@article{GhoshHoenscheidDueckersetal.2017,
  author    = {Ghosh, Sujal and H{\"o}nscheid, Andrea and D{\"u}ckers, Gregor and Ginzel, Sebastian and Gohlke, Holger and Gombert, Michael and Kempkes, Bettina and Klapper, Wolfram and Kuhlen, Michaela and Laws, Hans-J{\"u}rgen and Linka, Ren{\´e} Martin and Meisel, Roland and Mielke, Christian and Niehues, Tim and Schindler, Detlev and Schneider, Dominik and Schuster, Friedhelm R. and Speckmann, Carsten and Borkhardt, Arndt},
  title     = {Human RAD52 - a novel player in DNA repair in cancer and immunodeficiency},
  series = {Haematologica},
  volume    = {102},
  journal   = {Haematologica},
  number    = {2},
  doi       = {10.3324/haematol.2016.155838},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180862},
  pages     = {e69-e72},
  year      = {2017},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{HernandezJoseRamirezMinguillonetal.2018,
  author    = {Hern{\´a}ndez, Gonzalo and Jos{\´e} Ram{\´i}rez, Mar{\´i}a and Minguill{\´o}n, Jordi and Quiles, Paco and Ruiz de Garibay, Gorka and Aza-Carmona, Miriam and Bogliolo, Massimo and Pujol, Roser and Prados-Carvajal, Rosario and Fern{\´a}ndez, Juana and Garc{\´i}a, Nadia and L{\´o}pez, Adri{\`a} and Guti{\´e}rrez-Enr{\´i}quez, Sara and Diez, Orland and Ben{\´i}tez, Javier and Salinas, M{\´o}nica and Teul{\´e}, Alex and Brunet, Joan and Radice, Paolo and Peterlongo, Paolo and Schindler, Detlev and Huertas, Pablo and Puente, Xose S. and L{\´a}zaro, Conxi and {\`A}ngel Pujana, Miquel and Surrall{\´e}s, Jordi},
  title     = {Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1},
  series = {Nature Communications},
  volume    = {9},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-018-03433-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319929},
  year      = {2018},
  abstract  = {BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.},
  language  = {en}
}
@phdthesis{Hahn2024,
  author    = {Hahn, Sarah},
  title     = {Investigating non-canonical, 5' UTR-dependent translation of MYC and its impact on colorectal cancer development},
  doi       = {10.25972/OPUS-36420},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364202},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Colorectal cancer (CRC) is the second most common tumour disease in Germany, with the sequential accumulation of certain mutations playing a decisive role in the transition from adenoma to carcinoma. In particular, deregulation of the Wnt signalling pathway and the associated deregulated expression of the MYC oncoprotein play a crucial role. Targeting MYC thus represents an important therapeutic approach in the treatment of tumours. Since direct inhibition of MYC is challenging, various approaches have been pursued to date to target MYC indirectly. The MYC 5' UTR contains an internal ribosomal entry site (IRES), which has a particular role in the initiation of MYC translation, especially in multiple myeloma. As basis for this work, it was hypothesised on the basis of previous data that translation of MYC potentially occurs via its IRES in CRC as well. Based on this, two IRES inhibitors were tested for their potential to regulate MYC expression in CRC cells. In addition, alternative, 5' UTR-dependent translation of MYC and interacting factors were investigated. EIF3D was identified as a MYC 5' UTR binding protein which has the potential to regulate MYC expression in CRC. The results of this work suggest that there is a link between eIF3D and MYC expression/translation, rendering eIF3D a potential therapeutic target for MYC-driven CRCs.},
  subject      = {Myc},
  language  = {en}
}
@phdthesis{Yu2024,
  author    = {Yu, Yanying},
  title     = {Applied machine learning for the analysis of CRISPR-Cas systems},
  doi       = {10.25972/OPUS-32021},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320219},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Among the defense strategies developed in microbes over millions of years, the innate adaptive CRISPR-Cas immune systems have spread across most of bacteria and archaea. The flexibility, simplicity, and specificity of CRISPR-Cas systems have laid the foundation for CRISPR-based genetic tools. Yet, the efficient administration of CRISPR-based tools demands rational designs to maximize the on-target efficiency and off-target specificity. Specifically, the selection of guide RNAs (gRNAs), which play a crucial role in the target recognition of CRISPR-Cas systems, is non-trivial. Despite the fact that the emerging machine learning techniques provide a solution to aid in gRNA design with prediction algorithms, design rules for many CRISPR-Cas systems are ill-defined, hindering their broader applications. CRISPR interference (CRISPRi), an alternative gene silencing technique using a catalytically dead Cas protein to interfere with transcription, is a leading technique in bacteria for functional interrogation, pathway manipulation, and genome-wide screens. Although the application is promising, it also is hindered by under-investigated design rules. Therefore, in this work, I develop a state-of-art predictive machine learning model for guide silencing efficiency in bacteria leveraging the advantages of feature engineering, data integration, interpretable AI, and automated machine learning. I first systematically investigate the influential factors that attribute to the extent of depletion in multiple CRISPRi genome-wide essentiality screens in Escherichia coli and demonstrate the surprising dominant contribution of gene-specific effects, such as gene expression level. These observations allowed me to segregate the confounding gene-specific effects using a mixed-effect random forest (MERF) model to provide a better estimate of guide efficiency, together with the improvement led by integrating multiple screens. The MERF model outperformed existing tools in an independent high-throughput saturating screen. I next interpret the predictive model to extract the design rules for robust gene silencing, such as the preference for cytosine and disfavoring for guanine and thymine within and around the protospacer adjacent motif (PAM) sequence. I further incorporated the MERF model in a web-based tool that is freely accessible at www.ciao.helmholtz-hiri.de. When comparing the MERF model with existing tools, the performance of the alternative gRNA design tool optimized for CRISPRi in eukaryotes when applied to bacteria was far from satisfying, questioning the robustness of prediction algorithms across organisms. In addition, the CRISPR-Cas systems exhibit diverse mechanisms albeit with some similarities. The captured predictive patterns from one dataset thereby are at risk of poor generalization when applied across organisms and CRISPR-Cas techniques. To fill the gap, the machine learning approach I present here for CRISPRi could serve as a blueprint for the effective development of prediction algorithms for specific organisms or CRISPR-Cas systems of interest. The explicit workflow includes three principle steps: 1) accommodating the feature set for the CRISPR-Cas system or technique; 2) optimizing a machine learning model using automated machine learning; 3) explaining the model using interpretable AI. To illustrate the applicability of the workflow and diversity of results when applied across different bacteria and CRISPR-Cas systems, I have applied this workflow to analyze three distinct CRISPR-Cas genome-wide screens. From the CRISPR base editor essentiality screen in E. coli, I have determined the PAM preference and sequence context in the editing window for efficient editing, such as A at the 2nd position of PAM, A/TT/TG downstream of PAM, and TC at the 4th to 5th position of gRNAs. From the CRISPR-Cas13a screen in E. coli, in addition to the strong correlation with the guide depletion, the target expression level is the strongest predictor in the model, supporting it as a main determinant of the activation of Cas13-induced immunity and better characterizing the CRISPR-Cas13 system. From the CRISPR-Cas12a screen in Klebsiella pneumoniae, I have extracted the design rules for robust antimicrobial activity across K. pneumoniae strains and provided a predictive algorithm for gRNA design, facilitating CRISPR-Cas12a as an alternative technique to tackle antibiotic resistance. Overall, this thesis presents an accurate prediction algorithm for CRISPRi guide efficiency in bacteria, providing insights into the determinants of efficient silencing and guide designs. The systematic exploration has led to a robust machine learning approach for effective model development in other bacteria and CRISPR-Cas systems. Applying the approach in the analysis of independent CRISPR-Cas screens not only sheds light on the design rules but also the mechanisms of the CRISPR-Cas systems. Together, I demonstrate that applied machine learning paves the way to a deeper understanding and a broader application of CRISPR-Cas systems.},
  subject      = {Maschinelles Lernen},
  language  = {en}
}
@article{Gohla2019,
  author    = {Gohla, Antje},
  title     = {Do metabolic HAD phosphatases moonlight as protein phosphatases?},
  series = {BBA - Molecular Cell Research},
  volume    = {1866},
  journal   = {BBA - Molecular Cell Research},
  doi       = {10.1016/j.bbamcr.2018.07.007},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233168},
  pages     = {153-166},
  year      = {2019},
  abstract  = {Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as serine/threonine, tyrosine-, and histidine-phosphorylated proteins. To accomplish these tasks, HAD phosphatases are equipped with cap domains that control access to the active site and provide substrate specificity determinants. A number of capped HAD phosphatases impact protein phosphorylation, although structural data are consistent with small metabolite substrates rather than protein substrates. This review discusses the structures, functions and disease implications of the three closely related, capped HAD phosphatases pyridoxal phosphatase (PDXP or chronophin), phosphoglycolate phosphatase (PGP, also termed AUM or glycerol phosphatase) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP or HDHD2B). Evidence in support of small metabolite and protein phosphatase activity is discussed in the context of the diversity of their biological functions.},
  language  = {en}
}
@article{CasarottoTurcoComanduccietal.2019,
  author    = {Casarotto, Silvia and Turco, Francesco and Comanducci, Angela and Perretti, Alessio and Marotta, Giorgio and Pezzoli, Gianni and Rosanova, Mario and Isaias, Ioannis U.},
  title     = {Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage},
  series = {Brain Stimulation},
  volume    = {12},
  journal   = {Brain Stimulation},
  doi       = {10.1016/j.brs.2018.10.011},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222261},
  pages     = {152-160},
  year      = {2019},
  abstract  = {Background Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). Objective We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. Methods In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. Results We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. Conclusions These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.},
  language  = {en}
}
@article{EisenhoferPeitzschKadenetal.2019,
  author    = {Eisenhofer, Graeme and Peitzsch, Mirko and Kaden, Denise and Langton, Katharina and Mangelis, Anastasios and Pamporaki, Christina and Masjkur, Jimmy and Geroula, Aikaterini and Kurlbaum, Max and Deutschbein, Timo and Beuschlein, Felix and Prejbisz, Aleksander and Bornstein, Stefan R. and Lenders, Jacques W. M.},
  title     = {Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine},
  series = {Clinica Chimica Acta},
  volume    = {490},
  journal   = {Clinica Chimica Acta},
  doi       = {10.1016/j.cca.2018.12.019},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226598},
  pages     = {46-54},
  year      = {2019},
  abstract  = {Background Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites.},
  language  = {en}
}
@article{LieseSchoenvanderLindenetal.2019,
  author    = {Liese, J. G. and Schoen, C. and van der Linden, M. and Lehmann, L. and Goettler, D. and Keller, S. and Maier, A. and Segerer, F. and Rose, M. A. and Streng, A.},
  title     = {Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study},
  series = {Clinical Microbiology and Infection},
  volume    = {25},
  journal   = {Clinical Microbiology and Infection},
  doi       = {10.1016/j.cmi.2018.10.020},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236866},
  pages     = {857-864},
  year      = {2019},
  abstract  = {Objectives Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community-acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunization for infants. Methods Children <18 years of age hospitalized with pneumonia-associated PPE/PE necessitating pleural drainage or persisting >7 days were reported to the German Surveillance Unit for Rare Diseases in Childhood between October 2010 and June 2017. All bacteria detected in blood or pleural fluid (by culture/PCR) were included, with serotyping for Streptococcus pneumoniae. Results The median age of all 1447 PPE/PE patients was 5 years (interquartile range 3-10). In 488 of the 1447 children with PPE/PE (34\%), 541 bacteria (>40 species) were detected. Aerobic gram-positive cocci accounted for 469 of 541 bacteria detected (87\%); these were most frequently Streptococcus pneumoniae (41\%), Streptococcus pyogenes (19\%) and Staphylococcus aureus (6\%). Serotype 3 accounted for 45\% of 78 serotyped S. pneumoniae strains. Annual PPE/PE incidence varied between 14 (95\%CI 12-16) and 18 (95\%CI 16-21) PPE/PE per million children. Incidence of S. pneumoniae PPE/PE decreased from 3.5 (95\%CI 2.5-4.6) per million children in 2010/11 to 1.5 (95\%CI 0.9-2.4) in 2013/14 (p 0.002), followed by a re-increase to 2.2 (95\%CI 1.5-3.2) by 2016/17 (p 0.205). Conclusions In the era of widespread PCV immunization, cases of paediatric PPE/PE were still caused mainly by S. pneumoniae and, increasingly, by S. pyogenes. The re-increase in the incidence of PPE/PE overall and in S. pneumoniae-associated PPE/PE indicates ongoing changes in the bacterial aetiology and requires further surveillance.},
  language  = {en}
}
@article{SteinKantarjianGoekbugetetal.2019,
  author    = {Stein, Anthony S. and Kantarjian, Hagop and G{\"o}kbuget, Nicola and Bargou, Ralf and Litzow, Mark R. and Rambaldi, Alessandro and Ribera, Josep-Maria and Zhang, Alicia and Zimmerman, Zachary and Zugmaier, Gerhard and Topp, Max S.},
  title     = {Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation},
  series = {Biology of Blood and Marrow Transplantation},
  volume    = {25},
  journal   = {Biology of Blood and Marrow Transplantation},
  doi       = {10.1016/j.bbmt.2019.04.010},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239510},
  pages     = {1498-1504},
  year      = {2019},
  abstract  = {Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43\% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36\% at 1 year and 18\% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31\%) and 28 patients (44\%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.},
  language  = {en}
}
@article{HochleitnerChenBlumetal.2018,
  author    = {Hochleitner, Gernot and Chen, Fei and Blum, Carina and Dalton, Paul D. and Amsden, Brian and Groll, J{\"u}rgen},
  title     = {Melt electrowriting below the critical translation speed to fabricate crimped elastomer scaffolds with non-linear extension behaviour mimicking that of ligaments and tendons},
  series = {Acta Biomaterialia},
  volume    = {72},
  journal   = {Acta Biomaterialia},
  doi       = {10.1016/j.actbio.2018.03.023},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320846},
  pages     = {110-120},
  year      = {2018},
  abstract  = {Abstract Ligaments and tendons are comprised of aligned, crimped collagen fibrils that provide tissue-specific mechanical properties with non-linear extension behaviour, exhibiting low stress at initial strain (toe region behaviour). To approximate this behaviour, we report fibrous scaffolds with sinusoidal patterns by melt electrowriting (MEW) below the critical translation speed (CTS) by exploitation of the natural flow behaviour of the polymer melt. More specifically, we synthesised photopolymerizable poly(L-lactide-co-ε-caprolactone-co-acryloyl carbonate) (p(LLA-co-ε-CL-co-AC)) and poly(ε-caprolactone-co-acryloyl carbonate) (p(ε-CL-co-AC)) by ring-opening polymerization (ROP). Single fibre (f{\O} = 26.8 ± 1.9 µm) tensile testing revealed a customisable toe region with Young's Moduli ranging from E = 29 ± 17 MPa for the most crimped structures to E = 314 ± 157 MPa for straight fibres. This toe region extended to scaffolds containing multiple fibres, while the sinusoidal pattern could be influenced by printing speed. The synthesized polymers were cytocompatible and exhibited a tensile strength of σ = 26 ± 7 MPa after 104 cycles of preloading at 10\% strain while retaining the distinct toe region commonly observed in native ligaments and tendon tissue. Statement of Significance Damaged tendons and ligaments are serious and frequently occurring injuries worldwide. Recent therapies, including autologous grafts, still have severe disadvantages leading to a demand for synthetic alternatives. Materials envisioned to induce tendon and ligament regeneration should be degradable, cytocompatible and mimic the ultrastructural and mechanical properties of the native tissue. Specifically, we utilised photo-cross-linkable polymers for additive manufacturing (AM) with MEW. In this way, we were able to direct-write cytocompatible fibres of a few micrometres thickness into crimp-structured elastomer scaffolds that mimic the non-linear biomechanical behaviour of tendon and ligament tissue.},
  language  = {en}
}
@article{TesfamariamJakobWoeckeletal.2019,
  author    = {Tesfamariam, Y. and Jakob, T. and W{\"o}ckel, A. and Adams, A. and Weigl, A. and Monsef, I. and Kuhr, K. and Skoetz, N.},
  title     = {Adjuvant bisphosphonates or RANK-ligand inhibitors for patients with breast cancer and bone metastases: A systematic review and network meta-analysis},
  series = {Critical Reviews in Oncology / Hematology},
  volume    = {137},
  journal   = {Critical Reviews in Oncology / Hematology},
  doi       = {10.1016/j.critrevonc.2019.02.004},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240827},
  pages     = {1-8},
  year      = {2019},
  abstract  = {Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95\%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95\%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95\%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.},
  language  = {en}
}
@article{BrinkerHeklerHauschildetal.2019,
  author    = {Brinker, Titus J. and Hekler, Achim and Hauschild, Axel and Berking, Carola and Schilling, Bastian and Enk, Alexander H. and Haferkamp, Sebastian and Karoglan, Ante and von Kalle, Christof and Weichenthal, Michael and Sattler, Elke and Schadendorf, Dirk and Gaiser, Maria R. and Klode, Joachim and Utikal, Jochen S.},
  title     = {Comparing artificial intelligence algorithms to 157 German dermatologists: the melanoma classification benchmark},
  series = {European Journal of Cancer},
  volume    = {111},
  journal   = {European Journal of Cancer},
  doi       = {10.1016/j.ejca.2018.12.016},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220569},
  pages     = {30-37},
  year      = {2019},
  abstract  = {Background Several recent publications have demonstrated the use of convolutional neural networks to classify images of melanoma at par with board-certified dermatologists. However, the non-availability of a public human benchmark restricts the comparability of the performance of these algorithms and thereby the technical progress in this field. Methods An electronic questionnaire was sent to dermatologists at 12 German university hospitals. Each questionnaire comprised 100 dermoscopic and 100 clinical images (80 nevi images and 20 biopsy-verified melanoma images, each), all open-source. The questionnaire recorded factors such as the years of experience in dermatology, performed skin checks, age, sex and the rank within the university hospital or the status as resident physician. For each image, the dermatologists were asked to provide a management decision (treat/biopsy lesion or reassure the patient). Main outcome measures were sensitivity, specificity and the receiver operating characteristics (ROC). Results Total 157 dermatologists assessed all 100 dermoscopic images with an overall sensitivity of 74.1\%, specificity of 60.0\% and an ROC of 0.67 (range = 0.538-0.769); 145 dermatologists assessed all 100 clinical images with an overall sensitivity of 89.4\%, specificity of 64.4\% and an ROC of 0.769 (range = 0.613-0.9). Results between test-sets were significantly different (P < 0.05) confirming the need for a standardised benchmark. Conclusions We present the first public melanoma classification benchmark for both non-dermoscopic and dermoscopic images for comparing artificial intelligence algorithms with diagnostic performance of 145 or 157 dermatologists. Melanoma Classification Benchmark should be considered as a reference standard for white-skinned Western populations in the field of binary algorithmic melanoma classification.},
  language  = {en}
}
@article{BrinkerHeklerEnketal.2019,
  author    = {Brinker, Titus J. and Hekler, Achim and Enk, Alexander H. and Berking, Carola and Haferkamp, Sebastian and Hauschild, Axel and Weichenthal, Michael and Klode, Joachim and Schadendorf, Dirk and Holland-Letz, Tim and von Kalle, Christof and Fr{\"o}hling, Stefan and Schilling, Bastian and Utikal, Jochen S.},
  title     = {Deep neural networks are superior to dermatologists in melanoma image classification},
  series = {European Journal of Cancer},
  volume    = {119},
  journal   = {European Journal of Cancer},
  doi       = {10.1016/j.ejca.2019.05.023},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220539},
  pages     = {11-17},
  year      = {2019},
  abstract  = {Background Melanoma is the most dangerous type of skin cancer but is curable if detected early. Recent publications demonstrated that artificial intelligence is capable in classifying images of benign nevi and melanoma with dermatologist-level precision. However, a statistically significant improvement compared with dermatologist classification has not been reported to date. Methods For this comparative study, 4204 biopsy-proven images of melanoma and nevi (1:1) were used for the training of a convolutional neural network (CNN). New techniques of deep learning were integrated. For the experiment, an additional 804 biopsy-proven dermoscopic images of melanoma and nevi (1:1) were randomly presented to dermatologists of nine German university hospitals, who evaluated the quality of each image and stated their recommended treatment (19,296 recommendations in total). Three McNemar's tests comparing the results of the CNN's test runs in terms of sensitivity, specificity and overall correctness were predefined as the main outcomes. Findings The respective sensitivity and specificity of lesion classification by the dermatologists were 67.2\% (95\% confidence interval [CI]: 62.6\%-71.7\%) and 62.2\% (95\% CI: 57.6\%-66.9\%). In comparison, the trained CNN achieved a higher sensitivity of 82.3\% (95\% CI: 78.3\%-85.7\%) and a higher specificity of 77.9\% (95\% CI: 73.8\%-81.8\%). The three McNemar's tests in 2 × 2 tables all reached a significance level of p < 0.001. This significance level was sustained for both subgroups. Interpretation For the first time, automated dermoscopic melanoma image classification was shown to be significantly superior to both junior and board-certified dermatologists (p < 0.001).},
  language  = {en}
}
@phdthesis{Zuber2024,
  author    = {Zuber, Jonas Maximilian},
  title     = {Evaluation von Sedierungen und Allgemeinan{\"a}sthesien zur Durchf{\"u}hrung bildgebender Verfahren bei S{\"a}uglingen bis zum 6. Lebensmonat},
  doi       = {10.25972/OPUS-36111},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361111},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Vorliegende Untersuchung am Universit{\"a}tsklinikum W{\"u}rzburg sowie die Befragung von An{\"a}sthesisten/An{\"a}sthesistinnen im Raum der 3 DACH-L{\"a}nder zeigen, dass bildgebende Verfahren bei S{\"a}uglingen mit einer niedrigen Rate an Komplikationen, zumeist in medikament{\"o}ser Sedierung mit Propofol, durchgef{\"u}hrt werden. Wie international {\"u}blich ist im S{\"a}uglingsalter die Magnetresonanztomographie das bildgebende Verfahren der Wahl und wird, mit {\"u}berzeugender H{\"a}ufigkeit, erfolgreich durchgef{\"u}hrt. Die Untersuchung am Universit{\"a}tsklinikum W{\"u}rzburg legt nahe, dass m{\"a}nnliche S{\"a}uglinge h{\"a}ufiger eine Bildgebung ben{\"o}tigen und h{\"a}ufiger h{\"o}heren ASA-Kategorie zugeschrieben werden. Dabei scheinen sie auch h{\"a}ufiger Komplikationen zu erleben und bed{\"u}rfen daher besonderer Aufmerksamkeit. Eine eventuelle Alternative zur Sedierung kann dabei die „feed-and-sleep" Methode darstellen. In unserer Umfrage konnten wir erheben, dass diese Methode bisher wenig verbreitet ist, obwohl in diesem Zusammenhang eventuell Abl{\"a}ufe und Prozesszeiten strukturiert und optimiert werden k{\"o}nnen, da beispielsweise die Nach{\"u}berwachung entf{\"a}llt. Vorstellbar w{\"a}re beispielsweise, mehrere S{\"a}uglinge zum gleichen Zeitpunkt ins MRT zu bestellen, um gegebenenfalls den am fr{\"u}hesten eingeschlafenen S{\"a}ugling vorzuziehen. Diese Methode sollte zuk{\"u}nftig Einzug in die wissenschaftliche Untersuchung von bildgebenden Verfahren bei S{\"a}uglingen finden. Die Umfrage im deutschsprachigen Raum zeigt eine Leitlinien-gerechte Betreuung von S{\"a}uglingen f{\"u}r bildgebende Verfahren, die mit einer hohen Qualit{\"a}t, und zumeist erfolgreich von erfahrenen An{\"a}sthesisten/An{\"a}sthesistinnen durchgef{\"u}hrt wird. Eventuelle Verbesserungen k{\"o}nnen im Bereich der Ausbildung nachfolgender {\"A}rztinnen/{\"A}rzte und in der h{\"a}ufigeren Verwendung der „feed-and-sleep" Methode liegen, die vielen Kollegen/Kolleginnen bekannt ist, aber nur selten durchgef{\"u}hrt wird. Ziel ist eine qualitativ hochwertige, schnellstm{\"o}glich durchgef{\"u}hrte Bildgebung, die ohne oder mit der niedrigst m{\"o}glichen Dosierung eines sedierenden Medikamentes zu erreichen ist.},
  subject      = {Sedierung},
  language  = {de}
}
@phdthesis{Dalkmann2024,
  author    = {Dalkmann, Theresa},
  title     = {Evaluierung prognostischer und pr{\"a}diktiver Biomarker beim neoadjuvant vorbehandelten Rektumkarzinom},
  doi       = {10.25972/OPUS-36336},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363368},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Fragestellung. Osteopontin (OPN) kann im Blut nachgewiesen werden und wird bei vielen Tumorentit{\"a}ten exprimiert, wie auch der Tyrosinkinaserezeptor c-Met und sein Ligand, das Zytokin Hepatocyte Growth Factor (HGF). In der vorliegenden Arbeit untersuchten wir die prognostische und pr{\"a}diktive Wertigkeit der Plasmakonzentrationen von OPN, c-Met und HGF bei Patienten mit lokal fortgeschrittenem Rektumkarzinom (LARC). Methodik. Das Plasma von 63 Patienten mit LARC wurde untersucht. Die Blutentnahmen (EDTA-Plasma) erfolgten vor Therapiebeginn sowie im Verlauf. Die Plasmaspiegel von OPN, c-Met und HGF wurden mittels Enzyme-Linked Immunosorbent Assay analysiert. Die Konzentrationen wurden auf eine Korrelation mit den klinischen Parametern untersucht. Ergebnisse. 68 Patienten wurden neoadjuvant mit einer Radiochemotherapie behandelt, 63 Blutproben wurden untersucht. Initial befanden sich nach UICC 14 Patienten in Stadium II, 47 in Stadium III und 7 in Stadium IV. Das mediane Follow-Up betrug 29,87 Monate. 20 der 68 Patienten (29,4 \%) verstarben, 19 entwickelten Fernmetastasen. OPN korrelierte signifikant mit dem {\"U}berleben (p=0,001). OPN-Werte korrelierten mit dem pT-Stadium (R:0,445 p=0,018) und dem pUICC-Stadium (R:0,412 p=0,018), sowie mit dem Auftreten von Fernmetastasen (R:0,271 p=0,031). Eine Korrelation zwischen OPN und dem Therapieansprechen konnte gezeigt werden: pathologisch komplette Remission (pCR) (R:0,379 p=0,001), NAR-Score (R:0,373 p=0,015), TRG (R:0,380 p=0,020). Die logistische Regressionsanalyse ergab eine Pr{\"a}diktivit{\"a}t OPNs f{\"u}r pCR (OR:0,990 p=0,009), NAR-Score (OR:1,008 p=0,007), TRG (OR:0,459 p=0,008). C-Met und HGF korrelierten nicht mit dem {\"U}berleben. F{\"u}r c-Met und HGF ergab sich keine Korrelation zu initialen klinischen Daten und Therapieansprechen. Die logistische Regression ergab keinen pr{\"a}diktiven Wert. Schlussfolgerung. Die Plasmakonzentration von OPN besitzt prognostische und pr{\"a}diktive Wertigkeit beim LARC. Die Konzentrationen von c-Met und HGF sind nicht prognostisch f{\"u}r das {\"U}berleben oder pr{\"a}diktiv f{\"u}r das Therapieansprechen.},
  subject      = {Biomarker},
  language  = {de}
}
@phdthesis{Junghanns2024,
  author    = {Junghanns, Lara Madeleine},
  title     = {Resistenzmechanismen gegen Amphotericin B in humanpathogenen Hefepilzen},
  doi       = {10.25972/OPUS-36986},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369861},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Die 2009 erstmals entdeckte Spezies C. auris erlangte binnen k{\"u}rzester Zeit zunehmend weltweite Aufmerksamkeit. Vor allem die Tendenz der Multiresistenzentwicklung und das rasche Ausl{\"o}sen von nosokomialen Infektionen erschweren den Umgang und die Therapie von C. auris Infektionen im Vergleich zu anderen Candida Spezien. Diese Dissertationsarbeit umfasst eine systematische Resistenzanalyse der im NRZMyk vorhandenen Stammsammlung aus C. auris und C. parapsilosis Isolaten, um Aufschluss {\"u}ber den Wirkmechanismus von Amphotericin B in Hefepilzen zu erlangen. Anhand der zun{\"a}chst durchgef{\"u}hrten Amphotericin B-Resistenztestungen kristallisierten sich CAU37 und CAU43 mit MHK-Werten bis zu 12 µg/ml als stark Amphotericin B-resistente Isolate heraus. Die Analyse der Sequenzierungsergebnisse zeigte bei beiden St{\"a}mmen eine Mutation im ERG4 Gen an Position 576, welche nicht eindeutig als alleinige Ursache f{\"u}r die verminderte Amphotericin B-Empfindlichkeit festgelegt werden konnte. Dennoch wurde im Rahmen eines Survival Assays bei beiden Amphotericin B-resistenten Isolaten anf{\"a}nglich eine konzentrationsabh{\"a}ngige Aktivit{\"a}t gegen{\"u}ber Amphotericin B festgestellt, bevor ein Nachwachsen der Kulturen beobachtet wurde. Somit wurde die Vermutung aufgestellt, dass lediglich ein Teil der aufgebrachten Candida-Zellen abget{\"o}tet wird und dies in einer Vermehrung der {\"u}berlebenden Zellen resultiert. Des Weiteren konnte im Rahmen von Resistenztestungen mit dem Sphingolipidinhibitor Myriocin nachgewiesen werden, dass vor allem in Amphotericin B-resistenten Isolaten eine deutliche Wirkungsverst{\"a}rkung des Polyens hervorgerufen wird. Diese Sensitivit{\"a}tssteigerung ist allgemein bei allen C. auris Isolaten zu beobachten, f{\"a}llt bei resistenten St{\"a}mmen jedoch deutlich st{\"a}rker aus. Hierdurch kam die Annahme auf, dass Amphotericin B-Resistenzen auch in m{\"o}glichen Ver{\"a}nderungen des Sphingolipid-Haushaltes begr{\"u}ndet sein k{\"o}nnten. Dar{\"u}ber hinaus scheint Myriocin keinen Einfluss auf Fluconazol-resistente oder FKS-mutierte Echinocandin-resistente C. auris St{\"a}mme zu haben. Das ebenfalls untersuchte und von Myriocin abgeleitete Medikament Fingolimod hatte jedoch ebenfalls keinen wirkungsverst{\"a}rkenden Effekt. Allerdings reagierte ein Großteil der C. auris Isolate (57,6 \%) sensitiv gegen{\"u}ber dem neusten medizinisch bekannten Triazol Isavuconazol und es konnte erstmalig ein ECV-Wert von 0,03125 µg/ml festgelegt werden. Ein valider Vergleich von C. auris zu C. parapsilosis war aufgrund der mangelnden Anzahl an C. parapsilosis Isolaten jedoch nicht m{\"o}glich},
  subject      = {Candida},
  language  = {de}
}
@article{JeanclosAlbersenRamosetal.2019,
  author    = {Jeanclos, Elisabeth and Albersen, Monique and Ramos, R{\´u}ben J. J. and Raab, Annette and Wilhelm, Christian and Hommers, Leif and Lesch, Klaus-Peter and Verhoeven-Duif, Nanda M. and Gohla, Antje},
  title     = {Improved cognition, mild anxiety-like behavior and decreased motor performance in pyridoxal phosphatase-deficient mice},
  series = {BBA - Molecular Basis of Disease},
  volume    = {1865},
  journal   = {BBA - Molecular Basis of Disease},
  doi       = {10.1016/j.bbadis.2018.08.018},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323396},
  pages     = {193-205},
  year      = {2019},
  abstract  = {Pyridoxal 5′-phosphate (PLP) is an essential cofactor in the catalysis of ~140 different enzymatic reactions. A pharmacological elevation of cellular PLP concentrations is of interest in neuropsychiatric diseases, but whole-body consequences of higher intracellular PLP levels are unknown. To address this question, we have generated mice allowing a conditional ablation of the PLP phosphatase PDXP. Ubiquitous PDXP deletion increased PLP levels in brain, skeletal muscle and red blood cells up to 3-fold compared to control mice, demonstrating that PDXP acts as a major regulator of cellular PLP concentrations in vivo. Neurotransmitter analysis revealed that the concentrations of dopamine, serotonin, epinephrine and glutamate were unchanged in the brains of PDXP knockout mice. However, the levels of γ-aminobutyric acid (GABA) increased by ~20\%, demonstrating that elevated PLP levels can drive additional GABA production. Behavioral phenotyping of PDXP knockout mice revealed improved spatial learning and memory, and a mild anxiety-like behavior. Consistent with elevated GABA levels in the brain, PDXP loss in neural cells decreased performance in motor tests, whereas PDXP-deficiency in skeletal muscle increased grip strength. Our findings suggest that PDXP is involved in the fine-tuning of GABA biosynthesis. Pharmacological inhibition of PDXP might correct the excitatory/inhibitory imbalance in some neuropsychiatric diseases.},
  language  = {en}
}
@article{MuellerCosentinoFoerstneretal.2018,
  author    = {M{\"u}ller, Laura S. M. and Cosentino, Ra{\´u}l O. and F{\"o}rstner, Konrad U. and Guizetti, Julien and Wedel, Carolin and Kaplan, Noam and Janzen, Christian J. and Arampatzi, Panagiota and Vogel, J{\"o}rg and Steinbiss, Sascha and Otto, Thomas D. and Saliba, Antoine-Emmanuel and Sebra, Robert P. and Siegel, T. Nicolai},
  title     = {Genome organization and DNA accessibility control antigenic variation in trypanosomes},
  series = {Nature},
  volume    = {563},
  journal   = {Nature},
  doi       = {10.1038/s41586-018-0619-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224265},
  pages     = {121-125},
  year      = {2018},
  abstract  = {Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host1. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility2,3. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding4. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses—Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing—that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.},
  language  = {en}
}
@article{MunzRichterLoosetal.2018,
  author    = {Munz, Matthias and Richter, Gesa M. and Loos, Bruno G. and Jepsen, S{\o}ren and Divaris, Kimon and Offenbacher, Steven and Teumer, Alexander and Holtfreter, Birte and Kocher, Thomas and Bruckmann, Corinna and Jockel-Schneider, Yvonne and Graetz, Christian and Munoz, Loreto and Bhandari, Anita and Tennstedt, Stephanie and Staufenbiel, Ingmar and van der Velde, Nathalie and Uitterlinden, Andr{\´e} G. and de Groot, Lisette C. P. G. M. and Wellmann, J{\"u}rgen and Berger, Klaus and Krone, Bastian and Hoffmann, Per and Laudes, Matthias and Lieb, Wolfgang and Andre, Franke and Dommisch, Henrik and Erdmann, Jeanette and Schaefer, Arne S.},
  title     = {Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus},
  series = {Scientific Reports},
  volume    = {8},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-018-31980-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231647},
  year      = {2018},
  abstract  = {Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10-8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95\% CI = [1.02-1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95\% CI = [1.05-1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.},
  language  = {en}
}
@phdthesis{PaetzelgebDitter2024,
  author    = {P{\"a}tzel [geb. Ditter], Katharina Sabine},
  title     = {Molekulare Charakterisierung eines Mitgliedes der TNF-Rezeptor-Superfamilie des Fuchsbandwurmes \(Echinococcus\) \(multilocularis\)},
  doi       = {10.25972/OPUS-36939},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369397},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Die alveol{\"a}re Echinokokkose (AE), die durch den Fuchsbandwurm Echinococcus multilocularis verursacht wird, ist eine seltene jedoch schwere und oft t{\"o}dlich verlaufende Erkrankung. Aufgrund der sp{\"a}ten Diagnosestellung sind kurative Behandlungsmethoden h{\"a}ufig nicht durchf{\"u}hrbar und als einzige Behandlungsm{\"o}glichkeit bleibt eine lebenslange und nebenwirkungsreiche Therapie mit Benzimidazolen. Verbesserte Therapieoptionen durch die Entwicklung neuer Medikamente sind dringend notwendig. Hierf{\"u}r kann es hilfreich sein die Biologie des Fuchsbandwurmes und die Kommunikationswege zwischen Parasit und Wirt zu verstehen. Bereits in vorherigen Arbeiten als auch in dieser Arbeit erwiesen sich evolutionsgeschichtlich konservierte Signalwege als Kommunikationsweg zwischen dem Fuchsbandwurm und seinem Wirt von zentraler Rolle. Die Entschl{\"u}sselung des Echinococcus-Genoms gab Hinweise darauf, dass ein Mitglied der Tumornekrosefaktor-Rezeptor-Superfamilie, jedoch kein endogener TNF α {\"a}hnlicher Ligand im Genom kodiert wird. Ein Mitglied der TNFR-Superfamilie des Fuchsbandwurmes (EmTNFR) wurde in dieser Arbeit als membranst{\"a}ndiger Rezeptor mit einer intrazellul{\"a}ren Todesdom{\"a}ne (DD) und hoher {\"A}hnlichkeit zum humanen Typ 16 der TNF-Rezeptor-Superfamilie, auch 〖p75〗^NTR genannt, charakterisiert. Sowohl in bioinformatischen als auch in Sequenzanalysen wurden drei alternative Splicing-Formen von emtnfr (emtnfr, emtnfr-v2 und emtnfr-v3) nachgewiesen. emtnfr-v2 entsteht durch Alternatives Splicing und kodiert ein Protein, das keine intrazellul{\"a}re Todesdom{\"a}ne besitzt. emtnfr-v3 verwendet einen alternativen Transkriptionstart und wird von den letzten 3 Exons von emtnfr kodiert. emtnfr-v3, kodiert ein Protein ohne extrazellul{\"a}re Region, aber mit intrazellul{\"a}rer Todesdom{\"a}ne. Ein l{\"o}slicher TNF-Rezeptor konnte auf Proteinebene nicht nachgewiesen werden. Aufgrund von phylogenetischen Analysen und der Rezeptor-Struktur ist zu vermuten, dass EmTNFR ein p75NTR Homolog ist und damit der urspr{\"u}nglichen Form der TNF-Rezeptoren entspricht. Mitglieder eines intrazellul{\"a}ren TNF-Signalweges wurden in bioinformatischen Analysen beim Fuchsbandwurm E. multilocularis identifiziert. Expressionsuntersuchungen zeigten sowohl in Trankriptomdaten als auch auf Proteinebene eine starke Expression von EmTNFR in Prim{\"a}rzellen und im Metazestoden (MZ), dem pathogenen Stadium f{\"u}r den Zwischenwirt. Echinococcus-Stammzellkulturen zeigten nach RNA-Interferenz-basiertem Knockdown des EmTNFR-kodierenden Gens deutliche Entwicklungsdefekte. Des Weiteren zeigten Echinococcus-Stammzellkulturen nach einer Behandlung mit TNF-α, einem potentiellen Liganden des TNF-Rezeptors und einem zentralen Zytokin in der Immunabwehr des Zwischenwirtes, Entwicklungsfortschritte, wie eine verbesserte Bildung von MZ aus Stammzellen. Zus{\"a}tzlich wurde in whole-mount in situ Hybridisierungs-Versuchen eine ubiquit{\"a}re Expression von emtnfr in der Germinalschicht des MZ sowie eine Spezifit{\"a}t von emtnfr f{\"u}r den MZ, welcher urs{\"a}chlich f{\"u}r die AE ist, nachgewiesen. Somit scheinen sowohl EmTNFR als auch TNF-α eine wichtige Funktion bei der Entwicklung und Etablierung des Fuchsbandwurmes w{\"a}hrend der fr{\"u}hen Phase der Infektion des Zwischenwirtes zu haben. TNF-α k{\"o}nnte ein weiterer Faktor f{\"u}r den ausgepr{\"a}gten Organtropismus des Parasiten zur Leber sein, denn dort bestehen durch Kupfferzellen produzierte hohe lokale Konzentration von TNF-α. Zusammenfassend deuten die hier erarbeiteten Daten darauf hin, dass EmTNFR {\"u}ber die Bindung von Wirts-TNF-α bei der fr{\"u}hen Entwicklung des Echincoccus-Metazestoden eine Rolle spielt.},
  subject      = {Fuchsbandwurm},
  language  = {de}
}