Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.Grant support from: R01 CA175382/CA/NCI NIH HHS/United States, R21 CA191970/CA/NCI NIH HHS/United States, and R21 CA193958/CA/NCI NIH HHS/United State

Fast Monte Carlo simulations and singularities in the probability distributions of non-equilibrium systems

A numerical technique is introduced that reduces exponentially the time required for Monte Carlo simulations of non-equilibrium systems. Results for the quasi-stationary probability distribution in two model systems are compared with the asymptotically exact theory in the limit of extremely small noise intensity. Singularities of the non-equilibrium distributions are revealed by the simulations.Comment: 4 pages, 4 figure

The Hot R Coronae Borealis Star DY Centauri is a Binary

The remarkable hot R Coronae Borealis (RCB) star DY Cen is revealed to be the first and only binary system to be found among the RCB stars and their likely relatives, including the extreme helium stars and the hydrogen-deficient carbon stars. Radial velocity determinations from 1982 to 2010 have shown that DY Cen is a single-lined spectroscopic binary in an eccentric orbit with a period of 39.67 days. It is also one of the hottest and most H-rich member of the class of RCB stars. The system may have evolved from a common envelope to its current form.Spanish Ministry of Economy and Competitiveness AYA-2011-27754McDonald Observator

Influence of mismatch on the defects in relaxed epitaxial InGaAs/GaAs(100) films grown by molecular beam epitaxy

Thick (∼3 μm) films of InxGa1−xAs grown on GaAs(100) substrates, across the whole composition range, have been examined by transmission electron microscopy and double‐crystal x‐ray diffraction. The results were compared with the observed growth mode of the material determined by in situ reflection high‐energy electron diffraction in the molecular beam epitaxy growth system. The quality of the material degraded noticeably for compositions up to x∼0.5 associated with an increased density of dislocations and stacking faults. In contrast, improvements in quality as x approached 1.0 were correlated with the introduction of an increasingly more regular array of edge dislocations

Pan-European grading scales: lessons from national systems and the ECTS

This article assesses the impact of the Bologna Process on the grading schemes of EU member countries. In light of some problems regarding the implementation of the European Credit Transfer system (ECTS), the author proposes further reforms and offers some elements of a unified grading system for European higher education. The author explores the variation among Europe’s grading systems and the resulting lessons learned are shared here. Lastly, this article also argues that principles of justice and fairness, deemed central to academic freedom, are best upheld by the use of a unified grading system at national and European levels

Femoral Neck Shaft Angle in Men with Fragility Fractures

Introduction. Femoral neck shaft angle (NSA) has been reported to be an independent predictor of hip fracture risk in men. We aimed to assess the role of NSA in UK men. Methods. The NSA was measured manually from the DXA scan printout in men with hip (62, 31 femoral neck and 31 trochanteric), symptomatic vertebral (91), and distal forearm (67) fractures and 389 age-matched control subjects. Age, height, weight, and BMD (g/cm2: lumbar spine, femoral neck, and total femur) measurements were performed. Results. There was no significant difference in mean NSA between men with femoral neck and trochanteric hip fractures, so all further analyses of hip fractures utilised the combined data. There was no difference in NSA between those with hip fractures and those without (either using the combined data or analysing trochanteric and femoral neck shaft fractures separately), nor between fracture subjects as a whole and controls. Mean NSA was smaller in those with vertebral fractures (129.2° versus 131°: P = 0.001), but larger in those with distal forearm fractures (129.8° versus 128.5°: P = 0.01). Conclusions. The conflicting results suggest that femoral NSA is not an important determinant of hip fracture risk in UK men

Simultaneous Exoplanet Characterization and deep wide-field imaging with a diffractive pupil telescope

High-precision astrometry can identify exoplanets and measure their orbits and masses, while coronagraphic imaging enables detailed characterization of their physical properties and atmospheric compositions through spectroscopy. In a previous paper, we showed that a diffractive pupil telescope (DPT) in space can enable sub-microarcsecond accuracy astrometric measurements from wide-field images by creating faint but sharp diffraction spikes around the bright target star. The DPT allows simultaneous astrometric measurement and coronagraphic imaging, and we discuss and quantify in this paper the scientific benefits of this combination for exoplanet science investigations: identification of exoplanets with increased sensitivity and robustness, and ability to measure planetary masses to high accuracy. We show how using both measurements to identify planets and measure their masses offers greater sensitivity and provides more reliable measurements than possible with separate missions, and therefore results in a large gain in mission efficiency. The combined measurements reliably identify potentially habitable planets in multiple systems with a few observations, while astrometry or imaging alone would require many measurements over a long time baseline. In addition, the combined measurement allows direct determination of stellar masses to percent-level accuracy, using planets as test particles. We also show that the DPT maintains the full sensitivity of the telescope for deep wide-field imaging, and is therefore compatible with simultaneous scientific observations unrelated to exoplanets. We conclude that astrometry, coronagraphy, and deep wide-field imaging can be performed simultaneously on a single telescope without significant negative impact on the performance of any of the three techniques.Comment: 15 pages, 6 figures. This second paper, following the paper describing the diffractive pupil telescope (DPT) astrometric technique, shows how simultaneous astrometry and coronagraphy observations, enabled by the DPT concept, constrain the orbital parameters and mass of exoplanet

Prevention of childhood poisoning in the home: overview of systematic reviews and a systematic review of primary studies

Unintentional poisoning is a significant child public health problem. This systematic overview of reviews, supplemented with a systematic review of recently published primary studies synthesizes evidence on non-legislative interventions to reduce childhood poisonings in the home with particular reference to interventions that could be implemented by Children's Centres in England or community health or social care services in other high income countries. Thirteen systematic reviews, two meta-analyses and 47 primary studies were identified. The interventions most commonly comprised education, provision of cupboard/drawer locks, and poison control centre (PCC) number stickers. Meta-analyses and primary studies provided evidence that interventions improved poison prevention practices. Twenty eight per cent of studies reporting safe medicine storage (OR from meta-analysis 1.57, 95% CI 1.22–2.02), 23% reporting safe storage of other products (OR from meta-analysis 1.63, 95% CI 1.22–2.17) and 46% reporting availability of PCC numbers (OR from meta-analysis 3.67, 95% CI 1.84–7.33) demonstrated significant effects favouring the intervention group. There was a lack of evidence that interventions reduced poisoning rates. Parents should be provided with poison prevention education, cupboard/drawer locks and emergency contact numbers to use in the event of a poisoning. Further research is required to determine whether improving poison prevention practices reduces poisoning rates

Theory of Systematic Computational Error in Free Energy Differences

Systematic inaccuracy is inherent in any computational estimate of a non-linear average, due to the availability of only a finite number of data values, N. Free energy differences (DF) between two states or systems are critically important examples of such averages in physical, chemical and biological settings. Previous work has demonstrated, empirically, that the ``finite-sampling error'' can be very large -- many times kT -- in DF estimates for simple molecular systems. Here, we present a theoretical description of the inaccuracy, including the exact solution of a sample problem, the precise asymptotic behavior in terms of 1/N for large N, the identification of universal law, and numerical illustrations. The theory relies on corrections to the central and other limit theorems, and thus a role is played by stable (Levy) probability distributions.Comment: 5 pages, 4 figure

Webifying the computerized execution of Clinical Practice Guidelines

The means through which Clinical Practice Guidelines are dissemi-nated and become accessible are a crucial factor in their later adoption by health care professionals. Making these guidelines available in Clinical Decision Sup-port Systems renders their application more personal and thus acceptable at the moment of care. Web technologies may play an important role in increasing the reach and dissemination of guidelines, but this promise remains largely unful-filled. There is a need for a guideline computer model that can accommodate a wide variety of medical knowledge along with a platform for its execution that can be easily used in mobile devices. This work presents the CompGuide frame-work, a web-based and service-oriented platform for the execution of Computer-Interpretable Guidelines. Its architecture comprises different modules whose in-teraction enables the interpretation of clinical tasks and the verification of clinical constraints and temporal restrictions of guidelines represented in OWL. It allows remote guideline execution with data centralization, more suitable for a work en-vironment where physicians are mobile and not bound to a machine. The solution presented in this paper encompasses a computer-interpretable guideline model, a web-based framework for guideline execution and an Application Programming Interface for the development of other guideline execution systems.This work is part-funded by ERDF - European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the FCT – Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) within project FCOMP-01-0124-FEDER-028980 (PTDC/EEI-SII/1386/2012). The work of Tiago Oliveira is supported by doctoral grant by FCT (SFRH/BD/85291/2012)