N-cadherin as a therapeutic target in cancer.

During tumor progression, cancer cells undergo dramatic changes in the expression profile of adhesion molecules resulting in detachment from original tissue and acquisition of a highly motile and invasive phenotype. A hallmark of this change, also referred to as the epithelial-mesenchymal transition, is the loss of E- (epithelial) cadherin and the de novo expression of N- (neural) cadherin adhesion molecules. N-cadherin promotes tumor cell survival, migration and invasion, and a high level of its expression is often associated with poor prognosis. N-cadherin is also expressed in endothelial cells and plays an essential role in the maturation and stabilization of normal vessels and tumor-associated angiogenic vessels. Increasing experimental evidence suggests that N-cadherin is a potential therapeutic target in cancer. A peptidic N-cadherin antagonist (ADH-1) has been developed and has entered clinical testing. In this review, the authors discuss the biochemical and functional features of N-cadherin, its potential role in cancer and angiogenesis, and summarize the preclinical and clinical results achieved with ADH-1.

Field trials of low dose Bayluscide on snail hosts of schistosome and selected non-target organisms in sahelian Cameroon

More than 85% of all cases of schistosomiasis in Cameroon occur in the northern sahelian half of the country representing 20% of the population. Several workers have advocated the integrated approach to schistosomiasis control, including snail control, but the death and decay of aquatic organisms, and fish kill that often follows Bayluscide application at the dose of 1g/m³ decrease its acceptability. The present study was designed to assess the effect of lower Bayluscide doses on snail host and non-target fish, frog, the tadpole kill. Bayluscide was applied to study ponds at concentrations of 0, 0.25, 0.5, and 1 g/m³ (ppm). Pre and post application assessment of snails hosts of schistosomes, fish, frog, and tadpole kill were carried out. All 0.25, 0.5, and 1 g/m³ Bayluscide concentrations reduced snail population significantly. Bayluscide concentration of 0.50 g/m³ applied in two rounds of 0.25 g/m³ resulted in high snail mortality and low lethality to fish, frogs, and tadpoles. Further studies are needed to assess the cost-effectiveness of Bayluscide in the control of schistosomiasis following the simplified approach.

Attaining the minimum target of resolution WHA 54.19 for schistosomiasis control in the Rainforest Zone of the state of Pernambuco, Northeastern Brazil

Resolution 19 of the 54th World Health Assembly (WHA-54.19) urged member nations to promote preventive measures, ensure treatment and mobilize resources for control of schistosomiasis and soil-transmitted helminthiases (STH). The minimum target is to attend 75% of all school-age children at risk by year 2010. The Brazilian Ministry of Health (MoH) recommends biennial surveys of whole communities and treatment of the positives through the Schistosomiasis Control Program within the Unified Health System (PCE-SUS). However, by 2004 the PCE-SUS had covered only 8.4% of the 1.2 million residents in the Rainforest Zone of Pernambuco (ZMP). Six of the 43 municipalities still remained unattended. Only three of the municipalities already surveyed reached coverage of 25% or more. At least 154 thousand children in the 7-14 years old range have to be examined (and treated if positive) within the next five years to attend the minimum target of the WHA 54.19 for the ZMP. To make this target feasible, it is suggested that from 2006 to 2010 the PCE-SUS actions should be complemented with school-based diagnosis and treatment, involving health and educational organs as well as community associations to include both children in schools and non-enrolled school-age children.

The impact of social relationships on the maintenance of independence in advanced old age: findings of a Swiss Longitudinal Study .

The impact of social relationships on the maintenance of independence over periods of 12-18 months in a group of 306 octogenarians is assessed in this study. The study is based on the results of the Swilsoo (Swiss Interdisciplinary Longitudinal Study on the Oldest Old). Participants (80-84 years old at baseline) were interviewed five times between 1994 and 1999. Independence was defined as the capacity to perform without assistance eight activities of daily living. We distinguished in our analyses kinship and friendship networks and evaluated social relationships with the help of a series of variables serving as indicators of network composition and contact frequency. Logistic regression models were used to identify the short-term effects of social relationships on independence, after controlling for sociodemographic and health-related variables; independence at a given wave of interviews was interpreted in the light of social factors measured at the previous wave. Our analyses indicate that the existence of a close friend has a significant impact on the maintenance of independence (OR=1.58, p<0.05), which is not the case with the other variables concerning network composition. Kinship contacts were also observed to have a positive impact on independence (OR=1.12, p<0.01).

Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs.

Healing of cutaneous wounds, which is crucial for survival after an injury, proceeds via a well-tuned pattern of events including inflammation, re-epithelialisation, and matrix and tissue remodelling. These events are regulated spatio-temporally by a variety of growth factors and cytokines. The inflammation that immediately follows injury increases the expression of peroxisome proliferator-activated receptor (PPAR)-beta in the wound edge keratinocytes and triggers the production of endogenous PPARbeta ligands that activate the newly produced receptor. This elevated PPARbeta activity results in increased resistance of the keratinocytes to the apoptotic signals released during wounding, allowing faster re-epithelialisation. The authors speculate that, in parallel, ligand activation of PPARbeta in infiltrated macrophages attenuates the inflammatory response, which also promotes repair. Thus, current understanding of the roles of PPARbeta in different cell types implicated in tissue repair has revealed an intriguing intercellular cross-talk that coordinates, spatially and temporally, inflammation, keratinocyte survival, proliferation and migration, which are all essential for efficient wound repair. These novel insights into the orchestrating roles of PPARbeta during wound healing may be helpful in the development of drugs for acute and chronic wound disorders.

The Formal Independence of Regulators: A Comparison of 17 Countries and 7 Sectors

This article seeks to explain the pattern of delegation to independent regulatory agencies in Western Europe. Two types of arguments are advanced to explain variations in the formal independence of regulators. Firstly, the need for governments to increase their credible commitment capacity may lead them to delegate regulation to an agency that is partly beyond their direct control. Secondly, delegation may be a response to the political uncertainty problem, which arises when governments are afraid of being replaced by another coalition with different preferences, which could decide to change existing policy choices. In addition, veto players may constitute a functional equivalent of delegation, since they influence policy stability and therefore tend to mitigate both the credibility and the political uncertainty problems. These arguments are consistent with the results of the empirical analysis of the formal independence of regulators in seventeen countries and seven sectors.

Improving the production of the denatured recombinant N-terminal domain of rhoptry-associated protein 2 from a Plasmodium falciparum target in the pathology of anemia in falciparum malaria

Rhoptry-associated protein 2 (RAP2) is known to be discharged from rhoptry onto the membrane surface of infected and uninfected erythrocytes (UEs) ex vivo and in vitro and this information provides new insights into the understanding of the pathology of severe anemia in falciparum malaria. In this study, a hexahistidine-tagged recombinant protein corresponding to residues 5-190 of the N-terminal of Plasmodium falciparum RAP2 (rN-RAP2) was produced using a new method of solubilization and purification. Expression was induced with D-lactose, a less expensive alternative inducer to the more common isopropyl-²-D-thio-galactopyranosidase. The recombinant protein was purified using two types of commercially-available affinity columns, iminodiacetic and nitrilotriacetic. rN-RAP2 had immunogenic potential, since it induced high titers of anti-RAP2 antibodies in mice. These antibodies recognized full-length RAP2 prepared from Triton X-100 extracts from two strains of P. falciparum. In fact, the antibody recognized a 29-kDa product of RAP2 cleavage as well as 82 and 70-kDa products of RAP1 cleavage. These results indicate that the two antigens share sequence epitopes. Our expressed protein fragment was shown to contain a functional epitope that is also present in rhoptry-derived ring surface protein 2 which attaches to the surface of both infected and UEs and erythroid precursor cells in the bone marrow of malaria patients. Serum from malaria patients who developed anemia during infection recognized rN-RAP2, suggesting that this protein fragment may be important for epidemiological studies investigating whether immune responses to RAP2 exacerbate hemolysis in falciparum malaria patients.

Dissociation of allocentric and egocentric orientation: Effect on hippocampal place cells and place navigation

Navigation by means of cognitive maps appears to require the hippocampus; hippocampal place cells (PCs) appear to store spatial memories because their discharge is confined to cell-specific places called firing fields (FFs). Experiments with rats manipulated idiothetic and landmark-related information to understand the relationship between PC activity and spatial rotation. Rotating a circular arena in the caused a discrepancy between these cuse. This discrepancy caused most FFs to disappear in both the arena and room reference frames. However, FFs persisted in the rotating arena frame when the discrepancy was reduced by darkness or by a card in the arena. The discrepancy was increased by "field clamping" the rat in a room-defined FF location by rotations that countered its locomotion. Most FFs disspared and reappeared an hour or more after the clamp. Place-avoidance experiments showed that navigation uses independent idiothetic and exteroceptive memories. Rats learned to avoid the unmarked footshock region within a circular arena. When acquired on the stable arena in the light, the location of the punishment was learned by using both room and idiothetic cues; extinction in the dark transferred to the following session in the light. If, however, extinction occured during rotation, only the arena-frame avoidance was extinguished in darkness; the room-defined location was avoided when the light were turned back on. Idiothetic memory of room-defined avoidance was not formed during rotation in light; regardless of rotation with a randomly dispersed pellet. The resulting behaviour alternated between random pellet searching and target-directed navigation, making it possible to examine PC correlates of these two classes of spatial behaviour. The independence of idiothetic and exteroceptive spatial memories and the disruption of PC firing during rotation suggest that PCs may not be necessary for spatial cognition; this idea can be tested by recording during place-avoidance and preference tasks.

A new approach for potential drug target discovery through in silico metabolic pathway analysis using Trypanosoma cruzi genome information

The current drug options for the treatment of chronic Chagas disease have not been sufficient and high hopes have been placed on the use of genomic data from the human parasite Trypanosoma cruzi to identify new drug targets and develop appropriate treatments for both acute and chronic Chagas disease. However, the lack of a complete assembly of the genomic sequence and the presence of many predicted proteins with unknown or unsure functions has hampered our complete view of the parasite's metabolic pathways. Moreover, pinpointing new drug targets has proven to be more complex than anticipated and has revealed large holes in our understanding of metabolic pathways and their integrated regulation, not only for this parasite, but for many other similar pathogens. Using an in silicocomparative study on pathway annotation and searching for analogous and specific enzymes, we have been able to predict a considerable number of additional enzymatic functions in T. cruzi. Here we focus on the energetic pathways, such as glycolysis, the pentose phosphate shunt, the Krebs cycle and lipid metabolism. We point out many enzymes that are analogous to those of the human host, which could be potential new therapeutic targets.

An hybrid methodology for RL-based behavior coordination in a target following mission with an AUV

Proposes a behavior-based scheme for high-level control of autonomous underwater vehicles (AUVs). Two main characteristics can be highlighted in the control scheme. Behavior coordination is done through a hybrid methodology, which takes in advantages of the robustness and modularity in competitive approaches, as well as optimized trajectories

Intrinsic test of independence in contingency tables

A condition needed for testing nested hypotheses from a Bayesianviewpoint is that the prior for the alternative model concentratesmass around the small, or null, model. For testing independencein contingency tables, the intrinsic priors satisfy this requirement.Further, the degree of concentration of the priors is controlled bya discrete parameter m, the training sample size, which plays animportant role in the resulting answer regardless of the samplesize.In this paper we study robustness of the tests of independencein contingency tables with respect to the intrinsic priors withdifferent degree of concentration around the null, and comparewith other “robust” results by Good and Crook. Consistency ofthe intrinsic Bayesian tests is established.We also discuss conditioning issues and sampling schemes,and argue that conditioning should be on either one margin orthe table total, but not on both margins.Examples using real are simulated data are given

The neuroretina is a novel mineralocorticoid target: aldosterone up-regulates ion and water channels in Müller glial cells.

Glucocorticoids reduce diabetic macular edema, but the mechanisms underlying glucocorticoid effects are imperfectly elucidated. Glucocorticoids may bind to glucocorticoid (GR) and mineralocorticoid (MR) receptors. We hypothesize that MR activation may influence retinal hydration. The effect of the MR agonist aldosterone (24 h) on ion/water channel expression (real-time PCR, Western blot, immunofluorescence) was investigated on cultured retinal Müller glial cells (RMGs, which contribute to fluid homeostasis in the retina), in Lewis rat retinal explants, and in retinas from aldosterone-injected eyes. We evidenced cell-specific expression of MR, GR, and 11-beta-hydroxysteroid dehydrogenase type II. Aldosterone significantly enhances expression of sodium and potassium channels ENaC-alpha (6.5-fold) and Kir4.1 (1.9-fold) through MR and GR occupancy, whereas aquaporin 4 (AQP4, 2.9-fold) up-regulation is MR-selective. Aldosterone intravitreous injection induces retinal swelling (24% increase compared to sham-injected eyes) and activation of RMGs. It promotes additional localization of Kir4.1 and AQP4 toward apical microvilli of RMGs. Our results highlight the mineralocorticoid-sensitivity of the neuroretina and show that aldosterone controls hydration of the healthy retina through regulation of ion/water channels expression in RMGs. These results provide a rationale for future investigations of abnormal MR signaling in the pathological retina.

Search for a platelet-activating factor receptor in the Trypanosoma cruzi proteome: a potential target for Chagas disease chemotherapy

Chagas disease (CD) causes the highest burden of parasitic diseases in the Western Hemisphere and is therefore a priority for drug research and development. Platelet-activating factor (PAF) causes the CD parasite Trypanosoma cruzi to differentiate, which suggests that the parasite may express PAF receptors. Here, we explored the T. cruzi proteome for PAF receptor-like proteins. From a total of 23,000 protein sequences, we identified 29 hypothetical proteins that are predicted to have seven transmembrane domains (TMDs), which is the main characteristic of the G protein-coupled receptors (GPCRs), including the PAF receptor. The TMDs of these sequences were independently aligned with domains from 25 animal PAF receptors and the sequences were analysed for conserved residues. The conservation score mean values for the TMDs of the hypothetical proteins ranged from 31.7-44.1%, which suggests that if the putative T. cruzi PAF receptor is among the sequences identified, the TMDs are not highly conserved. These results suggest that T. cruzi contains several GPCR-like proteins and that one of these GPCRs may be a PAF receptor. Future studies may further validate the PAF receptor as a target for CD chemotherapy.