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Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
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.
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
We present the first measurement of fluctuations from event to event in the production of strange particles in collisions of heavy nuclei. The ratio of charged kaons to charged pions is determined for individual central Pb+Pb collisions. After accounting for the fluctuations due to detector resolution and finite number statistics we derive an upper limit on genuine non-statistical fluctuations, perhaps related to a first or second order QCD phase transition. Such fluctuations are shown to be very small.
Ein Ansatz für semantisches Selbstmanagement von verteilten Anwendungen im privaten Lebensumfeld
(2014)
Die Anreicherung des privaten Lebensumfelds mit intelligenten technischen Assistenzsystemen wird in den nächsten Jahrzehnten stark zunehmen. Als Teil dieser Entwicklung wird die Nutzung von externen und hauseigenen IT-Diensten steigen, wodurch sich auch die Komplexität der entstehenden Gesamtsysteme erhöht. Hier sind Ansätze gefordert, diese Systeme auch für technisch nicht versierte Benutzer produktiv nutzbar und beherrschbar zu gestalten, um eine Überforderung zu vermeiden. Im Umfeld häuslicher Dienstplattformen, die eine zentrale Rolle in solchen Systemen übernehmen, nimmt seit ein paar Jahren die Bedeutung der semantischen Modellierung von Diensten stark zu. Diese dient zum einen der formalen Repräsentation von zugehörigen Kontextinformationen, die durch Interaktion mit Sensoren und Aktoren entstehen, und zum anderen der Verbesserung der Interoperabilität zwischen Systemen unterschiedlicher Hersteller. Bisherige Ansätze beschränken sich jedoch auf den Einsatz eines zentralen Rechenknotens zur Ausführung der Dienstplattform und nutzen Semantik – wenn überhaupt – nur zur Verarbeitung von Kontextinformationen. Ein technisches Management des Gesamtsystems findet i.d.R. nicht statt.
Vor diesem Hintergrund ist das Ziel dieser Arbeit die Entwicklung eines Ansatzes für semantisches Selbstmanagement von verteilten dienstbasierten Anwendungen speziell im Umfeld häuslicher Dienstplattformen.
Die vorliegende Arbeit definiert zunächst formale Ontologien für Dienste, Dienstgütemanagement, Selbstmanagement und zugehörige Managementregeln, die zur Laufzeit mit konkreten Diensten und deren erfassten Leistungskenngrößen integriert werden. Durch einen modellgetriebenen Architekturansatz (Model Driven Architecture, MDA) wird ein technologieunabhängiges Management auf abstrakter Ebene ermöglicht, das die Wiederverwendbarkeit von Managementregeln in anderen Szenarien erlaubt.
Dieser Ansatz wird zunächst in eine Architektur für einen hochverfügbaren autonomen Manager überführt, der die Überwachung und Steuerung von Diensten und zugehörigen Dienstplattformen übernehmen kann und auf der aus dem Autonomic Computing bekannten MAPE-K-Kontrollschleife (Monitor, Analyze, Plan, Execute, Knowledge) basiert.
Den Abschluss der Arbeit bildet eine qualitative und quantitative Evaluation (mittels einer OSGi-basierten prototypischen Umsetzung) der erreichten Ergebnisse, die einen Einsatz über die Grenzen des privaten Lebensumfelds hinaus nahelegen.
Introduction: Langerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as "Histiocytosis X", "Type II Histiocytosis" or "Langerhans Cell Granulomatosis". Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis.
Methods and material: Eight closely cooperating centres collected patients' data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined.
Results: A total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9-134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3-50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed.
Conclusion: In the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
We investigate the long-standing question of the effect of proton-antiproton annihilation on the (anti-)proton yield, while respecting detailed balance for the five-body back-reaction for the first time in a full microscopic description of the late stages of heavy-ion collisions. This is achieved by employing a stochastic collision criterion in a hadronic transport approach (SMASH), which is used to account for the regeneration of (anti-)protons via 5π→p¯p. We investigate Au+Au and Pb+Pb collisions from √sNN=17.3GeV−5.02 TeV in a viscous hybrid approach. Our results show that back-reactions happen for a fraction of 15%–20% of all annihilations, independent of the beam energy or centrality of the system. The inclusion of the back-reaction results in the regeneration of half of the (anti-)proton yield lost to annihilations at midrapidity. We also find that, concerning the multiplicities, treating the back-reaction as a chain of two-body reactions is equivalent to a single 5-to-2 reaction.
The German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh) : a success story
(2016)
This article gives a comprehensive overview on the strategy, the development and the progress of the German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh). The program soon prompted positive results: more than 10 years now the courses had an average enrolment rate of 90 %, and employment-seeking graduates from the first courses mostly succeeded in quickly finding employment relevant to their training. With over 450 students enrolled to date, the degree program contributes significantly to the field of Environmental Chemistry and Ecotoxicology.
Cryo-electron tomography (CryoET) resolves individual macromolecules inside living cells. However, the complex composition and high density of cells challenge the faithful identification of features in tomograms. Here, we capitalize on recent advances in electron tomography and demonstrate that 3D template matching (TM) localizes a wide range of structures inside crowded eukaryotic cells with confidence 10 to 100-fold above the noise level. We establish a TM pipeline with systematically tuned parameters for automated, objective and comprehensive feature identification. High-fidelity and high-confidence localizations of nuclear pore complexes, vaults, ribosomes, proteasomes, lipid membranes and microtubules, and individual subunits, demonstrate that TM is generic. We resolve ~100-kDa proteins, connect the functional states of complexes to their cellular localization, and capture vaults carrying ribosomal cargo in situ. By capturing individual molecular events inside living cells with defined statistical confidence, high-confidence TM greatly speeds up the CryoET workflow and sets the stage for visual proteomics.