Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients

In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69+ and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites

Visceral Adipose Tissue Modulates Radiosensitivity in Oesophageal Adenocarcinoma

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Response to neoadjuvant chemoradiotherapy (NA CRT) is a clinical challenge. We examined if visceral adipose tissue and obesity status alter radiosensitivity in OAC. The radioresistant (OE33R) and radioresponsive (OE33P) OAC isogenic model was cultured with adipose tissue conditioned media from three patient cohorts: non-cancer patients, surgery only OAC patients and NA CRT OAC patients. Cell survival was characterised by clonogenic assay, metabolomic profiling by nuclear magnetic resonance spectroscopy and adipokine receptor gene expression by qPCR. A retrospective in vivo study compared tumour response to NA CRT in normal weight (n=53) versus overweight/obese patients (n=148). Adipose conditioned media (ACM) from all patient cohorts significantly increased radiosensitivity in radioresistant OE33R cells. ACM from the NA CRT OAC cohort increased radiosensitivity in OE33P cells. Metabolomic profiling demonstrated separation of the non-cancer and surgery only OAC cohorts and between the non-cancer and NA CRT OAC cohorts. Gene expression profiling of OE33P versus OE33R cells demonstrated differential expression of the adiponectin receptor-1 (AR1), adiponectin receptor-2 (AR2), leptin receptor (LepR) and neuropilin receptor-1 (NRP1) genes. In vivo overweight/obese OAC patients achieved an enhanced tumour response following NA CRT compared to normal weight patients. This study demonstrates that visceral adipose tissue modulates the cellular response to radiation in OA

A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Social consequences of harmful use of alcohol in Ireland. HRB Overview series 9.

The purpose of this overview is to compile and analyse the available data on the social consequences of harmful use of alcohol in Ireland. The methods involve a combination of archival data, survey research results and research literature

Mechanisms linking obesity, genomic instability and the radioresponse in oesophageal adenocarcinoma

THESIS 10789The increasing incidence of oesophageal adenocarcinoma (OAC) parallels the rapidly rising incidence of obesity. OAC is an exemplar model of obesity-associated cancer, with an increasing focus on the role of visceral adipose tissue (VAT). OAC confers a poor prognosis with five year survival of 20-40% in locally advanced diseased The current standard of care involves neoadjuvant chemoradiotherapy (NA-CRT). Tumour response to NA-CRT is the best predictor of survival, but resistance to therapy remains a significant clinical problem with only 15-30% of patients achieving a complete pathological response (pCR). The identification of biomarkers and molecular mechanisms of radioresistance would be of substantial clinical benefit, and is critical for improving the efficacy of treatment. Obesity is associated with the pathogenesis and progression of OAC, but the interaction between obesity and treatment response is unknown. Genomic instability is a hallmark of cancer associated with obesity. We hypothesised that genomic instability events are implicated In the interaction between obesity and the radioresponse in OAC

A profile of self-reported alcohol-related violence in Ireland.

In Ireland alcohol consumption rose sharply during the years of economic growth (1995-2006) and harmful use of alcohol is a serious issue. This article examines the association between alcoholrelated violence and alcohol consumption, based on the secondary analyses of two national surveys of adult and college student populations. In both the general and college populations, the factors most associated with alcohol-related violence (fights and assaults) were risky drinking (frequent), gender (male), and age(younger). While men are more commonly linked to alcohol-related violence, the risk of violence among women is emerging. In the general population younger women are more likely to be victims of violence(assaults) in comparison to their female student counterparts, while reported fights are similar. Reported fights for young men are higher in the general population in comparison to their male student counterparts while assaults are similar. This suggests that the drinking context of young adults in the general population is more diverse and supports the niche theory that greater number of outlets provide subgroups with attractive venues for problem drinking (Gruenewald, Remer, & Treno, 2009). The policy response has been limited and one-sided: prosecution of offending drinkers with no national alcohol strategy implemented in the past two decades