Probing the link between oestrogen receptors and oesophageal cancer

<p>Abstract</p> <p>Background</p> <p>Human oesophageal carcinoma is considered to be one of the most aggressive malignancies and has a very poor prognosis. The incidence of oesophageal cancer shows a gender bias and is higher in males compared with females, the ratio between males and females varying from 3:1 to 7:1. This sex ratio is not entirely attributable to differences in the prevalence of known risk factors between the sexes. The potential role of oestrogen receptors (ER) in oesophageal cancer has been debated for several years but the significance of the receptors in this cancer remains unknown. Most of the work has been based on immunohistochemistry and has not been validated with other available techniques. The inconsistencies in the published literature on the link between ER expression and oesophageal cancer warrant a thorough evaluation of the potential role of ERs in this malignancy. Even the expression of the two ER isoforms, ERα and ERβ, and its implications for outcome of treatments in histological subtypes of oesophageal tumours is ill defined. The aim of this article is to provide updated information from the available literature on the current status of ER expression in oesophageal cancer and to discuss its potential therapeutic role.</p> <p>Methods and Results</p> <p>We performed a comprehensive literature search and analysed the results regarding ER expression in oesophageal tumours with special emphasis on expression of different oestrogen receptors and the role of sex hormones in oesophageal cancer. This article also focuses on the significance of the two main ER subtypes and mechanisms underlying the presumed male predominance of this disease.</p> <p>Conclusion</p> <p>We postulate that differential oestrogen receptor status may be considered a biomarker of poor clinical outcome based on tissue dedifferentiation or advanced stage of the disease. Further, if we can establish the importance of oestrogen and its receptors in the context of oesophageal cancer, then this may lead to a new future direction in the management of this malignancy.</p

Pharmacological profile of vascular activity of human stem villous arteries

© 2019 Introduction: The function of the placental vasculature differs considerably from other systemic vascular beds of the human body. A detailed understanding of the normal placental vascular physiology is the foundation to understand perturbed conditions potentially leading to placental dysfunction. Methods: Behaviour of human stem villous arteries isolated from placentae at term pregnancy was assessed using wire myography. Effects of a selection of known vasoconstrictors and vasodilators of the systemic vasculature were assessed. The morphology of stem villous arteries was examined using IHC and TEM. Results: Contractile effects in stem villous arteries were caused by U46619, 5-HT, angiotensin II and endothelin-1 (p ≤ 0.05), whereas noradrenaline and AVP failed to result in a contraction. Dilating effects were seen for histamine, riluzole, nifedipine, papaverine, SNP and SQ29548 (p ≤ 0.05) but not for acetylcholine, bradykinin and substance P. Discussion: Stem villous arteries behave differently to vessels of the systemic vasculature and results indicate that the placenta is cut off from the systemic maternal vascular regulation. Particularly, endothelium-dependent processes were attenuated in the placental vasculature, creating a need to determine the role of the endothelium in the placenta in future studies

Evaluation of extraction and normalisation strategies for the analysis of lipids in placental vessels

The analysis of lipids in tough or fibrous biological tissues can be challenging due to difficulties in obtaining a representative sample following homogenisation of the tissue. Furthermore, the choice of normalisation method can have a major effect on the quality of quantitative results. Therefore, a range of mechanical homogenisation techniques and normalisation strategies were evaluated for application to human placental vessels. The findings showed that rotor-stator homogenisation in a suitable solvent and wet weight normalisation were the best combination of procedures for quantitative analysis of lipids in placental blood vessels

Untargeted analysis of plasma samples from pre-eclamptic women reveals polar and apolar changes in the metabolome

IntroductionPre-eclampsia is a hypertensive gestational disorder that affects approximately 5% of all pregnancies.ObjectivesAs the pathophysiological processes of pre-eclampsia are still uncertain, the present case–control study explored underlying metabolic processes characterising this disease.MethodsMaternal peripheral plasma samples were collected from pre-eclamptic (n = 32) and healthy pregnant women (n = 35) in the third trimester. After extraction, high-resolution mass spectrometry-based untargeted metabolomics was used to profile polar and apolar metabolites and the resulting data were analysed via uni- and multivariate statistical approaches.ResultsThe study demonstrated that the metabolome undergoes substantial changes in pre-eclamptic women. Amongst the most discriminative metabolites were hydroxyhexacosanoic acid, diacylglycerols, glycerophosphoinositols, nicotinamide adenine dinucleotide metabolites, bile acids and products of amino acid metabolism.ConclusionsThe putatively identified compounds provide sources for novel hypotheses to help understanding of the underlying biochemical pathology of pre-eclampsia

On the Role of the Difference in Surface Tensions Involved in the Allosteric Regulation of NHE-1 Induced by Low to Mild Osmotic Pressure, Membrane Tension and Lipid Asymmetry

The sodium-proton exchanger 1 (NHE-1) is a membrane transporter that exchanges Na+ for H+ ion across the membrane of eukaryotic cells. It is cooperatively activated by intracellular protons, and this allosteric regulation is modulated by the biophysical properties of the plasma membrane and related lipid environment. Consequently, NHE-1 is a mechanosensitive transporter that responds to osmotic pressure, and changes in membrane composition. The purpose of this study was to develop the relationship between membrane surface tension, and the allosteric balance of a mechanosensitive transporter such as NHE-1. In eukaryotes, the asymmetric composition of membrane leaflets results in a difference in surface tensions that is involved in the creation of a reservoir of intracellular vesicles and membrane buds contributing to buffer mechanical constraints. Therefore, we took this phenomenon into account in this study and developed a set of relations between the mean surface tension, membrane asymmetry, fluid phase endocytosis and the allosteric equilibrium constant of the transporter. We then used the experimental data published on the effects of osmotic pressure and membrane modification on the NHE-1 allosteric constant to fit these equations. We show here that NHE-1 mechanosensitivity is more based on its high sensitivity towards the asymmetry between the bilayer leaflets compared to mean global membrane tension. This compliance to membrane asymmetry is physiologically relevant as with their slower transport rates than ion channels, transporters cannot respond as high pressure-high conductance fast-gating emergency valves

Caspase-1-mediated Cytokine Release from Gestational Tissues, Placental and Cord Blood

Distinguishing between fetal and maternal inflammatory responses is necessary for understanding the immune interplay either side of the placenta. Fetal immunity reaches maturity during extrauterine life and while basic inflammatory responses afford a certain degree of protection in utero fetuses are vulnerable to infection. With the discovery of inflammasomes – intracellular scaffolds that facilitate the elaboration of reactions resulting in the release of mature interleukin-1 IL-1 - it is necessary to consider how are inflammatory stimuli are processed. The purinergic P2X7 receptor located on haematopoietic cells is a key intermediary in signal transduction initiated at Toll-like receptors (TLR) terminating in release of the mature IL-1 product. We demonstrate herein that IL-1 release from fetal membranes and mononuclear cells isolated from cord, placental and maternal blood, obtained at term, is P2X7- and caspase-1 dependent. The P2X7-dependent release of the cytokine, which was highest from choriodecidua, was attenuated by progesterone (P4), prolactin and an NFkB inhibitor. The NLRP3 inflammasome appears necessary for the processing of IL-1 in gestational tissues and leukocytes

The effect of pH and ion channel modulators on human placental arteries.

Chorionic plate arteries (CPA) are located at the maternofetal interface where they are able to respond to local metabolic changes. Unlike many other types of vasculature, the placenta lacks nervous control and requires autoregulation for controlling blood flow. The placental circulation, which is of low-resistance, may become hypoxic easily leading to fetal acidosis and fetal distress however the role of the ion channels in these circumstances is not well-understood. Active potassium channel conductances that are subject to local physicochemical modulation may serve as pathways through which such signals are transduced. The aim of this study was to investigate the modulation of CPA by pH and the channels implicated in these responses using wire myography. CPA were isolated from healthy placentae and pre-contracted with U46619 before testing the effects of extracellular pH using 1 M lactic acid over the pH range 7.4-6.4 in the presence of a variety of ion channel modulators. A change from pH 7.4 to 7.2 produced a 29±3% (n = 9) relaxation of CPA which increased to 61±4% at the lowest pH of 6.4. In vessels isolated from placentae of women with pre-eclampsia (n = 6), pH responses were attenuated. L-methionine increased the relaxation to 67±7% (n = 6; p<0.001) at pH 6.4. Similarly the TASK 1/3 blocker zinc chloride (1 mM) gave a maximum relaxation of 72±5% (n = 8; p<0.01) which compared with the relaxation produced by the TREK-1 opener riluzole (75±5%; n = 6). Several other modulators induced no significant changes in vascular responses. Our study confirmed expression of several ion channel subtypes in CPA with our results indicating that extracellular pH within the physiological range has an important role in controlling vasodilatation in the human term placenta

Congenital vaginal obstructions: Varied presentation and outcome

Congenital obstructing lesions of vagina, hydrometrocolpos, and hematocolpos, present at a variable time during early childhood and adolescence to different medical and surgical specialties. Twenty-six cases presenting over an 18-years period (1987–2005) were divided into three groups; Group A: neonates (6), Group B: adolescents (18), and Group C: adults (2). Common presentations in neonates (Group A) were abdominal mass (5), neonatal sepsis (3), and respiratory distress (2); whereas abdominal pain (18), voiding dysfunctions (13), and backache (7) were prevalent in adolescents (Group B). Adults (Group C) presented with inability to consummate and infertility (2). Four patients received erroneous treatment; exploratory laparotomy (1) and appendectomy (3). Urinary symptoms and associated urinary abnormalities were present in more than 50% of cases, especially those with complex anomalies. Management included excision of imperforate hymen (16) and transverse vaginal septum (8) through perineal (20) and abdominoperineal approach (4). Patients with urogenital sinus (1) and cloacal malformation (1) had staged reconstruction at 2.5 years of age following preliminary vesicostomy and colostomy at birth. On follow up (range 1–15 years; mean 7) more than 60% patients have menstrual irregularity (11), endometriosis (5), and infertility (4). In conclusion, rarity and variable presentation of congenital vaginal obstructions can lead to delayed diagnosis and erroneous management. A high index of suspicion and cross-sectional imaging help in early diagnosis and associated renal anomalies. A comprehensive management is imperative to preserve the reproductive potentials, as significant proportion of patients may experience sexual difficulties, menstrual irregularity, and infertility