55 results on '"Phillipou, A"'
Search Results
2. Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe
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Bradley, Erin, Fusani, Lucia, Chung, Chun-wa, Craggs, Peter D., Demont, Emmanuel H., Humphreys, Philip G., Mitchell, Darren J., Phillipou, Alex, Rioja, Inmaculada, Shah, Rishi R., Wellaway, Christopher R., Prinjha, Rab K., Palmer, David S., Kerr, William J., Reid, Marc, Wall, Ian D., and Cookson, Rosa
- Abstract
Small-molecule-mediated disruption of the protein–protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.
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- 2023
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3. Design and Characterization of 1,3-Dihydro‑2H‑benzo[d]azepin-2-ones as Rule-of‑5 Compliant Bivalent BET Inhibitors.
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Bamborough, Paul, Chung, Chun-wa, Goodwin, Nicole C., Mitchell, Darren J., Neipp, Christopher E., Phillipou, Alex, Preston, Alex, Prinjha, Rab K., Soden, Peter E., Watson, Robert J., and Demont, Emmanuel H.
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- 2023
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4. A peer mentoring program for eating disorders: improved symptomatology and reduced hospital admissions, three years and a pandemic on
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Raspovic, Anita, Duck, Rachael, Synnot, Andrew, Caldwell, Belinda, Phillipou, Andrea, Castle, David, Newton, Richard, Brennan, Leah, Jenkins, Zoe, Cunich, Michelle, Maguire, Sarah, and Miskovic-Wheatley, Jane
- Abstract
Peer mentoring involves people using their personal lived experiences to support others. A pilot Peer Mentoring Program for eating disorders (PMP) offered through Eating Disorders Victoria (EDV) was evaluated previously, showing positive findings. Subsequent demand for the program was high. As a result, the PMP has been running and evolving over time. Key changes included a broadening of program eligibility to all individuals with an eating disorder (versus only people recently discharged from hospital), larger participant numbers and a shift to largely online delivery due to COVID-19. This study evaluated this current version of the PMP. Five rounds of anonymised PMP data, from July 2020 to April 2022, were evaluated with mentee prior consent. Individuals in recovery from an eating disorder (mentees), had been paired with individuals recovered from an eating disorder for 2-years minimum (mentors). PMP rounds were 6-months, with fortnightly meetings. Mentees overall showed improvements in eating disorder symptoms and psychological wellbeing. Fewer mentee eating disorder-related hospital admissions during PMP participation were reported, compared to the 6-months prior. Feedback from mentees identified many positive benefits and some challenges. Overall, the results provide further support for the use of peer mentoring in eating disorder recovery.
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- 2024
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5. Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.
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Aylott, Helen E., Atkinson, Stephen J., Bamborough, Paul, Bassil, Anna, Chung, Chun-wa, Gordon, Laurie, Grandi, Paola, Gray, James R. J., Harrison, Lee A., Hayhow, Thomas G., Messenger, Cassie, Mitchell, Darren, Phillipou, Alexander, Preston, Alex, Prinjha, Rab K., Rianjongdee, Francesco, Rioja, Inmaculada, Seal, Jonathan T., Wall, Ian D., and Watson, Robert J.
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- 2021
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6. Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors
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Lucas, Simon C. C., Atkinson, Stephen J., Chung, Chun-wa, Davis, Rob, Gordon, Laurie, Grandi, Paola, Gray, James J. R., Grimes, Thomas, Phillipou, Alexander, Preston, Alex G., Prinjha, Rab K., Rioja, Inmaculada, Taylor, Simon, Tomkinson, Nicholas C. O., Wall, Ian, Watson, Robert J., Woolven, James, and Demont, Emmanuel H.
- Abstract
Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitroclearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71(GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivorat and dog pharmacokinetics.
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- 2021
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7. Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors
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Seal, Jonathan T., Atkinson, Stephen J., Bamborough, Paul, Bassil, Anna, Chung, Chun-wa, Foley, James, Gordon, Laurie, Grandi, Paola, Gray, James R. J., Harrison, Lee A., Kruger, Ryan G., Matteo, Jeanne J., McCabe, Michael T., Messenger, Cassie, Mitchell, Darren, Phillipou, Alex, Preston, Alex, Prinjha, Rab K., Rianjongdee, Francesco, Rioja, Inmaculada, Taylor, Simon, Wall, Ian D., Watson, Robert J., Woolven, James M., Wyce, Anastasia, Zhang, Xi-Ping, and Demont, Emmanuel H.
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The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23(GSK809) and furan 24(GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.
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- 2021
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8. Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System
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Greenhough, Luke A., Clarke, Gabriella, Phillipou, Alexander N., Mazani, Faith, Karamshi, Bhumika, Rowe, Sam, Rowland, Paul, Messenger, Cassie, Haslam, Carl P., Bingham, Ryan P., and Craggs, Peter D.
- Abstract
The predominant assay detection methodologies used for enzyme inhibitor identification during early-stage drug discovery are fluorescence-based. Each fluorophore has a characteristic fluorescence decay, known as the fluorescence lifetime, that occurs throughout a nanosecond-to-millisecond timescale. The measurement of fluorescence lifetime as a reporter for biological activity is less common than fluorescence intensity, even though the latter has numerous issues that can lead to false-positive readouts. The confirmation of hit compounds as true inhibitors requires additional assays, cost, and time to progress from hit identification to lead drug-candidate optimization. To explore whether the use of fluorescence lifetime technology (FLT) can offer comparable benefits to label-free-based approaches such as RapidFire mass spectroscopy (RF-MS) and a superior readout compared to time-resolved fluorescence resonance energy transfer (TR-FRET), three equivalent assays were developed against the clinically validated tyrosine kinase 2 (TYK2) and screened against annotated compound sets. FLT provided a marked decrease in the number of false-positive hits when compared to TR-FRET. Further cellular screening confirmed that a number of potential inhibitors directly interacted with TYK2 and inhibited the downstream phosphorylation of the signal transducer and activator of transcription 4 protein (STAT4).
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- 2021
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9. Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System
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Greenhough, Luke A., Clarke, Gabriella, Phillipou, Alexander N., Mazani, Faith, Karamshi, Bhumika, Rowe, Sam, Rowland, Paul, Messenger, Cassie, Haslam, Carl P., Bingham, Ryan P., and Craggs, Peter D.
- Abstract
The predominant assay detection methodologies used for enzyme inhibitor identification during early-stage drug discovery are fluorescence-based. Each fluorophore has a characteristic fluorescence decay, known as the fluorescence lifetime, that occurs throughout a nanosecond-to-millisecond timescale. The measurement of fluorescence lifetime as a reporter for biological activity is less common than fluorescence intensity, even though the latter has numerous issues that can lead to false-positive readouts. The confirmation of hit compounds as true inhibitors requires additional assays, cost, and time to progress from hit identification to lead drug-candidate optimization. To explore whether the use of fluorescence lifetime technology (FLT) can offer comparable benefits to label-free-based approaches such as RapidFire mass spectroscopy (RF-MS) and a superior readout compared to time-resolved fluorescence resonance energy transfer (TR-FRET), three equivalent assays were developed against the clinically validated tyrosine kinase 2 (TYK2) and screened against annotated compound sets. FLT provided a marked decrease in the number of false-positive hits when compared to TR-FRET. Further cellular screening confirmed that a number of potential inhibitors directly interacted with TYK2 and inhibited the downstream phosphorylation of the signal transducer and activator of transcription 4 protein (STAT4).
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- 2021
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10. GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins.
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Watson, Robert J., Bamborough, Paul, Barnett, Heather, Chung, Chun-wa, Davis, Rob, Gordon, Laurie, Grandi, Paola, Petretich, Massimo, Phillipou, Alex, Prinjha, Rab K., Rioja, Inmaculada, Soden, Peter, Werner, Thilo, and Demont, Emmanuel H.
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- 2020
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11. The contribution of sleep to anorexia nervosa severity
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Malcolm, Amy, Toh, Wei Lin, Crocker, Kaitlyn, and Phillipou, Andrea
- Abstract
Purpose: Anorexia nervosa (AN) is associated with poor sleep and altered circadian rhythms. Evidence is unclear as to whether these features relate to ongoing psychiatric symptoms of AN, or are merely concomitant with low weight. In this study, we sought to evaluate subjective sleep quality and sleep–wake preferences in a sample of individuals with lifetime AN. Furthermore, we aimed to examine whether sleep quality would significantly predict AN symptom severity, after accounting for demographic features and negative emotions (depression, anxiety and stress). Methods: Adults with a lifetime diagnosis of AN (n= 96) or no lifetime psychiatric diagnoses (NC; n= 246) completed an online survey assessing demographics, sleep quality, circadian sleep–wake preferences, eating disorder symptoms, and negative emotions. Results: AN participants reported significantly poorer sleep quality overall, including increased sleep disturbances, use of sleep medications, and daytime dysfunction, as compared to NC participants. Groups did not differ significantly in circadian sleep–wake preferences. Regression analysis showed that among AN participants, sleep quality and negative emotions significantly predicted AN symptom severity, while sex and body mass index (BMI) did not. Conclusion: The findings demonstrate that poor sleep quality was associated with more severe symptoms of AN, even when accounting for negative emotions and BMI. Future research should investigate causal interactions between sleep quality and AN symptom severity longitudinally and across different recovery stages. Level of evidence: Level III—Cohort and case–control analytic studies.
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- 2021
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12. GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins
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Watson, Robert J., Bamborough, Paul, Barnett, Heather, Chung, Chun-wa, Davis, Rob, Gordon, Laurie, Grandi, Paola, Petretich, Massimo, Phillipou, Alex, Prinjha, Rab K., Rioja, Inmaculada, Soden, Peter, Werner, Thilo, and Demont, Emmanuel H.
- Abstract
Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.
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- 2020
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13. Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode
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Lucas, Simon C. C., Atkinson, Stephen J., Bamborough, Paul, Barnett, Heather, Chung, Chun-wa, Gordon, Laurie, Mitchell, Darren J., Phillipou, Alexander, Prinjha, Rab K., Sheppard, Robert J., Tomkinson, Nicholas C. O., Watson, Robert J., and Demont, Emmanuel H.
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Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55(GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.
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- 2020
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14. Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation
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Liddle, John, Hutchinson, Jonathan P., Kitchen, Semra, Rowland, Paul, Neu, Margarete, Cecconie, Ted, Holmes, Duncan S., Jones, Emma, Korczynska, Justyna, Koumantou, Despoina, Lea, Jonathan D., Nickels, Leng, Pemberton, Michelle, Phillipou, Alex, Schneck, Jessica L., Sheehan, Hester, Tinworth, Christopher P., Uings, Iain, Wojno-Picon, Justyna, Young, Robert J., and Stratikos, Efstratios
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ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1. (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid is a natural product found in Dodonaea viscosathat constitutes a submicromolar, highly selective, and cell-active modulator of ERAP1. Although the compound activates hydrolysis of small model substrates, it is a competitive inhibitor for physiologically relevant longer peptides. Crystallographic analysis confirmed that the compound targets the regulatory site of the enzyme that normally binds the C-terminus of the peptide substrate. Our findings constitute a novel starting point for the development of selective ERAP1 modulators that have potential for further clinical development.
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- 2020
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15. Cellular Target Engagement Approaches to Monitor Epigenetic Reader Domain Interactions
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Phillipou, Alexander N., Lay, Charles S., Carver, Charlotte E., Messenger, Cassie, Evans, John P., Lewis, Antonia J., Gordon, Laurie J., Mahmood, Mahnoor, Greenhough, Luke A., Sammon, Douglas, Cheng, Aaron T., Chakraborty, Syandan, Jones, Emma J., Lucas, Simon C. C., Gatfield, Kelly M., Brierley, David J., and Craggs, Peter D.
- Abstract
Malfunctions in the basic epigenetic mechanisms such as histone modifications, DNA methylation, and chromatin remodeling are implicated in a number of cancers and immunological and neurodegenerative conditions. Within GlaxoSmithKline (GSK) we have utilized a number of variations of the NanoBRET technology for the direct measurement of compound–target engagement within native cellular environments to drive high-throughput, routine structure–activity relationship (SAR) profiling across differing epigenetic targets. NanoBRET is a variation of the bioluminescence resonance energy transfer (BRET) methodology utilizing proteins of interest fused to either NanoLuc, a small, high-emission-intensity luciferase, or HaloTag, a modified dehalogenase enzyme that can be selectively labeled with a fluorophore. The combination of these two technologies has enabled the application of NanoBRET to biological systems such as epigenetic protein–protein interactions, which have previously been challenging. By synergizing target engagement assays with more complex primary cell phenotypic assays, we have been able to demonstrate compound–target selectivity profiles to enhance cellular potency and offset potential liability risks. Additionally, we have shown that in the absence of a robust, cell phenotypic assay, it is possible to utilize NanoBRET target engagement assays to aid chemistry in progressing at a higher scale than would have otherwise been achievable. The NanoBRET target engagement assays utilized have further shown an excellent correlation with more reductionist biochemical and biophysical assay systems, clearly demonstrating the possibility of using such assay systems at scale, in tandem with, or in preference to, lower-throughput cell phenotypic approaches.
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- 2020
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16. Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review
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Yolland, Caitlin O. B., Phillipou, Andrea, Castle, David J., Neill, Erica, Hughes, Matthew E., Galletly, Cherrie, Smith, Zoe M., Francis, Paul S., Dean, Olivia M., Sarris, Jerome, Siskind, Dan, Harris, Anthony W. F., and Rossell, Susan L.
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Objectives:Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods:The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results:This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion:Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.
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- 2020
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17. Cellular Target Engagement Approaches to Monitor Epigenetic Reader Domain Interactions
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Phillipou, Alexander N., Lay, Charles S., Carver, Charlotte E., Messenger, Cassie, Evans, John P., Lewis, Antonia J., Gordon, Laurie J., Mahmood, Mahnoor, Greenhough, Luke A., Sammon, Douglas, Cheng, Aaron T., Chakraborty, Syandan, Jones, Emma J., Lucas, Simon C.C., Gatfield, Kelly M., Brierley, David J., and Craggs, Peter D.
- Abstract
Malfunctions in the basic epigenetic mechanisms such as histone modifications, DNA methylation, and chromatin remodeling are implicated in a number of cancers and immunological and neurodegenerative conditions. Within GlaxoSmithKline (GSK) we have utilized a number of variations of the NanoBRET technology for the direct measurement of compound–target engagement within native cellular environments to drive high-throughput, routine structure–activity relationship (SAR) profiling across differing epigenetic targets. NanoBRET is a variation of the bioluminescence resonance energy transfer (BRET) methodology utilizing proteins of interest fused to either NanoLuc, a small, high-emission-intensity luciferase, or HaloTag, a modified dehalogenase enzyme that can be selectively labeled with a fluorophore. The combination of these two technologies has enabled the application of NanoBRET to biological systems such as epigenetic protein–protein interactions, which have previously been challenging. By synergizing target engagement assays with more complex primary cell phenotypic assays, we have been able to demonstrate compound–target selectivity profiles to enhance cellular potency and offset potential liability risks. Additionally, we have shown that in the absence of a robust, cell phenotypic assay, it is possible to utilize NanoBRET target engagement assays to aid chemistry in progressing at a higher scale than would have otherwise been achievable. The NanoBRET target engagement assays utilized have further shown an excellent correlation with more reductionist biochemical and biophysical assay systems, clearly demonstrating the possibility of using such assay systems at scale, in tandem with, or in preference to, lower-throughput cell phenotypic approaches.
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- 2020
- Full Text
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18. Peer mentoring for eating disorders: results from the evaluation of a pilot program
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Beveridge, Jennifer, Phillipou, Andrea, Jenkins, Zoe, Newton, Richard, Brennan, Leah, Hanly, Freya, Torrens-Witherow, Benjamin, Warren, Narelle, Edwards, Kelly, and Castle, David
- Abstract
Eating disorders (EDs) are serious psychiatric illnesses that have high rates of morbidity and mortality, and low long-term recovery rates. Peer mentor programs (PMPs) have been associated with reduced psychiatric hospitalisation and shorter lengths of stay for those with other severe mental illnesses. The present study evaluated the feasibility and preliminary efficacy of a PMP for individuals with EDs in improving symptomatology and quality of life. Thirty mentees and seventeen mentors were recruited. The PMP involved thirteen sessions over 6 months. Participants completed measures assessing ED symptomatology, quality of life (QoL), mood and perceived disability. Changes in symptomatology before and after the PMP were tested by Wilcoxon signed rank tests. Semi-structured interviews were conducted for qualitative evaluation of the PMP. The program was deemed to have moderate feasibility with eight of 30 mentees, and two of 17 mentors withdrawing. Completion rates ranged from 2 to 16 sessions, and between 3 and 45 weeks. Mentees demonstrated improvements in body mass index, QoL, ED symptomatology, mood (depression, anxiety and tension/stress) and perceived disability from pre- to post-program. Mentors demonstrated significant increases in ED symptomatology, but no worsening of QoL, mood or perceived disability. Qualitative findings from both mentees and mentors were positive: emergent themes included hope for recovery, a sense of agency and inspiration gained from interaction with someone with lived experience of an ED. This pilot study suggests feasibility of the PMP for individuals with EDs. Mentees demonstrated improvements in ED symptomatology, QoL, mood and perceived disability. However, the increase in ED symptomatology reported by the mentors over the PMP highlights potential risks and the need for thorough monitoring while preliminary evaluation is undertaken. The mentoring relationship was a positive experience for both mentees and mentors, instilling an increased hope for recovery in mentees and an opportunity for mentors to reflect on their own recovery with increased confidence. The novel relationship formed throughout mentorship highlights a potential gap in current clinical support services, which warrants further exploration within a controlled trial. Australian and New Zealand Clinical Trials Registration Number: ACTRN12617001412325. Retrospectively registered: 05/10/2017. Date of first enrolment: 20/01/2017. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373741&isReview=true
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- 2019
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19. Correction: An evaluation of the predictive validity of the URICA and ANSOCQ scales for weight gain in adults with AN in an outpatient eating disorders program: a prospective cohort study
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Green, Jessica, Phillipou, Andrea, Castle, David, Cistullo, Leonardo, and Newton, Richard
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- 2023
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20. The importance of terminology, lived experience inclusion and scientific discussion regarding end-of-life care in anorexia nervosa: a response to Gaudiani et al.
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Phillipou, Andrea
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Whether or not to define ‘terminal anorexia nervosa’ has been a hotly debated topic in the eating disorders field recently. Being able to have open scientific debate on important topics such as this is essential for the progress of our field—but needs to be undertaken respectfully, allowing all perspectives to be heard. My personal perspective on this topic comes from being a researcher who sees individuals with anorexia nervosa (AN) across all stages of illness and recovery, as well as having had a loved one die from AN. Although I disagree with the terminology of ‘terminal AN’ and believe that establishing criteria has the potential to cause harm, I strongly believe in showing compassion to individuals with AN across all illness stages, including those who may wish to seek end-of-life care. This is a complex issue that our field requires guidance on, and we need to work in genuine collaboration with individuals with lived experience of AN to figure out how to appropriately approach end-of-life care when it is warranted.
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- 2023
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21. Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study
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Ravanfar, Parsa, Rushmore, R. Jarrett, Lyall, Amanda E., Cropley, Vanessa, Makris, Nikos, Desmond, Patricia, Velakoulis, Dennis, Shenton, Martha E., Bush, Ashley I., Rossell, Susan L., Pantelis, Christos, Syeda, Warda T., and Phillipou, Andrea
- Abstract
Background: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. Methods: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. Results: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. Conclusions: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.
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- 2023
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22. Feeling fat in eating disorders: Testing the unique relationships between feeling fat and measures of disordered eating in anorexia nervosa and bulimia nervosa.
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Linardon, Jake, Phillipou, Andrea, Castle, David, Newton, Richard, Harrison, Philippa, Cistullo, Leonardo L., Griffiths, Scott, Hindle, Annemarie, and Brennan, Leah
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Although widely discussed in theories of eating disorders, the experience of “feeling fat” in this population has received little research attention. This study tested the unique relationships between feeling fat and measures of problematic eating behaviours and attitudes. Data were analysed from individuals with anorexia nervosa (AN; n = 123) and bulimia nervosa (BN; n = 51). Correlations revealed considerable unshared variance between feeling fat and shape and weight over-evaluation and depressive symptoms. Moreover, when over-evaluation and depressive symptoms were controlled, feeling fat predicted unique variance in restraint and eating concerns. Findings offer some support for the idea that feeling fat is a distinct and important component of body image concerns in eating disorders. Further research that develops a standardized measure of feeling fat is required. Further research that examines whether feeling fat is an important treatment mechanism is also needed. [ABSTRACT FROM AUTHOR]
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- 2018
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23. Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis
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Siskind, D. J., Harris, M., Phillipou, A., Morgan, V. A., Waterreus, A., Galletly, C., Carr, V. J., Harvey, C., and Castle, D.
- Abstract
Aims.Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables.Methods.Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n= 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators.Results.One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups.Conclusions.Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.
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- 2017
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24. Psychological-health correlates of physical activity and sedentary behaviour during the COVID pandemic.
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Ringin, Elysha, Meyer, Denny, Neill, Erica, Phillipou, Andrea, Tan, Eric J., Toh, Wei Lin, Sumner, Philip J., Owen, Neville, Hallgren, Mats, Dunstan, David W., Rossell, Susan L., and Van Rheenen, Tamsyn E.
- Abstract
While physical inactivity is associated with adverse psychological outcomes, less is known about the psychological outcomes associated with sedentary behaviour, and specifically, its mentally active and passive forms. The COVID-19 pandemic represents a unique opportunity to study associations between these variables in light of widespread stay-at-home mandates and restrictions on outdoor exercise/social activities. Using a cross-sectional dataset acquired during the COVID-19 pandemic in Australia, we examined whether physical activity and sedentary behaviour were associated with subjective quality of life (sQoL) and subjective cognitive dysfunction, and whether these associations were mediated by depressive symptoms. 658 participants (males = 169, females = 489) self-reported data on physical activity and sedentary behaviour in an online survey during May 2020–May 2021. Data on physical activity and sedentary behaviour (both mentally active and passive types) was compared according to whether it was collected during or out of a lockdown period. Regression models were used to test associations of physical activity and sedentary behaviour with sQoL and subjective cognitive dysfunction, and whether these associations were mediated by depression severity. Physical activity was beneficially associated with sQoL, whereas sedentary behaviour (both total hours and the reduction of mentally active/increase in mentally passive behaviour) was detrimentally associated with sQoL. These associations were mediated by depression severity. Physical activity and sedentary behaviour were also indirectly associated with subjective cognitive dysfunction by virtue of their associations with depression severity. There are important differences in the psychological correlates of mentally passive and active sedentary behaviours. Our findings suggest that health promotion strategies should focus on not only increasing physical activity but also reducing passive sedentary behaviours as a means of maintaining good psychological health. • Physical activity (PA) or sedentary behaviour (SB) did not differ according to lockdown status. • Psychological outcomes correlated differently with mentally active and mentally passive SB. • Less mentally passive SB and more PA associated with better quality of life. • Depression severity mediated the association of PA/SB and subjective cognitive dysfunction. • Health promotion should focus on increasing PA and reducing mentally passive SB. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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25. Body dysmorphic disorder in men.
- Author
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Phillipou, Andrea and Castle, David
- Published
- 2015
26. Are personality disturbances in anorexia nervosa related to emotion processing or eating disorder symptomatology?
- Author
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Phillipou, Andrea, Gurvich, Caroline, Castle, David, and Rossell, Susan
- Abstract
Anorexia Nervosa (AN) is a psychiatric illness associated with a number of personality disturbances. However, whether these personality characteristics are related to eating disorder symptomatology or emotion regulation is unclear. The aim of this study was to investigate these relationships. Twenty-four individuals with AN and 25 age- and premorbid intelligence-matched controls completed the Personality Diagnostic Questionnaire, and scores were correlated with measures of emotionality and negative mood states, and eating disorder symptomatology. AN was associated with increased scores on schizoid, borderline, avoidant, dependent, obsessive compulsive, negativistic and depressive personality dimensions, relative to controls. In AN, eating disorder symptomatology did not significantly correlate with scores on any personality dimension. However, a number of personality characteristics were found to correlate with negative mood states. The findings suggest that personality disturbances in AN are not related to disorder-specific symptoms, but are related to negative mood states.
- Published
- 2015
- Full Text
- View/download PDF
27. Saccadic eye movements in body dysmorphic disorder.
- Author
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Beilharz, Francesca, Phillipou, Andrea, Castle, David J., and Rossell, Susan L.
- Abstract
Body dysmorphic disorder (BDD) is characterised by a preoccupation with perceived flaws in appearance, which significantly disrupts functioning and causes distress. The difference in self-perception characteristic of BDD has been related to a bias in visual processing across a variety of stimuli and tasks. However, it is unknown how BDD participants perform on basic saccade tasks using eye tracking. Eighteen BDD and 21 healthy control participants completed a battery of saccadic eye movement tasks (fixation, prosaccade, anti-saccade, and memory guided). No significant differences were noted between the groups regarding behavioural performance or patterns of eye movements; however, there was a trend for BDD participants to make increased anticipatory errors on the prosaccade task. Overall, BDD participants demonstrated largely intact saccadic eye movement characteristics which may differentiate BDD from other obsessive-compulsive related disorders, although future research using larger samples is required. It is consequently argued that abnormalities in visual processing apparent among people with BDD may reflect abnormalities in higher-order visual systems. • Compared saccadic eye movements of BDD and HC participants. • No group differences for patterns of eye movements or behavioural performance. • Saccadic processing appears intact among individuals with BDD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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28. Specific quantitation of urinary 6-hydroxymelatonin sulphate by gas chromatography mass spectrometry
- Author
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Fellenberg, A. J., Phillipou, G., and Seamark, R. F.
- Abstract
6-Hydroxymelatonin sulphate, a unique urinary metabolite of melatonin, has been measured in human subjects for the first time using as chromatography mass spectrometry and an isotope labelled internal standard. Urinary levels in both males and females were similar and ranged from 25-125 nmol 24 h-1. A significant nocturnal elevation of 6-hydroxymelatonin sulphate was also established in a male subject.
- Published
- 1980
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29. Measurement of Plasma Progesterone and its O-Methyloxime by Gas Chromatography—Nitrogen Detection
- Author
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Frith, R Gordon and Phillipou, George
- Abstract
A routine method for the quantitation of plasma progesterone, using only 1 ml of sample, has been developed based on gas chromatography—nitrogen detection of the O-methyloxime derivative. Simple solvent extraction of progesterone from plasma using cyclohexane as solvent and medrogestone as internal standard allows measurement at the 3 nmol/l level, while the coefficient of variation at 16, 64, and 127 nmol/l progesterone is 14, 7·5, and 6·5% respectively. Comparison with a radioimmunoassay gave a linear regression equation of Y = 0·84 x + 1·4, Syx= 7·8, r = 0·9255 (n = 55).
- Published
- 1981
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30. Capillary Gas Chromatographic Measurement of Neutral Urinary Steroids: Evaluation and Comparison with Alternative Methodology
- Author
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Phillipou, George, Frith, R Gordon, and James, Steve K.
- Abstract
The major neutral urinary steroids have been quantitated by capillary gas chromatography and the reproducibility and accuracy of the method have been fully evaluated. Typical intra- and inter-assay coefficients of variation for individual steroids ranged from 4·9 to 10·1% and from 15·6 to 21·5%, respectively. Comparison of steroid values with alternate and commonly employed procedures for measuring urinary 17-oxosteroids, total 17-oxogenic steroids, and cortisol and plasma dehydroepiandrosterone-sulphate yielded correlation coefficients between 0·71 and 0·79. A definite relationship between serum cortisol and urinary trihydroxy-pregnanedione was also shown. Urinary androstenedione metabolites, however, could not be significantly (P>0·05) correlated with the normalised androgen ratio in plasma.
- Published
- 1980
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31. Synthesis of haptens related to (Z)- and (E)-clomiphene
- Author
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Johnson, DW, Phillipou, G, and Seaborn, CJ
- Abstract
Syntheses of (Z)- and (E)-3-[4-(2-chloro-1,2- diphenylvinyl)phenoxy]propanoic acids (12) and (11),potential haptens for the individual quantitation of the Z and of the E isomers of clomiphene,2-[4-(2-chloro-1,2-diphenylvinyl)phenoxy]-N,N- diethylethanamine (2) and (1), by radioimmunoassay, are described.
- Published
- 1980
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32. Regeneration of a Steroid C 13 Angular Methyl Group from a Functionalized Precursor : Application to the Preparation of C 18-2H3 Steroids and C 18-2H3 D-Homosteroids
- Author
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Blair, IA, Frith, RG, Phillipou, G, and Seaborn, CJ
- Abstract
3β-Acetoxypregn-5-eno-18,20-lactone has been converted into 3β,20β-dimethoxypregn-5-ene (6) by using electrochemical deoxygenation of a C13 formyl intermediate as a key reaction. The electrochemicalreduction is also shown to be applicable to multiple deuterium labelling of the C13 angular methyl group in high isotopic purity.A facile preparation of 3β -hydroxy-l7α-methyl-D-homoandrost-5-en-l7a-one (10) and its respective C18-2H3 analogue from the ether (6) is described.
- Published
- 1979
- Full Text
- View/download PDF
33. Ion-Cyclotron Resonance Studies of Alkylsilyl Ions. I. The Reactions Between Alcohols and the Trimethylsilyl Cation.
- Author
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Blair, IA, Phillipou, G, and Bowie, JH
- Abstract
Nucleophilic attack of an alcohol (ROH) at the electrophilic silicon centre of the trimethylsilyl cation (Me3Si+) produces the 1 : 1 adduct Me3-O+(H)R(1). The adduct may fragment by loss of methane to yield Me2Si+-O-R; and this elimination is most pronounced when R = Me. When R ≥ C2H5, the major decomposition pathway of (1) involves elimination of the alkene [R-H] to produce Me3Si-O+H2, which may undergo further reaction with the neutral alcohol to reform (1). The proton transfer which accompanies the elimination of [R- H] from (1) originates predominantly from C2 of the alcohol; this suggests the intermediacy of a four-membered transition state in this reaction.
- Published
- 1979
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34. Copper-catalysed reactions of t-butyl perbenzoate with cis- and trans-p-menth-2-ene and other cyclic olefins.
- Author
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Beckwith, ALJ and Phillipou, G
- Abstract
Each of the olefins cis-p-menth-2-ene (23), its trans-isomer (24), 3-methylcyclohexene (10) and 4- methylcyclohexene (ll), when treated with t-butyl perbenzoate and cupric octanoate catalyst in benzene, affords a mixture of allylic benzoates which can be analysed by gas chromatography after reduction with lithium aluminium hydride. In most cases the reaction proceeds with a high degree of stereo- and regio-selectivity, the major products being those containing a disubstituted double bond and bearing a benzoate group in a trans relationship to an alkyl substituent. Evidence is presented in support of a free-radical chain mechanism involving preferential abstraction of allylic hydrogen atoms occupying quasi-axial positions, followed by ligand transfer from cupric carboxylate via a cyclic transition state. When catalysed by the bipyridyl complex of cupric octanoate the reaction is less selective and appears to proceed by a different mechanism.
- Published
- 1976
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35. E2 reactions of menthyl and neoisomenthyl toluene-p-sulphonates.
- Author
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Beckwith, ALJ and Phillipou, G
- Abstract
The reaction of menthyl toluene-p-sulphonate (7) with potassium t-butoxide in benzene-dimethyl sulphoxide proceeds regiospecifically to afford trans-p-menth-2-ene (1). Mixtures of olefins are obtained when sodium ethoxide in ethanol, potassium t-butoxide in t-butyl alcohol or tetrabutylammonium bromide in acetone are used. Neoisomenthyl toluene-p-sulphonate (9), prepared by a stereospecific route from piperitone, affords mixtures of cis-p-menth-2-ene (2) and p-menth-3-ene(3) when treated with strong bases. The results are consistent with the concept of variable E2 transition states.
- Published
- 1976
- Full Text
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36. Specific b-scission of 3b,5-cyclocholestan-6-yl radical.
- Author
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Beckwith, ALJ and Phillipou, G
- Abstract
The 3β,5-cyclo-5β-cholestan-6-yl radical (6), generated by interaction of triphenylstannane with 6β-chloro-3β,5-cyclo-5β-cholestane (12), undergoes β-scission by specific fission of the 4,5-bond to give the thermodynamically less stable possible radical product (8). The results of these and earlier experiments indicate that β-scission of cyclopropylcarbinyl radicals is under stereoelectronic control, and involves a transition state formed by primary interaction of the semi-occupied orbital with a βγ-σ* orbital.
- Published
- 1976
- Full Text
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37. Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit
- Author
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Rianjongdee, Francesco, Atkinson, Stephen J., Chung, Chun-wa, Grandi, Paola, Gray, James R. J., Kaushansky, Laura J., Medeiros, Patricia, Messenger, Cassie, Phillipou, Alex, Preston, Alex, Prinjha, Rab K., Rioja, Inmaculada, Satz, Alexander L., Taylor, Simon, Wall, Ian D., Watson, Robert J., Yao, Gang, and Demont, Emmanuel H.
- Abstract
Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60(GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
- Published
- 2021
- Full Text
- View/download PDF
38. Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
- Author
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Aylott, Helen E., Atkinson, Stephen J., Bamborough, Paul, Bassil, Anna, Chung, Chun-wa, Gordon, Laurie, Grandi, Paola, Gray, James R. J., Harrison, Lee A., Hayhow, Thomas G., Messenger, Cassie, Mitchell, Darren, Phillipou, Alexander, Preston, Alex, Prinjha, Rab K., Rianjongdee, Francesco, Rioja, Inmaculada, Seal, Jonathan T., Wall, Ian D., Watson, Robert J., Woolven, James M., and Demont, Emmanuel H.
- Abstract
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28(GSK452), 39(GSK737), and 36(GSK217).
- Published
- 2021
- Full Text
- View/download PDF
39. Peer mentoring for individuals with an eating disorder: a qualitative evaluation of a pilot program
- Author
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Hanly, Freya, Torrens-Witherow, Benjamin, Warren, Narelle, Castle, David, Phillipou, Andrea, Beveridge, Jennifer, Jenkins, Zoe, Newton, Richard, and Brennan, Leah
- Abstract
Background: After receiving intensive medical treatment; individuals with eating disorders often require ongoing care to maintain their recovery, build social networks, and reduce risk of relapse. Methods: To address this important transition period, a six-month peer mentoring program was developed and piloted in Melbourne, Australia. Twelve adults with a past history of an eating disorder (mentors) were paired with 14 individuals with a current eating disorder (mentees). Pairs met for thirteen mentoring sessions in community settings. Throughout the program mentees and mentors completed reflective questions online. Upon completion of the program, qualitative interviews were conducted. Both online reflections and interviews explored themes relating to perceived benefits and challenges of participation in the peer mentoring program, and the differences between mentoring and traditional treatment. Results: Thematic analysis identified several benefits for mentees; including hope, reconnection with others, and re-engaging with the world. The majority of mentees described their mentor as uniquely supportive due to their past experience of an eating disorder. Mentors reported experiencing benefits such as increased connection with self and others, and indicated that the experience helped them positively reframe their past experience of an eating disorder. Ending the relationship at the completion of the program was a significant challenge for both groups, and managing boundaries was deemed a main challenge by mentors. Conclusions: Overall, results indicated that this mode of informal support may be worthy of further investigation as an adjunct to clinical treatment programs for this population. Trial registration: Australian and New Zealand Clinical Trials registration number -
ACTRN12617001412325 - Date of registration – 05/10/2017 (Retrospectively registered)- Published
- 2020
- Full Text
- View/download PDF
40. Saccadic eye movements in body dysmorphic disorder
- Author
-
Beilharz, Francesca, Phillipou, Andrea, Castle, David J., and Rossell, Susan L.
- Abstract
Body dysmorphic disorder (BDD) is characterised by a preoccupation with perceived flaws in appearance, which significantly disrupts functioning and causes distress. The difference in self-perception characteristic of BDD has been related to a bias in visual processing across a variety of stimuli and tasks. However, it is unknown how BDD participants perform on basic saccade tasks using eye tracking. Eighteen BDD and 21 healthy control participants completed a battery of saccadic eye movement tasks (fixation, prosaccade, anti-saccade, and memory guided). No significant differences were noted between the groups regarding behavioural performance or patterns of eye movements; however, there was a trend for BDD participants to make increased anticipatory errors on the prosaccade task. Overall, BDD participants demonstrated largely intact saccadic eye movement characteristics which may differentiate BDD from other obsessive-compulsive related disorders, although future research using larger samples is required. It is consequently argued that abnormalities in visual processing apparent among people with BDD may reflect abnormalities in higher-order visual systems.
- Published
- 2020
- Full Text
- View/download PDF
41. Prediction of pregnancy‐induced hypertension by means of the urinary calcium:creatinine ratio
- Author
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Raniolo, Emanuel and Phillipou, George
- Abstract
Objective:To investigate the importance of the urinary calcium:creatinihe ratio as a prognostic marker for pregnancy‐induced hypertension. Design:A prospective study which measured the urinary calcium:creatinine ratio at 20‐30 weeks' gestation. Patients' medical records were examined, blind to all urinary assay results, to determine the development of pre‐eclampsia or gestational hypertension. Setting and subjects:A first‐morning urine sample was collected from 456 normotensive pregnant women, at 20–30 weeks' gestation, attending a hospital maternity outpatients' clinic for routine antenatal care. Results:The mean urinary calcium:creatinine ratio for women (n=392) with a normotensive outcome of pregnancy, 0.52 (SD 0.32), was not significantly different from the ratios in those women who developed pre‐eclampsia (n= 16), 0.49 (SD 0.32) or gestational hypertension (n= 48), 0.57 (SD 0.41). Significant risk factors for development of gestational hypertension, as estimated by logistic regression, were mean arterial blood pressure greater than 87.6 mmHg, Caucasian race, non‐smoking and nulliparity. Conclusions:Within the cohort studied, the calciumxreatinine ratio measured in asymptomatic women at 20–30 weeks' gestation was an unsatisfactory prognostic marker for development of pregnancy‐induced hypertension. The major interpopulation, as well as intrapopulation, variation in calcium levels suggests that previous reported findings may not be readily generalised.
- Published
- 1993
- Full Text
- View/download PDF
42. Electrochemical Reduction of 7-Oxo Steroids: Route to Multideuterated Biological Steroids
- Author
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Phillipou, G, Seaborn, CJ, and Blair, IA
- Abstract
Electrochemical reduction of saturated 7-oxo steroids is shown to be an efficient procedure for the preparation of the respective deoxygenated analogues. Use of deuterated reagents allows a facile route to the corresponding deuterated steroids.
- Published
- 1979
- Full Text
- View/download PDF
43. Demethylation of a steroid methyl ether with concomitant ring expansion.
- Author
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Blair, IA, Frith, RG, Phillipou, G, and Seaborn, CJ
- Abstract
Demethylation of pregn-5-ene-3β,20β-diol dimethyl ether with ferric chloride/acetic anhydride is shown to form the ring-expanded steroid 17α-methyl-D-homoandrost-5-ene-3β,17aβ-diol (1) in 75% isolated yield.
- Published
- 1978
- Full Text
- View/download PDF
44. An evaluation of the predictive validity of the URICA and ANSOCQ scales for weight gain in adults with AN in an outpatient eating disorders program: a prospective cohort study
- Author
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Green, Jessica, Phillipou, Andrea, Castle, David, Cistullo, Leonardo, and Newton, Richard
- Abstract
Background: The Transtheoretical Model (TTM) which focuses on stage of change has been the main conceptual model used in understanding the lack of motivation to change in patients with Anorexia Nervosa (AN). Whilst there is evidence to support the prognostic value of the TTM in AN, this evidence base sufferers from limitations including limited studies in adults and none in outpatient populations. The primary aim of this study was to clarify whether readiness to change, as measured by the University Rhode Island Change Assessment Scale (URICA) and the Anorexia Nervosa Stages of Change Questionnaire (ANSOCQ) could predict weight gain in adults with AN following treatment in an outpatient setting. Methods: This was a prospective cohort analysis, which selectively used data from an existing clinical database at an outpatient eating disorders service. 119 patients met eligibility criteria and were included in this study. This included all adult patients who had a diagnosis of AN and were assessed, but not necessarily treated at the outpatient eating disorders program (Group 1). A subgroup of 63 patients (Group 2) was also analysed which only included patients who had received treatment at the program. Baseline measures included the URICA score, the ANSOCQ score, the Eating Disorders Examination Questionnaire (EDE-Q) and body mass index (BMI). BMI was also measured on discharge. Results: The URICA scale had poor predictive validity for weight gain (r= 0.05, p= 0.725). The ANSOCQ had moderate predictive validity (Pearson’s r= 0.57, p= 0.007), and accounted for 32.7% of variance in weight gain. The URICA and ANSOCQ were moderately correlated in both groups. The URICA was moderately predictive of symptom severity, measured by the EDE-Q in both groups. The ANSOCQ was moderately correlated with the EDE-Q scores in both Groups 1 and 2. Conclusions: To the authors’ knowledge this is the only study evaluating stage of change, in an adult outpatient population with AN. The findings of this study suggest that while both the URICA and ANSOCQ were associated with eating disorder symptom severity, only the ANSOCQ was able to predict weight gain in outpatients with AN suggesting its greater utility in this context.
- Published
- 2017
- Full Text
- View/download PDF
45. Photograph.
- Author
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Phillipou, Dru
- Abstract
The poem "Photograph," by Dru Phillipou is presented. First Line: It is an old gloss photograph, the two of us sitting on Tetilla; Last Line: into my hand.
- Published
- 2011
46. Measurement of urinary steroid production rates using stable-isotopes and GC-MS
- Author
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Johnson, D. W., Phillipou, G., Blair, I. A., and Seamark, R. F.
- Abstract
The urinary production rate of pregnenolone has been determined for a male subject using 7,7-d2-pregnenolone as an isotopic tracer.
- Published
- 1979
- Full Text
- View/download PDF
47. Re: "Race/ethnicity and other risk factors for gestational diabetes".
- Author
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Phillipou, G
- Published
- 1993
- Full Text
- View/download PDF
48. P.059 Segmental Left Ventricular Function Estimated by Strain Echocardiography in Relation to Arterial Stiffness in Hypertensives. MRI Findings in Respect to Myocardial Fibrosis — Preliminary Report
- Author
-
Pavlopoulos, H., Grapsa, J., Phillipou, E., and Nihoyannopoulos, P.
- Abstract
Background: Left Ventricular (LV) diastolic function has been reported to be related with the presence of increased arterial stiffness in hypertension. Myocardial fibrosis is one of the main causes of diastolic dysfunction (DD). Aim: To investigate the role of arterial stiffness in segmental LV systolic function and the presence of fibrosis with Delayed Enhancement (DE) MRI in hypertension. Methods: We studied 20 consecutive hypertensive patients with mean age 51.6±6.1 years and normal EF 66.3±4.1%, with no history of coronary artery disease. All subjects had MRI with (DE) and 2D and colour doppler myocardial imaging of basal and mid LV segments (12) in the longitudinal axis. Mean longitudinal strain (S) and strain rate (SR) were averaged from each of the 12 segments assessed. Pulse wave velocity (PWV) carotid-femoral was measured. Results: The mean duration of hypertension was 10.4±5.7 yrs. Diastolic dysfunction was evident in 16 out of the 20 patients. PWV was increased in patients with diastolic dysfunction (12.6±2.3 vs. 10.6±1.4 m/s) compared to those without DD. Septal basal and mid segment had the lowest systolic strain (basal: 15±2.7%, mid: 19.5±3.1%) and strain rate value (basal: 1.1±0.2/s, mid: 1.4±0.3/s) in comparison to the other segments. PWV was correlated with septal mid SR (r = –0.60, P < 0.05) and septal basal and mid S (r = –0.67, P < 0.05 and r = –0.69, P < 0.05). PWV was also correlated with mean S and SR (r = –0.58, P < 0.05 and r = –0.49, P < 0.05) and PP (r = 0.47, P < 0.05).MRI with DE detected 2 patients (10%) having replacement fibrosis, but did not detect interstitial or perivascular fibrosis. Conclusion: Septal wall is the region mainly affected by the presence of hypertension in comparison to other segments. Arterial stiffness is related to global and regional longitudinal systolic function. MRI can exclude replacement but not subtle interstitial or perivascular fibrosis in hypertensive patients.
- Published
- 2006
- Full Text
- View/download PDF
49. P.058 Left Ventricular Function in Relation to Arterial Stiffness in Hypertension. The Prognostic Importance of Pulse Pressure in LV Remodelling — Preliminary Report
- Author
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Pavlopoulos, H., Phillipou, E., Grapsa, J., and Nihoyannopoulos, P.
- Abstract
Background: Increased arterial stiffness has been reported to affect LV diastolic function in hypertension. Pulse pressure (PP) is independently related to cardiovascular and all-cause mortality. Strain and strain rate deformation parameters can detect subtle changes of the left ventricular (LV) function. Aim: To investigate the role of arterial stiffness in Systolic LV function and the effect of Pulse pressure in hypertension. Methods: We studied 55 consecutive hypertensive patients and 25 controls, matched for age (49.7±5.7 vs. 45.5±4.1 yrs), with normal EF (66±2.5 vs. 64±3.3%, NS). All subjects had 2D and colour doppler myocardial imaging of basal and mid LV segments (12) in the longitudinal axis. Mean longitudinal strain (S) and strain rate (SR) were averaged from each of the 12 segments assessed. Pulse wave velocity (PWV) carotid-femoral was used for estimation of arterial compliance in 20 of the hypertensive patients. Results: The hypertensive group had higher pulse pressure (59.5±16.6 vs. 41.4±7.2 mmHg, P <0.001), and lower mean longitudinal S and SR (S: 18.1±2.2 vs. 20.5±2.0% P < 0.05 and SR: 1.34±0.16 vs. 1.54±0.13/s P < 0.05) compared to control. The patients with hypertrophy or diastolic dysfunction (DD) had higher PP than those without hypertrophy (65±15 vs. 46±11 mmHg, P <0.001) or DD (63±16 vs. 44±12 mmHg, P <0.001). Pulse pressure was correlated with LVMI (r = 0.51, P < 0.001), WT (r = 0.61, P < 0.001), RWT (r = 0.52, P < 0.001), mean SR (f = –0.58, P < 0.001), mean S (f = –0.51, P < 0.001), DT(r = 0.36, P < 0.05), A (r = 0.45, P < 0.05) and E/A (f = –0.54, P < 0.01). PWV was correlated with mean S and SR (f = –0.58, P < 0.05 and f = –0.49, P < 0.05) and PP (r = 0.47, P < 0.05). Conclusion: Pulse pressure is related with functional (S, SR) and structural (WT, LVMI, RWT) components of the left ventricle and with the arterial stiffness. Arterial stiffness seems to affect not only the diastolic, but also the longitudinal systolic function of the left ventricle.
- Published
- 2006
- Full Text
- View/download PDF
50. Haemostatic, fibrinolytic and lipid parameters in relation to the initial manifestation of coronary artery disease
- Author
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Narang, Rajiv, Phillipou, Helen, Meijer, Piet, Niththyananthan, Saro, Tousoulis, Dimitri, Lane, David, Kluft, Cornelis, Tuddenham, Edward, and Davies, Graham
- Published
- 1996
- Full Text
- View/download PDF
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