@article{LuetkensGrunzKunzetal.2023, author = {Luetkens, Karsten Sebastian and Grunz, Jan-Peter and Kunz, Andreas Steven and Huflage, Henner and Weißenberger, Manuel and Hartung, Viktor and Patzer, Theresa Sophie and Gruschwitz, Philipp and Erg{\"u}n, S{\"u}leyman and Bley, Thorsten Alexander and Feldle, Philipp}, title = {Ultra-high-resolution photon-counting detector CT arthrography of the ankle: a feasibility study}, series = {Diagnostics}, volume = {13}, journal = {Diagnostics}, number = {13}, issn = {2075-4418}, doi = {10.3390/diagnostics13132201}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362622}, year = {2023}, abstract = {This study was designed to investigate the image quality of ultra-high-resolution ankle arthrography employing a photon-counting detector CT. Bilateral arthrograms were acquired in four cadaveric specimens with full-dose (10 mGy) and low-dose (3 mGy) scan protocols. Three convolution kernels with different spatial frequencies were utilized for image reconstruction (ρ\(_{50}\); Br98: 39.0, Br84: 22.6, Br76: 16.5 lp/cm). Seven radiologists subjectively assessed the image quality regarding the depiction of bone, hyaline cartilage, and ligaments. An additional quantitative assessment comprised the measurement of noise and the computation of contrast-to-noise ratios (CNR). While an optimal depiction of bone tissue was achieved with the ultra-sharp Br98 kernel (S ≤ 0.043), the visualization of cartilage improved with lower modulation transfer functions at each dose level (p ≤ 0.014). The interrater reliability ranged from good to excellent for all assessed tissues (intraclass correlation coefficient ≥ 0.805). The noise levels in subcutaneous fat decreased with reduced spatial frequency (p \< 0.001). Notably, the low-dose Br76 matched the CNR of the full-dose Br84 (p 0.999) and superseded Br98 (p \< 0.001) in all tissues. Based on the reported results, a photon-counting detector CT arthrography of the ankle with an ultra-high-resolution collimation offers stellar image quality and tissue assessability, improving the evaluation of miniscule anatomical structures. While bone depiction was superior in combination with an ultra-sharp convolution kernel, soft tissue evaluation benefited from employing a lower spatial frequency.}, language = {en} } @article{ElsnerKunzWagneretal.2023, author = {Elsner, Clara and Kunz, Andreas Steven and Wagner, Nicole and Huflage, Henner and H{\"u}bner, Stefan and Luetkens, Karsten Sebastian and Bley, Thorsten Alexander and Schmitt, Rainer and Erg{\"u}n, S{\"u}leyman and Grunz, Jan-Peter}, title = {MRI-based evaluation of the flexor digitorum superficialis anatomy: investigating the prevalence and morphometry of the "chiasma antebrachii"}, series = {Diagnostics}, volume = {13}, journal = {Diagnostics}, number = {14}, issn = {2075-4418}, doi = {10.3390/diagnostics13142406}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362631}, year = {2023}, abstract = {Recent dissection studies resulted in the introduction of the term "chiasma antebrachii", which represents an intersection of the flexor digitorum superficialis (FDS) tendons for digits 2 and 3 in the distal third of the forearm. This retrospective investigation aimed to provide an MRI-based morphologic analysis of the chiasma antebrachii. In 89 patients (41 women, 39.3 ± 21.3 years), MRI examinations of the forearm (2010-2021) were reviewed by two radiologists, who evaluated all studies for the presence and length of the chiasma as well as its distance from the distal radioulnar and elbow joint. The chiasma antebrachii was identified in the distal third of the forearm in 88 patients (98.9\%), while one intersection was located more proximally in the middle part. The chiasma had a median length of 28 mm (interquartile range: 24-35 mm). Its distances to the distal radioulnar and elbow joint were 16 mm (8-25 mm) and 215 mm (187-227 mm), respectively. T1-weighted post-contrast sequences were found to be superior to T2- or proton-density-weighted sequences in 71 cases (79.8\%). To conclude, the chiasma antebrachii is part of the standard FDS anatomy. Knowledge of its morphology is important, e.g., in targeted injections of therapeutics or reconstructive surgery.}, language = {en} } @article{MoratinThoeleLangetal.2023, author = {Moratin, Helena and Th{\"o}le, Anna and Lang, Josephine and Ehret Kasemo, Totta and St{\"o}th, Manuel and Hagen, Rudolf and Scherzad, Agmal and Hackenberg, Stephan}, title = {Ag- but not ZnO-nanoparticles disturb the airway epithelial barrier at subtoxic concentrations}, series = {Pharmaceutics}, volume = {15}, journal = {Pharmaceutics}, number = {10}, issn = {1999-4923}, doi = {10.3390/pharmaceutics15102506}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357403}, year = {2023}, abstract = {Inhalation is considered to be the most relevant source of human exposure to nanoparticles (NPs); however, only a few investigations have addressed the influence of exposing the respiratory mucosal barrier to subcytotoxic doses. In the nasal respiratory epithelium, cells of the mucosa represent one of the first contact points of the human organism with airborne NPs. Disruption of the epithelial barrier by harmful materials can lead to inflammation in addition to potential intrinsic toxicity of the particles. The aim of this study was to investigate whether subtoxic concentrations of zinc oxide (ZnO)- and silver (Ag)-NPs have an influence on upper airway barrier integrity. Nasal epithelial cells from 17 donors were cultured at the air-liquid interface and exposed to ZnO- and Ag-NPs. Barrier function, quantified by transepithelial electrical resistance (TEER), decreased after treatment with 10 µg/mL Ag-NPs, but FITC-dextran permeability remained stable and no change in mRNA levels of tight junction proteins and E-cadherin was detected by real-time quantitative PCR (RT-qPCR). The results indicate that subtoxic concentrations of Ag-NPs may already induce damage of the upper airway epithelial barrier in vitro. The lack of similar disruption by ZnO-NPs of similar size suggests a specific effect by Ag-NPs.}, language = {en} } @article{IsraelRiehlButtetal.2023, author = {Israel, Ina and Riehl, Gabriele and Butt, Elke and Buck, Andreas K. and Samnick, Samuel}, title = {Gallium-68-labeled KISS1-54 peptide for mapping KISS1 receptor via PET: initial evaluation in human tumor cell lines and in tumor-bearing mice}, series = {Pharmaceuticals}, volume = {17}, journal = {Pharmaceuticals}, number = {1}, issn = {1424-8247}, doi = {10.3390/ph17010044}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355898}, year = {2023}, abstract = {Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [\(^{68}\)Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [\(^{68}\)Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [\(^{68}\)Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [\(^{68}\)Ga]KISS1-54 was obtained in a 77 ± 7\% radiochemical yield and at a >99\% purity. The [\(^{68}\)Ga]KISS1-54 cell uptake amounted to 0.6-4.4\% per 100,000 cells. Moreover, the accumulation of [\(^{68}\)Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [\(^{68}\)Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [\(^{68}\)Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.}, language = {en} } @article{OdorferVolkmann2023, author = {Odorfer, Thorsten M. and Volkmann, Jens}, title = {Deep brain stimulation for focal or segmental craniocervical dystonia in patients who have failed botulinum neurotoxin therapy - a narrative review of the literature}, series = {Toxins}, volume = {15}, journal = {Toxins}, number = {10}, issn = {2072-6651}, doi = {10.3390/toxins15100606}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357707}, year = {2023}, abstract = {(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT.}, language = {en} } @article{WatzlingKlausWeidemeieretal.2023, author = {Watzling, Martin and Klaus, Lorenz and Weidemeier, Tamara and Horder, Hannes and Ebert, Regina and Blunk, Torsten and Bauer-Kreisel, Petra}, title = {Three-dimensional breast cancer model to investigate CCL5/CCR1 expression mediated by direct contact between breast cancer cells and adipose-derived stromal cells or adipocytes}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {13}, issn = {2072-6694}, doi = {10.3390/cancers15133501}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362502}, year = {2023}, abstract = {The tumor microenvironment (TME) in breast cancer is determined by the complex crosstalk of cancer cells with adipose tissue-inherent cells such as adipose-derived stromal cells (ASCs) and adipocytes resulting from the local invasion of tumor cells in the mammary fat pad. This leads to heterotypic cellular contacts between these cell types. To adequately mimic the specific cell-to-cell interaction in an in vivo-like 3D environment, we developed a direct co-culture spheroid model using ASCs or differentiated adipocytes in combination with MDA-MB-231 or MCF-7 breast carcinoma cells. Co-spheroids were generated in a well-defined and reproducible manner in a high-throughput process. We compared the expression of the tumor-promoting chemokine CCL5 and its cognate receptors in these co-spheroids to indirect and direct standard 2D co-cultures. A marked up-regulation of CCL5 and in particular the receptor CCR1 with strict dependence on cell-cell contacts and culture dimensionality was evident. Furthermore, the impact of direct contacts between ASCs and tumor cells and the involvement of CCR1 in promoting tumor cell migration were demonstrated. Overall, these results show the importance of direct 3D co-culture models to better represent the complex tumor-stroma interaction in a tissue-like context. The unveiling of tumor-specific markers that are up-regulated upon direct cell-cell contact with neighboring stromal cells, as demonstrated in the 3D co-culture spheroids, may represent a promising strategy to find new targets for the diagnosis and treatment of invasive breast cancer.}, language = {en} } @phdthesis{Stark2024, author = {Stark, Irmgard Katharina}, title = {Einfluss von Interferon auf das Infektionsverhalten von Herpes simplex Virus 1 und seiner DUB - Mutante C65A in der Zellkultur}, doi = {10.25972/OPUS-35195}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351950}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Erforschung viraler Proteine ist wichtig, um virale Infektionen besser verstehen und damit therapieren zu k{\"o}nnen. Die Aufkl{\"a}rung der DUB-Funktion auf dem viralen Herpesprotein pUL36 erm{\"o}glicht ein besseres Verst{\"a}ndnis des Infektionshergangs und k{\"o}nnte zur Entwicklung eines Enzyminhibitors f{\"u}hren, der nur an diesem Enzym ansetzt, nachdem es sich von den zellul{\"a}ren DUBs unterscheidet (Kattenhorn et al., 2005). In dieser Arbeit konnten die vorherigen Daten, die eine st{\"a}rkere Hemmung der DUB- Mutante unter Interferoneinfluss zeigten, in unterschiedlichen Assay-Designs best{\"a}tigt werden. Auch Versuche mit einem anderen Herpes simplex Virus Strang, best{\"a}tigten die vorherigen Daten. Die Ergebnisse zeigen, dass die DUB-Funktion f{\"u}r HSV-1 wichtig ist f{\"u}r die virale Evasion der zellul{\"a}ren Immunantwort. Die genaue Funktion der DUB in der Infektion ist jedoch unklar. Aufgrund der vorbestehenden Datenlage erschien am wahrscheinlichsten, dass die DUB-Funktion vor Eindringen des Herpes Simplex Virus in den Zellkern zum Tragen kommt, womit es nach Abnahme des Interferons nicht zu einer viralen Reaktivierung k{\"a}me. Deshalb wurden Untersuchungen unternommen, um eine m{\"o}gliche Reaktivierung nach Abnahme des Interferons n{\"a}her zu untersuchen. Hierf{\"u}r wurden zwei verschiedene Experimente entwickelt. Einmal wurde das Interferon direkt nach Infektion und einmal 3 Tage nach Infektion (3dpi) abgenommen. Die Ergebnisse zeigten beide eine st{\"a}rkere Hemmung der DUB-HSV-1-Mutante unter Interferoneinfluss. Bei Abnahme des Interferons direkt nach Infektion lag bei Wildtyp und Mutante ein leichter Anstieg der Plaquezahlen vor, wobei dieser Effekt von der Dosis des Interferons abh{\"a}ngig war. Eine hohe Interferondosis beg{\"u}nstigte bei beiden eine st{\"a}rkere Hemmung, allerdings bei beiden auch eine leichte Erh{\"o}hung der Plaquezahl nach Abnahme. Bei einer niedrigen Dosis konnte nur eine st{\"a}rkere Hemmung der DUB-Mutante, jedoch keine Reaktivierung bei Wildtyp und Mutante nach Abnahme des Interferons gezeigt werden. Bei Abnahme drei Tage nach Infektion zeigte sich sowohl bei dem Wildtyp-Virus als auch der DUB- Mutante kein Anstieg in den Plaquezahlen. Es sind, nachdem Deubiquitinierung nicht nur eine Rolle in der Verhinderung des proteosomalen Abbaus von in die Zelle eingedrungenem Virus spielt, sondern auch der Zellregulation, mehrere Szenarien denkbar, die diesen Ph{\"a}notyp erkl{\"a}ren k{\"o}nnten. Die DUB-Funktion k{\"o}nnte zwar den proteosomalen Abbau durch Deubiqutinierung und damit Verhinderung der Markierung des Virus zum zellul{\"a}ren Abbau verhindern. Allerdings k{\"o}nnten sich durch einen langsameren Transport aus der Zelle oder in den Nucleus auch weniger Plaques bei der Mutante als wie beim Wildtyp unter Interferoneinfluss bilden, nachdem das Virus dann leichter Ziel antiviraler Proteine werden k{\"o}nnte. Oder die DUB-Funktion spielt eine Rolle beim Eintritt in den Kern durch Modifikationen anderer Proteine. Virengenome k{\"o}nnten auch durch eine fehlende DUB-Funktion reprimiert werden oder die Zelle durch Apoptose absterben. Interessanterweise konnte keine Hemmung der DUB-Mutante in Interferon behandelten U-2 OS Zellen gezeigt werden, von denen ein Defekt im STING- vermittelten Signalweg bekannt ist. Vielleicht zeigt dies, dass das STING-Protein an dem gezeigten DUB-Ph{\"a}notyp beteiligt ist. Nachgewiesen ist außerdem bereits eine Funktion des Enzyms bei der zweiten Umh{\"u}llung der Kapside bei Pseudorabiesvirus (M{\"o}hl, 2011). Weitere Untersuchungen unter Einsatz bspw. von Immunfluoreszenz, Proteasominhibitoren oder weiteren Zelllinien wie Saos-2, sind n{\"o}tig, um die genaue Funktion zu kl{\"a}ren.}, subject = {Interferon}, language = {de} } @article{GuederReinFlohretal.2023, author = {G{\"u}der, G{\"u}lmisal and Rein, Eva von and Flohr, Thomas and Weismann, Dirk and Schmitt, Dominik and St{\"o}rk, Stefan and Frantz, Stefan and Kratzer, Vincent and Kendi, Christian}, title = {Motion detectors as additional monitoring devices in the intensive care unit — a proof-of-concept study}, series = {Applied Sciences}, volume = {13}, journal = {Applied Sciences}, number = {16}, issn = {2076-3417}, doi = {10.3390/app13169319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362404}, year = {2023}, abstract = {Background: Monitoring the vital signs of delirious patients in an intensive care unit (ICU) is challenging, as they might (un-)intentionally remove devices attached to their bodies. In mock-up scenarios, we systematically assessed whether a motion detector (MD) attached to the bed may help in identifying emergencies. Methods: We recruited 15 employees of the ICU and equipped an ICU bed with an MD (IRON Software GmbH, Gr{\"u}nwald, Germany). Participants were asked to replay 22 mock-up scenes of one-minute duration each: 12 scenes with movements and 10 without movements, of which 5 were emergency scenes ("lying dead-still, with no or very shallow breathing"). Blinded recordings were presented to an evaluation panel consisting of an experienced ICU nurse and a physician, who was asked to assess and rate the presence of motions. Results: Fifteen participants (nine women; 173 ± 7.0 cm; 78 ± 19 kg) joined the study. In total, 286 out of 330 scenes (86.7\%) were rated correctly. Ratings were false negative (FN: "no movements detected, but recorded") in 7 out of 180 motion scenes (3.9\%). Ratings were false positive (FP: "movements detected, but not recorded") in 37 out of 150 scenes (24.7\%), more often in men than women (26 out of 60 vs. 11 out of 90, respectively; p \< 0.001). Of note, in 16 of these 37 FP-rated scenes, a vibrating mobile phone was identified as a potential confounder. The emergency scenes were correctly rated in 64 of the 75 runs (85.3\%); 10 of the 11 FP-rated scenes occurred in male subjects. Conclusions: The MD allowed for identifying motions of test subjects with high sensitivity (96\%) and acceptable specificity (75\%). Accuracy might increase further if activities are recorded continuously under real-world conditions.}, language = {en} } @article{HiewEibeckNguemenietal.2023, author = {Hiew, Shawn and Eibeck, Leila and Nguemeni, Carine and Zeller, Daniel}, title = {The influence of age and physical activity on locomotor adaptation}, series = {Brain Sciences}, volume = {13}, journal = {Brain Sciences}, number = {9}, issn = {2076-3425}, doi = {10.3390/brainsci13091266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362478}, year = {2023}, abstract = {Background: Aging increases individual susceptibility to falls and injuries, suggesting poorer adaptation of balance responses to perturbation during locomotion, which can be measured with the locomotor adaptation task (LAT). However, it is unclear how aging and lifestyle factors affect these responses during walking. Hence, the present study investigates the relationship between balance and lifestyle factors during the LAT in healthy individuals across the adult lifespan using a correlational design. Methods: Thirty participants aged 20-78 years performed an LAT on a split-belt treadmill (SBT). We evaluated the magnitude and rate of adaptation and deadaptation during the LAT. Participants reported their lifelong physical and cognitive activity. Results: Age positively correlated with gait-line length asymmetry at the late post-adaptation phase (p = 0.007). These age-related effects were mediated by recent physical activity levels (p = 0.040). Conclusion: Our results confirm that locomotor adaptive responses are preserved in aging, but the ability to deadapt newly learnt balance responses is compromised with age. Physical activity mediates these age-related effects. Therefore, gait symmetry post-adaptation could effectively measure the risk of falling, and maintaining physical activity could protect against declines in balance.}, language = {en} } @phdthesis{Reissland2024, author = {Reissland, Michaela}, title = {USP10 is a \(de\) \(novo\) tumour-specific regulator of β-Catenin and contributes to cancer stem cell maintenance and tumour progression}, doi = {10.25972/OPUS-31957}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319579}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Colorectal Cancer (CRC) is the third most common cancer in the US. The majority of CRC cases are due to deregulated WNT-signalling pathway. These alterations are mainly caused by mutations in the tumour suppressor gene APC or in CTNNB1, encoding the key effector protein of this pathway, β-Catenin. In canonical WNT-signalling, β-Catenin activates the transcription of several target genes, encoding for proteins involved in proliferation, such as MYC, JUN and NOTCH. Being such a critical regulator of these proto-oncogenes, the stability of β-Catenin is tightly regulated by the Ubiquitin-Proteasome System. Several E3 ligases that ubiquitylate and degrade β-Catenin have been described in the past, but the antagonists, the deubiquitylases, are still unknown. By performing an unbiased siRNA screen, the deubiquitylase USP10 was identified as a de novo positive regulator of β-Catenin stability in CRC derived cells. USP10 has previously been shown in the literature to regulate both mutant and wild type TP53 stability, to deubiquitylate NOTCH1 in endothelial cells and to be involved in the regulation of AMPKα signalling. Overall, however, its role in colorectal tumorigenesis remains controversial. By analysing publicly available protein and gene expression data from colorectal cancer patients, we have shown that USP10 is strongly upregulated or amplified upon transformation and that its expression correlates positively with CTNNB1 expression. In contrast, basal USP10 levels were found in non-transformed tissues, but surprisingly USP10 is upregulated in intestinal stem cells. Endogenous interaction studies in CRC-derived cell lines, with different extend of APCtruncation, revealed an APC-dependent mode of action for both proteins. Furthermore, by utilising CRISPR/Cas9, shRNA-mediated knock-down and overexpression of USP10, we could demonstrate a regulation of β-Catenin stability by USP10 in CRC cell lines. It is widely excepted that 2D cell culture systems do not reflect complexity, architecture and heterogeneity and are therefore not suitable to answer complex biological questions. To overcome this, we established the isolation, cultivation and genetically modification of murine intestinal organoids and utilised this system to study Usp10s role ex vivo. By performing RNA sequencing, dependent on different Usp10 levels, we were able to recapitulate the previous findings and demonstrated Usp10 as important regulator of β-dependent regulation of stem cell homeostasis. Since genetic depletion of USP10 resulted in down-regulation of β-Catenin-dependent transcription, therapeutic intervention of USP10 in colorectal cancer was also investigated. Commercial and newly developed inhibitors were tested for their efficacy against USP10, but failed to significantly inhibit USP10 activity in colorectal cancer cells. To validate the findings from this work also in vivo, development of a novel mouse model for colorectal cancer has begun. By combining CRISPR/Cas9 and classical genetic engineering with viral injection strategies, WT and genetically modified mice could be transformed and, at least in some animals, intestinal lesions were detectable at the microscopic level. The inhibition of USP10, which we could describe as a de novo tumour-specific regulator of β-Catenin, could become a new therapeutic strategy for colorectal cancer patients.}, subject = {Biomedizin}, language = {en} } @phdthesis{Gaballa2024, author = {Gaballa, Abdallah Hatem Hassan Hosny Ahmed}, title = {PAF1c drives MYC-mediated immune evasion in pancreatic ductal adenocarcinoma}, doi = {10.25972/OPUS-36045}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360459}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The expression of the MYC proto-oncogene is elevated in a large proportion of patients with pancreatic ductal adenocarcinoma (PDAC). Previous findings in PDAC have shown that this increased MYC expression mediates immune evasion and promotes S-phase progression. How these functions are mediated and whether a downstream factor of MYC mediates these functions has remained elusive. Recent studies identifying the MYC interactome revealed a complex network of interaction partners, highlighting the need to identify the oncogenic pathway of MYC in an unbiased manner. In this work, we have shown that MYC ensures genomic stability during S-phase and prevents transcription-replication conflicts. Depletion of MYC and inhibition of ATR kinase showed a synergistic effect to induce DNA damage. A targeted siRNA screen targeting downstream factors of MYC revealed that PAF1c is required for DNA repair and S-phase progression. Recruitment of PAF1c to RNAPII was shown to be MYC dependent. PAF1c was shown to be largely dispensable for cell proliferation and regulation of MYC target genes. Depletion of CTR9, a subunit of PAF1c, caused strong tumor regression in a pancreatic ductal adenocarcinoma model, with long-term survival in a subset of mice. This effect was not due to induction of DNA damage, but to restoration of tumor immune surveillance. Depletion of PAF1c resulted in the release of RNAPII with transcription elongation factors, including SPT6, from the bodies of long genes, promoting full-length transcription of short genes. This resulted in the downregulation of long DNA repair genes and the concomitant upregulation of short genes, including MHC class I genes. These data demonstrate that a balance between long and short gene transcription is essential for tumor progression and that interference with PAF1c levels shifts this balance toward a tumor-suppressive transcriptional program. It also directly links MYC-mediated S-phase progression to immune evasion. Unlike MYC, PAF1c has a stable, known folded structure; therefore, the development of a small molecule targeting PAF1c may disrupt the immune evasive function of MYC while sparing its physiological functions in cellular growth.}, subject = {Myc}, language = {en} } @phdthesis{vonderHeide2024, author = {von der Heide, Julia Magdalena}, title = {Ist eine Berechnung der Geometrie der Halswirbelk{\"o}rper anhand ihrer Morphologie im Kindesalter und somit eine Individualisierung der CVM-Methode m{\"o}glich?}, doi = {10.25972/OPUS-36075}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360753}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel der vorliegenden Studie war es zu untersuchen, ob anhand geometrischer Merkmale der HWK im Kindesalter eine sichere individuelle Vorhersage der Morphologie der HWK zum Ende der Entwicklung m{\"o}glich ist. Hierdurch k{\"o}nnte eine Individualisierung der CVM-Methode und somit eine Einsch{\"a}tzung des bereits verstrichenen Wachstums erfolgen. Zu diesem Zweck wurden insgesamt 1377 FRS-Aufnahmen von 267 Patienten - 110 weibliche und 157 m{\"a}nnliche - aus dem Archiv der Poliklinik f{\"u}r Kieferorthop{\"a}die des Universit{\"a}tsklinikums W{\"u}rzburg digitalisiert und untersucht. Die HWK wurden im Programm OnyxCeph (Herst.: Image Instruments GmbH) quantifiziert und die berechneten Werte mit der Software SPSS statistisch ausgewertet. Mittels linearer Regressionen wurde versucht, anhand der Morphologie der Wirbelk{\"o}rper vor dem puberalen Wachstumsschub auf die Geometrie der HWK im Erwachsenenalter zu schließen. Zur Illustrierung wurden Streudiagramm und die dazugeh{\"o}rigen Abfolgen von R{\"o}ntgenbildern dargestellt. Eine Sch{\"a}tzung der Geometrie der HWK im Erwachsenenalter w{\"u}rde bei den separat betrachteten Parametern und bei einer gemeinsamen Betrachtung der Parameter kaum zu korrekten Einsch{\"a}tzungen f{\"u}hren. Die Streudiagramme mit den Bilderabfolgen st{\"u}tzen diese These ebenfalls und illustrieren die m{\"o}gliche Fehleinsch{\"a}tzung der Geometrie. Die Ergebnisse der Studie zeigen erneut, dass die Geometrie der HWK im Erwachsenenalter sehr variabel ist, wie komplex die Entwicklung der HWK ist und dass anhand ihrer Geometrie im Kindesalter keine sichere Einsch{\"a}tzung der skelettalen Reife m{\"o}glich ist. Eine Individualisierung der CVM-Methode ist anhand der in dieser Studie untersuchten Parameter nicht m{\"o}glich. Somit l{\"a}sst sich schlussfolgern, dass die CVM-Methode nicht als alleinige Methode zur pr{\"a}zisen skelettalen Alterseinsch{\"a}tzung verl{\"a}sslich genutzt werden kann, sondern f{\"u}r eine sichere Beurteilung weitere Reifeindikatoren hinzugezogen werden sollten. Allerdings sollten hierzu zus{\"a}tzliche radiologische Untersuchungen, wie beispielsweise die Handr{\"o}ntgenaufnahme, nur dann durchgef{\"u}hrt werden, wenn diese dem ALARA-Prinzip entsprechen.}, subject = {Skelett}, language = {de} } @phdthesis{CruzdeCasas2024, author = {Cruz de Casas, Paulina}, title = {Sphingolipids as modulators of T cell function}, doi = {10.25972/OPUS-35969}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359698}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The immune system is responsible for the preservation of homeostasis whenever a given organism is exposed to distinct kinds of perturbations. Given the complexity of certain organisms like mammals, and the diverse types of challenges that they encounter (e.g. infection or disease), the immune system evolved to harbor a great variety of distinct immune cell populations with specialized functions. For instance, the family of T cells is sub-divided into conventional (Tconv) and unconventional T cells (UTCs). Tconv form part of the adaptive arm of the immune system and are comprised of αβ CD4+ or CD8+ cells that differentiate from na{\"i}ve to effector and memory populations upon activation and are essential during infection and cancer. Furthermore, UTCs, which include γδ T cells, NKT and MAIT, are involved in innate and adaptive immune responses, due to their dual mode of activation, through cytokines (innate-like) or TCR (adaptive), and function. Despite our understanding of the basic functions of T cells in several contexts, a great number of open questions related to their basic biology remain. For instance, the mechanism behind the differentiation of na{\"i}ve CD4+ and CD8+ T cells into effector and memory populations is not fully understood. Moreover, the exact function and relevance of distinct UTC subpopulations in a physiological context have not been fully clarified. Here, we investigated the factors mediating na{\"i}ve CD8+ T cell differentiation into effector and memory cells. By using flow cytometry, mass spectrometry, enzymatic assays, and transgenic mouse models, we found that the membrane bound enzyme sphingomyelin-phosphodiesterase acid-like 3b (Smpdl3b) is crucial for the maintenance of memory CD8+ T cells. Our data show that the absence of Smpdl3b leads to diminished CD8+ T cell memory, and a loss of stem-like memory populations due to an aggravated contraction. Our scRNA-seq data suggest that Smpdl3b could be involved in clathrinmediated endocytosis through modulation of Huntingtin interacting protein 1 (Hip1) levels, likely regulating TCR-independent signaling events. Furthermore, in this study we explored the role of UTCs in lymph node-specific immune responses. By using transgenic mouse models for photolabeling, lymph node transplantation models, infection models and flow cytometry, we demonstrate that S1P regulates the migration of tissue-derived UTC from tissues to draining lymph nodes, resulting in heterogeneous immune responses mounted by lymph nodes draining different tissues. Moreover, our unbiased scRNAseq and single lineage-deficient mouse models analysis revealed that all UTC lineages (γδ T cells, NKT and MAIT) are organized in functional units, based on transcriptional homogeneity, shared microanatomical location and migratory behavior, and numerical and functional redundancy. Taken together, our studies describe additional cell intrinsic (Smpdl3b) and extrinsic (S1Pmediated migration) functions of sphingolipid metabolism modulating T cell biology. We propose the S1P/S1PR1/5 signaling axis as the potential survival pathway for Smpdl3b+ memory CD8+ T cells and UTCs, mainly in lymph nodes. Possibly, Smpdl3b regulates S1P/S1PR signaling by balancing ligandreceptor endocytosis, while UTCs migrate to lymph nodes during homeostasis to be exposed to specific levels of S1P that assure their maintenance. Our results are clinically relevant, since several drugs modulating the S1P/S1PR signaling axis or the levels of Smpdl3b are currently used to treat human diseases, such as multiple sclerosis and B cell-mediated diseases. We hope that our discoveries will inspire future studies focusing on sphingolipid metabolism in immune cell biology.}, subject = {T-Lymphozyt}, language = {en} } @phdthesis{Wussmann2024, author = {Wußmann, Maximiliane}, title = {Humane organotypische 3D Modelle des Malignen Melanoms als in vitro Testsystem f{\"u}r die Bewertung der Wirksamkeit von anti-Tumor Therapeutika}, doi = {10.25972/OPUS-36100}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361005}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das maligne Melanom, eine der seltensten, aber gleichzeitig auch die t{\"o}dlichste dermatologische Malignit{\"a}t, gekennzeichnet durch die Neigung zu einer fr{\"u}hen Metastasierung sowie die rasche Entwicklung von Therapieresistenzen, z{\"a}hlt zu den Tumorentit{\"a}ten mit dem h{\"o}chsten Anstieg der Inzidenz weltweit. Mausmodelle werden h{\"a}ufig verwendet, um die Melanomagenese zu erforschen und neue effektive therapeutische Strategien zu entwickeln, spiegeln die menschliche Physiologie allerdings nur unzureichend wider. In zweidimensionalen (2D) Zellkulturen mangelt es dagegen an wichtigen Komponenten der Mikroumgebung des Tumors und dem dreidimensionalen Gewebekontext. Um dieses Manko zu beheben und die Entwicklung von auf den Menschen {\"u}bertragbaren Tumormodellen in der onkologischen Forschung voranzutreiben, wurde als Alternative zu Zellkulturen und Tierversuchen humane organotypische dreidimensionale (3D) Melanom-Modelle als in vitro Testsystem f{\"u}r die Bewertung der Wirksamkeit von anti-Tumor Therapeutika entwickelt. Im Zuge dieser Arbeit konnte das in vitro Melanom-Modell entscheidend weiterentwickelt werden. So konnten Modelle unterschiedlichster Komplexit{\"a}t etabliert werden, wobei abh{\"a}ngig von der Fragestellung einfachere epidermale bis hin zu unterschiedlich komplexen Vollhautmodellen Anwendung finden. Durch Simulation der Tumor-Mikroumgebung eignen sich diese zur pr{\"a}klinischen Validierung neuer Tumor-Therapeutika, sowie der Erforschung pathologischer Vorg{\"a}nge, von der Tumor-Formierung bis zur Metastasierung. Zudem konnten erfolgreich unterschiedlichste humane Melanomzelllinien ins Modell integriert werden; dadurch, dass sich diese durch ihre Treibermutationen, die zur Krankheitsentstehung beitragen, unterscheiden, stellen sie unterschiedliche Anspr{\"u}che an potentielle therapeutische Angriffspunkte und erm{\"o}glichen das Widerspiegeln vieler Melanom-Subtypen im Modell. Ferner ist es m{\"o}glich, verschiedene Stadien der Tumor-Entwicklung {\"u}ber die Zugabe von Melanomzellen in Einzelsuspension bzw. von Melanom-Sph{\"a}roiden widerzuspiegeln. Es konnte f{\"u}r bestimmte Therapie-Ans{\"a}tze, wie zielgerichtete Therapien, z.B. die Gabe von sich in der Klinik im Einsatz befindlicher BRAF-/MEK-Inhibitoren, gezeigt werden, dass sich die etablierten Modelle hervorragend als pr{\"a}klinische Testsysteme zur Wirksamkeitsbewertung eignen. Zudem bieten sich einzigartige M{\"o}glichkeiten, um die Interaktion humaner Tumorzellen und gesunder Zellen in einem Gewebeverband zu untersuchen. Ferner konnten drei neue technische Analyse-Verfahren zur nicht-invasiven Detektion der Tumor- Pro- und Regression, Beurteilung der Wirksamkeit von potenziellen Anti-Tumor-Therapien sowie der Evaluierung des Tumor-Metabolismusses implementiert werden. Perspektivisch erm{\"o}glichen immun-kompetente Melanom-Modelle die Austestung neuer Immun- und Zelltherapien in einem voll humanen System; gleichzeitig leisten die etablierten Modelle einen signifikanten Beitrag zur Reduktion von Tierexperimenten.}, subject = {Melanom}, language = {de} } @article{JockelSchneiderSchlagenhaufPetsosetal.2021, author = {Jockel-Schneider, Yvonne and Schlagenhauf, Ulrich and Petsos, Hari and R{\"u}ttermann, Stefan and Schmidt, Jana and Ziebolz, Dirk and Wehner, Christian and Laky, Markus and Rott, Thea and Noack, Michael and Noack, Barbara and Lorenz, Katrin}, title = {Impact of 0.1\% octenidine mouthwash on plaque re-growth in healthy adults: a multi-center phase 3 randomized clinical trial}, series = {Clinical Oral Investigations}, volume = {25}, journal = {Clinical Oral Investigations}, number = {7}, issn = {1432-6981}, doi = {10.1007/s00784-021-03781-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307629}, pages = {4681-4689}, year = {2021}, abstract = {Objectives To investigate plaque inhibition of 0.1\% octenidine mouthwash (OCT) vs. placebo over 5 days in the absence of mechanical plaque control. Materials and methods For this randomized, placebo-controlled, double-blind, parallel group, multi-center phase 3 study, 201 healthy adults were recruited. After baseline recording of plaque index (PI) and gingival index (GI), collection of salivary samples, and dental prophylaxis, subjects were randomly assigned to OCT or placebo mouthwash in a 3:1 ratio. Rinsing was performed twice daily for 30 s. Colony forming units in saliva were determined before and after the first rinse. At day 5, PI, GI, and tooth discoloration index (DI) were assessed. Non-parametric van Elteren tests were applied with a significance level of p < 0.05. Results Treatment with OCT inhibited plaque formation more than treatment with placebo (PI: 0.36 vs. 1.29; p < 0.0001). OCT reduced GI (0.04 vs. placebo 0.00; p = 0.003) and salivary bacterial counts (2.73 vs. placebo 0.24 lgCFU/ml; p < 0.0001). Tooth discoloration was slightly higher under OCT (DI: 0.25 vs. placebo 0.00; p = 0.0011). Mild tongue staining and dysgeusia occurred. Conclusions OCT 0.1\% mouthwash inhibits plaque formation over 5 days. It therefore can be recommended when regular oral hygiene is temporarily compromised. Clinical relevance When individual plaque control is compromised, rinsing with octenidine mouthwash is recommended to maintain healthy oral conditions while side effects are limited.}, language = {en} } @article{BruennertSeupelGoyaletal.2023, author = {Br{\"u}nnert, Daniela and Seupel, Raina and Goyal, Pankaj and Bach, Matthias and Schraud, Heike and Kirner, Stefanie and K{\"o}ster, Eva and Feineis, Doris and Bargou, Ralf C. and Schlosser, Andreas and Bringmann, Gerhard and Chatterjee, Manik}, title = {Ancistrocladinium A induces apoptosis in proteasome inhibitor-resistant multiple myeloma cells: a promising therapeutic agent candidate}, series = {Pharmaceuticals}, volume = {16}, journal = {Pharmaceuticals}, number = {8}, issn = {1424-8247}, doi = {10.3390/ph16081181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362887}, year = {2023}, abstract = {The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.}, language = {en} } @article{WinterSchulzSchmitteretal.2023, author = {Winter, Anna and Schulz, Stefan M. and Schmitter, Marc and M{\"u}ller-Richter, Urs and K{\"u}bler, Alexander and Kasper, Sylvia and Hartmann, Stefan}, title = {Comprehensive geriatric assessment and quality of life aspects in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)}, series = {Journal of Clinical Medicine}, volume = {12}, journal = {Journal of Clinical Medicine}, number = {17}, issn = {2077-0383}, doi = {10.3390/jcm12175738}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363096}, year = {2023}, abstract = {To define frailty in older cancer patients, the aim of this study was to assess the geriatric status and quality of life (QoL) aspects in patients suffering from recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) under palliative treatment. A comprehensive geriatric assessment (CGA) was performed on 21 r/m HNSCC patients at two defined assessments, and the QoL aspects and the impact of descriptive data were evaluated. The Kolmogorov-Smirnov test, Spearman's rho correlation, and two-way mixed ANOVA were used for statistical analysis. All patients were found to be "frail". Pain, fatigue, and the burden of illness were the highest-rated symptoms. Oral function and orofacial appearance were highly impaired. A significant impact of descriptive data on the CGA and QoL results was found (all p ≤ 0.05). Thus, the CGA results revealed high frailty, severe comorbidities, and high impairments in QoL aspects. The CGA and QoL results were negatively affected by the primary HNSCC treatment approach, the need for prosthetic treatment, and worse oral functional capacity. Therefore, frailty in r/m HNSCC patients seems to be multidimensional. The evaluation of the CGA and QoL aspects in r/m HNSCC patients can be recommended to detect special needs, organize aftercare, and improve the support for frail and vulnerable cancer patients to create a multidisciplinary treatment approach.}, language = {en} } @article{HellerReiterLeichtetal.2023, author = {Heller, Bianca and Reiter, Florian P. and Leicht, Hans Benno and Fiessler, Cornelia and Bergheim, Ina and Heuschmann, Peter U. and Geier, Andreas and Rau, Monika}, title = {Salt-intake-related behavior varies between sexes and is strongly associated with daily salt consumption in obese patients at high risk for MASLD}, series = {Nutrients}, volume = {15}, journal = {Nutrients}, number = {18}, issn = {2072-6643}, doi = {10.3390/nu15183942}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363107}, year = {2023}, abstract = {Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes a significant burden on Westernized regions. The Western diet, high in salt intake, significantly contributes to disease development. However, there are a lack of data on salt literacy and salt intake among MASLD patients in Germany. Our study aims to analyze daily salt intake and salt-intake-related behavior in MASLD patients. Methods: 234 MASLD patients were prospectively included. Daily salt intake and salt-intake-related behavior were assessed via a food frequency questionnaire (FFQ—DEGS) and a salt questionnaire (SINU). Statistical analyses were performed using SPSS. Results: Mean daily salt intake was higher in men than in women (7.3 ± 5 g/d vs. 5.3 ± 4 g/d; p \< 0.001). There was significant agreement between increased daily salt intake (6 g/d) and the behavioral salt index (SI) (p \< 0.001). Men exhibited higher SI scores compared to women, indicating lower awareness of salt in everyday life. Multivariate analysis identified specific salt-intake-related behaviors impacting daily salt consumption. Conclusions: Our study reveals a strong link between daily salt intake and salt-intake-related behavior, highlighting sex-specific differences in an MASLD cohort. To enhance patient care in high-cardiovascular-risk populations, specific behavioral approaches may be considered, including salt awareness, to improve adherence to lifestyle changes, particularly in male patients.}, language = {en} } @article{deJongDinizSalomaetal.2018, author = {de Jong, Simone and Diniz, Mateus Jose Abdalla and Saloma, Andiara and Gadelha, Ary and Santoro, Marcos L. and Ota, Vanessa K. and Noto, Cristiano and Curtis, Charles and Newhouse, Stephen J. and Patel, Hamel and Hall, Lynsey S. and O'Reilly, Paul F. and Belangero, Sintia I. and Bressan, Rodrigo A. and Breen, Gerome}, title = {Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, organization = {Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium}, doi = {10.1038/s42003-018-0155-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223622}, year = {2018}, abstract = {Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30\% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.}, language = {en} } @article{DekkerDiekstraPulitetal.2019, author = {Dekker, Annelot M. and Diekstra, Frank P. and Pulit, Sara L. and Tazelaar, Gijs H. P. and van der Spek, Rick A. and van Rheenen, Wouter and van Eijk, Kristel R. and Calvo, Andrea and Brunetti, Maura and Van Damme, Philip and Robberecht, Wim and Hardiman, Orla and McLaughlin, Russell and Chi{\`o}, Adriano and Sendtner, Michael and Ludolph, Albert C. and Weishaupt, Jochen H. and Pardina, Jesus S. Mora and van den Berg, Leonard H. and Veldink, Jan H.}, title = {Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-42091-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223686}, year = {2019}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61\%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.}, language = {en} } @article{DiehlSchmidLicataGoldhardtetal.2019, author = {Diehl-Schmid, Janine and Licata, Abigail and Goldhardt, Oliver and F{\"o}rstl, Hans and Yakushew, Igor and Otto, Markus and Anderl-Straub, Sarah and Beer, Ambros and Ludolph, Albert Christian and Landwehrmeyer, Georg Bernhard and Levin, Johannes and Danek, Adrian and Fliessbach, Klaus and Spottke, Annika and Fassbender, Klaus and Lyros, Epameinondas and Prudlo, Johannes and Krause, Bernd Joachim and Volk, Alexander and Edbauer, Dieter and Schroeter, Matthias Leopold and Drzezga, Alexander and Kornhuber, Johannes and Lauer, Martin and Grimmer, Timo}, title = {FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, organization = {FTLDc Study Group}, doi = {10.1038/s41398-019-0381-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225308}, year = {2019}, abstract = {C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.}, language = {en} } @phdthesis{Machwart2024, author = {Machwart, Khaled}, title = {Modulatorischer Einfluss von Levosimendan bei dem Isch{\"a}mie-Reperfusionsschaden auf die myokardiale Mitochondrienfunktion}, doi = {10.25972/OPUS-36102}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361021}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Studie untersuchte den Effekt von Levosimendan auf die mitochondriale Funktionen im Herzmuskel, insbesondere im Zusammenhang mit dem Isch{\"a}mie/Reperfusions-Schaden. Methoden: In der Studie wurde ein retrogrades Langendorff-Modell verwendet, um die Auswirkungen von Levosimendan, dem Isch{\"a}mie/Reperfusions-Schaden sowie deren Kombination auf die mitochondrialen Funktionen im Herzmuskel zu untersuchen. Dazu wurden vier verschiedene Gruppen von Rattenherzen entsprechend den experimentellen Bedingungen perfundiert, und ihre Funktionen wurden analysiert. Ergebnisse: Der Isch{\"a}mie/Reperfusions-Schaden beeintr{\"a}chtigte die myokardiale Ventrikelfunktion. Zus{\"a}tzlich wurde eine Hypopolarisation des mithochondrialen Membranpotentials in den mit Levosimendan oder Isch{\"a}mie behandelten Gruppen festgestellt. Die ATP-Synthese in den Gruppen mit Levosimendan und Isch{\"a}mie war reduziert. Schlussfolgerung: Levosimendan zeigt signifikante Einfl{\"u}sse auf die Atmungsfunktion der mitochondrialen Komplexe IV und V sowie auf das Membranpotential. Diese Ph{\"a}nomene k{\"o}nnten einem mito-K+ ATP-abh{\"a}ngigen Mechanismus zugrunde liegen. Obwohl Levosimendan w{\"a}hrend des Isch{\"a}mie/Reperfusionsschadens eine protektive Wirkung hinsichtlich einer Ca2+- {\"U}berlastung aufweist, bleibt der kumulative Einfluss der beeintr{\"a}chtigten ATP-Generierung auf die gesamte Myokardfunktion zu kl{\"a}ren.}, subject = {Isch{\"a}mie}, language = {de} } @phdthesis{Scheiner2024, author = {Scheiner, Christin}, title = {Vulnerability in adolescence: prevalence, pandemic impact and prevention}, doi = {10.25972/OPUS-35164}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351644}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {This compilation focuses on adolescent mental disorders and their prevention. It comprises three distinct studies, each contributing to a deeper understanding of this critical topic. This work addresses a critical gap in the understanding of, and approach to, adolescent mental health, and as a result reveals a critically important and urgently needed policy implication for action. The thematic structure of these studies begins with an examination of the epidemiology of child and adolescent mental disorders. Baseline data were collected from N = 877 adolescents with a mean age of 12.43 years (SD = 0.65). Mental health problems, such as depressive symptoms, non-suicidal self-injury, suicidal ideation, symptoms of eating disorders, and gender differences, are thoroughly examined. Results revealed a significant portion of our sample displaying mental health problems as early as the 6th and 7th grades, with girls generally being more affected than boys. The findings underscore the importance of early adolescence in the emergence of mental health problems and thereby emphasize the need for preventive measures. Moving beyond prevalence estimates, the compilation delves into the etiology of these disorders, exploring their potential correlation with a COVID-19 infection. Understanding the early signs and risk factors is crucial for timely support. While numerous studies have investigated potential risk and protective factors during the pandemic, our focus shifts to adolescents' coping when an infection with the virus was involved (N = 2,154, M = 12.31, SD = 0.67). We hypothesized that students infected or with close family members infected, would exhibit an increased psychopathology and a decreased functioning of protective factors such as self-efficacy or self-esteem. We found no connection between infection and the mental health status within our sample, but protective factors and mental well-being were positively associated. Thus, universal primary prevention appears to be the preferred approach for promoting mental health. Lastly, the compilation introduces LessStress, a noteworthy contribution to more evidence-based prevention programs. This universal approach is designed to reduce stress in schools, accompanied by a cluster-randomized trial to evaluate its effectiveness (estimated sample size N = 1,894). Existing studies have demonstrated the effectiveness of stress prevention, leading us to introduce a short and easy-to-implement prevention program. There is positive evidence for one-lesson interventions in schools for promoting well-being and health behaviors among adolescents. LessStress is designed based on a life skills approach that not only imparts psychoeducational content but also teaches skills relevant to everyday life and directly applicable. Throughout these studies, a common thread emerges: the pressing need to address mental disorders during childhood and adolescence. These formative years play a pivotal role in the development of mental health problems. These formative years play a crucial role in the development of mental health problems. They highlight the importance of epidemiological data collection and analysis based on the latest models to develop prevention interventions that are not only effective but also reach young people on a global level.}, subject = {Jugend}, language = {en} } @unpublished{HennigPrustyKauferetal.2022, author = {Hennig, Thomas and Prusty, Archana B. and Kaufer, Benedikt and Whisnant, Adam W. and Lodha, Manivel and Enders, Antje and Thomas, Julius and Kasimir, Francesca and Grothey, Arnhild and Herb, Stefanie and J{\"u}rges, Christopher and Meister, Gunter and Erhard, Florian and D{\"o}lken, Lars and Prusty, Bhupesh K.}, title = {Selective inhibition of miRNA 1 processing by a herpesvirus encoded miRNA}, edition = {accepted version}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267862}, year = {2022}, abstract = {Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily drugable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.}, language = {en} } @article{HartmannKnierimMaureretal.2023, author = {Hartmann, Nico and Knierim, Maria and Maurer, Wiebke and Dybkova, Nataliya and Hasenfuß, Gerd and Sossalla, Samuel and Streckfuss-B{\"o}meke, Katrin}, title = {Molecular and functional relevance of Na\(_V\)1.8-induced atrial arrhythmogenic triggers in a human SCN10A knock-out stem cell model}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {12}, issn = {1422-0067}, doi = {10.3390/ijms241210189}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362708}, year = {2023}, abstract = {In heart failure and atrial fibrillation, a persistent Na\(^+\) current (I\(_{NaL}\)) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na\(_V\)1.8 contributes to arrhythmogenesis by inducing a I\(_{NaL}\). Genome-wide association studies indicate that mutations in the SCN10A gene (Na\(_V\)1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na\(_V\)1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I\(_{NaL}\) and action potential duration. Ca\(^{2+}\) measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca\(^{2+}\) leak. The I\(_{NaL}\) was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na\(_V\)1.8. No effects on atrial APD\(_{90}\) were detected in any groups. Both SCN10A KO and specific blockers of Na\(_V\)1.8 led to decreased Ca\(^{2+}\) spark frequency and a significant reduction of arrhythmogenic Ca\(^{2+}\) waves. Our experiments demonstrate that Na\(_V\)1.8 contributes to I\(_{NaL}\) formation in human atrial CMs and that Na\(_V\)1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na\(_V\)1.8 could be a new target for antiarrhythmic strategies.}, language = {en} } @article{EwaldFuchsBoegeleinetal.2023, author = {Ewald, Andrea and Fuchs, Andreas and Boegelein, Lasse and Grunz, Jan-Peter and Kneist, Karl and Gbureck, Uwe and Hoelscher-Doht, Stefanie}, title = {Degradation and bone-contact biocompatibility of two drillable magnesium phosphate bone cements in an in vivo rabbit bone defect model}, series = {Materials}, volume = {16}, journal = {Materials}, number = {13}, issn = {1996-1944}, doi = {10.3390/ma16134650}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362824}, year = {2023}, abstract = {The use of bone-cement-enforced osteosynthesis is a growing topic in trauma surgery. In this context, drillability is a desirable feature for cements that can improve fracture stability, which most of the available cement systems lack. Therefore, in this study, we evaluated a resorbable and drillable magnesium-phosphate (MgP)-based cement paste considering degradation behavior and biocompatibility in vivo. Two different magnesium-phosphate-based cement (MPC) pastes with different amounts of phytic acid (IP 6) as setting retarder (MPC 22.5 and MPC 25) were implanted in an orthotopic defect model of the lateral femoral condyle of New Zealand white rabbits for 6 weeks. After explantation, their resorption behavior and material characteristics were evaluated by means of X-ray diffraction (XRD), porosimetry measurement, histological staining, peripheral quantitative computed tomography (pQCT), cone-beam computed tomography (CBCT) and biomechanical load-to-failure tests. Both cement pastes displayed comparable results in mechanical strength and resorption kinetics. Bone-contact biocompatibility was excellent without any signs of inflammation. Initial resorption and bone remodeling could be observed. MPC pastes with IP 6 as setting retardant have the potential to be a valuable alternative in distinct fracture patterns. Drillability, promising resorption potential and high mechanical strength confirm their suitability for use in clinical routine.}, language = {en} } @article{HeinzWildEidmannetal.2023, author = {Heinz, Tizian and Wild, Moritz and Eidmann, Annette and Weißenberger, Manuel and Rak, Dominik and Nedopil, Alexander Johannes and Rudert, Maximilian and Stratos, Ioannis}, title = {Impact of COVID-19 on fracture incidence in germany: a comparative age and gender analysis of pre- and post-outbreak periods}, series = {Healthcare}, volume = {11}, journal = {Healthcare}, number = {15}, issn = {2227-9032}, doi = {10.3390/healthcare11152139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362686}, year = {2023}, abstract = {In March 2020, Germany imposed a nationwide lockdown to curb the spread of COVID-19, prompting questions about the impact on the incidence of common fractures. This study examined 15 fracture types in pre-outbreak (2010-2019) and post-outbreak (2020-2021) periods, using data categorized by age (18-64 years, 65 years) and sex (male, female). Linear regression assessed annual growth rates, and mean fracture numbers were compared across periods for significant differences. Results indicated a positive correlation between fracture incidence rates and time for various types, such as cervical, thoracic, lumbar, and pelvic spine fractures, rib fractures, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures. Frequencies of proximal humerus, distal radius, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures in 2020 and 2021 were within predicted ranges from previous years. However, rib fractures and spinal fractures (cervical, thoracic, lumbar, and pelvic spine) occurred less frequently during this time. Notably, this study found a consistent decline in most fracture types for individuals aged 18-64 after the pandemic's onset, while the fracture incidence of hip fractures, often referred to as fragility fractures, for those over 65 remained unchanged. Fibula fractures showed the most considerable decrease in both age groups. In conclusion, the COVID-19 pandemic substantially impacted fracture incidence, with lower rates among individuals under 65 and unchanged fragility fractures in the elderly population.}, language = {en} } @article{EidmannHeinzOberfeldetal.2023, author = {Eidmann, Annette and Heinz, Tizian and Oberfeld, Jan and Weißenberger, Manuel and Rudert, Maximilian and Stratos, Ioannis}, title = {Epidemiology and trends in cartilage surgery of the foot and ankle in Germany: an analysis of national healthcare billing and reporting data from 2006 to 2020}, series = {Medicina}, volume = {59}, journal = {Medicina}, number = {7}, issn = {1648-9144}, doi = {10.3390/medicina59071256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362835}, year = {2023}, abstract = {Background and objectives: Cartilage surgery constitutes a standard intervention in foot and ankle procedures. Currently, there is a lack of epidemiological data on its frequency, age distribution, and surgical options for cartilage surgery. This study aimed to investigate the current landscape of cartilage surgery in Germany and identify the most common procedures from an epidemiological standpoint. Materials and methods: Medical billing and reporting data from the Federal Statistical Office of Germany, encompassing the period 2006-2020, was examined, including all foot and ankle cartilage surgical procedures (summarized under OPS codes 5-812 and 5-801). The dataset incorporated information on the affected joint, patient age and sex, and surgery type. Each surgical procedure was categorized as "debridement", "regeneration" or "refixation". Linear and nonlinear regression analyses were employed, with a statistical significance threshold of 0.05. Results: From the total of 136,501 procedures conducted during the study period, the most frequently performed interventions were microfracture (58,252) and chondroplasty (56,135), and thus, debridement procedures were in the leading position. The use of acellular membranes was the most used regenerative technique (n = 11,414). At the ankle joint, interventions were mostly arthroscopic and in men, while foot cartilage surgeries were preferably performed via open surgery and mostly in women. Age distribution analysis revealed two primary peaks: the first in the 20-25-year-old group (ankle and foot) and the second in the 45-50-year-old group (ankle) and 55-60-year-old group (foot). Refixation and regenerative procedures were more frequent among younger individuals, while debriding procedures were more frequent among older individuals. Regenerative procedures, particularly in the ankle, significantly increased over time. Conclusions: Cartilage surgery of the foot and ankle was common, with two primary age groups predominantly affected. Notably, recent years have witnessed a considerable rise in cartilage regenerative procedures.}, language = {en} } @phdthesis{Dereser2024, author = {Dereser, Katharina}, title = {Real World Next Generation M³P Panel-Sequenzierung f{\"u}r die personalisierte Therapie des Multiplen Myeloms}, doi = {10.25972/OPUS-35264}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352644}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Obwohl es in den letzten 10-15 Jahren gelang, multiple MM-Genome mittels NGS auf eine kosteneffiziente Art und mit geringem Zeit- und Materialaufwand zu sequenzieren und hierdurch zum Teil bahnbrechende Erkenntnisse gewonnen werden konnten, sind molekulargenetische Untersuchungen im diagnostischen Workflow des MMs bisher nicht ausreichend implementiert, um eine personalisierte Therapieentscheidung zu erm{\"o}glichen. Vor diesem Hintergrund wurde in der vorliegenden Arbeit eine Gruppe an Patienten mit NDMM und RRMM anhand klinischer Parameter charakterisiert und durch Verwendung des M³P-Panels auf das Vorliegen bestimmter molekulargenetischer Ver{\"a}nderungen untersucht. Zusammenfassend l{\"a}sst sich sagen, dass unsere Analyse die bisher ver{\"o}ffentliche M³P-Pr{\"a}valenz in MM-Tumorproben best{\"a}tigt. Zu den am h{\"a}ufigsten mutierten Genen geh{\"o}rten KRAS, NRAS, DIS3, ATM und BRAF. In der Gruppe der Patienten mit NRAS-Mutation oder del17p war die Zahl der relevanten Mutationen deutlich h{\"o}her als ohne Vorliegen der entsprechenden Ver{\"a}nderung. Der Nachweis eines Double-Hit-Myeloms war erwartungsgem{\"a}ß der st{\"a}rkste ung{\"u}nstige Faktor in unserer Kohorte. Unter den Patienten mit CRBN-Mutation waren alle IMiD-vorbehandelt und zeigten im Verlauf eine Refrakt{\"a}rit{\"a}t gegen{\"u}ber dieser Substanzgruppe auf. Bez{\"u}glich der {\"U}berlebensanalysen best{\"a}tigten unsere Ergebnisse bereits bekannte prognostische Risikofaktoren wie Hochrisikozytogenetik, insbesondere del17p und gain1q, eine TP53-Mutation sowie ISS- und R-ISS-Stadium III. Die Ergebnisse der Mutationsanalysen dieser Arbeit verdeutlichen den großen wissenschaftlichen und therapeutischen Nutzen, der von molekulargenetischen Untersuchungen ausgeht. Zuk{\"u}nftig werden auch beim MM Therapieentscheidungen auf Grundlage genetischer Diagnostik getroffen werden, mit dem Ziel die Behandlung f{\"u}r MM-Patienten weiter zu verbessern.}, subject = {Plasmozytom}, language = {de} } @phdthesis{MeyerSautter2024, author = {Meyer-Sautter, Pascal Willy}, title = {Evaluation der postoperativen empirischen antibiotischen Therapie intraabdomineller Infektionen aus Sicht des Antimicrobical Stewardships (AMS)}, doi = {10.25972/OPUS-35920}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359201}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziele: Das Ziel dieser Dissertation ist es, die empirischen antibiotische Therapien (PAT) bei komplizierten intraabdominellen Infektionen (cIAI) in den Jahren 2016 - 2018 in einem großen deutschen Maximalversorger zu evaluieren. Aktuelle Studien legen nahe, dass viele Patienten keine Nachteile durch k{\"u}rzere Therapien mit schmaler wirksamen Antibiotika oder das vermeiden einer nicht notwendigen antibiotischen Therapie haben. Methoden: Es wurde eine retrospektive Kohortenstudie durch Analyse von elektronischen Patientenakten an einem 1500-Betten-Universit{\"a}tsklinikum in Deutschland durchgef{\"u}hrt, bei der die Dauer der Antibiotikatherapie nach Notfalloperationen erhoben und mit antibiotischen Leitlinien durch die hausinterne Antibiotic-Stewardship-Abteilung (AMS) verglichen. Ergebnisse: 767 Patienten konnten eingeschlossen werden, davon erhielten 404 (52.7\%) eine PAT. Die Gesamtanzahl der Therapietage pro 100 Patiententagen ging von 47,0 auf 42,2 Tage zur{\"u}ck (p = 0,035) ohne einen Anstieg an Komplikationen. Patienten ohne Sepsis, bei denen eine initiale chirurgischer Fokuskontrolle m{\"o}glich war profitierten nicht von einer Therapiedauer {\"u}ber 4 Tage (160 vs 100 Patienten). Bei Patienten, bei denen diese Bedingungen nicht gegeben waren, zeigte sich ebenfalls kein Vorteil bei l{\"a}ngeren Behandlungen ({\"u}ber >7 Tage, 74 lang vs. 32 kurz behandelte Patienten). Es zeigte sich ebenfalls kein Vorteil von empirischen Therapien mit Carbapenem statt mit Piperacillin-Tazobactam (n=51 C vs n=40 vs Pip/Taz). Schlussfolgerung: Die Reduktion unn{\"o}tiger, zu breiter und zu langer antibiotischer Therapien bei cIAI ist ohne einen Anstieg der postoperativen Komplikationen m{\"o}glich. Weitere RCTs sind notwendig, um das Wissen um sichere Behandlungen zu vergr{\"o}ßern.}, subject = {Bakterielle Infektion}, language = {de} } @phdthesis{Kusan2024, author = {Kusan, Simon Ferdinand}, title = {Keimspektrum und antibiotische Therapie bei Morbus Crohn-assoziierten Abszessen : Eine retrospektive monozentrische Analyse}, doi = {10.25972/OPUS-35946}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359467}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser monozentrischen retrospektiven Analyse wurde das Keimspektrum und die antibiotische Therapie bei Morbus Crohn- assoziierten Abszessen untersucht.}, subject = {Antibiotikum}, language = {de} } @phdthesis{Knorr2024, author = {Knorr, Susanne}, title = {Pathophysiology of early-onset isolated dystonia in a DYT-TOR1A rat model with trauma-induced dystonia-like movements}, doi = {10.25972/OPUS-20609}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206096}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Early-onset torsion dystonia (DYT-TOR1A, DYT1) is an inherited hyperkinetic movement disorder caused by a mutation of the TOR1A gene encoding the torsinA protein. DYT-TOR1A is characterized as a network disorder of the central nervous system (CNS), including predominantly the cortico-basal ganglia-thalamo-cortical loop resulting in a severe generalized dystonic phenotype. The pathophysiology of DYTTOR1A is not fully understood. Molecular levels up to large-scale network levels of the CNS are suggested to be affected in the pathophysiology of DYT-TOR1A. The reduced penetrance of 30\% - 40\% indicates a gene-environmental interaction, hypothesized as "second hit". The lack of appropriate and phenotypic DYT-TOR1A animal models encouraged us to verify the "second hit" hypothesis through a unilateral peripheral nerve trauma of the sciatic nerve in a transgenic asymptomatic DYT-TOR1A rat model (∆ETorA), overexpressing the human mutated torsinA protein. In a multiscale approach, this animal model was characterized phenotypically and pathophysiologically. Nerve-injured ∆ETorA rats revealed dystonia-like movements (DLM) with a partially generalized phenotype. A physiomarker of human dystonia, describing increased theta oscillation in the globus pallidus internus (GPi), was found in the entopeduncular nucleus (EP), the rodent equivalent to the human GPi, of nerve-injured ∆ETorA rats. Altered oscillation patterns were also observed in the primary motor cortex. Highfrequency stimulation (HFS) of the EP reduced DLM and modulated altered oscillatory activity in the EP and primary motor cortex in nerve-injured ∆ETorA rats. Moreover, the dopaminergic system in ∆ETorA rats demonstrated a significant increased striatal dopamine release and dopamine turnover. Whole transcriptome analysis revealed differentially expressed genes of the circadian clock and the energy metabolism, thereby pointing towards novel, putative pathways in the pathophysiology of DYTTOR1A dystonia. In summary, peripheral nerve trauma can trigger DLM in genetically predisposed asymptomatic ΔETorA rats leading to neurobiological alteration in the central motor network on multiple levels and thereby supporting the "second hit" hypothesis. This novel symptomatic DYT-TOR1A rat model, based on a DYT-TOR1A genetic background, may prove as a valuable chance for DYT-TOR1A dystonia, to further investigate the pathomechanism in more detail and to establish new treatment strategies.}, subject = {Dystonie}, language = {en} } @phdthesis{PenaMosca2024, author = {Pe{\~n}a Mosca, Mar{\´i}a Josefina}, title = {Local regulation of T-cell immunity in the intestinal mucosa}, doi = {10.25972/OPUS-35266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352665}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {After priming in Peyer's patches (PPs) and mesenteric lymph nodes (mLN) T- cells infiltrate the intestine through lymphatic draining and homing through the bloodstream. However, we found that in mouse models of acute graft-versus-host disease (GvHD), a subset of alloreactive T-cells directly migrates from PPs to the adjacent intestinal lamina propria (LP), bypassing the normal lymphatic drainage and vascular trafficking routes. Notably, this direct migration occurred in irradiated and unirradiated GvHD models, indicating that irradiation is not a prerequisite for this observed behavior. Next, we established a method termed serial intravascular staining (SIVS) in mouse models to systematically investigate the trafficking and migration of donor T- cells in the early stages of acute GvHD initiation. We found that the direct migration of T-cells from PPs to LP resulted in faster recruitment of cells after allogeneic hematopoietic cell transplantation (allo-HCT). These directly migrating T-cells were found to be in an activated and proliferative state, exhibiting a TH1/TH17-like phenotype and producing cytokines such as IFN-γ and TNF-α. Furthermore, we observed that the directly migrating alloreactive T-cells expressed specific integrins (α4+, αE+) and chemokine receptors (CxCR3+, CCR5+, and CCR9+). Surprisingly, blocking these integrins and chemokine-coupled receptors did not hinder the direct migration of T- cells from PPs to LP, suggesting the involvement of alternative mechanisms. Previous experiments ruled out the involvement of S1PR1 and topographical features of macrophages, leading us to hypothesize that mediators of cytoskeleton reorganization, such as Coro1a, Dock2, or Cdc42, may play a role in this unique migration process. Additionally, we observed that directly migrating T-cells created a local inflammatory microenvironment, which attracts circulating T-cells. Histological analysis confirmed that alloreactive PPs-derived T-cells and bloodborne T-cells colocalized. We employed two experimental approaches, including either photoconversion of T-cells in PPs or direct transfer of activated T-cells into the vasculature, to demonstrate this colocalization. We hypothesize that cytokines released by migrating T-cells, such as IFN-γ and TNF-α, may play a role in recruiting T-cells from the vasculature, as inhibiting chemokine-coupled receptors did not impair recruitment.}, subject = {T-Lymphozyt}, language = {en} } @article{RighessoTerekhovGoetzetal.2021, author = {Righesso, L. A. R. and Terekhov, M. and G{\"o}tz, H. and Ackermann, M. and Emrich, T. and Schreiber, L. M. and M{\"u}ller, W. E. G. and Jung, J. and Rojas, J. P. and Al-Nawas, B.}, title = {Dynamic contrast-enhanced magnetic resonance imaging for monitoring neovascularization during bone regeneration — a randomized in vivo study in rabbits}, series = {Clinical Oral Investigations}, volume = {25}, journal = {Clinical Oral Investigations}, number = {10}, issn = {1432-6981}, doi = {10.1007/s00784-021-03889-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307614}, pages = {5843-5854}, year = {2021}, abstract = {Objectives Micro-computed tomography (μ-CT) and histology, the current gold standard methods for assessing the formation of new bone and blood vessels, are invasive and/or destructive. With that in mind, a more conservative tool, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), was tested for its accuracy and reproducibility in monitoring neovascularization during bone regeneration. Additionally, the suitability of blood perfusion as a surrogate of the efficacy of osteoplastic materials was evaluated. Materials and methods Sixteen rabbits were used and equally divided into four groups, according to the time of euthanasia (2, 3, 4, and 6 weeks after surgery). The animals were submitted to two 8-mm craniotomies that were filled with blood or autogenous bone. Neovascularization was assessed in vivo through DCE-MRI, and bone regeneration, ex vivo, through μ-CT and histology. Results The defects could be consistently identified, and their blood perfusion measured through DCE-MRI, there being statistically significant differences within the blood clot group between 3 and 6 weeks (p = 0.029), and between the former and autogenous bone at six weeks (p = 0.017). Nonetheless, no significant correlations between DCE-MRI findings on neovascularization and μ-CT (r =-0.101, 95\% CI [-0.445; 0.268]) or histology (r = 0.305, 95\% CI [-0.133; 0.644]) findings on bone regeneration were observed. Conclusions These results support the hypothesis that DCE-MRI can be used to monitor neovascularization but contradict the premise that it could predict bone regeneration as well.}, language = {en} } @article{LenzPahlHaucketal.2021, author = {Lenz, Dominic and Pahl, Jens and Hauck, Fabian and Alameer, Seham and Balasubramanian, Meena and Baric, Ivo and Boy, Nikolas and Church, Joseph A. and Crushell, Ellen and Dick, Anke and Distelmaier, Felix and Gujar, Jidnyasa and Indolfi, Giuseppe and Lurz, Eberhard and Peters, Bianca and Schwerd, Tobias and Serranti, Daniele and K{\"o}lker, Stefan and Klein, Christoph and Hoffmann, Georg F. and Prokisch, Holger and Greil, Johann and Cerwenka, Adelheid and Giese, Thomas and Staufner, Christian}, title = {NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency}, series = {Journal of Clinical Immunology}, volume = {41}, journal = {Journal of Clinical Immunology}, number = {8}, issn = {0271-9142}, doi = {10.1007/s10875-021-01110-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308362}, pages = {1781-1793}, year = {2021}, abstract = {Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell-intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of na{\"i}ve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.}, language = {en} } @article{EstradaKrebbersVossetal.2018, author = {Estrada, Veronica and Krebbers, Julia and Voss, Christian and Brazda, Nicole and Blazyca, Heinrich and Illgen, Jennifer and Seide, Klaus and J{\"u}rgens, Christian and M{\"u}ller, J{\"o}rg and Martini, Rudolf and Trieu, Hoc Khiem and M{\"u}ller, Hans Werner}, title = {Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, doi = {10.1038/s42003-018-0210-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227357}, year = {2018}, abstract = {Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.}, language = {en} } @article{HollaenderSchwenderBoehmeetal.2021, author = {Holl{\"a}nder, Olivia and Schwender, Kristina and B{\"o}hme, Petra and Fleckhaus, Jan and Haas, Cordula and Han, Yang and Heidorn, Frank and Klein-Unseld, Rachel and Lichtenwald, Julia and Naue, Jana and Neubauer, Jacqueline and Poetsch, Micaela and Schneider, Peter M. and Wagner, Wolfgang and Vennemann, Marielle}, title = {Forensische DNA-Methylierungsanalyse}, series = {Rechtsmedizin}, volume = {31}, journal = {Rechtsmedizin}, number = {3}, organization = {Arbeitsgemeinschaft Molekulare Alterssch{\"a}tzung der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM)}, issn = {0937-9819}, doi = {10.1007/s00194-021-00492-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307131}, pages = {192-201}, year = {2021}, abstract = {Die quantitative Analyse der relativen DNA-Methylierung gilt als eine der vielversprechendsten Methoden der molekularen Alterssch{\"a}tzung. Viele Studien der letzten Jahre identifizierten geeignete Positionen im Genom, deren DNA-Methylierung sich altersabh{\"a}ngig ver{\"a}ndert. F{\"u}r den Einsatz dieser Methode in der Routine- bzw. Fallarbeit ist es von großer Bedeutung, angewandte Analysetechniken zu validieren. Als ein Teilaspekt dieser Validierung sollte die Vergleichbarkeit der Analyseergebnisse zur DNA-Methylierung mithilfe der Mini- und Pyrosequenzierung zwischen verschiedenen Laboren evaluiert werden. Die Arbeitsgruppe „Molekulare Alterssch{\"a}tzung" der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM) f{\"u}hrte hierzu den ersten, technischen Ringversuch durch, der 4 Positionen in den Genen PDE4C, EDARADD, SST und KLF14 umfasste. Diese Marker waren in vorangegangenen Studien als altersabh{\"a}ngige Biomarker charakterisiert worden. Am Ringversuch nahmen 12 Labore teil, wobei jedes die Wahl zwischen der Minisequenzierung und/oder der Pyrosequenzierung f{\"u}r die quantitative Methylierungsanalyse hatte. Jedem teilnehmenden Labor wurden Blut- und Speichelproben von 3 Personen unterschiedlichen Alters {\"u}bersandt. Die Wahl der Reagenzien f{\"u}r die Probenbearbeitung wurde den Teilnehmern freigestellt. Die Ergebnisse der Minisequenzierung zeigten systematische Abweichungen zwischen den Laboren, die am ehesten auf die Verwendung unterschiedlicher Reagenzien und Analyseplattformen zur{\"u}ckzuf{\"u}hren sein k{\"o}nnen. Die Resultate der Pyrosequenzierung hingegen wiesen nicht auf systematische Abweichungen zwischen den Laboren hin, hier zeigte sich jedoch die Tendenz einer markerabh{\"a}ngigen Abweichung. Dar{\"u}ber hinaus konnten Unterschiede hinsichtlich technischer Probleme zwischen Laboren mit mehr Erfahrung in der jeweiligen Sequenzierungsmethode und Laboren mit weniger Erfahrung festgestellt werden. Sowohl die Beobachtung von systematischen als auch die von markerabh{\"a}ngigen Abweichungen l{\"a}sst den Schluss zu, dass eine {\"U}bertragung von Analysemethoden zwischen Laboren grunds{\"a}tzlich m{\"o}glich ist, eine Anpassung des jeweiligen Modells zur Alterssch{\"a}tzung jedoch notwendig sein kann.}, language = {de} } @article{ElMeseryRosenthalRauertWunderlichetal.2019, author = {El-Mesery, Mohamed and Rosenthal, Tina and Rauert-Wunderlich, Hilka and Schreder, Martin and St{\"u}hmer, Thorsten and Leich, Ellen and Schlosser, Andreas and Ehrenschwender, Martin and Wajant, Harald and Siegmund, Daniela}, title = {The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1860-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226666}, year = {2019}, abstract = {The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.}, language = {en} } @article{AdolphFleischhackGaabetal.2021, author = {Adolph, Jonas E. and Fleischhack, Gudrun and Gaab, Christine and Mikasch, Ruth and Mynarek, Martin and Rutkowski, Stefan and Sch{\"u}ller, Ulrich and Pfister, Stefan M. and Pajtler, Kristian W. and Milde, Till and Witt, Olaf and Bison, Brigitte and Warmuth-Metz, Monika and Kortmann, Rolf-Dieter and Dietzsch, Stefan and Pietsch, Torsten and Timmermann, Beate and Tippelt, Stephan}, title = {Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies}, series = {Journal of Neuro-Oncology}, volume = {155}, journal = {Journal of Neuro-Oncology}, number = {2}, organization = {German GPOH HIT-Network}, issn = {0167-594X}, doi = {10.1007/s11060-021-03867-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308302}, pages = {193-202}, year = {2021}, abstract = {Purpose Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. Methods Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. Results Median age at first recurrence was 7.6 years (IQR: 4.0-13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3-20.0) and 36.9 months (CI 29.7-53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74-1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50\%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. Conclusion No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.}, language = {en} } @article{DornquastReinholdSolaketal.2022, author = {Dornquast, Christina and Reinhold, Thomas and Solak, Saliha and Durak, Melike and Becher, Heiko and Riens, Burgi and Icke, Katja and Danquah, Ina and Willich, Stefan N. and Keil, Thomas and Krist, Lilian}, title = {Strategies to Enhance Retention in a Cohort Study Among Adults of Turkish Descent Living in Berlin}, series = {Journal of Immigrant and Minority Health}, volume = {24}, journal = {Journal of Immigrant and Minority Health}, number = {5}, doi = {10.1007/s10903-021-01309-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-344776}, pages = {1309-1317}, year = {2022}, abstract = {Retention is important for statistical power and external validity in long-term cohort studies. The aims of our study were to evaluate different retention strategies within a cohort study of adults of Turkish descent in Berlin, Germany, and to compare participants and non-participants. In 2011-2012, a population-based study was conducted among adults of Turkish descent to primarily examine recruitment strategies. 6 years later, the participants were re-contacted and invited to complete a self-report questionnaire regarding their health status, health care utilization, and satisfaction with medical services. The retention strategy comprised letters in both German and Turkish, phone calls, and home visits (by bilingual staff). We calculated the response rate and retention rate, using definitions of the American Association for Public Opinion Research, as well as the relative retention rate for each level of contact. Associations of baseline recruitment strategy, sociodemographic, migration-related and health-related factors with retention were investigated by logistic regression analysis. Of 557 persons contacted, 249 (44.7\%) completed the questionnaire. This was 50.1\% of those whose contact information was available. The relative retention rate was lowest for phone calls (8.9\%) and highest for home visits (18.4\%). Participants were more often non-smokers and German citizens than non-participants. For all remaining factors, no association with retention was found. In this study, among adults of Turkish descent, the retention rate increased considerably with every additional level of contact. Implementation of comprehensive retention strategies provided by culturally matched study personnel may lead to higher validity and statistical power in studies on migrant health issues.}, language = {en} } @article{AmerellerDeutschbeinJoshietal.2022, author = {Amereller, Felix and Deutschbein, Timo and Joshi, Mamta and Schopohl, Jochen and Schilbach, Katharina and Detomas, Mario and Duffy, Leo and Carroll, Paul and Papa, Sophie and St{\"o}rmann, Sylv{\`e}re}, title = {Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study}, series = {Pituitary}, volume = {25}, journal = {Pituitary}, number = {1}, issn = {1386-341X}, doi = {10.1007/s11102-021-01182-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308704}, pages = {152-158}, year = {2022}, abstract = {Objective Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH) Design Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH. Methods All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected. Results Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 \% of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002). Conclusions Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.}, language = {en} } @article{DietrichKrugKrastletal.2019, author = {Dietrich, Thomas and Krug, Ralf and Krastl, Gabriel and Tomson, Philip L.}, title = {Restoring the unrestorable! Developing coronal tooth tissue with a minimally invasive surgical extrusion technique}, series = {British Dental Journal}, volume = {226}, journal = {British Dental Journal}, doi = {10.1038/s41415-019-0268-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225333}, pages = {789-793}, year = {2019}, abstract = {Surgical extrusion is a recognised treatment option for teeth that have insufficient coronal tooth structure remaining due to deep caries, resorption or traumatic injury. However, the technique has not been widely adopted, arguably because extraction of a severely compromised tooth may be difficult to achieve in a gentle and predictable way. In this paper, we present our novel approach to surgical extrusion and subsequent management of teeth using a vertical extraction system (Benex), which has become the method of choice in the authors' practice for many teeth that would otherwise be deemed unrestorable. We describe the clinical procedure in detail and discuss the advantages and disadvantages compared to alternative approaches, including surgical crown lengthening and orthodontic extrusion.}, language = {en} } @phdthesis{Kruse2024, author = {Kruse, Daniel}, title = {Quantitative Analyse histologischer Aufnahmen der Haut}, doi = {10.25972/OPUS-35294}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352946}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Diese Arbeit hatte zum Ziel quantitative Analysen histologischer Aufnahmen der Haut nach unterschiedlichen Gesichtspunkten zu etablieren. Im ersten Abschnitt wurde die bildgest{\"u}tzte Quantifizierung der epidermalen Histomorphologie untersucht. Nach Sichtung und Beurteilung von 2145 hochaufl{\"o}senden Fotografien HE-gef{\"a}rbter Epidermis- und Vollhautmodellen jeglichen Zustands, wurde der BSGC-Score als Facettenklassifikation mit seinen insgesamt 40 Beurteilungskriterien aufgestellt. Die unterschiedlichen epidermalen Strata wurden mit Wichtungsfaktoren belegt. Die Bewertungskategorien sind mit einem Ampelsystem unterlegt. Eine Befundungsformel wurde aufgestellt. Weitere Bestandteile des BSGC-Scores sind eine Anleitung mit Bildbeilage sowie Dokumentationselemente. Die Anwendung erfolgte erfolgreich im Rahmen der Qualit{\"a}tssicherung an Chargentests und zur Verlaufsbeurteilung eines In-vitro-Verbrennungsmodells aus humaner Epidermis durch Schneider et al. (2021) Der BSGC-Score dient als z{\"u}gig durchf{\"u}hrbares Evaluationstool zur Befundung von In-vitro-Epidermismodellen und nicht als diagnostisches Mittel. Der zweite Abschnitt besch{\"a}ftigt sich mit der Vaskularisierung als Parameter der kutanen Wundheilung. Es wurden aSMA-IF-gef{\"a}rbte Abbildungen porciner Verwundungsmodelle betrachtet und nach der Entfernung dr{\"u}siger Strukturen Gef{\"a}ßanschnitte zu Beginn manuell ausgez{\"a}hlt. Hieraus wurden die n{\"o}tigen Einstellungen f{\"u}r die Bildbearbeitungssoftware ImageJ ermittelt und die Abbildungen dieser anschließend zugef{\"u}hrt. Es erfolgte die automatisierte Quantifizierung elliptischer Formationen mit einer Gr{\"o}ße ≥ 30 Pixel. Im n{\"a}chsten Schritt wurden die Abbildungen in die Bereiche Wundrand, Wundgrund und Wundheilung unterteilt. In dem Bereich Wundheilung zeigte sich eine signifikant gr{\"o}ßere Revaskularisierung als in Wundgrund. Abschließend erfolgte der Vergleich sekund{\"a}rer Wundauflagen. Der Vergleich der Quotienten Wundheilung/Wundgrund nicht-okklusiver und okklusiver Wundauflagen zeigte keinen signifikanten Unterschied in der Neovaskularisierung. Die isolierte Betrachtung der Revaskularisierung als einzelner Prozess der Wundheilung kann nicht als generelles Kriterium f{\"u}r die Gesamtbeurteilung dienen. Hier findet die gew{\"a}hlte Methodik ihre Limitation. Zuk{\"u}nftige Anwendungsbereiche des BSGC-Scores sind die Ausweitung auf Vollhautmodelle und andere Verwundungsmodalit{\"a}ten. Eine automatisierte und durch eine KI-gest{\"u}tzte Befundung ist ebenfalls aufgrund des zugrundeliegenden umfangreichen Datensatzes denkbar. Auch kann eine automatisierte softwaregest{\"u}tzte Quantifizierung der Vaskularisierung als {\"u}berblickende und z{\"u}gige Beurteilung der Wundheilung sinnvoll erscheinen.}, subject = {Wundheilung}, language = {de} } @phdthesis{RombachgebGrosso2024, author = {Rombach [geb. Grosso], Franziska}, title = {Der Interaktionsrezeptor des Masernvirus auf h{\"a}matopoetischen Zellen}, doi = {10.25972/OPUS-35339}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-353394}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Masernvirus (MV) kann in Erkrankten eine schwere, langanhaltende Immunsuppression verursachen, wodurch Infektionen mit opportunistischen Pathogenen beg{\"u}nstigt werden. Diese basiert auf einer Paralyse der h{\"a}matopoetischen Zellen, welche das Virus durch Kontakt eines viralen Glykoproteinkomplexes zu einem unbekannten RezeptorX auf der Zell- Oberfl{\"a}che induzieren kann. Kerncharakterisitika hiervon sind unter anderem die Herabregulation der Akt-Kinase-Phosphorylierung, die Inhibition der zellul{\"a}ren Proliferation und die Aktivierung der neutralen Sphingomyelinase 2 (NSM2). In einem kinetischen Phosphoproteom konnten zwei potentielle Interaktionsrezeptoren des MV identifiziert werden: CD43 und P2X3. Das hochglykosylierte Oberfl{\"a}chenmolek{\"u}l CD43 ist auf h{\"a}matopoetischen Zellen ubiquit{\"a}r exprimiert und reguliert in T-Zellen deren {\"U}berleben, Proliferation, Aktivierung, Migration und Adh{\"a}sion. P2X3 wird in h{\"a}matopoetischen Zellen nur in geringem Maße exprimiert. Seine funktionelle Bedeutung ist in diesem Kompartiment nicht bekannt. Beide Kandidaten wurden mittels CRISPR/Cas9 Verfahren einzeln oder kombiniert aus Jurkat-T-Zellen ablatiert, welche nachfolgend nach MV-Kontakt hinsichtlich der oben erw{\"a}hnten MV-modulierten Parameter getestet wurden. Zus{\"a}tzlich wurden iso- und allosterische P2X3-Inhibitoren an prim{\"a}ren und Jurkat-T-Zellen verwendet, um dessen Rolle in Ca2+-Mobilisierung und Proliferation nach T-Zell-Rezeptor Co-Stimulation zu analysieren. Die genetische Depletion beider Rezeptor-Kandidaten verringerte die Effekte des MV auf alle getesteten Parameter signifikant, was darauf hindeutet, dass beide Proteine entscheidend an der T-Zell-Suppression beteiligt sind. W{\"a}hrend die isosterische Inhibition von P2X3 keinen Effekt hatte, wurde die Proliferation prim{\"a}rer T-Zellen durch dessen allosterische Inhibition vor Co-Stimulation fast verdoppelt und die Effizienz der Ca2+-Mobilisierung in Jurkat- und prim{\"a}ren T-Zellen signifikant erh{\"o}ht. In P2X3-depletierten Jurkat-Zellen hingegen war die Ca2+-Mobilisierung nach Stimulation signifikant geringer als in WT-Zellen. In dieser Arbeit konnten zwei wichtige Mediatoren der MV induzierten T-Zell-Suppression identifiziert werden. Vor allem P2X3, dessen Expression, Regulation und funktionelle Bedeutung im h{\"a}matopoetischen Kompartiment noch nicht erforscht wurde, k{\"o}nnte ein vielversprechender Kandidat f{\"u}r eine antivirale Therapie darstellen, da ein klinisch getesteter P2X3-Inhibitor bereits verf{\"u}gbar ist.}, subject = {Masernvirus}, language = {de} } @article{MerzenichBaakenSchmidtetal.2022, author = {Merzenich, Hiltrud and Baaken, Dan and Schmidt, Marcus and Bekes, Inga and Schwentner, Lukas and Janni, Wolfgang and Woeckel, Achim and Bartkowiak, Detlef and Wiegel, Thomas and Blettner, Maria and Wollschl{\"a}ger, Daniel and Schmidberger, Heinz}, title = {Cardiac late effects after modern 3D-conformal radiotherapy in breast cancer patients: a retrospective cohort study in Germany (ESCaRa)}, series = {Breast Cancer Research and Treatment}, volume = {191}, journal = {Breast Cancer Research and Treatment}, number = {1}, issn = {0167-6806}, doi = {10.1007/s10549-021-06412-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308606}, pages = {147-157}, year = {2022}, abstract = {Purpose Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques reduce radiation exposure of the heart, but some exposure remains unavoidable. In a retrospective cohort study, we investigated cardiac mortality and morbidity of breast cancer survivors treated with recent RT in Germany. Methods A total of 11,982 breast cancer patients treated between 1998 and 2008 were included. A mortality follow-up was conducted until 06/2018. In order to assess cardiac morbidity occurring after breast cancer treatment, a questionnaire was sent out in 2014 and 2019. The effect of breast cancer laterality on cardiac mortality and morbidity was investigated as a proxy for radiation exposure. We used Cox Proportional Hazards regression analysis, taking potential confounders into account. Results After a median follow-up time of 11.1 years, there was no significant association of tumor laterality with cardiac mortality in irradiated patients (hazard ratio (HR) for left-sided versus right-sided tumor 1.09; 95\% confidence interval (CI) 0.85-1.41). Furthermore, tumor laterality was not identified as a significant risk factor for cardiac morbidity (HR = 1.05; 95\%CI 0.88-1.25). Conclusions Even though RT for left-sided breast cancer on average incurs higher radiation dose to the heart than RT for right-sided tumors, we found no evidence that laterality is a strong risk factor for cardiac disease after contemporary RT. However, larger sample sizes, longer follow-up, detailed information on individual risk factors and heart dose are needed to assess clinically manifest late effects of current cancer therapy.}, language = {en} } @article{KosmalaGruschwitzVeldhoenetal.2020, author = {Kosmala, Aleksander and Gruschwitz, Philipp and Veldhoen, Simon and Weng, Andreas Max and Krauss, Bernhard and Bley, Thorsten Alexander and Petritsch, Bernhard}, title = {Dual-energy CT angiography in suspected pulmonary embolism: influence of injection protocols on image quality and perfused blood volume}, series = {The International Journal of Cardiovascular Imaging}, volume = {36}, journal = {The International Journal of Cardiovascular Imaging}, number = {10}, issn = {1569-5794}, doi = {10.1007/s10554-020-01911-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314739}, pages = {2051-2059}, year = {2020}, abstract = {Abstract To compare intravenous contrast material (CM) injection protocols for dual-energy CT pulmonary angiography (CTPA) in patients with suspected acute pulmonary embolism with regard to image quality and pulmonary perfused blood volume (PBV) values. A total of 198 studies performed with four CM injection protocols varying in CM volume and iodine delivery rates (IDR) were retrospectively included: (A) 60 ml at 5 ml/s (IDR = 1.75gI/s), (B) 50 ml at 5 ml/s (IDR = 1.75gI/s), (C) 50 ml at 4 ml/s (IDR = 1.40gI/s), (D) 40 ml at 3 ml/s (IDR = 1.05gI/s). Image quality and PBV values at different resolution settings were compared. Pulmonary arterial tract attenuation was highest for protocol A (397 ± 110 HU; p vs. B = 0.13; vs. C = 0.02; vs. D < 0.001). CTPA image quality of protocol A was rated superior compared to protocols B and D by reader 1 (p = 0.01; < 0.001), and superior to protocols B, C and D by reader 2 (p < 0.001; 0.02; < 0.001). Otherwise, there were no significant differences in CTPA quality ratings. Subjective iodine map ratings did not vary significantly between protocols A, B, and C. Both readers rated protocol D inferior to all other protocols (p < 0.05). PBV values did not vary significantly between protocols A and B at resolution settings of 1, 4 and 10 (p = 0.10; 0.10; 0.09), while otherwise PBV values displayed a decreasing trend from protocol A to D (p < 0.05). Higher CM volume and IDR are associated with superior CTPA and iodine map quality and higher absolute PBV values.}, language = {en} } @article{OhlmannBoemickeBehnischetal.2022, author = {Ohlmann, Brigitte and B{\"o}micke, Wolfgang and Behnisch, Rouven and Rammelsberg, Peter and Schmitter, Marc}, title = {Variability of sleep bruxism — findings from consecutive nights of monitoring}, series = {Clinical Oral Investigations}, volume = {26}, journal = {Clinical Oral Investigations}, number = {4}, issn = {1436-3771}, doi = {10.1007/s00784-021-04314-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307645}, pages = {3459-3466}, year = {2022}, abstract = {Objectives To determine sleep bruxism (SB) behavior during five consecutive nights and to identify correlations between SB episodes per hour (SB index) and sleep-time masseter-muscle activity (sMMA). Material and methods Thirty-one participants were included in the study. Of these, 10 were classified as sleep bruxers (group SB-1) and nine as non-sleep bruxers (group non-SB). The bruxism status of these 19 patients was identified by means of questionnaires, an assessment of clinical symptoms, and electromyographic/electrocardiographic data (Bruxoff® device). The remaining 12 participants were also identified as bruxers, but based exclusively on data from the Bruxoff device (group SB-2). Data analysis included descriptive statistics and Spearman's correlation to assess the relationship between the SB index and sMMA. Results Participants in group SB-1 showed an overall mean SB index of 3.1 ± 1.6 and a mean total sMMA per night of 62.9 ± 38.3. Participants in group SB-2 had an overall mean SB index of 2.7 ± 1.5 and a mean total sMMA of 56.0 ± 29.3. In the non-SB group, participants showed an overall mean SB index of 0.8 ± 0.5 and a mean total sMMA of 56.8 ± 30.3. Spearman's correlation yielded values of - 0.27 to 0.71 for the correlation between sMMA and SB index. Conclusions The data revealed variable SB activity and the absence of a reliable correlation between sMMA and the SB index. Clinical relevance The high variation in SB activity and lack of correlation between sMMA and the SB index should be considered when diagnosing SB. Trial registration Clinical Trials [NIH], clinical trial no. NCT03039985.}, language = {en} } @misc{KosmalaGruschwitzVeldhoenetal.2022, author = {Kosmala, Aleksander and Gruschwitz, Philipp and Veldhoen, Simon and Weng, Andreas Max and Krauss, Bernhard and Bley, Thorsten Alexander and Petritsch, Bernhard}, title = {Correction to: Dual-energy CT angiography in suspected pulmonary embolism: infuence of injection protocols on image quality and perfused blood volume}, series = {The International Journal of Cardiovascular Imaging}, volume = {38}, journal = {The International Journal of Cardiovascular Imaging}, number = {3}, doi = {10.1007/s10554-021-02439-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350830}, pages = {707}, year = {2022}, abstract = {No abstract available.}, language = {en} } @article{DenkSchmidtSchurretal.2021, author = {Denk, S. and Schmidt, S. and Schurr, Y. and Schwarz, G. and Schote, F. and Diefenbacher, M. and Armendariz, C. and Dejure, F. and Eilers, M. and Wiegering, Armin}, title = {CIP2A regulates MYC translation (via its 5′UTR) in colorectal cancer}, series = {International Journal of Colorectal Disease}, volume = {36}, journal = {International Journal of Colorectal Disease}, number = {5}, doi = {10.1007/s00384-020-03772-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280092}, pages = {911-918}, year = {2021}, abstract = {Background Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that decreasing MYC expression may have significant therapeutic value. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level. Methods To determine the mechanism by which CIP2A regulates MYC in CRC, we dissected MYC translation and stability dependent on CIP2A in CRC cell lines. Results Knockdown of CIP2A reduced MYC protein levels without influencing MYC stability in CRC cell lines. Interfering with proteasomal degradation of MYC by usage of FBXW7-deficient cells or treatment with the proteasome inhibitor MG132 did not rescue the effect of CIP2A depletion on MYC protein levels. Whereas CIP2A knockdown had marginal influence on global protein synthesis, we could demonstrate that, by using different reporter constructs and cells expressing MYC mRNA with or without flanking UTR, CIP2A regulates MYC translation. This interaction is mainly conducted by the MYC 5′UTR. Conclusions Thus, instead of targeting MYC protein stability as reported for other tissue types before, CIP2A specifically regulates MYC mRNA translation in CRC but has only slight effects on global mRNA translation. In conclusion, we propose as novel mechanism that CIP2A regulates MYC on a translational level rather than affecting MYC protein stability in CRC.}, language = {en} } @article{ReddersenGuellmarTonndorfMartinietal.2021, author = {Reddersen, Kirsten and G{\"u}llmar, Andr{\´e} and Tonndorf-Martini, Silke and Sigusch, Bernd W. and Ewald, Andrea and Dauben, Thomas J. and Martin, Karin and Wiegand, Cornelia}, title = {Critical parameters in cultivation of experimental biofilms using the example of Pseudomonas fluorescens}, series = {Journal of Materials Science: Materials in Medicine}, volume = {32}, journal = {Journal of Materials Science: Materials in Medicine}, number = {9}, issn = {0957-4530}, doi = {10.1007/s10856-021-06568-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-309911}, year = {2021}, abstract = {Formation and treatment of biofilms present a great challenge for health care and industry. About 80\% of human infections are associated with biofilms including biomaterial centered infections, like infections of prosthetic heart valves, central venous catheters, or urinary catheters. Additionally, biofilms can cause food and drinking water contamination. Biofilm research focusses on application of experimental biofilm models to study initial adherence processes, to optimize physico-chemical properties of medical materials for reducing interactions between materials and bacteria, and to investigate biofilm treatment under controlled conditions. Exploring new antimicrobial strategies plays a key role in a variety of scientific disciplines, like medical material research, anti-infectious research, plant engineering, or wastewater treatment. Although a variety of biofilm models exist, there is a lack of standardization for experimental protocols, and designing experimental setups remains a challenge. In this study, a number of experimental parameters critical for material research have been tested that influence formation and stability of an experimental biofilm using the non-pathogenic model strain of Pseudomonas fluorescens. These parameters include experimental time frame, nutrient supply, inoculum concentration, static and dynamic cultivation conditions, material properties, and sample treatment during staining for visualization of the biofilm. It was shown, that all tested parameters critically influence the experimental biofilm formation process. The results obtained in this study shall support material researchers in designing experimental biofilm setups.}, language = {en} } @misc{BaurRamserKelleretal.2021, author = {Baur, Johannes and Ramser, Michaela and Keller, Nicola and Muysoms, Filip and D{\"o}rfer, J{\"o}rg and Wiegering, Armin and Eisner, Lukas and Dietz, Ulrich A.}, title = {Erratum to: Robotic hernia repair II. English version Robotic primary ventral and incisional hernia repair (rv-TAPP and r-Rives or r-TARUP). Video report and results of a series of 118 patients}, series = {Der Chirurg}, volume = {92}, journal = {Der Chirurg}, number = {SUPPL 1}, doi = {10.1007/s00104-021-01563-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326357}, pages = {S27}, year = {2021}, abstract = {No abstract available.}, language = {en} } @article{FanEbnerReichertetal.2019, author = {Fan, Sook-Ha and Ebner, Patrick and Reichert, Sebstian and Hertlein, Tobias and Zabel, Susanne and Lankapalli, Aditya Kumar and Nieselt, Kay and Ohlsen, Knut and G{\"o}tz, Friedrich}, title = {MpsAB is important for Staphylococcus aureus virulence and growth at atmospheric CO2 levels}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-11547-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227624}, year = {2019}, abstract = {The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.}, language = {en} } @article{NowotnyAhmedBensingetal.2021, author = {Nowotny, Hanna and Ahmed, S. Faisal and Bensing, Sophie and Beun, Johan G. and Br{\"o}samle, Manuela and Chifu, Irina and Claahsen van der Grinten, Hedi and Clemente, Maria and Falhammar, Henrik and Hahner, Stefanie and Husebye, Eystein and Kristensen, Jette and Loli, Paola and Lajic, Svetlana and Reisch, Nicole}, title = {Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis}, series = {Endocrine}, volume = {71}, journal = {Endocrine}, number = {3}, organization = {Endo ERN (MTG1)}, issn = {1355-008X}, doi = {10.1007/s12020-021-02649-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308769}, pages = {586-594}, year = {2021}, abstract = {Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20-50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.}, language = {en} } @article{BliziotisKluijtmansSotoetal.2022, author = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Soto, Sebastian and Tinnevelt, Gerjen H. and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Prehn, Cornelia and Adamski, Jerzy and Januszewicz, Andrzej and Reincke, Martin and Fassnacht, Martin and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.}, title = {Pre- versus post-operative untargeted plasma nuclear magnetic resonance spectroscopy metabolomics of pheochromocytoma and paraganglioma}, series = {Endocrine}, volume = {75}, journal = {Endocrine}, number = {1}, doi = {10.1007/s12020-021-02858-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326574}, pages = {254-265}, year = {2022}, abstract = {Purpose Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors. Design A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics. Methods Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods. Results Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected. Conclusions Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.}, language = {en} } @article{AdolfBraunFussetal.2020, author = {Adolf, Christian and Braun, Leah T. and Fuss, Carmina T. and Hahner, Stefanie and K{\"u}nzel, Heike and Handgriff, Laura and Sturm, Lisa and Heinrich, Daniel A. and Schneider, Holger and Bidlingmaier, Martin and Reincke, Martin}, title = {Spironolactone reduces biochemical markers of bone turnover in postmenopausal women with primary aldosteronism}, series = {Endocrine}, volume = {69}, journal = {Endocrine}, number = {3}, issn = {1355-008X}, doi = {10.1007/s12020-020-02348-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-315966}, pages = {625-633}, year = {2020}, abstract = {Context Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis. Patients and methods We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment. Study design Observational longitudinal cohort study. Setting Tertiary care hospital. Results Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers. Conclusion This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.}, language = {en} } @article{LiPamporakiFliedneretal.2021, author = {Li, Minghao and Pamporaki, Christina and Fliedner, Stephanie M. J. and Timmers, Henri J. L. M. and N{\"o}lting, Svenja and Beuschlein, Felix and Prejbisz, Aleksander and Remde, Hanna and Robledo, Mercedes and Bornstein, Stefan R. and Lenders, Jacques W. M. and Eisenhofer, Graeme and Bechmann, Nicole}, title = {Metastatic pheochromocytoma and paraganglioma: signs and symptoms related to catecholamine secretion}, series = {Discover Oncology}, volume = {12}, journal = {Discover Oncology}, issn = {2730-6011}, doi = {10.1007/s12672-021-00404-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-309901}, year = {2021}, abstract = {Background The presence or future development of metastatic pheochromocytomas or paragangliomas (mPPGLs) can be difficult to diagnose or predict at initial presentation. Since production of catecholamines from mPPGLs is different from non-metastatic tumors (non-mPPGLs), this study aimed to clarify whether presenting catecholamine-related signs and symptoms (cSS) might also differ. Methods The study included 249 patients, 43 with mPPGL and 206 with non-mPPGL. Clinical data at the time of biochemical diagnosis (i.e. at entry into the study) were used to generate a cumulative score of cSS for each patient. Results Patients with mPPGL were significantly younger (43.3 ± 14 vs. 48.9 ± 16.1 years) and included a lower proportion of females (39.5\% vs. 60.7\%) than patients with non-mPPGLs. Frequencies of signs and symptoms did not differ between the two groups. Patients with mPPGLs had lower (P < 0.001) urinary excretion of epinephrine (3.5 (IQR, 1.9—6.5) µg/day) than those with non-mPPGLs (19.1 (IQR, 4.3—70.2) µg/day). There was no difference in urinary excretion of norepinephrine. In patients with mPPGLs a high cSS score was associated with high urinary excretion of norepinephrine and normetanephrine. In contrast, in patients with non-mPPGLs, a high cSS was associated with high urinary excretion of epinephrine and metanephrine. Conclusion Although presenting signs and symptoms were associated with production of norepinephrine in patients with mPPGLs and of epinephrine in patients with non-mPPGLs, there were no differences in signs and symptoms between the two groups. Therefore, consideration of signs and symptoms does not appear helpful for distinguishing patients with and without mPPGLs.}, language = {en} } @article{MinnerSchreinerSaeger2021, author = {Minner, S. and Schreiner, J. and Saeger, W.}, title = {Adrenal cancer: relevance of different grading systems and subtypes}, series = {Clinical and Translational Oncology}, volume = {23}, journal = {Clinical and Translational Oncology}, number = {7}, issn = {1699-048X}, doi = {10.1007/s12094-020-02524-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308479}, pages = {1350-1357}, year = {2021}, abstract = {Purpose The subclassification of adrenal cancers according to the WHO classification in ordinary, myxoid, oncocytic, and sarcomatoid as well as pediatric types is well established, but the criteria for each subtype are not sufficiently determined and the relative frequency of the different types of adrenal cancers has not been studied in large cohorts. Therefore, our large collection of surgically removed adrenal cancers should be reviewed o establish the criteria for the subtypes and to find out the frequency of the various types. Methods In our series of 521 adrenal cancers the scoring systems of Weiss et al., Hough et al., van Slooten et al. and the new Helsinki score system were used for the ordinary type of cancer (97\% of our series) and the myxoid type (0.8\%). For oncocytic carcinomas (2\%), the scoring system of Bisceglia et al. was applied. Results Discrepancies between benign and malignant diagnoses from the first thee classical scoring systems are not rare (22\% in our series) and could be resolved by the Helsinki score especially by Ki-67 index (more than 8\% unequivocally malignant). Since all our cancer cases are positive in the Helsinki score, this system can replace the three elder systems. For identification of sarcomatoid cancer as rarest type in our series (0.2\%), the scoring systems are not practical but additional immunostainings used for soft tissue tumors and in special cases molecular pathology are necessary to differentiate these cancers from adrenal sarcomas. According to the relative frequencies of the different subtypes of adrenal cancers the main type is the far most frequent (97\%) followed by the oncocytic type (2\%), the myxoid type (0.8\%) and the very rare sarcomatoid type (0.2\%). Conclusions The Helsinki score is the best for differentiating adrenal carcinomas of the main, the oncocytic, and the myxoid type in routine work. Additional scoring systems for these carcinomas are generally not any longer necessary. Signs of proliferation (mitoses and Ki-67 index) and necroses are the most important criteria for diagnosis of malignancy.}, language = {en} } @article{DanyszDekundyScheschonkaetal.2021, author = {Danysz, Wojciech and Dekundy, Andrzej and Scheschonka, Astrid and Riederer, Peter}, title = {Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, number = {2}, doi = {10.1007/s00702-021-02306-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-330133}, pages = {127-169}, year = {2021}, abstract = {The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.}, language = {en} } @article{FerreiraGamazonAlEjehetal.2019, author = {Ferreira, Manuel A. and Gamazon, Eric R. and Al-Ejeh, Fares and Aittom{\"a}ki, Kristiina and Andrulis, Irene L. and Anton-Culver, Hoda and Arason, Adalgeir and Arndt, Volker and Aronson, Kristan J. and Arun, Banu K. and Asseryanis, Ella and Azzollini, Jacopo and Balma{\~n}a, Judith and Barnes, Daniel R. and Barrowdale, Daniel and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Bialkowska, Katarzyna and Blomqvist, Carl and Bogdanova, Natalia V. and Bojesen, Stig E. and Bolla, Manjeet K. and Borg, Ake and Brauch, Hiltrud and Brenner, Hermann and Broeks, Annegien and Burwinkel, Barbara and Cald{\´e}s, Trinidad and Caligo, Maria A. and Campa, Daniele and Campbell, Ian and Canzian, Federico and Carter, Jonathan and Carter, Brian D. and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Christiansen, Hans and Chung, Wendy K. and Claes, Kathleen B. M. and Clarke, Christine L. and Couch, Fergus J. and Cox, Angela and Cross, Simon S. and Czene, Kamila and Daly, Mary B. and de la Hoya, Miguel and Dennis, Joe and Devilee, Peter and Diez, Orland and D{\"o}rk, Thilo and Dunning, Alison M. and Dwek, Miriam and Eccles, Diana M. and Ejlertsen, Bent and Ellberg, Carolina and Engel, Christoph and Eriksson, Mikael and Fasching, Peter A. and Fletcher, Olivia and Flyger, Henrik and Friedman, Eitan and Frost, Debra and Gabrielson, Marike and Gago-Dominguez, Manuela and Ganz, Patricia A. and Gapstur, Susan M. and Garber, Judy and Garc{\´i}a-Closas, Montserrat and Garc{\´i}a-S{\´a}enz, Jos{\´e} A. and Gaudet, Mia M. and Giles, Graham G. and Glendon, Gord and Godwin, Andrew K. and Goldberg, Mark S. and Goldgar, David E. and Gonz{\´a}lez-Neira, Anna and Greene, Mark H. and Gronwald, Jacek and Guen{\´e}l, Pascal and Haimann, Christopher A. and Hall, Per and Hamann, Ute and He, Wei and Heyworth, Jane and Hogervorst, Frans B. L. and Hollestelle, Antoinette and Hoover, Robert N. and Hopper, John L. and Hulick, Peter J. and Humphreys, Keith and Imyanitov, Evgeny N. and Isaacs, Claudine and Jakimovska, Milena and Jakubowska, Anna and James, Paul A. and Janavicius, Ramunas and Jankowitz, Rachel C. and John, Esther M. and Johnson, Nichola and Joseph, Vijai and Karlan, Beth Y. and Khusnutdinova, Elza and Kiiski, Johanna I. and Ko, Yon-Dschun and Jones, Michael E. and Konstantopoulou, Irene and Kristensen, Vessela N. and Laitman, Yael and Lambrechts, Diether and Lazaro, Conxi and Leslie, Goska and Lester, Jenny and Lesueur, Fabienne and Lindstr{\"o}m, Sara and Long, Jirong and Loud, Jennifer T. and Lubiński, Jan and Makalic, Enes and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Maurer, Tabea and Mavroudis, Dimitrios and McGuffog, Lesley and Meindl, Alfons and Menon, Usha and Michailidou, Kyriaki and Miller, Austin and Montagna, Marco and Moreno, Fernando and Moserle, Lidia and Mulligan, Anna Marie and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Nevelsteen, Ines and Nielsen, Finn C. and Nikitina-Zake, Liene and Nussbaum, Robert L. and Offit, Kenneth and Olah, Edith and Olopade, Olufunmilayo I. and Olsson, H{\aa}kan and Osorio, Ana and Papp, Janos and Park-Simon, Tjoung-Won and Parsons, Michael T. and Pedersen, Inge Sokilde and Peixoto, Ana and Peterlongo, Paolo and Pharaoh, Paul D. P. and Plaseska-Karanfilska, Dijana and Poppe, Bruce and Presneau, Nadege and Radice, Paolo and Rantala, Johanna and Rennert, Gad and Risch, Harvey A. and Saloustros, Emmanouil and Sanden, Kristin and Sawyer, Elinor J. and Schmidt, Marjanka K. and Schmutzler, Rita K. and Sharma, Priyanka and Shu, Xiao-Ou and Simard, Jaques and Singer, Christian F. and Soucy, Penny and Southey, Melissa C. and Spinelli, John J. and Spurdle, Amanda B. and Stone, Jennifer and Swerdlow, Anthony J. and Tapper, William J. and Taylor, Jack A. and Teixeira, Manuel R. and Terry, Mary Beth and Teul{\´e}, Alex and Thomassen, Mads and Th{\"o}ne, Kathrin and Thull, Darcy L. and Tischkowitz, Marc and Toland, Amanda E. and Torres, Diana and Truong, Th{\´e}r{\`e}se and Tung, Nadine and Vachon, Celine M. and van Asperen, Christi J. and van den Ouweland, Ans M. W. and van Rensburg, Elizabeth J. and Vega, Ana and Viel, Alexandra and Wang, Qin and Wappenschmidt, Barbara and Weitzel, Jeffrey N. and Wendt, Camilla and Winqvist, Robert and Yang, Xiaohong R. and Yannoukakos, Drakoulis and Ziogas, Argyrios and Kraft, Peter and Antoniou, Antonis C. and Zheng, Wei and Easton, Douglas F. and Milne, Roger L. and Beesley, Jonathan and Chenevix-Trench, Georgia}, title = {Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators}, doi = {10.1038/s41467-018-08053-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228024}, year = {2019}, abstract = {Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.}, language = {en} } @article{BuchmannBaumannMengetal.2023, author = {Buchmann, J. and Baumann, N. and Meng, K. and Semrau, J. and Kuhl, J. and Pfeifer, K. and Vogel, H. and Faller, H.}, title = {Volitional Action Control and Depression in Chronic Pain: Does Action versus State Orientation Moderate the Relations of Pain-Related Cognitions to Depression?}, series = {Current Psychology}, volume = {42}, journal = {Current Psychology}, issn = {1046-1310}, doi = {10.1007/s12144-021-01914-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308508}, pages = {7591-7608}, year = {2023}, abstract = {In this study, we examined the conditional indirect and direct relations of pain-related cognitions to depression. Subjective helplessness was included as presumably mediating the relations of catastrophizing and thought suppression to depression due to motivational deficits. In addition, moderating effects of dispositional action versus state orientation were analyzed, whereby state orientation indicates volitional deficits in coping with distress. The study was based on self-report data from 536 patients with chronic non-specific low back pain at the beginning of inpatient rehabilitation. Moderated mediation analyses were performed. The indirect catastrophizing- and thought suppression-depression relations were (partially) mediated by subjective helplessness; and moderated by failure-related action versus state orientation. Moreover, action versus state orientation moderated the direct relation of thought suppression to depression. Results suggest that catastrophizing, thought suppression, and subjective helplessness do not lead to depression unless associated with self-regulatory inability (i.e., state orientation). In contrast, action-oriented patients more effectively self-regulate pain-related emotions, disengage from rumination, and distract from pain and thus better avoid the debilitating effects of negative pain-related cognitions on depression. Future research and treatment may more strongly focus on the role of motivational and volitional deficits underlying learned helplessness and depression in chronic pain.}, language = {en} } @article{NauePfeiferAugustinetal.2021, author = {Naue, Jana and Pfeifer, Manuel and Augustin, Christa and Becker, Julia and Fleckhaus, Jan and Grabm{\"u}ller, Melanie and Han, Yang and Heidorn, Frank and Hollaender, Olivia and Klein-Unseld, Rachel and Kulstein, Galina and Lichtenwald, Julia and Neubauer, Jacqueline and Suarez, Philippe and Haas, Cordula and Schneider, Peter M. and Vennemann, Marielle and B{\"o}hme, Petra}, title = {Forensische DNA-Methylierungsanalyse}, series = {Rechtsmedizin}, volume = {31}, journal = {Rechtsmedizin}, number = {3}, organization = {Arbeitsgemeinschaft Molekulare Alterssch{\"a}tzung der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM)}, issn = {0937-9819}, doi = {10.1007/s00194-021-00493-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307129}, pages = {202-216}, year = {2021}, abstract = {Mit der Entdeckung altersabh{\"a}ngiger epigenetischer Ver{\"a}nderungen, der DNA-Methylierung (DNAm), hat sich eine neue M{\"o}glichkeit aufgezeigt, das Alter eines Individuums zu sch{\"a}tzen. Die Methode wurde intensiv erforscht und ihre Anwendung in der forensischen Fallarbeit durch die Aktualisierung des \S 81e der Strafprozessordnung (StPO) in Deutschland reguliert. Zur Untersuchung des DNAm-Grades m{\"u}ssen neue Techniken etabliert und validiert werden. Dies macht die Pr{\"u}fung der Vergleichbarkeit von Messergebnissen aus verschiedenen forensischen Laboren erforderlich. Hierzu f{\"u}hrte die Arbeitsgruppe „Molekulare Alterssch{\"a}tzung" der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM) im Winter 2019/2020 den 2. Ringversuch (RV) zur quantitativen DNAm-Analyse mithilfe der Mini- und der Pyrosequenzierung durch. Dieser basierte auf den Erfahrungen des 1. RV 2018/2019, dessen Ergebnisse in dieser Ausgabe ebenfalls vorgestellt werden. Die aktuelle Studie umfasst Analyseergebnisse aus 12 Laboren (ingesamt 14 teilnehmende Labore), von denen einige beide Methoden angewandt haben. Zus{\"a}tzlich f{\"u}hrten 4 Labore eine Alterssch{\"a}tzung an den RV-Proben mit eigenen Markerkombinationen und Modellen durch. Da diese auf unterschiedlichen Referenzdaten und Markerkombinationen beruhen, erfolgte kein qualitativer Vergleich der Modelle, sondern das grunds{\"a}tzliche Potenzial der Methodik wurde verdeutlicht. Ziele des RV waren die Evaluierung der Vergleichbarkeit der DNAm-Messungen und die Bewertung m{\"o}glicher Einflussfaktoren, wie Extraktionsmethode und verwendetes Ger{\"a}t. Die Ergebnisse zeigen, dass sich die gemessenen DNAm-Werte der untersuchten Marker sowohl zwischen Mini- und Pyrosequenzierung als auch innerhalb der jeweiligen Methode zwischen den Laboren unterscheiden k{\"o}nnen, sodass mit Schwankungen gerechnet werden muss.}, language = {de} } @article{DubailHuberChantepieetal.2018, author = {Dubail, Johanne and Huber, C{\´e}line and Chantepie, Sandrine and Sonntag, Stephan and T{\"u}ys{\"u}z, Beyhan and Mihci, Ercan and Gordon, Christopher T. and Steichen-Gersdorf, Elisabeth and Amiel, Jeanne and Nur, Banu and Stolte-Dijkstra, Irene and van Eerde, Albertien M. and van Gassen, Koen L. and Breugem, Corstiaan C. and Stegmann, Alexander and Lekszas, Caroline and Maroofian, Reza and Karimiani, Ehsan Ghayoor and Bruneel, Arnaud and Seta, Nathalie and Munnich, Arnold and Papy-Garcia, Dulce and De La Dure-Molla, Muriel and Cormier-Daire, Val{\´e}rie}, title = {SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-05191-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226377}, year = {2018}, abstract = {Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.}, language = {en} } @article{RolfesRuckDavidetal.2022, author = {Rolfes, Leoni and Ruck, Tobias and David, Christina and Mencl, Stine and Bock, Stefanie and Schmidt, Mariella and Strecker, Jan-Kolja and Pfeuffer, Steffen and Mecklenbeck, Andreas-Schulte and Gross, Catharina and Gliem, Michael and Minnerup, Jens and Schuhmann, Michael K. and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Natural Killer Cells Are Present in Rag1\(^{-/-}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke}, series = {Translational Stroke Research}, volume = {13}, journal = {Translational Stroke Research}, number = {1}, issn = {1868-4483}, doi = {10.1007/s12975-021-00923-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308924}, pages = {197-211}, year = {2022}, abstract = {Rag1\(^{-/-}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{-/-}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{-/-}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{-/-}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{-/-}\) were comparable in number and function to those in WT mice. Rag1\(^{-/-}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1-/- controls. Our results indicate that NK cells from Rag1-/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.}, language = {en} } @article{PotreckMutkeWeylandetal.2021, author = {Potreck, Arne and Mutke, Matthias A. and Weyland, Charlotte S. and Pfaff, Johannes A. R. and Ringleb, Peter A. and Mundiyanapurath, Sibu and M{\"o}hlenbruch, Markus A. and Heiland, Sabine and Pham, Mirko and Bendszus, Martin and Hoffmann, Angelika}, title = {Combined Perfusion and Permeability Imaging Reveals Different Pathophysiologic Tissue Responses After Successful Thrombectomy}, series = {Translational Stroke Research}, volume = {12}, journal = {Translational Stroke Research}, number = {5}, issn = {1868-4483}, doi = {10.1007/s12975-020-00885-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308946}, pages = {799-807}, year = {2021}, abstract = {Despite successful recanalization of large-vessel occlusions in acute ischemic stroke, individual patients profit to a varying degree. Dynamic susceptibility-weighted perfusion and dynamic T1-weighted contrast-enhanced blood-brain barrier permeability imaging may help to determine secondary stroke injury and predict clinical outcome. We prospectively performed perfusion and permeability imaging in 38 patients within 24 h after successful mechanical thrombectomy of an occlusion of the middle cerebral artery M1 segment. Perfusion alterations were evaluated on cerebral blood flow maps, blood-brain barrier disruption (BBBD) visually and quantitatively on ktrans maps and hemorrhagic transformation on susceptibility-weighted images. Visual BBBD within the DWI lesion corresponded to a median ktrans elevation (IQR) of 0.77 (0.41-1.4) min-1 and was found in all 7 cases of hypoperfusion (100\%), in 10 of 16 cases of hyperperfusion (63\%), and in only three of 13 cases with unaffected perfusion (23\%). BBBD was significantly associated with hemorrhagic transformation (p < 0.001). While BBBD alone was not a predictor of clinical outcome at 3 months (positive predictive value (PPV) = 0.8 [0.56-0.94]), hypoperfusion occurred more often in patients with unfavorable clinical outcome (PPV = 0.43 [0.10-0.82]) compared to hyperperfusion (PPV = 0.93 [0.68-1.0]) or unaffected perfusion (PPV = 1.0 [0.75-1.0]). We show that combined perfusion and permeability imaging reveals distinct infarct signatures after recanalization, indicating the severity of prior ischemic damage. It assists in predicting clinical outcome and may identify patients at risk of stroke progression.}, language = {en} } @phdthesis{Choi2024, author = {Choi, Jihyoung}, title = {Development of an Add-On Electrode for Non-Invasive Monitoring in Bioreactor Cultures and Medical Devices}, doi = {10.25972/OPUS-35823}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358232}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Electrochemical impedance spectroscopy (EIS) is a valuable technique analyzing electrochemical behavior of biological systems such as electrical characterization of cells and biomolecules, drug screening, and biomaterials in biomedical field. In EIS, an alternating current (AC) power signal is applied to the biological system, and the impedance of the system is measured over a range of frequencies. In vitro culture models of endothelial or epithelial barrier tissue can be achieved by culturing barrier tissue on scaffolds made with synthetic or biological materials that provide separate compartments (apical and basal sides), allowing for further studies on drug transport. EIS is a great candidate for non-invasive and real-time monitoring of the electrical properties that correlate with barrier integrity during the tissue modeling. Although commercially available transendothelial/transepithelial electrical resistance (TEER) measurement devices are widely used, their use is particularly common in static transwell culture. EIS is considered more suitable than TEER measurement devices in bioreactor cultures that involve dynamic fluid flow to obtain accurate and reliable measurements. Furthermore, while TEER measurement devices can only assess resistance at a single frequency, EIS measurements can capture both resistance and capacitance properties of cells, providing additional information about the cellular barrier's characteristics across various frequencies. Incorporating EIS into a bioreactor system requires the careful optimization of electrode integration within the bioreactor setup and measurement parameters to ensure accurate EIS measurements. Since bioreactors vary in size and design depending on the purpose of the study, most studies have reported using an electrode system specifically designed for a particular bioreactor. The aim of this work was to produce multi-applicable electrodes and established methods for automated non-invasive and real-time monitoring using the EIS technique in bioreactor cultures. Key to the electrode material, titanium nitride (TiN) coating was fabricated on different substrates (materials and shape) using physical vapor deposition (PVD) and housed in a polydimethylsiloxane (PDMS) structure to allow the electrodes to function as independent units. Various electrode designs were evaluated for double-layer capacitance and morphology using EIS and scanning electron microscopy (SEM), respectively. The TiN-coated tube electrode was identified as the optimal choice. Furthermore, EIS measurements were performed to examine the impact of influential parameters related to culture conditions on the TiN-coated electrode system. In order to demonstrate the versatility of the electrodes, these electrodes were then integrated into in different types of perfusion bioreactors for monitoring barrier cells. Blood-brain barrier (BBB) cells were cultured in the newly developed dynamic flow bioreactor, while human umblical vascular endothelial cells (HUVECs) and Caco-2 cells were cultured in the miniature hollow fiber bioreactor (HFBR). As a result, the TiN-coated tube electrode system enabled investigation of BBB barrier integrity in long-term bioreactor culture. While EIS measurement could not detect HUVECs electrical properties in miniature HFBR culture, there was the possibility of measuring the barrier integrity of Caco-2 cells, indicating potential usefulness for evaluating their barrier function. Following the bioreactor cultures, the application of the TiN-coated tube electrode was expanded to hemofiltration, based on the hypothesis that the EIS system may be used to monitor clotting or clogging phenomena in hemofiltration. The findings suggest that the EIS monitoring system can track changes in ion concentration of blood before and after hemofiltration in real-time, which may serve as an indicator of clogging of filter membranes. Overall, our research demonstrates the potential of TiN-coated tube electrodes for sensitive and versatile non-invasive monitoring in bioreactor cultures and medical devices.}, subject = {Monitoring}, language = {en} } @phdthesis{Kutschka2024, author = {Kutschka, Ilona}, title = {Activation of the integrated stress response induces remodeling of cardiac metabolism in Barth Syndrome}, doi = {10.25972/OPUS-35818}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358186}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Barth Syndrome (BTHS) is an inherited X-chromosomal linked disorder, characterized by early development of cardiomyopathy, immune system defects, skeletal muscle myopathy and growth retardation. The disease displays a wide variety of symptoms including heart failure, exercise intolerance and fatigue due to the muscle weakness. The cause of the disease are mutations in the gene encoding for the mitochondrial transacylase Tafazzin (TAZ), which is important for remodeling of the phospholipid cardiolipin (CL). All mutations result in a pronounced decrease of the functional enzyme leading to an increase of monolysocardiolipin (MLCL), the precursor of mature CL, and a decrease in mature CL itself. CL is a hallmark phospholipid of mitochondrial membranes, highly enriched in the inner mitochondrial membrane (IMM). It is not only important for the formation of the cristae structures, but also for the function of different protein complexes associated with the mitochondrial membrane. Reduced levels of mature CL cause remodeling of the respiratory chain supercomplexes, impaired respiration, defects in the Krebs cycle and a loss of mitochondrial calcium uniporter (MCU) protein. The defective Ca2+ handling causes impaired redox homeostasis and energy metabolism resulting in cellular arrhythmias and defective electrical conduction. In an uncompensated situation, blunting mitochondrial Ca2+ uptake provokes increased mitochondrial emission of H2O2 during workload transitions, related to oxidation of NADPH, which is required to regenerate anti-oxidative enzymes. However, in the hearts and cardiac myocytes of mice with a global knock-down of the Taz gene (Taz-KD), no increase in mitochondrial ROS was observed, suggesting that other metabolic pathways may have compensated for reduced Krebs cycle activation. The healthy heart produces most of its energy by consuming fatty acids. In this study, the fatty acid uptake into mitochondria and their further degradation was investigated, which showed a switch of the metabolism in general in the Taz-KD mouse model. In vivo studies revealed an increase of glucose uptake into the heart and decreased fatty acid uptake and oxidation. Disturbed energy conversion resulted in activation of retrograde signaling pathways, implicating overall changes in the cell metabolism. Upregulated integrated stress response (ISR) was confirmed by increased levels of the downstream target, i.e., the activating transcription factor 4 (ATF4). A Tafazzin knockout mouse embryonal fibroblast cell model (TazKO) was used to inhibit the ISR using siRNA transfection or pharmaceutical inhibition. This verified the central role of II the ISR in regulating the metabolism in BTHS. Moreover, an increased metabolic flux into glutathione biosynthesis was observed, which supports redox homeostasis. In vivo PET-CT scans depicted elevated activity of the xCT system in the BTHS mouse heart, which transports essential amino acids for the biosynthesis of glutathione precursors. Furthermore, the stress induced signaling pathway also affected the glutamate metabolism, which fuels into the Krebs cycle via -ketoglutarate and therefore supports energy converting pathways. In summary, this thesis provides novel insights into the energy metabolism and redox homeostasis in Barth syndrome cardiomyopathy and its regulation by the integrated stress response, which plays a central role in the metabolic alterations. The aim of the thesis was to improve the understanding of these metabolic changes and to identify novel targets, which can provide new possibilities for therapeutic intervention in Barth syndrome.}, subject = {Herzmuskelkrankheit}, language = {en} } @phdthesis{Wilhelmi2024, author = {Wilhelmi, Kai Alexander}, title = {Untersuchung von Ver{\"a}nderungen der myelinisierten Nervenfasern durch Entmarkung in Haut- und Nervenbiopsien von Patienten mit Polyneuropathie}, doi = {10.25972/OPUS-36004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360046}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser Arbeit wurde durch das immunhistochemische Anf{\"a}rben von nodalen (Natriumkan{\"a}le, NF), paranodalen (Caspr, NF) und internodalen (MBP) Proteinen der in Fingerhautbiopsien vorhanden Nervenfasern untersucht, ob eine Ver{\"a}nderung der typischen Verteilungsmuster dieser Proteine, eine demyelinisierende Polyneuropathie anzeigen kann. Dazu wurden am Universit{\"a}tsklinikum W{\"u}rzburg prospektiv 93 Polyneuropathie-Patienten und 25 Kontrollpersonen rekrutiert. Bei allen Patienten wurden Hautstanzbiospien am Zeigefinger durchgef{\"u}hrt. Bei 35 Patienten mit schweren oder unklaren Verl{\"a}ufen, wurden konsiliarisch Nervus suralis Biopsien durchgef{\"u}hrt. Aus einem Abschnitt von 27 dieser Biopsien, konnten im Rahmen dieser Arbeit Zupfnervenpr{\"a}parate angefertigt und analog zu den Hautbiopsien ausgewertet werden. Aus der Routinediagnostik der Klinik flossen weiterhin die Ergebnisse der elektrophysiologischen Routinediagnostik und der Histologiebefund der Nervus suralis Biopsien in die Auswertung ein. Zusammenfassend kamen ver{\"a}nderte Natriumkanalbanden in Fingerhautbiopsien signifikant h{\"a}ufiger bei Patienten mit elektrophysiologisch als demyelinisierend befundeten Polyneuropathien, als bei Patienten mit elektrophysiologisch als axonal befundeten Polyneuropathien vor. Vielfach fanden sich ver{\"a}nderte Natriumkanalbanden inmitten para- und internodal unauff{\"a}lliger Schn{\"u}rringe und umgekehrt. Diese Beobachtung st{\"u}tzt die bereits in Vorarbeiten vorgeschlagene und in der aktuellen Leitlinie zur Diagnostik f{\"u}r Polyneuropathien aufgegriffene Entit{\"a}t der Paranodopathien (Uncini, Susuki, \& Yuki, 2013). M{\"o}glich w{\"a}re, dass eine ver{\"a}nderte Verteilung der Natriumkan{\"a}le die schnelle Leitf{\"a}higkeit beeintr{\"a}chtigen und somit trotz intakter Bemarkung, elektrophysiologisch das Bild einer demyelinisierenden Neuropathie vermittelt. Ein direkter Zusammenhang zwischen dem Auftreten von doppelten und verl{\"a}ngerten Natriumkanalbanden und einzelnen Messwerten (z.B. Amplituden und Latenzzeiten) fand sich nicht. Auch in den Zupfnervenpr{\"a}paraten der Nervus suralis Biopsien, konnten o.g. Verteilungsmuster untersucht werden. Deren Vorkommen zeigte sich als unabh{\"a}ngig vom elektrophysiologischen und histologischen Befund, von der {\"A}tiologie der PNP und von den gefundenen Ver{\"a}nderungen in den Hautbiopsien des betreffenden Patienten.}, subject = {Polyneuropathie}, language = {de} } @article{GerlichAndreicaKueffneretal.2020, author = {Gerlich, C. and Andreica, I. and K{\"u}ffner, R. and Krause, D. and Lakomek, H. J. and Reusch, A. and Braun, J.}, title = {Evaluation einer Basisschulung f{\"u}r Patienten mit rheumatoider Arthritis}, series = {Zeitschrift f{\"u}r Rheumatologie}, volume = {79}, journal = {Zeitschrift f{\"u}r Rheumatologie}, doi = {10.1007/s00393-020-00769-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280359}, pages = {737-748}, year = {2020}, abstract = {Hintergrund Ein neues Rahmenkonzept hat die flexible Ableitung und Nutzung von rheumatologischen Schulungsprogrammen f{\"u}r unterschiedliche Versorgungsbereiche erm{\"o}glicht. Auf dieser Grundlage wurde eine 5‑st{\"u}ndige Basisschulung f{\"u}r Patienten mit rheumatoider Arthritis (RA) entwickelt, es wurden rheumatologische Fach{\"a}rzte und Psychologen trainiert, und dann wurde die Wirksamkeit nach dem Wirkmodell der Patientenschulung evaluiert. Methoden Mit dem Studiendesign einer extern randomisierten Wartekontrollgruppenstudie mit 3 Messzeitpunkten wurde gepr{\"u}ft, wie sich die 5‑st{\"u}ndige Basisschulung auf das Erkrankungs- und Behandlungswissen sowie auf die Gesundheitskompetenz von RA-Patienten (n = 249) auswirkt. Weitere Fragen betrafen Einstellungsparameter, Kommunikationskompetenz, Erkrankungsauswirkungen und die Zufriedenheit mit der Schulung. Die Auswertungen erfolgten auf Intention-to-treat-Basis mit Kovarianzanalysen f{\"u}r die Hauptzielgr{\"o}ßen unter Ber{\"u}cksichtigung des Ausgangswertes. Ergebnisse Die Analysen zeigen, dass die Basisschulung RA wirksam ist. Noch 3 Monate nach der Schulung verf{\"u}gten die Schulungsteilnehmer {\"u}ber mehr Wissen und Gesundheitskompetenz als die Wartekontrollgruppe mit kleinem bis mittelgroßem Effekt (d = 0,37 bzw. 0,38). In den Nebenzielgr{\"o}ßen zeigten sich mit Ausnahme der Krankheitskommunikation keine weiteren Schulungseffekte. Diskussion Die Basisschulung bietet eine gute Grundlage, auf der weitere Interventionen zur Verbesserung von Einstellungs- und Erkrankungsparametern aufbauen k{\"o}nnen. Sie eignet sich damit als zentraler Baustein f{\"u}r die rheumatologische Versorgung auf verschiedenen Ebenen.}, language = {de} } @phdthesis{Kuehnemundt2024, author = {K{\"u}hnemundt, Johanna}, title = {Defined microphysiologic 3D tumour models with aspects from the tumour microenvironment for the evaluation of cellular immunotherapies}, doi = {10.25972/OPUS-27667}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276674}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells is highly effective in haematological malignancies. This success, however, has not been achieved in solid tumours so far. In contrast to hematologic malignancies, solid tumours include a hostile tumour microenvironment (TME), that poses additional challenges for curative effects and consistent therapeutic outcome. These challenges manifest in physical and immunological barriers that dampen efficacy of the CAR T cells. Preclinical testing of novel cellular immunotherapies is performed mainly in 2D cell culture and animal experiments. While 2D cell culture is an easy technique for efficacy analysis, animal studies reveal information about toxicity in vivo. However, 2D cell culture cannot fully reflect the complexity observed in vivo, because cells are cultured without anchorage to a matrix and only short-term periods are feasible. Animal studies provide a more complex tissue environment, but xenografts often lack human stroma and tumour inoculation occurs mostly ectopically. This emphasises the need for standardisable and scalable tumour models with incorporated TME-aspects, which enable preclinical testing with enhanced predictive value for the clinical outcome of immunotherapies. Therefore, microphysiologic 3D tumour models based on the biological SISmuc (Small Intestinal mucosa and Submucosa) matrix with preserved basement membrane were engaged and improved in this work to serve as a modular and versatile tumour model for efficacy testing of CAR T cells. In order to reflect a variety of cancer entities, TME-aspects, long-term stability and to enhance the read-out options they were further adapted to achieve scalable and standardisable defined microphysiologic 3D tumour models. In this work, novel culture modalities (semi-static, sandwich-culture) were characterised and established that led to an increased and organised tissue generation and long-term stability. Application of the SISmuc matrix was extended to sarcoma and melanoma models and serial bioluminescence intensity (BLI)-based in vivo imaging analysis was established in the microphysiologic 3D tumour models, which represents a time-efficient read-out method for quality evaluation of the models and treatment efficacy analysis, that is independent of the cell phenotype. Isolation of cancer-associated-fibroblasts (CAFs) from lung (tumour) tissue was demonstrated and CAF-implementation further led to stromal-enriched microphysiologic 3D tumour models with in vivo-comparable tissue-like architecture. Presence of CAFs was confirmed by CAF-associated markers (FAP, α-SMA, MMP-2/-9) and cytokines correlated with CAF phenotype, angiogenesis, invasion and immunomodulation. Additionally, an endothelial cell barrier was implemented for static and dynamic culture in a novel bioreactor set-up, which is of particular interest for the analysis of immune cell diapedesis. Studies in microphysiologic 3D Ewing's sarcoma models indicated that sarcoma cells could be sensitised for GD2-targeting CAR T cells. After enhancing the scale of assessment of the microphysiologic 3D tumour models and improving them for CAR T cell testing, the tumour models were used to analyse their sensitivity towards differently designed receptor tyrosine kinase-like orphan receptor 1 (ROR1) CAR T cells and to study the effects of the incorporated TME-aspects on the CAR T cell treatment respectively. ROR1 has been described as a suitable target for several malignancies including triple negative breast cancer (TNBC), as well as lung cancer. Therefore, microphysiologic 3D TNBC and lung cancer models were established. Analysis of ROR1 CAR T cells that differed in costimulation, spacer length and targeting domain, revealed, that the microphysiologic 3D tumour models are highly sensitive and can distinguish optimal from sub-optimal CAR design. Here, higher affinity of the targeting domain induced stronger anti-tumour efficacy and anti-tumour function depended on spacer length, respectively. Long-term treatment for 14 days with ROR1 CAR T cells was demonstrated in dynamic microphysiologic 3D lung tumour models, which did not result in complete tumour cell removal, whereas direct injection of CAR T cells into TNBC and lung tumour models represented an alternative route of application in addition to administration via the medium flow, as it induced strong anti-tumour response. Influence of the incorporated TME-aspects on ROR1 CAR T cell therapy represented by CAF-incorporation and/or TGF-β supplementation was analysed. Presence of TGF-β revealed that the specific TGF-β receptor inhibitor SD-208 improves ROR1 CAR T cell function, because it effectively abrogated immunosuppressive effects of TGF-β in TNBC models. Implementation of CAFs should provide a physical and immunological barrier towards ROR1 CAR T cells, which, however, was not confirmed, as ROR1 CAR T cell function was retained in the presence of CAFs in stromal-enriched microphysiologic 3D lung tumour models. The absence of an effect of CAF enrichment on CAR T cell efficacy suggests a missing component for the development of an immunosuppressive TME, even though immunomodulatory cytokines were detected in co-culture models. Finally, improved gene-edited ROR1 CAR T cells lacking exhaustion-associated genes (PD-1, TGF-β-receptor or both) were challenged by the combination of CAF-enrichment and TGF-β in microphysiologic 3D TNBC models. Results indicated that the absence of PD-1 and TGF-β receptor leads to improved CAR T cells, that induce strong tumour cell lysis, and are protected against the hostile TME. Collectively, the microphysiologic 3D tumour models presented in this work reflect aspects of the hostile TME of solid tumours, engage BLI-based analysis and provide long-term tissue homeostasis. Therefore, they present a defined, scalable, reproducible, standardisable and exportable model for translational research with enhanced predictive value for efficacy testing and candidate selection of cellular immunotherapy, as exemplified by ROR1 CAR T cells.}, subject = {Immuntherapie}, language = {en} } @article{GroebnerWorstWeischenfeldtetal.2018, author = {Gr{\"o}bner, Susanne N. and Worst, Barbara C. and Weischenfeldt, Joachim and Buchhalter, Ivo and Kleinheinz, Kortine and Rudneva, Vasilisa A. and Johann, Pascal D. and Balasubramanian, Gnana Prakash and Segura-Wang, Maia and Brabetz, Sebastian and Bender, Sebastian and Hutter, Barbara and Sturm, Dominik and Pfaff, Elke and H{\"u}bschmann, Daniel and Zipprich, Gideon and Heinold, Michael and Eils, J{\"u}rgen and Lawerenz, Christian and Erkek, Serap and Lambo, Sander and Waszak, Sebastian and Blattmann, Claudia and Borkhardt, Arndt and Kuhlen, Michaela and Eggert, Angelika and Fulda, Simone and Gessler, Manfred and Wegert, Jenny and Kappler, Roland and Baumhoer, Daniel and Stefan, Burdach and Kirschner-Schwabe, Renate and Kontny, Udo and Kulozik, Andreas E. and Lohmann, Dietmar and Hettmer, Simone and Eckert, Cornelia and Bielack, Stefan and Nathrath, Michaela and Niemeyer, Charlotte and Richter, G{\"u}nther H. and Schulte, Johannes and Siebert, Reiner and Westermann, Frank and Molenaar, Jan J. and Vassal, Gilles and Witt, Hendrik and Burkhardt, Birgit and Kratz, Christian P. and Witt, Olaf and van Tilburg, Cornelis M. and Kramm, Christof M. and Fleischhack, Gudrun and Dirksen, Uta and Rutkowski, Stefan and Fr{\"u}hwald, Michael and Hoff, Katja von and Wolf, Stephan and Klingebeil, Thomas and Koscielniak, Ewa and Landgraf, Pablo and Koster, Jan and Resnick, Adam C. and Zhang, Jinghui and Liu, Yanling and Zhou, Xin and Waanders, Angela J. and Zwijnenburg, Danny A. and Raman, Pichai and Brors, Benedikt and Weber, Ursula D. and Northcott, Paul A. and Pajtler, Kristian W. and Kool, Marcel and Piro, Rosario M. and Korbel, Jan O. and Schlesner, Matthias and Eils, Roland and Jones, David T. W. and Lichter, Peter and Chavez, Lukas and Zapatka, Marc and Pfister, Stefan M.}, title = {The landscape of genomic alterations across childhood cancers}, series = {Nature}, volume = {555}, journal = {Nature}, organization = {ICGC PedBrain-Seq Project, ICGC MMML-Seq Project,}, doi = {10.1038/nature25480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229579}, pages = {321-327}, year = {2018}, abstract = {Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8\% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50\% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.}, language = {en} } @article{HarnošCanizalJuraseketal.2019, author = {Harnoš, Jakub and Ca{\~n}izal, Maria Consuelo Alonso and Jur{\´a}sek, Miroslav and Kumar, Jitender and Holler, Cornelia and Schambony, Alexandra and Han{\´a}kov{\´a}, Kateřina and Bernat{\´i}k, Ondřej and Zdr{\´a}hal, Zbyn{\^e}k and G{\"o}m{\"o}ryov{\´a}, Krist{\´i}na and Gybeľ, Tom{\´a}š and Radaszkiewicz, Tomasz Witold and Kravec, Marek and Trant{\´i}rek, Luk{\´a}š and Ryneš, Jan and Dave, Zankruti and Fern{\´a}ndez-Llamazares, Ana Iris and V{\´a}cha, Robert and Tripsianes, Konstantinos and Hoffmann, Carsten and Bryja, V{\´i}tězslav}, title = {Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09651-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227837}, year = {2019}, abstract = {Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.}, language = {en} } @article{GottschalkRichterZiegleretal.2019, author = {Gottschalk, Michael G. and Richter, Jan and Ziegler, Christiane and Schiele, Miriam A. and Mann, Julia and Geiger, Maximilian J. and Schartner, Christoph and Homola, Gy{\"o}rgy A. and Alpers, Georg W. and B{\"u}chel, Christian and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Gloster, Andrew T. and Helbig-Lang, Sylvia and Kalisch, Raffael and Kircher, Tilo and Lang, Thomas and Lonsdorf, Tina B. and Pan{\´e}-Farr{\´e}, Christiane A. and Str{\"o}hle, Andreas and Weber, Heike and Zwanzger, Peter and Arolt, Volker and Romanos, Marcel and Wittchen, Hans-Ulrich and Hamm, Alfons and Pauli, Paul and Reif, Andreas and Deckert, J{\"u}rgen and Neufang, Susanne and H{\"o}fler, Michael and Domschke, Katharina}, title = {Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-019-0415-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227479}, year = {2019}, abstract = {Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.}, language = {en} } @article{GiampaoloWojcikKleinHesslingetal.2019, author = {Giampaolo, Sabrina and W{\´o}jcik, Gabriela and Klein-Hessling, Stefan and Serfling, Edgar and Patra, Amiya K.}, title = {B cell development is critically dependent on NFATc1 activity}, series = {Cellular \& Molecular Immunology}, volume = {16}, journal = {Cellular \& Molecular Immunology}, doi = {10.1038/s41423-018-0052-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233006}, pages = {508-520}, year = {2019}, abstract = {B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.}, language = {en} } @article{SchwabMeeuwsenEhlickeetal.2017, author = {Schwab, Andrea and Meeuwsen, Annick and Ehlicke, Franziska and Hansmann, Jan and Mulder, Lars and Smits, Anthal and Walles, Heike and Kock, Linda}, title = {Ex vivo culture platform for assessment of cartilage repair treatment strategies}, series = {ALTEX - Alternatives to animal experimentation}, volume = {34}, journal = {ALTEX - Alternatives to animal experimentation}, number = {2}, doi = {10.14573/altex.1607111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181665}, pages = {267-277}, year = {2017}, abstract = {There is a great need for valuable ex vivo models that allow for assessment of cartilage repair strategies to reduce the high number of animal experiments. In this paper we present three studies with our novel ex vivo osteochondral culture platform. It consists of two separated media compartments for cartilage and bone, which better represents the in vivo situation and enables supply of factors pecific to the different needs of bone and cartilage. We investigated whether separation of the cartilage and bone compartments and/or culture media results in the maintenance of viability, structural and functional properties of cartilage tissue. Next, we valuated for how long we can preserve cartilage matrix stability of osteochondral explants during long-term culture over 84 days. Finally, we determined the optimal defect size that does not show spontaneous self-healing in this culture system. It was demonstrated that separated compartments for cartilage and bone in combination with tissue-specific medium allow for long-term culture of osteochondral explants while maintaining cartilage viability, atrix tissue content, structure and mechanical properties for at least 56 days. Furthermore, we could create critical size cartilage defects of different sizes in the model. The osteochondral model represents a valuable preclinical ex vivo tool for studying clinically relevant cartilage therapies, such as cartilage biomaterials, for their regenerative potential, for evaluation of drug and cell therapies, or to study mechanisms of cartilage regeneration. It will undoubtedly reduce the number of animals needed for in vivotesting.}, language = {en} } @phdthesis{Broehl2024, author = {Br{\"o}hl, Kathleen}, title = {„Lanfranks ‚Chirurgia parva' in der Abschrift Konrad Schrecks von Aschaffenburg" als Quelle zur sp{\"a}tmittelalterlich-fr{\"u}hneuzeitlichen Traumatologie}, doi = {10.25972/OPUS-35922}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359227}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel der vorliegenden Arbeit ist es, „Lanfranks ‚Chirurgia parva' in der Abschrift Konrad Schrecks von Aschaffenburg"1 anhand der von Ralf Vollmuth in seiner Habilitationsschrift „Traumatologie und Feldchirurgie an der Wende vom Mittelalter zur Neuzeit" erarbeiteten Strukturvorgabe inhaltlich zu erschließen. Durch die Aufarbeitung verschiedener chirurgischer Fachb{\"u}cher und Manuale unter Verwendung einer gemeinsamen Strukturvorlage soll erm{\"o}glicht werden, medizinhistorische Quellen kritisch-kontrastiv zu vergleichen. Das bedeutet, dass die Quellen zuerst ediert und anschließend gegebenenfalls {\"u}bersetzt werden m{\"u}ssen. Im n{\"a}chsten Schritt werden die verwendeten Arzneimittel - pflanzlicher, tierischer, mineralischer Herkunft - identifiziert und bestimmt. Im Anschluss werden Monographien mit den bestimmenden Inhaltsstoffen und Eigenschaften erstellt. Anhand dieser Pflanzen- und Arzneistoffmonographien, die im Sinne einer Datenbank aufeinander aufbauen, sollte es dann m{\"o}glich sein, unter modernen pharmakologischen Gesichtspunkten die Wirksamkeit der verwendeten Arzneimittel zu erschließen. Eine ausreichende Zahl von Quellen, die nach einer gemeinsamen Strukturvorlage bearbeitet wurden, kann es schließlich erm{\"o}glichen, zu beurteilen, welche der beschriebenen Anwendungen repr{\"a}sentativ waren, welche Außenseiterstellung einnahmen oder nur theoretische Ans{\"a}tze bildeten, die praktisch keine Verwendung fanden.}, subject = {Lanfrancus, Mediolanensis}, language = {de} } @phdthesis{KellnergebFriedel2024, author = {Kellner [geb. Friedel], Theresa}, title = {Suizid durch Selbstverbrennung im Freien - Eine bildmorphologische Analyse der Intensit{\"a}t und Verteilung von Verbrennungen im Zusammenhang mit der K{\"o}rperposition w{\"a}hrend des Brandgeschehens}, doi = {10.25972/OPUS-35919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359193}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel dieser Dissertation ist es, etwaige Gemeinsamkeiten und Unterschiede hinsichtlich der Distribution und Intensit{\"a}t von Brandverletzungen bei suizidaler Selbstverbrennung im Freien in Abh{\"a}ngigkeit von der jeweiligen K{\"o}rperposition zum Auffindezeitpunkt anhand der Aktenlage herauszuarbeiten. Das Studienkollektiv umfasst 38 F{\"a}lle aus 9 deutschen rechtsmedizinischen Instituten, darunter 13 (34,2 \%) weibliche und 25 (65,8 \%) m{\"a}nnliche Suizidenten/-innen im Alter von 18 - 77 Jahren. Neben einer deskriptiven visuellen Analyse erfolgt die Auswertung der Verteilung der Verbrennungen mittels der Software BurnCase 3D, die es erm{\"o}glicht, eine Sortierung der einzelnen K{\"o}rperbereiche nach deren durchschnittlicher Verbrennungsintensit{\"a}t innerhalb verschiedener Cluster f{\"u}r die unterschiedlichen Auffindepositionen am Tatort (R{\"u}ckenlage, Bauchlage, Seitenlage, Aufrecht, Sitzend) vorzunehmen. Am ehesten auf das in aufrechter Haltung beginnende Brandgeschehen zur{\"u}ckzuf{\"u}hren ist eine cluster{\"u}bergreifend auftretende, intensive und nach kranial an Intensit{\"a}t abnehmende Verbrennung des Halses sowie der lateralen und perioralen Kopfbereiche. Geringe Verbrennungsfolgen weisen die distalen unteren Extremit{\"a}ten sowie die Auflagefl{\"a}chen des K{\"o}rpers auf dem Untergrund auf. Es zeigt sich eine Beeinflussung der lokalen Verbrennungstiefe durch ein hohes Fettgewebevorkommen. Ebenfalls cluster{\"u}bergreifend k{\"o}nnen verst{\"a}rkte Brandwirkungen an den Oberschenkelinnenseiten festgestellt werden. In R{\"u}cken- und Bauchlage liegt zudem eine h{\"o}here Verbrennungsintensit{\"a}t an den Flanken, den Arminnenseiten und im Unterbauchbereich vor. Bei in Seitenlage verbrannten K{\"o}rpern ergeben sich Hinweise darauf, dass die nach oben gerichtete K{\"o}rperseite vermehrt Verbrennungen aufweist. In aufrechter und sitzender Position konzentriert sich der Brandfokus {\"u}berwiegend auf Torso, Hals und Kopf. Zus{\"a}tzlich wurde eine Betrachtung des Entstehungsmusters kutaner Hitzerisse durchgef{\"u}hrt. Hier ergaben sich {\"U}bereinstimmungen u.a. mit dem Verlauf der Hautfaltlinien nach Pinkus. Ein K{\"o}rperschema mit Abbildung der beobachteten Orientierungen der Risse wurde angefertigt. Die wichtigsten Limitationen ergeben sich aus einer geringen Fallzahl, einer fotografischen Dokumentation, die nicht alle K{\"o}rperbereiche in ausreichender Qualit{\"a}t und Detailliertheit abdeckt, sowie dem subjektiven Bias hinsichtlich der Bewertung der Verbrennungsintensit{\"a}ten.}, subject = {Selbstverbrennung}, language = {de} } @phdthesis{Landmesser2024, author = {Landmesser, Patricia Sophia}, title = {Seropr{\"a}valenz von SARS-CoV-2 Antik{\"o}rpern bei Medizinstudierenden im zweiten klinischen Semester von Juli 2020 bis Juni 2021}, doi = {10.25972/OPUS-35924}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359246}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Im sechsten Semester des Medizinstudiums an der Julius-Maximilians-Universit{\"a}t W{\"u}rzburg findet das verpflichtende Praktikum „Impfkurs" statt. Im Rahmen dieses Kurses wurde vom Sommersemester 2020 bis zum Sommersemester 2021 ein standardisierter online Fragebogen erhoben, der unter anderem demographische Daten sowie Expositionsm{\"o}glichkeiten gegen{\"u}ber SARS-CoV-2 im privaten, beruflichen und universit{\"a}ren Umfeld erfragte. Zus{\"a}tzlich wurde im gleichen Zeitraum der SARS-CoV-2 Serostatus der Medizinstudierenden erhoben und ausgewertet und dieser mit den Daten des Fragebogens zusammengef{\"u}hrt. Daf{\"u}r wurden Blutproben entnommen, welche im Labor des Instituts f{\"u}r Virologie der Universit{\"a}t W{\"u}rzburg mittels Western Blot auf IgG/IgM/IgA Antik{\"o}rper gegen SARS-CoV-2 untersucht wurden.}, subject = {SARS-CoV-2}, language = {de} } @phdthesis{Adam2024, author = {Adam, Pia Sophie}, title = {Expression von PD-L1 und FGFR1-4 beim anaplastischen und gering differenzierten Schilddr{\"u}senkarzinom - Evaluation als pr{\"a}klinische diagnostische Marker}, doi = {10.25972/OPUS-35939}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359391}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50\% was observed in 42\% of ATC and 26\% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30\%) than in PDTC (5\%; p<0.01) and NT (0\%, p<0.001). 53\% of PDTC samples had PD-L1 expression ≤5\%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.}, subject = {Schilddr{\"u}senkrebs}, language = {de} } @phdthesis{Yu2024, author = {Yu, Yanying}, title = {Applied machine learning for the analysis of CRISPR-Cas systems}, doi = {10.25972/OPUS-32021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320219}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Among the defense strategies developed in microbes over millions of years, the innate adaptive CRISPR-Cas immune systems have spread across most of bacteria and archaea. The flexibility, simplicity, and specificity of CRISPR-Cas systems have laid the foundation for CRISPR-based genetic tools. Yet, the efficient administration of CRISPR-based tools demands rational designs to maximize the on-target efficiency and off-target specificity. Specifically, the selection of guide RNAs (gRNAs), which play a crucial role in the target recognition of CRISPR-Cas systems, is non-trivial. Despite the fact that the emerging machine learning techniques provide a solution to aid in gRNA design with prediction algorithms, design rules for many CRISPR-Cas systems are ill-defined, hindering their broader applications. CRISPR interference (CRISPRi), an alternative gene silencing technique using a catalytically dead Cas protein to interfere with transcription, is a leading technique in bacteria for functional interrogation, pathway manipulation, and genome-wide screens. Although the application is promising, it also is hindered by under-investigated design rules. Therefore, in this work, I develop a state-of-art predictive machine learning model for guide silencing efficiency in bacteria leveraging the advantages of feature engineering, data integration, interpretable AI, and automated machine learning. I first systematically investigate the influential factors that attribute to the extent of depletion in multiple CRISPRi genome-wide essentiality screens in Escherichia coli and demonstrate the surprising dominant contribution of gene-specific effects, such as gene expression level. These observations allowed me to segregate the confounding gene-specific effects using a mixed-effect random forest (MERF) model to provide a better estimate of guide efficiency, together with the improvement led by integrating multiple screens. The MERF model outperformed existing tools in an independent high-throughput saturating screen. I next interpret the predictive model to extract the design rules for robust gene silencing, such as the preference for cytosine and disfavoring for guanine and thymine within and around the protospacer adjacent motif (PAM) sequence. I further incorporated the MERF model in a web-based tool that is freely accessible at www.ciao.helmholtz-hiri.de. When comparing the MERF model with existing tools, the performance of the alternative gRNA design tool optimized for CRISPRi in eukaryotes when applied to bacteria was far from satisfying, questioning the robustness of prediction algorithms across organisms. In addition, the CRISPR-Cas systems exhibit diverse mechanisms albeit with some similarities. The captured predictive patterns from one dataset thereby are at risk of poor generalization when applied across organisms and CRISPR-Cas techniques. To fill the gap, the machine learning approach I present here for CRISPRi could serve as a blueprint for the effective development of prediction algorithms for specific organisms or CRISPR-Cas systems of interest. The explicit workflow includes three principle steps: 1) accommodating the feature set for the CRISPR-Cas system or technique; 2) optimizing a machine learning model using automated machine learning; 3) explaining the model using interpretable AI. To illustrate the applicability of the workflow and diversity of results when applied across different bacteria and CRISPR-Cas systems, I have applied this workflow to analyze three distinct CRISPR-Cas genome-wide screens. From the CRISPR base editor essentiality screen in E. coli, I have determined the PAM preference and sequence context in the editing window for efficient editing, such as A at the 2nd position of PAM, A/TT/TG downstream of PAM, and TC at the 4th to 5th position of gRNAs. From the CRISPR-Cas13a screen in E. coli, in addition to the strong correlation with the guide depletion, the target expression level is the strongest predictor in the model, supporting it as a main determinant of the activation of Cas13-induced immunity and better characterizing the CRISPR-Cas13 system. From the CRISPR-Cas12a screen in Klebsiella pneumoniae, I have extracted the design rules for robust antimicrobial activity across K. pneumoniae strains and provided a predictive algorithm for gRNA design, facilitating CRISPR-Cas12a as an alternative technique to tackle antibiotic resistance. Overall, this thesis presents an accurate prediction algorithm for CRISPRi guide efficiency in bacteria, providing insights into the determinants of efficient silencing and guide designs. The systematic exploration has led to a robust machine learning approach for effective model development in other bacteria and CRISPR-Cas systems. Applying the approach in the analysis of independent CRISPR-Cas screens not only sheds light on the design rules but also the mechanisms of the CRISPR-Cas systems. Together, I demonstrate that applied machine learning paves the way to a deeper understanding and a broader application of CRISPR-Cas systems.}, subject = {Maschinelles Lernen}, language = {en} } @article{BelicPageLazariotouetal.2019, author = {Belic, Stanislav and Page, Lukas and Lazariotou, Maria and Waaga-Gasser, Ana Maria and Dragan, Mariola and Springer, Jan and Loeffler, Juergen and Morton, Charles Oliver and Einsele, Hermann and Ullmann, Andrew J. and Wurster, Sebastian}, title = {Comparative Analysis of Inflammatory Cytokine Release and Alveolar Epithelial Barrier Invasion in a Transwell® Bilayer Model of Mucormycosis}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.03204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252477}, year = {2019}, abstract = {Understanding the mechanisms of early invasion and epithelial defense in opportunistic mold infections is crucial for the evaluation of diagnostic biomarkers and novel treatment strategies. Recent studies revealed unique characteristics of the immunopathology of mucormycoses. We therefore adapted an alveolar Transwell® A549/HPAEC bilayer model for the assessment of epithelial barrier integrity and cytokine response to Rhizopus arrhizus, Rhizomucor pusillus, and Cunninghamella bertholletiae. Hyphal penetration of the alveolar barrier was validated by 18S ribosomal DNA detection in the endothelial compartment. Addition of dendritic cells (moDCs) to the alveolar compartment led to reduced fungal invasion and strongly enhanced pro-inflammatory cytokine response, whereas epithelial CCL2 and CCL5 release was reduced. Despite their phenotypic heterogeneity, the studied Mucorales species elicited the release of similar cytokine patterns by epithelial and dendritic cells. There were significantly elevated lactate dehydrogenase concentrations in the alveolar compartment and epithelial barrier permeability for dextran blue of different molecular weights in Mucorales-infected samples compared to Aspergillus fumigatus infection. Addition of monocyte-derived dendritic cells further aggravated LDH release and epithelial barrier permeability, highlighting the influence of the inflammatory response in mucormycosis-associated tissue damage. An important focus of this study was the evaluation of the reproducibility of readout parameters in independent experimental runs. Our results revealed consistently low coefficients of variation for cytokine concentrations and transcriptional levels of cytokine genes and cell integrity markers. As additional means of model validation, we confirmed that our bilayer model captures key principles of Mucorales biology such as accelerated growth in a hyperglycemic or ketoacidotic environment or reduced epithelial barrier invasion upon epithelial growth factor receptor blockade by gefitinib. Our findings indicate that the Transwell® bilayer model provides a reliable and reproducible tool for assessing host response in mucormycosis.}, language = {en} } @article{HauerPoppTaheretal.2019, author = {Hauer, Nadine N. and Popp, Bernt and Taher, Leila and Vogl, Carina and Dhandapany, Perundurai S. and B{\"u}ttner, Christian and Uebe, Steffen and Sticht, Heinrich and Ferrazzi, Fulvia and Ekici, Arif B. and De Luca, Alessandro and Klinger, Patrizia and Kraus, Cornelia and Zweier, Christiane and Wiesener, Antje and Abou Jamra, Rami and Kunstmann, Erdmute and Rauch, Anita and Wieczorek, Dagmar and Jung, Anna-Marie and Rohrer, Tilman R. and Zenker, Martin and Doerr, Helmuth-Guenther and Reis, Andr{\´e} and Thiel, Christian T.}, title = {Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature}, series = {European Journal of Human Genetics}, volume = {27}, journal = {European Journal of Human Genetics}, doi = {10.1038/s41431-019-0362-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227899}, pages = {1061-1071}, year = {2019}, abstract = {Height is a heritable and highly heterogeneous trait. Short stature affects 3\% of the population and in most cases is genetic in origin. After excluding known causes, 67\% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36\%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.}, language = {en} } @article{GilderWackKaubetal.2018, author = {Gilder, Stuart A. and Wack, Michael and Kaub, Leon and Roud, Sophie C. and Petersen, Nikolai and Heinsen, Helmut and Hillenbrand, Peter and Milz, Stefan and Schmitz, Chistoph}, title = {Distribution of magnetic remanence carriers in the human brain}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-29766-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233035}, year = {2018}, abstract = {That the human brain contains magnetite is well established; however, its spatial distribution in the brain has remained unknown. We present room temperature, remanent magnetization measurements on 822 specimens from seven dissected whole human brains in order to systematically map concentrations of magnetic remanence carriers. Median saturation remanent magnetizations from the cerebellum were approximately twice as high as those from the cerebral cortex in all seven cases (statistically significantly distinct, p = 0.016). Brain stems were over two times higher in magnetization on average than the cerebral cortex. The ventral (lowermost) horizontal layer of the cerebral cortex was consistently more magnetic than the average cerebral cortex in each of the seven studied cases. Although exceptions existed, the reproducible magnetization patterns lead us to conclude that magnetite is preferentially partitioned in the human brain, specifically in the cerebellum and brain stem.}, language = {en} } @article{GotruvanGeffenNagyetal.2019, author = {Gotru, Sanjeev Kiran and van Geffen, Johanna P. and Nagy, Magdolna and Mammadova-Bach, Elmina and Eilenberger, Julia and Volz, Julia and Manukjan, Georgi and Schulze, Harald and Wagner, Leonard and Eber, Stefan and Schambeck, Christian and Deppermann, Carsten and Brouns, Sanne and Nurden, Paquita and Greinacher, Andreas and Sachs, Ulrich and Nieswandt, Bernhard and Hermanns, Heike M. and Heemskerk, Johan W. M. and Braun, Attila}, title = {Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-44751-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227455}, year = {2019}, abstract = {Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d-/- mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn2+ release upon activation. Platelets from Nbeal2-/- mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn2+ homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2-/- and Unc13d-/- mice, and the impairment could be partially restored by extracellular Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation.}, language = {en} } @article{GoreLocatelliZugmaieretal.2018, author = {Gore, Lia and Locatelli, Franco and Zugmaier, Gerhard and Handgretinger, Rupert and O'Brien, Maureen M. and Bader, Peter and Bhojwani, Deepa and Schlegel, Paul-Gerhardt and Tuglus, Catherine A. and Stackelberg, Arend von}, title = {Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia}, series = {Blood Cancer Journal}, volume = {8}, journal = {Blood Cancer Journal}, doi = {10.1038/s41408-018-0117-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230726}, year = {2018}, abstract = {no abstract available}, language = {en} } @article{FranchiniJonesXiongetal.2018, author = {Franchini, Paolo and Jones, Julia C. and Xiong, Peiwen and Kneitz, Susanne and Gompert, Zachariah and Warren, Wesley C. and Walter, Ronald B. and Meyer, Axel and Schartl, Manfred}, title = {Long-term experimental hybridisation results in the evolution of a new sex chromosome in swordtail fish}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-07648-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228396}, year = {2018}, abstract = {The remarkable diversity of sex determination mechanisms known in fish may be fuelled by exceptionally high rates of sex chromosome turnovers or transitions. However, the evolutionary causes and genomic mechanisms underlying this variation and instability are yet to be understood. Here we report on an over 30-year evolutionary experiment in which we tested the genomic consequences of hybridisation and selection between two Xiphophorus fish species with different sex chromosome systems. We find that introgression and imposing selection for pigmentation phenotypes results in the retention of an unexpectedly large maternally derived genomic region. During the hybridisation process, the sex-determining region of the X chromosome from one parental species was translocated to an autosome in the hybrids leading to the evolution of a new sex chromosome. Our results highlight the complexity of factors contributing to patterns observed in hybrid genomes, and we experimentally demonstrate that hybridisation can catalyze rapid evolution of a new sex chromosome.}, language = {en} } @phdthesis{Krings2024, author = {Krings, Moritz}, title = {Universit{\"a}re Psychiatrie um 1900 : Die Anfangsjahre der psychiatrischen Klinik in W{\"u}rzburg}, doi = {10.25972/OPUS-36140}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361407}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ende des 19. Jahrhunderts standen sich in Deutschland zwei verschiedene Arten psychiatrischer Institutionen gegen{\"u}ber, die Anstaltspsychiatrien auf der einen, die universit{\"a}ren psychiatrischen Kliniken auf der anderen Seite. Die psychiatriehistorische Forschung widmete sich {\"u}berwiegend psychiatrischen Anstalten w{\"a}hrend Kliniken hier unterrepr{\"a}sentiert sind. Die vorliegende Arbeit m{\"o}chte zur historischen Kenntnis universit{\"a}rer psychiatrischer Einrichtungen beitragen. Hierzu werden die Charakteristika einer psychiatrischen Klinik um 1900 anhand des Beispiels der psychiatrischen Klinik der Universit{\"a}t W{\"u}rzburg betrachtet. Der Fokus liegt hierbei neben Lage und Aufbau der Klinik sowie deren Personal auf den drei Bereichen Patient*innen, Forschung und Lehre.}, subject = {Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, language = {de} } @phdthesis{Zuber2024, author = {Zuber, Jonas Maximilian}, title = {Evaluation von Sedierungen und Allgemeinan{\"a}sthesien zur Durchf{\"u}hrung bildgebender Verfahren bei S{\"a}uglingen bis zum 6. Lebensmonat}, doi = {10.25972/OPUS-36111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361111}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Vorliegende Untersuchung am Universit{\"a}tsklinikum W{\"u}rzburg sowie die Befragung von An{\"a}sthesisten/An{\"a}sthesistinnen im Raum der 3 DACH-L{\"a}nder zeigen, dass bildgebende Verfahren bei S{\"a}uglingen mit einer niedrigen Rate an Komplikationen, zumeist in medikament{\"o}ser Sedierung mit Propofol, durchgef{\"u}hrt werden. Wie international {\"u}blich ist im S{\"a}uglingsalter die Magnetresonanztomographie das bildgebende Verfahren der Wahl und wird, mit {\"u}berzeugender H{\"a}ufigkeit, erfolgreich durchgef{\"u}hrt. Die Untersuchung am Universit{\"a}tsklinikum W{\"u}rzburg legt nahe, dass m{\"a}nnliche S{\"a}uglinge h{\"a}ufiger eine Bildgebung ben{\"o}tigen und h{\"a}ufiger h{\"o}heren ASA-Kategorie zugeschrieben werden. Dabei scheinen sie auch h{\"a}ufiger Komplikationen zu erleben und bed{\"u}rfen daher besonderer Aufmerksamkeit. Eine eventuelle Alternative zur Sedierung kann dabei die „feed-and-sleep" Methode darstellen. In unserer Umfrage konnten wir erheben, dass diese Methode bisher wenig verbreitet ist, obwohl in diesem Zusammenhang eventuell Abl{\"a}ufe und Prozesszeiten strukturiert und optimiert werden k{\"o}nnen, da beispielsweise die Nach{\"u}berwachung entf{\"a}llt. Vorstellbar w{\"a}re beispielsweise, mehrere S{\"a}uglinge zum gleichen Zeitpunkt ins MRT zu bestellen, um gegebenenfalls den am fr{\"u}hesten eingeschlafenen S{\"a}ugling vorzuziehen. Diese Methode sollte zuk{\"u}nftig Einzug in die wissenschaftliche Untersuchung von bildgebenden Verfahren bei S{\"a}uglingen finden. Die Umfrage im deutschsprachigen Raum zeigt eine Leitlinien-gerechte Betreuung von S{\"a}uglingen f{\"u}r bildgebende Verfahren, die mit einer hohen Qualit{\"a}t, und zumeist erfolgreich von erfahrenen An{\"a}sthesisten/An{\"a}sthesistinnen durchgef{\"u}hrt wird. Eventuelle Verbesserungen k{\"o}nnen im Bereich der Ausbildung nachfolgender {\"A}rztinnen/{\"A}rzte und in der h{\"a}ufigeren Verwendung der „feed-and-sleep" Methode liegen, die vielen Kollegen/Kolleginnen bekannt ist, aber nur selten durchgef{\"u}hrt wird. Ziel ist eine qualitativ hochwertige, schnellstm{\"o}glich durchgef{\"u}hrte Bildgebung, die ohne oder mit der niedrigst m{\"o}glichen Dosierung eines sedierenden Medikamentes zu erreichen ist.}, subject = {Sedierung}, language = {de} } @phdthesis{Dalkmann2024, author = {Dalkmann, Theresa}, title = {Evaluierung prognostischer und pr{\"a}diktiver Biomarker beim neoadjuvant vorbehandelten Rektumkarzinom}, doi = {10.25972/OPUS-36336}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363368}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Fragestellung. Osteopontin (OPN) kann im Blut nachgewiesen werden und wird bei vielen Tumorentit{\"a}ten exprimiert, wie auch der Tyrosinkinaserezeptor c-Met und sein Ligand, das Zytokin Hepatocyte Growth Factor (HGF). In der vorliegenden Arbeit untersuchten wir die prognostische und pr{\"a}diktive Wertigkeit der Plasmakonzentrationen von OPN, c-Met und HGF bei Patienten mit lokal fortgeschrittenem Rektumkarzinom (LARC). Methodik. Das Plasma von 63 Patienten mit LARC wurde untersucht. Die Blutentnahmen (EDTA-Plasma) erfolgten vor Therapiebeginn sowie im Verlauf. Die Plasmaspiegel von OPN, c-Met und HGF wurden mittels Enzyme-Linked Immunosorbent Assay analysiert. Die Konzentrationen wurden auf eine Korrelation mit den klinischen Parametern untersucht. Ergebnisse. 68 Patienten wurden neoadjuvant mit einer Radiochemotherapie behandelt, 63 Blutproben wurden untersucht. Initial befanden sich nach UICC 14 Patienten in Stadium II, 47 in Stadium III und 7 in Stadium IV. Das mediane Follow-Up betrug 29,87 Monate. 20 der 68 Patienten (29,4 \%) verstarben, 19 entwickelten Fernmetastasen. OPN korrelierte signifikant mit dem {\"U}berleben (p=0,001). OPN-Werte korrelierten mit dem pT-Stadium (R:0,445 p=0,018) und dem pUICC-Stadium (R:0,412 p=0,018), sowie mit dem Auftreten von Fernmetastasen (R:0,271 p=0,031). Eine Korrelation zwischen OPN und dem Therapieansprechen konnte gezeigt werden: pathologisch komplette Remission (pCR) (R:0,379 p=0,001), NAR-Score (R:0,373 p=0,015), TRG (R:0,380 p=0,020). Die logistische Regressionsanalyse ergab eine Pr{\"a}diktivit{\"a}t OPNs f{\"u}r pCR (OR:0,990 p=0,009), NAR-Score (OR:1,008 p=0,007), TRG (OR:0,459 p=0,008). C-Met und HGF korrelierten nicht mit dem {\"U}berleben. F{\"u}r c-Met und HGF ergab sich keine Korrelation zu initialen klinischen Daten und Therapieansprechen. Die logistische Regression ergab keinen pr{\"a}diktiven Wert. Schlussfolgerung. Die Plasmakonzentration von OPN besitzt prognostische und pr{\"a}diktive Wertigkeit beim LARC. Die Konzentrationen von c-Met und HGF sind nicht prognostisch f{\"u}r das {\"U}berleben oder pr{\"a}diktiv f{\"u}r das Therapieansprechen.}, subject = {Biomarker}, language = {de} } @phdthesis{Bredemeyer2024, author = {Bredemeyer, Cynthia Natascha}, title = {Akademisierung und Professionalisierung der Zahnheilkunde, insbesondere der Zahnchirurgie, in W{\"u}rzburg und Unterfranken im 19. Jahrhundert}, doi = {10.25972/OPUS-36387}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363878}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Arbeit befasst sich mit der Akademisierung und Professionalisierung der Zahnheilkunde, insbesondere der Zahnchirurgie, in W{\"u}rzburg und Unterfranken im 19. Jahrhundert. Dies wurde insbesondere anhand des zahnchirurgischen Teils der Lehrchirurgischen Instrumentensammlung der Universit{\"a}t W{\"u}rzburg bzw. des Juliusspitals erforscht. Der zahnchirurgische Teil der Instrumentensammlung war bisher noch nicht erforscht worden und besteht aktuell aus 34+1 Instrumenten, die f{\"u}r diese Arbeit komplett katalogisiert wurden. F{\"u}r die Entwicklung der Instrumente im Verlauf des 19. Jahrhunderts wurde die Provenienz der Teilsammlung ergr{\"u}ndet und diese in den Kontext der Akademisierungsbewegung des 19. Jahrhunderts eingeordnet. Die Forschung wurde anhand der tats{\"a}chlich in der Praxis t{\"a}tigen und nach und nach akademisch ausgebildeten Personen nachvollzogen. Hierzu wurden neben den Instrumenten als Quelle die Adressb{\"u}cher der Stadt W{\"u}rzburg und die Matrikel-, Personal- und Vorlesungsverzeichnisse der Universit{\"a}t W{\"u}rzburg des gesamten 19. Jahrhunderts systematisch durchgearbeitet. Außerdem wurden Lehrb{\"u}cher aus dem nichtakademischen zahnchirurigischen Bereich (Bader) mit denen aus dem sich beginnenden akademischen Bereich analysiert. Anhand dieser Forschungsarbeit konnte dargelegt werden, dass die Zahnchirurgie sich analog zur Chiurgie aus dem handwerklichen Bereich abgekoppelt und nach und nach auf verschiedenen Stufen akademisiert hat. Die Zahnchirurgie hat sich "von unten nach oben" durch das Bestreben nichtakademisch ausgebildeter Menschen akademisiert.}, subject = {Zahnchirurgie}, language = {de} } @phdthesis{Papay2024, author = {Papay, Marion}, title = {Notwendigkeit der pr{\"a}operativen Reposition von distalen, nach dorsal dislozierten Radiusfrakturen bei bestehender Operationsindikation im Hinblick auf das Schmerzniveau sowie postoperative Ergebnisse}, doi = {10.25972/OPUS-36388}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363882}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die distale Radiusfraktur geh{\"o}rt zu den h{\"a}ufigsten Frakturen in Deutschland mit einem Inzidenzanstieg im Alter unter Betonung des weiblichen Geschlechts. Dabei zeigt sich ein zunehmender Trend in Richtung operative Versorgung, allen voran die Versorgung mittels winkelstabiler Plattensysteme. Instabile, distale Radiusfrakturen werden dabei vor geplanter operativer Versorgung im Rahmen der Initialbehandlung {\"u}blicherweise geschlossen reponiert und im Gipsverband retiniert. Ziel der vorliegenden monozentrischen, prospektiv randomisierten Studie mit zwei Studiengruppen war es herauszufinden, ob sich das Unterlassen der Reposition vor geplanter Operation nachteilig auf das Schmerzniveau in der pr{\"a}operativen Phase auswirkt und ob sich durch die Dislokation Nachteile in Bezug auf den Nervus medianus im Sinne eines Traktionsschadens sowie bez{\"u}glich des klinisch-radiologischen Ausheilungsergebnisses zeigen. Die Studie zeigte, dass das Schmerzempfinden w{\"a}hrend der pr{\"a}operativen Gipsbehandlung unabh{\"a}ngig von einer vorherigen Reposition war. F{\"u}r den prim{\"a}ren Endpunkt an Tag 1 nach der Akutbehandlung konnte statistisch signifikante Nichtunterlegenheit der Gruppe ohne Reposition gegen{\"u}ber der Gruppe mit Reposition nachgewiesen werden. Gleiches galt f{\"u}r Tag 2, sowohl f{\"u}r die absoluten Schmerzniveaus als auch f{\"u}r die Schmerzlinderung. Das Unterlassen der Reposition hatte zudem keine nachteiligen Effekte auf den Nervus medianus. Gleiches zeigte sich f{\"u}r das klinische und radiologische Ausheilungsergebnis. F{\"u}r die funktionellen DASH- und Krimmer-Scores konnte ein Jahr postoperativ ebenfalls statistisch signifikante Nichtunterlegenheit der Gruppe ohne Reposition nachgewiesen werden. Diese Erkenntnisse best{\"a}tigen die in der Literatur vorhandenen Ergebnisse verschiedener Studien dahingehend, dass das Unterlassen der Reposition keine nachteiligen Effekte auf das postoperative Outcome hat. Einige Studien verdeutlichen zudem, dass es nach Reposition, insbesondere bei Vorliegen gewisser Risiko- und Instabilit{\"a}tsfaktoren, ohnehin zur sekund{\"a}ren Dislokation kommt, sodass die generelle Notwendigkeit der Reposition vor Gipsanlage sowohl vor einer operativen als auch vor einer konservativen Weiterbehandlung angezweifelt werden muss.}, subject = {distale Radiusfraktur}, language = {de} } @article{AllertFoersterSvenssonetal.2018, author = {Allert, Stefanie and F{\"o}rster, Toni M. and Svensson, Carl-Magnus and Richardson, Jonathan P. and Pawlik, Tony and Hebecker, Betty and Rudolphi, Sven and Juraschitz, Marc and Schaller, Martin and Blagojevic, Mariana and Morschh{\"a}user, Joachim and Figge, Marc Thilo and Jacobsen, Ilse D. and Naglik, Julian R. and Kasper, Lydia and Mogavero, Selene and Hube, Bernhard}, title = {\(Candida\) \(albicans\)-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers}, series = {mBio}, volume = {9}, journal = {mBio}, number = {3}, doi = {10.1128/mBio.00915-18}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221084}, pages = {1-20}, year = {2018}, abstract = {Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream. While the microbial and host mechanisms permitting bacterial gut translocation are well characterized, these mechanisms are still unclear for fungal pathogens such as Candida albicans, a leading cause of nosocomial fungal bloodstream infections. In this study, we dissected the cellular mechanisms of translocation of C. albicans across intestinal epithelia in vitro and identified fungal genes associated with this process. We show that fungal translocation is a dynamic process initiated by invasion and followed by cellular damage and loss of epithelial integrity. A screen of >2,000 C. albicans deletion mutants identified genes required for cellular damage of and translocation across enterocytes. Correlation analysis suggests that hypha formation, barrier damage above a minimum threshold level, and a decreased epithelial integrity are required for efficient fungal translocation. Translocation occurs predominantly via a transcellular route, which is associated with fungus-induced necrotic epithelial damage, but not apoptotic cell death. The cytolytic peptide toxin of C. albicans, candidalysin, was found to be essential for damage of enterocytes and was a key factor in subsequent fungal translocation, suggesting that transcellular translocation of C. albicans through intestinal layers is mediated by candidalysin. However, fungal invasion and low-level translocation can also occur via non-transcellular routes in a candidalysin-independent manner. This is the first study showing translocation of a human-pathogenic fungus across the intestinal barrier being mediated by a peptide toxin. IMPORTANCE Candida albicans, usually a harmless fungus colonizing human mucosae, can cause lethal bloodstream infections when it manages to translocate across the intestinal epithelium. This can result from antibiotic treatment, immune dysfunction, or intestinal damage (e.g., during surgery). However, fungal processes may also contribute. In this study, we investigated the translocation process of C. albicans using in vitro cell culture models. Translocation occurs as a stepwise process starting with invasion, followed by epithelial damage and loss of epithelial integrity. The ability to secrete candidalysin, a peptide toxin deriving from the hyphal protein Ece1, is key: C. albicans hyphae, secreting candidalysin, take advantage of a necrotic weakened epithelium to translocate through the intestinal layer.}, language = {en} } @phdthesis{Hahn2024, author = {Hahn, Sarah}, title = {Investigating non-canonical, 5' UTR-dependent translation of MYC and its impact on colorectal cancer development}, doi = {10.25972/OPUS-36420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Colorectal cancer (CRC) is the second most common tumour disease in Germany, with the sequential accumulation of certain mutations playing a decisive role in the transition from adenoma to carcinoma. In particular, deregulation of the Wnt signalling pathway and the associated deregulated expression of the MYC oncoprotein play a crucial role. Targeting MYC thus represents an important therapeutic approach in the treatment of tumours. Since direct inhibition of MYC is challenging, various approaches have been pursued to date to target MYC indirectly. The MYC 5' UTR contains an internal ribosomal entry site (IRES), which has a particular role in the initiation of MYC translation, especially in multiple myeloma. As basis for this work, it was hypothesised on the basis of previous data that translation of MYC potentially occurs via its IRES in CRC as well. Based on this, two IRES inhibitors were tested for their potential to regulate MYC expression in CRC cells. In addition, alternative, 5' UTR-dependent translation of MYC and interacting factors were investigated. EIF3D was identified as a MYC 5' UTR binding protein which has the potential to regulate MYC expression in CRC. The results of this work suggest that there is a link between eIF3D and MYC expression/translation, rendering eIF3D a potential therapeutic target for MYC-driven CRCs.}, subject = {Myc}, language = {en} } @phdthesis{Laqua2024, author = {Laqua, Caroline}, title = {Association of myocardial tissue characteristics and functional outcome in biopsy-verified myocarditis assessed by cardiac magnetic resonance imaging}, doi = {10.25972/OPUS-36390}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363903}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The relation between LV function and cardiac MRI tissue characteristics in separate myocardial segments and their change over time has yet to be explored in myocarditis. Thus, our research aimed to investigate possible associations between global and regional myocardial T1 and T2 times and peak strain in patients with suspected myocarditis. From 2012 to 2015, 129 patients with clinically suspected myocarditis of the prospective, observational MyoRacer-Trial underwent systematic biventricular EMB at baseline and cardiac MRI at baseline and after three months as a follow-up. We divided the LV myocardium into 17 segments and estimated the segmental myocardial strain using FT. We registered T1 and T2 maps to the cine sequences and transferred the segmentations used for FT to ensure conformity of the myocardial segments. Multi-level multivariable linear mixed effects regression was applied to investigate the relation of segmental myocardial strain to relaxation times and their respective change from baseline to follow-up. We found a significant improvement in myocardial peak strain from baseline to follow-up (p < 0.001; all p-values given for likelihood ratio tests) and significant associations between higher T1 and T2 times and lower segmental myocardial peak strain (p ranging from < 0.001 to 0.049). E.g., regression coefficient (Reg. coef.) for segmental radial peak strain in short axis view (SRPS_SAX) and T1 time: -1.9, 95\% CI (-2.6;-1.2) \%/100 ms, p < 0.001. A decrease in T1 and T2 times from baseline to follow-up was also significantly related to a recovery of segmental peak strains (p ranging from < 0.001 to 0.050). E.g., Reg. coef. for SRPS_SAX per ΔT1: -1.8, 95\% CI (-2.5;-1.0) \%/100 ms, p < 0.001. Moreover, the higher the baseline T1 time, the more substantial the functional recovery from baseline to follow-up (p ranging from 0.004 to 0.042, e.g., for SRPS_SAX: Reg. coef. 1.3, 95\% CI (0.4;2.1) \%/100 ms, p 0.004). We did not find an effect modification by the presence of myocarditis in the EMB (p > 0.1). Our cross-sectional and longitudinal analyses provide evidence of dose-dependent correlations between T1 and T2 relaxation times and myocardial peak strain in patients with clinical presentation of myocarditis, regardless of the EMB result. Thus, assessing strain values and mapping relaxation times helps estimate the functional prognosis in patients with clinically suspected myocarditis.}, subject = {Myokarditis}, language = {en} } @phdthesis{Stuerzebecher2024, author = {St{\"u}rzebecher, Paulina Elena}, title = {Die Rolle von LASP1 in der Pathogenese der Atherosklerose im murinen Modell}, doi = {10.25972/OPUS-23935}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239353}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das regulatorische Ger{\"u}st-Protein LASP1, welches aus der Krebsforschung bekannt ist, wurde 2012 in humanen Makrophagen, den Protagonisten der Atherosklerose nachgewiesen. LASP1 ist durch seine Lokalisation an dynamischen Aktinskelettkonstruktionen (vgl. Invadopodien, Podosomen), nachweislich an Zellmigration, Proliferation und Invasionsf{\"a}higkeit bestimmter Tumorzellen beteiligt. Aufgrund einer großen Schnittmenge der Entstehungsmechanismen und zugrundeliegenden Signalwegen von Krebserkrankungen und Atherosklerose wurde LASP1 im Zusammenhang der Atherosklerose untersucht. In einem 16 Wochen Hochfettdi{\"a}tversuch zeigten LASP1.Ldlr-/--M{\"a}use mehr atherosklerotische L{\"a}sionen in der Gesamtaorta als Ldlr-/--Tiere, was eine athero-protektive Rolle von LASP1 nahelegt. Passend hierzu f{\"u}hrte Stimulation mit oxLDL in Makrophagen zu einer Hochregulation von LASP1. Zus{\"a}tzlich internalisierten LASP1-/--Makrophagen signifikant mehr oxLDL im Vergleich zu LASP1-exprimierenden Zellen. Analog zu den Daten aus der Krebsforschung konnte eine reduzierte endotheliale Adh{\"a}sion sowie chemotaktische Migration von Ldlr.LASP1-/--Monozyten im Vergleich zu Ldlr-/-- Monozyten festgestellt werden. Dies ließe isoliert betrachtet eine pro-atherogene Rolle von LASP1 vermuten. Ein Nachweis von LASP1 im Zellkern von BMDMs konnte, zus{\"a}tzlich zum fehlenden Shuttelproteinpartner ZO-2, nicht erbracht werden. Die Interaktion von LASP1 mit Transkriptionsfaktoren scheint daher unwahrscheinlich. Kongruent mit diesen Ergebnissen zeigte sich keine Ver{\"a}nderung der Transkription, der Proteinexpression sowie Sekretion von TNF! und ADAM17 durch den LASP1-KO. Insgesamt kommt LASP1 eine zweifellos komplexe Rolle in der Atherogenese zu. Die Ergebnisse der HFD-Versuche legen nahe, dass die prim{\"a}r anti-atherosklerotischen Einfl{\"u}sse von LASP1 in vivo gegen{\"u}ber den eher pro-atherosklerotischen Effekten des Proteins in vitro {\"u}berwiegen.}, subject = {Arteriosklerose}, language = {de} } @phdthesis{Friedrich2024, author = {Friedrich, Anna-Lena}, title = {FoxO3-mediated, inhibitory effects of CNP on the profibrotic activation of lung fibroblasts}, doi = {10.25972/OPUS-35984}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359845}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Idiopathic Pulmonary Fibrosis (IPF) is a progressive parenchymal lung disease with limited therapeutic treatments. Pathologically altered lung fibroblasts, called myofibroblasts, exhibit increased proliferation, migration, and collagen production, and drive IPF development and progression. Fibrogenic factors such as Platelet derived growth factor-BB (PDGF-BB) contribute to these pathological alterations. Endogenous counter-regulating factors are barely known. Published studies have described a protective role of exogenously administered C-type Natriuretic Peptide (CNP) in pathological tissue remodeling, for example in heart and liver fibrosis. CNP and its cyclic GMP producing guanylyl cyclase B (GC-B) receptor are expressed in the lungs, but it is unknown whether CNP can attenuate lung fibrosis by this pathway. To address this question, we performed studies in primary cultured lung fibroblasts. To examine the effects of the CNP/GC-B pathway on PDGF-BB-induced collagen production, proliferation, and migration in vitro, lung fibroblasts were cultured from wildtype control and GC-B knockout mice. Human lung fibroblasts from patients with IPF and healthy controls were obtained from the UGMLC Biobank. In RIA experiments, CNP, at 10nM and 100nM, markedly and similarly increased cGMP levels in both the murine and human lung fibroblasts, demonstrating GC-B/cGMP signaling. CNP reduced PDGF-BB induced proliferation and migration of lung fibroblasts in BrdU incorporation and gap closure assays, respectively. CNP strongly decreased PDGF-BB-induced collagen 1/3 expression as measured by immunocytochemistry and immunoblotting. Importantly, the protective actions of CNP were preserved in IPF fibroblasts. It is known that the profibrotic actions of PDGF-BB are partly mediated by phosphorylation and nuclear export of Forkhead Box O3 (FoxO3), a transcription factor downregulated in IPF. CNP prevented PDGF-BB elicited FoxO3 phosphorylation and nuclear exclusion in both murine and human control and IPF fibroblasts. CNP signaling and functions were abolished in GC-B-deficient lung fibroblasts. Taken together, the results show that CNP moderates the PDGF-BB-induced activation and differentiation of human and murine lung fibroblasts to myofibroblasts. This effect is mediated CNP-dependent by GC-B/cGMP signaling and FoxO3 regulation. To follow up the patho-physiological relevance of these results, we are generating mice with fibroblast-restricted GC-B deletion for studies in the model of bleomycin-induced pulmonary fibrosis.}, subject = {Idiopathische pulmonale Fibrose}, language = {en} } @phdthesis{Menger2024, author = {Menger, Kristina Rebekka}, title = {Bauchlagerung f{\"u}r nicht-intubierte ARDS- und COVID-19 Patient/innen: eine systematische {\"U}bersichtsarbeit}, doi = {10.25972/OPUS-35986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359865}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Bauchlagerung von intubierten ARDS-Patient/innen mit einer schlechten Oxygenierung wird laut Leitlinie seit mehreren Jahren als supportive Therapiemaßnahme empfohlen. Im Rahmen der COVID-19 Pandemie wurde nun erstmalig die Bauchlagerung auch bei hypox{\"a}mischen, nicht-intubierten Patient/innen untersucht. Diese Fragestellung wurde in der vorliegenden Arbeit mittels einer systematischen {\"U}bersichtsarbeit betrachtet. Aufgrund der aktuellen Pandemiesituation wurden neben ARDS-Patient/innen im Allgemeinen insbesondere COVID-19 Patient/innen mit einem akuten Lungenversagen als Subgruppe untersucht. Am 21.11.2020 wurde eine systematische Suche nach Studien in den Datenbanken MEDLINE, Cochrane COVID-19 Study Register und Living Overview of the Evidence platform durchgef{\"u}hrt. Die Ergebnisse wurden, wo m{\"o}glich, in Form einer Meta-Analyse zusammengefasst, in Tabellen darstellt oder deskriptiv beschrieben. Das Risiko f{\"u}r Bias wurde jeweils f{\"u}r die eingeschlossenen kontrollierten Studien mittels ROBINS-I beurteilt. Die Vertrauensw{\"u}rdigkeit der Evidenz der gesamten Arbeit wurde mit Hilfe des GRADE-Ansatzes untersucht. Insgesamt wurden 30 Studien eingeschlossen, davon 4 kontrollierte Studien, keine RCTs. In 3 der kontrollierten Studien wurde die Bauchlagerung bei COVID-19 Patient/innen untersucht, in einer bei Patient/innen mit einem anderweitig verursachten ARDS. Es ist unklar, ob die Bauchlagerung die Intubationsrate (RR = 0,92; 95\% KI: 0,59 - 1,44; I² = 65\%; sehr niedrige Vertrauensw{\"u}rdigkeit der Evidenz), die Mortalit{\"a}t (RR = 0,55; 95\% KI: 0,23 - 1,30; I² = 60\%; sehr niedrige Vertrauensw{\"u}rdigkeit der Evidenz) und die Wahrscheinlichkeit f{\"u}r eine Aufnahme auf die Intensivstation (RR = 0,94; 95\% KI: 0,54 - 1,63; I2 = 71\%; sehr niedrige Vertrauensw{\"u}rdigkeit der Evidenz) verringern kann. Auch f{\"u}r die anderen betrachteten Endpunkte konnte kein signifikanter Effekt der Bauchlagerung nachgewiesen werden Im Vergleich der Subgruppen „Nicht-COVID-19" (8 Studien) und „COVID-19" (22 Studien) konnten in Bezug auf alle betrachteten Endpunkte keine relevanten Unterschiede festgestellt werden. Insgesamt ist die Evidenz nicht ausreichend, um Vor- und Nachteile der Bauchlagerung f{\"u}r nicht-intubierte ARDS Patient/innen gegen{\"u}ber der {\"u}blichen R{\"u}ckenlagerung aufzuzeigen und diese f{\"u}r die Praxis zu empfehlen.}, subject = {Bauchlage}, language = {de} } @phdthesis{Hajduk2024, author = {Hajduk, Maurice Martin}, title = {Darf es etwas mehr sein? Neuroenhancement im Studium - eine Befragung an W{\"u}rzburger Hochschulen}, doi = {10.25972/OPUS-35981}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359812}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Neuroenhancement (NE) bezeichnet die Einnahme psychotroper Substanzen mit dem Ziel der geistigen Leistungssteigerung oder Beruhigung. NE wird durch gesunde Perso- nen genutzt. Es besteht somit keine Indikation zur Einnahme psychotroper Wirkstoffe. Zum NE genutzte Substanzen sind z.B. Koffeintabletten, verschreibungspflichtige Medi- kamente oder illegale Substanzen. Die bisherige Forschung findet Hinweise auf einen Zusammenhang zwischen NE und ADHS-Symptomen, einigen Aspekten psychischer Gesundheit, sowie Substanzkonsum. Bisher gibt es keine Forschung zu NE am Hoch- schulstandort W{\"u}rzburg. Es wurde eine anonyme online Querschnittsbefragung im ersten Quartal 2021 durchge- f{\"u}hrt. Eingeladen waren 5600 Studierende der Julius-Maximilians-Universit{\"a}t W{\"u}rzburg und der Hochschule f{\"u}r angewandte Wissenschaften W{\"u}rzburg Schweinfurt. Der Frage- bogen bestand aus 53 Items und enthielt u. a. die folgenden validierten Messinstrumente: ASRS, PSS-10, PHQ-4 und AUDIT-C. Die Response Rate lag bei 18\% (n = 1011). Das Wissen {\"u}ber NE war weit unter den Stu- dierenden verbreitet. Die Pr{\"a}valenz f{\"u}r Neuroenhancement im Studium lag bei 12.7\%. Die drei meistgenannten Substanzen waren Koffeintabletten (6.6\%), Cannabis (4.5\%) und Methylphenidat (4.3\%). H{\"a}ufigster Anlass f{\"u}r NE war die Pr{\"u}fungsvorbereitung. Es zeigten sich deutliche Unterschiede zwischen den Fachbereichen, u.a. hinsichtlich der Pr{\"a}valenz von NE. ADHS-Symptomen, Stress, {\"A}ngstlichkeit, und Depressivit{\"a}t waren positiv mit NE assoziiert. Ein st{\"a}rkerer Effekt ergab sich f{\"u}r den Zusammenhang zwi- schen NE und riskanten Alkoholkonsum bzw. Tabakkonsum. Diese Ergebnisse wurden durch eine binomial logistische Regression best{\"a}tigt. Die konsumierten Substanzen, das Wissen {\"u}ber NE, die Pr{\"a}valenz von NE und die Gr{\"u}nde f{\"u}r dessen Nutzung f{\"u}gen sich nahtlos in die bisherige Forschung ein. Auch die Assoziation zwischen ADHS-Symptomen, Stress, {\"A}ngstlichkeit, Depressivit{\"a}t, riskan- tem Alkoholkonsum und Tabakkonsum best{\"a}tigt bisherige Forschungsergebnisse. Es konnte gezeigt werden, dass rund ein Zehntel der Studierenden NE bereits genutzt haben. In Anbetracht der gesundheitlichen Gefahren, die mit NE einhergehen ist die Etab- lierung bzw. der Ausbau von Aufkl{\"a}rung-, Beratungs- und Hilfsangeboten f{\"u}r Studie- rende anzustreben sowie weitere Forschung zum Thema indiziert.}, subject = {Psychische Gesundheit}, language = {de} } @phdthesis{Hammel2024, author = {Hammel, Clara}, title = {Einfluss longitudinaler Ver{\"a}nderungen der linksventrikul{\"a}ren Ejektionsfraktion auf das Langzeit{\"u}berleben bei Herzinsuffizienzpatienten mit leicht reduzierter Ejektionsfraktion oder reduzierter Ejektionsfraktion}, doi = {10.25972/OPUS-36002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360025}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Diese retrospektive Studie an der Universit{\"a}tsklinik W{\"u}rzburg diente der Beurteilung der longitudinalen Funktion in Bezug auf die Gesamtmortalit{\"a}t bei Patienten mit HFmrEF und HFrEF. Die Gruppierung erfolgte anhand der jeweiligen Baseline LVEF. Eine weitere Unterteilung erfolgte in eine isch{\"a}mische oder nicht-isch{\"a}mische Genese der HF. Die Subgruppen wurden anhand der Baseline klinischen Charakteristika sowie der echokardiographischen Parameter verglichen. Hier ließ sich ein relativ {\"a}hnliches Patientenklientel mit vergleichbarem Alter, Geschlecht, BMI sowie kardialen Risikofaktoren zeigen. Signifikante Unterschiede ergab der Vergleich des NYHA-Stadiums, der Nierenfunktion sowie des Auftretens von Myokardinfarkten. Die Ver{\"a}nderung der LVEF {\"u}ber die Zeit hat einen zentralen Stellenwert zur Evaluation des Outcomes von Patienten mit HFmrEF und HFrEF. Eine Verbesserung der LVEF fand sich signifikant h{\"a}ufiger bei HFrEF Patienten als bei HFmrEF Patienten, welche {\"u}ber die Zeit signifikant h{\"a}ufiger eine stabile LVEF aufwiesen. Außerdem war nach Auswertung der {\"U}berlebenskurven nach Kaplan-Meier in HFmrEF Patienten eine verbesserte oder unver{\"a}nderte LVEF {\"u}ber die Zeit mit einem besseren {\"U}berleben verbunden, vor allem bei Patienten mit isch{\"a}mischer {\"A}tiologie. In der HFrEF Gruppe konnte gezeigt werden, dass sowohl Patienten mit isch{\"a}mischer als auch mit nicht-isch{\"a}mischer {\"A}tiologie bei Vorliegen einer verbesserten oder unver{\"a}nderten LVEF {\"u}ber die Zeit ein besseres Outcome aufwiesen. Eine erniedrigte MAPSE bedeutete vor allem bei HFmrEF Patienten mit nicht-isch{\"a}mischer {\"A}tiologie ein schlechteres Outcome. Die Ergebnisse dienten unter anderem der weiteren Charakterisierung der HFmrEF und HFrEF Gruppe sowie der Identifikation von Faktoren zur Beurteilung der Ver{\"a}nderung der LVEF {\"u}ber die Zeit und der Prognose des Langzeit{\"u}berlebens beider Gruppen. Ziel f{\"u}r die Zukunft sollte sein, auch f{\"u}r HFmrEF Patienten evidenzbasierte Herzinsuffizienz Therapien zu etablieren.}, subject = {Transthorakale Echokardiographie}, language = {de} } @phdthesis{Morabbian2024, author = {Morabbian, Jasamin}, title = {Etablierung von Stammzell-Sph{\"a}roiden mit inkorporierten Biokeramik-Partikeln zur F{\"o}rderung der osteogenen Differenzierung}, doi = {10.25972/OPUS-36925}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369256}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In der vorliegenden Dissertationsarbeit wurden Sph{\"a}roide aus mesenchymalen Stammzellen aus dem Fettgewebe oder dem Knochenmark mittels der Micromold-Methode hergestellt. Den Sph{\"a}roiden wurden entweder Calciumphosphat- oder Calcium-Magnesium-Phosphat-Partikel hinzugef{\"u}gt. Zum einen sollte {\"u}berpr{\"u}ft werden, ob die Zugabe von Partikeln die osteogene Differenzierung der Sph{\"a}roide f{\"o}rdert und somit zur weiteren Entwicklung von k{\"o}rpereigenem Knochenersatzmaterial in der regenerativen Medizin beitr{\"a}gt. Zum anderen sollte festgestellt werden, ob eine der beiden Biokeramiken hinsichtlich der osteogenen Differenzierung {\"u}berlegen ist.}, subject = {Stammzelle}, language = {de} } @article{GhoshHoenscheidDueckersetal.2017, author = {Ghosh, Sujal and H{\"o}nscheid, Andrea and D{\"u}ckers, Gregor and Ginzel, Sebastian and Gohlke, Holger and Gombert, Michael and Kempkes, Bettina and Klapper, Wolfram and Kuhlen, Michaela and Laws, Hans-J{\"u}rgen and Linka, Ren{\´e} Martin and Meisel, Roland and Mielke, Christian and Niehues, Tim and Schindler, Detlev and Schneider, Dominik and Schuster, Friedhelm R. and Speckmann, Carsten and Borkhardt, Arndt}, title = {Human RAD52 - a novel player in DNA repair in cancer and immunodeficiency}, series = {Haematologica}, volume = {102}, journal = {Haematologica}, number = {2}, doi = {10.3324/haematol.2016.155838}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180862}, pages = {e69-e72}, year = {2017}, abstract = {No abstract available.}, language = {en} }