Breakdown of continuum models for spherical probe adhesion tests on micropatterned surfaces

Funding Information: SB, DY, EA, and RH acknowledge funding from the European Research Council (ERC) under the European Union's Seventh Framework Program (FP/2007–2013)/ERC Advanced Grant No. 340929 . RMM acknowledges the Alexander von Humboldt Foundation for awarding the “Virtual Humboldt Cluster on the Mechanics and Physics of Adhesion and Grip”.Peer reviewedPublisher PD

Polycomb Binding Precedes Early-Life Stress Responsive DNA Methylation at the Avp Enhancer

Early-life stress (ELS) in mice causes sustained hypomethylation at the downstream Avp enhancer, subsequent overexpression of hypothalamic Avp and increased stress responsivity. The sequence of events leading to Avp enhancer methylation is presently unknown. Here, we used an embryonic stem cell-derived model of hypothalamic-like differentiation together with in vivo experiments to show that binding of polycomb complexes (PcG) preceded the emergence of ELS-responsive DNA methylation and correlated with gene silencing. At the same time, PcG occupancy associated with the presence of Tet proteins preventing DNA methylation. Early hypothalamic-like differentiation triggered PcG eviction, DNA-methyltransferase recruitment and enhancer methylation. Concurrently, binding of the Methyl-CpG-binding and repressor protein MeCP2 increased at the enhancer although Avp expression during later stages of differentiation and the perinatal period continued to increase. Overall, we provide evidence of a new role of PcG proteins in priming ELS-responsive DNA methylation at the Avp enhancer prior to epigenetic programming consistent with the idea that PcG proteins are part of a flexible silencing system during neuronal development

Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers

Neoadjuvant chemotherapy (NACT) is frequently used in patients with early breast cancer. Randomized controlled trials have demonstrated similar survival after NACT or adjuvant chemotherapy (ACT). However, certain subtypes may benefit more when NACT contains regimes leading to high rates of pathologic complete response (pCR) rates. In this study we analyzed data using the OncoBox research from 94,638 patients treated in 55 breast cancer centers to describe the current clinical practice of and outcomes after NACT under routine conditions. These data were compared to patients treated with ACT. 40% of all patients received chemotherapy. The use of NACT increased over time from 5% in 2007 up to 17.3% in 2016. The proportion of patients receiving NACT varied by subtype. It was low in patients with HR-positive/HER2-negative breast cancer (5.8%). However, 31.8% of patients with triple-negative, 31.9% with HR-negative/HER2-positive, and 26.5% with HR-positive/HER2-positive breast cancer received NACT. The rates of pCR were higher in patients with HR-positive/HER2-positive, HR negative/HER2-positive and triple-negative tumors (36, 53 and 38%) compared to HR-positive/HER2-negative tumors (12%). PCR was achieved more often in HER2-positive and triple-negative tumors over time. This is the largest study on use and effects of NACT in German breast cancer centers. It demonstrates the increased use of NACT based on recommendations in current clinical guidelines. An improvement of pCR was shown in particular in HER2-positive and triple-negative breast cancer, which is consistent with data from randomized controlled trails

West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer

PURPOSE The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC). PATIENTS AND METHODS Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E)(90)/cyclophoshamide (C)(600) followed by four cycles of docetaxel (T)(100) or six cycles of T75C600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined. RESULT Of the 3,198 registered patients, 348 (RS <= 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v60.8%; pNO, 58.2% v59.5%; pT1, 57.6% v52.3%; HR positive, 81.4% v82.2%; RS greater than 25 [in H.R-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status. CONCLUSION In the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease. (C) 2019 by American Society of Clinical Oncolog