Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308–0.943, p < 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy.

Argonaute-2 (Ago2) is an essential component of microRNA biogenesis implicated in tumourigenesis. However Ago2 expression and localisation in breast cancer remains undetermined. The aim was to define Ago2 expression (mRNA and protein) and localisation in breast cancer, and investigate associations with clinicopathological details. Ago2 protein was stained in breast cancer cell lines and tissue microarrays (TMAs), with intensity and localization assessed. Staining intensity was correlated with clinicopathological details. Using independent databases, Ago2 mRNA expression and gene alterations in breast cancer were investigated. In the breast cancer TMAs, 4 distinct staining intensities were observed (Negative, Weak, Moderate, Strong), with 64.2% of samples stained weak or negatively for Ago2 protein. An association was found between strong Ago2 staining and, the Her2 positive or basal subtypes, and between Ago2 intensity and receptor status (Estrogen or Progesterone). In tumours Ago2 mRNA expression correlated with reduced relapse free survival. Conversely, Ago2 mRNA was expressed significantly lower in SK-BR-3 (HER2 positive) and BT-20 (Basal/Triple negative) cell lines. Interestingly, high levels of Ago2 gene amplification (10–27%) were observed in breast cancer across multiple patient datasets. Importantly, knowledge of Ago2 expression improves predictions of breast cancer subtype by 20%, ER status by 15.7% and PR status by 17.5%. Quantification of Ago2 improves the stratification of breast cancer and suggests a differential role for Ago2 in breast cancer subtypes, based on levels and cellular localisation. Further investigation of the mechanisms affecting Ago2 dysregulation will reveal insights into the molecular differences underpinning breast cancer subtypes.

Extracellular vesicles (EVs) shuttle microRNA (miRNA) throughout the circulation and are believed to represent a fingerprint of the releasing cell. We isolated and characterized serum EVs of breast tumour-bearing animals, breast cancer (BC) patients, and healthy controls. EVs were characterized using transmission electron microscopy (TEM), protein quantification, western blotting, and nanoparticle tracking analysis (NTA). Absolute quantitative (AQ)-PCR was employed to analyse EV-miR-451a expression. Isolated EVs had the appropriate morphology and size. Patient sera contained significantly more EVs than did healthy controls. In tumour-bearing animals, a correlation between serum EV number and tumour burden was observed. There was no significant relationship between EV protein yield and EV quantity determined by NTA, highlighting the requirement for direct quantification. Using AQ-PCR to relate miRNA copy number to EV yield, a significant increase in miRNA-451a copies/EV was detected in BC patient sera, suggesting potential as a novel biomarker of breast cancer.

Background: Approximately one-third of colorectal cancer (CRC) patients will suffer recurrence. MiRNAs are small non-coding RNAs that play important roles in gene expression. We aimed to correlate miRNA expression with aggressive clinicopathological characteristics and survival outcomes in CRC. Methods: Tumour samples were extracted from 74 CRC patients. MiRNAs were quantified using real-time reverse transcriptase polymerase chain reaction. Descriptive statistics and Cox regression analyses were performed to correlate miRNA targets with clinicopathological and outcome data. Results: Aberrant miR-21 and miR-135b expression correlate with increased nodal stage (p = 0.039, p = 0.022). Using univariable Cox regression analyses, reduced miR-135b (β-coefficient −1.126, hazard ratio 0.324, standard error (SE) 0.4698, p = 0.017) and increased miR-195 (β-coefficient 1.442, hazard ratio 4.229, SE 0.446, p = 0.001) predicted time to disease recurrence. Survival regression trees analysis illustrated a relative cut-off of ≤0.488 for miR-195 and a relative cut-off of >−0.218 for miR-135b; both were associated with improved disease recurrence (p < 0.001, p = 0.015). Using multivariable analysis with all targets as predictors, miR-195 (β-coefficient 3.187, SE 1.419, p = 0.025) was the sole significant independent predictor of recurrence. Conclusion: MiR-195 has strong value in predicting time to recurrence in CRC patients. Additionally, miR-21 and miR-135b predict the degree nodal burden. Future studies may include these findings to personalize therapeutic and surgical decision making.

Globally numerous regions have been identified with elevated arsenic within groundwater which can result in potential adverse health risks. In Ireland, a previous national-scale research assessment of groundwater identified isolated clusters of elevated arsenic and indicated that lithology was a major controlling factor on arsenic in groundwater. Complementary comparisons of national-scale and regional-scale groundwater assessments of arsenic are lacking in Europe when compared to other global regions. The aims of this study were to demonstrate the value of a regional-scale groundwater hydrochemistry dataset with an existing national-scale approach, describe anomalies that can become the focus of attention for public health and economic reasons, and to provide a wider context for arsenic in groundwater within Ireland and Europe. Regional-scale data using 470 locations comprising 1,493 analyses using several hydrochemical parameters (arsenic, pH, conductivity, iron, manganese, sodium, potassium, calcium, magnesium, and total hardness) in south west Ireland were integrated with geological, hydrogeological, and land use datasets. Statistical analysis was performed using a combination of methods including score tests of geological groups using an empirical cumulative distribution function plot in addition to spatial analysis. Results revealed that hydrochemical parameters exhibited different spatial clusters, which was generally associated with lithology. Arsenic was elevated in sandstone derived bedrock. Weak correlation of arsenic with other hydrochemical parameters were observed and redox-sensitive elements like manganese and iron showed a greater diversity in spatial occurrence. This study has shown that the variation of hydrochemical parameters are controlled by regional geology. Finally, the paper focuses on anomalies identified by concentrations of individual ions or statistical associations in the context of, for example, historical mineral exploration and mining in the area and also discusses whether groundwater chemistry sampling on this scale can assist in future mineral exploration, as well as guiding the future development of high quality public and private water supplies.

In Europe most environmental based water quality research has focused on both nutrient and microbial contamination which can arise from agricultural processes and inadequate wastewater treatment. Recent work in Ireland has linked the presence of arsenic in groundwater at elevated concentrations at national and subnational scales with bedrock lithology serving as a strong predictor variable. Groundwater data was collected as part of an environmental impact assessment for a road construction project and this resulting groundwater geochemistry dataset was used in this present study to assess the geochemical controls of arsenic in natural waters in addition to biological and nutrient contamination. Physiochemical parameters, trace elements, nutrients, organics, and microbiological parameters were collected for every quarter for four years (2004-2008) in 67 wells. Due to differing sampling procedures and limitations in the data, only one quarter (November 2005) was used to understand groundwater geochemistry in greater detail. Multivariate statistical techniques were used to overcome the presence of non-detect data. This is an important consideration as while methods exist for chemical data, methods incorporating biological data are limited. Elevated levels of nitrate in groundwater may arise from the runoff of septic tanks and/or agricultural practices in the area. Both pesticides and polycyclic aromatic hydrocarbons were not detected in any wells signifying no anthropogenic contamination inputs. However, fuel products such as methyl tert-butyl ether were detected and potentially illustrate point source contamination, these were detected in only one well. Geochemical data indicate that elevated arsenic concentrations are present within alkali-oxic groundwaters through the desorption from Fe and Mn oxyhydroxides, i.e. alkali desorption. This study examines of the geochemistry of arsenic in groundwater in Ireland at a local scale. In addition, the multivariate methods used in this study were able to fully integrate both chemical and biological censored data, which may be applied in other regions with similar data.