Publications by authors named "Susan N Perkins"

52 Publications

Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression.

PLoS One 2014 14;9(4):e94765. Epub 2014 Apr 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.

Obesity is an established colon cancer risk factor, while preventing or reversing obesity via a calorie restriction (CR) diet regimen decreases colon cancer risk. Unfortunately, the biological mechanisms underlying these associations are poorly understood, hampering development of mechanism-based approaches for preventing obesity-related colon cancer. We tested the hypotheses that diet-induced obesity (DIO) would increase (and CR would decrease) colon tumorigenesis in the mouse azoxymethane (AOM) model. In addition, we established that changes in inflammatory cytokines, growth factors, and microRNAs are associated with these energy balance-colon cancer links, and thus represent mechanism-based targets for colon cancer prevention. Mice were injected with AOM once a week for 5 weeks and randomized to: 1) control diet; 2) 30% CR diet; or 3) DIO diet. Mice were euthanized at week 5 (n = 12/group), 10 (n = 12/group), and 20 (n = 20/group) after the last AOM injection. Colon tumors were counted, and cytokines, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), adipokines, proliferation, apoptosis, and expression of microRNAs (miRs) were measured. The DIO diet regimen induced an obese phenotype (∼36% body fat), while CR induced a lean phenotype (∼14% body fat); controls were intermediate (∼26% body fat). Relative to controls, DIO increased (and CR decreased) the number of colon tumors (p = 0.01), cytokines (p<0.001), IGF-1 (p = 0.01), and proliferation (p<0.001). DIO decreased (and CR increased) IGFBP-3 and apoptosis (p<0.001). miRs including mir-425, mir-196, mir-155, mir-150, mir-351, mir-16, let-7, mir34, and mir-138 were differentially expressed between the dietary groups. We conclude that the enhancing effects of DIO and suppressive effects of CR on colon carcinogenesis are associated with alterations in several biological pathways, including inflammation, IGF-1, and microRNAs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986228PMC
January 2015

Inhibition of androgen-responsive LNCaP prostate cancer cell tumor xenograft growth by dietary phenethyl isothiocyanate correlates with decreased angiogenesis and inhibition of cell attachment.

Int J Oncol 2012 Apr 17;40(4):1113-21. Epub 2012 Jan 17.

Laboratory of Cellular Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Phenethyl isothiocyanate (PEITC) is a candidate anticancer compound found in certain cruciferous vegetables. In our tumor cell xenograft model, dietary administration of PEITC (100-150 mg/kg body weight/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth. We found that dietary treatment with PEITC significantly inhibited tumor platelet/endothelial cell adhesion molecule (PECAM-1/CD31) expression, a marker of angiogenesis. By contrast, we did not find the inhibitory effects of PEITC on tumor growth to be associated with alteration of specific markers for apoptosis, cell proliferation or androgen receptor-mediated pathways. Consistent with in vivo results, PEITC exerted little effects on cell proliferation, cell cycle and androgen-dependent pathways. Interestingly, PEITC significantly attenuated LNCaP cell plating efficiency that correlated with inhibition of integrin family proteins integrin β1, α2 and α6 mRNA expression. Thus, PEITC may be a dietary factor that inhibits androgen-responsive prostate tumor growth indirectly by selectively targeting factors involved in the tumor microenvironment.
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http://dx.doi.org/10.3892/ijo.2012.1335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584556PMC
April 2012

Differential effects of calorie restriction and exercise on the adipose transcriptome in diet-induced obese mice.

J Obes 2011 28;2011:265417. Epub 2011 Apr 28.

Department of Nutritional Sciences, University of Texas, Austin, TX 78712, USA.

We tested the hypothesis that obesity reversal by calorie restriction (CR) versus treadmill exercise (EX) differentially modulates adipose gene expression using 48 female C57BL/6 mice administered a diet-induced obesity (DIO) regimen for 8 weeks, then randomized to receive for 8 weeks either: (1) a control (AIN-76A) diet, fed ad libitum (DIO control); (2) a 30% CR regimen; (3) a treadmill EX regimen (with AIN-76A diet fed ad libitum); or (4) continuation of the DIO diet. Relative to the DIO controls, both CR and EX reduced adiposity by 35-40% and serum leptin levels by 80%, but only CR increased adiponectin and insulin sensitivity. Gene expression microarray analysis of visceral white adipose tissue revealed 209 genes responsive to both CR and EX, relative to the DIO group. However, CR uniquely altered expression of an additional 496 genes, whereas only 20 were uniquely affected by EX. Of the genes distinctly responsive to CR, 17 related to carbohydrate metabolism and glucose transport, including glucose transporter (GLUT) 4. Chromatin immunoprecipitation assays of the Glut4 promoter revealed that, relative to the DIO controls, CR significantly increased histone 4 acetylation, suggesting epigenetic regulation may underlie some of the differential effects of CR versus EX on the adipose transcriptome.
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http://dx.doi.org/10.1155/2011/265417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092555PMC
July 2011

Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia.

Cancer Prev Res (Phila) 2011 Jul 18;4(7):1030-40. Epub 2011 May 18.

Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.

Risk of pancreatic cancer, the fourth deadliest cancer in the United States, is increased by obesity. Calorie restriction (CR) prevents obesity, suppresses carcinogenesis in many models, and reduces serum levels of IGF-1. In the present study, we examined the impact of CR on a model of inflammation-associated pancreatitis and pancreatic dysplasia, with a focus on the mechanistic contribution of systemic IGF-1. Administration of a 30% CR diet for 14 weeks decreased serum IGF-1 levels and hindered pancreatic ductal lesion formation and dysplastic severity, relative to a higher calorie control diet, in transgenic mice overexpressing COX-2 [bovine keratin-5 promoter (BK5.COX-2)]. These findings in CR mice correlated with reductions in Ki-67-positive cells, vascular luminal size, VEGF expression, and phosphorylation and total expression of downstream mediators of the IGF-1 pathway. Cell lines derived from BK5.COX-2 ductal lesions (JC101 cells) formed pancreatic tumors in wild-type FVB mice that were significantly reduced in size by a 14-week CR regimen, relative to the control diet. To further understand the impact of circulating levels of IGF-1 on tumor growth in this model, we orthotopically injected JC101 cells into liver-specific IGF-1-deficient (LID) mice. The approximate 65% reduction of serum IGF-1 levels in LID mice resulted in significantly decreased burden of JC101 tumors, despite modestly elevated levels of circulating insulin and leptin. These data show that CR prevents development of dysplasia and growth of pancreatic cancer through alterations in IGF-1, suggesting that modulation of this pathway with dietary and/or pharmacologic interventions is a promising pancreatic cancer prevention strategy.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131443PMC
July 2011

Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer.

Nutr Cancer 2010 ;62(8):1074-86

University of Texas at Austin, Austin, Texas 78712, USA.

Over the past two decades, bioactive natural compounds have been shown to be a plausible adjunct to the treatment of breast cancer, the second leading cause of cancer death among American women. This study was designed to investigate the effects of ursolic acid (UA), a pentacyclic triterpene found in many foods and herbs, in a model of postmenopausal breast cancer. Ovariectomized C57BL/6 mice (n = 40) were randomized to receive control diet (AIN-93G) or diet supplemented with UA at 1 of 3 doses (wt/wt): 0.05%, 0.10%, or 0.25% (≈54, 106, or 266 mg/kg body weight/day, respectively). After 3 wk, syngeneic MMTV-Wnt-1 mammary tumor cells were injected in the mammary fat pad, and mice continued on their respective diets for 5 more wk. All UA doses decreased tumor cell proliferation, as assessed by Ki67 immunostaining; nevertheless, UA at 0.10% was most effective in inhibiting tumor take and decreasing tumor final tumor size. Modulation of Akt/mTOR signaling and induction of apoptosis appeared to mediate these effects on tumor growth. UA potently disrupted cell cycle progression and induced necrosis in a clonal MMTV-Wnt-1 mammary tumor cell line in vitro. This study supports the potential of UA as an antitumorigenic agent.
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http://dx.doi.org/10.1080/01635581.2010.492092DOI Listing
March 2011

Partners in the spiritual dance: learning clients' steps while minding all our toes.

J Marital Fam Ther 2010 Apr;36(2):229-43

Virginia Polytechnic Institute and State University, Virginia, USA.

We present four case illustrations highlighting the complex interplay of therapists' and clients' spirituality in therapy. Complexity, in these cases, results from (a) degrees of similarity and difference, both real and perceived, between clients' and therapists' spiritual beliefs and practices; (b) degrees of spiritual disclosure; (c) characteristics of the therapeutic relationship; and (d) geographic and cultural influences. Practicing therapists and therapist training programs can benefit from addressing how therapist and client spirituality intersect and influence therapy, how both similarity and difference present obstacles and opportunities, and how ambiguity and assumptions can contribute to misunderstandings. We believe that both the therapist's and the client's spiritualities are key influences in therapy that can contribute to the frustration, and the growth, of clients and therapists alike.
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http://dx.doi.org/10.1111/j.1752-0606.2009.00161.xDOI Listing
April 2010

Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research.

Carcinogenesis 2010 Jan 7;31(1):83-9. Epub 2009 Dec 7.

Department of Nutritional Sciences, The University of Texas at Austin, 103 West 24th Street, Austin, TX 78712, USA.

Calorie restriction (CR) is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenesis process, and many of the key studies in this field have been published in Carcinogenesis. Translation of the knowledge gained from CR research in animal models to cancer prevention strategies in humans is urgently needed given the worldwide obesity epidemic and the established link between obesity and increased risk of many cancers. This review synthesizes the evidence on key biological mechanisms underlying many of the beneficial effects of CR, with particular emphasis on the impact of CR on growth factor signaling pathways and inflammatory processes and on the emerging development of pharmacological mimetics of CR. These approaches will facilitate the translation of CR research into effective strategies for cancer prevention in humans.
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http://dx.doi.org/10.1093/carcin/bgp280DOI Listing
January 2010

Distinct effects of calorie restriction and exercise on mammary gland gene expression in C57BL/6 mice.

Cancer Prev Res (Phila) 2009 Dec 1;2(12):1076-87. Epub 2009 Dec 1.

Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Energy balance, including diet, weight, adiposity, and physical activity, is associated with carcinogenesis. Epidemiologic studies indicate that obesity and sedentary and/or active behavior are risk factors for breast cancer in postmenopausal women and survival in both premenopausal and postmenopausal breast cancer patients. Thus, understanding the influence of energy balance modulation on changes in gene expression patterns in the normal mammary gland is important for understanding mechanisms linking energy balance and breast cancer. In a 6-week-long study, female C57BL/6 mice (9-week-old) were randomized into four groups: (a) food consumed ad libitum (AL), (b) AL with access to running wheels (AL+EX), (c) 30% calorie restricted (CR), and (d) 30% CR with access to running wheels (CR+EX). CR mice received 70% of calories but 100% of all other nutrients compared with AL mice. Diet and exercise treatments, individually and combined, had significant effects on body composition and physical activity. Affymetrix oligomicroarrays were used to explore changes in gene expression patterns in total RNA samples from excised whole mammary glands. Contrasting AL versus CR resulted in 425 statistically significant expression changes, whereas AL versus AL+EX resulted in 45 changes, with only 3 changes included among the same genes, indicating that CR and EX differentially influence expression patterns in noncancerous mammary tissue. Differential expression was observed in genes related to breast cancer stem cells, the epithelial-mesenchymal transition, and the growth and survival of breast cancer cells. Thus, CR and EX seem to exert their effects on mammary carcinogenesis through distinct pathways.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798590PMC
December 2009

Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice.

Mol Carcinog 2009 Dec;48(12):1071-6

Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland 20892-4258, USA.

High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally, IGF-1 inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most do not survive, making it difficult to study how genetic ablation of IGF-1 affects colon tumorigenesis. To test the hypothesis that inhibition of IGF-1 prevents colon tumorigenesis, we utilized a preexisting mouse model containing a deletion of the igf1 gene in the liver through a Cre/loxP system. These liver-specific IGF-1 deficient (LID) mice display a 50-75% reduction in circulating IGF-1 levels. We conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice had a significant inhibition of colon tumor multiplicity in the proximal area of the colon compared to their wild-type littermates. We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor.
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http://dx.doi.org/10.1002/mc.20577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951004PMC
December 2009

Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer.

Med Sci Sports Exerc 2009 Aug;41(8):1597-605

University of Wisconsin, Madison, WI, USA.

Purpose: Physically active women have a reduced risk of breast cancer, but the dose of activity necessary and the role of energy balance and other potential mechanisms have not been fully explored in animal models. We examined treadmill and wheel running effects on mammary tumorigenesis and biomarkers in p53-deficient (p53(+/-)):MMTV-Wnt-1 transgenic mice.

Methods: Female mice (9 wk old) were randomly assigned to the following groups in experiment 1: treadmill exercise 5 d x wk(-1), 45 min x d(-1), 5% grade at 20 m x min(-1), approximately 0.90 km x d(-1) (TREX1, n = 20) or at 24 m x min(-1), approximately 1.08 km x d(-1) (TREX2, n = 21); or a nonexercise control (CON-TREX, n = 22). In experiment 2, mice were randomly assigned to voluntary wheel running (WHL, n = 21, 2.46 +/- 1.11 km x d(-1) (mean +/- SD)) or to a nonexercise control (CON-WHL, n = 22). Body composition was measured at approximately 9 wk and serum insulin-like growth factor 1 (IGF-1) at two to three monthly time points beginning at approximately 9 wk on study. Mice were sacrificed when tumors reached 1.5 cm, mice became moribund, or there was only one mouse per treatment group remaining.

Results: TREX1 (24 wk) and TREX2 (21 wk) had shorter median survival times than CON-TREX (34 wk; P < 0.01), whereas those of WHL and CON-WHL were similar (23 vs 24 wk; P = 0.32). TREX2 had increased multiplicity of mammary gland carcinomas compared with CON-TREX; WHL had a higher tumor incidence than CON-WHL. All exercising animals were lighter than their respective controls, and WHL had lower body fat than CON-WHL (P < 0.01). There was no difference in IGF-1 between groups (P > 0.05).

Conclusions: Despite beneficial or no effects on body weight, body fat, or IGF-1, exercise had detrimental effects on tumorigenesis in this p53-deficient mouse model of spontaneous mammary cancer.
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http://dx.doi.org/10.1249/MSS.0b013e31819f1f05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040490PMC
August 2009

Dietary calcium source influences body composition, glucose metabolism and hormone levels in a mouse model of postmenopausal obesity.

In Vivo 2009 Jul-Aug;23(4):527-35

Department of Nutritional Sciences, One University Station A2703, The University of Texas at Austin, Austin, TX 78712, U.S.A.

Background: The prevalence of obesity has risen dramatically, with postmenopausal women particularly prone to increased adiposity. Epidemiologic data suggest that dietary calcium, particularly from dairy products, can decrease weight gain. The aim of this study was to evaluate effects of different calcium sources in a mouse model of postmenopausal obesity.

Materials And Methods: Ovariectomized C57BL/6 mice were randomized to either low-fat (LF) or high-fat (HF) diets containing either calcium phosphate from non-fat dried milk and whey mineral concentrate (dairy) or calcium carbonate (supplement).

Results: Dairy, but not supplement, decreased weight gain and percent body fat in HF mice, with no effect on food consumption. Dairy improved insulin resistance and glucose tolerance, while supplement increased bone mineral density in LF mice. Dairy had no effect on bone.

Conclusion: The beneficial effects of dietary calcium on body weight and bone health after menopause may be significantly influenced by other dietary components.
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September 2009

Urothelial overexpression of insulin-like growth factor-1 increases susceptibility to p-cresidine-induced bladder carcinogenesis in transgenic mice.

Mol Carcinog 2009 Aug;48(8):671-7

Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas 78712, USA.

To establish a role for insulin-like growth factor-1 (IGF-1) in bladder cancer susceptibility, we tested the effect of p-cresidine, a potent bladder carcinogen, in transgenic (TG) mice with human IGF-1 expression in the bladder driven by the bovine keratin 5 promoter (referred to as BK5.IGF-1 TG mice). Indomethacin was also tested to determine if the cyclooxygenase (COX) pathway is a target for bladder cancer prevention in this model. Thirty-three female BK5.IGF-1 TG mice and 29 female nontransgenic littermates were randomized to the following treatments: (1) AIN-76A diet; (2) AIN-76A diet with 0.5% p-cresidine; or (3) AIN-76A diet with 0.5% p-cresidine + 0.00075% indomethacin. BK5.IGF-1 TG mice, with twofold greater total serum IGF-1 than nontransgenic mice, exhibited greatly increased susceptibility to p-cresidine-induced bladder tumors compared to nontransgenic mice. The most common type of bladder tumor in the BK5.IGF-1 TG mice was transitional cell carcinoma, which is the predominant type of bladder cancer observed in developed countries. Indomethacin inhibition of bladder tumor development in BK5.IGF-1 TG mice was not statistically significant. These results present further evidence for the role of IGF-1 in bladder cancer progression. In addition, these transgenic mice provide a useful model for studying the role of the IGF-1 pathway in bladder carcinogenesis and its prevention.
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http://dx.doi.org/10.1002/mc.20548DOI Listing
August 2009

C/EBPbeta regulates body composition, energy balance-related hormones and tumor growth.

Carcinogenesis 2009 May 4;30(5):832-40. Epub 2008 Dec 4.

Basic Research Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA.

The prevalence of obesity, an established epidemiologic risk factor for many chronic diseases including cancer, has been steadily increasing in the US over several decades. The mechanisms used to regulate energy balance and adiposity and the relationship of these factors to cancer are not completely understood. Here we have used knockout mice to examine the roles of the transcription factors CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta in regulating body composition and systemic levels of hormones such as insulin-like growth factor-1 (IGF-1), leptin and insulin that mediate energy balance. Dual-energy X-ray absorptiometry showed that C/EBPbeta, either directly or indirectly, modulated body weight, fat content and bone density in both males and females, while the effect of C/EBPdelta was minor and only affected adiposity and body weight in female animals. Levels of IGF-1, leptin and insulin in the serum were decreased in both male and female C/EBPbeta(-/-) mice, and C/EBPbeta was associated with their promoters in vivo. Moreover, colon adenocarcinoma cells displayed reduced tumorigenic potential when transplanted into C/EBPbeta-deficient animals, especially males. Thus, C/EBPbeta contributes to endocrine expression of IGF-1, leptin and insulin, which modulate energy balance and can contribute to cancer progression by creating a favorable environment for tumor cell proliferation and survival.
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http://dx.doi.org/10.1093/carcin/bgn273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675647PMC
May 2009

Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link.

Best Pract Res Clin Endocrinol Metab 2008 Aug;22(4):659-69

Department of Nutritional Sciences, University of Texas, Austin, TX, USA.

The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the US. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects on the carcinogenesis process and mechanistic targets of interventions that modulate energy balance, such as reduced-calorie diets and physical activity, have not been well characterized. The purpose of this review is to provide a strong foundation for the translation of mechanism-based research in this area by describing key animal and human studies of energy balance modulations involving diet or physical activity and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention is placed on signaling through the insulin and insulin-like growth factor-1 receptors, including components of the Akt and mammalian target of rapamycin (mTOR) signaling pathways downstream of these growth factor receptors. These pathways have emerged as potential targets for disrupting the obesity-cancer link. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.
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http://dx.doi.org/10.1016/j.beem.2008.08.009DOI Listing
August 2008

Exercise enhances vaccine-induced antigen-specific T cell responses.

Vaccine 2008 Oct 14;26(42):5407-15. Epub 2008 Aug 14.

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.

Regular moderate exercise has been proposed to enhance immune function, but its effects on immunity and their consequences have not been well studied. Mice without (AL) or with access (AL+EX) to voluntary running wheels were vaccinated with a model antigen (ovalbumin (OVA)) via intranasal or subcutaneous routes to target the mucosal and systemic immune compartments, respectively. EX enhanced OVA-specific CD4(+) T cell cytokine production and proliferation in all lymphoid organs examined without changes in cell distribution in any organ. These results suggest that coupling moderate exercise with vaccination may enhance vaccine efficacy for the prevention and/or therapy of numerous diseases.
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http://dx.doi.org/10.1016/j.vaccine.2008.07.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506022PMC
October 2008

Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo.

Carcinogenesis 2008 Oct 26;29(10):2001-10. Epub 2008 Jun 26.

Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, United States Department of Agriculture, 10300 Baltimore Avenue, Beltsville, MD 20705, USA.

Resveratrol is a phytochemical that has been under consideration for use as a prostate cancer chemopreventive agent. However, the efficacy, as well as the mechanisms of action of resveratrol on prostate cancer prevention, remains largely unknown. This study seeks to address these questions and examine the cancer preventive effects of resveratrol using complementary human LNCaP prostate cancer cell culture and xenograft models. In cultured LNCaP cells, we found that resveratrol inhibited cell growth. The growth inhibitory effects of resveratrol appeared to be through modulation of both androgen- and estrogen-mediated events. Global gene expression analysis using microarrays identified androgen-responsive genes as a group of genes universally affected by resveratrol in LNCaP cells in vitro. The effect of resveratrol on expression of these genes appeared to be through inhibition of both androgen- and estrogen-mediated transcription. In a xenograft model, resveratrol delayed LNCaP tumor growth and inhibited expression of a marker for steroid hormone responses. However, exposure to resveratrol also led to increased angiogenesis and inhibition of apoptosis in the xenograft. In summary, resveratrol may act through modulation of steroid hormone-dependent pathways to inhibit prostate cancer cell growth in both culture and xenografts, but exposure in vivo may be of concern.
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http://dx.doi.org/10.1093/carcin/bgn131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722852PMC
October 2008

Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones.

Nutr Cancer 2008 ;60(4):534-41

Laboratory of Biosystems and Cancer, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1758, USA.

Obesity increases incidence and mortality of breast cancer in postmenopausal women. Mechanisms underlying this association are poorly understood. Suitable animal models are needed to elucidate potential mechanisms for this association. To determine the effects of obesity on mammary tumor growth, nonovariectomized and ovariectomized C57BL/6 mice of various body weights (lean, overweight, and obese) were implanted subcutaneously with mammary tumor cells from syngeneic Wnt-1 transgenic mice. In mice, the lean phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status. Ovariectomy delayed Wnt-1 tumor growth consistent with the known hormone responsiveness of these tumors. However, obesity accelerated tumor growth in ovariectomized but not in nonovariectomized animals. Diet-induced obesity in a syngeneic mouse model of breast cancer enhanced tumor growth, specifically in the absence of ovarian hormones. These results support epidemiological evidence that obesity is associated with increased breast cancer incidence and mortality in postmenopausal but not premenopausal women. In contrast, maintaining a lean body weight phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status.
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http://dx.doi.org/10.1080/01635580801966195DOI Listing
November 2008

Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels.

Cancer Res 2008 May;68(10):3680-8

The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA.

Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-6271DOI Listing
May 2008

Physical activity and cancer prevention : pathways and targets for intervention.

Sports Med 2008 ;38(4):271-96

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

The prevalence of obesity, an established epidemiological risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Modulation of energy balance, via increased physical activity, has been shown in numerous comprehensive epidemiological reviews to reduce cancer risk. Unfortunately, the effects and mechanistic targets of physical activity interventions on the carcinogenesis process have not been thoroughly characterized. Studies to date suggest that exercise can exert its cancer-preventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. As discussed in this review, exercise may be altering tumour initiation events by modifying carcinogen activation, specifically by enhancing the cytochrome P450 system and by enhancing selective enzymes in the carcinogen detoxification pathway, including, but not limited to, glutathione-S-transferases. Furthermore, exercise may reduce oxidative damage by increasing a variety of anti-oxidant enzymes, enhancing DNA repair systems and improving intracellular protein repair systems. In addition to altering processes related to tumour initiation, exercise may also exert a cancer-preventive effect by dampening the processes involved in the promotion and progression stages of carcinogenesis, including scavenging reactive oxygen species (ROS); altering cell proliferation, apoptosis and differentiation; decreasing inflammation; enhancing immune function; and suppressing angiogenesis. A paucity of data exists as to whether exercise may be working as an anti-promotion strategy via altering ROS in initiated or preneoplastic models; therefore, no conclusions can be made about this possible mechanism. The studies directly examining cell proliferation and apoptosis have shown that exercise can enhance both processes, which is difficult to interpret in the context of carcinogenesis. Studies examining the relationship between exercise and chronic inflammation suggest that exercise may reduce pro-inflammatory mediators and reduce the state of low-grade, chronic inflammation. Additionally, exercise has been shown to enhance components of the innate immune response (i.e. macrophage and natural killer cell function). Finally, only a limited number of studies have explored the relationship between exercise and angiogenesis; therefore, no conclusions can be made currently about the role of exercise in the angiogenesis process as it relates to tumour progression. In summary, exercise can alter biological processes that contribute to both anti-initiation and anti-progression events in the carcinogenesis process. However, more sophisticated, detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the obesity-induced physiological changes that increase cancer risk.
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http://dx.doi.org/10.2165/00007256-200838040-00002DOI Listing
June 2008

Energy restriction and exercise differentially enhance components of systemic and mucosal immunity in mice.

J Nutr 2008 Jan;138(1):115-22

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

The prevalence of obesity, an established risk factor for several chronic diseases, including cancer, has risen dramatically over the past 4 decades. Dietary change and/or increased physical activity are the most commonly recommended lifestyle-based strategies for preventing or reversing obesity. One of several physiological systems that may be enhanced by dietary change and exercise is the immune system. In this study, we examined the effects of energy restriction (ER; 30% reduction relative to control energy intake) and/or exercise (EX; voluntary wheel running) on systemic and mucosal immune function. Female C57BL/6 mice were randomized into 4 treatment conditions: 1) controls consumed ad libitum (AL); 2) AL with access to running wheels (AL + EX); 3) 30% ER; and 4) 30% ER with access to running wheels (ER + EX). Both ER and EX reduced spleen weight and the number of splenic T and B lymphocytes (P < 0.05). ER enhanced natural killer (NK) cell function, but reduced concanavalin A (Con A)-induced T-cell proliferation (P < 0.05). In contrast, EX enhanced Con A-induced proliferation and cytokine production from Peyer's patch cells (P < 0.05). These data suggest that ER and EX enhance some, but not all, components of the immune system and are likely working via different biological mechanisms to regulate NK and T-cell function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431174PMC
http://dx.doi.org/10.1093/jn/138.1.115DOI Listing
January 2008

Research on persistent pain in late life: current topics and challenges.

J Women Aging 2007 ;19(3-4):5-19

Center for Gerontology, Virginial Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

Older women often experience pain in their daily lives. This article provides an overview of topics addressed in the geriatric pain research published between 1999 and 2004. New areas of emphasis of research have emerged such as the recognition of body mass and weight as a factor in persistent pain, while other areas have expanded, including the focus on pain among elders with cognitive impairments and the use of alternative treatment approaches. Understanding of pain in late life is hindered by study samples that lack diversity, treatment approaches that are narrowly focused, and a lack of attention to quality of life issues.
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http://dx.doi.org/10.1300/J074v19n03_02DOI Listing
December 2007

Extreme obesity reduces bone mineral density: complementary evidence from mice and women.

Obesity (Silver Spring) 2007 Aug;15(8):1980-7

Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

Objective: To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women.

Research Methods And Procedures: We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study.

Results: In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women.

Discussion: The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis.
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http://dx.doi.org/10.1038/oby.2007.236DOI Listing
August 2007

Energy balance and carcinogenesis: underlying pathways and targets for intervention.

Curr Cancer Drug Targets 2007 Aug;7(5):484-91

Division of Nutritional Sciences, University of Texas, Austin, TX 78712, USA.

The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the U.S. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects and mechanistic targets of interventions that modulate energy balance, such as reduced calorie diets and physical activity, on the carcinogenesis process have not been well characterized. The purpose of this review is to provide a strong foundation for future mechanistic-based research in this area by describing key animal and human studies of energy balance modulations involving diet, exercise, or pharmaceutical agents and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention in this review is placed on the components of the insulin/IGF-1/Akt pathway, which has emerged as a predominant target for disrupting the obesity-cancer link. Also discussed is the promise of global approaches, including genomics, proteomics, and metabolomics, for the elucidation of energy balance-responsive pathways. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.
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http://dx.doi.org/10.2174/156800907781386623DOI Listing
August 2007

Concentration-dependent effects of genistein on global gene expression in MCF-7 breast cancer cells: an oligo microarray study.

Breast Cancer Res Treat 2008 Jul 9;110(1):85-98. Epub 2007 Aug 9.

Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD, USA.

Breast cancer is the most commonly diagnosed cancer among US women; there is therefore great interest in developing preventive and treatment strategies for this disease. Because breast cancer incidence is much lower in countries where women consume high levels of soy, bioactive compounds in this food source have been studied for their effects on breast cancer. Genistein, found at high levels in soybeans and soy foods, is a controversial candidate breast cancer preventive phytochemical whose effects on breast cells are complex. To understand more clearly the molecular mechanisms underlying the effects of genistein on breast cancer cells, we used a DNA oligo microarray approach to examine the global gene expression patterns in MCF-7 breast cancer cells at both physiologic (1 or 5 microM) and pharmacologic (25 microM) genistein concentrations. Microarray analyses were performed on MCF-7 cells after 48 h of either vehicle or 1, 5, or 25 microM genistein treatment. We found that genistein altered the expression of genes belonging to a wide range of pathways, including estrogen- and p53-mediated pathways. At 1 and 5 microM, genistein elicited an expression pattern suggestive of increased mitogenic activity, confirming the proliferative response to genistein observed in cultured MCF-7 cells, while at 25 microM genistein effected a pattern that likely contributes to increased apoptosis, decreased proliferation and decreased total cell number, also consistent with cell culture results. These findings provide evidence for a molecular signature of genistein's effects in MCF-7 cells and lay the foundation for elucidating the mechanisms of genistein's biological impact in breast cancer cells.
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http://dx.doi.org/10.1007/s10549-007-9705-6DOI Listing
July 2008

Microarray analysis reveals that leptin induces autocrine/paracrine cascades to promote survival and proliferation of colon epithelial cells in an Apc genotype-dependent fashion.

Mol Carcinog 2008 Jan;47(1):9-21

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, USA.

The imbalance in systemic mediators of inflammation, such as leptin, is thought to be involved in obesity-associated cancers. In addition, systemic endocrine signals can influence the local autocrine/paracrine factors produced within this microenvironment to influence epithelial cell fate. We previously demonstrated that leptin preferentially promotes the survival and proliferation of colon epithelial cells possessing an Apc mutation (IMCE) but not model normal cells (YAMC). Therefore, the purpose of this study was to identify leptin-induced functional gene family changes which characterize the response of colon epithelial cells possessing an Apc mutation but not normal cells. Consistent with our knowledge of colon carcinogenesis, genes regulating the Wnt/beta-catenin-mediated pathway including Mdm2, Pik3r1, and Rb1 were upregulated by leptin. Importantly, leptin induced IGF-mediated pathway gene expression changes and their protein products in IMCE cells. In the IMCE cells IGFBP-6, IGF-1, and Crim1 expression was upregulated, while IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and Nov expression was downregulated by leptin treatment. These data establish a biologically plausible mechanistic link between the elevated levels of growth factors and the increased risk of colon cancer associated with obesity.
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http://dx.doi.org/10.1002/mc.20357DOI Listing
January 2008

Carbohydrate versus energy restriction: effects on weight loss, body composition and metabolism.

Ann Nutr Metab 2007 18;51(3):232-43. Epub 2007 Jun 18.

Division of Nutritional Sciences, Department of Human Ecology at the University of Texas at Austin, Austin, TX 78712, USA.

Background/aims: To compare weight loss, body composition, and metabolic changes in response to carbohydrate versus dietary energy restriction (DER) in obese mice.

Methods: One hundred C57BL/6 mice were randomized into five groups of 20. The group of high-carbohydrate (HC) mice consumed an HC diet ad libitum and the group of high-fat (HF) mice consumed an HF diet ad libitum for 14 weeks. Additional groups consumed the HF diet for 7 weeks ad libitum and during weeks 8-14 were switched to either a low-carbohydrate diet (LC) consumed ad libitum, the HC diet pair-fed (PF) to the energy intake of the LC group, or an HC DER regimen providing 70% of the energy intake of the HF group.

Results: At 14 weeks, the LC and HF groups weighed more and exhibited higher percent fat mass and lower bone mineral density than the HC, PF, and DER groups. Relative to the DER group, the LC group displayed comparable serum ketone bodies but higher serum glucose, triglycerides, cholesterol, leptin, insulin, and insulin-like growth factor-1.

Conclusions: In contrast to DER, the LC diet did not cause weight loss or reduce serum markers associated with obesity-related diseases other than diabetes in obese mice, suggesting that carbohydraterestriction without reduced energy intake does not induce weight loss.
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http://dx.doi.org/10.1159/000104143DOI Listing
October 2007

17beta-Estradiol differentially regulates androgen-responsive genes through estrogen receptor-beta- and extracellular-signal regulated kinase-dependent pathways in LNCaP human prostate cancer cells.

Mol Carcinog 2007 Feb;46(2):117-29

Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, U.S. Department of Agriculture, Beltsville, Maryland 20705, USA.

The molecular mechanism underlying the actions of estrogens in normal prostate physiology and prostate cancer development remains unclear. In the present study we tested the hypothesis that estrogens modulate androgen-dependent events in prostate cells by examining the effects of 17beta-estradiol (E2) on androgen-responsive genes (ARGs) in the androgenresponsive LNCaP cells. We found that LNCaP cells express estrogen receptor-beta (ER-beta) as the major form of ER and ER treatment with E2 led to an increase in cell growth. The proliferative effect of E2 correlated with induction of several ARGs by E2. Interestingly, some other ARGs did not respond to E2. Consistent with involvement of ER-beta, the induction of both cell growth and ARG mRNA levels by E2 was attenuated by the pure antiestrogen ICI 182,780. Moreover, we found ER-beta small interfering RNA attenuated induction of ARG mRNAs by E2. However, the effect of E2 on ARG mRNA appeared also to require the androgen receptor and to be mediated through activation of the extracellular-signal regulated kinase (ERK) pathway. These results provide mechanistic evidence supporting a direct effect of estrogen, mediated through ER-beta- and ERK-dependent pathways, on specific molecular targets in human prostate cancer cells.
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http://dx.doi.org/10.1002/mc.20254DOI Listing
February 2007

Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones.

Endocrinology 2006 Dec 7;147(12):5826-34. Epub 2006 Sep 7.

Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.
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http://dx.doi.org/10.1210/en.2006-0311DOI Listing
December 2006

Intestinal microbiota: a potential diet-responsive prevention target in ApcMin mice.

Mol Carcinog 2007 Jan;46(1):42-8

Department of Epidemiology and Preventive Medicine, The University of Maryland School of Medicine, Baltimore, Maryland 21201-1192, USA.

We previously reported that two dietary regimens, calorie restriction (CR) and a high olive oil-containing diet supplemented with a freeze-dried fruit and vegetable extract (OFV), reduced the development of intestinal adenomas in Apc(Min) mice by 57% and 33%, respectively, compared to control mice fed a defined diet ad libitum. The OFV diet was designed to have a strong effect on the composition of the intestinal microbiota through its high content of fiber, which represents a major source of fermentable substrate for the gut bacteria. We hypothesized that some of the observed effects of diet on intestinal carcinogenesis might be mediated by diet-related changes in the bacterial species that thrive in the gut. Therefore, we determined by fluorescent in situ hybridization (FISH) and denaturing gradient gel electrophoresis (DGGE) how the dietary interventions affected the composition of the intestinal microbiota, and we characterized specific microbiota changes that were associated with diet and reduced intestinal carcinogenesis. The OFV diet changed the overall composition of the intestinal microbiota, smaller changes were observed for the CR diet. Furthermore, we detected a 16S rDNA fragment associated with mice that did not develop polyps. Sequence analysis suggested that hitherto unidentified bacteria belonging to the family Lachnospiraceae (order Clostridiales) were its source. Thus, these bacteria may be an indicator of intestinal conditions associated with reduced intestinal carcinogenesis in Apc(Min) mice.
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http://dx.doi.org/10.1002/mc.20233DOI Listing
January 2007