R V Lord

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Publications (89)605.14 Total impact

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    ABSTRACT: The contribution of immune cells to the inflammasome that characterises type 2 diabetes mellitus and obesity is under intense research scrutiny. We hypothesised that early changes in glucose metabolism following gastric banding surgery may relate to systemic inflammation, particularly cell-mediated immunity. Obese participants (BMI 43.4 ± 4.9 kg/m(2), n = 15) with diabetes or impaired glucose tolerance (IGT) underwent laparoscopic adjustable gastric banding surgery. Measurements taken before, and at 2 and 12 weeks after surgery included: fasting glucose, glucose levels 2 h after a 75 g oral load, glucose incremental AUC, oral glucose insulin sensitivity index (OGIS), circulating immune cell numbers and activation, and adipokine levels. Subcutaneous and visceral adipose tissue were collected at surgery, and macrophage number and activation measured. There were significant reductions in fasting and 2 h glucose, as well as improved OGIS at 2 and 12 weeks. At 12 weeks, 80% of the diabetic participants reverted to normal glucose tolerance or IGT, and all IGT participants had normalised glucose tolerance. The 12 week fall in fasting glucose was significantly related to baseline lymphocyte and T lymphocyte numbers, and to granulocyte activation, but also to the magnitude of the 12 week reduction in lymphocyte and T lymphocyte numbers and TNF-α levels. In a model that explained 75% of the variance in the change in fasting glucose, the 12 week change in T lymphocytes was independently associated with the 12 week fall in fasting glucose. Rapid improvements in glucose metabolism after gastric banding surgery are related to reductions in circulating pro-inflammatory immune cells, specifically T lymphocytes. The contribution of immune cell-mediated inflammation to glucose homeostasis in type 2 diabetes and its improvement after bariatric surgery require further investigation.
    Diabetologia 09/2013; · 6.49 Impact Factor
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    Nicholas Clemons, Wayne Phillips, Reginald V N Lord
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    ABSTRACT: Esophageal adenocarcinoma develops in response to severe gastresophageal reflux disease through the precursor lesion Barrett's esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the USA has increased by over 600% in the past 40 y and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2 and the Wnt, Notch and Hedgehog signaling pathways.
    Cancer biology & therapy 06/2013; 14(9). · 3.29 Impact Factor
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    ABSTRACT: Bariatric surgery may be an effective treatment for obese heart failure patients, enabling access to cardiac transplantation and/or improvement of symptoms. We report the outcomes of two morbidly obese patients with end-stage heart failure, where obesity precluded cardiac transplantation and underwent laparoscopic gastric banding. A 42 year-old male with idiopathic dilated cardiomyopathy weighing 124.4kg (BMI 42kg/m(2)) lost 34kg and was successfully transplanted 11 months later. A 40 year-old woman with familial dilated cardiomyopathy weighing 105kg (BMI 40kg/m(2)) lost 14kg with sufficient symptomatic resolution to no longer require cardiac transplantation. In selected patients with severe heart failure and concomitant morbid obesity, bariatric surgery may be a reasonable treatment option.
    Heart Lung &amp Circulation 06/2012; · 1.25 Impact Factor
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    ABSTRACT: Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence. A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P<0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P<0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P=0.0043). The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia-dysplasia-adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
    Journal of Gastroenterology and Hepatology 05/2012; 27(9):1498-504. · 3.33 Impact Factor
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    ABSTRACT: Weight loss after bariatric surgery reduces cardiac risk and morbidity. We examined weight loss effects on arterial stiffness in morbidly obese subjects, in relation to cytokines, circulating and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)-based immune cells and gene expression. Obese subjects with type 2 diabetes mellitus (T2D) or impaired glucose tolerance (n = 14, mean±SEM body mass index 42.9kg/m(2)) underwent 24 weeks' caloric restriction, with gastric banding at 12 weeks. Measures were: arterial augmentation index (AIx), insulin resistance, circulating cytokines, immune cell activation markers, and SAT and VAT cytokine gene expression. Weight loss reduced AIx by 20% (p = 0.007), with falls in s-selectin (p = 0.001) and inter-cellular adhesion molecule (p = 0.04). Improved AIx related to reduced surface expression of the interleukin (IL)-2 receptor on T-lymphocytes (TL-IL2R) and granulocyte adhesion markers (r = 0.59, 0.64, respectively, p < 0.04). Higher VAT expression of interferon-γ and monocyte chemoattractant protein-1 associated with a blunted AIx response. A model of TL-IL2R expression, waist, weight and insulin resistance explained 73% of the variance in AIx reduction (p = 0.005). In morbidly obese dysglycaemic subjects, modest weight loss reduces arterial stiffness, the magnitude of which relates to improved markers of inflammation.
    Diabetes & Vascular Disease Research 04/2012; · 2.59 Impact Factor
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    ABSTRACT: Barrett’s esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus and csophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant diseases. To identify’ biomarkers associated with each stage of the Barrett’s process, relative mRNA expression levels of hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector (TaqMan system) in Barrett’s intestinal metaplasia (n —14), Barrett’s dysplasia (n =10), Barrett’s adenocarcinoma (n = 14), and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barren’s esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Alann-Whitney U test). hTERT expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher in histologically normal squamous esophagus tissues from cancer panents than in normal esophagus tissues from patients vrith no cancer (P = 0.013). Very high expression levels ([hTERT × 100: β-actin] >20) were found only in patients with cancer. These findings suggest that telomerase activation is an important early event in the development of Barrett’s esophagus and esophageal adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma, and that a widespread cancer ‘field’ effect is present in the esophagus of patients with Barrett’s cancer.
    Journal of Gastrointestinal Surgery 04/2012; 4(2):135-142. · 2.36 Impact Factor
  • R V N Lord
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    ABSTRACT: Mechanistic reasoning suggests that since antireflux surgery treats the gastroesophageal reflux that is the major known risk factor for Barrett's esophagus, it should have a beneficial effect on the biology of Barrett's disease. Due to a lack of adequate data, whether this is the case remains uncertain. Most studies, including several large population-based cohort studies, are observational studies that are subject to bias. Selection bias could be present, for example, if the patients undergoing one treatment had worse disease than those undergoing the comparator treatment, which seems possible for antireflux surgery and acid suppression medication therapy. A systematic review also suggests publication bias. The published data indicate that surgeons should not claim that antireflux surgery prevents the progression of Barrett's. Well-conducted prospective studies with postoperative pH studies suggest, however, that effective surgery may reduce the risk of Barrett's progression whereas ineffective surgery provides no benefit.
    Minerva chirurgica 02/2011; 66(1):1-6. · 0.39 Impact Factor
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    ABSTRACT: The origin of smooth muscle cells in developing atherosclerotic lesions is a controversial topic with accumulating evidence indicating that at least some arterial smooth muscle cells might originate from bone marrow-derived smooth muscle cell precursors circulating in the blood. The stem cell markers currently used for the identification of stem cells in the arterial intima can be expressed by a number of different cell types residing in the arterial wall, such as mast cells, endothelial cells and dendritic cells, which can make interpretation of the data obtained somewhat ambiguous. In the present study we examined whether the putative intestinal stem cell marker Musashi-1 is expressed in the arterial wall. Using a multiplexed tandem polymerase chain reaction method (MT-PCR) and immunohistochemistry, Musashi-1 expression was revealed in human coronary arterial wall tissue segments, and this finding was followed by the demonstration of significantly higher expression levels of Musashi-1 in atherosclerotic plaques compared with those in undiseased intimal sites. Double immunohistochemistry demonstrated that in the arterial wall Musashi-1 positive cells either did not display any specific markers of cells that are known to reside in the arterial intima or Musashi-1 was co-expressed by smooth muscle α-actin positive cells. Some Musashi-1 positive cells were found along the luminal surface of arteries as well as within microvessels formed in atherosclerotic plaques by neovascularization, which supports the possibility that Musashi-1 positive cells might intrude into the arterial wall from the blood and might even represent circulating smooth muscle cell precursors.
    Atherosclerosis 01/2011; 215(2):355-65. · 3.71 Impact Factor
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    ABSTRACT: Barrett's esophagus is an acquired metaplastic abnormality in which the normal stratified squamous epithelium lining of the esophagus is replaced by an intestinal-like columnar epithelium. While in itself a benign and asymptomatic disorder, the clinical importance of this relatively common condition relates to its role as a precursor lesion to esophageal adenocarcinoma, the incidence of which has dramatically increased in Western populations in recent years. Although known to arise as a consequence of chronic gastroesophageal reflux, the cellular and molecular mechanisms underlying development Barrett's esophagus and its progression to cancer remain unclear.
    Journal of Gastroenterology and Hepatology 12/2010; 26(4):639-48. · 3.33 Impact Factor
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    ABSTRACT: Widespread applicability of tissue-based mRNA expression screening for Barrett esophagus (BE) is likely to require (1) accurate methods for assaying archival formalin-fixed, paraffin-embedded (FFPE) histopathology specimens taken at endoscopy, and (2) validation studies of promising biomarkers in different patient cohorts. 30 genes were significantly differentially expressed by histopathology tissue type. The direction and magnitude of the differences were very similar to those found in previous studies using fresh frozen tissues. Novel upregulated genes were TSPAN8 (also known as CO-029), TSPAN24 (CD151), EGR1 and TCIRG1. Novel downregulated genes were DPYD, TSPAN29 (CD9) and Ets1. Strong associations between histopathology type and gene expression were observed with the overexpressed genes: cyclo-oxygenase-2 (COX-2), for which histopathology type explained 77.7% of the variation in expression, TSPAN1 (73.5%), TSPAN8 (62.9%), SPARC (62.1%), MMP7 (50.8%); and the under-expressed genes ADH7 (53.7%), APC (58.2%), RAR-gamma (51.3%). mRNA was isolated from 54 FFPE small endoscopic biopsies from patients with Barrett intestinal metaplasia (BE), esophageal adenocarcinoma (EAC), or control patients with a normal squamous-lined esophagus. Multiplexed tandem PCR (MT-PCR) was used to quantitate 50 selected candidate genes for BE and control genes in duplicate. Principal component analysis (PCA) was conducted to explore the presence of global differences in gene expression profiles. One-way analysis of variance (ANOVA) of the transformed data was used to identify genes that were differentially expressed between different histological subtypes. Differentially expressed genes with a fold change of ≥2 (upregulated) or ≤-2 (downregulated) are reported with the p value for each comparison (EAC vs. normal, EAC vs. BE and BE vs. normal). The Benjamini-Hochberg method was used to control the false discovery rate at 0.01 for all comparisons. Alterations in expression of select genes are strongly associated with BE or EAC or both. This study's findings for many highly differentially expressed genes are very similar to those previously reported, suggesting that these genes should be tested further in longitudinal studies for their potential role as biomarkers of progression to more advanced Barrett disease.
    Cancer biology & therapy 07/2010; 10(2):172-9. · 3.29 Impact Factor
  • Yuri V Bobryshev, Jinhua Lu, Reginald V N Lord
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    ABSTRACT: C1q, an element of the first component of complement, is known to be expressed by interdigitating and follicular dendritic cells in the spleen, where it has been suggested that C1q is involved in capturing immune complexes. The present study investigated whether C1q is expressed in Barrett's esophagus and esophageal adenocarcinoma and, if so, whether its expression is associated with dendritic cells. Endoscopic biopsy or operative surgical specimens were obtained from 15 patients with Barrett's esophagus, 13 patients with esophageal adenocarcinoma and 12 patients whose biopsy specimens did not show the presence of specialized intestinal metaplasia or adenocarcinoma. Barrett's esophagus was diagnosed by the presence of a macroscopic area of columnar-lined esophagus as well as microscopic intestinal metaplasia with goblet cells. Immunohistochemistry utilizing anti-C1q and markers for dendritic cells and macrophages was performed on sections of tissue samples embedded in paraffin. Double immunostaining with C1q/CD83 and C1q/CD68 was used to analyze the possible co-localization of C1q with dendritic cells and macrophages. The expression of C1q by dendritic cells and macrophages was also examined in in vitro studies using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. In all specimens studied, C1q expression was detected as being distributed irregularly throughout the lamina propria. A computerized quantitative analysis showed that C1q expression was significantly higher in tissue specimens without specialized intestinal-type metaplasia than in Barrett's esophagus specimens and specimens with adenocarcinoma. Double immunostaining revealed that dendritic cells and macrophages expressed C1q in all analyzed esophageal specimens. The expression of C1q by dendritic cells and macrophages was also demonstrated in in vitro studies using RT-PCR and Western blotting. The findings suggest that reduced levels of the expression of C1q by dendritic cells and macrophages in the esophagus may play a role in the formation of immune responses associated with the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
    Journal of Gastrointestinal Surgery 05/2010; 14(8):1207-13. · 2.36 Impact Factor
  • A Viardot, R V Lord, K Samaras
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    ABSTRACT: Obesity-related chronic inflammation is implicated in the pathogenesis of type 2 diabetes (T2D). The objective of the study was to determine the effects of weight loss on immune cells in T2D and prediabetes. Thirteen obese subjects with T2D or prediabetes underwent 24 wk dietary energy restriction with gastric banding surgery at 12 wk. Measures included weight, waist, and insulin resistance; surface activation marker expression on circulating immune cells; T-helper cell polarization: type 1 (Th1), type 2 (Th2); adipose tissue macrophage number and activation in sc and visceral adipose tissue. Mean total weight loss was 13.5%. There were significant decreases in expression of proinflammatory activation markers: granulocyte CD11b, monocyte CD66b, and T cell CD69 and CD25. Proinflammatory Th1 cell numbers fell by greater than 80%, as did the Th1 to Th2 ratio. The fall in Th1 to Th2 ratio related to weight (P < 0.05) and waist loss (P < 0.05). Reduction in immune cell activation was more pronounced in subjects with prediabetes. Weight and abdominal fat loss were predicted by lower activation of adipose tissue macrophage in sc and visceral adipose tissue (P < 0.05). Energy restriction before and after gastric banding attenuates activation of circulating immune cells of the innate and adaptive immune system in T2D and prediabetes. The role of immune cells in the chronic inflammation of obesity and T2D requires further investigation.
    The Journal of clinical endocrinology and metabolism 04/2010; 95(6):2845-50. · 6.50 Impact Factor
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    ABSTRACT: The cancer stem cell theory states that cancers contain tumor-forming cells that have the ability to self-renew as well as give rise to cells that differentiate. Cancer stem cells have been identified in several solid tumors, but stem cells in normal human esophagus or in Barrett's esophagus or adenocarcinoma have not been reported. Musashi-1 is expressed by the crypt base columnar cells identified as intestinal stem cells. In other diseases of the gastrointestinal tract, local inflammation of the tunica mucosa may be an initiating factor of alteration of focal tissue 'niches,' where dormant stem cells locate. The present study investigated whether Musashi-1 is expressed in the esophagus and its relation to immune inflammation of the mucosa in Barrett's esophagus and esophageal adenocarcinoma. A total of 41 esophageal tissue specimens from 41 patients were studied. Of these, 15 were esophageal adenocarcinoma, 17 were Barrett's esophagus (10 intestinal metaplasia and 7 dysplasia), and 9 were normal squamous esophagus tissue specimens from patients without esophageal pathology. Immunohistochemistry was performed using antibodies to Musashi-1 and to a set of cell type-specific markers. A multiplexed tandem polymerase chain reaction method was used to measure the relative mRNA expression levels of Musashi-1 and the specific dendritic cell marker dendritic cell-specific intercellular molecule-3 (ICAM-3)-grabbing nonintegrin. Immunohistochemistry demonstrated the presence of small numbers of Musashi-1+ cells scattered in the connective tissue stroma and within the epithelium in cardiac-type glands in biopsies from patients without Barrett's esophagus. Musashi-1 expression was present in Barrett's intestinal metaplasia and in dysplastic Barrett's in which the majority of epithelial cells in individual glands expressed this antigen. Expression of Musashi-1 was highest in esophageal adenocarcinoma, where it was most intense in glands that displayed features of early stages of adenocarcinoma formation. In contrast, Musashi-1 staining level was weaker in glands that displayed features of advanced adenocarcinoma. Double immunostaining with proliferating cell nuclear antigen showed low proliferation in the vast majority of Musashi-1+ cells. Musashi-1 mRNA expression levels were significantly higher in esophageal adenocarcinoma than in normal esophagus or Barrett's esophagus tissues. Dendritic cell-specific intercellular molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) mRNA expression levels were significantly increased in both Barrett's tissues and adenocarcinoma tissues. Expression of the putative stem cell marker Musashi-1 is absent in normal squamous epithelium, weak in esophageal cardiac-type glands and Barrett's esophagus, and markedly increased in adenocarcinoma, especially in glands displaying features of early cancer development. Musashi-1 expressing cells may be significant in the etiology of Barrett's esophagus and adenocarcinoma, and perhaps even a cell of origin for this disease. We speculate that immune inflammation occurring in Barrett's esophagus alters the mucosal microenvironment in a manner which is favorable to the activation of dormant stem cells.
    Diseases of the Esophagus 04/2010; 23(7):580-9. · 1.64 Impact Factor
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    ABSTRACT: Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age- and gender- matched controls). Metabolic parameters were measured in the fasted state: body composition by dual-energy X-ray absorptiometry and insulin action by hyperinsulinemic-euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase-PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein (MIP), interleukin-8 (IL-8)). Fasting glucose related to VAT expression of TNFalpha, MIP, serum amyloid A (SAA), IL-1alpha, IL-1beta, IL-8, and IL-8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element-binding protein (CREBP), IL-1beta, and IL-8. Insulin action related inversely to VAT complement C3 expression only. There were depot-specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol-binding protein-4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.
    Obesity 12/2009; 18(5):884-9. · 3.92 Impact Factor
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    ABSTRACT: FTO gene variants are linked to obesity. We tested for site-specific differences in FTO gene expression in subcutaneous and visceral adipose tissue (SAT and VAT, respectively) from individuals with and without type 2 diabetes mellitus (T2D) and the relationships between fasting glucose, in vivo insulin action, and measures of adiposity with FTO gene expression in adipose tissue. Paired subcutaneous and visceral fat were excised at elective surgery in n = 16 subjects (six with T2D, age-matched). Metabolic parameters were measured in fasted state; body composition by dual-energy X-ray absorptiometry; and insulin action by hyperinsulinemic euglycemic clamp. Adipose tissue mRNA gene expression was determined by quantitative RT-PCR. Subjects with T2D had SAT and VAT FTO mRNA expression similar to controls. There was no depot specificity between SAT and VAT FTO mRNA expression. Insulin action did not relate to SAT or VAT FTO mRNA expression. SAT FTO mRNA expression was related to fasting glucose and waist circumference only. SAT and VAT FTO mRNA expression was not related to direct measures of total or central abdominal adiposity. SAT FTO mRNA expression was related to SAT tumor necrosis factor-alpha and nuclear factor-kappaB mRNA expression. FTO gene expression is not increased in SAT and VAT in T2D and does not relate to insulin action. The links between FTO and metabolic complications of diabetes require further elucidation.
    Obesity Surgery 09/2009; 20(1):108-13. · 3.10 Impact Factor
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    ABSTRACT: Cystic fibrosis (CF) is the commonest inherited life-threatening disease in Caucasians. With increased longevity, more patients with CF are developing gastrointestinal complications including the distal intestinal obstruction syndrome (DIOS), in which ileocecal obstruction is caused by viscid mucofeculent material. The optimal management of DIOS is uncertain. The medical records of all patients with CF who underwent lung transplantation at this institution during a 15-year period were reviewed. The definition of DIOS required the presence of both clinical and radiological features of ileocecal obstruction. One hundred twenty-one patients with CF underwent lung transplantation during the study period. During a minimum 2-year follow-up, there were 17 episodes of DIOS in 13 (10.7%) patients. The development of DIOS was significantly associated with a past history of meconium ileus (odds ratio 20.7, 95% C.I. 5.09-83.9) or previous laparotomy (odds ratio 4.93, 95% C.I. 1.47-16.6). All six patients who developed DIOS during the transplantation admission had meconium ileus during infancy, and five had undergone pretransplant laparotomy for CF complications. First-line treatment for all patients was a combination of medication (laxatives, stool softeners, and bowel preparation formulas). This was successful in 14 of the 17 DIOS but needed to be given for up to 14 days. The other three patients required laparotomy with enterotomy and fecal disimpaction. This provided definitive resolution of DIOS except in one patient who presented late and died despite ileal decompression and ileostomy. DIOS occurred in approximately 10% of CF patients after lung transplantation. Patients with a history of meconium ileus or previous laparotomy are at high risk of developing DIOS. Patients with DIOS require early aggressive management with timely laparotomy with enterotomy and possible stoma formation when non-operative therapy is unsuccessful.
    Journal of Gastrointestinal Surgery 06/2009; 13(8):1448-53. · 2.36 Impact Factor
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    ABSTRACT: The thymidine kinase gene of the herpes simplex virus (HSV-tk) is a suicide gene when administrated with the prodrug ganciclovir (GCV). This study investigated the effectiveness of HSV-tk activation as gene therapy for gastroesophageal junction and gastric adenocarcinomas using either the stress-inducible Grp78 promoter or the murine leukemia virus long-terminal repeat (LTR) promoter. The HSV-tk gene, controlled by either the Grp78 promoter or the LTR promoter, was transduced into the gastroesophageal junction adenocarcinoma cell line SK-GT-5 and the gastric adenocarcinoma cell line MKN-74. Cell viability after exposure to varying concentrations of GCV was compared. The same cell lines were used to develop a nude mouse model for studies of the HSV-tk/GCV effect in vivo. The effect of intraperitoneal GCV injection on growth of the subcutaneous tumors was measured. HSV-TK expression was measured by Western blot and reverse transcription polymerase chain reaction. Cell viability in vitro was significantly lower in the HSV-tk expressing (HSV-tk+) cells compared to control (no HSV-tk) cells after exposure to GCV. MKN-74tk+ cells were more sensitive to GCV killing than SK-GT-5tk+ cells. After culture with 1 microg/ml GCV for 10 days, MKN-74/tk cells were totally killed, whereas most SK-GT-5/tk cells survived. Cell viability was significantly lower under glucose starvation conditions when HSV-tk expression was regulated by the Grp78 promoter compared with the LTR promoter. MKN-74 tumors formed with HSV-tk+ cells in nude mice were eliminated after administration of GCV for 3 weeks, but GCV had no effect on tumors formed from HSV-tk- cells. Eradication of tumor formed with Grp78-tk cells was faster than that with LTR-tk cells. HSV-TK protein and mRNA were expressed in the transduced, but not the non-transduced tumors. HSV-tk xwith ganciclovir suicide gene therapy results in significant cell killing in gastroesophageal junction and gastric adenocarcinoma cells both in vitro and in vivo, but complete tumor elimination only occurred with the gastric adenocarcinoma cell tumors. The most effective approach in this study used the Grp78 promoter in glucose-starvation stress conditions.
    Journal of Gastrointestinal Surgery 04/2009; 13(6):1044-51. · 2.36 Impact Factor
  • Gastroenterology 01/2009; 136(5). · 12.82 Impact Factor
  • Gastroenterology 01/2009; 136(5). · 12.82 Impact Factor
  • Gastroenterology 01/2009; 136(5). · 12.82 Impact Factor

Publication Stats

3k Citations
605.14 Total Impact Points

Institutions

  • 2013
    • Peter MacCallum Cancer Centre
      Melbourne, Victoria, Australia
  • 2009–2013
    • Garvan Institute of Medical Research
      • Cancer Research Program
      Darlinghurst, New South Wales, Australia
  • 2010–2012
    • St. Vincent's Hospital Sydney
      • Department of Upper Gastrointestinal Tract Surgery
      Sydney, New South Wales, Australia
  • 2009–2012
    • Saint Vincent Hospital
      Worcester, Massachusetts, United States
  • 2008–2012
    • University of New South Wales
      • • Faculty of Medicine
      • • Department of Surgery
      Kensington, New South Wales, Australia
  • 1999–2009
    • University of Southern California
      • • Department of Surgery
      • • Department of Cardiothoracic Surgery
      Los Angeles, CA, United States
  • 2000–2004
    • University of California, Los Angeles
      • • Department of Surgery
      • • Division of Cardiothoracic Surgery
      Los Angeles, CA, United States
  • 2003
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 2002
    • University of Southern Mississippi
      Mississippi, United States