ORCID Profile
0000-0002-2752-730X
Current Organisation
University of Adelaide
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-06-2016
Abstract: In idual and concerted actions of ER and PR highlight the prognostic and therapeutic value of PR in ER + /PR + breast cancers.
Publisher: Bioscientifica
Date: 07-07-2014
DOI: 10.1530/ERC-14-0248
Abstract: While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo . It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain in iduals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.
Publisher: Wiley
Date: 07-03-2011
Publisher: Oxford University Press (OUP)
Date: 12-2011
DOI: 10.1530/EJE-11-0482
Abstract: The measurement of serum testosterone in women is challenging due to lack of trueness, precision, and sensitivity of various available testosterone assays. Accurate assessment of testosterone in women is crucial especially in conditions associated with alleged over- or under-production of testosterone, such as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI). The aim of this study was to measure and compare androgen concentrations in women with PCOS, POI, and female controls and to evaluate the performance of extraction RIA and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in these women. Cross-sectional study. Carefully phenotyped women with POI ( n =208) or PCOS ( n =200) and 45 healthy, regularly cyclic female controls were included. Method comparison analyses were performed for total testosterone, androstenedione (AD), and DHEA, as measured by LC–MS/MS and extraction RIA. All androgen levels were significantly elevated in women with PCOS compared with POI patients ( P .05) and controls ( P .05). Women with POI presented with similar androgen concentrations as controls, except for AD. Compared with measurements by extraction RIA, testosterone, DHEA, and AD concentrations measured by LC–MS/MS were systematically lower. However, using extraction RIA and LC–MS/MS, testosterone, DHEA, and AD measurements were shown to have good agreement as assessed by Bland–Altman analysis and intraclass correlation coefficient: 0.95 (95% confidence interval 0.94–0.91), 0.83 (0.79–0.86), and 0.96 (0.95–0.97) respectively. LC–MS/MS, compared with a labor-intensive extraction RIA, shows good precision, sensitivity, and high accuracy for measuring female testosterone, DHEA, and AD concentrations under various clinical conditions. LC–MS/MS, therefore, represents a convenient and reliable assay for both clinical and research purposes, where androgen measurement in women is required.
Publisher: The Endocrine Society
Date: 08-2012
DOI: 10.1210/ME.2012-1107
Abstract: Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer.
Publisher: No publisher found
Date: 1972
DOI: 10.1016/0006-8993(72)90658-0
Abstract: Beta-blockers can help reduce mortality following acute myocardial infarction (MI) however, whether beta-blockers exert a class effect remains controversial. This study identified all patients with first ST-elevation MI for the period of 2003 to 2010 from the National Health Insurance claims database, Taiwan. We compared patients prescribed carvedilol, bisoprolol, and propranolol. Study outcomes included all-cause death, cardiovascular death, and recurrence of MI. The propensity scores were constructed using multinomial logistic regression to model the receipt of different beta-blockers. Treating carvedilol group as a reference, we employed a simultaneous three-group comparison approach using the Cox regression model with adjustment for the propensity scores to compare the relative risks of various outcomes. Among the 16836 patients, 7591 were prescribed carvedilol, 5934 bisoprolol, and 3311 propranolol. Mean follow-up time was one year. After accounting for baseline differences, patients treated with bisoprolol (HR 0.87, 95% CI 0.72-1.05, p = 0.14) or propranolol (HR 1.07, 95% CI 0.84-1.36, p = 0.58) had a similar risk of all-cause death in comparison with carvedilol. No significant differences were observed among three beta-blocker groups with regard to the risks of cardiovascular death and recurrence of MI. Our results suggest that beta-blockers exert a possible class effect in the treatment of acute MI.
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Bioscientifica
Date: 20-06-2014
DOI: 10.1530/ERC-14-0243
Abstract: While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.
Publisher: American Association for Cancer Research (AACR)
Date: 25-07-2022
DOI: 10.1158/2767-9764.CRC-21-0139
Abstract: Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a “viral mimicry” response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies. Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies.
Publisher: Bioscientifica
Date: 12-2016
DOI: 10.1530/ERC-16-0427
Abstract: The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to ‘push’ ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2015
DOI: 10.1038/NG.3458
Publisher: CSIRO Agriculture and Food
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 08-07-2015
DOI: 10.1038/NATURE14583
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.CELREP.2020.108585
Abstract: Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer s les, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2013
DOI: 10.1007/S12672-013-0135-0
Abstract: The androgen receptor (AR) is expressed in a majority of ovarian carcinomas, but its role in disease development remains unclear. In this study, AR and a novel AR molecular chaperone called small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) were investigated to assess their potential role in ovarian carcinogenesis. First, an AR and SGTA-positive ovarian cancer cell line was identified to examine whether SGTA influenced AR subcellular localization. Next, relative protein levels of AR and SGTA were measured in two sets of clinical s les: (1) 46 serous ovarian carcinomas (stages I-IV), 9 serous borderline tumors, and 11 benign ovarian tumors and (2) 24 patient-matched stage III primary and metastatic serous ovarian tumors. Ablation of SGTA protein in OVCAR3 cells significantly increased AR nuclear localization under basal (p ≤ 0.001) and androgen-stimulated (p ≤ 0.001) conditions. In the first clinical set, AR levels were significantly lower in early- (I/II) and late-stage (III/IV) cancers compared with benign (p ≤ 0.001) but not borderline ovarian tumors. SGTA alone did not discriminate between groups but the AR/SGTA ratio was significantly lower in carcinomas and borderline tumors compared with benign tumors (p ≤ 0.001 and 0.015, respectively). In the second clinical set, matched primary and metastatic serous ovarian cancers did not significantly differ for any parameter measured. Collectively, our results suggest that SGTA can influence AR signaling in ovarian cancer cells and that AR signaling capacity may be reduced with the development but not metastatic progression of serous ovarian cancer.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
DOI: 10.1007/S12672-014-0171-4
Abstract: The androgen receptor (AR) is widely expressed in human tissues and has biological function in many male and female organs. In particular, the AR plays a critical role in the biology and pathology of the prostate gland. AR activity inhibits breast growth and has pleiotropic actions in breast cancer that are subtype-dependent. Expression of AR splice variants (ARVs) and their role in prostate carcinogenesis has been elucidated in recent studies. We hypothesised that ARVs are also expressed in breast cancers and other hormone sensitive tissues. Herein, the expression of five previously identified ARV transcripts with documented transcriptional capacity (AR-V1, -V3, -V4, -V7, and -V9) was examined in 6 breast (MFM223, MDA-MB-453, MDA-MB-231, ZR75.1, MCF-7, T47D), two prostate (VCaP, LNCaP), and one liver (HepG2) cancer cell lines, a human embryonic kidney cell line (HEK293), and a panel of RNAs representing 21 different human tissues. Four ARVs (V1, V3, V7, V9) were detected to some degree in almost all cell lines and tissues. In addition, four novel ARVs containing a cryptic exon 9 (CE9) were detected in MDA-MB-453 and VCaP cells. Sequencing of ARV licons revealed a single nucleotide substitution within CE3 in lung and placental tissue s les that could be translated as an Ile (ATT)>Val (GTT) substitution in the AR-V7 variant protein. Collectively, these data provides insight into the potential complexity of AR transcriptional splicing events in breast cancer cell lines and erse human tissues, thereby establishing a rationale for further exploration of ARVs in breast cancer and other human pathologies.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2015
DOI: 10.1038/NATURE14959
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/0960-0760(95)00005-K
Abstract: Although the majority of primary human breast cancers express the androgen receptor (AR), the role of androgens in breast cancer growth and progression is poorly understood. We have investigated the effects of the naturally occurring androgen, dihydrotestosterone (DHT), and a synthetic non-metabolizable androgen, mibolerone, on the proliferation of six human breast cancer cell lines. The anti-proliferative and proliferative effects of androgens were only observed in cell lines that expressed the AR. Two of the AR-positive cell lines, T47-D and ZR-75-1 were growth inhibited in the presence of either DHT or mibolerone, while the proliferation of MCF-7 and MDA-MB-453 cells was increased by both androgens. Co-incubation of cultures with 1 nM DHT and a 100-fold excess of the androgen receptor antagonist, hydroxyflutamide, resulted in reversal of both inhibitory and stimulatory effects of DHT on T47-D, MCF-7 and MDA-MB-453 cell proliferation, indicating that DHT action is mediated by the AR in these lines. Hydroxyflutamide only partially reversed the DHT-induced growth inhibition of ZR-75-1 cultures, which suggests that growth inhibition of these cells may be mediated by non-AR pathways of DHT (or DHT metabolite) action. Mibolerone action on breast cancer cell growth was similar to that of DHT, with the exception that growth stimulation of MCF-7 and MDA-MB-453 cells was only partially reversed in the presence of a 100-fold excess of hydroxyflutamide. Anandron, another androgen receptor antagonist, was able to reverse all inhibitory and stimulatory actions of the androgens. AR antisense oligonucleotides reduced the level of immunoreactive AR expression in MDA-MB-453 and ZR-75-1 cells by more than 60%, but only reversed the growth inhibitory action of mibolerone in ZR-75-1 cultures. The results suggest that androgen action in breast cancer cell lines may not be solely mediated by binding of androgen to the AR. For ex le, metabolites of DHT with oestrogenic activity, or androgen binding to receptors other than the AR, may explain the ergent responses to androgens observed in different breast cancer cell lines.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2015
Publisher: Springer Science and Business Media LLC
Date: 06-2010
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.FERTNSTERT.2013.01.140
Abstract: To evaluate the expression and function of small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA), an androgen receptor (AR) molecular chaperone, in human ovarian tissues. Examine the effect of SGTA on AR subcellular localization in granulosa tumor cells (KGN) and SGTA expression in ovarian tissues. University-based research laboratory. Archived tissues from premenopausal women and granulosa cells from infertile women receiving assisted reproduction. None. AR subcellular localization and SGTA protein or mRNA levels. SGTA and AR proteins were expressed in the cytoplasm of KGN cells and exposure to androgen stimulated AR nuclear localization. SGTA protein knockdown increased AR nuclear localization at low (0-0.1 nmol/L) but not high (1-10 nmol/L) concentrations of androgen hormone. In ovarian tissues, SGTA was localized to the cytoplasm of granulosa cells at all stages of folliculogenesis and in thecal cells of antral follicles. SGTA protein levels were similar when comparing primordial and primary follicles within core biopsies (n = 40) from women with and without polycystic ovary syndrome (PCOS). Likewise, SGTA mRNA levels were not significantly different in granulosa cells from preovulatory follicles after hyperstimulation of women with and without PCOS. SGTA is present in human ovaries and has the potential to modulate AR signalling, but it may not be differentially expressed in PCOS.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2016
DOI: 10.1158/0008-5472.CAN-15-3372
Abstract: Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3′ to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα+ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα+ breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res 76(19) 5881–93. ©2016 AACR.
Publisher: Oxford University Press (OUP)
Date: 10-2005
DOI: 10.1095/BIOLREPROD.104.039362
Abstract: In this study, we test the hypothesis that the growth-promoting action of androgens on granulosa cells requires paracrine signaling from the oocyte. Mural granulosa cells (MGCs) from small antral (1-3 mm) prepubertal pig follicles were cultured in the presence or absence of denuded oocytes (DO) from the same follicles to determine whether mitogenic and/or steroidogenic responses, to combinations of FSH, insulin-like growth factor 1 (IGF1), and dihydrotestosterone (DHT) were influenced by oocyte-secreted factors (OSFs). To further explore the identity of such factors we performed the same experiments, substituting growth differentiation factor 9 (GDF9), a known OSF, for the DO. OSFs and GDF9 both potently enhanced IGF1-stimulated proliferation, and inhibited FSH-stimulated progesterone secretion. Alone, DHT had little effect on DNA synthesis, but significantly enhanced the mitogenic effects of OSFs or GDF9 in the presence of IGF1. Denuded oocytes, GDF9, and DHT independently inhibited FSH-stimulated progesterone secretion, and androgen, together with DO or GDF9, caused the most potent steroidogenic inhibition. Focusing on mitogenic effects, we demonstrate that both natural androgen receptor (AR) agonists, testosterone and DHT, dose-dependently augmented the mitogenic activity of DO or GDF9. Antiandrogen (hydroxyflutamide) treatment, which is used to block androgen receptor activity, opposed the interaction between androgen and GDF9. In conclusion, androgens stimulate porcine MGC proliferation in vitro by potentiating the growth-promoting effects of oocytes or GDF9, via a mechanism that involves the AR. These signaling pathways are likely to be important regulators of folliculogenesis in vivo, and may contribute to the excess follicle growth that is observed in androgen-treated female animals.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
Publisher: Wiley
Date: 16-08-2018
Publisher: CSIRO Publishing
Date: 2010
DOI: 10.1071/RD10091
Abstract: Lipid droplet proteins regulate the storage and utilisation of intracellular lipids. Evidence is emerging that oocyte lipid utilisation impacts embryo development, but lipid droplet proteins have not been studied in oocytes. The aim of the present study was to characterise the size and localisation of lipid droplets in mouse oocytes during the periovulatory period and to identify lipid droplet proteins as potential biomarkers of oocyte lipid content. Oocyte lipid droplets, visualised using a novel method of staining cumulus–oocyte complexes (COCs) with BODIPY 493/503, were small and diffuse in oocytes of preovulatory COCs, but larger and more centrally located after maturation in response to ovulatory human chorionic gonadotrophin (hCG) in vivo, or FSH + epidermal growth factor in vitro. Lipid droplet proteins Perilipin, Perilipin-2, cell death-inducing DNA fragmentation factor 45-like effector (CIDE)-A and CIDE-B were detected in the mouse ovary by immunohistochemistry, but only Perilipin-2 was associated with lipid droplets in the oocyte. In COCs, Perilipin-2 mRNA and protein increased in response to ovulatory hCG. IVM failed to induce Perilipin-2 mRNA, yet oocyte lipid content was increased in this context, indicating that Perilipin-2 is not necessarily reflective of relative oocyte lipid content. Thus, Perilipin-2 is a lipid droplet protein in oocytes and its induction in the COC concurrent with dynamic reorganisation of lipid droplets suggests marked changes in lipid utilisation during oocyte maturation.
Publisher: EMBO
Date: 30-10-2023
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: Springer Science and Business Media LLC
Date: 04-11-2021
DOI: 10.1038/S41467-021-26612-1
Abstract: Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.
Publisher: Elsevier BV
Date: 08-1973
DOI: 10.1016/0042-6989(73)90009-6
Abstract: Background. To improve clinical and public health outcomes through early human immunodeficiency virus (HIV) detection, fourth-generation antigen/antibody immunoassay (4IA) and supplemental testing results must be returned rapidly. Methods. We examined HIV testing data at Harborview Medical Center (HMC), Massachusetts General Hospital (MGH), and the Medical University of South Carolina (MUSC), which used 4IA and supplemental antibody and nucleic acid tests (NATs). At MGH and MUSC, HIV-1 Western blot (WB) and HIV-2 testing were conducted at a reference laboratory. We compared time from specimen collection to laboratory result for established (positive WB) and acute infections (reactive 4IA, negative/indeterminate WB, detectable NAT), and we calculated testing cost per positive-test result. Results. From 3731 (MUSC) to 19 774 (MGH) tests were conducted 0.01% (MGH) to 0.05% (HMC) were acute infections. Each laboratory had reactive 4IA, WB-negative, or indeterminate specimens without NAT (ie, potential acute infections). Time to result was 1.5 (HMC) to 5.2 days (MGH) for acute and 1.0 (HMC) to 5.2 days (MGH) for established infections. Costs were $1054 (MGH) to $1521 (MUSC). Conclusions. Conducting supplemental testing in-house lowered turnaround times, which may be further reduced with rapid HIV-1/HIV-2 differentiation tests. Hospitals may benefit from quantitative NATs not requiring physician orders, so all potential acute infections receive NAT.
Publisher: Springer Science and Business Media LLC
Date: 02-12-2014
DOI: 10.1038/ONC.2013.508
Publisher: American Chemical Society (ACS)
Date: 25-07-2023
Publisher: Bioscientifica
Date: 05-2019
DOI: 10.1530/ERC-18-0571
Abstract: The androgen receptor (AR) is a ligand-activated transcription factor that drives prostate cancer. Since therapies that target the AR are the mainstay treatment for men with metastatic disease, it is essential to understand the molecular mechanisms underlying oncogenic AR signaling in the prostate. miRNAs are small, non-coding regulators of gene expression that play a key role in prostate cancer and are increasingly recognized as targets or modulators of the AR signaling axis. In this review, we examine the regulation of AR signaling by miRNAs and vice versa and discuss how this interplay influences prostate cancer growth, metastasis and resistance to therapy. Finally, we explore the potential clinical applications of miRNAs implicated in the regulation of AR signaling in this prevalent hormone-driven disease.
Publisher: Oxford University Press (OUP)
Date: 19-08-2009
Publisher: Wiley
Date: 15-07-1974
Abstract: We used participant-produced photography to investigate everyday commuting practices in Cambridge, UK. Photovoice served as an observational method for producing ethnographically rich data. A total of 19 participants produced over 500 photos about their journeys to and from work and took part in photo-elicitation interviews. Three themes emerged. First, many images depicted 'well-being' in commuting, for ex le, beautiful landscapes. Second, during elicitation interviews, participants described positive images that they intended but failed to capture in photos. Third, those participants who did not depict well-being described a lack of choice in their commuting, while those who acknowledged well-being seemed to do so in order to make practices of commuting meaningful and habitable. While our interpretations of photos of well-being could be subject to a methodological fallacy relating to a preference for positive over negative images in lay photography, we nonetheless suggest that the rich visual and oral narratives indicate a 'real' experience, albeit elicited through the photovoice.
Publisher: Research Square Platform LLC
Date: 09-2020
DOI: 10.21203/RS.3.RS-62718/V1
Abstract: Antagonistic sex hormone activity occurs in mammary gland development, whereby estrogen stimulates and androgen inhibits post-pubertal growth, but the mechanistic basis of this is largely unknown. Whether sex hormone antagonism occurs in the context of breast cancer is also unclear. The estrogen receptor alpha (ER) unequivocally drives the majority of breast malignancies, but the role of the androgen receptor (AR) is controversial, particularly in the context of ER-positive (ER+) tumours resistant to standard-of-care ER targeting therapies. The controversy has constrained clinical implementation of new drugs that influence AR activity for treatment of this disease. Using a erse panel of cell line and patient-derived models of ER+ breast cancer, we demonstrate that activation, not suppression, of AR activity exerts potent anti-tumour activity in multiple clinically relevant contexts, including tumours resistant to ER targeting therapy. We also show that AR agonists can be combined with old and new (i.e. Palbociclib, a CDK4/6 inhibitor) standard-of-care agents to enhance therapeutic efficacy. Mechanistically, agonist activation of AR altered the distribution of ER and its coactivators (p300, SRC-3) on chromatin, resulting in repression of ER-regulated cell cycle genes and up-regulation of AR target genes, including known tumour suppressors. Consistent with the mechanistic findings, a gene signature of AR activity derived from in vivo models positively predicted disease survival in multiple large, well-annotated clinical cohorts of ER+ breast cancer, outperforming existing pan-cancer or breast cancer specific signatures. These findings provide compelling evidence that AR has a tumour suppressor role in ER+ breast cancer and resolves an important clinical controversy concerning the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
Publisher: Elsevier BV
Date: 08-1972
DOI: 10.1016/0006-8993(72)90290-9
Abstract: By definition, the terms sepsis and septic shock refer to a potentially fatal infectious state in which the early administration of an effective antibiotic is the most significant determinant of the outcome. Because of the global spread of resistant bacteria, the efficacy of antibiotics has been severely compromised.
Publisher: Elsevier BV
Date: 08-1973
DOI: 10.1016/0042-6989(73)90010-2
Abstract: Myosin IXa (Myo9a) is a motor protein that is highly expressed in the brain. However, the role of Myo9a in neurons remains unknown. Here, we investigated Myo9a function in hippoc al synapses. In rat hippoc al neurons, Myo9a localizes to the postsynaptic density (PSD) and binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit. Myo9a(+/-) mice displayed a thicker PSD and increased levels of PSD95 and surface AMPAR expression. Furthermore, synaptic transmission, long-term potentiation (LTP) and cognitive functions were impaired in Myo9a(+/-) mice. Together, these results support a key role for Myo9a in controlling the molecular structure and function of hippoc al synapses.
Publisher: Elsevier BV
Date: 05-2020
DOI: 10.1016/J.JSBMB.2019.105548
Abstract: Medroxyprogesterone acetate (MPA) is a first generation progestin that has been in clinical use for various hormonal conditions in women since the 1960s. Although developed as a progesterone receptor (PR) agonist, MPA also has strong binding affinity for other steroid receptors. This promiscuity confounds the mechanistic action of MPA in target cells that express multiple steroid receptors. This study is the first to assess the relative contribution of progesterone, androgen and glucocorticoid receptors in mediating the transcriptional activity of MPA on endogenous targets in breast cancer cells that endogenously express all three receptors at comparable levels. Gene expression profiling in estrogen receptor positive (ER+) ZR-75-1 breast cancer cells demonstrated that although the MPA-regulated transcriptome strongly overlapped with that of Progesterone (PROG), 5α-dihydrotestosterone (DHT) and Dexamethasone (DEX), it clustered most strongly with that of PROG, suggesting that MPA predominantly acts via the progesterone receptor (PR) rather than androgen receptor (AR) or glucocorticoid receptor (GR). Subsequent experiments manipulating levels of these receptors, either through specific culture conditions or with lentiviral shRNAs targeting in idual receptors, also revealed a stronger contribution of PR compared to AR and GR on the expression of endogenous target genes that are either commonly regulated by all ligands or specifically regulated only by MPA. A predominant contribution of PR to MPA action in ER+ T-47D breast cancer cells was also observed, although a stronger role for AR was evident in T-47D compared to that observed in ZR-75-1 cells. Network analysis of ligand-specific and commonly regulated genes demonstrated that MPA utilises different transcription factors and signalling pathways to inhibit proliferation compared with PROG. This study reaffirms the importance of PR in mediating MPA action in an endogenous breast cancer context where multiple steroid receptors are co-expressed and has potential implications for PR-targeting therapeutic strategies in ER+ breast cancer.
Publisher: Oxford University Press (OUP)
Date: 07-2004
Publisher: Cambridge University Press
Date: 19-12-2015
Publisher: Springer Science and Business Media LLC
Date: 30-06-2016
DOI: 10.1038/SREP28950
Abstract: Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) has been implicated as a co-chaperone and regulator of androgen and growth hormone receptor (AR, GHR) signalling. We investigated the functional consequences of partial and full Sgta ablation in vivo using Cre-lox Sgta -null mice. Sgta +/− breeders generated viable Sgta −/− offspring, but at less than Mendelian expectancy. S gta −/− breeders were subfertile with small litters and higher neonatal death ( P 0.02). Body size was significantly and proportionately smaller in male and female Sgta −/− (vs WT, Sgta +/− P 0.001) from d19. Serum IGF-1 levels were genotype- and sex-dependent. Food intake, muscle and bone mass and adiposity were unchanged in Sgta −/− . Vital and sex organs had normal relative weight, morphology and histology, although certain androgen-sensitive measures such as penis and preputial size and testis descent, were greater in Sgta −/− . Expression of AR and its targets remained largely unchanged, although AR localisation was genotype- and tissue-dependent. Generally expression of other TPR-containing proteins was unchanged. In conclusion, this thorough investigation of SGTA-null mutation reports a mild phenotype of reduced body size. The model’s full potential likely will be realised by genetic crosses with other models to interrogate the role of SGTA in the many diseases in which it has been implicated.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2013
Publisher: Impact Journals, LLC
Date: 05-11-2015
Publisher: Springer Science and Business Media LLC
Date: 18-01-2021
DOI: 10.1038/S41591-020-01168-7
Abstract: The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a erse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
Publisher: Bioscientifica
Date: 02-2019
DOI: 10.1530/ERC-18-0333
Abstract: The role of androgen receptor (AR) in endocrine-resistant breast cancer is controversial and clinical trials targeting AR with an AR antagonist (e.g., enzalutamide) have been initiated. Here, we investigated the consequence of AR antagonism using in vitro and in vivo models of endocrine resistance. AR antagonism in MCF7-derived tamoxifen-resistant (TamR) and long-term estrogen-deprived breast cancer cell lines were achieved using siRNA-mediated knockdown or pharmacological inhibition with enzalutamide. The efficacy of enzalutamide was further assessed in vivo in an estrogen-independent endocrine-resistant patient-derived xenograft (PDX) model. Knockdown of AR inhibited the growth of the endocrine-resistant cell line models. Microarray gene expression profiling of the TamR cells following AR knockdown revealed perturbations in proliferative signaling pathways upregulated in endocrine resistance. AR loss also increased some canonical ER signaling events and restored sensitivity of TamR cells to tamoxifen. In contrast, enzalutamide did not recapitulate the effect of AR knockdown in vitro , even though it inhibited canonical AR signaling, which suggests that it is the non-canonical AR activity that facilitated endocrine resistance. Enzalutamide had demonstrable efficacy in inhibiting AR activity in vivo but did not affect the growth of the endocrine-resistant PDX model. Our findings implicate non-canonical AR activity in facilitating an endocrine-resistant phenotype in breast cancer. Unlike canonical AR signaling which is inhibited by enzalutamide, non-canonical AR activity is not effectively antagonized by enzalutamide, and this has important implications in the design of future AR-targeted clinical trials in endocrine-resistant breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2014
DOI: 10.1007/S12020-014-0335-6
Abstract: Kit ligand (KITL) is an important granulosa cell-derived growth factor in ovarian folliculogenesis, but its expression and function in human granulosa cells are currently poorly understood. Based on studies performed in animal models, it was hypothesised that KITL gene expression in human granulosa cells is regulated by androgens and/or growth differentiation factor 9 (GDF9). We utilised two models of human granulosa cells, the KGN granulosa tumour cell line and cumulus granulosa cells obtained from preovulatory follicles of women undergoing assisted reproduction. Cells were treated with combinations of 5α-dihydrotestosterone (DHT), recombinant mouse GDF9, and the ALK4/5/7 inhibitor SB431542. KITL mRNA levels were measured by quantitative real-time PCR. No change in KITL mRNA expression was observed after DHT treatment under any experimental conditions, but GDF9 treatment resulted in a significant decrease in KITL mRNA levels in both KGN and cumulus cells. The effect of GDF9 was abolished by the addition of SB431542. These results indicate that KITL is not directly regulated by androgen signalling in human granulosa cells. Moreover, this study provides the first evidence that GDF9 negatively regulates KITL gene expression in human granulosa cells providing new information on the regulation of these important growth factors in the human ovary.
Publisher: Springer Science and Business Media LLC
Date: 06-2015
DOI: 10.1007/S10911-015-9344-1
Abstract: The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.
Publisher: Informa UK Limited
Date: 15-01-2012
DOI: 10.4161/CC.21195
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.MCE.2011.09.019
Abstract: Synthetic progestins are used clinically to treat a variety of women's health issues. Although progestins are designed to signal through the progesterone receptor (PR) to elicit specific pharmacological effects, they can also variably bind to and influence the activity of other nuclear receptors within target tissues, particularly the androgen and glucocorticoid receptors and, in some cases, they regulate mineralocorticoid and estrogen receptors. This article reviews current knowledge on progestin cross-talk to nuclear receptors other than PR, their resultant effect on receptor function in different in vitro models and the potential consequences of this activity for breast, ovarian and endometrial cancer. The impact of cell and tissue context, assay type, steroid metabolism and hormonal milieu in determining progestin-mediated activity are also presented. Collectively this review highlights the complexity of progestin action and the need for consideration of multiple mechanisms that act in concert to influence their ultimate biological activity.
Publisher: Wiley
Date: 20-09-2011
Publisher: Elsevier BV
Date: 08-2007
Publisher: The Endocrine Society
Date: 07-2006
DOI: 10.1210/JC.2006-0069
Abstract: Context: The cause of polycystic ovary syndrome (PCOS) is unknown, although genetic and environmental influences are clearly implicated. Some genetic studies have suggested the involvement of X-linked genes in PCOS, but the influence of X chromosome inactivation (XCI) on manifestation of this disorder has not previously been examined. Objective: The objective of the study was to test the null hypothesis that XCI has no influence on clinical presentation of PCOS. Design: We examined patterns of XCI between sister pairs with the same genotype at a polymorphic locus on the X chromosome in families with PCOS. Setting: The study was conducted at a private practice. Participants: PCOS was defined as hyperandrogenemia with chronic anovulation. Forty families were studied in which DNA was obtained from at least one parent, the proband, and one sister that could be accurately diagnosed as being affected or unaffected. Main Outcome Measure(s): Relative expression of two X-linked alleles was determined, and the ratio of one to the other represented the pattern of XCI. Results: The statistical odds on a different clinical presentation between sisters was approximately 29 times higher in sister pairs with different patterns of XCI, compared with sister pairs with the same pattern of XCI (odds ratio 28.9 95% confidence interval 4.0–206 P = 0.0008). Conclusions: This study provides evidence to refute the null hypothesis and propose a closer inspection of X-linked genes in PCOS, one in which both genotype and epigenotype are considered. Environmental determinants of PCOS may alter clinical presentation via epigenetic modifications, which currently remain undetected in traditional genetic analyses.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2021
Publisher: The Company of Biologists
Date: 15-09-2006
DOI: 10.1242/JCS.03105
Abstract: Oocytes regulate follicle growth by secreting paracrine growth factors that act on neighbouring granulosa cells (GCs). Those factors identified to date are mainly members of the transforming growth factor-β (TGFβ) superfamily, but little is known about which specific receptor/signalling system(s) they employ. This study was conducted to determine the requisite pathways utilised by oocytes to promote GC proliferation. We used an established oocyte-secreted mitogen bioassay, where denuded mouse oocytes are co-cultured with mural GCs. Oocytes, growth differentiation factor-9 (GDF9), TGFβ1 and activin-A all promoted GC DNA synthesis, but bone-morphogenetic protein 6 (BMP6) did not. Subsequently, we tested the capacity of various TGFβ superfamily receptor ectodomains (ECD) to neutralise oocyte- or specific growth factor-stimulated GC proliferation. The BMP type-II receptor (BMPR-II) ECD antagonised oocyte and GDF9 bioactivity dose-dependently, but had no or minimal effect on TGFβ1 and activin-A bioactivity, demonstrating its specificity. The TGFβR-II, activinR-IIA and activinR-IIB ECDs all failed to neutralise oocyte- or GDF9-stimulated GC DNA synthesis, whereas they did antagonise the activity of their respective native ligands. An activin receptor-like kinase (ALK) 4/5/7 inhibitor, SB431542, also antagonised both oocyte and GDF9 bioactivity in a dose-dependent manner. Consistent with these findings, oocytes, GDF9 and TGFβ1 all activated SMAD2/3 reporter constructs in transfected GC, and led to phosphorylation of SMAD2 proteins in treated cells. Surprisingly, oocytes did not activate the SMAD1/5/8 pathway in transfected GCs although exogenous BMP6 did. This study indicates that oocyte paracrine factors primarily utilise a similar signalling pathway first identified for GDF9 that employs an unusual combination of TGFβ superfamily receptors, the BMPR-II and a SMAD2/3 stimulatory ALK (4, 5 or 7), for transmitting their mitogenic actions in GC. This cell-signalling pathway may also have relevance in the hypothalamic-pituitary axis and in germ-somatic cell interactions in the testis.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2016
DOI: 10.1038/NRC.2016.116
Abstract: Most breast cancers are driven by oestrogen receptor-α. Anti-oestrogenic drugs are the standard treatment for these breast cancers however, treatment resistance is common, necessitating new therapeutic strategies. Recent preclinical and historical clinical studies support the use of progestogens to activate the progesterone receptor (PR) in breast cancers. However, widespread controversy exists regarding the role of progestogens in this disease, hindering the clinical implementation of PR-targeted therapies. Herein, we present and discuss data at the root of this controversy and clarify the confusion and misinterpretations that have consequently arisen. We then present our view on how progestogens may be safely and effectively used in treating breast cancer.
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: Elsevier BV
Date: 08-1973
DOI: 10.1016/0042-6989(73)90008-4
Abstract: Multi-colored fluorescent proteins targeted to plastids have provided new insights on the dynamic behavior of these organelles and their interactions with other cytoplasmic components and compartments. Sub-plastidic components such as thylakoids, stroma, the inner and outer membranes of the plastid envelope, nucleoids, plastoglobuli, and starch grains have been efficiently highlighted in living plant cells. In addition, stroma filled membrane extensions called stromules have drawn attention to the dynamic nature of the plastid and its interactions with the rest of the cell. Use of dual and triple fluorescent protein combinations has begun to reveal plastid interactions with mitochondria, the nucleus, the endoplasmic reticulum and F-actin and suggests integral roles of plastids in retrograde signaling, cell to cell communication as well as plant-pathogen interactions. While the rapid advances and insights achieved through fluorescent protein based research on plastids are commendable it is necessary to endorse meaningful observations but subject others to closer scrutiny. Here, in order to develop a better and more comprehensive understanding of plastids and their extensions we provide a critical appraisal of recent information that has been acquired using targeted fluorescent protein probes.
Start Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2010
Funder: Congressionally Directed Medical Research Programs
View Funded ActivityStart Date: 2007
End Date: 2009
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2007
End Date: 2010
Funder: National Health and Medical Research Council
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