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

Domestic ventilation rates, indoor humidity and dust mite allergens : are our homes causing the asthma pandemic?

This paper is concerned with historical changes in domestic ventilation rates, relative humidity and the associated risk of house dust mite colonization. A controlled trial evaluated allergen and water vapour control measures on the level of house dust mite (HDM) Der p1 allergen and indoor humidity, concurrently with changes in lung function in 54 subjects who completed the protocol. Mechanical heat recovery ventilation units significantly reduced moisture content in the active group, while HDM allergen reservoirs in carpets and beds were reduced by circa 96%. Self reported health status confirmed a significant clinical improvement in the active group. The study can form the basis for assessing minimum winter ventilation rates that can suppress RH below the critical ambient equilibrium humidity of 60% and thus inhibit dust mite colonization and activity in temperate and maritime in' uenced climatic regions

Calcium puffs are generic InsP₃-activated elementary calcium signals and are downregulated by prolonged hormonal stimulation to inhibit cellular calcium responses

Elementary Ca2+ signals, such as "Ca2+ puffs", which arise from the activation of inositol 1,4,5-trisphosphate receptors, are building blocks for local and global Ca2+ signalling. We characterized Ca2+ puffs in six cell types that expressed differing ratios of the three inositol 1,4,5-trisphosphate receptor isoforms. The amplitudes, spatial spreads and kinetics of the events were similar in each of the cell types. The resemblance of Ca2+ puffs in these cell types suggests that they are a generic elementary Ca2+ signal and, furthermore, that the different inositol 1,4,5-trisphosphate isoforms are functionally redundant at the level of subcellular Ca2+ signalling. Hormonal stimulation of SH-SY5Y neuroblastoma cells and HeLa cells for several hours downregulated inositol 1,4,5-trisphosphate expression and concomitantly altered the properties of the Ca2+ puffs. The amplitude and duration of Ca2+ puffs were substantially reduced. In addition, the number of Ca2+ puff sites active during the onset of a Ca2+ wave declined. The consequence of the changes in Ca2+ puff properties was that cells displayed a lower propensity to trigger regenerative Ca2+ waves. Therefore, Ca2+ puffs underlie inositol 1,4,5-trisphosphate signalling in diverse cell types and are focal points for regulation of cellular responses

Combinatorial Voter Control in Elections

Voter control problems model situations such as an external agent trying to affect the result of an election by adding voters, for example by convincing some voters to vote who would otherwise not attend the election. Traditionally, voters are added one at a time, with the goal of making a distinguished alternative win by adding a minimum number of voters. In this paper, we initiate the study of combinatorial variants of control by adding voters: In our setting, when we choose to add a voter~$v$, we also have to add a whole bundle $\kappa(v)$ of voters associated with $v$. We study the computational complexity of this problem for two of the most basic voting rules, namely the Plurality rule and the Condorcet rule.Comment: An extended abstract appears in MFCS 201

Conceptualizing the adventure-sports coach

As a comparatively recent development, the adventure-sports coach struggles for a clear and distinct identity. The generic term ‘instructor’ no longer characterizes the role and function of this subgroup of outdoor professionals. Indeed, although the fields of adventure/outdoor education and leadership are comparatively well researched, the arrival of this ‘new kid on the block’ appears to challenge both the adventure-sports old guard and traditional views of sports coaching. In an attempt to offer clarity and stimulate debate, this paper attempts to conceptualize the adventure-sports coach in the context of the existing roles in the field and current motivations for activity in the outdoors. We identify issues that are specific to the adventure-sports coach while also recognizing those skills and competencies shared with other professionals, both in the adventure sports profession and traditional sports coaching fields. Based on this review, we offer a conceptual model which may be used to focus debate, stimulate research and, at a possible later stage, to underpin accreditation, training and professional development

Decision making and risk management in adventure sports coaching

Adventure sport coaches practice in environments that are dynamic and high in risk, both perceived and actual. The inherent risks associated with these activities, individuals’ responses and the optimal exploitation of both combine to make the processes of risk management more complex and hazardous than the traditional sports where risk management is focused almost exclusively on minimization. Pivotal to this process is the adventure sports coaches’ ability to make effective judgments regarding levels of risk, potential benefits and possible consequences. The exact nature of this decision making process should form the basis of coaching practice and coach education in this complex and dynamic field. This positional paper examines decision making by the adventure sports coach in these complex, challenging environments and seeks to stimulate debate whilst offering a basis for future research into this topic

SICANE: a Detector Array for the Measurement of Nuclear Recoil Quenching Factors using Monoenergetic Neutron Beam

SICANE is a neutron scattering multidetector facility for the determination of the quenching factor (ratio of the response to nuclear recoils and to electrons) of cryogenic detectors used in direct WIMP searches. Well collimated monoenergetic neutron beams are obtained with inverse (p,n) reactions. The facility is described, and results obtained for the quenching factors of scintillation in NaI(Tl) and of heat and ionization in Ge are presented.Comment: 30 pages, Latex, 11 figures. Submitted to NIM

The ZEPLIN-III dark matter detector: instrument design, manufacture and commissioning

We present details of the technical design and manufacture of the ZEPLIN-III dark matter experiment. ZEPLIN-III is a two-phase xenon detector which measures both the scintillation light and the ionisation charge generated in the liquid by interacting particles and radiation. The instrument design is driven by both the physics requirements and by the technology requirements surrounding the use of liquid xenon. These include considerations of key performance parameters, such as the efficiency of scintillation light collection, restrictions placed on the use of materials to control the inherent radioactivity levels, attainment of high vacuum levels and chemical contamination control. The successful solution has involved a number of novel design and manufacturing features which will be of specific use to future generations of direct dark matter search experiments as they struggle with similar and progressively more demanding requirements.Comment: 25 pages, 19 figures. Submitted to Astropart. Phys. Some figures down sampled to reduce siz

Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: The PPALM study.

BACKGROUND: Preclinical data suggest that combined gamma-tocotrienol with pentoxifylline ameliorates radiotherapy-induced gastrointestinal damage. AIM: To test whether gastrointestinal symptoms arising after radiotherapy, and persisting after maximal medical therapy, can be improved using Tocovid SupraBio 200 mg and pentoxifylline 400 mg orally twice daily for one year. Patients stratified by severity of symptoms, and randomised to active treatment or matched placebo were assessed after 12 months. The primary end point was improvement in gastrointestinal symptoms measured using the Inflammatory Bowel Disease Questionnaire, bowel subset score. Changes in bio-markers of fibrosis were assessed. RESULTS: 62 patients, median age 66, 34(55%) treated for prostate, 21(34%) gynaecological, 6(10%) anal and one(1%) rectal cancer were recruited; 40(65%) randomised to treatment, 22(35%) to placebo, 39 months (median) after radiotherapy completion. Gamma tocotrienol was not detected in serum in 41% of treated patients, despite good compliance with study medication. Treatment was completed in 28(70%) and 17(77%) patients in the treatment and placebo groups respectively. No improvement in symptom scores nor in quality of life was identified. Thirteen serious adverse events occurred. A transient ischaemic attack, was possibly related to pentoxifylline, others were assessed as unlikely to be related to treatment. Levels of EGF, PDGF and FGF were significantly reduced and consistent trends in reduced inflammation were seen during treatment but were not sustained once treatment ended. SUMMARY: This single centre study closed prematurely and therefore data interpretation is of necessity limited. No clinical benefit was demonstrated. However, biochemical data suggest that this intervention does have anti-inflammatory and anti-fibrotic effects