A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Health-Related Quality of Life and Experiences of Sarcoma Patients during the COVID-19 Pandemic

Sarcomas are rare cancers with a spectrum of clinical needs and outcomes. We investigated care experiences and health-related quality of life (HRQoL) in sarcoma patients during the COVID-19 pandemic. Patients with appointments during the first two months of the UK lockdown were invited to complete a survey. Questions included views on care modifications, COVID-19 worry and psychosocial impact, and EORTC-QLQ-C30 items. 350 patients completed the survey; median age 58 (16–92) years. Care modifications included telemedicine (74%) and postponement of appointments (34%), scans (34%) or treatment (10%). Most felt the quality of care was not affected (72%), however, social life (87%) and emotional wellbeing (41%) were affected. Worry about COVID-19 infection was moderately high (mean 5.8/10) and significantly related to higher cancer-related worry; associated with lower emotional functioning irrespective of treatment intent. Curative patients (44%) with low resilient coping scores had significantly higher COVID-19 worry. Patients who did not know their treatment intent (22%) had significantly higher COVID-19 worry and insomnia. In summary, care experiences were generally positive; however, cancer-related worry, low resilient coping and uncertainty about treatment intent were associated with COVID-19 worry. These patients may benefit from additional psychological support during the pandemic and beyond.</jats:p

A Cluster Randomized Controlled Trial for a Multi-Level, Clinic-Based Smoking Cessation Program with Women in Appalachian Communities: Study Protocol for the Break Free Program

BACKGROUND: The cervical cancer burden is high among women living in Appalachia. Cigarette smoking, a cervical cancer risk factor, is also highly prevalent in this population. This project aims to increase smoking cessation among women living in Appalachia by embedding a smoking cessation program within a larger, integrated cervical cancer prevention program. METHODS: The broader program, the Take CARE study, is a multi-site research collaborative designed to address three risk factors for cervical cancer incidence and mortality: tobacco use, human papillomavirus (HPV) infection, and cervical cancer screening. Break Free is a primary care clinic-based implementation program that aims to promote smoking cessation among female smokers in Appalachia by standardizing clinical practice protocols. Break Free includes: (1) implementation of a tobacco user identification system in the Electronic Health Record, (2) clinic staff and provider training on the Ask, Advise and Refer (AAR) model, (3) provider implementation of AAR to identify and treat women who want to quit smoking within the next 6 months, (4) facilitated access to cessation phone counseling plus pharmacotherapy, and (5) the bundling of Break Free tobacco cessation with HPV vaccination and cervical cancer screening interventions in an integrated approach to cervical cancer prevention. The study spans 35 Appalachian health clinics across 10 healthcare systems. We aim to enroll 51 adult female smokers per health system (total N = 510). Baseline and follow-up data will be obtained from participant (provider and patient) surveys. The primary outcome is self-reported 12-month point prevalence abstinence among enrolled patients. All randomized patients are asked to complete follow-up surveys, regardless of whether they participated in tobacco treatment. Data analysis of the primary aims will follow intent-to-treat methodology. Secondary outcomes will assess program implementation and cost effectiveness. DISCUSSION: Addressing high tobacco use rates is critical for reducing cervical cancer morbidity and mortality among women living in Appalachia. This study evaluates the implementation and effectiveness of a smoking cessation program in increasing smoking cessation among female smokers. If results demonstrate effectiveness and sustainability, implementation of this program into other health care clinics could reduce both rates of smoking and cervical cancer. Trial registration NCT04340531 (April 9, 2020)

Hidden politics of power and governmentality in transitional justice and peacebuilding:The problem of ‘bringing the local back in’

This paper examines ‘the local’ in peacebuilding by examining how ‘local’ transitional justice projects can become spaces of power inequalities. The paper argues that focusing on how ‘the local’ contests or interacts with ‘the international’ in peacebuilding and post-conflict contexts obscures contestations and power relations amongst different local actors, and how inequalities and power asymmetries can be entrenched and reproduced through internationally funded local projects. The paper argues that externally funded projects aimed at emancipating ‘locals’ entrench inequalities and create local elites that become complicit in governing the conduct and participation of other less empowered ‘locals’. The paper thus proposes that specific local actors—often those in charge of externally funded peacebuilding projects—should also be conceptualised as governing agents: able to discipline and regulate other local actors’ voices and their agency, and thus (re)construct ideas about what ‘the local’ is, or is not

Navigating New Landscapes: The Contribution of Socio-Legal Scholarship in Mapping the Plurality of International Economic Law and Locating Power in International Economic Relations

The evolution of international economic law in the past two decades has been characterised by the growth and diversification of international economic actors, the expansion in the substantive areas governed by international law, and, crucially, the proliferation of multiple sites of international economic governance. This web of multi-layered international economic governance is, in turn, underpinned by complex dynamics of power which structure the legal and economic relations between the subjects of international economic law and other actors impacted by international legal rules and regulation. The challenge for international legal scholarship lay not only in mapping the multiple sites of international economic governance but also in unmasking the power dynamics inherent in international economic relations. Locating and analysing power relations underlying international economic law is to crucial to understanding the cause and effect of international economic rules and institutions for rulemaking. Conventional legal scholarship with its doctrinal focus, while useful in providing the foundational basis for analysis, cannot adequately capture the complexity of contemporary international economic law. Socio-legal approaches may be able to overcome these epistemological limitations by supplying: a) the methodologies to study international economic law beyond a focus on rules and institutions; and b) the critical theoretical lens to understand the power dynamics inherent in international legal relations. The objective of this paper is twofold: firstly, it will seek to identify the contributions of socio-legal approaches to the study of international economic law; and secondly, it will explore how socio-legal scholarship can provide a methodological and theoretical framework to construct an understanding of the pluralistic nature of international economic regulatory regimes and their underlying dynamics of power. In doing so, the paper will also consider the value of juxtaposing an empirical methodology for mapping legal regimes with a critical normative approach for analysing power relations in international economic law

The MeerKAT Galaxy Cluster Legacy Survey: I. Survey overview and highlights

Please abstract in the article.The South African Radio Astronomy Observatory (SARAO), the National Research Foundation (NRF), the National Radio Astronomy Observatory, US National Science Foundation, the South African Research Chairs Initiative of the DSI/NRF, the SARAO HCD programme, the South African Research Chairs Initiative of the Department of Science and Innovation.http://www.aanda.orghj2022Physic

Early childhood teachers in Lebanon : beliefs and practices

The purpose of this study is to investigate the relationship between the beliefs and practices of Lebanese early childhood teachers and whether they differ in relation to school’s socioeconomic status, class size, grade level, extent of teachers’ educational background, their teaching experience or other situational factors. The study is comprised of 135 preschool and kindergarten teachers who responded to a questionnaire that is based on the Teachers Questionnaire devised by Charlesworth et al. (1991; 1993). Twenty – one schools representing part of the private schools in Lebanon were purposively selected based on their socioeconomic status and their regional diversity. Six participants were interviewed using semi-structured interviews with open-ended questions. Eighteen teachers were observed using the CPI inventory (Hyson et al, 1991) to compare self-reported classroom practices with actual observed practices. Factor analysis revealed seven factors related to appropriate and inappropriate self-reported beliefs and eight factors related to appropriate and inappropriate selfreported practices. Analysis of Variance (ANOVA) showed a moderate association between Lebanese early childhood teachers’ developmentally appropriate beliefs and practices (r= 0.47, p=0.001). A stronger correlation was found between teachers’ self-reported inappropriate beliefs and practices (r=0.62, p=0.001). The findings were consistent with previous studies done in the United States. When observed, teachers’ beliefs appeared more developmentally appropriate, but they follow a more developmentally inappropriate practice. Appropriate and inappropriate beliefs and practices can be predicted by certain teacher characteristics and school characteristics. Multivariate Analysis (MANOVA) revealed that teachers’ level of general education, training, age, salary, and parent’s and principal’s support were related to beliefs and practices of teachers. In addition, teachers’ beliefs and practices significantly differ depending on school’s socioeconomic status, class size, and grade level they teach in. Table summaries, interview data and classroom observation supported much of the information gathered through the questionnaire.EThOS - Electronic Theses Online ServiceGBUnited Kingdo