Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.

Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor-positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care.Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Psychosocial effects of disaster in children and adolescents: significance and management.

This article provides a synthesis of the literature addressing the psychological and social effects on children and adolescents after disasters, and the factors that contribute to protecting this population from experiencing related symptoms. Clinical implications are presented for health care providers to reduce the possibility of long-term psychopathologies based on the National Commission on Children and Disasters 2010 Report.

Exploring nursing students' level of preparedness for disaster response.

This descriptive study explores students' perceptions of personal and program preparedness for disasters. Participants in this online survey included 1,348 nursing students from every state plus Guam, Puerto Rico, and theVirgin Islands. The study explored three questions: a) the level of preparedness, including learning about different types of disasters, preparing disaster plans, creating disaster kits, and participating in community disaster response efforts; b) the impact of disasters on nursing students; and c) strategies to assist nursing students during disasters. Results indicated that nursing students throughout the country are generally not well prepared for disasters. Nurse educators need to develop strategies to prepare their students for disasters. The American Red Cross provides templates for organizations, including colleges and universities, to prepare their campuses for emergencies. Faculty need to collaborate with staff and students to develop and implement plans appropriate for their programs.

Implementing a leadership course and mentor model for students in the National Student Nurses' Association.

To help student development as responsible and accountable leaders, a mentor model was incorporated into an established voluntary leadership course offered each semester. The student joins the National Student Nurses' Association, completes leadership projects, and contracts for the course grade. The mentor model is a leadership option that pairs senior students wanting to mentor with junior students wishing to be mentored. The authors describe the outcomes of the leadership-mentor experience.

Comparison of three teaching methods on 4- through 7-year-old children's understanding of the lungs in relation to a peak flow meter in the management of asthma: a pilot study.

This pilot study of 19 children compared three methods of teaching 4- through 7-year-old children about their lungs in relation to a peakflow meter. One group saw a doll with three-dimensional lungs, another group saw a puppet with inflatable lungs, and a comparison group received usual Asthma Clinic education. Knowledge of the lungs was measured pre- and post-teaching through two body knowledge assessment instruments. Four children in the Puppet Group improved their posttest scores, compared to three in the Doll Group and two in the Usual Care Group. Continued psychometric studies of the instruments and similar studies with larger sample sizes need to be conducted.