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The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
Background: Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo.
Methods: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days.
Results: Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0–78.5] years, dialysis vintage 28.0 [11.0–45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7–80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225–300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5–98.0] to 99.0 [98.0–99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [− 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant.
Conclusions: Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies.
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).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Um die kontinuierlich auf uns einströmende Menge an Reizen zu verarbeiten, ist es wichtig, die Informationen genau zu selektieren. Ein hilfreicher Mechanismus ist hierbei die Aufmerksamkeit gezielt nur auf eine Informationsquelle zu richten und zu verarbeiten.
So ist es möglich, selbst in komplexen Situationen, wie zum Beispiel einer Feier mit vielen verschiedenen Gesprächen, ganz gezielt ein einzelnes herauszufiltern.
Der Effekt von Aufmerksamkeit auf auditory steady-state Responses (aSSR) wurde in der Vergangenheit schon in verschiedenen Studien mit unterschiedlichen Messverfahren und Stimuli untersucht. Dabei wurden teils widersprüchliche Ergebnisse gefunden, die entweder gar keine oder auf sehr kleine Frequenzbereiche beschränkte Aufmerksamkeitseffekte fanden.
Das Ziel dieser Studie war es, die Auswirkungen von Aufmerksamkeit auf die aSSR innerhalb eines größeren Frequenzspektrums (11 Hz, 23 Hz, 41 Hz, 73 Hz und 97 Hz) zu analysieren. Für diesen Zweck wurden den Probanden nach Instruktion der zu beachtenden Seite jeweils zwei benachbarte Modulationsfrequenzen während vier aufeinander folgenden Blöcken dichotisch präsentiert. Die Probanden wurden angewiesen, Trägerfrequenzänderungen auf der zu beachtenden Seite durch Betätigen einer Maustaste anzugeben. Die Registrierung der aSSR-Antworten geschah mittels Elektroenzephalogramm (EEG). Auch die durch die Stimulation hervorgerufene P300 wurde dargestellt.
Bezüglich des Effekts von Aufmerksamkeit auf die aSSRs zeigte sich nach Analyse der gewonnenen Daten im Frequenzbereich von 23 Hz eine Auswirkung. Diese stellte sich in Form einer Amplitudensteigerung auf der jeweils durch den Probanden beachteten Präsentationsseite dar. Bei einer Modulationsfrequenz von 41 Hz kam es bei Präsentation auf der rechten Seite zu höheren Amplituden als bei Präsentation auf der linken Seite. Bei 73 Hz und 97 Hz konnte keinerlei Auswirkung weder der Aufmerksamkeit noch der Präsentationsseite registriert werden. Auffällig war bei den präsentierten Tönen im 20 Hz und 70 Hz Bereich auch eine im Vergleich zu den anderen Frequenzbereichen (11 Hz, 41 Hz und 97 Hz) verlängerte Reaktionszeit der Probanden. In Kombination mit der Modulation der aSSR-Amplitude durch Aufmerksamkeit bei 23 Hz könnte dies ein Hinweis auf einen förderlichen Einfluss der Aufgabenschwierigkeit auf die Detektierbarkeit von Aufmerksamkeitseffekten sein.
Im Gegensatz hierzu zeigte die dargestellte P300 in allen präsentierten Blöcken einen deutlichen Effekt der Aufmerksamkeit. Dieser äußerte sich ebenfalls in einer Steigerung der Amplitude.
Es scheint also zumindest ein moderater Einfluss von Aufmerksamkeit auf die aSSRs zu existieren. Gleichzeitig wirkt dieser allerdings stark abhängig von gewähltem Stimulus und Messmethode. Der Effekt von Aufmerksamkeit auf die P300 konnte dagegen gut repliziert werden und scheint daher bei dichotischer Stimulation ein deutlicher Marker für Aufmerksamkeit zu sein.
Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs).
Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups.
Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier built based upon data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal.
Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697).
Background: Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter–enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organization of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability.
Results: We have extended our TEPIC framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We designed a novel machine learning approach that allows the prioritization of TFs binding to distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer–promoter loops involving YY1 in different cell lines.
Conclusion: We present a novel approach that can be used to prioritize TFs involved in distal and promoter-proximal regulatory events by integrating chromatin accessibility, conformation, and gene expression data. We show that the integration of chromatin conformation data can improve gene expression prediction and aids model interpretability.
Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.
Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs).
Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups.
Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier applied to the data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal.
Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697)
IL-1 family member IL-33 exerts a variety of immune activating and regulating properties and has recently been proposed as a prognostic biomarker for cancer diseases, although its precise role in tumor immunity is unclear. Here we analyzed in vitro conditions influencing the function of IL-33 as an alarmin and a co-factor for the activity of cytotoxic CD8+ T cells in order to explain the widely discussed promiscuous behavior of IL-33 in vivo. Circulating IL-33 detected in the serum of healthy human volunteers was biologically inactive. Additionally, bioactivity of exogenous recombinant IL-33 was significantly reduced in plasma, suggesting local effects of IL-33, and inactivation in blood. Limited availability of nutrients in tissue causes necrosis and thus favors release of IL-33, which—as described before—leads to a locally high expression of the cytokine. The harsh conditions however influence T cell fitness and their responsiveness to stimuli. Nutrient deprivation and pharmacological inhibition of mTOR mediated a distinctive phenotype characterized by expression of IL-33 receptor ST2L on isolated CD8+ T cells, downregulation of CD8, a transitional CD45RAlowROlow phenotype and high expression of secondary lymphoid organ chemokine receptor CCR7. Under nutrient deprivation, IL-33 inhibited an IL-12 induced increase in granzyme B protein expression and increased expression of GATA3 and FOXP3 mRNA. IL-33 enhanced the TCR-dependent activation of CD8+ T cells and co-stimulated the IL-12/TCR-dependent expression of IFNγ. Respectively, GATA3 and FOXP3 mRNA were not regulated during TCR-dependent activation. TCR-dependent stimulation of PBMC, but not LPS, initiated mRNA expression of soluble IL-33 decoy receptor sST2, a control mechanism limiting IL-33 bioactivity to avoid uncontrolled inflammation. Our findings contribute to the understanding of the compartment-specific activity of IL-33. Furthermore, we newly describe conditions, which promote an IL-33-dependent induction of pro- or anti-inflammatory activity in CD8+ T cells during nutrient deprivation.