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Wjst M.,Institute of Lung Biology and Disease
BMC Medical Ethics | Year: 2010

Background. Large-scale genetic data sets are frequently shared with other research groups and even released on the Internet to allow for secondary analysis. Study participants are usually not informed about such data sharing because data sets are assumed to be anonymous after stripping off personal identifiers. Discussion. The assumption of anonymity of genetic data sets, however, is tenuous because genetic data are intrinsically self-identifying. Two types of re-identification are possible: the "Netflix" type and the "profiling" type. The "Netflix" type needs another small genetic data set, usually with less than 100 SNPs but including a personal identifier. This second data set might originate from another clinical examination, a study of leftover samples or forensic testing. When merged to the primary, unidentified set it will re-identify all samples of that individual. Even with no second data set at hand, a "profiling" strategy can be developed to extract as much information as possible from a sample collection. Starting with the identification of ethnic subgroups along with predictions of body characteristics and diseases, the asthma kids case as a real-life example is used to illustrate that approach. Summary. Depending on the degree of supplemental information, there is a good chance that at least a few individuals can be identified from an anonymized data set. Any re-identification, however, may potentially harm study participants because it will release individual genetic disease risks to the public. © 2010 Wjst; licensee BioMed Central Ltd.

Hecker M.,Justus Liebig University | Zaslona Z.,Justus Liebig University | Kwapiszewska G.,Justus Liebig University | Niess G.,Justus Liebig University | And 14 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed. Objectives: The objective of this study was to assess the possible contribution of the IL-13 system to IPAH. Methods: Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC. Measurements and Main Results: Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G0/G1 arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects. Conclusions: The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.

Leppkes M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Maueroder C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Hirth S.,Johannes Gutenberg University Mainz | Nowecki S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 20 more authors.
Nature Communications | Year: 2016

Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.

Sanchez-Antequera Y.,TU Munich | Sanchez-Antequera Y.,Institute of Lung Biology and Disease | Mykhaylyk O.,TU Munich | Van Til N.P.,Erasmus Medical Center | And 8 more authors.
Blood | Year: 2011

Research applications and cell therapies involving genetically modified cells require reliable, standardized, and cost-effective methods for cell manipulation. We report a novel nanomagnetic method for integrated cell separation and gene delivery. Gene vectors associated with magnetic nanoparticles are used to transfect/transduce target cells while being passaged and separated through a high gradient magnetic field cell separation column. The integrated method yields excellent target cell purity and recovery. Nonviral and lentiviral magselectofection is efficient and highly specific for the target cell population as demonstrated with a K562/Jurkat T-cell mixture. Both mouse and human enriched hematopoietic stem cell pools were effectively transduced by lentiviral magselectofection, which did not affect the hematopoietic progenitor cell number determined by in vitro colony assays. Highly effective reconstitution of T and B lymphocytes was achieved by magselectofected murine wild-type lineage-negative Sca-1 + cells transplanted into Il2rg-/- mice, stably expressing GFP in erythroid, myeloid, T-, and B-cell lineages. Furthermore, nonviral, lentiviral, and adenoviral magselectofection yielded high transfection/transduction efficiency in human umbilical cord mesenchymal stem cells and was fully compatible with their differentiation potential. Upscaling to a clinically approved automated cell separation device was feasible. Hence, once optimized, validated, and approved, the method may greatly facilitate the generation of genetically engineered cells for cell therapies. © 2011 by The American Society of Hematology.

Yildirim A.O.,University of Marburg | Yildirim A.O.,Institute of Lung Biology and Disease | Muyal V.,University of Marburg | John G.,Justus Liebig University | And 5 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy. Objectives: To investigate whether therapeutic application of palifermin (ΔN23-KGF) is able to induce a regenerative response in distal lungparenchyma after induction of pulmonaryemphysema. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg ΔN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase. Measurements and Main Results: Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase-induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. ΔN23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanceddifferentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-β1, TGF-β2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. ΔN23-KGF induced the expression of TGF-β1 in and release of active TGF-β1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-β1 but not ΔN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of ΔN23-KGF in LA-4/MLF cocultures. Conclusions: Our data demonstrate that therapeutic application of ΔN23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-β1.

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