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Institute
Hornung, Claudia ; Poehlein, Anja ; Haack, Frederike Svenja ; Schmidt, Martina ; Dierking, Katja ; Pohlen, Andrea ; Schulenburg, Hinrich ; Blokesch, Melanie ; Plener, Laure ; Jung, Kirsten ; Bonge, Andreas ; Krohn-Molt, Ines ; Utpatel, Christian ; Timmermann, Gabriele ; Spieck, Eva ; Pommerening-Röser, Andreas ; Bode, Edna ; Bode, Helge Björn ; Daniel, Rolf ; Schmeißer, Christel ; Streit, Wolfgang R.
Janthinobacteria commonly form biofilms on eukaryotic hosts and are known to synthesize antibacterial and antifungal compounds. Janthinobacterium sp. HH01 was recently isolated from an aquatic environment and its genome sequence was established. The genome consists of a single chromosome and reveals a size of 7.10 Mb, being the largest janthinobacterial genome so far known. Approximately 80% of the 5,980 coding sequences (CDSs) present in the HH01 genome could be assigned putative functions. The genome encodes a wealth of secretory functions and several large clusters for polyketide biosynthesis. HH01 also encodes a remarkable number of proteins involved in resistance to drugs or heavy metals. Interestingly, the genome of HH01 apparently lacks the N-acylhomoserine lactone (AHL)-dependent signaling system and the AI-2-dependent quorum sensing regulatory circuit. Instead it encodes a homologue of the Legionella- and Vibrio-like autoinducer (lqsA/cqsA) synthase gene which we designated jqsA. The jqsA gene is linked to a cognate sensor kinase (jqsS) which is flanked by the response regulator jqsR. Here we show that a jqsA deletion has strong impact on the violacein biosynthesis in Janthinobacterium sp. HH01 and that a jqsA deletion mutant can be functionally complemented with the V. cholerae cqsA and the L. pneumophila lqsA genes.
Griesinger, Frank ; Eberhardt, Wilfried E. E. ; Nusch, Arnd ; Reiser, Marcel ; Zahn, Mark-Oliver ; Maintz, Christoph ; Bernhardt, Christiane ; Losem, Christoph ; Stenzinger, Albrecht ; Heukamp, Lukas ; Büttner, Reinhard ; Marschner, Sebastian ; Jänicke, Martina ; Fleitz, Annette ; Spring, Lisa ; Sahlmann, Jörg ; Karatas, Aysun ; Hipper, Annette ; Weichert, Wilko ; Heilmann, Monika ; Sadjadian, Parvis ; Gleiber, Wolfgang ; Grah, Christian ; Waller, Cornelius ; Reck, Martin ; Rittmeyer, Achim ; Christopoulos, Petros ; Sebastian, Martin ; Thomas, Michael
Sievers, Philipp ; Henneken, Sophie C. ; Blume, Christina ; Sill, Martin ; Schrimpf, Daniel ; Stichel, Damian ; Okonechnikov, Konstantin ; Reuss, David ; Benzel, Julia ; Maaß, Kendra K. ; Kool, Marcel ; Sturm, Dominik ; Zheng, Tuyu ; Ghasemi, David R. ; Kohlhof-Meinecke, Patricia ; Cruz, Ofelia ; Suñol, Mariona ; Lavarino, Cinzia ; Ruf, Viktoria ; Boldt, Henning B. ; Pagès, Mélanie ; Pouget, Celso ; Schweizer, Leonille ; Kranendonk, Mariëtte E. G. ; Akhtar, Noreen ; Bunkowski, Stephanie ; Stadelmann, Christine ; Schüller, Ulrich ; Müller, Wolf C. ; Dohmen, Hildegard ; Acker, Till ; Harter, Patrick Nikolaus ; Mawrin, Christian ; Beschorner, Rudi ; Brandner, Sebastian ; Snuderl, Matija ; Abdullaev, Zied ; Aldape, Kenneth ; Gilbert, Mark R. ; Armstrong, Terri S. ; Ellison, David W. ; Capper, David ; Ichimura, Koichi ; Reifenberger, Guido ; Grundy, Richard G. ; Jabado, Nada ; Krskova, Lenka ; Zapotocky, Michal ; Vicha, Ales ; Varlet, Pascale ; Wesseling, Pieter ; Rutkowski, Stefan ; Korshunov, Andrey ; Wick, Wolfgang ; Pfister, Stefan ; Jones, David T. W. ; Deimling, Andreas von ; Pajtler, Kristian Wilfried ; Sahm, Felix
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
DGK and DZHK position paper on genome editing: basic science applications and future perspective
(2021)
Brandes, Ralf ; Dueck, Anne ; Engelhardt, Stefan ; Kaulich, Manuel ; Kupatt, Christian ; De Angelis, Maria Teresa ; Leisegang, Matthias ; Le Noble, Ferdinand ; Moretti, Alessandra ; Müller, Oliver J. ; Skryabin, Boris V. ; Thum, Thomas ; Wurst, Wolfgang
For a long time, gene editing had been a scientific concept, which was limited to a few applications. With recent developments, following the discovery of TALEN zinc-finger endonucleases and in particular the CRISPR/Cas system, gene editing has become a technique applicable in most laboratories. The current gain- and loss-of function models in basic science are revolutionary as they allow unbiased screens of unprecedented depth and complexity and rapid development of transgenic animals. Modifications of CRISPR/Cas have been developed to precisely interrogate epigenetic regulation or to visualize DNA complexes. Moreover, gene editing as a clinical treatment option is rapidly developing with first trials on the way. This article reviews the most recent progress in the field, covering expert opinions gathered during joint conferences on genome editing of the German Cardiac Society (DGK) and the German Center for Cardiovascular Research (DZHK). Particularly focusing on the translational aspect and the combination of cellular and animal applications, the authors aim to provide direction for the development of the field and the most frequent applications with their problems.
Thill, Marc ; Friedrich, Michael ; Kolberg-Liedtke, Cornelia ; Albert, Ute-Susann ; Banys-Paluchowski, Maggie ; Bauerfeind, Ingo ; Blohmer, Jens-Uwe ; Budach, Wilfried ; Dall, Peter ; Fallenberg, Eva Maria ; Fasching, Peter Andreas ; Fehm, Tanja ; Gerber, Bernd ; Gluz, Oleg ; Harbeck, Nadia ; Heil, Jörg ; Huober, Jens ; Jackisch, Christian ; Kreipe, Hans-H. ; Krug, David ; Kühn, Thorsten ; Kümmel, Sherko ; Loibl, Sibylle ; Lüftner, Diana ; Lux, Michael Patrick ; Maass, Nicolai ; Mundhenke, Christoph ; Nitz, Ulrike ; Park-Simon, Tjoung-Won ; Reimer, Toralf ; Rhiem, Kerstin ; Rody, Achim ; Schmidt, Marcus ; Schneeweiss, Andreas ; Schütz, Florian ; Sinn, Peter ; Solbach, Christine ; Solomayer, Erich-Franz ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Witzel, Isabell ; Wöckel, Achim ; Müller, Volkmar ; Janni, Wolfgang ; Ditsch, Nina
Assfalg, Volker ; Selig, Katharina ; Tolksdorf, Johanna ; Meel, Marieke van ; Vries, Erwin de ; Ramsoebhag, Anne‐Marie ; Rahmel, Axel ; Renders, Lutz ; Novotny, Alexander ; Matevossian, Edouard ; Schneeberger, Stefan ; Rosenkranz, Alexander ; Berlakovich, Gabriela ; Ysebaert, Dirk ; Knops, Noël ; Kuypers, Dirk ; Weekers, Laurent ; Muehlfeld, Anja ; Rump, Lars‐Christian ; Hauser, Ingeborg A. ; Pisarski, Przemyslaw ; Weimer, Rolf ; Fornara, Paolo ; Fischer, Lutz ; Kliem, Volker ; Sester, Urban ; Stippel, Dirk ; Arns, Wolfgang ; Hau, Hans‐Michael ; Nitschke, Martin ; Hoyer, Joachim ; Thorban, Stefan ; Weinmann‐Menke, Julia ; Heller, Katharina ; Banas, Bernhard ; Schwenger, Vedat ; Nadalin, Silvio ; Lopau, Kai ; Hüser, Norbert ; Heemann, Uwe
In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re‐transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15‐year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re‐DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re‐DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re‐DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.
Ring, Klaus ; Gerhardt, Wolfgang ; Hauf, Volker ; Schroeder-Hohenwarth, Hanns Christian ; Deusinger, Ingrid ; Riesenhuber, Heinz
Öztürk, Fatma Cagla ; Akkuş, Baki ; Atanasov, Dinko ; Beyer, Heinrich F. ; Bosch, Fritz ; Boutin, David ; Brandau, Carsten ; Bühler, Paul ; Çakirli Mutlu, Rabia Burcu ; Chen, Ruijiu ; Chen, Weidong ; Chen, Xiangcheng ; Dillmann, Iris ; Dimopoulou, Christina ; Enders, Wolfgang ; Essel, Hans G. ; Faestermann, Thomas ; Forstner, Oliver ; Gao, Bing-Shui ; Geissel, Hans ; Gernhäuser, Roman ; Grisenti, Robert Evaristo ; Gumberidze, Alexandre ; Hagmann, Siegbert ; Heftrich, Tanja ; Heil, Michael ; Herdrich, Marc Oliver ; Hillenbrand, Pierre-Michel ; Izumikawa, Takuji ; Kienle, Paul ; Klaushofer, Christoph ; Kleffner, Carl-Michael ; Kozhuharov, Christophor ; Knöbel, Ronja ; Kovalenko, Oleksandr ; Kreim, Susanne ; Kühl, Thomas ; Lederer-Woods, Claudia ; Lestinsky, Michael ; Litvinov, Sergey A. ; Litvinov, Yuri A. ; Liu, Zhong ; Ma, Xinwen ; Maier, Ludwig W. ; Mei, Bo ; Miura, Hiroshi ; Mukha, Ivan ; Najafi, Mohammad Ali ; Nagae, Daisuke ; Nishimura, Takuro ; Nociforo, Chiara ; Nolden, Fritz ; Ohtsubo, Takashi ; Öktem, Yeşim ; Omika, Shunichiro ; Ozawa, Akira ; Petridis, Nikolaos ; Piotrowski, Jeremi ; Reifarth, René ; Roßbach, Jörg ; Sánchez Alarcón, Rodolfo Marcelo ; Sanjari, Mohammad Shahab ; Scheidenberger, Christoph ; Sidhu, Ragandeep Singh ; Simon, Haik ; Spillmann, Uwe ; Steck, Markus ; Stöhlker, Thomas ; Sun, Baohua ; Susam, Lidya Amon ; Suzaki, Fumi ; Suzuki, Takeshi ; Torilov, Sergey Yu. ; Trageser, Christian ; Trassinelli, Martino ; Trotsenko, Sergiy ; Tu, Xiaolin ; Walker, Philip M. ; Wang, M. ; Weber, Günter ; Weick, Helmut ; Winckler, Nicolas ; Winters, Danyal Ferdinant Alexander ; Woods, Philip John ; Yamaguchi, Takayuki ; Xu, X.D. ; Yan, X.L. ; Yang, Jiancheng ; Yuan, You-Jin ; Zhang, Yuhu ; Zhou, Xiaohong
An experiment addressing electron capture (EC) decay of hydrogen-like 142Pm60+ions has been conducted at the experimental storage ring (ESR) at GSI. The decay appears to be purely exponential and no modulations were observed. Decay times for about 9000 individual EC decays have been measured by applying the single-ion decay spectroscopy method. Both visually and automatically analysed data can be described by a single exponential decay with decay constants of 0.0126(7)s−1 for automatic analysis and 0.0141(7)s−1 for manual analysis. If a modulation superimposed on the exponential decay curve is assumed, the best fit gives a modulation amplitude of merely 0.019(15), which is compatible with zero and by 4.9 standard deviations smaller than in the original observation which had an amplitude of 0.23(4).
Marganiec, Justyna ; Wamers, Felix ; Aksouh, Farouk ; Aksyutina, Yuliya ; Álvarez-Pol, Héctor ; Aumann, Thomas ; Beceiro-Novo, Saul ; Bertulani, Carlos A. ; Boretzky, Konstanze ; Garcia Borge, Maria José ; Chartier, Marielle ; Chatillon, Audrey ; Chulkov, Leonid V. ; Cortina Gil, Dolores ; Emling, Hans ; Ershova, Olga ; Fraile Prieto, Luis Mario ; Fynbo, Hans Otto Uldall ; Galaviz Redondo, Daniel ; Geissel, Hans ; Heil, Michael ; Hoffmann, Dieter H. H. ; Hoffmann, Jan ; Johansson, Håkan T. ; Jonson, Björn ; Karagiannis, Christos ; Kiselev, Oleg A. ; Kratz, Jens-Volker ; Kulessa, Reinhard ; Kurz, Nikolaus ; Langer, Christoph ; Lantz, Mattias ; Le Bleis, Tudi ; Lemmon, Roy Crawford ; Litvinov, Yuri A. ; Mahata, Kripamay ; Müntz, Christian ; Nilsson, Thomas ; Nociforo, Chiara ; Nyman, Göran Hugo ; Ott, Wolfgang ; Panin, Valerii ; Paschalis, Stefanos ; Perea Martinez, Angel ; Plag, Ralf ; Reifarth, René ; Richter, Achim ; Rodriguez-Tajes, Carme ; Rossi, Dominic M. ; Riisager, Karsten ; Savran, Deniz ; Schrieder, Gerhard ; Simon, Haik ; Stroth, Joachim ; Sümmerer, Klaus ; Tengblad, Olof ; Typel, Stefan ; Weick, Helmut ; Wiescher, Michael ; Wimmer, Christine
New experimental data for dissociation of relativistic 17Ne projectiles incident on targets of lead, carbon, and polyethylene targets at GSI are presented. Special attention is paid to the excitation and decay of narrow resonant states in 17Ne. Distributions of internal energy in the three-body system have been determined together with angular and partial-energy correlations between the decay products in different energy regions. The analysis was done using existing experimental data on 17Ne and its mirror nucleus 17N. The isobaric multiplet mass equation is used for assignment of observed resonances and their spins and parities. A combination of data from the heavy and light targets yielded cross sections and transition probabilities for the Coulomb excitations of the narrow resonant states. The resulting transition probabilities provide information relevant for a better understanding of the 17Ne structure.
Das erstmals Ende 2002 im Süden Chinas aufgetretene schwere akute respiratorische Syndrom (SARS) führte bis zum August 2003 zu insgesamt über 8000 Erkrankungen und über 700 Todesfällen. Eine von der Weltgesundheitsorganisation (WHO) ins Leben gerufene Kooperation verschiedener Laboratorien weltweit ermöglichte innerhalb von nur vier Wochen die Identifizierung des kausalen Agens, eines bislang unbekannten Coronavirus (vorläufig bezeichnet als SARS-assoziiertes Coronavirus oder SARS-CoV), welches die Koch’schen Postulate erfüllt. Der Erreger lässt sich (unter Hochsicherheitsbedingungen) gut in Zellkulturen vermehren, was weitere Studien zur Stabilität sowie die Entwicklung von antiviral wirksamen Substanzen und Impfstoffen erleichtert.
Obwohl schon rasch diagnostische Labortests, insbesondere zum Nachweis der viralen Nukleinsäure und virusspezifischer Antikörper, zur Verfügung standen, basiert die Falldefinition von SARS weiterhin auf klinisch-epidemiologischen Kriterien. In Hinblick auf die Gefahr eines (saisonalen) Wiederauftretens der Infektion müssen die verfügbaren Labormethoden dringend überprüft und weiter verbessert werden.
SARS ist ein gutes Beispiel dafür, wie schnell sich eine Infektionskrankheit über den internationalen Reiseverkehr ausbreiten kann, aber auch dafür, wie wichtig in einem solchen Falle eine gut koordinierte internationale Kooperation ist; durch Einsatz neuester, aber auch bewährter konventioneller Labormethoden und ständigen Austausch aktueller (Zwischen-)Ergebnisse sowie von Patientenproben und Reagenzien führte eine bisher einmalige Zusammenarbeit schnell zu einem Durchbruch. Dies lässt auf ähnliche Fortschritte beim Kampf gegen weitere neuartige Infektionserreger hoffen.
The structures of seven di- or tetrasubstituted p-benzoquinone derivatives O=C(XC=CH )2C=O and O=C(XC=CX)2C=O with substituents X = -OCH3, -N(CH2)5, - N(CH2CH2)2O, -Cl, -CN and -⊕N(HC=CH)2C-N(CH3)2 are presented and discussed in comparison with published ones substituted by X = -Si(CH3)3, -C6H5, -N(CH3)2, -⊕N(HC=CH)2CN(CH3)2, -O⊖ , and - NO2. Based on the introduction, in which halfwave-reduction potentials, geometry-optimized quantum-chemical calculations on substituent perturbation and known structural data of p-benzoquinone derivatives are used to characterize their molecular ground states. The structural changes indicate how substituent perturbations might be rationalized. Of the categories defined - imperturbed, donor, donor/acceptor and acceptor perturbed - the donorsubstituted p-benzoquinones do exhibit the largest differences, often called cyanine distorsion. In very satisfactory agreement with extensive semiempirical calculations, all effects determined experimentally are discussed in terms of varying charge distribution. With respect to the biochemical importance of p-benzoquinone derivatives, this first structural summary points out important facets.
Chelate complexes of 1,2-dimesitoylbenzene radical anion with alkali metal cations exhibit in aprotic solution extremely large ESR /ENDOR metal coupling constants. For rationalization, structures of both the neutral molecule (H3C)3H2C6 - CO - C6H4 - CO - C6H2(CH3)3, in which the two carbonyl groups are twisted out of the benzene ring plane by dihedral angles of ± 3̄7̄°, and a sodium contact ion quadruple have been determined. One of the dimers [dimesitoylbenzeneH⊖ (Na⊕H2N H2C - CH2NH2)]2, although generated by Na metal mirror reduction of 1,2-dimesitoylbenzene in aprotic DME solution with added ethylendiamine for better electron transfer, surprisingly contains two 245 pm short (!) hydrogen bridges ⊖O ··· (H)O and in addition two solvation bridges e ⊖O ··· Na⊕(H2NH2C - CH2NH2) ··· O⊖. Results of MNDO calculations based on the experimental coordinates support the proposed concept.
Schaller-Paule, Martin A. ; Yalachkov, Yavor Vasilev ; Steinmetz, Helmuth ; Friedauer, Lucie ; Hattingen, Elke ; Miesbach, Wolfgang ; Weber, Frank ; Kirchmayr, Konstantin ; Schäfer, Jan Hendrik ; Förch, Christian
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Eckardt, Jan-Niklas ; Stasik, Sebastian ; Kramer, Michael ; Röllig, Christoph ; Krämer, Alwin ; Scholl, Sebastian ; Hochhaus, Andreas ; Crysandt, Martina ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Kunzmann, Volker ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Herbst, Regina ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Baldus, Claudia ; Kaufmann, Martin ; Rácil, Zdenek ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Mayer, Jiří ; Serve, Hubert ; Müller-Tidow, Carsten ; Ehninger, Gerhard ; Stölzel, Friedrich ; Kroschinsky, Frank ; Schetelig, Johannes ; Bornhäuser, Martin ; Thiede, Christian ; Middeke, Jan Moritz
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Settelmeier, Stephan ; Kessler, Lukas ; Varasteh, Zohreh ; Mahabadi, Amir Abbas ; Michel, Christian Lars ; Papathanasiou, Maria ; Laschinsky, Christina ; Rischpler, Christoph ; Fendler, Wolfgang P. ; Schlosser, Thomas Wilfried ; Umutlu, Lale ; Herrmann, Ken ; Rassaf, Tienush ; Kersting, David
Koschade-Rixner, Sebastian E. ; Stratmann, Jan Alexander ; Miesbach, Wolfgang ; Steffen, Björn ; Serve, Hubert ; Finkelmeier, Fabian ; Brandts, Christian Hubertus ; Ballo, Olivier Karl Friedrich
Objectives and Methods: Intracranial hemorrhage (ICH) in acute myeloid leukemia (AML) patients is a major concern due to the increased risk of mortality. Few studies have examined ICH specifically in newly diagnosed AML patients receiving intensive induction chemotherapy (IC) and prophylactic platelet transfusions during thrombocytopenia <10/nL. This retrospective cohort study included 423 newly diagnosed AML patients without acute promyelocytic leukemia who underwent IC between 2007 and 2019. We assessed risk factors, clinical features, and outcomes of ICH.
Results: 17 of 423 patients (4%) suffered ICH during hospital stay, and 4 patients (24%) died directly because of ICH despite routine prophylactic platelet transfusions. Patients with ICH had a negatively impacted overall survival (median OS, 20.1 vs. 104.8 months) and were more likely not to continue with curative treatment. Main risk factors were female gender, severe thrombocytopenia, and decreased fibrinogen. Patients with subsequent ICH also had laboratory signs of liver dysfunction.
Conclusions: Intracranial hemorrhage remains a potentially deadly complication with notable incidence despite prophylactic platelet substitution, suggesting that additional prophylactic interventions may be required to further reduce the frequency of ICH in high-risk patients. Unrecognized genetic factors may simultaneously predispose to AML and platelet dysfunction with ICH.
Happel, Christian ; Kranert, Wolfgang Tilman ; Gröner, Daniel ; Baumgarten, Justus ; Halstenberg, Jörg ; Bockisch, Benjamin ; Sabet, Amir ; Grünwald, Frank
Aim: Radioiodine therapy (RIT) may trigger the development of Graves’ ophthalmopathy (GO) or exacerbate pre-existing subclinical GO. Therefore, glucocorticoid administration is recommended for patients with pre-existing GO. Aim of this study was to analyze the influence of glucocorticoid therapy with methylprednisolone on intratherapeutic effective half-life (EHL) of radioiodine-131 in patients with Graves’ disease (GD) as recent studies showed an effect for prednisolone.
Methods: In a retrospective study, 264 patients with GD who underwent RIT without any additional antithyroid medication were evaluated. Intrathyroidal EHL was determined pre- and intratherapeutically. Patients with co-existing GO (n = 43) received methylprednisolone according to a fixed scheme starting 1 day prior to RIT, patients without GO (n = 221) did not receive any protective glucocorticoid medication. The ratios of EHL during RIT and during radioiodine uptake test (RIUT) were compared.
Results: Patients receiving methylprednisolone showed a slight decrease of the mean EHL from 5.63 d (RIUT) to 5.39 d (RIT) (p > 0.05). A comparable result was obtained in patients without glucocorticoids (5.71 d (RIUT) to 5.47 d (RIT); p > 0.05). The ratios of the EHL between RIT and RIUT failed to show a significant difference between the two groups. EHL is therefore not significantly influenced by an additional protective treatment with methylprednisolone.
Conclusions: In the present study a decreased intrathyroidal EHL under glucocorticoid medication with methylprednisolone could not be detected. Therefore, co-medication with methylprednisolone in patients with GO may be preferred to avoid an intratherapeutic decrease of EHL by accompanying protective glucocorticoides.
Lehr, Christopher ; Wamers, Felix ; Aksouh, Farouk ; Aksyutina, Yuliya ; Álvarez-Pol, Héctor ; Atar, Leyla ; Aumann, Thomas ; Beceiro-Novo, Saul ; Bertulani, Carlos A. ; Boretzky, Konstanze ; Garcia Borge, Maria José ; Caesar, Christoph ; Chartier, Marielle ; Chatillon, Audrey ; Chulkov, Leonid V. ; Cortina Gil, Dolores ; Díaz Fernández, Paloma ; Emling, Hans ; Ershova, Olga ; Fraile Prieto, Luis Mario ; Fynbo, Hans Otto Uldall ; Galaviz Redondo, Daniel ; Geissel, Hans ; Heil, Michael ; Heine, Marcel ; Hoffmann, Dieter H. H. ; Holl, Matthias ; Johansson, Håkan T. ; Jonson, Björn ; Karagiannis, Christos ; Kiselev, Oleg A. ; Kratz, Jens-Volker ; Kulessa, Reinhard ; Kurz, Nikolaus ; Langer, Christoph ; Lantz, Mattias ; Le Bleis, Tudi ; Lemmon, Roy Crawford ; Litvinov, Yuri A. ; Löher, Bastian ; Mahata, Kripamay ; Marganiec-Galązka, Justyna ; Müntz, Christian ; Nilsson, Thomas ; Nociforo, Chiara ; Ott, Wolfgang ; Panin, Valerii ; Paschalis, Stefanos ; Perea Martinez, Angel ; Plag, Ralf ; Reifarth, René ; Richter, Achim ; Riisager, Karsten ; Rodriguez-Tajes, Carme ; Rossi, Dominic M. ; Savran, Deniz ; Scheit, Heiko ; Schrieder, Gerhard ; Schrock, Philipp ; Simon, Haik ; Stroth, Joachim ; Sümmerer, Klaus ; Tengblad, Olof ; Weick, Helmut ; Wimmer, Christine
The proton drip-line nucleus 17Ne is investigated experimentally in order to determine its two-proton halo character. A fully exclusive measurement of the 17Ne(p, 2p)16F∗ →15O+p quasi-free one-proton knockout reaction has been performed at GSI at around 500 MeV/nucleon beam energy. All particles resulting from the scattering process have been detected. The relevant reconstructed quantities are the angles of the two protons scattered in quasi-elastic kinematics, the decay of 16F into 15O (including γ decays from excited states) and a proton, as well as the 15O+p relative-energy spectrum and the 16F momentum distributions. The latter two quantities allow an independent and consistent determination of the fractions of l = 0 and l = 2 motion of the valence protons in 17Ne. With a resulting relatively small l = 0 component of only around 35(3)%, it is concluded that 17Ne exhibits a rather modest halo character only. The quantitative agreement of the two values deduced from the energy spectrum and the momentum distributions supports the theoretical treatment of the calculation of momentum distributions after quasi-free knockout reactions at high energies by taking into account distortions based on the Glauber theory. Moreover, the experimental data allow the separation of valence-proton knockout and knockout from the 15O core. The latter process contributes with 11.8(3.1) mb around 40% to the total proton-knockout cross section of 30.3(2.3) mb, which explains previously reported contradicting conclusions derived from inclusive cross sections.
Scheidt, Moritz von ; Bauer, Sabine ; Ma, Angela ; Hao, Ke ; Kessler, Thorsten ; Vilne, Baiba ; Wang, Ying ; Hodonsky, Chani J. ; Ghosh, Saikat K.B. ; Mokry, Michal ; Gao, Hua ; Kawai, Kenji ; Sakamoto, Atsushi ; Kaiser, Juliane ; Bongiovanni, Dario ; Fleig, Julia ; Oldenbuettel, Lilith ; Chen, Zhifen ; Moggio, Aldo ; Sager, Hendrik ; Hecker, Judith S. ; Bassermann, Florian ; Mägdefessel, Lars ; Miller, Clint L. ; Koenig, Wolfgang ; Zeiher, Andreas M. ; Dimmeler, Stefanie ; Graw, Matthias ; Braun, Christian ; Ruusalepp, Arno ; Leeper, Nicholas J. ; Kovacic, Jason C. ; Björkegren, Johan L.M. ; Schunkert, Heribert
Background: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.
Methods: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.
Results: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTM visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways.
Conclusions: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.