An empirical ethics analysis of breast cancer screening in Australia

Breast screening is controversial. Despite many supporters and a large evidence base, some experienced breast screening experts disagree with selected policies and practices. I sought to examine the reasoning of people who have influenced breast screening in Australia. I used an empirical ethics approach, combining empirical study with theoretical analysis. I interviewed Australians with expertise and influence in breast screening across a range of professional roles. I found that participants drew on values as well as evidence when talking and reasoning about breast screening. Participants expressed a range of interpretations and prioritisations for each value and experts’ disagreements were based, at least in part, on these differences. Experts did not always acknowledge the role of values in shaping their views or recognise different ways of conceptualising or prioritising values. I recommend including values in decision making for breast screening policy and practice. I provide guidance about formats for values based discussions. I conclude that values play an important but often unrecognised role in shaping breast screening policy and practice, and propose regular review of values to deliver breast screening in the most ethically sound manner

New Generation of Educators Initiative: Transforming teacher preparation.

The focus of the New Generation of Educators Initiative (NGEI) was to answer the question "What would it take to transform teacher education?" From 2016 to 2019, with support from the S. D. Bechtel, Jr. Foundation, teacher education programs at 10 California State University (CSU) campuses partnered with local school districts to design and demonstrate innovative practices that could transform teacher preparation. This report documents the learnings from multiple participants in this transformative work, including Foundation program staff and representatives from partnerships between universities and school districts

Public involvement in the governance of population-level biomedical research: unresolved questions and future directions.

Population-level biomedical research offers new opportunities to improve population health, but also raises new challenges to traditional systems of research governance and ethical oversight. Partly in response to these challenges, various models of public involvement in research are being introduced. Yet, the ways in which public involvement should meet governance challenges are not well understood. We conducted a qualitative study with 36 experts and stakeholders using the World Café method to identify key governance challenges and explore how public involvement can meet these challenges. This brief report discusses four cross-cutting themes from the study: the need to move beyond individual consent; issues in benefit and data sharing; the challenge of delineating and understanding publics; and the goal of clarifying justifications for public involvement. The report aims to provide a starting point for making sense of the relationship between public involvement and the governance of population-level biomedical research, showing connections, potential solutions and issues arising at their intersection. We suggest that, in population-level biomedical research, there is a pressing need for a shift away from conventional governance frameworks focused on the individual and towards a focus on collectives, as well as to foreground ethical issues around social justice and develop ways to address cultural diversity, value pluralism and competing stakeholder interests. There are many unresolved questions around how this shift could be realised, but these unresolved questions should form the basis for developing justificatory accounts and frameworks for suitable collective models of public involvement in population-level biomedical research governance

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14months and median OS was 7.8months. Intracranial RR was 12%, while intracranial CBR was 27%. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3%). Intrinsic subtyping revealed 19 of 21 tumors (79%) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users

Early Pregnancy Atherogenic Profile in a First Pregnancy and Hypertension Risk 2 to 7 Years After Delivery

Background: Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results: Among 4471 primiparous women, we related first-trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80 mm Hg or antihypertensive use) 2 to 7 years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6 mm Hg], glucose [5.0 versus 4.8 mmol/L], insulin [77.6 versus 60.1 pmol/L], triglycerides [1.4 versus 1.3 mmol/L], and high-sensitivity C-reactive protein [5.6 versus 4.0 nmol/L], and lower high-density lipoprotein cholesterol [1.8 versus 1.9 mmol/L]; P<0.05) than women without an APO/GDM. They were also more likely to develop hypertension after delivery (32.8% versus 18.1%, P<0.05). Accounting for confounders and factors routinely assessed antepartum, higher glucose (relative risk [RR] 1.03 [95% CI, 1.00-1.06] per 0.6 mmol/L), high-sensitivity C-reactive protein (RR, 1.06 [95% CI, 1.02-1.11] per 2-fold higher), and triglycerides (RR, 1.27 [95% CI, 1.14-1.41] per 2-fold higher) were associated with later hypertension. Higher physical activity was protective (RR, 0.93 [95% CI, 0.87-0.99] per 3 h/week). When evaluated as latent profiles, the nonobese group with higher lipids, high-sensitivity C-reactive protein, and insulin values (6.9% of the cohort) had increased risk of an APO/GDM and later hypertension. Among these factors, 7% to 15% of excess RR was related to APO/GDM. Conclusions: Individual and combined first-trimester atherogenic characteristics are associated with APO/GDM occurrence and hypertension 2 to 7 years later