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  1. AU="Axelgaard, Esben"
  2. AU="Kachingwe, Martin"
  3. AU="Yokoyama, Ryuto"
  4. AU="Luck, Jennifer N"
  5. AU="Min Soo Kim"
  6. AU="Piotr Dylewicz"
  7. AU="Mankel, A"
  8. AU="Lia, Andrea"
  9. AU=Wang Yong
  10. AU="Mckay, Victoria"
  11. AU="Yanqun Liu"
  12. AU="Doyon, Yannick"
  13. AU=Ho-Yen Colan M
  14. AU="Tarnawski, Miroslaw"
  15. AU="Mark Pickering"
  16. AU=Felson Marcus
  17. AU="Antje Garten"
  18. AU="Pijpers, Judith"
  19. AU=Ciacchini Benedetta AU=Ciacchini Benedetta

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  1. Artikel ; Online: Therapeutic gene editing in haematological disorders with CRISPR/Cas9.

    Jensen, Trine I / Axelgaard, Esben / Bak, Rasmus O

    British journal of haematology

    2019  Band 185, Heft 5, Seite(n) 821–835

    Abstract: The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas)9 platform offers an efficient way of making precise genetic changes to the human genome. This can be employed for disruption, addition and correction of genes, ...

    Abstract The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas)9 platform offers an efficient way of making precise genetic changes to the human genome. This can be employed for disruption, addition and correction of genes, thereby enabling a new class of genetic therapies that can be applied to haematological disorders. Here we review recent technological advances in the CRISPR/Cas9 methodology and applications in haematology for curing monogenic genetic disorders and for engineering novel chimeric antigen receptor (CAR) T cells to treat haematological malignancies. Furthermore, we discuss current challenges for full clinical implementation of CRISPR/Cas9, and reflect on future trajectories of the technology.
    Mesh-Begriff(e) CRISPR-Cas Systems/genetics ; Gene Editing/methods ; Hematologic Diseases/genetics ; Humans
    Sprache Englisch
    Erscheinungsdatum 2019-03-12
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80077-6
    ISSN 1365-2141 ; 0007-1048
    ISSN (online) 1365-2141
    ISSN 0007-1048
    DOI 10.1111/bjh.15851
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin.

    Axelgaard, Esben / Østergaard, Jakob Appel / Thiel, Steffen / Hansen, Troels Krarup

    Journal of diabetes research

    2017  Band 2017, Seite(n) 6368780

    Abstract: Mannan-binding lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the lectin pathway of the complement system upon recognition of ... ...

    Abstract Mannan-binding lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (
    Mesh-Begriff(e) Albuminuria/urine ; Animals ; Blood Glucose/metabolism ; Creatinine/urine ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Kidney/metabolism ; Kidney/pathology ; Mannose-Binding Lectin/genetics ; Mannose-Binding Lectin/metabolism ; Mice ; Mice, Knockout
    Chemische Substanzen Blood Glucose ; Mannose-Binding Lectin ; Creatinine (AYI8EX34EU)
    Sprache Englisch
    Erscheinungsdatum 2017-02-28
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2711897-6
    ISSN 2314-6753 ; 2314-6745
    ISSN (online) 2314-6753
    ISSN 2314-6745
    DOI 10.1155/2017/6368780
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes.

    Axelgaard, Esben / Østergaard, Jakob Appel / Haxha, Saranda / Thiel, Steffen / Hansen, Troels Krarup

    Mediators of inflammation

    2017  Band 2017, Seite(n) 9403754

    Abstract: Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the ... ...

    Abstract Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway. To test this hypothesis, we induced diabetes by injection of low-dose streptozotocin in MBL double-knockout (MBL/DKO) mice. Development of diabetes was followed by measurements of blood glucose and urine albumin-to-creatinine ratio. Fluorophore-labelled recombinant MBL was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL, thus indicating MBL-mediated systemic complement activation in these animals. These new findings indicate a global role of MBL during late diabetes-mediated vascular complications in various tissues.
    Sprache Englisch
    Erscheinungsdatum 2017
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1137605-3
    ISSN 1466-1861 ; 0962-9351
    ISSN (online) 1466-1861
    ISSN 0962-9351
    DOI 10.1155/2017/9403754
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  4. Artikel ; Online: Targeted regulation of transcription in primary cells using CRISPRa and CRISPRi.

    Jensen, Trine I / Mikkelsen, Nanna S / Gao, Zongliang / Foßelteder, Johannes / Pabst, Gabriel / Axelgaard, Esben / Laustsen, Anders / König, Saskia / Reinisch, Andreas / Bak, Rasmus O

    Genome research

    2021  Band 31, Heft 11, Seite(n) 2120–2130

    Abstract: Targeted transcriptional activation or interference can be induced with the CRISPR-Cas9 system (CRISPRa/CRISPRi) using nuclease-deactivated Cas9 fused to transcriptional effector molecules. These technologies have been used in cancer cell lines, ... ...

    Abstract Targeted transcriptional activation or interference can be induced with the CRISPR-Cas9 system (CRISPRa/CRISPRi) using nuclease-deactivated Cas9 fused to transcriptional effector molecules. These technologies have been used in cancer cell lines, particularly for genome-wide functional genetic screens using lentiviral vectors. However, CRISPRa and CRISPRi have not yet been widely applied to ex vivo cultured primary cells with therapeutic relevance owing to a lack of effective and nontoxic delivery modalities. Here we develop CRISPRa and CRISPRi platforms based on RNA or ribonucleoprotein (RNP) delivery by electroporation and show transient, programmable gene regulation in primary cells, including human CD34
    Mesh-Begriff(e) CRISPR-Cas Systems ; Endonucleases/genetics ; Gene Expression Regulation ; Genome ; RNA, Guide, CRISPR-Cas Systems/genetics ; Transcriptional Activation
    Chemische Substanzen RNA, Guide, CRISPR-Cas Systems ; Endonucleases (EC 3.1.-)
    Sprache Englisch
    Erscheinungsdatum 2021-08-18
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.275607.121
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: STING activation counters glioblastoma by vascular alteration and immune surveillance.

    Joseph, Justin V / Blaavand, Mathilde S / Cai, Huiqiang / Vernejoul, Fabienne / Knopper, Rasmus W / Lindhardt, Thomas B / Skipper, Kristian A / Axelgaard, Esben / Reinert, Line / Mikkelsen, Jacob G / Borghammer, Per / Degn, Søren E / Perouzel, Eric / Hager, Henrik / Hansen, Brian / Kalucka, Joanna M / Vendelbo, Mikkel / Paludan, Søren R / Thomsen, Martin K

    Cancer letters

    2023  Band 579, Seite(n) 216480

    Abstract: Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New ... ...

    Abstract Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.
    Mesh-Begriff(e) Humans ; Brain Neoplasms/immunology ; Brain Neoplasms/metabolism ; Glioblastoma/immunology ; Glioblastoma/metabolism ; Immunotherapy/methods ; Tumor Microenvironment ; Immunity, Innate
    Chemische Substanzen STING1 protein, human
    Sprache Englisch
    Erscheinungsdatum 2023-11-04
    Erscheinungsland Ireland
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2023.216480
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  6. Artikel ; Online: Ficolin B in Diabetic Kidney Disease in a Mouse Model of Type 1 Diabetes.

    Holt, Charlotte Berg / Østergaard, Jakob Appel / Axelgaard, Esben / Nielsen, Gitte Krogh / Endo, Yuichi / Thiel, Steffen / Hansen, Troels Krarup

    Mediators of inflammation

    2015  Band 2015, Seite(n) 653260

    Abstract: Background: The innate immune system may have adverse effects in diabetes and cardiovascular disease. The complement system seems to play a key role through erroneous complement activation via hyperglycaemia-induced neoepitopes. Recently mannan-binding ... ...

    Abstract Background: The innate immune system may have adverse effects in diabetes and cardiovascular disease. The complement system seems to play a key role through erroneous complement activation via hyperglycaemia-induced neoepitopes. Recently mannan-binding lectin (MBL) was shown to worsen diabetic kidney changes. We hypothesize that mouse ficolin B exerts detrimental effects in the diabetic kidney as seen for MBL.
    Methods: We induced diabetes with streptozotocin in female wild-type mice and ficolin B knockout mice and included two similar nondiabetic groups. Renal hypertrophy and excretion of urinary albumin and creatinine were quantified to assess diabetic kidney damage.
    Results: In the wild-type groups, the kidney weighed 24% more in the diabetic mice compared to the controls. The diabetes-induced increase in kidney weight was 29% in the ficolin B knockout mice, that is, equal to wild-type animals (two-way ANOVA, P = 0.60). In the wild-type mice the albumin-to-creatinine ratio (ACR) was 32.5 mg/g higher in the diabetic mice compared to the controls. The difference was 62.5 mg/g in the ficolin B knockout mice, but this was not significantly different from the wild-type animals (two-way ANOVA, P = 0.21).
    Conclusions: In conclusion, the diabetes-induced effects on kidney weight and ACR were not modified by the presence or absence of ficolin B.
    Mesh-Begriff(e) Albumins/metabolism ; Animals ; Creatinine/metabolism ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Female ; Kidney/metabolism ; Kidney/pathology ; Lectins/genetics ; Lectins/metabolism ; Mice ; Mice, Knockout ; Ficolins
    Chemische Substanzen Albumins ; Lectins ; Creatinine (AYI8EX34EU)
    Sprache Englisch
    Erscheinungsdatum 2015-08-03
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1137605-3
    ISSN 1466-1861 ; 0962-9351
    ISSN (online) 1466-1861
    ISSN 0962-9351
    DOI 10.1155/2015/653260
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  7. Artikel ; Online: Investigations on collectin liver 1.

    Axelgaard, Esben / Jensen, Lisbeth / Dyrlund, Thomas F / Nielsen, Hans J / Enghild, Jan J / Thiel, Steffen / Jensenius, Jens C

    The Journal of biological chemistry

    2013  Band 288, Heft 32, Seite(n) 23407–23420

    Abstract: Collectins are pattern recognition molecules of the innate immune system showing binding to carbohydrate structures on microorganisms in a calcium-dependent manner. Recently, three novel collectins, collectin liver 1 (CL-L1), collectin kidney 1 (CL-K1 ... ...

    Abstract Collectins are pattern recognition molecules of the innate immune system showing binding to carbohydrate structures on microorganisms in a calcium-dependent manner. Recently, three novel collectins, collectin liver 1 (CL-L1), collectin kidney 1 (CL-K1 and CL-11), and collectin placenta 1 (CL-P1), were discovered. The roles of these three collectins remain largely unknown. Here, we present a time-resolved immunofluorometric assay for quantification of CL-L1. The concentration of CL-L1 in donor plasma (n = 210) was distributed log-normally with a median value of 3.0 μg/ml (range 1.5-5.5 μg/ml). We observed on average 30% higher concentrations of CL-L1 in plasma as compared with serum. Size analysis by gel-permeation chromatography showed CL-L1 in serum to elute as large 700-800-kDa complexes and smaller 200-300-kDa complexes. CL-L1 showed specific binding to mannose-TSK beads in a Ca(2+)-dependent manner. This binding could be inhibited by mannose and glucose, but not galactose, indicating that CL-L1 binds via its carbohydrate-recognition domain and has ligand specificity similar to that of mannan-binding lectin. Western blot analysis of CL-L1 showed the presence of several oligomeric forms in serum. Ontogeny studies showed CL-L1 to be present at birth at near adult levels. CL-L1 levels exhibit low variation in healthy adults over a 1-year period. During acute-phase responses, the CL-L1 levels display only minor variations. In serum, CL-L1 was found in complexes with mannan-binding lectin-associated serine proteases, suggesting a role in the lectin pathway of complement activation. The presented data establish a basis for future studies on the biological role of CL-L1.
    Mesh-Begriff(e) Adult ; Collectins/blood ; Complement Pathway, Mannose-Binding Lectin/physiology ; Female ; Fluorescent Antibody Technique ; Follow-Up Studies ; HEK293 Cells ; Hexoses/blood ; Humans ; Male ; Protein Multimerization ; Serum/metabolism
    Chemische Substanzen COLEC10 protein, human ; Collectins ; Hexoses
    Sprache Englisch
    Erscheinungsdatum 2013-06-27
    Erscheinungsland United States
    Dokumenttyp Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M113.492603
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  8. Artikel ; Online: The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria.

    Christiansen, Stig Hill / Murphy, Ronan A / Juul-Madsen, Kristian / Fredborg, Marlene / Hvam, Michael Lykke / Axelgaard, Esben / Skovdal, Sandra M / Meyer, Rikke Louise / Sørensen, Uffe B Skov / Möller, Arne / Nyengaard, Jens Randel / Nørskov-Lauritsen, Niels / Wang, Mikala / Gadjeva, Mihaela / Howard, Kenneth A / Davies, Jane C / Petersen, Eskild / Vorup-Jensen, Thomas

    Scientific reports

    2017  Band 7, Heft 1, Seite(n) 15653

    Abstract: Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. ... ...

    Abstract Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma. As judged from flow cytometric assays, bacterial killing by GA occurred within minutes. Laboratory strains of Escherichia coli and P. aeruginosa were killed by a process of condensing intracellular contents. Efficient killing by GA was also demonstrated in Acinetobacter baumannii clinical isolates and approximately 50% of clinical isolates of P. aeruginosa from chronic airway infection in CF patients. By contrast, the Gram-positive Staphylococcus aureus cells appeared to be protected from GA by an increased formation of nm-scale particulates. Our data identify GA as an attractive drug repurposing candidate to treat infections with Gram-negative bacteria.
    Mesh-Begriff(e) Acinetobacter baumannii/drug effects ; Acinetobacter baumannii/pathogenicity ; Anti-Bacterial Agents/pharmacology ; Anti-Infective Agents/chemistry ; Anti-Infective Agents/pharmacology ; Drug Resistance, Bacterial/genetics ; Escherichia coli/drug effects ; Escherichia coli/pathogenicity ; Glatiramer Acetate/pharmacology ; Gram-Negative Bacteria/drug effects ; Gram-Negative Bacteria/pathogenicity ; Humans ; Immunologic Factors/pharmacology ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Methicillin-Resistant Staphylococcus aureus/pathogenicity ; Microbial Sensitivity Tests ; Pseudomonas aeruginosa/drug effects ; Pseudomonas aeruginosa/pathogenicity ; Staphylococcal Infections/drug therapy ; Staphylococcal Infections/microbiology
    Chemische Substanzen Anti-Bacterial Agents ; Anti-Infective Agents ; Immunologic Factors ; Glatiramer Acetate (5M691HL4BO)
    Sprache Englisch
    Erscheinungsdatum 2017-11-15
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-017-15969-3
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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