ORCID Profile
0000-0003-1392-3472
Current Organisations
University of Western Australia
,
Garvan Institute of Medical Research
,
UNSW Sydney
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Publisher: Cold Spring Harbor Laboratory
Date: 30-01-2020
DOI: 10.1101/2020.01.29.911883
Abstract: Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 expression, in contrast to HGSOC in which CCNE1 lification drives increased cyclin E1 gene expression. Instead, BRCA1 loss stabilized cyclin E1 during the cell cycle. Using siRNA we showed that BRCA1 loss leads to stabilization of cyclin E1 by reducing phospho-cyclin E1-T62, and conversely the overexpression of BRCA1 increased phospho-T62. Mutation of cyclin E1-T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/ BRCA1 mutation in the BLBC cohort had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in BRCA1 mutated cell lines. Treatment of BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2021
DOI: 10.1038/S41523-021-00312-X
Abstract: Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 lification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/ BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
Publisher: Cold Spring Harbor Laboratory
Date: 12-06-2020
DOI: 10.1101/2020.06.09.140921
Abstract: Resistance to endocrine therapy is a major clinical challenge in the management of estrogen receptor (ER)-positive breast cancer. In this setting p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment resistant ER-positive breast cancer. We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate antitumor effects in p53 wildtype and p53 mutant ER positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and -resistant ER positive breast cancer. We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant resistant patient derived xenograft model. We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programs.
Publisher: Springer Science and Business Media LLC
Date: 07-11-2022
DOI: 10.1186/S12961-022-00901-7
Abstract: In 2019, WHO prioritized updating recommendations relating to three labour induction topics: labour induction at or beyond term, mechanical methods for labour induction, and outpatient labour induction. As part of this process, we aimed to review the evidence addressing factors beyond clinical effectiveness (values, human rights and sociocultural acceptability, health equity, and economic and feasibility considerations) to inform WHO Guideline Development Group decision-making using the WHO-INTEGRATE evidence-to-decision framework, and to reflect on how methods for identifying, synthesizing and integrating this evidence could be improved. We adapted the framework to consider the key criteria and sub-criteria relevant to our intervention. We searched for qualitative and other evidence across a variety of sources and mapped the eligible evidence to country income setting and perspective. Eligibility assessment and quality appraisal of qualitative evidence syntheses was undertaken using a two-step process informed by the ENTREQ statement. We adopted an iterative approach to interpret the evidence and provided both summary and detailed findings to the decision-makers. We also undertook a review to reflect on opportunities to improve the process of applying the framework and identifying the evidence. Using the WHO-INTEGRATE framework allowed us to explore health rights and equity in a systematic and transparent way. We identified a lack of qualitative and other evidence from low- and middle-income settings and in populations that are most impacted by structural inequities or traditionally excluded from research. Our process review highlighted opportunities for future improvement, including adopting more systematic evidence mapping methods and working with social science researchers to strengthen theoretical understanding, methods and interpretation of the evidence. Using the WHO-INTEGRATE evidence-to-decision framework to inform decision-making in a global guideline for induction of labour, we identified both challenges and opportunities relating to the lack of evidence in populations and settings of need and interest the theoretical approach informing the development and application of WHO-INTEGRATE and interpretation of the evidence. We hope these insights will be useful for primary researchers as well as the evidence synthesis and health decision-making communities, and ultimately contribute to a reduction in health inequities.
Publisher: Wiley
Date: 06-04-2022
DOI: 10.1002/CJP2.269
Abstract: Basal‐like breast cancer (BLBC) has a greater overlap in molecular features with high‐grade serous ovarian cancer (HGSOC) than with other breast cancer subtypes. Similarities include BRCA1 mutation, high frequency of TP53 mutation, and lification of CCNE1 (encoding the cyclin E1 protein) in 6–34% of cases, and these features can be used to group patients for targeted therapies in clinical trials. In HGSOC, we previously reported two subsets with high levels of cyclin E1: those in which CCNE1 is lified, have intact homologous recombination (HR), and very poor prognosis and a CCNE1 non‐ lified subset, with more prevalent HR defects. Here, we investigate whether similar subsets are identifiable in BLBC that may allow alignment of patient grouping in clinical trials of agents targeting cyclin E1 overexpression. We examined cyclin E1 protein and CCNE1 lification in a cohort of 76 BLBCs and validated the findings in additional breast cancer datasets. Compared to HGSOC, CCNE1 lified BLBC had a lower level of lification (3.5 versus 5.2 copies) and lower relative cyclin E1 protein, a lack of correlation of lification with expression, and no association with polyploidy. BLBC with elevated cyclin E1 protein also had prevalent HR defects, and high‐level expression of the cyclin E1 deubiquitinase ubiquitin‐specific protease 28 (USP28). Using a meta‐analysis across multiple studies, we determined that cyclin E1 protein overexpression but not lification is prognostic in BLBC, while both cyclin E1 overexpression and lification are prognostic in HGSOC. Overall CCNE1 gene lification is not equivalent between BLBC and HGSOC. However, high cyclin E1 protein expression can co‐occur with HR defects in both BLBC and HGSOC, and is associated with poor prognosis in BLBC.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NEDT.2015.04.014
Abstract: One form of assessment that tests students' theoretical skills and confidence in their clinical practice is known as the Objective Structured Clinical Assessment (OSCA). Traditionally it was first launched from medical education, and is now being incorporated by other disciplines, such as nursing. This review seeks to present the best available evidence into strategies that help reduce first year nursing students' anxiety levels prior to undergoing OSCA and clinical placement. A systematic literature search was performed using Medline and CINAHL. This review considered any English language original research published between 2005 and 2013. A literature search located 117 articles. Eight articles were identified as meeting the inclusion in criteria. Majority of studies reported simulation session prior to the OSCA increased students confidence and reduced their anxiety levels. This resulted in students' reporting that they valued the OSCA as a worthwhile assessment. However there were four major themes: that students were anxious about attending the OSCA that adequate preparation was seen as a coping strategy that simulation was a further cause for anxiety and that the simulation experience could also be used as an OSCA tool. Students who have been exposed to simulation scenarios before the OSCA are able to cope much better during the OSCA. Therefore, it is highly recommended to incorporate simulation scenarios into the nursing curricula for first year nursing students' clinical units to help reduce their anxiety levels prior to OCSA.
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 18-08-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-2021
Abstract: Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer.
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: CRC Press
Date: 02-08-2020
Publisher: MDPI AG
Date: 14-05-2021
DOI: 10.3390/ELECTRONICS10101171
Abstract: Fog computing is an emerging computing paradigm that has come into consideration for the deployment of Internet of Things (IoT) applications amongst researchers and technology industries over the last few years. Fog is highly distributed and consists of a wide number of autonomous end devices, which contribute to the processing. However, the variety of devices offered across different users are not audited. Hence, the security of Fog devices is a major concern that should come into consideration. Therefore, to provide the necessary security for Fog devices, there is a need to understand what the security concerns are with regards to Fog. All aspects of Fog security, which have not been covered by other literature works, need to be identified and aggregated. On the other hand, privacy preservation for user’s data in Fog devices and application data processed in Fog devices is another concern. To provide the appropriate level of trust and privacy, there is a need to focus on authentication, threats and access control mechanisms as well as privacy protection techniques in Fog computing. In this paper, a survey along with a taxonomy is proposed, which presents an overview of existing security concerns in the context of the Fog computing paradigm. Moreover, the Blockchain-based solutions towards a secure Fog computing environment is presented and various research challenges and directions for future research are discussed.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2023
Publisher: ASME Press
Date: 2011
Publisher: MDPI AG
Date: 13-08-2020
Abstract: Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.
Publisher: ACM
Date: 29-01-2019
Publisher: MDPI AG
Date: 09-06-2022
Abstract: Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.
Publisher: American Astronomical Society
Date: 03-2022
Abstract: Gravitational waves from binary neutron star mergers can be used as alerts to enable prompt follow-up observations. In particular, capturing prompt electromagnetic and astroparticle emissions from the moment of a binary merger presents unique constraints on the timescale and sky localization for online gravitational-wave detection. Here we present the expected performance of the SPIIR online detection pipeline that is designed for this purpose in the upcoming international LIGO–Virgo’s 4th Science Run (O4). Using simulated Gaussian data for the two LIGO observatories with expected O4 sensitivity, we demonstrate that there is a nonnegligible opportunity to deliver premerger warnings at least 10 s before the final plunge. These alerts are expected to be issued at a nominal rate of one binary neutron star coalescence per year and localized within a median searched area of 300 deg 2 . We envision such detection to be extremely useful for follow-up observatories with a large field of view such as the Murchison Widefield Array radio facility in Western Australia.
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: Cold Spring Harbor Laboratory
Date: 28-05-2023
DOI: 10.1101/2023.05.24.23290442
Abstract: The addition of PARP inhibitors to chemotherapy has been assessed in ∼80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy. A systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function ( BRCA1 , BRCA2 , BRCAPRO, ATM, ERCC1, SFLN11). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and fixed or random effects modelling. Subgroup analyses were conducted on biomarker selection and type of malignancy. Nine studies comprising 2,084 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients with a DNA repair biomarker (HR 0.52, 95% confidence interval (CI) 0.43-0.63 p 0.00001), but there was no benefit in patients who lacked a biomarker (HR 0.94, 95% CI 0.82–1.08 p = 0.38). Subgroup analysis showed that BRCA mutation and SFLN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in ovarian, breast and small cell lung cancers. The addition of PARP inhibitors was associated with increased grade 3/4 side effects, and particularly neutropenia. Combination therapy only increases PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitise patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of altered DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as in idual arms of treatment can also confer benefit.
Publisher: IEEE
Date: 07-2011
No related grants have been discovered for Liz Caldon.