Mark Hull

University of Leeds · School of Medicine

Background The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer chemoprevention, aligned with an excellent safety profile. Therefore, we aimed to test the efficacy of EPA and aspirin, alone and in combination and compared with a placebo, in individuals with sporadic colorect...

The omega-3 fatty acid eicosapentaenoic acid (EPA) and aspirin are candidate colorectal cancer (CRC) chemoprevention agents, which both have proof-of-concept for anti-CRC activity in man, aligned with an excellent safety profile. Methods A randomised, placebo-controlled 2 × 2 factorial trial of EPA free fatty acid (FFA) 2 g daily (E; either as the...

Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macr...

Background & aims: The prescription of opiate medications is increasing. Individuals with inflammatory bowel diseases (IBD) can develop serious complications from opiate use, but few data are available on the prescription of these drugs to patients with IBD. We examined trends in prescriptions of opiates and their association with all-cause mortal...

Objective Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the fae...

As pre-clinical and clinical research interest in ω-3 polyunsaturated fatty acids (PUFA) increases, so does the need for a fast, accurate and reproducible analytical method to measure fatty acids (FA) in biological samples in order to validate potential prognostic and predictive biomarkers, as well as establishing compliance in ω-3 PUFA interventio...

We investigated red blood cell (RBC) PUFA profiles, and the predictive value of RBC EPA content for tumour EPA exposure and clinical outcomes, in the EMT study, a randomised trial of EPA in patients awaiting colorectal cancer (CRC) liver metastasis surgery (A.J. Cockbain et al., 2014). There was a significant increase in RBC EPA in the EPA group (n...

Background: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episo...

Aim: To determine whether aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) prevent colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD). Methods: We performed a systematic review and meta-analysis. We searched for articles reporting the risk of CRC in patients with IBD related to aspirin or NA-NSAID u...

Background & aims: There are conflicting data on the role of obesity in Crohn's disease (CD) and the effect on long-term clinical outcomes is poorly studied. Some evidence suggests obesity is associated with diminished responsiveness to biological agents, especially anti-tumour necrosis factor antibodies. Methods: We aimed to examine the influen...

Supplementation with n-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for patients with inflammatory bowel diseases (IBD). In this study we analyzed the pharmacokinetic profile of eicosapentaenoic acid (EPA), as the free fatty acid (FFA), in an enteric-coated preparation, in 10 ulcerative colitis (UC) and 10 Crohn's disease (CD) patien...

Introduction Self-expanding metal stents (SEMS) are an important treatment modality in palliation of malignant dysphagia, either alone or in addition to chemotherapy or radiotherapy. However, the optimal timing of stent insertion remains uncertain when considering prognosis in advanced malignancy. We present a large single centre experience of pati...

Introduction In recent years, the role of oesophageal stenting for malignant dysphagia has evolved alongside other palliative treatments for oesophageal cancer. Management has become increasingly multidisciplinary and different considerations affect decisions about the timing and appropriateness of palliative stenting. We sought to assess the curre...

Introduction Patients with ulcerative colitis (UC) have an increased risk for colorectal cancer. The yield of surveillance can be improved by addition of newer endoscopic methods like chromoendoscopy (CE)1and HDWLE when compared to standard definition endoscopy.2There are no studies comparing HDCE and HDWLE. The aim of this trial is to compare the...

Goals: To evaluate the role of folic acid supplementation in colorectal cancer (CRC) chemoprevention in patients with inflammatory bowel disease (IBD). Background: CRC is a serious complication of IBD. Folic acid supplementation has been shown to be chemopreventative in sporadic CRC. Patients with IBD are at risk of folate deficiency though inte...

Recent publications in Gut 1 ,2 have highlighted the beneficial role of the National Institute for Health Research (NIHR) Clinical Research Network in supporting clinical gastroenterology research in the UK.3 On an European level, the European Clinical Research Infrastructures Network provides integrated support to multinational clinical research p...

Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid...

Background: Colorectal cancers (CRCs) detected through the NHS Bowel Cancer Screening Programme (BCSP) have been shown to have a more favourable outcome compared to non-screen-detected cancers. The aim was to identify whether this was solely due to the earlier stage shift of these cancers, or whether other factors were involved. Methods: A combi...

Objective: The hypothesis that sleeve gastrectomy (SG) is not associated with an increase in mucosal colorectal cancer (CRC) biomarkers, unlike Roux-en-Y gastric bypass (RYGB), was tested. Design and methods: Rectal mucosa, blood, and urine were obtained from morbidly obese patients (n = 23) before and after (median 28 months) SG, as well as fro...

In recent years there has been an increasing awareness of the role of the microenvironment surrounding breast cancer epithelium, particularly the carcinoma-associated fibroblast (CAF), in modulating the behaviour of breast tumours. MicroRNAs, a family of small non-coding RNAs that are key in the post-transcriptional regulation of mRNAs, have a role...

Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resecti...

Pathological features of the breast cancer cases included in this study.

Components of pathways identified by Gene Ontology analyses as enriched in the proteins differentially expressed between controlk/d and 26k/d fibroblasts.

MiR-26b knock-down or control breast fibroblasts do not have differential influences on MCF7 cell growth at a range of different seeding densities.

Expression of miR-26b predicts breast cancer recurrence.

Published miR-26b targets.

Transient miR-26b up-regulation in breast fibroblasts induced dramatic growth inhibition and apoptosis.

MCF7 cell migration is not stimulated by breast fibroblasts with reduced miR-26b when the cells are seeded in separate chambers of trans-wells.

Microarray data of miRNA expression levels from NFs and CAFs and normal and cancer epithelial cells from FFPE breast tissue.

Protein expression levels in triplicate samples of 26k/d (T1, T2, and T3) and controlk/d (C1, C2, and C3) fibroblasts as determined by mass spectrometry.

MiRNAs consistently up- or down-regulated in CAFs compared with NFs in both FFPE breast tissue and the tissue culture model.

Carcinoma-associated fibroblasts (CAFs) influence behaviour of cancer cells but roles of microRNAs in this interaction are unknown. We report microRNAs that are differentially expressed between breast normal fibroblasts and CAFs of estrogen receptor positive cancers, and explore influences of one of these, miR-26b, on breast cancer biology. We iden...

Background: The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC)...

We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a case–control genetic epidemiological study of IL-4Rα single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BAL...

Introduction Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid which has anti-colorectal cancer (CRC) activity. The molecular mechanism (s) underlying the anti-neoplastic activity of EPA are not understood. Trihydroxy-EPA, also known as Resolvin E1 (RvE1), is an oxygenated derivative of EPA, that has been shown to inhibit NK-κB s...

Introduction Colorectal cancers detected through the NHS Bowel Cancer Screening Programme (BCSP) have been shown to have a more favourable outcome compared to non-screen detected cancers. The aim of this study was to identify whether this was solely due to the earlier stage shift of these cancers, or whether there were other factors involved. Metho...

Objective: The purpose was to determine whether obesity surgery is associated with a long-term increased risk of colorectal cancer. Background: Long-term cancer risk after obesity surgery is not well characterized. Preliminary epidemiological observations and human tissue biomarker studies recently suggested an increased risk of colorectal cance...

Background Prostaglandin (PG) E2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variab...

Methods.

Individual paired values of enzyme immunoreactivity, activity and NAD/NADH levels from the periphery (blue) and centre (yellow) of 20 CRCLM.

15-PGDH IHC on tissue microarrays of primary CRCs and matched CRCLM.

LIM1863 human CRC cells cultured in the absence.

The effect of acute hypoxia 15-PGDH mRnA expression and PGE2 levels in medium conditioned by HCA-7 human cRc cells.

Quantitiative immunohistochemistry analysis.

The strong link between inflammation and colorectal carcinogenesis provides the rationale for using anti-inflammatory agents for chemoprevention of colorectal cancer (CRC). Several naturally occurring substances with anti-inflammatory properties, used in a purified 'nutraceutical' form, including omega-3 polyunsaturated fatty acids (PUFAs) such as...

Tumour invasion and metastasis is the most common cause of death from cancer. For epithelial cells to invade surrounding tissues and metastasise, an epithelial-mesenchymal transition (EMT) is required. We have demonstrated that FGFR1 expression is increased in bladder cancer and that activation of FGFR1 induces an EMT in urothelial carcinoma (UC) c...

A. Actin cytoskeletal changes in 94-10-FR1 cells cultured with FGF2 and fixed at the specific time points (minutes) shown (bars = 30 µm). B. Flow cytometry results indicating increased cell size (FSC) in FGF2 treated 94-10-FR1 cells. C. Scratch assay demonstrating increase migration of 94-10-FR1 cells compared to control (bars = 100 µm). D. Western...

A. 94-10-Y766F show little change in morphology after culture with FGF2 compared to 94-10-FR1 cells (bars = 100 µm). B. Flow cytometry showing no change in cell size of 94-10-Y766F cells culture with FGF2. C. Western blot showing E-cadherin and plakoglobin expression levels in 94-10-FR1 and 94-10-Y766F cells cultured with heparin or heparin and FGF...

The NHS Bowel Cancer Screening Programme (BCSP) uses faecal occult blood (FOB) testing to select patients aged 60-69 years for colonoscopy. To examine the association between aspirin use and the detection of colorectal neoplasia in screened patients undergoing colonoscopy. Data were collected prospectively on individuals who underwent colonoscopy f...

Faecal calprotectin (FCP) is a non-invasive biomarker of intestinal inflammation, levels of which are reported to be elevated in individuals with increased body mass index (BMI). We investigated whether weight loss (WL), induced by dietary and behavioural change in a community weight loss programme (Slimming World), was associated with a reduction...

Mouse models are becoming increasingly important in the study of molecular mechanisms of colorectal disease and in the development of novel therapeutics. To enhance this phase of preclinical research, cost-effective, easy to use noninvasive imaging is required to detect and monitor changes in the colon wall associated with disease pathology. This s...

The omega-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) has antineoplastic activity at early stages of colorectal carcinogenesis, relevant to chemoprevention of colorectal cancer (CRC). We tested the hypothesis that EPA also has anti-CRC activity at later stages of colorectal carcinogenesis, relevant to treatment of metastatic CRC...

Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial...

ApcMin/+ mice spontaneously develop multiple intestinal adenomas along the length of the small intestine and colon. Currently little is known about the role of the immune system in regulating intestinal tumorigenesis in these animals. This study characterised small intestinal intraepithelial lympho-- cyte (IEL) populations in C56BL/6J ApcMin/+ mice...

Chemoprevention of cancer has been described as the prevention of cancer by agents which prevent, arrest or reverse the initiation of carcinogenesis or the progression of neoplastic cells to cancer. Chemoprevention of cancer is now an established intervention for three of the commonest cancers worldwide. Prevention of hepatocellular cancer by mass...

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are naturally occurring omega (ω)-3 long-chain polyunsaturated fatty acids (PUFAs), which are found in highest quantities in oily fish such as sardines and mackerel. Epidemiological studies of the association between fish intake, ω-3 PUFA intake or blood ω-3 PUFA levels and colorectal cance...

Omega (ω)-3 polyunsaturated fatty acids (PUFAs) are naturally occurring substances that are well tolerated and have been used extensively for the prevention of cardiovascular disease. More recently, ω-3 PUFAs have been recognised to have anticancer activity. There is also evidence suggesting improved efficacy and/or tolerability of conventional can...

IntroductionWe have previously shown that putative mucosal biomarkers of colorectal cancer (CRC) risk (rectal epithelial cell mitosis frequency and crypt size) are significantly higher in morbidly obese (body mass index (BMI) >40 kg/m2) patients than normal weight controls. These biomarkers were further increased up to 3 years after Roux-en-Y gastr...

Excess body weight (EBW) is an independent risk factor for many human malignancies, including cancers throughout the gastrointestinal and hepatobiliary tract from the esophagus to the colorectum. The relative risk of gastrointestinal cancer in obese individuals is approximately 1.5-2.0 times that for normal weight individuals, with organ-specific a...

Rectal epithelial cell mitosis and crypt size, as well as expression of proinflammatory genes including macrophage migration inhibitory factor (MIF), are increased 6 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients. Tests were carried out to determine whether these putative colorectal cancer risk biomarkers remained elevated...

In the absence of official guidance for the management of colonic wall thickening identified by computed tomography (CT), a common clinical dilemma surrounds the volume of colonoscopies subsequently performed. To identify whether colonic wall thickening identified at CT consistently warrants colonoscopy, consecutive colonoscopies performed at Leeds...