An increase in N-Ras expression is associated with development of hormone refractory prostate cancer in a subset of patients

Protein expression of H, K and N-Ras was assessed in hormone sensitive and hormone refractory prostate tumour pairs from 61 patients by immunohistochemistry. Expression of H-Ras and K- Ras was not associated with any known clinical parameters. In contrast an increase in N-Ras membrane expression in the transition from hormone sensitive to hormone refractory prostate cancer was associated with shorter time to relapse (p=0.01) and shorter disease specific survival (p=0.008). In addition, patients with an increase in N-Ras membrane expression had lower levels of PSA at relapse (p=0.02) and expression correlated with phosphorylated MAP kinase (p=0.010) and proliferation index (Ki67, p=0.02). These results suggest that in a subgroup patients N-Ras expression is associated with development of hormone refractory prostate cancer via activation of the MAP kinase cascade

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

Biofeedback therapy for faecal incontinence: a rural and regional perspective

INTRODUCTION: Faecal incontinence is the involuntary loss of liquid or solid stool with or without the patient's awareness. It affects 8-11% of Australian community dwelling adults and up to 72% of nursing home residents with symptoms causing embarrassment, loss of self-respect and possible withdrawal from normal daily activities. Biofeedback, a technique used to increase patient awareness of physiological processes not normally considered to be under voluntary control, is a safe, conservative first-line therapy that has been shown to reduce symptom severity and improve patient quality of life. The Townsville Hospital, a publicly funded regional hospital with a large rural catchment area, offers anorectal biofeedback for patients with faecal incontinence, constipation and chronic pelvic pain. The aim of this report is to describe the effect of the biofeedback treatment on the wellbeing of regional and rural participants in a study of biofeedback treatment for faecal incontinence in the Townsville Hospital clinic. METHODS: There were 53 regional (14 male) and 19 rural (5 male) participants (mean age 62.1 years) enrolled in a biofeedback study between January 2005 and October 2006. The program included 4 sessions one week apart, 4 weeks home practice of techniques learnt and a final follow-up reassessment session. Session one included documenting relevant history, diet, fibre, and fluid intake and treatment goals; anorectal function and proctometrographic measurements were assessed. Patients were taught relaxation (diaphragmatic) breathing in session two with a rectal probe and the balloon inserted, prior to inflating the balloon to sensory threshold. In session three, patients were taught anal sphincter and pelvic floor exercises linking the changes in anal pressures seen on the computer monitor with the exercises performed and sensations felt. Session four included improving anal and pelvic floor exercises, learning a defecation technique and receiving instructions for 4 weeks home practice. At the fifth session, home practice and bowel charts were reviewed and anorectal function was reassessed. Symptom severity and quality of life were assessed by surveying participants prior to sessions one and two and following session five. Patients were interviewed after session five to determine their satisfaction with the therapy and the helpfulness of individual program components. They were mailed a follow-up survey 2 years later. RESULTS: Regional participants lived within 30 min drive of the clinic (median distance 8 km) while rural participants travelled up to 903 km (median 339 km, p<0.001) to attend the clinic. Faecal Incontinence risk factors were similar for rural and regional participants. Rural participants reported poorer general health (p=0.004) and their symptoms affected their lifestyle more negatively (p=0.028). Participants' incontinence (p<0.001) and quality of life (p<0.001) improved significantly over the treatment period. Improvement for rural participants over the course of treatment was marginally better than that of regional participants, although not significantly. More than 97% of patients reported that the biofeedback program was very/extremely helpful and all participants attending the final session reported that they would advise a friend in a similar situation not to wait, but seek help immediately, with more than half specifically citing the biofeedback program. Two years later regional participants' symptoms and quality of life continued to improve while rural participants' quality of life had regressed to pre-treatment levels. CONCLUSIONS: For equivalent long term improvement in faecal continence and quality of life to be achieved in both regional and rural participants, an additional follow-up session with the biofeedback therapist, ongoing local support provided by continence advisors, or both, should be investigated for rural patients

Enhanced Fault Tree analysis and modelling considerations of a Polymer Electrolyte Membrane Fuel Cell

With the recent increase in interest in environmental issues and climate change concerns, the scientific community have been tasked with developing low carbon technologies to mitigate against climate change. One of the most promising technologies is the hydrogen fuel cell, particularly when integrated into an automobile. Hydrogen Fuel Cells are an electro-chemical, zero-emission energy conversion and power generation device. Their only output products are heat, electrical energy, and water vapour. There are three main hurdles to the commercial uptake of this technology; Infrastructure, Cost and Reliability. An understanding of the reliability of fuel cells can be obtained through in-depth reliability analysis including techniques such as Failure Mode and Effect Analysis (FMEA) and Fault Tree analysis (FTA) amongst others. As hydrogen fuel cells are a relatively new technology this in-depth analysis is still in its infancy, and needs development. This research has extended the work on FTA of the Polymer Electrolyte Membrane Fuel Cell (PEMFC) systems. Detailed analysis has explored the inherent complexity of the PEMFC system where issues with using a basic FTA for a PEMFC, such as dependencies between failure modes, and disparities between failure mode operating principles, are discussed. The integration of the Markov technique, which can deal with dependencies, within the Fault tree approach is suggested as a mechanism to enhance the accuracy of the modelling of a PEMFC

An ordering heuristic to develop the binary decision diagram based on structural importance

This article was published in the journal, Reliability Engineering & System Safety [© Elsevier] and is also available at: http://www.sciencedirect.com/science/journal/09518320Fault tree analysis is often used to assess risks within industrial systems. The technique is commonly used although there are associated limitations in terms of accuracy and efficiency when dealing with large fault tree structures. The most recent approach to aid the analysis of the fault tree diagram is the Binary Decision Diagram (BDD) methodology. To utilise the technique the fault tree structure needs to be converted into the BDD format. Converting the fault tree requires the basic events of the tree to be placed in an ordering. The ordering of the basic events is critical to the resulting size of the BDD, and ultimately affects the performance and benefits of this technique. A number of heuristic approaches have been developed to produce an optimal ordering permutation for a specific tree. These heuristic approaches do not always yield a minimal BDD structure for all trees. This paper looks at a heuristic that is based on the structural importance measure of each basic event. Comparing the resulting size of the BDD with the smallest generated from a set of six alternative ordering heuristics, this new structural heuristic produced a BDD of smaller or equal dimension on 77 percent of trials

Search for CP Violation in Charged D Meson Decays

We report results of a search for CP violation in the singly Cabibbo-suppressed decays D+ -> K- K+ pi+, phi pi+, K*(892)0 K+, and pi- pi+ pi+ based on data from the charm hadroproduction experiment E791 at Fermilab. We search for a difference in the D+ and D- decay rates for each of the final states. No evidence for a difference is seen. The decay rate asymmetry parameters A(CP), defined as the difference in the D+ and D- decay rates divided by the sum of the decay rates, are measured to be: A(CP)(K K pi) = -0.014 +/- 0.029, A(CP)(phi pi) = -0.028 +/- 0.036, A(CP)(K*(892) K) = -0.010 +/- 0.050, and A(CP)(pi pi pi) = -0.017 +/- 0.042.Comment: 13 pages, 5 figures, 1 table; Elsevier LaTe

Search for Rare and Forbidden Dilepton Decays of the D+, Ds, and D0 Charmed Mesons

We report the results of a search for flavor-changing neutral current, lepton-flavor violating, and lepton-number violating decays of D+, Ds, and D0 mesons (and their antiparticles) into modes containing muons and electrons. Using data from Fermilab charm hadroproduction experiment E791, we examine the pi,l,l and K,l,l decay modes of D+ and Ds and the l+l- decay modes of D0. No evidence for any of these decays is found. Therefore, we present branching-fraction upper limits at 90% confidence level for the 24 decay modes examined. Eight of these modes have no previously reported limits, and fourteen are reported with significant improvements over previously published results.Comment: 12 pages, 3 figures, LaTeX, elsart.cls, epsf.sty, amsmath.sty Submitted to Physics Letters