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Institute
- Theodor-Boveri-Institut für Biowissenschaften (187)
- Graduate School of Life Sciences (124)
- Institut für Anorganische Chemie (73)
- Medizinische Klinik und Poliklinik I (72)
- Medizinische Klinik und Poliklinik II (68)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (63)
- Institut für Psychologie (60)
- Neurologische Klinik und Poliklinik (54)
- Institut für Informatik (51)
- Institut für Organische Chemie (51)
Schriftenreihe
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- SKZ – Das Kunststoff-Zentrum (1)
- Servicezentrum Medizin-Informatik (Universitätsklinikum) (1)
- Spanish National Center for Biotechnology (CNB-CSIC) (1)
- Spectral Service AG (1)
- TH Köln (1)
- Technische Universität Darmstadt (1)
- Universidade de São Paulo, Programa de Pós-Graduação em Letras Clássicas, São Paulo, Brasil (1)
- University Medical Center Göttingen, Department of Cellular Biochemistry, Göttingen (1)
- University of Applied Sciences Aschaffenburg (1)
- University of Applied Sciences Potsdam (1)
- University of Cologne (1)
- University of Leipzig, Faculty of Life Sciences, Institute for Biology (1)
- University of Padova, Italy (1)
- Universität Belgrad, Serbien (1)
- Universität Erlangen, Institut für Geschichte und Ethik der Medizin (1)
- Universität Hamburg (1)
- Universität Kassel, Fachbereich Gesellschaftswissenschaften, Mittelalterliche Geschichte (1)
- Universität Leipzig (1)
- Universität Salzburg, Fachbereich Germanistik (1)
- Université de Montréal (1)
- VIGEA, Italy (1)
- Wilhelm-Conrad-Röntgen-Forschungszentrum für komplexe Materialsysteme (1)
- Zentrallabor, Universitätsklinikum Würzburg (1)
- Zentrum für Infektionsforschung (ZINF) Würzburg (1)
Nägele, Virginie ; Zugmaier, Gerhard ; Goebeler, Maria-Elisabeth ; Viardot, Andreas ; Bargou, Ralf ; Kufer, Peter ; Klinger, Matthias
Blinatumomab is a first-in-class immunotherapy based on the bispecific T-cell engager (BiTE®) immune-oncology platform, which redirects CD3+ T cells to kill CD19+ target cells. The objective of this analysis was to describe the correlation between B- and T-cell kinetics and response to blinatumomab in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). The clinical efficacy of treatment with blinatumomab in patients with r/r NHL was recently investigated in a phase 1 dose-escalation and expansion trial (NCT00274742) wherein 76 patients received blinatumomab by continuous intravenous infusion at various doses (0.5–90 μg/m2/day). B-Cell depletion and expansion of CD3+, CD4+, and CD8+ T cells was analyzed in patients stratified per clinical response (complete response [CR], n = 16; partial response [PR], stable disease [SD], or progressive disease [PD], n = 54) for at least 4 weeks (additional 4 weeks after clinical benefit) from the date of administration of blinatumomab until dose-limiting toxicity or PD. B-cell depletion kinetics were faster in patients who had a CR than in patients who did not have a complete response (PR, SD, or PD). T-cell expansion (T-cell counts exceeding the baseline level on day 22) was more pronounced in patients with CR than in patients without CR. T-cell expansion in patients with CR correlated with increased T-cell counts of both CD4+ and CD8+ T cells compared with patients without CR. Patients with r/r NHL who achieved a CR had faster B-cell depletion and increased expansion of CD3+, CD4+, and CD8+ T cells than patients who did not achieve a CR.
Nabeebaccus, Adam A ; Verma, Sharwari ; Zoccarato, Anna ; Emanuelli, Giulia ; Santos, Celio XC. ; Streckfuss-Bömeke, Katrin ; Shah, Ajay M.
In response to cardiac injury, increased activity of the hexosamine biosynthesis pathway (HBP) is linked with cytoprotective as well as adverse effects depending on the type and duration of injury. Glutamine-fructose amidotransferase (GFAT; gene name gfpt) is the rate-limiting enzyme that controls flux through HBP. Two protein isoforms exist in the heart called GFAT1 and GFAT2. There are conflicting data on the relative importance of GFAT1 and GFAT2 during stress-induced HBP responses in the heart.
Using neonatal rat cardiac cell preparations, targeted knockdown of GFPT1 and GFPT2 were performed and HBP activity measured. Immunostaining with specific GFAT1 and GFAT2 antibodies was undertaken in neonatal rat cardiac preparations and murine cardiac tissues to characterise cell-specific expression. Publicly available human heart single cell sequencing data was interrogated to determine cell-type expression. Western blots for GFAT isoform protein expression were performed in human cardiomyocytes derived from induced pluripotent stem cells (iPSCs).
GFPT1 but not GFPT2 knockdown resulted in a loss of stress-induced protein O-GlcNAcylation in neonatal cardiac cell preparations indicating reduced HBP activity. In rodent cells and tissue, immunostaining for GFAT1 identified expression in both cardiac myocytes and fibroblasts whereas immunostaining for GFAT2 was only identified in fibroblasts. Further corroboration of findings in human heart cells identified an enrichment of GFPT2 gene expression in cardiac fibroblasts but not ventricular myocytes whereas GFPT1 was expressed in both myocytes and fibroblasts. In human iPSC-derived cardiomyocytes, only GFAT1 protein was expressed with an absence of GFAT2.
In conclusion, these results indicate that GFAT1 is the primary cardiomyocyte isoform and GFAT2 is only present in cardiac fibroblasts. Cell-specific isoform expression may have differing effects on cell function and should be considered when studying HBP and GFAT functions in the heart.
Muzerelle, Aude ; Soiza-Reilly, Mariano ; Hainer, Cornelia ; Ruet, Pierre-Louis ; Lesch, Klaus-Peter ; Bader, Michael ; Alenina, Natalia ; Scotto-Lomassese, Sophie ; Gaspar, Patricia
Proper maternal care is an essential factor of reproductive success in mammals, involving a repertoire of behaviors oriented toward the feeding and care of the offspring. Among the neurotransmitters involved in the initiation of these behaviors, serotonin (5-HT) seems to play an important role. Here we compared pup-oriented maternal behaviors in mice with constitutive 5-HT depletion, the tryptophan hydroxylase 2-knock-out (Tph2-KO) and the Pet1-KO mice. We report that the only common pup-oriented defect in these 2 hyposerotoninergic models is a defective nursing in parturient mice and altered nursing-like (crouching) behavior in virgin mice, while pup retrieval defects are only present in Tph2-KO. Despite a normal mammary gland development and milk production, the defect in appropriate nursing is responsible for severe growth retardation and early lethality of pups born to hyposerotonergic dams. This nursing defect is due to acute rather constitutive 5-HT depletion, as it is reproduced by adult knockdown of Tph2 in the dorsal raphe nucleus in mothers with a prior normal maternal experience. We conclude that 5-HT innervation from the dorsal raphe is required for both the initiation and maintenance of a normal nursing behavior. Our findings may be related to observations of reduced maternal/infant interactions in human depression.
Muszynska, Aleksandra ; Guendel, Andre ; Melzer, Michael ; Moya, Yudelsy Antonia Tandron ; Röder, Marion S. ; Rolletschek, Hardy ; Rutten, Twan ; Munz, Eberhard ; Melz, Gilbert ; Ortleb, Stefan ; Borisjuk, Ljudmilla ; Börner, Andreas
The development of crop varieties that are resistant to lodging is a top priority for breeding programmes. Herein, we characterize the rye mutant ´Stabilstroh’ (‘stable straw’) possessing an exceptional combination of high lodging resistance, tall posture and high biomass production. Nuclear magnetic resonance imaging displayed the 3-dimensional assembly of vascular bundles in stem. A higher number of vascular bundles and a higher degree of their incline were the features of lodging-resistant versus lodging-prone lines. Histology and electron microscopy revealed that stems are fortified by a higher proportion of sclerenchyma and thickened cell walls, as well as some epidermal invaginations. Biochemical analysis using Fourier-transform infrared spectroscopy and inductively coupled plasma-optical emission spectrometry further identified elevated levels of lignin, xylan, zinc and silicon as features associated with high lodging resistance. Combined effects of above features caused superior culm stability. A simplistic mathematical model showed how mechanical forces distribute within the stem under stress. Main traits of the lodging-resistant parental line were heritable and could be traced back to the genetic structure of the mutant. Evaluation of lodging-resistant wheat ‘Babax’ (‘Baviacora’) versus contrasting, lodging-prone, genotype ´Pastor´ agreed with above findings on rye. Our findings on mechanical stability and extraordinary culm properties may be important for breeders for the improvement of lodging resistance of tall posture cereal crops.
Musto, Pellegrino ; Engelhardt, Monika ; Caers, Jo ; Bolli, Niccolo' ; Kaiser, Martin ; van de Donk, Niels ; Terpos, Evangelos ; Broijl, Annemiek ; de Larrea, Carlos Fernández ; Gay, Francesca ; Goldschmidt, Hartmut ; Hajek, Roman ; Vangsted, Annette Juul ; Zamagni, Elena ; Zweegman, Sonja ; Cavo, Michele ; Dimopoulos, Meletios ; Einsele, Hermann ; Ludwig, Heinz ; Barosi, Giovanni ; Boccadoro, Mario ; Mateos, Maria-Victoria ; Sonneveld, Pieter ; San Miguel, Jesus
According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of “monoclonal gammopathy of undetermined significance-like”, in which patients never progress during their lifetimes, to “early multiple myeloma”, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a “split personality” makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.
The latency of spontaneous eye blinks marks relevant visual and auditory information processing
(2021)
Eye blinks are influenced by external sensory and internal cognitive factors, as mainly shown in the visual domain. In previous studies, these factors corresponded to the time period of task-relevant sensory information and were often linked to a motor response. Our aim was to dissociate the influence of overall sensory input duration, task-relevant information duration, and the motor response to further understand how the temporal modulation of blinks compares among sensory modalities.
Using a visual and an auditory temporal judgment task, we found that blinks were suppressed during stimulus presentation in both domains and that the overall input length had a significant positive relationship with the length of this suppression (i.e., with the latency of the first blink after stimulus onset). Importantly, excluding the influence of the overall sensory input duration we could show that the duration of task-relevant input had an additional influence on blink latency in the visual and the auditory domain. Our findings further suggest that this influence was not based on sensory input but on top–down processes. We could exclude task difficulty and the timing of the motor response as driving factors in the blink modulation.
Our results suggest a sensory domain–independent modulation of blink latencies, introduced by changes in the length of the task-relevant, attended period. Therefore, not only do blinks mark the timing of sensory input or the preparation of the motor output, but they can also act as precise indicators of periods of cognitive processing.
Background
Sudden unexpected infant death (SUID) continues to be a major contributor to infant mortality in the United States. The objective was to analyze time trends in SUID and their association with immunization coverage.
Methods
The number of deaths and live births per year and per state (1992–2015) was obtained from the Centers for Disease Control and Prevention (CDC). We calculated infant mortality rates (i.e., deaths below one year of age) per 1000 live births for SUID. We obtained data on immunization in children aged 19–35 months with three doses or more of diphtheria-tetanus-pertussis (3+ DTP), polio (3+ Polio), and Haemophilus influenzae type b (3+ Hib) as well as four doses or more of DTP (4+ DTP) from the National Immunization Survey, and data on infant sleep position from the Pregnancy Risk Assessment Monitoring System (PRAMS) Study. Data on poverty and race were derived from the Current Population and American Community Surveys of the U.S. Census Bureau. We calculated mean SUID mortality rates with 95% confidence interval (CI) as well as the annual percentage change using breakpoint analysis. We used Poisson regression with random effects to examine the dependence of SUID rates on immunization coverage, adjusting for sleep position and poverty (1996–2015). In a second model, we additionally adjusted for race (2000–2015).
Results
Overall, SUID mortality decreased in the United States. The mean annual percent change was − 9.6 (95% CI = − 10.5, − 8.6) between 1992 and 1996, and − 0.3 (95% CI = − 0.4, − 0.1) from 1996 onwards. The adjusted rate ratios for SUID mortality were 0.91 (95% CI = 0.80, 1.03) per 10% increase for 3+ DTP, 0.88 (95% CI = 0.83, 0.95) for 4+ DTP, 1.00 (95% CI = 0.90, 1.10) for 3+ polio, and 0.95 (95% CI = 0.89, 1.02) for 3+ Hib. After additionally adjusting for race, the rate ratios were 0.76 (95% CI = 0.67, 0.85) for 3+ DTP, 0.83 (95% CI = 0.78, 0.89) for 4+ DTP, 0.81 (95% CI = 0.73, 0.90) for 3+ polio, and 0.94 (95% CI = 0.88, 1.00) for 3+ Hib.
Conclusions
SUID mortality is decreasing, and inversely related to immunization coverage. However, since 1996, the decline has slowed down.
Mueller, Jonathan Wolf ; Vogg, Nora ; Lightning, Thomas Alec ; Weigand, Isabel ; Ronchi, Cristina L ; Foster, Paul A ; Kroiss, Matthias
Context
The adrenal cortex produces specific steroid hormones including steroid sulfates such as dehydroepiandrosterone sulfate (DHEAS), the most abundant steroid hormone in the human circulation. Steroid sulfation involves a multistep enzyme machinery that may be impaired by inborn errors of steroid metabolism. Emerging data suggest a role of steroid sulfates in the pathophysiology of adrenal tumors and as potential biomarkers.
Evidence Acquisition
Selective literature search using “steroid,” “sulfat*,” “adrenal,” “transport,” “mass spectrometry” and related terms in different combinations.
Evidence Synthesis
A recent study highlighted the tissue abundance of estrogen sulfates to be of prognostic impact in adrenocortical carcinoma tissue samples using matrix-assisted laser desorption ionization mass spectrometry imaging. General mechanisms of sulfate uptake, activation, and transfer to substrate steroids are reasonably well understood. Key aspects of this pathway, however, have not been investigated in detail in the adrenal; these include the regulation of substrate specificity and the secretion of sulfated steroids. Both for the adrenal and targeted peripheral tissues, steroid sulfates may have relevant biological actions beyond their cognate nuclear receptors after desulfation. Impaired steroid sulfation such as low DHEAS in Cushing adenomas is of diagnostic utility, but more comprehensive studies are lacking. In bioanalytics, the requirement of deconjugation for gas-chromatography/mass-spectrometry has precluded the study of steroid sulfates for a long time. This limitation may be overcome by liquid chromatography/tandem mass spectrometry.
Conclusions
A role of steroid sulfation in the pathophysiology of adrenal tumors has been suggested and a diagnostic utility of steroid sulfates as biomarkers is likely. Recent analytical developments may target sulfated steroids specifically.
Müller, Frank ; Kleinert, Evelyn ; Hillermann, Nele ; Simmenroth, Anne ; Hummers, Eva ; Zychlinsky Scharff, Anna ; Dopfer, Christian ; Happle, Christine ; Jablonka, Alexandra
Background:
Currently, health care systems worldwide are challenged with providing care to an increasing number of migrants, refugees, and displaced persons. In this article, we report on disease burden and drug prescription patterns in a large refugee cohort in Germany.
Methods:
We conducted a cross-sectional study of anonymized medical records including demographic data, diagnoses, and drug prescriptions in two refugee reception centres between 2015 and 2019. Refugees and migrants received medical assistance exclusively through the on-site clinics. Thus, this study represents all medical visits of the housed residents.
Results:
In total, n = 15531 diagnoses from n = 4858 patients in a cohort of n = 10431 accommodated refugees were recorded. N = 11898 medications were prescribed. Overall, 29.8% of all refugees sought medical attention. Half of the patients were female (49.6%), the average age was 23.8 years (SD [standard deviation] 17.0, min 0, max 81), and 41.5% were minors (<18 years). Most patients had Middle Eastern or Northern African origin (63.9%). The largest proportion of diagnoses belonged to the ICD (International Statistical Classification of Diseases and Related Health Problems) category "R" (miscellaneous, 33.5%), followed by diseases of the respiratory system (category "J", 16.5%), or the musculoskeletal system (category "M", 7.1%). Non-steroidal anti-inflammatory drugs were most frequently prescribed.
Conclusions:
This analysis in two large refugee centres in Germany shows that about one third of refugees seek medical attention upon initial arrival. Complaints are manifold, with a high prevalence of respiratory infections.
A principal hires an agent to provide a verifiable service. Initially, the agent can exert unobservable effort to reduce his disutility from providing the service. If the agent is free to waive his right to quit, he may voluntarily sign a contract specifying an inefficiently large service level, while there are insufficient incentives to exert effort. If the agent’s right to quit is inalienable, the underprovision of effort may be further aggravated, but the service level is ex post efficient. Overall, it turns out that the total surplus can be larger when agents are not permitted to contractually waive their right to quit work. Yet, we also study an extension of our model in which even the agent can be strictly better off when the parties have the contractual freedom to waive the agent’s right to quit.