Biology of brain metastases and novel targeted therapies: Time to translate the research

Brain metastases (BM) occur in 20% to 40% of patients with cancer and result in significant morbidity and poor survival. The main therapeutic options include surgery, whole brain radiotherapy, stereotactic radiosurgery and chemotherapy. Although significant progress has been made in diagnostic and therapeutic methods, the prognosis in these patients remains poor. Furthermore, the poor penetrability of chemotherapy agents through the blood brain barrier (BBB) continues to pose a challenge in the management of this disease. Preclinical evidence suggests that new targeted treatments can improve local tumor control but our clinical experience with these agents remains limited. In addition, several clinical studies with these novel agents have produced disappointing results. This review will examine the knowledge of targeted therapies in BM. The preclinical and clinical evidence of their use in BM induced by breast cancer, non-small cell lung cancer and melanoma will be presented. In addition, we will discuss the role of antiangiogenic and radiosensitising agents in the treatment of BM and the current strategies available to increase BBB permeability. A better understanding of the mechanism of action of these agents will help us to identify the best targets for testing in future clinical studies.     

Field-based video observations of wild barnacle cyprid behaviour in response to textural and chemical settlement cues

Many marine invertebrate larvae respond behaviourally to environmental settlement cues, yet behaviours are often only inferred from settlement patterns or are limited to laboratory studies. The behaviour of wild cypris larvae of Semibalanus balanoides L. was filmed on settlement tiles in the field. Tiles were of five different textures with a nested treatment of crude conspecific adult extract (AE). The effects of texture and AE on eleven defined behaviours were analysed. Texture affected the gross and net exploratory distances, velocity, acceleration and time spent exploring. AE attracted more cyprids during the first minute of immersion and increased the time spent on surfaces. Relatively few arrivals that either travel far and fast, or exit the surface rapidly, may indicate a lower chance of settlement. An increase in time spent on a surface may increase the probability of being in contact with the surface when the sign stimulus to settle occurs.     

Properties of Confined Square-well Fluids using the Gibbs Ensemble Simulation Technique

In this work we have used the extension of the Gibbs ensemble simulation technique to inhomogeneous fluids [Panagiotopoulos, A.Z. (1987) "Adsorption and capillary condensation of fluid in cylindrical pores by Monte Carlo simulation in the Gibbs ensemble", Mol. Phys. , 62 (3), 701-719], which has been applied to adsorption phenomena of confined fluids. Fluid molecules are described by spherical particles interacting via a square-well potential. The fluid is confined in two types of walls: symmetrical (two hard walls) and non-symmetrical (one square-well wall and one hard wall). In order to analyze the behavior of the confined fluid by varying the potential parameters, we evaluated the bulk and confined densities, the internal energies and the density profiles for different supercritical temperatures. A variety of adsorption profiles can be obtained by using this model. The simulation data reported here complements the available simulation data for this system and can be useful in the development of inhomogeneous fluid theories. Since the square-well parameters can be related to real molecules this system can also be used to understand real adsorption systems.     

On the altitudinal limits of birds on BasilC Peak (Bioko Island; Equatorial Guinea)

Pérez del Val, J. 2000. On the altitudinal limits of birds on Basile Peak (Bioko Island; Equatorial Guinea). Ostrich 71(1 & 2): 342.

The lower altitudinal limit of the montane avifauna in Africa has generally been set at 1 500- 800 m, corresponding to vegetation belts of the main mountain ranges of East Africa. However, much lower limits have been reported from the East Usambaras (Tanzania), Mount Cameroon, and Bioko Island. Basilé Peak is a volcano of 3 011 m which constitutes the northern half of Bioko Island. Below 400–900 m the forest has been logged and largely replaced by cocoa plantations, but the vegetation is relatively undisturbed at higher altitudes. Annual rainfall ranges between 2 000 mm and 3 500 mm. From January 1990 to July 1992 mist-nets were set at 13 standardised stations on Basilé Peak; 1 427 birds of 71 species were captured. Previous data from non-standardised mist-netting at 6 other localities, together with sight and sound records, published data, and 1 047 skins in the collections of Museo Naçional de Ciençias Naturales (Madrid), Estacion Biologica de Donaiia (Sevilla) and the Natural History Museum (Tring) were also used to compile distribution lists. From published botanical surveys, I recognised four vegetation zones: Lowland Rain Forest up to 800 m; Mountain Rain Forest at 80CL1 800 m; Araliaceus Forest 1 800–2 500 m; and Ericaceus Stands above 2 500 m. An analysis of similarity (using the index of Czechanowski) grouped 68 bird species into altitudinal classes at 200 m intervals. This suggests a division between lowland and montane birds at 800–1 000 m, broadly coinciding with the change between Lowland and Mountain Rain Forest. There does not seem to be a discrete bird community restricted to either of the upper zones (Araliaceus Forest or Ericaeus Stands), with only the Yellow Bishop Euplectes capensis restricted to the upper 500 m of the mountain. Most species which reach the summit are found in all vegetation zones, notably the endemic subspecies of the African Goshawk Accipiter tachiro lopezi. It is suggested that low temperatures, high rainfall, and in particular the seasonal distribution of rainfall, may explain the lower altitudinal limits of the montane avifauna on Bioko and on Mount Cameroon.     

The mitochondrial oxoglutarate carrier: from identification to mechanism

The 2-oxoglutarate carrier (OGC) belongs to the mitochondrial carrier protein family whose members are responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. Initially, OGC was characterized by determining substrate specificity, kinetic parameters of transport, inhibitors and molecular probes that form covalent bonds with specific residues. It was shown that OGC specifically transports oxoglutarate and certain carboxylic acids. The substrate specificity combination of OGC is unique, although many of its substrates are also transported by other mitochondrial carriers. The abundant recombinant expression of bovine OGC in Escherichia coli and its ability to functionally reconstitute into proteoliposomes made it possible to deduce the individual contribution of each and every residue of OGC to the transport activity by a complete set of cys-scanning mutants. These studies give experimental support for a substrate binding site constituted by three major contact points on the even-numbered α-helices and identifies other residues as important for transport function through their crucial positions in the structure for conserved interactions and the conformational changes of the carrier during the transport cycle. The results of these investigations have led to utilize OGC as a model protein for understanding the transport mechanism of mitochondrial carriers.     

PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP^SC) has been studied in depth, the physiological role of PrP^C remains elusive and controversial. PrP^C is a cell‐surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP^C in animals and in cellular models. In this article, we present PrP^C‐dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP^C over‐expression enhances cell proliferation and cell cycle re‐entrance after serum stimulation, while PrP^C silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP^C in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP^C in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP^C over‐expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT‐Cdc42‐N‐WASP‐dependent pathway.