Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients

<b>Purpose</b>: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer. <b>Experimental Design</b>: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival. <b>Results</b>: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (<i>P</i>=0.03). <b>Conclusion</b>: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit

County-level USA: No Robust Relationship between Geoclimatic Variables and Cognitive Ability

Using a sample of ~3,100 U.S. counties, we tested geoclimatic explanations for why cognitive ability varies across geography. These models posit that geoclimatic factors will strongly predict cognitive ability across geography,even when a variety of common controls appear in the regression equations.Our results generally do not support UV radiation (UVR) based or other geoclimatic models. Specifically, although UVR alone predicted cognitive ability at the U.S. county-level (β = -.33), its validity was markedly reduced in the presence of climatic and demographic covariates (β = -.16), and was reduced even further with a spatial lag (β = -.10). For climate models,average temperature remained a significant predictor in the regression equation containing a spatial lag (β = .35). However, the effect was in the wrong direction relative to typical cold weather hypotheses. Moreover,when we ran the analyses separately by race/ethnicity, no consistent pattern appeared in the models containing the spatial lag. Analyses of gap sizes across counties were also generally inconsistent with predictions from the UVR model. Instead, results seemed to provide support for compositional models

Elastic timber gridshells - structures with an integrated design

A timber gridshell is a special type of structure that establishes a new framework for lightweight construction. It is possible to create a wide variety of shapes and geometries, therefore guaranteeing an enormous architectural freedom. However, given the variety of forms and the difficulty they can present, it is necessary to use different tools and information to support this complex process.The present paper explores the interaction between the information and the different tools used by architects and engineers during the designing and construction process of an elastic timber gridshell, by presenting a real case study with 42m(2)(6,5mx6,5m) after being erected, built with the intent to explore the design and constructive process together with integrated form finding methods. In the paper, both the architect's and the engineer's optimization goals are performed on the same case study. The designing process will be presented and the construction of the elastic gridshell will be described.Una malla estructural de madera es un tipo especial de estructura que establece un nuevo marco para la construcción ligera. Es posible crear una amplia variedad de formas y geometrías, garantizando así una enorme libertad arqui-tectónica. Sin embargo, dada la variedad de formas y la complejidad que pueden presentar es necesario utilizar difer-entes herramientas e información para avalar este complejo proceso. El presente trabajo explora la interacción entre la información y las diferentes herramientas utilizadas por arquitectos e ingenieros durante el proceso de diseño y construcción de una malla elástica de madera, presentando un caso de estu-dio real con 42m2 (6,5mx6,5m), después de la elevación, construida con la intención de explorar el diseño y el proceso constructivo junto con métodos de integración de “form finding”. En el trabajo, los objetivos de optimización tanto del arquitecto como del ingeniero se realizan sobre el mismo caso de estudio. Se presentará el proceso de diseño y se descri-birá la construcción de la malla elástica.This work is financed by FEDER funds through the Competitively Factors Operational Programme - COMPETE and by national funds through FCT -Foundation for Science and Technology within the scope of the project POCI01-0145-FEDER-007633. The support of the Foundation for Science and Technology (FCT) through doctoral fellowship SFRH/BD/104677/2014 is grateful

Positron lifetime measurements on neutron‐irradiated InP crystals

Neutron‐irradiated InP single crystals have been investigated by positron‐lifetime measurements. The samples were irradiated with thermal neutrons at different fluences yielding concentrations for Sn‐transmuted atoms between 2×1015 and 2×1018 cm−3. The lifetime spectra have been analyzed into one exponential decay component. The mean lifetimes show a monotonous increase with the irradiation dose from 246 to 282 ps. The increase in the lifetime has been associated to a defect containing an Indium vacancy. Thermal annealing at 550 °C reduces the lifetime until values closed to those obtained for the as‐grown and conventionally doped InP [email protected] ; [email protected]

Depressive symptoms in women's midlife in relation to their body weight before, during and after childbearing years

OBJECTIVE: This study aimed to examine how weight and weight changes related to pregnancy were associated with depressive symptoms 11–16 years after childbirth. METHOD: We followed 16,998 first‐time mothers from the Danish National Birth Cohort up till 16 years after birth and estimated associations between depressive symptoms and pre‐pregnancy body mass index (BMI) (kg m(−2)), weight changes in different time periods, and BMI‐adjusted waist circumference 7 years after birth (WC(BMI), cm). Depressive symptoms were estimated by the Center for Epidemiologic Studies Depression 10‐item scale. Multiple logistic regression analyses were used to estimate odds ratios (OR) and 95% confidence intervals. RESULTS: Compared with normal‐weight, we found that underweight, overweight and obesity were associated with greater odds of depressive symptoms (1.29, 1.24 and 1.73, respectively). Compared with weight change ±1 BMI unit during the total follow‐up period, greater odds for depressive symptoms were observed with weight loss (OR 1.14, 0.96–1.36) or gain of 2–2.99 kg m(−2) (OR 1.11, 0.92–1.33) or gain of ≥3 kg m(−2) (OR 1.68, 1.46–1.94). WC(BMI) > 2.2 cm was associated with greater odds of depressive symptoms (OR 1.16, 0.99–1.36) than waist circumference as predicted by BMI. CONCLUSION: Low and high pre‐pregnancy BMI, weight changes and WC(BMI) larger than predicted were associated with more depressive symptoms in midlife

Activation of phospholipase A2 by Hsp70 in vitro

Corrigendum to “Activation of phospholipase A2 by Hsp70 in vitro” Biochimica et Biophysica Acta (BBA) – Biomembranes Vol. 1838, Issue 7, July 2014, Pages 1921 10.1016/j.bbamem.2014.03.020Peer reviewe