Obesity and Cancer Research [1 ed.] 9781614704669, 9781606923887

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

OBESITY AND CANCER RESEARCH

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

OBESITY AND CANCER RESEARCH

PAULINE R. RAMONDE AND

EVA H. FOCHAS Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

EDITORS

Nova Biomedical Books New York Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

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All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Obesity and cancer research / [edited by] Pauline R. Ramonde and Eva H. Fochas. p. ; cm. ISBN 978-1-61470-466-9 (eBook) 1. Cancer--Nutritional aspects. 2. Obesity--Complications. 3. Cancer--Etiology. I. Ramonde, Pauline R. II. Fochas, Eva H. [DNLM: 1. Obesity--complications. 2. Neoplasms--etiology. 3. Risk Factors. 4. Treatment Outcome. WD 210 O118 2009] RC268.45.O24 2009 616.99'4071--dc22 2008043938

Published by Nova Science Publishers, Inc.    New York Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

CONTENTS

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Preface

vii

Chapter 1

Obesity and the Circadian Clock Oren Froy

Chapter 2

Lymphoma and Obesity Eleanor V. Willett and Eve Roman

35

Chapter 3

Obesity and Risk for Salivary Gland Tumors Zsuzsaanna Suba

71

Chapter 4

Adipogenic Risk Factors In Breast Cancer Sita Aggarwal, William Hansel, Jeff Gimble and Nitin Chakravarti

87

Chapter 5

The Effect of Obesity on Malignancy of the Gastrointestinal Tract Stephen DH Malnick, Ehud Melzer and Alon Basovitz

103

Chapter 6

Influence and Implications of Nutrition and Metabolic Factors on the Growth and Survival of Pediatric Cancer Cells: The IGF Connection Aru Narendran, Alexander K.C. Leung and Josephine Ho

Chapter 7

Chapter 8

Chapter 9

Gastric Cancer after Roux-en-Y Gastric Bypass for Morbid Obesity - The Utility of Double-Balloon Endoscopy Nobumi Tagaya, Kazunori Kasama and Keiichi Kubota Rapid genotyping of Trp64Arg Polymorphism of the β3-Adrenergic Receptor Gene and −3826 A to G Variant of the Uncoupling Protein-1 Gene using Real-time Fluorescent PCR Arizumi Kikuchi, Yuko Kuramoto, Nobuyasu Noritake, Hiroshi Murase, Osami Daimaru, Takeo Nakakita and Shinichi Itoh Metformin and Antineoplastic Action Dragan Micic, Goran Cvijovic, Mirjana Sumarac-Dumanovic and Vladimir Trajkovic

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1

119

133

145

151

vi Chapter 10

Contents Prostate Cancer Screening: A Greek View K. Stamatiou and F. Sofras

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Index

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161 167

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PREFACE Chapter 1 - Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus that responds to the environmental light-dark cycle. The SCN clock receives light information from the retina and transmits synchronization cues to peripheral clocks in the liver, heart, etc., regulating cellular and physiological functions. The circadian clock also regulates metabolism and energy homeostasis in peripheral tissues by mediating the expression and/or activity of certain metabolic enzymes, hormones, and transport systems. Pronounced biological rhythms extend life span, as longevity was increased in older hamsters given fetal suprachiasmatic nuclei implants that restored higher amplitude rhythms. Destruction of the SCN results eventually in the absence of bodily rhythms. Disruption of circadian rhythms leads to hormone imbalance, psychological and sleep disorders, cancer proneness, and malignant growth. Recent data suggest that disruption of circadian rhythms in the SCN and peripheral tissues leads to manifestations of the metabolic syndrome and hyperphagia. Indeed, shift work and sleep deprivation in humans have been shown to be associated with increased adiposity. Similarly, homozygous Clock (a key gene of the biological clock) mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome. Bmal1-/- (a key gene of the biological clock) knockout mice, similarly to Clock mutant mice, exhibited suppressed diurnal variations in glucose and triglycerides as well as abolished gluconeogenesis. In addition, high-fat diet disrupts circadian rhythms. Interestingly, Bmal1-/knockout mice have reduced life span. Thus, disruption in circadian rhythms leads to obesity and reduced life expectancy, whereas resetting of circadian rhythms leads to well-being and increased longevity. Chapter 2 - It has been suggested that an individual’s level of adiposity may influence subsequent lymphoma risk, since nutritional state is known to alter immune function. The epidemiological evidence on this topic is reviewed here. Whilst several studies have reported statistically significant associations for excess weight and non-Hodgkin lymphoma (NHL), others have not. The evidence is similarly inconsistent for Hodgkin Lymphoma, but because of its comparative rarity, data are more limited. Several studies have examined risks for NHL in relation to Body Mass Index (BMI), and with a view to synthesising the available evidence, a number of meta-analyses and individual record-based combined re-analyses have recently been conducted. By summarising case-control and cohort data in this manner, it has

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Pauline R. Ramonde and Eva H. Fochas

become clear that the risks associated with obesity display considerable heterogeneity, varying between studies, geographic areas and ethnic group. In general, however, NHL risks among the obese appear to be elevated in North America and Northern Europe, but lower elsewhere. NHL itself comprises a heterogeneous group of disorders, yet the evidence suggests that associations with adiposity may be similar for the disease subtypes. Where associations with obesity are reported, lymphoma risks are typically below two-fold, lower than for obesity-related conditions such as cardiovascular disease, type 2 diabetes and breast, endometrial and prostate cancers. While obesity may not be a major risk factor for lymphoma, an area worthy of future study is the effect obesity has on presentation, treatment and prognosis of lymphoma. Chapter 3 - Visceral type obesity has close associations with insulin resistance and is regarded as high risk for both cardiovascular diseases and malignancies. Among obesityassociated tumors, cancers of the gastrointestinal tract, kidney, breast, pancreas, ovary and prostate were registered. Increased mass of visceral fat tissue has decreased insulin sensitivity and the reactive hyperinsulinemia provokes excessive lipolysis. High fatty acid levels in the portal circulation further increase the insulin resistance. As the elevated serum levels of glucose, insulin and IGFs have crucial role in cancer induction, visceral obesity means a high tumor risk. Correlations among visceral obesity and tumor risk are also strongly affected by the increased adipocytokine production of the mass of fatty tissue. These mediators thoroughly influence the insulin sensitivity and may have role in the inflammatory processes and tumor initiation. Obesity affects hormonal changes including increase in androgen, IGF and insulin levels and decrease of estrogen level. Recently, estrogen has been regarded as a potential mediator of the obesity induced breast cancer. However, a decreased obesity associated breast cancer risk was observed among postmenopausal cases treated by hormone replacement, which suggests that correlations between obesity and breast cancer are not mediated by estrogen. Obesity affects disadvantageously the tumor progression. Among obese patients with breast and colon cancers beneficial effects of physical activity and weight loss were observed, which decreased the risk of local recurrences and metastatic spread of tumors and improved life expectancies. In the present work a retrospective controlled study was performed to clarify the epidemiological associations between obesity, insulin resistance (elevated fasting glucose and type-2 diabetes) and salivary gland tumors. Salivary gland tumors had been surgically removed and histologically diagnosed (SGT group). Tumor free control patients underwent to dental surgeries were randomly selected (control group). Rates of cases with high body mass index (BMI), with elevated fasting glucose level and type-2 diabetes were established in the SGT and control groups. Obesity exhibited a significantly increased prevalence among pooled SGT cases as compared with the tumor-free controls (p30 kg/m2 has been increasing worldwide. About half the adult population in developed countries is either overweight or obese and a similar proportion of the urban adult population of developing countries. This excess bodyweight is linked to an increase in the risk of cardiovascular disease, type 2 diabetes and fatty liver. In addition it appears that excess body weight is an important risk factor for several cancers. Recently a systematic review and meta-analysis quantified the risk of cancer associated with an increase in BMI [1]. This study had strict inclusion criteria and compared associations across 20 cancer types and between sexes and populations with 282 137 incident cases from 141 articles. An increased BMI was found to be associated with an increased risk of thyroid, renal and colon cancers, esophageal adenocarcinoma, multiple myeloma, leukemia and nonHodgkin lymphoma in both sexes. In addition there was an increase in rectal carcinoma and malignant melanoma in men and gallbladder, pancreas, endometrial and postmenopausal breast cancers in women. In this analysis, cancer of the liver was not found to be present with an increased incidence. Cancer of the liver or hepatoma is a complication of cirrhosis. One of the main causes of cirrhosis is hepatitis C virus and hepatitis B virus (HCV and HBV) and also non-alcoholic fatty liver disease NAFLD). There is a clear link between NAFLD and obesity and thus it is likely there is an link to malignancy. Grouping liver cancer as one entity in terms of the meta-analysis may result in underestimating this relationship.

CANCER OF THE GALLBLADDER The recent meta-analysis by Renehan et al found and odds ratio of 1.59 for gallbladder cancer in obese women but not in men [1]. There may be a connection to the presence of cholelithiasis. A Japanese study of more than 100,000 at least middle-aged subjects through more than 1,200,000 person-years of follow-up found an odds ratio of 2.53 for cholelithiasis and biliary tract cancer. This was for both gallbladder (OR 3.01) and extrahepatic bile duct

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cancer (OR 2.12). An increased BMI was associated with an increased risk of extrahepatic bile duct cancer (p=0.03 ) but was not modified by a history of cholelithiasis [2]. A case-control study by Ahrens et al [3] of 153 patients with extra-hepatic biliary tract disease in men and 1421 controls found an OR of 4.68 for gall bladder tumors and an OR of 2.58 for a BMI greater than 30 at the age of 35. Similarly a meta-analysis of the relationship between obesity and gallbladder cancer based on published studies from 1966 to February 2007 with a total of 3288 cases found overweight individuals to have a OR 1.15 and obese individuals to have a OR of 1.66 respectively for gallbladder cancer. This was stronger in obese women than for obese men (1.88 vs 1.35). There may be a relationship between dietary factors and gallbladder cancer. A high intake of energy and carbohydrate increases the risk for gallbladder cancer and there is a protective effect of fruits and vegetables [4].

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POLYPS, CARCINOMA OF THE COLON AND OBESITY Colorectal adenomas are thought to be precursor lesions for colorectal cancer. The polypcancer sequence is now well established and the genetics are being unraveled [5,6]. It appears that there is a significant relationship between obesity and colorectal neoplasia. Bird et al examined data from 483 men and women aged 50-75 years of age who underwent sigmoidoscopy at a HMO in Southern California and compared them to 483 age and gender matched controls [7]. The prevalence of adenomas was increased in those patients with a higher BMI, large weight changes and a positive energy balance (net weight gain in the previous 10 years).The odds ratio on multi-variate analysis for the presence of adenomatous polyps was 2.1 for those in the highest quintile of BMI compared to those in the lowest. Compared with those subjects who had a net weight loss during the decade prior to sigmoidoscopy, subjects with net weight gains of 1.5-4.5 kg or > to 4.5 kg had adjusted odds ratio of 2.5 and 1.8 respectively. This increase in the risk for colorectal polyps due to obesity and weight gain has also been found in African-American women [8]. This effect of obesity on the prevalence of colonic adenomas has not been universally found. A study of 1744 Korean men and women found an increase in the prevalence of colonic adenomas and advanced polyps with age and more so in men than in women. A positive association between BMI and colonic adenomas was present only in men less than 40 years of age and women less than fifty years of age and in premenopausal women according to their hormonal status [9]. Body composition has also been shown to be a factor in the recurrent growth of adenomas. A cohort of 28 patients with colorectal polyps aged 50-75 years of age was compared to age and gender-matched polyp-free healthy controls. Triceps skinfold thickness was highly associated with adenoma growth, as were total body fat percentage and body mass index [10]. A larger study has also found an association between body size and recurrence of colorectal adenomas. Jacobs et al followed up 2465 subjects with baseline adenomas and follow-up colonoscopy data from 2 controlled trials. During the course of a mean follow-up period of 3.1 years a BMI> 30 kg/m2 was associated with an 17% increase in the odds for

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adenoma recurrence. This was not statistically significant overall but was for men (OR 1.36). A similar non-significant trend was found for waist circumference. The effect of BMI was significant in the subgroup of advanced adenoma recurrence in men as compared with nonadvanced lesions (OR 1.26). In addition, there was an association of obesity and the odds of adenoma recurrence amongst those subjects with a family history of colorectal cancer (OR2.25) [11]. An association between weight gain and risk for colorectal adenoma has also been found in the insulin resistance atherosclerosis study. In this study colonoscopy was performed on 600 participants regardless of symptoms with a mean age of 64. Multivariate analysis was used to assess the association between colorectal adenomas and measures of adiposity and weight change over the 10 year period prior to colonoscopy. In this study too, obesity was positively associated with the risk of colorectal adenomas, more so in women (OR4.42) than in men (OR1.26). The risk of adenomas was increased in those who gained weight compared with those who maintained weight over the approximately 5 and 10 years of the study. In addition there was a stronger association with obesity measured at the time of colonoscopy. This suggests a possible promoter role for obesity in the growth of colorectal adenomas [12]. Obesity is closely linked to glucose intolerance. A case-control study of 105 patients with advanced colorectal adenomas and 105 patients with confirmed colorectal cancers found significantly higher levels of mean BMI and serum glucose in both the advanced adenoma and cancer groups compared to healthy controls [13]. The metabolic syndrome is characterized by central obesity, impaired glucose tolerance, hypertension, low HDL cholesterol and hypertriglyceridemia [14]. The metabolic syndrome may be linked with colorectal adenomas. A Korean group reported on 2531 patients undergoing screening colonoscopy. 731 patients had adenomas and the other 1800 patients had normal colonoscopy findings, nonpolyp benign lesions or hyperplasic polyps. The metabolic syndrome was present in 17% in the adenoma group and 11% in the control group. In addition the metabolic syndrome was found to be associated with an increased risk of colorectal adenomas on regression analysis (OR 1.51). Furthermore, waist circumference was noted to be an individual risk factor for colorectal adenomas. Metabolic syndrome was more common in those patients with polyps in the proximal rather than distant colon, with multiple (< 3) polyps and for advanced adenomas [15]. This suggests that waist circumference can be used to identify patients at higher risk for adenomas. A further study in an Asian population has confirmed the link between the metabolic syndrome and an increased risk for colorectal adenomas [16]. This was a case-control study of 756 cases of colorectal adenoma and 1751 cases with no polyps who underwent colonoscopy during a 7 year period. The metabolic syndrome was defined by Asian or Japanese criteria. The odds ratio for colorectal adenomas associated with obesity were 1.38 and the risk was more pronounced for proximal lesions. It has been suggested that elevated serum insulin levels are linked to the presence of colonic adenomas. There is a direct proliferative/antiapoptotic effect of insulin and insulinrelated growth factor 1 on colorectal neoplasms [17]. The relation to insulin will be discussed subsequently in this review. Adipose tissue releases cytokines to the circulation and aspirin, which may affect the levels of these cytokines has been shown to decrease the risk of colorectal adenomas [18]. Data from the Aspirin/Folate Polyp Prevention Study suggests that this effect of aspirin may

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be more pronounced in obese subjects. The risk ratio for advanced adenomas in obese subjects (BMI > 30)was 0.44 compared with placebo vs 1.23 amongst those with a normal weight. This was at a dose of 325 mg but not seen with a dose of 81 mg [19]. The United Kingdom Colorectal Adenoma Prevention Trial included patients who had a colonic adenoma removed in the previous 6 months and were randomized to receive 300 mg of aspirin per day or 0.5 mg of folate in a randomized double-blind placebo-controlled trial. 99 of 434 (22.8%) of patients receiving aspirin had an adenoma recurrence versus 121 of 419(28.9%) receiving placebo (RR 0.63), whereas there was no change in risk for patients receiving folate supplementation [20].

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CANCER OF THE PANCREAS More than 85% of pancreatic cancers are pancreatic ductal adenocarcinomas found in the exocrine portion of the pancreas. The other 15% of tumors are composed of islet tumors of the endocrine pancreas and other nonadenocarcinoma tumors. In most epidemiologic studies, endocrine tumors are excluded or consist of a minority of cases. In the 1990s several case-control studies found no association between an elevated BMI and pancreatic cancer [21,22,23]. There are several limitations to these studies such as a high case fatality, data inaccuracies including weight and height being obtained from proxies and low participation rates. There are 18 cohort studies published which report positive associations (summarized in [24]). 10 of these were prospective cohort studies including more than 10,000 cases of pancreatic cancer. They have found a relative risk of cancer of the pancreas in obese individuals (BMI>30 kg/m2) ranging from 1.2-3.0. However, seven prospective studies have not found an association with recent BMI. Three of these did not include a category of exclusively obese individuals, 2 found an association with other measures of obesity (weight gain of 12 or more kilograms as adults, waist-to-hip ratio) and one reported a statistically significant association with BMI at age 40 years. In addition, there has been found an elevated risk for pancreatic cancer among overweight and obese men and women in 4 recent case-control studies in which only direct interviews were used. A meta-analysis of 14 studies on obesity and pancreatic cancer found a 19% increase in risk in obese patients compared to those of normal weight (RR 1.19) [25]. It is likely that this meta-analysis underestimated the effect of obesity, since all studies were included despite design problems. The RR was higher after excluding case-control studies with proxy data and those studies that had not adjusted for smoking.

PANCREATIC CANCER AND DIABETES MELLITUS The diagnosis of type 2 (non-insulin dependent) diabetes is often made several months prior to the diagnosis of cancer of the pancreas. In these patients it is probable that undetected cancer of the pancreas is responsible for the new-onset of diabetes. Despite epidemiologic evidence of an association between diabetes and pancreatic cancer there is also a possibility of reverse causation-that diabetes is a risk factor itself for carcinoma

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of the pancreas. An examination of the duration of diabetes prior to the appearance of the cancer of the pancreas may provide a clue to this reverse etiology. A 1995 meta-analysis of 20 studies estimated that long-standing diabetes (5 years or more) increased pancreatic cancer risk 2-fold [26]. More recently a meta-analysis based on 50 studies found a weaker but still significant, relationship RR 1.5 [27]. Since results from both cohort and case-control studies are similar, bias is unlikely to explain this excess risk. Furthermore blood glucose levels are related to pancreatic cancer risk. Two studies, the Whitehall study and the Chicago Heart Association Detection Project, stratified individuals according to serum glucose 1 or 2 hours following an oral 50 gram glucose load. A postload glucose of >11.1 mmol/L was associated with a 2-4 times increase in the risk of death from pancreatic cancer over a 25 year period [28,29]. In the latter study, there was only a slight weakening of this association when deaths within the first 10 years of follow-up were excluded. In the Chicago study, the RR was higher in women than in men (RR 2.39 women vs 1.68 men) and were unchanged after excluding deaths in the first 5 years of follow-up [28]. There is also a relationship between fasting glucose and pancreatic cancer. The Korean Cancer Prevention Study [30] followed participants were for 10 years. Diabetes was defined as a fasting serum glucose greater than 7.0 mmol/L and participants with diabetes had a RR of pancreatic cancer death of 1.71 for men and women. This was only slightly attenuated by excluding deaths in the first 5 years (RR 1.5). The Alpha-Tocopherol Beta carotene (ATBC) Cancer Prevention Study measured serum glucose levels in stored blood samples from the 169 pancreatic cancer cases diagnosed between 5 and 16.7 years of follow-up and a subset of 400 of the cohort. A RR of 2.13 was found for those with a fasting glucose greater than or equal to 7.0 mmol/L compared to those with a fasting glucose less than this [31]. In all 4 of these studies, a statistically significant dose-response effect was found between glucose levels and pancreatic cancer. In the Korean study, this risk was even present in women for relatively low glucose levels, a RR of 1.45 for women with glucose levels between 90 -109 nmg/dl compared to women with levels less than 90 mg/dL. Data from, the ATBC study has also shown a link between prediagnostic serum insulin levels and pancreatic cancer risk. A 2-fold increase in risk was observed after excluding cases diagnosed in the first 5 years of follow-up, for those patients who had the highest quartiles versus those with the lowest quartiles of insulin levels. The above data suggests a causal role for type 2 DM in the etiology of pancreatic cancer.

ADENOCARCINOMA OF THE ESOPHAGUS The incidence of esophageal adenocarcinoma (and the gastro-esophageal junction) is increasing rapidly in many countries (more so in men and white population). In the United States the incidence of esophageal adenocarcinoma has increased about 400% in the past 30 years, the most rapid increase rate of any other cancer [32,33]. The incidence of squamous cell carcinoma has declined or remained stable in the United States over the past 30 years. Such differences may imply a major change in causal exposures (obesity for example) or major changes in detection and diagnosis of these carcinomas, although the second statement

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is probably not the explanation, since there have been no major systematic changes in detection or diagnosis [34]. Barrett's esophagus is a metaplastic lesion, primarily confined to the lower esophagus. It substantially increases the risk for developing esophageal adenocarcinoma. Estimates for the risk of progressing from Barrett's esophagus to esophageal adenocarcinima are approximately 0.5-1% per year [35]. The strongest associated risk factor for Barrett's esophagus is gastroesophageal reflux disease (GERD). The hypothesis is that frequent exposure to acid refluxate erodes the squamous epithelium which may be replaced with goblet cell metaplasia, this in turn is termed Barrett's esophagus [36]. Previous population-based studies have found a link between obesity and gastroesophageal reflux disease (GERD) symptoms in the United States, UK, Norwegian and Spanish populations, [37-42] and two of these studies showed a gradual increase in GERD symptoms as BMI increased [37,38]. Further evidence for the link between obesity and reflux comes from the Nurses Health Study showing a dose-dependent relationship between reflux symptoms and BMI, even with moderate weight gain [43]. However, two large populationbased studies, did not find any association [44,45]. Obesity (BMI >30) has been shown to increase esophageal acid exposure on 24 hour pH monitoring. In addition waist circumference was shown on multivariate analysis to explain some of this association [46]. The mechanism for the reflux may be related to abnormal postprandial lower esophageal function [47]. The association with waist circumference has not been shown in Blacks or Asians [48] and in a meta-analysis, the results from Europe were much more heterogeneous than from the United States [49]. GERD has been widely assumed to explain the increased risk of esophageal adenocarcinoma in obese populations. The questions are: 1. Is obesity also associated with an increased risk of developing Barrett's esophagus once GERD is present? 2. Is obesity also associated with an increased risk of developing esophageal adenocarcinoma once Barrett's esophagus is present? A recent systematic review and meta-analysis by Cook et al [50] has shed light on the first question. The authors of this study concluded that increasing BMI does not present an increased risk of Barrett's esophagus above what would be expected from GERD alone. Therefore BMI has no value in predicting which GERD patient has an increased risk of developing Barrett's esophagus. Although this systemic review had limitations and the way to truly ascertain whether there is an association between GERD and obesity would be to study a cohort of GERD patients over a prolonged period of time evaluating whether obesity predicts progression to Barrett's esophagus. In summary, obesity does not appear to be more than a weak risk factor for the progression from GERD to Barrett's esophagus. A number of studies have found an association between obesity and a significantly increased risk of esophageal cancer [51,52]. Some of these studies have found an increased risk even among people who had no reflux symptoms. The most recent and convincing of these studies by Whiteman et al [53] studied 800 patients with adenocarcinomas of the esophagus and the gastro-esophageal junction.

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They found consistently higher risks of esophageal adenocarcinoma among obese people than those in the healthy weight range. Moreover their data showed that the risk associated with obesity was independent of reflux symptoms and other risk factors. Also the risks of combined obesity and frequent reflux symptoms were significantly higher than the sum of these independent risk factors. For example people the odds ratio (OR) of esophageal adenocarcinoma among obese people with no reflux symptoms was 2.2 while the OR of obese people and frequent reflux symptoms was 16.5. So if obesity does not simply increase the risk for esophageal adenocarcinoma by promoting GERD, what other factors are involved? Increased body fat leads to an increase in insulin production which in turn leads to synthesis of insulin-like growth factor. These hormones have been shown to inhibit apoptosis and stimulate cell proliferation [54]. Leptin (which is increased in obesity) has been shown to have mitogenic and angiogenic effects especially in inflamed tissue [55]. In summary it seems that obesity is a significant risk factor for esophageal adenocarcinoma, and not simply by being a risk factor for GERD. It seems likely that obesity is especially significant in increasing the risk for esophageal adenocarcinoma once Barrett's esophagus is present. This may be important clinically in surveillance of obese patients with Barrett's esophagus and maybe even as an indication for bariatric surgery in these patients. The association of obesity with GERD, Barrett's esophagus and esophageal adenocarcinoma is still not clear. A study which investigates this entire pathway within a single population may answer some of the questions.

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HEPATOCELLULAR CARCINOMA Hepatocellular carcinoma is a primary carcinoma that develops in a cirrhotic liver. The two major causes of cirrhosis in the developed world are hepatitis C and non-alcoholic steatohepatitis (NASH). For both of these conditions, there is a significant effect of obesity on the development of carcinoma. Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence in developed countries and is one of the most common causes of crytpogenic cirrhosis. It is strongly linked to the metabolic syndrome, of which obesity is a central component, and is in fact regarded as the hepatic manifestation of the metabolic syndrome [56,57]. NAFLD is a spectrum of diseases ranging from simple steatosis to steatohepatitis (NASH) and cirrhosis with all of its concomitant complications. Patients with NAFLD especially those with mainly steatosis, respond favourably to weight reduction and a recent large study showed that achieving ≥ 5% weight reduction by lifestyle modifications was associated with improvement and even normalization of liver enzymes in subjects with impaired liver function tests [58]. Nonalcoholic fatty liver disease is thought to be present in around 20 to 30% of the adult population of the United States, whereas steatohepatitis is present in around 2 to 3%. It is a subset of patients with steatohepatitis, who have a high rate of progression to cirrhosis. Obesity is known to be an independent risk factor for the development of steatohepatitis Hepatitis C is a common viral infection of the liver present in approximately 150 million people worldwide. By one estimate, 20% of infected patients will develop cirrhosis after 20

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years of infection and 30% after 30 years. In addition, there appears to be a link between hepatitis C infection, and diabetes and impaired glucose tolerance [59]. There are many factors that influence the progression of steatosis to steatohepatitis and cirrhosis, obesity being one of the major ones. A recent report of a cohort of 2126 patients all from one the Veterans Affairs health care centers in the northwest United States from 1994 to 2005 and who had a diagnosis of cirrhosis recorded in inpatient or outpatient medical records, found a hundred patients diagnosed with hepatocellular carcinoma over a mean 3.6 year follow-up period [60]. This suggests an incidence of 1.6 per hundred patient years for the development of hepatocellular carcinoma. Multivariate analysis, determined hepatitis C, hepatitis B and overweight and obesity to be independent predictive factors for the development of hepatocellular carcinoma. In addition, obesity, independently enhances the risk for development of hepatocellular carcinoma in a cohort of patients with hepatitis C virus infection. A study from Japan, of 1431 patients with chronic hepatitis C, found a hazard ratio of 1.86 for overweight and 3.1 for obesity compared to underweight patients [61] for the development of hepatocellular carcinoma . Furthermore, there may be a synergistic effect of both of obesity and diabetes, on the development of hepatocellular carcinoma. A recent study from Taiwan, of 23,820 residents followed up for 14 years, found a hundred times increase in the risk for development of hepatocellular carcinoma in patients with either hepatitis B are hepatitis C, who had both obesity and diabetes [62].

POSSIBLE MECHANISMS FOR A LINK OF OBESITY TO CANCER

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Hyperinsulinemia Colon Cancer Hyperinsulinemia is a characteristic of the metabolic syndrome and has been suggested to be an underlying factor linking obesity, physical inactivity, type 2 diabetes mellitus and a western dietary pattern and lifestyle. Physical activity has been shown to increase insulin sensitivity and to lower circulating insulin, independently of its effect on adiposity [63] Insulin has growth-promoting properties and increases free insulin-like growth factor (IGF-1) levels. Hyperinsulinemia can be assessed by measuring serum insulin levelsin non-fasting and post glucose load situations and in addition by determination of C-peptide which is an indicator of insulin secretion. Several reports (reviewed in [24]) have reported links of colorectal cancer to either 2 hours postglucose load insulin level or a high C-peptide level. In addition, two studies have found an increased risk of adenoma in patients with high concentrations of insulin [64] or C-peptide [65] whereas one study did not found an association between fasting plasma insulin and increased risk of adenomas [66]. Insulin has many effects and it is unclear which are the most critical in carcinogenesis. In a rat model, insulin level during a 10 hour euglycemic clamp, correlated with colorectal epithelial cell proliferation in a dose-dependent manner, suggesting a role for hyperinsulinemia and cell turnover [67]. In the Physicians' Health Study, C-peptide level was more strongly associated with colon cancer risk than was the metabolic syndrome [68] and

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the association with C-peptide became even stronger after controlling for the metabolic syndrome . Many of the growth-promoting effects of insulin are thought to operate via the insulinlike growth factor-1 (IGF-1) axis. IGF-1 is bound to IGF-binding proteins and insulin can reduce the levels of these binding proteins, which increases IGF bioavailability [24]. Studies of circulating IGF-1 in relation to the risk of colon cancer or adenoma have found a slight increase in risk, but in some studies only after the results were adjusted for both IGF-1 and IGFBP-III levels. It is of interest to note that acromegaly, in which there is an abnormal elevation of IGF-1 from excessive growth hormone secretion has an increased risk of colorectal cancer [69,70]. The effects of both insulin and IGF-1 concentrations in relation to colon neoplasia risk have been examined in several studies. In a Japanese study fasting and 2h post-load glucose levels were more strongly linked to the presence of advanced adenomas than total circulating IGF-1 and IGFBP-III. In addition insulin and IGF-1 were found to influence risk independently [71]. In the Nurses' Health Study a link between the IGF-1 and IGFBP-III ratio and the colon cancer risk was found mainly in women with low C-peptide levels but not in women who were overweight or who had high C-peptide levels [72]. Further studies are required in order to better understand relationship between insulin, growth factors and binding proteins and colorectal neoplasia risk. Pancreatic Cancer Pancreatic cancer has also been linked to IGF and its binding proteins. Two retrospective trials have looked at the link between IGFs and the risk for pancreatic cancer. In one, pancreatic cancer patients were shown to have elevated levels of serum IGF-1, IGFBP-III and IGFBP-1 compared to controls [73]. However, another case-control study of 20 patients and their controls found no association between pancreatic cnacer and serum levels of IGFBP-I II or III [74]. These studies are limited since plasma samples were collected after the diagnosis of cancer was made which may influence by their serum levels.. Prospective studies provide more reliable information. There are two such studies in the literature, each with fewer than 100 cases, that have examined the link between IGF-1 and IGFBP-III levels and pancreatic cancer risk. No association was found in the ATBC study [75], whereas in a study from Japan a slightly higher risk for pancreatic cancer was found in people with elevated levels of plasma IGF-1 or IGFBP-III [76]. Thus, at present there is insufficient data to determine if there is a relationship between IGFs and pancreatic cancer. In summary, obesity has a multifactorial impact on both the development and progression of several malignancies of the gastrointestinal tract and liver. Further investigation of the link between obesity and malignancy may deepen our understanding of the pathogenesis of cancer. In view of the recent epidemic of obesity, it is of crucial public health interest to examine further the effects of weight reduction on both the development of malignancy, its progression and response to treatment.

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[32] Blot WJ, McLaughin JK. The changing epidemiology of esophageal cancer. Semin Oncol 1999;26:2-8 [33] Blot WJ, Devesa SS, Kneller RW et al. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287-9 [34] Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142-6 [35] Jankowski JA, Provenzale D, Moayyedi P. Esophageal adenocarcinoma arising from Barrett's metaplasia has regional variations in the west. Gastroenterology 2002;122:588–90. [36] Wild CP, Hardie LJ. Reflux, Barrett's oesophagus, and adenocarcinoma: Burning questions. Nat Rev Cancer 2003;3:676–84. [37] Locke GR III, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ III. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106:642-9. [38] Murray L, Johnston B, Lane A, Harvey I, Donovan J, Nair P. Relationship between body mass and gastro-oesophageal reflux symptoms :the Bristol Helicobacter Project. Int J Epidemiol 2003;32:645-50. [39] Nilsson M, Johnsen R, , Ye W, Hveem K, Lagergren J et al. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. JAMA 2003;290:66-72. [40] Delgado-Aros S, Locke GR 3rd, Camilleri M, Talley NJ, Fett S, Zinsmeister AR et al. Obesity is associated with increased risk of gastrointestinal symptoms: A populationbased study. Am J Gastroenterol 2004;99:1801-6. [41] Nandurkar S, Locke Gr 3rd, Fett S, Zinsmeister AR, Cameron AJ, Talley NJ. Relationship between body mass index, diet, exercise and gastroesophageal reflux symptoms in a community. Aliment Pharmacol Ther 2004;20:497-505. [42] Diaz-Rubio M, Moreno-Elola-Olaso C,Rey E, Locke GR 3rd, Rodriguez-Artalejo F . Symptoms of gastro-oesophageal reflux: Prevalence, duration, severity and associated symptoms in a Spanish population. Aliment Pharmacol Ther 2004;19:95-105. [43] Jacobson BC, Somers SC, Fuchs C, Kelly CP, Camargo CA Jr. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006;354:2340-8. [44] Lagergren J, Bergstrom R, Nyren O. No relation between body mass and gastrooesophageal reflux symptoms in a Swedish population-based study. Gut 2000;47:26-9. [45] Andersen LI, Jensen G. Risk factors for benign oesophageal disease in a random population sample. J Intern Med 1991;230:5-10. [46] El-Serag HB, Ergun GA, Pandolfino J, Fitgerald S, Tran T, Kramer JR. Obesity increases esophageal acid exposure. Gut 2007; 56:749-55 [47] Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007;132:883-9. [48] Corley DA, Kubo A, Zhao W. Abdominal obesity, ethnicity and gastroesophageal reflux disease. Gut. 2007;56:756-62. [49] Corley DA, Kubo A. Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis. Am J Gastroenterol 2006;101:2619-28. [50] Cook MB, Greenwood DC, Hardie LJ, et al. A systematic review and meta-analysis of increasing adiposity on Barrett's esophagus. Am J Gastroenterol 2008;103:292-300

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[51] Chow WH, Blot WJ, Vaughn TL, et al. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst 1998;90:150-5. [52] Lagergren J, Bergstrom R, Nyren O. Association between body mass nad adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 1999;130:883990 [53] Whiteman DC, Sadeghi S, Pandeya N, et al. Conbined effects of obesity, acid reflux and smoking on the risk of adenocarcinoma of the oesophegus. Gut 2008;57:173-180 [54] Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346-53 [55] Konturek PC, Brzozowski T, Sulekova Z, et al. Role of leptin in ulcer healing. Eur J Pharmacol 2001; 414: 87–97 [56] Malnick SD, Beergabel M, Knobler H. Non-alcoholic fatty liver : a common manifestation of a metabolic disorder. QJM 2003;96:699-709. [57] Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143: 722-8. [58] Suzuki A, Lindor K, St Saver J, Lymp J, Mendes F, Muto A, et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol 2005; 43:10606 [59] Decock S, Verslype C, Fevery J. Hepatitis C and insulin resistance: mutual interactions. A review. Acta Clin Belg. 2007;62:111-9. [60] Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007;5:938-45. [61] Ohki T, Tateishi R, Sato T, Masuzaki R, Imamura J, Goto T, Yamashiki N, Yoshida H, Kanai F, Kato N, Shiina S, Yoshida H, Kawabe T, Omata M. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. Clin Gastroenterol Hepatol. 2008;6:459-64. [62] Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, Wang LY, Sun CA, Lu SN, Chen DS, Chen CJ. Metabolic Factors and Risk of Hepatocellular Carcinoma by Chronic Hepatitis B/C Infection: A Follow-up Study in Taiwan. Gastroenterology. 2008 Apr 4 EPub ahead of print. [63] Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res 2003;35:694-704. [64] Keku TO, Lund PK, Galanko J, Simmons JG, Woosley JT, Sandler RS. Insulin resistance, apoptosis and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2005;14:2076-81. [65] Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson SeE et al. C-peptide, insulinlike biding protein-1, glycosylated hemoglobin and the risk of distal colorectal adenoma in women. Cancer Epidemiol Biomarkers Prev 2006;15:750-55. [66] Ishii T, Kono S, Abe H, Eguchi H, Shimazaki K, Hatano B, Hamada H. Glucose intolerance ,plasma insulin levels and colonic adenomas in Japanese men. Jpn J Cancer Res 2001;92:836-40.

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[67] Tran TT, Naigamwalla D, Oprescu AI, Lam L, McKeown-Eyssen G, Bruce WR, Giacca A. Hyperinsulinemia but not other factors associated with insulin resistance, acutely enhances colorectal epithelial cell proliferation in vivo. Endocrinology 2006;147:1830-7. [68] Ma J, Giovannucci E, Pollak M, Leavitt A, Tao Y, Gaziano JM, Stampfer MJ. A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 2004;96:546-53. [69] Orme SM, McNally RJ, Cartwrigh RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 1998;83:2730-4. [70] Baris D, Gridley G, Ron E, Welderpass E, Mellemkajer L, Ekborn A et al. Acromegaly and cancer risk: a cohort study in Sweden and Denmark. Cancer Causes Control 2002;13:395-400. [71] Terramukai S, Rohan T, Lee KY, Eguchi H, Oda T, Kono S. Insulin- like growth factor (IGF)-1, IGF-binding protein-3and colorectal adenomas in Japanese men. Jpn J Cancer Res 2002;93:1187-94. [72] Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, et al. A prospective study of C-peptide insulin-like growth factor-I, insulin -like growth factor binding protein-I and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2005;14:850-55. [73] Kama E, Surazynski A, Orlowski K, Laszkiewicz J, Puchalski Z, Nawrat P et al. Serum and tissue level of insulin-like growth factor 1 (IGF-1) and IGF-1 binding proteins is an index of pancreatitis and pancreatic cancer. Int J Exp Pathol 2002;83:239-45. [74] Evans JD, Eggo MC, Donovan IA, Bramhall SR, Neoptolomos JP. Serum levels of insulin-like growth factors (IGF-1 and IGF-II) and their binding protein (IGFBP-3) are not elevated in pancreatic cancer. Int J Pancreatol 1997;22:95-100 [75] Stolzenberg-Solomon RZ, Limburg P,Pollak M, Taylor PR, Virtamo J, Albanes D. Insulin-like growth factor (IGF)-1, IGF- binding protein-3 and pancreatic cancer in male smokers. Cancer Epidemiol Biomarkers Prev 2004;13:438-44. [76] Lin Y, Tamakoshi A, Kikuchi S, Yagyu K, Obata Y,Ishibashi T, et al. Serum insulinlike growth factor-1, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death. Int J Cancer 2004:110:584-588.

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In: Obesity and Cancer Research Editors: Pauline R. Ramonde and Eva H. Fochas

ISBN 978-1-60692-388-7 © 2009 Nova Science Publishers, Inc.

Chapter 6

INFLUENCE AND IMPLICATIONS OF NUTRITION AND METABOLIC FACTORS ON THE GROWTH AND SURVIVAL OF PEDIATRIC CANCER CELLS: THE IGF CONNECTION Aru Narendran, Alexander K.C. Leung∗ and Josephine Ho University of Calgary, Alberta Children’s Hospital, Calgary, Alberta, Canada

ABSTRACT Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

It is has been known for some time that the nutritional and metabolic factors present during early life may influence the risk for a number of childhood diseases including cancer. However, the nature and function of the molecular mechanisms and the physiological pathways that mediate these processes are not completely known. Our growing knowledge regarding the insulin-like growth factor (IGF) family of proteins and their involvement in cancer cell growth, has provided a paradigm to investigate the mechanisms of somatic growth regulation and cancer in children. IGF-I and IGF-II are known to be nutritionally regulated and in concert with their binding proteins, insulin-like growth factor binding proteins (IGFBPs), participate in somatic growth regulation during early development. A strong association between IGF-I levels and growth parameters such as height has been described. It has been postulated that IGF-I levels in later life are programmed by early nutrition which in turn, may influence the association between diet and cancer. At the molecular level, IGF proteins regulate cell proliferation, differentiation and apoptosis in normal and malignant cells. Expression of IGFs and their functionally active receptors has been described in a variety of pediatric tumors. Laboratory studies have shown that the inhibition of IGF activity severely impairs the growth of malignant cells.

∗

Correspondence concerning this article should be addressed to: Dr. Alexander K.C. Leung, #200, 233 - 16th Avenue NW Calgary, Alberta, Canada T2M 0H5. Telefax: (403) 230-3322; e-mail: [email protected].

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Aru Narendran, Alexander K.C. Leung and Josephine Ho This review describes the evidence that implicates the presence and activity of the IGFaxis in the growth and survival of pediatric cancer cells.

Keywords: Pediatric tumors, insulin-like growth factors, cell growth regulation, leukemia and neuroblastoma

INTRODUCTION Cancer epidemiological surveys have shown that nutritional history is a predictor for the development cancer. Dietary and metabolic factors influence the expression of IGFs and their regulatory proteins through the action of hormones such as growth hormone (GH). Recent advances in cell biology and cancer pathway analyses have provided strong evidence for the involvement of IGF-axis in the growth and survival of a number of pediatric tumor models. These observations have initiated several new studies and renewed interest to understand the relationship between the regulation of IGFs and the biology of pediatric malignancies.

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THE INSULIN-LIKE GROWTH FACTOR SYSTEM Besides insulin, the IGF family consists of insulin-like growth factors (IGFs) I and II (IGF-I, IGF-II) which share sequence homology and tertiary structure. In addition, the functional components of this system include their corresponding receptors (Insulin receptor, IR, IGF-IR and IGF-IIR) and circulating binding proteins (insulin-like growth factor binding proteins, IGFBPs). The six IGFBPs that show high affinity for IGFs have extremely low affinity to insulin providing one of the mechanisms that separate insulin and IGFs into distinct functional systems [1]. While insulin is primarily involved in metabolic homeostasis, IGFs appear to exert significant influence on cellular proliferation, differentiation and apoptosis. IGFs carry the unique property of being able exert their influence systemically as hormones, and locally, as autocrine and paracrine growth regulators [2]. By virtue of their ability to affect cellular mitogenesis, apoptosis and metabolic processes, these factors play a key role in the growth, survival and differentiation of various cells and tissues [2]. This enables IGFs to play a central role in normal growth and development as well as to regulate the homeostatic mechanisms that maintain physiological functions of fully differentiated tissues [3,4]. Most IGFs in circulation are produced by the liver, under the regulation of endocrine factors that are greatly influenced by nutritional status [5]. For instance, growth hormone (GH) has been shown to stimulate the production of IGF-I and this stimulatory function is significantly reduced by malnutrition [6]. The endocrine regulation of IGFs expression appears to be complex. In addition to nutritional status, blood insulin levels also modulate IGF-I and IGFBPs gene expression in the liver [7]. As endocrine peptides, IGFs and IGFBPs are synthesized mostly by the liver and carried by blood circulation to exert their activity on responsive tissues. Recent studies indicate that additional production of these proteins by various organs allows IGFs to exert their influence locally in the tissue microenvironment.

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Sex steroids and pituitary factors have also been shown to regulate IGF-I expression in reproductive organs. Bone expression of IGF-I appears to be regulated by estrogen and parathyroid hormone (PTH). However, the overall bioavailability and signaling of IGFs are regulated by the action and availability of IGFBPs. These proteins have similar affinity for IGFs as that of IGF-IR and can effectively compete with free receptors for IGF-I and IGF-II. However, this inhibitory function is off-set by their ability to bind and prolong the half-life of IGFs. The nature and mechanisms involved in these regulatory processes are not completely understood. Recent studies have also indicated that IGFBPs possess growth regulatory properties independent of IGFs interaction, including the induction of apoptosis and modulation of cell migration [8]. The IGF family of proteins interacts with at least four types of receptors: IGF-IR, IGFIIR, insulin receptor (IR) and the hybrids that form as a consequence of interactions between the receptors of insulin and IGFs. Interaction of ligands results in conformational changes in the IGF-IR and activates its intrinsic tyrosine kinase activity. Upon phosphorylation, the cytoplasmic portion of the receptor facilitates the docking of several receptor substrates such as insulin receptor substrates (IRS) and Src (Rous sarcoma oncogene) homology and collagen (Shc) [9]. This results in the activation of down-stream signaling pathways that stimulate proliferation and inhibit apoptosis. At least two such pathways have been identified. One involves the recruitment of growth factor receptor-bound protein-2/son of sevenless (Grb2/SOS) of activated IRS-I or Shc leading to recruitment of Ras and activation of the Raf1/MAPK/ERK pathway, resulting in the activation of down-stream nuclear factors and cellular proliferation. The second pathway follows the activation of phosphatidylinositol 3’ kinase by the phosphorylated IRS-1 and the activation of Akt. Activation of Akt subsequently leads to increased protein synthesis by mammalian target of rapamycin (mTOR) and the inactivation of the anti-apoptotic protein Bad [10].

INSULIN-LIKE GROWTH FACTORS IN FETAL AND POSTNATAL GROWTH Expression of IGFs has been demonstrated in fetal tissue [11-14]. Genetic studies have shown that although both IGF-I and IGF-II are needed for fetal development, IGF-I is essential for normal postnatal growth and development. Newborn mice homozygous for a targeted disruption of IGF-I exhibited significant growth deficiency and died early [15]. Those that survived showed impaired growth rate and attained only 30% of weight of wildtype adult mice. In humans, cross sectional studies of children have found IGF-I to be positively associated with current height and, in some cases, with body mass index (BMI) [16-18]. Woods and colleagues have reported a case of IGF-I gene deletion in a young boy with a genetic defect characterizing homozygous partial deletion of the coding region of IGFI and consequently, absent circulating IGF-I [19]. This boy showed profound growth retardation and organ hypoplasia. During puberty, increased sex steroid levels stimulate GH secretion that results in increased expression of IGF-I in the liver and in circulation [20]. In both prepubertal and pubertal children, GH levels correlate with insulin resistance and insulin secretion [21]. Increased insulin secretion suppresses hepatic IGFBP-1 production, which

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helps to increase the bioavailability of IGF-I to further stimulate somatic growth. Thus, insulin, GH, IGF-I and the IGFBPs may act in concert to promote growth [22].

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INSULIN-LIKE GROWTH FACTORS AND CANCER Epidemiological studies have provided evidence to implicate IGFs in the induction and progression of a number of different malignancies. Large prospective studies have shown a link between increased levels of IGF-I or IGFBP-3 and higher risk for of breast, lung, prostate, and colon cancers. [5,23]. IGF-IR has been shown to be over-expressed in cancer cells compared to normal cells [24-26] and that many of these cells that are positive for functional IGF-IR. Inhibition of IGF-IR using antisense technology or blocking antibodies restricts the growth of tumor cells in a number of experimental models [27]. Molecular studies have also shown that IGFs are critical for the excessive growth properties found in a number of different malignancies For example, the loss of genomic imprinting that silences one allele has been shown to result in IGF2 over-expression [28]. Loss of imprinting of IGF2 has been shown to increase the risk of colorectal cancer [29]. The observation that the IGF2 over-expression is seen more extensively in colon cancer cells compared to normal colonic mucosa indicates a key role for IGF2 in the growth of this malignancy [30,31]. Recent studies have also demonstrated a key role for IGF-IR in the induction of angiogenesis and metastasis of human cancers [32]. In addition, IGF-IR signaling modulates the activity of other growth promoting cytokines such as vascular endothelial growth factor (VEGF) [33] and epidermal growth factor receptor [34]. A number of recent studies have indicated the influence of nutritional factors on IGF level and cancer risk [31]. Birth weight and size have been shown to be associated with increased cancer risk in adults [35,36]. A recent study by Thygesen and colleagues has shown that overweight and obesity are modifiable risk factors for colon cancer in men and that weight has an important influence on cancer risk, even in later life [37]. There is now strong evidence that obesity is a negative prognostic marker in certain cancers and cancer related mortality [38-41]. Studies in animal models have supported these clinical observations [42]. The findings by Dunn and colleagues have shown that caloric restriction mediated protection against chemical carcinogenesis is linked to a reduction in IGF-I levels [43]. Currently, the exact mechanisms that link obesity and IGF-mediated pathways to cancer have not been fully understood. It has been postulated that prolonged hyperinsulinemia that exists in obese individuals because of insulin resistance decreases the production of IGFBP-1 and IGFBP-2 that leads to an increase in bioavailable IGF-I that in turn generates conditions that favor tumor growth [38,39,44].

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INSULIN-LIKE GROWTH FACTOR AND PEDIATRIC MALIGNANCIES

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Neuroblastoma Neuroblastoma (NB), a malignant tumor of young children, is characterized by a wide range of clinical behaviors, from spontaneous regression to rapid progression. Expression of IGFs has been demonstrated in NB tumor specimens and cell lines [45,46]. Experimental studies have shown that IGFs can stimulate the growth of NB cells while inhibiting apoptosis [47–51]. IGFs have also been shown to enhance the metastatic properties of NB [52–55]. Studies by van Golen and colleagues have shown that NB cells that express high levels of IGF-IR adhere tightly to bone stromal cells with distinct morphological changes [56]. When injected directly into bone, such cells form both osteolytic lesions and secondary tumors in other sites. These results are consistent with the notion that IGF-IR expression in NB cells increases tumor cell interaction with the bone microenvironment, resulting in enhanced growth, survival and metastasis. IGF-I has also been implicated in the expression of VEGF and increased angiogenesis in NB cells [57]. Using glucose-induced apoptosis in NB cells as an experimental model, Leinninger and co-workers have investigated how IGF-IR protects neuroblastoma cells from apoptosis induced by different mechanisms [58]. It has been found that in this experimental model, IGF-I-mediated signaling prevents glucose induced apoptosis by blocking mitochondrial swelling, mitochondrial membrane depolarization (MMD) and caspase-3 activation. Based on such findings, agents that target IGF mediated pathways have been investigated as potential therapeutic agents for NB. NVP-AEW541 is a small molecular weight targeted inhibitor of IGF-IR that has shown significant anti-tumor activity against NB cell lines in vitro and in animal models [59]. Meyer and colleagues have investigated the anti-tumor effects of nordihydroguaiaretic acid (NDGA), a phenolic compound isolated from the creosote bush (Larrea divaricata) that inhibits the phosphorylation and activation of the IGFIR. It was found that NDGA mediated IGF-IR inactivation results in decreased proliferation and motility and increased apoptosis. NDGA activity has also been shown to decrease tumor growth in xenograft models [60].

Leukemia Hematopoietic cells as well as normal lymphocytes and lymphoblastic cell lines have been shown to express IGFs, IGFBPs and IGF receptors [61-67]. The expression of IGF-IR has been demonstrated on human B-lineage and T-lineage acute lymphoblastic leukemias (ALL) [68] and the inhibition of IGF function has been found to inhibit the proliferation in lymphoblastic cell lines [69]. In addition, alterations in the serum levels of IGFs, IGFBP-2, 3 and 4 have been described in children with acute lymphoblastic leukemia (ALL) at presentation [70,71]. An increased risk of an event such as lack of remission or relapse appears to correlate highly with the finding of elevated IGFBP-2 and low IGFBP-3 at the time of diagnosis [70]. In vitro studies have also provided evidence for the ability of IGF-I to

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stimulate the growth of leukemic blast cells [72]. Interestingly, elevated IGFBP-2 levels have also been shown to be associated with an increased risk for relapse after hematopoietic stem cell transplant in childhood leukemia [73]. The expression of components of the IGF-axis has also been described in pediatric acute myelogenous leukemia (AML) [74]. Compared to cells from healthy donors, children with AML have significantly higher levels of leukemia IGFBP-2 but lower levels of IGF-I and IGFBP-3. However, the relationship between the expression of IGF-related proteins and the potential to relapse in pediatric AML remains to be elucidated.

Central Nervous System (CNS) Tumors IGFs are considered to be key growth factors in the development of the central nervous system. In the brain, IGF related molecules are detectable during embryonal and early postnatal development stages and decrease progressively later in life [75,76]. Wide-spread expression of IGF-II and IGF-IR in various pediatric brain tumors has been described [77]. A study by Del Valle and co-workers has demonstrated the expression of IGF-IR and its major signaling molecule, insulin receptor substrate 1 in tumor specimens obtained from medulloblastoma patients [78]. Importantly, immunohistochemical studies have shown the existence of IGF-IR in its active (phosphorylated) form in majority of these specimens.

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Hepatoblastoma Hepatoblastoma is a rare pediatric liver tumor with unknown etiology. Molecular studies have demonstrated a severely disturbed IGF-axis with increased expression of IGF2 gene in most of these tumor specimens [79,80].

Rhabdomyosarcoma Rhabdomyosarcoma is the most common soft tissue sarcoma in children and young adults. Studies have shown that IGF-IR plays a critical role in the control of the growth of rhabdomyosarcoma [81,82]. Insulin-like growth factor II (IGF-II) acts as an autocrine growth and motility factor in human rhabdomyosarcoma cells, and high levels of IGF-II mRNA expression have been demonstrated in rhabdomyosarcoma [83]. Data provided by Minniti and colleagues have shown the expression of IGF-II localized to the rhabdomyosarcoma tumor cells themselves and not to the surrounding stroma, suggesting the presence of an IGFII autocrine loop in these tumors [84].

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Wilms' Tumor or Nephroblastoma Wilms' tumor or nephroblastoma is the most frequent primary renal neoplasm in children. Available evidence implicates IGF-IR activation in the etiology and/or progression of this disease. For example, the levels of IGF-IR mRNA in the tumors were found to be significantly higher than in the normal adjacent kidney [85]. Furthermore, the expression of IGF-IR mRNA appears to be under the inhibitory control of the tumor suppressor WT1. Thus, deletion or mutation of the WT1 gene could result in over-expression of the IGF-IR resulting in increased autocrine/paracrine growth stimulation.

Osteosarcoma and Ewing’s Tumor Abnormal expression or activation of the IGF-axis has also been described in osteosarcoma cells and in the Ewing's family of tumors [86,87].

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CONCLUSION It is evident from the current literature that IGFs are abnormally expressed in a large number of pediatric malignancies. In addition, tumors that do not show alterations in expression are responsive to and may be dependent on these growth factors for their survival and proliferation. For those who are investigating the relationships between nutrition, obesity and cancer risk in children, these findings offer a paradigm to develop future studies and strategies for intervention. Recent epidemiological findings have strongly indicated that factors such as body weight and growth parameters may be associated with risks of developing childhood malignancies [38,88,89]. There is also a large body of biological data to point towards the contribution of early nutrition, somatic growth regulation and IGF-axis in the pathogenesis of many cancers [90,91]. In the coming years, studies to further understand the molecular components and physiological mechanisms involved in these processes may provide effective targeted approaches for the prevention and treatment of childhood cancers.

ACKNOWLEDGMENT Dr. Aru Narendran is supported by the Kids Cancer Care Foundation Alberta (KCCFA).

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[75] LeRoith, D; Werner, H; Faria, TN; Kato, H; Adamo, M; Roberts, CT, Jr. Insulin-like growth factor receptors. Implications for nervous system function. Ann. N. Y. Acad. Sci. 1993 27;692:22-32. [76] Glick, RP; Unterman, TG; Blaydes, L; Hollis, R. Insulin-like growth factors in central nervous system tumors. Ann N Y Acad Sci. 1993 27;692:223-229. [77] Ogino, S; Kubo, S; Abdul-Karim, FW; Cohen, ML. Comparative immunohistochemical study of insulin-like growth factor II and insulin-like growth factor receptor type 1 in pediatric brain tumors. Pediatr. Dev. Pathol. 2001;4:23-31. [78] Del Valle, L; Enam, S; Lassak, A; Wang, JY; Croul, S; Khalili, K; Reiss, K. Insulinlike growth factor I receptor activity in human medulloblastomas. Clin. Cancer Res. 2002;8:1822-1830. [79] Gray, SG; Eriksson, T; Ekström, C; Holm, S; von Schweinitz, D; Kogner, P; Sandstedt, B; Pietsch, T; Ekström, TJ. Altered expression of members of the IGF-axis in hepatoblastomas. Br. J. Cancer. 2000;82:1561-1567. [80] von Horn, H; Tally, M; Hall, K; Eriksson, T; Ekström, TJ; Gray, SG. Expression levels of insulin-like growth factor binding proteins and insulin receptor isoforms in hepatoblastomas. Cancer Lett. 2001;162:253-260. [81] Kalebic, T; Blakesley, V; Slade, C; Plasschaert, S; Leroith, D; Helman, LJ. Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R. Int. J. Cancer. 1998;76:223-227. [82] McManus, MJ; Hutt, PJ; Maihle, NJ. Phosphotyrosyl proteins in childhood rhabdomyosarcomas: phosphorylation of catenins and components of the insulin-like growth factor type I receptor signaling cascade. J. Pediatr. Hematol. Oncol. 1997;19:319-26. [83] El-Badry, OM; Minniti, C; Kohn, EC; Houghton, PJ; Daughaday, WH; Helman, LJ. Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differ. 1990;1:325-331. [84] Minniti, CP; Tsokos, M; Newton, WA, Jr; Helman, LJ. Specific expression of insulinlike growth factor-II in rhabdomyosarcoma tumor cells. Am. J. Clin. Pathol. 1994;101:198-203. [85] Werner, H; Roberts, CT, Jr; Rauscher, FJ, 3rd; LeRoith, D. Regulation of insulin-like growth factor I receptor gene expression by the Wilms' tumor suppressor WT1. J. Mol. Neurosci. 1996;7:111-123. [86] Raile, K; Höflich, A; Kessler, U; Yang, Y; Pfuender, M; Blum, WF; Kolb, H; Schwarz, HP; Kiess, W. Human osteosarcoma (U-2 OS) cells express both insulin-like growth factor-I (IGF-I) receptors and insulin-like growth factor-II/mannose-6phosphate (IGFII/M6P) receptors and synthesize IGF-II: autocrine growth stimulation by IGF-II via the IGF-I receptor. J. Cell Physiol. 1994;159:531-541. [87] Manara, MC; Landuzzi, L; Nanni, P; Nicoletti, G; Zambelli, D; Lollini, PL; Nanni, C; Hofmann, F; García-Echeverría, C; Picci, P; Scotlandi, K. Preclinical in vivo study of new insulin-like growth factor-I receptor--specific inhibitor in Ewing's sarcoma. Clin. Cancer Res. 2007;13:1322-1330. [88] Renehan, AG; Roberts, DL; Dive, C. Obesity and cancer: pathophysiological and biological mechanisms. Arch. Physiol. Biochem. 2008;114:71-83.

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[89] Milne, E; Laurvick, CL; Blair, E; Bower, C; de Klerk, N. Fetal growth and acute childhood leukemia: looking beyond birth weight. Am. J. Epidemiol. 2007;166:151159. [90] Grimberg, A. Mechanisms by which IGF-I may promote cancer. Cancer Biol. Ther. 2003;2:630-635. [91] Bach, LA. The insulin-like growth factor system: towards clinical applications. Clin. Biochem. Rev. 2004;25:155-164.

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Chapter 7

GASTRIC CANCER AFTER ROUX-EN-Y GASTRIC BYPASS FOR MORBID OBESITY — THE UTILITY OF DOUBLE-BALLOON ENDOSCOPY Nobumi Tagaya1,∗, Kazunori Kasama2 and Keiichi Kubota1 1

Second Department of Surgery, Dokkyo Medical University, Japan Minimally Invasive Surgery Center, Yotsuya Medical Cube, Japan

2

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ABSTRACT The prevalence of morbid obesity in the human population is steadily increasing, posing a serious health problem that significantly increases the risk of mortality associated with complications such as hypertension, and cardiovascular or pulmonary diseases. We have been applying laparoscopic Roux-en-Y gastric bypass (RYGB) for treatment of morbid obesity since February 2002. Although this ameliorates the complications associated with morbid obesity, investigation of the excluded stomach resulting from this surgical procedure is still an unsolved issue. In patients with a family history of gastric cancer, resection of the remnant stomach is sometimes added in view of the cancer risk, but this requires a longer operation time and has a risk of unexpected complications. There are two problems associated with this procedure: the high occurrence rate of gastric cancer in Japan, and how to investigate the excluded stomach. To resolve these problems we have introduced double-balloon intestinal endoscopy (DBE) to observe the excluded stomach. Here we present the use of DBE for the excluded stomach after laparoscopic RYGB for morbid obesity in four patients. No problems with advancing the endoscope were encountered during observation. We used an overtube to insert the scope further without forming redundant loops in the small intestine, and two balloons to grip the intestinal wall. Although performing DBE ∗

Correspondence concerning this article should be addressed to: Nobumi Tagaya, MD, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. Tel: 81-282-87-2158, Fax: 81-282-86-6317; E-mail: [email protected].

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involves a learning curve, there were no major obstacles regarding the observation and passage of the scope into the esophagus, gastric small pouch, lifted jejunum, jejunojejuno anastomosis, Y-loop, duodenum and excluded stomach. Use of the double-balloon technique makes it possible to access the gastrointestinal tract after laparoscopic RYGB irrespective of the length between the gastrojejunostomy and the jejunojejunostomy. However, as there have been a few reports of gastric cancer arising from the excluded stomach, it will be necessary to perform long-term follow-up and re-evaluate this technique.

Keywords: Roux-en-Y gastric bypass, double-balloon intestinal endoscopy, excluded stomach, morbid obesity, bariatric surgery, gastric cancer

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INTRODUCTION The prevalence of morbid obesity in the human population is steadily increasing, posing a serious health problem that significantly increases the risk of mortality associated with complications such as hypertension, and cardiovascular or pulmonary diseases. Since February 2002, we have been applying various types of laparoscopic bariatric surgery including adjustable gastric banding, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy or biliopancreatic diversion with duodenal switch for treatment of morbid obesity. These procedures have allowed the patients to achieve weight loss and ameliorated the complications associated with morbid obesity. However, investigation of the excluded stomach resulting from RYGB is still an unsolved problem. In patients who have a family history of gastric cancer, resection of the remnant stomach is added because of the high cancer risk, but this added procedure increases the operation time and has a risk of unexpected intraoperative complications. Therefore, we need to establish and apply an adequate follow-up system for patients who have undergone laparoscopic RYGB for morbid obesity. Several reports have described investigation of the excluded stomach using an inserted gastrostomy tube with site markers, retrograde endoscopy, virtual gastroduodenoscopy or double-balloon enteroscopy (DBE) [1-9]. Here we describe the utility of DBE for the excluded stomach after laparoscopic RYGB for morbid obesity. Table 1. Patient’s characteristics

No

Sex

Age

1 2 3 4

50 37 48 42

M F M M

Preoperative BMI (Kg/m2) 46 35.1 39.8 50

Preoperative endoscopic findings chronic gastritis hemorrhagic mucosa NP NP

Eradication therapy

HP + + -

+ + + +

BMI: body mass index, HP: helicobacter pylori, NP: nothing particular.

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Figure 1. The double-balloon endoscope with overtube.

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PATIENTS AND METHODS Recently, after obtaining individual informed consent, we carried out DBE in four patients who had undergone laparoscopic RYGB for morbid obesity. They were informed of, and understood the possible intra- or postprocedural complications associated with DBE. Table 1 shows the patients’ characteristics. They comprised three males and one female with a mean age of 44 years (range, 37-50 years). The mean preoperative and preprocedural body mass indices (BMI) ranged from 35.1 to 50 kg/m2 with a mean of 42.7 kg/m2 and 21.1 to 32.9 kg/m2 with a mean of 25.7 kg/m2, respectively. The postoperative period from gastric bypass to DBE examination ranged from 7 to 23 months with a mean of 14 months. Two of the patients were found to have Helicobacter pylori (HP) infection prior to surgery, but all four patients underwent preoperative eradication therapy. In fact, we routinely performed eradication therapy for all RYGB candidates. The preoperative pathological diagnosis of the stomach before RYGB was chronic gastritis in one patient, hemorrhagic gastric mucosa in one and no particular mucosal type in two. Ante-colic and ante-gastric reconstruction of the jejunal limb was performed in all patients. We used a DBE system (Fujinon EN-450P5/20, EN-450T5/W, Fuji Photo Optical Co., Ltd., Ohmiya, Japan: working length, 200 cm; outer diameter, 8.5 and 9.4 mm; and working channel, 2.2 and 2.8 mm) with a soft latex overtube (Fujinon TS-12140, Fuji Photo Optical Co., Ltd., Ohmiya, Japan: length, 145 cm; and outer diameter, 12.2 mm) (Figure 1). The DBE procedure introduced by Yamamoto et al. [10-12] improved access to the small intestine. This system consists of a dedicated endoscope that allows a balloon to be mounted at its tip, an overtube with a balloon mounted at its distal end, and a balloon pump controller (Fujinon PB-10) to inflate or deflate the balloon. The DBE can be inserted further without forming redundant loops in the small intestine by using the two balloons to grip the intestinal wall. This procedure was performed with the patient under conscious sedation in left lateral recumbency under fluoroscopic control by one endoscopist manipulating the endoscope and one assistant supporting the management of the overtube and controller. Figure 2 shows a schema of the DBE procedure. The procedure was carried out using the retrograde route, through the gastrojejunostomy created between the small

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gastric pouch and the distal end of the jejunal limb (Figure 3), jejunal limb, and jejunojejunostomy (Figure 4) via the duodenum up to the pyloric ring (Figure 5) and the excluded stomach (Figure 6). After reaching the excluded stomach, biopsy of the gastric mucosa was routinely performed to evaluate the present condition of the excluded stomach. The pathological changes that had occurred between the preoperative period and the present were evaluated, and the patients were assigned an appropriate DBE follow-up interval on the basis of these results. Gastrojejunostomy

Antecolic Antegastric route

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Jejunijejunostomy Figure 2. Procedural schema of double-balloon endoscopy for reconstruction of the gastrointestinal tract.

Figure 3. A double-balloon endoscopic view of the gastrojejunal anastomosis shows two orifices of the long jejunal limb and the jejunal stump. Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

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Figure 4. A double-balloon endoscopic view of the jejunojejunal anastomosis shows the two orifices of the afferent and efferent loops, and the presence of bile within the lumen.

Figure 5. A double-balloon endoscopic view of the pyloric ring.

RESULTS The surgically altered gastrointestinal tract was successfully observed by DBE in all patients, although some episodes of contact bleeding due to the endoscope were encountered. This procedure was continued with the loaded overtube and two balloons using the same method as that for an ordinary oral intestinal endoscope. DBE reached the excluded stomach in all patients. There were no major obstacles to either observation or passage through the esophagus, gastric small pouch, gastrojejunal anastomosis, long jejunal limb, jejunojejunal anastomosis, duodenum and excluded stomach due to unexpected intraabdominal adhesions resulting from the laparoscopic procedure or patient intolerance. The length of the jejunal

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limb was 120 cm in two patients and 150 cm in two. The duration of the procedure ranged from 20 to 87 min with a mean of 52 min. In all patients, after reaching the jejunojejunal anastomosis, the endoscope was advanced inside the common limb before it was noticed that the lumen had the wrong features, and therefore it was pulled back. There were no procedural complications including intestinal bleeding or perforation, or trouble with the endoscopy instruments. Endoscopic observation of the excluded stomach revealed mild to moderate gastritis in all patients and bile-lake in two. The pathological diagnoses of the excluded stomach were atrophic gastritis in three patients and atrophic gastric mucosa with intestinal metaplasia in one (Table 2). No patients had clinical symptoms associated with the condition of the excluded stomach. All were able to return home without any untoward sequelae on the same day.

Figure 6. A double-balloon endoscopic view shows a bile lake and gastritis in the excluded stomach.

Table 2. Procedural results of double-balloon endoscopy No 1

Postoperative period (m) 23

Procedural time (min) 20

Length of limb (cm) 150

2 3 4

14 7 11

30 70 87

120 120 150

Endoscopic findings of double-balloon atrophic mucosa with intestinal metaplasia atrophic gastritis atrophic gastritis atrophic gastritis

m:month.

DISCUSSION RYGB has become one of the most effective procedures for treatment of morbid obesity, allowing a steady loss of excess body weight and amelioration of several diseases associated

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with obesity. However, the existence of the excluded stomach produced by RYGB cannot be ignored because the stomach is one of the organs showing the highest frequency of cancer. Furthermore, bleeding from peptic disease has been found in 8 (0.3%) out of 3000 patients [13], and perforated peptic ulcer has been described in 11 (0.3%) out of 4300 patients [14]. The physiological and histological conditions of the excluded stomach after RYGB are unknown due to the difficulty of observation via the route of reconstruction. To resolve this problem, several attempts have been made to reach the excluded stomach. Retrograde endoscopy for the excluded stomach using a pediatric colonoscope was accomplished in 33 of 51 patients (65 %) [1] and 53 of 78 attempts were successful in 68 patients (68%) [2]. Failures resulted from either the gastrojejunostomy being too narrow to admit the endoscope or inability to advance the scope beyond the angulations of the jejunojejunostomy or ligament of Treitz due to stretching of the curved intestine without advancement of the endoscope tip using the regular push method. Creation of a percutaneous route by a long needle puncture to the excluded stomach under interventional radiological guidance followed by percutaneous endoscopic observation through a gastrostomy [3-5] or percutaneous gastrostomy tube into the excluded stomach with radio-opaque site marking during the gastric bypass operation [6] has been introduced for investigation of gastrointestinal bleeding sites, but this approach has not been used routinely because immediate treatments for a critical condition can not be applied. Furthermore, Sundbom et al. [5] stated that as access to the excluded stomach was needed in less than 1% of cases, routine application of a gastrostomy tube at every RYGB seemed unnecessary. Silecchia et al. [7] reported virtual gastroduodenoscopy as a new method for endoluminal imaging of the gastrointestinal tract. Attractive advantages of virtual over conventional endoscopy are its minimal invasiveness, avoidance of sedation, and better patient outcome. However, it has several limitations: the fine mucosal detail, hypervascularity, and friability evident on fiberoptic gastroscopy are not well depicted in the endoluminal view, and flat and small lesions are difficult to detect because of insufficient resolution or poor patient preparation; residual food in the stomach and duodenum can be confused with pathological lesions; the time and cost associated with the procedure are still excessive; finally, it is impossible to obtain samples for histological evaluation. If further investigation is needed, the percutaneous access tract can be subsequently dilated for endoscopy and eventual biopsy. Recently, Sakai et al. [8] introduced the use of DBE to reach the excluded stomach after RYGB for morbid obesity. Subsequently Kuga et al. [9] from same institution presented an additional report. In 35 of 40 patients (87.5%), the excluded stomach was reached using DBE. The mean age of the patients was 44.5 years and 85.0% were women. The mean period between RYGB and DBE was 77.3 months. The success rates of DBE including our study were superior to the results of retrograde endoscopy. The average time required to reach the excluded stomach was 24.9 min (range; 5-75 min). Technical reasons for failure in 5 patients included a very long duodenobiliopancreatic limb associated with bowel adhesions in 3, stricture of the enteroenteroanastomosis in one and narrowing of the gastric pouch preventing passage of the overtube in one, respectively. Tolerance was good, and no complications were recorded during or after DBE. DBE solves the problem of how to evaluate the excluded stomach after RYGB for morbid obesity. Our initial results of DBE were similar to those of Kuga et al. [9] However, the longer procedure time was caused by difficulty in determining

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which of the two orifices was the afferent limb. As Sinar et al. [1] have mentioned, at enteroenterostomy, the presence or absence of bile within the lumen is a poor indicator of postoperative anatomy, and observation of contractions coming toward the endoscope is the most reliable indicator of which of the two orifices is the afferent limb. However, during insertion of the overtube, there is a risk of injury of the small bowel due to trapping between the endoscope and the overtube, or damage to the balloon. It is necessary to bear these situations in mind, and always check the patients’ vital signs. Furthermore, wireless capsule endoscopy [15,16] is a revolutionary new examination method that facilitates endoscopic imaging of the entire intestine without discomfort and without confining patients to a medical facility [12]. Although it is expected to be useful as an initial minimally invasive examination, it cannot be used as for biopsy or treatment, and has a risk of entrapment by strictures. Moreover, as the movement of the capsule is totally dependent on peristalsis, it is currently not suitable for application in anti-peristalsis conditions such as RYGB for morbid obesity. However, we believe that a combination of these two new enteroscopy techniques will make it possible to establish a follow-up system for the excluded stomach after RYGB in the near future. Gastric cancer of the excluded stomach after gastric bypass for morbid obesity has been reported in six patients [17-22], ranging in age from 38 to 71 years with a mean of 56 years (Table 3). They comprised two males and four females, and the gastric cancer developed from 4 to 22 years (mean: 11.5 years) after gastric bypass. In 5 of the 6 patients, cancer was diagnosed at an advanced stage. The location of the cancer was the antrum in 5 patients and the body in one. Three patients died of gastric cancer in the excluded stomach 3 and 26 months after surgery. This delayed diagnosis of cancer is a concern in reconstruction of the gastrointestinal tract after gastric bypass. As nausea and vomiting are often considered normal symptoms after bariatric surgery, further examination is not carried out to clarify the cause. Another factor hindering early diagnosis of gastric cancer concerns lesions arising in the excluded stomach, which become difficult to explore by retrograde endoscopy [21]. Furthermore, De Roover et al. [23] reported a diffuse large B-cell lymphoma with subphrenic abscess formation that was diagnosed as a perforated gastric ulcer 3 years after RYGB. However, in the USA, the actual incidence of gastric cancer after gastric bypass for morbid obesity is low compared with the annual incidence of gastric cancer in the general population [24]. It has been suggested that the low incidence of gastric cancer after gastric bypass is due to lack of contact of food with the excluded stomach [20,25]. Furthermore, Inoue et al. [26] showed that RYGB reduced the risk of gastric cancer in an experimental model of dietaryinduced carcinogenesis. Lack of direct contact with carcinogens, lower bile reflux, and lower bacterial concentration of the gastric content may be responsible for these observations, which suggest that RYGB may be a safe option for treatment of morbid obesity even in areas with a high incidence of gastric cancer. In any event, the main risk associated with cancer after gastric bypass appears to be related to the late diagnosis of malignancy. Although morbid obesity itself appears to be an independent risk factor for development of gastric cancer [27], an investigation of new or modified upper gastrointestinal symptoms may allow earlier diagnosis of malignancy [23]. Therefore, routine follow-up by endoscopy, particularly DBE, is required for earlier detection of change in the excluded stomach. To establish the

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usefulness of DBE for examining the excluded stomach after RYGB for morbid obesity, it will be necessary to experience a large number of DBE procedures. Table 3. Gastric cancer after gastric bypass Author (year) Raijman (1991)

Age

Sex

38

F

Postoperative period (year) 5

Lord (1997) Khitin (2003) Escalona

71

F

57

Symptom

Site

Epigastric pain Low-grade fever

Body

13

Anemia

F

22

51

F

8

Corsini

57

M

Watkins (2007)

63

M

Treatment

Prognosis Died (3m)

Antrum

Distal gastrectomy Evacuation of abscess Distal gastrectomy

Epigastric pain Distention Epigastric pain Nausea

Antrum

Gastrectomy

Alive (4d)

Antrum

Alive (8m)

4

Abdominal pain Body weight loss

Antrum

17

Abdominal pain Emesis, dehydration

Antrum

Total gastrectomy Lymph node dissection Gastroenterostom y (Unresectable) Total gastrectomy Lymph node dissection

Alive (3m)

Died (3m)

Died (26m)

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m: month, d: day.

Preoperative observation and biopsy by endoscopy is mandatory for evaluating the condition of the stomach and anticipating the occurrence of cancer. Preoperative pathological findings become one of the markers of strict follow-up after bariatric surgery. In general, intestinal metaplasia is a step towards the development of dysplasia. The described steps are gastritis, atrophy, intestinal metaplasia and dysplasia [28]. Intestinal metaplasia has been considered an important factor for development of gastric cancer. Siner [1] and Flickinger [2] et al. reported that a high percentage (87%) of patients have bile-associated gastritis in the distal portion of the stomach after gastric bypass in comparison with the proximal portion (9%), and also found significantly more severe and diffuse gastritis in the distal than in the proximal portion endoscopically. Moreover, Voellimger et al. [29] stated that in patients with precancerous lesions such as adenomatous polyps, dysplasia, intestinal metaplasia and Menetrier’s disease with high risk of developing gastric cancer, resection of the bypassed stomach can be considered at the time of RYGB. In our study, one patient showed intestinal metaplasia on DBE, and will therefore require strict follow-up. Kuga et al. [9] reported that preoperative endoscopy demonstrated normal mucosa in 25 patients (71.4%) and gastritis in 10 (28.6%). However, endoscopic findings of DBE were normal in 9 patients (25.7%), whereas in 26 (74.3%), various types of gastritis, including erythematous, erosive, hemorrhagic erosive, and atrophic, were seen. Although two patients (5.7%) were confirmed to have intestinal metaplasia histologically, no cancer was documented. Moreover, bile in the excluded stomach was found in 24 of 35 patients (68.6%) and 7 (20%) tested positive for HP in spite of preoperative eradication therapy. It will be necessary to clarify the effects of these factors on the gastric mucosa by regular DBE monitoring. However, El-Zimaity et al. [30] reported that no dysplasia or cancer was detected in patients with intestinal metaplasia who

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were followed for 9 years endoscopically, and they observed that the type of intestinal metaplasia varied, and that eradication of HP did not decrease the incidence of metaplasia on follow-up. On the other hand, Leung et al. [31] reported that intestinal metaplasia was reduced after eradication of HP. In fact, none of the patients reported previously to have intestinal metaplasia detected endoscopically in the excluded stomach have been reported to develop cancer. These issues will also need to be clarified by long-term follow-up using DBE. In conclusion, the use of the double-balloon technique has made it possible to access the gastrointestinal tract after RYGB irrespective of the length between gastrojejunostomy and jejunojejunostomy. We expect that early treatment for cancer arising in the excluded stomach will become possible and that the prognosis of affected patients will be improved.

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Sinar DR, Flickinger EG, Park HK, et al. (1985). Retrograde endoscopy of the bypassed stomach segment after gastric bypass surgery: unexpected lesions. South Med J, 78, 255-258. Flickinger EG, Sinar DR, Prories WJ, et al. (1985). The bypassed stomach. Am J Surg, 149, 151-156. Meland JM. (1984). Radiological examination of the obese patient, In: Linner JH (Ed.), Surgery for morbid obesity. (pp 149-153). New York: Springer-Verlag. McNeely GF, Stork JJ, Macgregor AMC, et al. (1991). Percutaneous examination of the bypassed stomach. Obes Surg, 1, 427-430. Sundbom M, Nyman R, Hedenstrom H, et al. (2001). Investigation of the excluded stomach after Roux-en-Y gastric bypass. Obes Surg, 11, 25-27. Fobi MAL, Chicola K, Lee H. (1998). Access to the bypassed stomach after gastric bypass. Obes Surg, 8, 289-295. Silecchia G, Catalano C, Gentileschi P, et al. (2002). Virtual gastroduodenoscopy: A new look at the bypassed stomach and duodenum after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Obes Surg, 12, 39-48. Sakai P, Kuga R, Safatle-Ribeiro AV, et al. (2005). Is it feasible to reach the excluded stomach after Roux-en-Y gastric bypass for morbid obesity? The use of the doubleballoon enteroscope. Endoscopy, 37, 566-569. Kuga R, Safatle-Ribeiro AV, Faintuch J, et al. (2007). Endoscopic findings in the excluded stomach after Roux-en-Y gastric bypass surgery. Arch Surg, 142, 942-946. Yamamoto Y, Sekine Y, Sato Y, et al. (2001). Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc, 53, 216-220. Yamamoto Y, Sugano K. (2003). A new method of enteroscopy-the double-balloon method. Can J Gastroenterol, 17, 273-274. Yamamoto Y, Kita H. (2005). Enteroscopy. J Gastroenterol, 40, 555-562. Printen KJ, LeFavre J, Alden J. (1983). Bleeding from the bypassed stomach following gastric bypass. Surg Gynecol Obstet, 156, 65-66.

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[14] Macgregor AM, Pickens NE, Thoburn EK. (1999). Perforated peptic ulcer following gastric bypass for obesity. Am Surg, 65, 222-225. [15] Iddan G, Meron G, Glukhovsky A, Swain P. (2000). Wireless capsule endoscopy. Nature, 405, 417. [16] Appleyard M, Glukhovsky A, Swain P. (2001). Wireless-capsule diagnostic endoscopy for recurrent small-bowel bleeding. N Engl J Med, 344, 232-233. [17] Raijman I, Stoher SV, Donegan WL. (1991). Gastric cancer after gastric bypass for obesity. J Clin Gastroenterol, 13, 191-194. [18] Lord RV, Edwards PD, Coleman MJ, et al. (1997). Gastric cancer in the bypassed segment after operation for morbid obesity. Aust NZ J Surg, 67, 580-582. [19] Khitin L, Roses RE, Birkett DH. (2003). Cancer in the gastric remnant after gastric bypass: a case report. Curr Surg, 60, 521-523. [20] Escalona A, Guzman S, Ibanez L, et al. (2005). Gastric cancer after Roux-en-Y gastric bypass. Obes Surg, 15, 423-427. [21] Corsini DA, Simoneti CA, Moreira G et al. (2006). Cancer in the excluded stomach 4 years after gastric bypass. Obes Surg, 16, 932-934. [22] Watkins BJ, Blackmun S, Kuehner. (2007). Gastric adenocarcinoma after Roux-en-Y gastric bypass: access and evaluation of excluded stomach. Surg Obes Relat Dis, 3, 644-7. [23] De Roover A, Detry O, De Leval L, et al. (2006). Report of two cases of gastric cancer after bariatric surgery: lymphoma of the bypassed stomach after Roux-en-Y gastric bypass and gastrointestinal stromal tumor (GIST) after vertical banded gastroplasty. Obes Surg, 16, 928-931. [24] Wingo PA, Ries LA, Giovino GA, et al. (1999). Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst, 91, 675-690. [25] Papadia FS, Scopinaro N. (2006). Gastric cancer and Roux-en-Y gastric bypass. Obes Surg, 16, 1552. [26] Inoue H, Rubino F, Shimada Y, et al. (2007). Risk of gastric cancer after Roux-en-Y gastric bypass. Arch Surg, 142, 947-953. [27] Calle E, Rodriguez C, Walker-Thurmond K et al. (2003). Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med, 348, 1625-1638. [28] Correa P. (2004). Is gastric cancer preventable? Gut, 54, 1217-1219. [29] Voellinger D, Inabnet W. (2002). Laparoscopic Roux-en-Y gastric bypass with remnant gastrectomy for focal intestinal metaplasia of the gastric antrum. Obes Surg, 12, 695698. [30] El-Zimiaty HMT, Ramchatesingh J, Ali Saeed M, et al. (2001). Gastric intestinal metaplasia: subtypes and natural history. J Clin Pathol, 54, 679-683. [31] Luung WK, Lin SR, Wong WM, et al. (2004). Factors predicting progression of gastric inteastinal metaplasia: results of a randomized trial on Helicobacter pylori eradication. Gut, 53, 1244-1249.

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

In: Obesity and Cancer Research Editors: Pauline R. Ramonde and Eva H. Fochas

ISBN 978-1-60692-388-7 © 2009 Nova Science Publishers, Inc.

Chapter 8

RAPID GENOTYPING OF TRP64ARG POLYMORPHISM OF THE β3-ADRENERGIC RECEPTOR GENE AND −3826 A TO G VARIANT OF THE UNCOUPLING PROTEIN-1 GENE USING REAL-TIME FLUORESCENT PCR Arizumi Kikuchi1,∗, Yuko Kuramoto1, Nobuyasu Noritake2, Hiroshi Murase2, Osami Daimaru1,2, Takeo Nakakita1,2 and Shinichi Itoh3 Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

1

Daiyukai 2nd Medical & Science Research Laboratories, 25 Azaicho, Ichinomiya-city, Aichi 491-0113, Japan 2 Daiyukai General Hospital, 1-1-9 Sakura, Ichinomiya-city, Aichi 491-8551, Japan 3 Daiyukai 1st Hospital, 1-6-12 Hagoromo, Ichinomiya-city, Aichi 491-8551, Japan

ABSTRACT The Trp64Arg polymorphism in the β3-adrenergic receptor (β3ADR) gene and the −3826 A to G variant in the uncouplig protein-1 (UCP-1) gene are associated with weight gain and metabolic syndromes. In this chapter, we describe a nevel method for the detection of the Trp64Arg polymorphism in the β3ADR gene and the −3826 A to G variant in the UCP-1 gene by LightCycler technology with fluorescent probe melting analysis. LightCycler technology with fluorescent probe melting analysis is an easy and fast option for the detection of the Trp64Arg polymorphism in the β3ADR gene and the −3826 A to G variant in the UCP-1 gene, and should be considered by researchers when determining the optimum technique.

∗

Correspondence concerning this article should be addressed to: Arizumi Kikuchi, Tel: +81-586-53-3661; Fax: +81-586-53-3771; E-mail: [email protected].

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The β3-adrenergic receptor (β3ADR) gene assists in the efficient accumulation of energy and is implicated in the pathogenesis of metabolic syndromes. In particular, it has been suggested that the Trp64Arg genetic polymorphism of the β3ADR gene is associated with an increased tendency to gain weight [1], and to develop abdominal obesity and insulin resistance [2]. This polymorphism has also been shown to be associated with difficulty in losing weight [3,4] and a high body mass index [5,6]. The prevalence of the Arg allele of the Trp64Arg polymorphism may contribute to the increased susceptibility to endometrial cancer in obese or overweight individuals [7]. Uncoupling protein-1 (UCP-1) is a key mediator of thermogenic function in brown adipose tissue, where it is expressed predominantly in the inner mitochondrial membrane [8]. It has been demonstrated that the A to G variant at position −3826 in the 5′- flanking region of the UCP-1 gene is associated with an increased capacity to gain weight [9,10]. Moreover, the Trp64Arg polymorphism of the β3ADR gene and the A to G (−3826) polymorphism of the UCP-1 gene have been shown to have a synergic effect on weight gain in obese subjects [11]. These polymorphisms have also been linked to resting metabolic rate [11], resistance to achieving and maintaining weight loss in obese subjects [12], and premenopausal obesity in women [13]. On the basis of these results it is theoretically possible to provide “made-to-order” weight loss guidance using the combined effects of these two genetic variations. PCR restruction fragment length polymorphism analysis (PCR-RFLP) is commonly used to analyze the Trp64Arg polymorphism in the β3ADR gene and the −3826 A to G variant in the UCP-1 gene. However, PCR-RFLP is time-consuming and requires many manipulative steps. We previously reported the use of the LightCycler technology with fluorescent probe melting curve analysis to detect the Trp64Arg genetic polymorphism in the β3ADR gene and −3826 A to G variant in the UCP-1 gene [14]. PCR was performed with the LightCycler 1.5 instrument (Roche Applied Science, Germany) and the melting curve analysis. It included processing of a negative derivative of fluorescence (−dF/dT) and was performed using the LightCycler Software. Our method has a turn around time of approximately 45min after DNA preparation. Representative results for the genotypes in the β3ADR gene are shown in Figure 1(a). The melting peak of the β3ADR gene of a normal homozygous sample was observed at 66.7°C; the peak of a Trp64Arg homozygous sample was observed at 62.9°C. The Trp64Arg heterozygous sample showed two melting peaks. The representative results for the UCP-1 gene for the three different genotypes (GG genotype, AG genotype, and AA genotype) are shown in Figure 1(b). The melting peak of the GG genotype was observed at 44.6°C, whereas the peak of the AA genotype was at 48.9°C. The AG genotype showed two melting peaks. When developing the system for UCP-1 genetic variation, we made modifications to the detection system. It is a generally accepted principle that probes should be designed with neighboring arrangements including target SNP complementarity. However, we did not obtain a sufficient melting curve when we designed the probes using this technique; it was difficult to make a distinction between the homozygous and heterozygous samples on the melting curve. Therefore, we designed a sensor probe with only one base in the sequence that was non-complementary. As a result, the Tm value led to a change in the three-dimensional structure, and a smoother falling off of the amplicon and probe.

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(a)

Fluorescence -d(F2)/dt

Trp64Arg homozygous

Normal homozygous

Trp64Arg heterozygous

water

Temperature (゜C) (b)

Fluorescence -d(F2)/dt

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GG genotype

AA genotype

AG genotype

water

Temperature (゜C) Figure 1. Melting curve analysis of the β3ADR and UCP-1 gene. (a) Trp64Arg polymorphism of β3ADR gene. Dotted line, Trp64Arg homozygous; dashed line, Trp64Arg heterozygous; thick-solid line, Normal homozygous. (b) −3826 A to G variant of the UCP-1 gene. Dotted line, GG genotype; dashed line, AG genotype; thick-solid line, AA genotype.

We analyzed samples obtained from human peripheral blood of unrelated healthy Japanese volunteers (n = 50). In the 50 samples tested for the β3ADR gene, 68.0% were normal homozygous, 6.0% were Trp64Arg homozygous and 26.0% were Trp64Arg heterozygous type. Similarly, for the UCP-1 gene, 28.0% were GG genotype, 44.0% were AG genotype, and 28.0% were AA genotype [14]. The frequency distribution recorded in this

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study is in general agreement with that reported in other studies conducted in the Japanese population [3,6,12]. The reliability of the proposed assay was confirmed by the PCR-RFLP method [11,15]. For genotyping of each sample, it was confirmed that our results showed a 100% match with results obtained by PCR-RFLP. We used the LightCycler 1.5 instrument in this chapter, but for the same method, it is possible to use other equipments that use fluorescent probe and melting curve analysis for SNP analysis. If the equipment can measure greater number of samples, it can be used for a large scale population. Because this SNP analysis uses a fluorescent probe and melting profile, analysis does not depend on the enzyme reaction. It is advantageous because the procedure for the melting curve analysis can be performed repeatedly, if necessary. In probe design, GC rich targets, direct repeats, homopolymeric runs and inverse repeats should be avoided. However, there are cases where this based unavoidable the position of target SNP, and these cases may have difficulty with optimization of the measurement. We hope not only to inform the researchers who study these SNP but also to widely inform others about an example that such an improvement can be made by this modification.

REFERENCES [1]

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[2]

[3]

[4]

[5]

[6]

[7]

Clement, K. Vaisse, C. Manning, B. S. Basdevant, A. Guy-Grand, B. Ruiz, J. Silver, K. D. Shuldiner, A. R. Froguel, P. & Strosberg, A. D. (1995). Genetic variation in the β3adrenergic-receptor gene and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med, 333, 352-354. Widen, E. Lehto, M. Kanninen, T. Walston, J. Shuldiner, A. R. & Groop, L. C. (1995). Association of a polymorphism in the β3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med, 333, 348-351. Yoshida, T. Sakane, N. Umekawa, T. Sakai, M. Takahashi, T. & Kondo, M. (1995). Mutation of β3-adrenergic-receptor gene and response to treatment of obesity. Lancet, 346, 1433-1444. Sakane, N. Yoshida, T. Umekawa, T. Kogure, A. Takakura, Y. & Kondo, M. (1997). Effects of Trp64Arg mutation in the β3-adrenergic receptor gene on weight loss, body fat distribution, glycemic control, and insulin resistance in obese type 2 diabetic patients. Diabetes Care, 20, 1887-1890. Kadowaki, H. Yasuda, K. Iwamoto, K. Otabe, S. Shimokawa, K. Silver, K. Walston, J. Yoshida, H. Kosaka, K. & Yamada, N. (1995). A mutation in the β3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects. Biochem Biophys Res Commun, 215, 555-560. Fujisawa, T. Ikegami, H. Kawaguchi, Y. & Ogihara, T. (1998). Meta-analysis of the association of Trp64Arg polymorphism of β3-adrenergic receptor gene with body mass index. J Clin Endocrinol Metab, 83, 2441-2444. Rabol, K. Przybylowska, K. Lukaszek, M. Pertynski, T. & Blasiak, J. (2004). An associated between the Trp64Arg polymorphism in the β3-adrenergic receptor gene and endometrial cancer & obesity. J Exp Clin Cancer Res, 23, 669-674.

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Rapid Genotyping of Trp64Arg Polymorphism… [8] [9]

[10]

[11]

[12]

[13]

[14]

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[15]

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Nicholls, D. G. & Locke, R. M. (1984). Thermogenic mechanisms in brown fat. Physiol Rev, 64, 1-64. Oppert, J. M. Vohl, M. C. Chagnon, M. Dionne, F. T. Cassard-Doulcier, A. M. Ricqier, D. & Perussel, L. & Bouchard, C. (1994). DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. Int J Obes Metab Disord, 18, 526-531. Clement, K. Ruiz. J. Cassarddoulcier, A. M. Bouillaud, F. Ricquier, D. Basdevant, A. Guy-Grand, B. & Froguel, P. (1996). Additive effect of A→G (−3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta-3-adrenergic receptor gene on weight-gain in morbid-obesity. Int J Obes Metab Disord, 20, 1062-1066. Valve, R. Heikkinen, S. Rissanen, A. Laakso, M. & Unsitupa, M. (1998) Synergistic effect of polymorphisms in uncoupling protein-1 and β3-adrenergic receptor genes on basal metabolic-rate in obese Finns. Diabetologia, 41, 357-361. Kogure, A. Yoshida, T. Sakane, N. Umekawa, T. Takakura, Y. & Kondo, M. (1998). Synergic effect of polymorphisms in uncoupling protein 1 and β3-adrenergic receptor genes on weight loss in obese Japanese. Diabetologia, 41, 1399. Fogelholm, M. Valve, R. Kukkonen-Harjula, K. Nenonen, A. Hakkarainen, V. Laakso, M. & Unsitupa, M. (1998). Additive effects of the mutations in the β3-adrenergic receptor and uncoupling protein-1 genes on weight loss and weight maintenance in Finnish woman. J Clin Endocrinol Metab, 83, 4246-4250. Kikuchi, A. Kuramoto, Y. Noritake, N. Murase, H. Daimaru, O. Nakakita, T. & Itoh, S. (2007). Rapid genotyping using real-time fluorescent PCR of the Trp64Arg polymorphism of the β3-adrenergic receptor gene and the −3826 A to G variant of the uncoupling protein-1 gene. Biochem Genet, 45, 769-773. Walston, J. Silver, K. Bogardus, C. Knowler, W. C. Celi, F. S. Austin, S. Manning, B. Strosberg, A. D. Stern, M. P. & Raben, N. et al. (1995). Time of onset of non-insulindependent diabetes mellitus and genetic variation in the β3-adrenergic-receptor gene. N Engl J Med, 333, 343-347.

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

In: Obesity and Cancer Research Editors: Pauline R. Ramonde and Eva H. Fochas

ISBN 978-1-60692-388-7 © 2009 Nova Science Publishers, Inc.

Chapter 9

METFORMIN AND ANTINEOPLASTIC ACTION Dragan Micic1, Goran Cvijovic1, Mirjana Sumarac – Dumanovic1 and Vladimir Trajkovic2 1

Institute of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia 2 Institute of Immunology, School of Medicine, Belgrade, Serbia

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ABSTRACT Metformin is the most frequently used drug in treatment of type 2 diabetes, particularly in obese patients. One of the potential mechanisms for his beneficial metabolic effect is activation of AMP-activated protein kinase (AMPK). AMPK is one of the key players in regulation of energy homeostasis, especially in skeletal muscles, liver and adipose tissue. Exercise, adiponectin and leptin are some of the activators of this pathway stimulating increased glucose uptake by increased GLUT-4 translocation to plasma membrane. LKB1, the upstream kinase in this pathway, is the tumor suppressor expected to inhibit initiation/growth of tumors and the activator of phosphorylation of threonin-172 of AMPK. Thus, AMPK pathway is meeting point of biochemical pathways mediating energy homeostasis and those mediating suppression of tumor genesis. We may speculate that activation of AMPK using metformin will inhibit LKB1 sensitive tumor initiation/growth. In vitro studies have shown reduced basal proliferation rate as well as abolished stimulation of breast cancer cell line with IGF-I or insulin induced marked cell proliferation during incubation with metformin. A few clinical studies reported reduced incidence of neoplastic diseases in diabetic patients treated with metforminin in comparison to diet or other antidiabetic agents. In conclusion, we may speculate that metformin could have antineoplastic effect, especially in LKB1 sensitive tumors (breast, prostate, ovary).

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INTRODUCTION Metformin is recommended as first line therapy and the most frequently used drug in treatment of type 2 diabetes [1]. The principal mechanism of metformin action is reduction of hepatic glucose production, but improvement in peripheral insulin action and β-cell function, reduction of lipolysis in adipocytes and intestinal glucose absorption were also demonstrated [2]. Molecular basis for this clinical effects were evaluated in in vivo and in vitro studies, and it was demonstrated that metformin (in clinically relevant concentrations) made suppression of mitochondrial respiratory chain [3], increased insulin receptor tyrosine kinase activity [4], stimulation of translocation of GLUT 4 transporters to the plasma membrane [5], and activation of AMP-activated protein kinase (AMPK)[6]. Beside his long-time known antihyperglycaemic effect, metformin recently established his role in prevention of type 2 diabetes [7] and in therapy of polycystic ovary syndrome [8] and NASH [9]. Finally, the latest reports speculate that metformin could be potential agent for prevention and treatment of neoplastic disease [10-16]. Previously, a number of epidemiological studies identified an increased risk of development of cancer (breast, colorectal, prostate, pancreas,…) in people with impaired glucose tolerance, insulin resistance and type 2 diabetes [17-21]. Subsequently, in a last two years two large observational studies were published reporting a reduced incidence of neoplastic disease in diabetic patients treated with metformin. Evans et al. [10] reported that of 11876 patients with newly diagnosed type 2 type 2 diabetes, 923 were admitted to hospital with malignant cancer during observation period (1993-2001). Receipt of metformin was associated with a reduced risk of cancer in this group of patients, and more importantly, a greater protective effect was observed with increasing duration of exposure to metformin as well as with total number of prescriptions dispensed. Few months later Bowker et al. [11] reported that in a cohort of 10309 people newly treated for type 2 diabetes and followed for about 5 years those who were exposed to sulfonylureas or exogenous insulin were significantly more likely to have cancer-related death than people exposed to metformin. The cancer mortality rate in the metformin group was about two-thirds of that in the sulfonylurea group. Moreover, the risk of cancer-related mortality was even greater for insulin exposure (90% relative increase) than for sulfonylurea exposure (30% relative increase). At the same time many in vitro and in vivo studies were published suggesting antineoplastic effect of metformin on tumor cells of colon, prostate, breast and gliomas [1216]. AMPK system was proposed as key point for metformin action.

AMPK AMPK is intracellular energy sensor that is activated by rising AMP and acts by switching on ATP-generating catabolic pathways while switching off ATP-requiring processes [22]. It is heterotrimeric complex comprising a catalytic α subunit and regulatory β and γ subunit [23]. In humans, there are two or three distinct genes encoding each subunit (α1, α2, β1, β2, γ1, γ2, γ3), so there are 12 possible αβγ combinations [24]. AMPK is in inactive form unless it has been phosphorylated by upstream kinases at a threonine residue

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(Thr-172) in response to cellular stresses that deplete cellular energy levels and increase AMP/ATP ratio (glucose deprivation, hypoxia, hyperosmotic stress, tissue ischemia, muscle contraction/exercise)[24]. The ability to directly sense cellular energy put AMPK on ideal position to ensure that cell division, which is highly energy-consuming process, only proceeds if cells have enough metabolic resources to support this process [25]. Activated AMPK restores cellular energy levels by stimulation of catabolic processes such as glucose uptake and/or glycolysis and fatty acid oxidation [25]. Considering antineoplastic activity of metformin through AMPK system, story begins with activation of AMPK with metabolic stress under physiological condition – exercise or contraction of skeletal muscle [26]. Actually, during exercise AMPK triggers glucose uptake by skeletal muscles in an insulinindependent manner, phosphorylates and inhibits glycogen synthase and increases fatty acid oxidation [27]. Randomized clinical trials have suggested reduction in the incidence of recurrence of colon and breast cancer in patients who undertake long-term exercise [28]. Such exercise would increase AMPK levels so we may speculate that the reduction of the incidence of recurrence of these cancers could be in some part due to AMPK role in inhibition of cell growth [25]. The fact that metformin activates AMPK system opened further ideas about metformin as antineoplastic-agent. Another observation that opened the gate of the METFORMIN AS ANTINEOPLASTIC AGENT field was that tumor suppressor gene – LKB1, is one of the essential factors for activation of AMPK by exercise and metformin [29,30,31]. LKB-1 is an upstream kinase in AMPK pathway and is responsible for phosporylation of Thr-172 and activation of AMPK. Actually, AMPK could not be activated by metformin analogues in mammalian cells that lacked LKB-1 expression [32], while in mices lacking expression of LKB-1 markedly reduced AMPK activity in liver was observed as well as the lost of blood glucose reduction effect of metformin [30]. LKB-1 gene is lost in Peutz-Jeghers syndrome, characterized by multiple gastro-intestinal polyps and increases risk of epithelial malignancies, including breast cancer [25]. Beside LKB-1, there are other possible activators of AMPK – various calcium mobilizing agents (vitamin D compounds), via Ca(2+)/calmodulin –dependent protein kinase kinase (CaMKK)[33]. Activation of AMPK system by metformin inhibits growth of tumor cells using three different pathways in tissue dependent manner – inhibition of mTOR (mammalian Target Of Rapamycin) and FAS (fatty acid synthesis), and stimulation of p53/p21 axis [16]. mTOR is a serine-threonine protein kinase that belongs to the PIKK (phosphoinositide 3kinase (PI3K)-related kinase) family. It is integrated in into two multiprotein complexes: TORC1 and TORC2, and is regulated by extracellular (growth factors – insulin and insulinlike growth factors) and intracellular (nutrients – amino acids and glucose) signals essential for cell growth. Those growth factors and nutrients enhance mTORC1 function followed by increased phosphorylation of ribosomal S6 kinase (S6K), regulator of protein translation, while the key role of mTORC2 is to phosphorylate the Akt/PKB [16]. mTORC1 consists of mTOR, raptor (regulatory associated proteinof mTOR) and mLST8, while mTORC2 consists of mTOR, Rictor (rapamycin insensitive companion), Sin-1 and mLST8. mTORC1 is regulated by nutrients and PI3K/Akt signaling pathway via phosphorylation of TSC2 protein. Actually, in addition to growth factor signals TSC1-TSC2 complex regulates mTOR activity. Phosphorylation of TSC2 by PI3K/Akt leads to inhibition of TSC2 and subsequent mTORC1

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activation. In the absence of growth promoting stimuli, TSC2 binds to TSC1 to form tumor suppressor complex, which has growth-inhibitory activity via suppression of mTOR [34,35]. mTOR is up-regulated in many cancer cells as a result of genetic alterations or aberrant activation of the components of PI3K/Akt pathway leading to dysregulation of cell proliferation, growth, differentiation and survival [16,34]. Aberrant activation of this pathway in breast cancer cells is through stimulation of epidermal growth factor receptor (EGFR), the estrogen receptor (ER), insulin and IGF1 receptors stimulating cell proliferation and cancer progression [36]. The clinical implications of mTOR activation were observed in that invasive breast cancers overexpressive in mTOR have three times greater risk of recurrence and shorter disease-free survival [37]. Experimental studies with metformin on epithelial cells demonstrated that metformin through activation of AMPK pathway reduces cellular proliferation as a consequence of reduction of mTOR activation, S6K inactivation and general reduction of mRNA translation and protein synthesis. Activation of AMPK suppresses mTOR activation induced by growth factors and amino acids directly or indirectly via TSC2 [14,38]. Second model suggesting the possible anti-cancer effect of metformin through AMPK pathway is inhibition of fatty acid synthesis [16]. Fatty acid synthesis is increased in many cancer cells, particularly breast cancer, as a result of high expression of fatty acid synthase (FAS), a key enzyme for fatty acid synthesis [39]. High levels of FAS are associated with the malignant phenotype of breast and ovarian cancers, while inhibition on FAS suppresses cancer proliferation and induces cell death through apoptosis [16]. Activation of AMPK via metformin leads to suppression of FAS gene expression and inactivation of acetyl-CoA carboxylase (ACC). This causes reduction in lipogenesis and synthesis of the ACC product malonyl-CoA resulting in increased fatty acid oxidation [40]. This reduced expression of FAS and ACC results in suppression of prostate cancer cell proliferation [41]. Finally, it has been suggested that AMPK activation promotes the survival of bioenergetically stressed stromal cells in part through p53 activation. p53 is tumor suppressor that is often mutated in cancer. In response to genotoxic stress p53 induces a transcriptional response that can result in cell cycle arrest or apoptosis. At the same time p53 demonstrated prosurvival role in cells metabolically impaired by glucose deprivation. AMPK dependent activation of p53 allows to cells to arrest their proliferation until glucose is restored by redirection of metabolism to enhance β-oxidation of fatty acids and taking-up and capturing extracellular glucose [42]. Also, p53 has one of the essential roles in autophagy. Autophagy is process that allows the cells to survive during deprivation of extracellular nutrients by degradation and metabolism of part of their cytoplasm [13]. This function of p53 can be activated by AMPK pathway using metformin, also [13]. All of these parts of AMPK pathway that promotes anti-neoplastic effect of metformin probably are tissue specific – metformin inhibits cell growth via α1AMPK subunit in MCF-7 breast cancer cells with moderate decrese in cyclin D1 levels while the antiproliferative effect of metformin on prostate cancer cells was the result of direct inhibition of mTOR independently of AMPK with marked decrease in cyclin D1 levels [14,15]. So, we shall make a review about metformin effects on particular tumor cell lines.

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METFORMIN AND GLIOMA CELLS Gliomas are extremely aggressive neuroectodermal tumors that represent the most common primary malignancy in human central nervous system. They are incurable in the most cases and their resistance to apoptosis may contribute to chemotherapy and radiation resistance. Cell motility apparently contributes to the invasive phenotype of malignant gliomas, and interference with cell motility resulted in increased susceptibility of glioma to apoptosis. Recently, it was demonstrated that metformin can inhibit in vitro migration of malignant glioma cells. Simultaneously, it was shown that glioma cells are express both AMPKα1 and AMPKα2, and pharmacological activation of AMPK reduced glioma cell growth [43,44]. We have demonstrated that metformin have dual cell density-dependent anticancer action manifested either as a cell cycle arrest or caspase-dependent apoptotic death in low-density or high-density glioma cells [12]. In low-density glioma cells metformin inhibits the increase in glioma cell number in dose dependent manner and the highest concentration of the drug (8mM) completely blocked the proliferation of glioma cells. The proportion of cells in the G0/G1 cell cycle phase was significantly increased in metformintreated glioma cultures suggesting that antiglioma effect of metformin was mainly consequence of cell cycle arrest. At the same time, mitochondrial function was not affected. This antiproliferative effect was reversible, after removal of the drug glioma cells regained their proliferative capacity. Simultaneously, in confluent glioma cells after 48 hours of incubation with metformin initial number of the glioma cells was reduced to < 30% of control values. In this group of glioma cells metformin induced activation of AMPK pathway with downstream activation of MAPK family member JNK. This activation leads to mitochondrial membrane depolarization and subsequent release of the small molecules such as cytochrome c that activate capase cascade and apoptosis. Collapse of mitochondrial membrane generates ROS, providing positive feedback mechanism and leading to further mitochondrial and cell injury. Interesting finding was that removal of the glucose from culture cell medium reduced the proapoptotic capacity of metformin further suggesting that glycolytic products rather than glucose deficiency due to excessive glycolysis could contribute to metformin-induced glioma cell death. In both low-density and confluent glioma cells primary astrocytes were completely resistant to antiproliferative and apoptotic effect of metformin [12].

METFORMIN AND PROSTATE CANCER Ben Sahra et al. [15] nicely demonstrated in vitro and in vivo antitumoral effect of metformin on prostate cancer cells. In vitro study demonstrated that metformin induced a dose dependent and strong inhibition of cell proliferation in prostate cancer cells with up to 54% of decrease in cell viability (with 5 mM metformin). At same time, there was only 20% decrease in cell viability in normal prostate cells suggesting that metformin may specifically affect proliferation of cancer cells.Incubation with metformin led to increasing number of cells in G0/G1 phase (80% after 48h and 93% after 72h). Cyclin D1 levels were no longer detectable after 48h in cultures treated with metformin [15]. Cyclin D1 is one of the most important factors for G1/S transition and usually is overexpressed in both primary prostate

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cancer samples and androgen dependent bone metastasis [45,46]. Its function is primarily to activate cyclin dependent kinase (CDK), which than phosphorylates the retinoblastoma protein (Rb). Upon phosphorylation Rb releases transcription factor E2F which is than able to activate the transcription of genes required for G1/S transition [47]. In arrested cells, metformin prevented the increase of Rb phosphorylation, and E2F1protein levels and led to reduction in mRNA of E2F1 and cyclin D1 [15]. Interestingly, metformin induced AMPK activation in prostate cancer cells, but its antiproliferative effect was consequence of direct inhibition of mTOR pathway and subsequent downregulation of S6K1 phophorylation, independently of AMPK. Actually, inhibition of AMPK could not prevent cell arrest in G0/G1 phase induced by metformin [15]. In vivo study demonstrated that oral and intraperitoneal application of metformin induced up to 55% inhibition of tumor growth and significant reduction in cyclin D1 levels.

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METFORMIN AND BREAST CANCER Previously epidemiological studies identified an increased risk of development of breast cancer in patient with type 2 diabetes [18]. MCF-7 breast cancer cells were demonstrated to be responsive to insulin and insulin-like growth factors [48,49]. Incubation of these cells with metformin induced activation of AMPK in dose-dependent manner. Activation of AMPK was associated with inhibition of mTOR pathway and decreased phosphorylation of S6K. Inhibition of AMPK using siRNA blocked antiproliferative effect of metformin suggesting that metformin exerts inhibition of cell growth directly and only through AMPK pathway [14]. There has been extensive research to develop mTOR inhibitors. Therapeutic response to rapamycin are disappointing. Rapamycin analogues are more promising but they may cause immunosuppression and trigger negative feedback loop through which Akt pathway is activated and enhance cell proliferation [16].

METFORMIN AND COLON CANCER Two different roles for eventual contribution of AMPK pathway in treatment of colon cancer were described [13,50,51]. First, it was suggested that selenium and the EGCG (epigallocatechin-3-gallate, one of the major compounds of green tea) through generation of ROS activates AMPK pathway that subsequently abrogate COX-2 expression, and COX-2 and Prostaglandin E2 production in cancer cells [50,51]. Activation of AMPK pathway with selenium and EGCG lead in vitro and in vivo to the inhibition of proliferation and apoptosis of colon cancer cells, as well to the reduction of solid xenogaft tumor. Furthermore, combination treatment with selenium/EGCG with standard chemotherapy agents markedly reduced tumor cell viability comparing to treatment with 5-FU or Etoposide alone. This is particularly important considering that these effects were demonstrated in chemo-resistant HT-29 colon cancer cells [50,51]. Another way of possible involvement of AMPK in anticancer treatment was demonstrated in p53-deficient colon cancer cells [13]. Systemic treatment with metformin, through activation of AMPK, inhibits tumor growth in p53-

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deficient colon cancer cells in vivo, while there was no effect in p53-positive cancer cells. Further analysis of tumor tissue treated with metformin revealed clusters of apoptotic cells in p53-deficient cells, especially in border regions that were under nutrient limitation, while electron microscopy showed no increase in autophagosome –positive cells. On contrary, p53 positive cells demonstrated significant increase in autophagosomes in nutrient deprived cells [13]. It was speculated that p53, besides its role as a tumor suppressor, have a prosurvival role in cells metabolically impaired by glucose limitation. Activation of p53 by glucose deprivation is AMPK dependent, leading to beta oxidation of fatty acids, capturing of extracellular glucose and induction of autophagy (survival pathway that allows cells to metabolize part of their own cytoplasm when access to extracellular nutrients is limited). Recently, autophagy was reported to be important factor for survival of tumor cells in the center of the tumors [52]. Loss of p53 impairs the ability of cancer cells to respond to metabolic changes induced by metformin and to survive under conditions of nutrient deprivation. Treatment with metformin induced apoptosis in vivo in this type of cancer cells that are usually resistant to existing forms of chemotherapy or radiotherapy [13].

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CONCLUSION Considering all mentioned in vitro and in vivo studies we might suppose that metformin could be optimal adjuvant therapy in treatment of previously mentioned cancers. It is important to notice that in the most of the studies metformin was used in pharmacological doses (0,5-8mM) that are higher than therapeutic concentrations achieved in patients with type 2 diabetes. But as it was previously reported metformin accumulates in tissues at concentrations several-fold higher than those in blood [53] indicating that therapeutically active concentrations could be attained during cancer treatment. We can expect that in a following years a lot of research and clinical studies shall be performed to confirm, or to reject, hypothesis that metformin may have role as an antineoplastic agent.

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[21] Gapstur, SM; Gann, PH; Colangelo, LA et al. Postload plasma glucose concentration and 27-year prostate cancer mortality (United States). Cancer Causes Control, 2001; 12: 763-772. [22] Carling D. The AMP-activated protein kinase cascade – a unifying system for energy control. Trends in Biochemical Science, 2004; 29: 18-24. [23] Hardie, DG; Hawley, SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioassays, 2001; 23: 1112-1119. [24] Hardie, DG; Scott, JW; Pan, DA; Hudson, ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Letters, 2003; 546: 113-120. [25] Alessi, DR; Sakamoto, K; Bayascas, JR. Lkb-1-dependent signaling pathways. Annual Review of Biochemistry, 2006; 75: 137-163. [26] Hutber, CA; Hardie, DG; Winder, WW. Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase. American Journal of Physiology, 1997; 272: E 262-266. [27] Winder, WW; Hardie, DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. American Journal of Physiology, 1999; 277: E1-10. [28] Willer A. Reduction of the individual cancer risk by physical exercise. Onkologie, 2003; 26: 283-289. [29] Woods, A; Johnstone, SR; Dickerson, K et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Current Biology, 2003; 13: 2004-2008. [30] Shaw, RJ; Lamia, KA; Vasquez, D et al. The kinase LKB-1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005; 310: 16421646. [31] Thomson, DM; Brown, JD; Fillmore, N et al. LKB-1 and the regulation of malonyl-Co A and fatty acid oxidation in muscle. American Journal of Physiological Endocrinology and Metabolism, 2007; 293: E1572-1579. [32] Hawley, SA; Boudeau, J; Reid, JL et al. Complexes between LKB-1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. Journal of Biology, 2003; 2:28. [33] Hoyer-Hansen, M; Jaattela, M. AMP-activated protein kinase: a universal regulator of autophagy? Autophagy, 2007; 3: 381-3. [34] Inoki, K; Corradetti, MN; Guan, KL. Dysregulation of TSC-mTOR pathway in human disease. Nature Genetics, 2005; 37: 19-24. [35] Van Slegtenhorst, M; Nellist, M; Nagelkerken, B et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Human Molecular Genetics, 1998; 7: 1053-1057. [36] Mita, MM; Mita, A; Rowinsky, EK. Mammalian target of rapamycin: a new molecular target for breast cancer. Clinical Breast Cancer, 2003; 4: 126-137. [37] Bose, S; Chandran, S; Mirocha, JM; Bose, N. The akt pathway in human breast cancer: a tissue-array-based analysis. Modern Pathology, 2006; 19: 238-245. [38] Shaw, RJ; Bardeesy, N; Manning, BD et al. The LKB-1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell, 2004; 6: 91-99.

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[39] Kuhajda, FP; Pizer, ES; Li, JN et al. Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proceedings of the National Academy of Sciences of the United States of America, 2000; 97: 3450-3454. [40] Zhou, G; Myers, R; Li, Y et al. Role of AMP-activated protein kinase in mechanism of metfomin action. Journal of Clinical Investigation, 2001; 108: 1167-1174. [41] Xiang, X; Saha, AK; Wen, R et al. AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. Biochemical and Biophysical Research Communications, 2004; 321: 161-167. [42] Jones, RG; Plas, DR; Kubek, S et al. AMP-activated protein kinase induces a p53dependent metabolic checkpoint. Molecular Cell, 2005; 18: 283-293. [43] Giese, A; Bjerkvig, R; Berens, M; Westphal, M. Cost of migration: invasion of malignant gliomas and implications for treatment. Journal of Clinical Oncology, 2003; 21: 1624-1636. [44] Rattan, R; Giri, S; Singh, A; Singh, I. 5-Aminoimidazole-4-carboxamide-1-beta-Dribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. Journal of Biological Chemistry, 2005; 280: 39582-39593. [45] Han, EK; Lim, JT; Arber, N et al. Cyclin D1 expression in human prostate carcinoma cell lines and primary tumors. Prostate, 1998; 35: 95-101. [46] Drobnjak, M; Osman, I; Scher, I et al. Overexpression of cyclin D1 is associated with metastatic prostate cancer to bone. Clinical Cancer Research, 2000; 6: 1891-1895. [47] Matsushime, H; Quelle, DE; Shurtleff, SA et al. D-type cycline-dependent kinase activity in mammalian cells. Molecular and Cellular Biology, 1994; 14: 2066-2076. [48] Sachdev, D; Singh, R; Fujita-Yamaguchi, Y et al. Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implication for antiinsulin-like growth factor therapy in breast cancer. Cancer Research, 2006; 66: 23912402. [49] Goodwin, PJ; Ennis, M; Pritchard, KI et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. Journal of Clinical Oncology, 2002; 20: 42-51. [50] Hwang, JT; Ha, J; Park, IJ et al. Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway. Cancer Letters, 2007; 247: 115-121. [51] Hwang, JT; Kim, YM; Surh, YJ et al. Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells. Cancer Research, 2006; 66 (20): 10057-10063. [52] Degenhardt, K; Mathew, R; Beaudoin, B et al. Autophagy promotes tumor cells survival and restricts necrosis, inflammation and tumorigenesis. Cancer Cell, 2006; 10: 51-64. [53] Wilcock, C; Bailey, CJ. Accumaltion of metformin by tissues of the normal and diabetic mouse. Xenobiotica, 1994; 24: 49-57.

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In: Obesity and Cancer Research Editors: Pauline R. Ramonde and Eva H. Fochas

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Chapter 10

PROSTATE CANCER SCREENING: A GREEK VIEW K. Stamatiou∗ and F. Sofras Department of Urology, General Hospital of Thebes, University of Crete School of Medicine, Thebes, Greece

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ABSTRACT The purpose of this report is to present the prostate cancer screening attitudes in a country, where while prostate cancer is not very common, annual prostate cancer mortality rates remained unchanged despite the increased intensity of prostate cancer screening since the introduction of PSA examination in 1996. In Greece, there is currently no official recommendation and many of PSA examinations result from the patient’s belief in the benefit of early diagnosis. The magnitude of this opportunistic screening is not known, however the prevalence of unofficial PC screening with PSA serum examination has been estimated that reaches extremely high numbers in urban areas, with most of males over 50 years old being screened at least once a year. On the contrary, overall PC screening is rare in rural and isolated areas. The abnormal distribution of unofficial prostate cancer screening in our country necessitates the introduction of intervention strategies that will prove effective for both rural and urban populations.

Keywords: Prostate cancer; Prostate-specific antigen; Screening test

∗

Correspondence concerning this article should be addressed to: Dr. Stamatiou N. Konstantinos, 2 Salepoula str. 18536, Piraeus Greece. e-mail:[email protected]

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ABBREVIATIONS

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(PC) (DRE) (PSA)

Prostate cancer; Digital rectal exam; Prostate-specific antigen.

Prostate cancer (PC) is the most frequent cancer among males in the western world and the second leading cause of cancer death in this population after lung cancer [1]. Unless in cases of urinary tract obstruction, metastases, and related disorders which occur in advanced disease, PC is usually asymptomatic, therefore efforts to reduce the mortality of the disease are based in earlier diagnosis and treatment. Available tests to detect prostate cancer include the digital rectal exam (DRE) and the prostate-specific antigen test (PSA). At the moment, there is no single, effective screening test for early PC in healthy men: neither the PSA test nor the DRE is 100% accurate. Comparisons of screening tests carried out on the same asymptomatic patients show that a raised PSA level is much more sensitive test than DRE [2]. Generally speaking, the higher the PSA level, the more likely it is that there is a cancer in the prostate. The higher the PSA level in someone with PC, the more likely it is that the cancer has spread. However, PSA levels alone do not give enough information to distinguish between benign prostate conditions and cancer. In fact, the level of PSA may also be high in men who have an infection or inflammation of the prostate or benign prostatic hyperplasia. Other factors that go into interpreting PSA scores include age and the size of prostate. Another important issue is that PSA itself can't tell how dangerous the cancer is: some PCs, particularly those of an aggressive nature, may not produce much PSA. In addition, PC is a highly unpredictable disease and current knowledge can't always predict what type of cancer is present in any particular case: some PCs become a serious threat to health by growing quickly, spreading beyond the prostate gland to other parts of the body, and causing death but others grow slowly and never become a serious threat to health or affect how long a man lives. From 1994 onwards the use of the PSA testing has been approved for the detection of PC and in consequence it has been used widely in PC screening. Justifiable concern about overdiagnosis and over treating rose since [3]. On one hand, evidence supports the usefulness of PSA serum evaluation for the screening of PC; several studies show an eventual increase in the prostate cancer detection rate and a shift towards earlier pathological stage and less invasive forms [4]. On the other hand, there is no clear evidence that the decrease in deaths from PC is due to early detection and treatment based on PSA or due to other factors [5]. Moreover, there is evidence that screening may cause over-diagnosis of slow-growing indolent cancer and may lead to unnecessary or inappropriate invasive treatment which can have serious risks and side effects, including urinary incontinence, erectile dysfunction or bowel dysfunction. For these reasons, screening tests for PC is still under study, and clinical trials evaluating the usefulness of PC screening are taking place in many countries. Full results from these studies are expected in several years. Currently, there is no standard recommendation for PC screening. Screening is presently discouraged by the EC Advisory Committee on Cancer Prevention for its negative effects are evident and its benefits still

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uncertain [6]. According to the U.S. Preventive Services Task Force, evidence is insufficient to recommend in favor of, or against routine PC screening [7], while, there are no official recommendations for PC screening provided by European Association of Urology, member of which is the Hellenic Urologic Association. Even the American Cancer Society has modified its position on men eligible for prostate cancer screening from “should undergo digital rectal examination and PSA testing annually” to “recommends that both the PSA testing and digital examination be offered annually” [8]. Similarly, American Academy of Family Physician and US Preventive Services task Force do not recommend routine screening in low-risk patients [8]. The above-mentioned professional organizations and health agencies as well as most of medical experts agree that it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake PC screening. On the other hand, men particularly those aged >50 years, have several reasons –the belief in the benefit of early diagnosis, the need to have trust, and a desire for reliable screening resembling women- to undergo routine testing for PSA [9]. Information and decision aids have been proved to increase patient knowledge about PC screening and to support physician’s judgment and to promote shared decision-making as well. Therefore they consist the current mainstays of PC screening strategy. After all, every man can have balanced information on the pros and cons of PC screening to help him make an informed decision, while, physicians who perform PSA screening can maintain strong clinical acumen and judgment when deciding whom to screen. Under the light of this evidence, prostate cancer screening in low-risk populations is a very controversial issue. PC risk appears to be associated with both genetic (race), dietary practices (fat consumption) and environmental factors (ambient sunlight exposure) and mortality rates differ among geographical regions. In several geographical regions such as Eastern Asia, where both PC incidence and mortality rates are 50 times lower than in northern Europe and northern America [10] screening for prostate cancer is worthless since the disease does not constitute a serious public health problem. Despite the fact that Greece stands in a geographical region, where histological and clinical PC is not very common [11,12], there is considerable demand for the PSA test amongst men worried about the disease. It is often that many men aged less than 50 and above 70 not informed about the risks and benefits of PC screening, are seeking for serum PSA examination and many of PSA examinations result from the perspective of patient’s knowledge on prostate cancer. Greek men concerns about prostate cancer are in part justifiable however, annual prostate cancer mortality rates in Greece remained unchanged despite the increased intensity of the PSA screening since the introduction of PSA examination in 1996 [13]. In Greece, there is currently no official recommendation and PC screening is being performed unofficially in patients visiting outpatient departments of most Greek hospitals, as well as in men visiting consulting rooms. Actually, patient’s anxiety increase the likelihood of getting the screening test, by acting powerfully on the screening decisions of physicians, whose clinical judgment would otherwise make them least, inclined to order the test. It is also notable that a General Practitioner, Family Doctor, or Internist requests most of the PSA tests. The exact magnitude of this opportunistic screening is not known, however according to the official reports of the ministry of public health 31% of men between 45-54 years of age

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and more than 50% of men over 65 yoa undergo serum PSA test yearly [14]. Due to the geographical peculiarity of our country and to the organizational problems of the national health care system it is hard to conclude that PSA screening implementation hadn’t any effect in prostate cancer mortality. In fact, more than half of the country’s population live in two large urban areas (those of Athens in the Southern Greece and Thessaloniki in the Northern Greece), while the remaining live in small towns and in rural or isolated areas, having different level of access to the health services and consequently different screening behavior. The prevalence of unofficial PC screening with PSA serum examination has been estimated that reaches extremely high numbers in the abovementioned urban areas. In contrast, overall PC screening is rare in rural and isolated areas [14]. Indeed, most hospitals are located in the two larger cities (which count for more than half of the country’s population), while only primary health care settings exist in rural and/or isolated areas. Αthens and the remaining of Attica region has the greater number of specialized medical doctors and hospital beds (65,13 and 56,39 /10.000 residents respectively) and therefore can accept patients from other regions of country. On the contrary, the neighbouring region of Viotia has limited number of both specialized medical doctors and hospital beds. Other regions may have satisfactory number of medical doctors but few hospital beds: In Thrace for example there are 41,06 medical doctors and 32,43 hospital beds /10.000 residents. Generally, wide fluctuations exist in the distribution and the availability of health care services between different -even neighbouringregions of Greece and consequently different intensity of the PSA screening is conducing in various regions. In rural and isolated areas where, a subject would never visit a physician, unless symptomatic, the overall number of PSA measurements is low. This results in a dramatical increase of health care costs and/or a possible high rate of over- treated premalignant conditions and cancers in urban areas, while in rural areas the diagnosis of prostate cancer is often attained at a stage when cure is not possible. Disparities in prostate cancer screening rates have been also noticed among men with different educational level. A recent study demonstrated that prostate cancer screening is significantly more frequent among those with higher education. On the contrary, low-literacy populations show low prostate cancer screening rates [14]. A relation between socioeconomical level and PC screening has been also observed with more than 80% of men of higher socio-economical level and less than 65% of men of median and low socioeconomical level seeking consultation from health care providers [13]. The relative percentages for PSA testing and digital rectal examination are 60,4 and 52,4% versus 19,7 and 8,2% (Table 1). These inequalities in the usage of health care services in Greece are mainly dye to the multiple split of funds and their unequal benefits, as well as in the continuous devalorisation of National Health System. Although government and medical and cancer councils have never recommended prostate cancer screening in Greece, the ministry of public health is developing a national screening program targeting to decrease disparities in the screening behavior among Greeks. Under those circumstances, patient participation in prostate cancer screening decisionmaking will require a multidimentional approach that seeks to adequately prepare patients to participate in decision-making. Yet, against a background of decreased enthusiasm and interest for PC screening, most of public and private insurances have adopted PSA serum examination on the standard annual

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check up and this opportunistic screening significantly increases the health care costs. To our knowledge, men who undergo PC screening by PSA alone are exposed to the potential harms of diagnostic follow-up, to a possible over detection of clinically insignificant PC’s and, if actively treated, to further increase of the overall health care costs. According to the perspective of the authors, patients should be thoroughly informed of the limitations of PSA screening and, in consultation with urological specialists, make the personal decision of whether to receive it. Therefore, a project to support shared decisionmaking and informed choice for men considering testing for prostate cancer should be undertaken. In an environment where so little is known about how such decisions are made, the above concept would be a step forward. Table 1. Prostate cancer screening behaviour and socio-economical level

PSA DRE

High 60,4 52,4

Socio-economical level Median-high Low 23,5 19,7 13,4 8,2

Total 29 13,2

REFERENCES [1]

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[2]

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American Cancer Society. Cancer Facts and Figures (2007). Available at: http://www.cancer.org/downloads. Gosselaar C, Kranse R, Roobol MJ, Roemeling S, Schröder FH.The interobserver variability of digital rectal examination in a large randomized trial for the screening of prostate cancer. Prostate. 2008 Apr 11; [Epub ahead of print] Auvinen A, Calais Da Silva F, Denis LJ, Hugosson J, Schroeder F. The European Randomised Study for Prostate Cancer (ERSPC). International Cooperation and Preliminary Data. New York: Parthenon, 1996: 167–72 No author listed. The International Prostate Screening Trial Evaluation Group. Rationale for randomised trials of prostate cancer screening. Eur J Cancer 1999; 35: 262–71 de Koning HJ, Auvinen A, Berenguer-Sanchez A et al. Large-scale randomized prostate cancer screening trials; program performance in the ERSPC and PLCO trials. Int J Cancer 2002; 97: 237–44 Advisory Committee on Cancer Prevention. Position paper. Recommendations on cancer screening in European Union. Eur J Cancer 2000;36:1473–8 No author listed. Agency for Healthcare Research and Quality "The Guide to Clinical Preventive Services 2005: Recommendations of the U.S. Preventive Services Task Force" 2005. Zoorob R, Anderson R, Cefalu C, Sidani M. Cancer screening guidelines. Am J Fam Physician 2001;63:1101–12.

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Haggerty J, Tudiver F, Brown JB, Herbert C, Ciampi A, Guibert R Patients’ anxiety and expectations. How they influence family physicians’ decisions to order cancer screening tests. Can Fam Physician. 2005; 51(12): 1659. GLOBOCAN 2000 [database online]. International Agency for Research on Cancer, Lyon, France. Cancer incidence, mortality and prevalence worldwide. Database version 1.0 (built November 30, 2000). Deliveliotis C, Alivizatos G, Karayiannis A, Kontothanasis D, Makrychoritis K, Lysiotis P, Dimopoulos MA. The value of prostatic specific antigen in the early diagnosis of prostatic cancer: a Greek view. Br J Urol. 1995;75(5):637-41. Stamatiou K, Alevizos A, Agapitos E, Sofras F. Incidence of impalpable carcinoma of the prostate and of non-malignant and precarcinomatous lesions in Greek male population: an autopsy study. Prostate. 2006;66(12):1319-28 Stamatiou K, Skolarikos A, Heretis I, Papadimitriou V, Alevizos A, Ilias G, Karanasiou V, Mariolis A, Sofras F. Does educational printed material manage to change compliance with prostate cancer screening? World J Urol. 2008 Apr 18; [Epub ahead of print] Τoundas G . Society and Health. Odisseas-Nea Igia, Athens 2004.

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[14]

K. Stamatiou and F. Sofras

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Index

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A Aβ, 17 abdominal, 144 aberrant, ix, 86, 87, 89, 152 absorption, 12, 27, 150 acarbose, 19 access, x, 18, 19, 24, 26, 36, 132, 133, 137, 140, 141, 155, 162 accounting, 37 acid, 6, 10, 72, 89, 107, 113, 114, 121, 127, 151, 152 acromegaly, 110, 115 activation, x, 20, 87, 89, 91, 93, 96, 100, 119, 121, 122, 123, 127, 149, 150, 151, 152, 153, 154, 155 activators, x, 149, 151, 158 acute, 10, 48, 57, 96, 121, 123, 128, 129 acute leukemia, 96 acute lymphoblastic leukemia, 121, 128 acute myelogenous leukemia, 121, 123, 128 Adams, 111 adenine, 16 adenocarcinoma, 72, 76, 96, 107, 108, 113, 114, 141 adenocarcinoma of the esophagus, 113, 114 adenocarcinomas, 79, 87, 105, 108, 114 adenoma, 76, 80, 104, 105, 109, 110, 111, 112, 114 adenomas, 76, 103, 104, 105, 110, 111, 112, 115 adenosine, 7, 32, 93 adenosine triphosphate, 7, 32 adhesions, 135, 137 adipocyte, 6, 10, 11, 18, 21, 81, 86, 88, 89, 91, 94, 95, 96, 97 adipocytes, ix, 10, 11, 73, 80, 85, 86, 87, 88, 92, 93, 98, 99, 100, 150, 156 adipocytokines, 17, 80, 90, 95 adipogenic, ix, 10, 11, 86, 87, 89

adiponectin, ix, x, 6, 8, 10, 17, 22, 32, 73, 85, 87, 90, 92, 98, 99, 149 adipose, ix, x, 8, 10, 11, 17, 21, 33, 74, 86, 88, 93, 94, 96, 98, 99, 100, 144, 149 adipose tissue, ix, x, 8, 10, 11, 17, 21, 33, 74, 86, 88, 94, 98, 99, 100, 144, 149 adiposity, vii, 1, 10, 29, 35, 41, 44, 55, 64, 71, 95, 104, 109, 114 adjustment, 71, 74, 155 adolescence, 102 adolescents, 22, 125 adrenal insufficiency, 24 adrenaline, 10, 20 adult, 8, 39, 41, 45, 49, 52, 58, 59, 66, 71, 97, 102, 109, 119 adult population, 102, 109 adults, 41, 66, 67, 79, 105, 120, 141 aetiology, 36, 81 Africa, 38, 41 African American, 45, 49, 82, 111 African American women, 82, 111 African-American, 103 afternoon, 31 age, 3, 9, 15, 24, 27, 36, 37, 41, 42, 45, 47, 48, 49, 50, 51, 52, 54, 57, 58, 59, 65, 76, 78, 80, 86, 93, 94, 103, 104, 105, 111, 133, 137, 138, 160, 161 ageing, 21, 26 agent, 87, 93, 150, 151, 155 agents, xi, 75, 88, 93, 121, 149, 151, 154 aggressiveness, 93 aging, 15, 24, 26, 30, 32 aging process, 26 agonist, 18, 88 aid, 62 AIDS, 40 Alberta, 50, 117, 123

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Index

alcohol, ix, 68, 85 alcohol consumption, ix, 85 algorithm, 155 allele, 120, 144 allergic, 2 allergic rhinitis, 2 alpha, 9, 18, 20, 27, 28, 97, 99, 157 alternative, 62 alters, 73, 80 AM, 66, 67, 78, 97, 124, 141, 156 amelioration, 137 American Cancer Society, ix, 85, 161, 163 American Diabetes Association, 155 amino, 6, 14, 16, 89, 151, 152 amino acid, 6, 14, 16, 151, 152 amino acids, 14, 16, 151, 152 amphetamine, 7 amplitude, vii, 1, 3, 8, 10, 27 analog, 15 anastomosis, x, 132, 134, 135 anatomy, 138 androgen, viii, 69, 73, 74, 75, 154 androgens, 73 Anemia, 139 angiogenesis, 91, 94, 100, 120, 121, 125 angiogenic, 93, 100, 108 angiotensin, ix, 85 animal models, 91, 120, 121 animals, 2, 3, 8, 13, 15, 27, 73, 80, 86, 89, 92 anorexia, 7 antagonist, 7 antagonists, 7, 93 anthracene, 99 anthropometry, 54, 56 antiangiogenic, 100 antiapoptotic, 104 anti-apoptotic, 119 anticancer, 30, 153, 154 anti-cancer, 152 antidiabetic, xi, 87, 149, 156 antigen, 159, 160, 164 antineoplastic, xi, 149, 150, 151, 155 antiobesity, 30 antisense, 120 antitumor, 100, 127, 158 anti-tumor, 121 antrum, 138, 141 anxiety, 161, 163 apoptosis, ix, 22, 85, 88, 93, 95, 96, 99, 108, 114, 117, 118, 119, 121, 126, 127, 152, 153, 154, 156

apoptotic, 87, 99, 127, 153, 155 Apoptotic, 158 apoptotic cells, 155 apoptotic effect, 153 appetite, 6, 7, 9, 18 application, 137, 138, 154 arrest, 88, 93, 99, 152, 153, 154, 156 Asia, 36, 62, 161 Asian, 42, 68, 104, 112 aspirin, 105 associations, vii, viii, 35, 53, 54, 55, 56, 64, 69, 70, 71, 72, 73, 75, 86, 102, 105 asthma, 2 astrocytes, 153 asymptomatic, 40, 160 Athens, 162, 164 atherosclerosis, 104 Atlas, 96 ATP, 7, 150 atrophy, 139 attacks, 2 attention, 36, 73, 86 attitudes, xi, 159 Australia, 38, 44, 50, 54 Austria, 44, 51, 67 autocrine, 88, 89, 91, 93, 98, 100, 118, 122, 123, 126, 127, 129 autonomic, 18, 30 autonomic neuropathy, 30 autophagy, 152, 155, 157 autopsy, 164 availability, 13, 19, 119, 162 avoidance, 70, 137

B bacterial, 138 Bangladesh, 42 bariatric surgery, 108, 132, 138, 139, 141 basic fibroblast growth factor, 93 Bayesian, 65 B-cell, 36, 63, 66, 138 B-cell lymphoma, 36, 63, 138 behavior, 2, 7, 13, 14, 16, 28, 29, 30, 31, 86, 162 beneficial effect, viii, 69 benefits, 83, 94, 160, 161, 162 benign, viii, ix, 70, 76, 77, 78, 92, 104, 113, 160 benign prostatic hyperplasia, 160 benign tumors, viii, 70, 76, 77, 78 beta, 97, 100, 147, 155, 157, 158

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Index bias, 64, 106 bile, 103, 135, 136, 138, 139 bile duct, 103 biliary tract, 103, 111 biliopancreatic, 132 biliopancreatic diversion, 132 binding, ix, 5, 6, 11, 14, 16, 28, 71, 73, 80, 82, 87, 88, 93, 96, 97, 98, 110, 112, 114, 115, 117, 118, 123, 124, 127, 128, 129 binding globulin, 82 bioavailability, 110, 119, 120 biochemical, x, 149 biological, vii, 1, 2, 3, 4, 6, 9, 13, 16, 28, 30, 36, 71, 99, 102, 123, 126, 129 biological processes, 36 biological rhythms, vii, 1, 2, 16 biologically, 91 biology, 118 biomarkers, ix, 86 biophysical, 95, 99, 100 biopsy, 134, 137, 138, 139 birth, ix, 47, 53, 85, 124, 125, 126, 129 birth weight, 126, 129 birthweight, 126 black, 51, 54, 66 Blacks, 107 blast cells, 121 bleeding, 135, 137, 141 blocks, 88, 89, 127 blood, 22, 29, 30, 47, 72, 76, 100, 106, 118, 151, 155 blood glucose, 22, 29, 76, 106, 151 blood pressure, 30, 72 body mass index (BMI), vii, viii, 9, 20, 27, 31, 32, 35, 41, 42, 43, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 60, 61, 63, 64, 65, 66, 67, 70, 71, 72, 73, 75, 76, 80, 82, 102, 103, 104, 105, 107, 111, 112, 113, 119, 132, 133, 144, 146 body composition, 41, 125 body fat, 8, 41, 44, 55, 64, 80, 104, 108, 111, 146, 147 body size, 104, 111 body temperature, 2, 4, 13, 25 body weight, 8, 20, 21, 22, 27, 70, 71, 72, 75, 114, 123 bone, 121, 127, 154, 158 Bose, 157 Boston, 20, 23, 28 bowel, 137, 141, 160 brain, 3, 4, 5, 7, 13, 18, 20, 33, 122, 129 brain stem, 13

169

brain tumor, 122, 129 BRCA1, 88, 96 breast, v, viii, ix, xi, 35, 38, 46, 54, 60, 64, 69, 70, 71, 73, 74, 75, 79, 80, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 120, 125, 126, 149, 150, 151, 152, 154, 156, 157, 158 breast cancer, viii, ix, xi, 38, 46, 64, 69, 71, 73, 74, 79, 80, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 125, 126, 149, 151, 152, 154, 156, 157, 158 breast carcinoma, 90, 93, 97, 100 breathlessness, 64 British, 50, 57, 82, 98, 156 British Columbia, 50, 57 bulimia, 79 Burkitt lymphoma, 36 bypass, v, x, 131, 132, 133, 137, 138, 139, 140, 141

C Ca2+, 97 caffeine, 16, 17 calcium, 151 California, 46, 47, 49, 66, 103 calmodulin, 151 caloric restriction, 15, 26, 28, 30, 120 calorie, 13, 15, 18, 24, 46 Cambodia, 42 Canada, 38, 50, 57, 66, 71, 112, 117 cancer, iii, iv, v, vii, viii, ix, x, xi, 1, 3, 14, 15, 16, 19, 20, 21, 37, 39, 41, 44, 46, 47, 48, 50, 51, 52, 53, 54, 56, 57, 59, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 78, 79, 80, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 115, 117, 118, 120, 123, 124, 125, 126, 127, 128, 129, 131, 132, 137, 138, 139, 140, 141, 146, 150, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164 cancer cells, v, ix, x, 71, 86, 87, 88, 93, 100, 117, 118, 120, 152, 153, 154 cancer progression, 93, 98, 152 cancer screening, xi, 159, 161, 162, 163 cancer treatment, ix, 85, 155 cancers, viii, 36, 37, 38, 44, 54, 60, 64, 69, 70, 71, 75, 78, 86, 89, 98, 102, 112, 120, 123, 151, 152, 155, 162 candidates, 72, 133 capacity, 144, 146, 153

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Index

capsule, 138, 141 carbohydrate, 15, 70, 103 carbohydrates, 15, 87 carcinogen, 89, 92 carcinogenesis, 22, 73, 82, 86, 88, 91, 92, 93, 97, 110, 120, 138 carcinogens, 138 carcinoma, 76, 81, 100, 102, 103, 106, 108, 109, 111, 112, 125, 164 carcinomas, 89, 97, 107, 125 cardiovascular, viii, x, 2, 9, 35, 47, 64, 69, 70, 72, 86, 102, 131, 132 cardiovascular disease, viii, 9, 35, 47, 64, 69, 70, 72, 102 Caribbean, 70 carotene, 106 casein, 6, 20 caspase, 121, 153 caspase-dependent, 153 catabolic, 150 catalytic, 150 Caucasian, 45, 48, 51 Caucasians, 41 causation, 106 cDNA, 17 cell, ix, xi, 3, 4, 16, 36, 63, 72, 73, 76, 79, 81, 87, 88, 89, 90, 91, 93, 95, 96, 97, 99, 107, 108, 110, 117, 118, 119, 121, 124, 125, 126, 127, 128, 149, 150, 151, 152, 153, 154, 156, 158 cell adhesion, 87, 90 cell cycle, 93, 152, 153, 156 cell death, 87, 152, 153 cell differentiation, 88 cell division, 151 cell fate, 89 cell growth, ix, 89, 93, 95, 117, 118, 126, 151, 152, 153, 154, 156 cell line, xi, 90, 91, 93, 97, 121, 125, 126, 128, 149, 152, 158 cell lines, 90, 91, 93, 121, 125, 126, 128, 152, 158 cell surface, 93 cellulitis, 59 central nervous system (CNS), 3, 7, 122, 128, 153 central obesity, 71, 104 certainty, 62 cervical, 72 cervical cancer, 72 Chad, 42 chemical, 120 chemistry, 22, 99

chemotherapy, 64, 68, 153, 154 Chemotherapy, 64 Chicago, 47, 106 childhood, ix, 29, 38, 85, 117, 121, 123, 128, 129 children, ix, 117, 119, 121, 122, 123, 125, 128 China, 70 cholelithiasis, 103, 111 cholesterol, 6, 9, 11, 104 Chromosomes, 98 chronic, 14, 21, 36, 53, 63, 66, 97, 109, 114, 132, 133 chronic lymphocytic leukemia, 36, 53, 63, 66 chronotherapy, 18 cigarette smoking, 52 circadian, vii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 circadian clock, vii, 1, 2, 3, 5, 6, 8, 11, 12, 13, 16, 17, 18, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 circadian oscillator, 13, 19, 20, 25, 28, 29 circadian rhythm, vii, 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31, 32 circadian rhythmicity, 4, 6, 11, 12, 14, 17, 19, 25, 31 circadian rhythms, vii, 1, 2, 3, 4, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 21, 22, 24, 26, 28, 29, 30, 32 circadian timing, 28 circulation, viii, 69, 72, 105, 118, 119 cirrhosis, 102, 108, 109, 114 citric, 6 civil servant, 50 civil servants, 50 classification, 36, 40, 57, 65 classified, 36, 37 clinical, xi, 28, 36, 70, 87, 89, 91, 94, 95, 120, 121, 130, 136, 149, 150, 151, 152, 155, 160, 161 clinical judgment, 161 clinical symptoms, 136 clinical trial, 87, 89, 151, 160 clinical trials, 87, 89, 151, 160 clinicopathologic, 125 cloning, 33 clusters, 155 c-met, 93 Co, 133, 157, 163 cocaine, 7 coding, 89, 119 codon, 98 cofactors, 28

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Index cohort, vii, 35, 44, 45, 46, 47, 48, 50, 51, 52, 54, 56, 60, 61, 62, 63, 65, 66, 67, 71, 79, 80, 82, 91, 98, 103, 105, 106, 107, 109, 111, 115, 141, 150, 158 colic, 133 collaboration, 68 collagen, 119 colon, viii, 54, 69, 70, 71, 75, 79, 80, 86, 98, 102, 103, 104, 110, 111, 112, 120, 125, 126, 150, 151, 154, 158 colon cancer, viii, 69, 71, 75, 80, 102, 110, 111, 120, 125, 126, 154, 158 colonoscopy, 104 colorectal, 38, 71, 73, 74, 81, 83, 99, 103, 104, 105, 109, 110, 111, 112, 114, 115, 120, 125, 126, 150 colorectal cancer, 71, 73, 74, 81, 83, 103, 104, 109, 110, 115, 120, 125, 126 combat, 2, 93 combined effect, 144 communication, 66 community, 112, 113 complementarity, 144 complementary, 144 compliance, 164 complications, iv, x, 108, 131, 132, 133, 136, 138 components, 4, 16, 17, 21, 28, 87, 99, 118, 121, 123, 128, 129, 152 composition, 66, 73, 80, 103 compounds, 151, 154 concentration, 5, 7, 8, 91, 98, 112, 138, 153, 157 conception, 73 confidence, 57, 61, 62 confidence interval, 57, 61, 62 confidence intervals, 57, 62 conformational, 119 confusion, 125 Congress, iv connective tissue, 88 consensus, 65, 155 consent, 76 consolidation, 10 construction, 25, 44, 47, 48 consulting, 161 consumption, 2, 30, 86, 161 contractions, 138 control, vii, viii, 6, 7, 9, 10, 12, 13, 14, 15, 20, 21, 24, 28, 29, 35, 44, 45, 47, 48, 49, 50, 51, 52, 53, 56, 57, 58, 59, 60, 61, 62, 63, 66, 68, 70, 71, 73, 75, 76, 77, 80, 81, 82, 86, 89, 95, 103, 104, 105, 106, 110, 111, 112, 122, 125, 133, 146, 153, 157 control group, viii, 70, 77, 104

171

controlled, viii, 10, 11, 14, 69, 79, 83, 104, 105, 156 controlled trials, 104 conversion, 74, 87 coordination, 3, 21 copyright, iv correlation, ix, 32, 70, 73, 75, 78, 91, 92, 93 correlations, viii, 44, 69, 70, 71, 72, 73, 75 corticosterone, 6, 12, 13, 20, 23, 27, 31 cortisol, 22, 25 costs, 163 cough, 64 COX-2, 89, 154 COX-2 enzyme, 89 CREB, ix, 86, 87, 88, 96 Crete, 159 cross-sectional, 41 crosstalk, 88, 96 cross-talk, 18 C-terminal, 28 cues, vii, 1, 2, 14, 18, 26 culture, 153 currency, 7 cycles, 2, 12, 16, 73 cyclic AMP, 96 cyclin D1, 95, 98, 152, 154, 156, 158 cycling, 17 cyclooxygenase, 89, 158 cyclooxygenase-2, 89, 158 cytochrome, 6, 32, 153 cytochrome oxidase, 6, 32 cytokine, ix, 4, 24, 75, 86 cytokines, 9, 31, 73, 87, 105, 120 cytometry, 40 cytoplasm, 5, 6, 152, 155 cytotoxicity, 87 Czech Republic, 58

D damping, 4 data analysis, 94 database, 164 death, 14, 25, 71, 80, 86, 106, 115, 126, 150, 153, 156, 160 deaths, 86, 106, 160 debt, 30 deception, 60 decisions, 161, 163 defects, 76, 78 defense, 112

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Index

deficiency, 17, 20, 25, 27, 74, 75, 82, 119, 153 deflate, 133 degenerate, 25 degradation, 6, 20, 89, 90, 91, 152 degree, 17, 41, 87 dehiscence, 59 dehydration, 139 dehydrogenase, 7 delays, 5, 15, 17 Delta, 97 demand, 161 Denmark, 49, 53, 115 density, 153 depolarization, 121, 127, 153 deposition, 55 deprivation, 10, 18, 151, 152, 155 desire, 161 destruction, 4 desynchronization, 14, 27 detection, ix, x, 36, 40, 55, 85, 107, 139, 143, 144, 160, 163 developed countries, 36, 44, 70, 86, 102, 108 developing countries, 70, 102 dexamethasone, 15 diabetes, viii, 9, 12, 15, 17, 22, 27, 28, 29, 30, 31, 33, 47, 60, 69, 70, 72, 74, 76, 77, 78, 81, 82, 83, 86, 99, 105, 106, 109, 112, 125, 146, 147, 150, 155, 156 diabetes mellitus, 22, 81, 82, 83, 105, 147, 156 diabetic, xi, 8, 12, 15, 17, 19, 27, 29, 30, 31, 73, 80, 93, 146, 149, 150, 156, 158 diabetic patients, xi, 146, 149, 150, 156 diagnostic, 36, 40, 64, 78, 141, 161, 163 diamond, 62 diet, vii, ix, xi, 2, 10, 11, 12, 17, 24, 26, 27, 44, 113, 117, 126, 149, 156 dietary, 12, 15, 17, 26, 36, 45, 95, 103, 111, 138, 161 dietary fat, 12 diets, 17, 19, 86 differentiated cells, ix, 85 differentiation, ix, 10, 11, 18, 21, 86, 87, 88, 89, 94, 95, 96, 97, 99, 117, 118, 124, 152 digestive enzymes, 13 dinucleotides, 16 direct repeats, 146 discomfort, 138 disease-free survival, 152 diseases, ix, 3, 78, 86, 108, 117, 137 disorder, 25 distal, 114, 133, 139

distribution, xi, 36, 80, 125, 146, 159, 162 diurnal, vii, 1, 7, 8, 10, 11, 12, 14, 17, 19, 23, 25, 27 DNA, 5, 16, 21, 28, 100, 144, 147 DNA damage, 21 doctors, 162 donors, 121 dopamine, 26 dorsomedial nucleus, 4 dose-response relationship, 29, 55 down-regulation, 92 drinking, 68 Drosophila, 3, 24 drugs, 72 dry, 21 duodenum, x, 132, 134, 135, 137, 140 duration, 9, 13, 22, 31, 106, 113, 136, 150 dyslipidemia, 72, 73, 75 dysplasia, 139 dysregulated, 92 dysregulation, 89, 152, 157

E earth, 2 East Asia, 38, 70 Eastern Europe, 38 eating, 9, 15, 23, 78 E-cadherin, 90 economic, 70 efficacy, 88, 100 Egypt, 42 El Salvador, 38 elderly, 38, 40 electrical, 32 electron, 155 electron microscopy, 155 electronic, iv electrostatic, iv embryonic, 10, 11, 97 embryonic stem, 97 embryonic stem cells, 97 emigration, 48 employees, 47 encoding, 11, 124, 150 endocrine, ix, 2, 4, 6, 16, 30, 73, 80, 81, 85, 92, 95, 98, 105, 118 endocrine system, 2 endogenous, vii, 1, 2, 7, 9, 11, 12, 73, 74, 75, 80, 82, 98 endometrial cancer, 71, 73, 74, 80, 81, 82, 144, 146

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Index endometrial carcinoma, 72, 80 endometrium, 54, 60, 64, 70, 74, 75 endoscope, x, 131, 133, 135, 137, 138 endoscopic, 132, 134, 135, 136, 137, 138, 139 endoscopy, v, x, 131, 132, 134, 136, 137, 138, 139, 140, 141 endothelial progenitor cells, 100 energy, vii, x, 1, 4, 5, 6, 7, 8, 9, 12, 15, 29, 33, 44, 64, 66, 67, 91, 103, 112, 144, 149, 150, 157 England, 46, 48, 51 English, 45, 66 enlargement, 82 enthusiasm, 162 entrapment, 138 environment, 86, 163 environmental, vii, 1, 161 environmental factors, 161 enzymatic, 74 enzyme, 7, 8, 11, 22, 88, 146, 152 enzymes, vii, 1, 2, 6, 28 epidemic, 40, 43, 64, 65, 102, 111 epidemiologic studies, 44, 45, 64, 105 epidemiological, vii, viii, ix, 35, 36, 68, 69, 70, 79, 86, 94, 102, 118, 123, 150, 154 epidemiology, 2, 41, 43, 44, 113 epidermal, 88, 120, 152 epidermal growth factor, 88, 120, 152 epidermal growth factor receptor, 88, 120, 152 epinephrine, 30 epithelia, 75, 87 epithelial cell, 87, 89, 91, 95, 110, 115, 152 epithelial cells, 87, 89, 91, 95, 152 epithelium, 91, 107 Epstein-Barr virus, 37, 54 equilibrium, 16 equipment, 146 erectile dysfunction, 160 erythematous, 139 esophageal, 70, 72, 81, 102, 106, 107, 108, 113 Esophageal, 113 esophageal adenocarcinoma, 70, 72, 81, 102, 106, 107, 108, 113 esophageal cancer, 108, 113 esophagus, x, 79, 102, 106, 107, 108, 114, 132, 135 estradiol, 91 estrogen, viii, 69, 71, 73, 74, 75, 78, 79, 80, 81, 82, 83, 86, 91, 99, 113, 119, 152 Estrogen, 79, 82 Estrogen replacement therapy, 79 estrogens, 71, 73, 74, 75, 81, 90, 98

173

ethanol, 16 Ethiopia, 42 ethnic groups, 40 ethnicity, 45, 47, 113 etiology, iv, 106, 122 Europe, viii, 35, 38, 42, 62, 63, 65, 107, 161 European, 36, 65, 68, 111, 155, 160, 163 European Union, 163 evening, 12 evidence, vii, x, 2, 9, 13, 20, 35, 36, 54, 55, 56, 64, 68, 79, 82, 92, 94, 97, 102, 106, 107, 118, 120, 121, 122, 156, 160, 161 ewe, 17 examinations, xi, 159, 161 excess body weight, 102, 137 excitation, 8 exercise, 113, 151 exocrine, 105 exogenous, 75, 79, 150 expert, iv experts, 161 exposure, 31, 93, 107, 113, 150, 161 extracellular, 87, 93, 151, 152, 155, 158 extracellular matrix, 87 eye, 10 eye movement, 10

F failure, 91, 137 familial, 89 family, ix, x, 11, 51, 89, 93, 96, 104, 117, 118, 119, 123, 125, 131, 132, 151, 153, 163 family history, x, 104, 131, 132 family physician, 163 Far East, 70 fasting, viii, 9, 14, 17, 31, 69, 76, 77, 78, 91, 106, 109, 110 Fasting, 76, 81, 98, 113, 158 fasting glucose, viii, 69, 76, 77, 78, 106 fat, viii, ix, 10, 11, 12, 15, 17, 24, 27, 30, 32, 44, 50, 54, 55, 67, 69, 70, 71, 72, 79, 80, 85, 86, 87, 88, 89, 92, 93, 94, 147, 161 fatigue, 3 fats, 15 fatty acid, viii, 7, 10, 11, 12, 22, 69, 72, 151, 152, 155, 157, 158 fatty acids, 11, 12, 22, 152, 155 February, x, 53, 56, 103, 131, 132 feedback, 4, 6, 154

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Index

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174

feeding, vii, 1, 2, 4, 6, 7, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 32 females, 54, 76, 138 fetal, vii, 1, 3, 119 fetal tissue, 119 fetus, 124 fever, 139 fibrinolysis, 27 fibroblast, 10, 88, 95 fibroblasts, 11, 15, 23, 32, 87, 93 Fiji, 38 Finland, 58 Finns, 146, 147 fitness, 41 flight, 18 flow, 18, 36, 40, 75 flow rate, 75 fluctuations, 23, 162 fluorescence, 144 focal adhesion kinase, 127 folate, 105 Folate, 105 folic acid, 112 follicular, 36, 63 follicular lymphoma, 36, 63 food, 2, 7, 8, 9, 10, 13, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 52, 137, 138 food intake, 7, 8, 9, 13, 18, 20, 26, 29 forebrain, 24 frameshift mutation, 23, 31, 32 France, 58, 164 free radical, 15, 22 frequency distribution, 145 fruits, 103 functional activation, 99 funds, 162

G gall bladder, 103 gallbladder, 86, 102, 103, 111 Gamma, 22 gastrectomy, 139, 141 gastric, v, x, 68, 79, 97, 113, 114, 125, 131, 132, 133, 135, 137, 138, 139, 140, 141 gastric mucosa, 133, 136, 140 gastric ulcer, 68, 138 gastritis, 132, 133, 136, 139 gastro-esophageal junction, 106, 108 gastroesophageal reflux, 72, 81, 107, 113, 114

gastroesophageal reflux disease, 107, 113, 114 gastrointestinal, v, viii, x, 2, 13, 69, 71, 82, 101, 110, 113, 132, 134, 135, 137, 138, 140, 141 gastrointestinal bleeding, 137 gastrointestinal tract, v, viii, x, 2, 69, 71, 101, 110, 132, 134, 135, 137, 138, 140 gastrojejunostomy, x, 132, 133, 137, 140 gastroscopy, 137 gender, ix, 29, 65, 70, 76, 78, 102, 103, 111, 125 gene, v, vii, x, 1, 5, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 23, 24, 25, 26, 27, 30, 31, 32, 33, 78, 88, 89, 91, 96, 97, 98, 118, 119, 122, 123, 124, 125, 127, 129, 143, 144, 145, 146, 147, 151, 152, 157 gene expression, 5, 6, 10, 11, 13, 14, 15, 16, 17, 23, 24, 27, 30, 31, 32, 33, 91, 118, 124, 127, 129, 152 gene promoter, 96 generation, 154 genes, 2, 4, 5, 6, 7, 10, 11, 17, 18, 25, 26, 32, 80, 88, 89, 90, 91, 97, 124, 147, 150, 154 genetic, 36, 86, 119, 144, 147, 152, 161 genetic alteration, 152 genetic defect, 119 genetics, 103, 111 Geneva, 65 genomic, 30, 120 genomics, 29 genotoxic, 152 genotype, 144, 145 genotypes, 144 Germany, 58, 68, 144 girls, 8 gland, viii, ix, 69, 70, 75, 76, 82, 85, 87, 89, 91, 97 glioma, 153 gliomas, 150, 153, 158 glucagon, 6, 12, 28 glucocorticoids, 15 gluconeogenesis, vii, 2, 12, 72 glucose, vii, viii, x, 2, 5, 6, 9, 11, 12, 14, 16, 17, 18, 20, 24, 28, 29, 31, 47, 66, 69, 70, 72, 73, 75, 76, 80, 81, 104, 106, 109, 110, 112, 113, 121, 127, 149, 150, 151, 152, 153, 155, 156, 157 glucose metabolism, 6, 11, 12, 24, 66, 73, 75, 80, 112 glucose regulation, 31 glucose tolerance, 12, 156 GLUT, x, 149, 150 glycogen, 6, 21, 89, 91, 100, 151 glycogen synthase kinase, 89, 91, 100 glycolysis, 151, 153

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Index glycosylated, 114 glycosylated hemoglobin, 114 government, iv, 162 grades, 56, 62 grants, 53, 57, 59 Greece, xi, 99, 159, 161, 162 Greeks, 162 green tea, 154 Greenland, 66 groups, viii, 15, 48, 50, 63, 70, 76, 77, 89, 91, 104 growth, v, ix, x, 14, 22, 71, 73, 81, 83, 86, 87, 90, 91, 93, 95, 96, 99, 100, 102, 103, 104, 105, 109, 110, 111, 112, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 149, 151, 152, 156, 158 growth factor, 81, 83, 86, 90, 93, 95, 99, 100, 102, 105, 110, 112, 114, 115, 118, 119, 122, 123, 124, 125, 126, 127, 128, 129, 151, 152, 158 growth factors, 81, 83, 86, 95, 100, 110, 122, 123, 124, 125, 128, 151, 152 growth hormone, 22, 110, 118, 125, 128 growth inhibition, 87, 96 growth rate, 73, 119 guidance, 137, 144 guidelines, 163

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H half-life, 119 Harvard, 53 Hawaii, 45 hazards, 59, 62, 63 healing, 114 health, x, 28, 45, 46, 47, 48, 53, 57, 64, 80, 86, 109, 112, 124, 126, 131, 132, 160, 161, 162 health care, 48, 86, 109, 161, 162 health care costs, 162 health care system, 161 health services, 162 heart, vii, 1, 4, 13, 15, 18, 27, 30, 33, 47, 60, 98, 106 heart disease, 27, 60 heart rate, 13, 18 Hebrew, 1 height, ix, 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 80, 82, 105, 117, 119, 124 helicobacter pylori, 68, 132, 133, 141 helix, 5 hematologic, 36 hematopoietic, 49, 66, 100, 121, 128 hematopoietic cells, 128

175

hematopoietic stem cell, 121, 128 hepatic functions, 23 hepatitis, 102, 108, 109, 114 hepatitis B, 102, 109, 114 hepatitis C, 102, 108, 109, 114 hepatocarcinogenesis, 31 hepatocellular, 48, 109, 114 hepatocellular carcinoma, 48, 109, 114 hepatocyte, ix, 85, 90, 100 hepatocyte growth factor, ix, 85, 90, 100 hepatoma, 19, 102 heredity, ix, 85 heterodimer, 5, 11 heterogeneity, viii, 35, 56, 57, 62 heterogeneous, viii, 31, 35, 36, 57, 62, 107 heterotrimeric, 150 high blood pressure, 81 high fat, 12, 19 high risk, viii, 69, 71, 72, 139 high-density lipoprotein, 9 higher education, 162 high-fat, vii, 2, 10, 11, 23, 27 hip, 9, 31, 46, 50, 52, 54, 55 histochemical, 21 histological, 76, 137, 161 histone, 88, 96 HIV, 45, 48, 49, 51, 53, 57, 58, 59 homeostasis, vii, x, 1, 4, 6, 7, 11, 24, 25, 28, 33, 67, 88, 89, 118, 149, 157 homogeneous, 36, 56 homolog, 16 homology, 118, 119 hormone, vii, viii, 1, 3, 6, 7, 9, 15, 18, 26, 29, 69, 73, 74, 75, 80, 81, 82, 90, 93, 125 hormones, vii, ix, 1, 2, 6, 25, 74, 85, 86, 108, 118, 126 hospital, 44, 48, 51, 52, 53, 54, 150, 162 hospital beds, 162 hospitals, 48, 51, 58, 161 host, 14, 19 household, 51 human, x, 3, 16, 19, 24, 25, 27, 28, 31, 32, 33, 53, 59, 80, 81, 87, 88, 89, 93, 95, 96, 97, 98, 99, 100, 120, 121, 122, 124, 125, 126, 127, 128, 129, 131, 132, 145, 147, 153, 157, 158 humans, vii, 1, 2, 6, 7, 8, 12, 23, 24, 27, 28, 29, 70, 99, 119, 150 Hungary, 69 hybrids, 119 hyperglycaemia, 155

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176

hyperglycemia, 8, 11, 12 hyperinsulinemia, viii, 69, 72, 74, 81, 102, 110, 120, 146 hyperlipidemia, 11, 12 hypertension, x, 26, 60, 70, 72, 79, 104, 131, 132 hypertensive, 2 hypertriglyceridemia, 104 hypertrophic cardiomyopathy, 25 hypoglycemia, 12 hypogonadism, 30 hypoplasia, 119 hypothalamic, 7, 12, 13, 19, 20, 22, 24, 25, 26, 29, 32 hypothalamus, vii, 1, 3, 4, 6, 7, 17, 21, 27 hypothesis, ix, 70, 75, 107, 155, 157 hypoxia, 91, 127, 151 hypoxia-inducible factor, 127 hysterectomy, 79

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I identification, 31, 36, 47, 52 IGF, v, viii, ix, xi, 69, 71, 73, 81, 98, 109, 110, 112, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 127, 128, 129, 149 IGF-1, 98, 109, 110, 115 IGF-I, ix, xi, 71, 81, 115, 117, 118, 119, 120, 121, 122, 124, 125, 127, 128, 129, 149 IGF-IR, 118, 119, 120, 121, 122, 125 IL-6, ix, 86 imaging, 32, 137, 138 imbalances, 64 immune function, vii, 35, 36 immune response, 91 immunodeficiency, 36 immunohistochemical, 122, 129 immunophenotype, 36 immunosuppression, 36, 154 immunosuppressive, 36 impaired glucose tolerance, 9, 22, 83, 104, 109, 150 implants, vii, 1, 3, 76 implementation, 161 imprinting, 120, 125 in situ, 111 in vitro, 27, 30, 71, 92, 121, 127, 150, 153, 154, 155, 156, 158 in vivo, 16, 21, 27, 28, 91, 93, 115, 127, 129, 150, 153, 154, 155, 156, 158 inactivation, 119, 121, 152 inactive, 93, 150

incidence, xi, 8, 9, 37, 38, 39, 41, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 58, 59, 65, 67, 70, 73, 78, 79, 80, 81, 86, 92, 94, 95, 102, 106, 109, 111, 113, 115, 126, 138, 140, 149, 150, 151, 156, 161, 164 inclusion, 57, 102 incubation, xi, 149, 153 incurable, 153 India, 65 Indian, 111 indication, 41, 62, 108 indices, 54, 55, 60, 133 indolent, 36, 40, 56, 160 induction, viii, 30, 69, 78, 93, 119, 120, 155 industry, 20, 48 infection, 68, 109, 133, 160 infections, 59 inferences, 36 infertility, 60 inflammation, 82, 88, 97, 158, 160 inflammatory, viii, 69, 73, 87, 89, 97 inflammatory disease, 89 inflammatory response, 89 informed consent, 133 inguinal, 10 inheritance, 20 inherited, 23, 32, 36 inherited disorder, 36 inhibition, ix, 88, 89, 94, 117, 121, 151, 152, 153, 154 inhibitor, 28, 93, 97, 100, 121, 129, 156, 158 inhibitors, 88, 89, 93, 94, 96, 100, 154 inhibitory, 93, 119, 122, 152 inhibitory effect, 93 initiation, viii, x, 69, 71, 73, 74, 149, 155 injection, 8 injury, iv, 138, 153 innate immunity, 21 insertion, 76, 138 insight, 7, 23 insomnia, 3 instability, 6 instruments, 136 insulin, viii, ix, xi, 6, 9, 12, 15, 17, 22, 30, 60, 69, 70, 71, 72, 73, 74, 75, 77, 78, 80, 82, 86, 91, 93, 95, 98, 99, 104, 106, 108, 109, 110, 113, 114, 115, 117, 118, 119, 120, 122, 124, 125, 126, 127, 128, 129, 130, 144, 146, 147, 149, 150, 151, 152, 154, 156, 158 Insulin like growth factor, 124

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Index insulin resistance, viii, ix, 69, 70, 71, 72, 73, 74, 75, 77, 78, 80, 82, 95, 99, 104, 113, 114, 115, 119, 120, 125, 144, 146, 150, 156 insulin sensitivity, viii, 12, 69, 72, 73, 109 insulin-like growth factor, ix, 71, 75, 86, 108, 109, 110, 114, 115, 117, 118, 124, 125, 126, 127, 128, 129, 130, 151, 154, 158 insulin-like growth factor I, 124, 125, 126, 127, 128, 129 intensity, xi, 159, 161, 162 interaction, 88, 96, 119, 121 Interaction, 119, 157 interactions, 5, 89, 114, 119 interference, 153 interleukin, 9, 73 Interleukin-1, 96 interleukin-6, 9, 73 international, 41, 86 International Agency for Research on Cancer, 37, 80, 164 interpretation, 62 interrelations, 21 interval, 62, 134 intervention, xi, 123, 156, 159 intervention strategies, xi, 159 interview, 44, 45, 47, 48, 50, 57 interviews, 105 intestine, 3, 133, 137, 138 intraoperative, 132 intraperitoneal, 154 intrauterine growth retardation, 125 intrinsic, 10, 119 invasive, ix, 85, 86, 88, 96, 138, 152, 153, 160 invasive cancer, 86 involution, ix, 85 Ireland, 58 ischemia, 151 ischemic, 100 isoforms, 129 Israel, 1, 32, 38, 101 Italy, 38, 44, 48, 59

J January, 75 Japan, x, 44, 59, 70, 109, 110, 111, 131, 133, 143 Japanese, 45, 103, 104, 110, 115, 145, 146, 147 jejunum, x, 132 Jerusalem, 1 jet lag, 3, 14, 21

177

Jordan, 97 judgment, 161 Jun, 66, 68 Jung, 111, 125

K kidney, viii, 13, 15, 54, 69, 70, 71, 72, 79, 122 kinase, x, 6, 19, 20, 89, 91, 93, 119, 129, 149, 150, 151, 154, 156, 157, 158 kinase activity, 89, 119, 150, 156, 158 kinases, 93, 150, 157 King, 17, 21, 31 knockout, vii, 2, 10, 12 Korea, 44, 50, 67, 98, 112 Korean, 103, 104, 106, 113

L lactate dehydrogenase, 6 lactation, 91 laminin, 96 laminin-5, 96 language, 49 laparoscopic, x, 131, 132, 133, 136, 140 large-scale, 111 later life, ix, 117, 120 latex, 133 Latino, 45 lead, 5, 9, 11, 16, 154, 160 learning, x, 132 leptin, ix, x, 6, 7, 8, 9, 10, 12, 13, 17, 19, 20, 22, 23, 25, 27, 28, 29, 30, 31, 32, 66, 73, 82, 85, 87, 90, 91, 92, 93, 98, 99, 114, 149 lesions, 14, 19, 20, 25, 30, 72, 88, 103, 104, 121, 137, 138, 140, 164 leukaemia, 128 leukemia, 44, 63, 71, 96, 102, 118, 121, 122, 129 leukemias, 66 leukemic, 121, 127, 128 leukemic cells, 128 licenses, 45 life expectancy, vii, 2, 16 life span, vii, 1, 2, 3, 15, 16, 24 life style, ix, 85, 86 lifestyle, 36, 70, 81, 86, 108, 109, 111, 114, 156 lifetime, 50, 86, 94 ligament, 137 ligand, 87, 95, 96

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Index

ligands, 87, 89, 95, 96, 119, 124 likelihood, 71, 161 limbic system, 26 limitation, 155 limitations, 105, 107, 137, 163 linear, 71 linkage, 12, 66 links, 32, 94, 109 linolenic acid, 87, 95 lipase, 8, 21 lipid, 5, 7, 10, 11, 22, 23, 25, 72, 73, 75, 86, 87, 94 lipid metabolism, 5, 10, 11, 23, 75 lipids, 86, 98, 112 lipolysis, viii, 10, 12, 69, 72, 150 lipoprotein, 8, 21, 72 literacy, 162 literature, 64, 110, 123 liver, vii, x, 1, 3, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23, 24, 30, 31, 72, 102, 108, 109, 110, 114, 118, 119, 122, 149, 151, 156, 157 liver cancer, 102 liver disease, 108, 109, 114, 156 liver enzymes, 108 liver function tests, 108 localization, 5, 97, 124 location, 3, 13, 62, 138 locomotor activity, 4, 10, 12, 13, 18, 24 longevity, vii, 1, 3, 15, 23, 28, 30 long-term, x, 132, 140, 151 Los Angeles, 45, 49 Louisiana, 46, 85 Louisiana State University, 85 low-density, 153 lower esophageal sphincter, 113 lumen, 135, 136, 138 lung, 86, 96, 120, 124, 141, 160 lung cancer, 86, 96, 141, 160 lymph, 64, 93 lymph node, 64, 93 lymphocyte, 37 lymphocytes, 121, 127 lymphoid, 36, 65 lymphoid tissue, 36 lymphoma, vii, 35, 36, 37, 38, 41, 44, 45, 48, 49, 51, 53, 55, 56, 57, 63, 64, 65, 66, 67, 68, 141 lymphomagenesis, 36 lymphomas, 36, 37, 54, 65, 66

M macronutrients, 26 macrophages, 87, 100 magnetic, iv maintenance, 88, 147 males, xi, 76, 133, 138, 159, 160 malic, 7, 8 malignancy, v, 46, 47, 49, 50, 51, 52, 71, 101, 102, 110, 120, 138, 153 malignant, vii, viii, ix, 1, 3, 21, 36, 66, 67, 68, 70, 76, 77, 78, 87, 91, 102, 117, 121, 128, 150, 152, 153, 158, 162, 164 malignant cells, ix, 87, 117 malignant growth, vii, 1, 3, 21 malignant melanoma, 102 malignant tumors, 76, 77 malnutrition, 15, 70, 118 Malta, 38 Mammalian, 157 mammalian cell, 20, 151, 158 mammalian cells, 20, 151, 158 mammals, 2, 3, 4, 15, 18, 21, 23, 24, 28, 29, 33 management, 79, 133 mantle, 36, 56 mantle cell lymphoma, 36, 56 mapping, 31 marginal zone lymphoma, 37, 56 Marx, 21 matrix, 88 matrix metalloproteinase, 88 Mauritius, 38 meals, 2, 13, 19, 26 measurement, 41, 44, 47, 146 measures, 71, 104, 105 mechanical, iv median, 162 mediators, viii, 10, 69, 73, 75 Medicaid, 49 Medicare, 49 medicine, 32, 94, 96 medulloblastoma, 122 medulloblastomas, 129 melanin, 7, 29 melanocyte stimulating hormone, 28 melanoma, 66 melatonin, 3, 8, 28 melting, x, 143, 144, 146 men, ix, 20, 22, 27, 37, 38, 39, 40, 41, 42, 43, 47, 50, 54, 55, 56, 61, 62, 66, 67, 70, 71, 72, 74, 77, 78,

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Index 79, 81, 82, 102, 103, 104, 105, 106, 111, 113, 115, 120, 126, 160, 161, 162, 163 menopausal, 71, 74, 92, 93 menopause, 73, 83 messenger ribonucleic acid, 17, 124 messenger RNA, 88 meta-analysis, 53, 56, 60, 62, 64, 67, 102, 103, 105, 106, 107, 111, 112, 114, 126 metabolic, v, vii, ix, x, 1, 2, 6, 7, 9, 10, 11, 12, 16, 17, 18, 24, 30, 31, 33, 72, 75, 78, 82, 86, 90, 102, 104, 108, 109, 110, 112, 114, 117, 118, 143, 144, 147, 149, 151, 155, 157, 158 metabolic changes, 75, 78, 155 metabolic disorder, 11, 12, 78, 90, 114 metabolic disturbances, 9, 112 metabolic pathways, 11 metabolic rate, 7, 144 metabolic syndrome, vii, x, 1, 2, 9, 11, 12, 18, 24, 30, 31, 72, 82, 86, 102, 104, 108, 109, 110, 112, 114, 143, 144 metabolism, vii, 1, 2, 5, 6, 9, 11, 12, 13, 15, 16, 20, 24, 28, 29, 32, 33, 75, 80, 81, 86, 152 metastases, ix, 85, 93, 160 metastasis, 120, 121, 124, 125, 126, 127, 154 metastatic, viii, 69, 71, 87, 93, 121, 158 metformin, xi, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158 mice, vii, 1, 7, 8, 10, 11, 12, 13, 14, 15, 17, 18, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 88, 89, 92, 93, 97, 99, 100, 119, 126 microarray, 17, 20 microenvironment, 118, 121 Middle East, 38 middle-aged, 27, 103, 126 migration, 119, 124, 153, 158 milk, ix, 85 Minnesota, 57 minority, 105 misleading, 62 mitochondria, 15, 156 mitochondrial, 72, 121, 127, 144, 150, 153 mitochondrial membrane, 121, 144, 153 mitogen, 91, 127 mitogen-activated protein kinase, 91, 127 mitogenesis, 118 mitogenic, 93, 100, 108 mitotic, 81 models, 26, 87, 118, 120, 121 modulation, 8, 89, 100, 119 molecular mechanisms, ix, 86, 93, 94, 117

179

molecular weight, 99, 121 molecules, 18, 122, 153 Møller, 53 Mongolia, 38 monkeys, 28 monocyte, 100 Moon, 97, 111 morbidity, 70 morning, 8, 29 morphological, 121 morphology, 36 mortality, x, xi, 14, 46, 51, 53, 66, 67, 70, 71, 74, 79, 80, 81, 82, 86, 95, 102, 112, 120, 131, 132, 141, 150, 156, 157, 159, 160, 161, 162, 164 mortality rate, xi, 86, 150, 159, 161 motor activity, 31 mouse, 6, 14, 17, 20, 21, 22, 31, 32, 33, 89, 158 mouse model, 22, 89 movement, 138 mRNA, 11, 17, 21, 22, 23, 32, 88, 91, 95, 98, 122, 152, 154 mucosa, 120, 132, 134, 136, 139 multiple myeloma, 102 multivariate, 107 muscle, 5, 18, 21, 29, 72, 151, 157 muscle contraction, 151 muscles, 151 mutant, vii, 1, 8, 12, 13, 21, 27, 31 mutants, 3, 12 mutation, 12, 19, 25, 30, 89, 123, 146, 147 mutations, 7, 8, 10, 23, 24, 31, 89, 97, 98, 124, 147 myocardial infarction, 2

N narcolepsy, 8, 22, 25, 27 nation, 38, 41, 141 national, 37, 47, 52, 54, 86, 161, 162 National Academy of Sciences, 158 Native Hawaiian, 45 natural, 141 Nauru, 41 nausea, 138 Nebraska, 45 necrosis, 78, 158 neoplasia, 97, 103, 110, 125 neoplasm, 122 neoplasms, iv, 48, 65, 105 neoplastic, xi, 149, 150, 152 neoplastic diseases, xi, 149

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180

nephroblastoma, 122 nervous system, 29, 122, 128 network, 28 neural network, 19 neuroblastoma, 118, 120, 121, 126, 127 neuroendocrine, 9, 27, 29, 75 neurons, 4, 7, 15, 17, 19, 20, 22, 23, 32, 96 neuropeptide, 7, 17, 25, 30 neuropeptides, 7 New England, 79, 80, 81, 94, 96, 156 New Jersey, 46 New York, iii, iv, 82, 140, 163 New Zealand, 38 Newton, 129 Non-Hodgkin lymphoma (NHL), vii, 35, 36, 37, 38, 39, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 64, 65, 67, 68, 102 nicotinamide, 16 Nielsen, 82 Nixon, 25 nocturnal asthma, 18 non-alcoholic fatty liver, 102 non-invasive, ix, 85 non-small cell lung cancer, 95 noradrenaline, 20 normal, ix, 3, 9, 13, 17, 32, 41, 46, 47, 48, 49, 51, 55, 60, 62, 63, 64, 72, 86, 87, 88, 91, 95, 97, 104, 105, 117, 118, 119, 120, 121, 122, 127, 128, 138, 139, 144, 145, 153, 158 normal aging, 3 normalization, 108 North America, viii, 35, 38, 44, 62, 63 North Carolina, 46 Norway, 46 nuclear, 5, 7, 11, 21, 26, 28, 90, 96, 119 nuclear receptors, 7 nuclei, vii, 1, 7, 13, 20, 29 nucleus, 4, 5, 6, 7, 13, 19, 22, 25, 26, 28, 87, 89, 90 nucleus accumbens, 13 nutrient, 15, 26, 112, 155 nutrients, 2, 16, 19, 112, 151, 152, 155 nutrition, v, ix, 2, 18, 21, 23, 26, 36, 117, 123

O obese, vii, viii, x, 1, 8, 9, 10, 11, 12, 17, 19, 22, 26, 30, 32, 33, 35, 41, 54, 55, 56, 57, 62, 64, 69, 71, 72, 73, 74, 76, 81, 86, 91, 92, 98, 102, 103, 105, 107, 108, 120, 140, 144, 146, 147, 149, 156

obese patients, viii, x, 9, 10, 32, 64, 69, 71, 73, 86, 105, 108, 149 obesity, v, vii, viii, ix, x, 2, 6, 7, 8, 9, 10, 11, 12, 16, 18, 19, 20, 22, 23, 24, 27, 28, 29, 30, 31, 32, 35, 36, 41, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 85, 86, 87, 89, 90, 92, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 107, 108, 109, 110, 111, 112, 113, 114, 120, 123, 126, 131, 132, 133, 137, 138, 140, 141, 144, 146, 147 observations, 73, 74, 75, 94, 118, 120, 138 obstruction, 160 occupational, 51 odds ratio, 62, 63, 103, 104, 108 Odds Ratio, 61 offshore, 27 older people, 23 olfactory, 19 olfactory bulb, 19 oncogene, 79, 92, 96, 97, 99, 119, 127, 128, 156 oncology, 65, 82, 85, 95, 98, 156, 158 online, 37, 164 optimization, 146 oral, 47, 75, 76, 78, 82, 106, 135, 154 oral cancers, 78 orexin A, 7 organ, 32, 49, 86, 119 organism, 3 organization, 15, 23, 26 organizations, 161 orthodox, 90 oscillation, 3, 6, 7, 12, 13, 21 oscillations, 11, 19, 26, 32 oscillator, 5, 13, 15, 28 osteosarcoma, 14, 123, 129 outcome of interest, 44 outpatient, 109, 161 ovarian, 72, 74, 81, 126, 152 ovarian cancer, 152 ovarian cancers, 152 ovariectomized, 17 ovary, viii, xi, 69, 71, 91, 149, 156 overweight, 9, 41, 54, 59, 64, 71, 72, 73, 102, 103, 105, 109, 110, 120, 144 oxidation, 72, 151, 152, 155, 157 oxidative, 15 oxidative damage, 15 oxidative stress, 15

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P pacemaker, 3, 4, 13, 19, 21, 23, 26 pain, 59, 139 pancreas, viii, 13, 69, 71, 102, 105, 106, 112, 150 pancreatic, 72, 105, 106, 110, 112, 113, 115, 156 pancreatic cancer, 105, 106, 110, 112, 113, 115, 156 pancreatitis, 115 paper, 44, 163 paracrine, 89, 91, 95, 98, 118, 123, 126, 127 parathyroid, 119 parathyroid hormone, 119 paraventricular, 4, 7, 25 paraventricular nucleus, 4, 25 parenteral, 26 parotid, 76, 82 parotid gland, 82 pathogenesis, 87, 91, 110, 123, 126, 144 pathophysiological, 15, 126, 129 pathophysiology, 3 pathways, ix, x, 21, 72, 91, 94, 97, 117, 119, 120, 121, 149, 150, 151 patients, viii, ix, x, 9, 12, 17, 25, 27, 31, 32, 40, 44, 52, 53, 56, 59, 64, 68, 70, 71, 72, 73, 74, 76, 77, 78, 81, 82, 83, 85, 87, 91, 92, 98, 99, 103, 104, 105, 106, 107, 108, 109, 110, 112, 114, 122, 128, 131, 132, 133, 135, 137, 138, 139, 140, 146, 150, 151, 155, 160, 161, 162, 163 pediatric, v, ix, 117, 118, 121, 122, 123, 124, 129, 137 Pennsylvania, 46, 53 peptic ulcer, 137, 141 peptide, 98, 109, 110, 114, 115, 124 peptides, 12, 17, 21, 30, 118 per capita, 86 perforation, 136 performance, 163 perinatal, 124 periodic, 13, 19 periodicity, 24 Peripheral, 29, 100 peripheral blood, 36, 145 peripheral oscillators, 4, 13, 14, 15 peristalsis, 138 Peroxisome, 95, 96 personal, 163 pH, 107 pharmacological, 153, 155 phase shifts, 30 phenolic, 121

181

phenotype, 12, 125, 152, 153 phenotypes, 12 phosphate, 7 phosphorylates, 6, 90, 151, 154 phosphorylation, x, 19, 87, 89, 119, 121, 127, 129, 149, 151, 154 Phosphorylation, 151 photoperiod, 8, 17, 21, 29 physical activity, viii, 9, 44, 66, 67, 68, 69, 71, 80 physical exercise, 157 physicians, 110, 161 physiological, vii, ix, 1, 2, 13, 16, 26, 74, 75, 117, 118, 123, 137, 151 physiology, 2, 3, 13, 16 pineal, 8 pineal gland, 8 pituitary, 19, 119 placebo, 105 placenta, 91 plants, 2 plasma, x, 12, 18, 20, 23, 25, 28, 29, 31, 73, 90, 110, 112, 115, 124, 149, 150, 157 plasma membrane, x, 73, 149, 150 play, 8, 11, 15, 88, 91, 118 political, 70 polycystic ovarian syndrome, 74 polycystic ovary syndrome, 150 polymerase, 40 polymerase chain reaction (PCR), v, 40, 143, 144, 146, 147 polymorphism, v, x, 98, 143, 144, 145, 146, 147 polymorphisms, 66, 67, 91, 98, 144, 147 Polynesia, 41 polyp, 103 polyps, 103, 104, 111, 139, 151 polyunsaturated fat, 87 polyunsaturated fatty acid, 87 poor, 88, 92, 98, 125, 137, 138 population, x, 2, 4, 10, 24, 32, 36, 37, 41, 44, 49, 50, 52, 53, 54, 57, 58, 59, 64, 66, 71, 81, 91, 102, 104, 106, 107, 108, 111, 113, 131, 132, 138, 146, 160, 162, 164 positive correlation, 86, 91 positive feedback, 18, 153 postmenopausal, viii, 69, 71, 74, 78, 79, 80, 82, 83, 91, 92, 93, 98, 102 postmenopausal women, 71, 74, 79, 80, 83, 91, 93, 98 postoperative, 133, 138 PPARγ, 11, 87

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Index

precancerous lesions, 139 prediction, 62, 128 predictors, 27, 79, 114 pregnant, 21 premenopausal, 73, 74, 91, 92, 93, 103, 144 premenopausal women, 73, 74, 103 preoperative, 133, 139 preparation, iv, 137, 144 prepubertal, 119 prevention, ix, 70, 72, 80, 85, 97, 102, 112, 123, 150 preventive, 47 primary care, 32 primary tumor, 158 private, 50, 162 probability, 76 probe, x, 143, 144, 146 procedures, 41, 132, 137, 139, 161 producers, 78 production, viii, 7, 69, 71, 73, 74, 87, 91, 92, 100, 108, 118, 119, 120, 150, 154 progesterone, 74, 80 prognosis, viii, 35, 64, 65, 88, 90, 91, 92, 98, 102, 126, 140 prognostic marker, 89, 98, 120 program, 47, 162, 163 programming, 27 pro-inflammatory, 100 prokineticin, 4 prolactin, 98, 99 proliferation, ix, xi, 86, 87, 88, 91, 93, 96, 108, 110, 115, 117, 118, 119, 121, 123, 125, 126, 127, 128, 149, 152, 153, 154, 158 promote, 10, 71, 72, 87, 91, 100, 120, 129, 161 promoter, 5, 6, 88, 96, 104 promoter region, 5 property, iv, 118 proposition, 19 prostate, viii, ix, xi, 35, 38, 60, 64, 69, 71, 72, 75, 85, 86, 112, 120, 126, 149, 150, 152, 153, 157, 158, 159, 160, 161, 162, 163, 164 prostate cancer, vi, viii, ix, xi, 35, 85, 126, 152, 153, 157, 158, 159, 160, 161, 162, 163, 164 prostate carcinoma, 158 prostate gland, 160 protease inhibitors, 93 proteases, 93 protection, 120 protein, x, 5, 6, 7, 10, 14, 15, 18, 19, 20, 24, 25, 27, 28, 29, 67, 71, 87, 88, 89, 91, 96, 112, 114, 115,

119, 124, 127, 128, 143, 144, 147, 149, 150, 151, 152, 154, 156, 157, 158 protein synthesis, 119, 152 proteins, ix, 6, 8, 15, 89, 91, 110, 115, 117, 118, 119, 122, 123, 124, 127, 128, 129 protooncogene, 89 proximal, 88, 96, 104, 139 proxy, 105 psychological, vii, 1, 3 puberty, ix, 85, 119, 125 public, 2, 41, 94, 102, 111, 161, 162 public health, 2, 41, 94, 102, 111, 161, 162 pulmonary edema, 2

Q quartile, 47 questionnaire, 45, 46, 52

R race, 47, 49, 51, 57, 79, 161 radiation, 14, 22, 153 radio, 137 radiological, 137 radiotherapy, 155 random, 49, 53, 62, 113 range, 9, 19, 38, 41, 54, 55, 57, 60, 62, 63, 65, 76, 108, 121, 133, 137 rapamycin, 119, 151, 154, 157 ras, 95 rat, 7, 11, 15, 17, 18, 19, 20, 21, 22, 25, 26, 28, 29, 32, 95, 110, 124 rats, 8, 10, 12, 14, 15, 17, 18, 19, 20, 23, 25, 26, 27, 30, 31, 99, 156 reactive oxygen, 15 reactive oxygen species, 15 real-time, v, 32, 143, 147 receptor-negative, 74, 87 receptor-positive, 87 receptors, ix, 6, 17, 26, 27, 89, 93, 117, 118, 119, 121, 126, 128, 129, 152 reconstruction, 133, 134, 137, 138 recovery, 9, 12 rectal examination, 161, 162, 163 rectum, 111 recurrence, 71, 74, 104, 105, 111, 151, 152 redox, 16, 21, 28 reduction, 13, 15, 54, 108, 120, 150, 151, 152, 154

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Index refractory, 96 regional, 37, 113 registered nurses, 52 Registry, 57 regression, 104, 112, 114, 121 regression analysis, 104, 112, 114 regular, 15, 137, 140 regulation, ix, x, 4, 5, 6, 8, 10, 18, 19, 21, 22, 25, 29, 30, 31, 32, 33, 78, 95, 117, 118, 123, 124, 127, 149, 157, 158 regulators, 6, 118 relapse, 121, 122, 128 relationship, 2, 9, 12, 14, 16, 21, 36, 81, 82, 87, 91, 102, 103, 106, 107, 110, 118, 122, 125 relationships, 22, 70, 123 relative size, 62 relatives, 17 relaxation, 113 relevance, 28 reliability, 146 remission, 121, 128 renal, 2, 72, 79, 81, 102, 122, 125 renal cell carcinoma, 125 reparation, 74 reproductive organs, 119 research, iv, 94, 95, 96, 97, 98, 99, 100, 154, 155 researchers, x, 72, 143, 146 resection, x, 131, 132, 139 residues, 90 resistance, ix, 8, 70, 72, 73, 74, 78, 80, 82, 114, 144, 153 resistin, ix, 8, 10, 73, 85, 90 resolution, 137 resources, 45, 151 respiratory, 150, 155 responsiveness, 25, 30 restitution, 18 retardation, 26, 119 retina, vii, 1, 3, 14 retinoblastoma, 154 retinohypothalamic tract, 3, 14, 22 retinoic acid, 6, 11, 16, 30 retinoic acid receptor, 6 retirees, 54 returns, 13 revascularization, 100 revolutionary, 138 rheumatoid arthritis, 97 rhythm, vii, 1, 4, 6, 12, 19, 24, 25, 27, 28 rhythmicity, 3, 6, 11, 22, 29

183

rhythms, vii, 1, 2, 3, 4, 5, 7, 8, 11, 12, 13, 14, 15, 16, 18, 19, 24, 26, 27, 28, 29, 32, 33 ribosomal, 151 risk, vii, viii, ix, x, 3, 9, 20, 35, 36, 37, 44, 45, 47, 53, 54, 55, 56, 57, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 78, 79, 80, 81, 82, 83, 85, 86, 87, 90, 91, 92, 94, 95, 98, 99, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 117, 120, 121, 123, 125, 126, 128, 131, 132, 138, 150, 151, 152, 154, 156, 157, 161 risk factors, 36, 67, 71, 78, 82, 91, 108, 111, 113, 120 risks, vii, 35, 44, 53, 54, 55, 56, 57, 60, 61, 62, 63, 64, 108, 123, 126, 160, 161 rodent, 15, 18, 87, 95 rodents, 6, 10, 12, 14, 15, 86 rosiglitazone, 88 rural, xi, 65, 159, 162 rural areas, 162 Russia, 41 Russian, 38

S Salivary gland, viii, 69, 75 salivary glands, 75, 76, 78 salt, 24, 26 sample, 49, 59, 113, 144, 146 sampling, 41 Saudi Arabia, 42 Scandinavia, 42, 44 schema, 133, 134 school, 50 school work, 50 science, 94 sclerosis, 37 scores, 160 search, 112 Seattle, 20, 49 secrete, 88, 93, 100 secretion, 4, 6, 8, 10, 12, 13, 17, 109, 110, 119, 127 secular, 65 sedation, 133, 137 sedentary, 41 selenium, 154 Self, 45, 46, 47, 48, 49, 50, 51, 52, 60, 126 self esteem, 60 self-report, 9, 47, 52, 54, 57, 58, 59 sensitivity, 10, 12, 88, 89, 95 sequelae, 136

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184

Index

Serbia, 149 series, 65 serine, 93, 151 serpin, 93 serum, viii, xi, 12, 22, 28, 69, 72, 74, 80, 91, 92, 98, 99, 104, 106, 109, 110, 112, 121, 124, 126, 128, 159, 160, 161, 162 services, iv, 162 severity, 113 sex, 9, 36, 37, 38, 45, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 62, 76, 80, 82, 119 sex hormones, 80 sex steroid, 119 shape, 87 sharing, 4 sheep, 8, 21 Shell, 26 shock, 20 side effects, 160 sigmoidoscopy, 103 sign, 17, 79 signal transduction, 97 signaling, 17, 18, 20, 22, 23, 24, 73, 89, 90, 91, 97, 99, 100, 119, 120, 121, 122, 124, 126, 127, 129, 151, 157, 158 signaling pathway, 18, 89, 91, 100, 119, 124, 151, 157, 158 signaling pathways, 18, 91, 119, 124, 157, 158 signalling, 97, 128 signals, 4, 13, 14, 16, 89, 151 signs, 138 siRNA, 93, 154 sites, 54, 67, 70, 72, 75, 97, 121, 124, 137 skeletal muscle, x, 11, 25, 149, 151, 156 skin, 46, 47, 52 skin cancer, 46, 47, 52 sleep, vii, 1, 2, 3, 4, 6, 8, 9, 10, 16, 17, 19, 22, 24, 25, 26, 27, 29, 30, 31, 32 sleep apnea, 9, 31 sleep deprivation, vii, 1, 10, 17 sleep disorders, vii, 1, 3 sleep disturbance, 27, 31 sleeping hours, 29 sleep-wake cycle, 2, 3, 25 sleeve gastrectomy, 132 small intestine, x, 21, 29, 131, 133 smokers, 113, 115 smoking, ix, 47, 51, 68, 85, 105, 114 SNP, 89, 144, 146 social, 57, 59

social factors, 57 society, 86, 94 sodium, 16 South America, 41, 70 Southeast Asia, 41 Spain, 59 specialists, 163 species, 8 spectrum, 108 squamous cell, 78, 107 squamous cell carcinoma, 107 stages, 122 statistical analysis, 76 statistics, 55 stem cells, 93, 100 steroid, 74, 75, 81, 82 steroid hormone, 74, 75, 82 steroid hormones, 74, 75, 82 steroids, 73, 119 stomach, x, 131, 132, 133, 135, 136, 137, 138, 139, 140, 141 storage, 10, 11, 72 strategies, 87, 123 stress, 30, 60, 151, 152 stretching, 137 strictures, 138 stroke, 60 stroma, 87, 122 stromal, 87, 88, 96, 121, 141, 152 stromal cells, 87, 88, 96, 121, 152 substitution, 28, 89 substrates, 119 success rate, 137 sucrose, 24 sulfonylurea, 150 Sun, 114, 126 sunlight, 161 supply, 44 suppression, xi, 7, 21, 93, 96, 149, 150, 152 suppressor, x, 21, 88, 96, 122, 129, 149, 151, 152, 155, 157 suprachiasmatic, vii, 1, 3, 14, 17, 18, 19, 22, 23, 24, 25, 26, 30, 32, 33 suprachiasmatic nuclei (SCN) , vii, 1, 3, 4, 6, 7, 11, 13, 14, 15, 25, 26 suprachiasmatic nucleus, 17, 18, 19, 22, 23, 24, 30, 32 surface area, 64 surgeries, viii, 70 surgery, 133, 138, 140

Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Index

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Surgery, 75, 131, 140 surgical, x, 59, 76, 95, 131 surgical intervention, 76 surveillance, 65, 108 survival, v, ix, x, 3, 14, 27, 64, 71, 74, 79, 81, 82, 85, 88, 96, 102, 117, 118, 121, 123, 127, 152, 155, 158 survival rate, ix, 85 susceptibility, 75, 86, 92, 97, 144, 153 Sweden, 47, 49, 52, 54, 66, 67, 71, 81, 82, 99, 115 swelling, 121 switching, 150 Switzerland, 65 sympathetic, 75, 96 sympathetic nervous system, 75 symptom, 56 symptoms, 3, 59, 64, 104, 107, 108, 113, 138 synchronization, vii, 1, 15 syndrome, vii, 1, 11, 20, 74, 82, 104, 108, 110, 146, 151, 156 synergistic, 109 synergistic effect, 109 synthesis, 10, 17, 74, 81, 108, 151, 152 synthetic, 28 systematic, 9, 67, 95, 102, 107, 111, 112, 114, 126 systematic review, 67, 95, 102, 107, 111, 112, 114, 126 systemic circulation, 72 systems, vii, 1, 6, 9, 13, 16, 30, 75, 89, 118

T Taiwan, 65, 109, 114 targets, 25, 89, 146 taste, 15 T-cell, 36, 55, 56, 127 T-cells, 127 technology, x, 120, 143, 144 temperature, 4, 13, 18, 25 temporal, 8, 15, 16, 36 testis, 91 theory, 15, 22 therapeutic, 71, 88, 93, 94, 121, 124, 126, 155, 156, 157 therapeutic agents, 121 therapeutic interventions, 88 therapy, 73, 74, 80, 82, 87, 88, 91, 95, 96, 132, 133, 139, 150, 155, 158 Thessaloniki, 162 Thiamine, 25

185

Thomson, 80, 157 threat, 160 three-dimensional, 144 threonine, 150, 151 thyroid, 18, 102, 125 thyroid carcinoma, 125 time, ix, x, 2, 3, 6, 9, 10, 12, 13, 14, 16, 17, 20, 22, 24, 29, 36, 41, 44, 54, 56, 73, 86, 104, 107, 117, 121, 131, 132, 136, 137, 139, 144, 150, 152, 153 time periods, 41 timing, 10, 14, 32, 47 Timmer, 111 tissue, viii, ix, 2, 10, 11, 14, 24, 27, 33, 69, 72, 73, 74, 75, 85, 87, 88, 90, 91, 98, 100, 105, 108, 115, 118, 122, 124, 151, 152, 155, 157 TNF, ix, 73, 86 TNF-alpha, ix, 86 TNF-α, 9, 73 tobacco, 141 tobacco smoking, 141 Tocopherol, 106 Tokyo, 30 tolerance, 12 Topotecan, 127 total cholesterol, 12 total energy, 52 total parenteral nutrition, 14 toxin, 6 transcript, 7, 8 transcription, ix, 5, 6, 11, 28, 31, 86, 87, 88, 89, 90, 91, 96, 154 transcription factor, ix, 5, 6, 11, 31, 86, 87, 88, 89, 90, 96, 154 transcription factors, ix, 5, 6, 86, 87, 89, 90 transcriptional, 4, 20, 31, 88, 90, 96, 152 transcriptomics, 10 transcripts, 2, 33 transducer, 91 transforming growth factor, 4 transgenic, 19, 21, 25, 89 transgenic mice, 21 transition, 154 transitions, 70 translation, 5, 151, 152 translational, 4 translocation, x, 5, 87, 149, 150, 156 transmembrane, 89 transmits, vii, 1, 4, 18 transplant, 121 transplantation, 49, 128

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186

transport, vii, 1, 6, 10 trend, 55, 57, 64, 104 trial, 78, 79, 83, 105, 141, 156, 163 triggers, 151 triglyceride, 10, 12 triglycerides, vii, 2, 9, 12 trust, 161 tumor, viii, x, 3, 9, 14, 21, 31, 32, 37, 54, 69, 70, 71, 72, 73, 74, 75, 76, 86, 88, 90, 91, 93, 95, 96, 99, 118, 120, 121, 122, 123, 126, 129, 141, 149, 150, 151, 152, 154, 156, 157, 158 tumor cells, 93, 120, 122, 129, 150, 151, 155, 158 tumor growth, 14, 91, 94, 120, 121, 126, 154, 155 tumor invasion, 88 tumor necrosis factor, 9, 90, 99 tumor progression, viii, 3, 14, 21, 32, 69, 71, 126 tumor proliferation, 94 tumorigenesis, 89, 92, 100, 158 tumorigenic, 95 tumors, viii, ix, x, 65, 69, 70, 71, 72, 73, 74, 75, 76, 77, 82, 86, 87, 88, 89, 91, 93, 99, 103, 105, 117, 118, 121, 122, 123, 128, 129, 149, 153, 155 tumour, 21, 64 turnover, 20, 110 type 1 diabetes, 12 type 2 diabetes, viii, x, 9, 12, 17, 35, 64, 75, 76, 102, 109, 149, 150, 154, 155, 156, 157 type 2 diabetes mellitus, 109 tyrosine, 119, 127, 150 Tyrosine, 127

U U.S. Preventive Services Task Force, 160, 163 ulcer, 114 UN, 97 undifferentiated, 89 United Kingdom (UK), 35, 36, 37, 42, 44, 46, 68, 105, 107, 155 United States, 65, 66, 67, 70, 107, 109, 112, 156, 157, 158 universality, 65 urban, xi, 65, 102, 159, 162 urban areas, xi, 159, 162 urban population, xi, 159 urinary, 160 urinary tract, 160

V values, 8, 46, 62, 153 variability, 25, 127, 163 variable, 55 variables, 55 variance, 62 variation, 8, 10, 12, 18, 21, 29, 31, 36, 38, 41, 62, 65, 86, 144, 146, 147 vascular, 91, 99, 120, 125, 127 vascular endothelial growth factor (VEGF), 91, 99, 120, 125, 127 vasculature, 26 vegetables, 103 ventricle, 4 veterans, 51, 54, 66 Victoria, 50, 57 viral, 109 viral infection, 109 virus, 6, 53, 59, 68, 102, 109 virus infection, 109 viruses, 36 vitamin D, 151 vitamin E, 156 vomiting, 138

W waist-to-hip ratio, 44, 50, 52, 54, 55, 105 waking, 9 war, 94 Washington, 49 weight changes, 103, 111 weight control, 9, 80 weight gain, x, 70, 71, 80, 103, 104, 105, 107, 111, 143, 144 weight loss, viii, 56, 69, 71, 78, 102, 103, 132, 139, 144, 146, 147 weight reduction, 108, 111 well-being, vii, 2, 3, 16 western diet, 109 wild type, 3, 12, 129 wireless, 138 Wisconsin, 57 Wistar rats, 14 Wnt signaling, ix, 86, 87, 89, 90, 97 women, ix, 8, 37, 38, 39, 41, 42, 43, 46, 47, 50, 52, 54, 55, 61, 62, 66, 67, 68, 70, 71, 72, 73, 74, 77,

Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Index 78, 80, 81, 82, 91, 96, 102, 103, 104, 105, 106, 110, 113, 114, 115, 137, 144, 161 workers, 3, 8, 9, 24, 27, 44, 47, 48, 121, 122 World Health Organisation, 36, 65 World Health Organization (WHO), 37, 41, 42, 57, 65

Y yield, 94 young adults, 22, 122 young women, 98

Z

X Zeitgeber, 30

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xenograft, 121 xenografts, 93

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Obesity and Cancer Research, edited by Pauline R. Ramonde, and Fochas, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,