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Velikyan, I. & Eriksson, O. (2020). Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics. Theranostics, 10(1), 437-461
Open this publication in new window or tab >>Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics
2020 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 10, no 1, p. 437-461Article, review/survey (Refereed) Published
Abstract [en]

In the light of theranostics/radiotheranostics and prospective of personalized medicine in diabetes and oncology, this review presents prior and current advances in the development of radiolabeled imaging and radiotherapeutic exendin-based agents targeting glucagon-like peptide-1 receptor. The review covers chemistry, preclinical, and clinical evaluation. Such critical aspects as structure-activity-relationship, stability, physiological potency, kidney uptake, and dosimetry are discussed.

Keywords
Exendin-4, insulinoma, GLP-1, diabetes, PET, SPECT
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-398791 (URN)10.7150/thno.38366 (DOI)000497314800030 ()
Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2019-12-11Bibliographically approved
Eriksson, O., Velikyan, I., Haack, T., Bossart, M., Evers, A., Laitinen, I., . . . Wagner, M. (2019). Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates. Scientific Reports, 9, Article ID 14960.
Open this publication in new window or tab >>Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 14960Article in journal (Refereed) Published
Abstract [en]

The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [Ga-68]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [Ga-68]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 mu g/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [Ga-68]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [Ga-68]GaDO3A-S01-GCG binding in liver. [Ga-68]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 mu g/kg. In vivo K-d for [Ga-68]Ga-DO3A-S01-GCG corresponded to 0.7 mu g/kg, which indicates high potency. The test-retest reproducibility for [Ga-68]Ga-DO3A-S01-GCG binding in liver was 5.7 +/- 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 +/- 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [Ga-68]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [Ga-68]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-399094 (URN)10.1038/s41598-019-51530-0 (DOI)000490988200019 ()31628379 (PubMedID)
Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2019-12-16Bibliographically approved
Velikyan, I., Haack, T., Bossart, M., Evers, A., Laitinen, I., Larsen, P., . . . Eriksson, O. (2019). First-in-class positron emission tomography tracer for the glucagon receptor. EJNMMI Research, 9, Article ID 17.
Open this publication in new window or tab >>First-in-class positron emission tomography tracer for the glucagon receptor
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2019 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 9, article id 17Article in journal (Refereed) Published
Abstract [en]

The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement.

Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat.

Results: [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals.

Conclusion: [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.

Keywords
Glucagon, GCG, GLP-1 receptor, Dual agonist, Type 2 diabetes
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-378994 (URN)10.1186/s13550-019-0482-0 (DOI)000459043900002 ()30771019 (PubMedID)
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Eriksson, O. (2019). GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass. Current Diabetes Reports, 19(8), Article ID 49.
Open this publication in new window or tab >>GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass
2019 (English)In: Current Diabetes Reports, ISSN 1534-4827, E-ISSN 1539-0829, Vol. 19, no 8, article id 49Article, review/survey (Refereed) Published
Abstract [en]

Purpose of Review Quantitative markers for beta-cell mass (BCM) in human pancreas are currently lacking. Medical imaging using positron emission tomography (PET) markers for beta-cell restricted targets may provide an accurate and non-invasive measurement of BCM, to assist diagnosis and treatment of metabolic disease. GPR44 was recently discovered as a putative marker for beta cells and this review summarizes the developments so far. Recent Findings Several small molecule binders targeting GPR44 have been radiolabeled for PET imaging and evaluated in vitro and in small and large animal models. C-11-AZ12204657 and C-11-MK-7246 displayed a dose-dependent and GPR44-mediated binding to beta cells both in vitro and in vivo, with negligible uptake in exocrine pancreas. Summary GPR44 represents an attractive target for visualization of BCM. Further progress in radioligand development including clinical testing is expected to clarify the role of GPR44 as a surrogate marker for BCM in humans.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Beta-cell imaging, Islet imaging, Beta-cell mass, GPR44, PET, Diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-390420 (URN)10.1007/s11892-019-1164-z (DOI)000473164900004 ()31250117 (PubMedID)
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Elksnis, A., Martinell, M., Eriksson, O. & Espes, D. (2019). Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass. Frontiers in Physiology, 10, Article ID 107.
Open this publication in new window or tab >>Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass
2019 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, article id 107Article, review/survey (Refereed) Published
Abstract [en]

Type 2 diabetes (T2D) is a complex and heterogeneous disease which affects millions of people worldwide. The classification of diabetes is at an interesting turning point and there have been several recent reports on sub-classification of T2D based on phenotypical and metabolic characteristics. An important, and perhaps so far underestimated, factor in the pathophysiology of T2D is the role of oxidative stress and reactive oxygen species (ROS). There are multiple pathways for excessive ROS formation in T2D and in addition, beta-cells have an inherent deficit in the capacity to cope with oxidative stress. ROS formation could be causal, but also contribute to a large number of the metabolic defects in T2D, including beta-cell dysfunction and loss. Currently, our knowledge on beta-cell mass is limited to autopsy studies and based on comparisons with healthy controls. The combined evidence suggests that beta-cell mass is unaltered at onset of T2D but that it declines progressively. In order to better understand the pathophysiology of T2D, to identify and evaluate novel treatments, there is a need for in vivo techniques able to quantify beta-cell mass. Positron emission tomography holds great potential for this purpose and can in addition map metabolic defects, including ROS activity, in specific tissue compartments. In this review, we highlight the different phenotypical features of T2D and how metabolic defects impact oxidative stress and ROS formation. In addition, we review the literature on alterations of beta-cell mass in T2D and discuss potential techniques to assess beta-cell mass and metabolic defects in vivo.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
type 2 diabetes, diabetes classification, oxygen stress, reactive oxygen species, beta-cell, beta-cell mass, imaging, positron emission tomography
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-378233 (URN)10.3389/fphys.2019.00107 (DOI)000458732800001 ()
Funder
Swedish Child Diabetes FoundationSwedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceErnfors FoundationSwedish Diabetes AssociationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Eriksson, O., Selvaraju, R., Berglund, M. & Espes, D. (2019). Metabolically Active Brown Adipose Tissue Is Found in Adult Subjects with Type 1 Diabetes.. International Journal of Molecular Sciences, 20(23), Article ID E5827.
Open this publication in new window or tab >>Metabolically Active Brown Adipose Tissue Is Found in Adult Subjects with Type 1 Diabetes.
2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 23, article id E5827Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes (T1D) is characterized by the loss of insulin-producing cells and hence insulin secretion and metabolic control. In addition to insulin, there are a number of hormones and cytokines that influence metabolism, and many of these can be secreted from brown adipose tissue (BAT). However, the presence and activity of BAT in T1D have not been studied, despite the fact that preclinical studies have shown that transplantation of BAT in mouse models of T1D can restore metabolic control. The metabolic activity of BAT, white adipose tissue (WAT), and skeletal muscle was investigated in patients with T1D (n = 11) by 2-deoxy-2-(18F)fluoro-D-glucose PET/CT after cold stimulation. Functional BAT was detected in 4 out of 11 individuals with T1D with a prevalence of 36%. The glucose utilization rate in the supraclavicular BAT regions ranged from 0.75-38.7 µmol × min-1 × 100 g-1. The glucose utilization per gram tissue was higher in BAT when compared with both WAT (p = 0.049) and skeletal muscle (p = 0.039). However, no correlation between BAT activity and metabolic control or insulin requirements was found. In conclusion, for the first time, cold-induced BAT was detected in patients with T1D with a wide range in metabolic activity. Contrary to findings in animal models, the metabolic activity of BAT had negligible impact on insulin requirements or metabolic control in T1D under normal physiological conditions.

Keywords
brown adipose tissue, metabolic control, positron emission tomography, type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-399124 (URN)10.3390/ijms20235827 (DOI)000504428300009 ()31757005 (PubMedID)
Funder
Magnus Bergvall FoundationFredrik och Ingrid Thurings StiftelseScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-12-12 Created: 2019-12-12 Last updated: 2020-01-22Bibliographically approved
Rosqvist, F., Kullberg, J., Ståhlman, M., Cedernaes, J., Heurling, K., Johansson, H.-E., . . . Risérus, U. (2019). Overeating saturated fat promotes fatty liver and ceramides compared to polyunsaturated fat: a randomized trial. Journal of Clinical Endocrinology and Metabolism, 104(12), 6207-6219
Open this publication in new window or tab >>Overeating saturated fat promotes fatty liver and ceramides compared to polyunsaturated fat: a randomized trial
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2019 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 12, p. 6207-6219Article in journal (Refereed) Published
Abstract [en]

CONTEXT: Saturated fat (SFA) versus polyunsaturated fat (PUFA) may promote non-alcoholic fatty liver disease (NAFLD) by yet unclear mechanisms.

OBJECTIVE: To investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans.

DESIGN: Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction.

SETTING: General community.Participants: n=61 overweight or obese men and women.

INTERVENTION: Muffins high in either palm (SFA)- or sunflower oil (PUFA) were added to the habitual diet.

MAIN OUTCOME MEASURE: Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots.

RESULTS: By design, body weight gain was similar in SFA (2.31±1.38 kg) and PUFA (2.01±1.90 kg) groups, P=0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat or total body fat compared with PUFA. SFA consistently increased, while PUFA reduced circulating ceramides; changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction.

CONCLUSIONS: Saturated fat markedly induces liver fat and serum ceramides whereas dietary polyunsaturated fat prevent liver fat accumulation, reduce ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Nutrition and Dietetics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-391140 (URN)10.1210/jc.2019-00160 (DOI)31369090 (PubMedID)
Funder
Swedish Research Council, K2015-54X-22081-04-3Swedish Research Council, 2016-01040Swedish Research Council, 2015-02781Swedish Heart Lung Foundation, 20160491Stockholm County Council, ALF 20150447Ernfors FoundationSwedish Nutrition Foundation (SNF)EXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2020-03-20Bibliographically approved
Espes, D., Manell, E., Rydén, A., Carlbom, L., Weis, J., Jensen-Waern, M., . . . Eriksson, O. (2019). Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI. Acta Diabetologica, 56(10), 1113-1120
Open this publication in new window or tab >>Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI
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2019 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 56, no 10, p. 1113-1120Article in journal (Refereed) Published
Abstract [en]

AIMS: Perfusion of the pancreas and the islets of Langerhans is sensitive to physiological stimuli and is dysregulated in metabolic disease. Pancreatic perfusion can be assessed by both positron emission tomography (PET) and magnetic resonance imaging (MRI), but the methods have not been directly compared or benchmarked against the gold-standard microsphere technique.

METHODS: Pigs (n = 4) were examined by [15O]H2O PET and intravoxel incoherent motion (IVIM) MRI technique simultaneously using a hybrid PET/MRI scanner. The pancreatic perfusion was measured both at basal conditions and after intravenous (IV) administration of up to 0.5 g/kg glucose.

RESULTS: Pancreatic perfusion increased by 35%, 157%, and 29% after IV 0.5 g/kg glucose compared to during basal conditions, as assessed by [15O]H2O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [15O]H2O PET and IVIM MRI (r = 0.81, R2 = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [15O]H2O PET was within a 15% error of margin of the microsphere technique.

CONCLUSION: Pancreatic perfusion by [15O]H2O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [15O]H2O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Diabetes, Hybrid scanner, PET/MRI scanner, Pancreas perfusion
National Category
Endocrinology and Diabetes Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-383433 (URN)10.1007/s00592-019-01353-2 (DOI)000486160600003 ()31028528 (PubMedID)
Funder
Ernfors FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Diabetes AssociationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in SwedenScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-05-14 Created: 2019-05-14 Last updated: 2019-10-31Bibliographically approved
Eriksson, J., Roy, T., Sawadjoon, S., Bachmann, K., Sköld, C., Larhed, M., . . . Odell, L. R. (2019). Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass. Nuclear Medicine and Biology, 71, 1-10
Open this publication in new window or tab >>Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
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2019 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed) Published
Abstract [en]

Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-381559 (URN)10.1016/j.nucmedbio.2019.04.002 (DOI)000475837000001 ()
Funder
Swedish Research Council, 2018-05133Knut and Alice Wallenberg FoundationSwedish Child Diabetes FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-09-13Bibliographically approved
Kang, N.-Y., Soetedjo, A. A., Amirruddin, N. S., Chang, Y.-T., Eriksson, O. & Teo, A. K. (2019). Tools for Bioimaging Pancreatic beta Cells in Diabetes. Trends in Molecular Medicine, 25(8), 708-722
Open this publication in new window or tab >>Tools for Bioimaging Pancreatic beta Cells in Diabetes
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2019 (English)In: Trends in Molecular Medicine, ISSN 1471-4914, E-ISSN 1471-499X, Vol. 25, no 8, p. 708-722Article, review/survey (Refereed) Published
Abstract [en]

When diabetes is diagnosed, the majority of insulin-secreting pancreatic beta cells are already dysfunctional or destroyed. This beta cell dysfunction/destruction usually takes place over many years, making timely detection and clinical intervention difficult. For this reason, there is immense interest in developing tools to bioimage beta cell mass and/or function noninvasively to facilitate early diagnosis of diabetes as well as to assist the development of novel antidiabetic therapies. Recent years have brought significant progress in beta cell imaging that is now inching towards clinical applicability. We explore here the need to bioimage human beta cells noninvasively in various types of diabetes, and we discuss current and emerging tools for bioimaging beta cells. Further developments in this field are expected to facilitate beta cell imaging in diabetes.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-391427 (URN)10.1016/j.molmed.2019.05.004 (DOI)000477707700007 ()31178230 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-10-03 Created: 2019-10-03 Last updated: 2019-10-03Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-2515-8790

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