HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Vidding and the perversity of critical pleasure: Sex, violence, and voyeurism in "Closer" and "On the Prowl"

Analysis of two fan vids ("Closer" by Killa and T. Jonesy, and "On the Prowl" by Sisabet and Sweetestdrain) in the context of theories of vidding reveals that vids have a unique ability to combine analytic detachment and pleasurable investment. I analyze these two vids through Roland Barthes's provocative suggestion that reading criticism demands from the reader a perverse voyeurism of the critic's pleasure in the text to argue that they are examples of the ways in which many vids function as pleasurable criticism that invites viewers of such vids to enter voyeuristically into that pleasure. Both vids use tropes of sexual violence to characterize not only the mass media they respond to, but also the nature of fandom and of transformative fan readings. "On the Prowl" criticizes and celebrates the fan through constructing different audiences for a series of self-portraits; "Closer" does the same thing by constructing Spock as a portrait of the fan. The narratives of sadism and rape constructed by the vids both disturb and seduce the viewer, thus forming perverse texts that that problematize pleasure while simultaneously reinscribing it

Me thoughts I heard one calling, talking to God in the poetry of John Donne, George Herbert, Christina Rossetti, and Gerard Manley Hopkins

grantor: University of TorontoThis study approaches the religious poetry of John Donne, George Herbert, Christina Rossetti, and Gerard Manley Hopkins from the viewpoint of an atheist or agnostic reader who believes that when these poets speak to God they are really speaking to themselves. I draw on the theories of Ludwig Feuerbach and Julia Kristeva to examine the dialogue of the subject with itself in the form of a poem constructed as a prayer. I concentrate on two central aspects of religious poetry: the construction of the self, and the nature of poetry. Chapter One contextualizes Feuerbach's idea that God is humanity's externalization of itself within the history of Christian theology, showing that the four poets differ in the degree to which they regard God as "human" and therefore close to the self, or "Other" and therefore distant and terrifying. The more "human" the poet's God is, the more likely it is that the poet will inscribe God's speech and reactions into his or her poem. Chapter Two tackles the formal qualities of the poetry, drawing specifically on Kristeva's categories of the symbolic and the semiotic, in an attempt to characterize rhyme, rhythm, alliteration, paradox, puns, and so on as one or the other. It concludes that secular theory cannot exhaust, but can partly illuminate, the meaning of religious poetry. The third chapter approaches the poetry by means of the theological distinction between 'agape'-love and 'eros'-love, and Kristeva's distinction between idealistic and narcissistic love. I attempt to demonstrate both the different ways in which the poets express both love and hate towards God, and the way the poets unconsciously use God as a means by which they can achieve self-love, or express self-hate. The first three chapters concentrate on ways to read the poets against themselves; the fourth and final chapter returns to the poets' own intentions in examining their attitudes towards the compatibility or otherwise of poetry and religion. It situates Kristeva's argument, that poetry is always subversive of religion, within the large body of criticism which argues for the close relation of poetry and religion.Ph.D

Marvellous Codes: The Fiction of Margaret Mahy

When I was about eight years old, Margaret Mahy gave a reading of her book 'The Wind Between the Stars' in the library of my Dunedin primary school. I remember being slightly disconcerted by that reading: perhaps, at that time, my idea of an author was of someone in tweeds and twinset, instead of a rainbow-coloured fright wig. I was certainly unsettled by the book, in which the wind was far wilder and more unruly than I wished to imagine. Unsettlement gave way to exhilaration when, aged fourteen, I bought 'The Changeover', recently published in hardback. It was one of the first books I had bought with my own money; I was drawn to it because I had read others of Mahy's books, because it was widely celebrated, and because it was such a beautifully produced object: not only was the cover designed by Bruce Hogarth tantalising, but its pages were a smooth, gleaming white, and were bound firmly into its dark cover. I remember sniffing the pages, seduced by the whiff of printer's ink, before reading it

Different factors limit early- and late-season windows of opportunity for monarch development.

Seasonal windows of opportunity are intervals within a year that provide improved prospects for growth, survival, or reproduction. However, few studies have sufficient temporal resolution to examine how multiple factors combine to constrain the seasonal timing and extent of developmental opportunities. Here, we document seasonal changes in milkweed (Asclepias fascicularis)-monarch (Danaus plexippus) interactions with high resolution throughout the last three breeding seasons prior to a precipitous single-year decline in the western monarch population. Our results show early- and late-season windows of opportunity for monarch recruitment that were constrained by different combinations of factors. Early-season windows of opportunity were characterized by high egg densities and low survival on a select subset of host plants, consistent with the hypothesis that early-spring migrant female monarchs select earlier-emerging plants to balance a seasonal trade-off between increasing host plant quantity and decreasing host plant quality. Late-season windows of opportunity were coincident with the initiation of host plant senescence, and caterpillar success was negatively correlated with heatwave exposure, consistent with the hypothesis that late-season windows were constrained by plant defense traits and thermal stress. Throughout this study, climatic and microclimatic variations played a foundational role in the timing and success of monarch developmental windows by affecting bottom-up, top-down, and abiotic limitations. More exposed microclimates were associated with higher developmental success during cooler conditions, and more shaded microclimates were associated with higher developmental success during warmer conditions, suggesting that habitat heterogeneity could buffer the effects of climatic variation. Together, these findings show an important dimension of seasonal change in milkweed-monarch interactions and illustrate how different biotic and abiotic factors can limit the developmental success of monarchs across the breeding season. These results also suggest the potential for seasonal sequences of favorable or unfavorable conditions across the breeding range to strongly affect monarch population dynamics

Different factors limit early‐ and late‐season windows of opportunity for monarch development

Abstract Seasonal windows of opportunity are intervals within a year that provide improved prospects for growth, survival, or reproduction. However, few studies have sufficient temporal resolution to examine how multiple factors combine to constrain the seasonal timing and extent of developmental opportunities. Here, we document seasonal changes in milkweed (Asclepias fascicularis)–monarch (Danaus plexippus) interactions with high resolution throughout the last three breeding seasons prior to a precipitous single‐year decline in the western monarch population. Our results show early‐ and late‐season windows of opportunity for monarch recruitment that were constrained by different combinations of factors. Early‐season windows of opportunity were characterized by high egg densities and low survival on a select subset of host plants, consistent with the hypothesis that early‐spring migrant female monarchs select earlier‐emerging plants to balance a seasonal trade‐off between increasing host plant quantity and decreasing host plant quality. Late‐season windows of opportunity were coincident with the initiation of host plant senescence, and caterpillar success was negatively correlated with heatwave exposure, consistent with the hypothesis that late‐season windows were constrained by plant defense traits and thermal stress. Throughout this study, climatic and microclimatic variations played a foundational role in the timing and success of monarch developmental windows by affecting bottom‐up, top‐down, and abiotic limitations. More exposed microclimates were associated with higher developmental success during cooler conditions, and more shaded microclimates were associated with higher developmental success during warmer conditions, suggesting that habitat heterogeneity could buffer the effects of climatic variation. Together, these findings show an important dimension of seasonal change in milkweed–monarch interactions and illustrate how different biotic and abiotic factors can limit the developmental success of monarchs across the breeding season. These results also suggest the potential for seasonal sequences of favorable or unfavorable conditions across the breeding range to strongly affect monarch population dynamics

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc