| 1. |
- Kizilkaya, Hüsün S., et al.
(författare)
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Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes
- 2024
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Ingår i: Nature Metabolism. - 2522-5812. ; 6:7, s. 1268-1281
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Tidskriftsartikel (refereegranskat)abstract
- Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.
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| 4. |
- Portinson Hylander, Jens, et al.
(författare)
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(Im)mobilising citizens : Governing individual transport under COVID-19 and climate change in Sweden
- 2024
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Ingår i: Transportation Research Part D. - : Elsevier. - 1361-9209 .- 1879-2340.
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Tidskriftsartikel (refereegranskat)abstract
- One striking effect from policy responses by governments to address the COVID-19 pandemic was the repression of mobility, resulting in altered volumes and patterns of passenger transport on a global scale. Building on governance and governmentality theories we provide a comparative analysis of the management of COVID-19 and climate change by the Swedish state in relation to individual mobility and transport. We find that the governance approach in the two cases differ significantly, with a unified state response to COVID-19 being based on a perception of acute crisis combined with solidarity appeals to citizens. In contrast, climate change is marked by a distributed network governance, a conceptualisation of future crisis, and individuals being invoked primarily as economic agents. We discuss whether a stronger leadership by the state combined with appeals to civic solidarity may open new policy avenues for sustainable mobility.
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| 5. |
- Soegaard, Knaerke, et al.
(författare)
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"I am just trying to live a life!" : a qualitative study of the lived experience of pressure ulcers in people with spinal cord injuries
- 2024
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Ingår i: Journal of tissue viability. - : Elsevier. - 0965-206X. ; 33:1, s. 50-59
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pressure ulcers (PUs) are frequently reported in people with spinal cord injuries (SCI). Wound management in people with SCI involves relieving pressure on the affected area by means of immobilisation and bed rest. The healing time of a PU can vary, but often takes several months or even years, causing people to stay in bed for prolonged periods of time.OBJECTIVE: This study aims to explore the perspectives and lived experiences of people with SCI who are affected by PUs.DESIGN: and method: This study is a qualitative explorative study that employs individual semi-structured in-depth interviews to obtain the narratives of people with SCI and a pressure ulcer. We used a phenomenological-hermeneutic approach that was inspired by Ricoeur's theory of interpretation. The analysis was performed in three levels: Naïve reading, structural analysis and critical interpretation and discussion.PARTICIPANTS: and setting: Ten people with SCI who were being treated in the Danish healthcare system for their PU participated in this study: six participants had experienced a complete traumatic SCI, three had an incomplete traumatic SCI, and one had a non-traumatic complete SCI. The study included nine men and one woman, aged 49-81 years (mean 64). Nine had a PU in the seating area, while one had the ulcer on the leg.RESULTS: The analysis revealed three themes: 1. Struggling to balance prevention with an active, meaningful life, 2. Challenges and consequences of pressure relief protocols and bed rest, 3. Experiencing prolonged and incoherent treatment with varying levels of staff engagement and competencies.CONCLUSIONS: People with SCI and a PU have difficulty balancing their active, redefined lives when subjected to a strict pressure relief protocol. The consequences of immobility caused by pressure relief include reduced social and community participation and decreased quality of life. PU treatment is experienced as incoherent and unnecessarily lengthy, leading to a deterioration in the wounds. Improving PU treatment for people with SCI is of utmost importance and has the potential to benefit not only the people with SCI but also the healthcare system and the economy.
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| 6. |
- Aarnio, Mikko, et al.
(författare)
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Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
- 2017
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Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter. - 1877-8860 .- 1877-8879. ; 17:1, s. 418-424
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.
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| 7. |
- Aarnio, Mikko, et al.
(författare)
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Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl positron emission tomography and computed tomography
- 2022
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 163:3, s. 489-495
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.
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| 8. |
- Abouzayed, Ayman, et al.
(författare)
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Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer
- 2021
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced 99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers.Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG2-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG2-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) were radiolabeled with 99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [99mTc]Tc-maSSS-PEG2-RM26.Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [99mTc]Tc-maSSS-PEG2-RM26 outperformed [99mTc]Tc-maSES-PEG2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [99mTc]Tc-maSSS-PEG2-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [99mTc]Tc-maSSS-PEG2-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [99mTc]Tc-maSSS-PEG2-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10−3 mGy/MBq), and the effective dose is 3.49 × 10−3 mSv/MBq.Conclusion: The GRPR antagonist maSSS-PEG2-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced 99mTc and used for imaging of GRPR-expressing prostate cancer.
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| 9. |
- Alhuseinalkhudhur, Ali, et al.
(författare)
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Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.
- 2023
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 64:9, s. 1364-1370
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Tidskriftsartikel (refereegranskat)abstract
- Imaging using the human epidermal growth factor receptor 2 (HER2)-binding tracer 68Ga-labeled ZHER2:2891-Cys-MMA-DOTA ([68Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [68Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [68Ga]Ga-ABY-025 PET/CT, [18F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [18F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [68Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [68Ga]Ga-ABY-025 PET/CT cutoff SUVmax of 6.0 predicted a Δ-TLG lower than -25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67-0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (-71% [95% CI, -58% to -83%]; P < 0.0001) than in MBC (-27% [95% CI, -16% to -38%]; P < 0.0001), but [68Ga]Ga-ABY-025 SUVmax was similar in both with a mean SUVmax of 9.8 (95% CI, 6.3-13.3) and 13.9 (95% CI, 10.5-17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [68Ga]Ga-ABY-025 PET/CT SUVmax (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [68Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [68Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.
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| 10. |
- Alhuseinalkhudhur, Ali, et al.
(författare)
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Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
- 2020
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Ingår i: EJNMMI Research. - : SPRINGEROPEN. - 2191-219X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with Ga-68-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between Ga-68-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of Ga-68-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.Methods: Dynamic Ga-68-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K-1) and irreversible binding (K-i) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to K-i.Results: Characterization of HER2 expression in smaller liver metastases was improved using parametric images. K-i values from parametric images agreed very well with VOI-based gold standard (R-2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with K-i values from both the two-tissue compartment model and Patlak method (R-2 = 0.87 and 0.95, both p < 0.001). Ga-68-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).Conclusion: Ga-68-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein K-i highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.
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