28 research outputs found
Intimate cell conjugate formation and exchange of membrane lipids precede apoptosis induction in target cells during antibody-dependent, granulocyte-mediated cytotoxicity
No full textAb-dependent polymorphonuclear granulocyte (PMN)-mediated cytotoxicity may play an important role in the control of malignant diseases. However, little is known as to which particular pathways are used for the killing of malignant cells by PMN. The production of reactive oxygen intermediates (ROI) has been observed to occur during Ab-dependent, cell-mediated cytotoxicity (ADCC). However, PMN from a patient with chronic granulomatous disease demonstrated strong ADCC against malignant lymphoma cells. Furthermore, the inhibition of ROI production in PMN from healthy donors had no significant effect on ADCC. Therefore, ROI production by the NADPH oxidase of PMN does not appear to be mandatory for PMN-mediated ADCC. Recent data suggest a role for perforins in PMN-mediated cytotoxicity. However, in our assays concanamycin A, an inhibitor of perforin-mediated ADCC by mononuclear cells, had no inhibitory effect on PMN-mediated ADCC. Using electron microscopy we observed that PMN and their target cells intimately interact with the formation of interdigitating membrane protrusions. During PMN and target cell contact there was a mutual exchange of fluorescent membrane lipid dyes that was strongly increased in the presence of tumor-targeting Abs. This observation may be closely related to the recently described process of trogocytosis by lymphocytes. The presence of transient PMN-tumor cell aggregates and the accumulation of PMN with tumor cell-derived membrane lipids and vice versa were associated with effective ADCC as measured by chromium-release or apoptosis induction. <br/
Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies
No full textStudies with gene-modified mice have recently reinforced the importance of Fc receptor-mediated effector mechanisms for the therapeutic efficacy of rituxan and herceptin — two clinically approved antibodies for the treatment of tumor patients. We investigated Fc receptor-dependent tumor cell killing by mononuclear and granulocytic effector cells — comparing human IgG1 antibodies against CD20 or HER-2/neu with their respective Fc?RI (CD64)-, Fc?RIII (CD16)-, or Fc?RI (CD89)-directed bispecific derivatives. With blood from healthy donors as effector source, human IgG1 and Fc?RIII (CD16)-directed bispecific antibodies proved most effective in recruiting mononuclear effector cells, whereas tumor cell killing by granulocytes was most potently triggered by Fc?RI-directed bispecific constructs. Granulocyte-mediated tumor cell lysis was significantly enhanced when blood from G-CSF- or GM-CSF-treated patients was investigated. Interestingly, however, both myeloid growth factors improved effector cell recruitment by different mechanisms, which were furthermore dependent on the tumor target antigen, and on the selected cytotoxic Fc receptor
Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing
No full textAntibodies against human leukocyte antigen (HLA) class II, such as 1D10 or Lym-1, are currently being evaluated for the treatment of B-cell lymphomas. Previous studies have demonstrated that, in addition to IgG Fc receptors, the human myeloid IgA receptor (Fcalpha RI, CD89) also effectively triggered tumor cell killing. Therefore, we used the variable light and heavy chain sequences from another murine anti-HLA class II hybridoma, F3.3, to generate a panel of chimeric human/mouse antibodies, including human immunoglobulin A1 (IgA1), IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody production was accomplished by stable transfection of baby hamster kidney cells, and binding activity and specificity were confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. All constructs demonstrated similar binding to HLA class II. Functional studies revealed that chimeric IgG1, IgA1, and IgA2 triggered similar levels of tumor cell lysis. Analyses of effector populations, however, demonstrated that killing by chimeric IgG1 constructs was triggered mainly by human mononuclear cells and complement, while IgA1 and IgA2 mediated effective lysis by polymorphonuclear neutrophils. Importantly, IgG1 and both IgA isotypes were equally effective at killing freshly isolated human chronic lymphocytic leukemia cells. Chimeric IgA antibodies against HLA class II may constitute attractive reagents for lymphoma therapy
Starting points and methods for improving the efficiency of the innovation management in the food industry
No full textIn der Arbeit werden die Innovationsaktivitäten der Ernährungsindustrie untersucht. Ausgehend von einer Analyse der Situation und der Rahmenbedingungen der Branche und einer Ableitung des Handlungsbedarfs werden Innovationsprozesse theoretisch betrachtet und Ansatzpunkte für Effizienzsteigerungen entwickelt. Anschließend erfolgt eine empirische Analyse der Innovationsaktivitäten mit einem Sample von 265 Fällen. Auf Grundlage der theoretischen und empirischen Ergebnisse werden zwei Ansätze zu Effizienzsteigerung der Produktentwicklung durch frühzeitige Einbindung von Kunden in den Innovationsprozeß entwickelt und in Pilotprojekten umgesetzt.In this thesis the innovation activities of the German food processing industry are analysed. Based on an in deep study of the situation of and the framework for the food industry innovation processes are analysed theoretically and starting points for efficiency improvement are derived. Subsequently, an empirical analysis of the innovation activities and previously derived hypotheses is performed using a sample of 265 cases of the food industry. On the basis of the empirical findings two methodological approaches for an early and in deep integration of customers in the innovation process were adopted for the food industry and implemented in pilot companies
Ansatzpunkte und Methoden zur Effizienzsteigerung im Innovationsmanagement der Ernährungsindustrie
No full textLeichen-Predigt bey der Beerdigung des Wohlseligen Fürstlich Lippischen Herrn Regierungs- und Cammerpräsidenten Ferdinand Bernhard von Hoffmann
No full textgehalten am 25ten Febr. 1802 und auf Verlangen zum Druck übergeben von Johann Carl Ludwig StockmeyerVorlageform d. Erscheinungsvermerks: Lemgo, mit Meyerschen Schriften, 1802In Fraktu
Reflections on Teaching the First Day of Contracts Class
No full textABSTRACT
A veteran of the law school classroom offers his thoughts on why Contracts is the most significant course in the first-year curriculum, why the study of contract law should begin with the subject of remedies, and why the “hairy hand” case of The Paper Chase fame makes an ideal starting point. The author also shares his first-day advice on how to succeed in law school. Along the way he explains why he prefers a problems-based casebook, opposes use of commercial briefs and outlines, and makes robust use of a course website.</jats:p
Oportunidades perdidas. Alzamientos federalistas en Chile (1827 y 1828)
No full textThis article studies two important military uprisings that historiography usually associates with the federalist political project: the uprising of Enrique Campino (1827) and of Pedro Urriola (1828). To do this, this work questions the federalist nature of these uprisings, as well as the reasons for their failure. And, the author maintains that, contrary to the usual stand of historiography on the matter, the cause of the failure of the federalist project in Chile can be attributed not only to the difficulties associated with the application of that project, but also to the political indecision on accepting the conquest of the government by armed means.Este artículo estudia dos importantes alzamientos castrenses que la historiografía suele asociar al proyecto político federalista: el de Enrique Campino (1827) y el de Pedro Urriola (1828). Para ello, este trabajo se interroga sobre el carácter federalista de estas sublevaciones, así como sobre las razones de su fracaso. Además, se sostiene que, contrariamente a lo que historiografía ha solido decir al respecto, la causa del fracaso del proyecto federalista en Chile puede encontrarse no sólo en las dificultades que supuso la aplicación de ese proyecto, sino también en la indecisión política de aceptar la conquista del gobierno por la vía armada
El Ejército de Chile en vísperas de la Guerra del Pacífico. Los problemas del enganche (1866-1879)
No full textIn the context of the life of the Army of Chile during the interwar period (1866-1879), this work aims to explain the constant disparity between the forces that were legally authorized and those that were actually recruited, the second ones being numerically inferior to the first. To reach such an explanation, four main factors are analyzed: wages of troops, conditions in the Arauco area, and defects of the recruitment. Refining the first two, the author is inclined to assign greater importance to the last two.En el contexto de la vida del Ejército de Chile en un período entreguerras (1866-1879), este trabajo apunta a explicar la disparidad constante entre las fuerzas legalmente autorizadas y las efectivamente enganchadas, siendo las segundas numéricamente inferiores a las primeras. Para arribar a tal explicación, se analizan cuatro factores principales: sueldos de las tropas, condiciones de la vida militar en general, condiciones de la vida militar en la zona de Arauco, y defectos del enganche. Matizando los dos primeros, la autora se inclina por asignarle mayor importancia a los dos últimos
Logic and Formal Languages]: Mathematical Logic—mechanical theorem proving
No full textAbstract. An exponential lower bound on the circuit complexity of deciding the weak monadic second-order theory of one successor (WS1S) is proved. Circuits are built from binary operations, or 2-input gates, which compute arbitrary Boolean functions. In particular, to decide the truth of logical formulas of length at most 610 in this second-order language requires a circuit containing at least 10 125 gates. So even if each gate were the size of a proton, the circuit would not fit in the known universe. This result and its proof, due to both authors, originally appeared in 1974 in the Ph.D. thesis of the first author. In this article, the proof is given, the result is put in historical perspective, and the result is extended to probabilistic circuits.
