particles of polystyrene as control, and the cellular lactate content was analyzed using a bioluminescent assay. Quiescent M0 macrophages, as well as alternatively activated M2 macrophages, exhibited increased glycolytic metabolism upon exposure to aluminum-based adjuvants, indicating a metabolic reprogramming of the cells. Phagocytosis of aluminous adjuvants could result in an intracellular depot of aluminum ions, which may induce or support a metabolic reprogramming of the macrophages. The resulting increase in inflammatory macrophages could thus prove to be an important factor in the immune-stimulating properties of aluminum-based adjuvants.
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| 5. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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| 6. |
- Eriksson, Irene, et al.
(författare)
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Telephone nurses' strategies for managing difficult calls : A qualitative content analysis
- 2020
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Ingår i: Nursing Open. - : John Wiley & Sons. - 2054-1058. ; 7:6, s. 1671-1679
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To describe telenurses' strategies for managing difficult calls. Background: Telenursing is a growing and complex area and places great demands on telenurses' knowledge and skills and on their ability to communicate and listen. To become emotionally concerned is central to telenurses' experiences of difficult calls. Design: A descriptive qualitative study. Methods: The data were collected during February 2017 through individual interviews with 19 telenurses at call centres and primary healthcare centres. Data were analysed with qualitative content analysis. Result: The analysis revealed an essential strategy illustrated by the theme “to be calm and secure in themselves.” Further categories described telenurses' strategies to manage difficult calls, labelled as: “to show commitment and interest,” “to have structure in the call and use support systems,” “to pause the call” and “to reflect on difficult calls.” The results show that telenurses need multiple strategies to help them to navigate difficult calls.
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| 7. |
- Gillsjö, Catharina, Senior Lecturer, 1963-, et al.
(författare)
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Balance in life as a prerequisite for community-dwelling older adults' sense of health and well-being after retirement : an interview-based study
- 2021
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Ingår i: International Journal of Qualitative Studies on Health and Well-being. - : Informa UK Limited. - 1748-2623 .- 1748-2631. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE This study aimed to describe community-dwelling older adults’ perceptions of health and well-being in life after retirement.METHODS This study is part of a larger project using a mixed-methods design to address lifestyles’ influence on community-dwelling older adults’ health. Individual semi-structured interviews were conducted with 18 older adults in age 70 to 95 years. Data were analysed according to a phenomenographic approach.RESULTS The results encompass four categories describing variations in community-dwelling older adults’ perceptions of health and well-being after retirement: feeling well despite illness and disease, interacting with and being useful for oneself and others, independently embracing opportunities and engaging in life, and maintaining a healthy lifestyle.CONCLUSIONS The absence of illness and disease is not a clear prerequisite for a sense of health and well-being. To promote and preserve health and well-being after retirement, older adults strived for—and coached themselves to uphold—a balance in life, focusing on not burdening others. This life orientation after retirement must be acknowledged by society at large, especially from an ageist perspective, and in health and social care to preserve and promote health and well-being.
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| 8. |
- Gillsjö, Catharina, Senior Lecturer, 1963-, et al.
(författare)
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Lifestyle's influence on community-dwelling older adults' health : A mixed-methods study design
- 2021
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Ingår i: Contemporary Clinical Trials Communications. - Amsterdam : Elsevier. - 2451-8654. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aging often involves health problems and difficulties, such as physical and psychological impairments, isolation, and loneliness, causing social and existential consequences. Studies have explored aging from different perspectives. However, few studies have examined healthy older adults’ genetic backgrounds, lifestyles, and meaning in life separately or in combination. This study aims to describe how healthy older adults experience aging, health, lifestyles, and meaning in life and explore potential genetic correlations.Methods and Design: The project will comprise three main parts: a quantitative section featuring the development and testing of a lifestyle questionnaire, a quantitative genetic analysis, and a qualitative interview study. Participants will be community-dwelling, healthy, older adults between 70 and 95 years of age. A sample size of 800 older adults will be invited to participate in seminars in collaboration with the national Swedish association Active Seniors. Data will be collected through lifestyle questionnaire, DNA extracted from saliva samples, and interviews. Based on questionnaire responses, profile groups will be created and compared statistically with variations in genetic backgrounds, providing the basis for recruiting participants to the qualitative interviews.Discussion: This study's expected outcome will be to gain knowledge about variations in genetic backgrounds correlated with individual experiences regarding aging, health, and meaning in life. This knowledge can improve the understanding of motivations for healthy lifestyle changes. The results can reveal potential implications for individual prerequisites to healthy aging and how health-promoting aging and lifestyle counseling can be adjusted to meet individual needs.
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| 9. |
- Holm, Anna, et al.
(författare)
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Absence de papillomavirus humain à risque élevé dans le papillome inversé naso-sinusien p16 positif : [Absence of high-risk human papillomavirus in p16 positive inverted sinonasal papilloma]
- 2020
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Ingår i: Annales Francaises d'Oto-Rhino-Laryngologie et de Pathologie Cervico-Faciale. - : Elsevier. - 1879-7261. ; 137:3, s. 186-191
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Tidskriftsartikel (refereegranskat)abstract
- Le papillome inversé naso-sinusien (PINS) est une tumeur relativement rare dont l’étiologie est mal connue. Elle se caractérise par une agressivité locale et un fort potentiel de récidive en dépit d’une histologie bénigne.Objectif: L’objectif de cette étude était d’identifier la présence du papillomavirus humain (HPV) et de son marqueur de substitution, la protéine p16, dans des prélèvements tissulaires de PINS issus d’une cohorte régionale.Matériels et méthodes: À partir de notre cohorte régionale de 88 patients atteints de PINS traités entre 1984 et 2014, 54 sujets ont été sélectionnés et inclus dans cette étude. La technologie PCR a été réalisée sur 53 prélèvements et la coloration immunohistochimique pour recherche de p16 a été réalisée sur 54 prélèvements. L’ADN a été extrait après confirmation histopathologique du PINS. Un génotypage pour 13 types de HPV à risque élevé, 5 types de HPV à risque oncogène et 6 types de HPV à faible risque a été réalisé à l’aide du test de dépistage HPV PapilloCheck®.Résultats: L’analyse HPV a été réalisable sur 38 des 53 prélèvements. Sur ces 38 prélèvements, seuls 2 étaient positifs pour HPV 11. L’analyse immunohistochimique a montré que p16 était présent dans l’épithélium de tous les prélèvements, et dans les régions papillomateuses de 37 prélèvements.Conclusion: Étant donné que seuls 2 sur 38 PINS étaient positifs pour HPV (type 11) et que, dans le même temps, p16 était positif dans l’épithélium de tous les prélèvements et dans 37 des 38 régions papillomateuses, nous avons conclu que p16 ne peut pas être utilisé comme marqueur de substitution pour l’infection HPV à risque élevé dans le PINS. Nous préparons actuellement une étude multicentrique prospective afin d’augmenter la puissance de l’étude et de pouvoir mieux évaluer les implications cliniques de HPV et de p16 dans le PINS.
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| 10. |
- Holm, Anna, et al.
(författare)
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Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papilloma
- 2020
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Ingår i: European Annals of Otorhinolaryngology, Head and Neck Diseases. - : Elsevier Masson SAS. - 1879-7296 .- 1879-730X. ; 137:3, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Sinonasal inverted papilloma (SIP) is a relatively rare disease, and its etiology is not understood. It is characterized by locally aggressive growth and a strong tendency to recur despite its benign histology.Aims: The aim of this study was to identify the presence of human papilloma virus (HPV) and its surrogate marker p16 in SIP tissue samples from a regional cohort.Material and methods: Subjects were identified from our regional center cohort of 88 SIP patients treated between 1984–2014. From these subjects, 54 were included in this study. Of these, 53 biopsies were analyzed with PCR, and 54 samples were immunohistochemically stained for p16. DNA was extracted from histopathologically verified SIP. Genotype screening for 13 high risk-, 5 oncogenic and 6 low risk HPV types was performed using the PapilloCheck® HPV-screening test.Results: HPV analysis was successful for 38 of 53 samples. Of the 38 successfully analyzed samples, only 2 samples were positive for HPV 11. Notably, p16 was present in the epithelia in all samples, and in the papilloma lesions in 37 samples.Conclusion: Since only 2 out of 38 SIPs were positive for HPV (type 11), and at the same time p16 was positive in epithelia in all samples and in 37 of 38 papilloma lesions of the samples, it is concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP. We are currently planning a prospective, multicenter study in order to increase the study power and in order to be able to better evaluate the clinical implications of HPV-and p16 in SIP.
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