Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer.

Purpose A large-panel gene expression analysis was conducted to identify biomarkers associated with the effectiveness of adding palbociclib to fulvestrant.Methods The PALOMA-3 ( ClinicalTrials.gov identifier: NCT01942135) trial randomly assigned 521 endocrine-pretreated patients with metastatic breast cancer to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Primary analysis was first conducted on 10 genes on the basis of pathway biology and evidence from previous studies followed by a systematic panel-wide search among 2,534 cancer-related genes. The association of gene expression with the effect of palbociclib on progression-free survival (PFS) was evaluated using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. An independent breast cancer cohort from the Preoperative Palbociclib (POP) Clinical Trial ( ClinicalTrials.gov identifier: NCT02008734) was used for validation, in 61 patients with primary breast cancer treated with 2 weeks of palbociclib.Results In the PALOMA-3 trial, 302 patients had tumor tissue analyzed (palbociclib arm, 194 patients; placebo arm, 108 patients). Palbociclib efficacy was lower in patients with high versus low cyclin E1 (CCNE1) mRNA expression (median PFS: palbociclib arm, 7.6 v 14.1 months; placebo arm, 4.0 v 4.8 months, respectively; interaction P unadjusted = .00238; false discovery rate-adjusted P = .0238). CCNE1 mRNA was more predictive in metastatic than in archival primary biopsy tissue samples. No significant interaction was found between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1. Palbociclib was efficacious in both luminal A and luminal B tumors. High CCNE1 mRNA expression was associated with poor antiproliferative activity of palbociclib in the POP trial (P = .005).Conclusion Addition of palbociclib to fulvestrant demonstrated efficacy in all biomarker groups, although high CCNE1 mRNA expression was associated with relative resistance to palbociclib

Cultivating a Professional Culture of Peace and Inclusion: Conceptualizing Practical Applications of Peace Leadership in Schools

Beyond the role of educating students across all academic domains, school leaders are tasked with the monumental responsibility of creating positive, engaged systems and cultures that embrace the growing cultural, economic, linguistic, and cognitive diversity in the United States landscape. With collective goals to create peaceful learning environments with capacity to serve diverse learners, many school leaders have embraced school-wide prevention and intervention efforts, such as Multi-Tiered Systems of Support (MTSS) for social-emotional and behavioral development of students. Unfortunately, due to the inherent complexities and fragmentation of such efforts, many school leaders have continued to experience significant barriers to sustainable systems change. Throughout the following discussion, the authors argue that the school-wide programs most commonly utilized in schools lack the explicit organizational structures for integrating culturally responsive practice, leadership development, and collaborative community building processes that are essential to sustainable implementation. Therefore, this conceptual paper aims to explore the possibilities for practical applications of the Integral Perspective of Peace Leadership (IPPL, McIntyre Miller and Green, 2015) within school systems change efforts by shifting focus from direct student skill development toward a more integrated and systems-oriented approach aimed at strengthening culture and capacity within communities of educational leaders. The IPPL can “connect the dots” and provide a strong foundation through which school-wide change is possible and more sustainable. By challenging individuals, schools, communities, and organizations to examine and include Innerwork; theories, behaviors and practices, or Knowledge building; Communities of practice; and Environment work, such as systems and global thinking (McIntyre Miller and Green, 2015), the implementation of the IPPL may “challenge issues of violence and aggression and build positive, inclusive social systems and structures” (McIntyre Miller, 2016, p. 223). The purpose of this paper is twofold. First, there is a discussion of how the elements of the IPPL connect to school culture and system change. Second, specific examples, such as character development, mindfulness, school-wide positive behavior supports, social-emotional learning, professional learning communities, home-school connection, systems thinking, and distributed leadership, will demonstrate how school leaders might engage, using consultants and an implementation team, in the work to create positive, equitable school cultures

The Compact Linear Collider (CLIC) - 2018 Summary Report

The Compact Linear Collider (CLIC) is a TeV-scale high-luminosity linear $e^+e^-$ collider under development at CERN. Following the CLIC conceptual design published in 2012, this report provides an overview of the CLIC project, its current status, and future developments. It presents the CLIC physics potential and reports on design, technology, and implementation aspects of the accelerator and the detector. CLIC is foreseen to be built and operated in stages, at centre-of-mass energies of 380 GeV, 1.5 TeV and 3 TeV, respectively. CLIC uses a two-beam acceleration scheme, in which 12 GHz accelerating structures are powered via a high-current drive beam. For the first stage, an alternative with X-band klystron powering is also considered. CLIC accelerator optimisation, technical developments and system tests have resulted in an increased energy efficiency (power around 170 MW) for the 380 GeV stage, together with a reduced cost estimate at the level of 6 billion CHF. The detector concept has been refined using improved software tools. Significant progress has been made on detector technology developments for the tracking and calorimetry systems. A wide range of CLIC physics studies has been conducted, both through full detector simulations and parametric studies, together providing a broad overview of the CLIC physics potential. Each of the three energy stages adds cornerstones of the full CLIC physics programme, such as Higgs width and couplings, top-quark properties, Higgs self-coupling, direct searches, and many precision electroweak measurements. The interpretation of the combined results gives crucial and accurate insight into new physics, largely complementary to LHC and HL-LHC. The construction of the first CLIC energy stage could start by 2026. First beams would be available by 2035, marking the beginning of a broad CLIC physics programme spanning 25-30 years

Update of the CLIC Positron Source

The baseline positron source of CLIC has been optimised for the 3 TeV c.o.m. energy. Now the first stage of the CLIC is proposed to be at 380 GeV. Recently, the positron transmission efficiency from the tungsten target to the damping rings injection has been improved by 2.5 times. This opened the possibility for an optimisation of the whole positron source, comprising the injector linacs, aimed at improving its performance and its overall power efficiency. In this paper the key parameters of the positron source, which include the current and the energy of the primary electron beam, the thickness of the crystal and amorphous tungsten targets, the distance between the two targets, the adiabatic matching device (AMD) and pre-injector linacs, are optimized to improve the overall power efficiency

Optimization of the CLIC positron source using a start-to-end simulation approach involving multiple simulation codes

International audienceA start-to-end optimization simulation toolkit for the CLIC positron source has been developed using multiple simulation codes to model adequately different areas of the positron source. The positron source includes the targets using channeling and pair-production processes, the adiabatic matching device and the pre-injector and injector linacs. The primary electron beams with energies of 5 GeV and 3 GeV are optimized with this toolkit as well as the target parameters. Finally rf parameters or the linear accelerators are optimized involving a particle tracking code. Using this approach the yield of the CLIC positron source has been increased by a factor 2 resulting in significant cost savings