ORCID Profile
0000-0002-8431-5338
Current Organisation
University of Adelaide
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Plant Developmental and Reproductive Biology | Horticultural Production | Horticultural Crop Growth and Development
Publisher: Public Library of Science (PLoS)
Date: 10-03-2009
Publisher: MDPI AG
Date: 16-07-2019
DOI: 10.3390/NU11071609
Abstract: Trace elements such as zinc, copper, and selenium are essential for reproductive health, but there is limited work examining how circulating trace elements may associate with fertility in humans. The aim of this study was to determine the association between maternal plasma concentrations of zinc, copper, and selenium, and time to pregnancy and subfertility. Australian women (n = 1060) who participated in the multi-centre prospective Screening for Pregnancy Endpoints study were included. Maternal plasma concentrations of copper, zinc and selenium were assessed at 15 ± 1 weeks’ gestation. Estimates of retrospectively reported time to pregnancy were documented as number of months to conceive subfertility was defined as taking more than 12 months to conceive. A range of maternal and paternal adjustments were included. Women who had lower zinc (time ratio, 1.20 (0.99–1.44)) or who had lower selenium concentrations (1.19 (1.01–1.40)) had a longer time to pregnancy, equivalent to a median difference in time to pregnancy of around 0.6 months. Women with low selenium concentrations were also at a 1.46 (1.06–2.03) greater relative risk for subfertility compared to women with higher selenium concentrations. There were no associations between copper and time to pregnancy or subfertility. Lower selenium and zinc trace element concentrations, which likely reflect lower dietary intakes, associate with a longer time to pregnancy. Further research supporting our work is required, which may inform recommendations to increase maternal trace element intake in women planning a pregnancy.
Publisher: Public Library of Science (PLoS)
Date: 05-12-2012
Publisher: Springer Science and Business Media LLC
Date: 29-07-2020
Publisher: MDPI AG
Date: 28-02-2021
DOI: 10.3390/NU13030800
Abstract: Imbalanced maternal micronutrient status, poor placentation, and oxidative stress are associated with greater risk of pregnancy complications, which impact mother and offspring health. As selenium, iodine, and copper are essential micronutrients with key roles in antioxidant systems, this study investigated their potential protective effects on placenta against oxidative stress. First trimester human placenta explants were treated with different concentrations of selenium (sodium selenite), iodine (potassium iodide), their combination or copper (copper (II) sulfate). The concentrations represented deficient, physiological, or super physiological levels. Oxidative stress was induced by menadione or antimycin. Placenta explants were collected, fixed, processed, and embedded for laser ablation inductively coupled plasma-mass spectrometry (LA ICP-MS) element imaging or immunohistochemical labelling. LA ICP-MS showed that placenta could uptake selenium and copper from the media. Sodium selenite and potassium iodide reduced DNA damage and apoptosis (p 0.05). Following oxidative stress induction, a higher concentration of sodium selenite (1.6 µM) was needed to reduce DNA damage and apoptosis while both concentrations of potassium iodide (0.5 and 1 µM) were protective (p 0.05). A high concentration of copper (40 µM) increased apoptosis and DNA damage but this effect was no longer significant after induction of oxidative stress. Micronutrients supplementation can increase their content within the placenta and an optimal maternal micronutrient level is essential for placenta health.
Publisher: Oxford University Press (OUP)
Date: 22-03-2014
DOI: 10.1093/BIOINFORMATICS/BTU161
Abstract: Summary: High-throughput gene expression microarrays are currently the most efficient method for transcriptome-wide expression analyses. Consequently, gene expression data available through public repositories have largely been obtained from microarray experiments. However, the metadata associated with many publicly available expression microarray datasets often lacks s le sex information, therefore limiting the reuse of these data in new analyses or larger meta-analyses where the effect of sex is to be considered. Here, we present the massiR package , which provides a method for researchers to predict the sex of s les in microarray datasets. Using information from microarray probes representing Y chromosome genes, this package implements unsupervised clustering methods to classify s les into male and female groups, providing an efficient way to identify or confirm the sex of s les in mammalian microarray datasets. Availability and implementation: massiR is implemented as a Bioconductor package in R . The package and the vignette can be downloaded at bioconductor.org and are provided under a GPL-2 license. Contact: sam.buckberry@adelaide.edu.au Supplementary information: Supplementary data are available at Bioinformatics online
Publisher: Springer Science and Business Media LLC
Date: 09-11-2017
DOI: 10.1038/S41598-017-15085-2
Abstract: Zinc is an essential micronutrient in pregnancy and zinc deficiency impairs fetal growth. We used a mouse model of moderate zinc deficiency to investigate the physiological mechanisms by which zinc is important to placental morphogenesis and the maternal blood pressure changes during pregnancy. A 26% reduction in circulating zinc (P = 0.005) was exhibited in mice fed a moderately zinc-deficient diet. Zinc deficiency in pregnancy resulted in an 8% reduction in both near term fetal and placental weights (both P 0.0001) indicative of disrupted placental development and function. Detailed morphological analysis confirmed changes to the placental labyrinth microstructure. Continuous monitoring of maternal mean arterial pressure (MAP) revealed a late gestation decrease in the zinc-deficient dams. Differential expression of a number of regulatory genes within maternal kidneys supported observations on MAP changes in gestation. Increased MAP late in gestation is required to maintain perfusion of multiple placentas within rodent pregnancies. Decreased MAP within the zinc-deficient dams implies reduced blood flow and nutrient delivery to the placenta. These findings show that adequate zinc status is required for correct placental morphogenesis and appropriate maternal blood pressure adaptations to pregnancy. We conclude that insufficient maternal zinc intake from before and during pregnancy is likely to impact in utero programming of offspring growth and development largely through effects to the placenta and maternal cardiovascular system.
Publisher: Elsevier BV
Date: 10-2011
Publisher: Oxford University Press (OUP)
Date: 02-2000
Abstract: The role of BRCA1 in sporadic breast and ovarian cancers remains elusive. Direct involvement of BRCA1 in the development of breast and ovarian cancer is suggested by the finding that the BRCA1 promoter region CpG island is methylated in a proportion of breast and ovarian cancers. The aim of this study was to compare the incidence of BRCA1 promoter region methylation in tumours in which loss of BRCA1 has been shown to play a role in pathogenesis (breast and ovarian carcinomas) with the incidence in tumours in which BRCA1 is unlikely to play a role in pathogenesis. Promoter region hypermethylation was significantly more common (P < 0.008) in breast and ovarian cancer (6/38 tumours methylated) than in colon cancer (0/35 tumours methylated) or in leukaemias (0/19 s les methylated). The restriction of BRCA1 promoter region hypermethylation to breast and ovarian cancer is consistent with a pathogenetic role of BRCA1 promoter methylation in these tumours. We suggest that the rarity of observed BRCA1 mutations in sporadic breast and ovarian cancer is due to the greater likelihood of BRCA1 inactivation by non-mutational mechanisms such as methylation.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2021
Publisher: Wiley
Date: 24-01-2012
DOI: 10.1002/IJC.26414
Abstract: Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes, ID4, NR2F1 and PTGDS, which were expressed at consistently lower levels in clinical prostate cancer compared to nonmalignant tissues, formed a signature that predicted biochemical relapse (hazard ratio 2.2, p = 0.038). We believe that our findings support the value of this novel mouse model of prostate cancer to identify candidate therapeutic targets and/or biomarkers of human disease.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2010
DOI: 10.1158/1055-9965.EPI-10-0555
Abstract: Background: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. Methods: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. Results: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P & 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P & 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. Conclusions: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting in idual patient response to epigenetic therapies. Cancer Epidemiol Biomarkers Prev 19(10) 2611–22. ©2010 AACR.
Publisher: Oxford University Press (OUP)
Date: 23-09-2021
Abstract: Many studies assert a negative influence of inappropriate maternal diet and nutritional status during pregnancy on offspring, not only in utero but throughout life, because of the role in the programing of noncommunicable diseases. Telomere length is a biomarker of aging, and shorter telomeres are associated with chronic disease later in life. Maternal nutrition and nutritional status may be an important determinant of offspring telomere length. A systematic review was conducted to determine the effect of maternal nutrition and nutritional status in pregnancy on offspring telomere length. This systematic review was conducted according to PRISMA guidelines. Database searches of PubMed, CINAHL, Scopus, Medline, and Web of Science were performed. Included studies assessed the association between maternal nutrition (dietary intake and nutritional status) during pregnancy and offspring telomere length measured in cord blood, serum, plasma, and peripheral blood mononuclear cells. Three authors screened and determined the quality of the articles disagreements were resolved by a fourth author. All authors compared the compiled data. Seven studies were extracted and evaluated. Studies comprised a double-blind placebo-controlled trial (n = 1), prospective cohort studies (n = 5), and a cross-sectional study (n = 1). Higher circulating maternal folate and 25-hydroxyvitamin D3 concentrations, along with higher maternal dietary caffeine intakes, were associated with longer offspring telomere length, whereas higher dietary intake of carbohydrate, folate, n-3 polyunsaturated fatty acids, vitamin C, or sodium was not. The limited but suggestive evidence highlights the need for further research to be conducted in this area, particularly longitudinal studies involving larger cohorts of pregnant women. PROSPERO registration no. CRD42019136506
Publisher: Cambridge University Press (CUP)
Date: 19-02-2020
DOI: 10.1017/S2040174420000094
Abstract: Preecl sia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. In iduals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero . The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preecl tic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.
Publisher: American Society of Hematology
Date: 06-2001
DOI: 10.1182/BLOOD.V97.11.3633
Abstract: Loss of A, B, and H antigens from the surface of red blood cells has been a recurrent observation in patients with hematologic malignancy, particularly those malignancies in which the myeloid lineage is involved. To better understand this phenomenon, a 2-color flow cytometric method was developed to determine quantitative and qualitative alterations of A, B, and H antigens in patients with myeloid malignancies. Characteristic patterns, dependent on the genotype, were seen for healthy in iduals from each of the blood groups. Fifty-five percent (16/29) of patients of blood group A, B, or AB had a proportion of red cells with decreased expression of A or B antigens compared with no changes in 127 healthy A, B, and AB in iduals. In most cases, the changes were not detected by routine serologic typing. The loss of A or B antigens was the primary change in 28% (8/29) of patients. In 17% (5/29) of patients, loss of A or B antigens was an indirect consequence of loss of the precursor H antigen. Alterations involving both the H and the A or B antigens were seen in 10% (3/29) of patients. Loss of H was also detected in 21% (6/28) of group O patients whereas none of 51 healthy O in iduals showed changes. Alterations of ABO antigens can now be considered a common event in myeloid malignancy.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Springer US
Date: 2009
Publisher: MDPI AG
Date: 15-10-2016
DOI: 10.3390/NU8100641
Publisher: Elsevier BV
Date: 09-2015
Publisher: Bioscientifica
Date: 07-2013
DOI: 10.1530/ERC-13-0204
Abstract: Epigenetic modifications, such as DNA methylation, are widely studied in cancer as they are stable and easy to measure genome wide. DNA methylation changes have been used to differentiate benign from malignant tissue and to predict tumor recurrence or patient outcome. Multiple genome wide DNA methylation studies in breast and prostate cancers have identified genes that are differentially methylated in malignant tissue compared with non-malignant tissue or in association with hormone receptor status or tumor recurrence. Although this has identified potential biomarkers for diagnosis and prognosis, what is highlighted by reviewing these studies is the similarities between breast and prostate cancers. In particular, the gene families athways targeted by DNA methylation in breast and prostate cancers have significant overlap and include homeobox genes, zinc finger transcription factors, S100 calcium binding proteins, and potassium voltage-gated family members. Many of the gene pathways targeted by aberrant methylation in breast and prostate cancers are not targeted in other cancers, suggesting that some of these targets may be specific to hormonal cancers. Genome wide DNA methylation profiles in breast and prostate cancers will not only define more specific and sensitive biomarkers for cancer diagnosis and prognosis but also identify novel therapeutic targets, which may be direct targets of agents that reverse DNA methylation or which may target novel gene families that are themselves DNA methylation targets.
Publisher: CSIRO Publishing
Date: 2009
DOI: 10.1071/SRB09ABS166
Abstract: The World Health Organization has stated that 75% of adults worldwide are overweight, and in Australia nearly 25% of men are obese. Obesity is associated with an increased risk of cardiovascular disease, type 2 diabetes and cancer, with 30 to 40% of the latter possibly preventable by maintaining a healthy weight (The International Association for the Study of Obesity). Prostate cancer is the most commonly diagnosed cancer in men and there is increasing evidence that obesity increases the risk of prostate cancer mortality. High birth weight, an indication of excess nutrition during foetal development, has been associated with an increased risk of childhood and adult obesity, and for cancer. Using an animal model, we investigated whether obese mothers are more likely to have obese sons who are at an increased risk of developing prostate abnormalities and thus prostate cancer, in adulthood. Female rats were fed with either a control diet (4g fat/kg) or high fat diet (100g fat/kg) from before mating and throughout pregnancy. Prostate tissues were collected from the male offspring at 90 days (post-puberty) and 180 days (young adult). Histological analysis of the day 90 prostates identified hyperplasia in 100% of the ventral lobes (VL) and 64% of the dorsolateral lobes (DLP) in offspring of the maternal high fat group compared to 0% in each respectively, in those of the maternal control diet group. The VL is the most hormone sensitive prostate lobe of the rat, while the DLP is considered the equivalent of the human peripheral zone, the region from which the majority of human prostate cancers arise. These results suggest for the first time that maternal high fat diet may induce prostate abnormalities in male offspring that may in turn, predispose to an increased risk of prostate cancer in later life.
Publisher: Bioscientifica
Date: 07-2016
DOI: 10.1530/REP-16-0014
Abstract: Epigenetic modifications, and particularly DNA methylation, have been studied in many tissues, both healthy and diseased, and across numerous developmental stages. The placenta is the only organ that has a transient life of 9 months and undergoes rapid growth and dynamic structural and functional changes across gestation. Additionally, the placenta is unique because although developing within the mother, its genome is identical to that of the foetus. Given these distinctive characteristics, it is not surprising that the epigenetic landscape affecting placental gene expression may be different to that in other healthy tissues. However, the role of epigenetic modifications, and particularly DNA methylation, in placental development remains largely unknown. Of particular interest is the fact that the placenta is the most hypomethylated human tissue and is characterized by the presence of large partially methylated domains (PMDs) containing silenced genes. Moreover, how and why the placenta is hypomethylated and what role DNA methylation plays in regulating placental gene expression across gestation are poorly understood. We review genome-wide DNA methylation studies in the human placenta and highlight that the different cell types that make up the placenta have very different DNA methylation profiles. Summarizing studies on DNA methylation in the placenta and its relationship with pregnancy complications are difficult due to the limited number of studies available for comparison. To understand the key steps in placental development and hence what may be perturbed in pregnancy complications requires large-scale genome-wide DNA methylation studies coupled with transcriptome analyses.
Publisher: Future Medicine Ltd
Date: 03-2017
Abstract: Aim: To determine whether dynamic DNA methylation changes in the human placenta can be used to predict gestational age. Materials & methods: Publicly available placental DNA methylation data from 12 studies, together with our own dataset, using Illumina Infinium Human Methylation BeadChip arrays. Results & conclusion: We developed an accurate tool for predicting gestational age of placentas using 62 CpG sites. There was a higher predicted gestational age for placentas from early onset preecl sia cases, but not term preecl sia, compared with their chronological age. Therefore, early onset preecl sia is associated with placental aging. Gestational age acceleration prediction from DNA methylation array data may provide insight into the molecular mechanisms of pregnancy disorders.
Publisher: Oxford University Press (OUP)
Date: 27-05-2014
Publisher: Cold Spring Harbor Laboratory
Date: 07-03-2022
DOI: 10.1101/2022.03.03.22271882
Abstract: The human placenta is a rapidly developing transient organ that is key to pregnancy success. Early development of the conceptus occurs in a low oxygen environment before oxygenated maternal blood begins to flow into the placenta at ∼10-12 weeks’ gestation. This process is likely to substantially affect overall placental gene expression. Transcript variability underlying gene expression has yet to be profiled. In this study, accurate transcript expression profiles were identified for 84 human placental chorionic villus tissue s les collected across 6-23 weeks’ gestation. Differential gene expression (DGE), differential transcript expression (DTE) and differential transcript usage (DTU) between 6-10 weeks’ and 11-23 weeks’ gestation groups were assessed. In total, 229 genes had significant DTE yet no significant DGE. Integration of DGE and DTE analyses found that differential expression patterns of in idual transcripts were commonly masked upon aggregation to the gene-level. Of the 611 genes that exhibited DTU, 534 had no significant DGE or DTE. The four most significant DTU genes ADAM10, VMP1, GPR126 , and ASAH1 , were associated with hypoxia-responsive pathways. Transcript usage is a likely regulatory mechanism in early placentation. Identification of functional roles will facilitate new insight in understanding the origins of pregnancy complications.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Public Library of Science (PLoS)
Date: 28-09-2011
Publisher: American Association for Cancer Research (AACR)
Date: 29-07-2009
DOI: 10.1158/0008-5472.CAN-09-0452
Abstract: There is emerging evidence that the balance between estrogen receptor-α (ERα) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERα were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERα-positive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERα transactivation activity and 17β-estradiol–stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERα signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17β-estradiol on breast cancer cells. [Cancer Res 2009 (15):6131–40]
Publisher: Public Library of Science (PLoS)
Date: 29-06-2015
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.BBCAN.2008.12.001
Abstract: There are numerous diseases associated with abnormal hormonal regulation and these include cancers of the breast and prostate. There is substantial evidence that early hormonal perturbations (in utero or during early development) are associated with increased disease susceptibility later in life. These perturbations may arise from exposure to environmental agents or endocrine disruptors which mimic hormones and disrupt normal hormonal signaling. Epigenetic alterations have often been proposed as the underlying mechanism by which early hormonal perturbations may give rise to disease in adulthood. Currently, there is minimal evidence to support a direct link between early hormonal perturbations and epigenetic modifications or between epigenetic alterations and subsequent onset of cancer. Given that epigenetic modifications may play an important role in hormone-dependent cancers, it is essential to better understand the relationship between the hormonal environment and epigenetic modifications in both normal and disease states. In this review, we highlight several important studies which support the hypothesis that: hormonal perturbations early in life may result in epigenetic changes that may modify hormone receptor function, thereby contributing to an increased risk of developing hormone-related cancers.
Publisher: Apollo - University of Cambridge Repository
Date: 2017
DOI: 10.17863/CAM.22338
Publisher: Frontiers Media SA
Date: 13-10-2016
Publisher: Cambridge University Press (CUP)
Date: 22-12-2020
DOI: 10.1017/S2040174420001257
Abstract: Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases ( Dnmt1 and Dnmt3a ) and imprinted genes ( Peg3, Snrpn, Kcnq1 , and Cdkn1c ) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations ( n = 6–13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 ( P 0.05), with decreased Cdkn1c (19%, P 0.05) and increased Kcnq1 (1.6-fold, P 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively ( P 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.
Publisher: Wiley
Date: 15-05-2020
DOI: 10.1111/HIS.14081
Abstract: Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-α (ERα) expression and androgen receptor (AR) expression in predicting breast cancer outcome. ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERα expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with (≥1%) ERα-positive cancers with low (<20.7%) ApoD positivity, or those showing high (≥78%) AR positivity and low (<20.7%) ApoD positivity had better OS than other patient groups. ApoD expression could be used to predict breast cancer prognosis independently of ERα and AR expression.
Publisher: Wiley
Date: 04-12-2018
DOI: 10.1002/IJC.31906
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PLACENTA.2015.11.014
Abstract: Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops covered areas of placental regulation and nutrient handling: 1) placental epigenetics 2) placental mitochondrial function 3) placental transport systems.
Publisher: American Association for Cancer Research (AACR)
Date: 2007
DOI: 10.1158/1535-7163.MCT-06-0144
Abstract: Growth of prostate cancer cells is initially dependent on androgens, and androgen ablation therapy is used to control tumor growth. Unfortunately, resistance to androgen ablation therapy inevitably occurs, and there is an urgent need for better treatments for advanced prostate cancer. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA vorinostat), are promising agents for the treatment of a range of malignancies, including prostate cancer. SAHA inhibited growth of the androgen-responsive LNCaP prostate cancer cell line at low micromolar concentrations and induced caspase-dependent apoptosis associated with chromatin condensation, DNA fragmentation, and mitochondrial membrane depolarization at higher concentrations (≥5 μmol/L). Gene profiling and immunoblot analyses showed a decrease in androgen receptor (AR) mRNA and protein in LNCaP cells cultured with SAHA compared with control cells, with a corresponding decrease in levels of the AR-regulated gene, prostate-specific antigen. Culture of LNCaP cells in steroid-free medium markedly sensitized the cells to SAHA. Moreover, a combination of low, subeffective doses of SAHA and the AR antagonist bicalutamide resulted in a synergistic reduction in cell proliferation and increase in caspase-dependent cell death. Addition of exogenous androgen prevented the induction of cell death, indicating that suppression of androgen signaling was required for synergy. At the subeffective concentrations, these agents had no effect, alone or in combination, on proliferation or death of AR-negative PC-3 prostate cancer cells. Our findings indicate that SAHA is effective in targeting the AR signaling axis and that androgen deprivation sensitizes prostate cancer cells to SAHA. Consequently, combinatorial treatments that target different components of the AR pathway may afford a more effective strategy to control the growth of prostate cancer cells. [Mol Cancer Ther 2007 (1):51–60]
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.TIBTECH.2021.03.009
Abstract: Driven by a lack of appropriate human placenta models, recent years have seen the introduction of bioengineered in vitro models to better understand placental health and disease. Thus far, the focus has been on the maternal-foetal barrier. However, there are many other physiologically and pathologically significant aspects of the placenta that would benefit from state-of-the-art bioengineered models, in particular, integrating advanced culture systems with contemporary biological concepts such as organoids. This critical review defines and discusses the key parameters required for the development of physiologically relevant in vitro models of the placenta. Specifically, it highlights the importance of cell type, mechanical forces, and culture microenvironment towards the use of physiologically relevant models to improve the understanding of human placental function and dysfunction.
Publisher: Cambridge University Press (CUP)
Date: 11-09-2017
DOI: 10.1017/S2040174417000733
Abstract: Developmental origins of health and disease (DOHaD) is the study of how the early life environment can impact the risk of chronic diseases from childhood to adulthood and the mechanisms involved. Epigenetic modifications such as DNA methylation, histone modifications and non-coding RNAs are involved in mediating how early life environment impacts later health. This review is a summary of the Epigenetics and DOHaD workshop held at the 2016 DOHaD Society of Australia and New Zealand Conference. Our extensive knowledge of how the early life environment impacts later risk for chronic disease would not have been possible without animal models. In this review we highlight some animal model ex les that demonstrate how an adverse early life exposure results in epigenetic and gene expression changes that may contribute to increased risk of chronic disease later in life. Type 2 diabetes and cardiovascular disease are chronic diseases with an increasing incidence due to the increased number of children and adults that are obese. Epigenetic changes such as DNA methylation have been shown to be associated with metabolic health measures and potentially predict future metabolic health status. Although more difficult to elucidate in humans, recent studies suggest that DNA methylation may be one of the epigenetic mechanisms that mediates the effects of early life exposures on later life risk of obesity and obesity related diseases. Finally, we discuss the role of the microbiome and how it is a new player in developmental programming and mediating early life exposures on later risk of chronic disease.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
Publisher: MDPI AG
Date: 02-09-2020
DOI: 10.3390/NU12092678
Abstract: A healthy pregnancy is important for the growth and development of a baby. An adverse pregnancy outcome is associated with increased chronic disease risk for the mother and offspring. An optimal diet both before and during pregnancy is essential to support the health of the mother and offspring. A key mediator of the effect of maternal nutrition factors on pregnancy outcomes is the placenta. Complicated pregnancies are characterized by increased oxidative stress in the placenta. Selenium and iodine are micronutrients that are involved in oxidative stress in placental cells. To date, there has been no comprehensive review investigating the potential synergistic effect of iodine and selenium in the placenta and how maternal deficiencies may be associated with increased oxidative stress and hence adverse pregnancy outcomes. We undertook a hypothesis-generating review on selenium and iodine, to look at how they may relate to pregnancy complications through oxidative stress. We propose how they may work together to impact pregnancy and placental health and explore how deficiencies in these micronutrients during pregnancy may impact the future health of offspring.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.EJCB.2015.10.004
Abstract: Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arterioles is a common clinical finding in studies of pregnancies complicated by preecl sia, suggesting that the mechanisms mediating invasion of these cells is perturbed. The placenta initially develops in a low oxygen environment of 1-2% oxygen until after the 10th week of pregnancy. During this time oxygen concentration exerts a major influence over trophoblast activity and, hypoxia inducible factors are proposed to be one of many key regulators of first trimester trophoblast behaviour. We used a global gene expression microarray approach to identify signalling pathways and hypoxia-responsive genes of interest involved in invasion of the first trimester trophoblast cell line HTR8/SVneo under hypoxic conditions where HIF-1 was active. Additionally, first trimester placental s les from different gestational age groups were labelled with anti HIF-1α and HIF-2α to evaluate whether HIFs are differentially expressed and localised across two periods of placental development: (1) early first trimester characterised by hypoxia (6-8 weeks) and (2) late first trimester after initiation of maternal blood flow into the placenta (10-12 weeks). Invasion of HTR8/SVneo was assessed in real-time and was significantly increased in 1% compared with 5% and 21% oxygen and did not differ between 5% and 21% oxygen treatments. Eighty-eight genes were differentially expressed between cells cultured in 1% oxygen (where HIF-1α protein was localised to the nucleus) and 5% oxygen (where HIF-1α was mainly cytoplasmic). 65% of the genes were predicted to contain HIF-1α:HIF-1β transcription factor binding sites. While HIF-2α staining intensity in trophoblasts of late first trimester placenta was higher than early first trimester (+57%) the percentage of positively stained trophoblast nuclei did not differ between the two time points. There was no difference in the expression level of any of the hypoxia responsive genes of interest, IGFBP3, P4HA1, P4HA2, ANGPTL4 and MMP1 between early and late first trimester placenta. While HIF-1α and its downstream targets are clearly induced in HTR8/SVneo during in vitro hypoxic conditions, it appears that hypoxia inducible factors and genes are not altered throughout the first 7-12 weeks of placental development, during which the onset of maternal blood flow to the intervillous space takes place.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.GEP.2016.05.001
Abstract: Extravillous cytotrophoblasts isolated from first trimester placenta, and immortalised cell lines derived from them, have the intrinsic ability to form endothelial-like tubes when cultured on Matrigel™ extracellular matrix. This in vitro tube formation may model placental angiogenesis and/or endovascular differentiation by trophoblasts. To interpret the relevance of this phenomenon to placental development, we used a gene expression microarray approach to identify which genes and pathways are associated with the tube-forming phenotype of HTR8/SVneo first trimester trophoblasts (HTR8-M), compared with HTR8/SVneo not forming tubes on plastic culture surface (HTR8-P). Furthermore, we used weighted gene co-expression network analysis (WGCNA) of microarray data to identify modules of co-expressed genes underlying the biological processes. There were 481 genes differentially expressed between HTR8-M and HTR8-P and these were significantly enriched for blood vessel development and related gene ontologies. WGCNA clustered the genes into 9 co-expression modules. One module was significantly associated with HTR8-M (p = 1.15E-05) and contained genes involved in actin cytoskeleton organization, cell migration and blood vessel development, consistent with tube formation on Matrigel. Another module was significantly associated with HTR8-P (p = 1.94E-05) and was enriched for genes involved in mitosis, consistent with proliferation by cells on plastic which do not differentiate. Up-regulation of angiogenesis and vascular development pathways in endovascular trophoblasts in vivo could underpin spiral artery remodelling processes, which are defective in preecl tic pregnancies.
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-05-2018
DOI: 10.1158/1078-0432.CCR-17-1199
Abstract: Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219 validation cohort, n = 418 77% and 79% estrogen receptor alpha (ERα) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41 P = 0.015) and validation (HR, 0.50 P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts (P & 0.0001). Among the combined ERα-positive cases, those with comparable or higher levels of AR (AR:ERα-positivity ratio & .87) had the best outcomes (P & 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer. Clin Cancer Res 24(10) 2328–41. ©2018 AACR.
Publisher: Wiley
Date: 28-07-2021
DOI: 10.1111/MCN.13064
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.CANLET.2012.02.011
Abstract: Epigenome alterations are characteristic of nearly all human malignancies and include changes in DNA methylation, histone modifications and microRNAs (miRNAs). However, what induces these epigenetic alterations in cancer is largely unknown and their mechanistic role in prostate tumorigenesis is just beginning to be evaluated. Identification of the epigenetic modifications involved in the development and progression of prostate cancer will not only identify novel therapeutic targets but also prognostic and diagnostic markers. This review will focus on the use of epigenetic modifications as biomarkers for prostate cancer.
Publisher: Oxford University Press (OUP)
Date: 04-05-2018
Abstract: Is preconception dietary intake associated with reduced fecundity as measured by a longer time to pregnancy (TTP)? Lower intake of fruit and higher intake of fast food in the preconception period were both associated with a longer TTP. Several lifestyle factors, such as smoking and obesity, have consistently been associated with a longer TTP or infertility, but the role of preconception diet in women remains poorly studied. Healthier foods or dietary patterns have been associated with improved fertility, however, these studies focused on women already diagnosed with or receiving treatments for infertility, rather than in the general population. This was a multi-center pregnancy-based cohort study of 5628 nulliparous women with low-risk singleton pregnancies who participated in the Screening for Pregnancy Endpoints (SCOPE) study. A total of 5598 women were included. Data on retrospectively reported TTP and preconception dietary intake were collected during the first antenatal study visit (14-16 weeks' gestation). Dietary information for the 1 month prior to conception was obtained from food frequency questions for fruit, green leafy vegetables, fish and fast foods, by a research midwife. Use of any fertility treatments associated with the current pregnancy was documented (yes, n = 340, no, n = 5258). Accelerated failure time models with log normal distribution were conducted to estimate time ratios (TR) and 95% CIs. The impact of differences in dietary intake on infertility (TTP >12 months) was compared using a generalized linear model (Poisson distribution) with robust variance estimates, with resulting relative risks (RR) and 95% CIs. All analyses were controlled for a range of maternal and paternal confounders. Sensitivity analyses were conducted to explore potential biases common to TTP studies. Lower intakes of fruit and higher intakes of fast food were both associated with modest increases in TTP and infertility. Absolute differences between the lowest and highest categories of intake for fruit and fast food were in the order of 0.6-0.9 months for TTP and 4-8% for infertility. Compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1-<3 times/day (TR = 1.06, 95% CI: 0.97-1.15), 1-6 times/week (TR = 1.11, 95% CI: 1.01-1.22) or <1-3 times/month (TR = 1.19, 95% CI: 1.03-1.36), corresponded to 6, 11 and 19% increases in the median TTP (Ptrend = 0.007). Similarly, compared with women who consumed fast food ≥4 times/week, the adjusted effects of consuming fast food ≥2- 0-<2 times/week (TR 0.79, 95% CI 0.69-0.89) or no fast food (TR = 0.76, 95% CI: 0.61-0.95), corresponded to an 11, 21 and 24% reduction in the median TTP (Ptrend <0.001). For infertility, compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1-<3 times/day, 1-6 times/week or <1-3 times/month corresponded to a 7, 18 and 29% increase in risk of infertility (Ptrend = 0.043). Similarly, compared with women who consumed fast food ≥4 times/week, the adjusted effects of consuming fast food ≥2- 0-<2 times/week, or no fast food, corresponded to an 18, 34 and 41% reduced risk of infertility (Ptrend <0.001). Pre-pregnancy intake of green leafy vegetables or fish were not associated with TTP or infertility. Estimates remained stable across a range of sensitivity analyses. Collection of dietary data relied on retrospective recall and evaluated a limited range of foods. Paternal dietary data was not collected and the potential for residual confounding cannot be eliminated. Compared to prospective TTP studies, retrospective TTP studies are prone to a number of potential sources of bias. These findings underscore the importance of considering preconception diet for fecundity outcomes and preconception guidance. Further research is needed assessing a broader range of foods and food groups in the preconception period. The SCOPE database is provided and maintained by MedSciNet AB (medscinet.com). The Australian SCOPE study was funded by the Premier's Science and Research Fund, South Australian Government (www.dfeest.sa.gov.au/science-research remiers-research-and-industry-fund). The New Zealand SCOPE study was funded by the New Enterprise Research Fund, Foundation for Research Science and Technology Health Research Council (04/198) Evelyn Bond Fund, Auckland District Health Board Charitable Trust. The Irish SCOPE study was funded by the Health Research Board of Ireland (CSA/2007/2 www.hrb.ie). The UK SCOPE study was funded by National Health Service NEAT Grant (Neat Grant FSD025), Biotechnology and Biological Sciences Research council (www.bbsrc.ac.uk/funding GT084) and University of Manchester Proof of Concept Funding (University of Manchester) Guy's and St. Thomas' Charity (King's College London) and Tommy's charity (www.tommys.org/ King's College London and University of Manchester) and Cerebra UK (www.cerebra.org.uk University of Leeds). L.E.G. is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (ID 1070421). L.J.M. is supported by a SACVRDP Fellowship a program collaboratively funded by the National Heart Foundation, the South Australian Department of Health and the South Australian Health and Medical Research Institute. L.C.K. is supported by a Science Foundation Ireland Program Grant for INFANT (12/RC/2272). C.T.R. was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (GNT1020749). There are no conflicts of interest to declare. Not applicable.
Publisher: Wiley
Date: 10-07-2013
DOI: 10.1002/PROS.22554
Abstract: Krüppel-like factor (KLF) 6 is a candidate tumor suppressor gene in prostate cancer, but the mechanisms contributing to its loss of expression are poorly understood. We characterized KLF6 expression and DNA methylation status during prostate tumorigenesis in humans and mice. KLF6 expression was assessed in matched human non-malignant (NM) and tumor prostate tissues (n = 22) by quantitative real-time PCR (qPCR) and in three independent human prostate cancer cohorts bioinformatically. QPCR for KLF6 expression and methylation-sensitive PCR (MSP) were performed in human prostate LNCaP cancer cells after 5-aza-2'-deoxycytidine treatment. Klf6 protein levels and DNA promoter methylation were assessed in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors by immunohistochemistry and MSP, respectively. KLF6 splice variants expression was increased (P = 0.0015) in human prostate tumors compared to NM tissues. Overall, KLF6 was decreased in metastatic compared to primary prostate cancers and reduced expression in primary tumors was associated with a shorter time to relapse (P = 0.0028). Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in up-regulation of KLF6 expression (two-fold P = 0.002) and a decrease in DNA methylation of the KLF6 promoter in LNCaP cells. Klf6 protein levels significantly decreased with progression in the TRAMP model of prostate cancer (P < 0.05), but there was no difference in Klf6 promoter methylation. KLF6 expression was decreased in both clinical prostate cancer and the TRAMP model with disease progression, but this could not be explained by DNA methylation of the KLF6 promoter.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.JSBMB.2007.10.014
Abstract: Androgen signaling, mediated by the androgen receptor (AR), is a critical factor influencing growth of normal and malignant breast cells. Given the increasing use of exogenous androgens in women, a better understanding of androgen action in the breast is essential. This study compared the effects of 5alpha-dihydrotestosterone (DHT) and a synthetic androgen, mibolerone, on estradiol (E(2))-induced proliferation of breast cancer cells. DHT modestly inhibited E(2)-induced proliferation and mibolerone significantly inhibited proliferation in T-47D cells. The effects of both androgens could be reversed by an AR antagonist, suggesting that their actions were mediated, in part, by AR. Whereas high physiological doses (10-100nM) of DHT reduced E(2)-mediated induction of the estrogen-regulated gene progesterone receptor (PR) to basal levels, mibolerone at lower doses (1nM) eliminated PR expression, suggesting that mibolerone may also act via the PR. In the AR positive, PR-negative MCF-7 cells, mibolerone had modest effects on E(2)-induced proliferation, but was a potent inhibitor of proliferation in the AR positive, PR positive MCF-7M11 PRA cells. The effects of mibolerone in breast cancer cells were similar to those of the progestin, medroxyprogesterone acetate. Our results demonstrate that mibolerone can have both androgenic and progestagenic actions in breast cancer cells.
Publisher: Hindawi Limited
Date: 10-1999
DOI: 10.1002/(SICI)1098-1004(199910)14:4<289::AID-HUMU3>3.0.CO;2-A
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2020
DOI: 10.1101/2020.06.25.20139709
Abstract: During early human placental development, extravillous cytotrophoblasts (EVT) invade the uterine vasculature to sequester a maternal blood supply. The impact of this on placental gene expression has not been established for normal pregnancy. Using RNA sequencing, we profiled placental chorionic villous tissues from 96 pregnancies at 6-23 weeks of gestation. We identified 1,048 genes that were differentially expressed between 6-10 weeks’ and 11-23 weeks’ of gestation. These are predominantly genes that are enriched in transcription factor signalling, inflammatory response and cell adhesion. Using a co-expression network and gene set enrichment analyses, we reveal three distinct phases of gene expression coincident with phases of maternal blood flow to the placenta that impact immune function and are likely driven by oxygen tension, potentially in a sex-specific manner. These data represent a comprehensive transcriptional profile of early placental development and point to significant environmental, genetic and regulatory triggers that drive gene expression.
Publisher: Informa UK Limited
Date: 30-09-2014
DOI: 10.4161/EPI.26197
Publisher: Wiley
Date: 04-2018
DOI: 10.1002/JPPR.1438
Publisher: Public Library of Science (PLoS)
Date: 04-12-2018
Publisher: Springer Science and Business Media LLC
Date: 2000
Publisher: Informa UK Limited
Date: 19-08-2021
Publisher: PeerJ
Date: 26-11-2021
DOI: 10.7717/PEERJ.12525
Abstract: The term ‘superfoods’ is used to market foods considered to have significant health benefits. ‘Superfoods’ are claimed to prevent diseases as well as improving overall health, though the lack of explicit criteria means that any food can be labelled ‘super’ without support from scientific research. Typically, these ‘superfoods’ are rich in a particular nutrient for ex le antioxidants or omega-3 fatty acids. The objective of this study was to investigate the nutritional properties of a selection of superfood seeds: flax, chia, hulled sunflower and two types of processed hemp seeds and determine whether they may have potential health benefits. We developed a simple aqueous extraction method for ground seeds and analysed their composition by mineral, protein and monosaccharide analyses. Cell viability assays were performed on Caco-2 and IEC-6 intestinal epithelial cells using increasing doses of the prepared extracts. Increased cell viability was observed in both cell lines with increasing concentrations of the flax seed, chia seed or hulled sunflower extracts ( P 0.05). Compositional analyses revealed the presence of polysaccharides, proteins and essential minerals in the aqueous extracts and in vitro assays showed sunflower had the highest antioxidant activity. However, differences in extract composition and antioxidant properties could not be directly related to the observed increase in cell viability suggesting that other components in the extracts may be responsible. Future studies will further characterize these extracts and investigate whether they are beneficial for gastrointestinal health.
Publisher: Informa UK Limited
Date: 21-11-2012
DOI: 10.3109/14767058.2012.743520
Abstract: To investigate the association of polymorphisms in the vascular endothelial growth factor (VEGF) family genes (VEGFA rs699947, VEGFA rs3025039, PGF rs1042886, KDR rs2071559 and KDR rs2305948) with preecl sia in Sinhalese women in Sri-Lanka. We conducted a case-control study where 175 nulliparous Sinhalese women with preecl sia and 171 normotensive women matched for age, ethnicity, parity and BMI were recruited in tertiary care maternity hospitals in Sri-Lanka. Preecl sia was diagnosed using international guidelines. DNA extracted from peripheral venous blood and was genotyped using the Sequenom MassARRAY system. χ(2)-test was used to compare the distribution of allele and genotype frequencies between the cases and the control subjects. The frequency of PGF rs1042886 variant allele (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.1-2.1) and dominant genotype model (aOR 1.6, 95% CI 1.0-2.4) were increased in preecl tic women compared to controls. VEGFA rs699947, VEGFA rs3025039, KDR rs2071559, and KDR rs2305948 polymorphisms were not associated with preecl sia. Maternal PGF rs1042886 polymorphism is associated with preecl sia in Sinhalese women in Sri-Lanka.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Future Science Ltd
Date: 07-2003
DOI: 10.2144/03351BM01
Publisher: Elsevier BV
Date: 09-2014
Publisher: American Association for Cancer Research (AACR)
Date: 07-2010
DOI: 10.1158/1055-9965.EPI-10-0059
Abstract: Background: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue s ling, handling, and storage might affect biomarker expression or invalidate tissue s les as analytes for some technologies. Methods: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP s les were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores. Results: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these s les into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue. Conclusions: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear. Impact: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided. Cancer Epidemiol Biomarkers Prev 19(7) 1755–65. ©2010 AACR.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.PLACENTA.2017.06.009
Abstract: A significant proportion of children born preterm will experience some level of neurodevelopmental impairment. Changes in placental function have been observed with many antenatal conditions that are risk factors for preterm birth and/or poor neurodevelopment including fetal growth restriction and in-utero inflammation. This review will highlight placental factors that have been studied to understand the underlying mechanisms and identify biomarkers that lead to poor child neurodevelopmental outcomes. These include changes in gross morphological and histopathological structure and the placental inflammatory response to prenatal infection. Further, we will describe the placenta's role as both a barrier to maternally-derived bioactive substances critical for normal fetal brain development, such as cortisol, and a source of neuroactive steroids and neurotrophins known to have critical functions in neuronal proliferation, axonal growth, myelination and the regulation of apoptosis. Finally, emerging data supporting the potential utility of novel placental biomarkers in the early prediction of poor neurodevelopmental outcome in infants born both preterm and term will be discussed. These include the assessment of genetic variants (e.g. single nucleotide polymorphisms in placental tissue) and epigenetic biomarkers (e.g. placental microRNAs and placental DNA methylation). With the placenta the key tissue regulating the fetal environment, integration of observed changes in placental function with genetic and epigenetic variations may advance our ability to predict future infant health. Ultimately, this may facilitate targeted allocation of health resources with the aim of improving lifelong neurodevelopmental capability.
Publisher: Springer Netherlands
Date: 2013
Publisher: Bioscientifica
Date: 02-2017
DOI: 10.1530/JOE-16-0300
Abstract: Preterm birth is associated with increased risk of type 2 diabetes (T2D) in adulthood however, the underlying mechanisms are poorly understood. We therefore investigated the effect of preterm birth at ~0.9 of term after antenatal maternal betamethasone on insulin sensitivity, secretion and key determinants in adulthood, in a clinically relevant animal model. Glucose tolerance and insulin secretion (intravenous glucose tolerance test) and whole-body insulin sensitivity (hyperinsulinaemic euglycaemic cl ) were measured and tissue collected in young adult sheep (14 months old) after epostane-induced preterm (9M, 7F) or term delivery (11M, 6F). Glucose tolerance and disposition, insulin secretion, β-cell mass and insulin sensitivity did not differ between term and preterm sheep. Hepatic PRKAG2 expression was greater in preterm than in term males ( P = 0.028), but did not differ between preterm and term females. In skeletal muscle, SLC2A4 ( P = 0.019), PRKAA2 ( P = 0.021) and PRKAG2 ( P = 0.049) expression was greater in preterm than in term overall and in males, while INSR ( P = 0.047) and AKT2 ( P = 0.043) expression was greater in preterm than in term males only. Hepatic PRKAG2 expression correlated positively with whole-body insulin sensitivity in males only. Thus, preterm birth at 0.9 of term after betamethasone does not impair insulin sensitivity or secretion in adult sheep, and has sex-specific effects on gene expression of the insulin signalling pathway. Hence, the increased risk of T2D in preterm humans may be due to factors that initiate preterm delivery or in early neonatal exposures, rather than preterm birth per se .
Publisher: MDPI AG
Date: 03-12-2016
DOI: 10.3390/GENES7120117
Publisher: Bioscientifica
Date: 03-2017
DOI: 10.1530/REP-16-0517
Abstract: The preimplantation embryo in vivo is exposed to numerous growth factors in the female reproductive tract, which are not recapitulated in embryo culture media in vitro . The IGF2 and plasminogen activator systems facilitate blastocyst development. We hypothesized that the addition of IGF2 in combination with urokinase plasminogen activator (uPA) and plasminogen could improve rates of blastocyst hatching and implantation in mice. B6BcF1 and CBAB6F2 mouse embryos were ided into one of four supplemented culture media treatment groups: (1) control (media only) (2) 12.5 nM IGF2 (3) 10 µg/mL uPA and 5 µg/mL plasminogen or (4) a combination of IGF2, uPA and plasminogen treatments. Embryo development to blastocyst stage and hatching were assessed before transfer to pseudopregnant recipient females and implantation, pregnancy rates and postnatal growth were assessed. After 90.5 h of culture, IGF2 + U + P treatment increased the percentage of B6BcF1 embryos that were hatching/hatched and percentage developing to blastocyst stage compared with controls ( P 0.02). Following B6BcF1 embryo transfer, IGF2 + U + P treatment increased implantation sites at day 8 of pregnancy compared with controls ( P 0.05). Replication in the CBAB6F2 mouse strain showed significant improvements in pregnancy rates at days 8 and 18 but not in blastocyst development. No adverse effects were seen on gestational age, litter size or birthweight, or the reproductive capacity of offspring of IGF2 + U + P treated embryos. For embryos susceptible to detrimental effects of in vitro culture, IGF2, uPA and plasminogen supplementation of culture media can improve pregnancy success, but the effect of treatment is dependent on the mouse strain.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.MCE.2013.11.002
Abstract: Medroxyprogesterone acetate (MPA) has widely been used in hormone replacement therapy (HRT), and is associated with an increased risk of breast cancer, possibly due to disruption of androgen receptor (AR) signaling. In contrast, the synthetic HRT Tibolone does not increase breast density, and is rapidly metabolized to estrogenic 3α-OH-tibolone and 3β-OH-tibolone, and a delta-4 isomer (Δ(4)-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and Δ(4)-TIB, but not MPA, stabilize AR protein levels, initiate specific AR intramolecular interactions critical for AR transcriptional regulation, and increase proliferation of AR positive MDA-MB-453 breast cancer cells. Structural modeling and molecular dynamic simulation indicate that Δ(4)-TIB induces a more stable AR structure than does DHT, and MPA a less stable one. Microarray expression analyses confirms that the molecular actions of Δ(4)-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Oxford University Press (OUP)
Date: 06-2023
Abstract: Pregnancy complications can impact the mother and child’s health in the short and longterm resulting in an increased risk of chronic disease later in life. Telomere length is a biomarker of future cardiometabolic diseases and may offer a novel way of identifying offspring most at risk for future chronic diseases. To qualitatively explore General Practitioners’ (GPs) perspectives on the feasibility and uptake for recommending a telomere screening test in children who were born after a pregnancy complication. Twelve semi-structured interviews were conducted with GPs within metropolitan Adelaide, South Australia. Interviews were audio recorded, transcribed verbatim, and analysed for codes and themes. Two themes were generated: ethical considerations and practical considerations. Ethically, the GP participants discussed barriers including consenting on behalf of a child, parental guilt, and the impact of health insurance, whereas viewing it for health promotion was a facilitator. For practical considerations, barriers included the difficulty in identifying people eligible for screening, maintaining medical communication between service providers, and time and financial constraints, whereas linking screening for telomere length with existing screening would facilitate uptake. GPs were generally supportive of potential telomere screening in infants, particularly via a saliva test that could be embedded in current antenatal care. However, several challenges, such as lack of knowledge, ethical considerations, and time and financial constraints, need to be overcome before such a test could be implemented into practice.
Publisher: Oxford University Press (OUP)
Date: 02-2002
Abstract: Intercellular communication via gap junctions is a mechanism for tumor suppression. Connexin 26 (Cx26) is a structural component of gap junctions expressed by breast epithelial cells. Expression levels of Cx26 are reduced in many breast tumors. Methylation-sensitive single-stranded conformation analysis showed variable methylation in the promoter region CpG island in 11 out of 20 (55%) breast cancer patients. Heterogeneity in methylation patterns was observed both between and within tumors. The degree of methylation ranged from a few CpG dinucleotides to almost all the CpG dinucleotides in the analyzed region. The most frequently methylated CpG was in an Sp1 site known to be important for Cx26 gene expression. One of eight breast cancer cell lines (MD-MBA-453) was methylated in the promoter region and did not express Cx26. Treatment of MDA-MB-453 with 5-aza-2'-deoxycytidine resulted in the re-expression of Cx26 mRNA. Methylation of the promoter region is likely to be an important mechanism in modulating the expression of Cx26 in breast cancer.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S1046-2023(02)00065-8
Abstract: Methylation-sensitive single-strand conformation analysis (MS-SSCA) is a method of screening for methylation changes at CpG sites in a region of DNA. After bisulfite modification, the region of interest is lified using primers specific for bisulfite-modified sequences. The lified products are denatured and run on a nondenaturing polyacrylamide gel. The sequence differences caused by methylation lead to the formation of different secondary structures (conformers) with different mobilities. MS-SSCA is a convenient and rapid method for screening large numbers of s les for methylation. In idual bands can readily be isolated and sequenced allowing more detailed analysis of methylation changes. In this article, we present a protocol for MS-SSCA and outline strategies for the design of primers for lifying bisulfite-modified DNA sequences.
Publisher: Cold Spring Harbor Laboratory
Date: 22-08-2020
DOI: 10.1101/2020.08.19.20177873
Abstract: MicroRNAs (miRNAs) are increasingly seen as important regulators of placental development and opportunistic biomarker targets. Given the difficulty in obtaining s les from early gestation and subsequent paucity of the same, investigation of the role of miRNAs in early gestation human placenta has been limited. To address this, we generated miRNA profiles using 96 placentas from presumed normal pregnancies, across early gestation, in combination with matched profiles from maternal plasma. Placenta s les range from 6–23 weeks’ gestation, a time period that includes placenta from the early, relatively low but physiological (6–10 weeks’ gestation) oxygen environment, and later, physiologically normal oxygen environment (11–23 weeks’ gestation). We identified 637 miRNAs with expression in 86 s les (after removing poor quality s les), showing a clear gestational age gradient from 6–23 weeks’ gestation. We identified 374 differentially expressed (DE) miRNAs between placentas from 6–10 weeks’ versus 11–23 weeks’ gestation. We see a clear gestational age group bias in miRNA clusters C19MC, C14MC, miR-17∼92 and paralogs, regions that also include many DE miRNAs. Proportional change in expression of placenta-specific miRNA clusters was reflected in maternal plasma. The presumed introduction of oxygenated maternal blood into the placenta (between ∼10–12 weeks’ gestation) changes the miRNA profile of the chorionic villus, particularly in placenta-specific miRNA clusters. Data presented here comprise a clinically important reference set for studying early placenta development and may underpin the generation of minimally invasive methods for monitoring placental health.
Publisher: MDPI AG
Date: 27-06-2017
DOI: 10.3390/IJMS18071371
Publisher: Frontiers Media SA
Date: 31-03-2022
DOI: 10.3389/FENDO.2022.838737
Abstract: A poorly functioning placenta results in impaired exchanges of oxygen, nutrition, wastes and hormones between the mother and her fetus. This can lead to restriction of fetal growth. These growth restricted babies are at increased risk of developing chronic diseases, such as type-2 diabetes, hypertension, and kidney disease, later in life. Animal studies have shown that growth restricted phenotypes are sex-dependent and can be transmitted to subsequent generations through both the paternal and maternal lineages. Altered epigenetic mechanisms, specifically changes in DNA methylation, histone modifications, and non-coding RNAs that regulate expression of genes that are important for fetal development have been shown to be associated with the transmission pattern of growth restricted phenotypes. This review will discuss the subsequent health outcomes in the offspring after growth restriction and the transmission patterns of these diseases. Evidence of altered epigenetic mechanisms in association with fetal growth restriction will also be reviewed.
Publisher: Springer Science and Business Media LLC
Date: 03-01-2017
Publisher: Springer Science and Business Media LLC
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 02-2018
DOI: 10.1038/S41598-018-19655-W
Abstract: Genotyping-by-sequencing (GBS) or restriction-site associated DNA marker sequencing (RAD-seq) is a practical and cost-effective method for analysing large genomes from high ersity species. This method of sequencing, coupled with methylation-sensitive enzymes (often referred to as methylation-sensitive restriction enzyme sequencing or MRE-seq), is an effective tool to study DNA methylation in parts of the genome that are inaccessible in other sequencing techniques or are not annotated in microarray technologies. Current software tools do not fulfil all methylation-sensitive restriction sequencing assays for determining differences in DNA methylation between s les. To fill this computational need, we present msgbsR , an R package that contains tools for the analysis of methylation-sensitive restriction enzyme sequencing experiments. msgbsR can be used to identify and quantify read counts at methylated sites directly from alignment files (BAM files) and enables verification of restriction enzyme cut sites with the correct recognition sequence of the in idual enzyme. In addition, msgbsR assesses DNA methylation based on read coverage, similar to RNA sequencing experiments, rather than methylation proportion and is a useful tool in analysing differential methylation on large populations. The package is fully documented and available freely online as a Bioconductor package ( ackages/release/bioc/html/msgbsR.html ).
Publisher: MDPI AG
Date: 19-04-2022
DOI: 10.3390/IJMS23094506
Abstract: The human placenta is a rapidly developing transient organ that is key to pregnancy success. Early development of the conceptus occurs in a low oxygen environment before oxygenated maternal blood begins to flow into the placenta at ~10–12 weeks’ gestation. This process is likely to substantially affect overall placental gene expression. Transcript variability underlying gene expression has yet to be profiled. In this study, accurate transcript expression profiles were identified for 84 human placental chorionic villus tissue s les collected across 6–23 weeks’ gestation. Differential gene expression (DGE), differential transcript expression (DTE) and differential transcript usage (DTU) between 6–10 weeks’ and 11–23 weeks’ gestation groups were assessed. In total, 229 genes had significant DTE yet no significant DGE. Integration of DGE and DTE analyses found that differential expression patterns of in idual transcripts were commonly masked upon aggregation to the gene-level. Of the 611 genes that exhibited DTU, 534 had no significant DGE or DTE. The four most significant DTU genes ADAM10, VMP1, GPR126, and ASAH1, were associated with hypoxia-responsive pathways. Transcript usage is a likely regulatory mechanism in early placentation. Identification of functional roles will facilitate new insight in understanding the origins of pregnancy complications.
Publisher: Elsevier BV
Date: 12-2015
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2005
DOI: 10.1158/0008-5472.CAN-04-3077
Abstract: Previously, we reported that androgen receptor (AR), but not estrogen receptor (ER) or progesterone receptor (PR), is predictive of response to the synthetic progestin, medroxyprogesterone acetate (MPA), in a cohort of 83 patients with metastatic breast cancer. To further investigate the role of AR in determining response to MPA in this cohort, we analyzed AR levels by immunohistochemistry with two discrete antisera directed at either the NH2 or the COOH termini of the receptor. Compared with tumors that responded to MPA (n = 31), there was a significant decrease in the intensity and extent of AR immunoreactivity with both AR antisera in tumors from nonresponders (n = 52). Whereas only a single AR immunostaining pattern was detected in responders to MPA, reflecting concordance of immunoreactivity with the two AR antisera, tumors from nonresponders exhibited four distinct AR immunostaining patterns: (a) concordance with the two antibodies (31%), (b) staining only with the COOH-terminal antibody (33%), (c) staining only with the NH2-terminal antibody (22%), or (d) no immunoreactivity with either NH2- or COOH-terminal antibody (14%). DNA sequencing and functional analysis identified inactivating missense gene mutations in the ligand-binding domain of the AR in tumors from two of nine nonresponders positive with the NH2-terminal AR antisera but negative for COOH-terminal immunoreactivity and lacking specific, high-affinity dihydrotestosterone binding in tumor cytosol fractions. Tumors with more AR than the median level (37 fmol/mg protein) had significantly lower levels of PR (30 fmol/mg protein) than tumors with low AR (PR 127 fmol/mg protein) despite comparable levels of ER. Ligand-dependent activation of the AR in human T47D and MCF-7 breast cancer cells resulted in inhibition of estradiol-stimulated cell proliferation and a reduction in the capacity of the ER to induce expression of the PR. These effects could be reversed using a specific AR antisense oligonucleotide. Increasing the ratio of AR to ER resulted in a greater androgen-dependent inhibition of ER function. Collectively, these data suggest that reduced levels of AR or impaired AR function contribute to the failure of MPA therapy potentially due to abrogation of the inhibitory effect of AR on ER signaling.
Publisher: European Respiratory Society (ERS)
Date: 02-2018
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JTEMB.2017.11.016
Abstract: Maternal micronutrient deficiencies in pregnancy can have profound effects on fetal development and pregnancy outcome. Plasma trace minerals including copper, zinc, selenium and iron have been shown to be extremely important in supporting reproduction. We sought to determine whether there is an association between maternal trace mineral status in early pregnancy and pregnancy complications using a prospective cohort study of 1065 pregnant Australian women who were recruited as part of the Screening for Pregnancy Endpoints (SCOPE) study in Adelaide. Copper, zinc, selenium and iron present in the plasma were measured using mass spectrometry in s les collected at 15±1 weeks' gestation. After adjusting for covariates, women with lower plasma copper ( 32.5μmol/L) (aRR=0.87 95% CI=0.76, 0.99 and aRR=0.88 95% CI=0.78, 1.00, respectively). This was also observed when adjusting for plasma zinc and selenium status (<27.9μmol/L: aRR=0.81 95% CI=0.69, 0.96 and 27.9-32.5μmol/L: aRR=0.84 95% CI=0.72, 0.98). Combined low copper and zinc status was also associated with a reduced risk of any pregnancy complication as compared with high copper and zinc status (aRR=0.80 95% CI=0.70, 0.93). These results provide justification for further work into elucidating the mechanistic role of trace elements in early pregnancy, as well as their interactions in supporting successful pregnancy outcomes.
Publisher: Wiley
Date: 10-03-2019
Abstract: To determine: (1) the association between metabolic syndrome (MetS), time to pregnancy (TTP), and infertility (2) associations between in idual and an increasing number of MetS components, TTP, and infertility and (3) whether these relationships differ by body mass index (BMI 12 months) were compared using a generalised linear model (Poisson distribution) with robust variance estimates (relative risks, RRs 95% CIs). All analyses (entire cohort and split by BMI) were controlled for a range of maternal and paternal confounding factors. Time to pregnancy and infertility. Of the 5519 women included, 12.4% (n = 684) had MetS. Compared with women without MetS, women with MetS had a longer TTP (adjusted TR 1.30 95% CI 1.15-1.46), which was similar in women who were obese and in women who were not obese. Marginal estimates for median TTP in women with MetS versus without MetS was 3.1 months (3.0-3.3 months) versus 4.1 months (3.6-4.5 months), respectively. Women with MetS were at a 62% greater risk for infertility and were at a greater risk for infertility whether they were obese (adjusted RR 1.62 95% CI 1.15-2.29) or not (adjusted RR 1.73 95% CI 1.33-2.23). Reduced high-density lipoprotein cholesterol (HDL-C) and raised triglycerides (TGs) were the main in idual components associated with risk for infertility. Metabolic syndrome is associated with longer TTP and infertility, independent of obesity. Additional studies, before pregnancy, are required to support our findings and to determine the applicability of which combinations of metabolic abnormalities pose the greatest risk to delayed fertility, or whether in idual components are amenable to modification. Metabolic syndrome is associated with longer time to pregnancy and infertility, independent of obesity.
Publisher: Bioscientifica
Date: 20-06-2012
DOI: 10.1530/ERC-12-0065
Abstract: Recent evidence indicates that the estrogen receptor-α-negative, androgen receptor (AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype its proliferation is stimulated by androgens such as 5α-dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that the AR gene in MDA-MB-453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the ergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype.
Publisher: Frontiers Media SA
Date: 20-12-2019
Publisher: Springer Science and Business Media LLC
Date: 20-06-2018
Publisher: Frontiers Media SA
Date: 03-08-2021
Abstract: Kushen root, from the woody legume Sophora flavescens , is a traditional Chinese medicine that is a key ingredient in several promising cancer treatments. This activity is attributed in part to two quinolizidine alkaloids (QAs), oxymatrine and matrine, that have a variety of therapeutic activities in vitro . Genetic selection is needed to adapt S. flavescens for cultivation and to improve productivity and product quality. Genetic ersity of S. flavescens was investigated using genotyping-by-sequencing (GBS) on 85 plants grown from seeds collected from 9 provinces of China. DArTSeq provided over 10,000 single nucleotide polymorphism (SNP) markers, 1636 of which were used in phylogenetic analysis to reveal clear regional differences for S. flavescens . One accession from each region was selected for PCR-sequencing to identify gene-specific SNPs in the first two QA pathway genes, lysine decarboxylase (LDC) and copper amine oxidase (CAO). To obtain SfCAO sequence for primer design we used a targeted transcript capture and assembly strategy using publicly available RNA sequencing data. Partial gene sequence analysis of SfCAO revealed two recently duplicated genes, SfCAO1 and SfCAO2 , in contrast to the single gene found in the QA-producing legume Lupinus angustifolius . We demonstrate high efficiency converting SNPs to Kompetitive Allele Specific PCR (KASP) markers developing 27 new KASP markers, 17 from DArTSeq data, 7 for SfLDC , and 3 for SfCAO1 . To complement this genetic ersity analysis a field trial site has been established in South Australia, providing access to erse S. flavescens material for morphological, transcriptomic, and QA metabolite analysis. Analysis of dissected flower buds revealed that anthesis occurs before buds fully open suggesting a potential for S. flavescens to be an inbreeding species, however this is not supported by the relatively high level of heterozygosity observed. Two plants from the field trial site were analysed by quantitative real-time PCR and levels of matrine and oxymatrine were assessed in a variety of tissues. We are now in a strong position to select erse plants for crosses to accelerate the process of genetic selection needed to adapt kushen to cultivation and improve productivity and product quality.
Publisher: Informa UK Limited
Date: 30-04-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-2010
DOI: 10.1158/1538-7445.AM10-5367
Abstract: Combined hormone replacement therapy (cHRT) comprised of equine estrogens and the synthetic progestin medroxyprogesterone acetate (MPA) increases breast cancer risk in post-menopausal women [1], via as yet undetermined mechanisms. In addition to the progesterone receptor (PR), MPA binds with high affinity to the androgen receptor (AR), and therefore has the potential to elicit actions distinct to those of natural progesterone, which does not bind AR. We have proposed that MPA increases breast cancer risk by binding to the AR and interfering with the ability of endogenous AR ligands to inhibit proliferation of normal breast epithelial cells [2, 3]. To further investigate this proposal, we examined the effect of MPA on 5α-dihydrotestosterone (DHT)-induced AR signaling in normal human breast tissue and in a breast cancer cell line (ZR75-1) that expresses estrogen receptor alpha (ERα), PR, and AR. Normal human breast tissues was obtained from 12 post-menopausal women following surgery for benign or malignant disease. Normal histology was confirmed by a pathologist. Breast tissues (3mm3) were cultured in triplicate for 48 hours on gelatine sponges soaked in media containing 10% steroid deplete fetal calf serum (FCS) and DHT (1nM), MPA (1nM), or the AR antagonist, bicalutamide (Bic 1uM), alone and in combination. Following culture, expression of AR, Ki67 (a marker of cell proliferation) and bcl-2 (a pro-survival factor) was assessed by immunohistochemistry. ZR75-1 cells were cultured for 24 and 48 hours in 10% steroid deplete FCS supplemented with DHT, MPA or the combination, followed by immunoblot analysis to detect AR and an androgen-regulated protein, FKBP5. Statistical analysis was preformed by Wilcoxon signed-rank test unless otherwise stated. Normal human breast tissues possessed significantly higher levels of immunoreactive AR than ERα or PR (p& .0001 t-test for unequal variances). Treatment with DHT significantly increased AR expression (p=0.02) and decreased the percentage of Ki67 positive cells (p=0.03), but had no effect on expression of bcl-2. The effects of DHT on AR and Ki67 were reversed by co-incubation with Bic (p& .05) or MPA (p& .05). In ZR75 cells, DHT increased AR protein levels at 24 and 48 hours and increased FKBP5 protein levels at 48 hours. Co-incubation with MPA reversed the effects of DHT on AR and FKBP5 proteins. Collectively, these data support our hypothesis that MPA interferes with the action of endogenous AR ligands in normal and malignant human breast epithelial cells. This interference of androgen action corresponds to an increased proliferation index in normal human breast epithelial cells, which feasibly contributes to an increased risk of developing breast cancer. 1. Chlebowski., R.T., et al., Jama, 2003. 289: 3243-53 2. Birrell, S.N., et al., Faseb J, 2007. 21 2285-93 3. Peters, A.A., et al., Cancer Res, 2009. 69: 6131-40 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research 2010 Apr 17-21 Washington, DC. Philadelphia (PA): AACR Cancer Res 2010 (8 Suppl):Abstract nr 5367.
Publisher: Wiley
Date: 25-04-2022
DOI: 10.1002/DMRR.3532
Abstract: Gestational diabetes (GDM) is associated with several adverse outcomes for the mother and child. Higher levels of in idual lipids are associated with risk of GDM and metabolic syndrome (MetS), a clustering of risk factors also increases risk for GDM. Metabolic factors can be modified by diet and lifestyle. This review comprehensively evaluates the association between MetS and its components, measured in early pregnancy, and risk for GDM. Databases (Cumulative Index to Nursing and Allied Health Literature, PubMed, Embase, and Cochrane Library) were searched from inception to 5 May 2021. Eligible studies included ≥1 metabolic factor (waist circumference, blood pressure, fasting plasma glucose (FPG), triglycerides, and high‐density lipoprotein cholesterol), measured at weeks' gestation. At least two authors independently screened potentially eligible studies. Heterogeneity was quantified using I 2 . Data were pooled by random‐effects models and expressed as odds ratio and 95% confidence intervals (CIs). Of 7213 articles identified, 40 unique articles were included in meta‐analysis. In analyses adjusting for maternal age and body mass index, GDM was increased with increasing FPG (odds ratios [OR] 1.92 95% CI 1.39–2.64, k = 7 studies) or having MetS (OR 2.52 1.65, 3.84, k = 3). Women with overweight (OR 2.17 95% CI 1.89, 2.50, k = 12) or obesity (OR 4.34 95% CI 2.79–6.74, k = 9) also were at increased risk for GDM. Early pregnancy assessment of glucose or the MetS, offers a potential opportunity to detect and treat in idual risk factors as an approach towards GDM prevention weight loss for pregnant women with overweight or obesity is not recommended. Systematic review registration: PROSPERO CRD42020199225.
Start Date: 03-2022
End Date: 03-2025
Amount: $513,272.00
Funder: Australian Research Council
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