A popular species for food and sport, the European catfish (Silurus glanis) is well-studied in its native range, but little studied in its introduced range. Silurus glanis is the largestbodied freshwater fish of Europe and is historically known to take a wide range of food items including human remains. As a result of its piscivorous diet, S. glanis is assumed to be an invasive fish species presenting a risk to native species and ecosystems. To assess the potential risks of S. glanis introductions, published and 'grey' literature on the species' environmental biology (but not aquaculture) was extensively reviewed. Silurus glanis appears well adapted to, and sufficiently robust for, translocation and introduction outside its native range. A nest-guarding species, S. glanis is long-lived, rather sedentary and produces relatively fewer eggs per body mass than many fish species. It appears to establish relatively easily, although more so in warmer (i.e. Mediterranean) than in northern countries (e.g. Belgium, UK). Telemetry data suggest that dispersal is linked to flooding/spates and human translation of the species. Potential impacts in its introduced European range include disease transmission, hybridization (in Greece with native endemic Aristotle's catfish [Silurus aristotelis]), predation on native species and possibly the modification of food web structure in some regions. However, S. glanis has also been reported (France, Spain, Turkmenistan) to prey intensively on other non-native species and in its native Germany to be a poor biomanipulation tool for top-down predation of zooplanktivorous fishes. As such, S. glanis is unlikely to exert trophic pressure on native fishes except in circumstances where other human impacts are already in force. In summary, virtually all aspects of the environmental biology of introduced S. glanis require further study to determine the potential risks of its introduction to novel environments.

The impact of the parasitic swimbladder nematode, Anguillicola crassus Kuwahara, Niimi & Itagaki, on European eel populations is assessed with reference to published research on its origin and rapid dissemination, life cycle and transmission dynamics, and its pathogenic effect. The parasite was originally endemic to East Asia, but has transferred from its native host, the Japanese eel, Anguilla japonica Temminck & Schlegel, to the European eel, Anguilla anguilla (L.) and American eel, Anguilla rostrata (Le Seur). Anguillicola crassus is a very successful colonizer and is now known to occur in four continents (Asia, Europe, Africa and America). The nematode can severely impair swimbladder function and has caused mortalities in both farmed and wild populations in the presence of other stressors. Anguillicola crassus may impair the capacity of European eels to complete the spawning migration, although direct evidence is not available to support this hypothesis. Areas for future research are recommended.K E Y W O R D S : Anguillicola crassus, eels parasite, nematode, pathology, swimbladder.

BRAF is a serine-threonine-specific protein kinase that is mutated in 2% of human cancers. Oncogenic BRAF is a validated therapeutic target that constitutively activates mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling, driving tumor cell proliferation and survival. Drugs designed to target BRAF have been developed, but it is difficult to prove that they mediate their antitumor effects by inhibiting BRAF rather than by working through off-target effects. We generated drug-resistant versions of oncogenic BRAF by mutating the gatekeeper residue. Signaling by the mutant proteins was resistant to the small-molecule inhibitor sorafenib, but sorafenib still inhibited the growth of tumors driven by the mutant protein. In contrast, both BRAF signaling and tumor growth were resistant to another RAF drug, PLX4720. These data provide unequivocal evidence that sorafenib mediates its antitumor effects in a manner that is independent of its ability to target oncogenic BRAF, whereas PLX4720 inhibits tumor growth by targeting oncogenic BRAF directly.

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.