Alves, Frauke

[["dc.bibliographiccitation.firstpage","6367"],["dc.bibliographiccitation.issue","22"],["dc.bibliographiccitation.journal","Theranostics"],["dc.bibliographiccitation.lastpage","6383"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Napp, Joanna"],["dc.contributor.author","Markus, M. Andrea"],["dc.contributor.author","Heck, Joachim G."],["dc.contributor.author","Dullin, Christian"],["dc.contributor.author","Möbius, Wiebke"],["dc.contributor.author","Gorpas, Dimitris"],["dc.contributor.author","Feldmann, Claus"],["dc.contributor.author","Alves, Frauke"],["dc.date.accessioned","2019-07-09T11:49:44Z"],["dc.date.available","2019-07-09T11:49:44Z"],["dc.date.issued","2018"],["dc.description.abstract","Treatment of inflammatory disorders with glucocorticoids (GCs) is often accompanied by severe adverse effects. Application of GCs via nanoparticles (NPs), especially those using simple formulations, could possibly improve their delivery to sites of inflammation and therefore their efficacy, minimising the required dose and thus reducing side effects. Here, we present the evaluation of NPs composed of GC betamethasone phosphate (BMP) and the fluorescent dye DY-647 (BMP-IOH-NPs) for improved treatment of inflammation with simultaneous in vivo monitoring of NP delivery. Methods: BMP-IOH-NP uptake by MH-S macrophages was analysed by fluorescence and electron microscopy. Lipopolysaccharide (LPS)-stimulated cells were treated for 48 h with BMP-IOH-NPs (1×10-5-1×10-9 M), BMP or dexamethasone (Dexa). Drug efficacy was assessed by measurement of interleukin 6. Mice with Zymosan-A-induced paw inflammation were intraperitoneally treated with BMP-IOH-NPs (10 mg/kg) and mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI) were treated intranasally with BMP-IOH-NPs, BMP or Dexa (each 2.5 mg/kg). Efficacy was assessed in vivo by paw volume measurements with µCT and ex vivo by measurement of paw weight for Zymosan-A-treated mice, or in the AAI model by in vivo x-ray-based lung function assessment and by cell counts in the bronchoalveolar lavage (BAL) fluid and histology. Delivery of BMP-IOH-NPs to the lungs of AAI mice was monitored by in vivo optical imaging and by fluorescence microscopy. Results: Uptake of BMP-IOH-NPs by MH-S cells was observed during the first 10 min of incubation, with the NP load increasing over time. The anti-inflammatory effect of BMP-IOH-NPs in vitro was dose dependent and higher than that of Dexa or free BMP, confirming efficient release of the drug. In vivo, Zymosan-A-induced paw inflammation was significantly reduced in mice treated with BMP-IOH-NPs. AAI mice that received BMP-IOH-NPs or Dexa but not BMP revealed significantly decreased eosinophil numbers in BALs and reduced immune cell infiltration in lungs. Correspondingly, lung function parameters, which were strongly affected in non-treated AAI mice, were unaffected in AAI mice treated with BMP-IOH-NPs and resembled those of healthy animals. Accumulation of BMP-IOH-NPs within the lungs of AAI mice was detectable by optical imaging for at least 4 h in vivo, where they were preferentially taken up by peribronchial and alveolar M2 macrophages. Conclusion: Our results show that BMP-IOH-NPs can effectively be applied in therapy of inflammatory diseases with at least equal efficacy as the gold standard Dexa, while their delivery can be simultaneously tracked in vivo by fluorescence imaging. BMP-IOH-NPs thus have the potential to reach clinical applications."],["dc.identifier.doi","10.7150/thno.28324"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15757"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59620"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1838-7640"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/4.0"],["dc.subject.ddc","610"],["dc.title","Therapeutic Fluorescent Hybrid Nanoparticles for Traceable Delivery of Glucocorticoids to Inflammatory Sites"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4538"],["dc.bibliographiccitation.issue","32"],["dc.bibliographiccitation.journal","Oncogene"],["dc.bibliographiccitation.lastpage","4550"],["dc.bibliographiccitation.volume","36"],["dc.contributor.author","Dovmark, T. H."],["dc.contributor.author","Saccomano, M."],["dc.contributor.author","Hulikova, A."],["dc.contributor.author","Alves, Frauke"],["dc.contributor.author","Swietach, P."],["dc.date.accessioned","2019-07-09T11:44:49Z"],["dc.date.available","2019-07-09T11:44:49Z"],["dc.date.issued","2017"],["dc.description.abstract","Glycolytic cancer cells produce large quantities of lactate that must be removed to sustain metabolism in the absence of oxidative phosphorylation. The only venting mechanism described to do this at an adequate rate is H+-coupled lactate efflux on monocarboxylate transporters (MCTs). Outward MCT activity is, however, thermodynamically inhibited by extracellular acidity, a hallmark of solid tumours. This inhibition would feedback unfavourably on metabolism and growth, raising the possibility that other venting mechanisms become important in under-perfused tumours. We investigated connexin-assembled gap junctions as an alternative route for discharging lactate from pancreatic ductal adenocarcinoma (PDAC) cells. Diffusive coupling (calcein transmission) in vitro was strong between Colo357 cells, weaker yet hypoxia-inducible between BxPC3 cells, and very low between MiaPaCa2 cells. Coupling correlated with levels of connexin-43 (Cx43), a protein previously linked to late-stage disease. Evoked lactate dynamics, imaged in Colo357 spheroids using cytoplasmic pH as a read-out, indicated that lactate anions permeate gap junctions faster than highly-buffered H+ ions. At steady-state, junctional transmission of lactate (a chemical base) from the spheroid core had an alkalinizing effect on the rim, producing therein a milieu conducive for growth. Metabolite assays demonstrated that Cx43 knockdown increased cytoplasmic lactate retention in Colo357 spheroids (diameter ~150 μm). MiaPaCa2 cells, which are Cx43 negative in monolayer culture, showed markedly increased Cx43 immunoreactivity at areas of invasion in orthotopic xenograft mouse models. These tissue areas were associated with chronic extracellular acidosis (as indicated by the marker LAMP2 near/at the plasmalemma), which can explain the advantage of junctional transmission over MCT in vivo. We propose that Cx43 channels are important conduits for dissipating lactate anions from glycolytic PDAC cells. Furthermore, lactate entry into the better-perfused recipient cells has a favourable alkalinizing effect and supplies substrate for oxidative phosphorylation. Cx43 is thus a novel target for influencing metabolite handling in junctionally-coupled tumours."],["dc.identifier.doi","10.1038/onc.2017.71"],["dc.identifier.pmid","28368405"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14914"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59103"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/289648/EU//IONTRAC"],["dc.relation.issn","1476-5594"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.subject.mesh","Acidosis, Lactic"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Carcinoma, Pancreatic Ductal"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Connexin 43"],["dc.subject.mesh","Gap Junctions"],["dc.subject.mesh","Glycolysis"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Lactic Acid"],["dc.subject.mesh","Lysosomal-Associated Membrane Protein 2"],["dc.subject.mesh","Male"],["dc.subject.mesh","Mice"],["dc.subject.mesh","Mice, Nude"],["dc.subject.mesh","Monocarboxylic Acid Transporters"],["dc.subject.mesh","Neoplasm Transplantation"],["dc.subject.mesh","Pancreatic Neoplasms"],["dc.subject.mesh","Phosphorylation"],["dc.subject.mesh","RNA, Small Interfering"],["dc.subject.mesh","Spheroids, Cellular"],["dc.title","Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","1407"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Missbach-Guentner, Jeannine"],["dc.contributor.author","Pinkert-Leetsch, Diana"],["dc.contributor.author","Dullin, Christian"],["dc.contributor.author","Ufartes, Roser"],["dc.contributor.author","Hornung, Daniel"],["dc.contributor.author","Tampe, Bjoern"],["dc.contributor.author","Zeisberg, Michael"],["dc.contributor.author","Alves, Frauke"],["dc.date.accessioned","2019-07-09T11:45:05Z"],["dc.date.available","2019-07-09T11:45:05Z"],["dc.date.issued","2018"],["dc.description.abstract","The increasing number of patients with end stage chronic kidney disease not only calls for novel therapeutics but also for pioneering research using convincing preclinical disease models and innovative analytical techniques. The aim of this study was to introduce a virtual histology approach using micro computed tomography (µCT) for the entire murine kidney in order to close the gap between single slice planar histology and a 3D high resolution dataset. An ex vivo staining protocol based on phosphotungstic acid diffusion was adapted to enhance renal soft tissue x-ray attenuation. Subsequent CT scans allowed (i) the detection of the renal cortex, medulla and pelvis in greater detail, (ii) the analysis of morphological alterations, (iii) the quantification of the volume as well as the radio-opacity of these portions and (iv) the quantification of renal fibrotic remodeling based on altered radio-opacity using the unilateral ureteral obstruction model. Thus, virtual histology based on PTA contrast enhanced CT will in future help to refine the outcome of preclinical research on kidney associated murine disease models."],["dc.identifier.doi","10.1038/s41598-018-19773-5"],["dc.identifier.pmid","29362427"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15031"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59157"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","3D virtual histology of murine kidneys -high resolution visualization of pathological alterations by micro computed tomography."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","4595"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Ramos-Gomes, Fernanda"],["dc.contributor.author","Bode, Julia"],["dc.contributor.author","Sukhanova, Alyona"],["dc.contributor.author","Bozrova, Svetlana V."],["dc.contributor.author","Saccomano, Mara"],["dc.contributor.author","Mitkovski, Miso"],["dc.contributor.author","Krueger, Julia Eva"],["dc.contributor.author","Wege, Anja K."],["dc.contributor.author","Stuehmer, Walter"],["dc.contributor.author","Samokhvalov, Pavel S."],["dc.contributor.author","Baty, Daniel"],["dc.contributor.author","Chames, Patrick"],["dc.contributor.author","Nabiev, Igor"],["dc.contributor.author","Alves, Frauke"],["dc.date.accessioned","2019-07-09T11:45:17Z"],["dc.date.available","2019-07-09T11:45:17Z"],["dc.date.issued","2018"],["dc.description.abstract","Early detection of malignant tumours and, especially, micrometastases and disseminated tumour cells is still a challenge. In order to implement highly sensitive diagnostic tools we demonstrate the use of nanoprobes engineered from nanobodies (single-domain antibodies, sdAbs) and fluorescent quantum dots (QDs) for single- and two-photon detection and imaging of human micrometastases and disseminated tumour cells in ex vivo biological samples of breast and pancreatic metastatic tumour mouse models expressing human epidermal growth factor receptor 2 (HER2) or carcinoembryonic antigen (CEA). By staining thin (5-10 µm) paraffin and thick (50 µm) agarose tissue sections, we detected HER2- and CEA-positive human tumour cells infiltrating the surrounding tissues or metastasizing to different organs, including the brain, testis, lung, liver, and lymph nodes. Compared to conventional fluorescently labelled antibodies the sdAb-HER2-QD and sdAb-CEA-QD nanoprobes are superior in detecting micrometastases in tissue sections by lower photobleaching and higher brightness of fluorescence signals ensuring much better discrimination of positive signals versus background. Very high two-photon absorption cross-sections of QDs and small size of the nanoprobes ensure efficient imaging of thick tissue sections unattainable with conventional fluorescent probes. The nanobody-QD probes will help to improve early cancer diagnosis and prognosis of progression by assessing metastasis."],["dc.identifier.doi","10.1038/s41598-018-22973-8"],["dc.identifier.pmid","29545609"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15088"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59199"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/246479/EU//NAMDIATREAM"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Single- and two-photon imaging of human micrometastases and disseminated tumour cells with conjugates of nanobodies and quantum dots."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","254"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Neoplasia"],["dc.bibliographiccitation.lastpage","263"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Schneider, Manuela"],["dc.contributor.author","Wortmann, Markus"],["dc.contributor.author","Mandal, Pankaj Kumar"],["dc.contributor.author","Arpornchayanon, Warangkana"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Alves, Frauke"],["dc.contributor.author","Strieth, Sebastian"],["dc.contributor.author","Conrad, Marcus"],["dc.contributor.author","Beck, Heike"],["dc.date.accessioned","2022-03-01T11:44:19Z"],["dc.date.available","2022-03-01T11:44:19Z"],["dc.date.issued","2010"],["dc.description.abstract","The selenoenzyme glutathione peroxidase 4 (GPx4) has been described to control specific cyclooxygenases (COXs) and lipoxygenases (LOXs) that exert substantiated functions in tumor growth and angiogenesis. Therefore, we hypothesized a putative regulatory role of GPx4 during tumor progression and created transformed murine embryonic fibroblasts with inducible disruption of GPx4. GPx4 inactivation caused rapid cell death in vitro, which could be prevented either by lipophilic antioxidants or by 12/15-LOX-specific inhibitors, but not by inhibitors targeting other LOX isoforms or COX. Surprisingly, transformed GPx4(+/-) cells did not die when grown in Matrigel but gave rise to tumor spheroids. Subcutaneous implantation of tumor cells into mice resulted in knockout tumors that were indistinguishable in volume and mass in comparison to wild-type tumors. However, further analysis revealed a strong vascular phenotype. We observed an increase in microvessel density as well as a reduction in the number of large diameter vessels covered by smooth muscle cells. This phenotype could be linked to increased 12/15-LOX activity that was accompanied by an up-regulation of basic fibroblast growth factor and down-regulation of vascular endothelial growth factor A protein expression. Indeed, pharmacological inhibition of 12/15-LOX successfully reversed the tumor phenotype and led to \"normalized\" vessel morphology. Thus, we conclude that GPx4, through controlling 12/15-LOX activity, is an important regulator of tumor angiogenesis as well as vessel maturation."],["dc.identifier.doi","10.1593/neo.91782"],["dc.identifier.fs","567900"],["dc.identifier.pii","S1476558610801046"],["dc.identifier.pmid","20234819"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6890"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102992"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","1476-5586"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Apoptosis"],["dc.subject.mesh","Arachidonate 12-Lipoxygenase"],["dc.subject.mesh","Arachidonate 15-Lipoxygenase"],["dc.subject.mesh","Blotting, Western"],["dc.subject.mesh","Cell Adhesion"],["dc.subject.mesh","Cell Culture Techniques"],["dc.subject.mesh","Cell Movement"],["dc.subject.mesh","Cell Proliferation"],["dc.subject.mesh","Cell Transformation, Neoplastic"],["dc.subject.mesh","Embryo, Mammalian"],["dc.subject.mesh","Enzyme-Linked Immunosorbent Assay"],["dc.subject.mesh","Extracellular Matrix"],["dc.subject.mesh","Fibroblast Growth Factor 2"],["dc.subject.mesh","Fibroblasts"],["dc.subject.mesh","Fluorescent Antibody Technique"],["dc.subject.mesh","Genes, ras"],["dc.subject.mesh","Glutathione Peroxidase"],["dc.subject.mesh","Immunoenzyme Techniques"],["dc.subject.mesh","Mice"],["dc.subject.mesh","Mice, Inbred C57BL"],["dc.subject.mesh","Mice, Knockout"],["dc.subject.mesh","Mice, SCID"],["dc.subject.mesh","Neoplasms, Experimental"],["dc.subject.mesh","Neovascularization, Pathologic"],["dc.subject.mesh","Pregnancy Proteins"],["dc.subject.mesh","Proto-Oncogene Proteins c-myc"],["dc.subject.mesh","RNA, Messenger"],["dc.subject.mesh","Reverse Transcriptase Polymerase Chain Reaction"],["dc.subject.mesh","Spheroids, Cellular"],["dc.subject.mesh","Vascular Endothelial Growth Factor A"],["dc.title","Absence of Glutathione Peroxidase 4 Affects Tumor Angiogenesis through Increased 12/15-Lipoxygenase Activity"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","7712"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Albers, Jonas"],["dc.contributor.author","Markus, M. Andrea"],["dc.contributor.author","Alves, Frauke"],["dc.contributor.author","Dullin, Christian"],["dc.date.accessioned","2019-07-09T11:45:38Z"],["dc.date.available","2019-07-09T11:45:38Z"],["dc.date.issued","2018"],["dc.description.abstract","Examination of histological or immunohistochemically stained 2D sections of embedded tissue is one of the most frequently used tools in biomedical research and clinical routine. Since to date, targeted sectioning of specific regions of interest (ROI) in the sample is not possible, we aimed at developing a guided sectioning approach based on x-ray 3D virtual histology for heavy ion stained murine lung samples. For this purpose, we increased the contrast to noise ratio of a standard benchtop microCT by 5-10-fold using free-propagation phase contrast imaging and thus substantially improved image quality. We then show that microCT 3D datasets deliver more precise anatomical information and quantification of the sample than traditional histological sections, which display deformations of the tissue. To quantify these deformations caused by sectioning we developed the \"Displacement Index (DI)\", which combines block-matching with the calculation of the local mutual information. We show that the DI substantially decreases when a femtosecond laser microtome is used for sections as opposed to a traditional microtome. In conclusion, our microCT based virtual histology approach can be used as a supplement and a guidance tool for traditional histology, providing 3D measurement capabilities and offering the ability to perform sectioning directly at an ROI."],["dc.identifier.doi","10.1038/s41598-018-26086-0"],["dc.identifier.pmid","29769600"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15268"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59272"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","X-ray based virtual histology allows guided sectioning of heavy ion stained murine lungs for histological analysis."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]