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Identification of β2-microglobulin as a urinary biomarker for chronic allograft nephropathy using proteomic methods

2011-08, Johnston, Olwyn, Cassidy, Hilary, O'Connell, Séin, O'Riordan, Aisling, Gallagher, William M., Maguire, Patricia B., Wynne, Kieran, Cagney, Gerard, Ryan, Michael P., Conlon, Peter J., McMorrow, Tara

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.

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Examination of cell-host-biomaterial interactions via high-throughput technologies : a re-appraisal

2010-09, Power, Karen Ann, Fitzgerald, Kathleen T., Gallagher, William M.

Biomaterials are required to act harmoniously when exposed to the body or bodily fluids. Investigating cellular or in vivo phenotypic responses and protein adsorption to the material surface helps to determine the associated biocompatibility. Past limitations on progress in this field include time-consuming cell-based screening tools and a limited understanding of the complex nature of cell–biomaterial interactions. While high-throughput technologies by their nature are a rapid tool to derive meaning from multifaceted systems and, in recent years, the biomaterial community is beginning to take advantage of these technologies, the key observation in this Leading Opinion Paper is that the biomaterials community has been slow to accept these methods as an addition to their traditional experimentation workflow. The purpose of this paper is to review the definition and recent usage of high-throughput experiments in order to examine biomaterial interactions at the cellular and wider host level, especially as they become more relevant within the biomaterials arena encapsulating tissue engineering, gene, drug and stem cell delivery systems. The technologies under focus include rapid cell-based screening, transcriptomics and proteomics.

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Clinical Decision Support Systems in Breast Cancer: A Systematic Review

2020-02-06, Mazo, Claudia, Kearns, Cathriona, Mooney, Catherine, Gallagher, William M.

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.

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Multi-Gene Prognostic Signatures and Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in ER-Positive, HER2-Negative Breast Cancer Patients

2020-05-01, Mazo, Claudia, Barron, Stephen, Mooney, Catherine, Gallagher, William M.

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.

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The analysis of serum response factor expression in bone and soft tissue prostate cancer metastases

2014-02, O'Hurley, Gillian, Prencipe, Maria, Lundon, Dara, O'Neill, Amanda, Boyce, Susie, Gallagher, William M., Morrissey, Colm, Watson, R. William, et al.

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.

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BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer

2018-03-20, Shields, Sarah, Conroy, Emer, O'Grady, Tony, McGoldrick, Aloysius, Dempsey, Eugene, Reilly, Rebecca, Fan, Yue, Matallanas, David, McCann, Amanda, Gallagher, William M., Coppinger, Judith A., et al.

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.

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Commercialized biomarkers: new horizons in prostate cancer diagnostics

2015-02-24, Murphy, Lisa, Prencipe, Maria, Gallagher, William M., Watson, R. William

Limitations with current clinical tools available for diagnosis and prognosis of prostate cancer (PCa) have resulted in overdiagnosis and costly overtreatment, which is affecting the outcomes and quality of life of men. The biotech industry is investing significant resources into developing more specific biomarkers for PCa detection and patient stratification that would greatly advance the decision-making processes behind PCa management and treatment. In this review, we focus on those biomarkers that have been translated into commercial tests available to clinicians. Since these tests aim to fill specific gaps during the decision-making process of PCa management, we have grouped them based on the clinical question they claim to address, that is, improved PCa screening, false-negative biopsy dilemma, prognostic tests following a positive biopsy and tests predicting relapse/metastases after surgery. We evaluate each test with respect to its development, platform, clinical validation, biomatrix, regulatory approval status and cost.

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MetSizeR: selecting the optimal sample size for metabolomic studies using an analysis based approach

2013-11-21, Nyamundanda, Gift, Gormley, Isobel Claire, Fan, Yue, Gallagher, William M., Brennan, Lorraine

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.

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Understanding and Attitudes toward Cancer Clinical Trials among Patients with a Cancer Diagnosis: National Study through Cancer Trials Ireland

2020-07-16, Kearns, Cathriona, Feighery, Ronan, Mc Caffrey, John, Higgins, Michaela, Smith, Martina, Gallagher, William M., Kelly, Ciara, Kelly, Catherine M., et al.

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.

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Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer

2016-09-21, Burke, Lorraine, Butler, Clare T., Murphy, Adrian G., Moran, Bruce, Gallagher, William M., O'Sullivan, Jacintha, Kennedy, Breandán

Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF, and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore, CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target.Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target.