| 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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| 2. |
- Mathey, Carina M., et al.
(författare)
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Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus
- 2024
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Ingår i: Journal of Allergy and Clinical Immunology. - 0091-6749 .- 1097-6825. ; 153:4, s. 1073-1082
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Tidskriftsartikel (refereegranskat)abstract
- Background: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. Objective: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. Methods: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. Results: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. Conclusions: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Brusselaers, N., et al.
(författare)
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Evaluation of science advice during the COVID-19 pandemic in Sweden
- 2022
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Ingår i: Humanities & Social Sciences Communications. - : Springer Science and Business Media LLC. - 2662-9992. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Sweden was well equipped to prevent the pandemic of COVID-19 from becoming serious. Over 280 years of collaboration between political bodies, authorities, and the scientific community had yielded many successes in preventive medicine. Sweden's population is literate and has a high level of trust in authorities and those in power. During 2020, however, Sweden had ten times higher COVID-19 death rates compared with neighbouring Norway. In this report, we try to understand why, using a narrative approach to evaluate the Swedish COVID-19 policy and the role of scientific evidence and integrity. We argue that that scientific methodology was not followed by the major figures in the acting authorities-or the responsible politicians-with alternative narratives being considered as valid, resulting in arbitrary policy decisions. In 2014, the Public Health Agency merged with the Institute for Infectious Disease Control; the first decision by its new head (Johan Carlson) was to dismiss and move the authority's six professors to Karolinska Institute. With this setup, the authority lacked expertise and could disregard scientific facts. The Swedish pandemic strategy seemed targeted towards "natural" herd-immunity and avoiding a societal shutdown. The Public Health Agency labelled advice from national scientists and international authorities as extreme positions, resulting in media and political bodies to accept their own policy instead. The Swedish people were kept in ignorance of basic facts such as the airborne SARS-CoV-2 transmission, that asymptomatic individuals can be contagious and that face masks protect both the carrier and others. Mandatory legislation was seldom used; recommendations relying upon personal responsibility and without any sanctions were the norm. Many elderly people were administered morphine instead of oxygen despite available supplies, effectively ending their lives. If Sweden wants to do better in future pandemics, the scientific method must be re-established, not least within the Public Health Agency. It would likely make a large difference if a separate, independent Institute for Infectious Disease Control is recreated. We recommend Sweden begins a self-critical process about its political culture and the lack of accountability of decision-makers to avoid future failures, as occurred with the COVID-19 pandemic.
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| 7. |
- Carlbom, Lina, et al.
(författare)
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Whole-body MRI including diffusion-weighted MRI compared with 5-HTP PET/CT in the detection of neuroendocrine tumors
- 2017
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 122:1, s. 43-50
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Tidskriftsartikel (refereegranskat)abstract
- AIM: We wanted to explore if whole-body magnetic resonance imaging (MRI) including diffusion-weighted (DW) and liver-specific contrast agent-enhanced imaging could be valuable in lesion detection of neuroendocrine tumors (NET). [11C]-5-Hydroxytryptophan positron emission tomography/computed tomography (5-HTP PET/CT) was used for comparison.MATERIALS AND METHODS: Twenty-one patients with NET were investigated with whole-body MRI, including DW imaging (DWI) and contrast-enhanced imaging of the liver, and whole-body 5-HTP PET/CT. Seven additional patients underwent upper abdomen MRI including DWI, liver-specific contrast agent-enhanced imaging, and 5-HTP PET/CT.RESULTS: There was a patient-based concordance of 61% and a lesion-based concordance of 53% between the modalities. MRI showed good concordance with PET in detecting bone metastases but was less sensitive in detecting metastases in mediastinal lymph nodes. MRI detected more liver metastases than 5-HTP PET/CT.CONCLUSION: Whole-body MRI with DWI did not detect all NET lesions found with whole-body 5-HTP PET/CT. Our findings indicate that MRI of the liver including liver-specific contrast agent-enhanced imaging and DWI could be a useful complement to whole-body 5-HTP PET/CT.
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| 8. |
- Eissler, Nina, et al.
(författare)
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Affibody PET Imaging of HER2-Expressing Cancers as a Key to Guide HER2-Targeted Therapy
- 2024
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 12:5
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Forskningsöversikt (refereegranskat)abstract
- Human epidermal growth factor receptor 2 (HER2) is a major prognostic and predictive marker overexpressed in 15-20% of breast cancers. The diagnostic reference standard for selecting patients for HER2-targeted therapy is based on the analysis of tumor biopsies. Previously patients were defined as HER2-positive or -negative; however, with the approval of novel treatment options, specifically the antibody-drug conjugate trastuzumab deruxtecan, many breast cancer patients with tumors expressing low levels of HER2 have become eligible for HER2-targeted therapy. Such patients will need to be reliably identified by suitable diagnostic methods. Biopsy-based diagnostics are invasive, and repeat biopsies are not always feasible. They cannot visualize the heterogeneity of HER2 expression, leading to a substantial number of misdiagnosed patients. An alternative and highly accurate diagnostic method is molecular imaging with radiotracers. In the case of HER2, various studies demonstrate the clinical utility and feasibility of such approaches. Radiotracers based on Affibody((R)) molecules, small, engineered affinity proteins with a size of similar to 6.5 kDa, are clinically validated molecules with favorable characteristics for imaging. In this article, we summarize the HER2-targeted therapeutic landscape, describe our experience with imaging diagnostics for HER2, and review the currently available clinical data on HER2-Affibody-based molecular imaging as a novel diagnostic tool in breast cancer and beyond.
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| 9. |
- Framke, Elisabeth, et al.
(författare)
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Contribution of income and job strain to the association between education and cardiovascular disease in 1.6 million Danish employees
- 2020
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 41:11, s. 1164-1178
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We examined the extent to which associations between education and cardiovascular disease (CVD) morbidity and mortality are attributable to income and work stress.Methods and results: We included all employed Danish residents aged 30–59 years in 2000. Cardiovascular disease morbidity analyses included 1 638 270 individuals, free of cardiometabolic disease (CVD or diabetes). Mortality analyses included 41 944 individuals with cardiometabolic disease. We assessed education and income annually from population registers and work stress, defined as job strain, with a job-exposure matrix. Outcomes were ascertained until 2014 from health registers and risk was estimated using Cox regression. During 10 957 399 (men) and 10 776 516 person-years (women), we identified 51 585 and 24 075 incident CVD cases, respectively. For men with low education, risk of CVD was 1.62 [95% confidence interval (CI) 1.58–1.66] before and 1.46 (95% CI 1.42–1.50) after adjustment for income and job strain (25% reduction). In women, estimates were 1.66 (95% CI 1.61–1.72) and 1.53 (95% CI 1.47–1.58) (21% reduction). Of individuals with cardiometabolic disease, 1736 men (362 234 person-years) and 341 women (179 402 person-years) died from CVD. Education predicted CVD mortality in both sexes. Estimates were reduced with 54% (men) and 33% (women) after adjustment for income and job strain.Conclusion: Low education predicted incident CVD in initially healthy individuals and CVD mortality in individuals with prevalent cardiometabolic disease. In men with cardiometabolic disease, income and job strain explained half of the higher CVD mortality in the low education group. In healthy men and in women regardless of cardiometabolic disease, these factors explained 21–33% of the higher CVD morbidity and mortality.
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| 10. |
- Hanson, Claudia, et al.
(författare)
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National health governance, science and the media: drivers of COVID-19 responses in Germany, Sweden and the UK in 2020
- 2021
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Ingår i: BMJ Global Health. - : BMJ. - 0959-8138 .- 2059-7908. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic is an unprecedented global crisis in which governments had to act in a situation of rapid change and substantial uncertainty. The governments of Germany, Sweden and the UK have taken different paths allowing learning for future pandemic preparedness. To help inform discussions on preparedness, inspired by resilience frameworks, this paper reviews governance structures, and the role of science and the media in the COVID-19 response of Germany, Sweden and the UK in 2020. We mapped legitimacy, interdependence, knowledge generation and the capacity to deal with uncertainty. Our analysis revealed stark differences which were linked to pre-existing governing structures, the traditional role of academia, experience of crisis management and the communication of uncertainty—all of which impacted on how much people trusted their government. Germany leveraged diversity and inclusiveness, a ‘patchwork quilt’, for which it was heavily criticised during the second wave. The Swedish approach avoided plurality and largely excluded academia, while in the UK’s academia played an important role in knowledge generation and in forcing the government to review its strategies. However, the vivant debate left the public with confusing and rapidly changing public health messages. Uncertainty and the lack of evidence on how best to manage the COVID-19 pandemic—the main feature during the first wave—was only communicated explicitly in Germany. All country governments lost trust of their populations during the epidemic due to a mix of communication and transparency failures, and increased questioning of government legitimacy and technical capacity by the public.
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