Molecular imaging for the quantitative assessment of tumor proliferation, progression and the early assessment of molecular targeted treatment response

Molecular imaging allows for in vivo monitoring of important processes for tumor development, tumor growth and, finally, treatment response. The major goal of this study was to investigate different multi-modal imaging techniques for the assessment of different tumor specific molecular processes (Jacobs et al., 2005a; Ullrich et al., 2008a; Ullrich et al., 2008b). In the first step, I investigated the use of [18F]FLT for the non-invasive in vivo assessment of tumor proliferation in different types of tumor models in men and mice. [18F]FLT reacts as a substrate of thymidinkinase 1 (TK1) that is highly expressed during S-phase of the cell cycle. Shields et al could show that the accumulation of [18F]FLT reflects cells entering the s-phase in vitro and in vivo (Shields et al., 1998). Here, we first sought to analyze the accuracy of [18F]FLT to detect tumor cell proliferation in patients with gliomas. We investigated the dynamic [18F]FLT distribution for the asessment of tumor cell proliferation in vivo (Ullrich et al., 2008a). In patients with newly diagnosed high grade gliomas we showed by the use of kinetic analyses that the phosphorylation rate of [18F]FLT by thymidine kinase 1 can be detected and, most importantly, is related to tumor cell proliferation as in vitro assessed by Ki-67 immunostaining. We concluded that [18F]FLT PET represents an accurate marker for the in vivo assessment of tumor cell proliferation in patients with gliomas. We next hypothesized that [18F]FLT PET might provide a sensitive marker for monitoring treatment induced G1 arrest in Non small cell lung cancer (NSCLC). Herewith, we analyzed [18F]FLT in comparison to [18F]FDG PET as a marker for monitoring anti-proliferative treatment response. In collaboration with the Cancer Genomic Group by Dr. Roman Thomas we investigated the potential of [18F]FLT to detect treatment response to specific Epithelial growth factor receptor (EGFR) inhibition in an EGFR-dependent NSCLC model. We used two EGFR-inhibition sensitive cell lines harboring the L858R mutation leading to oncogenic dependency on EGFR signaling. To validate the specificity of EGFR-inhibition we applied the EGFR inhibition resistant cell line H1975 harboring both the L858R and the T790M mutation. The T790M mutation prevents Erlotinib from binding to the intracellular domain of the EGFR. Only two days after initiation of treatment we observed a striking decrease in [18F]FLT uptake in the EGFR-mutant tumor xenograft due to 6 therapy induced G1 arrest. The specificity of this approach is confirmed by a complete lack of [18F]FLT response in the T790M EGFR-resistant xenografts. Moreover, the reduction of [18F]FLT uptake after 2 days translated into dramatic tumor shrinkage 6 days later (Ullrich et al., 2008c). Together, these data strongly suggest [18F]FLT PET as a robust marker to assess tumor proliferation, to detect induction of G1 arrest and, thus, to detect therapy response at a very early time point. Tumor growth requires new vessel formation as a critical step in tumor progression. In a recent study our group found a significant correlation between the expression of CD31 and [11C]MET uptake in gliomas (Kracht et al., 2003). [11C]MET is transported via the L amino acid transporter that is expressed on endothelial cells suggesting this tracer for imaging angiogenesis. Based on these findings we further investigated the relationship between [11C]MET uptake and angiogenesis during tumor progression by comparing uptake ratios of [11C]MET and the expression of the vascular endothelial growth factor (VEGF) in patients with gliomas. Here, we again found a significant correlation between changes in VEGF expression and [11C]MET uptake (Ullrich et al., 2009). Moreover, increase in [11C]MET uptake of more than 14,6 % was highly sensitive and specific to detect malignant progression in patients with gliomas. In summary, multi-modal imaging enables to assess tumor relevant processes, to monitor changes in tumor growth and, finally, to assess treatment response to agents targeting those processes

Ein dänisches "Beschäftigungswunder?" (A Danish “employment miracle”)

"Denmark is one of the European countries which has been able to reduce unemployment drastically in recent years; the unemployment figure has fallen by more than 120,000 since its peak of 340,000 in 1994. This success deserves particular attention because the policy followed in Denmark differs very clearly from that in the other countries with employment policy success; there is no sign of an accentuated liberalisation of the labour market, nor does the secret behind the Danish success lie in promoting part-time work or enforcing reductions in working time. As is shown in this report, the reduction of unemployment goes back to several policies acting in combination which tackled the problem almost simultaneously: a fiscal policy which first (in 1994) gave an expansionary impulse of a total of 1.2 % of the GDP and reformed the tax and social security systems; a labour market policy which increased the pressure on people to take up employment, used existing instruments (early retirement regulations) to a greater extent and developed new ones (sabbatical models), thus reducing the labour force potential by some 100,000 at short notice; and finally a wages policy which pursued a moderate course in spite of strong economic expansion and arranged wage determination more flexibly. One key to success is the fact that a stronger macroeconomic growth came about in Denmark not least as a result of this change in policy, but the higher growth explains the increase in employment only partially; the other policies also contribute to this. The method used to solve the employment problem in Denmark can not easily be applied to Germany, in view of the difference in size alone and the special problems of eastern Germany. Nevertheless this report emphasises three elements of reform that could also point the way ahead for Germany: firstly the concerted procedure mentioned which also led to the various measures having an increased effect especially in the initial phase. Secondly keeping to the schedule. Virtually all the measures taken were limited in time and in the following period the plans for phasing them out were also adhered to. Thirdly Denmark is an example of how a high level of social security need not stand in the way of reducing unemployment, provided that the other conditions are appropriate for this. In particular the high level of basic security probably contributed to the acceptance of the cuts which are also unavoidable in Denmark." (Author's abstract, IAB-Doku) ((en))Arbeitslosigkeitsbekämpfung, Beschäftigungspolitik, Arbeitsmarktentwicklung, Arbeitskosten, Sozialpolitik, Dänemark

Texture-defined objects influence responses of blowfly motion-sensitive neurons under natural dynamical conditions

Ullrich T, Kern R, Egelhaaf M. Texture-defined objects influence responses of blowfly motion-sensitive neurons under natural dynamical conditions. Frontiers in Integrative Neuroscience. 2014;8:34.The responses of visual interneurons of flies involved in the processing of motion information do not only depend on the velocity, but also on other stimulus parameters, such as the contrast and the spatial frequency content of the stimulus pattern. These dependencies have been known for long, but it is still an open question how they affect the neurons’ performance in extracting information about the structure of the environment under the specific dynamical conditions of natural flight. Free-flight of blowflies is characterized by sequences of phases of translational movements lasting for just 30–100 ms interspersed with even shorter and extremely rapid saccade-like rotational shifts in flight and gaze direction. Previous studies already analyzed how nearby objects, leading to relative motion on the retina with respect to a more distant background, influenced the response of a class of fly motion sensitive visual interneurons, the horizontal system (HS) cells. In the present study, we focused on objects that differed from their background by discontinuities either in their brightness contrast or in their spatial frequency content. We found strong object-induced effects on the membrane potential even during the short intersaccadic intervals, if the background contrast was small and the object contrast sufficiently high. The object evoked similar response increments provided that it contained higher spatial frequencies than the background, but not under reversed conditions. This asymmetry in the response behavior is partly a consequence of the depolarization level induced by the background. Thus, our results suggest that, under the specific dynamical conditions of natural flight, i.e., on a very short timescale, the responses of HS cells represent object information depending on the polarity of the difference between object and background contrast and spatial frequency content

Influence of environmental information in natural scenes and the effects of motion adaptation on a fly motion-sensitive neuron during simulated flight

Ullrich TW, Kern R, Egelhaaf M. Influence of environmental information in natural scenes and the effects of motion adaptation on a fly motion-sensitive neuron during simulated flight. Biology Open. 2015;4(1):13-21.Gaining information about the spatial layout of natural scenes is a challenging task that flies need to solve, especially when moving at high velocities. A group of motion sensitive cells in the lobula plate of flies is supposed to represent information about self-motion as well as the environment. Relevant environmental features might be the nearness of structures, influencing retinal velocity during translational self-motion, and the brightness contrast. We recorded the responses of the H1 cell, an individually identifiable lobula plate tangential cell, during stimulation with image sequences, simulating translational motion through natural sceneries with a variety of differing depth structures. A correlation was found between the average nearness of environmental structures within large parts of the cell's receptive field and its response across a variety of scenes, but no correlation was found between the brightness contrast of the stimuli and the cell response. As a consequence of motion adaptation resulting from repeated translation through the environment, the time-dependent response modulations induced by the spatial structure of the environment were increased relatively to the background activity of the cell. These results support the hypothesis that some lobula plate tangential cells do not only serve as sensors of self-motion, but also as a part of a neural system that processes information about the spatial layout of natural scenes

Antiphopholipid antibodies and functional activated protein C resistance in patients with breast cancer during anthracycline-based chemotherapy administered through an intravenous port-catheter device

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Reduced thermal expansion by surface-mounted nanoparticles in a pillared-layered metal-organic framework

Control of thermal expansion (TE) is important to improve material longevity in applications with repeated temperature changes or fluctuations. The TE behavior of metal-organic frameworks (MOFs) is increasingly well understood, while the impact of surface-mounted nanoparticles (NPs) on the TE properties of MOFs remains unexplored despite large promises of NP@MOF composites in catalysis and adsorbate diffusion control. Here we study the influence of surface-mounted platinum nanoparticles on the TE properties of Pt@MOF (Pt@Zn2(DP-bdc)2dabco; DP-bdc2-=2,5-dipropoxy-1,4-benzenedicarboxylate, dabco=1,4-diazabicyclo[2.2.2]octane). We show that TE is largely retained at low platinum loadings, while high loading results in significantly reduced TE at higher temperatures compared to the pure MOF. These findings support the chemical intuition that surface-mounted particles restrict deformation of the MOF support and suggest that composite materials exhibit superior TE properties thereby excluding thermal stress as limiting factor for their potential application in temperature swing processes or catalysis

Thoughts on opportunities from high-energy nuclear collisions

This document summarizes thoughts on opportunities from high-energy nuclear collisions.Comment: 10 pages, pd

In-Vivo Visualization of Tumor Microvessel Density and Response to Anti-Angiogenic Treatment by High Resolution MRI in Mice

Purpose: Inhibition of angiogenesis has shown clinical success in patients with cancer. Thus, imaging approaches that allow for the identification of angiogenic tumors and the detection of response to anti-angiogenic treatment are of high clinical relevance. Experimental Design: We established an in vivo magnetic resonance imaging (MRI) approach that allows us to simultaneously image tumor microvessel density and tumor vessel size in a NSCLC model in mice. Results: Using microvessel density imaging we demonstrated an increase in microvessel density within 8 days after tumor implantation, while tumor vessel size decreased indicating a switch from macro- to microvessels during tumor growth. Moreover, we could monitor in vivo inhibition of angiogenesis induced by the angiogenesis inhibitor PTK787, resulting in a decrease of microvessel density and a slight increase in tumor vessel size. Conclusions: We present an in vivo imaging approach that allows us to monitor both tumor microvessel density and tumor vessel size in the tumor. Moreover, this approach enables us to assess, early-on, treatment effects on tumor microvessel density as well as on tumor vessel size. Thus, this imaging-based strategy of validating anti-angiogenic treatment effects ha