Gallagher, William M.
Gallagher, William M.
Gallagher, William M.
Now showing 1 - 10 of 13
- PublicationWhat are the mechanisms that enable the reciprocal involvement of seldom heard groups in health and social care research? A rapid realist review protocol(Health Research Board, 2018-02)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;Background: The University College Dublin (UCD) PPI Ignite Connect Network will fundamentally embed public and patient involvement (PPI) in health-related research, education and training, professional practice and administration in UCD’s institutional structures and procedures. A significant focus of the programme of work is on actively engaging and developing long-term reciprocal relationships with seldom heard groups, via our ten inaugural partners. Methods: This rapid realist review will explore what are the mechanisms that are important in actively engaging seldom heard groups in health and social care research. The review process will follow five iterative steps: (1) clarify scope, (2) search for evidence, (3) appraise primary studies and extract data, (4) synthesise evidence and draw conclusions, and (5) disseminate findings. The reviewers will consult with expert and reference panels to focus the review, provide local contextual insights and develop a programme theory consisting of context–mechanism–outcome configurations. The expert panel will oversee the review process and agree, via consensus, the final programme theory. Review findings will follow the adopted RAMESES guideline and will be disseminated via a report, presentations and peer-reviewed publication. Discussion: The review will update and consolidate evidence on the mechanisms that enable the reciprocal engagement and participation of ‘seldom heard’ groups in health and social care research. Via the expert and reference process, we will draw from a sizeable body of published and unpublished research and grey literature. The local contextual insights provided will aid the development of our programme theories. This new evidence will inform the design and development of the UCD PPI Ignite program focused on ensuring sustained reciprocal partnerships. 413
- PublicationBAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer(Impact Journals, 2018-03-20)
; ; ; ; ; ; ; ; ; ; ;Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC. 110Scopus© Citations 10
- PublicationMulti-Gene Prognostic Signatures and Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in ER-Positive, HER2-Negative Breast Cancer Patients(MDPI, 2020-05-01)
; ; ;Determining which patients with early-stage breast cancer should receive chemotherapy is an important clinical issue. Chemotherapy has several adverse side effects, impacting on quality of life, along with significant economic consequences. There are a number of multi-gene prognostic signatures for breast cancer recurrence but there is less evidence that these prognostic signatures are predictive of therapy benefit. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective over-treatment. The aim of this work was to assess if the OncoMasTR prognostic signature can predict pathological complete response (pCR) to neoadjuvant chemotherapy, and to compare its predictive value with other prognostic signatures: EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes. Gene expression datasets from ER-positive, HER2-negative breast cancer patients that had pre-treatment biopsies, received neoadjuvant chemotherapy and an assessment of pCR were obtained from the Gene Expression Omnibus repository. A total of 813 patients with 66 pCR events were included in the analysis. OncoMasTR, EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. OncoMasTR, EndoPredict and Oncotype DX prognostic scores were moderately well correlated according to the Pearson’s correlation coefficient. Association with pCR was estimated using logistic regression. The odds ratio for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude for all four signatures. Additionally, the four signatures were significant predictors of pCR. OncoMasTR added significant predictive value to EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes signatures as determined by bivariable and trivariable analysis. In this in silico analysis, OncoMasTR, EndoPredict, Oncotype DX, and Tumor Infiltrating Leukocytes were significantly predictive of pCR to neoadjuvant chemotherapy in ER-positive and HER2-negative breast cancer patients. 111Scopus© Citations 12
- PublicationIdentification of β2-microglobulin as a urinary biomarker for chronic allograft nephropathy using proteomic methods(Wiley, 2011-08)
; ; ; ; ; ; ; ; ; ;Chronic allograft nephropathy (CAN) remains the leading cause of renal graft loss after the first year following renal transplantation. This study aimed to identify novel urinary proteomic profiles, which could distinguish and predict CAN in susceptible individuals. Experimental Design: The study included 34 renal transplant patients with histologically proven CAN and 36 patients with normal renal transplant function. High-throughput proteomic profiles were generated from urine samples with three different ProteinChip arrays by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Following SELDI a biomarker pattern software analysis was performed which led to the identification of a novel biomarker pattern that could distinguish patients with CAN from those with normal renal function. Results: An 11.7 kDa protein identified as β2 microglobulin was the primary protein of this biomarker pattern, distinguishing CAN from control patients (ROC = 0.996). SELDI-TOF-MS comparison of purified β2 microglobulin protein and CAN urine demonstrated identical 11.7 kDa protein peaks. Significantly higher concentrations of β2 microglobulin were found in the urine of patients with CAN compared to the urine of normal renal function transplant recipients (p<0.001). Conclusions and clinical relevance: Whilst further validation in a larger more diverse patient population is required to determine if this β2 microglobulin protein biomarker will provide a potential means of diagnosing CAN by non-invasive methods in a clinical setting, this study clearly shows a capability to stratify control and disease patients. 962Scopus© Citations 20
- PublicationRelationship between serum response factor and androgen receptor in prostate cancer(Wiley, 2015-11)
; ; ; ; ; ; ;Background: Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. Materials and Methods: Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. Results: To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. Conclusion: Our data support SRF as a promising therapeutic target in combination with current treatments. Prostate 75:1704–1717, 2015. © 2015 Wiley Periodicals, Inc. 448Scopus© Citations 5
- PublicationPreclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer(Nature Publishing Group, 2016-10-14)
; ; ; ; ; ; ; ;Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvβ3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC. 335Scopus© Citations 14
- PublicationThe analysis of serum response factor expression in bone and soft tissue prostate cancer metastases(Wiley, 2014-02)
; ; ; ; ; ; ; ;Castration-resistant prostate cancer (CRPC) represents a challenge to treat with no effective treatment options available. We recently identified serum response factor (SRF) as a key transcription factor in an in vitro model of castration resistance where we showed that SRF inhibition resulted in reduced cellular proliferation. We also demonstrated an association between SRF protein expression and CRPC in a cohort of castrate-resistant transurethral resections of the prostate (TURPS). The mechanisms regulating the growth of CRPC bone and visceral metastases have not been explored in depth due to the paucity of patient-related material available for analysis. In this study, we aim to evaluate SRF protein expression in prostate cancer (PCa) metastases, which has not previously been reported. 395Scopus© Citations 15
- PublicationMetSizeR: selecting the optimal sample size for metabolomic studies using an analysis based approach(BioMed Central, 2013-11-21)
; ; ; ;Background: Determining sample sizes for metabolomic experiments is important but due to the complexity of these experiments, there are currently no standard methods for sample size estimation in metabolomics. Since pilot studies are rarely done in metabolomics, currently existing sample size estimation approaches which rely on pilot data can not be applied. Results: In this article, an analysis based approach called MetSizeR is developed to estimate sample size for metabolomic experiments even when experimental pilot data are not available. The key motivation for MetSizeR is that it considers the type of analysis the researcher intends to use for data analysis when estimating sample size. MetSizeR uses information about the data analysis technique and prior expert knowledge of the metabolomic experiment to simulate pilot data from a statistical model. Permutation based techniques are then applied to the simulated pilot data to estimate the required sample size. Conclusions: The MetSizeR methodology, and a publicly available software package which implements the approach, are illustrated through real metabolomic applications. Sample size estimates, informed by the intended statistical analysis technique, and the associated uncertainty are provided. 294Scopus© Citations 78
- PublicationClinical Decision Support Systems in Breast Cancer: A Systematic Review(MDPI, 2020-02-06)
; ; ;Breast cancer is the most frequently diagnosed cancer in women, with more than 2.1 million new diagnoses worldwide every year. Personalised treatment is critical to optimising outcomes for patients with breast cancer. A major advance in medical practice is the incorporation of Clinical Decision Support Systems (CDSSs) to assist and support healthcare staff in clinical decision-making, thus improving the quality of decisions and overall patient care whilst minimising costs. The usage and availability of CDSSs in breast cancer care in healthcare settings is increasing. However, there may be differences in how particular CDSSs are developed, the information they include, the decisions they recommend, and how they are used in practice. This systematic review examines various CDSSs to determine their availability, intended use, medical characteristics, and expected outputs concerning breast cancer therapeutic decisions, an area that is known to have varying degrees of subjectivity in clinical practice. Utilising the methodology of Kitchenham and Charter, a systematic search of the literature was performed in Springer, Science Direct, Google Scholar, PubMed, ACM, IEEE, and Scopus. An overview of CDSS which supports decision-making in breast cancer treatment is provided along with a critical appraisal of their benefits, limitations, and opportunities for improvement. 266Scopus© Citations 36
- PublicationUnderstanding and Attitudes toward Cancer Clinical Trials among Patients with a Cancer Diagnosis: National Study through Cancer Trials Ireland(MDPI, 2020-07-16)
; ; ; ; ; ; ; ;Cancer clinical trials (CCTs) are critical to translation and development of better therapies to improve outcomes. CCTs require adequate patient involvement but accrual rates are low globally. Several known barriers impede participation and knowing how subpopulations differ in understanding of CCTs can foster targeted approaches to aid accrual and advance cancer treatments. We conducted the first nationwide survey of 1089 patients attending 14 Irish cancer centres, assessing understanding of fundamental concepts in CCT methodology and factors that influence participation, to help tailor patient support for accrual to CCTs. Two-thirds (66%) of patients reported never having been offered a CCT and only 5% of those not offered asked to participate. Misunderstanding of clinical equipoise was prevalent. There were differences in understanding of randomisation of treatment by age (p < 0.0001), ethnicity (p = 0.035) and marital status (p = 0.013), and 58% of patients and 61% previous CCT participants thought that their doctor would ensure better treatment in CCTs. Females were slightly more risk averse. Males indicated a greater willingness to participate in novel drug trials (p = 0.001, p = 0.003). The study identified disparities in several demographics; older, widowed, living in provincial small towns and fewer years-educated patients had generally poorer understanding of CCTs, highlighting requirements for targeted support in these groups. 158Scopus© Citations 3