HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Changing Fields of Solidarity in France: A Cross-field Analysis of Migration, Unemployment and Disability

AbstractThis chapter evaluates the implications of recent crises for solidarity organisations in France. The main aim is to assess whether solidarity remains nationally bounded or otherwise follows some consistent pattern of transnationalisation. By focusing on the fields of migration, unemployment and disability, the chapter examines the main attributes of solidarity organisations; in particular, the analysis aims to evaluate how transnational features relate to endogenous characteristics, such as activities, roles and networks affecting their particular experiences within changing fields of solidarity. Crucially, findings show that the economic crisis and welfare retrenchment in France have well served the purpose of governments willing to pre-empt strong political challenge by potential solidarity movements

Phosphorylation of AIB1 at Mitosis Is Regulated by CDK1/CYCLIN B

Although the AIB1 oncogene has an important role during the early phase of the cell cycle as a coactivator of E2F1, little is known about its function during mitosis.Mitotic cells isolated by nocodazole treatment as well as by shake-off revealed a post-translational modification occurring in AIB1 specifically during mitosis. This modification was sensitive to the treatment with phosphatase, suggesting its modification by phosphorylation. Using specific inhibitors and in vitro kinase assays we demonstrate that AIB1 is phosphorylated on Ser728 and Ser867 by Cdk1/cyclin B at the onset of mitosis and remains phosphorylated until exit from M phase. Differences in the sensitivity to phosphatase inhibitors suggest that PP1 mediates dephosphorylation of AIB1 at the end of mitosis. The phosphorylation of AIB1 during mitosis was not associated with ubiquitylation or degradation, as confirmed by western blotting and flow cytometry analysis. In addition, luciferase reporter assays showed that this phosphorylation did not alter the transcriptional properties of AIB1. Importantly, fluorescence microscopy and sub-cellular fractionation showed that AIB1 phosphorylation correlated with the exclusion from the condensed chromatin, thus preventing access to the promoters of AIB1-dependent genes. Phospho-specific antibodies developed against Ser728 further demonstrated the presence of phosphorylated AIB1 only in mitotic cells where it was localized preferentially in the periphery of the cell.Collectively, our results describe a new mechanism for the regulation of AIB1 during mitosis, whereby phosphorylation of AIB1 by Cdk1 correlates with the subcellular redistribution of AIB1 from a chromatin-associated state in interphase to a more peripheral localization during mitosis. At the exit of mitosis, AIB1 is dephosphorylated, presumably by PP1. This exclusion from chromatin during mitosis may represent a mechanism for governing the transcriptional activity of AIB1

Perceived economic self‑sufficiency: a countryand generation‑comparative approach

We thank Michael Camasso and Radha Jagannathan as well as Asimina Christoforou, Gerbert Kraaykamp, Fay Makantasi, Tiziana Nazio, Kyriakos Pierrakakis, Jacqueline O’Reilly and Jan van Deth for their contribution to the CUPESSE project (Seventh Framework Programme; Grant Agreement No. 61325). CUPESSE received additional funding from the Mannheim Centre for European Social Research (MZES) and the Field of Focus 4 “Self-Regulation and Regulation: Individuals and Organisations” at Heidelberg University. We further acknowledge helpful comments on this article by two anonymous reviewers. Julian Rossello provided valuable research assistance.Electronic supplementary material The online version of this article (https ://doi.org/10.1057/ s4130 4-018-0186-3) contains supplementary material, which is available to authorized users.Existing datasets provided by statistical agencies (e.g. Eurostat) show that the economic and financial crisis that unfolded in 2008 significantly impacted the lives and livelihoods of young people across Europe. Taking these official statistics as a starting point, the collaborative research project “Cultural Pathways to Economic Self-Sufficiency and Entrepreneurship in Europe” (CUPESSE) generated new survey data on the economic and social situation of young Europeans (18–35 years). The CUPESSE dataset allows for country-comparative assessments of young people’s perceptions about their socio-economic situation. Furthermore, the dataset includes a variety of indicators examining the socio-economic situation of both young adults and their parents. In this data article, we introduce the CUPESSE dataset to political and social scientists in an attempt to spark a debate on the measurements, patterns and mechanisms of intergenerational transmission of economic self-sufficiency as well as its political implications.CUPESSE project (Seventh Framework Programme; Grant Agreement No. 61325

Trajectories of Solidarities in France Across Fields of Vulnerability

This chapter approaches the study of solidarity in France by comparing three important vulnerable groups, namely, the disabled, the unemployed, and refugees. The way we approach solidarity hinges on an important distinction between two different meanings of solidarity: solidarity understood as an input and solidarity understood as an output. In particular, we distinguish between two main \u201ctrajectories of solidarity\u201d, which helps us to understand the way certain individual variables (such as self-identification and proximity) combine with political variables (like voting, an interest in politics, or the reading of newspapers) in very different ways. Our main finding is the political trajectory of solidarity can have a remarkable potential even when it comes to helping vulnerable people outside the national boundaries of the political community in France

Promoting social Europe? The development of European youth unemployment policies (1997 – 2010)

The institutions of the European Union have intensified their political efforts to combat youth employment since the beginning of the millennium. Youth-specific policy initiatives have been launched since the financial and economic crisis of 2008, and the overall subsequent rise of unemployment rates amongst young people. In this article, we analyse and assess these developments on the basis of an analysis of European policy documents and interviews. Our conclusions are twofold. One the one hand, we argue that the Europe 2020 Strategy and its flagship initiatives devoted to youth do not constitute a new policy field or approach, but are rather the outcome of an incrementalist logic of policy development – not fully supported by neither business associations nor trade unions. On the other hand, an European youth unemployment strategy is perceivably not oriented towards full ‘flexicurity’, because it privileges activation against security, and pushes policy developments towards a minimalist regime of precarious protection. Both developments are explained by the ideational and strategic structures of the European policy arena, i.e., by established discourses and bargains within the EU

Trascending marginalization: the mobilization of the unemployed in France, Germany and Italy in comparative perspective

Mobilization by the unemployed has traditionally been considered a highly improbable phenomenon. However, recent observations challenge such a supposition. Our article compares protest waves in France, Germany, and Italy, where the unemployed successfully organized themselves and acted on their own behalf for several months. We argue that mobilization of the unemployed— although it empirically proved to be a possibility—remains very fragile, particularly depending on beneficial “windows of opportunities.” Our analysis is above all interested in deciphering macrostructural conditions and opportunity structures, arguing that the unemployed benefited from external developments causing changes in potential mobilizing resources, and brought about new allies and political entrepreneurs. At the same time, however, these opportunity structures were actively exploited and, at the same time, their opening was fostered by the mobilization itself