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A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation.
Die Wahrscheinlichkeit einer pathologischen Komplettremission (pCR) bei Brustkrebs nach neoadjuvanter Chemotherapie (NACT) nimmt zu; vor allem in den Subgruppen der tripel-negativen und HER-2-positiven Tumoren. Daher stellt sich die Frage, ob bei einer Komplettremission nach NACT eine operative Therapie der Brust notwendig ist, und ob es einen Vorteil für das onkologische Behandlungsergebnis hat, wenn kein Tumor mehr nachgewiesen werden kann. Ein Verzicht auf die Operation und gegebenenfalls auch auf die Radiotherapie ist jedoch nur auf der Basis einer verlässlichen pCR-Diagnose ohne Operation denkbar. Bildgebende Verfahren erreichen derzeit nicht die nötige Sensitivität und Spezifität, um die Diagnose einer pathologischen Komplettremission sicher zu stellen. Daher sind weitere Studien nötig, um herauszufinden, welche Methode die bestmögliche Evaluation des Tumoransprechens auf NACT erlaubt. Erste vielversprechende Ergebnisse zeigen sich in Studien zu bildgebungsgesteuerten, minimalinvasiven Biopsien nach NACT. Diese evaluieren die Möglichkeit einer pCR-Diagnose vor der Operation und könnten die Grundlage für weitere Studien zu einem möglichen Verzicht auf eine Operation in diesem ausgewählten Kollektiv sein.
The likelihood of pathological complete remission (pCR) of breast cancer following neoadjuvant chemotherapy (NACT) is increasing; most of all in the triple negative and HER2 positive tumour subgroups. The question thus arises whether or not breast surgery is necessary when there is complete remission after NACT, and whether it provides any improvement of the oncological treatment result when tumour is no longer detectable. Avoiding surgery and possibly even radiotherapy would only be conceivable on the basis of a reliable diagnosis of pCR without operating. Current imaging does not achieve the necessary sensitivity and specificity to assure the diagnosis of pathological complete remission. Further studies are therefore required to determine which methods are best able to evaluate tumour response to NACT. Studies on image-guided, minimally invasive biopsies after NACT have delivered first promising results towards diagnosing pCR before surgery and could provide the basis for further studies on the possibility of avoiding surgery in this specific patient collective.
Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinct HOX genes
(2017)
Background: Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinct HOX genes, including the osteogenic master regulator DLX3. A comprehensive mechanism that regulates SENP3 transcriptional function was not understood.
Results: Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3. We demonstrate that FLII is associated with SENP3 and the MLL1/2 complex. We further show that FLII determines SENP3 recruitment and MLL1/2 complex assembly on the DLX3 gene. Consequently, FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. Most importantly, FLII-mediated SENP3 regulation governs osteogenic differentiation of human mesenchymal stem cells.
Conclusion: Altogether, these data reveal a crucial functional interconnection of FLII with the sumoylation machinery that converges on epigenetic regulation and cell fate determination.
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.
Background: Aside from the fully licensed herbal medicines there are products on the European pharmaceutical market which are registered by virtue of their longstanding traditional use. The normal registration procedure does not apply to them because presently they do not meet the legal requirements for a full license as set out in the relevant European Union Directive. One of these requirements, “proof of tradition”, has so far been dealt with in different ways and fails to meet the criteria of good practice.
Method: This analysis is based on a selective literature search in PubMed and in databases of medical and pharmaceutical history, interviews with licensing experts, a consensus meeting attended by researchers with a background in general medicine, phytotherapy, medical and pharmaceutical history, biometry, ethnopharmacology, pharmacognosy and the pharmaceutical industry.
Results and discussion: The 2004 EU Directive, which governs the registration of Traditional Herbal Medicinal Products and demands proof of tradition, is a regulatory construct and, above all, the outcome of a political process that has ended in a pragmatic compromise. The concept of tradition applied in the Directive does not sufficiently reflect the semantic breadth of the term. The only condition defined is that a specific commercial preparation needs to have been on the market for 30 years (15 of them inside the EU). Such an approach does not make full scientific use of the evidence available because the information excerpted from historical sources, if adequately processed, may yield valuable insights. This applies to indications, modes of application, efficacy and product safety (innocuousness). Such criteria should enter in full into the benefit-risk-analysis of applied preparations, in the registration process as well as in the therapeutic practice.
Conclusion: When registering Traditional Herbal Medicinal Products the criterion of evidence-based medicine will only be met if all the facts available are assessed and evaluated, over and above the formally stipulated regulatory provisions (30 years, product reference). To this end, the scientific methods (from among the natural, life or cultural sciences), which are recognized as authoritative in each case, must be applied.
The paper presents a reading of "celestinesque literature" - texts surrounding Fernando de Rojas’ famous novel 'La Celestina' (1499) - in view of the question, to what extent the term "marranism" may serve as a philological rather than a biographical category. Dealing with Stephen Gilman’s exemplary studies, the paper shows how Rojas’ text subverts some of the most important metaphorical structures used by philologists to represent "marranism" and to read "marrano literature." Celestinesque novels, on the other hand, develop their own notion of "philology:" the "love" that they narrate also reflects the "desire of the logos" that works throughout their language.
"In der Machination", so Walter Benjamin, "hat die neue Bühne den Gott." Das gilt nicht nur für die Theatermaschinerie, die den Gott auf der Barockbühne erscheinen lässt, sondern ebenso für die weiteren Bedeutungen des Wortes: "Machination" im Sinn des kunstfertigen Verstands und der trügerischen List, wie sie sich in der Intrige, dem dramatischen Kern des Trauerspiels, verkörpert. Der Aufsatz entfaltet den Zusammenhang zwischen Machination und Theophanie in einem Vergleich zwischen den barocken Dichtern Gryphius und Racine. Während die Spiele des Ersteren sich vorrangig auf die anschauliche Wirkung der Maschine stützen, um die Souveränität des 'christlichen' Gesetzes zu demonstrieren, präsentieren sich die Dramen des Letzteren als Musterbeispiele für ingeniöse Handlungsführung im Namen eines Regelwerks, dessen poetologische Autorität als 'göttlich' anerkannt wird. Zwischen diesen beiden Modellen theatralen Spiels vermittelt die Analyse einer Edition der aristotelischen Poetik, die Daniel Heinsius herausgegeben hat und einen besonderen Schwerpunkt auf die Deutung des deus ex machina legt.
Der Aufsatz untersucht am Beispiel des Märtyrerspiels "Catharina von Georgien" die Charakteristik der Gryph'schen Trauerspielsprache zwischen "erhabenem Stil" und sermo humilis. Unter Rückgriff auf die einschlägigen Studien Auerbachs wird besonderes Augenmerk auf das problematische Verhältnis zwischen dem christlichen Gegenstand - der Passion als Erniedrigung des Gottessohnes - und der barocken Stillehre gelegt: Solange das Trauerspiel dem "erhabenen Stil" den Vorzug gibt, kann es das christliche Heilsgeschehen nur verfremdend wiederholen.
With reference to the martyr-play "Catharina von Georgien," my paper examines the rhetorical characteristics of Gryphius' mourning-plays as a movement between "elevated style" and sermo humilis. Drawing upon Auerbach's important studies on this subject, it highlights the problematic relationship between the play's Christian subject - the passion as humiliation of the divine Son - and baroque notions of (stylistic) elevation: As long as the mourning-play gives preference to "elevated style," it can only restage Christian salvation through its distortion.
Der Aufsatz arbeitet im Rückgriff auf Richard Alewyns bekannte Studie markante Modifikationen von Opitz' Antigone-Übersetzung auf syntaktischer, stilistischer und semantischer Ebene heraus: Während die sophokleische Tragödie vom Oxymoron geprägt ist, zeichnet sich Opitz' Übersetzung durch die Klärung des paradoxen Ausdrucks zur äußerlichen Antithese aus. Dank ihr kann die widerspruchsreiche Tragödie zum moralischen Exempel vereinfacht werden. Der Grund für diese Umdichtung wird – abweichend von Alewyn – im rhetorischen Sprachverständnis des Übersetzers gesucht: Die Eigenart seines "Teutschs" liegt in der zwiespältigen Orientierung an griechischer Tragödie und lateinischer Gerichtsrhetorik begründet. Dementsprechend kann auch die Charakteristik des "teutschen" Trauerspiels (das sich auf die griechische Tragödie beruft, aber zumeist ein religiöses Exempel statuiert) in diesem Zwiespalt einer neu zu schaffenden Trauerspielsprache verankert werden.