WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients

Flexibility and Fairness in Liberal Market Economies: The Comparative Impact of the Legal Environment and High Performance Work Systems

This paper compares management flexibility in employment decision-making in the United States and Canada through a cross-national survey of organizations in representative jurisdictions in each country, Pennsylvania and Ontario respectively, that investigates the impact of differences in their legal environments. The results indicate that, compared to their Ontario counterparts, organizations in Pennsylvania have a higher degree of flexibility in employment outcomes, such as higher dismissal and discipline rates, yet do not experience any greater flexibility or simplicity in management hiring and firing decisions. One explanation for this result may lie in the finding that organizations in Pennsylvania experience greater legal pressures on decision making, reflecting the generally more intense conflict in the employment law system in the United States. By contrast, high performance work systems, which some have looked to as a possible management-driven mechanism for enhancing fairness in employment, had more modest effects

Are the Spanish Long-Term Unemployed Unemployable?

Long-term unemployment reached unprecedented levels in Spain in the wake of the Great Recession and it still affects around 57% of the unemployed. We document the sources that contributed to the rise in long-term unemployment and analyze its persistence using state-ofthe- art duration models. We find pervasive evidence of negative duration dependence, while personal characteristics such as mature age, lack of experience, and entitlement to unemployment benefits are key to understand the cross-sectional differences in the incidence of long-term unemployment. The negative impact of low levels of skills and education is muted by the large share of temporary contracts, but once we restrict attention to employment spells lasting at least one month these factors also contribute to a higher risk of long-term unemployment. Surprisingly, workers from the construction sector do not fare worse than similar workers from other sectors. Finally, self-reported reservation wages are found to respond strongly to the cycle, but much less to individual unemployment duration. In view of these findings, we argue that active labour market policies should play a more prominent role in the fight against long-term unemployment while early activation should be used to curb inflows.This is a revised version of the Presidential Address of the 40th Simposio de la Asociación Española de Economía delivered by the first author in Girona (December 2015). We are grateful to Manuel Arellano, Rolf Campos, Mario Izquierdo, Ernesto Villanueva, and seminar participants at the Banco de España, the European Central Bank, the International Labor Office, and the University of Edinburgh for comments, to Yolanda Rebollo- Sanz for help with the data set, and to Lucía Gorjón and Ingeborg Kukla for excellent research assistance. Bentolila thanks the Economics Department of Universidad Carlos III de Madrid for their hospitality. García-Pérez and Jansen gratefully acknowledge financial support from MINECO/FEDER (grants ECO2015-65408-R and ECO2015-69631-P)

Design Considerations for Tumor-Targeted Nanoparticles

Inorganic/organic hybrid nanoparticles are potentially useful in biomedicine, but to avoid non-specific background fluorescence and long-term toxicity, they need to be cleared from the body within a reasonable timescale1. Previously, we have shown that rigid spherical nanoparticles such as quantum dots can be cleared by the kidneys if they have a hydrodynamic diameter of approximately 5.5 nm and a zwitterionic surface charge2. Here, we show that quantum dots functionalized with high-affinity small-molecule ligands that target tumours can also be cleared by the kidneys if their hydrodynamic diameter is less than this value, which sets an upper limit of 5–10 ligands per quantum dot for renal clearance. Animal models of prostate cancer and melanoma show receptor-specific imaging and renal clearance within 4 h post-injection. This study suggests a set of design rules for the clinical translation of targeted nanoparticles that can be eliminated through the kidneys.National Science Foundation (U.S.) (NSF-0070319)National Institutes of Health (U.S.) (NIH GM68762)National Institutes of Health (U.S.) (NIH grant no. R33-EB-000673)National Institutes of Health (U.S.) ( NIH grant no. R01-CA-115296)National Institutes of Health (U.S.) (MIT-Harvard NanoMedical Consortium (1U54-CA119349, a Center of Cancer Nanotechnology Excellence))Bank of AmericaMedical Foundation, inc. (Charles A. King Trust Postdoctoral Research Fellowship Program)cance

Relative Pose from Deep Learned Depth and a Single Affine Correspondence

We propose a new approach for combining deep-learned non-metric monocular depth with affine correspondences (ACs) to estimate the relative pose of two calibrated cameras from a single correspondence. Considering the depth information and affine features, two new constraints on the camera pose are derived. The proposed solver is usable within 1-point RANSAC approaches. Thus, the processing time of the robust estimation is linear in the number of correspondences and, therefore, orders of magnitude faster than by using traditional approaches. The proposed 1AC+D solver is tested both on synthetic data and on 110395 publicly available real image pairs where we used an off-the-shelf monocular depth network to provide up-to-scale depth per pixel. The proposed 1AC+D leads to similar accuracy as traditional approaches while being significantly faster. When solving large-scale problems, e.g., pose-graph initialization for Structure-from-Motion (SfM) pipelines, the overhead of obtaining ACs and monocular depth is negligible compared to the speed-up gained in the pairwise geometric verification, i.e., relative pose estimation. This is demonstrated on scenes from the 1DSfM dataset using a state-of-the-art global SfM algorithm. Source code: https://github.com/eivan/one-ac-pos