@article{ZugmaierToppAlekaretal.2014,
  author    = {Zugmaier, G. and Topp, M. S. and Alekar, S. and Viardot, A. and Horst, H.-A. and Neumann, S. and Stelljes, M. and Bargou, R. C. and Goebeler, M. and Wessiepe, D. and Degenhard, E. and Goekbuget, N. and Klinger, M.},
  title     = {Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia},
  series = {Blood Cancer Journal},
  volume    = {4},
  journal   = {Blood Cancer Journal},
  number    = {e244},
  issn      = {2044-5385},
  doi       = {10.1038/bcj.2014.64},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115433},
  year      = {2014},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{ZoranSeelbinderWhiteetal.2022,
  author    = {Zoran, Tamara and Seelbinder, Bastian and White, Philip Lewis and Price, Jessica Sarah and Kraus, Sabrina and Kurzai, Oliver and Linde, Joerg and H{\"a}der, Antje and Loeffler, Claudia and Grigoleit, Goetz Ulrich and Einsele, Hermann and Panagiotou, Gianni and Loeffler, Juergen and Sch{\"a}uble, Sascha},
  title     = {Molecular profiling reveals characteristic and decisive signatures in patients after allogeneic stem cell transplantation suffering from invasive pulmonary aspergillosis},
  series = {Journal of Fungi},
  volume    = {8},
  journal   = {Journal of Fungi},
  number    = {2},
  issn      = {2309-608X},
  doi       = {10.3390/jof8020171},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262105},
  year      = {2022},
  abstract  = {Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.},
  language  = {en}
}
@phdthesis{Zoran2022,
  author    = {Zoran, Tamara},
  title     = {Multilevel analysis of the human immune response to \(Aspergillus\) \(fumigatus\) infection: Characteristic molecular signatures and individual risk factors},
  doi       = {10.25972/OPUS-29851},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-298512},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Although the field of fungal infections advanced tremendously, diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised patients continues to be a challenge. Since IPA is a multifactorial disease, investigation from different aspects may provide new insights, helpful for improving IPA diagnosis. This work aimed to characterize the human immune response to Aspergillus fumigatus in a multilevel manner to identify characteristic molecular candidates and risk factors indicating IPA, which may in the future support already established diagnostic assays. We combined in vitro studies using myeloid cells infected with A. fumigatus and longitudinal case-control studies investigating patients post allogeneic stem cell transplantation (alloSCT) suffering from IPA and their match controls. Characteristic miRNA and mRNA signatures indicating A. fumigatus-infected monocyte-derived dendritic cells (moDCs) demonstrated the potential to differentiate between A. fumigatus and Escherichia coli infection. Transcriptome and protein profiling of alloSCT patients suffering from IPA and their matched controls revealed a distinctive IPA signature consisting of MMP1 induction and LGAL2 repression in combination with elevated IL-8 and caspase-3 levels. Both, in vitro and case-control studies, suggested cytokines, matrix-metallopeptidases and galectins are important in the immune response to A. fumigatus. Identified IPA characteristic molecular candidates are involved in numerous processes, thus a combination of these in a distinctive signature may increase the specificity. Finally, low monocyte counts, severe GvHD of the gut (grade ≥ 2) and etanercept administration were significantly associated with IPA diagnosis post alloSCT. Etanercept in monocyte-derived macrophages (MDM) infected with A. fumigatus downregulates genes involved in the NF-κB and TNF-α pathway and affects the secretion of CXCL10. Taken together, identified characteristic molecular signatures and risk factors indicating IPA may in the future in combination with established fungal biomarkers overcome current diagnostic challenges and help to establish tailored antifungal therapy. Therefore, further multicentre studies are encouraged to evaluate reported findings.},
  subject      = {Aspergillus fumigatus},
  language  = {en}
}
@phdthesis{Zopf2011,
  author    = {Zopf, Waltraud},
  title     = {Identifikation von uniparentaler Disomie bei mikrosatellitenstabilen und mikrosatelliteninstabilen kolorektalen Karzinomen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69620},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Im Rahmen dieser Arbeit wurden Gewebe von jeweils 15 kolorektalen MSI- und CSIPrim{\"a}rtumoren, sowie 3 MSI- und 2 CSI-Tumorzelllinien mittels SNP-Arrayanalyse molekulargenetisch auf uniparentale Disomie (UPD) untersucht. Es konnte best{\"a}tigt werden, dass die uniparentale Disomie ein wichtiger Mechanismus zur Inaktivierung von Tumorsuppressorgenen zu sein scheint. Die Ergebnisse zeigen, dass nicht nur in MSI-Tumoren, sondern auch in CSI-Tumoren UPD nachgewiesen werden konnte, wobei der UPD-Anteil an identifizierten LOH-Regionen in MSI-Tumoren mit 94\% gegen{\"u}ber 41\% in CSI-Tumoren deutlich h{\"o}her lag. Interessanterweise wurde auch in 68\% der korrespondierenden MSI- und in 27\% der entsprechenden CSINormalgewebe UDP festgestellt, was daraufhin deutet, dass hier m{\"o}glicherweise schon kanzerogene Vorstufen vorliegen. Die Verteilung der UPDs in den 15 Tumorproben der jeweiligen Tumortypen (MSI und CSI) war innerhalb der einzelnen Proben und innerhalb der einzelnen Chromosomen sehr heterogen, es wurden jedoch gemeinsam Regionen mit UPD gefunden. Bei 27\% der MSI-Tumoren wurde eine neue Kandidatenregion auf Chromosom 6 (6pter-p22) identifiziert, die auch einige potentielle Tumorkandidatengene, wie das Tumorsuppressorgen NOL7 oder den Transkriptionsfaktor AP2a enth{\"a}lt. In CSI-Tumoren waren die monoallelischen Regionen mit 59\% haupts{\"a}chlich durch Deletionen charakterisiert, w{\"a}hrend die MSITumore im Gegensatz nur 3\% Deletionen aufwiesen. In CSI-Tumoren fielen insbesondere vier Bereiche auf den Chromosomen 18, 17, 8 und 22 durch allelische Verluste auf und best{\"a}tigen damit eine Reihe von fr{\"u}heren Ergebnissen. In bestimmten Regionen (z.B. 22q12.1) wurden sowohl Deletionen als auch UPD festgestellt. Die Region 5q22.2 war fast auschließlich von uniparentaler Disomie betroffen. Ob die UPD vor allem in fr{\"u}hen Stadien der Kolonkarzinogenese eine Rolle spielt und in sp{\"a}teren Stadien eher in chromosomaler, bzw. Mikrosatelliteninstabilit{\"a}t vorkommt, werden weitere Studien zeigen m{\"u}ssen.},
  subject      = {Colonkrebs},
  language  = {de}
}
@phdthesis{Zirbs2008,
  author    = {Zirbs, Dominik Sebastian},
  title     = {Untersuchungen zur Effizienz einer hochaktiven antiretroviralen Therapie bei Patienten mit HIV-Infektion},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-28895},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Untersuchungen zur Effizienz einer hochaktiven antiretroviralen Therapie bei Patienten mit HIV-Infektion},
  subject      = {HIV},
  language  = {de}
}
@article{ZioutiRummlerSteynetal.2021,
  author    = {Ziouti, Fani and Rummler, Maximilian and Steyn, Beatrice and Thiele, Tobias and Seliger, Anne and Duda, Georg N. and Bogen, Bjarne and Willie, Bettina M. and Jundt, Franziska},
  title     = {Prevention of bone destruction by mechanical loading is not enhanced by the Bruton's tyrosine kinase inhibitor CC-292 in myeloma bone disease},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {8},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22083840},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284943},
  year      = {2021},
  abstract  = {Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.},
  language  = {en}
}
@article{ZimnyKoobLietal.2022,
  author    = {Zimny, Sebastian and Koob, Dennis and Li, Jingguo and Wimmer, Ralf and Schiergens, Tobias and Nagel, Jutta and Reiter, Florian Paul and Denk, Gerald and Hohenester, Simon},
  title     = {Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through PI3K p110 alpha signaling},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {15},
  issn      = {2073-4409},
  doi       = {10.3390/cells11152344},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281806},
  year      = {2022},
  abstract  = {Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.},
  language  = {en}
}
@article{ZieglerWeissSchmittetal.2017,
  author    = {Ziegler, Sabrina and Weiss, Esther and Schmitt, Anna-Lena and Schlegel, Jan and Burgert, Anne and Terpitz, Ulrich and Sauer, Markus and Moretta, Lorenzo and Sivori, Simona and Leonhardt, Ines and Kurzai, Oliver and Einsele, Hermann and Loeffler, Juergen},
  title     = {CD56 Is a Pathogen Recognition Receptor on Human Natural Killer Cells},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  number    = {6138},
  doi       = {10.1038/s41598-017-06238-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170637},
  year      = {2017},
  abstract  = {Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response.},
  language  = {en}
}
@article{ZhouWuchterEgereretal.2019,
  author    = {Zhou, Xiang and Wuchter, Patrick and Egerer, Gerlinde and Kriegsmann, Mark and Mataityte, Aiste and Koelsche, Christian and Witzens-Harig, Mathias and Kriegsmann, Katharina},
  title     = {Role of virological serum markers in patients with both hepatitis B virus infection and diffuse large B-cell lymphoma},
  series = {European Journal of Haematology},
  volume    = {103},
  journal   = {European Journal of Haematology},
  number    = {4},
  doi       = {10.1111/ejh.13300},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258442},
  pages     = {410-416},
  year      = {2019},
  abstract  = {Background Causality between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression-free survival (PFS) in patients with both HBV infection and DLBCL. Methods In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co-infection were excluded from this study. We retrospectively analyzed patients' demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA) on OS and PFS. Results The majority of patients (n = 21, 62\%) had advanced disease stage (III/IV) at diagnosis. In the first-line therapy, 24 patients (70\%) were treated with R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti-HBe positive patients had a statistically significant better OS and PFS compared with anti-HBe negative group (both P < .0001). Viremia with HBV-DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001). Conclusion High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL.},
  language  = {en}
}
@article{ZhouSteinhardtDuelletal.2020,
  author    = {Zhou, Xiang and Steinhardt, Maximilian Johannes and D{\"u}ll, Johannes and Krummenast, Franziska and Danhof, Sophia and Meckel, Katharina and Nickel, Katharina and Grathwohl, Denise and Leicht, Hans-Benno and Rosenwald, Andreas and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, Martin},
  title     = {Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib-resistant non-nodal leukemic mantle cell lymphoma},
  series = {European Journal of Haematology},
  volume    = {104},
  journal   = {European Journal of Haematology},
  number    = {4},
  doi       = {10.1111/ejh.13382},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215513},
  pages     = {352 -- 355},
  year      = {2020},
  abstract  = {We herein report the case of a 73-year-old male patient who was diagnosed with leukemic non-nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second-line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single-agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2-4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression-free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab-intolerant patient with an ibrutinib-resistant MCL. This case suggests that obinutuzumab- and venetoclax-based combination therapy might be salvage therapy in patients with ibrutinib-resistant MCL.},
  language  = {en}
}
@article{ZhouSteinhardtGrathwohletal.2020,
  author    = {Zhou, Xiang and Steinhardt, Maximilian J. and Grathwohl, Denise and Meckel, Katharina and Nickel, Katharina and Leicht, Hans-Benno and Krummenast, Franziska and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, Klaus M.},
  title     = {Multiagent therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab ("Pom-PAD-Dara") in relapsed/refractory multiple myeloma},
  series = {Cancer Medicine},
  volume    = {9},
  journal   = {Cancer Medicine},
  number    = {16},
  doi       = {10.1002/cam4.3209},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218029},
  pages     = {5819-5826},
  year      = {2020},
  abstract  = {Background Even in the era of novel immunotherapies for multiple myeloma (MM), treatment of late-stage relapsed/refractory (RR) patients remains challenging. The aim of our study was to analyze the efficacy and safety of the five-drug combination pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab ("Pom-PAD-Dara") in RRMM. Methods We retrospectively analyzed data of 56 patients with RRMM who received Pom-PAD-Dara between September 2016 and May 2019. Results Patients were heavily pretreated with a median of four prior lines of therapy, including autologous and allogenic stem cell transplant in 50 (89\%) and six (11\%) patients, respectively. The overall response rate (ORR) was 78\% and we observed partial remission, very good partial remission, and complete remission in 27 (48\%), 13 (23\%) and four (7\%) patients, respectively. Median progression-free survival was 7 months (95\% CI, 3.3-10.7) and the median overall survival was not reached at 24 months. Adverse events grade ≥ 3 were observed 41 (73\%) patients and included neutropenia (n = 28, 50\%), anemia (n = 22, 39\%), thrombocytopenia (n = 21, 38\%), and pneumonia (n = 6, 11\%). Conclusion Pom-PAD-Dara represents a promising multiagent regimen in heavily pretreated RRMM patients with high ORR and an acceptable safety profile.},
  language  = {en}
}
@article{ZhouRuckdeschelPeteretal.2022,
  author    = {Zhou, Xiang and Ruckdeschel, Anna and Peter, Jessica and B{\"o}ckle, David and Hornburger, Hannah and Danhof, Sophia and Steinhardt, Maximilian Johannes and Heimeshoff, Larissa and Einsele, Hermann and Kort{\"u}m, Klaus Martin and Rasche, Leo},
  title     = {Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma},
  series = {Hematological Oncology},
  volume    = {40},
  journal   = {Hematological Oncology},
  number    = {2},
  doi       = {10.1002/hon.2949},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257495},
  pages     = {202-211},
  year      = {2022},
  abstract  = {The multi-agent therapy "VDT-PACE" represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a "modified VDT-PACE" incorporating new generation anti-MM agents daratumumab and carfilzomib ("Dara-KDT-P(A)CE"). We retrospectively analyzed 38 patients with RRMM treated with "Dara-KDT-P(A)CE". The median age was 62 (range 45-82) years, and the patients were heavily pretreated with a median of 5 (range 2-12) prior lines of therapy. Twenty-one (55\%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81\%) patients. The patients received a median of 2 (range 1-10) cycles of this therapy, and the overall response rate (ORR) was 70\%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65\% and 79\%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95\% CI 2.7-5.4) and 8.4 (95\% CI 6.7-10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, "Dara-KDT-P(A)CE" is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.},
  language  = {en}
}
@article{ZhouRascheKortuemetal.2020,
  author    = {Zhou, Xiang and Rasche, Leo and Kort{\"u}m, K. Martin and Danhof, Sophia and Hudecek, Michael and Einsele, Hermann},
  title     = {Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.620312},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219911},
  year      = {2020},
  abstract  = {In the last few years, monoclonal antibodies (mAbs) such as elotuzumab and daratutumab have brought the treatment of multiple myeloma (MM) into the new era of immunotherapy. More recently, chimeric antigen receptor (CAR) modified T cell, a novel cellular immunotherapy, has been developed for treatment of relapsed/refractory (RR) MM, and early phase clinical trials have shown promising efficacy of CAR T cell therapy. Many patients with end stage RRMM regard CAR T cell therapy as their "last chance" and a "hope of cure". However, severe adverse events (AEs) and even toxic death related to CAR T cell therapy have been observed. The management of AEs related to CAR T cell therapy represents a new challenge, as the pathophysiology is not fully understood and there is still no well-established standard of management. With regard to CAR T cell associated toxicities in MM, in this review, we will provide an overview of experience from clinical trials, pathophysiology, and management strategies.},
  language  = {en}
}
@article{ZhouFluechterNickeletal.2020,
  author    = {Zhou, Xiang and Fl{\"u}chter, Patricia and Nickel, Katharina and Meckel, Katharina and Messerschmidt, Janin and B{\"o}ckle, David and Knorz, Sebastian and Steinhardt, Maximilian Johannes and Krummenast, Franziska and Danhof, Sophia and Einsele, Hermann and Kort{\"u}m, K. Martin and Rasche, Leo},
  title     = {Carfilzomib based treatment strategies in the management of relapsed/refractory multiple myeloma with extramedullary disease},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {4},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12041035},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203704},
  year      = {2020},
  abstract  = {Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40-80) years. Twenty (44\%) and 25 (56\%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59\%. Extramedullary response was evaluable in 33 patients, nine (27\%) of them achieved partial remission (PR) (ORR = 27\%). In 15 (33\%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95\% CI, 3.5-6.5) and ten (95\% CI, 7.5-12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.},
  language  = {en}
}
@article{ZhouDierksKertelsetal.2020,
  author    = {Zhou, Xiang and Dierks, Alexander and Kertels, Olivia and Samnick, Samuel and Kircher, Malte and Buck, Andreas K. and Haertle, Larissa and Knorz, Sebastian and B{\"o}ckle, David and Scheller, Lukas and Messerschmidt, Janin and Barakat, Mohammad and Truger, Marietta and Haferlach, Claudia and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin and Lapa, Constantin},
  title     = {The link between cytogenetics/genomics and imaging patterns of relapse and progression in patients with relapsed/refractory multiple myeloma: a pilot study utilizing 18F-FDG PET/CT},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12092399},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211157},
  year      = {2020},
  abstract  = {Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1-10) lines of therapy. Six (25\%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUV\(_{max}\)) in patients harboring del(17p) compared with those without del(17p) (p = 0.025). Moreover, a high SUV\(_{max}\) of >15 indicated significantly shortened progression-free survival (PFS) (p = 0.01) and overall survival (OS) (p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUV\(_{max}\) of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/TP53 alteration and high SUV\(_{max}\) on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point.},
  language  = {en}
}
@article{ZhouDierksKertelsetal.2020,
  author    = {Zhou, Xiang and Dierks, Alexander and Kertels, Olivia and Kircher, Malte and Schirbel, Andreas and Samnick, Samuel and Buck, Andreas K. and Knorz, Sebastian and B{\"o}ckle, David and Scheller, Lukas and Messerschmidt, Janin and Barakat, Mohammad and Kort{\"u}m, K. Martin and Rasche, Leo and Einsele, Hermann and Lapa, Constantin},
  title     = {18F-FDG, 11C-Methionine, and 68Ga-Pentixafor PET/CT in patients with smoldering multiple myeloma: imaging pattern and clinical features},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {8},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12082333},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211240},
  year      = {2020},
  abstract  = {This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.},
  language  = {en}
}
@article{ZhouBaiMeckeletal.2021,
  author    = {Zhou, Xiang and Bai, Tao and Meckel, Katharina and Song, Jun and Jin, Yu and Kort{\"u}m, Martin K. and Eisele, Hermann and Hou, Xiaohua and Rasche, Leo},
  title     = {COVID-19 infection in patients with multiple myeloma: a German-Chinese experience from W{\"u}rzburg and Wuhan},
  series = {Annals of Hematology},
  volume    = {100},
  journal   = {Annals of Hematology},
  issn      = {0939-5555},
  doi       = {10.1007/s00277-020-04184-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235108},
  pages     = {843-846},
  year      = {2021},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{ZaitsevaHoffmannLoestetal.2023,
  author    = {Zaitseva, Olena and Hoffmann, Annett and L{\"o}st, Margaretha and Anany, Mohamed A. and Zhang, Tengyu and Kucka, Kirstin and Wiegering, Armin and Otto, Christoph and Wajant, Harald},
  title     = {Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1194610},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323116},
  year      = {2023},
  abstract  = {Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.},
  language  = {en}
}
@article{ZaitsevaAnanyWajantetal.2023,
  author    = {Zaitseva, Olena and Anany, Mohamed and Wajant, Harald and Lang, Isabell},
  title     = {Basic characterization of antibodies targeting receptors of the tumor necrosis factor receptor superfamily},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1115667},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311407},
  year      = {2023},
  abstract  = {Many new immunotherapeutic approaches aim on the stimulatory targeting of receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) using antibodies with intrinsic or conditional agonism. There is an initial need to characterize corresponding TNFRSF receptor (TNFR)-targeting antibodies with respect to affinity, ligand binding, receptor activation and the epitope recognized. Here, we report a collection of simple and matched protocols enabling the detailed investigation of these aspects by help of Gaussia princeps luciferase (GpL) fusion proteins and analysis of interleukin-8 (IL8) production as an easily measurable readout of TNFR activation. In a first step, the antibodies and antibody variants of interest are transiently expressed in human embryonal kidney 293 cells, either in non-modified form or as fusion proteins with GpL as a reporter domain. The supernatants containing the antibody-GpL fusion proteins can then be used without further purification in cell-free and/or cellular binding studies to determine affinity. Similarly, binding studies with mutated TNFR variants enable the characterization of the antibody binding site within the TNFR ectodomain. Furthermore, in cellular binding studies with GpL fusion proteins of soluble TNFL molecules, the ability of the non-modified antibody variants to interfere with TNFL-TNFR interaction can be analyzed. Last but not least, we describe a protocol to determine the intrinsic and the Fc gamma receptor (FcγR)-dependent agonism of anti-TNFR antibodies which exploits i) the capability of TNFRs to trigger IL8 production in tumor cell lines lacking expression of FcγRs and ii) vector- and FcγR-transfected cells, which produce no or only very low amounts of human IL8. The presented protocols only require standard molecular biological equipment, eukaryotic cell culture and plate readers for the quantification of luminescent and colorimetric signals.},
  language  = {en}
}
@article{ZacherWollankaSaueretal.2023,
  author    = {Zacher, Magdalena and Wollanka, Nele and Sauer, Christina and Haßtenteufel, Kathrin and Wallwiener, Stephanie and Wallwiener, Markus and Maatouk, Imad},
  title     = {Prenatal paternal depression, anxiety, and somatic symptom burden in different risk samples: an explorative study},
  series = {Archives of Gynecology and Obstetrics},
  volume    = {307},
  journal   = {Archives of Gynecology and Obstetrics},
  number    = {4},
  doi       = {10.1007/s00404-022-06612-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324465},
  pages     = {1255-1263},
  year      = {2023},
  abstract  = {Purpose Growing evidence implies that transition to parenthood triggers symptoms of mental burden not only in women but likewise in men, especially in high-risk pregnancies. This is the first study that examined and compared the prevalence rates of depression, anxiety, and somatic symptom burden of expectant fathers who face different risk situations during pregnancy. Methods Prevalence rates of paternal depression (Edinburgh postnatal depression scale), anxiety (generalized anxiety disorder seven), and somatic symptom burden (somatic symptom scale eight) were examined in two risk samples and one control group in the third trimester of their partners' pregnancy: risk sample I (n = 41) consist of expectant fathers whose partners were prenatally hospitalized due to medical complications; risk sample II (n = 52) are fathers whose partners were prenatally mentally distressed; and control group (n = 70) are those non-risk pregnancies. Results On a purely descriptive level, the data display a trend of higher symptom burden of depression, anxiety, and somatic symptoms in the two risk samples, indicating that expectant fathers, whose pregnant partners were hospitalized or suffered prenatal depression, were more prenatally distressed. Exploratory testing of group differences revealed an almost three times higher prevalence rate of anxiety in fathers whose partner was hospitalized (12.2\%) compared to those non-risks (4.3\%). Conclusion Results underline the need for screening implementations for paternal prenatal psychological distress, as well as specific prevention and treatment programs, especially for fathers in risk situations, such as their pregnant partners' prenatal hospitalization. The study was registered with the German clinical trials register (DRKS00020131) on 2019/12/09.},
  language  = {en}
}
@article{YuWolfThuseketal.2021,
  author    = {Yu, Yidong and Wolf, Ann-Katrin and Thusek, Sina and Heinekamp, Thorsten and Bromley, Michael and Krappmann, Sven and Terpitz, Ulrich and Voigt, Kerstin and Brakhage, Axel A. and Beilhack, Andreas},
  title     = {Direct Visualization of Fungal Burden in Filamentous Fungus-Infected Silkworms},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {2},
  issn      = {2309-608X},
  doi       = {10.3390/jof7020136},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228855},
  year      = {2021},
  abstract  = {Invasive fungal infections (IFIs) are difficult to diagnose and to treat and, despite several available antifungal drugs, cause high mortality rates. In the past decades, the incidence of IFIs has continuously increased. More recently, SARS-CoV-2-associated lethal IFIs have been reported worldwide in critically ill patients. Combating IFIs requires a more profound understanding of fungal pathogenicity to facilitate the development of novel antifungal strategies. Animal models are indispensable for studying fungal infections and to develop new antifungals. However, using mammalian animal models faces various hurdles including ethical issues and high costs, which makes large-scale infection experiments extremely challenging. To overcome these limitations, we optimized an invertebrate model and introduced a simple calcofluor white (CW) staining protocol to macroscopically and microscopically monitor disease progression in silkworms (Bombyx mori) infected with the human pathogenic filamentous fungi Aspergillus fumigatus and Lichtheimia corymbifera. This advanced silkworm A. fumigatus infection model could validate knockout mutants with either attenuated, strongly attenuated or unchanged virulence. Finally, CW staining allowed us to efficiently visualize antifungal treatment outcomes in infected silkworms. Conclusively, we here present a powerful animal model combined with a straightforward staining protocol to expedite large-scale in vivo research of fungal pathogenicity and to investigate novel antifungal candidates.},
  language  = {en}
}
@article{WongWinterHartigetal.2014,
  author    = {Wong, David and Winter, Oliver and Hartig, Christina and Siebels, Svenja and Szyska, Martin and Tiburzy, Benjamin and Meng, Lingzhang and Kulkarni, Upasana and F{\"a}hnrich, Anke and Bommert, Kurt and Bargou, Ralf and Berek, Claudia and Van, Trung Chu and Bogen, Bjarne and Jundt, Franziska and Manz, Rudolf Armin},
  title     = {Eosinophils and Megakaryocytes Support the Early Growth of Murine MOPC315 Myeloma Cells in Their Bone Marrow Niches},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0109018},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115269},
  pages     = {e109018},
  year      = {2014},
  abstract  = {Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315. BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315. BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient Delta dblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.},
  language  = {en}
}
@article{WolterHanselmannPattschulletal.2017,
  author    = {Wolter, Patrick and Hanselmann, Steffen and Pattschull, Grit and Schruf, Eva and Gaubatz, Stefan},
  title     = {Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy},
  series = {Oncotarget},
  volume    = {8},
  journal   = {Oncotarget},
  number    = {7},
  doi       = {10.18632/oncotarget.14466},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171851},
  pages     = {11160-11172},
  year      = {2017},
  abstract  = {The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells. Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.},
  language  = {en}
}
@article{WolfBraunHainingetal.2016,
  author    = {Wolf, Karen and Braun, Attila and Haining, Elizabeth J. and Tseng, Yu-Lun and Kraft, Peter and Schuhmann, Michael K. and Gotru, Sanjeev K. and Chen, Wenchun and Hermanns, Heike M. and Stoll, Guido and Lesch, Klaus-Peter and Nieswandt, Bernhard},
  title     = {Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {1},
  doi       = {10.1371/journal.pone.0147664},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146399},
  pages     = {e0147664},
  year      = {2016},
  abstract  = {Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.},
  language  = {en}
}
@phdthesis{Winterberg2011,
  author    = {Winterberg, Torsten},
  title     = {Klinische Parameter und deren Einfluss auf den Verlauf der prim{\"a}ren Hochdosischemotherapie mit autologer Stammzelltransplantation beim Multiplen Myelom},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71203},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {In dieser Arbeit wurden die Daten von 90 konsekutiven Patienten mit Multiplem Myelom, welche im Zeitraum vom 11.04.2005 bis zum 08.11.2010 mit einer Hochdosischemotherapie und autologer Stammzelltransplantation in den Kliniken Essen S{\"u}d behandelt wurden, retrospektiv untersucht und statistisch ausgewertet. Es konnte gezeigt werden, dass ein gutes Ansprechen nach den Induktionstherapien mit einem guten Ansprechen sechzig Tage nach der Transplantation korreliert. Einen Zusammenhang zwischen dem initialen Ausmaß der Endorgansch{\"a}den und dem Verlauf oder dem Ansprechen der Hochdosischemotherapie mit autologer Stammzelltransplantation konnte nicht gefunden werden. Das kalendarische Alter spielt im Gegensatz zum Allgemeinzustand und den Vorerkrankungen bei der Einsch{\"a}tzung der zu erwartenden Toxizit{\"a}t eine untergeordnete Rolle. Die beiden Hauptfaktoren, die den Verlauf einer Hochdosischemotherapie mit anschließender peripherer Stammzelltransplantation beeinflussten, waren die Dauer der G-CSF Therapie und die Anzahl der {\"u}bertragenen Stammzellen. W{\"a}hrend die unterschiedlich lange G-CSF Gabe (ab Tag „+3" vs. Tag „+7") nur zu einer schnelleren Regeneration der Leukozyten f{\"u}hrt und keinen relevanten Effekt auf die untersuchten klinischen Parameter Fieber, Dauer der intraven{\"o}sen Antibiotikatage, Ausmaß der Mukositis und die Aufenthaltsdauer der Patienten hatte, f{\"u}hrte die Steigerung der Anzahl der {\"u}bertragenen Stammzellen zu einer signifikant schnelleren Regeneration von Thrombozyten und Leukozyten, einem R{\"u}ckgang der Transfusionsh{\"a}ufigkeit an Erythrozyten und einem geringeren Verbrauch an intraven{\"o}sen Antibiotika. Zusammenfassend ist die G-CSF Gabe ab Tag „+7" nach Hochdosistherapie ausreichend, eine l{\"a}ngere Gabe erbringt keinen relevanten klinischen Vorteil. Zudem sollte auf eine ausreichende Menge an {\"u}bertragenen Stammzellen geachtet werden. Zur Beurteilung der zu erwartenden Toxizit{\"a}t ist die Anwendung des HCT-CI-Score einfach und praktikabel.},
  subject      = {Plasmozytom},
  language  = {de}
}
@phdthesis{Wilke2018,
  author    = {Wilke, Philipp},
  title     = {Expression von MTUS1 in Kolorektalen Karzinomen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168020},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Im Rahmen dieser Arbeit wurden zun{\"a}chst bei den gesammelten 14 Tumoren mit einem putativen allelischen Verlust im Bereich 8p21.3-22 nochmals eine LOH-Analyse durchgef{\"u}hrt und die Voruntersuchungen best{\"a}tigt. Als zweiter Schritt konnte die Etablierung des MTUS1-Antik{\"o}rpers erfolgreich durchgef{\"u}hrt werden. Die Paraffinbl{\"o}cke wurde aus dem Institut f{\"u}r Pathologie herausgesucht und selbstst{\"a}ndig Schnitte davon angefertigt. Die immunhistochemische Analyse der MTUS1-Expression ergab einen Expressionsverlust bei 7 von 14 Tumoren und eine Reduktion der Expression bei weiteren 3 der 14 Tumoren. Bei insgesamt 7 von 14 Tumoren scheint somit die Expression von dem allelischen Verlust assoziiert zu sein. Allerdings konnte bei den {\"u}brigen 7 Tumoren eine Expression des MTUS1-Gens nachgewiesen werden. Ein allelischer Verlust f{\"u}hrt somit nicht immer zu einer Inaktivierung von MTUS1. MTUS1 wird somit nicht immer nach dem klassischen Mechanismen der Knudson-Hypothese (Mutation des ersten Allels gefolgt von der Deletion des zweiten Alles) inaktiviert. M{\"o}glicherweise kann in weiteren Studien ein anderes Gen in dem entsprechenden Bereich identifiziert werden, das im Rahmen eines allelischen Verlustes immer komplett inaktiviert wird. Außerdem sollten, da andere Studien eine Relevanz von MTUS1 als Tumorsupressorgen beim kolorektalen Karzinom und auch bei anderen Tumoren zeigen konnten, weitere Studien durchgef{\"u}hrt werden, in denen alternativen Inaktivierungsmechanismen von MTUS1 untersucht werden.},
  subject      = {27.9c},
  language  = {de}
}
@article{WilhelmSmetakSchaeferEckartetal.2014,
  author    = {Wilhelm, Martin and Smetak, Manfred and Schaefer-Eckart, Kerstin and Kimmel, Brigitte and Birkmann, Josef and Einsele, Hermann and Kunzmann, Volker},
  title     = {Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells},
  series = {Journal of Translational Medicine},
  volume    = {12},
  journal   = {Journal of Translational Medicine},
  number    = {45},
  doi       = {10.1186/1479-5876-12-45},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117290},
  year      = {2014},
  abstract  = {Background: The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical gamma delta T lymphocytes. Methods: Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS (R) device according to the manufacturer's instructions. On average, patients received 2.17 x 10(6)/kg (range 0.9-3.48) γδ T cells with <1\% CD4-or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m(2) day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x10(6) IU/m(2) IL-2 on day +1 until day +6 for the induction of gamma delta T cell proliferation in vivo. Results: This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment. Conclusion: This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.},
  language  = {en}
}
@phdthesis{Wilhelm2010,
  author    = {Wilhelm, Daniela Elisabeth},
  title     = {Die Rolle von GSK3 im Rahmen der angeborenen Immunabwehr gegen Aspergillus fumigatus},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71674},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Aspergillus fumigatus ist ein ubiquit{\"a}r vorkommender Schimmelpilz, dessen Sporen vom Menschen t{\"a}glich zu hunderten mit der Atemluft aufgenommen werden. Aufgrund ihrer geringen Gr{\"o}ße gelangen die Konidien leicht bis in die Alveolen der Lunge, wo sie normalerweise sofort vom angeborenen Immunsystem beseitigt werden. Immunsupprimierte Menschen leiden an einer qualitativen oder quantitativen Einschr{\"a}nkung dieses Teiles der Immunabwehr, weshalb die Inokulation der Sporen bei ihnen zur Ausl{\"o}sung der lebensgef{\"a}hrlichen Invasiven Aspergillose f{\"u}hren kann, deren Mortalit{\"a}t in der Hochrisikogruppe der Patienten nach h{\"a}matopoetischer Stammzelltransplantation {\"u}ber 90\% betr{\"a}gt. Bei diesen Patienten gewinnt die adaptive Immunabwehr an Bedeutung. Dendritische Zellen geh{\"o}ren dem angeborenen Immunsystem an und besitzen einzigartige F{\"a}higkeiten zur Aktivierung und Steuerung der erworbenen Immunabwehr. Durch die Aktivierung naiver T-Zelen und die Sekretion bestimmter immunmodulatorischer Zytokine bestimmen sie die Art der konsekutiv asugel{\"o}sten T-Helferzellantwort. Lediglich eine T-Helfer 1-Zellantwort wird hierbei mit einer erh{\"o}hten Resistenz gegen{\"u}ber der invasiven Aspergillose in Verbindung gebracht. Die Zytokinsekretion der Dendritischen Zellen wird durch intrazellul{\"a}re Signalkaskaden reguliert, welche sich an ihre PRRs anschließen. F{\"u}r die Erkennung des bakteriellen LPS durch den TLR wurde die Regulation der immunmodulatorischen Zytokine durch die Serin-Threonin-Kinase GSK3 festgestellt. In der vorliegenden Arbeit wurde untersucht, ob es bei der Erkennung von Aspergillus fumigatus durch humane dendritische Zellen ebenfalls einen Zusammenhang mit GSK3 und der Sekretion immunmodulatorischer Zytokine gibt. Daf{\"u}r wurden aus humanen Monozyten generierte dendritische Zellen mit rekombinanten Antigenen von Aspergillus fumigatus sowie verschiedenen Morphologien stiumuliert und teilweise mit dem GSK3-Inhibitor LiCl gehemmt. Anschließend wurde die Expression bestimmter immunmodulatorischer Zytokine und der GSK3 mittels quantitativer real-time RT-PCR bestimmt. Hierbei konnte f{\"u}r eines der getesteten Antigene, Aspf 1, ein deutlicher Einfluss auf die GSK3-Expression der Zellen festgestellt werden. Ein paralleler Anstieg der Expression proinflammatorischer Zytokine erh{\"a}rtete die Annahme einer immunregulierenden Rolle der GSK3 bei der Erkennung von Aspergillus fumigatus. Einen deutlicheren Hinweis auf den Zusammenhang zwischen der Aktivit{\"a}t der GSK3 und der Expression proinflammatorischer Zytokine erbrachte die Inhibierung mittels LiCl. Die mit Aspergillus fumigatus stimulierten Zellen reagierten hierauf im Vergleich zu den nicht-inhibierten Zellen mit einer Reduktion der IL12p35-Expression um 86,1\% sowie mit einer Reduktion der IL23-Expression um 49,5\%. Der letzte Teil der Experimente sollte ausgehend von der Vorstellung, dass verschiedene Aspergillus-Morphologien von unterschiedlichen Rezeptoren erkannt werden quantitative Unterschiede der GSK3-Beteiligung bei der Erkennung von Aspergillus fumigatus durch dendritische Zellen zeigen. Obwohl alle Morphologien des Schimmelpilzes einen Einfluss auf die GSK3-Expression der Zellen zeigten, konnten hierbei keine einheitlichen quantitativen Unterschiede festgestellt werden. Zusammengefasst konnte in der vorliegenden Arbeit die Beteiligung von GSK3 bei der Erkennung von Aspergillus fumigatus durch humane dendritische Zellen gezeigt werden. Außerdem konnten Hinweise auf eine immunregulierende Rolle der GSK3 bei der Abwehr des fakultativ pathogenen Schimmelpilzes erbracht werden, wobei die genaue Einbindung der Serin-Threonin-Kinase in dieser Situation noch unklar ist und weitere Experimente erforderlich macht.},
  subject      = {Aspergillus fumigatus},
  language  = {de}
}
@article{WildeLiebLeichtetal.2021,
  author    = {Wilde, Anne-Christin Beatrice and Lieb, Charlotte and Leicht, Elise and Greverath, Lena Maria and Steinhagen, Lara Marleen and Wald de Chamorro, Nina and Petersen, J{\"o}rg and Hofmann, Wolf Peter and Hinrichsen, Holger and Heyne, Renate and Berg, Thomas and Naumann, Uwe and Schwenzer, Jeannette and Vermehren, Johannes and Geier, Andreas and Tacke, Frank and M{\"u}ller, Tobias},
  title     = {Real-world clinical management of patients with primary biliary cholangitis — a retrospective multicenter study from Germany},
  series = {Journal of Clinical Medicine},
  volume    = {10},
  journal   = {Journal of Clinical Medicine},
  number    = {5},
  issn      = {2077-0383},
  doi       = {10.3390/jcm10051061},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234003},
  year      = {2021},
  abstract  = {Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3\% of patients, respectively. In 83.8\% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2\%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60\%, p = 0.005), Barcelona (13 vs. 34\%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75\%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74\%, p = 0.004; Barcelona: 50 vs. 84\%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86\%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.},
  language  = {en}
}
@article{WiegeringIsbertDietzetal.2014,
  author    = {Wiegering, Armin and Isbert, Christoph and Dietz, Ulrich A. and Kunzmann, Volker and Ackermann, Sabine and Kerscher, Alexander and Maeder, Uwe and Flentje, Michael and Schlegel, Nicolas and Reibetanz, Joachim and Germer, Christoph-Thomas and Klein, Ingo},
  title     = {Multimodal therapy in treatment of rectal cancer is associated with improved survival and reduced local recurrence - a retrospective analysis over two decades},
  doi       = {10.1186/1471-2407-14-816},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110606},
  year      = {2014},
  abstract  = {Background The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival. Methods Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010. Results The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6\% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6\% vs. 60\%) and adjuvant chemotherapy (37.9\% vs. 58.4\%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60\% to 79\%. Conclusion In our study population, the implementation of treatment changes over the last decade improved the patient's outcome significantly. Improvements were most evident for UICC stage III rectal cancer.},
  language  = {en}
}
@phdthesis{Wicovsky2007,
  author    = {Wicovsky, Andreas},
  title     = {Die Rolle von TRAF1 und JNK bei der TNF-vermittelten Apoptose},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-23689},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {TNF (Tumor Nekrose Faktor) vermittelt seine biologischen Funktionen durch Interaktionen mit TNFR1 (TNFRezeptor 1) und TNFR2 (TNFRezeptor 2). In fr{\"u}heren Arbeiten konnte gezeigt werden, dass der TNFR2 sowohl durch die Induktion von membrangebundenem TNF als auch durch die proteasomale Degradation von TRAF2 (TNFRezeptor-assozierter Faktor 2) die TNFR1-vermittelte Apoptose verst{\"a}rken kann. Des Weiteren war bekannt, dass TRAF1 (TNFRezeptor-assozierter Faktor 1), ein anderes Mitglied der TRAF-Familie, mit TRAF2 Heterotrimere bilden kann und zudem nach TNF-induzierter NFkappaB- (nuclear factor kappaB) Aktivierung verst{\"a}rkt exprimiert wird. In der vorliegenden Arbeit konnte nun erstmals gezeigt werden, dass TRAF1 in beide TNFR-Signalkomplexe rekrutiert wird und darin in einem TRAF2/TRAF1-Heterotrimer TRAF2 funktionell ersetzen kann. Dar{\"u}ber hinaus verhindert TRAF1 die Rekrutierung von TRAF2 in lipid rafts sowie dessen anschließende proteasomale Degradation. Auf diese Weise kann TRAF1 die TNFR2-abh{\"a}ngige Verst{\"a}rkung der TNFR1-induzierten Apoptose verhindern. Im zweiten Teil der vorliegenden Arbeit wurde die TNF-vermittelte Aktivierung der JNK (c-Jun N-terminale Kinase), dessen Regulation durch ROS (reactive oxygen species), Caspasen (Cysteinyl-Aspartat-spezifische Proteasen) sowie NFkappaB-induzierte Faktoren untersucht. TNF induziert in den meisten Zellen zun{\"a}chst nach zehn bis 30 Minuten eine transiente JNK-Aktivierung, woraufhin bei NFkB-inhibierten Zellen eine zweite andauernde JNK-Aktivierung folgt. Die meisten in der Literatur beschriebenen Studien gehen dabei von einem ROS-abh{\"a}ngigen, Caspase-unabh{\"a}ngigen Mechanismus der persistierenden JNK-Aktivierung aus. Des Weiteren wurde in den vor allem bei embryonale Mausfibroblasten durchgef{\"u}hrten Untersuchungen davon ausgegangen, dass bestimmte NFkappaB-induzierte Radikalf{\"a}nger die andauernde Aktivierung der JNK verhindern. In dieser Arbeit konnte gezeigt werden, dass in den humanen Zelllinien KB, Jurkat und HaCaT die andauernde Aktivierung der JNK, im Gegensatz zur transienten JNK-Aktivierung, Caspase-abh{\"a}ngig verl{\"a}uft. Es ergab sich {\"u}berdies, dass die inhibierende Wirkung des NFkB-Signalweges auf die persistierende JNK-Aktivierung in diesen Zelllinien in erster Linie auf die indirekte Verhinderung der Apoptose durch die Induktion von antiapoptotischen Proteinen wie Flip-L (FLICE-inhibitory protein long) und IAPs (inhibitor of apoptosis) zur{\"u}ckzuf{\"u}hren ist, als auf die direkte Expression von Radikalf{\"a}ngern. Zudem wurde in den untersuchten Zelllinien die Caspase-vermittelte Spaltung von MEKK-1 (MAP/ERK kinase kinase-1) und p21WAF/Cip 1 nachgewiesen, von denen bekannt ist, dass die Spaltprodukte eine JNK-stimulierende Wirkung haben. Dennoch m{\"u}ssen k{\"u}nftige Studien zeigen, ob die Spaltung von p21WAF/Cip 1 und MEKK-1 in Fragmente mit JNK-stimulierender Aktivit{\"a}t oder andere Caspasesubstrate f{\"u}r die Caspase-vermittelte andauernde Aktivierung der JNK verantwortlich sind.},
  language  = {de}
}
@article{WhiteWiederholdLoeffleretal.2016,
  author    = {White, P. Lewis and Wiederhold, Nathan P. and Loeffler, Juergen and Najvar, Laura K. and Melchers, Willem and Herrera, Monica and Bretagne, Stephane and Wickes, Brian and Kirkpatrick, William R. and Barnes, Rosemary A. and Donnelly, J. Peter and Patterson, Thomas F.},
  title     = {Comparison of nonculture blood-based tests for diagnosing invasive aspergillosis in an animal model},
  series = {Journal of Clinical Microbiology},
  volume    = {54},
  journal   = {Journal of Clinical Microbiology},
  number    = {4},
  doi       = {10.1128/JCM.03233-15},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189674},
  pages     = {960-966},
  year      = {2016},
  abstract  = {The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and beta-D-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and beta-D-glucan were 73\%, 65\%, 68\%, and 46\%, respectively. The corresponding specificities were 92\%, 79\%, 80\%, and 100\%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and beta-D-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and beta-D-glucan proved optimal (area under the curve AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.},
  language  = {en}
}
@article{WhiteSpringerWiseetal.2022,
  author    = {White, P. Lewis and Springer, Jan and Wise, Matt P. and Einsele, Hermann and L{\"o}ffler, Claudia and Seif, Michelle and Prommersberger, Sabrina and Backx, Matthijs and L{\"o}ffler, J{\"u}rgen},
  title     = {A clinical case of COVID-19-associated pulmonary aspergillosis (CAPA), illustrating the challenges in diagnosis (despite overwhelming mycological evidence)},
  series = {Journal of Fungi},
  volume    = {8},
  journal   = {Journal of Fungi},
  number    = {1},
  issn      = {2309-608X},
  doi       = {10.3390/jof8010081},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302438},
  year      = {2022},
  abstract  = {The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6\% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA.},
  language  = {en}
}
@article{WernerSolnesJavadietal.2018,
  author    = {Werner, Rudolf and Solnes, Lilja and Javadi, Mehrbod and Weich, Alexander and Gorin, Michael and Pienta, Kenneth and Higuchi, Takahiro and Buck, Andreas and Pomper, Martin and Rowe, Steven and Lapa, Constantin},
  title     = {SSTR-RADS Version 1.0 as a Reporting System for SSTR-PET Imaging and Selection of Potential PRRT Candidates: A Proposed Standardization Framework},
  series = {Journal of Nuclear Medicine},
  journal   = {Journal of Nuclear Medicine},
  issn      = {0161-5505},
  doi       = {10.2967/jnumed.117.206631},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161298},
  year      = {2018},
  abstract  = {Reliable standards and criteria for somatostatin receptor (SSTR) positron emission tomography (PET) are still lacking. We herein propose a structured reporting system on a 5-point scale for SSTR-PET imaging, titled SSTR-RADS version 1.0, which might serve as a standardized assessment for both diagnosis and treatment planning in neuroendocrine tumors (NET). SSTR-RADS could guide the imaging specialist in interpreting SSTR-PET scans, facilitate communication with the referring clinician so that appropriate work-up for equivocal findings is pursued, and serve as a reliable tool for patient selection for planned Peptide Receptor Radionuclide Therapy.},
  subject      = {Standardisierung},
  language  = {en}
}
@article{WernerWeichKircheretal.2018,
  author    = {Werner, Rudolf A. and Weich, Alexander and Kircher, Malte and Solnes, Lilja B. and Javadi, Mehrbod S. and Higuchi, Takahiro and Buck, Andreas K. and Pomper, Martin G. and Rowe, Steven and Lapa, Constantin},
  title     = {The theranostic promise for neuroendocrine tumors in the late 2010s - Where do we stand, where do we go?},
  series = {Theranostics},
  volume    = {8},
  journal   = {Theranostics},
  number    = {22},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170264},
  pages     = {6088-6100},
  year      = {2018},
  abstract  = {More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@article{WernerWeichHiguchietal.2017,
  author    = {Werner, Rudolf A. and Weich, Alexander and Higuchi, Takahiro and Schmid, Jan S. and Schirbel, Andreas and Lassmann, Michael and Wild, Vanessa and Rudelius, Martina and Kudlich, Theodor and Herrmann, Ken and Scheurlen, Michael and Buck, Andreas K. and Kropf, Saskia and Wester, Hans-J{\"u}rgen and Lapa, Constantin},
  title     = {Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach},
  series = {Theranostics},
  volume    = {7},
  journal   = {Theranostics},
  number    = {6},
  doi       = {10.7150/thno.18754},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158008},
  pages     = {1489-1498},
  year      = {2017},
  abstract  = {C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50\% of G2 and 80\% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@article{WernerBundschuhBundschuhetal.2018,
  author    = {Werner, Rudolf A. and Bundschuh, Ralph A. and Bundschuh, Lena and Javadi, Mehrbod S. and Higuchi, Takahiro and Weich, Alexander and Sheikhbahaei, Sara and Pienta, Kenneth J. and Buck, Andreas K. and Pomper, Martin G. and Gorin, Michael A. and Lapa, Constantin and Rowe, Steven P.},
  title     = {MI-RADS: Molecular Imaging Reporting and Data Systems - A Generalizable Framework for Targeted Radiotracers with Theranostic Implications},
  series = {Annals of Nuclear Medicine},
  journal   = {Annals of Nuclear Medicine},
  issn      = {0914-7187},
  doi       = {10.1007/s12149-018-1291-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166995},
  year      = {2018},
  abstract  = {Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader's confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@unpublished{WernerBundschuhBundschuhetal.2019,
  author    = {Werner, Rudolf A. and Bundschuh, Ralph A. and Bundschuh, Lena and Fanti, Stefano and Javadi, Mehrbod S. and Higuchi, Takahiro and Weich, A. and Pienta, Kenneth J. and Buck, Andreas K. and Pomper, Martin G. and Gorin, Michael A. and Herrmann, Ken and Lapa, Constantin and Rowe, Steven P.},
  title     = {Novel Structured Reporting Systems for Theranostic Radiotracers},
  series = {Journal of Nuclear Medicine},
  journal   = {Journal of Nuclear Medicine},
  issn      = {0161-5505},
  doi       = {10.2967/jnumed.118.223537},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174629},
  year      = {2019},
  abstract  = {Standardized reporting is more and more routinely implemented in clinical practice and such structured reports have a major impact on a large variety of medical fields, e.g. laboratory medicine, pathology, and, recently, radiology. Notably, the field of nuclear medicine is constantly evolving, as novel radiotracers for numerous clinical applications are developed. Thus, framework systems for standardized reporting in this field may a) increase clinical acceptance of new radiotracers, b) allow for inter- and intra-center comparisons for quality assurance, and c) may be used in (global) multi-center studies to ensure comparable results and enable efficient data abstraction. In the last two years, several standardized framework systems for positron emission tomography (PET) radiotracers with potential theranostic applications have been proposed. These include systems for prostate-specific membrane antigen (PSMA)-targeted PET agents for the diagnosis and treatment of prostate cancer (PCa) and somatostatin receptor (SSTR)-targeted PET agents for the diagnosis and treatment of neuroendocrine neoplasias. In the present review, those standardized framework systems for PSMA- and SSTR-targeted PET will be briefly introduced followed by an overview of their advantages and limitations. In addition, potential applications will be defined, approaches to validate such concepts will be proposed, and future perspectives will be discussed.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@article{WernerBeykanHiguchietal.2016,
  author    = {Werner, Rudolf A. and Beykan, Seval and Higuchi, Takahiro and L{\"u}ckerath, Katharina and Weich, Alexander and Scheurlen, Michael and Bluemel, Christina and Herrmann, Ken and Buck, Andreas K. and Lassmann, Michael and Lapa, Constantin and H{\"a}nscheid, Heribert},
  title     = {The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy},
  series = {Oncotarget},
  volume    = {7},
  journal   = {Oncotarget},
  number    = {27},
  doi       = {10.18632/oncotarget.9775},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177318},
  pages     = {41233-41241},
  year      = {2016},
  abstract  = {Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3\%, range: -27\% to +19\%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3­clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.},
  language  = {en}
}
@phdthesis{Werner2023,
  author    = {Werner, Andrea},
  title     = {K{\"o}rperpsychotherapie: Grundlagen - Konzepte - Anwendungsgebiete},
  doi       = {10.25972/OPUS-26516},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265161},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {K{\"o}rperpsychotherapie etabliert sich zunehmend und ist keine neue Entdeckung. Bereits vor {\"u}ber 120 Jahren war bekannt, dass {\"u}ber den K{\"o}rper die Psyche erreicht werden kann und damit die verbale Psychotherapie effektiver und gegebenenfalls erst m{\"o}glich wurde. Wissenschaftliche Untersuchungen sprechen daf{\"u}r, dass K{\"o}rperpsychotherapie heute als f{\"u}nfte S{\"a}ule der allgemein anerkannten psychotherapeutischen Verfahren (PA, TP, VT, ST) angesehen werden kann. Sie hat sich aus der atemtherapeutischen und der Bewegung der Gymnastik sowie der Verwendung in der Psychoanalyse entwickelt. Sie ist weitestgehend in die tiefenpsychologische und verhaltenstherapeutische Psychotherapie integriert und kann zu den humanistischen Verfahren gez{\"a}hlt werden. Anwendung findet die K{\"o}rperpsychotherapie beispielsweise in der Psychosomatischen Medizin sowie auf verschiedenen Gebieten der Psychotherapie. Laut den hier vorgelegten Befunden erreicht die Arbeit am K{\"o}rper nonverbal Verarbeitetes, das sich tief in das implizite K{\"o}rperged{\"a}chtnis eingegraben hat, lange bevor ein junger Mensch das Sprechen erlernte. Eine M{\"o}glichkeit, dies konzeptuell einzuordnen und therapeutisch nutzbar zu machen, ist das Modell der „verk{\"o}rperten Selbstwahrnehmung" nach Fogel, das Teile des K{\"o}rperschemas beinhaltet. In der Bindungsbeziehung nicht ad{\"a}quates Eingehen auf die kindlichen Bed{\"u}rfnisse hat weitreichende Folgen auf das weitere Leben. In Untersuchungen konnte gezeigt werden, wie sich St{\"o}rungen in der Entwicklung eines Kindes in Form von K{\"o}rperschemast{\"o}rungen und K{\"o}rperdissoziationen, in Emotionsregulations- und als Entwicklungstraumast{\"o}rung manifestieren k{\"o}nnen. Diese sind weit verbreitet und Teil einer Gesellschaft, die auf Leistung und Effizienz ausgerichtet ist und in Zusammenhang mit chronischem Stress stehen. Evolutionsgeschichtlich begr{\"u}ndete {\"U}berlebensmuster werden durch chronischen Stress aktiviert und sind Ursache zahlreicher Erkrankungen. Hierf{\"u}r liefert Porges mit seiner Polyvagal-Theorie einen neuen neurobiologischen Erkl{\"a}rungsansatz. Durch eine Imbalance stressausl{\"o}sender und entspannender Faktoren zugunsten des Stresses werden k{\"o}rpereigene Selbstheilungskr{\"a}fte der Selbstregulation verhindert und die Resilienzf{\"a}higkeit eingeschr{\"a}nkt. Selbstregulation und Resilienz sind vorhanden, wenn das Ruhe- und Bindungssystem dominiert im Gegensatz zur Kampf-, Flucht- und Erstarrungsreaktion. In seiner Hypothese zeigt Porges auf, wie das autonome Nervensystem Verhaltensweisen beeinflusst und wie diesen begegnet werden kann. Durch den sympathischen Zweig wird die An- und Verspannungsreaktion auf k{\"o}rperlicher Seite mit den auch auf der psychischen Seite verbundenen Reaktionen vermittelt. Diesem kann durch die parasympathisch vermittelte Oxytocin-Freisetzung begegnet werden. Durch eine Balance dieser beiden Waagschalen kann k{\"o}rperliche und seelische Gesundheit sowie Resilienzf{\"a}higkeit gef{\"o}rdert werden. Die K{\"o}rperpsychotherapie bietet auch aus meiner Sicht eine noch untersch{\"a}tzte M{\"o}glichkeit, die Balance wieder herzustellen. Eine Methode, die positive durch Oxytocin vermittelte heilsame Reaktionen in Gang zu setzt, stellt die ber{\"u}hrende K{\"o}rperarbeit dar wie sie beispielsweise nach der Rosen-Methode praktiziert wird. K{\"o}rperpsychotherapie im Allgemeinen kann in der Behandlung von Depressionen, Angst- und psychosomatischen St{\"o}rungen hilfreich sein. Sie ist empirisch in einer umfassenden Theorie begr{\"u}ndet und fundiert auf neurobiologischen und neurowissenschaftlichen Erkenntnissen. Aus Sicht der Autorin handelt es sich bei der K{\"o}rperpsychotherapie angesichts der vorliegenden Befunde und theoretischen Wirkkonzepte um einen therapeutischen Ansatz, der wesentlich dazu beitragen kann, die Behandlung psychischer St{\"o}rungen kosteneffizienter und wirksamer zu gestalten. Um differenzierter zwischen theoretischem Potential und tats{\"a}chlich nachweisbaren Effekten k{\"o}rperpsychotherapeutischer Methoden unterscheiden zu k{\"o}nnen, ist es aus meiner Sicht dringend zu empfehlen, k{\"o}rperpsychotherapeutische Arbeitsans{\"a}tze exakter zu erforschen. Beispielsweise w{\"a}re es lang- oder mittelfristig auch w{\"u}nschenswert, Forschungsdaten f{\"u}r eine pr{\"a}zisere Indikationsstellung zur Verf{\"u}gung zu haben. Dabei w{\"a}re beispielweise zu kl{\"a}ren, welche Verfahren f{\"u}r welche St{\"o}rungsbilder, in welchem Behandlungssetting und f{\"u}r welche Behandlungsdauer in Frage kommen. Auch fehlen hinsichtlich der Kontraindikationen belastbare Forschungsdaten zu den oben benannten Empfehlungen diverser Vertreter der K{\"o}rperpsychotherapie. Aufgrund des hohen Erkl{\"a}rungspotentials f{\"u}r das individuelle Erleben psychisch beeintr{\"a}chtigter Personen, das beispielsweise die Polyvagal-Theorie nach Porges oder die verk{\"o}rperte Selbstwahrnehmung nach Fogel bieten, erscheint mir auch die Forderung nach einer Ber{\"u}cksichtigung k{\"o}rperpsychotherapeutischer Theorien und Methoden in der Ausbildung von {\"A}rzten und Psychologen nachvollziehbar und sinnvoll. Aufgrund der in dieser Arbeit zusammengetragenen Ergebnisse halte ich es f{\"u}r dringend empfehlenswert, die K{\"o}rperpsychotherapie als eigenst{\"a}ndiges Behandlungselement in die fachgerechte Versorgung psychisch Erkrankter aufzunehmen, sofern keine der erw{\"a}hnten Kontraindikationen dem widersprechen.},
  subject      = {K{\"o}rperpsychotherapie},
  language  = {de}
}
@article{WendlerBurmesterSoerensenetal.2014,
  author    = {Wendler, J{\"o}rg and Burmester, Gerd R. and S{\"o}rensen, Helmut and Krause, Andreas and Richter, Constanze and Tony, Hans-Peter and Rubbert-Roth, Andrea and Bartz-Bazzanella, Peter and Wassenberg, Siegfried and Haug-Rost, Iris and D{\"o}rner, Thomas},
  title     = {Rituximab in patients with rheumatoid arthritis in routine practice (GERINIS): six-year results from a prospective, multicentre, non-interventional study in 2,484 patients},
  series = {Arthritis Research \& Therapy},
  volume    = {16},
  journal   = {Arthritis Research \& Therapy},
  number    = {2},
  doi       = {10.1186/ar4521},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121184},
  pages     = {R80},
  year      = {2014},
  abstract  = {INTRODUCTION: The aim of this study was to evaluate the safety and efficacy of rituximab (RTX) in a large cohort of patients with rheumatoid arthritis in routine care, and to monitor changes in daily practice since the introduction of RTX therapy. METHODS: This was a multicentre, prospective, non-interventional study conducted under routine practice conditions in Germany. Efficacy was evaluated using Disease Activity Score in 28 joints (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed by recording adverse drug reactions (ADRs). Physician and patient global efficacy and tolerability assessments were also evaluated. RESULTS: Overall, 2,484 patients (76.7\% female, mean age 56.4 years, mean disease duration 11.7 years) received RTX treatment (22.7\% monotherapy). The total observation period was approximately six-years (median follow-up 14.7 months). RTX treatment led to improvements in DAS28 and HAQ-DI that were sustained over multiple courses. DAS28 improvements positively correlated with higher rheumatoid factor levels up to 50 IU/ml. Response and tolerability were rated good/very good by the majority of physicians and patients. Mean treatment intervals were 10.5 and 6.8 months for the first and last 400 enrolled patients, respectively. Infections were the most frequently reported ADRs (9.1\%; 11.39/100 patient-years); approximately 1\% of patients per course discontinued therapy due to ADRs. CONCLUSIONS: Prolonged RTX treatment in routine care is associated with good efficacy and tolerability, as measured by conventional parameters and by physicians' and patients' global assessments. Rheumatoid factor status served as a distinct and quantitative biomarker of RTX responsiveness. With growing experience, physicians repeated treatments earlier in patients with less severe disease activity.},
  language  = {en}
}
@article{WeissbachHerediaGuerreroBarnsteineretal.2020,
  author    = {Weißbach, Susann and Heredia-Guerrero, Sofia Catalina and Barnsteiner, Stefanie and Großhans, Lukas and Bodem, Jochen and Starz, Hanna and Langer, Christian and Appenzeller, Silke and Knop, Stefan and Steinbrunn, Torsten and Rost, Simone and Einsele, Hermann and Bargou, Ralf Christian and Rosenwald, Andreas and St{\"u}hmer, Thorsten and Leich, Ellen},
  title     = {Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12020455},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200617},
  year      = {2020},
  abstract  = {Approximately 20\% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.},
  language  = {en}
}
@phdthesis{Weiss2023,
  author    = {Weiß, Ronja},
  title     = {Untersuchungen zur Kreuzreaktivit{\"a}t von Cytomegalievirus-spezifischen T-Lymphozyten und Tumorassoziierten Antigenen},
  doi       = {10.25972/OPUS-30340},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303405},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Bei Patienten mit Erkrankungen des blutbildenden Systems ist die h{\"a}matopoetische Stammzelltransplantation (HSZT) eine h{\"a}ufig eingesetzte kurative Therapie. Im Rahmen dieser Transplantation werden nicht nur vom Spender gewonnene h{\"a}matopoetische Stammzellen auf den Empf{\"a}nger {\"u}bertragen, sondern immer auch im peripheren Blut vorhandene T-Zellen. Dies kann zum einen einen positiven Effekt zum anderen aber auch negative Folgen f{\"u}r den transplantierten Patienten mit sich bringen. Eine negative Auswirkung w{\"a}re die sogenannte Graft-vesus-Host Disease (GvHD), bei der die T-Zellen des Spenders Zellen des Empf{\"a}ngers als fremd erkennen und angreifen. Klinisch manifestiert sich dies vor allem an Leber, Haut und Darm mit Ikterus, Dermatitiden und Diarrhoen. Einen gew{\"u}nschten Effekt, den die {\"u}bertragenen T-Zellen vor allem bei Patienten mit akuter myeloischer Leuk{\"a}mie (AML) mit sich bringen k{\"o}nnen, ist der sogenannte Graft-versus-Leukemia (GvL) Effekt. Dabei richten sich vom Spender stammende Immunzellen gegen die Tumorzellen des Empf{\"a}ngers und senken damit das Rezidivrisiko der Leuk{\"a}mie. In verschiedenen Studien konnte eine positive Korrelation von CMV-Reaktivierung nach HSZT und einem niedrigerem Rezidivrisiko der h{\"a}matopoetischen Grunderkrankung gezeigt werden. Diese Doktorarbeit widmet sich auf Grundlage dessen der Frage, ob Cytomegalievirus (CMV)-spezifische cytotoxische T-Zellen (CTL) direkt durch Kreuzreaktivit{\"a}t zum GvL-Effekt beitragen. Zun{\"a}chst wurden periphere mononukle{\"a}re Zellen (PBMC) aus dem Blut neun gesunder Spender isoliert, die als CMV-seropositiv ausgetestet wurden. Diese wurden mit dem CMVpp65-(NLVPMVATV)-Einzelpeptid stimuliert und in Kultur angereichert. Zus{\"a}tzlich wurden die expandierten CMV-spezifischen CTL durch eine spezifische Selektion {\"u}ber den Aktivierungsmarker CD137 weiter angereichert. Nach Expansion und Anreicherung zeigten jeweils 75\% (Spender 1), 67\% (Spender 2), 74\% (Spender 3), 86\% (Spender 4), 81\% (Spender5), 80\% (Spender 6), 84\% (Spender 7), 51\% (Spender 8) und 69\% (Spender 9) der CD3+/CD8+-T-Zellen eine IFN-γ-Produktion und CD107a-Expression nach Stimulation mit dem CMVpp65-Einzelpeptid. IFN-γ als Effektormolek{\"u}l der zytotoxischen Granula der CTL und CD107a als Degranulationsmarker beweisen die spezifische Zytotoxizit{\"a}t. Somit konnte die erfolgreiche Anreicherung funktionsf{\"a}higer CMVpp65-spezifischer CTL gezeigt werden. Um zu untersuchen, ob diese nun kreuzreaktiv tumorassoziierte Antigene (TAA) erkennen, wurden sie ebenfalls mit folgenden TAA stimuliert: WT1, Proteinase 3, PRAME, NY-ESO, Muc1 und Bcl-2. Die Stimulation erfolgte entweder {\"u}ber die direkte Zugabe von Einzelpeptiden bzw. Peptidpools oder {\"u}ber die Beladung und Pr{\"a}sentation dieser Peptide bzw. Peptidpools {\"u}ber dendritische Zellen (DC). Die DC wurden aus Monozyten des jeweiligen Spenders generiert. Im Falle von drei Spendern zeigt sich ebenfalls eine deutliche zytotoxische Funktion nach Stimulation mit dem WT1-(DFKDCERRF)-Einzelpeptid durch IFN-γ-Produktion und CD107a-Expression bei 75\% (Spender 1), 35\% (Spender 4) und 33\% (Spender 7) der CD3+/CD8+-T-Zellen. Wie zuvor erw{\"a}hnt lag der Anteil der CD3+/CD8+-T-Zellen mit spezifischer Zytotoxizit{\"a}t nach Stimulation mit dem CMVpp65-(NLVPMVATV)-Einzelpeptid bei diesen drei besagten Spendern bei 74\% (Spender1), 86\% (Spender 4) und 84\% (Spender7). So ergab sich f{\"u}r diese drei Spender eine gemeinsame Schnittmenge von 48,92\% (Spender 1), 21,07\% (Spender 4) und 17,45\% (Spender 7) derjenigen Zellen, die sowohl nach Stimulation mit CMVpp65-(NLVPMVATV)-Einzelpeptid und WT-(DFKDCERRF)-Einzelpeptid eine zytotoxische Funktion zeigten, sodass von einer kreuzreaktiven Erkennung dieser beiden Peptide in diesen drei Spendern ausgegangen werden muss. Die f{\"u}r diese Spender gezeigte kreuzreaktive Erkennung k{\"o}nnte zum GvL-Effekt bei Leuk{\"a}mie/Myelom-Patienten nach HSZT beitragen.},
  subject      = {Kreuzreaktion},
  language  = {de}
}
@phdthesis{Weiss2021,
  author    = {Weiß, Esther},
  title     = {Host-pathogen interactions of natural killer cells and Aspergillus fumigatus: Relevance of immune cell cross-talk and fungal recognition receptors},
  doi       = {10.25972/OPUS-20607},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206077},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {The human pathogen Aspergillus (A.) fumigatus is a fungal mold that can cause severe infections in immunocompromised hosts. Pathogen recognition and immune cell cross-talk are essential for clearing fungal infections efficiently. Immune cell interactions in particular may enhance individual cell activation and cytotoxicity towards invading pathogens. This study analyzed the reciprocal cell activation of natural killer (NK) cells and monocyte-derived dendritic cells (moDCs) after stimulation with A. fumigatus cell wall fractions and whole-cell lysates. Furthermore, the impact of the on moDCs expressed fungal receptors Dectin-1 and TLR-2 on NK cell activation was analyzed. Stimulation of moDCs with ligands for Dectin-1 and TLR-2 and transfer of soluble factors on autologous NK cells showed that moDCs could induce NK cell activation solely by secreting factors. In summary, both cell types could induce reciprocal cell activation if the stimulated cell type recognized fungal morphologies and ligands. However, moDCs displayed a broader set of A. fumigatus receptors and, therefore, could induce NK cell activation when those were not activated by the stimulus directly. Consequently, new fungal receptors should be identified on NK cells. The NK cell characterization marker CD56 was reduced detected in flow cytometry after fungal co-culture. Notably, this decreased detection was not associated with NK cell apoptosis, protein degradation, internalization, or secretion of CD56 molecules. CD56 was shown to tightly attach to hyphal structures, followed by its concentration at the NK-A. fumigatus interaction site. Actin polymerization was necessary for CD56 relocalization, as pre-treatment of NK cells with actin-inhibitory reagents abolished CD56 binding to the fungus. Blocking of CD56 suppressed fungal mediated NK cell activation and secretion of the immune-recruiting chemokines MIP-1α, MIP-1β, and RANTES, concluding that CD56 is functionally involved in fungal recognition by NK cells. CD56 binding to fungal hyphae was inhibited in NK cells obtained from patients during immune-suppressing therapy after allogeneic stem cell transplantation (alloSCT). Additionally, reduced binding of CD56 correlated with decreased actin polymerization of reconstituting NK cells challenged with the fungus. The immune-suppressing therapy with corticosteroids negatively influenced the secretion of MIP-1α, MIP-1β, and RANTES in NK cells after fungal stimulation ex vivo. Similar results were obtained when NK cells from healthy donors were treated with corticosteroids prior to fungal co-culture. Thus, corticosteroids were identified to have detrimental effects on NK cell function during infection with A. fumigatus.},
  subject      = {Nat{\"u}rliche Killerzelle},
  language  = {en}
}
@article{WeissRauGeier2014,
  author    = {Weiss, Johannes and Rau, Monika and Geier, Andreas},
  title     = {Non-Alcoholic Fatty Liver Disease Epidemiology, Clinical Course, Investigation, and Treatment},
  series = {Deautsches {\"A}rzteblatt International},
  volume    = {111},
  journal   = {Deautsches {\"A}rzteblatt International},
  number    = {26},
  doi       = {10.3238/arztebl.2014.0447},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119557},
  pages     = {447-52},
  year      = {2014},
  abstract  = {Background: The global obesity epidemic has increased the prevalence of fatty liver disease. At present, 14\% to 27\% of the general population in the industrialized world has non-alcoholic fatty liver disease (NAFLD). Methods: We review pertinent publications retrieved by a selective search of the PubMed database for the years 1995 to 2013. Results: The term "non-alcoholic fatty liver disease" covers cases of a wide spectrum of severity, ranging from bland fatty liver without any inflammation and with little or no tendency to progress all the way to non-alcoholic steatohepatitis (NASH) with inflammatory reactions and hepatocyte damage, with or without fibrosis. Some 5\% to 20\% of patients with NAFLD develop NASH, which undergoes a further transition to higher-grade fibrosis in 10\% to 20\% of cases. In fewer than 5\% of cases, fibrosis progresses to cirrhosis. These approximate figures lead to an estimate of 0.05\% to 0.3\% for the prevalence of cirrhosis in the general population. About 2\% of all cirrhosis patients per year develop hepatocellular carcinoma. The diagnosis of fatty liver disease can be suspected initially on the basis of abnormally high aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) levels and abnormal ultrasonographic findings. The positive predictive value of an ultrasonographic study for mild steatosis is 67\% at most. The NAFLD fibrosis score, which is computed on the basis of multiple parameters (age, body-mass index, diabetes status, ASAT, ALAT, platelet count, and albumin level), has a positive predictive value of 82\% to 90\% and a negative predictive value of 88\% to 93\%. Liver biopsy is the gold standard for diagnosis but should be performed sparingly in view of its rare but sometimes life-threatening complications, such as hemorrhage. The treatment of NAFLD and NASH consists mainly of changes in lifestyle and nutrition. Conclusion: NAFLD can, in principle, be reversed. This is only possible with weight reduction by at least 3\% to 5\%.},
  language  = {en}
}
@article{WeissSchlegelTerpitzetal.2020,
  author    = {Weiss, Esther and Schlegel, Jan and Terpitz, Ulrich and Weber, Michael and Linde, J{\"o}rg and Schmitt, Anna-Lena and H{\"u}nniger, Kerstin and Marischen, Lothar and Gamon, Florian and Bauer, Joachim and L{\"o}ffler, Claudia and Kurzai, Oliver and Morton, Charles Oliver and Sauer, Markus and Einsele, Hermann and Loeffler, Juergen},
  title     = {Reconstituting NK Cells After Allogeneic Stem Cell Transplantation Show Impaired Response to the Fungal Pathogen Aspergillus fumigatus},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.02117},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212581},
  year      = {2020},
  abstract  = {Delayed natural killer (NK) cell reconstitution after allogeneic stem cell transplantation (alloSCT) is associated with a higher risk of developing invasive aspergillosis. The interaction of NK cells with the human pathogen Aspergillus (A.) fumigatus is mediated by the fungal recognition receptor CD56, which is relocated to the fungal interface after contact. Blocking of CD56 signaling inhibits the fungal mediated chemokine secretion of MIP-1α, MIP-1β, and RANTES and reduces cell activation, indicating a functional role of CD56 in fungal recognition. We collected peripheral blood from recipients of an allograft at defined time points after alloSCT (day 60, 90, 120, 180). NK cells were isolated, directly challenged with live A. fumigatus germ tubes, and cell function was analyzed and compared to healthy age and gender-matched individuals. After alloSCT, NK cells displayed a higher percentage of CD56\(^{bright}\)CD16\(^{dim}\) cells throughout the time of blood collection. However, CD56 binding and relocalization to the fungal contact side were decreased. We were able to correlate this deficiency to the administration of corticosteroid therapy that further negatively influenced the secretion of MIP-1α, MIP-1β, and RANTES. As a consequence, the treatment of healthy NK cells ex vivo with corticosteroids abrogated chemokine secretion measured by multiplex immunoassay. Furthermore, we analyzed NK cells regarding their actin cytoskeleton by Structured Illumination Microscopy (SIM) and flow cytometry and demonstrate an actin dysfunction of NK cells shown by reduced F-actin content after fungal co-cultivation early after alloSCT. This dysfunction remains until 180 days post-alloSCT, concluding that further actin-dependent cellular processes may be negatively influenced after alloSCT. To investigate the molecular pathomechansism, we compared CD56 receptor mobility on the plasma membrane of healthy and alloSCT primary NK cells by single-molecule tracking. The results were very robust and reproducible between tested conditions which point to a different molecular mechanism and emphasize the importance of proper CD56 mobility.},
  language  = {en}
}
@phdthesis{Weil2018,
  author    = {Weil, Frederik},
  title     = {Einfluss von Spendermerkmalen und Kulturmedien auf die histomorphologische Qualit{\"a}t von humanen artifiziellen Vollhautmodellen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161882},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Humane artifizielle Vollhautmodelle gewinnen im Bereich des Tissue Engineerings zunehmend an Bedeutung und werden mittlerweile in vielen verschiedenen Fachbereichen erforscht, optimiert und sogar als die Grundlagenforschung unterst{\"u}tzende Tierersatzmodelle angewendet. Dieses geht mit hohen Anspr{\"u}chen an Qualit{\"a}t und Reproduzierbarkeit dergleichen einher. In der vorliegenden Arbeit wurde erstmals der Einfluss von Kulturbedingen und Spendermaterial auf die Qualit{\"a}t humaner in vitro hergestellter Vollhautmodelle systematisch untersucht. Dazu wurde zun{\"a}chst ein Katalog an histomorphologischen Qualit{\"a}tskriterien erarbeitet, der sich an echten humanen Hautbiopsien orientierte und eine Gewichtung dieser Kriterien im Hinblick auf die Verwendung als echte Hautersatzmodelle erlaubte. F{\"u}r die Herstellung der Hautmodelle wurden die etablierten Medien KGM 2 , KGM 2 variant und EpiLife ® und deren Kultivierungsprotokolle verwendet. Die zellul{\"a}re Grundlage der vorliegenden Untersuchungen bildeten die Pr{\"a}putien von sechzehn Kindern nach Zirkumzision. Keratinozyten und Fibroblasten wurden isoliert und mit den drei oben genannten Medien und zugrundeliegenden Kultivierungsprotokollen wurden in jeweils dreifacher Ausf{\"u}hrung insgesamt 144 humane Vollhautmodelle erstellt, welche dann entsprechend des Bewertungskataloges beurteilt wurden. Die zugrunde gelegten Bewertungs- und G{\"u}tekriterien entsprachen histomorphologischen Parametern. Dazu geh{\"o}rten die Dicke von Epidermis und Dermis, die Adh{\"a}renz zwischen Epidermis und Dermis sowie die Abwesenheit von Zellkernen im Stratum corneum der Epidermis. F{\"u}r die Analyse der Einflussfaktoren Spenderalter und Kultivierungsmedium wurden Regressionsmodelle mittels Generalized Estimating Equations angewandt. Das Spenderalter und das Kultivierungsmedium wurden dabei unabh{\"a}ngig voneinander in einer univariaten Analyse untersucht. Bei der Untersuchung des Einflusses des Kulturmediums auf die terminale Differenzierung innerhalb der Epidermis zeigte sich, dass durch Kultivierung mit EpiLife ® signifikant weniger Vollhautmodelle mit Zellkernen im Stratum corneum hergestellt wurden, im Vergleich zur Kultur mit KGM 2 oder KGM 2 variant. Der Einfluss des Kulturmediums auf die Epidermis- und Dermis-Dicke war jeweils nicht signifikant. Trotzdem zeigte sich ein Trend mit einer d{\"u}nneren Epidermis und Dermis nach EpiLife ® -Kultivierung. Bei der Analyse des Spenderalters konnte ein positiver Einfluss eines j{\"u}ngeren Spenders auf die Dicke der Epidermis im Vollhautmodell gezeigt werden. Die Epidermis-Dicke war signifikant gr{\"o}ßer, je j{\"u}nger ein Vorhautspender war. Ein h{\"o}heres Spenderalter dagegen f{\"u}hrte zu signifikant weniger Abl{\"o}sung der Epidermis von der Dermis. Keinen Einfluss hatte das Spenderalter auf die Dermis-Dicke und auf die Abwesenheit von Zellkernen in der Hornschicht. Die drei signifikanten Assoziationen in der univariaten Analyse wurden in einer multivariablen Analyse untersucht. Hierbei zeigte sich der Einfluss des Spenderalters auf die Epidermis-Dicke und die dermo-epidermale Adh{\"a}sion unter Einfluss der Kulturmedien, der Abwesenheit von Zellkernen in der Hornschicht und der Dermis-Dicke als Kovariablen ebenfalls signifikant. Auch blieb der Einfluss von EpiLife ® auf die Abwesenheit von Zellkernen in der Hornschicht in der multivariablen Analyse signifikant. Es konnte hierbei außerdem ein signifikanter Einfluss der Dermis auf die Epidermis mit Schrumpfung der Epidermis bei Gr{\"o}ßerwerden der Dermis gezeigt werden. In einer durchgef{\"u}hrten komplexen statistischen Analyse mittels General Linear Model wurde der Einfluss einer Spender-Medium-Interaktion analysiert, ohne das Spenderalter als Variable mit einzubeziehen. Es zeigte sich ein signifikanter Einfluss der Interaktion des Spenders mit dem Kulturmedium auf die Epidermisund Dermis-Dicke und damit auf die Qualit{\"a}t der in vitro hergestellten Vollhautmodelle. Einerseits bestand also ein unabh{\"a}ngiger Einfluss des Spenderalters und des Mediums, andererseits gab es einen Einfluss von der Abh{\"a}ngigkeit einer optimalen Spender-Medium-Kombination auf die Vollhautmodellqualit{\"a}t. Zusammenfassend konnte in der vorliegenden Arbeit erstmals das komplexe Zusammenspiel von Spenderfaktoren und Kultivierungsbedingungen und deren Auswirkungen auf die Qualit{\"a}t von humanen Vollhautmodellen aufgezeigt werden. Diese Ergebnisse haben Relevanz f{\"u}r den Einsatz dieser Modelle als Tierersatzmodelle in der Forschung. Unter Ber{\"u}cksichtigung dieser Ergebnisse k{\"o}nnen optimierte organotypische Vollhautmodelle in vitro hergestellt werden, sodass zuk{\"u}nftig komplexere Hautmodelle generiert werden k{\"o}nnen. In einer Folgearbeit sollen die hier erarbeiteten Grundlagen helfen, Hautmodelle in der Erforschung der akuten GvHD der Haut zu bearbeiten.},
  subject      = {Optimierung},
  language  = {de}
}
@article{WeichRogollGawlasetal.2021,
  author    = {Weich, Alexander and Rogoll, Dorothee and Gawlas, Sophia and Mayer, Lars and Weich, Wolfgang and Pongracz, Judit and Kudlich, Theodor and Meining, Alexander and Scheurlen, Michael},
  title     = {Wnt/β-catenin signaling regulates CXCR4 expression and [\(^{68}\)Ga] Pentixafor internalization in neuroendocrine tumor cells},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {2},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11020367},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228914},
  year      = {2021},
  abstract  = {Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [\(^{68}\)Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [\(^{68}\)Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.},
  language  = {en}
}
@phdthesis{WeberWeigand2007,
  author    = {Weber-Weigand, Dorothee},
  title     = {Herzminutenvolumenbestimmung nach dem Fickschen Prinzip : Vergleich von zwei Methoden in Ruhe und unter Belastung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-26004},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Das Ficksche Prinzip gilt als der Goldstandard der Bestimmung des Herzminutenvolumens. Neben der invasiven Bestimmung {\"u}ber einen Pulmonaliskatheter steht die nicht-invasive R{\"u}ckatmungsmethode (Rebreahting) zur Verf{\"u}gung. Bereits 1996 ist von FW Schardt eine weitere nicht-invasive ergospirometrische Variante vorgestellt worden, die ohne R{\"u}ckatmung auskommt. Hier wird der gemischt-ven{\"o}sen Kohlendioxidgehalt basierend auf den Kohlendioxidverbrauch berechnet. Ziel der Arbeit ist eine vergleichende Darstellung der Bestimmungsmethode nach Schardt mit dem als Referenzmethode dienenden R{\"u}ckatmungsverfahren. Besonderes Augenmerk wird auf Messungen unter hohen Belastungen gelegt, denn hier neigt das Rebreathingverfahren zur Untersch{\"a}tzung des Herzminutenvolumens, zudem wird die R{\"u}ckatmung selbst f{\"u}r den Patienten unertr{\"a}glich. Parallel wurde bei 36 Probanden das Herzminutenvolumen sowohl durch Rebreathing (Qt) wie auch nach Schardt (HMV) ergospirometrisch auf dem Fahrradergometer (in 50 Watt Stufen) bis maximal 350 Watt bestimmt. Ausgewertet wurde die absolute bzw. prozentuale Abweichung des HMV von Qt, sowie HMV vom Mittelwert beider Methoden nach Bland/Altman bzw. Critchley/Critchley. Unter Einbeziehung der Ergebnisse aller Belastungsstufen wird deutlich, dass die Werte f{\"u}r HMV bei niedrigeren Ausgangswerten unter den Werten der R{\"u}ckatmungsmethode (Qt) liegen. Dagegen werden bei hohen Belastungen f{\"u}r HMV h{\"o}here Werte berechnet als f{\"u}r Qt. Die gr{\"o}ßten Abweichungen sind in Ruhe die zu erkennen. Die Abweichung des HMV vom Mittelwert beider Methoden liegt in Ruhe im Mittel bei 18,8\%, unter niedriger Belastung bei 8,7-9,4\%. Die Grenzen der {\"U}bereinstimmung {\"u}berschreiten jedoch die Grenzen der Genauigkeit. Die niedrigsten Abweichungen sind bei mittelschwerer Belastung (150-200 Watt) zu verzeichnen, sowie geringe Abweichungen unter sehr hoher Belastung (1,2-4,0\%). Die Grenzen der {\"U}bereinstimmung liegen innerhalb der Grenzen der Genauigkeit. Die prozentuale Abweichung der Ergebnisse f{\"u}r das Herzminutenvolumen nach Schardt vom Mittelwert beider Methoden liegt {\"u}ber allen Belastungsstufen innerhalb der von Critchley und Critchley geforderten +/- 20 Prozent. Insgesamt konnte gezeigt werden, dass die Methode nach Schardt eine Variante des Fickschen Prinzips liefert, die als einfache, nicht invasive Maßnahme auch unter hoher Belastung und bei wiederholten Messungen anwendbar ist und insbesondere unter mittleren und hohen Belastungen mit der Rebreathingmethode austauschbar ist.},
  subject      = {Herzzeitvolumen},
  language  = {de}
}
@phdthesis{WebergebSpalek2018,
  author    = {Weber [geb. Spalek], Evelyn},
  title     = {Poststation{\"a}res Management Helicobacter pylori positiver Patienten im Raum Aschaffenburg},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156634},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {2009 wurde die deutsche S3-Leitlinie „Helicobacter pylori und gastroduodenale Ulkuskrankheit" publiziert, in der klare Empfehlungen f{\"u}r die Diagnostik, die Indikationen f{\"u}r eine Eradikation, die Therapie und das Follow-Up beschrieben sind. Das Management der H. pylori Infektion im praktischen Alltag zeigt nach dieser Arbeit indessen ein anderes Bild. Ein Optimierungsbedarf f{\"u}r die Zukunft kann daraus abgeleitet werden. Diese Arbeit besch{\"a}ftigt sich mit dem poststation{\"a}ren Management von Patienten mit einer H. pylori Infektion im Raum Aschaffenburg. Hierzu wurden 199 Patienten identifiziert, bei denen im Rahmen eines station{\"a}ren Aufenthaltes im Klinikum Aschaffenburg im Jahr 2011 eine H. pylori Infektion diagnostiziert worden war. Aus den Patientenakten wurden alle relevanten Daten entnommen, wie zum Beispiel Diagnose, Indikation zur H. pylori Eradikation und deren station{\"a}re Initiierung beziehungsweise Empfehlung an den Hausarzt. Nachfolgend wurden die 97 Haus{\"a}rzte der 199 Patienten angeschrieben und um das ausf{\"u}llen eines Fragebogens gebeten. Dieser enthielt sechs Fragen zum poststation{\"a}ren Management der Patienten mit H. pylori Infektion. W{\"a}hrend des station{\"a}ren Aufenthaltes war bei 88/199 Patienten (44,2\%) die Eradikationstherapie begonnen und bei 24 von ihnen (12,1\%) bereits abgeschlossen worden. Bei den anderen 64 Patienten sollte die Medikation ambulant fortgef{\"u}hrt werden. Bei 77 Patienten (38,7\%) wurde dem Hausarzt die Einleitung einer ambulanten Eradikationsbehandlung empfohlen. 34 Patienten verließen das Krankenhaus ohne Therapie und auch ohne entsprechende Therapieempfehlung. Die R{\"u}cklaufquote der Frageb{\"o}gen betrug 46,2\% (92 von 199 Patienten). Die nachfolgenden Ergebnisse beziehen sich auf diese 92 Patienten (entspricht 100\%). Zwei Drittel der Patienten (n=61) stellten sich direkt im Anschluss an die Entlassung aus station{\"a}rer Behandlung ihrem Hausarzt vor. Bei 30 Patienten f{\"u}hrte der Hausarzt die station{\"a}re begonnene Eradikationstherapie fort (32,6\%) oder initiierte sie bei 28 Patienten selbst (30,4\%). 17 Patienten erhielten keine Eradikation (18,5\%). Die Gr{\"u}nde hierf{\"u}r waren unterschiedlich, am h{\"a}ufigsten lag ein Informationsdefizit zwischen Klinik und Hausarzt vor. Die franz{\"o}sische Triple-Therapie wurde mit 39 mal am h{\"a}ufigsten verordnet, die italienische Triple-Therapie wurde 20 Patienten verschrieben. Andere Behandlungsprotokolle fanden nur vereinzelt Anwendung. Eine Kontrolle des Eradikationserfolges wurde bei 35 Patienten (38\%) vorgenommen. Bezieht man die Eradikationskontrolle ausschließlich auf die therapierten Patienten erfolgte diese in der H{\"a}lfte der F{\"a}lle (49,3\%). Von den Patienten mit H. pylori Eradikation und Kontrolle des Eradikationserfolges (n=35) konnten 31 (88,6\%) erfolgreich behandelt werden. Die Vorgehensweise nach erfolgloser H. pylori Eradikation umfasste den Versuch einer Zweitlinientherapie, die {\"U}berweisung zum Gastroenterologen und den Verzicht auf weitere Maßnahmen. Zusammenfassend zeigt diese Erhebung, dass es einen klaren Optimierungsbedarf in der Anwendung der Empfehlungen aus der Leitlinie bedarf. Dieser Aspekt sollte zuk{\"u}nftig vermehrt Ber{\"u}cksichtigung finden, nicht zuletzt in der Aktualisierung der Leitlinie 2016.},
  subject      = {Ambulante Behandlung},
  language  = {de}
}
@article{WalterGrussNeidlingeretal.2020,
  author    = {Walter, Steffen and Gruss, Sascha and Neidlinger, Jana and Stross, Isabelle and Hann, Alexander and Wagner, Martin and Seufferlein, Thomas and Walter, Benjamin},
  title     = {Evaluation of an Objective Measurement Tool for Stress Level Reduction by Individually Chosen Music During Colonoscopy—Results From the Study "ColoRelaxTone"},
  series = {Frontiers in Medicine},
  volume    = {7},
  journal   = {Frontiers in Medicine},
  doi       = {10.3389/fmed.2020.00525},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212337},
  year      = {2020},
  abstract  = {Background and Aims: Colonoscopy as standard procedure in endoscopy is often perceived as uncomfortable for patients. Patient's anxiety is therefore a significant issue, which often lead to avoidance of participation of relevant examinations as CRC-screening. Non-pharmacological anxiety management interventions such as music might contribute to relaxation in the phase prior and during endoscopy. Although music's anxiolytic effects have been reported previously, no objective measurement of stress level reduction has been reported yet. Focus of this study was to evaluate the objective measurement of the state of relaxation in patients undergoing colonoscopy. Methods: Prospective study (n = 196) performed at one endoscopic high-volume center. Standard colonoscopy was performed in control group. Interventional group received additionally self-chosen music over earphones. Facial Electromyography (fEMG) activity was obtained. Clinician Satisfaction with Sedation Instrument (CSSI) and Patients Satisfaction with Sedation Instrument (PSSI) was answered by colonoscopists and patients, respectively. Overall satisfaction with music accompanied colonoscopy was obtained if applicable. Results: Mean difference measured by fEMG via musculus zygomaticus major indicated a significantly lower stress level in the music group [7.700(±5.560) μV vs. 4.820(±3.330) μV; p = 0.001]. Clinician satisfaction was significantly higher with patients listening to music [82.69(±15.04) vs. 87.3(±15.02) pts.; p = 0.001]. Patient's satisfaction was higher but did not differ significantly. Conclusions: We conclude that self-chosen music contributes objectively to a reduced stress level for patients and therefore subjectively perceived satisfaction for endoscopists. Therefore, music should be considered as a non-pharmacological treatment method of distress reduction especially in the beginning of endoscopic procedures.},
  language  = {en}
}
@phdthesis{Wallstein2021,
  author    = {Wallstein, Marion Alice},
  title     = {Einfluss von Hypoxie auf die Interaktion von moDCs und T-Zellen mit \(Aspergillus\) \(fumigatus\)},
  doi       = {10.25972/OPUS-23854},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238543},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Die invasive Aspergillose ist eine gef{\"u}rchtete Erkrankung besonderes bei immunsupprimierten Patienten, die eine Stammzelltransplanation erhalten sollen. Diese Patienten leiden in der Regel an einer h{\"a}matologischen Grunderkrankung wie einer Leuk{\"a}mie oder einem Lymphom. Das Prinzip der Stammzelltransplanatation ist es, das kranke Knochenmark mittels Chemotherapie und Bestrahlung zu zerst{\"o}ren und es dann mit gesunden Stammzellen zu ersetzen. W{\"a}hrend dieser Konditionierung ist der Patient also ohne eigene Abwehrzellen. In dieser Phase gestaltet sich die rechtzeitige Diagnose h{\"a}ufig als schwierig, weil die konventionellen Diagnosemethoden von der Anwesenheit von neutrophilen Granulozyten abh{\"a}ngen. H{\"a}ufig ist die Infektion bei der Entwicklung von unspezifischen Symptomen wie Fieber oder Dyspnoe schon weit fortgeschritten. Hat sich der Pilz in der Lunge ausgebreitet, so kommt es zur Ausbildung einer Hypoxie und im Verlauf auch zu einer Hypox{\"a}mie aufgrund einer Diffusionsst{\"o}rung in den entz{\"u}ndeten Lungenabschnitten. Ziel dieser Arbeit war es, den Einfluss von Hypoxie auf die Interaktion zwischen dendritischen Zellen und T-Zellen besser zu verstehen. Dendritische Zellen spielen eine entscheidende Rolle bei der Immunabwehr von Pilzinfektion und bilden das Verbindungsst{\"u}ck zwischen angeborenen und erworbenen Immunsystem. T-Zellen {\"u}bernehmen ebenfalls wichtige Aufgaben bei der Abwehr von Pilzinfektionen, indem sie Interferon gamma produzieren. Zudem sollte die Funktion verschiedener Botenstoffe in Signalkaskaden n{\"a}her untersucht werden. Es konnte gezeigt werden, dass die Infektion von dendritischen Zellen mit Aspergillus fumigatus unter Hypoxie, die dendritischen Zellen anschließend unter Normoxie dazu bef{\"a}higt, eine verst{\"a}rkte adaptive Immunantwort hervorzurufen. Hypoxie k{\"o}nnte somit als zus{\"a}tzlicher Faktor verwendet werden, um dendritische Zellen als effektive Adjuvantien in einer Impfung gegen Aspergillus fumigatus zu verwenden. Urs{\"a}chlich f{\"u}r die verst{\"a}rkte F{\"a}higkeit naive T-Zellen zu aktivieren, scheint zum einen die Apoptose und zum anderen eine verst{\"a}rkte Produktion von Interleukin 12p70 zu sein.},
  subject      = {Dendritische Zelle},
  language  = {de}
}
@phdthesis{Wallstabe2022,
  author    = {Wallstabe, Lars},
  title     = {Development and preclinical evaluation of tumour-reactive T cells expressing a chemically programmable chimeric antigen receptor},
  doi       = {10.25972/OPUS-17907},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179071},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {The genetic modification of T cells for the expression a chimeric antigen receptor (CAR) endows them with a new specificity for an antigen. Adoptive immunotherapy with CD19-CAR T cells has achieved high rates of sustained complete remissions in B cell malignancies. However, the downregulation or loss of the targeted antigen after mono-specific CAR T cell therapy, e.g. against CD19 or CD22, has been reported. Targeting multiple antigens on tumour cells, sequentially or simultaneously, could overcome this limitation. Additionally, targeting multiple antigens with CAR T cells could drive the translation from hematologic malignancies to prevalent solid cancers, which often express tumour-associated antigens heterogeneously. We hypothesised that expression of a universal CAR, which can be programmed with hapten-like molecules, could endow T cells with specificities for multiple antigens. In this study we introduce a novel chemically programmable CAR (cpCAR) based on monoclonal antibody h38C2. Our data show, that cpCARs form a reversible chemical bond to molecules containing a diketone-group and therefore can be programmed to acquire multiple specificities. We programmed cpCAR T cells with hapten-like compounds against integrins αvβ3 and α4β1 as well as the folate receptor. We observed tumour cell lysis, IFN ɣ and IL-2 production and proliferation of programmed cpCAR T cells against tumour cells expressing the respective target antigen in vitro. As a reference to cpCARs programmed against αvβ3, we further introduced novel conventional αvβ3-CARs. These CARs, based on humanised variants of monoclonal antibody LM609 (hLM609), directly bind to integrin αvβ3 via their scFv. The four αvβ3-CAR constructs comprised either an scFv with higher affinity (hLM609v7) or lower affinity (hLM609v11) against αvβ3 integrin and either a long (IgG4 hinge, CH2, CH3) or short (IgG4 hinge) extracellular spacer. We selected the hLM609v7-CAR with short spacer, which showed potent anti-tumour reactivity both in vitro and in a murine xenograft model, for comparison with the cpCAR programmed against αvβ3. Our data show specific lysis of αvβ3-positive tumour cells, cytokine production and proliferation of both hLM609-CAR T cells and cpCAR T cells in vitro. However, conventional hLM609-CAR T cells mediated stronger anti-tumour effects compared to cpCAR T cells in the same amount of time. In line with the in vitro data, complete destruction of tumour lesions in a murine melanoma xenograft model was only observed for mice treated with conventional αvβ3-CAR T cells. Collectively, we introduce a cpCAR, which can be programmed against multiple tumour antigens, and hLM609-CARs specific for the integrin αvβ3. The cpCAR technology bears the potential to counteract current limitations, e.g. antigen loss, of current monospecific CAR T cell therapy. Targeting αvβ3 integrin with CAR T cells could have clinical applications in the treatment of solid malignancies, because αvβ3 is not only expressed on a variety of solid malignancies, but also on tumour-associated vasculature and fibroblast.},
  subject      = {Tumorimmunologie},
  language  = {en}
}
@article{WallstabeBussemerGroeberBeckeretal.2020,
  author    = {Wallstabe, Julia and Bussemer, Lydia and Groeber-Becker, Florian and Freund, Lukas and Alb, Mirian and Dragan, Mariola and Waaga-Gasser, Ana Maria and Jakubietz, Rafael and Kneitz, Hermann and Rosenwald, Andreas and Rebhan, Silke and Walles, Heike and Mielke, Stephan},
  title     = {Inflammation-Induced Tissue Damage Mimicking GvHD in Human Skin Models as Test Platform for Immunotherapeutics},
  series = {ALTEX},
  volume    = {37},
  journal   = {ALTEX},
  number    = {3},
  doi       = {10.14573/altex.1907181},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229974},
  pages     = {429-440},
  year      = {2020},
  abstract  = {Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.},
  language  = {en}
}
@article{WagnerDrouetTeschnerWolschkeetal.2021,
  author    = {Wagner-Drouet, Eva and Teschner, Daniel and Wolschke, Christine and Sch{\"a}fer-Eckart, Kerstin and G{\"a}rtner, Johannes and Mielke, Stephan and Schreder, Martin and Kobbe, Guido and Hilgendorf, Inken and Klein, Stefan and Verbeek, Mareike and Ditschkowski, Markus and Koch, Martina and Lindemann, Monika and Schmidt, Traudel and Rascle, Anne and Barabas, Sascha and Deml, Ludwig and Wagner, Ralf and Wolff, Daniel},
  title     = {Comparison of cytomegalovirus-specific immune cell response to proteins versus peptides using an IFN-γ ELISpot assay after hematopoietic stem cell transplantation},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {2},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11020312},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228843},
  year      = {2021},
  abstract  = {Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4\% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8\(^+\) counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.},
  language  = {en}
}
@phdthesis{Wagner2020,
  author    = {Wagner, Leonard},
  title     = {Zinc homeostasis in megakaryocytes},
  doi       = {10.25972/OPUS-21452},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214526},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Zinc is an essential trace element for all living organisms. In mammals, including humans and mice, it is required for normal growth, development, hematopoiesis and immune defense. This thesis investigates the influence of zinc on the development of megakaryocytes (MKs), the cells responsible for bone marrow-derived platelet production. Furthermore, a detailed analysis of the expression of zinc import and export transporters (Slc39a/Slc30a genes) is carried out, firstly over the course of MK differentiation and secondly dependent on extracellular zinc.},
  subject      = {Zink},
  language  = {en}
}
@phdthesis{Vaeth2005,
  author    = {V{\"a}th, Thomas},
  title     = {Die Cerebrale Toxoplasmose bei AIDS : Untersuchungen zur Pharmakokinetik von Sulfadiazin unter Urinalkalisierung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-20042},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Die cerebrale Toxoplasmose stellt eine wichtige opportunistische Infektion im Verlauf einer HIV-Infektion dar. Unter der Standardtherapie mit Sulfadiazin kommt es h{\"a}ufig zu nephrotoxischen Nebenwirkungen aufgrund einer Kristallisation des Sulfadiazin und seines Metaboliten N4-Acetylsulfadiazin im Harntrakt. Die Therapie dieser Nebenwirkung erfordert unter Anderem die Alkalisierung des Harns. In der vorliegenden Arbeit wurde der Einfluss einer Urinalkalisierung auf die Pharmakokinetik beider Stoffe in vivo untersucht.},
  language  = {de}
}
@phdthesis{vonBibra2019,
  author    = {von Bibra, Mirjam},
  title     = {Lopinavir- und Efavirenz-Serumkonzentrationen bei antiretroviral behandelten HIV-infizierten Kindern in S{\"u}dafrika},
  doi       = {10.25972/OPUS-18463},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-184635},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {In der antiretroviralen Therapie bei Kindern bleibt die Rolle von Therapeutischem Drug Monitoring bisher unklar. Es war Ziel vorliegender Arbeit, bei Kindern unter antiretroviraler Therapie (ART) in S{\"u}dafrika die Lopinavir (LPV) und Efavirenz (EFV) Serumkonzentrationen in der klinischen Routine zu messen und Risikofaktoren f{\"u}r unzureichende Medikamentenexposition zu identifizieren. Zu diesem Zweck wurde eine prospektive Erhebung im Tygerberg Hospital, Stellenbosch durchgef{\"u}hrt. Siebenundf{\"u}nfzig Serumkonzentrationen von 53 Patienten wurden mit einer etablierten High-performance liquid Chromatography (HPLC) Methode im Universit{\"a}tsklinikum W{\"u}rzburg gemessen. F{\"u}r Efavirenz wird in der Literatur ein therapeutischer Bereich von 1.000-4.000 ng/ml empfohlen. Bei Lopinavir wurden die Serumkonzentrationen vorliegender Arbeit ins Verh{\"a}ltnis zu der pharmakokinetischen Gr{\"o}ße Cmin von 5.500 ng/ml gesetzt. Es wurde das Serum von 53 HIV-infizierten Kindern im Alter von 0,2-15,8 Jahren untersucht. Insgesamt zeigten 12 Kinder Serumkonzentrationen außerhalb des therapeutischen Bereichs bei EFV oder kleiner Cmin bei LPV. Eine LPV-haltige ART nahmen 29 der Kinder ein (Medianalter 1,83 Jahre). Eine Messung der Konzentration von Lopinavir zeigte eine mittlere Serumkonzentration von 8.618±6018 (nicht nachweisbar-24.629) ng/ml. 17\% der LPV-Serumkonzentrationen waren kleiner Cmin. Bei der Untersuchung folgender Faktoren zeigten sich keine signifikanten Unterschiede der mittleren Serumkonzentrationen und keine Assoziation mit Serumkonzentrationen <Cmin: Geschlecht, Dauer der ART <12 Monate, Anzahl der CD4-Lymphozyten, Viruslast, Komorbidit{\"a}ten und angegebene Therapieadh{\"a}renz. Kinder im fortgeschrittenen HIV-Stadium nach World Health Organization (WHO) Stadium IV zeigten mit 6.817±4.273 ng/ml niedrigere LPV-Serumkonzentrationen als Kinder in WHO Stadien I, II, III mit 11.331±6.819 ng/ml. Der Unterschied war allerdings nicht signifikant. (p=0,074) Tendenziell waren die LPV-Serumkonzentrationen bei Kindern mit Untergewicht (n=9) mit 6.859±4.322 ng/ml niedriger als bei normalgewichtigen Kindern (n=9) mit einer mittleren LPV-Serumkonzentration von 10.542±6.275 ng/ml (p=0,133). Es fiel weiterhin auf, dass 3 von 10 Kinder mit gastroenteritischen Symptomen in den letzten sieben Tagen Serumkonzentrationen <Cmin zeigten. (p=0,358) Ein ART-Regime mit dem Nicht-Nukleosidischen Reverse-Transkriptase-Inhibitor Efavirenz nahmen 24 der untersuchten Kinder ein (Medianalter 9,3 Jahre). Die Zeit von EFV-Einnahme bis zur Blutentnahme variierte zwischen 12 und 19 Stunden. Es konnte eine große Varianz mit 156-36.340 ng/ml gemessen werden. Im Mittel war die Serumkonzentration 4.049±6862 ng/ml. 27\% der Serumkonzentrationen lagen außerhalb des therapeutischen Bereichs. F{\"u}r folgende Faktoren zeigte sich keine signifikante Assoziation mit nicht-therapeutischen EFV-Serumkonzentrationen: Geschlecht, WHO Stadium, Dauer der ART >12 Monate, HI-Viruslast, Komorbidit{\"a}ten, Untergewicht und angegebene Therapieadh{\"a}renz. Kinder mit CD4-Lymphozyten <350 Zellen/µl Blut zeigten signifikant h{\"a}ufiger Serumkonzentrationen außerhalb des therapeutischen Bereichs als Kinder mit >350 CD4-Lymphozyten/µl Blut. (p=0,016) Bei dem Vergleich des Anteils der EFV-Serumkonzentrationen im therapeutischen Bereich zeigte sich ein signifikanter Unterschied zwischen ambulant vorgestellten versus hospitalisierten Patienten (p=0.009). Es ließ sich eine Assoziation zwischen hospitalisierten Patienten und nicht-therapeutischen Serumkonzentrationen finden. Es zeigte sich außerdem bei Kindern, die eine Rifampicin-haltige tuberkulostatische Therapie gleichzeitig zur ART einnahmen, ein Trend zu nicht therapeutischen EFV-Serumkonzentrationen (p=0,076) bei sehr kleiner Fallzahl. Die Ergebnisse dieser Arbeit zeigen, zusammen mit den Ergebnissen anderer Studien, dass mithilfe von Therapeutischem Drug Monitoring von Efavirenz und Lopinavir Risikosituationen f{\"u}r Therapieversagen oder Medikamententoxizit{\"a}t fr{\"u}hzeitig erkannt werden k{\"o}nnen.},
  subject      = {HIV},
  language  = {de}
}
@phdthesis{Vollmuth2010,
  author    = {Vollmuth, Christina},
  title     = {Untersuchungen zum {\"U}berleben bei zwei zeitlich definierten Kohorten von Patienten mit multiplem Myelom},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-53769},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Das multiple Myelom, eine maligne Plasmazell-Dyskrasie, ist bis heute unheilbar. Eine Verbesserung des medianen {\"U}berlebens von weniger als 2 auf {\"u}ber 3 Jahre wurde erstmals 1996 durch eine prospektiv randomisierte Studie von Attal et al. gezeigt. Die retrospektive Analyse zweier zeitlich definierter Kohorten, Kohorte 1 (1990-1996) und Kohorte 2 (1997-2002), zur {\"U}berpr{\"u}fung des Therapieerfolges am Universit{\"a}tsklinikum W{\"u}rzburg zeigt unter Ber{\"u}cksichtigung aller Patienten keinen {\"U}berlebensvorteil f{\"u}r Patienten der 2.Kohorte. Signifikant profitiert haben allerdings Patienten bis max. 65 Jahre der Kohorte 2, die durch die HD-Therapie ein 5-J{\"U}L von 50\% (Kohorte 2) vs.32\% (Kohorte 1) erreichten, wohingegen sich f{\"u}r {\"a}ltere Patienten keine signifikant messbaren {\"U}berlebensvorteile ergaben.},
  subject      = {Plasmozytom},
  language  = {de}
}
@article{VargasWagnerShaikhetal.2022,
  author    = {Vargas, Juan Gamboa and Wagner, Jennifer and Shaikh, Haroon and Lang, Isabell and Medler, Juliane and Anany, Mohamed and Steinfatt, Tim and Mosca, Josefina Pe{\~n}a and Haack, Stephanie and Dahlhoff, Julia and B{\"u}ttner-Herold, Maike and Graf, Carolin and Viera, Estibaliz Arellano and Einsele, Hermann and Wajant, Harald and Beilhack, Andreas},
  title     = {A TNFR2-Specific TNF fusion protein with improved in vivo activity},
  series = {Frontiers in Immunology},
  volume    = {13},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2022.888274},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-277436},
  year      = {2022},
  abstract  = {Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity. Methods Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems. Results STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300\% in vivo 5 days after treatment. Treg numbers remained as high as 200\% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD. Conclusions NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.},
  language  = {en}
}
@article{vandeDonkPalumboJohnsenetal.2014,
  author    = {van de Donk, Niels W. C. J. and Palumbo, Antonio and Johnsen, Hans Erik and Engelhardt, Monika and Gay, Francesca and Gregersen, Henrik and Hajek, Roman and Kleber, Martina and Ludwig, Heinz and Morgan, Gareth and Musto, Pellegrino and Plesner, Torben and Sezer, Orhan and Terpos, Evangelos and Waage, Anders and Zweegman, Sonja and Einsele, Hermann and Sonneveld, Pieter and Lokhorst, Henk M.},
  title     = {The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network},
  series = {Haematologica},
  volume    = {99},
  journal   = {Haematologica},
  number    = {6},
  issn      = {0390-6078},
  doi       = {10.3324/haematol.2013.100552},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116050},
  pages     = {984 - 996},
  year      = {2014},
  abstract  = {Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenstrom's macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance.},
  language  = {en}
}
@phdthesis{Umrath2013,
  author    = {Umrath, Veronika},
  title     = {Charakterisierung der Homing-Rezeptor-Expression nach allogener Stammzelltransplantation - neue Biomarker f{\"u}r eine akute Graft-versus-Host-Disease?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-102191},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Homing- und Chemokin-Rezeptoren k{\"o}nnen wichtige Informationen liefern {\"u}ber Aktivierungsstand und Organspezifit{\"a}t der einzelnen Zelle, aber auch {\"u}ber Hom{\"o}ostase und Gleichgewicht von T-Zellen untereinander. Mittels FACS-Analyse konnte in murinen Transplantationsmodellen durch die Hochregulation einzelner Homing-Rezeptoren auf T-Zellen die Entwicklung einer aGvHD vorhergesagt werden. Ob sich ein solches diagnostisches Fenster auch beim Menschen darstellen k{\"o}nnte, sollte in einer klinischen Pilotstudie untersucht werden. Zu diesem Zweck wurde der Expressionsverlauf von 19 verschiedenen Aktivierungsmarkern, Chemokin- und Homingrezeptoren auf T-Zell-Subpopulationen bei allogen transplantierten Patienten charakterisiert. Anschließend wurde versucht, eine Assoziation zwischen der H{\"o}he der jeweiligen Rezeptorexpression und der sp{\"a}teren Entwicklung einer akuten Graft-versus-Host-Disease herzustellen. Die Expression der meisten untersuchten Rezeptoren nahm im Zeitverlauf ab und war insgesamt nur schwach ausgepr{\"a}gt. Dabei zeigte sich insbesondere im fr{\"u}hen Verlauf nach SZT eine hohe relative Expression dieser Marker bei Patienten ohne aGvHD verglichen mit Patienten mit aGvHD im Verlauf. Insofern scheint eine hohe relative Expression dieser Rezeptoren kein Hinweis auf eine gesteigerte Alloreaktivit{\"a}t der jeweiligen T-Zellen zu sein. Gleichzeitig schien die absolute Anzahl an rezeptorpositiven Zellen eher positiv mit einer aGvHD korreliert zu sein. Die erh{\"o}hte Anzahl rezeptorpositiver Zellen errechnete sich allerdings aus der h{\"o}heren absoluten Anzahl aller T-Zellen bei Patienten mit aGvHD. Damit war diese nicht rezeptorspezifisch, so dass sich Rezeptoren vom Expressionstyp 1 nicht eignen, um in der klinischen Routine eine aGvHD vorherzusagen. Einige Rezeptoren waren auf T-Helfer-Zellen auf mittlerem Niveau konstant exprimiert. F{\"u}r manche von diesen zeigten sich unterschiedlich hohe relative Expressionsniveaus vor GvHD-Beginn bei Grad 2-4 verglichen mit Grad 1. Die absolute Anzahl rezeptorpositiver Zellen war bei allen Rezeptoren bei aGvHD Grad 2-4 h{\"o}her als bei Grad 1. Die Expression einiger Marker war auf T-Zellen ausgepr{\"a}gt, aber im Zeitverlauf fluktuierend. F{\"u}r die Expression von beta 7 integrin allein und auch f{\"u}r dessen Koexpression zusammen mit CD 49d alpha 4 deuteten sich bei Patienten mit aGvHD Grad 2-4 h{\"o}here relative und absolute Werte an als f{\"u}r Patienten mit aGvHD Grad 1. Die Expression der {\"u}brigen hoch exprimierten Rezeptoren schien nicht vom Ausmaß der sp{\"a}ter einsetzenden aGvHD beeinflusst zu werden. Ob durch FACS-Analyse der Rezeptoren CLA, CCR 4, CD 45RA und/oder alpha 4 beta 7 allein oder in Kombination tats{\"a}chlich die alloreaktiven T-Zellen der aGvHD charakterisiert und quantifiziert werden k{\"o}nnen, muss an einem gr{\"o}ßeren Patientenkollektiv untersucht werden. Da zum jetzigen Zeitpunkt der pr{\"a}diktive Wert dieser Marker weder postuliert noch ausgeschlossen werden kann, erscheint eine weitergehende Untersuchung sinnvoll.},
  subject      = {Graft-versus-host-disease},
  language  = {de}
}
@phdthesis{Ulrich2021,
  author    = {Ulrich, Jakob Johannes},
  title     = {Checkpoint inhibierende anti-TNFRSF Rezeptor Antik{\"o}rper-Fusionsproteine},
  doi       = {10.25972/OPUS-24156},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241568},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Es sollten Checkpoint inhibierende anti-TNFRSF Rezeptor Antik{\"o}rper-Fusionsproteine hergestellt und charakterisiert werden. Die agonistische Aktivit{\"a}t TNFR-spezifischer Antik{\"o}rper wird maßgeblich durch eine Immobilisation {\"u}ber Fcγ-Rezeptoren beeinflusst. In dieser Arbeit erfolgte die Immobilisation der Antik{\"o}rper-Fusionsproteine {\"u}ber den PD-L1. In funktionellen Assays konnte eine Aktivit{\"a}tssteigerung der TNFR-spezifischen Dom{\"a}nen mittels PD-L1 vermittelter Immobilisation gezeigt werden.},
  subject      = {Monoklonaler Antik{\"o}rper},
  language  = {de}
}
@phdthesis{Ulrich2015,
  author    = {Ulrich, Anne-Kathrin},
  title     = {Longitudinale monozentrische klinische Evaluation zum therapeutischen Drug Monitoring von Posaconazol unter besonderer Ber{\"u}cksichtigung spezifischer Interaktionen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118763},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {Die Prognose von h{\"a}matologischen und onkologischen Systemerkrankungen wird dank immer komplexerer und intensiverer Therapien zunehmend besser. Im Zuge dessen spielen Infektionskomplikationen und insbesondere systemische Mykosen, eine immer gr{\"o}ßere Rolle. Die Zahl der antimykotischen Wirkstoffe ist begrenzt. Die zunehmenden Resistenzen verschlechtern die Situation zus{\"a}tzlich. Mit der Einf{\"u}hrung von Posaconazol, einem Wirkstoff aus der Gruppe der Triazole, steht ein Pr{\"a}parat mit sehr breitem antimykotischem Wirkspektrum zur Verf{\"u}gung. Entsprechend der Daten aus einer therapeutischen Studie sind ausreichend hohe Medikamentenspiegel zur Erzielung einer klinischen Effektivit{\"a}t erforderlich. Dieses Triazol wird im Gegensatz zu anderen und insbesondere zu Voriconazol nicht {\"u}ber Cytochrom P450 metabolisiert. Es ist jedoch ein Substrat f{\"u}r die Uridindiphosphatglucuronosyltransferase und unterliegt hier ebenso relevanten Interaktionen mit anderen Medikamenten. Diese bestehen zumeist in Ver{\"a}nderungen der Aktivit{\"a}t der abbauenden Enzyme sowohl durch Induktion wie auch durch Inhibition. Zudem zeichnet sich dieses Triazol besonders als orale Suspension durch eine eingeschr{\"a}nkte Resorption aus. Diese ist unter anderem abh{\"a}ngig von der Magens{\"a}ure, einer begleitenden Nahrungsaufnahme der Dosisintervalle und ist limitiert. So konnten durch eine Dosissteigerung {\"u}ber 800 mg am Tag keine h{\"o}heren Serumkonzentrationen erzielt werden. Daher erscheint die therapeutische Spiegelbestimmung von Posaconazol zumindest bei Verwendung der Suspension sehr sinnvoll. In dieser Arbeit wurden f{\"u}r Posaconazol patientenbezogene Einflussfaktoren und spezifische Ver{\"a}nderungen des Serumspiegels durch verschiedene Komedikationen untersucht. Die Daten stammen aus einer W{\"u}rzburger Patientenkohorte, bestehend aus {\"u}berwiegend h{\"a}matologischen Patienten, die eine antimykotische Therapie oder Prophylaxe von Januar 2006 bis M{\"a}rz 2008 in station{\"a}rer oder ambulanter Behandlung in der Medizinischen Klinik und Poliklinik II der Universit{\"a}tsklinik W{\"u}rzburg erhalten haben. Es konnte gezeigt werden, dass die Posaconzolspiegel unabh{\"a}ngig von Alter und Geschlecht der Patienten sind. Im Gegensatz zu anderen Arbeiten konnten wir einen kontinuierlichen Anstieg der Serumspiegel bei langer Posaconazoleinnahme nachweisen. Zudem konnte in dieser Arbeit erstmals ein Anstieg der Posaconazolkonzentrationen bei Patienten mit h{\"o}herem BMI gezeigt werden. Von unseren untersuchten Laborparametern zeigte sich bei erh{\"o}hten Posaconazolspiegeln eine signifikante Erh{\"o}hung der GPT. Die anderen Transaminasen und Cholestaseparameter zeigten in der Korrelation mit dem Posaconazolspiegel keine signifikanten {\"A}nderungen. Bez{\"u}glich der Nierenretentionsparameter zeigte sich eine signifikante Erniedrigung der GFR bei h{\"o}heren Posaconazolspiegeln. Dies gilt entsprechend gegenl{\"a}ufig f{\"u}r die Kreatininwerte. Auf Grund der Plasmaeiweißbindung von Posaconazol stiegen die Spiegel mit h{\"o}herem Albumin und Gesamteiweiß signifikant an. Von unseren beobachteten Komedikationen zeigte sich eine signifikante Erniedrigung des Posaconazolserumspiegels bei gleichzeitiger Gabe von Pantoprazol. Ciclosporin und Mycophenolat-Mofetil erh{\"o}hten den Posaconazolspiegel signifikant. Bei den Patienten, die Lorazepam erhielten, zeigte sich ein Trend zu erniedrigten Posaconazolspiegeln. F{\"u}r Temazepam zeigten sich einmalig signifikant erh{\"o}hte Posaconazolspiegel. Es ist davon auszugehen, dass die Posaconazolserumspiegel in jedem Fall durch die gleichzeitige Gabe dieser Benzodiazepine ver{\"a}ndert werden k{\"o}nnen. Weitere Untersuchungen hierzu erfolgten bereits und sind erforderlich. Bedingt durch diese Ergebnisse ist ein Therapeutisches Drug Monitoring besonders bei Patienten mit zahlreicher Komedikation dringend zu empfehlen, da potentielle Interaktionen die Bioverf{\"u}gbarkeit von Posaconazol nicht nur signifikant, sondern auch in einem relevanten Bereich ver{\"a}ndern k{\"o}nnen.},
  subject      = {Antimykotikum},
  language  = {de}
}
@phdthesis{Ullmann2023,
  author    = {Ullmann, Monika Anna},
  title     = {Clostridioides difficile Infektionen im Klinikum Aschaffenburg-Alzenau - Retrospektive Analyse des Zeitraums 01/2013-05/2015 -},
  doi       = {10.25972/OPUS-32808},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328085},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Die CDI ist weltweit die h{\"a}ufigste Ursache der antibiotikaassoziierten nosokomialen Diarrhoe. Sie geht mit steigender Inzidenz, Hospitalisierung und hohen Behandlungskosten in Milliardenh{\"o}he einher. Auch im ambulanten Sektor werden steigende Infektionszahlen gemeldet, die nicht nur ein Problem f{\"u}r die Krankenh{\"a}user, sondern auch f{\"u}r die Pflegeeinrichtungen darstellen. Ziel dieser Arbeit war es, retrospektiv die CDI-F{\"a}lle des Klinikums Aschaffenburg-Alzenau (ausgenommen Kinderklinik) im Zeitraum 01.01.2013 - 25.05.2015 zu erfassen und die antibiotische Initialtherapie zu ermitteln. F{\"u}r die Diagnose einer CDI wurde ein positiver Toxinnachweis in der Stuhlkultur vorausgesetzt. Im weiteren Fokus standen die Rezidivh{\"a}ufigkeit, die antibiotische Folgetherapie, die Komplikationen bis hin zu den Todesursachen sowie Pr{\"a}ventionsmaßnahmen. Im o.g. Zeitraum waren 299 Patienten und Patientinnen mit einer CDI hospitalisiert. Das mittlere Alter lag bei 73,8 Jahren. Es handelte sich in der Mehrzahl um multimorbide und immunsupprimierte Patienten und Patientinnen. 61\% waren antibiotisch vorbehandelt. Am h{\"a}ufigsten verwendet wurden Breitbandpenicilline (36\%), Cephalosporine der 3. Generation (12\%) und Fluorchinolone (10\%). {\"U}ber 1/3 der Patienten und Patientinnen wurde mit Mehrfachkombinationen behandelt und bei 2\% war eine zytostatische Behandlung vorausgegangen. In der Initialtherapie der CDI kam bei fast der H{\"a}lfte Erkrankten (47\%) Metronidazol zur Anwendung. Die Rezidivrate lag bei 20\%, Mehrfachrezidive traten bei 5,7\% auf. Die antibiotische Folgetherapie der CDI erfolgte bei 39\% der Patienten und Patientinnen mit Vancomycin oder Fidaxomicin entsprechend den damals geltenden Empfehlungen leitlinienkonform. Rund ¼ aller Erkrankten verstarben, davon 17\% CDI-assoziiert. Der f{\"a}kale Stuhltransfer, der ab dem 2. Rezidiv empfohlen wird, und die Genotypisierung bei Mehrfachrezidiven wurde in keinem Fall durchgef{\"u}hrt. 2021 wurde die CDI-Behandlungsleitlinie der ESCMID aktualisiert. Statt dem Einsatz von Metronidazol werden nun Fidaxomicin oder Vancomycin, in Rezidivsituationen die Standardantibiose um den Antik{\"o}rper Bezlotoxumab erg{\"a}nzt. 06/2023 erschien die Konsultationsfassung der S2k-Leitlinie "Gastrointestinale Infektionen und Morbus Whipple" der DGVS. Die Empfehlungen gleichen sich. Es kann festgehalten werden, dass die CDI auch im Klinikum Aschaffenburg-Alzenau ein ernstes Problem darstellt, das Pr{\"a}ventionsmaßnahmen bedarf. Die Rezidiv- und Todesraten sind hoch. In dieser Arbeit konnte best{\"a}tigt werden, dass der unbedachte Einsatz von Antibiotika ein wichtiger Hauptrisikofaktor f{\"u}r die Entstehung einer CDI ist. Daher sollte die Indikation f{\"u}r eine antibiotische Therapie streng gestellt werden. Die Daten zeigen ferner, dass die Umsetzung aktueller Leitlinienempfehlungen nicht oder zeitlich verz{\"o}gert erfolgte. Seit der Etablierung und Umsetzung des ABS 2017 am Klinikum Aschaffenburg-Alzenau konnte ein R{\"u}ckgang der CDI um 21\% verzeichnet werden. Ein ABS ist eine M{\"o}glichkeit die konsequente Anwendung aktueller Empfehlungen im klinischen Alltag umzusetzen und so zu einer h{\"o}heren Erfolgsrate der Behandlung und einer niedrigeren Rezidivrate beizutragen. Die Umsetzung einer gezielten fr{\"u}hen Diagnostik, Schutz- und Isoliermaßnahmen, Surveillance und regelm{\"a}ßige Fort- und Weiterbildung der Mitarbeiter*innen sind weitere wichtige Bausteine, die zur Pr{\"a}vention der CDI beitragen.},
  subject      = {Clostridium-difficile-Infektion},
  language  = {de}
}
@article{UllmannSchmidtHieberBertzetal.2016,
  author    = {Ullmann, Andrew J. and Schmidt-Hieber, Martin and Bertz, Hartmut and Heinz, Werner J. and Kiehl, Michael and Kr{\"u}ger, William and Mousset, Sabine and Neuburger, Stefan and Neumann, Silke and Penack, Olaf and Silling, Gerda and Vehreschild, J{\"o}rg Janne and Einsele, Hermann and Maschmeyer, Georg},
  title     = {Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016},
  series = {Annals of Hematology},
  volume    = {95},
  journal   = {Annals of Hematology},
  number    = {9},
  organization    = {Infectious Diseases Working Party of the German Society for Hematology and Medical Oncology (AGIHO/DGHO) and the DAG-KBT (German Working Group for Blood and Marrow Transplantation)},
  doi       = {10.1007/s00277-016-2711-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187587},
  pages     = {1435-1455},
  year      = {2016},
  abstract  = {Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria.},
  language  = {en}
}
@article{TsamadouFuerstVucinicetal.2017,
  author    = {Tsamadou, Chrysanthi and F{\"u}rst, Daniel and Vucinic, Vladan and Bunjes, Donald and Neuchel, Christine and Mytilineos, Daphne and Gramatzki, Martin and Arnold, Renate and Wagner, Eva Maria and Einsele, Hermann and M{\"u}ller, Carlheinz and Schrezenmeier, Hubert and Mytilineos, Joannis},
  title     = {Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients},
  series = {Haematologica},
  volume    = {102},
  journal   = {Haematologica},
  number    = {11},
  doi       = {10.3324/haematol.2017.169805},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173325},
  pages     = {1947-1955},
  year      = {2017},
  abstract  = {The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53\% vs. 38\%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95\%=0.48-0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50\% vs. 18\%, P=0.005; HR=0.40, CI 95\%=0.22-0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post-transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.},
  language  = {en}
}
@article{TrinksReinhardDrobnyetal.2021,
  author    = {Trinks, Nora and Reinhard, Sebastian and Drobny, Matthias and Heilig, Linda and L{\"o}ffler, J{\"u}rgen and Sauer, Markus and Terpitz, Ulrich},
  title     = {Subdiffraction-resolution fluorescence imaging of immunological synapse formation between NK cells and A. fumigatus by expansion microscopy},
  series = {Communications Biology},
  volume    = {4},
  journal   = {Communications Biology},
  number    = {1},
  doi       = {10.1038/s42003-021-02669-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264996},
  year      = {2021},
  abstract  = {Expansion microscopy (ExM) enables super-resolution fluorescence imaging on standard microscopes by physical expansion of the sample. However, the investigation of interactions between different organisms such as mammalian and fungal cells by ExM remains challenging because different cell types require different expansion protocols to ensure identical, ideally isotropic expansion of both partners. Here, we introduce an ExM method that enables super-resolved visualization of the interaction between NK cells and Aspergillus fumigatus hyphae. 4-fold expansion in combination with confocal fluorescence imaging allows us to resolve details of cytoskeleton rearrangement as well as NK cells' lytic granules triggered by contact with an RFP-expressing A. fumigatus strain. In particular, subdiffraction-resolution images show polarized degranulation upon contact formation and the presence of LAMP1 surrounding perforin at the NK cell-surface post degranulation. Our data demonstrate that optimized ExM protocols enable the investigation of immunological synapse formation between two different species with so far unmatched spatial resolution.},
  language  = {en}
}
@phdthesis{Trebing2014,
  author    = {Trebing, Johannes},
  title     = {CD70-abh{\"a}ngige und spezifische Aktivierung von TRAILR1 oder TRAILR2 durch scFv:CD70-TRAIL-Mutanten},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111592},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Das Ziel dieser Arbeit bestand darin, den T-Zell-inhibierenden Effekt eines CD70-blockierenden Antik{\"o}rpers mit einer Fc-unabh{\"a}ngigen Zelltod-induzierenden Aktivit{\"a}t auf CD70-exprimierende Tumoren zu kombinieren. Dazu wurden Fusionsproteine hergestellt und untersucht, die aus einer CD70-bindenden scFv-Dom{\"a}ne sowie aus einer TRAIL-Dom{\"a}ne bestehen. Der CD70-spezifische monoklonale Antik{\"o}rper lαhCD70 sowie der beretis bekannte hCD70-spezifische Antik{\"o}rper 1F6 blockieren mit hoher Effizienz die CD27/CD70-Interaktion von CD70-exprimierenden Zelllinien (Mino, OVCAR-3, U-266) und inhibieren dadurch die Induktion der IL8-Produktion durch diese Zellen in kokultivierten HT1080-CD27-Zellen. IL8 wird durch den klassischen NFκB-Signalweg reguliert und ist f{\"u}r den pro-angiogenetischen Effekt von entscheidender Bedeutung (Abb. 2, 3). Mit Hilfe zellul{\"a}rer Gleichgewichtsbindungsstudien mit mono- und trimeren scFv:lαhCD70-GpL-Fusionsproteinen (Abb. 4) auf Mino- und OVCAR-3-Zellen konnte gezeigt werden, dass die Trimerisierung in beiden Zelllinien zu einer Steigerung der apparenten Affinit{\"a}t der scFv:lαhCD70-CD70 Interaktion f{\"u}hrt und damit einen Effekt auf die CD70-Belegung hat (Abb. 5). F{\"u}r die Konstruktion der Fusionsproteine wurde sowohl Wildtyp-TRAIL als auch TRAIL-Mutanten mit Pr{\"a}ferenz f{\"u}r den TRAILR1 oder TRAILR2 verwendet. Die TRAILR-Pr{\"a}ferenz der verwendeten TRAIL-Mutanten (wt, mutR1, mutR2) wurde nicht nur in zellul{\"a}ren GpL-Bindungsstudien (Abb. 7) sondern zus{\"a}tzlich auch in TRAILR Immobilisierungsexperimenten (Abb. 8) bewiesen. Hier zeigte sich, dass bei TRAILR1 keine Interaktion mit TRAILmutR2, so wie bei TRAILR2 keine signifikante Bindung mit TRAILmutR1 erfolgte. Nur der TRAIL-Wildtyp band signifikant an beide TRAIL-Todesrezeptoren. Vitalit{\"a}tsexperimente (Abb. 10) und Western-Blot Analysen der Caspase-Prozessierung (Abb. 11) best{\"a}tigten die starke TRAILR1- bzw. TRAILR2-Spezifit{\"a}t der TRAILmutR1- und TRAILmutR2-Varianten. Im Gegensatz zu den unvernetzten l{\"o}slichen TRAIL-Trimeren waren nur die quervernetzten TRAIL-TNC-Varianten in der Lage, eine signifikante Apoptose-Signalkaskade bei relativ geringen Konzentrationen zu induzieren. Die toxischen ED50-Konzentrationen der unoligomerisierten TRAIL-Formen lagen um einen Faktor 100 h{\"o}her als die der oligomerisierten Varianten. Zusammenfassend zeigten die ED50-Werte der Zytotoxizit{\"a}tsexperimente von M2-oligomerisierten zu -unoligomerisierten trimeren TRAIL-Varianten bei allen Fusionskonstrukten und Zelllinien eine eindeutige Verst{\"a}rkung der Apoptoseinduktion durch die M2-Quervernetzung. Bei Jurkat- und Mino-Zellen konnte gr{\"o}ßtenteils erst nach Oligomerisierung {\"u}berhaupt eine Bioaktivit{\"a}t bzw. eine Zelltodinduktion beobachtet werden. In OVCAR-3-Zellen zeigte sich eine 100-1000 fache apoptotische Verst{\"a}rkung durch die Oligomerisierung (Abb. 10). Weiterhin zeigten Zytotoxizit{\"a}tsexperimente, dass sich durch Bindung an hCD70 das Ausmaß der Toxizit{\"a}t der Fusionsproteine auf allen CD70-exprimierenden Zelllinien 10-100x verst{\"a}rkte (Abb. 15, 17). In {\"U}bereinstimmung mit der verst{\"a}rkten TRAIL-Todesrezeptor-Aktivierung durch die CD70-Bindung der scFv-TRAIL-Fusionsproteine, konnte durch eine CD70-Blockade die Caspase-8 Aktivierung und die Prozessierung von Caspase-3 signifikant unterbunden werden (Abb. 18). Die Trimerisierung des scFv:lαhCD70-Antik{\"o}rpers f{\"u}hrte zu keiner Apoptose und beeinflußte auch nicht die Aktivit{\"a}t von TRAIL (Abb. 19) was belegt, dass die beobachteten Effekte auf einer st{\"a}rkeren TRAIL-induzierten Apoptose nach CD70-Bindung der Konstrukte beruhen muss. Die Fusionsproteine beseitigen somit nachweislich einerseits das Problem der limitierenden Aktivit{\"a}t von l{\"o}slichem TRAIL {\"u}ber ihre Verankerung an CD70 (Abb. 15-20) und anderseits die potentielle unerw{\"u}nschte CD70-vermittelte protumorale CD27-Stimulation (Abb. 3). Dar{\"u}ber hinaus k{\"o}nnten die TRAILR-spezifischen TRAIL-Mutanten helfen, Nebeneffekte zu reduzieren, die prim{\"a}r durch den jeweils anderen TRAIL-Todesrezeptor vermittelt werden. Jedoch sind weiter Forschungen insbesondere in vivo Experimente notwendig, um Aussagen {\"u}ber Funktionalit{\"a}t, Halbwertszeiten, sowie Effektivit{\"a}t und Vertr{\"a}glichkeit treffen zu k{\"o}nnen.},
  subject      = {Apoptosis},
  language  = {de}
}
@article{ToppvanMeertenHouotetal.2021,
  author    = {Topp, Max S. and van Meerten, Tom and Houot, Roch and Minnema, Monique C. and Bouabdallah, Krimo and Lugtenburg, Pieternella J. and Thieblemont, Catherine and Wermke, Martin and Song, Kevin W. and Avivi, Irit and Kuruvilla, John and D{\"u}hrsen, Ulrich and Zheng, Yan and Vardhanabhuti, Saran and Dong, Jinghui and Bot, Adrian and Rossi, John M. and Plaks, Vicki and Sherman, Marika and Kim, Jenny J. and Kerber, Anne and Kersten, Marie Jos{\´e}},
  title     = {Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma},
  series = {British Journal of Haematology},
  volume    = {195},
  journal   = {British Journal of Haematology},
  number    = {3},
  doi       = {10.1111/bjh.17673},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258342},
  pages     = {388-398},
  year      = {2021},
  abstract  = {Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93\% and 61\%, respectively (grade ≥ 3, 2\% and 17\%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73\% and 51\%, respectively, and 51\% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.},
  language  = {en}
}
@article{TonyBurmesterSchulzeKoopsetal.2011,
  author    = {Tony, Hans-Peter and Burmester, Gerd and Schulze-Koops, Hendrik and Grunke, Mathias and Henes, Joerg and K{\"o}tter, Ina and Haas, Judith and Unger, Leonore and Lovric, Svjetlana and Haubitz, Marion and Fischer-Betz, Rebecca and Chehab, Gamal and Rubbert-Roth, Andrea and Specker, Christof and Weinerth, Jutta and Holle, Julia and M{\"u}ller-Ladner, Ulf and K{\"o}nig, Ramona and Fiehn, Christoph and Burgwinkel, Philip and Budde, Klemens and S{\"o}rensen, Helmut and Meurer, Michael and Aringer, Martin and Kieseier, Bernd and Erfurt-Berge, Cornelia and Sticherling, Michael and Veelken, Roland and Ziemann, Ulf and Strutz, Frank and von Wussow, Praxis and Meier, Florian MP and Hunzelmann, Nico and Schmidt, Enno and Bergner, Raoul and Schwarting, Andreas and Eming, R{\"u}diger and Schwarz-Eywill, Michael and Wassenberg, Siegfried and Fleck, Martin and Metzler, Claudia and Zettl, Uwe and Westphal, Jens and Heitmann, Stefan and Herzog, Anna L. and Wiendl, Heinz and Jakob, Waltraud and Schmidt, Elvira and Freivogel, Klaus and D{\"o}rner, Thomas and Hertl, Michael and Stadler, Rudolf},
  title     = {Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)},
  series = {Arthritis Research \& Therapy},
  volume    = {13},
  journal   = {Arthritis Research \& Therapy},
  number    = {R75},
  doi       = {10.1186/ar3337},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142856},
  pages     = {1-14},
  year      = {2011},
  abstract  = {Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0\% with systemic lupus erythematosus, 15.7\% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1\% multiple sclerosis and 10.0\% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0\% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3\% of patients showed no response, 45.1\% showed a partial response and 41.6\% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm)},
  language  = {en}
}
@article{ThiemHesbacherKneitzetal.2019,
  author    = {Thiem, Alexander and Hesbacher, Sonja and Kneitz, Hermann and di Primio, Teresa and Heppt, Markus V. and Hermanns, Heike M. and Goebeler, Matthias and Meierjohann, Svenja and Houben, Roland and Schrama, David},
  title     = {IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression},
  series = {Journal of Experimental \& Clinical Cancer Research},
  volume    = {38},
  journal   = {Journal of Experimental \& Clinical Cancer Research},
  doi       = {10.1186/s13046-019-1403-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201016},
  pages     = {397},
  year      = {2019},
  abstract  = {Background Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma. Methods We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway. Results For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression. Conclusions While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.},
  language  = {en}
}
@phdthesis{Theiss2008,
  author    = {Theiß, Regina},
  title     = {Modulation des genetischen Imprint der Immunglobulinrezeptoren durch passagere B- Zelldepletion mit anti-CD20 Antik{\"o}rpern bei Rheumatoider Arthritis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-33545},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Die zentrale Rolle von B- Zellen in der Pathogenese und Therapie von Autoimmunerkrankungen hat in den letzten Jahren zu unterschiedlichen therapeutischen Ans{\"a}tzen gef{\"u}hrt, B- Zellen direkt oder indirekt zu targetieren. Der bisher effektivste Ansatz stellt der monoklonale anti- CD20 Antik{\"o}rper Rituximab dar. Nach Gabe von Rituximab kommt es zu einer passageren, in der Regel sechs bis neun Monate anhaltenden peripheren B- Zelldepletion. Die anti- CD20 vermittelte B- Zelldepletion stellt zwar ein vielversprechendes Therapieverfahren in der Behandlung der Rheumatoiden Arthritis dar, derzeit ist noch wenig {\"u}ber das Regenerationsverhalten von B- Zellen nach Therapie mit Rituximab bekannt. Daher wurde in dieser Arbeit die B-Zellrepopulation insbesondere hinsichtlich der Modulation des Mutationsmusters des B- Zellrezeptors untersucht. Dazu wurde die VH4- Familie des Immunglobulinrezeptors- prospektiv vor und nach anti- CD20 vermittelter B- Zelldepletion analysiert. Bei drei Patienten (A-C) wurden die Ig-VH4 Gene aus genomischer DNA peripherer B- Zellen amplifiziert, subkloniert und sequenziert. Die Analyse erfolgte zu drei verschiedenen Zeitpunkten: Vor Therapie, in der fr{\"u}hen Regenerationsphase mit einem B- Zellanteil von 1\% bis 1,3\% im peripheren Blut und in der sp{\"a}ten Regenerationsphase, zwei bis drei Monate nach der fr{\"u}hen Regenerationsphase Mini Gene wie VH4-34 und VH4-39, die in Verbindung mit Autoimmunit{\"a}t stehen, waren vor Einleitung der Therapie relativ {\"u}berexprimiert. Die Behandlung mit Rituximab f{\"u}hrte bei allen drei Patienten zu einer Ver{\"a}nderung des Repertoires der regenerierenden B- Zellen mit einer reduzierten Benutzung der VH4-39 Gene, außerdem bei Patient A zus{\"a}tzlich der VH4-34 Gene. Tief greifende Ver{\"a}nderungen fanden sich w{\"a}hrend der fr{\"u}hen Regenerationsphase durch den Nachweis einer rezirkulierenden Population hochmutierter B- Zellen, die in einer durchgef{\"u}hrten Immunoph{\"a}notypisierung mit spezifischen Oberfl{\"a}chenmarkdern als Plasmazellen identifiziert wurden. Da Plasmazellen kein CD20 Molek{\"u}l exprimieren, werden sie durch eine anti-CD20 vermittelte Therapie nicht direkt eliminiert. Sie zirkulieren w{\"a}hrend der Phase der B- Zelldepletion aber auch nicht im peripheren Blut. Interessanterweise sind sie in der fr{\"u}hen Regenerationsphase in der Peripherie als erste mit hohem relativem Anteil nachweisbar. Daher wurde untersucht, ob auch Plasmazellen durch die Therapie moduliert werden, obwohl sie durch Rituximab nicht direkt targetiert werden. Hierf{\"u}r wurden die Sequenzen mit hochmutiertem Ig- Rezeptor (>9 Mutationen/Sequenz) im Verlauf einer detaillierten Analyse zugef{\"u}hrt. Dabei wurde insbesondere das Mutationsmuster in RGYW/WRCY Hotspot Motiven und in den CDR- Regionen untersucht. Die Analyse der Mutationsh{\"a}ufigkeit in RGYW/WRCY Hotspot Motiven erlaubt eine Absch{\"a}tzung, in wieweit die somatische Hypermutation der B- Zellen durch T- Zell abh{\"a}ngige Differenzierung erfolgte. Die als Plasmazellen identifizierten hochmutierten Sequenzen zeigten vor der Therapie Charakteristika einer aktiven Erkrankung mit einem verminderten Targeting der RGYW/WRCY Motive. Dagegen zeigte sich in den rezirkulierenden Plasmazellen w{\"a}hrend der fr{\"u}hen Regenerationsphase ein zunehmendes Targeting der RGYW/WRCY Motive. Dies spricht f{\"u}r einen Repertoire Shift zu mehr T- Zell abh{\"a}ngigen B- Zell Mutationen. Ein Zustand, wie er bei Gesunden beobachtet wird. Um die Hypothese einer Rituximab- induzierten Modulation des Plasmazellkompartimentes weiter zu untermauern, wurde der R/S Quotient, d.h. das Verh{\"a}ltnis von Silent zu Replacement Mutationen in den hypervariablen Regionen (CDRs) der hochmutierten Plasmazell-Ig Sequenzen bestimmt. Interessanterweise fanden sich in der Regenerationsphase signifikant erh{\"o}hte R/S Ratios in den rezirkulierenden Plasmazellen.. Die signifikante Zunahme an Replacement Mutationen in den CDR- Regionen, welche sich in einer Zunahme des R/S Verh{\"a}ltnisses wiederspiegelt, kann als Entwicklung des Ig- Repertoires durch positive Antigenselektion interpretiert werden und weist somit eine Rituximab- induzierte Ver{\"a}nderung auf, wie man sie sonst bei gesunden Individuen findet. Zusammenfassend zeigt unsere Studie, dass die transiente anti- CD20 vermittelte B- Zelldepletion auch zu einer indirekten Modulation des Plasmazellkompartimentes f{\"u}hrt. Insbesondere werden postrekombinatorische Imprints des B- Zell Rezeptors, wie somatische Hypermutation und Antigen Selektion, ver{\"a}ndert, die mit hoher Wahrscheinlichkeit f{\"u}r die Entstehung von Autoimmunit{\"a}t bei der Rheumatoiden Arthritis eine Rolle spielen. Zus{\"a}tzlich kann die Modulation des genetischen Imprints der Ig Rezeptoren bei der Rheumatoiden Arthritis eventuell als m{\"o}glicher Biomarker entwickelt werden, um ein Ansprechen auf die Therapie vorherzusagen. Dies bedarf weiterer Untersuchungen, um tiefer greifende Einblicke in Prozesse zu erlangen, die durch zuk{\"u}nftige Therapien beeinflussbar werden.},
  subject      = {Rheumatoide Arthritis},
  language  = {de}
}
@article{TerposKleberEngelhardtetal.2015,
  author    = {Terpos, Evangelos and Kleber, Martina and Engelhardt, Monika and Zweegman, Sonja and Gay, Francesca and Kastritis, Efstathios and van de Donk, Niels W. C. J. and Bruno, Benedetto and Sezer, Orhan and Broijl, Annemiek and Bringhen, Sara and Beksac, Meral and Larocca, Alessandra and Hajek, Roman and Musto, Pellegrino and Johnsen, Hans Erik and Morabito, Fortunato and Ludwig, Heinz and Cavo, Michele and Einsele, Hermann and Sonneveld, Pieter and Dimopoulos, Meletios A. and Palumbo, Antonio},
  title     = {European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications},
  series = {Haematologica},
  volume    = {100},
  journal   = {Haematologica},
  number    = {10},
  doi       = {10.3324/haematol.2014.117176},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141913},
  pages     = {1254 -- 1266},
  year      = {2015},
  abstract  = {The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin < 10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).},
  language  = {en}
}
@article{TappeLauruschkatStrobeletal.2022,
  author    = {Tappe, Beeke and Lauruschkat, Chris D. and Strobel, Lea and Pantale{\´o}n Garc{\´i}a, Jezreel and Kurzai, Oliver and Rebhan, Silke and Kraus, Sabrina and Pfeuffer-Jovic, Elena and Bussemer, Lydia and Possler, Lotte and Held, Matthias and H{\"u}nniger, Kerstin and Kniemeyer, Olaf and Sch{\"a}uble, Sascha and Brakhage, Axel A. and Panagiotou, Gianni and White, P. Lewis and Einsele, Hermann and L{\"o}ffler, J{\"u}rgen and Wurster, Sebastian},
  title     = {COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds},
  series = {Frontiers in Immunology},
  volume    = {13},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2022.954985},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283558},
  year      = {2022},
  abstract  = {Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.},
  language  = {en}
}
@article{SanchezMaldonadoMonizDiezterHorstetal.2020,
  author    = {S{\´a}nchez-Maldonado, Jose Manuel and Mo{\~n}iz-D{\´i}ez, Ana and ter Horst, Rob and Campa, Daniele and Cabrera-Serrano, Antonio Jos{\´e} and Mart{\´i}nez-Bueno, Manuel and Garrido-Collado, Mar{\´i}a del Pilar and Hern{\´a}ndez-Mohedo, Francisca and Fern{\´a}ndez-Puerta, Laura and L{\´o}pez-Nevot, Miguel {\´A}ngel and Cunha, Cristina and Gonz{\´a}lez-Sierra, Pedro Antonio and Springer, Jan and Lackner, Michaela and Alcazar-Fuoli, Laura and Fianchi, Luana and Aguado, Jos{\´e} Mar{\´i}a and Pagano, Livio and L{\´o}pez-Fern{\´a}ndez, Elisa and Clavero, Esther and Potenza, Leonardo and Luppi, Mario and Moratalla, Lucia and Solano, Carlos and Sampedro, Antonio and Cuenca-Estrella, Manuel and Lass-Fl{\"o}rl, Cornelia and Canzian, Federico and Loeffler, Juergen and Li, Yang and Einsele, Hermann and Netea, Mihai G. and V{\´a}zquez, Lourdes and Carvalho, Agostinho and Jurado, Manuel and Sainz, Juan},
  title     = {Polymorphisms within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis: a two-stage case control study in the context of the aspBIOmics consortium},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {1},
  issn      = {2309-608X},
  doi       = {10.3390/jof7010004},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220107},
  year      = {2020},
  abstract  = {Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4\(_{rs7526628T/T}\) genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4\(_{rs7526628T}\) allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2\(_{rs12137965G}\) allele increased the risk of IA by 60\% (p = 0.0017), whereas each copy of the MAPKAPK2\(_{rs17013271T}\) allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2\(_{rs12137965G}\) allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2\(_{rs17013271T}\) allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.},
  language  = {en}
}
@phdthesis{Sutor2016,
  author    = {Sutor, Dominic Christian},
  title     = {Induktion von FGF19 \& FXR in humanen HT-29 Zellen unter Verwendung der nukle{\"a}ren Agonisten Vitamin D3, Vitamin A \& CDCA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141152},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2016},
  abstract  = {Ziel dieser Arbeit ist es, weitere Einblicke in die Aktivierung von FGF19 und FXR durch diverse nukle{\"a}re Agonisten und deren spezifischer Rezeptoren zu gewinnen. Hierbei soll im humanen Zellmodell versucht und mittels DNA-Analyse untersucht werden, welche messbaren molekularbiologischen Auswirkungen eine Behandlung mit unterschiedlichen Substanzen in variierenden Konzentrationen bewirkt. Genauer soll betrachtet werden, ob sich Vitamin A und Vitamin D als Induktoren von FGF19 in menschlichen Darmzelllinien eignen, da dies bereits im Mausmodel demonstriert werden konnte. Dieser initialen Vermutung folgend, sollen auch die m{\"o}glichen Wechselwirkungen und Synergismen untersucht werden - welche Mechanismen liegen diese zu Grunde und {\"u}ber welche molekularen Signalwege werden dies vermuteten Effekte vermittelt. Hierdurch soll ein besseres Verst{\"a}ndnis f{\"u}r die Rezeptor und Agonistenabh{\"a}ngigen Abl{\"a}ufe erm{\"o}glicht werden, um m{\"o}gliche R{\"u}ckschl{\"u}sse auf weitere Funktionen bereits bekannter Vertreter zu erlauben. Aufgrund der bereits oben beschriebenen Tiermodelle und der daraus gewonnenen Einsichten w{\"u}rde sich durch ein noch besseres Verst{\"a}ndnis des FGF15/19 und des Farnesoid X Rezeptors in menschlichen Zellen, auf eine zuk{\"u}nftige Anwendung in analytischen und/oder therapeutischen Bereichen hoffen lassen. Diese Arbeit soll sich deshalb den Fragen widmen, ob eine FGF19 Induktion in humanen Darmzellen durch die nukle{\"a}ren Agonisten VD3, 9-cis RA und CDCA, {\"a}hnlich dem Mausmodel, m{\"o}glich ist und welche Faktoren dabei Einfl{\"u}sse auf die beschriebenen Effekte haben.},
  subject      = {Fibroblastenwachstumsfaktor},
  language  = {de}
}
@article{SudarevicTroyaFuchsetal.2023,
  author    = {Sudarevic, Boban and Troya, Joel and Fuchs, Karl-Hermann and Hann, Alexander and Vereczkei, Andras and Meining, Alexander},
  title     = {Design and development of a flexible 3D-printed endoscopic grasping instrument},
  series = {Applied Sciences},
  volume    = {13},
  journal   = {Applied Sciences},
  number    = {9},
  issn      = {2076-3417},
  doi       = {10.3390/app13095656},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319186},
  year      = {2023},
  abstract  = {(1) Background: Interventional endoscopic procedures are growing more popular, requiring innovative instruments and novel techniques. Three-dimensional printing has demonstrated great potential for the rapid development of prototypes that can be used for the early assessment of various concepts. In this work, we present the development of a flexible endoscopic instrument and explore its potential benefits. (2) Methods: The properties of the instrument, such as its maneuverability, flexibility, and bending force, were evaluated in a series of bench tests. Additionally, the effectiveness of the instrument was evaluated in an ex vivo porcine model by medical experts, who graded its properties and performance. Furthermore, the time necessary to complete various interventional endoscopic tasks was recorded. (3) Results: The instrument achieved bending angles of ±216° while achieving a bending force of 7.85 (±0.53) Newtons. The time needed to reach the operating region was 120 s median, while it took 70 s median to insert an object in a cavity. Furthermore, it took 220 s median to insert the instrument and remove an object from the cavity. (4) Conclusions: This study presents the development of a flexible endoscopic instrument using three-dimensional printing technology and its evaluation. The instrument demonstrated high bending angles and forces, and superior properties compared to the current state of the art. Furthermore, it was able to complete various interventional endoscopic tasks in minimal time, thus potentially leading to the improved safety and effectiveness of interventional endoscopic procedures in the future.},
  language  = {en}
}
@phdthesis{Stuehler2010,
  author    = {St{\"u}hler, Claudia},
  title     = {Strategies to prevent graft-versus-host disease and augment anti-fungal immunity in allogeneic hematopoietic stem cell transplant recipients},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-51957},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Allogeneic hematopoietic stem cell transplantation (HSCT) is often the only effective treatment for patients with hematological malignancies, but its curative potential is often limited by the development of acute or chronic graft-versus-host disease (GvHD). Although extensive immunosuppressive therapy is highly efficient in the prevention or treatment of GvHD, it greatly increases the risk for life-threatening opportunistic fungal or viral infections and the recurrence of malignant disease. The possibility to selectively deplete alloreactive T cells from donor grafts prior or after transplantation would greatly diminish the need for immunosuppressive therapy in the transplant recipient and thereby greatly improve its clinical outcome. The molecular chaperone heat shock protein of 90 kDa (Hsp90) has been previously shown to stabilize many signal transduction proteins involved in T lymphocyte activation and proliferation and is furthermore able to exert anti-apoptotic effects in different cell types. The aim of this study was therefore to investigate the possibility to selectively target activated, proliferating T cells in lymphocyte populations by inhibition of Hsp90, without compromising viability and function of non-reactive T cell populations including pathogen-specific T lymphocytes. It could be shown in this work, that activated T cells are indeed more prone to apoptotic cell death in the presence of Hsp90 inhibitors than resting cells and that treatment of mixed lymphocyte cultures with such inhibitors eliminates the proliferation of alloreactive cells. In contrast, T cells remaining in a resting state during inhibitor treatment remain viable and also display functional virus-specific responses after inhibitor removal. These data suggest, that Hsp90 could represent a novel target for selective depletion of alloreactive T cells and that application of Hsp90 inhibitors could be a potential approach to prevent or treat GvHD without impairing pathogen-specific T cell immunity. In the second part of this work, the immune responses to strictly defined antigens of the opportunistic pathogenic fungus Aspergillus fumigatus were characterized. Opportunistic fungal infections are highly prevalent in immunocompromized and immunosuppressed individuals, especially in HSCT recipients suffering from GvDH. Although antifungal treatment is permanently improved, invasive fungal infections are still often fatal. In healthy individuals clinical disease is rare, because innate and adaptive immunity act in conjunction to protect the host. Therefore one possible strategy to prevent and treat life-threatening fungal infections in immunocompromized patients is to improve host resistance by augmenting the antifungal functions of the immune system, for example by vaccination or adoptive transfer of antigen-specific T cells. Based on previous findings, the objective of this dissertation was to identify and characterize distinct immunogenic A. fumigatus antigens that could be used for clinical application like vaccination or ex vivo generation of antigen-specific T cells and to characterize the interaction of this antigen-specific lymphocytes with cells of the innate immune system. First, memory T cell responses to different recombinant A. fumigatus proteins in healthy individuals were evaluated. The majority of tested donors displayed stable CD4+ TH1 responses to the Crf1 protein, whereas responses to the other antigens tested could only be detected in a limited number of donors, qualifying Crf1 as potential candidate antigen for clinical use. It was also possible to identify an immunodominant MHC class II DRB1*04-restricted epitope of Crf1 and to generate T cell clones specific for this epitope. This Crf1-specific T cell clones could be specifically activated by dendritic cells fed with synthetic peptide, recombinant protein or germinating A. fumigatus conidia or outgrown hyphae. Interestingly, these A. fumigatus-specific T cell clones also responded to stimulation with Candida albicans, which likewise causes opportunistic infections in immunocompromized patients and encodes for a glucosyltransferase similar to A. fumigatus Crf1. It was also possible to show that supernatant harvested from activated Crf1-specific T cell cultures was able to significantly increase fungal killing by monocytes. These data indicate that the specified FHT epitope of the A. fumigatus protein Crf1 could be potentially used as antigen for vaccination protocols or for the generation of Aspergillus-specific effector T cells for adoptive transfer.},
  subject      = {Transplantat-Wirt-Reaktion},
  language  = {en}
}
@article{StoelzelMohrKrameretal.2016,
  author    = {St{\"o}lzel, F. and Mohr, B. and Kramer, M. and Oelschl{\"a}gel, U. and Bochtler, T. and Berdel, W. E. and Kaufmann, M. and Baldus, C. D. and Sch{\"a}fer-Eckart, K. and Stuhlmann, R. and Einsele, H. and Krause, S. W. and Serve, H. and H{\"a}nel, M. and Herbst, R. and Neubauer, A. and Sohlbach, K. and Mayer, J. and Middeke, J. M. and Platzbecker, U. and Schaich, M. and Kr{\"a}mer, A. and R{\"o}llig, C. and Schetelig, J. and Bornh{\"a}user, M. and Ehninger, G.},
  title     = {Karyotype complexity and prognosis in acute myeloid leukemia},
  series = {Blood Cancer Journal},
  volume    = {6},
  journal   = {Blood Cancer Journal},
  doi       = {10.1038/bcj.2015.114},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164530},
  pages     = {e386},
  year      = {2016},
  abstract  = {A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with 4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.},
  language  = {en}
}
@article{StrunzVuilleDitBilleFoxetal.2022,
  author    = {Strunz, Patrick-Pascal and Vuille-Dit-Bille, Raphael N. and Fox, Mark R. and Geier, Andreas and Maggiorini, Marco and Gassmann, Max and Fruehauf, Heiko and Lutz, Thomas A. and Goetze, Oliver},
  title     = {Effect of high altitude on human postprandial \(^{13}\)C-octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception},
  series = {Neurogastroenterology and Motility},
  volume    = {34},
  journal   = {Neurogastroenterology and Motility},
  number    = {3},
  doi       = {10.1111/nmo.14225},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259611},
  year      = {2022},
  abstract  = {Objective At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by \(^{13}\)C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate. Methods A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. Statistical analysis: variance analyses, bivariate correlation, and multilinear regression analysis. Results After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). \(^{13}\)CO\(_{2}\) exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated \(^{13}\)CO\(_{2}\)-generation under these conditions. Conclusion Quantification of \(^{13}\)C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. \(^{13}\)C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.},
  language  = {en}
}
@article{StrunzFroehlichGernertetal.2021,
  author    = {Strunz, Patrick-Pascal and Froehlich, Matthias and Gernert, Michael and Schwaneck, Eva Christina and Fleischer, Anna and Pecher, Ann-Christin and Tony, Hans-Peter and Henes, Joerg Christoph and Schmalzing, Marc},
  title     = {Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.723349},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245574},
  year      = {2021},
  abstract  = {Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment for systemic sclerosis (SSc), but it also can cause immunological adverse events (iAEs). Therefore, we aimed to determine the frequency of iAEs [engraftment syndrome (ES) and secondary autoimmune disorder (sAD)] and to identify potential risk factors for their development in a retrospective analysis on 22 patients similarly transplanted due to SSc. While nine patients (41\%) suffered from ESs, seven sADs occurred in six patients (27\%). Patients who developed ES were older in our cohort (52.45 vs. 42.58 years, p = .0433, Cohen's d = 0.86), and cardiac involvement by SSc was associated with development of ES (OR = 40.11, p = .0017). Patients with manifestation of sAD had a higher modified Rodnan skin score (mRSS) reduction after aHSCT (90.50\% vs. 60.00\%, p = .0064, r = .65). Thus, IAEs are common after aHSCT for SSc and can occur in different stages during and after aHSCT with characteristic clinical manifestations. Good cutaneous response after aHSCT might be considered as a risk factor for sAD, and higher age at aHSCT and cardiac involvement might be considered as risk factors for the development of ES.},
  language  = {en}
}
@phdthesis{Strizek2006,
  author    = {Strizek, Brigitte Sabine},
  title     = {Assoziation der renalen Na+,K+-ATPase mit dem ERM-Protein Moesin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-17842},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Die Na+,K+-ATPase ist das wichtigste Na+ und K+ transportierende integrale Membranprotein des menschlichen K{\"o}rpers. Es ist verantwortlich f{\"u}r die Ausbildung eines transmembran{\"a}ren Na+ und K+ Gradienten und die Aufrechterhaltung des Membranpotentials, das f{\"u}r die osmotische Stabilit{\"a}t der Zellen, Erregbarkeit von Nerven- und Muskelzellen und diverse Transportvorg{\"a}nge unerl{\"a}sslich ist. Die Beschr{\"a}nkung der Na+,K+-ATPase auf die basolateralen Zellwandabschnitte, erm{\"o}glichen den gerichteten Transport von NaCl und Wasser durch Epithelien von Darm und Niere. Die polare Verteilung der Na+,K+-ATPase scheint durch die Bindung {\"u}ber Ankyrin an das Spektrinzytoskelett zustande zu kommen. Außer mit Ankyrin konnte eine Assoziation der renalen Na+,K+-ATPase mit Aktin und zwei bis dahin unbekannten Proteinen Pasin 1 und 2 nachgewiesen werden. Ziel dieser Arbeit war es, zu untersuchen, ob es sich bei dem als Pasin 2 benannten Protein um Moesin, ein Mitglied der FERM Familie (Protein 4.1, Ezrin, Radixin, Moesin) handelt. Diese Proteine fungieren als Verbindungselemente zwischen integralen Membranproteinen und dem Aktinzytoskelett. Pasin 2 wurde aus Schweinenieren isoliert und massenspektrometrisch sequenziert. Anschließend wurde die Sequenz mit der von Moesin verglichen und die Identit{\"a}t der beiden Proteine best{\"a}tigt. Aus Schweinenieren isoliertes Pasin 2 reagierte zudem im Immunoblot spezifisch mit anti-Moesin Antik{\"o}rpern und zeigte in der Immunfluoreszenz eine Kolokalisation mit der Na+,K+-ATPase. Anschließend konnte in vitro durch Kosedimentation eine direkte Bindung von rekombinantem Moesin an die Na+,K+-ATPase nachgewiesen werden. Da sich die Bindungsstelle f{\"u}r andere Membranproteine auf dem aminoterminalen Anteil der ERM Proteine befindet, wurde untersucht, ob dies auch f{\"u}r die Na+,K+-ATPase zutrifft. Durch Bindungsstudien mit rekombinanten N-terminalen Moesin konnte dies best{\"a}tigt werden. Dies legt die Vermutung nahe, dass die renale Na+,K+-ATPase neben Ankyrin auch {\"u}ber Moesin mit dem Zytoskelett verbunden ist. Zus{\"a}tzlich zeigte sich, dass die Bindung von Moesin an die Na+,K+-ATPase durch einen Antik{\"o}rper gegen die große zytoplasmatische Dom{\"a}ne der Na+,K+-ATPase verhindert werden kann, was die Moesinbindung an dieser Dom{\"a}ne wahrscheinlich macht. Da sich sowohl die Bindungsstelle f{\"u}r Ankyrin als auch das aktive Zentrum des Enzyms auf dieser Dom{\"a}ne befinden, k{\"o}nnte die Moesinbindung sowohl Einfluss auf die Aktivit{\"a}t als auch auf die Ankyrinbindung der Na+,K+-ATPase aus{\"u}ben, wie auch die Bindung des erythrozyt{\"a}ren Anionenaustauschers (AE1) an Ankyrin durch das Protein 4.1 ver{\"a}ndert werden kann.},
  language  = {de}
}
@article{StringarisSekineKhoderetal.2014,
  author    = {Stringaris, Kate and Sekine, Takuya and Khoder, Ahmad and Alsuliman, Abdullah and Razzaghi, Bonni and Sargeant, Ruhena and Pavlu, Jiri and Brisley, Gill and de Lavallade, Hugues and Sarvaria, Anushruthi and Sarvaria, Anushruthi and Mielke, Stephan and Apperley, Jane F. and Shpall, Elisabeth J. and Barrett, A. John and Rezvani, Katayoun},
  title     = {Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia},
  series = {Haematologica},
  volume    = {99},
  journal   = {Haematologica},
  number    = {5},
  issn      = {1592-8721},
  doi       = {10.3324/haematol.2013.087536},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116550},
  pages     = {836-847},
  year      = {2014},
  abstract  = {The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF-alpha and IFN-gamma production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-alpha production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-alpha and IFN-gamma production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival.},
  language  = {en}
}
@phdthesis{Strifler2018,
  author    = {Strifler, Susanne},
  title     = {Eine sp{\"a}te, dritte Hochdosis-Chemotherapie als wirksame Rezidivbehandlung des fortgeschrittenen multiplen Myeloms},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149373},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Das multiple Myelom muss trotz aller Therapierfolge in den letzten drei Jahrzehnten seit Einf{\"u}hrung der Melphalan-basierten Hochdosistherapie mit autologer Stammzell-Transplantation als eine unheilbare maligne h{\"a}matologische Systemerkrankung angesehen werden. Trotz einer großen Anzahl vielversprechender neuer Therapieoptionen im Bereich von IMiDs, PIs und g{\"a}nzlich neuer immuntherapeutischer Behandlungsans{\"a}tze stellt dabei die Behandlung eines Myelom-Patienten im sp{\"a}ten Krankheitsrezidiv nach Versagen von Lenalidomid und Bortezomib eine therapeutische Herausforderung dar. Daneben erweisen sich dabei im klinischen Alltag mit zunehmender Zahl an Vortherapien insbesondere auch Behandlungs-assoziierte Toxizit{\"a}ten als den Behandlungserfolg limitierende Faktoren. Diese retrospektive Analyse zeigt, dass eine dritte Melphalan-Hochdosistherapie mit anschließender autologer Stammzelltransplantation in dieser Situation eine wirkungsvolle Therapieoption darstellt, die zum einen ein {\"u}berzeugendes Ansprechen (ORR 59 \%) bewirkt, und {\"u}ber diese unmittelbare Wirksamkeit hinaus zu einem Zugewinn Progressions-freier {\"U}berlebenszeit von im Mittel 9 Monaten f{\"u}hrt. Zudem kann insbesondere auch die neuerliche autologe Transplantation durch eine Verbesserung der h{\"a}ufig Therapie-assoziiert ersch{\"o}pften h{\"a}matopoetischen Funktion dazu beitragen, dass Patienten im nahezu unweigerlich auftretenden neuerlichen Rezidiv durch bessere Therapieadh{\"a}renz und h{\"o}here Therapieintensit{\"a}t maximal von Folgetherapien profitieren. Dieser Effekt spiegelt sich in einem gemessen an einem trotz intensiv vortherapierter Patienten langen mittleren {\"U}berlebens von 26 Monaten wider. Trotz hoher Therapieeffektivit{\"a}t zeigt sich dabei ein g{\"u}nstiges Sicherheitsprofil mit einer Therapie-assoziierten Mortalit{\"a}t von 4,9 \%. Daneben konnte diese Arbeit in einer großen Kohorte best{\"a}tigen, dass eine lange Kryokonservierung autologer Stammzellen nicht nur in vitro sondern auch in vivo nicht zu einem Qualit{\"a}tsverlust und somit beeintr{\"a}chtigtem Stammzell-Engraftment f{\"u}hrt. Insgesamt kann sich die ASCT3 im sp{\"a}ten Krankheitsrezidiv in ihrer Wirksamkeit und Sicherheit in refrakt{\"a}ren/relabierten F{\"a}llen mit Proteasomen-Inhibitoren sowie immunmodulatorischen Substanzen der zweiten bzw. dritten Generation messen lassen, ist jedoch ebenso wenig wie diese im alleinigen Einsatz in der Lage, den negativ-prognostischen Einfluss einer Doppel-Refrakt{\"a}rit{\"a}t bzw. einer Hochrisiko-Zytogenetik vollst{\"a}ndig zu {\"u}berwinden. Hieraus ergeben sich neue Ans{\"a}tze f{\"u}r Therapiekonzepte, die beispielsweise immunmodulatorische Substanzen sowie Proteasomen-Inhibitoren der neueren und neuesten Generation ebenso wie Antik{\"o}rper-basierte Therapien im Rahmen einer prospektiven Studie mit einer dritten Hochdosistherapie und anschließender autologer Stammzelltransplantation kombinieren k{\"o}nnten, um das Gesamt{\"u}berleben von Myelom-Patienten weiter zu verl{\"a}ngern.},
  subject      = {Plasmozytom},
  language  = {de}
}
@phdthesis{Streit2022,
  author    = {Streit, Anne},
  title     = {Pr{\"a}valenz von medikamentenassoziierten Kiefernekrosen und deren Risikofaktoren bei Patienten mit Erkrankungen aus dem rheumatischen Formenkreis},
  doi       = {10.25972/OPUS-28026},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280267},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Einleitung: Das Ziel dieser Studie war die Einsch{\"a}tzung der Pr{\"a}valenz der medikamentenassoziierten Kieferosteonekrose (MRONJ) in einem Kollektiv von Patienten mit Osteoporose und rheumatischer Grunderkrankung. Zudem wurden Risikofaktoren sowie pr{\"a}ventive Maßnahmen betrachtet. Methoden: Insgesamt wurden 198 Patienten in der Rheumatologischen Ambulanz in Zusammenarbeit mit der Mund-Kiefer-Gesichtschirurgie (MKG) des Universit{\"a}tsklinikums in W{\"u}rzburg in einem Zeitraum von 14 Monaten rekrutiert. Es wurden Telefoninterviews mit allen Patienten gef{\"u}hrt. Auff{\"a}llige Patienten wurden in der MKG untersucht, zahn{\"a}rztliche Unterlagen wurden angefordert und evaluiert. Zus{\"a}tzlich erfolgte eine retrospektive Analyse der elektronischen Patientenakten. Ergebnisse: Die Pr{\"a}valenz der MRONJ betrug in unserem Patientenkollektiv 1,5 \% (n=3). Alle Patientinnen mit MRONJ bekamen das Bisphosponat (BP) oral, eine Patientin bekam es zus{\"a}tzlich intraven{\"o}s und eine weitere Patientin bekam zus{\"a}tzlich Denosumab. Die Patientengruppe mit Kieferosteonekrose hatte im Vergleich zu den Patienten ohne Kieferosteonekrose innerhalb des Kollektivs eine statistisch signifikant h{\"o}here Gesamttherapiedauer der Osteoporose (p≤0,0001), einen niedrigeren durchschnittlichen FFbH (p=.031) und eine niedrigere Knochendichte (Femur) (p=.009). Nur 38,4 \% der Patienten im Gesamtkollektiv f{\"u}hlten sich {\"u}ber das Risiko einer MRONJ aufgekl{\"a}rt. Nur 25,3 \% der Patienten gaben an, zu Beginn der BP-Therapie bei einer zahn{\"a}rztlichen Kontrolluntersuchung gewesen zu sein. Schlussfolgerung: Die Pr{\"a}valenz von 1,5 \% f{\"u}r diese dramatische unerw{\"u}nschte Arztneimittelwirkung unterstreicht das hohe Risiko rheumatologisch erkrankter Patienten. Ein prospektives Register zur Erfassung von MRONJ bei diesem besonderen Risikokollektiv w{\"a}re empfehlenswert. Die Daten zur Pr{\"a}vention der MRONJ zeigen, dass die geforderten Maßnahmen zur Vermeidung einer MRONJ bisher nur unzureichend umgesetzt werden.},
  subject      = {Osteoporose},
  language  = {de}
}
@article{StraubVollmerLametal.2022,
  author    = {Straub, Anton and Vollmer, Andreas and L{\^a}m, Thi{\^e}n-Tr{\´i} and Brands, Roman C. and Stapf, Maximilian and Scherf-Clavel, Oliver and Bittrich, Max and Fuchs, Andreas and K{\"u}bler, Alexander C. and Hartmann, Stefan},
  title     = {Evaluation of advanced platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam},
  series = {Clinical Oral Investigations},
  volume    = {26},
  journal   = {Clinical Oral Investigations},
  number    = {12},
  doi       = {10.1007/s00784-022-04663-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324515},
  pages     = {7033-7044},
  year      = {2022},
  abstract  = {Objectives Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a "bio-carrier" for antibiotics previously applied intravenously. Materials and methods We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients' blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls. Results Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing. Conclusions The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect. Clinical relevance We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections.},
  language  = {en}
}
@phdthesis{Strack2009,
  author    = {Strack, Christina Elisabeth},
  title     = {Modulation der Genexpression des antimikrobiellen Peptids LL-37 in Abh{\"a}ngigkeit von exogenen Faktoren},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-38956},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {In st{\"a}ndigem Kontakt mit zahlreichen Mikroorganismen ben{\"o}tigt unser K{\"o}rper eine Vielzahl an Mechanismen zur Abwehr krankheitserregender Keime. Antimikrobielle Peptide unterst{\"u}tzen als Effektormolek{\"u}le die einzellige Epithelschicht des Darms, die als Mukosabarriere unseren K{\"o}rper vor dem Eindringen pathogener Keime bewahrt. Die Expression des antimikrobiellen Peptids LL-37, auch Cathelicidin genannt, stellt eine Strategie des angeborenen Immunsystems zur Abwehr von Mikroorganismen im Kolon dar. Die Expression des Cathelicidin Gens camp kann, wie in der vorliegenden Arbeit untersucht wurde, durch exogene Faktoren, wie die biologisch aktive Form des Vitamin D3, das 1,25(OH)2D3, die kurzkettige Fetts{\"a}ure Butyrat und das Ern{\"a}hrungssupplement Intestamin®, angeregt werden. Die Stimulation der Zellen mit den genannten Substanzen f{\"u}hrte in allen gestesteten Zelllinien zeit- und dosisabh{\"a}ngig zu einer Steigerung der Expression des Cathelicidin Gens. Die Induktion der camp-Expression durch 1,25(OH)2D3 wird durch die Existenz eines Vitamin D Response Elements (VDRE) in der Promoterrregion des camp-Gens begr{\"u}ndet, an das der Vitamin D-Rezeptor Komplex als ligandenabh{\"a}ngiger Transkriptionsfaktor bindet und die Genexpression vermittelt. Die Auswirkungen von Butyrat auf die Genexpression des Cathelicidins werden auf die Modifikation des Acetylierungsstatus der Histonproteine zur{\"u}ckgef{\"u}hrt. Butyrat bewirkt durch eine reversible Hemmung der Histondeacetylase die Hyperacetylierung bestimmter Kernhistone und greift auf diese Weise in die Regulation der Gentranskription ein. Das enterale Ern{\"a}hrungssupplement Intestamin®, das als Pharmakonutrition speziell f{\"u}r schwerkranke Patienten entwickelt wurde, ist reich an Glutamin-Dipeptiden, Tributyrin und Antioxidantien. Der Effekt, den Intestamin® auf die Expression des Cathelicidin Gens aus{\"u}bt, ist wahrscheinlich auf Tributyrin zur{\"u}ckzuf{\"u}hren. Tributyrin, der Ester aus Glycerin und Butyrat, wird durch Hydrolyse zu Butyrat umgesetzt und bewirkt vermutlich die Steigerung der camp-Expression. Eine Co-Stimulation von GEKI 02 Zellen mit 1,25(OH)2D3 plus Butyrat erzielte nach 48 Stunden eine weitere Steigerung der Expression des Cathelicidin Gens gegen{\"u}ber beiden Einzelsubstanzen. In allen anderen getesteten Zelllinien zeigte sich keine synergetische Wirkung der beiden Substanzen. Auch eine Co-Stimulation mit Intestamin® plus Butyrat konnte nicht zu einer st{\"a}rkeren Zunahme der camp-Expression f{\"u}hren als eine Behandlung mit beiden Einzelsubstanzen. Eine synergetische Wirkung der Substanzen 1,25(OH)2D3 und Butyrat in GEKI 02 Zellen k{\"o}nnte durch die Acetylierung der Histone bedingt sein, die eine Auflockerung der Chromatinstruktur bewirkt, was wiederum die Bindung von Transkriptionsfaktoren wie dem Vitamin D-Rezeptor Komplex erleichtert. Die fehlende synergetische Wirkung in allen anderen getesteten Zelllinien k{\"o}nnte mit der Tatsache in Zusammenhang stehen, dass die Induktion der camp-Expression zeitabh{\"a}ngig ist: Vitamin D3 erzielte nach 24 Stunden, Butyrat nach 48 Stunden die deutlichsten Auswirkungen auf die Genexpression des Cathelicidins. Der Einfluss des MEK/ERK Signalweges auf die durch 1,25(OH)2D3, Butyrat und Intestamin® induzierte camp-Expression wurde in den durchgef{\"u}hrten Versuchen mittels des spezifischen MEK 1/2 Inhibitors U0126 untersucht. U0126 blockierte die Induktion des Cathelicidin Gens durch Intestamin® und Butyrat, was die Beteiligung des Signalweges MEK/ERK belegt. Vitamin D3 dagegen {\"u}bt seinen Einfluss auf LL-37 nicht {\"u}ber den Signalweg MEK/ERK aus. Obwohl Vitamin D3 und Butyrat die Expression des Cathelicidin Gens camp induzieren, konnte die Inkubation der Zellen mit beiden Substanzen die antimikrobielle Aktivit{\"a}t der Kolonepithelzellen gegen{\"u}ber E.coli im Vergleich zu unbehandelten Kontrollzellen nicht steigern. Urs{\"a}chlich hierf{\"u}r k{\"o}nnte neben der Wahl eines apathogenen Bakterienstammes das Mikromilieu der Umgebung sein. Außer der Konzentration des Peptids spielen insbesondere der pH-Wert und die Salzkonzentration des Kulturmediums eine wichtige Rolle, da sie die Ausbildung der Sekund{\"a}rstruktur, n{\"a}mlich der \&\#945;-helikalen Konformation, des LL-37 beeinflussen, die f{\"u}r die Interaktion mit Biomembranen erforderlich ist. Aufgrund der zunehmenden Resistenzentwicklung von Bakterien gegen{\"u}ber herk{\"o}mmlichen Antibiotika, w{\"a}chst das Interesse an der Erforschung antimikrobieller Peptide. Exogene Faktoren wie 1,25(OH)2D3, Butyrat und Intestamin® k{\"o}nnen eine Steigerung der Expression des Cathelicidin Gens erzielen. Ob sich dieser Effekt allerdings auch in-vivo zeigt und eventuell therapeutischen Einsatz finden k{\"o}nnte, m{\"u}ssen weitere Studien kl{\"a}ren.},
  subject      = {Calcitriol},
  language  = {de}
}
@article{StephanTascilarYalcinMutluetal.2023,
  author    = {Stephan, Marlene and Tascilar, Koray and Yalcin-Mutlu, Melek and Hagen, Melanie and Haschka, Judith and Reiser, Michaela and Hartmann, Fabian and Kleyer, Arnd and Hueber, Axel J. and Manger, Bernhard and Figueiredo, Camille and Cobra, Jayme Fogagnolo and Tony, Hans-Peter and Finzel, Stephanie and Kleinert, Stefan and Wendler, J{\"o}rg and Schuch, Florian and Ronneberger, Monika and Feuchtenberger, Martin and Fleck, Martin and Manger, Karin and Ochs, Wolfgang and Schmitt-Haendle, Matthias and Lorenz, Hannes Martin and N{\"u}sslein, Hubert and Alten, Rieke and Henes, Joerg and Kr{\"u}ger, Klaus and Schett, Georg and Rech, J{\"u}rgen},
  title     = {Physical function of RA patients tapering treatment — a post hoc analysis of the randomized controlled RETRO trial},
  series = {Journal of Clinical Medicine},
  volume    = {12},
  journal   = {Journal of Clinical Medicine},
  number    = {11},
  issn      = {2077-0383},
  doi       = {10.3390/jcm12113723},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319349},
  year      = {2023},
  abstract  = {Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50\% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.},
  language  = {en}
}
@article{SteinhardtZhouKrummenastetal.2020,
  author    = {Steinhardt, Maximilian Johannes and Zhou, Xiang and Krummenast, Franziska and Meckel, Katharina and Nickel, Katharina and B{\"o}ckle, David and Messerschmidt, Janin and Knorz, Sebastian and Dierks, Alexander and Heidemeier, Anke and Lapa, Constantin and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, Klaus Martin},
  title     = {Sequential CD38 monoclonal antibody retreatment leads to deep remission in a patient with relapsed/refractory multiple myeloma},
  series = {International Journal of Immunopathology and Pharmacology},
  volume    = {34},
  journal   = {International Journal of Immunopathology and Pharmacology},
  doi       = {10.1177/2058738420980258},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236235},
  pages     = {1-5},
  year      = {2020},
  abstract  = {We report on a currently 76-year-old female patient with relapsed/refractory (RR) multiple myeloma (MM) treated at our institution. This patient had received six lines of therapy including tandem autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs and CD38 antibody MOR202. At the last relapse, she progressed during treatment with pomalidomide and MOR202. In an individualized therapy concept, we started a multi-agent salvage therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and CD38 antibody daratumumab ("Pom-PAD-Dara"), which resulted in a stringent complete remission with minimal residual disease (MRD) negativity after nine cycles. So far, our patient shows a progression free survival of more than 12 months. Our case demonstrates the feasibility of successful CD38 antibody retreatment in a patient with heavily pretreated CD38 antibody resistant MM.},
  language  = {en}
}
@article{SteinhardtKrummenastRosenwaldetal.2022,
  author    = {Steinhardt, Maximilian J. and Krummenast, Franziska C. and Rosenwald, Andreas and Gerhard-Hartmann, Elena and Heidemeier, Anke and Einsele, Hermann and Topp, Max S. and Duell, Johannes},
  title     = {R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement},
  series = {Journal of Cancer Research and Clinical Oncology},
  volume    = {148},
  journal   = {Journal of Cancer Research and Clinical Oncology},
  number    = {1},
  issn      = {1432-1335},
  doi       = {10.1007/s00432-021-03663-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267731},
  pages     = {205-214},
  year      = {2022},
  abstract  = {Purpose Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. Methods We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. Results Overall response rate to Ping-Pong was 100\% measured by CT/MRI, including 93.75\% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75\% after a 4.8-year follow-up currently. Conclusion Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.},
  language  = {en}
}
@article{SteinhardtCejkaChenetal.2024,
  author    = {Steinhardt, Maximilian J. and Cejka, Vladimir and Chen, Mengmeng and B{\"a}uerlein, Sabrina and Sch{\"a}fer, Julia and Adrah, Ali and Ihne-Schubert, Sandra M. and Papagianni, Aikaterini and Kort{\"u}m, K. Martin and Morbach, Caroline and St{\"o}rk, Stefan},
  title     = {Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study},
  series = {Journal of Clinical Medicine},
  volume    = {13},
  journal   = {Journal of Clinical Medicine},
  number    = {1},
  issn      = {2077-0383},
  doi       = {10.3390/jcm13010283},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-356024},
  year      = {2024},
  abstract  = {Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1\% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5\% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.},
  language  = {en}
}
@article{SteinhardtWiercinskaPhametal.2020,
  author    = {Steinhardt, M. J. and Wiercinska, E. and Pham, M. and Grigoleit, G. U. and Mazzoni, A. and Da-Via, M. and Zhou, X. and Meckel, K. and Nickel, K. and Duell, J. and Krummenast, F. C. and Kraus, S. and Hopkinson, C. and Weissbrich, B. and M{\"u}llges, W. and Stoll, G. and Kort{\"u}m, K. M. and Einsele, H. and Bonig, H. and Rasche, L.},
  title     = {Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes},
  series = {Journal of Translational Medicine},
  volume    = {18},
  journal   = {Journal of Translational Medicine},
  doi       = {10.1186/s12967-020-02337-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229307},
  year      = {2020},
  abstract  = {Background Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.},
  language  = {en}
}
@phdthesis{Stein2007,
  author    = {Stein, Thorsten},
  title     = {Einfluss inhalativer Allergene auf die Zilienschlagfrequenz der Nasenschleimhaut bei Allergikern in vitro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27837},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Es wurde der m{\"o}gliche Effekt verschiedener Typ I-Allergene auf die Zilienschlagfrequenz der Nasenmuschelschleimhaut bei Allergikern in vitro untersucht. Durch die Pr{\"a}paration der Gewebeproben und die in vitro Durchf{\"u}hrung der Untersuchungen wurde der Einfluss m{\"o}glicher anderer Komponenten des mukoziliaren Systems gegen{\"u}ber vergleichbaren in vivo Untersuchungen minimiert. Wir erhielten die Gewebeproben durch Entnahme mit einer Biopsiezange aus zuvor operativ gewonnenen Nasenmuscheln. Die Proben wurden unmittelbar postoperativ gewaschen, in N{\"a}hrmedium M199 aufbewahrt und mit Carbogen {\"a}quilibriert, so dass eine konstante Zilienaktivit{\"a}t mit Hilfe eines etablierten Verfahrens {\"u}ber mehrere Stunden gew{\"a}hrleistet war. Die Frequenzmessung erfolgte mittels Durchlichtmikroskopie und photometrischer Methode in Kombination mit einer digitalen Spektrumanalyse {\"u}ber 15 bzw. 30 Minuten, entweder in Allergen-L{\"o}sung zweier Konzentrationen oder in allergenfreier Kontroll-L{\"o}sung. Wir fanden keinen Unterschied zwischen den basalen Zilienschlagfrequenzen von Allergikern und Nichtallergikern. Ebenso waren weder Anstieg noch Abfall der Zilienschlagfrequenz nach Allergenexposition zu beobachten. Der Frequenzverlauf war konstant und auf dem gleichen Niveau wie bei Zilien von Nichtallergikern bzw. Zilien von Allergikern in Kontroll-L{\"o}sung. Daran {\"a}nderte auch die Verdoppelung des Beobachtungszeitraums in Kombination mit einer Erh{\"o}hung der Allergenkonzentration auf das F{\"u}nffache einer in vivo voll wirksamen Standard-Intrakutan-Konzentration des f{\"u}r den betreffenden Allergiker relevanten Typ-I-Allergens nichts. Aus den Ergebnissen folgern wir, dass Allergene die Zilient{\"a}tigkeit nicht direkt beeinflussen. Die von anderen Autoren festgestellte Hemmung oder Stimulation der Zilienaktivit{\"a}t bei tierexperimentellen in vivo-Untersuchungen muss auf eine indirekte Wirkung, ausgehend von anderen Bestandteilen des mukoziliaren Systems wie Mediatorenfreisetzung oder Ver{\"a}nderungen der Schleimschicht, zur{\"u}ckzuf{\"u}hren sein.},
  subject      = {Allergie},
  language  = {de}
}
@phdthesis{Steimer2021,
  author    = {Steimer, Ann-Kathrin},
  title     = {Adh{\"a}renz bei oraler Capecitabin-Therapie - Zusammenh{\"a}nge mit Angstst{\"o}rungen},
  doi       = {10.25972/OPUS-24964},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249647},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Laut Sch{\"a}tzungen des Robert Koch-Instituts erkranken j{\"a}hrlich fast 500.000 Personen an einer Krebserkrankung, mit steigender Tendenz. Durch stetige Fortschritte in der Forschung kam es durch die Entwicklung einer Chemotherapie in Tablettenform zu einem Paradigmenwechsel in der Krebstherapie. F{\"u}r ein optimales Therapie-Outcome ist es von großer Bedeutung, dass die Patienten ein adh{\"a}rentes Verhalten zeigen. Weiterhin zeigt sich in der bisherigen Literatur, dass psychische Komorbidit{\"a}ten die Adh{\"a}renz und damit den Behandlungserfolg gleichermaßen beeinflussen k{\"o}nnen. Dies wurde in der vorliegenden Arbeit evaluiert. Die Studie umfasste insgesamt 69 Krebspatientinnen und -Patienten, die eine Chemotherapie mit Capecitabin erhielten. Untersucht wurden Gruppenunterschiede zwischen soziodemografischen und klinischen Variablen auf der einen Seite und Adh{\"a}renz auf der anderen Seite sowie die klinisch relevante Belastung durch Angstsymptome. Zur Datenerhebung wurden zum einen der MARS-Fragebogen zur Erfassung der Adh{\"a}renz und zum anderen der GAD-7 zur Erfassung der Angstsymptomatik verwendet. Adh{\"a}rentes Verhalten in Bezug auf die Einnahme von Capecitabin zeigte sich bei 75.4\% der Personen im untersuchten Studienkollektiv. Dieses Ergebnis steht in Einklang mit bisherigen Publikationen, die ebenfalls den Zusammenhang zwischen Adh{\"a}renz bei Capecitabin untersuchten. Die weitere Hypothese war, dass h{\"o}here Angstbelastungen unter Patienten signifikant mit einer verminderten Adh{\"a}renz in Zusammenhang stehen. Dies konnte in der vorliegenden Studie jedoch nicht festgestellt werden. Einerseits zeigte zwar nur ein geringer Anteil der untersuchten Patienten Hinweise einer Angstst{\"o}rung (7\%), andererseits wurde festgestellt, dass nicht alle dieser Patienten eine psychotherapeutische Behandlung erhielten. F{\"u}r zuk{\"u}nftige Forschungen w{\"a}re zu {\"u}berlegen, weitere Messinstrumente zur Diagnostik einer niederschwelligen Angst einzusetzen. Weiterhin w{\"a}ren ein gr{\"o}ßeres Therapieangebot und umfassendere psychosoziale Unterst{\"u}tzung dringend erforderlich. Abschließend bleibt festzuhalten, dass in Zukunft weitere Studien, v.a. auch mit gr{\"o}ßeren Fallzahlen sowie L{\"a}ngsschnitt- oder Follow-up-Studien zu diesem Forschungsthema dringend indiziert sind.},
  subject      = {Capecitabin},
  language  = {de}
}
@article{StegnervanEeuwijkAngayetal.2017,
  author    = {Stegner, David and van Eeuwijk, Judith M.M. and Angay, Oğuzhan and Gorelashvili, Maximilian G. and Semeniak, Daniela and Pinnecker, J{\"u}rgen and Schmithausen, Patrick and Meyer, Imke and Friedrich, Mike and D{\"u}tting, Sebastian and Brede, Christian and Beilhack, Andreas and Schulze, Harald and Nieswandt, Bernhard and Heinze, Katrin G.},
  title     = {Thrombopoiesis is spatially regulated by the bone marrow vasculature},
  series = {Nature Communications},
  volume    = {8},
  journal   = {Nature Communications},
  number    = {127},
  doi       = {10.1038/s41467-017-00201-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170591},
  year      = {2017},
  abstract  = {In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts.},
  language  = {en}
}
@article{StaudtZieglerMartinVisekrunaetal.2023,
  author    = {Staudt, Sarah and Ziegler-Martin, Kai and Visekruna, Alexander and Slingerland, John and Shouval, Roni and Hudecek, Michael and Van den Brink, Marcel and Luu, Maik},
  title     = {Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1269015},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328019},
  year      = {2023},
  abstract  = {The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.},
  language  = {en}
}
@article{SpringerWaltherRickertsetal.2019,
  author    = {Springer, Jan and Walther, Grit and Rickerts, Volker and Hamprecht, Axel and Willinger, Birgit and Teschner, Daniel and Einsele, Hermann and Kurzai, Oliver and Loeffler, Juergen},
  title     = {Detection of Fusarium Species in Clinical Specimens by Probe-Based Real-Time PCR},
  series = {Journal of Fungi},
  volume    = {5},
  journal   = {Journal of Fungi},
  number    = {4},
  issn      = {2309-608X},
  doi       = {10.3390/jof5040105},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193111},
  pages     = {105},
  year      = {2019},
  abstract  = {The mold Fusarium is a ubiquitous fungus causing plant, animal and human infections. In humans, Fusarium spp. are the major cause of eye infections in patients wearing contact lenses or after local trauma. Systemic infections by Fusarium spp. mainly occur in immunosuppressed patients and can disseminate throughout the human body. Due to high levels of resistance to antifungals a fast identification of the causative agent is an urgent need. By using a probe-based real-time PCR assay specific for the genus Fusarium we analysed several different clinical specimens detecting Fusarium spp. commonly found in clinical samples in Germany. Also, a large collection of lung fluid samples of haematological patients was analysed (n = 243). In these, two samples (0.8\%) were reproducibly positive, but only one could be confirmed by sequencing. For this case of probable invasive fungal disease (IFD) culture was positive for Fusarium species. Here we describe a rapid, probe-based real-time PCR assay to specifically detect DNA from a broad range of Fusarium species and its application to clinically relevant specimens.},
  language  = {en}
}
@article{SpringerHeldMengolietal.2021,
  author    = {Springer, Jan and Held, J{\"u}rgen and Mengoli, Carlo and Schlegel, Paul Gerhardt and Gamon, Florian and Tr{\"a}ger, Johannes and Kurzai, Oliver and Einsele, Hermann and Loeffler, Juergen and Eyrich, Matthias},
  title     = {Diagnostic performance of (1→3)-β-D-glucan alone and in combination with aspergillus PCR and galactomannan in serum of pediatric patients after allogeneic hematopoietic stem cell transplantation},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {3},
  issn      = {2309-608X},
  doi       = {10.3390/jof7030238},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234179},
  year      = {2021},
  abstract  = {Data on biomarker-assisted diagnosis of invasive aspergillosis (IA) in pediatric patients is scarce. Therefore, we conducted a cohort study over two years including 404 serum specimens of 26 pediatric patients after allogeneic hematopoietic stem cell transplantation (alloSCT). Sera were tested prospectively twice weekly for Aspergillus-specific DNA, galactomannan (GM), and retrospectively for (1→3)-β-D-glucan (BDG). Three probable IA and two possible invasive fungal disease (IFD) cases were identified using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSGERC) 2019 consensus definitions. Sensitivity and specificity for diagnosis of probable IA and possible IFD was 80\% (95\% confidential interval (CI): 28-99\%) and 55\% (95\% CI: 32-77\%) for BDG, 40\% (95\% CI: 5-85\%) and 100\% (95\% CI: 83-100\%) for GM, and 60\% (95\% CI: 15-95\%) and 95\% (95\% CI: 75-100\%) for Aspergillus-specific real-time PCR. However, sensitivities have to be interpreted with great caution due to the limited number of IA cases. Interestingly, the low specificity of BDG was largely caused by false-positive BDG results that clustered around the date of alloSCT. The following strategies were able to increase BDG specificity: two consecutive positive BDG tests for diagnosis (specificity 80\% (95\% CI: 56-94\%)); using an optimized cutoff value of 306 pg/mL (specificity 90\% (95\% CI: 68-99\%)) and testing BDG only after the acute posttransplant phase. In summary, BDG can help to diagnose IA in pediatric alloSCT recipients. However, due to the poor specificity either an increased cutoff value should be utilized or BDG results should be confirmed by an alternative Aspergillus assay.},
  language  = {en}
}
@article{SpinnerWilleSchwerdtfegeretal.2015,
  author    = {Spinner, Christoph D and Wille, Florian and Schwerdtfeger, Christiane and Thies, Philipp and Tanase, Ursula and Von Figura, Guido and Schmid, Roland M and Heinz, Werner J and Klinker, Hartwig Hf},
  title     = {Pharmacokinetics of chewed vs. swallowed raltegravir in a patient with AIDS and MAI infection: some new conflicting data},
  series = {AIDS Research and Therapy},
  volume    = {12},
  journal   = {AIDS Research and Therapy},
  number    = {1},
  doi       = {10.1186/s12981-014-0041-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144058},
  year      = {2015},
  abstract  = {Background: While HIV, AIDS and atypical Mycobacterium infections are closely linked, the use of Integrase-Inhibitor based cART, notably raltegravir-based regimens is more widespread. RAL should be double-dosed to 800 mg semi-daily in situation of rifampicin co-medication, because RAL is more rapidly metabolized due to rifampicin-induced Uridine-5'-diphosph-gluronosyl-transferase (UGT1A1). Recently, it was speculated that chewed RAL might lead to increased absorption, which might compensate the inductive effect of rifampicin-rapid metabolized RAL, as part of cost-saving effects in countries with high-tuberculosis prevalence and less economic power. Methods: We report measurement of raltegravir pharmacokinetics in a 34-year AIDS-patient suffering from disseminated Mycobacterium avium infection with necessity of parenteral rifampicin treatment. RAL levels were measured with HPLC (internal standard: carbamazepine, LLQ 11 ng/ml, validation with Valistat 2.0 program (Arvecon, Germany)). For statistical analysis, a two-sided Wilcoxon signed rank test for paired samples was used. Results: High intra-personal variability in raltegravir serum levels was seen. Comparable C\(_{max}\) concentrations were found for 800 mg chewed and swallowed RAL, as well as for 400 mg chewed and swallowed RAL. While C\(_{max}\) seems to be more dependent from overall RAL dosing than from swallowed or chewed tablets, increased AUC(12) is clearly linked to higher RAL dosages per administration. Anyway, chewed raltegravir showed a rapid decrease in serum levels. Conclusions: We found no evidence that chewed 400 mg semi-daily raltegravir in rifampicin co-medication leads to optimized pharmacokinetics. There is need for more data from randomized trials for further recommendations.},
  language  = {en}
}