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Gohlke B.O.,German Cancer Consortium DKTK | Preissner R.,Charite - Medical University of Berlin | Preissner S.,Charite - Medical University of Berlin
Nucleic Acids Research | Year: 2014

Pain is more than an unpleasant sensory experience associated with actual or potential tissue damage: it is the most common reason for physician consultation and often dramatically affects quality of life. The management of pain is often difficult and new targets are required for more effective and specific treatment. SuperPain (http://bioinformatics.charite.de/superpain/) is freely available database for pain-stimulating and pain-relieving compounds, which bind or potentially bind to ion channels that are involved in the transmission of pain signals to the central nervous system, such as TRPV1, TRPM8, TRPA1, TREK1, TRESK, hERG, ASIC, P2X and voltage-gated sodium channels. The database consists of ∼8700 ligands, which are characterized by experimentally measured binding affinities. Additionally, 100 000 putative ligands are included. Moreover, the database provides 3D structures of receptors and predicted ligand-binding poses. These binding poses and a structural classification scheme provide hints for the design of new analgesic compounds. A user-friendly graphical interface allows similarity searching, visualization of ligands docked into the receptor, etc. © 2013 The Author(s). Published by Oxford University Press.

The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4BG12V/G13D/Q61K, NRASQ61L/Q61R or BRAFV600E, lead to tremendous increase in their activities, resulting in constitutively active extracellular signal–regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAFV600E, Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAFV600E/K harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.329. © 2015 Macmillan Publishers Limited

Louis D.N.,Harvard University | Perry A.,University of California at San Francisco | Reifenberger G.,Heinrich Heine University Dusseldorf | von Deimling A.,German Cancer Consortium DKTK | And 7 more authors.
Acta Neuropathologica | Year: 2016

The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M–mutant; RELA fusion–positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma—a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors. © 2016, Springer-Verlag Berlin Heidelberg.

Rauscher I.,German Cancer Consortium DKTK | Rauscher I.,German Cancer Research Center | Eiber M.,TU Munich | Souvatzoglou M.,TU Munich | And 2 more authors.
Journal of Nuclear Medicine | Year: 2014

PET/MR is a new multimodal imaging technique that is expected to improve diagnostic performance, especially in oncologic patients in certain indications. Apart from the clinical relevance of PET with 18F-FDG, various other tracers exist and are increasingly used, which allow insights into multiple physiologic and biologic processes. In this review, we discuss the current and potential future applications of hybrid PET/MR, focusing on non- 18F-FDG tracers. The combination of PET and MR in hybrid whole-body PET/MR systems has the potential to combine excellent morphologic, functional, and biologic information in 1 imaging session with precise image coregistration, thus paving the way for the concept of multimodal multiparametric imaging for future more widespread clinical use. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Laubender R.P.,German Cancer Consortium DKTK | Laubender R.P.,Ludwig Maximilians University of Munich | Laubender R.P.,German Cancer Research Center | Bender R.,Institute for Quality and Efficiency in Health Care IQWiG | Bender R.,University of Cologne
Statistics in Medicine | Year: 2014

Recently, Laubender and Bender (Stat.Med.2010; 29: 851-859) applied the average risk difference (RD) approach to estimate adjusted RD and corresponding number needed to treat measures in the Cox proportional hazards model. We calculated standard errors and confidence intervals by using bootstrap techniques. In this paper, we develop asymptotic variance estimates of the adjusted RD measures and corresponding asymptotic confidence intervals within the counting process theory and evaluated them in a simulation study. We illustrate the use of the asymptotic confidence intervals by means of data of the Düsseldorf Obesity Mortality Study. © 2013 John Wiley & Sons, Ltd.

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