Wnt/beta-catenin/Tcf signaling: A critical pathway in gastrointestinal tumorigenesis

Cancers of the gastrointestinal tract, including the liver, bile ducts, and pancreas, constitute the largest group of malignant tumors. Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of cancer-related deaths. Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like p53. Identification of the interaction of APC with the proto-oncogene beta-catenin has linked colorectal carcinogenesis to the Wnt-signal transduction pathway. The main function of APC is thought to be the regulation of free beta-catenin in concert with the glycogen synthase kinase 3beta (GSK-3beta) and Axin proteins. Loss of APC function, inactivation of Axin or activating beta-catenin mutations result in the cellular accumulation of beta-catenin. Upon translocation to the nucleus beta-catenin serves as an activator of T-cell factor (Tcf)-dependent transcription leading to an increased expression of several specific target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations are almost exclusively found in colorectal cancers, deregulation of Wnt/beta-catenin/Tcf signaling is also common in other gastrointestinal and extra-gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the Writ pathway is deregulated by inactivation of Axin or stabilizing mutations of beta-catenin. The majority of hepatoblastomas and a group of gastric cancers also carry beta-catenin mutations. Clearly, this pathway harbors great potential for future applications in cancer diagnostics, staging, and therapy. Copyright (C) 2002 S. Karger AG, Basel

Application of Single-Station Sigma and Site-Response Characterization in a Probabilistic Seismic-Hazard Analysis for a New Nuclear Site

Aleatory variability in ground-motion prediction, represented by the standard deviation (sigma) of a ground-motion prediction equation, exerts a very strong influence on the results of probabilistic seismic-hazard analysis (PSHA). This is especially so at the low annual exceedance frequencies considered for nuclear facilities; in these cases, even small reductions in sigma can have a marked effect on the hazard estimates. Proper separation and quantification of aleatory variability and epistemic uncertainty can lead to defensible reductions in sigma. One such approach is the single-station sigma concept, which removes that part of sigma corresponding to repeatable site-specific effects. However, the site-to-site component must then be constrained by site-specific measurements or else modeled as epistemic uncertainty and incorporated into the modeling of site effects. The practical application of the single-station sigma concept, including the characterization of the dynamic properties of the site and the incorporation of site-response effects into the hazard calculations, is illustrated for a PSHA conducted at a rock site under consideration for the potential construction of a nuclear power plant.Civil, Architectural, and Environmental Engineerin

Nonverbal Emotion Recognition and Performance: Differences Matter Differently

PURPOSE: This paper aims to explore and test the relationship between emotion recognition skill and assessment center performance after controlling for both general mental ability (GMA) and conscientiousness. It also seeks to test whether participant sex or race moderated these relationships. DESIGN/METHODOLOGY/APPROACH: Using independent observers as raters, the paper tested 528 business students participating in a managerial assessment center, while they performed four distinct activities of: an in-basket task; a team meeting for an executive hiring decision; a team meeting to discuss customer service initiatives; and an individual speech.FINDINGS: Emotion recognition predicted assessment center performance uniquely over both GMA and conscientiousness, but results varied by race. Females were better at emotion recognition overall, but sex neither was related to assessment center performance nor moderated the relationship between it and emotion recognition. The paper also found that GMA moderated the emotion recognition/assessment performance link, as the former was important to performance only for people with low levels of GMA. PRACTICAL IMPLICATIONS: The results seem to contradict those who argue that E-IQ is an unqualified predictor of performance. Emotional recognition is not uniformly valuable; instead, it appears to benefit some groups more than others. ORIGINALITY/VALUE: The paper clarifies the emotional intelligence literature by providing further support for the predictive validity of emotion recognition in performance contexts, and by separating out how emotional recognition benefits certain population groups more

Imbibition in mesoporous silica: rheological concepts and experiments on water and a liquid crystal

We present, along with some fundamental concepts regarding imbibition of liquids in porous hosts, an experimental, gravimetric study on the capillarity-driven invasion dynamics of water and of the rod-like liquid crystal octyloxycyanobiphenyl (8OCB) in networks of pores a few nanometers across in monolithic silica glass (Vycor). We observe, in agreement with theoretical predictions, square root of time invasion dynamics and a sticky velocity boundary condition for both liquids investigated. Temperature-dependent spontaneous imbibition experiments on 8OCB reveal the existence of a paranematic phase due to the molecular alignment induced by the pore walls even at temperatures well beyond the clearing point. The ever present velocity gradient in the pores is likely to further enhance this ordering phenomenon and prevent any layering in molecular stacks, eventually resulting in a suppression of the smectic phase in favor of the nematic phase.Comment: 18 pages, 8 figure

Interpreting intraplate tectonics for seismic hazard : a UK historical perspective

It is notoriously difficult to construct seismic source models for probabilistic seismic hazard assessment in intraplate areas on the basis of geological information, and many practitioners have given up the task in favour of purely seismicity-based models. This risks losing potentially valuable information in regions where the earthquake catalogue is short compared to the seismic cycle. It is interesting to survey how attitudes to this issue have evolved over the past 30 years. This paper takes the UK as an example, and traces the evolution of seismic source models through generations of hazard studies. It is found that in the UK, while the earliest studies did not consider regional tectonics in any way, there has been a gradual evolution towards more tectonically based models. Experience in other countries, of course, may differ

Comparison of performance of four instruments in evaluating the effects of salmeterol on asthma quality of life

Quality of life measures are increasingly used as important efficacy endpoints in studies of drugs for asthma. The purpose of this study was to assess both the sensitivity to change and the construct validity of four different quality of life instruments in patients with asthma. In a double-blind, parallel group study, 120 moderate asthma patients, aged between 18-70 yrs, received either inhaled salmeterol 50 micrograms b.i.d. or inhaled salbutamol 400 micrograms b.i.d. In addition to respiratory outcomes, quality of life was measured at a 6 weeks follow-up using: 1) Asthma Quality of Life Questionnaire (AQLQ); 2) Living With Asthma Questionnaire (LWAQ); 3) Sickness Impact Profile (SIP); 4) Rating Scale (RS); and Standard Gamble (SG) utilities. Salmeterol led to significant improvements over salbutamol on virtually all clinical outcomes. Although all the quality of life instruments showed the same trend in favour of salmeterol, only the AQLQ and RS utilities showed significantly greater improvement on salmeterol than on salbutamol. Except for the AQLQ, the correlation between change in lung function and change in quality of life was generally low. Whereas, the AQLQ correlated well with the patient's overall assessment of efficacy (r = 0.64), the LWAQ, SIP and

Hazard-consistent response spectra in the Region of Murcia (Southeast Spain): comparison to earthquake-resistant provisions

Hazard-consistent ground-motion characterisations of three representative sites located in the Region of Murcia (southeast Spain) are presented. This is the area where the last three damaging events in Spain occurred and there is a significant amount of data for comparing them with seismic hazard estimates and earthquake-resistant provisions. Results of a probabilistic seismic hazard analysis are used to derive uniform hazard spectra (UHS) for the 475-year return period, on rock and soil conditions. Hazard deaggregation shows that the largest hazard contributions are due to small, local events for short-period target motions and to moderate, more distant events for long-period target motions. For each target motion and site considered, the associated specific response spectra (SRS) are obtained. It is shown that the combination of two SRS, for short- and long-period ground motions respectively, provides a good approximation to the UHS at each site. The UHS are compared to design response spectra contained in current Spanish and European seismic codes for the 475-year return period. For the three sites analysed, only the Eurocode 8 (EC8) type 2 spectrum captures the basic shape of the UHS (and not the EC8 type 1, as could be expected a priori). An alternative response spectrum, anchored at short- and long-period accelerations, is tested, providing a close match to the UHS spectra at the three sites. Results underline the important contribution of the frequent, low-to-moderate earthquakes that characterize the seismicity of this area to seismic hazard (at the 475-year return period)

A consensus research agenda for optimising nasal drug delivery

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors