15 research outputs found

    PersonalfĂĽhrung im heterogenen Kollegium von Grund- und Mittelschulen in Bayern

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    Personalführung bei zunehmend heterogenen Lehrkräften wird zusehends wichtiger für Schulleitung. Eine theoretische und praktische Neuorientierung in diesem bisher übersehenen Feld erscheint notwendig. Dazu werden in der Schulleitungsforschung Erkenntnisse zur differenzierenden Personalführung gesucht. In der Betriebswirtschaftslehre sowie in der Praxis von Unternehmen werden Neuerungen im Umgang mit größerer Diversität bei den Mitarbeitern analysiert. Erfahrungen aus der Praxis von Schulleitungen werden mithilfe offener Interviews ausgewertet. Nach kritischer Auswahl der Übertragungsmöglichkeiten wird eine Integration zu einem neuen Ansatz von differenzierender Personalführung versucht. Konkrete Vorschläge zur Reform der Ausbildung der Schulleitungen und zur Umsetzung in der Praxis zeigen mögliche Wege der nötigen Verbesserung auf

    Construction and analysis of a modular model of caspase activation in apoptosis

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    <p>Abstract</p> <p>Background</p> <p>A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic) and intracellular (intrinsic) signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC) and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins.</p> <p>Results</p> <p>A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines.</p> <p>Conclusion</p> <p>Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.</p

    TRAIL receptor and CD95 signal to mitochondria via FADD, Caspase-8/10, Bid, and Bax but differentially regulate events downstream from truncated Bid

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    The death receptor ligand TRAIL arouses much interest for clinical application. We found that TRAIL receptor could induce cytochrome c (Cyt c) release from mitochondria in cells that failed to respond to CD95. Therefore, we examined whether these two closely related death receptors use different intermediates to convey the apoptotic signal to mitochondria. Dominant negative FADD, FLIPL, or a Bid mutant lacking cleavage sites for caspase-8/10 completely inhibited Cyt crelease in response to either receptor. Depletion of Bid from TRAIL- or CD95-activated cytosols blocked their capacity to mediate Cytc release from mitochondria in vitro, whereas Bax depletion reduced it. We conclude that FADD, caspase-8/10, and caspase-cleaved Bid are required for TRAIL receptor and CD95 signaling to mitochondria, whereas Bax is a common accessory. In vitro, caspase-8 treatment of cytosol from CD95-resistant cells permitted generation of truncated Bid and its association with mitochondria. However, this cytosol impaired the ability of truncated Bid to liberate Cyt c from exogenous mitochondria. We conclude that the TRAIL receptor can bypass or neutralize the activity of cytosolic factor that blocks truncated Bid function. This may benefit the capacity of TRAIL to break apoptosis resistance in tumor cells

    CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma

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    Although subtypes of pancreatic ductal adenocarcinoma (PDAC) were described, this malignancy is clinically still treated as a single disease. Here, we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers—HNF1A and KRT81—that enable stratification of tumors into different subtypes by immunohistochemistry. Individuals bearing tumors of these subtypes show significant differences in overall survival and their tumors differ in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or shRNA-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4 alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and is highly expressed in several additional malignancies. These findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance

    Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis

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    Many cancers harbor oncogenic mutations of KRAS . Effectors mediating cancer progression, invasion, and metastasis in KRAS- mutated cancers are only incompletely understood. Here we identify cancer cell-ex- pressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non- small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and inva- sion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph ves- sels and with shortened metastasis-free survival of KRAS- mutated colorectal cancer patients
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