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Article ; Online: Targeting growth hormone in cancer: future perspectives.

Wang, Yue / Jamieson, Stephen M F / Perry, Jo K

2023 Volume 30, Issue 9

Abstract: Decades of published research support a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with ... ...

Abstract	Decades of published research support a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with anticancer therapy or radiation. Here we discuss challenges associated with using growth hormone receptor (GHR) antagonists in preclinical models and considerations for translation, such as the identification of predictive biomarkers for selecting patients and for monitoring drug efficacy. Ongoing research will determine whether suppressing GH signalling pharmacologically will also reduce the risk of developing cancer. An increase in GH-targeted drugs in preclinical development will ultimately provide new tools to test anticancer efficacy of blocking the GH signalling pathway.
MeSH term(s)	Humans ; Growth Hormone/therapeutic use ; Growth Hormone/metabolism ; Receptors, Somatotropin/metabolism ; Human Growth Hormone/metabolism ; Neoplasms/drug therapy ; Signal Transduction
Chemical Substances	Growth Hormone (9002-72-6) ; Receptors, Somatotropin ; Human Growth Hormone (12629-01-5)
Language	English
Publishing date	2023-07-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-23-0033
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Zs.A 4192: Show issues

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Article ; Online: The 20-kDa Placental GH Variant: A New and Improved Growth Hormone?

Vickers, Mark H / Perry, Jo K

Endocrinology

2020 Volume 161, Issue 10

MeSH term(s)	Animals ; Female ; Growth Hormone ; Human Growth Hormone ; Humans ; Male ; Mice ; Placenta ; Placental Hormones ; Pregnancy
Chemical Substances	Placental Hormones ; Human Growth Hormone (12629-01-5) ; Growth Hormone (9002-72-6)
Language	English
Publishing date	2020-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqaa147
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Uh III Zs.72: Show issues

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Article: Identification of 27 allele-specific regulatory variants in Parkinson's disease using a massively parallel reporter assay.

Farrow, Sophie L / Gokuladhas, Sreemol / Schierding, William / Pudjihartono, Michael / Perry, Jo K / Cooper, Antony A / O'Sullivan, Justin M

NPJ Parkinson's disease

2024 Volume 10, Issue 1, Page(s) 44

Abstract: Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson's disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence ... ...

Abstract	Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson's disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence disease development, and/or potential subtypes, remain largely elusive. To address this, we used a massively parallel reporter assay (MPRA) to screen the regulatory function of 5254 variants that have a known or putative connection to PD. We identified 138 loci with enhancer activity, of which 27 exhibited allele-specific regulatory activity in HEK293 cells. The identified regulatory variant(s) typically did not match the original tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within HEK293 cells, confirms that at least a subset of the PD associated regions mark functional gene regulatory elements. Future functional studies that confirm the putative targets of the empirically verified regulatory variants will be crucial for gaining a greater understanding of how gene regulatory network(s) modulate PD risk.
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2819218-7
ISSN	2373-8057
ISSN	2373-8057
DOI	10.1038/s41531-024-00659-5
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Article ; Online: Growth hormone receptor agonists and antagonists: From protein expression and purification to long-acting formulations.

Wang, Yue / Kim, Minah / Buckley, Chantal / Maynard, Heather D / Langley, Ries J / Perry, Jo K

Protein science : a publication of the Protein Society

2023 Volume 32, Issue 9, Page(s) e4727

Abstract: Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to ... ...

Abstract	Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to manufacture with multiple challenges from recombinant protein generation through to the development of long-acting formulations required to improve the circulating half-life of the drug. In this review, we summarize methodologies and approaches used for making and purifying recombinant GH and GHA proteins, and strategies to improve pharmacokinetic and pharmacodynamic properties, including PEGylation and fusion proteins. Therapeutics that are in clinical use or are currently under development are also discussed.
MeSH term(s)	Humans ; Human Growth Hormone/genetics ; Human Growth Hormone/pharmacology ; Recombinant Proteins/genetics ; Recombinant Proteins/pharmacology ; Receptors, Somatotropin/agonists ; Receptors, Somatotropin/antagonists & inhibitors
Chemical Substances	Human Growth Hormone (12629-01-5) ; Recombinant Proteins ; Receptors, Somatotropin
Language	English
Publishing date	2023-07-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4727
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Development and characterisation of a novel inhibitory anti-GH monoclonal antibody.

Lu, Man / Buckley, Chantal / Wang, Yue / Langley, Ries J / Perry, Jo K

Journal of molecular endocrinology

2023 Volume 72, Issue 1

Abstract: Excess growth hormone (GH) has been implicated in multiple cancer types and there is increasing interest in the development of therapeutic inhibitors targeting GH-GH receptor (GHR) signalling. Here we describe a panel of anti-GH monoclonal antibodies ( ... ...

Abstract	Excess growth hormone (GH) has been implicated in multiple cancer types and there is increasing interest in the development of therapeutic inhibitors targeting GH-GH receptor (GHR) signalling. Here we describe a panel of anti-GH monoclonal antibodies (mAbs) generated using a hybridoma approach and identify two novel inhibitory mAbs (1-8-2 and 1-46-3) that neutralised GH signalling. mAbs 1-8-2 and 1-46-3 exhibited strong inhibitory activity against GH-dependent cell growth in a Ba/F3-GHR cell viability assay, with EC50 values of 1.00 ± 0.27 and 0.5 ± 0.1 µg/mL, respectively. Cross-reactivity with the human placental hormones, placental lactogen (PL) and placental GH, was observed by ELISA, but neither antibody cross-reacted with mouse GH or human prolactin (PRL). mAb 1-8-2 had a binding affinity for GH of KD 0.62 ± 0.5 nM, while mAb 1-46-3 had a KD of 2.68 ± 0.53 nM, as determined by bio-layer interferometry. mAb 1-46-3 inhibited GH-dependent signal transduction in T-47D and LNCaP cancer cell lines and reduced GH-dependent cell growth and migration in the breast cancer cell line T-47D. mAb 1-46-3 inhibited T-47D cell viability more effectively than the GHR antagonist B2036. In conclusion, we describe two novel inhibitory anti-GH mAbs and provide in vitro evidence supporting development of these entities as anti-cancer therapeutics.
MeSH term(s)	Animals ; Female ; Humans ; Mice ; Pregnancy ; Antibodies, Monoclonal/pharmacology ; Cell Line ; Growth Hormone/immunology ; Placenta/metabolism ; Receptors, Somatotropin/metabolism ; Signal Transduction
Chemical Substances	Antibodies, Monoclonal ; Growth Hormone (9002-72-6) ; Receptors, Somatotropin ; pegvisomant (N824AOU5XV)
Language	English
Publishing date	2023-12-13
Publishing country	England
Document type	Journal Article
ZDB-ID	645012-x
ISSN	1479-6813 ; 0952-5041
ISSN (online)	1479-6813
ISSN	0952-5041
DOI	10.1530/JME-23-0071
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Zs.A 2406: Show issues

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Article ; Online: Development of best practice guidelines for clinical and community service providers to prevent suicide in LGBTQA+ young people: A Delphi expert consensus study.

Strauss, Penelope / Marion, Larissa / Hill, Nicole Tm / Gilbey, Dylan / Waters, Zoe / Moore, Julia K / Costanza, Marco / Lamblin, Michelle / Robinson, Jo / Lin, Ashleigh / Perry, Yael

The Australian and New Zealand journal of psychiatry

2024 Volume 58, Issue 5, Page(s) 425–434

Abstract: Objective: The aim of this study was to develop best practice guidelines for preventing suicide and reducing suicidal thoughts and behaviours in LGBTQA+ young people (lesbian, gay, bisexual, trans, queer/questioning, asexual, and those of other diverse ... ...

Abstract	Objective: The aim of this study was to develop best practice guidelines for preventing suicide and reducing suicidal thoughts and behaviours in LGBTQA+ young people (lesbian, gay, bisexual, trans, queer/questioning, asexual, and those of other diverse sexualities and genders) within clinical and community service settings in Australia. Methods: We conducted a Delphi expert consensus study. A systematic literature search and interviews with key informants informed an initial 270-item questionnaire. Two expert panels completed the questionnaire, delivered over two rounds: (1) Australian professionals with expertise in LGBTQA+ mental health/suicide prevention and (2) Australian LGBTQA+ young people aged 14-25 with lived experience of suicidal thoughts and/or behaviours. Items endorsed as 'essential' or 'important' by >80% of both expert panels were included in the guidelines. Results: A total of 115 people participated in the Delphi process; Conclusion: These guidelines are the first of their kind in Australia. They provide practical support to service providers regardless of prior training in LGBTQ+ identities or mental health, with the aim of reducing suicidal thoughts and behaviours, and preventing suicide, in LGBTQA+ young people.
MeSH term(s)	Humans ; Sexual and Gender Minorities/psychology ; Delphi Technique ; Suicide Prevention ; Male ; Female ; Young Adult ; Adolescent ; Adult ; Australia ; Practice Guidelines as Topic/standards ; Consensus ; Suicidal Ideation ; Health Personnel
Language	English
Publishing date	2024-01-13
Publishing country	England
Document type	Journal Article
ZDB-ID	221140-3
ISSN	1440-1614 ; 0004-8674
ISSN (online)	1440-1614
ISSN	0004-8674
DOI	10.1177/00048674231223697
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Zs.A 856: Show issues

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Article ; Online: Interpretation of the role of germline and somatic non-coding mutations in cancer: expression and chromatin conformation informed analysis.

Pudjihartono, Michael / Perry, Jo K / Print, Cris / O'Sullivan, Justin M / Schierding, William

Clinical epigenetics

2022 Volume 14, Issue 1, Page(s) 120

Abstract: Background: There has been extensive scrutiny of cancer driving mutations within the exome (especially amino acid altering mutations) as these are more likely to have a clear impact on protein functions, and thus on cell biology. However, this has come ... ...

Abstract	Background: There has been extensive scrutiny of cancer driving mutations within the exome (especially amino acid altering mutations) as these are more likely to have a clear impact on protein functions, and thus on cell biology. However, this has come at the neglect of systematic identification of regulatory (non-coding) variants, which have recently been identified as putative somatic drivers and key germline risk factors for cancer development. Comprehensive understanding of non-coding mutations requires understanding their role in the disruption of regulatory elements, which then disrupt key biological functions such as gene expression. Main body: We describe how advancements in sequencing technologies have led to the identification of a large number of non-coding mutations with uncharacterized biological significance. We summarize the strategies that have been developed to interpret and prioritize the biological mechanisms impacted by non-coding mutations, focusing on recent annotation of cancer non-coding variants utilizing chromatin states, eQTLs, and chromatin conformation data. Conclusion: We believe that a better understanding of how to apply different regulatory data types into the study of non-coding mutations will enhance the discovery of novel mechanisms driving cancer.
MeSH term(s)	Amino Acids/genetics ; Chromatin/genetics ; DNA Methylation ; Germ Cells ; Humans ; Mutation ; Neoplasms/genetics
Chemical Substances	Amino Acids ; Chromatin
Language	English
Publishing date	2022-09-28
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-022-01342-3
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Article: The growth hormone receptor interacts with transcriptional regulator HMGN1 upon GH-induced nuclear translocation.

Jain, Lekha / Vickers, Mark H / Jacob, Bincy / Middleditch, Martin J / Chudakova, Daria A / Ganley, Austen R D / O'Sullivan, Justin M / Perry, Jo K

Journal of cell communication and signaling

2023 Volume 17, Issue 3, Page(s) 925–937

Abstract: Growth hormone (GH) actions are mediated through binding to its cell-surface receptor, the GH receptor (GHR), with consequent activation of downstream signalling. However, nuclear GHR localisation has also been observed and is associated with increased ... ...

Abstract	Growth hormone (GH) actions are mediated through binding to its cell-surface receptor, the GH receptor (GHR), with consequent activation of downstream signalling. However, nuclear GHR localisation has also been observed and is associated with increased cancer cell proliferation. Here we investigated the functional implications of nuclear translocation of the GHR in the human endometrial cancer cell-line, RL95-2, and human mammary epithelial cell-line, MCF-10A. We found that following GH treatment, the GHR rapidly translocates to the nucleus, with maximal localisation at 5-10 min. Combined immunoprecipitation-mass spectrometry analysis of RL95-2 whole cell lysates identified 40 novel GHR binding partners, including the transcriptional regulator, HMGN1. Moreover, microarray analysis demonstrated that the gene targets of HMGN1 were differentially expressed following GH treatment, and co-immunoprecipitation showed that HMGN1 associates with the GHR in the nucleus. Therefore, our results suggest that GHR nuclear translocation might mediate GH actions via interaction with chromatin factors that then drive changes in specific downstream transcriptional programs.
Language	English
Publishing date	2023-04-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2299380-0
ISSN	1873-961X ; 1873-9601
ISSN (online)	1873-961X
ISSN	1873-9601
DOI	10.1007/s12079-023-00741-2
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Article ; Online: Genetic Code Expansion Enables Site-Specific PEGylation of a Human Growth Hormone Receptor Antagonist through Click Chemistry.

Tamshen, Kyle / Wang, Yue / Jamieson, Stephen M F / Perry, Jo K / Maynard, Heather D

Bioconjugate chemistry

2020 Volume 31, Issue 9, Page(s) 2179–2190

Abstract: Regulation of human growth hormone (GH) signaling has important applications in the remediation of several diseases including acromegaly and cancer. Growth hormone receptor (GHR) antagonists currently provide the most effective means for suppression of ... ...

Abstract	Regulation of human growth hormone (GH) signaling has important applications in the remediation of several diseases including acromegaly and cancer. Growth hormone receptor (GHR) antagonists currently provide the most effective means for suppression of GH signaling. However, these small 22 kDa recombinantly engineered GH analogues exhibit short plasma circulation times. To improve clinical viability, between four and six molecules of 5 kDa poly(ethylene glycol) (PEG) are nonspecifically conjugated to the nine amines of the GHR antagonist designated as B2036 in the FDA-approved therapeutic pegvisomant. PEGylation increases the molecular weight of B2036 and considerably extends its circulation time, but also dramatically reduces its bioactivity, contributing to high dosing requirements and increased cost. As an alternative to nonspecific PEGylation, we report the use of genetic code expansion technology to site-specifically incorporate the unnatural amino acid propargyl tyrosine (pglY) into B2036 with the goal of producing site-specific protein-polymer conjugates. Substitution of tyrosine 35 with pglY yielded a B2036 variant containing an alkyne functional group without compromising bioactivity, as verified by a cellular assay. Subsequent conjugation of 5, 10, and 20 kDa azide-containing PEGs via the copper-catalyzed click reaction yielded high purity, site-specific conjugates with >89% conjugation efficiencies. Site-specific attachment of PEG to B2036 is associated with substantially improved in vitro bioactivity values compared to pegvisomant, with an inverse relationship between polymer size and activity observed. Notably, the B2036-20 kDa PEG conjugate has a molecular weight comparable to pegvisomant, while exhibiting a 12.5 fold improvement in half-maximal inhibitory concentration in GHR-expressing Ba/F3 cells (103.3 nM vs 1289 nM). We expect that this straightforward route to achieve site-specific GHR antagonists will be useful for GH signal regulation.
MeSH term(s)	Azides/chemistry ; Catalysis ; Click Chemistry ; Copper/chemistry ; Genetic Code ; Human Growth Hormone/analogs & derivatives ; Human Growth Hormone/chemistry ; Human Growth Hormone/genetics ; Humans ; Polyethylene Glycols/chemistry ; Tyrosine/analogs & derivatives ; Tyrosine/genetics
Chemical Substances	Azides ; Human Growth Hormone (12629-01-5) ; Polyethylene Glycols (3WJQ0SDW1A) ; Tyrosine (42HK56048U) ; Copper (789U1901C5) ; pegvisomant (N824AOU5XV)
Language	English
Publishing date	2020-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1024041-x
ISSN	1520-4812 ; 1043-1802
ISSN (online)	1520-4812
ISSN	1043-1802
DOI	10.1021/acs.bioconjchem.0c00365
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Zs.A 3400: Show issues

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Article ; Online: Evaluation of breath, plasma, and urinary markers of lactose malabsorption to diagnose lactase non-persistence following lactose or milk ingestion.

Shrestha, Aahana / Barnett, Matthew P G / Perry, Jo K / Cameron-Smith, David / Milan, Amber M

BMC gastroenterology

2020 Volume 20, Issue 1, Page(s) 204

Abstract: Background: Adult lactase non-persistence (LNP) is due to low lactase expression, resulting in lactose malabsorption (LM). LNP is a genetic trait, but is typically determined by LM markers including breath H: Methods: Fourty healthy young women were ... ...

Abstract	Background: Adult lactase non-persistence (LNP) is due to low lactase expression, resulting in lactose malabsorption (LM). LNP is a genetic trait, but is typically determined by LM markers including breath H Methods: Fourty healthy young women were challenged with 50 g lactose then randomized for separate cross-over visits to ingest 750 mL milk (37.5 g lactose) as conventional (both A1 and A2 β-casein) and A1 β-casein-free (a2 Milk™) milk. Blood, breath and urine were collected prior to and up to 3 h following each challenge. The presence of C/T Results: Genetic testing identified 14 out of 40 subjects as having LNP (C/C Conclusion: This study showed accurate diagnosis of LNP by breath H Trial registration: ACTRN12616001694404 . Registered prospectively on December 9, 2016.
MeSH term(s)	Adult ; Animals ; Breath Tests ; Eating ; Female ; Humans ; Hydrogen/analysis ; Lactase/genetics ; Lactose ; Lactose Intolerance/diagnosis ; Lactose Intolerance/genetics ; Milk/chemistry
Chemical Substances	Hydrogen (7YNJ3PO35Z) ; Lactase (EC 3.2.1.108) ; Lactose (J2B2A4N98G)
Language	English
Publishing date	2020-06-29
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial
ISSN	1471-230X
ISSN (online)	1471-230X
DOI	10.1186/s12876-020-01352-6
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