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Article ; Online: Role of ADAM10 as a CD30 Sheddase in Classical Hodgkin Lymphoma.

Hansen, Hinrich P / Paes Leme, Adriana F / Hallek, Michael

2020 Volume 11, Page(s) 398

Abstract: Cancer cells generally recruit and influence non-malignant immune cells to support the tumor growth. Classical Hodgkin lymphoma (cHL) is a good example because the affected lymphoid tissue contains only a few malignant Hodgkin and Reed-Sternberg (H-RS) ... ...

Abstract	Cancer cells generally recruit and influence non-malignant immune cells to support the tumor growth. Classical Hodgkin lymphoma (cHL) is a good example because the affected lymphoid tissue contains only a few malignant Hodgkin and Reed-Sternberg (H-RS) cells, which are supported by a massive infiltrate of lymphocytes, fibroblasts, and innate immune cells. The transmembrane receptor CD30, which is selectively expressed on the H-RS cells, plays an important role, not only in cell stimulation and intercellular communication but also in tumor diagnosis and targeted tumor therapy. Different protein processing pathways influence its functionality. Depending on the conditions, the receptor is internalized or released. The release of CD30 occurs either as an intact molecule, embedded in the membrane of extracellular vesicles (EVs), or as a cleaved soluble ectodomain (sCD30). CD30 cleavage is predominantly catalyzed by ADAM10. The enzyme is catalytically active in cells as well as in EVs and gradually releases sCD30. Because the circulation contains no CD30
MeSH term(s)	ADAM10 Protein/immunology ; Cell Communication/immunology ; Extracellular Vesicles/immunology ; Hodgkin Disease/immunology ; Humans ; Ki-1 Antigen/immunology
Chemical Substances	Ki-1 Antigen ; ADAM10 Protein (EC 3.4.24.81)
Language	English
Publishing date	2020-03-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.00398
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Article: Stromal cells support the survival of human primary chronic lymphocytic leukemia (CLL) cells through Lyn-driven extracellular vesicles.

de Oliveira, Thaís Dolzany / Vom Stein, Alexander / Rebollido-Rios, Rocio / Lobastova, Liudmila / Lettau, Marcus / Janssen, Ottmar / Wagle, Prerana / Nguyen, Phuong-Hien / Hallek, Michael / Hansen, Hinrich P

Frontiers in medicine

2023 Volume 9, Page(s) 1059028

Abstract: Introduction: In chronic lymphocytic leukemia (CLL), the tumor cells receive survival support from stromal cells through direct cell contact, soluble factors and extracellular vesicles (EVs). The protein tyrosine kinase Lyn is aberrantly expressed in ... ...

Abstract	Introduction: In chronic lymphocytic leukemia (CLL), the tumor cells receive survival support from stromal cells through direct cell contact, soluble factors and extracellular vesicles (EVs). The protein tyrosine kinase Lyn is aberrantly expressed in the malignant and stromal cells in CLL tissue. We studied the role of Lyn in the EV-based communication and tumor support. Methods: We compared the Lyn-dependent EV release, uptake and functionality using Lyn-proficient (wild-type) and -deficient stromal cells and primary CLL cells. Results: Lyn-proficient cells caused a significantly higher EV release and EV uptake as compared to Lyn-deficient cells and also conferred stronger support of primary CLL cells. Proteomic comparison of the EVs from Lyn-proficient and -deficient stromal cells revealed 70 significantly differentially expressed proteins. Gene ontology studies categorized many of which to organization of the extracellular matrix, such as collagen, fibronectin, fibrillin, Lysyl oxidase like 2, integrins and endosialin (CD248). In terms of function, a knockdown of CD248 in Lyn Conclusion: Our data provide preclinical evidence that the tyrosine kinase Lyn crucially influences the EV-based communication between stromal and primary B-CLL cells by raising EV release and altering the concentration of functional molecules of the extracellular matrix.
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2022.1059028
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Article: NKp30 and its ligands: emerging players in tumor immune evasion from natural killer cells.

Pogge von Strandmann, Elke / Shatnyeva, Olga / Hansen, Hinrich P

Annals of translational medicine

2015 Volume 3, Issue 20, Page(s) 314

Language	English
Publishing date	2015-12-14
Publishing country	China
Document type	Journal Article
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.3978/j.issn.2305-5839.2015.09.08
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Article: CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin.

Lobastova, Liudmila / Lettau, Marcus / Babatz, Felix / de Oliveira, Thais Dolzany / Nguyen, Phuong-Hien / Pauletti, Bianca Alves / Schauss, Astrid C / Dürkop, Horst / Janssen, Ottmar / Paes Leme, Adriana F / Hallek, Michael / Hansen, Hinrich P

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 698503

Abstract: CD30, a member of the TNF receptor superfamily, is selectively expressed on a subset of activated lymphocytes and on malignant cells of certain lymphomas, such as classical Hodgkin Lymphoma (cHL), where it activates critical bystander cells in the tumor ... ...

Abstract	CD30, a member of the TNF receptor superfamily, is selectively expressed on a subset of activated lymphocytes and on malignant cells of certain lymphomas, such as classical Hodgkin Lymphoma (cHL), where it activates critical bystander cells in the tumor microenvironment. Therefore, it is not surprising that the CD30 antibody-drug conjugate Brentuximab Vedotin (BV) represents a powerful, FDA-approved treatment option for CD30
Language	English
Publishing date	2021-07-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.698503
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Article ; Online: Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion.

Yu, Xiaojie / Elfimova, Natalia / Müller, Marion / Bachurski, Daniel / Koitzsch, Ulrike / Drebber, Uta / Mahabir, Esther / Hansen, Hinrich P / Friedman, Scott L / Klein, Sabine / Dienes, Hans Peter / Hösel, Marianna / Buettner, Reinhard / Trebicka, Jonel / Kondylis, Vangelis / Mannaerts, Inge / Odenthal, Margarete

Cellular and molecular gastroenterology and hepatology

2022 Volume 13, Issue 6, Page(s) 1701–1716

Abstract: Background & aims: Liver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source ... ...

Abstract	Background & aims: Liver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source for ECM production. MicroRNA29a (miR-29a) is a crucial antifibrotic miRNA that is repressed during fibrosis, resulting in up-regulation of collagen synthesis. Methods: Intracellular and extracellular miRNA levels of primary and immortalized myofibroblastic HSC in response to profibrogenic stimulation by transforming growth factor β (TGFβ) or platelet-derived growth factor-BB (PDGF-BB) or upon inhibition of vesicular transport and autophagy processes were determined by quantitative polymerase chain reaction. Autophagy flux was studied by electron microscopy, flow cytometry, immunoblotting, and immunocytochemistry. Hepatic and serum miR-29a levels were quantified by using both liver tissue and serum samples from a cohort of chronic hepatitis C virus patients and a murine CCl Results: In our study, we show that TGFβ and PDGF-BB resulted in decrease of intracellular miR-29a and a pronounced increase of vesicular miR-29a release into the supernatant. Strikingly, miR-29a vesicular release was accompanied by enhanced autophagic activity and up-regulation of the autophagy marker protein LC3. Moreover, autophagy inhibition strongly prevented miR-29a secretion and repressed its targets' expression such as Col1A1. Consistently, hepatic miR-29a loss and increased LC3 expression in myofibroblastic HSC were associated with increased serum miR-29a levels in CCl Conclusions: We provide evidence that activation-associated autophagy in HSC induces release of miR-29a, whereas inhibition of autophagy represses fibrogenic gene expression in part through attenuated miR-29a secretion.
MeSH term(s)	Animals ; Autophagy ; Becaplermin/metabolism ; Hepatic Stellate Cells/pathology ; Hepatitis C, Chronic/metabolism ; Hepatitis C, Chronic/pathology ; Humans ; Liver Cirrhosis/pathology ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Transforming Growth Factor beta/metabolism
Chemical Substances	MIRN29 microRNA, mouse ; MIRN29a microRNA, human ; MicroRNAs ; Transforming Growth Factor beta ; Becaplermin (1B56C968OA)
Language	English
Publishing date	2022-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2819778-1
ISSN	2352-345X ; 2352-345X
ISSN (online)	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2022.02.013
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Article ; Online: An improved fluorescent substrate for assaying soluble and membrane-associated ADAM family member activities.

Moss, Marcia L / Minond, Dmitriy / Yoneyama, Toshie / Hansen, Hinrich P / Vujanovic, Nikola / Rasmussen, Fred H

Analytical biochemistry

2016 Volume 507, Page(s) 13–17

Abstract: A fluorescent resonance energy transfer substrate with improved sensitivity for ADAM17, -10, and -9 (where ADAM represents a disintegrin and metalloproteinase) has been designed. The new substrate, Dabcyl-Pro-Arg-Ala-Ala-Ala-Homophe-Thr-Ser-Pro-Lys(FAM)- ... ...

Abstract	A fluorescent resonance energy transfer substrate with improved sensitivity for ADAM17, -10, and -9 (where ADAM represents a disintegrin and metalloproteinase) has been designed. The new substrate, Dabcyl-Pro-Arg-Ala-Ala-Ala-Homophe-Thr-Ser-Pro-Lys(FAM)-NH2, has specificity constants of 6.3 (±0.3) × 10(4) M(-1) s(-1) and 2.4 (±0.3) × 10(3) M(-1) s(-1) for ADAM17 and ADAM10, respectively. The substrate is more sensitive than widely used peptides based on the precursor tumor necrosis factor-alpha (TNF-alpha) cleavage site, PEPDAB010 or Dabcyl-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Lys(FAM)-NH2 and Mca-Pro-Leu-Ala-Gln-Ala-Val-Dpa-Arg-Ser-Ser-Arg-NH2. ADAM9 also processes the new peptide more than 18-fold better than the TNF-alpha-based substrates. The new substrate has a unique selectivity profile because it is processed less efficiently by ADAM8 and MMP1, -2, -3, -8, -9, -12, and -14. This substrate provides a unique tool in which to assess ADAM17, -10, and -9 activities.
MeSH term(s)	ADAM Proteins/analysis ; ADAM Proteins/chemistry ; ADAM Proteins/metabolism ; Cell Line, Tumor ; Cell Membrane/metabolism ; Fluorescence Resonance Energy Transfer ; Fluorescent Dyes/chemistry ; Humans ; Hydrolysis ; Regression Analysis ; Solubility
Chemical Substances	Fluorescent Dyes ; ADAM Proteins (EC 3.4.24.-)
Language	English
Publishing date	2016-08-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2016.05.001
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Article ; Online: Extracellular vesicles released from chronic lymphocytic leukemia cells exhibit a disease relevant mRNA signature and transfer mRNA to bystander cells.

Reiners, Katrin S / Shatnyeva, Olga / Vasyutina, Elena / Bösl, Teresa / Hansen, Hinrich P / Hallek, Michael / Herling, Marco / von Strandmann, Elke Pogge

Haematologica

2017 Volume 102, Issue 3, Page(s) e100–e103

MeSH term(s)	Antigens, CD/genetics ; Antigens, CD/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; B-Lymphocytes/secretion ; Bystander Effect/genetics ; Bystander Effect/immunology ; Extracellular Vesicles/chemistry ; Extracellular Vesicles/immunology ; Extracellular Vesicles/pathology ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Neoplasm Proteins/genetics ; Neoplasm Proteins/immunology ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/immunology ; RNA Splicing Factors/genetics ; RNA Splicing Factors/immunology ; RNA Transport ; RNA, Messenger/genetics ; RNA, Messenger/immunology ; Signal Transduction ; Syk Kinase/genetics ; Syk Kinase/immunology ; Toll-Like Receptor 9/genetics ; Toll-Like Receptor 9/immunology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology ; src-Family Kinases/genetics ; src-Family Kinases/immunology
Chemical Substances	Antigens, CD ; Neoplasm Proteins ; Proto-Oncogene Proteins ; RNA Splicing Factors ; RNA, Messenger ; TCL1A protein, human ; TLR9 protein, human ; Toll-Like Receptor 9 ; Tumor Necrosis Factor-alpha ; SYK protein, human (EC 2.7.10.2) ; Syk Kinase (EC 2.7.10.2) ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2017
Publishing country	Italy
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2016.153197
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Article: Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer.

Zhao, Jiangang / Schlößer, Hans A / Wang, Zhefang / Qin, Jie / Li, Jiahui / Popp, Felix / Popp, Marie Christine / Alakus, Hakan / Chon, Seung-Hun / Hansen, Hinrich P / Neiss, Wolfram F / Jauch, Karl-Walter / Bruns, Christiane J / Zhao, Yue

Cancers

2019 Volume 11, Issue 6

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs' TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs' TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.
Language	English
Publishing date	2019-06-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11060874
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Article: Extracellular vesicle measurements with nanoparticle tracking analysis - An accuracy and repeatability comparison between NanoSight NS300 and ZetaView.

Bachurski, Daniel / Schuldner, Maximiliane / Nguyen, Phuong-Hien / Malz, Alexandra / Reiners, Katrin S / Grenzi, Patricia C / Babatz, Felix / Schauss, Astrid C / Hansen, Hinrich P / Hallek, Michael / Pogge von Strandmann, Elke

Journal of extracellular vesicles

2019 Volume 8, Issue 1, Page(s) 1596016

Abstract: The expanding field of extracellular vesicle (EV) research needs reproducible and accurate methods to characterize single EVs. Nanoparticle Tracking Analysis (NTA) is commonly used to determine EV concentration and diameter. As the EV field is lacking ... ...

Abstract	The expanding field of extracellular vesicle (EV) research needs reproducible and accurate methods to characterize single EVs. Nanoparticle Tracking Analysis (NTA) is commonly used to determine EV concentration and diameter. As the EV field is lacking methods to easily confirm and validate NTA data, questioning the reliability of measurements remains highly important. In this regard, a comparison addressing measurement quality between different NTA devices such as Malvern's NanoSight NS300 or Particle Metrix' ZetaView has not yet been conducted. To evaluate the accuracy and repeatability of size and concentration determinations of both devices, we employed comparative methods including transmission electron microscopy (TEM) and single particle interferometric reflectance imaging sensing (SP-IRIS) by ExoView. Multiple test measurements with nanospheres, liposomes and ultracentrifuged EVs from human serum and cell culture supernatant were performed. Additionally, serial dilutions and freeze-thaw cycle-dependent EV decrease were measured to determine the robustness of each system. Strikingly, NanoSight NS300 exhibited a 2.0-2.1-fold overestimation of polystyrene and silica nanosphere concentration. By measuring serial dilutions of EV samples, we demonstrated higher accuracy in concentration determination by ZetaView (% BIAS range: 2.7-8.5) in comparison with NanoSight NS300 (% BIAS range: 32.9-36.8). The concentration measurements by ZetaView were also more precise (% CV range: 0.0-4.7) than measurements by NanoSight NS300 (% CV range: 5.4-10.7). On the contrary, quantitative TEM imaging indicated more accurate EV sizing by NanoSight NS300 (% D
Language	English
Publishing date	2019-04-01
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	2683797-3
ISSN	2001-3078
ISSN	2001-3078
DOI	10.1080/20013078.2019.1596016
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Article: Hodgkin Lymphoma-Derived Extracellular Vesicles Change the Secretome of Fibroblasts Toward a CAF Phenotype.

Dörsam, Bastian / Bösl, Teresa / Reiners, Katrin S / Barnert, Sabine / Schubert, Rolf / Shatnyeva, Olga / Zigrino, Paola / Engert, Andreas / Hansen, Hinrich P / von Strandmann, Elke Pogge

Frontiers in immunology

2018 Volume 9, Page(s) 1358

Abstract: Secretion of extracellular vesicles (EVs) is a ubiquitous mechanism of intercellular communication based on the exchange of effector molecules, such as growth factors, cytokines, and nucleic acids. Recent studies identified tumor-derived EVs as central ... ...

Abstract	Secretion of extracellular vesicles (EVs) is a ubiquitous mechanism of intercellular communication based on the exchange of effector molecules, such as growth factors, cytokines, and nucleic acids. Recent studies identified tumor-derived EVs as central players in tumor progression and the establishment of the tumor microenvironment (TME). However, studies on EVs from classical Hodgkin lymphoma (cHL) are limited. The growth of malignant Hodgkin and Reed-Sternberg (HRS) cells depends on the TME, which is actively shaped by a complex interaction of HRS cells and stromal cells, such as fibroblasts and immune cells. HRS cells secrete cytokines and angiogenic factors thus recruiting and inducing the proliferation of surrounding cells to finally deploy an immunosuppressive TME. In this study, we aimed to investigate the role of tumor cell-derived EVs within this complex scenario. We observed that EVs collected from Hodgkin lymphoma (HL) cells were internalized by fibroblasts and triggered their migration capacity. EV-treated fibroblasts were characterized by an inflammatory phenotype and an upregulation of alpha-smooth muscle actin (α-SMA), a marker of cancer-associated fibroblasts. Analysis of the secretome of EV-treated fibroblast revealed an enhanced release of pro-inflammatory cytokines (e.g., IL-1α, IL-6, and TNF-α), growth factors (G-CSF and GM-CSF), and pro-angiogenic factors such as VEGF. These soluble factors are known to promote HL progression. In line, ingenuity pathway analysis identified inflammatory pathways, including TNF-α/NF-κB-signaling, as key factors directing the EV-dependent phenotype changes in fibroblasts. Confirming the
Language	English
Publishing date	2018
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01358
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