HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer.

PURPOSE: Knowledge on whether low expressions of HER2 have prognostic impact in early-stage breast cancer (BC) and on its response to current chemotherapy protocols can contribute to medical practice and development of new drugs for this subset of patients, changing treatment paradigms. This study aims to evaluate the impact of HER2-low status on response to neoadjuvant chemotherapy (NACT) and survival outcomes in early-stage HER2-negative BC. METHODS: Records from all BC patients treated with NACT from January 2007 to December 2018 in a single cancer center were retrospectively reviewed. HER2-negative (immunohistochemistry [IHC] 0, + 1, or + 2 non-amplified by in situ hybridization [ISH]) patients were included. HER2-low was defined by IHC + 1 or + 2 ISH non-amplified and HER2-0 by IHC 0. The coprimary objectives were to compare pathological complete response (pCR) and relapse-free survival (RFS) between luminal/HER2-low versus luminal/HER2-0 populations and between triple negative (TNBC)/HER2-low versus TNBC/HER2-0. RESULTS: In total, 855 HER2-negative patients were identified. The median follow-up was 59 months. 542 patients had luminal subtype (63.4%) and 313 had TNBC (36.6%). 285 (33.3%) were HER2-low. Among luminal patients, 145 had HER2 IHC + 1 (26.8%) and 91 had IHC + 2/ISH non-amplified (16.8%). In TNBC, 36 had HER2 IHC + 1 (11.5%) and 13 had IHC + 2/ISH non-amplified (4.2%). Most patients had locally advanced tumors, regardless of subtype or HER2-low status. For luminal disease, pCR was achieved in 13% of HER2-low tumors versus 9.5% of HER2-0 (p = 0.27). Similarly, there was no difference in pCR rates among TNBC: 51% versus 47% in HER2-low versus HER2-0, respectively (p = 0.64). HER2-low was also not prognostic for RFS, with 5-year RFS rates of 72.1% versus 71.7% (p = 0.47) for luminal HER2-low/HER2-0, respectively, and 75.6% versus 70.8% (p = 0.23) for TNBC HER2-low/HER2-0. CONCLUSION: Our data does not support HER2-low as a biologically distinct BC subtype, with no prognostic value on survival outcomes and no predictive effect for pCR after conventional NACT.

Consumers' reactions to nutrition and ingredient labelling for wine - A cross-country discrete choice experiment.

The purpose of this study is to examine consumers' reactions to the introduction of nutrition and ingredient labelling for wine, a product that is so far still exempt from mandatory nutrition and ingredient labelling. It also analyses the effect of positive and negative information about the use of ingredients in wine on consumers' choice. Representative samples for wine consumers from three distinctly different countries representing old and new wine markets (Australia, n = 745; Germany, n = 716; Italy, n = 715) completed a discrete choice experiment (DCE) with graphically simulated wine back labels. For each country, respondents were randomly allocated to a reference group and two different treatment conditions where they received newspaper-like information (positive, negative) before making choices. Results for the reference condition show that consumers across all three countries have a significant positive utility for detailed nutrition information. Instead, ingredient information only receives a positive utility in Italy, whereas German and Australian respondents do not receive utility from ingredient labelling. When consumers in the treatment group are confronted with negative media information the attribute importance of ingredients significantly increases across all three countries, clean labelled products without ingredients are preferred, and a significantly higher share of consumers in Germany and Italy prefer not to buy any wine. The treatment effect of positive media information on consumers' wine choice is lower than that of negative information. The results of the study have implications for the pending new regulation of wine labelling and for communication strategies of the wine industry that should actively inform consumers about the necessity of ingredients in wine production.

Increasing consumers' attention capture and food choice through bottom-up effects.

To guide consumers in their decision process, especially food products often carry labels indicating production method or nutritional content. However, past research shows that many labels are rarely attended to in the consumer's decision process. In order to enhance the effectiveness of such labels and to increase choice likelihood of labeled products, the label must capture attention. We address the question of how a single label on the product packaging can capture attention through bottom-up effects and increase choice through increased attention capture. To this end, we conducted a combined eye tracking and choice experiment manipulating the surface size and visual saliency - the two most important bottom-up effects on attention - of the Danish organic label across three food product categories. Results show a strong and significant increase in attention capture towards a larger and more visually salient label. Most importantly, the effect of attention capture carried over into increased choice likelihood. Both marketers and policy makers might benefit from this approach, which provides directions for designing product labels that can influence attention capture and product choice.

Using the animal to the last bit: Consumer preferences for different beef cuts.

Meat is expensive to produce, making it is essential to understand the importance consumers pay to different meat cuts. Previous research on consumers' meat choices has mainly focused on meat species, while consumer preferences for meat cuts has so far only received limited interest. The aim of this study is to shed some light into this relatively unexplored area by answering four research questions. First, this study intends to show the relative importance meat cuts play in relation to other extrinsic product attributes. Secondly, this paper looks into differences in choice criteria between regular and special occasions. Third, consumer segments that differ in their preferences and beef purchase are identified, and, finally, the meat purchase portfolios of these segments are revealed. A stated preference methodology of a discrete choice experiment with cut-specific prices covering several meat cuts simultaneously is proposed to answer the research questions. The sample consists of 1500 respondents representative of the Italian population in terms of age, gender and geographic location The results shows that meat cut is the most important factor when choosing bovine meat followed by quality certification (origin), production technique, the type of breed and price. In terms of consumption occasions, we observe significantly lower price sensitivity for marbled steaks and cutlets for special occasions compared to normal occasions. Segmentation analysis shows that while the choices of two segments (comprising about 40% of the sample) are mostly driven by extrinsic product attributes, the remaining segments are mostly driven by meat cuts. These varying preferences are also reflected in the purchase portfolios of the different segments, while less variability is detected from a socio-demographic perspective.

Towards grapevine root architectural models to adapt viticulture to drought.

To sustainably adapt viticultural production to drought, the planting of rootstock genotypes adapted to a changing climate is a promising means. Rootstocks contribute to the regulation of scion vigor and water consumption, modulate scion phenological development and determine resource availability by root system architecture development. There is, however, a lack of knowledge on spatio-temporal root system development of rootstock genotypes and its interactions with environment and management that prevents efficient knowledge transfer into practice. Hence, winegrowers take only limited advantage of the large variability of existing rootstock genotypes. Models of vineyard water balance combined with root architectural models, using both static and dynamic representations of the root system, seem promising tools to match rootstock genotypes to frequently occurring future drought stress scenarios and address scientific knowledge gaps. In this perspective, we discuss how current developments in vineyard water balance modeling may provide the background for a better understanding of the interplay of rootstock genotypes, environment and management. We argue that root architecture traits are key drivers of this interplay, but our knowledge on rootstock architectures in the field remains limited both qualitatively and quantitatively. We propose phenotyping methods to help close current knowledge gaps and discuss approaches to integrate phenotyping data into different models to advance our understanding of rootstock x environment x management interactions and predict rootstock genotype performance in a changing climate. This could also provide a valuable basis for optimizing breeding efforts to develop new grapevine rootstock cultivars with optimal trait configurations for future growing conditions.

The positive frequency-dependent electrophysiological effects of the IKur inhibitor XEN-D0103 are desirable for the treatment of atrial fibrillation.

BACKGROUND: Selective inhibitors of Kv1.5 channels are being developed for the treatment of atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to investigate the effects of the highly selective Kv1.5 inhibitor XEN-D0103 on human atrial action potentials (APs) at high excitation rates and to assess safety. METHODS: Intracellular APs (stimulation rates 1-5 Hz) were measured in right atrial trabeculae from patients in sinus rhythm (SR), chronic AF (cAF; AF of >6 months duration), and paroxysmal AF (pAF). The safety and tolerability of XEN-D0103 were tested in a double-blind, randomized, placebo-controlled phase 1 study. RESULTS: Depending on its concentration, XEN-D0103 elevated the plateau potential. At 1 Hz, XEN-D0103 (3 µM) shortened action potential duration at 90% repolarization (APD90) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD90 and ERP at 2 and 3 Hz. At high rates, more SR and pAF preparations failed to capture excitation in the presence of the drug than in its absence. XEN-D0103 (10 µM) did not significantly affect human ventricular APs. Even with plasma concentrations reaching 7000 ng/mL, XEN-D0103 did not increase ∆∆QTcF (QT interval corrected by the Fridericia formula) in the analysis of electrocardiograms of healthy volunteers, and no subjects receiving an active treatment had a QT or QTcF interval >450 ms, or increase in QTcF from baseline >30 ms. CONCLUSION: APD prolongation and suppression of APs by XEN-D0103 at high stimulation rates in SR and pAF tissue, but not cAF, could be of therapeutic benefit for reducing AF burden. This concept needs to be confirmed in clinical trials.

Application of the RIMARC algorithm to a large data set of action potentials and clinical parameters for risk prediction of atrial fibrillation.

Ex vivo recorded action potentials (APs) in human right atrial tissue from patients in sinus rhythm (SR) or atrial fibrillation (AF) display a characteristic spike-and-dome or triangular shape, respectively, but variability is huge within each rhythm group. The aim of our study was to apply the machine-learning algorithm ranking instances by maximizing the area under the ROC curve (RIMARC) to a large data set of 480 APs combined with retrospectively collected general clinical parameters and to test whether the rules learned by the RIMARC algorithm can be used for accurately classifying the preoperative rhythm status. APs were included from 221 SR and 158 AF patients. During a learning phase, the RIMARC algorithm established a ranking order of 62 features by predictive value for SR or AF. The model was then challenged with an additional test set of features from 28 patients in whom rhythm status was blinded. The accuracy of the risk prediction for AF by the model was very good (0.93) when all features were used. Without the seven AP features, accuracy still reached 0.71. In conclusion, we have shown that training the machine-learning algorithm RIMARC with an experimental and clinical data set allows predicting a classification in a test data set with high accuracy. In a clinical setting, this approach may prove useful for finding hypothesis-generating associations between different parameters.

Effects of IKur blocker MK-0448 on human right atrial action potentials from patients in sinus rhythm and in permanent atrial fibrillation.

Selective blockers of the Kv1.5 channel have been developed for the treatment of atrial fibrillation (AF), but little is known how these atrial-selective drugs affect human action potentials (APs). Therefore we have investigated the Kv1.5 blocker MK-0448 (N-{6-[(1S)-1-(4-fluorophenyl)-2,2-di(pyridin-3-yl)ethyl]pyridin-2-yl}methanesulfon- amide) in right atrial trabeculae from patients in sinus rhythm (SR), permanent AF (>6 months), and intermittent AF. MK-0448 blocked Kv1.5 current in an expression system and concentration-dependently elevated the plateau phase of atrial APs. In SR preparations stimulated at 1 Hz, MK-0448 (3 µM) shortened action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP), but in permanent AF preparations, MK-0448 prolonged APD90 and ERP. The effects of MK-0448 in intermittent AF resembled those in SR preparations. Block of IKs is probably more prominent in AF because of reduced repolarization reserve due to AF-induced remodeling.

Inter-subject variability in human atrial action potential in sinus rhythm versus chronic atrial fibrillation.

AIMS: Human atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions. METHODS AND RESULTS: Human AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in G(K1), G(Kur) and G(to), consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in I(K1) and I(NaK) underlies variability in APD90, variability in I(Kur), I(CaL) and I(NaK) modulates variability in APD50 and combined variability in Ito and I(Kur) determines variability in APD20. The large variability in human atrial AP triangulation is mostly determined by I(K1) and either I(NaK) or I(NaCa) depending on the model. CONCLUSION: Experimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF.

Attention and choice: a review on eye movements in decision making.

This paper reviews studies on eye movements in decision making, and compares their observations to theoretical predictions concerning the role of attention in decision making. Four decision theories are examined: rational models, bounded rationality, evidence accumulation, and parallel constraint satisfaction models. Although most theories were confirmed with regard to certain predictions, none of the theories adequately accounted for the role of attention during decision making. Several observations emerged concerning the drivers and down-stream effects of attention on choice, suggesting that attention processes plays an active role in constructing decisions. So far, decision theories have largely ignored the constructive role of attention by assuming that it is entirely determined by heuristics, or that it consists of stochastic information sampling. The empirical observations reveal that these assumptions are implausible, and that more accurate assumptions could have been made based on prior attention and eye movement research. Future decision making research would benefit from greater integration with attention research.