ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

PMCID: PMC3446380This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A Social Capital Approach to Understanding Community Resilience during the Covid-19 Pandemic

As the world begins to take stock of the impact of Covid-19, this paper provides a critical review of the role of mutual aid groups in the UK community response. Drawing on inter-views with community members and selective case studies, this position paper considers what forms of social capital impact on availability of mutual aid support in the community response to Covid-19. Based on our own experiences and Covid-19 specific research, we found that communities with social capital have been among the most organised in providing formal mutual aid, and sometimes this has extended to supporting the more marginalised and disadvantaged communities. The phenomenon of collective resilience in the pandemic, and in particular the activities of mutual aid groups as described in this paper, testify to the relevance of key concepts in social and community psychology. Without psychological ‘groupness’ there would be no adaptive community response. Further research is needed to better understand the role that social capital played in both the individual and community resilience of those offering and receiving mutual aid. This is of particular importance, given that communities lacking social capital are more vulnerable to social exclusion, in a global context where societal inequalities are widening. Whilst appreciating the limitations of social capital (particularly that it does not explain the new group relationships and forms of solidarity that have emerged), we argue that developing social capital, particularly bridging and linking social capital, can help to build community resilience and promote inclusions in communities bearing the collective economic and societal burden of the pandemic

ESR1 Is Co-Expressed with Closely Adjacent Uncharacterised Genes Spanning a Breast Cancer Susceptibility Locus at 6q25.1

Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1×10−7). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co-activation is not directly mediated by ERα. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences on the recently identified relationship between SNPs in this region and breast cancer risk

Molecular response to aromatase inhibitor treatment in primary breast cancer

BackgroundAromatase inhibitors such as anastrozole and letrozole are highly effective suppressants of estrogen synthesis in postmenopausal women and are the most effective endocrine treatments for hormone receptor positive breast cancer in such women. Little is known of the molecular effects of these agents on human breast carcinomas in vivo.MethodsWe randomly assigned primary estrogen receptor positive breast cancer patients to treatment with anastrozole or letrozole for 2 weeks before surgery. Expression profiling using cDNA arrays was conducted on pretreatment and post-treatment biopsies. Sample pairs from 34 patients provided sufficient RNA for analysis.ResultsProfound changes in gene expression were seen with both aromatase inhibitors, including many classical estrogen-dependent genes such as TFF1, CCND1, PDZK1 and AGR2, but also many other genes that are likely to represent secondary responses; decrease in the expression of proliferation-related genes were particularly prominent. Many upregulated genes are involved in extracellular matrix remodelling, including collagens and members of the small leucine-rich proteoglycan family (LUM, DCN, and ASPN). No significant differences were seen between letrozole and anastrozole in terms of molecular effects. The gene changes were integrated into a Global Index of Dependence on Estrogen (GIDE), which enumerates the genes changing by at least twofold with therapy. The GIDE varied markedly between tumours and related significantly to pretreatment levels of HER2 and changes in immunohistochemically detected Ki67.ConclusionOur findings identify the transcriptional signatures associated with aromatase inhibitor treatment of primary breast tumours. Larger datasets using this approach should enable identification of estrogen-dependent molecular changes, which are the determinants of benefit or resistance to endocrine therapy

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

'I was worried coming in because I don't really know why it was arranged': the subjective experience of new patients and their primary caregivers attending a memory clinic

Whilst in the Western world, memory clinics are fast becoming an evolving feature of the Geriatric Service landscape, little is known from a user's perspective about the expectations and experiences of people with memory problems referred to a memory clinic for the first time and about the attitudes and concerns of their family caregivers. This article reports quantitative and qualitative data emerging from a study of 28 patients with dementia and their family caregivers who attended a first appointment at a National Memory Clinic in Ireland. Data show that despite initially feeling unnerved by the clinic appointment, immediately afterwards the majority of patients felt content with the assessment process, were satisfied with the explanations and information received, felt the appointment had benefited them and by the end of the visit felt more positive than negative about their experience. A large number of patients who responded to a question about feedback, requested that this information be given to them in writing as well as orally. Some recommendations are made about small procedural changes which can be made to help to demystify the memory clinic experience

Drill core from seismically active sandstone gas reservoir yields clues to internal deformation mechanisms

Europe’s largest gas field, the Groningen field (the Netherlands), is widely known for induced subsidence and seismicity caused by gas pressure depletion and associated compaction of the sandstone reservoir. Whether compaction is elastic or partly inelastic, as implied by recent experiments, is a key factor in forecasting system behavior and seismic hazard. We sought evidence for inelastic deformation through comparative microstructural analysis of unique drill core recovered from the seismogenic center of the field in 2015, 50 yr after gas production started, versus core recovered before production (1965). Quartz grain fracturing, crack healing, and stress-induced Dauphiné twinning are equally developed in the 2015 and 1965 cores, with the only measurable effect of gas production being enhanced microcracking of sparse K-feldspar grains in the 2015 core. Interpreting these grains as strain markers, we suggest that reservoir compaction involves elastic strain plus inelastic compression of weak clay films within grain contacts