Ein neuer Signaltransduktionsweg für muskelinvasive Urothelkarzinome

Das Urothelkarzinom ist die vierthäufigste maligne Tumorerkrankung des Mannes. Bei Frauen steht es an siebzehnter Stelle aller bösartigen Tumorentitäten. Somit sind Männer viermal häufiger betroffen als Frauen. Allerdings weisen Frauen eine höhere Mortalität auf, da die Rate an muskelinvasiv wachsenden Karzinomen höher ist als bei Männern. Außerdem wird die Diagnose bei Frauen häufig in späteren Stadien gestellt. Die Unterscheidung in muskelinvasive und nicht-muskelinvasive Urothelkarzinome ist von besonderer Relevanz für die Therapie und Prognose. Sobald ein Urothelkarzinom den Harnblasenmuskel infiltriert, ist eine radikale Operation notwendig, die die Entfernung der gesamten Blase mit umliegenden Strukturen einschließt. Diese Eingriffe sind mit einem hohen Risiko und einer erhöhten Mortalität verbunden. Außerdem weisen muskelinvasive Karzinome höhere Rezidiv- und Metastasierungsraten auf. Es ist also von besonderem Interesse, herauszufinden, welche Signaltransduktionswege zu einem muskelinvasiven Wachstum der Harnblasenkarzinome führen. Die Epidemiologie bezüglich Geschlechterverteilung gibt Hinweise auf die Bedeutung des Östrogen- und Androgensignalwegs in der Entstehung und Progression des Tumors. In dieser Arbeit wird ein möglicher Signalweg dargestellt, der die Progression von Urothelzellen zu einem muskelinvasiv wachsenden Tumor erklären könnte. Experimente mit HTB-9, einer Zellkultur aus einem muskelinvasiven Urothelkarzinom, erlauben Rückschlüsse auf die Rolle einzelner Zielgene und setzen den Östrogenrezeptor ß, Androgenrezeptor, die miRNA-708, Endothelin-1 und E-Cadherin in Beziehung zueinander. Die einzelnen Targets konnten durch unterschiedliche Methoden in den Tumorzellen nachgewiesen werden. Aus diesen Erkenntnissen lässt sich ein Signalweg ableiten, der Angriffspunkte für zukünftige Diagnostik und Therapieplanung bietet

Orthostatic hypotension, cognition and structural brain imaging in hemodynamically impaired patients

Background: Orthostatic hypotension (OH) is associated with an increased risk of dementia, potentially attributable to cerebral hypoperfusion. We investigated which patterns and characteristics of OH are related to cognition or to potentially underlying structural brain injury in hemodynamically impaired patients and healthy reference participants. Methods: Participants with carotid occlusive disease or heart failure, and reference participants from the Heart-Brain Connection Study underwent OH measurements, neuropsychological assessment and brain MRI. We analyzed the association between OH, global cognitive functioning, white matter hyperintensity (WMH) volume and brain parenchymal fraction with linear regression. We stratified by participant group, severity and duration of OH, chronotropic incompetence and presence of orthostatic symptoms. Results: Of 337 participants (mean age 67.3 ± 8.8 years, 118 (35.0%) women), 113 (33.5%) had OH. Overall, presence of OH was not associated with cognitive functioning (β: −0.12 [−0.24–0.00]), but we did observe worse cognitive functioning in those with severe OH (≥ 30/15 mmHg; β: −0.18 [−0.34 to −0.02]) and clinically manifest OH (β: −0.30 [−0.52 to −0.08]). These associations did not differ significantly by OH duration or chronotropic incompetence, and were similar between patient groups and reference participants. Similarly, both severe OH and clinically manifest OH were associated with a lower brain parenchymal fraction, and severe OH also with a somewhat higher WMH volume. Conclusions: Severe OH and clinically manifest OH are associated with worse cognitive functioning. This supports the notion that specific patterns and characteristics of OH determine its impact on brain health.</p

Managing understory light conditions in boreal mixedwoods through variation in the intensity and spatial pattern of harvest: A modelling approach

In the context of partial harvesting, adequately managing post-harvest light conditions are essential to obtain a desired composition of tree species regeneration. The objective of this study was to determine how varying the intensity and spatial pattern of harvest would affect understory light conditions in boreal mixedwood stands of northwestern Quebec using the spatially explicit SORTIE-ND light model. The model was evaluated based on comparisons of observed and predicted light levels in both mapped and un-mapped plots. In mapped plots, reasonably accurate predictions of the overall variation in light levels were obtained, but predictions tended to lack spatial precision. In un-mapped plots, SORTIE-ND accurately predicted stand-level mean GLI (Gap Light Index) under a range of harvest intensities. The model was then used to simulate nine silvicultural treatments based on combinations of three intensities of overstory removal (30%, 45% and 60% of basal area) and three harvest patterns (uniform, narrow strips, large gaps). Simulations showed that increasing overstory removal had less impact on light conditions with uniform harvests, and a more marked effect with more aggregated harvest patterns. Whatever the harvest intensity, uniform cuts almost never created high light conditions (GLI > 50%). Gap cuts, on the other hand, resulted in up to 40% of microsites receiving GLI > 50%. Our results suggest that either a 30% strip or gap cut or a 45–60% uniform partial harvest could be used to accelerate the transition from an aspen dominated composition to a mixedwood stand because both types of cut generate the greatest proportion of moderately low light levels (e.g., 15–40% GLI). These light levels tend to favour an accelerated growth response among shade-tolerant conifers, while preventing excessive recruitment of shade-intolerant species. A better understanding of how spatial patterns of harvest interact with tree removal intensity to affect understory light conditions can provide opportunities for designing silvicultural prescriptions that are tailored to species’ traits and better suited to meet a variety of management objectives

Antiviral Responses following L-Leucyl-L-Leucine Methyl Esther (LLME)-Treated Lymphocyte Infusions: Graft-versus-Infection without Graft-versus-Host Disease

Although allogeneic hematopoietic progenitor cell transplant (HPCT) is curative therapy for many disorders, it is associated with significant morbidity and mortality, which can be related to graft-versus-host disease (GVHD) and the immunosuppressive measures required for its prevention and/or treatment. Whether the immunosuppression is pharmacologic or secondary to graft manipulation, the graft recipient is left at increased risk of the threatening opportunistic infection. Refractory viral diseases in the immunocompromised host have been treated by infusion of virus-specific lymphotyces and by unmanipulated donor lymphocyte infusion (DLI) therapy. L-leucyl-L-leucine methyl ester (LLME) is a compound that induces programmed cell death of natural killer (NK) cells, monocytes, granulocytes, most CD8+ T cells, and a small fraction of CD4+ T cells. We have undertaken a study of the use of LLME-treated DLI following T cell-depleted allogeneic HPCT, specifically to aid with immune reconstitution. In this ongoing clinical trial, we have demonstrated the rapid emergence of virus-specific responses following LLME DLI with minimal associated GVHD. This paper examines the pace of immune recovery and the rapid development of antiviral responses in 6 patients who developed viral infections during the time period immediately preceding or coincident with the administration of the LLME DLI

Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan

Model matchmaking via the Solve-RD Rare Disease Models &amp; Mechanisms Network (RDMM-Europe)

In biomedical research, particularly for rare diseases (RDs), there is a critical need for model organisms to unravel the mechanistic basis of diseases, perform biomarker studies and develop potential therapeutic interventions. Within Solve-RD, an EU-funded research project with the aim of solving large numbers of previously unsolved RDs, the European Rare Disease Models &amp; Mechanisms Network (RDMM-Europe) has been established.</p

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Morning and Evening-Type Differences in Slow Waves during NREM Sleep Reveal Both Trait and State-Dependent Phenotypes

Brain recovery after prolonged wakefulness is characterized by increased density, amplitude and slope of slow waves (SW, <4 Hz) during non-rapid eye movement (NREM) sleep. These SW comprise a negative phase, during which cortical neurons are mostly silent, and a positive phase, in which most neurons fire intensively. Previous work showed, using EEG spectral analysis as an index of cortical synchrony, that Morning-types (M-types) present faster dynamics of sleep pressure than Evening-types (E-types). We thus hypothesized that single SW properties will also show larger changes in M-types than in E-types in response to increased sleep pressure. SW density (number per minute) and characteristics (amplitude, slope between negative and positive peaks, frequency and duration of negative and positive phases) were compared between chronotypes for a baseline sleep episode (BL) and for recovery sleep (REC) after two nights of sleep fragmentation. While SW density did not differ between chronotypes, M-types showed higher SW amplitude and steeper slope than E-types, especially during REC. SW properties were also averaged for 3 NREM sleep periods selected for their decreasing level of sleep pressure (first cycle of REC [REC1], first cycle of BL [BL1] and fourth cycle of BL [BL4]). Slope was significantly steeper in M-types than in E-types in REC1 and BL1. SW frequency was consistently higher and duration of positive and negative phases constantly shorter in M-types than in E-types. Our data reveal that specific properties of cortical synchrony during sleep differ between M-types and E-types, although chronotypes show a similar capacity to generate SW. These differences may involve 1) stable trait characteristics independent of sleep pressure (i.e., frequency and durations) likely linked to the length of silent and burst-firing phases of individual neurons, and 2) specific responses to increased sleep pressure (i.e., slope and amplitude) expected to depend on the synchrony between neurons