J V Reynolds

St. James's Hospital, Dublin, Leinster, Ireland

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Publications (173)626.95 Total impact

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    ABSTRACT: In Barrett associated tumorigenesis, oxidative phosphorylation and glycolysis are reprogrammed early in the disease and act mutually to promote disease progression. However, the link between energy metabolism and its connection with other central cellular processes within the Barrett microenvironment is unknown. The aim of this study was to examine the relationship between metabolism (ATP5B/GAPDH), hypoxia (HIF1α), inflammation (IL1β/SERPINA3), p53 and obesity status using in-vivo and ex-vivo models of Barrett esophagus. At the protein level, ATP5B (r=0.71, P<0.0001) and p53 (r=0.455, P=0.015) were found to be strongly associated with hypoxia. In addition, levels of ATP5B (r=0.53, P=0.0031) and GAPDH (r=-0.39, P=0.357) were positively associated with p53 expression. Moreover, we demonstrate that ATP5B (r=0.8, P<0.0001) and GAPDH (r=0.43, P=0.022) were positively associated with IL1β expression. Interestingly, obesity was negatively associated with oxidative phosphorylation (r=-0.6016, P=0.0177) but positively associated with glycolysis (r=0.743, P0.0015). Comparable correlations were exhibited in the ex-vivo explant tissue between metabolism, p53, hypoxia, inflammation and angiogenesis (P<0.05). Identifying and exploring these underlying molecular mechanisms linking metabolism to these key cellular processes helps in understanding how these different cellular processes interact and could provide some insight into the development of targeted therapies influencing these processes.
    Preview · Article · Dec 2015 · Cancer letters
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    ABSTRACT: Purpose Oesophageal adenocarcinoma is an exemplar model of obesity-associated cancer. Locally advanced disease is treated with neoadjuvant chemoradiotherapy, and survival rates are highest in patients demonstrating a pathological response following neoadjuvant therapy. Given that 55 % of oesophageal adenocarcinoma patients are obese, uncovering the effect of adipose tissue on radioresponse is clinically relevant. This study investigates if adipose tissue activates genomic instability events in radioresponsive (OE33P) and radioresistant (OE33R) oesophageal cancer cell lines and tumour samples. Methods OE33R and OE33P were cultured with adipose-conditioned media derived from oesophageal adenocarcinoma patients (n = 10). Anaphase bridges, a marker of genomic instability, were enumerated in both cell lines following treatment with adipose media, and normalised to cell number. Genomic instability is regulated by the spindle assembly complex. Expression of two spindle assembly complex genes (MAD2L2, BUB1B) was assessed using qPCR, and validated in patient tumour specimens from viscerally obese (n = 46) and nonobese patients (n = 41). Results Adipose-conditioned media increased anaphase bridging in OE33R (p < 0.0001), with a threefold increase in OE33R compared to OE33P (p < 0.01). Levels of anaphase bridges in OE33R cells correlated with visceral obesity status as measured by waist circumference (R = 0.709, p = 0.03) and visceral fat area (R = 0.794, p = 0.006). Adipose tissue altered expression of MAD2L2 in vitro. In vivo, MAD2L2 expression was higher in viscerally obese oesophageal adenocarcinoma patients compared with nonobese patients (p < 0.05). Conclusions Anaphase bridge levels are influenced by obesity and radiosensitivity status in oesophageal adenocarcinoma. Furthermore, visceral adipose-conditioned media stimulates dysregulation of the spindle assembly complex in oesophageal adenocarcinoma patients.
    Preview · Article · Oct 2015 · Clinical and Translational Oncology
  • J. Elliott · D. Waters · N. O'Farrell · S. King · C. Muldoon · C. Johnston · N. Ravi · J. V. Reynolds

    No preview · Article · Sep 2015 · Irish Journal of Medical Science

  • No preview · Article · Jun 2015 · Irish Journal of Medical Science
  • J. Witherspoon · D. O'Toole · N. Ravi · J. V. Reynolds

    No preview · Article · Mar 2015 · Irish Journal of Medical Science
  • A. Zaborowski · H. M. Heneghan · A. Granahan · S. King · N. Ravi · J. V. Reynolds

    No preview · Article · Mar 2015 · Irish Journal of Medical Science
  • E. M. O'Connor · S. Croghan · J. V. Reynolds

    No preview · Article · Mar 2015 · Irish Journal of Medical Science
  • P. N. Stassen · J. A. Elliott · J. Gibney · C. W. Le Roux · J. V. Reynolds

    No preview · Article · Mar 2015 · Irish Journal of Medical Science
  • S Croghan · O McCormack · C Muldoon · N Ravi · J V Reynolds
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    ABSTRACT: A 53-year-old man underwent neo-adjuvant chemo-radiotherapy and a 2 stage oesophagectomy for a junctional oesophageal tumour in 1996. In March 2012, a metachronous oesophageal tumour was identified, 7cm above the anastomotic margin, on a background of non-inflamed squamous mucosa. He is currently being managed with chemo-radiotherapy. Oesophageal cancer is associated with a historically poor survival rate, with primary concerns being local recurrence or death from disseminated disease. This case highlights the challenges which must be faced, as treatment strategies improve and consequently survival rates increase.
    No preview · Article · Feb 2015 · Irish medical journal
  • P. Lawlor · T. Moran · M. Brennan · F. Macarthy · N. Ravi · J. V. Reynolds

    No preview · Article · Feb 2015 · Irish Journal of Medical Science
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    ABSTRACT: Background The role of CT–PET after neoadjuvant chemoradiation (nCRT) for prediction of pathological response and oncological outcome in oesophageal and junctional adenocarcinoma (OAC) is unclear. The relationship between complete metabolic response (cMR), pathological complete response (pCR) and nodal status has not been clarified.Methods Patients with locally advanced OAC selected to receive nCRT and surgery with curative intent, on the basis of staging that included CT–PET positivity, were included. Repeat scanning (PET2) with an identical protocol was performed 2–4 weeks after completion of nCRT (cisplatin and 5-fluorouracil plus 44 Gy radiation). Changes in [18F]fluorodeoxyglucose uptake, considered as either a maximum standardized uptake value (SUVmax) or a relative reduction (%ΔSUVmax), and PET-predicted nodal status following nCRT were compared with histopathological response, histological node positivity and survival.ResultsOne hundred consecutive patients with PET-positive OAC were studied. Following nCRT, PET2 identified M1 disease in 2·0 per cent of patients. There were no significant associations between PET2 SUVmax or %ΔSUVmax with respect to primary tumour stage (ypT) (P = 0.216 and P = 0·975 respectively), tumour regression grade (P = 0·109 and P = 0·232), pCR (P = 0·633 and P = 0·870) or complete resection (R0) (P = 0·440 and P = 0·235). The sensitivity of PET2 for ypN was 10 per cent. %ΔSUVmax was not associated with disease-free or overall survival (P = 0·162 and P = 0·154 respectively). Of 46 patients with a cMR on PET2, 37 (80 per cent) had histological evidence of residual tumour in the resected specimen, and cMR was not associated with overall survival benefit (P = 0·478).ConclusionCT–PET following nCRT for OAC has poor prognostic and discriminatory value for clinical application.
    No preview · Article · Dec 2014 · British Journal of Surgery
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    ABSTRACT: Contemporary clinical management of Barrett's esophagus has highlighted the lack of accurate predictive markers of disease progression to esophageal cancer. This study aims to examine alterations in mitochondrial energy metabolism profiles across the entire disease progression sequence in Barrett's esophagus. An in-vitro model was used to screen 84 genes associated with mitochondrial energy metabolism. Three energy metabolism genes (ATP12A, COX4I2, COX8C) were significantly altered across the in-vitro Barrett's disease sequence. In-vivo validations across the Barrett's sequence demonstrated differential expression of these genes. Tissue microarrays demonstrated significant alterations in both epithelial and stromal oxidative phosphorylation (ATP5B and Hsp60) and glycolytic (PKM2 and GAPDH) protein markers across the in-vivo Barrett's sequence. Levels of ATP5B in sequential follow up surveillance biopsy material segregated Barrett's non progressors and progressors to HGD and cancer. Utilizing the Seahorse XF24 flux analyzer, in-vitro Barrett's and adenocarcinoma cells exhibited altered levels of various oxidative parameters. We show for the first time that mitochondrial energy metabolism is differentially altered across the metaplasia-dysplasia-adenocarcinoma sequence and that oxidative phosphorylation profiles have predictive value in segregating Barrett's non progressors and progressors to adenocarcinoma.
    No preview · Article · Aug 2014 · Cancer Letters

  • No preview · Article · Jul 2014
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    ABSTRACT: Background: The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. Methods: Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. Results: Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34%, (16/47). Disease recurrence occurred in 19 patients (19/47, 40%). Median overall survival was 22 months, with 4-year survival of 47%. Chemotoxicities were consistent with those previously reported for this regimen. Conclusion: This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF.
    No preview · Article · May 2014 · Irish Journal of Medical Science
  • T Moran · P Lawlor · M Brennan · N Ravi · J V Reynolds
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    ABSTRACT: Manometry is the gold standard investigation of innate or acquired motility disorders in the oesophagus. New technology in the form of high-resolution manometry (HRM) may supplant traditional water-perfused manometry and enhance standardisation of manometric interpretation and reporting. This study reports on a 10-year experience of 5,184 consecutive patients using the traditional methods, and an early experience with HRM. Of 5,184 patients assessed, 4,509 (87 %) had both pH and manometry and 675 (13 %) had manometry only. 3,523 (78 %) of the pH /manometry group had normal motility, 635 (14 %) showed ineffective motility (IM), 213 (5 %) a non-specific motility disturbance (NSMD), 42 (0.9 %) achalasia, 58 (1.3 %) nutcracker oesophagus, 22 (0.5 %) hypertensive LOS (HLOS), 8 (0.2 %) diffuse oesophageal spasm (DOS) and 8 (0.2 %) had scleroderma. For those referred solely for manometry only, 324 (48 %) had normal motility, 72 (11 %) IM, 51 (8 %) NSMD, 175 (26 %) achalasia, 16 (2 %) nutcracker oesophagus, 32 (5 %) HLOS, 1 (0.1 %) DOS and 4 (0.6 %) had scleroderma. 92 patients to date have been studied with HRM, with enhanced definition of lower oesophageal sphincter (LOS) function. For patients referred for reflux related symptoms, motility disorders are present in 22 % of the cases. Conversely, of the patients referred for dysphagia, motility disturbances are detected in 52 % of the cases sent for manometry. Our initial experience shows that HRM technology is adding a valuable dimension and clearer understanding of motility patterns in the dysphagic patient.
    No preview · Article · May 2014 · Irish Journal of Medical Science
  • J M Howard · M C Cathcart · L Healy · P Beddy · C Muldoon · G P Pidgeon · J V Reynolds
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    ABSTRACT: Oesophageal adenocarcinoma is an exemplar model of an obesity-associated adenocarcinoma. Altered secretion of adipokines by visceral fat is believed to play a key role in tumorigenesis. This study examined leptin receptor (ObR) and adiponectin receptor (AdipoR1 and AdipoR2) expression in oesophageal cancer, and its relationship with patient obesity status, clinicopathological data and patient survival. Tissue microarrays were constructed from paraffin-embedded oesophagectomy specimens. ObR, AdipoR1 and AdipoR2 expression was quantified by immunohistochemistry. Anthropometric data were measured at the time of diagnosis, and obesity status was assessed using visceral fat area determined by computed tomography and body mass index. Receptor expression was correlated with various clinicopathological and anthropometric variables. Patient survival was estimated using the Kaplan-Meier method, and results compared between those with low versus high receptor expression. A Cox multivariable regression model was used to assess the relationship between survival and a number of co-variables. All 125 tumours analysed expressed AdipoR1 and AdipoR2, whereas 96·8 per cent expressed ObR. There was no significant difference in tumour pathological features or patient obesity status between tumours with low versus high ObR expression. A high level of AdipoR1 expression was significantly associated with increased patient age, obesity and less advanced tumour (T) category. Expression of AdipoR2 was inversely associated with T category (P = 0·043). Low AdipoR1 expression was an independent predictor of improved overall survival (hazard ratio 0·56, 95 per cent confidence interval 0·35 to 0·90; P = 0·017). The association between adiponectin receptor expression, obesity status and tumour category and survival suggests a potential mechanism linking obesity and oesophageal cancer.
    No preview · Article · May 2014 · British Journal of Surgery
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    ABSTRACT: Barrett's esophagus (BE) arising from chronic gastro-oesophageal reflux (GERD) is the main pathologic precursor of esophageal adenocarcinoma (EAC). The risk of progression to high-grade dysplasia (HGD) and EAC is unclear, and recent population studies from Denmark and Northern Ireland suggest that this has been overestimated in the past. No data exist from the Republic of Ireland. A detailed clinical, endoscopic, and pathologic database was established in one center as a proposed pilot for a national registry, and initial and follow-up data were abstracted by a data manager. One thousand ninety-three patients were registered, 60 patients with HGD were excluded, leaving 1033, with a median age of 59 and 2 : 1 male to female ratio, and 3599 person-years of follow-up. The overall incidence of HGD/EAC was 1.33% per year overall, 0.85% if the first year is excluded. Within the first year after index endoscopy, 18 cases of HGD or EAC were identified, and 30 following the first year. Low-grade dysplasia (LGD) on index endoscopy was associated with an incidence of progression of 6.5% per year, and 3.1% when tertiary referrals were excluded. These data provide important demographic and clinical information on the population of Irish patients with BE, with incidence rates of progression higher than recently published population-based registry series, perhaps relating to sampling and pathological assessment. Low-grade dysplasia on initial biopsy is a significant proxy marker of risk of progression.
    No preview · Article · Jan 2014 · Diseases of the Esophagus
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    ABSTRACT: Maple syrup urine disease (MSUD) has an incidence of 1:125,000 newborns in Ireland. Patients, when fasting, or in a catabolic state build up toxic metabolites leading to progressive neurological dysfunction. We describe the necessary peri-operative management of a patient with MSUD who developed symptomatic gallstones requiring a laparoscopic cholecystectomy.
    No preview · Article · Oct 2013 · Irish medical journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: Maple syrup urine disease (MSUD) has an incidence of 1:125,000 newborns in Ireland. Patients, when fasting, or in a catabolic state build up toxic metabolites leading to progressive neurological dysfunction. We describe the necessary peri-operative management of a patient with MSUD who developed symptomatic gallstones requiring a laparoscopic cholecystectomy.
    No preview · Article · Oct 2013 · Irish medical journal
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    ABSTRACT: Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5 years. Reflux disease (GERD) and Barrett's esophagus (BE) are major risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett's, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fuelled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.
    No preview · Article · Aug 2013 · Cancer letters

Publication Stats

3k Citations
626.95 Total Impact Points

Institutions

  • 1998-2015
    • St. James's Hospital
      • Department of Vascular and Endovascular Surgery
      Dublin, Leinster, Ireland
    • Dublin Dental University Hospital
      Dublin, Leinster, Ireland
  • 1993-2015
    • Trinity College Dublin
      • • Department of Surgery
      • • Centre for Health Sciences
      Dublin, Leinster, Ireland
  • 2010
    • Dublin City University
      Dublin, Leinster, Ireland
  • 2003-2006
    • Saint James School Of Medicine
      Park Ridge, Illinois, United States
  • 1992-1998
    • The Adelaide and Meath Hospital Ireland
      Dublin, Leinster, Ireland
    • St. Vincent’s Hospital, Fairview
      Dublin, Leinster, Ireland
  • 1997
    • St. Vincent Hospital
      Green Bay, Wisconsin, United States
  • 1995-1997
    • St. James University
      Сент-Джеймс, New York, United States
  • 1996
    • St. Vincent's Private Hospital
      Dublin, Leinster, Ireland
  • 1992-1993
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 1989
    • Hospital of the University of Pennsylvania
      • Department of Surgery
      Philadelphia, Pennsylvania, United States