@article{RobinsonHutmacherDalton2019, author = {Robinson, Thomas M. and Hutmacher, Dietmar W. and Dalton, Paul D.}, title = {The next frontier in melt electrospinning: taming the jet}, series = {Advanced Functional Materials}, volume = {29}, journal = {Advanced Functional Materials}, doi = {10.1002/adfm.201904664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204819}, pages = {1904664}, year = {2019}, abstract = {There is a specialized niche for the electrohydrodynamic jetting of melts, from biomedical products to filtration and soft matter applications. The next frontier includes optics, microfluidics, flexible electronic devices, and soft network composites in biomaterial science and soft robotics. The recent emphasis on reproducibly direct-writing continual molten jets has enabled a spectrum of contemporary microscale 3D objects to be fabricated. One strong suit of melt processing is the capacity for the jet to solidify rapidly into a fiber, thus fixing a particular structure into position. The ability to direct-write complex and multiscaled architectures and structures has greatly contributed to a large number of recent studies, explicitly, toward fiber-hydrogel composites and fugitive inks, and has expanded into several biomedical applications such as cartilage, skin, periosteum, and cardiovascular tissue engineering. Following the footsteps of a publication that summarized melt electrowriting literature up to 2015, the most recent literature from then until now is reviewed to provide a continuous and comprehensive timeline that demonstrates the latest advances as well as new perspectives for this emerging technology.}, language = {en} } @article{StaussBrunnerBerberichSiebeltetal.2016, author = {Stauss, Dennis and Brunner, Cornelia and Berberich-Siebelt, Friederike and H{\"o}pken, Uta E. and Lipp, Martin and M{\"u}ller, Gerd}, title = {The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6}, series = {Embo Journal}, volume = {35}, journal = {Embo Journal}, number = {8}, doi = {10.15252/embj.201591459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189506}, pages = {881-898}, year = {2016}, abstract = {Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4\(^+\) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses.}, language = {en} } @article{BeckTitzeHuebneretal.2015, author = {Beck, Hanna and Titze, Stephanie I. and H{\"u}bner, Silvia and Busch, Martin and Schlieper, Georg and Schultheiss, Ulla T. and Wanner, Christoph and Kronenberg, Florian and Krane, Vera and Eckardt, Kai-Uwe and K{\"o}ttgen, Anna}, title = {Heart Failure in a Cohort of Patients with Chronic Kidney Disease: The GCKD Study}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0122552}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143315}, pages = {e0122552}, year = {2015}, abstract = {Background and Aims Chronic kidney disease (CKD) is a risk factor for development and progression of heart failure (HF). CKD and HF share common risk factors, but few data exist on the prevalence, signs and symptoms as well as correlates of HF in populations with CKD of moderate severity. We therefore aimed to examine the prevalence and correlates of HF in the German Chronic Kidney Disease (GCKD) study, a large observational prospective study. Methods and Results We analyzed data from 5,015 GCKD patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m\(^{2}\) or with an eGFR >= 60 and overt proteinuria (>500 mg/d). We evaluated a definition of HF based on the Gothenburg score, a clinical HF score used in epidemiological studies (Gothenburg HF), and self-reported HF. Factors associated with HF were identified using multivariable adjusted logistic regression. The prevalence of Gothenburg HF was 43\% (ranging from 24\% in those with eGFR >90 to 59\% in those with eGFR<30 ml/min/1.73m2). The corresponding estimate for self-reported HF was 18\% (range 5\%-24\%). Lower eGFR was significantly and independently associated with the Gothenburg definition of HF (p-trend <0.001). Additional significantly associated correlates included older age, female gender, higher BMI, hypertension, diabetes mellitus, valvular heart disease, anemia, sleep apnea, and lower educational status. Conclusions The burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD.}, language = {en} } @article{JanssenHoffmannKannoetal.2020, author = {Janssen, Jan P. and Hoffmann, Jan V. and Kanno, Takayuki and Nose, Naoko and Grunz, Jan-Peter and Onoguchi, Masahisa and Chen, Xinyu and Lapa, Constantin and Buck, Andreas K. and Higuchi, Takahiro}, title = {Capabilities of multi-pinhole SPECT with two stationary detectors for in vivo rat imaging}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, doi = {10.1038/s41598-020-75696-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230616}, year = {2020}, abstract = {We aimed to investigate the image quality of the U-SPECT5/CT E-Class a micro single-photon emission computed tomography (SPECT) system with two large stationary detectors for visualization of rat hearts and bones using clinically available \(^{99m}\)Tc-labelled tracers. Sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR) of the small-animal SPECT scanner were investigated in phantom studies using an ultra-high-resolution rat and mouse multi-pinhole collimator (UHR-RM). Point source, hot-rod, and uniform phantoms with \(^{99m}\)Tc-solution were scanned for high-count performance assessment and count levels equal to animal scans, respectively. Reconstruction was performed using the similarity-regulated ordered-subsets expectation maximization (SROSEM) algorithm with Gaussian smoothing. Rats were injected with similar to 100 MBq [\(^{99m}\)TcTc-MIBI or similar to 150 MBq [\(^{99m}\)Tc]Tc-HMDP and received multi-frame micro-SPECT imaging after tracer distribution. Animal scans were reconstructed for three different acquisition times and post-processed with different sized Gaussian filters. Following reconstruction, CNR was calculated and image quality evaluated by three independent readers on a five-point scale from 1="very poor" to 5="very good". Point source sensitivity was 567 cps/MBq and radioactive rods as small as 1.2 mm were resolved with the UHR-RM collimator. Collimator-dependent uniformity was 55.5\%. Phantom CNR improved with increasing rod size, filter size and activity concentration. Left ventricle and bone structures were successfully visualized in rat experiments. Image quality was strongly affected by the extent of post-filtering, whereas scan time did not have substantial influence on visual assessment. Good image quality was achieved for resolution range greater than 1.8 mm in bone and 2.8 mm in heart. The recently introduced small animal SPECT system with two stationary detectors and UHR-RM collimator is capable to provide excellent image quality in heart and bone scans in a rat using standardized reconstruction parameters and appropriate post-filtering. However, there are still challenges in achieving maximum system resolution in the sub-millimeter range with in vivo settings under limited injection dose and acquisition time.}, language = {en} } @article{DeebGiordanoRossietal.2016, author = {Deeb, Wissam and Giordano, James J. and Rossi, Peter J. and Mogilner, Alon Y. and Gunduz, Aysegul and Judy, Jack W. and Klassen, Bryan T. and Butson, Christopher R. and Van Horne, Craig and Deny, Damiaan and Dougherty, Darin D. and Rowell, David and Gerhardt, Greg A. and Smith, Gwenn S. and Ponce, Francisco A. and Walker, Harrison C. and Bronte-Stewart, Helen M. and Mayberg, Helen S. and Chizeck, Howard J. and Langevin, Jean-Philippe and Volkmann, Jens and Ostrem, Jill L. and Shute, Jonathan B. and Jimenez-Shahed, Joohi and Foote, Kelly D. and Wagle Shukla, Aparna and Rossi, Marvin A. and Oh, Michael and Pourfar, Michael and Rosenberg, Paul B. and Silburn, Peter A. and de Hemptine, Coralie and Starr, Philip A. and Denison, Timothy and Akbar, Umer and Grill, Warren M. and Okun, Michael S.}, title = {Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies}, series = {Frontiers in Integrative Neuroscience}, volume = {10}, journal = {Frontiers in Integrative Neuroscience}, number = {38}, doi = {10.3389/fnint.2016.00038}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168493}, year = {2016}, abstract = {This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.}, language = {en} } @article{DresenPimientoPateletal.2023, author = {Dresen, Ellen and Pimiento, Jose M. and Patel, Jayshil J. and Heyland, Daren K. and Rice, Todd W. and Stoppe, Christian}, title = {Overview of oxidative stress and the role of micronutrients in critical illness}, series = {Journal of Parenteral and Enteral Nutrition}, volume = {47}, journal = {Journal of Parenteral and Enteral Nutrition}, doi = {10.1002/jpen.2421}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318186}, pages = {S38 -- S49}, year = {2023}, abstract = {Inflammation and oxidative stress represent physiological response mechanisms to different types of stimuli and injury during critical illness. Its proper regulation is fundamental to cellular and organismal survival and are paramount to outcomes and recovery from critical illness. A proper maintenance of the delicate balance between inflammation, oxidative stress, and immune response is crucial for resolution from critical illness with important implications for patient outcome. The extent of inflammation and oxidative stress under normal conditions is limited by the antioxidant defense system of the human body, whereas the antioxidant capacity is commonly significantly compromised, and serum levels of micronutrients and vitamins significantly depleted in patients who are critically ill. Hence, the provision of antioxidants and anti-inflammatory nutrients may help to reduce the extent of oxidative stress and therefore improve clinical outcomes in patients who are critically ill. As existing evidence of the beneficial effects of antioxidant supplementation in patients who are critically ill is still unclear, actual findings about the most promising anti-inflammatory and antioxidative candidates selenium, vitamin C, zinc, and vitamin D will be discussed in this narrative review. The existing evidence provided so far demonstrates that several factors need to be considered to determine the efficacy of an antioxidant supplementation strategy in patients who are critically ill and indicates the need for adequately designed multicenter prospective randomized control trials to evaluate the clinical significance of different types and doses of micronutrients and vitamins in selected groups of patients with different types of critical illness.}, language = {en} } @article{KobsarKoehnlechnerKlingleretal.2022, author = {Kobsar, Anna and Koehnlechner, Karina and Klingler, Philipp and Niklaus, Marius and Zeller-Hahn, Julia and Koessler, Angela and Weber, Katja and Boeck, Markus and Koessler, Juergen}, title = {The effect of short-term refrigeration on platelet responsiveness}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-21124-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301390}, year = {2022}, abstract = {Storage of platelet concentrates (PC) at cold temperature (CT) is discussed as an alternative to the current standard of storage at room temperature (RT). Recently, we could show that cold-induced attenuation of inhibitory signaling is an important mechanism promoting platelet reactivity. For developing strategies in blood banking, it is required to elucidate the time-dependent onset of facilitated platelet activation. Thus, freshly prepared platelet-rich-plasma (PRP) was stored for 1 and 2 h at CT (2-6 °C) or at RT (20-24 °C), followed by subsequent comparative analysis. Compared to RT, basal and induced vasodilator-stimulated phosphoprotein (VASP) phosphorylation levels were decreased under CT within 1 h by approximately 20\%, determined by Western blot analysis and flow cytometry. Concomitantly, ADP- and collagen-induced threshold aggregation values were enhanced by up to 30-40\%. Furthermore, platelet-covered areas on collagen-coated slides and aggregate formation under flow conditions were increased after storage at CT, in addition to induced activation markers. In conclusion, a time period of 1-2 h for refrigeration is sufficient to induce an attenuation of inhibitory signaling, accompanied with an enhancement of platelet responsiveness. Short-term refrigeration may be considered as a rational approach to obtain PC with higher functional reactivity for the treatment of hemorrhage.}, language = {en} } @article{PageWallstabeLotheretal.2021, author = {Page, Lukas and Wallstabe, Julia and Lother, Jasmin and Bauser, Maximilian and Kniemeyer, Olaf and Strobel, Lea and Voltersen, Vera and Teutschbein, Janka and Hortschansky, Peter and Morton, Charles Oliver and Brakhage, Axel A. and Topp, Max and Einsele, Hermann and Wurster, Sebastian and Loeffler, Juergen}, title = {CcpA- and Shm2-Pulsed Myeloid Dendritic Cells Induce T-Cell Activation and Enhance the Neutrophilic Oxidative Burst Response to Aspergillus fumigatus}, series = {Frontiers in Immunology}, volume = {12}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2021.659752}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239493}, year = {2021}, abstract = {Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4\(^+\) and CD8\(^+\) T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA.}, language = {en} } @article{ClausHubertBecheretal.2019, author = {Claus, Heike and Hubert, Kerstin and Becher, D{\"o}rte and Otto, Andreas and Pawlik, Marie-Christin and Lappann, Ines and Strobel, Lea and Vogel, Ulrich and Johswich, Kay}, title = {A homopolymeric adenosine tract in the promoter region of nspA influences factor H-mediated serum resistance in Neisseria meningitidis}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-39231-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200956}, pages = {2736}, year = {2019}, abstract = {Although usually asymptomatically colonizing the human nasopharynx, the Gram-negative bacterium Neisseria meningitidis (meningococcus) can spread to the blood stream and cause invasive disease. For survival in blood, N. meningitidis evades the complement system by expression of a polysaccharide capsule and surface proteins sequestering the complement regulator factor H (fH). Meningococcal strains belonging to the sequence type (ST-) 41/44 clonal complex (cc41/44) cause a major proportion of serogroup B meningococcal disease worldwide, but they are also common in asymptomatic carriers. Proteome analysis comparing cc41/44 isolates from invasive disease versus carriage revealed differential expression levels of the outer membrane protein NspA, which binds fH. Deletion of nspA reduced serum resistance and NspA expression correlated with fH sequestration. Expression levels of NspA depended on the length of a homopolymeric tract in the nspA promoter: A 5-adenosine tract dictated low NspA expression, whereas a 6-adenosine motif guided high NspA expression. Screening German cc41/44 strain collections revealed the 6-adenosine motif in 39\% of disease isolates, but only in 3.4\% of carriage isolates. Thus, high NspA expression is associated with disease, but not strictly required. The 6-adenosine nspA promoter is most common to the cc41/44, but is also found in other hypervirulent clonal complexes.}, language = {en} } @article{BankogluArnoldHeringetal.2018, author = {Bankoglu, Ezgi Eyluel and Arnold, Charlotte and Hering, Ilona and Hankir, Mohammed and Seyfried, Florian and Stopper, Helga}, title = {Decreased chromosomal damage in lymphocytes of obese patients after bariatric surgery}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {11195}, doi = {10.1038/s41598-018-29581-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177090}, year = {2018}, abstract = {The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.}, language = {en} } @article{FriedrichHartigPruessetal.2022, author = {Friedrich, Maximilian and Hartig, Johannes and Pr{\"u}ss, Harald and Ip, Wang Chi and Volkmann, Jens}, title = {Rapidly progressive dementia: Extending the spectrum of GFAP-astrocytopathies?}, series = {Annals of Clinical and Translational Neurology}, volume = {9}, journal = {Annals of Clinical and Translational Neurology}, number = {3}, doi = {10.1002/acn3.51513}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312957}, pages = {410-415}, year = {2022}, abstract = {Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a steroid-responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Beyond clinical presentation and imaging, diagnosis relies on detection of GFAP-antibodies (AB) in CSF. Using quantitative behavioral, serologic, and immunohistochemical analyses, we characterize two patients longitudinally over 18-24 months who presented with rapidly progressive neurocognitive deterioration in the context of GFAP-AB in CSF and unremarkable cranial MRI studies. Intensified immunotherapy was associated with clinical stabilization. The value of GFAP-AB screening in selected cases of rapidly progressive dementias is discussed.}, language = {en} } @article{ManukjanWiegeringReindletal.2020, author = {Manukjan, Georgi and Wiegering, Verena and Reindl, Tobias and Strauß, Gabriele and Klopocki, Eva and Schulze, Harald and Andres, Oliver}, title = {Novel variants in FERMT3 and RASGRP2 - Genetic linkage in Glanzmann-like bleeding disorders}, series = {Pediatric Blood \& Cancer}, volume = {67}, journal = {Pediatric Blood \& Cancer}, number = {2}, doi = {10.1002/pbc.28078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208129}, pages = {e28078}, year = {2020}, abstract = {Defects of platelet intracellular signaling can result in severe platelet dysfunction. Several mutations in each of the linked genes FERMT3 and RASGRP2 on chromosome 11 causing a Glanzmann-like bleeding phenotype have been identified so far. We report on novel variants in two unrelated pediatric patients with severe bleeding diathesis—one with leukocyte adhesion deficiency type III due to a homozygous frameshift in FERMT3 and the other with homozygous variants in both, FERMT3 and RASGRP2 . We focus on the challenging genetic and functional variant assessment and aim to accentuate the risk of obtaining misleading results due to the phenomenon of genetic linkage.}, language = {en} } @article{TanBabakVenkatesanetal.2019, author = {Tan, Aaron and Babak, Maria V. and Venkatesan, Gopalakrishnan and Lim, Clarissa and Klotz, Karl-Norbert and Herr, Deron Raymond and Cheong, Siew Lee and Federico, Stephanie and Spalluto, Giampiero and Ong, Wei-Yi and Chen, Yu Zong and Loo, Jason Siau Ee and Pastorin, Giorgia}, title = {Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy}, series = {Molecules}, volume = {24}, journal = {Molecules}, number = {20}, issn = {1420-3049}, doi = {10.3390/molecules24203661}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193271}, pages = {3661}, year = {2019}, abstract = {Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30\% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.}, language = {en} } @article{KressJessenMarquardtetal.2021, author = {Kreß, Julia Katharina Charlotte and Jessen, Christina and Marquardt, Andr{\´e} and Hufnagel, Anita and Meierjohann, Svenja}, title = {NRF2 enables EGFR signaling in melanoma cells}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms22083803}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260222}, year = {2021}, abstract = {Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is only expressed in a subgroup of melanomas with poor prognosis. The insight into regulators of EGFR expression and activation is important for the understanding of the development of this malignant melanoma phenotype. Here, we describe that the transcription factor NRF2, the master regulator of the oxidative and electrophilic stress response, mediates the expression and activation of EGFR in melanoma by elevating the levels of EGFR as well as its ligands EGF and TGFα. ChIP sequencing data show that NRF2 directly binds to the promoter of EGF, which contains a canonical antioxidant response element. Accordingly, EGF is induced by oxidative stress and is also increased in lung adenocarcinoma and head and neck carcinoma with mutationally activated NRF2. In contrast, regulation of EGFR and TGFA occurs by an indirect mechanism, which is enabled by the ability of NRF2 to block the activity of the melanocytic lineage factor MITF in melanoma. MITF effectively suppresses EGFR and TGFA expression and therefore serves as link between NRF2 and EGFR. As EGFR was previously described to stimulate NRF2 activity, the mutual activation of NRF2 and EGFR pathways was investigated. The presence of NRF2 was necessary for full EGFR pathway activation, as NRF2-knockout cells showed reduced AKT activation in response to EGF stimulation compared to controls. Conversely, EGF led to the nuclear localization and activation of NRF2, thereby demonstrating that NRF2 and EGFR are connected in a positive feedback loop in melanoma. In summary, our data show that the EGFR-positive melanoma phenotype is strongly supported by NRF2, thus revealing a novel maintenance mechanism for this clinically challenging melanoma subpopulation.}, language = {en} } @article{BraunEvdokimovFranketal.2022, author = {Braun, Alexandra and Evdokimov, Dimitar and Frank, Johanna and Pauli, Paul and Wabel, Thomas and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome}, series = {Journal of Religion and Health}, volume = {61}, journal = {Journal of Religion and Health}, number = {1}, issn = {1573-6571}, doi = {10.1007/s10943-020-01177-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269135}, pages = {524-539}, year = {2022}, abstract = {Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome.}, language = {en} } @article{HankeRauschSosnowskietal.2022, author = {Hanke, Kathrin and Rausch, Tanja K. and Sosnowski, Runa and Paul, Pia and Spiegler, Juliane and M{\"u}ller, Mirja and K{\"o}nig, Inke R. and G{\"o}pel, Wolfgang and Herting, Egbert and H{\"a}rtel, Christoph}, title = {Early skin-to-skin contact does not affect cerebral tissue oxygenation in preterm infants <32 weeks of gestation}, series = {Children}, volume = {9}, journal = {Children}, number = {2}, issn = {2227-9067}, doi = {10.3390/children9020211}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262290}, year = {2022}, abstract = {Aim: It was the aim of our study to determine the regional cerebral tissue oxygenation saturation (rcSO\(_2\)) as an additional monitoring parameter during early skin-to-skin contact (SSC) in preterm infants with a gestational age of <32 gestational weeks. Methods: We conducted two observational convenience sample studies using additional monitoring with near-infrared spectroscopy (NIRS) in the first 120 h of life: (a) NIRS 1 (gestational age of 26 0/7 to 31 6/7 weeks) and (b) NIRS 2 (gestational age of 24 0/7 to 28 6/7 weeks). The rcSO\(_2\) values were compared between resting time in the incubator (period I), SSC (period II) and handling nursing care (period III). For the comparison, we separated the sequential effects by including a "wash-out phase" of 1 h between each period. Results: During the first 120 h of life 38/53 infants in NIRS 1 and 15/23 infants in NIRS 2 received SSC, respectively. We found no remarkable differences for rcSO\(_2\) values of NIRS 1 patients between SSC time and period I (95\% confidence interval (CI) for the difference in \%: SSC vs. period I [1; 3]). In NIRS 2, rcSO\(_2\) values during SSC were only 2\% lower compared with period I [median [1. quartile; 3. quartile] in \%; 78 [73; 82] vs. 80 [74; 85]] but were similar to period III [78 [72; 83]]. In a combined analysis, a small difference in rcSO\(_2\) values between SSC and resting times was found using a generalized linear mixed model that included gender and gestational age (OR 95\% CI; 1.178 [1.103; 1.253], p < 0.0001). Episodes below the cut-off for "hypoxia"; e.g., <55\%, were comparable during SSC and periods I and III (0.3-2.1\%). No FiO\(_2\) adjustment was required in the vast majority of SSC episodes. Conclusions: Our observational data indicate that rcSO\(_2\) values of infants during SSC were comparable to rcSO\(_2\) values during incubator care and resting time. This additional monitoring supports a safe implementation of early SSC in extremely preterm infants in NICUs.}, language = {en} } @article{GerovaWickeChiharaetal.2021, author = {Gerova, Milan and Wicke, Laura and Chihara, Kotaro and Schneider, Cornelius and Lavigne, Rob and Vogel, J{\"o}rg}, title = {A grad-seq view of RNA and protein complexes in Pseudomonas aeruginosa under standard and bacteriophage predation conditions}, series = {mbio}, volume = {12}, journal = {mbio}, number = {1}, doi = {10.1128/mBio.03454-20}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259054}, pages = {e03454-20}, year = {2021}, abstract = {The Gram-negative rod-shaped bacterium Pseudomonas aeruginosa is not only a major cause of nosocomial infections but also serves as a model species of bacterial RNA biology. While its transcriptome architecture and posttranscriptional regulation through the RNA-binding proteins Hfq, RsmA, and RsmN have been studied in detail, global information about stable RNA-protein complexes in this human pathogen is currently lacking. Here, we implement gradient profiling by sequencing (Grad-seq) in exponentially growing P. aeruginosa cells to comprehensively predict RNA and protein complexes, based on glycerol gradient sedimentation profiles of >73\% of all transcripts and ∼40\% of all proteins. As to benchmarking, our global profiles readily reported complexes of stable RNAs of P. aeruginosa, including 6S RNA with RNA polymerase and associated product RNAs (pRNAs). We observe specific clusters of noncoding RNAs, which correlate with Hfq and RsmA/N, and provide a first hint that P. aeruginosa expresses a ProQ-like FinO domain-containing RNA-binding protein. To understand how biological stress may perturb cellular RNA/protein complexes, we performed Grad-seq after infection by the bacteriophage ΦKZ. This model phage, which has a well-defined transcription profile during host takeover, displayed efficient translational utilization of phage mRNAs and tRNAs, as evident from their increased cosedimentation with ribosomal subunits. Additionally, Grad-seq experimentally determines previously overlooked phage-encoded noncoding RNAs. Taken together, the Pseudomonas protein and RNA complex data provided here will pave the way to a better understanding of RNA-protein interactions during viral predation of the bacterial cell. IMPORTANCE Stable complexes by cellular proteins and RNA molecules lie at the heart of gene regulation and physiology in any bacterium of interest. It is therefore crucial to globally determine these complexes in order to identify and characterize new molecular players and regulation mechanisms. Pseudomonads harbor some of the largest genomes known in bacteria, encoding ∼5,500 different proteins. Here, we provide a first glimpse on which proteins and cellular transcripts form stable complexes in the human pathogen Pseudomonas aeruginosa. We additionally performed this analysis with bacteria subjected to the important and frequently encountered biological stress of a bacteriophage infection. We identified several molecules with established roles in a variety of cellular pathways, which were affected by the phage and can now be explored for their role during phage infection. Most importantly, we observed strong colocalization of phage transcripts and host ribosomes, indicating the existence of specialized translation mechanisms during phage infection. All data are publicly available in an interactive and easy to use browser.}, language = {en} } @article{DoryabTaskinStahlhutetal.2021, author = {Doryab, Ali and Taskin, Mehmet Berat and Stahlhut, Philipp and Schr{\"o}ppel, Andreas and Wagner, Darcy E. and Groll, J{\"u}rgen and Schmid, Otmar}, title = {A Biomimetic, Copolymeric Membrane for Cell-Stretch Experiments with Pulmonary Epithelial Cells at the Air-Liquid Interface}, series = {Advanced Functional Materials}, volume = {31}, journal = {Advanced Functional Materials}, number = {10}, doi = {10.1002/adfm.202004707}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225645}, year = {2021}, abstract = {Chronic respiratory diseases are among the leading causes of death worldwide, but only symptomatic therapies are available for terminal illness. This in part reflects a lack of biomimetic in vitro models that can imitate the complex environment and physiology of the lung. Here, a copolymeric membrane consisting of poly(ε-)caprolactone and gelatin with tunable properties, resembling the main characteristics of the alveolar basement membrane is introduced. The thin bioinspired membrane (≤5 μm) is stretchable (up to 25\% linear strain) with appropriate surface wettability and porosity for culturing lung epithelial cells under air-liquid interface conditions. The unique biphasic concept of this membrane provides optimum characteristics for initial cell growth (phase I) and then switch to biomimetic properties for cyclic cell-stretch experiments (phase II). It is showed that physiologic cyclic mechanical stretch improves formation of F-actin cytoskeleton filaments and tight junctions while non-physiologic over-stretch induces cell apoptosis, activates inflammatory response (IL-8), and impairs epithelial barrier integrity. It is also demonstrated that cyclic physiologic stretch can enhance the cellular uptake of nanoparticles. Since this membrane offers considerable advantages over currently used membranes, it may lead the way to more biomimetic in vitro models of the lung for translation of in vitro response studies into clinical outcome.}, language = {en} } @article{GergsJahnSchulzetal.2022, author = {Gergs, Ulrich and Jahn, Tina and Schulz, Nico and Großmann, Claudia and Rueckschloss, Uwe and Demus, Uta and Buchwalow, Igor B. and Neumann, Joachim}, title = {Protein phosphatase 2A improves cardiac functional response to ischemia and sepsis}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms23094688}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284035}, year = {2022}, abstract = {Reversible protein phosphorylation is a posttranslational modification of regulatory proteins involved in cardiac signaling pathways. Here, we focus on the role of protein phosphatase 2A (PP2A) for cardiac gene expression and stress response using a transgenic mouse model with cardiac myocyte-specific overexpression of the catalytic subunit of PP2A (PP2A-TG). Gene and protein expression were assessed under basal conditions by gene chip analysis and Western blotting. Some cardiac genes related to the cell metabolism and to protein phosphorylation such as kinases and phosphatases were altered in PP2A-TG compared to wild type mice (WT). As cardiac stressors, a lipopolysaccharide (LPS)-induced sepsis in vivo and a global cardiac ischemia in vitro (stop-flow isolated perfused heart model) were examined. Whereas the basal cardiac function was reduced in PP2A-TG as studied by echocardiography or as studied in the isolated work-performing heart, the acute LPS- or ischemia-induced cardiac dysfunction deteriorated less in PP2A-TG compared to WT. From the data, we conclude that increased PP2A activity may influence the acute stress tolerance of cardiac myocytes.}, language = {en} } @article{HoltfrerichSchwarzSprengeretal.2016, author = {Holtfrerich, Sarah K. C. and Schwarz, Katharina A. and Sprenger, Christian and Reimers, Luise and Diekhof, Esther K.}, title = {Endogenous Testosterone and Exogenous Oxytocin Modulate Attentional Processing of Infant Faces}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0166617}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166783}, pages = {e0166617}, year = {2016}, abstract = {Evidence indicates that hormones modulate the intensity of maternal care. Oxytocin is known for its positive influence on maternal behavior and its important role for childbirth. In contrast, testosterone promotes egocentric choices and reduces empathy. Further, testosterone decreases during parenthood which could be an adaptation to increased parental investment. The present study investigated the interaction between testosterone and oxytocin in attentional control and their influence on attention to baby schema in women. Higher endogenous testosterone was expected to decrease selective attention to child portraits in a face-in-the-crowd-paradigm, while oxytocin was expected to counteract this effect. As predicted, women with higher salivary testosterone were slower in orienting attention to infant targets in the context of adult distractors. Interestingly, reaction times to infant and adult stimuli decreased after oxytocin administration, but only in women with high endogenous testosterone. These results suggest that oxytocin may counteract the adverse effects of testosterone on a central aspect of social behavior and maternal caretaking.}, language = {en} } @article{RymaTylekLiebscheretal.2021, author = {Ryma, Matthias and Tylek, Tina and Liebscher, Julia and Blum, Carina and Fernandez, Robin and B{\"o}hm, Christoph and Kastenm{\"u}ller, Wolfgang and Gasteiger, Georg and Groll, J{\"u}rgen}, title = {Translation of collagen ultrastructure to biomaterial fabrication for material-independent but highly efficient topographic immunomodulation}, series = {Advanced materials}, volume = {33}, journal = {Advanced materials}, number = {33}, doi = {10.1002/adma.202101228}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256381}, year = {2021}, abstract = {Supplement-free induction of cellular differentiation and polarization solely through the topography of materials is an auspicious strategy but has so far significantly lagged behind the efficiency and intensity of media-supplementation-based protocols. Consistent with the idea that 3D structural motifs in the extracellular matrix possess immunomodulatory capacity as part of the natural healing process, it is found in this study that human-monocyte-derived macrophages show a strong M2a-like prohealing polarization when cultured on type I rat-tail collagen fibers but not on collagen I films. Therefore, it is hypothesized that highly aligned nanofibrils also of synthetic polymers, if packed into larger bundles in 3D topographical biomimetic similarity to native collagen I, would induce a localized macrophage polarization. For the automated fabrication of such bundles in a 3D printing manner, the strategy of "melt electrofibrillation" is pioneered by the integration of flow-directed polymer phase separation into melt electrowriting and subsequent selective dissolution of the matrix polymer postprocessing. This process yields nanofiber bundles with a remarkable structural similarity to native collagen I fibers, particularly for medical-grade poly(ε-caprolactone). These biomimetic fibrillar structures indeed induce a pronounced elongation of human-monocyte-derived macrophages and unprecedentedly trigger their M2-like polarization similar in efficacy as interleukin-4 treatment.}, language = {en} } @article{WasmusDudek2020, author = {Wasmus, Christina and Dudek, Jan}, title = {Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies}, series = {Life}, volume = {10}, journal = {Life}, number = {11}, issn = {2075-1729}, doi = {10.3390/life10110277}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219286}, year = {2020}, abstract = {The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95\% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.}, language = {en} } @article{KadeBakirciTandonetal.2022, author = {Kade, Juliane C. and Bakirci, Ezgi and Tandon, Biranche and Gorgol, Danila and Mrlik, Miroslav and Luxenhofer, Robert and Dalton, Paul D.}, title = {The Impact of Including Carbonyl Iron Particles on the Melt Electrowriting Process}, series = {Macromolecular Materials and Engineering}, volume = {307}, journal = {Macromolecular Materials and Engineering}, number = {12}, issn = {1438-7492}, doi = {10.1002/mame.202200478}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318482}, year = {2022}, abstract = {Melt electrowriting, a high-resolution additive manufacturing technique, is used in this study to process a magnetic polymer-based blend for the first time. Carbonyl iron (CI) particles homogenously distribute into poly(vinylidene fluoride) (PVDF) melts to result in well-defined, highly porous structures or scaffolds comprised of fibers ranging from 30 to 50 µm in diameter. This study observes that CI particle incorporation is possible up to 30 wt\% without nozzle clogging, albeit that the highest concentration results in heterogeneous fiber morphologies. In contrast, the direct writing of homogeneous PVDF fibers with up to 15 wt\% CI is possible. The fibers can be readily displaced using magnets at concentrations of 1 wt\% and above. Combined with good viability of L929 CC1 cells using Live/Dead imaging on scaffolds for all CI concentrations indicates that these formulations have potential for the usage in stimuli-responsive applications such as 4D printing.}, language = {en} } @article{SchmidtSticherlingSardyetal.2020, author = {Schmidt, Enno and Sticherling, Michael and S{\´a}rdy, Mikl{\´o}s and Eming, R{\"u}diger and Goebeler, Matthias and Hertl, Michael and Hofmann, Silke C. and Hunzelmann, Nicolas and Kern, Johannes S. and Kramer, Harald and Nast, Alexander and Orzechowski, Hans-Dieter and Pfeiffer, Christiane and Schuster, Volker and Sitaru, Cassian and Zidane, Miriam and Zillikens, Detlef and Worm, Margitta}, title = {S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update}, series = {JDDG: Journal der Deutschen Dermatologischen Gesellschaft}, volume = {18}, journal = {JDDG: Journal der Deutschen Dermatologischen Gesellschaft}, number = {5}, doi = {10.1111/ddg.14097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217806}, pages = {516 -- 526}, year = {2020}, 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{Keicher2024, author = {Keicher, Franca}, title = {Muskul{\"a}re Einfl{\"u}sse der Rotatorenmanschette auf die Early Onset Arthrose der Schulter}, doi = {10.25972/OPUS-36055}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360557}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Introduction: The etiology of early onset shoulder arthritis (EOA) remains unclear. Due to the influence of the muscles of the rotator cuff (RC) on glenohumeral kinematics, muscular causes are being discussed. The aim of the study was to identify corresponding factors on EOA based on volume measurements of the RC and examinations of the adjacent bony structures in MRI imaging, as well as the collection of patient-specific characteristics. Methods: In a case-control study, shoulders of 15 patients (14 men, 1 woman) with shoulder arthritis before the age of 60 and 13 control subjects (13 men) were examined. Anthropometric body measurements and clinical characteristics were collected. The volumes of the RC were calculated using manual tracing of the individual muscle cross- sections on MRI scans. In addition, the angles between the coracoid or scapular spine and scapular body were measured. The position of the scapula to the thorax was determined by recording the angle of the scapula to the plane of the table. The glenoid retroversion, morphological types, and humeral head subluxation were also collected. The analysis was conducted using descriptive and comparative statistical methods, as well as logistic and linear regression analyses. Results: The volumes of the RC did not differ significantly between the patients with EOA and the control subjects, either in absolute terms or in relative proportions. However, significantly higher values of thorax circumference and diameter, body weight, and BMI were found in the diseased individuals compared to the controls. Furthermore, these individuals were significantly more likely to have occupations that expended more than 1400 kcal per day. The risk of EOA increased with the steeper angle of the scapula to the thorax. Patients with B2-glenoid had significantly larger angles between the coracoid and scapular body as well as higher values of transverse thorax diameter, than those with B1-glenoid. Regardless of whether EOA was present or not, engaging in overhead sports was associated with a higher subluxation index. Conclusion: While the RC did not show any abnormalities in EOA patients, male gender, BMI, thoracic shape and scapular position, as well as certain occupations and sports, were associated with EOA. Further studies are needed to investigate these risk factors in EOA more precisely and develop possible treatment concepts. Peripheral shoulder muscles (such as teres major or pectoralis major) should also be included in the investigations.}, subject = {Arthrose}, language = {de} } @phdthesis{Rehlinghaus2024, author = {Rehlinghaus, Christine}, title = {Retrospektive Evaluation der intraven{\"o}sen Dexamethason- bzw. Methylprednisolon-Pulstherapie bei ausgepr{\"a}gter Alopecia areata}, doi = {10.25972/OPUS-36071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360711}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Hintergrund: Bei der Entscheidung f{\"u}r eine intraven{\"o}se Kortikosteroid-Pulstherapie bei schweren Formen der AA ist die Abw{\"a}gung von Therapieaufwand, Nebenwirkungen und Risiken einerseits und der Erfolgsaussicht andererseits von zentraler Bedeutung. Ziel: Ziel dieser retrospektiven Analyse war es daher, die Wirksamkeit und Sicherheit der intraven{\"o}sen Kortikosteroid-Pulstherapie bei Patient:innen mit ausgepr{\"a}gter AA klinikintern als qualit{\"a}tssichernde Maßnahme zu untersuchen, prognostisch bedeutsame Faktoren f{\"u}r den Therapieeffekt zu ermitteln und hierdurch die beste Indikation herauszuarbeiten. Methode: 126 Patient:innen (13 Kinder und Jugendliche) erhielten Dexamethason 100 mg (122 Patienten) oder Methylprednisolon 20-30 mg/kg/KG (max. 1000 mg, 4 Patienten) an drei aufeinanderfolgenden Tagen f{\"u}r ein bis drei Zyklen. Ergebnisse: Patienten mit einer AA partialis bzw. diffusa zeigten im Hinblick auf ein vollst{\"a}ndiges oder kosmetisch akzeptables Wiederwachstum die besten Ansprechraten (44,3\%, n=43). Unter den Ophiasis-Patienten und den Patienten mit AA totalis/universalis sprach nur etwa ein Viertel auf die Therapie an (Ophiasis 23,8\%, n=5; AA totalis/universalis: 25\%, n=2). Schwerwiegende unerw{\"u}nschte Nebenwirkungen wurden nicht beobachtet. Schlussfolgerung: In der vorliegenden Untersuchung ließen sich eine l{\"a}ngere Bestandsdauer der Erkrankung und Erkrankungsepisode ({\"u}ber 6 Monate), ein schwerer Auspr{\"a}gungsgrad (Ophiasis, AA totalis/universalis) und krankheitstypische Nagelver{\"a}nderungen als wichtige ung{\"u}nstige prognostische Faktoren nachweisen. Dagegen wirkten sich die untersuchten Kriterien Alter, Geschlecht, atopisches Ekzem und andere Erkrankungen des atopischen Formenkreises, Schilddr{\"u}sen- und Autoimmunerkrankungen in der Eigenanamnese sowie AA in der Familienanamnese nicht negativ auf den Behandlungserfolg aus. Patienten mit AA partialis und einer Bestandsdauer der AA von maximal 6 Monaten haben die besten Erfolgsaussichten.}, subject = {Alopecia areata}, language = {de} } @phdthesis{Fieber2024, author = {Fieber, Tabea}, title = {Retrospektive unizentrische Analyse des Komplikationsmanagements bei Anastomoseninsuffizienz nach linksseitiger Kolon- und Rektumresektion}, doi = {10.25972/OPUS-36073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360730}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Eine gef{\"u}rchtete Komplikation nach Resektionen am Kolon mit Wiederherstellung der Kontinuit{\"a}t ist das Auftreten einer Anastomoseninsuffizienz (AI). Der Prozess der Diagnosestellung und das therapeutische Vorgehen sind zentrumsspezifisch und sehr heterogen. Ziel dieser Promotionsarbeit war die deskriptive Darstellung der Pr{\"a}valenz, Diagnostik und Therapie von AI, um anhand dieser Daten ein bestimmtes zu favorisierendes Vorgehen zur AI-Behandlung herauszuarbeiten. Es wurde eine retrospektive unizentrische Analyse durchgef{\"u}hrt. Diese umfasste eine Kohorte von 744 Patienten, welche von 2009 bis 2013 am Universit{\"a}tsklinikum W{\"u}rzburg unter Kontinuit{\"a}tserhalt kolorektal reseziert wurden. Es erfolgte eine deskriptive und statistische Auswertung mittels uni- und multivariater Analysen in Bezug auf Demographie, Risikofaktoren f{\"u}r die Entwicklung einer AI und den Erfolg der einzelnen Therapiekonzepte. W{\"a}hrend der Nachbeobachtungsphase vom im Mittel 2,5 Jahren entwickelten 10,48\% der Patienten eine AI. 60\% der Insuffizienzen wurden w{\"a}hrend der ersten 7 postoperativen Tage detektiert. Als Risikofaktoren konnten indikationsunabh{\"a}ngig m{\"a}nnliches Geschlecht, offener Zugangsweg und pulmonale Erkrankungen herausgearbeitet werden. Indikationsspezifisch zeigte sich eine Zunahme des AI-Risikos bei Divertikulitis-Patienten mit pulmonalen Erkrankungen (OR 4,5) und Cortisoneinnahme (OR 5,4). Auff{\"a}llig wurden Patienten mit AI durch heterogene und teils unspezifische Symptome - am h{\"a}ufigsten durch Fieber (28,21\%) und auff{\"a}llige Laborwerte (48,72\%). Eine folgende CT-Diagnostik best{\"a}tigte die Diagnose in 76,32\% der F{\"a}lle und war in 24,48\% falsch negativ. Patienten mit schlechtem AZ bei Diagnose der AI zeigten eine signifikant h{\"o}here Mortalit{\"a}t. Ein protektives Stoma konnte eine AI nicht verhindern, aber ihre Symptome und die Schwere des Verlaufs abmildern. Gemessen an der {\"U}berlebensrate und der Revisionspflichtigkeit unterschieden sich die durchgef{\"u}hrten Maßnahmen beim Versuch der kontinuit{\"a}tserhaltenden Therapie nicht in Bezug auf den Erfolg der Therapie. Wie Insuffizienz- und Mortalit{\"a}tsrate nach AI zeigen, ist diese unizentrische Analyse international vergleichbar. Die Ableitung einer generellen Empfehlung zur therapeutischen Vorgehensweise bei AI ist nicht m{\"o}glich. Vielmehr sind alle dargestellten Maßnahmen zur Beherrschung der AI sinnvoll, w{\"a}hrend die Wahl der Vorgehensweise weiterhin eine Individualentscheidung bleibt.}, subject = {Darmanastomose}, language = {de} } @phdthesis{Enzensberger2024, author = {Enzensberger, Eva}, title = {Stellenwert der Dobutamin-Stress-Echokardiographie bei der Unterscheidung einer hochgradigen von einer pseudo-hochgradigen Aortenklappenstenose und Bestimmung deren echokardiographischer Pr{\"a}diktoren}, doi = {10.25972/OPUS-36014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360146}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel dieser Studie war es, zu eruieren, ob die DSE zur Unterscheidung einer TS- von einer PSAS beitragen kann. Ebenfalls untersuchten wir, ob es bestimmte echokardiographische Pr{\"a}diktoren f{\"u}r eine TS- und eine PSAS gibt und ob die LVEF bei Patienten mit einer LGAS eine entscheidende Rolle spielt. Methoden: Es wurde bei 130 Patienten mit einer asymptomatischen AS im Uniklinikum W{\"u}rzburg zwischen Januar 2011 und Dezember 2016 sowohl eine TTE als auch eine DSE durchgef{\"u}hrt. Mittels TTE wurden verschiedene echokardiographische Daten erhoben und falls die Patienten eine AVAi  0,6 cm2/m2 und eine PGmean < 40 mmHg aufwiesen, wurden sie in die Studie eingeschlossen. Sie wurden in zwei Gruppen aufgeteilt, je nachdem ob sie eine LGAS mit einer LVEF  50\% oder < 50\% aufwiesen. Bei allen Patienten wurde in der DSE die AVAproj berechnet und sie wurden daraufhin in zwei Untergruppen aufgeteilt, Patienten mit einer AVAproj  1 cm2 wurden der Gruppe mit einer hochgradigen LGAS (TS-LGAS) und Patienten mit einer AVAproj > 1cm2 der Gruppe mit einer pseudo-hochgradigen LGAS (PS-LGAS) zugeteilt. Alle Patientendaten wurden manuell ausgewertet. Das klinische Follow Up fand fr{\"u}hestens ein Jahr nach der DSE statt und bestand aus einem Telefoninterview oder einer klinischen Untersuchung. Ergebnisse: Die DSE ist zur Diagnose einer TS-LGAS bei Patienten mit einer erhaltenen LVEF von großem Nutzen. Die in der TTE gemessene AVA ist ein unabh{\"a}ngiger Pr{\"a}diktor f{\"u}r eine TS-LGAS bei Patienten mit erhaltener und reduzierter LVEF. Eine verringerte MAPSE und eine reduzierte TDI-s´ sprechen bei Patienten mit erhaltener LVEF f{\"u}r eine TS-LGAS. Bei Patienten mit reduzierter LVEF weisen ein erh{\"o}hter sPAP und eine verringerte AV Geschwindigkeits Ratio auf eine TS-LGAS hin. Bei Zweifeln k{\"o}nnen weitere bildgebende Verfahren zur Diagnosefindung hinzugezogen werden.}, subject = {Aortenstenose}, language = {de} } @phdthesis{Buchta2024, author = {Buchta, Ulrike}, title = {H{\"o}rergebnisse und Vestibularisfunktion nach transtemporaler Resektion von intrameatalen Vestibularisschwannomen mit Evaluation der postoperativen, konservativen H{\"o}rger{\"a}teversorgung}, doi = {10.25972/OPUS-36024}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360246}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Vestibularisschwannom ist ein Tumor, dessen Entstehung noch nicht vollst{\"a}ndig gekl{\"a}rt ist. Jeder kann von dieser seltenen Erkrankung betroffen sein. Darum ist es wichtig, die Ergebnisse der verschiedenen Therapieoptionen regelm{\"a}ßig aufzuarbeiten und die M{\"o}glichkeiten einer H{\"o}rrehabilitation mit konventionellen oder implantierbaren H{\"o}rsystemen sowie Ans{\"a}tze zur Schwindelrehabilitation oder einer m{\"o}glichen Pr{\"a}habilitation zu evaluieren. Mit der transtemporalen mikrochirurgischen Tumorexstirpation kann eine Heilung und bei einem großen Teil der Patienten auch ein H{\"o}rerhalt erzielt werden. Je j{\"u}nger die Patienten sind, aber vor allem auch je besser sie vor der Operation h{\"o}ren, desto h{\"o}her sind auch die Chancen auf einen H{\"o}rerhalt. Es zeigte sich jedoch auch, dass bei Patienten mit initial schlechterem H{\"o}ren, welche dann operiert wurden, dieses zum Teil wieder verbessert werden konnte. Daher sind Ans{\"a}tze, mehr Patienten eine transtemporale Tumorresektion anzubieten durchaus sinnvoll, auch um die Chancen auf eine H{\"o}rverbesserung zu erm{\"o}glichen. Des Weiteren sollte auch bei Patienten mit Schwindelbeschwerden eine Operation als Behandlungsoption erwogen werden. Die Pr{\"a}habilitation mit Gentamicin-Injektionen in das Mittelohr scheint eine neue M{\"o}glichkeit zu sein, das zentrale Nervensystem schon auf den Ausfall des Vestibularorgans vorzubereiten. Durch die ototoxische Wirkung des Gentamicins und den potenziellen H{\"o}rverlust, w{\"a}re jedoch eine Kombination dieser Pr{\"a}habilitation mit einem h{\"o}rerhaltenden Eingriff {\"u}ber den transtemporalen Zugang risikobehaftet. Eine zentrale Kompensation der Schwindelbeschwerden sollte nach dem Eingriff mit einer gezielten Schwindelrehabilitation unterst{\"u}tzt werden. W{\"a}hrend bei dieser vor allem physiotherapeutische {\"U}bungen angewandt werden, gibt es im Hinblick auf eine H{\"o}rrehabilitation schon verschiedene medizintechnische Optionen. Aktuell gibt es vor allem Studien zu den implantierbaren H{\"o}rhilfen und neue Daten zu den konservativen M{\"o}glichkeiten einer H{\"o}rrehabilitation sind eher die Ausnahme. Die Nutzung einer konservativen H{\"o}rhilfe sollte jedoch vor dem Entscheid zu einer operativen L{\"o}sung {\"u}ber implantierbare Systeme konsequent angewandt werden. Die in dieser Arbeit aufgezeigten positiven Momente bei der Versorgung von VS-Patienten pr{\"a}- und posttherapeutisch mit herk{\"o}mmlichen H{\"o}rger{\"a}ten sollten weiteren Eingang in die klinische Routine finden.}, subject = {Akustikustumor}, 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} } @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{BalasubramanianSkafHolzgrabeetal.2018, author = {Balasubramanian, Srikkanth and Skaf, Joseph and Holzgrabe, Ulrike and Bharti, Richa and F{\"o}rstner, Konrad U. and Ziebuhr, Wilma and Humeida, Ute H. and Abdelmohsen, Usama R. and Oelschlaeger, Tobias A.}, title = {A new bioactive compound from the marine sponge-derived Streptomyces sp. SBT348 inhibits staphylococcal growth and biofilm formation}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.01473}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221408}, year = {2018}, abstract = {Staphylococcus epidermidis, the common inhabitant of human skin and mucosal surfaces has emerged as an important pathogen in patients carrying surgical implants and medical devices. Entering the body via surgical sites and colonizing the medical devices through formation of multi-layered biofilms leads to refractory and persistent device-related infections (DRIs). Staphylococci organized in biofilms are more tolerant to antibiotics and immune responses, and thus are difficult-to-treat. The consequent morbidity and mortality, and economic losses in health care systems has strongly necessitated the need for development of new anti-bacterial and anti-biofilm-based therapeutics. In this study, we describe the biological activity of a marine sponge-derived Streptomyces sp. SBT348 extract in restraining staphylococcal growth and biofilm formation on polystyrene, glass, medically relevant titan metal, and silicone surfaces. A bioassay-guided fractionation was performed to isolate the active compound (SKC3) from the crude SBT348 extract. Our results demonstrated that SKC3 effectively inhibits the growth (MIC: 31.25 \(\mu\)g/ml) and biofilm formation (sub-MIC range: 1.95-<31.25 \(\mu\)g/ml) of S. epidermidis RP62A in vitro. Chemical characterization of SKC3 by heat and enzyme treatments, and mass spectrometry (HRMS) revealed its heat-stable and non-proteinaceous nature, and high molecular weight (1258.3 Da). Cytotoxicity profiling of SKC3 in vitro on mouse fibroblast (NIH/3T3) and macrophage (J774.1) cell lines, and in vivo on the greater wax moth larvae Galleria mellonella revealed its non-toxic nature at the effective dose. Transcriptome analysis of SKC3 treated S. epidermidis RP62A has further unmasked its negative effect on central metabolism such as carbon flux as well as, amino acid, lipid, and energy metabolism. Taken together, these findings suggest a potential of SKC3 as a putative drug to prevent staphylococcal DRIs.}, language = {en} } @article{JoosSaadatmandSchnabeletal.2018, author = {Joos, J. P. and Saadatmand, A. R. and Schnabel, C. and Viktorinov{\´a}, I. and Brand, T. and Kramer, M. and Nattel, S. and Dobrev, D. and Tomancak, P. and Backs, J. and Kleinbongard, P. and Heusch, G. and Lorenz, K. and Koch, E. and Weber, S. and El-Armouche, A.}, title = {Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-21372-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323637}, year = {2018}, abstract = {Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.}, language = {en} } @article{KnopSpilgiesRuflietal.2019, author = {Knop, Janin and Spilgies, Lisanne M. and Rufli, Stefanie and Reinhart, Ramona and Vasilikos, Lazaros and Yabal, Monica and Owsley, Erika and Jost, Philipp J. and Marsh, Rebecca A. and Wajant, Harald and Robinson, Mark D. and Kaufmann, Thomas and W. Wei-Lynn, Wong}, title = {TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1938-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325946}, year = {2019}, abstract = {The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap-/- macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap-/- myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.}, language = {en} }