Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis

Background: CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis. Methodology: Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies. Significance: For the first time, successful generation of anti-G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer

Principles of sound ecotoxicology

We have become progressively more concerned about the quality of some published ecotoxicology research. Others have also expressed concern. It is not uncommon for basic, but extremely important, factors to apparently be ignored. For example, exposure concentrations in laboratory experiments are sometimes not measured, and hence there is no evidence that the test organisms were actually exposed to the test substance, let alone at the stated concentrations. To try to improve the quality of ecotoxicology research, we suggest twelve basic principles that should be considered, not when presenting findings to the regulators, but at the stage of experimental design. These principles range from accurately defining the exposure through to carefully considering essential aspects of experimental design as well as unbiased analysis and reporting of the results. Although not all principles will apply to all studies, we offer these principles in the hope that they will improve the quality of the science that is presented to regulators. Science is an evidence-based discipline, and it is important that we and the regulators can trust the evidence presented to us. Significant resources often have to be devoted to refuting the results of poor research when those resources could be utilised more effectively

Roach (Rutilus rutilus) reproductive cycle: a study of biochemical and histological parameters in a low contaminated site

Fish reproduction is subjected to worrying trends in many aquatic environments. In this study, we report the absence of histological and biochemical alterations in fish sampled in a low contaminated site (characterised by the absence of detectable oestrogenic activity and mutagenicity in sediment extracts). A total of 474 roach (Rutilus rutilus) were monthly sampled during 18 months, and no intersex fish were recorded after careful histological examination, thus indicating that the incidence of this phenomenon may be very low under natural conditions. Furthermore, mean male plasma vitellogenin concentration was 24 ng ml(-1) and was only slightly elevated during the spawning period (up to 120 ng ml(-1)) indicating that these low values may be characteristic of a low contaminated site. Of the male roach, 45.3% were sampled, a sex-ratio that did not significantly deviated from the expected 1:1 ratio between male and female. Results also showed that natural conditions can greatly affect the reproductive cycle of roach. Gametogenesis showed a biphasic pattern with first gonad maturation between September and December and a final maturation occurring at the end of winter/early spring. Under decreasing temperatures, particularly below 6A degrees C, gametogenesis was stopped or even regressed with secondary oocytes becoming rare under histological observation. Conversely, elevated temperatures during the winter lead to an earlier gonad maturation