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Introduction: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients.
Methods: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks.
Results: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients.
Conclusion: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.
Following publication of the data presented by von Minckwitz and colleagues it has been brought to our attention that some patients should be scored differently. Stable disease was seen in three of the eighteen patients instead of two of the eighteen patients: one patient with transitional cell carcinoma treated at 4 µg/kg scFv(FRP5)-ETA per day, and two breast cancer patients treated at 4 and 12.5 µg/kg scFv(FRP5)-ETA per day. Disease progression occured in 9 of the eighteen patients evaluated (see corrected Table 2 overleaf). This does not affect the conclusions of our study. In addition we would like to correct the following errors: patient IDs for patients U01 and U02 in the original Table 2 were interchanged. In addition, patient N03 had a grade 3 elevation of gamma-glutamyl transferase, and not grade 2 (see corrected Table 2 overleaf).
A Large Ion Collider Experiment (ALICE) has been conceived and constructed as a heavy-ion experiment at the LHC. During LHC Runs 1 and 2, it has produced a wide range of physics results using all collision systems available at the LHC. In order to best exploit new physics opportunities opening up with the upgraded LHC and new detector technologies, the experiment has undergone a major upgrade during the LHC Long Shutdown 2 (2019-2022). This comprises the move to continuous readout, the complete overhaul of core detectors, as well as a new online event processing farm with a redesigned online-offline software framework. These improvements will allow to record Pb-Pb collisions at rates up to 50 kHz, while ensuring sensitivity for signals without a triggerable signature.
A Large Ion Collider Experiment (ALICE) has been conceived and constructed as a heavy-ion experiment at the LHC. During LHC Runs 1 and 2, it has produced a wide range of physics results using all collision systems available at the LHC. In order to best exploit new physics opportunities opening up with the upgraded LHC and new detector technologies, the experiment has undergone a major upgrade during the LHC Long Shutdown 2 (2019-2022). This comprises the move to continuous readout, the complete overhaul of core detectors, as well as a new online event processing farm with a redesigned online-offline software framework. These improvements will allow to record Pb-Pb collisions at rates up to 50 kHz, while ensuring sensitivity for signals without a triggerable signature.
A Large Ion Collider Experiment (ALICE) has been conceived and constructed as a heavy-ion experiment at the LHC. During LHC Runs 1 and 2, it has produced a wide range of physics results using all collision systems available at the LHC. In order to best exploit new physics opportunities opening up with the upgraded LHC and new detector technologies, the experiment has undergone a major upgrade during the LHC Long Shutdown 2 (2019–2022). This comprises the move to continuous readout, the complete overhaul of core detectors, as well as a new online event processing farm with a redesigned online-offline software framework. These improvements will allow to record Pb-Pb collisions at rates up to 50 kHz, while ensuring sensitivity for signals without a triggerable signature.
Seit gut einem Jahrzehnt wird in Deutschland gewartet: Auf Literatur wird gewartet, auf den großen Berlin-Roman, auf den großen Nachwende-Roman. Und trotz diverser Romane, die Wiedervereinigung und Berlin zum Thema erhoben, ob nun von Günter Grass oder Thomas Brussig, wird weiter gewartet, kann es anscheinend kein Autor recht machen, wird unterhaltsames Erzählen begehrt oder eine Darstellung auf der Höhe moderner Erzählkunst verlangt. Doch die Alternative ist vielleicht falsch gestellt: Könnte denn nicht ein kunstvoll geschriebener Roman mit präziser und variantenreicher Sprache, ausgeklügelten Erzählstrukturen auch unterhaltsam sein? Schließlich ist Döblins nicht gerade schlichter Roman "Berlin Alexanderplatz" ja auch ein Lesevergnügen, vergleichbar mit "Joyces Ulysses" oder Pynchons "Gravity’s Rainbow". Nun lassen sich solche Romane schlecht wiederholen, hinge jeder Nachahmung des Stils der Verdacht an, Plagiat oder Kopie zu sein. Etwas Ähnliches wäre also immer etwas Anderes, neuartig, artifiziell und darin genaueres Abbild seiner Zeit als die Vielzahl schlichter Romane, die von Berlin oder der Wiedervereinigung erzählen. Nun, in letzter Zeit mehren sich im deutschen Feuilleton Stimmen, die eine gewisse, dementsprechende Kunst des Erzählens bei Ulrich Peltzer ausmachen, weswegen hier die Gelegenheit ergriffen wird, einen Gang durch seine drei letzten Publikationen ["Stefan Martinez", "Alle oder keiner", "Bryant Park"] zu unternehmen, um die Entwicklung derselben darzustellen - im Hinterkopf die Frage: Liegt hier vielleicht schon einer der erwarteten großen Berlin-Romane vor?
Artenreiche, extensiv bewirtschaftete Mähwiesen des Verbandes Arrhenatherion elatioris (planar-kolline Frischwiesen), im Flach- und Hügelland vorkommend. Der Lebensraumtyp schließt sowohl trockene Ausbildungen, typische Ausbildungen frischer, sowie Ausbildungen feuchter bis wechselfeuchter Standorte ein. Im Gegensatz zum Intensivgrünland sind Flachland-Mähwiesen blütenreich und wenig gedüngt. Der erste Heuschnitt erfolgt nicht vor der Hauptblütezeit der Gräser.
Methodik
(2002)
Die vegetationskundliche und strukturelle Zuordnung der Lebensraumtypen erfolgt nach der vorrangig von Braun-Blanquet entwickelten Vegetationsklassifizierung, einer hierarchischen Gliederung der Vegetationstypen (Syntaxonomie), die die Ebenen der Assoziation, des Verbandes, der Ordnung und der Klasse umfasst. Hierbei ist die Assoziation die grundlegende Einheit, in der die Pflanzengesellschaften zusammengefasst werden, die sich durch gleiche charakteristische Arten(gruppen)kombinationen auszeichnen. Der Verband vereinigt ähnliche Assoziationen. Das sind bereits umfassendere, jedoch standörtlich noch recht einheitliche Vegetationseinheiten. In Ordnungen werden ähnliche Verbände zusammengefasst. Die Klasse vereinigt ähnliche Ordnungen.