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Institute
Winkelmann, Anne Ria ; Schneider, Markus ; Hartmann, Sylvia ; Schnitzbauer, Andreas ; Zeuzem, Stefan ; Peveling-Oberhag, Jan Franz-Josef ; Hansmann, Martin-Leo ; Walter, Dirk Henning
Immune-modulating therapy is a promising therapy for patients with cholangiocarcinoma (CCA). Microsatellite instability (MSI) might be a favorable predictor for treatment response, but comprehensive data on the prevalence of MSI in CCA are missing. The aim of the current study was to determine the prevalence of MSI in a German tertiary care hospital. Formalin-fixed paraffin-embedded tissue samples, obtained in the study period from 2007 to 2015 from patients with CCA undergoing surgical resection with curative intention at Johann Wolfgang Goethe University hospital, were examined. All samples were investigated immunohistochemically for the presence of MSI (expression of MLH1, PMS2, MSH2, and MSH6) as well as by pentaplex polymerase chain reaction for five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24). In total, 102 patients were included, presenting intrahepatic (n = 35, 34.3%), perihilar (n = 42, 41.2%), and distal CCA (n = 25, 24.5%). In the immunohistochemical analysis, no loss of expression of DNA repair enzymes was observed. In the PCR-based analysis, one out of 102 patients was found to be MSI-high and one out of 102 was found to be MSI-low. Thus, MSI seems to appear rarely in CCA in Germany. This should be considered when planning immune-modulating therapy trials for patients with CCA.
Paczkowska, Julia ; Janiszewska, Joanna ; Bein, Julia ; Schneider, Markus ; Bednarek, Kinga ; Ustaszewski, Adam ; Hartmann, Sylvia ; Hansmann, Martin-Leo ; Giefing, Maciej
DNA methylation was shown previously to be a crucial mechanism responsible for transcriptional deregulation in the pathogenesis of classical Hodgkin lymphoma (cHL). To identify epigenetically inactivated miRNAs in cHL, we have analyzed the set of miRNAs downregulated in cHL cell lines using bisulfite pyrosequencing. We focused on miRNAs with promoter regions located within or <1000 bp from a CpG island. Most promising candidate miRNAs were further studied in primary Hodgkin and Reed-Sternberg (HRS) cells obtained by laser capture microdissection. Last, to evaluate the function of identified miRNAs, we performed a luciferase reporter assay to confirm miRNA: mRNA interactions and therefore established cHL cell lines with stable overexpression of selected miRNAs for proliferation tests. We found a significant reverse correlation between DNA methylation and expression levels of mir-339-3p, mir-148a-3p, mir-148a-5p and mir-193a-5 demonstrating epigenetic regulation of these miRNAs in cHL cell lines. Moreover, we demonstrated direct interaction between miR-148a-3p and IL15 and HOMER1 transcripts as well as between mir-148a-5p and SUB1 and SERPINH1 transcripts. Furthermore, mir-148a overexpression resulted in reduced cell proliferation in the KM-H2 cell line. In summary, we report that mir-148a is a novel tumor suppressor inactivated in cHL and that epigenetic silencing of miRNAs is a common phenomenon in cHL.
Magunia, Harry ; Lederer, Simone ; Verbuecheln, Raphael ; Gilot, Bryant ; Köppen, Michael ; Häberle, Helene ; Mirakaj, Valbona ; Hofmann, Pascal ; Marx, Gernot ; Bickenbach, Johannes ; Nohe, Boris ; Lay, Michael ; Spies, Claudia D. ; Edel, Andreas ; Schiefenhövel, Fridtjof ; Rahmel, Tim ; Putensen, Christian ; Sellmann, Timur ; Koch, Thea ; Brandenburger, Timo ; Kindgen-Milles, Detlef ; Brenner, Thorsten ; Berger, Marc ; Zacharowski, Kai ; Adam, Elisabeth ; Posch, Matthias ; Mörer, Onnen ; Scheer, Christian S. ; Sedding, Daniel ; Weigand, Markus A. ; Fichtner, Falk ; Nau, Carla ; Prätsch, Florian ; Wiesmann, Thomas ; Koch, Christian ; Schneider, Gerhard ; Lahmer, Tobias ; Straub, Andreas ; Meiser, Andreas ; Weiß, Manfred ; Jungwirth, Bettina ; Wappler, Frank ; Meybohm, Patrick ; Herrmann, Johannes ; Malek, Nisar Peter ; Kohlbacher, Oliver ; Biergans, Stephanie ; Rosenberger, Peter
Background: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.
Tillmann, Marietta ; Messer, Michael ; Bingmer, Markus ; Schiemann, Julia ; Neininger, Ralph ; Roeper, Jochen ; Schneider, Gaby
Poster presentation from Twentieth Annual Computational Neuroscience Meeting: CNS*2011 Stockholm, Sweden. 23-28 July 2011. In statistical spike train analysis, stochastic point process models usually assume stationarity, in particular that the underlying spike train shows a constant firing rate (e.g. [1]). However, such models can lead to misinterpretation of the associated tests if the assumption of rate stationarity is not met (e.g. [2]). Therefore, the analysis of nonstationary data requires that rate changes can be located as precisely as possible. However, present statistical methods focus on rejecting the null hypothesis of stationarity without explicitly locating the change point(s) (e.g. [3]). We propose a test for stationarity of a given spike train that can also be used to estimate the change points in the firing rate. Assuming a Poisson process with piecewise constant firing rate, we propose a Step-Filter-Test (SFT) which can work simultaneously in different time scales, accounting for the high variety of firing patterns in experimental spike trains. Formally, we compare the numbers N1=N1(t,h) and N2=N2(t,h) of spikes in the time intervals (t-h,t] and (h,t+h]. By varying t within a fine time lattice and simultaneously varying the interval length h, we obtain a multivariate statistic D(h,t):=(N1-N2)/V(N1+N2), for which we prove asymptotic multivariate normality under homogeneity. From this a practical, graphical device to spot changes of the firing rate is constructed. Our graphical representation of D(h,t) (Figure 1A) visualizes the changes in the firing rate. For the statistical test, a threshold K is chosen such that under homogeneity, |D(h,t)|<K holds for all investigated h and t with probability 0.95. This threshold can indicate potential change points in order to estimate the inhomogeneous rate profile (Figure 1B). The SFT is applied to a sample data set of spontaneous single unit activity recorded from the substantia nigra of anesthetized mice. In this data set, multiple rate changes are identified which agree closely with visual inspection. In contrast to approaches choosing one fixed kernel width [4], our method has advantages in the flexibility of h.
Triebskorn, Rita ; Amler, Klaus ; Blaha, Ludek ; Gallert, Claudia ; Giebner, Sabrina ; Güde, Hans ; Henneberg, Anja ; Hess, Stefanie ; Hetzenauer, Harald ; Jedele, Klaus ; Jung, Ralph-Michael ; Kneipp, Sven ; Köhler, Heinz-R. ; Krais, Stefanie ; Kuch, Bertram ; Lange, Claudia ; Löffler, Herbert ; Maier, Diana ; Metzger, Jörg ; Müller, Michael ; Oehlmann, Jörg ; Osterauer, Raphaela ; Peschke, Katharina ; Raizner, Jürgen ; Rey, Peter ; Rault, Magali ; Richter, Doreen ; Sacher, Frank ; Scheurer, Marco ; Schneider-Rapp, Jutta ; Seifan, Merav ; Spieth, Markus ; Vogel, Hans-Joachim ; Weyhmüller, Michael ; Winter, Josef ; Wurm, Karl
The project focuses on the efficiency of combined technologies to reduce the release of micropollutants and bacteria into surface waters via sewage treatment plants of different size and via stormwater overflow basins of different types. As a model river in a highly populated catchment area, the river Schussen and, as a control, the river Argen, two tributaries of Lake Constance, Southern Germany, are under investigation in this project. The efficiency of the different cleaning technologies is monitored by a wide range of exposure and effect analyses including chemical and microbiological techniques as well as effect studies ranging from molecules to communities.
Zirafi, Onofrio ; Kim, Kyeong-Ae ; Ständker, Ludger ; Mohr, Katharina B. ; Sauter, Daniel ; Heigele, Anke ; Kluge, Silvia F. ; Wiercinska, Eliza ; Chudziak, Doreen ; Richter, Rudolf ; Moepps, Barbara ; Gierschik, Peter ; Vas, Virag ; Geiger, Hartmut ; Lamla, Markus ; Weil, Tanja ; Burster, Timo ; Zgraja, Andreas ; Daubeuf, Francois ; Frossard, Nelly ; Hachet-Haas, Muriel ; Heunisch, Fabian ; Reichetzeder, Christoph ; Galzi, Jean-Luc ; Pérez-Castells, Javier ; Canales-Mayordomo, Angeles ; Jiménez-Barbero, Jesus ; Giménez-Gallego, Guillermo ; Schneider, Marion ; Shorter, James ; Telenti, Amalio ; Hocher, Berthold ; Forssmann, Wolf-Georg ; Bönig, Halvard-Björn ; Kirchhoff, Frank ; Münch, Jan
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
Niedermeier, Dennis ; Hartmann, Susan ; Clauss, Tina ; Wex, Heike ; Kiselev, Alexei ; Sullivan, Ryan C. ; DeMott, Paul J. ; Petters, Markus D. ; Reitz, Paul ; Schneider, Johannes ; Mikhailov, Eugene ; Sierau, Berko ; Stetzer, Olaf ; Reimann, Bernd ; Bundke, Ulrich ; Shaw, Raymond A. ; Buchholz, Angela ; Mentel, Thomas F. ; Stratmann, Frank
During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influence of various surface modifications on the ice nucleating ability of Arizona Test Dust (ATD) particles in the immersion freezing mode. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤T≤−28 °C. The pure ATD particles nucleated ice over a broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T>−35 °C) and a slight increase in the second branch (T≤−35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. The strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor and the resulting significant reductions in IN potential are of importance for atmospheric ice cloud formation. Our findings suggest that the IN concentration can decrease by up to one order of magnitude for the conditions investigated.
Niedermeier, Dennis ; Hartmann, Susan ; Clauss, Tina ; Wex, Heike ; Kiselev, Alexei ; Sullivan, Ryan C. ; DeMott, Paul J. ; Petters, Markus D. ; Reitz, Paul ; Schneider, Johannes ; Mikhailov, Eugene ; Sierau, Berko ; Stetzer, Olaf ; Reimann, Bernd ; Bundke, Ulrich ; Shaw, Raymond A. ; Buchholz, Angela ; Mentel, Thomas F. ; Stratmann, Frank
Niedermeier, Dennis ; Hartmann, Susan ; Clauss, Tina ; Wex, Heike ; Kiselev, Alexei ; Sullivan, Ryan C. ; DeMott, Paul J. ; Petters, Markus D. ; Reitz, Paul ; Schneider, Johannes ; Mikhailov, Eugene ; Sierau, Berko ; Stetzer, Olaf ; Reimann, Bernd ; Bundke, Ulrich ; Shaw, Raymond A. ; Buchholz, Angela ; Mentel, Thomas F. ; Stratmann, Frank
During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influences of various surface modifications on the immersion freezing behavior of Arizona Test Dust (ATD) particles. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤ T ≤ −28 °C. The pure ATD particles nucleated ice over a~broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T > −35 °C) and a slight increase in the second branch (T≤ −35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. From an atmospheric point of view, and here specifically the influences of atmospheric aging on the IN ability of dust particles, the strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor, and the resulting significant reductions in IN potential, are certainly very interesting.
An iridium(III/IV/V) redox series featuring a terminal imido complex with triplet ground state
(2018)
Kinauer, Markus ; Diefenbach, Martin ; Bamberger, Heiko ; Demeshko, Serhiy ; Reijerse, Edward J. ; Volkmann, Christian ; Würtele, Christian ; Slageren, Joris van ; Bruin, Bas de ; Holthausen, Max C. ; Schneider, Sven
The iridium(III/IV/V) imido redox series [Ir(NtBu){N(CHCHPtBu2)2}]0/+/2+ was synthesized and examined spectroscopically, magnetically, crystallographically and computationally. The monocationic iridium(IV) imide exhibits an electronic doublet ground state with considerable ‘imidyl’ character as a result of covalent Ir–NtBu bonding. Reduction gives the neutral imide [Ir(NtBu){N(CHCHPtBu2)2}] as the first example of an iridium complex with a triplet ground state. Its reactivity with respect to nitrene transfer to selected electrophiles (CO2) and nucleophiles (PMe3), respectively, is reported.