Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy

Gaze fixation improves the stability of expert juggling

Novice and expert jugglers employ different visuomotor strategies: whereas novices look at the balls around their zeniths, experts tend to fixate their gaze at a central location within the pattern (so-called gaze-through). A gaze-through strategy may reflect visuomotor parsimony, i.e., the use of simpler visuomotor (oculomotor and/or attentional) strategies as afforded by superior tossing accuracy and error corrections. In addition, the more stable gaze during a gaze-through strategy may result in more accurate movement planning by providing a stable base for gaze-centered neural coding of ball motion and movement plans or for shifts in attention. To determine whether a stable gaze might indeed have such beneficial effects on juggling, we examined juggling variability during 3-ball cascade juggling with and without constrained gaze fixation (at various depths) in expert performers (n = 5). Novice jugglers were included (n = 5) for comparison, even though our predictions pertained specifically to expert juggling. We indeed observed that experts, but not novices, juggled significantly less variable when fixating, compared to unconstrained viewing. Thus, while visuomotor parsimony might still contribute to the emergence of a gaze-through strategy, this study highlights an additional role for improved movement planning. This role may be engendered by gaze-centered coding and/or attentional control mechanisms in the brain

Predicting Eye Fixations on Complex Visual Stimuli Using Local Symmetry

Most bottom-up models that predict human eye fixations are based on contrast features. The saliency model of Itti, Koch and Niebur is an example of such contrast-saliency models. Although the model has been successfully compared to human eye fixations, we show that it lacks preciseness in the prediction of fixations on mirror-symmetrical forms. The contrast model gives high response at the borders, whereas human observers consistently look at the symmetrical center of these forms. We propose a saliency model that predicts eye fixations using local mirror symmetry. To test the model, we performed an eye-tracking experiment with participants viewing complex photographic images and compared the data with our symmetry model and the contrast model. The results show that our symmetry model predicts human eye fixations significantly better on a wide variety of images including many that are not selected for their symmetrical content. Moreover, our results show that especially early fixations are on highly symmetrical areas of the images. We conclude that symmetry is a strong predictor of human eye fixations and that it can be used as a predictor of the order of fixation

Testis-specific glyceraldehyde-3-phosphate dehydrogenase: origin and evolution

<p>Abstract</p> <p>Background</p> <p>Glyceraldehyde-3-phosphate dehydrogenase (GAPD) catalyses one of the glycolytic reactions and is also involved in a number of non-glycolytic processes, such as endocytosis, DNA excision repair, and induction of apoptosis. Mammals are known to possess two homologous GAPD isoenzymes: GAPD-1, a well-studied protein found in all somatic cells, and GAPD-2, which is expressed solely in testis. GAPD-2 supplies energy required for the movement of spermatozoa and is tightly bound to the sperm tail cytoskeleton by the additional N-terminal proline-rich domain absent in GAPD-1. In this study we investigate the evolutionary history of GAPD and gain some insights into specialization of GAPD-2 as a testis-specific protein.</p> <p>Results</p> <p>A dataset of GAPD sequences was assembled from public databases and used for phylogeny reconstruction by means of the Bayesian method. Since resolution in some clades of the obtained tree was too low, syntenic analysis was carried out to define the evolutionary history of GAPD more precisely. The performed selection tests showed that selective pressure varies across lineages and isoenzymes, as well as across different regions of the same sequences.</p> <p>Conclusions</p> <p>The obtained results suggest that GAPD-1 and GAPD-2 emerged after duplication during the early evolution of chordates. GAPD-2 was subsequently lost by most lineages except lizards, mammals, as well as cartilaginous and bony fishes. In reptilians and mammals, GAPD-2 specialized to a testis-specific protein and acquired the novel N-terminal proline-rich domain anchoring the protein in the sperm tail cytoskeleton. This domain is likely to have originated by exonization of a microsatellite genomic region. Recognition of the proline-rich domain by cytoskeletal proteins seems to be unspecific. Besides testis, GAPD-2 of lizards was also found in some regenerating tissues, but it lacks the proline-rich domain due to tissue-specific alternative splicing.</p