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

Supersymmetric particle mass measurement with invariant mass correlations

The kinematic end-point technique for measuring the masses of supersymmetric particles in R-Parity conserving models at hadron colliders is re-examined with a focus on exploiting additional constraints arising from correlations in invariant mass observables. The use of such correlations is shown to potentially resolve the ambiguity in the interpretation of quark+lepton end-points and enable discrimination between sequential two-body and three-body lepton-producing decays. The use of these techniques is shown to improve the SUSY particle mass measurement precision for the SPS1a benchmark model by at least 20-30% compared to the conventional end-point technique.Comment: 29 pages, 23 .eps figures, JHEP3 style; v2 adds some references and small clarifications to text; v3 adds some more clarifications to the tex

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

Supersymmetric particle mass measurement with the boost-corrected contransverse mass

A modification to the contransverse mass (MCT) technique for measuring the masses of pair-produced semi-invisibly decaying heavy particles is proposed in which MCT is corrected for non-zero boosts of the centre-of-momentum (CoM) frame of the heavy states in the laboratory transverse plane. Lack of knowledge of the mass of the CoM frame prevents exact correction for this boost, however it is shown that a conservative correction can nevertheless be derived which always generates an MCT value which is less than or equal to the true value of MCT in the CoM frame. The new technique is demonstrated with case studies of mass measurement with fully leptonic ttbar events and with SUSY events possessing a similar final state.Comment: 33 pages, 33 .eps figures, JHEP3 styl

A hybrid method for determining particle masses at the Large Hadron Collider with fully identified cascade decays

A new technique for improving the precision of measurements of SUSY particle masses at the LHC is introduced. The technique involves kinematic fitting of events with two fully identified decay chains. We incorporate both event ETmiss constraints and independent constraints provided by kinematic end-points in experiment invariant mass distributions of SUSY decay products. Incorporation of the event specific information maximises the information used in the fit and is shown to reduce the mass measurement uncertainites by ~30% compared to conventional fitting of experiment end-point constraints for the SPS1a benchmark model.Comment: 10 pages, 2 .eps figures, JHEP3 styl

Targeted Decorin Gene Therapy Delivered with Adeno-Associated Virus Effectively Retards Corneal Neovascularization \u3cem\u3ein vivo\u3c/em\u3e

Decorin, small leucine-rich proteoglycan, has been shown to modulate angiogenesis in nonocular tissues. This study tested a hypothesis that tissue-selective targeted decorin gene therapy delivered to the rabbit stroma with adeno-associated virus serotype 5 (AAV5) impedes corneal neovascularization (CNV) in vivo without significant side effects. An established rabbit CNV model was used. Targeted decorin gene therapy in the rabbit stroma was delivered with a single topical AAV5 titer (100 μl; 5x10^12 vg/ml) application onto the stroma for two minutes after removing corneal epithelium. The levels of CNV were examined with stereomicroscopy, H&E staining, lectin, collagen type IV, CD31 immunocytochemistry and CD31 immunoblotting. Real-time PCR quantified mRNA expression of pro- and anti-angiogenic genes. Corneal health in live animals was monitored with clinical, slit-lamp and optical coherence tomography biomicroscopic examinations. Selective decorin delivery into stroma showed significant 52% (p\u3c0.05), 66% (p\u3c0.001), and 63% (p\u3c0.01) reduction at early (day 5), mid (day 10), and late (day 14) stages of CNV in decorin-delivered rabbit corneas compared to control (no decorin delivered) corneas in morphometric analysis. The H&E staining, lectin, collagen type IV, CD31 immunostaining (57–65, p\u3c0.5), and CD31 immunoblotting (62–67%, p\u3c0.05) supported morphometric findings. Quantitative PCR studies demonstrated decorin gene therapy down-regulated expression of VEGF, MCP1 and angiopoietin (pro-angiogenic) and up-regulated PEDF (anti-angiogenic) genes. The clinical, biomicroscopy and transmission electron microscopy studies revealed that AAV5– mediated decorin gene therapy is safe for the cornea. Tissue-targeted AAV5-mediated decorin gene therapy decreases CNV with no major side effects, and could potentially be used for treating patients

Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumours

We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab

Transverse mass and invariant mass observables for measuring the mass of a semi-invisibly decaying heavy particle

Formulae are derived for the positions of end-points in the invariant mass and transverse mass distributions obtained from the products of heavy states decaying to pairs of semi-invisibly decaying lighter states. Formulae are derived both for the special case where the two decay chains are identical and the more general case where they are different. The formulae are tested with a simple case study of heavy SUSY higgs particles decaying to gauginos at the LHC.Comment: 13 pages, 8 eps figure

Collider signatures of goldstini in gauge mediation

We investigate the collider signatures of the multiple goldstini scenario in the framework of gauge mediation. This class of models is characterized by a visible sector (e.g. the MSSM or any extension) coupled by gauge interactions to more than one SUSY breaking sector. The spectrum consists of a light gravitino LSP, behaving as a goldstino, and a number of neutral fermions (the pseudo-goldstini) with a mass between that of the LSP and that of the lightest particle of the observable sector (LOSP). We consider the two situations where the LOSP is either a gaugino-like neutralino or a stau and we assume only one pseudo-goldstino of a mass of O(100) GeV. The coupling of the LOSP to the pseudo-goldstino can be enhanced with respect to those of the gravitino giving rise to characteristic signatures. We show that the decay modes of the LOSP into a SM particle and a pseudo-goldstino can be significant. For both LOSP scenarios we analyze (pseudo)-goldstini production at colliders. Compared to standard gauge mediation the final state spectrum is softer and more structured.Comment: v2: analysis of the stau LOSP scenario added, sections rearranged, and Introduction and Conclusions rewritten to include the added scenario. Version to appear in JHE

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