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1.
Cancer Chemother Pharmacol ; 88(2): 307-312, 2021 08.
Article in English | MEDLINE | ID: mdl-33944970

ABSTRACT

PURPOSE: This study aimed to provide a better understanding of the impact of paclitaxel chemotherapy on breath alcohol in an Irish population. METHODS: Patients attending the Oncology Day Unit at Beaumont Hospital were invited to participate on the day of their treatment. The brand of paclitaxel used was Actavis Pharma Inc and contained 6 mg/mL paclitaxel in 50% Ethanol/ 50% Cremophor EL. Breath alcohol concentration was measured using the AlcoSense ™ Breathalyser on three separate visits. The primary end-point was the number of patients who were above the legal threshold for drink driving in Ireland. RESULTS: In total, 50 patients were recruited. 36 (68%) were female. The most common diagnosis was breast cancer (56%). Ten (20%) patients had metastatic disease and 4 (8%) had liver metastases. The mean paclitaxel dose administered was 118 mg. The mean amount of ethanol infused was 7.7 g. 27 patients had a detectable breath alcohol level on at least one visit. The mean breath alcohol concentration was 2 mcg/100 mL or 0.02 mg/L of breath. The maximum concentration of ethanol in exhaled breath was 11 mcg/100 mL or 0.11 mg/L which is 50% of the statutory limit for drink driving in Ireland. A weak correlation was observed between ethanol concentration in exhaled breath and the total amount of ethanol administered. Although no patient exceeded the general limit for drink driving in Ireland, three (6%) participants had a breath alcohol concentration above the threshold for professional, learner or novice drivers. CONCLUSION: Although definitive conclusions are limited by relatively small numbers, it seems unlikely that weekly paclitaxel infusions pose any significant risk to patients driving.


Subject(s)
Antineoplastic Agents, Phytogenic/metabolism , Ethanol/metabolism , Paclitaxel/metabolism , Adult , Aged , Antineoplastic Agents, Phytogenic/therapeutic use , Breath Tests/methods , Female , Humans , Ireland , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/metabolism , Paclitaxel/therapeutic use , Prospective Studies
2.
Reproduction ; 149(5): 523-32, 2015 May.
Article in English | MEDLINE | ID: mdl-25713425

ABSTRACT

Abnormal trophoblast function is associated with fetal growth restriction (FGR). The JAK-STAT pathway is one of the principal signalling mechanisms by which cytokines and growth factors modulate cell proliferation, differentiation, cell migration and apoptosis. The expression of placental JAK-STAT genes in human idiopathic FGR is unknown. In this study, we propose the hypothesis that JAK-STAT pathway genes are differentially expressed in idiopathic FGR-affected pregnancies and contribute to abnormal feto-placental growth by modulating the expression of the amino acid transporter SNAT2, differentiation marker CGB/human chorionic gonadotrophin beta-subunit (ß-hCG) and apoptosis markers caspases 3 and 8, and TP53. Expression profiling of FGR-affected placentae revealed that mRNA levels of STAT3, STAT2 and STAT5B decreased by 69, 52 and 50%, respectively, compared with gestational-age-matched controls. Further validation by real-time PCR and immunoblotting confirmed significantly lower STAT3 mRNA and STAT3 protein (total and phosphorylated) levels in FGR placentae. STAT3 protein was localised to the syncytiotrophoblast (ST) in both FGR and control placentae. ST differentiation was modelled by in vitro differentiation of primary villous trophoblast cells from first-trimester and term placentae, and by treating choriocarcinoma-derived BeWo cells with forskolin in cell culture. Differentiation in these models was associated with increased STAT3 mRNA and protein levels. In BeWo cells treated with siRNA targeting STAT3, the mRNA and protein levels of CGB/ß-hCG, caspases 3 and 8, and TP53 were significantly increased, while that of SNAT2 was significantly decreased compared with the negative control siRNA. In conclusion, we report that decreased STAT3 expression in placentae may contribute to abnormal trophoblast function in idiopathic FGR-affected pregnancies.


Subject(s)
Apoptosis , Fetal Growth Retardation/pathology , Placenta/cytology , STAT3 Transcription Factor/metabolism , Trophoblasts/pathology , Adult , Blotting, Western , Case-Control Studies , Cell Differentiation , Cell Proliferation , Cells, Cultured , Cohort Studies , Female , Fetal Growth Retardation/genetics , Fetal Growth Retardation/metabolism , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Infant, Low Birth Weight , Male , Placenta/metabolism , Pregnancy , Pregnancy Trimester, First , Pregnancy Trimester, Third , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/genetics , Trophoblasts/metabolism
3.
Placenta ; 35(2): 117-24, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24331737

ABSTRACT

INTRODUCTION: Pre-eclampsia (PE) has a familial association, with daughters of women who had PE during pregnancy having more than twice the risk of developing PE themselves. Through genome-wide linkage and genetic association studies in PE-affected families and large population samples, we previously identified the following as positional candidate maternal susceptibility genes for PE; ACVR1, INHA, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2. The aims of this study were to determine mRNA expression levels of previously identified candidate maternal pre-eclampsia susceptibility genes from normotensive and severe PE (SPE) pregnancies and correlate mRNA expression levels with the clinical severity of SPE. METHODS: Third trimester decidual tissues were collected from both normotensive (n = 21) and SPE pregnancies (n = 24) and mRNA expression levels were determined by real-time PCR. Gene expression was then correlated with several parameters of clinical severity in SPE. Statistical significance was determined by Mann-Whitney U test and Spearman's Correlation. RESULTS: The data demonstrate significantly increased decidual mRNA expression levels of ACVR1, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2 in SPE (p < 0.05). Increased mRNA expression levels of several genes - INHA, INHBB, COL4A1 and COL4A2 were correlated with earlier onset of PE and earlier delivery of the fetus (p < 0.05). CONCLUSION: These results suggest altered expression of maternal susceptibility genes may play roles in PE development and the course of disease severity.


Subject(s)
Decidua/metabolism , Genetic Predisposition to Disease/genetics , Inhibin-beta Subunits/biosynthesis , Pre-Eclampsia/genetics , Pre-Eclampsia/metabolism , RNA, Messenger/metabolism , Activin Receptors, Type I/biosynthesis , Adult , Collagen Type IV/biosynthesis , Female , Humans , Inhibins/biosynthesis , Pregnancy , Pregnancy Trimester, Third
4.
Placenta ; 34(4): 299-309, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23484914

ABSTRACT

The placenta provides critical transport functions between the maternal and fetal circulations during intrauterine development. Formation of this interface is controlled by nuclear transcription factors including homeobox genes. Here we summarize current knowledge regarding the expression and function of homeobox genes in the placenta. We also describe the identification of target transcription factors including PPARγ, biological pathways regulated by homeobox genes and their role in placental development. The role of the nuclear receptor PPARγ, ligands and target genes in human placental development is also discussed. A better understanding of these pathways will improve our knowledge of placental cell biology and has the potential to reveal new molecular targets for the early detection and diagnosis of pregnancy complications including human fetal growth restriction.


Subject(s)
Genes, Homeobox/physiology , PPAR gamma/genetics , Placenta Diseases/pathology , Placenta/pathology , Placentation , Placentation/genetics , Animals , Cell Differentiation , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p57/physiology , Female , Fetal Growth Retardation/genetics , Homeodomain Proteins/physiology , Humans , Mice , Placenta Diseases/genetics , Placentation/physiology , Pregnancy , Proto-Oncogene Proteins c-jun/physiology , Proto-Oncogene Proteins c-myc/physiology , Transcription Factors/physiology , Trophoblasts/physiology
5.
Placenta ; 31(4): 347-50, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20207415

ABSTRACT

Measuring trophoblast function involves performing end-point assays that represent the response at a single time point. New technology from Roche Applied Science enables continuous monitoring of cells in real-time using specialized culture dishes containing micro-electrodes. The xCELLigence System allows continuous measurement and quantification of cell adhesion, proliferation, migration and invasion, thus creating a true picture of trophoblast function. Lag and log growth phases can be determined thus pinpointing optimal times to treat and harvest cells. Use of this system will provide valuable insights into trophoblast functions as well as the behaviour of other cell types found at the maternal-fetal interface.


Subject(s)
Cytological Techniques/methods , Electrophysiological Phenomena , Trophoblasts/physiology , Cell Adhesion , Cell Movement , Cell Proliferation , Cells, Cultured , Cytological Techniques/instrumentation , Electric Impedance , Female , Humans , Pregnancy , Trophoblasts/cytology
6.
Exp Cell Res ; 314(7): 1455-64, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18314101

ABSTRACT

In early pregnancy, fetal trophoblasts selectively invade and remodel maternal spiral arteries. A healthy pregnancy is dependent on this adaptation to allow sufficient maternal blood to reach the placenta and the developing fetus. However, little is known of the role played by trophoblasts in this adaptation process. In this study, the interactions between trophoblast cells (TC) and vascular smooth muscle cells (VSMC) were examined using novel live cell image analysis methods which allow quantitative assessment of the behaviour of these two cell types in co-culture. TC and VSMC were simultaneously tracked in co-culture and, for each cell type, directionality, speed and the cell-cell interaction were assessed. The overall migratory behaviour of TC was markedly different in the presence of VSMC with co-cultured TC migrating further with directional movement while mono-cultured TC moved more randomly. Furthermore, TC were shown to specifically target VSMC, suggesting that invading TC may initiate targeted vascular remodelling. Analysis of movement behaviour and cell-cell attraction will be useful in other co-culture systems in addition to answering important questions in the reproductive field.


Subject(s)
Cell Communication , Fetus/cytology , Imaging, Three-Dimensional , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Trophoblasts/cytology , Biomechanical Phenomena , Cell Movement , Cell Survival , Coculture Techniques , Female , Humans , Organ Specificity , Pregnancy , Reproducibility of Results , Time Factors
7.
Hum Reprod ; 22(11): 2834-41, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17905750

ABSTRACT

BACKGROUND: During pregnancy, extravillous trophoblast invades the uterine wall and enters the spiral arteries. Remodelling ensues, with loss of vascular smooth muscle cells (SMCs) to create high flow, low resistance vessels. Pregnancies complicated by pre-eclampsia are characterized by incomplete arterial remodelling. Endovascular trophoblast is not easily accessible for studies to establish the pathogenesis of pre-eclampsia, so we have developed a model appropriate to carry out mechanistic studies of vessel wall transformation. METHODS AND RESULTS: Segments of human spiral artery were perfused with the choriocarcinoma cell line, BeWo; cells invaded the vessel wall and induced apoptosis of vascular SMC. Perfusion of vessels with BeWo-conditioned medium also induced SMC apoptosis, indicating the presence of a soluble apoptotic factor. BeWo express Fas ligand (FasL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Treatment of BeWo-conditioned medium with antibodies against FasL inhibited vascular SMC apoptosis in vitro. Antibodies that blocked TRAIL receptor function had no effect. Extracellular matrix degradation is also a prerequisite for vascular remodelling; BeWo express matrix metalloproteinase-12 (MMP-12) and BeWo-conditioned medium increased MMP-12 expression in spiral artery SMC. CONCLUSIONS: BeWo induce arterial remodelling via FasL- and MMP-12-dependent mechanisms. BeWo-derived factors up-regulate protease expression in spiral artery SMC to facilitate matrix breakdown.


Subject(s)
Apoptosis , Arteries/pathology , Choriocarcinoma/pathology , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/pathology , Pre-Eclampsia/pathology , Cell Line, Tumor , Cell Proliferation , Coculture Techniques , Extracellular Matrix/metabolism , Fas Ligand Protein/biosynthesis , Female , Humans , Matrix Metalloproteinase 12/biosynthesis , Pregnancy , TNF-Related Apoptosis-Inducing Ligand/biosynthesis
8.
Metabolism ; 46(1): 41-7, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9005967

ABSTRACT

Activation of the polyol pathway under hyperglycemic conditions is proposed to contribute to the development of diabetic nephropathy. The mechanisms by which this activation may lead to functional and structural changes within the kidney are yet to be definitively established. We have examined in vitro the steps linking increased polyol pathway activity resulting from hyperglycemia to prostaglandin production. Following the demonstration of increased prostaglandin E (PGE) levels in glomeruli from diabetic rats (14.9 +/- 2.5 v 59.1 +/- 19.4 ng PGE/mg protein), a specific inhibitor of aldose reductase, HOE-843, was used in vitro to analyze the response to hyperglycemia of the steps preceding prostaglandin production. In explants of glomeruli from control animals, increasing the glucose concentration in vitro from 5.6 mmol/L to 25 mmol/L resulted in a significant increase in the flux of glucose through the pentose phosphate pathway ([PPP] 1.29 +/- 0.08 v 2.00 +/- 0.11 nmol/h), de novo diacylglycerol synthesis (2.2 +/- 0.1 v 3.1 +/- 0.2 micromol/mg protein), membrane protein kinase C (PKC) activity (18.7 +/- 0.5 v 24.3 +/- 0.75 pmol/microg protein), and in vitro phospholipase A2 (PLA2) activity (2.18 +/- 0.46 v 3.83 +/- 1.07 nmol arachidonic acid hydrolyzed/min/mg cytosolic protein). For all parameters measured, the increase resulting from the increased glucose concentration could be prevented by in vitro addition of HOE-843 for 24 hours before measurement. These findings provide evidence to suggest a mechanism linking increased polyol pathway activity and an increase in PLA2 activity to increased prostaglandin production, which is observed in diabetes of recent onset and may ultimately lead to changes associated with the development of diabetic nephropathy.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Diglycerides/metabolism , Glucose/metabolism , Phospholipases A/metabolism , Protein Kinase C/metabolism , Aldehyde Reductase/physiology , Animals , Arachidonic Acids/analysis , Arachidonic Acids/metabolism , Cell Membrane/enzymology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diglycerides/analysis , Enzyme Activation , Fluorenes/pharmacology , Glucose/analysis , Hydantoins/pharmacology , Hyperglycemia/blood , Hyperglycemia/metabolism , In Vitro Techniques , Kidney Glomerulus/chemistry , Kidney Glomerulus/enzymology , Kidney Glomerulus/metabolism , Male , Phospholipases A/analysis , Phospholipases A2 , Prostaglandins E/analysis , Prostaglandins E/metabolism , Protein Kinase C/analysis , Rats , Rats, Sprague-Dawley , Sorbitol/metabolism , Streptozocin , Time Factors
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