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

Synthetic Observations of Simulated Radio Galaxies I: Radio and X-ray Analysis

We present an extensive synthetic observational analysis of numerically- simulated radio galaxies designed to explore the effectiveness of conventional observational analyses at recovering physical source properties. These are the first numerical simulations with sufficient physical detail to allow such a study. The present paper focuses on extraction of magnetic field properties from nonthermal intensity information. Synchrotron and inverse-Compton intensities provided meaningful information about distributions and strengths of magnetic fields, although considerable care was called for. Correlations between radio and X-ray surface brightness correctly revealed useful dynamical relationships between particles and fields. Magnetic field strength estimates derived from the ratio of X-ray to radio intensity were mostly within about a factor of two of the RMS field strength along a given line of sight. When emissions along a given line of sight were dominated by regions close to the minimum energy/equipartition condition, the field strengths derived from the standard power-law-spectrum minimum energy calculation were also reasonably close to actual field strengths, except when spectral aging was evident. Otherwise, biases in the minimum- energy magnetic field estimation mirrored actual differences from equipartition. The ratio of the inverse-Compton magnetic field to the minimum-energy magnetic field provided a rough measure of the actual total energy in particles and fields in most instances, within an order of magnitude. This may provide a practical limit to the accuracy with which one may be able to establish the internal energy density or pressure of optically thin synchrotron sources.Comment: 43 pages, 14 figures; accepted for publication in ApJ, v601 n2 February 1, 200

Advanced-stage cervix cancer: rapid tumour growth rather than late diagnosis

Either diagnostic delay or tumour biology are possible factors governing the degree of spread at diagnosis of cervical cancer. To try to identify the most important parameter contributing to advanced stage, the duration of symptoms were recorded from patients scheduled for radiotherapy (n = 141) or radical hysterectomy (n = 36). In 146 cases tumour proliferation rates were evaluated following in vivo labelling with the DNA precursor BrdUrd. For symptomatic patients there was no association between duration of symptoms and stage at presentation. There was a significant trend for patients with increasing tumour stage to have more rapidly proliferating tumours with higher mean labelling index (LI) measurements (P = 0.001) and a shorter mean potential doubling time (Tpot) (P = 0.023). Socio economic deprivation may be associated with shorter Tpot values. The conclusion from this data is that stage at diagnosis is more dependent on the biological behaviour of the tumour, as expressed by proliferation rates, than delay in presentation. © 2000 Cancer Research Campaig