Role of NEU3 Overexpression in the Prediction of Efficacy of EGFR-Targeted Therapies in Colon Cancer Cell Lines

The epidermal growth factor receptor (EGFR), through the MAP kinase and PI3K-Akt-mTOR axis, plays a pivotal role in colorectal cancer (CRC) pathogenesis. The membrane-associated NEU3 sialidase interacts with and desialylates EGFR by promoting its dimerization and downstream effectors’ activation. Among the targeted therapies against EGFR, the monoclonal antibody cetuximab is active only in a subgroup of patients not carrying mutations in the MAP kinase pathway. In order to better understand the EGFR-NEU3 interplay and the mechanisms of pharmacological resistance, we investigated the role of NEU3 deregulation in cetuximab-treated CRC cell lines transiently transfected with NEU3 using Western blot analysis. Our results indicate that NEU3 overexpression can enhance EGFR activation only if EGFR is overexpressed, indicating the existence of a threshold for NEU3-mediated EGFR activation. This enhancement mainly leads to the constitutive activation of the MAP kinase pathway. Consequently, we suggest that the evaluation of NEU3 expression cannot entirely substitute the evaluation of EGFR because EGFR-negative cases cannot be stimulated by NEU3. Furthermore, NEU3-mediated hyperactivation of EGFR is counterbalanced by the administration of cetuximab, hypothesizing that a combined treatment of NEU3- and EGFR-targeted therapies may represent a valid option for CRC patients, which must be investigated in the future.     

Shared book reading: When and how questions affect young children's word learning.

Shared book reading, and the conversation that accompanies it, can facilitate young children's vocabulary growth. To identify the features of extratextual questions that help 3-year-olds learn unfamiliar words during shared book reading, two experiments explored the impact of cognitive demand level, placement, and an approximation to scaffolding. Asking questions about target words improved children's comprehension and production of word–referent associations, and children with larger vocabularies learned more than children with smaller vocabularies. Neither the demand level nor placement of questions differentially affected word learning. However, an approximation to scaffolding, in which adults asked low demand questions when words first appeared and high demand questions later, did facilitate children's deeper understanding of word meanings as assessed with a definition task. These results are unique in experimentally demonstrating the value for word learning of shifting from less to more challenging input over time. Discussion focuses on why a scaffolding-like procedure improves children's acquisition of elaborated word meanings. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modelling the VO2 kinetic response to heavy intensity exercise in children

The purpose of this study was to apply a series of mathematical models in order to investigate the nature of the kinetic response to heavy intensity exercise with children and identify a suitable model with which to estimate parameters of the response. Sixty two children (35 male, 27 female aged 10-15 years) completed four transitions from baseline pedalling to 40% of the difference between their previously determined anaerobic threshold and peak VO2 on an electronically braked cycle ergometer. Initially three models were fitted to the averaged response profiles following the end of phase 1. and their residuals compared; 1, a single exponential with a delay term; 2, an exponential and linear term with independent delays; and 3, a double exponential with independent delays. Up to 95% of the response profiles were better fitted by either model 2 or 3 (p < 0.05), and model 3 was a statistically better fit (p < 0.05) than model 2 in 77% of cases. Residual inspection confirmed the superior fit by model 3. A fourth model which consisted of a single exponential with a delay term was fitted within the phase 2 fitting window. Estimated parameters (A1 and tau1), using model 4 were not significantly different from model 3, and model 4 was identified as the model of choice due to the wide confidence intervals in tau2 and A2 using model 3. It was concluded that the nature of the response to heavy intensity exercise in children is similar to that previously reported with adults and that the response should be modelled accordingly.     

Dopamine D? receptor stimulation of the nucleus accumbens or the medial preoptic area promotes the onset of maternal behavior in pregnancy-terminated rats.

There is good evidence that interference with the mesolimbic dopamine (DA) system results in impaired maternal responding in postpartum female rats. However, whether activation of the mesolimbic DA system is capable of promoting maternal behavior has not been investigated. This study examined whether increasing DA activity in various brain regions of pregnancy-terminated, naive female rats would stimulate the onset of maternal behavior. Experiments 1 and 2 examined the effects of microinjection of various doses (0, 0.2, or 0.5 μg/0.5 μl/side) of a D? DA receptor agonist, SKF 38393, or a D? DA receptor agonist, quinpirole, into the nucleus accumbens (NA) on latency to show full maternal behavior, and Experiment 3 determined the effects of SKF 38393 injection into a control site. Finally, because the medial preoptic area (MPOA) is also important for maternal behavior, receives DA input, and expresses DA receptors, the authors examined whether microinjection of SKF 38393 into MPOA was capable of stimulating the onset of maternal behavior. Results indicated that microinjection of SKF 38393 into either the NA or the MPOA facilitates maternal responding in pregnancy-terminated rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of spatial location in remembering and forgetting peripheral words.

This study examined whether spatial location mediates intentional forgetting of peripherally presented words. Using an item-method directed forgetting paradigm, words were presented in peripheral locations at study. A recognition test presented all words at either the same or a different location relative to study. Results showed that while recognition of Remember words was unaffected by test location, when Forget words were presented in the same location at test as at study, recognition accuracy was significantly greater than when presented in a different location. Experiment 2 showed that the speed to localize a previously studied word was faster when it was presented in the same rather than a different study-test location but that the magnitude of this spatial priming was unaffected by memory instruction. We suggest that the location of peripherally presented words is represented in memory and can aid the retrieval of poorly encoded words. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The preattentive emperor has no clothes: A dynamic redressing.

Preattentive models of early vision have not been supported by the evidence. Instead, an input filtering system, which is dynamically reconfigured so as to optimize performance on the task at hand, is proposed. As a case in point, the authors examined Sagi and Julesz's (1985a) claim that detection tasks are processed preattentively and efficiently (shallow search slopes), whereas discrimination tasks require focal attention and yield inefficient steep slopes. In 5 visual search experiments, efficiency was found to depend not on the nature of the task but on whether the task is single or dual. The second component of a dual task, whether detection or discrimination, is performed inefficiently if it does not fit the configuration of the input system, which had been set optimally for the first component. But, even the second component is processed efficiently if there is enough time to reconfigure the system after processing the first component. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The relationship between alcohol consumption patterns and car, work, sports and home accidents for different age groups

The purpose of this study was to examine the relationship between alcohol consumption patterns and car, work, sports and home accidents for different age groups. A secondary analysis of data from a randomized household survey of 10385 Canadians was conducted. Overall, alcohol consumption patterns were significantly associated with car collisions, work and sports accidents for younger age groups (i.e. 15-24 and 25-34), but this relationship was not significant for the older age groups.     

Effect of Bilayer Phospholipid Composition and Curvature on Ligand Transfer by the α-Tocopherol Transfer Protein

We report here our preliminary investigations on the mechanism of α-TTP-mediated ligand transfer as assessed using fluorescence resonance energy transfer (FRET) assays. These assays monitor the movement of the model α-tocopherol fluorescent derivative ((R)-2,5,7,8-tetramethyl-chroman-2-[9-(7-nitro-benzo[1,2,5]oxadiazol-4-yl amino)-nonyl]-chroman-6-ol; NBD-Toc) from protein to acceptor vesicles containing the fluorescence quencher TRITC-PE. We have found that α-TTP utilizes a collisional mechanism of ligand transfer requiring direct protein–membrane contact, that rates of ligand transfer are greater to more highly curved lipid vesicles, and that such rates are insensitive to the presence of anionic phospholipids in the acceptor membrane. These results point to hydrophobic features of α-TTP dominating the binding energy between protein and membrane. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. An erratum to this article can be found at     

Integrated radiation hybrid and yeast artificial chromosome map of chromosome 9p

OBJECTIVES: To determine concentrations of chondroitin sulphate (CS) and keratan sulphate (KS) epitopes, glycosaminoglycans (GAGs) and hyaluronan (HA) in knee synovial fluid (SF) from normal subjects and patients with osteoarthritis (OA) or rheumatoid arthritis (RA), to test whether these variables may be used as markers of the OA process. METHODS: OA was subdivided into large joint OA (LJOA), nodal generalised OA (NGOA), and OA with calcium pyrophosphate crystal deposition (CPA). Clinical assessment of inflammation (0-6) was undertaken on OA and RA knees. Knee SF was examined by enzyme linked immunosorbent assay for: CS epitopes, using monoclonal antibodies 3-B-3 and 7-D-4; KS epitope using monoclonal antibody 5-D-4; and HA, using biotinylated HA binding region of cartilage proteoglycan. Total sulphated GAGs were measured by dye binding with 1:9 dimethylmethylene blue. RESULTS: Increased SF 3-B-3 concentrations and 3-B-3/GAG ratio were found in OA, compared with RA or normal knees, with higher 3-B-3 and 3-B-3/GAG in LJOA and NGOA than in CPA. SF 7-D-4 and 7-D-4/GAG were reduced in RA, compared with normal and OA; SF 5-D-4 was reduced in OA compared with normal. GAG and HA concentrations were decreased in both OA and RA. No correlations with radiographic scores were observed, but SF 7-D-4 was lower in 'inflamed' compared with 'non-inflamed' RA and OA knees. In patients with bilateral samples there were strong correlations between right and left knees for all SF variables. CONCLUSIONS: Changed concentrations of SF CS and KS can be detected in OA with a profile that differs from that seen in RA. Clinical subgrouping and local joint inflammation may influence these measures, supporting different pathogenesis within OA subgroups and requirement for careful patient characterisation in SF studies.