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Purpose: To correlate inflammatory and proangiogenic key cytokines from undiluted vitreous of treatment-naïve central retinal vein occlusion (CRVO) patients with SD-OCT parameters.
Methods: Thirty-five patients (age 71.1 years, 24 phakic, 30 nonischemic) underwent intravitreal combination therapy, including a single-site 23-gauge core vitrectomy. Twenty-eight samples from patients with idiopathic, non-uveitis floaterectomy served as controls. Interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF-A) levels were correlated with the visual acuity (logMar), category of CRVO (ischemic or nonischemic) and morphologic parameters, such as central macular thickness-CMT, thickness of neurosensory retina-TNeuro, extent of serous retinal detachment-SRT and disintegrity of the IS/OS and others.
Results: The mean IL-6 was 64.7pg/ml (SD ± 115.8), MCP-1 1015.7 ( ± 970.1), and VEGF-A 278.4 ( ± 512.8), which was significantly higher than the control IL-6 6.2 ± 3.4pg/ml (P=0.06), MCP-1 253.2 ± 73.5 (P<0.0000001) and VEGF-A 7.0 ± 4.9 (P<0.0006). All cytokines correlated highly with one another (correlation coefficient r=0.82 for IL-6 and MCP-1; r=0.68 for Il-6 and VEGF-A; r=0.64 for MCP-1 and VEGF-A). IL-6 correlated significantly with CMT, TRT, SRT, dIS/OS, and dELM. MCP-1 correlated significantly with SRT, dIS/OS, and dELM. VEGF-A correlated not with changes in SD-OCT, while it had a trend to be higher in the ischemic versus the nonischemic CRVO group (P=0.09).
Conclusions: The inflammatory cytokines were more often correlated with morphologic changes assessed by SD-OCT, whereas VEGF-A did not correlate with CRVO-associated changes in SD-OCT. VEGF inhibition alone may not be sufficient in decreasing the inflammatory response in CRVO therapy.
In Spanien blickte man, wie wohl in keinem anderen Land Europas, auf reiche Erfahrungen mit der Inkorporation großer Gruppen Fremdgläubiger, auf massenhafte und nicht immer von äußerem Zwang freie Erwachsenentaufen zurück. Im 15. Jahrhundert hatten die Taufen von Juden, im 16. Jahrhundert die von Muslimen zu zahlreichen politischen, rechtlichen und theologischen Problemen geführt. Weitere Dimensionen erhielten die Fragen nach Taufe, Orthodoxie und Kirchenangehörigkeit durch die Reformation in Europa einerseits und die Mission in Lateinamerika andererseits. ...
Thirty years ago, in 1983, Harold Berman’s Law and Revolution: The Formation of the Western Legal Tradition was first published. His work had an enormous impact on legal scholarship all over the world. Many aspects of his central thesis – that there was something akin to a "papal revolution" in eleventh century Europe; that this "revolution" set a pattern for future epochs of transformation; that the special relation between Religion and Law was a distinct feature of the "Western Legal Tradition" – were largely discussed by legal historians, historians and social scientists. Others, like his "Social Theory of Law", received less attention. Although there had been strong criticism by scholars, especially medievalists, on some aspects of Berman’s work, it has become a standard reference in scholarly writings, not least outside of Europe. Since its appearance in 1983, Law and Revolution has been translated into German, French, Chinese, Japanese, Russian, Polish, Portuguese, Spanish, Italian, and Lithuanian. Twenty years later, in 2003, with his project entitled Law and Revolution II: The Impact of the Protestant Reformations on the Western Legal Tradition, Berman presented the second volume of what was thought to be a trilogy. Twenty years had gone by, the political world order had changed, but Berman’s main point, the importance of analyzing the role of Religion and Law, and the specific constellation of these two modes of normative thought, had gained new currency. In 2007, Harold J. Berman passed away, but not without having opened his historical and legal thought to the challenges of a globalized world. ...
Die Erforschung der spätantik-frühmittelalterlichen Taufpraxis stützt sich in großem Maß auf schriftliche Quellen, vor allem wenn es um die im weitesten Sinne rechtshistorischen Aspekte des Themas geht. Aber die Heranziehung von Sachquellen, den "Überresten" im Sinne der geschichtswissenschaftlichen Methodik, ist ebenso wichtig für das Verständnis beispielsweise von Normen und Wirklichkeiten. Der am Max-Planck-Institut für europäische Rechtsgeschichte eingerichtete Forschungsschwerpunkt "Rechtsräume" versucht daher, diese beiden Quellengruppen zusammenzuführen. Insofern ist der hier vorzustellende archäologische Befund von besonderer Bedeutung, nicht nur wegen seiner unmittelbaren Nähe zum Tagungsort der in diesem Band dokumentierten Sektion des Mainzer Historikertages. Im Folgenden werden Holger Grewe, der in Ingelheim tätige Grabungsleiter, und Sebastian Ristow, der archäologische Experte für Baptisterien des ersten Jahrtausends, sowie Caspar Ehlers, der Leiter des Forschungsschwerpunktes am MPIeR, einen Aufsehen erregenden Fund aus Ingelheim, der eng mit dem Thema "Taufe" verbunden ist, vorstellen und kurz kommentieren. ...
"Every time a society finds itself in crisis it instinctively turns its eyes towards its origins and looks there for a sign." With this citation from Octavio Paz, the 1990 Nobel Prize winner in literature, Berman concluded his Law and Revolution: The Formation of the Western Legal Tradition in 1983. There is a sense in which, thirty years later, this quote remains utterly appropriate, certainly at the beginning of a re-assessment of Berman’s thoughts on the particular topic of the religious origins of modern commercial and financial institutions. Five years on from the start of the financial crisis, triggered by the collapse of Lehman Brothers on 15 September 2008, it is worthwhile recalling, perhaps, that the sign perceived by Berman in the history of mercantile law was a sign that pointed towards the fundamental interconnectedness of belief systems and business. Berman was profoundly convinced of the vital, historical link between religion, trust, and economic prosperity. ...
Orthotopic bladder cancer xenografts are essential for testing novel therapies and molecular manipulations of cell lines in vivo. Current xenografts rely on tumor cell inoculation by intravesical instillation or direct injection into the bladder wall. Instillation is limited by the lack of cell lines that are tumorigenic when delivered in this manner. The invasive model inflicts morbidity on the mice by the need for laparotomy and mobilization of the bladder. Furthermore this procedure is complex and time-consuming. Three bladder cancer cell lines (UM-UC1, UM-UC3, UM-UC13) were inoculated into 50 athymic nude mice by percutaneous injection under ultrasound guidance. PBS was first injected between the muscle wall and the mucosa to separate these layers, and tumor cells were subsequently injected into this space. Bioluminescence and ultrasound were used to monitor tumor growth. Contrast-enhanced ultrasound was used to study changes in tumor perfusion after systemic gemcitabine/cisplatin treatment. To demonstrate proof of principle that therapeutic agents can be injected into established xenografts under ultrasound guidance, oncolytic virus (VSV) was injected into UM-UC3 tumors. Xenograft tissue was harvested for immunohistochemistry after 23–37 days. Percutaneous injection of tumor cells into the bladder wall was performed efficiently (mean time: 5.7 min) and without complications in all 50 animals. Ultrasound and bioluminescence confirmed presence of tumor in the anterior bladder wall in all animals 3 days later. The average tumor volumes increased steadily over the study period. UM-UC13 tumors showed a marked decrease in volume and perfusion after chemotherapy. Immunohistochemical staining for VSV-G demonstrated virus uptake in all UM-UC3 tumors after intratumoral injection. We have developed a novel method for creating orthotopic bladder cancer xenograft in a minimally invasive fashion. In our hands this has replaced the traditional model requiring laparotomy, because this model is more time efficient, more precise and associated with less morbidity for the mice.
Eine erstaunliche Tatsache: Ein amerikanischer Rechtswissenschaftler, im Denken des common law geschult, dann hervorgetreten vor allem mit Studien zur Rechtsvergleichung und zum Recht der Sowjetunion, schreibt in vorgerückten Jahren ein umfassendes Werk über die mittelalterlichen Ursprünge der Rechtstradition des Westens. Diese verankert er in jenem politisch-religiösen Konflikt, den wir einmal unter dem Begriff "Investiturstreit" kennen gelernt haben. Inzwischen wird er als Vorspiel der "Renaissance des 12. Jahrhunderts" gesehen. Für Berman handelt es sich jedoch um die "päpstliche Revolution", the Papal Revolution. Diesem Band "Law and Revolution" von 1983 hatte Berman im hohen Alter 2003 noch einen zweiten mit dem gleichen Titel folgen lassen, dessen Gegenstand ebenfalls im Untertitel genauer umschrieben wird: "The impact of the protestant reformations on the Western legal tradition". ...
Alle historische Forschung basiert auf einer Selektion von Themen, die sich aus dem Kontext ergeben, in dem diese Selektion stattfindet. Historische Forschung ist selbst zeitgebunden, und das beeinflusst ihre Perspektiven und Fragestellungen, nicht aber ist die Geschichtswissenschaft in der Lage, eine zeitlose Wahrheit über die Vergangenheit zu erschließen. Eine Suche nach dem "wie es eigentlich gewesen ist" muss auch daran scheitern, dass historische Forschung immer mit Wissen und Nicht-Wissen zugleich konfrontiert wird. Auch die rechtshistorische Forschung ist stets ein Subjekt ihrer Zeit, und auch sie muss akzeptieren, dass historisches Wissen notwendigerweise unvollständig ist. Die Rechtsgeschichte kann immer nur Fragmente der Objektivität der Geschichte rekonstruieren, sie kann nur "die sichtbare Seite einer Gesellschaft – Institutionen, Denkmäler, Werke, Gegenstände" zugänglich machen, nicht aber ihre "verborgene, unsichtbare Seite: Vorstellungen, Wünsche, Ängste, Verdrängungen, Träume". Tradition, heißt es dazu bei Harold Berman auch, "ist mehr als historische Kontinuität. Eine Tradition ist eine Mischung aus bewußten und unbewußten Elementen." ...
Die von Franz Dölger entwickelte Vorstellung, dass sich die Staaten und Herrschaften im östlichen wie westlichen Mittelalter als eine "Familie der Könige" begriffen, die als ein gleichsam rechtliches Institut die politische Welt konstituierte, wird einer Kritik unterworfen. Danach hätten sich die Herrscher der Welt (nicht nur der christlichen, sondern z. B. auch die sassanidischen Perser) als eine "Familie" begriffen, mit dem (ost-)römischen Kaiser an der Spitze und abgestuft denn "Brüder", "Söhne", "Freunde" usw. Dies wird angezweifelt.
Dabei konzentriert sich die Darstellung, die sich als ein Versuch begreift, eine längst überfällige Diskussion zu initiieren, auf die spätantiken und frühmittelalterlichen Quellen, auf die sich Dölger berief. Das Ergebnis dieser Untersuchung ist ein negatives: Das Konzept einer "Familie der Könige" lässt sich in den herangezogenen Quellen nicht finden. Diplomatische Formeln, die sich bis in den Alten Orient oder die hellenistischen Staaten zurückverfolgen lassen, kann man nicht als Belege für ein nach Dölger Ende des 3. Jahrhunderts entstandenes System betrachten.
In einem Schlussteil werden die Entstehungsumstände der Dölgerschen "Familie der Könige" – der relevante Aufsatz erschien im Jahre 1940 – sowie seine Haltung zum Nationalsozialismus thematisiert. Die Möglichkeit (Sicherheit ließe sich durch intensive weitergehende Forschungen erreichen), dass Dölger sein aufs Mittelalter bezogenes Konzept im Kontext seiner Involvierung in aktuelle Diskussionen über die "Ordnung" Südosteuropas (inkl. Griechenlands) in bestimmten NS-dominierten think tanks entwickelte, wird als reale Möglichkeit gesehen. Als Erkenntnisinstrument der Spätantike- und Mittelalterforschung jedenfalls fällt die "Familie der Könige" nach Ansicht des Verfassers aus.
Nicht die Entwicklung des Sakraments der Taufe während der tausendjährigen byzantinischen Geschichte gilt es hier zu erörtern; der liturgiewissenschaftliche Aspekt wird in diesen Zeilen bestenfalls einen Randaspekt darstellen. Stattdessen werde ich mich auf einige Aspekte konzentrieren (wenn auch in unterschiedlicher Intensität), die dem vorgegebenen Thema – (gesellschaftliche) Inklusion und Exklusion – entsprechen. Es soll also um ausgewählte Aspekte des Themenkomplexes "Taufe" gehen, die Relevanz für die Rechtsgeschichte, aber auch für die Gesellschaftsgeschichte in einem allgemeineren Sinne (inklusive gewisser Bezüge zur politischen Geschichte bzw. zur Missionsgeschichte) aufweisen. ...
In Germany, the termination of employment contracts is a central and often intensely debated legal issue today. This is not surprising since employment termination entails substantial risks for the person affected and threatens the very foundation of his or her economic existence. This is why both politics and legal dogmatics place the individual engaged in dependent work at the centre of concern as a subject requiring protection. In Germany, labour law ("Arbeitsrecht") emerged as an independent field of law focusing on the persona of the dependent worker ("Arbeitnehmer") and its typified normative ascriptions. This process took place in the course of the 20th century, as the concept of the principal requirement that employees be protected against unforeseen or unjustified dismissal became increasingly established, giving rise to very intricate regulations. Social security is a guiding motif of this legislation which regards contract termination primarily as a risk. It is often not considered that this constellation is a very new one. Defined conceptions of the interests of the parties to labour contracts also existed before 1900, but social security was then not a central criterion. At that time, many people perceived the termination of their employment as an opportunity rather than primarily as a risk. Employers, on the other hand, aimed to keep people in their service for as long as possible. In the late 19th century, the enforcement of labour performance by legal means and normative instruments, which no longer plays any role today, was still an important issue. This provides occasion to investigate the freedom of working people from the perspective of the history of law, whereby this article focuses on the history of the German-speaking territories. ...
The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.
Dry grasslands of NW Bulgarian mountains : first insights into diversity, ecology and syntaxonomy
(2013)
We present the data of the 3rd research expedition of the European Dry Grasslands Group (EDGG), which was conducted in 2011 in two contrasting areas in NW Bulgarian mountains. The aim was to collect plot data for comparing Bulgarian dry grasslands with those of other parts of Europe in terms of syntaxonomy and biodiversity. We sampled 15 nested-plot series (0.0001–100 m²) and 68 normal plots (10 m²) covering the full variety of dry grassland types occurring in the Vratsa area (Balkan Mts.) and the Koprivshtitsa area (Sredna Gora Mt.). In the plots all vascular plants, terricolous non-vascular plants and a set of soil and other environmental parameters were determined. By applying modified TWIN-SPAN, we distinguished 10 floristically well characterised vegetation types at the association level. After comparison with the regional and European literature, we propose to place them within three classes and five orders: Festuco-Brometea with the orders Stipo pulcherrimae-Festucetalia pallentis (xerophilous dry grasslands of base-rich rocks; alliance Saturejion montanae), Brachypodietalia pinnati (meso-xeric, basiphilous grasslands; alliances Cirsio-Brachypodion pinnati and Chyrsopogono grylli-Danthonion calycinae), Calluno-Ulicetea with the order Nardetalia stricae (lowland to montane Nar-dus swards; alliance Violion caninae), and Koelerio-Corynephoretea with the orders Sedo-Scleranthetalia (open communities of skeleton-rich, acidic soils; alliance unclear) and Trifolio arvensis-Festucetalia ovinae (closed, meso-xeric, acidophilous grasslands; alliance Armerio rumelicae-Potentillion). The Violion caninae with the association Festuco rubrae-Genistelletum sagittalis is reported from Bulgaria for the first time, while the two occurring Koelerio-Corynephoretea communities are described as new associations (Cetrario aculeatae-Plantaginetum radicatae, Plantagini radicatae-Agrostietum capillaris). According to DCA the main floristic gradient was largely determined by soil conditions, differentiating the Festuco-Brometea communities on soils with high pH and high humus content from the Koelerio-Corynephoretea communities on acidic, humus-poor soils, while the Calluno-Ulicetea stands are the connecting link. At 10 m2 Festuco-Brometea and Calluno-Ulicetea stands were richer in species across all investigated taxa and in vascular plants than Koelerio-Corynephoretea stands; the latter were richest in lichen species, while bryophyte richness did not differ significantly among syntaxa. Among the Bulgarian classes, the species-area relationships tended to be steepest in the Festuco-Brometea (i.e. highest beta diversity), but both alpha and beta diversity clearly fell behind the Festuco-Brometea communities in the Transylvanian Plateau, Romania, located less than 500 km north of the study region. Overall, our study contributes to a more adequate placement of the Bulgarian dry grasslands in the European syntaxonomic system and provides valuable data for large-scale analyses of biodiversity patterns.
Der diesjährige 8. Trockenrasen-Sonderteil von Tuexenia beginnt mit einen Bericht über die aktuellen Aktivitäten der European Dry Grassland Group (EDGG). Zunächst geben wir einen Überblick über die Entwicklung der Mitgliederzahl und den aktuellen Vorstand, der im Mai 2013 gewählt wurde. Dann berichten wir vom letzten European Dry Grassland Meeting in Prespa (Griechenland, 2012) und informieren über künftige Tagungen und Forschungsexpeditionen der EDGG. Schließlich war und ist die EDGG sehr aktiv darin, Special Features in internationalen Fachzeitschriften herauszugeben. Im zweiten Teil des Vorwortes geben wir eine Einführung zu den sechs Artikeln des diesjährigen Trockenrasen-Sonderteils: Zwei davon beschäftigen sich Biodiversitätsanalyen von Grasland-Ökotonen in einer Flusslandschaft in Lettland bzw. von brachgefallenen Alvar-Trockenrasen in Estland. Der dritte Artikel behandelt die Ökologie und Vergesellschaftung einer Grassippe (Avenula adsurgens subsp. adsurgens) im brachgefallenen, montanen Grasland der Karpaten (Slowakei). Die letzten drei Artikel schließlich sind der Beschreibung und Syntaxonomie von Trockenrasen gewidmet: Zwei davon bilden den Start einer neuen Serie über die pannonischen Trockenrasen Österreichs (Allgemeine Einführung und Trockenrasen des Wienerwalds), während der letzte die Ergebnisse der dritten EDGG-Forschungsexpedition im Jahr 2011 nach Bulgarien präsentiert. Schließlich geben wir einen Ausblick über künftige Pläne für das Special Feature.
Visible light is a better co-inducer of apoptosis for curcumin-treated human melanoma cells than UVA
(2013)
Curcumin attracts worldwide scientific interest due to its anti-proliferative and apoptosis inducing effects on different tumor cells at concentrations ranging from 10 to 150 µM (3.7–55 µg/ml). Unfortunately, because of a low oral bioavailability, only low and pharmacologically ineffective serum levels are achievable. In this study, an alternative treatment concept consisting of low concentration curcumin (0.2–5 µg/ml) and irradiation with UVA or visible light (VL) has been tested. The experimental results show clearly that this treatment decreases the proliferation and the viability of human melanoma cells while the cell membrane integrity remains intact. We identified the onset of apoptosis characterized by typical markers such as active caspases 8, 9 and 3 as well as DNA fragmentation accompanied by the loss of cell adhesion. The mitochondrial apoptosis signaling pathway is predominant due to an early activation of caspase-9. The present data indicate a higher efficacy of a combination of curcumin and VL than curcumin and UVA. Reduced effects as a result of light absorption by heavily pigmented skin are unlikely if VL is used. These results indicate that a combination of curcumin and light irradiation may be a useful additional therapy in the treatment of malignant disease.
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.
Author Summary: The sensitivity of a cell to a dose of radiation is largely affected by its current position within the cell cycle. While under normal circumstances progression through the cell cycle will be asynchronous in a tumour mass, external influences such as chemo- or radiotherapy can induce a synchronisation. Such a common progression of the inner clock of the cancer cells results in the critical dependence on the effectiveness of any drug or radiation dose on a suitable timing for its administration. We analyse the exact evolution of the radiosensitivity of a sample tumour spheroid in a computer model, which enables us to predict time windows of decreased or increased radiosensitivity. Fractionated radiotherapy schedules can be tailored in order to avoid periods of high resistance and exploit the induced radiosensitivity for an increase in therapy efficiency. We show that the cell cycle effects can drastically alter the outcome of fractionated irradiation schedules in a spheroid cell system. By using the correct observables and continuous monitoring, the cell cycle sensitivity effects have the potential to be integrated into treatment planing of the future and thus to be employed for a better outcome in clinical cancer therapies.
Introduction: We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT.
Patients and Methods: The immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher.
Results: Patients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11).
Conclusion: Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies.
O objetivo deste trabalho é divulgar e analisar os resultados de uma pesquisa realizada em três instituições paulistanas nas quais se ensina/aprende alemão como língua estrangeira. A pesquisa teve como objetivo geral investigar as crenças que alunos de língua alemã mantêm em relação a seu processo de aprendizagem. O corpus, coletado a partir de questionários e entrevistas, revelou muitas dessas crenças, referentes, por exemplo, à aprendizagem de gramática. Os resultados também apontam para a existência de uma relação entre as crenças e a adoção de determinadas estratégias de aprendizagem. Durante a análise, buscou-se identificar possíveis origens para as crenças detectadas, bem como os efeitos potenciais das mesmas sobre a aprendizagem da língua alemã. No presente artigo, algumas das crenças constatadas no estudo serão descritas e analisadas em relação a pressupostos teóricos e metodológicos da didática de línguas estrangeiras para o ensino de gramática.
Wie wenige hat Harald Weinrich innerhalb seines Arbeitsgebietes Impulse gesetzt, wobei sein Fach selbst mit "Sprachwissenschaft" nur unzureichend benannt ist. Er kennt die Literatur so gut wie wenige andere und versteht es, Sprache und Literatur in Zusammenhänge zu bringen, die immer sehenswert und lesenswert sind. Weinrichs Lebensaufgabe ist gar nicht auf die Philologie begrenzt, sondern berücksichtigte immer schon die Bildungs- und Kulturpolitik zunächst in Deutschland, später mit seinem Wechsel nach Frankreich die in Europa. [...] Dem hier dokumentierten Interview ging ein längeres Gespräch in Münster voraus; die Fragen wurden später schriftlich gestellt und beantwortet. Die Fragen stammen von Werner Heidermann, der auch die Übersetzung des Gesprächs besorgte.
Deutsche und Brasilianisch-Portugiesische Fassung.
Background: Exercise seems to minimize prostate cancer specific mortality risk and treatment related side effects like fatigue and incontinence. However the influence of physical activity on the immunological level remains uncertain. Even prostate cancer patients undergoing palliative treatment often have a relatively long life span compared to other cancer entities. To optimize exercise programs and their outcomes it is essential to investigate the underlying mechanisms. Further, it is important to discriminate between different exercise protocols and therapy regimes.
Methods/Design: The ProImmun study is a prospective multicenter patient preference randomized controlled trial investigating the influence of a 24 week endurance exercise program in 80–100 prostate cancer patients by comparing patients undergoing Antiandrogen therapy combined with exercise (AE), Antiandrogen therapy without exercise (A), Chemotherapy with exercise(CE) or Chemotherapy without exercise (C). The primary outcome of the study is a change in prostate cancer relevant cytokines and hormones (IL-6, MIF, IGF-1, Testosterone). Secondary endpoints are immune cell ratios, oxidative stress and antioxidative capacity levels, VO2 peak, fatigue and quality of life. Patients of the intervention group exercise five times per week, while two sessions are supervised. During the supervised sessions patients (AE and CE) exercise for 33 minutes on a bicycle ergometer at 70-75% of their VO2 peak. To assess long term effects and sustainability of the intervention two follow-up assessments are arranged 12 and 18 month after the intervention.
Discussion: The ProImmun study is the first trial which primarily investigates immunological effects of a six month endurance exercise program in prostate cancer patients during palliative care. Separating patients treated with Antiandrogen therapy from those who are additionally treated with Chemotherapy might allow a more specific view on the influence of endurance training interventions and the impact of different therapy protocols on the immune function.
Trial registration: German Clinical Trials Register: DRKS00004739
Valley View University (VVU) is a private university located within the dry forest zone of the Accra plains; an area strongly affected by urban sprawl. The campus covers approx. 105 ha. Considerable portions of it are yet undeveloped and covered with savannah thickets. In 2002, the university has committed itself to become Africa's first "ecological university". In the context of two projects, substantial improvements have been made in terms of sanitation, water supply, energy-saving buildings and organic agriculture. The further development of the campus was designed in a detailed "ecological masterplan". In this context, we carried out a floristic inventory of the savannah thickets and found more than 100 plant species; the majority of which represent the species pool of the unique mixture of dry forest and savannah thicket species, which is typical for the region. As the remainder of dry forests and savannah thickets in the Accra plains become increasingly threatened by urban sprawl and overgrazing, the VVU administration has agreed to preserve the species-rich thickets. This is a valuable contribution to a more sustainable development of the region.
O artigo analisa os paralelos entre o retrato do 'sujeito moderno em crise' visto no romance "Die Leiden des jungen Werthers" de Goethe e, por outro lado, o perfil psicossocial do 'homem do sentimento' do século XVIII, fruto da cultura da Empfindsamkeit. Defendo a perspectiva de que, no romance, Goethe não apenas se utiliza do formato literário mais tradicional da Empfindsamkeit (o do romance epistolar), como também se apropria de topói e técnicas discursivas que lhe são próprias em registro radicalmente heterodoxo. A argumentação nos ligará a uma dedução da visão do conceito de subjetividade moderna com que Goethe trabalha em sua fase final do Sturm und Drang, e que o situa como importante nome do discurso filosófico da modernidade.
Der vorliegende Beitrag untersucht Wolfgang Herrndorfs Roman "Sand" (2011) auf die ihm zu Grunde liegenden Verkettungen von Fehlern, Zufällen und die Logik des Absurden. Es werden dabei zunächst die verschiedenen Konnotationen des Wüstenmotivs und ihre dazugehörigen Traditionslinien in den Blick genommen. Im Anschluss wird gezeigt, inwiefern diese thematische Ausprägung des Antilogischen auch auf die Ebene der Rezeption übertragen werden kann, indem formale Kategorien wie Erzählposition, Zeitstruktur und Plotmuster untersucht werden. Am Beispiel des Homonyms 'Mine' und seines Homophons 'Miene' wird schließlich herausgearbeitet, wie der Roman mit (semantischen) Missverständnissen und Fehlinterpretationen spielt und solchermaßen zum "Aufbewahrungsort des Falschen" wird.
Botho Strauß hat die Frage der Sehnsucht nach Transzendenz von verschiedenen Gesichtspunkten aus immer wieder in seinem Werk behandelt. Da ist zunächst der Punkt, wie Gesellschaftstheorien und Weltbilder, denen er ursprünglich selbst gefolgt ist, diese Sehnsucht in eine falsche Richtung gelenkt und die wirkliche Rolle von Technologie unbehandelt gelassen haben. Strauß' eigene Analyse, die Überlegungen vor allem aus den Naturwissenschaften aufnimmt, vernachlässigt aber die Bedeutung schöpferischer Aktivität. Ein weiterer Gesichtspunkt ergibt sich aus Strauß' Darstellung des unglücklichen Bewusstseins des modernen Individuums und den Versuchen, dieses zu transzendieren. In einem letzten Punkt wird dann Strauß' eigener Versuch erörtert, im Kunstwerk Transzendenz zu schaffen. Der Artikel macht hier erneut auf die unterbelichtete Rolle schöpferischer Aktivität aufmerksam.
Neste artigo, comparamos duas traduções em língua portuguesa do romance "Verstörung" (primeira edição em língua alemã em 1967) do escritor austríaco Thomas Bernhard: a tradução portuguesa (1986, por Leopoldina Almeida) e a brasileira (1999, por Hans Peter Welper e José Laurenio de Melo). Partimos da premissa de que "Verstörung" é um livro com uma dimensão performativa acentuada, ou seja, a perturbação que dá nome ao livro não está representada apenas no enredo e na caracterização dos personagens, mas também – ou sobretudo – no estilo, na linguagem do texto em alemão. Discutimos e comparamos diferentes soluções tradutórias nas referidas versões em português, assim como os paratextos que constam nas duas publicações. Constatamos duas posturas divergentes ao lidar com as especificidades da linguagem da obra, ambas com consequências para o seu efeito performativo. Por fim, sugerimos que essas posturas possam ser reflexos das diferenças da própria crítica literária em relação a Thomas Bernhard em dois momentos diversos.
Neste artigo, apresentamos uma análise dos processos de diálogo e conflito cultural que influenciam a formação e o deslocamento de identidade das personagens no filme "Bagdá Café". O objetivo principal deste trabalho é analisar o movimento identitário das personagens à luz das teorias culturais de Bakthin e Bhabha. Para tanto, buscamos identificar e descrever os conflitos de cunho cultural neste espaço, caracterizado pela mudança e fluidez.
Movement of organisms is one of the key mechanisms shaping biodiversity, e.g. the distribution of genes, individuals and species in space and time. Recent technological and conceptual advances have improved our ability to assess the causes and consequences of individual movement, and led to the emergence of the new field of ‘movement ecology’. Here, we outline how movement ecology can contribute to the broad field of biodiversity research, i.e. the study of processes and patterns of life among and across different scales, from genes to ecosystems, and we propose a conceptual framework linking these hitherto largely separated fields of research. Our framework builds on the concept of movement ecology for individuals, and demonstrates its importance for linking individual organismal movement with biodiversity. First, organismal movements can provide ‘mobile links’ between habitats or ecosystems, thereby connecting resources, genes, and processes among otherwise separate locations. Understanding these mobile links and their impact on biodiversity will be facilitated by movement ecology, because mobile links can be created by different modes of movement (i.e., foraging, dispersal, migration) that relate to different spatiotemporal scales and have differential effects on biodiversity. Second, organismal movements can also mediate coexistence in communities, through ‘equalizing’ and ‘stabilizing’ mechanisms. This novel integrated framework provides a conceptual starting point for a better understanding of biodiversity dynamics in light of individual movement and space-use behavior across spatiotemporal scales. By illustrating this framework with examples, we argue that the integration of movement ecology and biodiversity research will also enhance our ability to conserve diversity at the genetic, species, and ecosystem levels.
BACKGROUND: The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm.
METHODS: One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non-erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided.
RESULTS: Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs -2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse.
CONCLUSIONS: Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis.
Few sequence alignment methods have been designed specifically for integral membrane proteins, even though these important proteins have distinct evolutionary and structural properties that might affect their alignments. Existing approaches typically consider membrane-related information either by using membrane-specific substitution matrices or by assigning distinct penalties for gap creation in transmembrane and non-transmembrane regions. Here, we ask whether favoring matching of predicted transmembrane segments within a standard dynamic programming algorithm can improve the accuracy of pairwise membrane protein sequence alignments. We tested various strategies using a specifically designed program called AlignMe. An updated set of homologous membrane protein structures, called HOMEP2, was used as a reference for optimizing the gap penalties. The best of the membrane-protein optimized approaches were then tested on an independent reference set of membrane protein sequence alignments from the BAliBASE collection. When secondary structure (S) matching was combined with evolutionary information (using a position-specific substitution matrix (P)), in an approach we called AlignMePS, the resultant pairwise alignments were typically among the most accurate over a broad range of sequence similarities when compared to available methods. Matching transmembrane predictions (T), in addition to evolutionary information, and secondary-structure predictions, in an approach called AlignMePST, generally reduces the accuracy of the alignments of closely-related proteins in the BAliBASE set relative to AlignMePS, but may be useful in cases of extremely distantly related proteins for which sequence information is less informative. The open source AlignMe code is available at https://sourceforge.net/projects/alignme/, and at http://www.forrestlab.org, along with an online server and the HOMEP2 data set.
Aberrant epigenetic regulators control expansion of human CD34+ hematopoietic stem/progenitor cells
(2013)
Transcription is a tightly regulated process ensuring the proper expression of numerous genes regulating all aspects of cellular behavior. Transcription factors regulate multiple genes including other transcription factors that together control a highly complex gene network. The transcriptional machinery can be “hijacked” by oncogenic transcription factors, thereby leading to malignant cell transformation. Oncogenic transcription factors manipulate a variety of epigenetic control mechanisms to fulfill gene regulatory and cell transforming functions. These factors assemble epigenetic regulators at target gene promoter sequences, thereby disturbing physiological gene expression patterns. Retroviral vector technology and the availability of “healthy” human hematopoietic CD34+ progenitor cells enable the generation of pre-leukemic cell models for the analysis of aberrant human hematopoietic progenitor cell expansion mediated by leukemogenic transcription factors. This review summarizes recent findings regarding the mechanism by which leukemogenic gene products control human hematopoietic CD34+ progenitor cell expansion by disrupting the normal epigenetic program.
The leukemia-associated fusion protein RUNX1/ETO is generated by the chromosomal translocation t(8;21) which appears in about 12% of all de novo acute myeloid leukemias (AMLs). Essential for the oncogenic potential of RUNX1/ETO is the oligomerization of the chimeric fusion protein through the nervy homology region 2 (NHR2) within ETO. In previous studies, we have shown that the intracellular expression of peptides containing the NHR2 domain inhibits RUNX1/ETO oligomerization, thereby preventing cell proliferation and inducing differentiation of RUNX1/ETO transformed cells. Here, we show that introduction of a recombinant TAT-NHR2 fusion polypeptide into the RUNX1/ETO growth-dependent myeloid cell line Kasumi-1 results in decreased cell proliferation and increased numbers of apoptotic cells. This effect was highly specific and mediated by binding the TAT-NHR2 peptide to ETO sequences, as TAT-polypeptides containing the oligomerization domain of BCR did not affect cell proliferation or apoptosis in Kasumi-1 cells. Thus, the selective interference with NHR2-mediated oligomerization by peptides represents a challenging but promising strategy for the inhibition of the leukemogenic potential of RUNX1/ETO in t(8;21)-positive leukemia.
Rückschläge werfen eine neue Technologie um Jahrzehnte zurück – besonders, wenn Menschenleben zu beklagen sind. Bei der Gentherapie wird aber oft vergessen, dass sie nur bei Patienten angewendet wird, für die es keine konventionelle Therapie mehr gibt. Nach der Euphorie und den Rückschlägen der Anfangsjahre können Forscher nun die ersten Erfolge vorweisen.
As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-κB (NF-κB) signaling and a tumor necrosis factor-α (TNFα)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth in vivo underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-κB DNA binding and enhanced NF-κB transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-κB DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-κB pathway. BV6-stimulated NF-κB activation leads to elevated mRNA levels of TNFα and additional NF-κB target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-κB signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-κB target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNFα autocrine/paracrine loop by the TNFα-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-κB signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics.
Reproducing the characteristics and the functional responses of the blood–brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.
Am 30. September 2012 ist der Romanist und Kulturwissenschaftler Karlheinz Barck, den alle Freunde "Carlo" nannten, in Berlin gestorben. Zu seinem Angedenken erscheint nachfolgend der bislang unveröffentlichte Text ‚Leonardo-Effekte: Perspektiven aus der Differenzierung von Natur- und Geisteswissenschaften‘. Ursprünglich war dieser Text als erster von insgesamt vier Beiträgen gedacht, die den Themenschwerpunkt eines Hefts von 'NTM. Zeitschrift für Geschichte der Wissenschaften, Technik und Medizin' bilden würden. Sie sollten ein zusammenhängendes Ergebnis des von 2001-2005 am Berliner Zentrum für Literaturforschung (so der damalige Name) laufenden Forschungsprojekts "Leonardo-Effekte. Exemplarische Konstellationen aus der Trennungsgeschichte von Natur- und Geisteswissenschaften: 1800 - 1900 - 2000" darstellen. Während die Texte von Christina Brandt, Mai Wegener und Caroline Welsh (der drei Mitarbeiterinnen am Projekt) einem Peer-review-Verfahren unterzogen wurden und im zweiten und dritten Heft der genannten Zeitschrift 2009 erschienen, stockte die Bearbeitung von Carlos Text, sodass er hier zum ersten Mal abgedruckt wird.
Mitochondrial cristae morphology is highly variable and altered under numerous pathological conditions. The protein complexes involved are largely unknown or only insufficiently characterized. Using complexome profiling we identified apolipoprotein O (APOO) and apolipoprotein O-like protein (APOOL) as putative components of the Mitofilin/MINOS protein complex which was recently implicated in determining cristae morphology. We show that APOOL is a mitochondrial membrane protein facing the intermembrane space. It specifically binds to cardiolipin in vitro but not to the precursor lipid phosphatidylglycerol. Overexpression of APOOL led to fragmentation of mitochondria, a reduced basal oxygen consumption rate, and altered cristae morphology. Downregulation of APOOL impaired mitochondrial respiration and caused major alterations in cristae morphology. We further show that APOOL physically interacts with several subunits of the MINOS complex, namely Mitofilin, MINOS1, and SAMM50. We conclude that APOOL is a cardiolipin-binding component of the Mitofilin/MINOS protein complex determining cristae morphology in mammalian mitochondria. Our findings further assign an intracellular role to a member of the apolipoprotein family in mammals.
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
In Kiefernbeständen des Naturschutzgebietes Mallertshofer Holz wurden, stratifiziert nach Besto-ckungstypen, Vegetationsaufnahmen angefertigt, klassifiziert und mittels Ordination und Zeiger-wertanalyse standörtlich und dynamisch interpretiert. Bei homogenen primären Standortbedingungen folgt die Vegetation einem starken Nährstoffgradienten, bedingt durch unterschiedliche extensive Vornutzungen, Selbstmelioration und Stickstoffeintrag. Für das Management der Wälder ergeben sich daraus drei Optionen: 1. Fortsetzung der selbstgesteuerten Entwicklung eutropher Kiefernforste; 2. aktiver Waldumbau durch Einbringen von Schattbaumarten der potenziellen natürlichen Vegetation; 3. gezielte Auflichtung und Ausmagerung durch starke Eingriffe in Gehölzbestand (Ganzbaumernte) und Bodenvegetation (Beweidung). Der Naturschutzwert des Gebietes kann durch ein Nebeneinander der Varianten 2 und 3 gesichert und optimiert werden.
Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.
Representing uncertainty in a spatial invasion model that incorporates human-mediated dispersal
(2013)
Most modes of human-mediated dispersal of invasive species are directional and vector-based. Classical spatial spread models usually depend on probabilistic dispersal kernels that emphasize distance over direction and have limited ability to depict rare but influential long-distance dispersal events. These aspects are problematic if such models are used to estimate invasion risk. Alternatively, a geographic network model may be better at estimating the typically low likelihoods associated with human-mediated dispersal events, but it should also provide a reasonable account of uncertainties that could affect perception of its risk estimates. We developed a network model that assesses the likelihood of dispersal of invasive forest pests in camper-transported firewood in North America. We built the model using data from the U.S. National Recreation Reservation Service, which document visitor travel between populated places and federal campgrounds across the U.S. and Canada. The study area is depicted as a set of coarse-resolution map units. Based on repeated simulations, the model estimates the probability that each unit is a possible origin and destination for firewood-facilitated forest pest invasions. We generated output maps that summarise, for each U.S. state and Canadian province, where (outside the state or province) a camper-transported forest pest likely originated. Treating these output maps as a set of baseline scenarios, we explored the sensitivity of these “origin risk” estimates to additive and multiplicative errors in the probabilities of pest transmission between locations, as well as random changes in the structure of the underlying travel network. We found the patterns of change in the origin risk estimates due to these alterations to be consistent across all states and provinces. This indicates that the network model behaves predictably in the presence of uncertainties, allowing future work to focus on closing knowledge gaps or more sophisticated treatments of the impact of uncertainty on model outputs.
Increasing trends in global trade make it extremely difficult to prevent the entry of all potential invasive species (IS). Establishing early detection strategies thus becomes an important part of the continuum used to reduce the introduction of invasive species. One part necessary to ensure the success of these strategies is the determination of priority survey areas based on invasion pressure. We used a pathway-centred conceptual model of pest invasion to address these questions: what role does global trade play in invasion pressure of plant ecosystems and how could an understanding of this role be used to enhance early detection strategies? We concluded that the relative level of invasion pressure for destination ecosystems can be influenced by the intensity of pathway usage (import volume and frequency), the number and type of pathways with a similar destination, and the number of different ecological regions that serve as the source for imports to the same destination. As these factors increase, pressure typically intensifies because of increasing a) propagule pressure, b) likelihood of transporting pests with higher intrinsic invasion potential, and c) likelihood of transporting pests into ecosystems with higher invasibility. We used maritime containerized imports of live plants into the contiguous U.S. as a case study to illustrate the practical implications of the model to determine hotspot areas of relative invasion pressure for agricultural and forest ecosystems (two ecosystems with high potential invasibility). Our results illustrated the importance of how a pathway-centred model could be used to highlight potential target areas for early detection strategies for IS. Many of the hotspots in agricultural and forest ecosystems were within major U.S. metropolitan areas. Invasion ecologists can utilize pathway-centred conceptual models to a) better understand the role of human-mediated pathways in pest establishment, b) enhance current methodologies for IS risk analysis, and c) develop strategies for IS early detection-rapid response programs.
Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon-α monotherapy in 1992 to the approval of telaprevir- and boceprevir-based triple therapies with pegylated interferon-α and ribavirin in 2011, the chances of curing patients infected with HCV genotype 1 have improved from <10% to approximately 70%. Significant further improvements are on the horizon, which may well cure virtually all hepatitis C patients with an all-oral, interferon-free regimen in the very near future. These exciting developments are reviewed in the present article.
Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naïve patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance.
This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations.
Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans.
Despite numerous clinical studies, which have investigated the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) in various brain diseases, our knowledge of the cellular and molecular mechanisms underlying rTMS-based therapies remains limited. Thus, a deeper understanding of rTMS-induced neural plasticity is required to optimize current treatment protocols. Studies in small animals or appropriate in vitro preparations (including models of brain diseases) provide highly useful experimental approaches in this context. State-of-the-art electrophysiological and live-cell imaging techniques that are well established in basic neuroscience can help answering some of the major questions in the field, such as (i) which neural structures are activated during TMS, (ii) how does rTMS induce Hebbian plasticity, and (iii) are other forms of plasticity (e.g., metaplasticity, structural plasticity) induced by rTMS? We argue that data gained from these studies will support the development of more effective and specific applications of rTMS in clinical practice.
Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25–150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60–120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = −0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder.
Metrical patterning and rhyme are frequently employed in poetry but also in infant-directed speech, play, rites, and festive events. Drawing on four line-stanzas from nineteenth and twentieth German poetry that feature end rhyme and regular meter, the present study tested the hypothesis that meter and rhyme have an impact on aesthetic liking, emotional involvement, and affective valence attributions. Hypotheses that postulate such effects have been advocated ever since ancient rhetoric and poetics, yet they have barely been empirically tested. More recently, in the field of cognitive poetics, these traditional assumptions have been readopted into a general cognitive framework. In the present experiment, we tested the influence of meter and rhyme as well as their interaction with lexicality in the aesthetic and emotional perception of poetry. Participants listened to stanzas that were systematically modified with regard to meter and rhyme and rated them. Both rhyme and regular meter led to enhanced aesthetic appreciation, higher intensity in processing, and more positively perceived and felt emotions, with the latter finding being mediated by lexicality. Together these findings clearly show that both features significantly contribute to the aesthetic and emotional perception of poetry and thus confirm assumptions about their impact put forward by cognitive poetics. The present results are explained within the theoretical framework of cognitive fluency, which links structural features of poetry with aesthetic and emotional appraisal.
DEAD box helicases catalyze the ATP-dependent destabilization of RNA duplexes. Whereas duplex separation is mediated by the helicase core shared by all members of the family, flanking domains often contribute to binding of the RNA substrate. The Thermus thermophilus DEAD-box helicase Hera (for “heat-resistant RNA-binding ATPase”) contains a C-terminal RNA-binding domain (RBD). We have analyzed RNA binding to the Hera RBD by a combination of mutational analyses, nuclear magnetic resonance and X-ray crystallography, and identify residues on helix α1 and the C-terminus as the main determinants for high-affinity RNA binding. A crystal structure of the RBD in complex with a single-stranded RNA resolves the RNA–protein interactions in the RBD core region around helix α1. Differences in RNA binding to the Hera RBD and to the structurally similar RBD of the Bacillus subtilis DEAD box helicase YxiN illustrate the versatility of RNA recognition motifs as RNA-binding platforms. Comparison of chemical shift perturbation patterns elicited by different RNAs, and the effect of sequence changes in the RNA on binding and unwinding show that the RBD binds a single-stranded RNA region at the core and simultaneously contacts double-stranded RNA through its C-terminal tail. The helicase core then unwinds an adjacent RNA duplex. Overall, the mode of RNA binding by Hera is consistent with a possible function as a general RNA chaperone.