Gene expression profiles of inflammatory breast cancer: correlation with response to neoadjuvant chemotherapy and metastasis-free survival.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive disease. To date, no molecular feature reliably predicts either the response to chemotherapy (CT) or the survival. Using DNA microarrays, we searched for multigene predictors. PATIENTS AND METHODS: The World IBC Consortium generated whole-genome expression profiles of 137 IBC and 252 non-IBC (nIBC) samples. We searched for transcriptional profiles associated with pathological complete response (pCR) to neoadjuvant anthracycline-based CT and distant metastasis-free survival (DMFS) in respective subsets of 87 and 106 informative IBC samples. Correlations were investigated with predictive and prognostic gene expression signatures published in nIBC (nIBC-GES). Supervised analyses tested genes and activation signatures of 19 biological pathways and 234 transcription factors. RESULTS: Three of five tested prognostic nIBC-GES and the two tested predictive nIBC-GES discriminated between IBC with and without pCR, as well as two interferon activation signatures. We identified a 107-gene signature enriched for immunity-related genes that distinguished between responders and nonresponders in IBC. Its robustness was demonstrated by external validation in three independent sets including two IBC sets and one nIBC set, with independent significant predictive value in IBC and nIBC validation sets in multivariate analysis. We found no robust signature associated with DMFS in patients with IBC, and neither of the tested prognostic GES, nor the molecular subtypes were informative, whereas they were in our nIBC series (220 stage I-III informative samples). CONCLUSION: Despite the relatively small sample size, we show that response to neoadjuvant CT in IBC is, as in nIBC, associated with immunity-related processes, suggesting that similar mechanisms responsible for pCR exist. Analysis of a larger IBC series is warranted regarding the correlation of gene expression profiles and DMFS.

Plant sterols: a neutron diffraction study of sitosterol and stigmasterol in soybean phosphatidylcholine membranes.

Neutron scattering experiments have been performed on oriented Soybean phosphatidylcholine (SPC) bilayers, containing sitosterol or stigmasterol, two major sterols of plant plasma membranes. Sitosterol and stigmasterol were either protonated or deuterated on position C25 of the lateral chain. Incorporation of sitosterol leads to an increase of the hydrophobic thickness of SPC bilayers of 1.2 and 2 A when present, at 16 and 30 mol%, respectively. On the other hand, no change was observed when stigmasterol is present in the bilayer at its maximal solubility of 16 mol%. These results are in agreement with the fact that sitosterol is more efficient than stigmasterol to order acyl chains of SPC, as already shown with other biophysical techniques. In order to get more insight into the behavior of the lateral chains of the two sterols, the proton-deuterium contrast method was used in order to locate the (2)H25 atoms of the two sterols. For sitosterol, this atom was found close to the center of the bilayer at +/-(1.6+/-0.2 A), with a width, nu=2.5+/-0.5 A. For stigmasterol, the difference profile could be fitted in two different ways: either two possible locations are found at +/-(2.3+/-0.2 A) and +/-(10+/-0.2 A) with the same width, nu=2.5+/-0.5 A or only one broad distribution at +/-(6.1+/-0.3 A), nu=8.5+/-0.7 A. The results are discussed in terms of difference of dynamics for the lateral chain of the two sterols.

Cholesterol orientation and dynamics in dimyristoylphosphatidylcholine bilayers: a solid state deuterium NMR analysis.

Proton decoupled deuterium NMR spectra of oriented bilayers made of DMPC and 30 mol % deuterated cholesterol acquired at 76.8 MHz (30 degreesC) have provided a set of very accurate quadrupolar splitting for eight C-D bonds of cholesterol. Due to the new precision of the experimental data, the original analysis by. Biochemistry. 23:6062-6071) had to be reconsidered. We performed a systematic study of the influence on the precision and uniqueness of the data-fitting procedure of: (i) the coordinates derived from x-ray, neutron scattering, or force field-minimized structures, (ii) internal mobility, (iii) the axial symmetry hypothesis, and (iv) the knowledge of some quadrupolar splitting assignments. Good agreement between experiment and theory could be obtained only with the neutron scattering structure, for which both axial symmetry hypothesis and full order parameter matrix analysis gave satisfactory results. Finally, this work revealed an average orientation of cholesterol slightly different from those previously published and, most importantly, a molecular order parameter equal to 0.95 +/- 0.01, instead of 0.79 +/- 0.03 previously found for the same system at 30 degreesC. Temperature dependence in the 20-50 degreesC range shows a constant average orientation and a monotonous decrease of cholesterol Smol, with a slope of -0.0016 K-1. A molecular order parameter of 0.89 +/- 0.01 at 30 degreesC was determined for a DMPC/16 mol % of cholesterol.