1,589 research outputs found
Von der Gemeinschaftsgewalt zur Gewaltgemeinschaft? Zum Wandel der Straßenkultur
No full textZdun S, Strasser H. Von der Gemeinschaftsgewalt zur Gewaltgemeinschaft? Zum Wandel der Straßenkultur. In: Hitzler R, Honer A, Pfadenhauer M, eds. Posttraditionale Gemeinschaften. Theoretische Bestimmungen und ethnographische Deutungen. Wiesbaden: VS Verl. für Sozialwiss.; 2008: 310-326
A conceptual framework for cautious escalation of anticancer treatment: How to optimize overall benefit and obviate the need for de-escalation trials.
No full textBACKGROUND
The developmental workflow of the currently performed phase 1, 2 and 3 cancer trial stages lacks essential information required for the determination of the optimal efficacy threshold of new anticancer regimens. Due to this there is a serious risk of overdosing and/or treating for an unnecessary long time, leading to excess toxicity and a higher financial burden for society. But often post-approval de-escalation trials for dose-optimization and treatment de-intensification are not performed due to failing resources and time. Therefore, the developmental workflow needs to be restructured toward cautious systemic cancer treatment escalation, in order to guarantee optimal efficacy and sustainability.
METHODS
In this manuscript we discuss opportunities to produce the information needed for cautious escalation, based on models of cancer growth and cancer kill kinetics as well as exploratory biomarkers, for the purpose of designing the optimal phase 3 superiority trial. Subsequently, we compare the sample size needed for a phase 3 superiority trial, followed by a necessary de-escalation trial with the sample size needed for a multi-arm phase 3 trial with intervention arms of differing intensity. All essential items are structured within a Framework for Cautious Escalation (FCE). The discussion uses illustrations from the breast cancer setting, but aims to be applicable for all cancers.
RESULTS
The FCE is a promising model of clinical development in oncology to prevent overtreatment and associated issues, especially with regard to the number of repetitive treatment cycles. It will hopefully increase the relevance and success rate of clinical trials, to deliver improved patient-centric outcomes
Purification, crystallization and preliminary crystallographic data of the m(3)G cap-binding domain of human snRNP import factor snurportin 1
No full textThe nuclear import of spliceosomal UsnRNPs is mediated by the transport adaptor snurportin 1 (SPN1), which specifically recognizes the 2,2,7-trimethylguanosine (m(3)G) cap at the 5' end of UsnRNAs. Human SPN1 was overexpressed as a GST-fusion protein in Escherichia coli and purified to homogeneity Since full-length SPN1 did not crystallize, limited proteolysis experiments were performed and stable digestion products were analyzed for functionality with respect to m(3)G cap-binding activity and subsequently used for crystallization trials. Well diffracting single crystals of a truncated SPN1 m(3)G cap-binding domain (residues 79-300) were obtained after two rounds of seeding. The crystals belong to space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = b = 57.47, c = 130.09 Angstrom, alpha = beta = gamma = 90degrees. Crystals contain one molecule in the asymmetric unit and diffract to a resolution limit of 2.9 Angstrom
Identifying non-invasible habitats for marine copepods using temperature-dependent R0.
No full textIf a non-indigenous species is to thrive and become invasive it must first persist under its new set of environmental conditions. Net reproductive rate (R 0) represents the average number of female offspring produced by a female over its lifetime, and has been used as a metric of population persistence. We modeled R 0 as a function of ambient water temperature (T) for the invasive marine calanoid copepod Pseudodiaptomus marinus, which is introduced to west coast of North America from East Asia by ship ballast water. The model was based on temperature-dependent stage-structured population dynamics given by a system of ordinary differential equations. We proposed a methodology to identify habitats that are non-invasible for P. marinus using the threshold of R 0(T) < 1 in order to identify potentially invasible habitats. We parameterized the model using published data on P. marinus and applied R 0(T) to identify the range of non-invasible habitats in a global scale based on sea surface temperature data. The model predictions matched the field evidence of species occurrences well
Identifying non-invasible habitats for marine copepods using temperature-dependent R0
No full textIf a non-indigenous species is to thrive and become invasive it must first persist under its new set of environmental conditions. Net reproductive rate (R 0) represents the average number of female offspring produced by a female over its lifetime, and has been used as a metric of population persistence. We modeled R 0 as a function of ambient water temperature (T) for the invasive marine calanoid copepod Pseudodiaptomus marinus, which is introduced to west coast of North America from East Asia by ship ballast water. The model was based on temperature-dependent stage-structured population dynamics given by a system of ordinary differential equations. We proposed a methodology to identify habitats that are non-invasible for P. marinus using the threshold of R 0(T) < 1 in order to identify potentially invasible habitats. We parameterized the model using published data on P. marinus and applied R 0(T) to identify the range of non-invasible habitats in a global scale based on sea surface temperature data. The model predictions matched the field evidence of species occurrences well
What comes next in glycobiology
No full textGlycans, with their variable compositions and highly dynamic conformations, vastly expand the heterogeneity of whatever factor or cell they are attached to. These properties make them crucial contributors to biological function and organismal health and also very difficult to study. That may be changing as we look to the future of glycobiology.Fil: Seeberger, Peter H.. Max Planck Institute Of Biochemistry.; AlemaniaFil: Ge, Yun. Shenzhen Bay Laboratory; ChinaFil: Szymanski, Christine M.. University of Georgia; Estados UnidosFil: Kolarich, Daniel. Griffith University. Griffith School Of Engineering; AustraliaFil: Thaysen Andersen, Morten. Nagoya University; JapónFil: Packer, Nicolle H.. Mcquarie University; AustraliaFil: Fadda, Elisa. University of Southampton; Reino UnidoFil: Davis, Benjamin. University of Oxford; Reino UnidoFil: Nishihara, Shoko. Soka University; JapónFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Kwong, Peter D.. National Institutes of Health; Estados Unidos. Columbia University; Estados UnidosFil: Strasser, Richard. University Of Natural Resources And Life Sciences
Influence of the N-terminus and the E2-loop onto the binding kinetics of the antagonist mepyramine and the partial agonist phenoprodifen to H1R
No full textNumerous competitive radioligand binding studies revealed significant differences between human and guinea pig histamine H-1-receptors (hH(1)R and gpH(1)R), e.g. for the partial H1R agonist phenoprodifen. But until now, there are only few studies with regard to binding kinetics at H1R. Previous studies from our group revealed an influence of the exchange of N-terminus and E2-loop between hH(1)R and gpH(1)R onto affinity of phenoprodifen to H1R (Strasser A, Wittmann HJ, Seifert R, J Pharmacol Exp Ther 326:783-791, 2008). The aim of this study was, therefore, to examine the impact of the N-terminus and the E2-loop on binding kinetics of the H1R. The wild type hH(1)R and gpH(1)R and the chimeric h(gpE2)H(1)R (E2-loogp from guinea pig) and h(gpNgpE2)H(1)R (N-terminus and E2-loop from guinea pig) were co-expressed with regulator of G-protein signaling protein RGS4 in Sf9 insect cells and kinetic binding studies were performed using the antagonist [H-3]-mepyramine as radioligand. The rate constants for association and dissociation were, in dependence of the ligand, different between hH(1)R and gpH(1)R. Furthermore, the rate constants for association at h(gpNgpE2)H(1)R were significantly different compared to hH(1)R and gpH(1)R. Molecular dynamic simulation studies detected different interactions of amino acid side chains on the extracellular surface of the receptor. Based on these findings, the influence of extracellular surface onto binding kinetics and binding affinity can be explained. Thus, the extracellular surface of G protein-coupled receptors for biogenic amines, exhibits influence onto kinetics of ligand binding, onto ligand recognition and ligand guiding into the binding pocket. (C) 2011 Elsevier Inc. All rights reserved
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