Cork Breast Research Group - Doctoral Theses

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    Surguvant inflammation and metabolism in colorectal surgery
    (University College Cork, 2020) Fleming, Christina A.; Redmond, Henry Paul; Corrigan, Mark; European Association for Cancer Research; Cork University Hospital
    Background: It is believed that dysregulated perioperative inflammation (POI) and altered cellular and systemic metabolism in the perioperative period may predispose to colon cancer recurrence. This thesis examined the ability to harness perioperative body composition, cell free DNA (cfDNA) and metabolomic data and apply these as prognostic markers and potential therapeutic targets in the treatment of colon cancer. Hypothesis: Perioperative non-invasive methods of predicting clinical and cancer outcomes may be adopted in colon cancer, in particular anthropometric measurement, cfDNA analysis and profiling of the systemic metabolome. Aims: The aims of this thesis were as follows: 1. Analyse the association between CT-generated body composition parameters (BCPs), inflammation and colon cancer outcomes 2. Novel identification of the perioperative dynamics of cfDNA in colon cancer 3. Explore the perioperative metabolome in colorectal surgery 4. Investigate the effect of ‘surguvant’ systemic anti-inflammatory therapy on the perioperative metabolome in colorectal cancer surgery Methods: The association between CT-generated BCPs and five-year cancer recurrence and disease-specific mortality (DSM) were analysed using Mantel Cox log-rank test and Kaplan Meier curves generated. Inflammatory mediators driving these associations were characterised from pre-operative serum samples. Perioperative circulating cfDNA levels were measured at seven different times points (pre-operative and postoperative at 3hours, 6hours, 24hours, 48hours, POD3 and POD5). CEA levels were measured on the same patients for two years post-operatively. Comparison in trend (D) as defined by logistic regression was compared for perioperative cfDNA and post-operative CEA for identifying early colon cancer recurrence. The perioperative metabolome was characterised in patients undergoing both benign and cancer related colorectal surgery from serum samples (pre-operative, POD1 and POD5) using a Bligh-Dyer technique and GC-mass spectrometry. Metabolomic findings were explored to identify biomarker potential for predicting 30-day morbidity and five-year cancer outcomes (recurrence and DSM). The impact of body composition and systemic perioperative systemic anti-inflammatory therapy on the metabolome was also explored. Statistical analysis was performed using SPSS (v.26) and metabolomic analysis using MetaboAnalyst (v.5). Results: Both low skeletal muscle area (SMA) and high visceral to total fat ration (V:TFR) were associated with increased post-operative infectious complications [low SMA, OR 2.13 (95% CI 0.849-5.359)p=0.044; high V:TFR, OR 3.20 (95% CI 0.945-10.840)p=0.011] and five-year cancer recurrence [low SMA, HR 2.30 (95% CI 0.412-2.891)p=0.043; high V:TFR, HR 5.781(95% CI 0.662-9.450) p=0.024]. High V:TFR was also associated with five-year DSM [HR 5.916(95% CI 0.438-7.999)p=0.017]. Patients with low SMA who developed a cancer recurrence had higher circulating CRP(p=0.003), IL-6(p=0.004), VEGF(p=0.007) and CD14(p=0.029) and lower albumin(p=0.010), IL-2(p<0.001), IL-10 (p=0.004) and IFNg(p=0.018) levels. Those with high V:TFR who developed recurrence had higher levels of IL-6(p=0.030) and TNFa(p=0.029). Perioperative cfDNA was significantly associated with early cancer recurrence from 48Hrs (p=0.012) post-operatively [POD3 (p=0.01), POD5 (p=0.001)]. For identifying early recurrence, DcfDNA in the immediate perioperative period had a specificity of 97% (95%CI 86.51-99.87%) and 77.5% sensitivity (95%CI 62.5-87.7%). DCEA measured over the first two years post-operatively had similar accuracy 88.9% specificity (95%CI 56.5-99.4%) and 76.5% sensitivity (95%CI 63.24-86%) although valuable DCEA changes only occurred when recurrent disease was macroscopically evident. A differential perioperative metabolome was identified in benign (B-CRS) compared to colorectal cancer surgery (C-CRS). The urea cycle was most active in B-CRS and glycine and serine metabolism most active in C-CRS and in both cases followed by glutamate metabolism and ammonia recycling. Higher levels of ribose-5-phosphate (p=0.001), alanine (p=0.02), serine (p=0.01) and lactic acid (p<0.001) were observed throughout the perioperative period in patients with high V:TFR and higher succinic acid (p=0.03) in patients with low SMA. In stage II/III colon cancer through combined analysis of six specific metabolite concentrations (serine, proline, threonine, pyruvic acid, tryptophan, butanoic acid) a robust biomarker model for five year cancer recurrence was created [AUC 0.855 (95%CI 0.585-0.97) p<0.01]. Perioperatively, systemic anti-inflammatory therapy altered the measured metabolome. Conclusion: Body composition, cfDNA dynamics and metabolome alterations associated with poor prognosis in colon cancer may be identified in the perioperative period and could provide prognostic information for adjuvant therapy and surveillance decisionmaking. Metabolomic data in particular could further identify a potential for therapeutic targeting.
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    Macrophage polarisation: the impact of M1 versus M2 polarisation on host innate immune responses to bacterial infection
    (University College Cork, 2015-12) Foley, Niamh M.; Redmond, Henry Paul; Wang, Jianghuai
    Background and Aim: Infection is a global burden causing millions of deaths per annum worldwide. In the US sepsis is the tenth leading cause of death with the mortality associated with severe sepsis estimated at 30-50%. Innate immunity is a generic response mediated by the host to protect it from bacterial infection. The recognition of foreign microbes leads to activation of pattern recognition receptors and recruitment of macrophages. In acute bacterial infections, activated macrophages polarised to M1 or M2 states play a major role in the host cytokine response which drives the immune response until the host has overcome the invading microbial pathogen. The aim of this study was to 1) to characterise the cytokine profile of M1 and M2 polarised macrophages 2) to investigate the changes in the cytokine profile of polarised macrophages in response to bacterial stimulation 3) to examine the role of the MAPK and NFκB signalling pathways in the response of naïve and polarised macrophages to bacterial infection. Results: (i) polarisation of macrophages to an M1 state resulted in a higher secretion of pro-inflammatory cytokines (IL-6, IL12p70 and TNF-.). (ii) following bacterial stimulation M1 polarised macrophages had reduced pro-inflammatory cytokine release. (iii) M1 polarised macrophages have reduced MAPK and NFκB signalling as detected by western blot analysis. Conclusion: Following bacterial stimulation M1 polarised macrophages had reduced pro-inflammatory cytokine release which may in part be due to reduced MAPK and NFκB signalling. This data suggests that M1 polarisation states may play important roles in an endotoxin tolerant phenomenon in acute bacterial sepsis.