TY - JOUR A1 - Stojanović, Stevan D. A1 - Fuchs, Maximilian A1 - Fiedler, Jan A1 - Xiao, Ke A1 - Meinecke, Anna A1 - Just, Annette A1 - Pich, Andreas A1 - Thum, Thomas A1 - Kunz, Meik T1 - Comprehensive bioinformatics identifies key microRNA players in ATG7-deficient lung fibroblasts JF - International Journal of Molecular Sciences N2 - Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of ATG7-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. Method: We have generated ATG7-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. Results: The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in ATG7-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a-5p related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. Conclusions: We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes. The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research. KW - bioinformatics KW - miR KW - proteomics KW - functional network analysis KW - senescence KW - lung fibrosis KW - autophagy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285181 SN - 1422-0067 VL - 21 IS - 11 ER - TY - JOUR A1 - Kaltdorf, Martin A1 - Breitenbach, Tim A1 - Karl, Stefan A1 - Fuchs, Maximilian A1 - Kessie, David Komla A1 - Psota, Eric A1 - Prelog, Martina A1 - Sarukhanyan, Edita A1 - Ebert, Regina A1 - Jakob, Franz A1 - Dandekar, Gudrun A1 - Naseem, Muhammad A1 - Liang, Chunguang A1 - Dandekar, Thomas T1 - Software JimenaE allows efficient dynamic simulations of Boolean networks, centrality and system state analysis JF - Scientific Reports N2 - The signal modelling framework JimenaE simulates dynamically Boolean networks. In contrast to SQUAD, there is systematic and not just heuristic calculation of all system states. These specific features are not present in CellNetAnalyzer and BoolNet. JimenaE is an expert extension of Jimena, with new optimized code, network conversion into different formats, rapid convergence both for system state calculation as well as for all three network centralities. It allows higher accuracy in determining network states and allows to dissect networks and identification of network control type and amount for each protein with high accuracy. Biological examples demonstrate this: (i) High plasticity of mesenchymal stromal cells for differentiation into chondrocytes, osteoblasts and adipocytes and differentiation-specific network control focusses on wnt-, TGF-beta and PPAR-gamma signaling. JimenaE allows to study individual proteins, removal or adding interactions (or autocrine loops) and accurately quantifies effects as well as number of system states. (ii) Dynamical modelling of cell–cell interactions of plant Arapidopsis thaliana against Pseudomonas syringae DC3000: We analyze for the first time the pathogen perspective and its interaction with the host. We next provide a detailed analysis on how plant hormonal regulation stimulates specific proteins and who and which protein has which type and amount of network control including a detailed heatmap of the A.thaliana response distinguishing between two states of the immune response. (iii) In an immune response network of dendritic cells confronted with Aspergillus fumigatus, JimenaE calculates now accurately the specific values for centralities and protein-specific network control including chemokine and pattern recognition receptors. KW - cellular signalling networks KW - computer modelling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313303 VL - 13 ER - TY - JOUR A1 - Czysch, Christian A1 - Medina‐Montano, Carolina A1 - Zhong, Zifu A1 - Fuchs, Alexander A1 - Stickdorn, Judith A1 - Winterwerber, Pia A1 - Schmitt, Sascha A1 - Deswarte, Kim A1 - Raabe, Marco A1 - Scherger, Maximilian A1 - Combes, Francis A1 - De Vrieze, Jana A1 - Kasmi, Sabah A1 - Sandners, Niek N. A1 - Lienenklaus, Stefan A1 - Koynov, Kaloian A1 - Räder, Hans‐Joachim A1 - Lambrecht, Bart N. A1 - David, Sunil A. A1 - Bros, Matthias A1 - Schild, Hansjörg A1 - Grabbe, Stephan A1 - De Geest, Bruno G. A1 - Nuhn, Lutz T1 - Transient Lymph Node Immune Activation by Hydrolysable Polycarbonate Nanogels JF - Advanced Functional Materials N2 - The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline‐type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vivo. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate‐based nanogels may also be of great importance for clinical translation. KW - biodegradable KW - immunodrug delivery KW - lymph nodes KW - nanogels KW - polycarbonates Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287255 VL - 32 IS - 35 ER - TY - JOUR A1 - Jordan, Martin C. A1 - Jovic, Sebastian A1 - Gilbert, Fabian A1 - Kunz, Andreas A1 - Ertl, Maximilian A1 - Strobl, Ute A1 - Jakubietz, Rafael G. A1 - Jakubietz, Michael G. A1 - Meffert, Rainer H. A1 - Fuchs, Konrad F. T1 - Qualitätssteigerung der Abrechnungsprüfung durch Smartphone-basierte Fotodokumentation in der Unfall-, Hand-, und Plastischen Chirurgie JF - Der Unfallchirurg N2 - Hintergrund Die Fotodokumentation von offenen Frakturen, Wunden, Dekubitalulzera, Tumoren oder Infektionen ist ein wichtiger Bestandteil der digitalen Patientenakte. Bisher ist unklar, welchen Stellenwert diese Fotodokumentation bei der Abrechnungsprüfung durch den Medizinischen Dienst der Krankenkassen (MDK) hat. Fragestellung Kann eine Smartphone-basierte Fotodokumentation die Verteidigung von erlösrelevanten Diagnosen und Prozeduren sowie der Verweildauer verbessern? Material und Methoden Ausstattung der Mitarbeiter mit digitalen Endgeräten (Smartphone/Tablet) in den Bereichen Notaufnahme, Schockraum, OP, Sprechstunden sowie auf den Stationen. Retrospektive Auswertung der Abrechnungsprüfung im Jahr 2019 und Identifikation aller Fallbesprechungen, in denen die Fotodokumentation eine Erlösveränderung bewirkt hat. Ergebnisse Von insgesamt 372 Fallbesprechungen half die Fotodokumentation in 27 Fällen (7,2 %) zur Bestätigung eines Operationen- und Prozedurenschlüssels (OPS) (n = 5; 1,3 %), einer Hauptdiagnose (n = 10; 2,7 %), einer Nebendiagnose (n = 3; 0,8 %) oder der Krankenhausverweildauer (n = 9; 2,4 %). Pro oben genanntem Fall mit Fotodokumentation ergab sich eine durchschnittliche Erlössteigerung von 2119 €. Inklusive Aufwandpauschale für die Verhandlungen wurde somit ein Gesamtbetrag von 65.328 € verteidigt. Diskussion Der Einsatz einer Smartphone-basierten Fotodokumentation kann die Qualität der Dokumentation verbessern und Erlöseinbußen bei der Abrechnungsprüfung verhindern. Die Implementierung digitaler Endgeräte mit entsprechender Software ist ein wichtiger Teil des digitalen Strukturwandels in Kliniken. N2 - Background Photographic documentation of wounds, decubitus ulcers, tumors, open fractures and infections is an important part of digital patient files. It is unclear whether the photographic documentation has an effect on medical accounting with health insurance companies. Objective It was hypothesized that Smartphone-based systematic photographic documentation can improve the confirmation of proceeds-relevant diagnoses and procedures as well as the duration. Material and methods Staff in the emergency room, operating theater, outpatient clinic and on the wards were equipped with digital devices (Smartphone, tablet) including a photo-app. Medical accounting with the health insurance companies and identification of all case conferences in which the photographic documentation had effected a change in proceeds were analyzed for 2019 in a retrospective manner. Results Overall, 372 cases were discussed of which 27 cases were affected by the digital photographic documentation. Photographic documentation was used for clarification of the operative procedure (n = 5), primary diagnosis (n = 10), secondary diagnosis (n = 3), and length of hospitalization (n = 9). An average of 2119 € was negotiated and added per case affected by photographic documentation. Hereby, a level 1 trauma center gained an estimated 65,328 € in revenue. Discussion The use of Smartphone based photographic documentation can improve the overall quality of patient files and thus avoid loss of revenue. The implementation of digital devices with corresponding software is an important component of the digital structural change in hospitals. KW - Digitalisierung KW - Gesundheits-App KW - Künstliche Intelligenz KW - Plattform KW - Strukturwandel KW - artificial intelligence KW - database KW - digital transformation KW - photo app KW - surgery Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232415 SN - 0177-5537 VL - 124 ER - TY - JOUR A1 - Vey, Johannes A1 - Kapsner, Lorenz A. A1 - Fuchs, Maximilian A1 - Unberath, Philipp A1 - Veronesi, Giulia A1 - Kunz, Meik T1 - A toolbox for functional analysis and the systematic identification of diagnostic and prognostic gene expression signatures combining meta-analysis and machine learning JF - Cancers N2 - The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in ~1 h and describes the workflow in detail for use by researchers with limited bioinformatics training. KW - bioinformatics tool KW - R package KW - machine learning KW - meta-analysis KW - biomarker signature KW - gene expression analysis KW - survival analysis KW - functional analysis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193240 SN - 2072-6694 VL - 11 IS - 10 ER - TY - JOUR A1 - Boelch, Sebastian P. A1 - Rueckl, Kilian A1 - Fuchs, Clara A1 - Jordan, Martin A1 - Knauer, Markus A1 - Steinert, Andre A1 - Rudert, Maximilian A1 - Luedemann, Martin T1 - Comparison of elution characteristics and compressive strength of biantibiotic-loaded PMMA bone cement for spacers: Copal\(^®\) spacem with gentamicin and vancomycin versus Palacos\(^®\) R+G with vancomycin JF - BioMed Research International N2 - Purpose. Copal\(^®\) spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal\(^®\) spacem and of Palacos\(^®\) R+G at different vancomycin loadings in the powder of the cements. We hypothesized that antibiotic elution of Copal\(^®\) spacem is superior at comparable compressive strength. Methods. Compression test specimens were fabricated using Copal\(^®\) spacem manually loaded with 0.5 g gentamicin and additionally 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (COP specimens) and using 0.5 g gentamicin premixed Palacos\(^®\) R+G manually loaded with 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (PAL specimens). These specimens were used for determination of gentamicin and vancomycin elution (in fetal calf serum, at 22°C) and for determination of compressive strength both prior and following the elution tests. Results. Cumulative gentamicin concentrations (p < 0.005) and gentamicin concentration after 28 days (p ≤ 0.043) were significantly lower for COP specimens compared to PAL specimens. Cumulative vancomycin concentrations were significantly higher (p ≤ 0.043) for COP specimens after the second day. Vancomycin concentrations after 28 days were not significantly higher for the Copal specimens loaded with 2 g and 4 g of vancomycin. Compressive strength was not significantly different between COP specimens and PAL specimens before elution tests. Compressive strength after the elution tests was significantly lower (p = 0.005) for COP specimens loaded with 2 g of vancomycin. Conclusion. We could not demonstrate consistent superior antibiotic elution from Copal\(^®\) spacem compared to Palacos\(^®\) R+G for fabricating gentamicin and vancomycin loaded spacers. The results do not favor Copal\(^®\) spacem over Palacos\(^®\) R+G for the use as a gentamicin and vancomycin biantibiotic-loaded spacer. KW - Copal\(^®\) spacem KW - PMMA bone cement KW - elution KW - compressive strength Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177435 VL - 2018 IS - 4323518 ER - TY - JOUR A1 - Kühnemundt, Johanna A1 - Leifeld, Heidi A1 - Scherg, Florian A1 - Schmitt, Matthias A1 - Nelke, Lena C. A1 - Schmitt, Tina A1 - Bauer, Florentin A1 - Göttlich, Claudia A1 - Fuchs, Maximilian A1 - Kunz, Meik A1 - Peindl, Matthias A1 - Brähler, Caroline A1 - Kronenthaler, Corinna A1 - Wischhusen, Jörg A1 - Prelog, Martina A1 - Walles, Heike A1 - Dandekar, Thomas A1 - Dandekar, Gudrun A1 - Nietzer, Sarah L. T1 - Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing JF - ALTEX N2 - High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments. KW - modular tumor tissue models KW - invasiveness KW - bioreactor culture KW - combinatorial drug predictions KW - immunotherapies Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231465 VL - 38 ER - TY - JOUR A1 - Kerwagen, Fabian A1 - Fuchs, Konrad F. A1 - Ullrich, Melanie A1 - Schulze, Andres A1 - Straka, Samantha A1 - Krop, Philipp A1 - Latoschik, Marc E. A1 - Gilbert, Fabian A1 - Kunz, Andreas A1 - Fette, Georg A1 - Störk, Stefan A1 - Ertl, Maximilian T1 - Usability of a mHealth solution using speech recognition for point-of-care diagnostic management JF - Journal of Medical Systems N2 - The administrative burden for physicians in the hospital can affect the quality of patient care. The Service Center Medical Informatics (SMI) of the University Hospital Würzburg developed and implemented the smartphone-based mobile application (MA) ukw.mobile1 that uses speech recognition for the point-of-care ordering of radiological examinations. The aim of this study was to examine the usability of the MA workflow for the point-of-care ordering of radiological examinations. All physicians at the Department of Trauma and Plastic Surgery at the University Hospital Würzburg, Germany, were asked to participate in a survey including the short version of the User Experience Questionnaire (UEQ-S) and the Unified Theory of Acceptance and Use of Technology (UTAUT). For the analysis of the different domains of user experience (overall attractiveness, pragmatic quality and hedonic quality), we used a two-sided dependent sample t-test. For the determinants of the acceptance model, we employed regression analysis. Twenty-one of 30 physicians (mean age 34 ± 8 years, 62% male) completed the questionnaire. Compared to the conventional desktop application (DA) workflow, the new MA workflow showed superior overall attractiveness (mean difference 2.15 ± 1.33), pragmatic quality (mean difference 1.90 ± 1.16), and hedonic quality (mean difference 2.41 ± 1.62; all p < .001). The user acceptance measured by the UTAUT (mean 4.49 ± 0.41; min. 1, max. 5) was also high. Performance expectancy (beta = 0.57, p = .02) and effort expectancy (beta = 0.36, p = .04) were identified as predictors of acceptance, the full predictive model explained 65.4% of its variance. Point-of-care mHealth solutions using innovative technology such as speech-recognition seem to address the users’ needs and to offer higher usability in comparison to conventional technology. Implementation of user-centered mHealth innovations might therefore help to facilitate physicians’ daily work. KW - mHealth KW - digital Health KW - speech recognition KW - usability KW - user-centered design KW - clinical systems Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324002 VL - 47 IS - 1 ER - TY - JOUR A1 - Straub, Anton A1 - Vollmer, Andreas A1 - Lâm, Thiên-Trí A1 - Brands, Roman C. A1 - Stapf, Maximilian A1 - Scherf-Clavel, Oliver A1 - Bittrich, Max A1 - Fuchs, Andreas A1 - Kübler, Alexander C. A1 - Hartmann, Stefan T1 - Evaluation of advanced platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam JF - Clinical Oral Investigations N2 - Objectives Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a “bio-carrier” for antibiotics previously applied intravenously. Materials and methods We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients’ blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls. Results Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing. Conclusions The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect. Clinical relevance We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections. KW - osteonecrosis of the jaw KW - osteoradionecrosis KW - antiresorptive drug-related osteonecrosis of the jaw KW - ARONJ KW - oral microbiome KW - agar diffusion test Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324515 VL - 26 IS - 12 ER -