Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (<i>P</i>=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (<i>P</i>=0.014), and an increase in expression of pAkt<sup>473</sup> and pAR<sup>210</sup> were associated with decreased disease-specific survival (<i>P</i>=0.0019 and 0.0015, respectively). Protein expression of pAkt<sup>473</sup> and pAR<sup>210</sup> also strongly correlated (<i>P</i><0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

A holistic multi-methodology for sustainable renovation

A review of the barriers for building renovation has revealed a lack of methodologies, which can promote sustainability objectives and assist various stakeholders during the design stage of building renovation/retrofitting projects. The purpose of this paper is to develop a Holistic Multi-methodology for Sustainable Renovation, which aims to deal with complexity of renovation projects. It provides a framework through which to involve the different stakeholders in the design process to improve group learning and group decision-making, and hence make the building renovation design process more robust and efficient. Therefore, the paper discusses the essence of multifaceted barriers in building renovation regarding cultural changes and technological/physical changes. The outcome is a proposal for a multi-methodology framework, which is developed by introducing, evaluating and mixing methods from Soft Systems Methodologies (SSM) with Multiple Criteria Decision Making (MCDM). The potential of applying the proposed methodology in renovation projects is demonstrated through a case study

Tamoxifen resistance in early breast cancer: statistical modelling of tissue markers to improve risk prediction

BACKGROUND: For over two decades, the Nottingham Prognostic Index (NPI) has been used in the United Kingdom to calculate risk scores and inform management about breast cancer patients. It is derived using just three clinical variables - nodal involvement, tumour size and grade. New scientific methods now make cost-effective measurement of many biological characteristics of tumour tissue from breast cancer biopsy samples possible. However, the number of potential explanatory variables to be considered presents a statistical challenge. The aim of this study was to investigate whether in ER+ tamoxifen-treated breast cancer patients, biological variables can add value to NPI predictors, to provide improved prognostic stratification in terms of overall recurrence-free survival (RFS) and also in terms of remaining recurrence free while on tamoxifen treatment (RFoT). A particular goal was to enable the discrimination of patients with a very low risk of recurrence. METHODS: Tissue samples of 401 cases were analysed by microarray technology, providing biomarker data for 72 variables in total, from AKT, BAD, HER, MTOR, PgR, MAPK and RAS families. Only biomarkers screened as potentially informative (i.e., exhibiting univariate association with recurrence) were offered to the multivariate model. The multiple imputation method was used to deal with missing values, and bootstrap sampling was used to assess internal validity and refine the model. RESULTS: Neither the RFS nor RFoT models derived included Grade, but both had better predictive and discrimination ability than NPI. A slight difference was observed between models in terms of biomarkers included, and, in particular, the RFoT model alone included HER2. The estimated 7-year RFS rates in the lowest-risk groups by RFS and RFoT models were 95 and 97%, respectively, whereas the corresponding rate for the lowest-risk group of NPI was 89%. CONCLUSION: The findings demonstrate considerable potential for improved prognostic modelling by incorporation of biological variables into risk prediction. In particular, the ability to identify a low-risk group with minimal risk of recurrence is likely to have clinical appeal. With larger data sets and longer follow-up, this modelling approach has the potential to enhance an understanding of the interplay of biological characteristics, treatment and cancer recurrence. British Journal of Cancer (2010) 102, 1503 - 1510. doi:10.1038/sj.bjc.6605627 www.bjcancer.co

Severe or critical hypotension during post cardiac arrest care is associated with factors available on admission - a post hoc analysis of the TTH48 trial

Purpose: We explored whether severe or critical hypotension can be predicted, based on patient and resuscitation characteristics in out-of-hospital cardiac arrest (OHCA) patients. We also explored the association of hypotension with mortality and neurological outcome. Materials and methods: We conducted a post hoc analysis of the TTH48 study (NCT01689077), where 355 out-of-hospital cardiac arrest (OHCA) patients were randomized to targeted temperature management (TTM) treatment at 33 degrees C for either 24 or 48 h. We recorded hypotension, according to four severity categories, within four days from admission. We used multivariable logistic regression analysis to test association of admission data with severe or critical hypotension. Results: Diabetes mellitus (OR 3.715, 95% CI 1.180-11.692), longer ROSC delay (OR 1.064, 95% CI 1.022-1.108), admission MAP (OR 0.960, 95% CI 0.929-0.991) and non-shockable rhythm (OR 5.307, 95% CI 1.604-17.557) were associated with severe or critical hypotension. Severe or critical hypotension was associated with increased mortality and poor neurological outcome at 6 months. Conclusions: Diabetes, non-shockable rhythm, longer delay to ROSC and lower admission MAP were predictors of severe or critical hypotension. Severe or critical hypotension was associated with poor outcome. (C) 2020 Published by Elsevier Inc.Peer reviewe

Modelling diverse root density dynamics and deep nitrogen uptake — a simple approach

We present a 2-D model for simulation of root density and plant nitrogen (N) uptake for crops grown in agricultural systems, based on a modification of the root density equation originally proposed by Gerwitz and Page in J Appl Ecol 11:773–781, (1974). A root system form parameter was introduced to describe the distribution of root length vertically and horizontally in the soil profile. The form parameter can vary from 0 where root density is evenly distributed through the soil profile, to 8 where practically all roots are found near the surface. The root model has other components describing root features, such as specific root length and plant N uptake kinetics. The same approach is used to distribute root length horizontally, allowing simulation of root growth and plant N uptake in row crops. The rooting depth penetration rate and depth distribution of root density were found to be the most important parameters controlling crop N uptake from deeper soil layers. The validity of the root distribution model was tested with field data for white cabbage, red beet, and leek. The model was able to simulate very different root distributions, but it was not able to simulate increasing root density with depth as seen in the experimental results for white cabbage. The model was able to simulate N depletion in different soil layers in two field studies. One included vegetable crops with very different rooting depths and the other compared effects of spring wheat and winter wheat. In both experiments variation in spring soil N availability and depth distribution was varied by the use of cover crops. This shows the model sensitivity to the form parameter value and the ability of the model to reproduce N depletion in soil layers. This work shows that the relatively simple root model developed, driven by degree days and simulated crop growth, can be used to simulate crop soil N uptake and depletion appropriately in low N input crop production systems, with a requirement of few measured parameters

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome