Association of PET-based estradiol-challenge test for breast cancer progesterone receptors with response to endocrine therapy

Clinical estrogen receptor (ER) testing for breast cancer is limited in predicting response to endocrine therapy (ET). In this phase 2 clinical trial, authors demonstrate that the responsiveness to ET can be predicted by use of PET/CT with 21-[18F]fluorofuranylnorprogesterone (FFNP) to detect the change in tumor progesterone receptor (PgR) levels after a one-day estradiol challenge

17β-Estradiol dysregulates innate immune responses to Pseudomonas aeruginosa respiratory infection and is modulated by estrogen receptor antagonism

ABSTRACT Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of Pseudomonas aeruginosa infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to P. aeruginosa . We used wild-type and CF mice, which we hormone manipulated, inoculated with P. aeruginosa , and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to P. aeruginosa . We found that female mice inoculated with P. aeruginosa died earlier and showed slower bacterial clearance than males ( P &lt; 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to P. aeruginosa challenge earlier than progesterone- or vehicle-supplemented mice ( P = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased P. aeruginosa killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with P. aeruginosa and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to P. aeruginosa . ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy. </jats:p

Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands

Estrogens play a crucial role in the development and function of female reproductive tissues. They have positive effects on the maintenance of bone mineral density, on the liver, and on the cardiovascular and central nervous systems. Selective Estrogen Receptor Modulators (SERMs) are particularly attractive as therapeutic agents because they are able to block estrogen action at those sites where stimulation would be undesirable, such as the breast and uterus, but at the same time stimulate estrogen actions in other tissues where they are desired, such as the bone and liver. Most synthetic estrogen receptor ligands possess a phenolic ring, mimicking the phenolic "Aring" of the natural ligand estradiol. In an attempt to increase the structural diversity of estrogen receptor (ER) ligands, we designed and synthesized molecules containing unprecedented replacements of the prototypical phenolic "A-ring" of estrogens with an oxime and a hydroxy- (salicylaldoximes) or aminomoieties (anthranylaldoximes), forming intramolecularly H-bonded pseudocycles. These new classes of compounds showed interesting ER binding properties on both receptor subtypes (ERα and ERβ). These results proved that the six-membered ring formed by an intramolecular hydrogen bond, and containing an exocyclic oxime OH, is an effective stereoelectronic replacement of the phenolic ring of typical ER ligands

A case control study of breast cancer risk and exposure to injectable progestogen contraceptives

No Abstract

Standardization of epidemiological surveillance of acute rheumatic fever

Acute rheumatic fever (ARF) is a multiorgan inflammatory disorder that results from the body’s autoimmune response to pharyngitis or a skin infection caused by Streptococcus pyogenes (Strep A). Acute rheumatic fever mainly affects those in low- and middle-income nations, as well as in indigenous populations in wealthy nations, where initial Strep A infections may go undetected. A single episode of ARF puts a person at increased risk of developing long-term cardiac damage known as rheumatic heart disease. We present case definitions for both definite and possible ARF, including initial and recurrent episodes, according to the 2015 Jones Criteria, and we discuss current tests available to aid in the diagnosis. We outline the considerations specific to ARF surveillance methodology, including discussion on where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare, administrative database review), participant eligibility, and the surveillance population. Additional considerations for ARF surveillance, including implications for secondary prophylaxis and follow-up, ARF registers, community engagement, and the impact of surveillance, are addressed. Finally, the core elements of case report forms for ARF, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed

Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor

Recent studies have identified a series of estrogen receptor (ER)interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER alpha-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-angstrom crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the beta-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences. In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER alpha, particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity

Mortality after admission for acute myocardial infarction in Aboriginal and non-Aboriginal people in New South Wales, Australia: a multilevel data linkage study

Background - Heart disease is a leading cause of the gap in burden of disease between Aboriginal and non-Aboriginal Australians. Our study investigated short- and long-term mortality after admission for Aboriginal and non-Aboriginal people admitted with acute myocardial infarction (AMI) to public hospitals in New South Wales, Australia, and examined the impact of the hospital of admission on outcomes. Methods - Admission records were linked to mortality records for 60047 patients aged 25–84 years admitted with a diagnosis of AMI between July 2001 and December 2008. Multilevel logistic regression was used to estimate adjusted odds ratios (AOR) for 30- and 365-day all-cause mortality. Results - Aboriginal patients admitted with an AMI were younger than non-Aboriginal patients, and more likely to be admitted to lower volume, remote hospitals without on-site angiography. Adjusting for age, sex, year and hospital, Aboriginal patients had a similar 30-day mortality risk to non-Aboriginal patients (AOR: 1.07; 95% CI 0.83-1.37) but a higher risk of dying within 365 days (AOR: 1.34; 95% CI 1.10-1.63). The latter difference did not persist after adjustment for comorbid conditions (AOR: 1.12; 95% CI 0.91-1.38). Patients admitted to more remote hospitals, those with lower patient volume and those without on-site angiography had increased risk of short and long-term mortality regardless of Aboriginal status. Conclusions - Improving access to larger hospitals and those with specialist cardiac facilities could improve outcomes following AMI for all patients. However, major efforts to boost primary and secondary prevention of AMI are required to reduce the mortality gap between Aboriginal and non-Aboriginal people