ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia

Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected (n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis

Legitimacy intermediation in the multilevel European polity and its collapse in the euro crisis

This essay re-examines the dual – republican and liberal – foundations of democratic legitimacy in the Western traditions of normative political theory. Considered in isolation, the European Union conforms to liberal standards but cannot satisfy republican criteria. Given these conflicting standards, debates on the alleged European democratic deficit have remained inconclusive. Moreover, they have failed to pay sufficient attention to the multilevel character of the European polity and to the normative potential of legitimacy intermediation in its two-step compliance and legitimating relationships. I argue, however, that the capacity of democratic member states to legitimate the exercise of European governing functions is being destroyed in the present euro crisis, and I briefly discuss the implications of this new constellation.In der westlichen Tradition der normativen politischen Theorie beruht demokratische Legitimität auf der doppelten Grundlage republikanischer und liberaler Prinzipien. Für sich betrachtet entspricht die Europäische Union zwar liberalen Kriterien, aber eben nicht den republikanischen Anforderungen. Angesichts so unterschiedlicher Kriterien konnte es auch im Streit über das angebliche europäische Demokratiedefizit keine Einigung geben. Überdies ignorierte diese Diskussion den Mehrebenen-Charakter der europäischen Politik und das normative Potenzial der Legitimationsvermittlung zwischen Union und Bürgern durch die demokratisch verfassten Mitgliedstaaten. Die gegenwärtige Eurokrise allerdings zerstört die Fähigkeit demokratischer Mitgliedstaaten, die Ausübung europäischer Herrschaftsfunktionen zu legitimieren. Der Aufsatz erörtert die Implikationen dieser neuen Konstellation.1 Introduction 2 Legitimacy discourses The republican discourse The liberal discourse Differences 3 Constitutional democracies – and the European Union? 4 Legitimacy intermediation in the multilevel European polity 5 The end of legitimacy intermediation in the euro crisis Monetary Union and the failure of output legitimacy Rescuing the euro through supranational intervention 6 Legitimate supranational government? Input-oriented European legitimacy? 7 Reducing the burden on European legitimacy Reference

Mutationen und Promotormethylierung des Polycomb Repressive Complex 2 bei akuter lymphoblastischer Leukämie im Kindesalte

In der vorliegenden Arbeit sollte die Prävalenz und klinische Bedeutung von PRC2-Mutationen in einer nicht selektierten Patientenkohorte von 152 Kindern mit ALL bestimmt werden. Des Weiteren sollte der Methylierungsstatus der Genpromotoren von EZH2, EED und SUZ12 gemessen werden, um mögliche alternative Aktivierungs- oder Inaktivierungsmechanismen des PRC2 zu identifizieren

Infrastructure, logistics and clinical practice management of acute trauma hemorrhage and coagulopathy: a survey across German trauma centers

Purpose!#!Early detection and management of acute trauma hemorrhage and coagulopathy have been associated with improved outcomes, but local infrastructure, logistics and clinical strategies may differ.!##!Methods!#!To assess local differences in infrastructure, logistics and clinical management of acute trauma hemorrhage and coagulopathy we have conducted a web-based survey amongst clinicians working in DGU!##!Results!#!137/1875 respondents completed the questionnaire yielding a response rate of 7.3%. The majority specified to work as head of department or senior consultant (95%) in trauma/orthopedic surgery (80%) of supraregional (38%), regional (34%) or local (27%) trauma centers. Conventional coagulation assays are most frequently used to monitor bleeding trauma patients. Only half of the respondents (53%) rely on extended coagulation tests, e.g. viscoelastic hemostatic assays. Tests to assess preinjury use of direct oral anticoagulants and platelet inhibitors are still not widely available and vary according to level of care. Conventional blood products are widely available but there remain differences between trauma centers of different level of care to access other hemostatic therapies, e.g. coagulation factor concentrates. Trauma centers of higher level of care are more likely to implement treatment protocols.!##!Conclusion!#!This survey confirms still existing differences in infrastructure, logistics and clinical practice management for the detection of acute trauma hemorrhage and coagulopathy amongst DG

Diabetes as risk factor for pancreatic cancer: hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells

Type 2 diabetes mellitus (T2DM) is associated with hyperglycemia and a risk to develop pancreatic ductal adenocarcinoma (PDAC), one of the most fatal malignancies. Cancer stem cells (CSC) are essential for initiation and maintenance of tumors, and acquisition of CSC-features is linked to epithelial-mesenchymal-transition (EMT). The present study investigated whether hyperglycemia promotes EMT and CSC-features in premalignant and malignant pancreatic ductal epithelial cells (PDEC). Under normoglycemia (5 mM D-glucose), Panc1 PDAC cells but not premalignant H6c7-kras cells exhibited a mesenchymal phenotype along with pronounced colony formation. While hyperglycemia (25 mM D-glucose) did not impact the mesenchymal phenotype of Pancl cells, CSC-properties were aggravated exemplified by increased Nanog expression and Nanog-dependent formation of holo- and meroclones. In H6c7-kras cells, high glucose increased secretion of Transforming-Growth-Factor-betal (TGF-beta 1) as well as TGF-beta 1 signaling, and in a TGF-beta 1-dependent manner reduced E-cadherin expression, increased Nestin expression and number of meroclones. Finally, reduced E-cadherin expression was detected in pancreatic ducts of hyperglycemic but not normoglycemic mice. These data suggest that hyperglycemia promotes the acquisition of mesenchymal and CSC-properties in PDEC by activating TGF-beta signaling and might explain how T2DM facilitates pancreatic tumorigenesis. (C) 2017 Elsevier B.V. All rights reserved

Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study

Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories (n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB, respectively, during the study period and 98% of laboratories were able to detect MR 4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1 IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance. </p

A search for flaring very-high-energy cosmic gamma-ray sources with the L3+C muon spectrometer

The L3+C muon detector at the CERN electron-positron collider, LEP, is used for the detection of very-high-energy cosmic gamma-ray sources through the observation of muons of energies above 20, 30, 50 and 100 GeV. Daily or monthly excesses in the rate of single-muon events pointing to some particular direction in the sky are searched for. The periods from mid July to November 1999, and April to November 2000 are considered. Special attention is also given to a selection of known gamma-ray sources. No statistically significant excess is observed for any direction or any particular source. (c) 2006 Elsevier B.V. All rights reserved