bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B101: Menopausal hormone therapy and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition
Authors: Tsilidis Konstantinos K. ,   on behalf of the EPIC collaborators
Published: January 2011

Use of estrogen-only menopausal hormone therapy (HT) has been consistently associated with an increased risk of ovarian cancer, although uncertainty still exists about the association with other types of HT. We assessed the association of various types of HT use at baseline with risk of ovarian cancer among 126,920 post-menopausal women recruited into the European Prospective Investigation into Cancer and Nutrition (EPIC), after excluding women with prevalent cancer at recruitment and women with bilateral ovariectomy. After an average of 9 years follow-up, 424 ovarian cancers were diagnosed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models stratified by EPIC recruitment center and age at enrolment (≤50, 51-53, 54-56, 57-59, 60-62, 63-65, >65 years), and adjusted for body mass index (BMI; continuous), cigarette smoking (never, former, current), unilateral ovariectomy (yes, no), hysterectomy (yes, no), age at menarche (<12, 12, 13, 14, ≥15), number of full-term pregnancies (0, 1, 2, 3, ≥4), and duration of oral contraceptive use (never use, ever use: ≤1, 2-4, 5-9, ≥10 years). A total of 56,534 women (45%) had ever used HT and 37,630 (30%) were current users at recruitment. Among current users, 69% used estrogen plus progestin HT, 18% used estrogen-only HT, 3% used tibolone, 2% used other preparations and 8% had missing information on type of HT use. The risk of ovarian cancer increased with increasing duration of ever HT use (P-trend, 0.04), although only women with use of five or more years had a significantly increased risk relative to never users (HR, 1.45; 95% CI, 1.08 — 1.94). Compared to baseline never use, current use of any HT was positively associated with risk (HR, 1.29; 95% CI, 1.01 — 1.65). Current use of estrogen-only HT was associated with a higher risk of ovarian cancer (HR, 1.63; 95% CI, 1.08 — 2.47), but use of estrogen plus progestin HT was not significantly associated with risk (HR, 1.20; 95% CI, 0.89 — 1.62). Use of tibolone was associated with a two-fold greater risk of ovarian cancer (HR, 2.19; 95% CI, 1.06 — 4.50), but this association was based on only eight exposed cases. The association of HT use and ovarian cancer did not differ significantly according to specific hormonal constituents, regimens and routes of administration of HT, or by ovarian cancer histology, EPIC-participating country, and baseline characteristics (BMI, smoking, parity, and oral contraceptive use). When we repeated the analysis by imposing additional censorship on all participants at 4, 6, 8, and 10 years of follow-up, to evaluate the assumption that HT use reported at recruitment remained constant throughout the follow-up, the findings were very similar. Our results are compatible with an increased risk of ovarian cancer for HT use, especially for women using estrogen-only therapy.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B101.
Abstract B23: Comparison of epithelial proliferation and lobular involution in normal and benign breast tissues
Authors: Degnim Amy C. , Frost Marlene H. , Hartmann Lynn C. , Maloney Shaun D. , Hoskin Tanya L. , Benetti Lorelle L. , Vierkant Robert A. , Allers Teresa M. , Pankratz V. Shane , Radisky Derek C. , Visscher Daniel W.
Published: January 2011

Background: Epithelial proliferation in benign breast disease (BBD) is a well-established biomarker of breast cancer risk, and BBD tissues can be used as a platform to assess other biomarkers for breast cancer risk. Lobular involution (the degree of age-related atrophy in lobules) is a new biomarker, with greater degrees of involution associated with lower breast cancer risk. Successful application of tissue biomarkers of risk to breast tissues from normal women would be valuable for risk prediction in the general population. We hypothesized that normal breast tissue samples would differ from BBD tissues in these histologic features of breast cancer risk, with less epithelial proliferation but a similar degree of involution compared to BBD tissues.

Methods: Core biopsy samples from the Mayo Benign Breast Disease Cohort Study were compared to core biopsy samples of normal breast tissue obtained from the Susan G. Komen for the Cure Tissue Bank at IU Simon Cancer Center (KTB), a unique resource of breast tissue from donor women without any known breast abnormalities. All core biopsies were assessed histologically by a single breast pathologist for degree of epithelial proliferation (classified as non-proliferative, proliferative without atypia, or atypical hyperplasia) and extent of lobular involution (classified as none, 1-24%, 25-74%, or >75% of lobules). Data were analyzed using chi-square tests and logistic regression.

Results: Overall, 318 Mayo BBD and 303 normal (KTB) core breast biopsy samples were evaluated. As anticipated, significantly less epithelial proliferation was present in normal samples compared to BBD samples. Proliferative disease occurred in 9/303 (3%) of normals versus 79/318 (25%) of BBD, and atypical hyperplasia was seen in 2/303 (0.7%) of normal samples versus 24/318 (8%) of BBD core biopsies, p < 0.0001. This difference remained significant after adjusting for age (which was greater overall in the BBD samples). Complete involution was more frequent in normal compared to BBD tissues, although the difference did not reach statistical significance. The age-adjusted odds ratio of complete involution in normal versus BBD tissues was 1.46 (95% CI 0.98-2.17, p = 0.06), suggesting a possible delay or failure of involution in women with BBD.

Conclusions: Histologic features of normal breast tissues are different from those of BBD tissues, with less epithelial proliferation and more lobular involution, consistent with a lower risk of breast cancer expected for women with normal breast tissue compared to those with benign breast disease. Normal breast tissues are a valuable and distinct resource that should be considered for biomarker validation studies.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B23.
Abstract B27: DNA polymorphisms in sex hormone pathway genes and risk of esophageal squamous cell carcinoma
Authors: Hyland Paula L. , Hu Nan , Wheeler Bill , Yu Kai , Cook Michael B. , Dawsey Sanford M. , Abnet Christian C. , Goldstein Alisa M. , Freedman Neal D. , Taylor Philip R.
Published: January 2011

Background: Esophageal cancer (EC) is the sixth most common cancer in the world and exhibits a dramatic geographic distribution in incidence and histological subtype. In China, EC is the fourth leading cause of cancer death, the predominant histologic type being squamous cell carcinoma (ESCC), as opposed to adenocarcinoma which is more common in developed counties of the western world. Recently it has been suggested that sex hormones may be associated with the risk of aero-digestive tract cancers including those of the colon, head and neck, and stomach. To evaluate the potential role of sex hormones in ESCC, we examined sex hormone metabolizing gene variants and ESCC risk in a high risk population from north central China.

Methods: A combined total of 1027 ESCC cases and 1452 controls from separate studies were genotyped for 752 tagged SNPs in 46 sex hormone-related genes. SNP-, gene-, and pathway-based associations with ESCC risk were evaluated using the adaptive rank-truncated product (ARTP) method and the additive model within unconditional logistic regression adjusted for age and sex. Statistical significance was determined through use of a permutation-based sampling procedure (20,000 permutations).

Results: No significant pathway-based association was observed when all 46 sex hormone genes were considered together (P=0.16). Gene-based associations with ESCC were observed for 6 genes: SULT2B1 (ARTP P=0.012), CYP1B1 (P=0.019), CYP3A7 (P=0.03), CYP3A5 (P=0.033), SHBG (P=0.037), and CYP11A1 (P=0.038). Of examined individual SNPs, sixty three SNPs in 21 genes were also statistically significant (P<0.05). Among the strongest effects observed were rs4149455 in SULT2B1 (per allele OR 0.81, 95% CI 0.72-0.91, P=0.0007); rs9341266 in CYP1B1 (OR 1.45, 1.16-1.82, P=0.001); rs17161780 in CYP3A5 (OR 1.19, 1.04-1.35, P=0.009); rs2005548 in CYP3A7 (OR 1.15, 1.02-1.29, P=0.02), and rs727428 in SHBG (OR 0.85, 0.76-0.96, P=0.01).

Conclusion: Genetic variation in specific sex hormone-related genes may contribute to ESCC risk among Chinese individuals at high risk for ESCC.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B27.
Abstract B36: Circulating FGF-23 is associated with metachronous colorectal adenomas
Authors: Jacobs Elizabeth T. , Martinez Maria Elena , Buckmeier Julie A. , Lance Peter , May Melissa , Thompson Patricia A. , Jurutka Peter W.
Published: January 2011

Fibroblast growth factor-23 (FGF-23) is a phosphaturic peptide and a key component of an endocrine feedback loop with the hormonal vitamin D metabolite 1,25(OH)2D. It is both induced by and represses the synthesis of 1,25(OH)2D in a concerted effort to maintain both calcium and phosphate homeostasis. Vitamin D has been shown to be inversely related to colorectal neoplasia; therefore, we hypothesized that the effect of FGF-23 on 1,25(OH)2D concentrations could have implications for the risk of colorectal neoplasia. The purpose of this study was to prospectively evaluate the association between circulating concentrations of FGF-23 and odds of metachronous (recurrent) colorectal adenomas, the precursors to colorectal cancer. FGF-23 levels were assessed in 100 male and female participants from the Ursodeoxycholic Acid trial, 50 of whom had a metachronous colorectal adenoma and 50 who did not. Compared to the lowest tertile of FGF-23, the adjusted ORs (95% CIs) for the second and third tertiles were 2.80 (0.94-8.31) and 3.41 (1.09-10.67), respectively; a significant trend was shown for the relationship between FGF-23 concentration and odds for metachronous adenoma (p=0.03). In addition, there was a statistically significant inverse relationship between FGF-23 and 1,25(OH)2D, with those in the highest tertile of circulating 1,25(OH)2D having the lowest concentrations of FGF-23. Levels of FGF-23 were 81.4 + 36.6 RU/ml, 75.0 + 34.5 RU/ml, 55.7 + 15.8 RU/ml for low, medium, and high tertiles of 1,25(OH)2D, respectively (p-trend=0.001). In contrast, no statistically significant trend was observed between FGF-23 and 25(OH)D concentrations, with FGF-23 levels of 66.4 + 223.4 RU/ml, 69.1 + 38.6 RU/ml, and 76.1 + 40.7 RU/ml among participants who were vitamin D insufficient (<20 ng/ml); sub-optimal (>20 ng/ml and <30 n/ml), and sufficient (>30 ng/ml); p-trend=0.28. This work provides novel evidence of an association between FGF-23 and risk for colorectal neoplasia, and the results support an important role for FGF-23 as a potential risk biomarker of early colorectal carcinogenesis. The effects of FGF-23 may be mediated through biologic effects on individual 1,25(OH)2D levels. Further studies in larger populations are necessary for confirmation of these results.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B36.
Abstract B4: Impact of obesity on the effectiveness of aromatase inhibitors (AIs): Can breast cancer survivors on AIs lose weight compared to non-AI users?
Authors: Klemp Jennifer R. , Aversman Sonya , Befort Christie , Harvey Katherine , Khan Qamar J. , Sharma Priyanka , Kimler Bruce , Phillips Teresa , Fabian Carol J.
Published: January 2011

Background and Objectives: Weight at diagnosis and weight gain after diagnosis are associated with increased risk of breast cancer (BrCa) recurrence and mortality. In addition, post-menopausal obese breast cancer survivors on anti-hormonal therapy were 40% more likely to develop a local recurrence and 46% more likely to develop a distant recurrence compared to their normal weight counterparts. This evaluation was conducted to examine if a diet/exercise/behavioral weight loss intervention for overweight breast cancer survivors: 1) would impact BrCa risk biomarkers and 2) would the response differ by aromatase inhibitor (AI) status.

Methods: 84 BrCa survivors with a BMI 25-45 kg/m,2 ≥3 months from chemotherapy were recruited, and 52 agreed to participate. 6 (11%) participants did not complete the intervention. The 6-month intervention included: 225 minutes/week of aerobic exercise, resistance training, 1200-1500 calorie/day diet, and weekly group behavioral meetings. Pre and postintervention assessments included: anthropometrics (weight, BMI), body composition (DEXA % body fat), and serum biomarkers (estradiol, testosterone, SHBG, IGF-1/IGFBP3, insulin, leptin, adiponectin, glucose, CRP, cholesterol). Results are shown for 52 women (median age 52 ± 8 years) who initiated the program and 45 (87%) who completed the 6-month intervention.

Results: Women were approximately 4.25 years from diagnosis, their median weight at diagnosis was 84.1 kg (±15.8), and BMI was 31.3 kg/m2 (±5.6). Median pre-intervention weight was 91.8 kg (±13.4) and participants lost an average of 10.6 kg (±6.0)* or 13.3% (±28.8)* of their starting weight after the 6-month intervention. BMI decreased from 32.6 kg/m2 (±4.7) to 28.2 kg/m2 (±4.7)* and total percent body fat decreased by 5.6% (±4.5)*. Favorable changes in serum biomarkers of BrCa risk were observed for insulin*, leptin*, adiponectin*, and estradiol*. When comparing AI users to nonusers the significant favorable change in estradiol was not seen for those on AI's. There was a significant difference in decrease in % body fat* between AI users and nonusers. No other differences were significant. (*p-values <0.05)

Conclusions: Overall, results suggest a 6-month diet/exercise/behavioral weight loss intervention in overweight post-menopausal BrCa survivors results in a significant decrease in weight and change in serum biomarkers of BrCa risk in both current AI users and nonusers, however, due to the small sample size significant between group difference were not seen. Larger studies evaluating the effects of weight and weight loss based on exposure to antihormonal therapy are needed.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B4.
Abstract B53: Metformin treatment suppresses colorectal aberrant crypt foci in humans: Results from a short-term feasibility study
Authors: Hosono Kunihiro , Takahashi Hirokazu , Sakai Eiji , Uchiyama Takashi , Endo Hiroki , Nakajima Atsushi
Published: January 2011

Metformin is a biguanide derivative that has been widely used for diabetic treatment. Previously, we reported the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effects of metformin on rectal aberrant crypt foci (ACF), which are the endoscopic surrogate marker of colorectal cancer. We prospectively randomized 30 non-diabetic patients with ACF to treatment with metformin (250 mg/day; n = 15) or no treatment (control; n = 15); 27 patients were evaluable for endpoint analyses (12 metformin; 15 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory-endpoint analyses). In addition, the proliferative activity of the colonic epithelium was examined by determining the proliferating cell nuclear antigen labeling index, and the apoptotic activity by terminal deoxynucleotidyl transferase dUTP nick end labeling. At 1 month, significant decrease in the mean number of ACF per person was observed in the metformin group (8.54 ± 6.37 before treatment versus 5.32 ± 4.87 at 1 month; P = 0.009), whereas in the control group the mean number of ACF did not change significantly. The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. The present study demonstrated that metformin has the potential to suppress colonic epithelial proliferation and rectal ACF formation in humans, suggesting that its promise for the chemoprevention of colorectal cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B53.
Abstract B68: EGCG and theaflavin are direct inhibitors of the oncogenic lipid kinase, sphingosine kinase 1
Authors: Hengst Jeremy A. , Wang XuJun , Desai Dhimant , Amin Shantu , Yun Jong K.
Published: January 2011

Epigallocatechin-3-gallate (EGCG) and theaflavin are polyphenols from green and black tea, respectively, that have been shown to have anti-cancer/anti-inflammatory effects through their antioxidant properties. Recent studies indicate that these tea polyphenols may also target the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) signaling pathway. Therefore we examined whether these tea polyphenols can directly inhibit SphK1 catalytic activity. To accomplish this, we performed in vitro SphK activity assays to determine the kinetics properties of EGCG and theaflavin toward SphK1. These analyses indicate that EGCG, and its related tea polyphenols theaflavin, GCG and catechin all directly inhibit SphK1 catalytic activity. Further kinetic analysis indicates that EGCG is a non-competitive inhibitor of SphK1 (Ki = 450-500 nM). These data are the first demonstration of a direct inhibitory effect of tea polyphenols on SphK1 catalytic activity. Importantly, given the oncogenic role of SphK1, they suggest that SphK1 is a target of the anti-cancer/anti-inflammatory actions of the tea polyphenols such as EGCG and theaflavin. They further suggest that inhibiting SphK1 activity, using tea polyphenols, can be an effective chemopreventative strategy and that the structures of these polyphenols could serve as novel molecular scaffolds for the development of SphK inhibitors.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B68.
Abstract B81: Racial differences in serum adiponectin and leptin before and after weight loss
Authors: Azrad Maria , Gower Barbara A. , Hunter Gary R. , Nagy Tim R.
Published: January 2011

Background: In vitro and in vivo data have shown that adiponectin is antiangiogenic and that leptin increases angiogenesis. The divergent roles that these two adipocytokines play in cancer biology may be underlying mechanisms for racial disparities in cancer severity and mortality. The purpose of this study was to determine whether there were differences in serum concentrations of adiponectin and leptin before and after weight loss in healthy premenopausal African-American (AA) and European-American (EA) women.

Methods: Sixty-three African-American (AA) and 58 European-American (EA) premenopausal women were weight-reduced from body mass index (BMI) 27-30 kg/m2 to BMI≤24 kg/m2. Body composition measurements and fasting blood samples were collected before and after weight loss. Repeated-measures mixed models were used to assess the change in adiponectin and leptin from baseline to the weight-reduced state and whether there were racial differences after adjusting for covariates.

Results: Following weight loss leptin significantly decreased and adiponectin significantly increased similarly in both racial groups. Mix-model analyses indicated that adiponectin differed with race after adjusting for age, time, intra-abdominal fat, interleukin-6, limb fat and trunk fat (p=0.039). Adjusted least squared means (mean 95% confidence interval) showed that AA women had lower adiponectin relative to EA women at baseline [7.64 (6.8, 8.59) µg/ml vs 9.59 (8.61, 10.7) µg/ml, p=0.011] and in the weight-reduced state [9.84 (8.77, 11.0) µg/ml vs 11.5 (10.3, 12.8) µg/ml, p=0.075]. Mixed-model analyses indicated that leptin differed with race after adjusting for age, time, total fat mass, estradiol, testosterone and insulin (p<.0001). According to the adjusted least squared means, AA women had higher leptin relative to EA women at baseline [25.1 (22.8, 27.7) ng/dl vs 19.6 (18.0, 21.4) ng/dl, p=0.0003] and in the weight-reduced state [12.1 (10.6, 13.7) ng/dl vs 8.23 (7.32, 9.24), p<.0001].

Conclusions: Weight reduction may reduce the risk for cancer severity and mortality through increased serum adiponectin and reduced leptin in both AA and EA women. However, AA women may have worse outcomes as a result of cancer compared to EA women due to differences in the serum concentrations of these adipocyte derived factors that influence tumor angiogenesis.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B81.
Abstract B82: Metabolic risk factors and colorectal adenoma risk in Korean population
Authors: Kim Byung Chang , Shin Aesun , Hong Chang Won , Sohn Dae Kyung , Han Kyung Su , Chang Hee Jin , Kim Jeongseon , Oh Jae Hwan
Published: January 2011

Recent epidemiologic studies reported that diabetes mellitus and metabolic syndrome increase the risk of colorectal neoplasms. Although the exact mechanism is not clearly explained, it might be mediated by several process including insulin resistance, dysregulation of insulin-like growth factor axis, oxidative stress, DNA damage, and adipokine production. The objective of the current study was to assess the associations between metabolic risk factors and the risk for developing colorectal adenomatous polyp according to detailed clinical information on polyps in a large colonoscopy-based study. The study participants visited the National Cancer Center, Korea for cancer screening between April 2007 and April 2009. A total of 1,771 newly diagnosed colorectal adenoma patients and 4,967 polyp-free controls were included in the analysis. Metabolic syndrome was defined based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria with a modified waist circumference for Asian population.

In men, high body mass index, waist circumference, blood pressure, and triglyceride were associated with an increased risk for colorectal adenoma. Possessing three and more metabolic risk factors was associated with an increased risk for adenoma (OR = 1.49, 95% CI = 1.23-1.81). The association between metabolic syndrome and colorectal adenoma was observed for the risk for right colon adenoma (OR = 1.64, 95% CI 1.27-2.10) or adenomas in multiple anatomical locations (OR = 1.55, 95% CI = 1.12-2.15). In women, high waist circumference and triglyceride were associated with an increased risk for adenoma, and metabolic syndrome was associated with a high risk for adenoma (OR = 1.45, 95% CI 1.09-1.94), especially that for adenoma of left colon (OR = 1.62, 95% CI = 1.02-2.59). In conclusion, metabolic risk factors and metabolic syndrome were risk factors for colorectal adenoma, and the increased risks were more prominent for right colon adenoma in men and left colon adenoma in women.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B82.
Abstract CN05-04: Early molecular changes in prostate carcinogenesis
Authors: Nelson William G. , Haffner Michael C. , Aryee Martin J. , Esopi David M. , Isaacs William B. , Bova G. Steven , Meeker Alan K. , Netto George , Marzo Angelo M. De , Yegnasubramanian Srinivasan
Published: January 2011

After castration was shown by Charles Huggins in 1941 to be an effective treatment for advanced prostate cancer, androgenic hormones were assumed to be responsible in some way for disease development.

Nonetheless, the manner in which androgens might contribute to prostatic carcinogenesis has remained elusive over the subsequent seven decades. Androgen levels decline steadily throughout adulthood in men, just as prostate cancers begin to appear (Rohrmann S et al. J Clin Endocrinol Metabol 92:2519-25, 2007). In addition, the action of testosterone, and its metabolite dihydrotestosterone, on prostate epithelial cells in adult men tends to be the promotion of terminal differentiation by activating transcription of target genes, such as PSA and TMPRSS2, which form the secretion elaborated by the prostate for the ejaculate. By driving terminal differentiation of normal prostate cells, androgens seem unlikely to cause neoplastic transformation. However, new insights into the generation of somatic genome rearrangements that create fusion oncogenes in prostate cells have revealed a new mechanism of androgen receptor-associated cancer pathogenesis. The fusion oncogene TMPRSS2-ERG, present in at least half of all prostate cancer cases, may be the most common somatic gene fusion event in all of human cancer (Tomlins SA et al. Science 310:644-8, 2005). We have found that androgen receptor-triggered transcription in prostate cells leads to the recruitment of topoisomerase II-beta (TOP2B) by the receptor to sites of TMPRSS2-ERG genomic breakpoints, promoting TOP2B-mediated DNA double strand breaks and de novo TMPRSS2-ERG fusion transcripts. The results implicate androgens in the creation of TMPRSS2-ERG rearrangements, via a mechanism involving the androgen receptor and TOP2B, and provide new hints as to how prostate cancers might be better prevented.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN05-04.
Abstract CN08-02: Implications of the cancer stem cell hypothesis for breast cancer prevention
Authors: Kakarala Madhuri , Sun Duxin , Wicha Max S.
Published: January 2011

The cancer stem cell hypothesis proposes that cancers arise in cell populations that either dysregulate or acquire the stem cell property of self-renewal. Resulting cancers are hierarchically organized and driven by a subpopulation that retains stem cell properties. This suggests that dysregulation of self-renewal plays an important role in early stages of carcinogenesis and that an understanding of the pathways which regulate self-renewal may lead to new strategies for cancer prevention. Our laboratory has identified markers including CD44+/CD24- and Aldehyde dehydrogenase which have proven useful in identifying populations of normal and transformed breast epithelial cells. Furthermore, we have developed in vitro and animal models to elucidate pathways which regulate self-renewal in these cells. These studies, and others, suggest that stem cell self-renewal is regulated by an interaction of intrinsic and extrinsic pathways. Intrinsic regulation occurs through interacting developmental pathways including Notch, hedgehog, Wnt and Akt. Cytokine networks in the stem cell niche including IL-8 and IL6 also play important roles in stem cell regulation. These pathways may also contribute to the well-known links between inflammation and cancer. Inflammatory cytokines may contribute to clonal expansion of stem cell populations which can then acquire secondary genetic changes resulting in expression of the fully malignant phenotype. We have demonstrated that dietary components including curcumin and sulforaphane which have been shown to have chemopreventive properties are able to target Wnt signaling in stem cell populations. These and other studies support the approach of targeting stem cell self-renewal pathways for cancer prevention.

References:

1. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol 28:4006-12, 2010.

2. Kakarala M, Brenner DE, Korkaya H, et al: Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat, 2009.

3. Li Y, Zhang T, Korkaya H, et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16:2580-90, 2010.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN08-02.
Abstract ED01-02: Untargeted plasma metabolite profiling: Strategies and approaches for comprehensive characterization of gene mutations and drug actions
Authors: Gross Steven S. , Chen Qiuying
Published: January 2011

The small molecule metabolome (< 1000 Da) defines a cell's phenotype on a moment-to-moment basis. Notably, the composition of the metabolome remains a biomedical frontier, since it is not predicted by other “omic” information (neither the genome, transcriptome nor proteome) and is only partially defined at present. Accordingly, tools for defining molecular structures, NMR and mass spectrometry (MS), have provided the essential platforms for current metabolomic studies. This presentation will describe the use of MS-based workflows for broad untargeted metabolite profiling. A proof-of-principal study will be described, showing that thousands of plasma metabolites can be effectively surveyed in a mouse model and metabolic consequences of a gene deletion or drug treatment can be specified. Additionally, the potential of untargeted metabolite profiling to screen neonatal plasma for rare inborn errors of metabolism will be considered and preliminary findings will be described.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED01-02.
Abstract ED01-03: Metabolomics of disease progression
Authors: Beecher Christopher , Rajendiran Thekkelnaycke , Chinnaiyan Arul
Published: January 2011

While the total potential of a biological systems response is defined by their genes, and the organism's desired response (to its current status) may be embodied in their transcripts, the metabolome embodies what an organism is actually of doing at a biochemical level. For this reason the metabolomic data may be quite diagnostic of a given disease state, that may or may not be dictated by either the genetic or transcriptomic levels. In this presentation we will discuss an application of metabolomics to define a series of biomarkers. The subsequent explorations of the details of this biomarker have revealed mechanisms that are likely to be significant to the progression of cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED01-03.
Abstract ED06-02: Understanding the structure and function of the gut microbiota
Authors: Young Vincent B.
Published: January 2011

Until recently, the study of complex microbial communities was limited by the culture-based methodologies that only captured a subset of the diversity present. The advent of molecular methods for the study of microbial consortia has allowed us to greatly increase our understanding of the structure, function and dynamics of the indigenous human microbiota. In this opening lecture of the session I will introduce the techniques and strategies for studying the structure and function of complex consortia of microbes, with a focus on the community that inhabits the gastrointestinal tract. Using the example of Clostridium difficile infection following antibiotic administration as an example, I will demonstrate how changes in the community structure of the gut microbiota can be monitored over time. The associated functional changes associated with changes in microbial community structure will be discussed. We have recently applied culture-independent molecular methods, largely based on retrieval of 16S rRNA-encoding gene sequences, to investigate the role of the indigenous microbiota in C. difficile infection (CDI). Through studies of human patients with CDI we have demonstrated that recurrent disease is associated with an overall decrease in the diversity of the fecal microbiota. We have leveraged a recently described murine model of CDI to conduct more detailed studies of the role of the microbiota in C. difficile infection. Data from this model system indicates that a subset of the indigenous microbiota is important in mediating colonization resistance against C. difficile and possibly in modulating the effects of C. difficile toxin. This example will allow the audience to understand and appreciate the growing number of studies that are examining associations between the community structure of the gut microbiota and a variety of disease states including colorectal cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED06-02.
Abstract PL05-03: Global trends in cancer: The imperative for prevention
Authors: Thun Michael J. , Jemal Ahmedin , Carter Brian D. , Ward Elizabeth M.
Published: January 2011

Despite the encouraging decrease in the incidence and death rates from all cancers combined in the United States, and the decrease in death rates from selected cancers in many industrialized countries, the number of people affected by cancer continues to increase rapidly worldwide. More than 12 million new cases and 7.5 million cancer deaths are estimated to have occurred globally in 2008. The number of deaths from cancer has increased by 25% since 1990 and is projected to nearly double (to 13.1 million) by 2030. Moreover, the global increase in the disease burden from cancer disproportionately affects low- and medium-resource countries, which currently account for nearly two-thirds of all cancer deaths, and are projected to contribute over 70% by 2030.

Underlying this global increase in the cancer burden and its disproportionate impact on economically developing countries is a combination of both demographic changes and the shifting distribution of major risk factors. Three particularly important factors are the growth and aging of populations (especially longer life expectancy for massive numbers of young adults in developing countries), the entrenchment of modifiable risk factors (particularly cigarette smoking, Western diet, and physical inactivity), and the slower decline in cancers related to infectious etiologies in low-resource countries than in high-resource countries.

Given these trends, the success of future efforts in global cancer control will require considerably greater emphasis on the development and implementation of effective population-level approaches to cancer prevention and early detection than exist currently in most countries. This talk will describe several successful models of tobacco control and interventions against chronic infections caused by hepatitis B and human papillomavirus that have been developed and implemented in high-risk developing countries. Other talks in the session will describe promising examples of population-level prevention in the U.S., Australia, and Canada.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL05-03.
Abstract PR-07: A new resource to accelerate research into the cause and prevention of breast cancer: The Love/Avon Army of Women
Authors: Love Susan M.
Published: January 2011

Background: It is well-established that there is a need for more research into the cause and prevention of breast cancer. While many studies are done in cell lines and laboratory animals, translation of findings to women often falters due to perceived difficulty in recruiting women for research. The Dr. Susan Love Research Foundation received a grant from the Avon Foundation to form the Love/Avon Army of Women (AOW): an online recruitment resource designed to partner women with the research community in an effort to accelerate breast cancer research.

Methods: The AOW was launched in 2008 with the goal of recruiting 1 million women interested in participating in breast cancer research. Researchers interested in having the AOW recruit for their studies submit a proposal to be reviewed by the AOW Scientific Advisory Committee, comprised of nominees from AACR and NBCC. If a study is accepted, a mass e-mail describing the study procedures and inclusion/exclusion criteria is sent to the entire AOW database. Women sign up at www.armyofwomen.org to join the AOW. Women aren't committing to participating in a particular study, but agree to receive AOW e-mails about breast cancer research studies. If the individual is interested and qualifies for a study, she undergoes a secondary online screening and then her contact information is passed on to the principal investigator.

Results: Over 336,500 women have signed up, including survivors and healthy women, ranging from age 18 to 100, representing all 50 U.S. states and 49 countries. To date, the AOW has recruited for 34 studies, both regional and national, that vary from biomarker and circadian rhythm research to psychosocial and quality-of-life studies. With over 44,000 AOW members having participated in the research process, this method of recruitment has been found to be effective and efficient. The diversity of the AOW members has proved beneficial for many studies such as those needing to enroll African American women, women of varying sexual orientations, or young survivors.

Many studies were closed to enrollment within the first 48 hours after accruing all subjects while others were very quickly overenrolled by 5% to 10%. This overwhelming response has led many researchers to seek additional funding to increase their statistical significance and accommodate all eligible subjects.

Conclusions: The Love/Avon Army of Women is a novel resource for scientists to accelerate accrual, expand the number and diversity of their subject population and to obtain exactly the type of specimens they need when they need it. This new partnership between women and scientists can revolutionize research and accelerate efforts to eradicate breast cancer.

This talk is also presented as Poster A62.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-07.
The Burden of Chronic Kidney Disease on Developing Nations: A 21st Century Challenge in Global Health
Authors: Nugent Rachel A. , Fathima Sana F. , Feigl Andrea B. , Chyung Dorothy
Published: January 2011

Chronic diseases present a significant challenge to 21st century global health policy. In developing nations, the growing prevalence of chronic diseases such as chronic kidney disease has severe implications on health and economic output. The rapid rise of common risk factors such as diabetes, hypertension, and obesity, especially among the poor, will result in even greater and more profound burdens that developing nations are not equipped to handle. Attention to chronic diseases, chronic kidney disease in particular, has been lacking, largely due to the global health community’s focus on infectious diseases and lack of awareness. There is a critical need for funding in and to developing countries to implement more comprehensive, cost-effective, and preventative interventions against chronic diseases. This paper examines the epidemiology of chronic diseases, the growing prevalence of chronic kidney disease and its implications for global public health, and the associated health and economic burdens. Finally, a summary review of cost-effective interventions and funding needs is provided.
Lipid Disorders and Their Relevance to Outcomes in Chronic Kidney Disease
Authors: Vaziri Nosratola D. , Norris Keith
Published: January 2011

Cardiovascular disease is the major cause of death in patients with chronic kidney disease (CKD). Cardiovascular disease and many other complications of CKD are mediated by oxidative stress, inflammation, and dyslipidemia. This review provides a concise overview of the nature and mechanisms of CKD-induced lipid disorders and their adverse consequences. Lipid abnormalities in end-stage renal disease are characterized by: (a) reduced serum apoA-1 and high-density lipoprotein (HDL) concentrations, impaired HDL maturation and defective HDL antioxidant, anti-inflammatory and reverse cholesterol transport properties; (b) impaired clearance of very low-density lipoprotein and chylomicrons by the muscle and adipose tissue and of their remnants by the liver leading to hypertriglyceridemia, accumulation of intermediate-density lipoprotein and chylomicron remnants, and (c) oxidative modification of LDL and lipoprotein remnants favored by their structural abnormalities, oxidative stress, and impaired HDL antioxidant activity. Together these abnormalities result in: (a) uptake of oxidized LDL and remnant particles by macrophages and resident cells in the artery wall which along with impaired HDL-mediated reverse cholesterol transport causes foam cell formation and atherosclerosis, (b) production of inflammatory mediators and reactive oxygen species by leukocytes and macrophages in response to stimulation by oxidized LDL and phospholipids leading to intensification of oxidative stress and inflammation, (c) dissemination of oxidative stress by circulating oxidized lipids and lipoproteins via lipid peroxidation chain reaction, (d) heightened injurious effects of oxidative stress and inflammation due to diminished antioxidant, anti-inflammatory and antithrombotic activities of HDL, and finally (e) impaired ability of very low-density lipoprotein and chylomicron to deliver lipid fuel to muscle and adipose tissue contributing to muscle weakness and cachexia which commonly occur in end-stage renal disease patients.
The Path to Wearable Ultrafiltration and Dialysis Devices
Authors: Leonard Edward F. , Cortell Stanley , Jones James
Published: January 2011

Wearable blood processing devices offer an attractive solution to problems inherent in clinic-based, intermittent end-stage renal disease therapies. What is involved in transitioning even a part of the current clinic-based population to ambulatory therapy has not been clearly enumerated. This paper addresses what a first-generation wearable device might accomplish, how issues of safety will need to be addressed, and what will make the device attractive to, and manageable by, the patient. Medical, technological, and economic issues are identified.
Micronutrients and Cardiorenal Disease: Insights into Novel Assessments and Treatment
Authors: McCullough Peter A.
Published: January 2011

Chronic kidney disease (CKD) is a recognized risk multiplier for development of cardiovascular disease (CVD), with CVD events representing the leading cause of morbidity and mortality in patients with CKD. The nature of CKD as a risk state relates both to the nature of CKD and the antecedent development of CVD. In addition, patients with CKD have increased rates of multiple conventional cardiac risk factors. The essence of the relationship appears to be bidirectional, and therapy directed at improving natural history of chronic disease on one system generally improves prognosis in the other. Hence the term ‘cardiorenal syndrome’ (CRS) is used to describe the complex interrelationships between the two organ systems. While focus on therapeutic targets has been dominated by interest in neurohormonal mechanisms, little attention has been given to micronutrients and their potential effects in CRS. As renal function declines, cellular metabolism changes profoundly, and when artificial means of solute removal are initiated by peritoneal dialysis or hemodialysis, there are considerable shifts of many micronutrients that may affect cardiovascular health predominantly through the mechanism of increasing labile iron-dependent oxidative stress. Release of labile iron at the tissue level appears to be most important in acute CRS, whereas phosphate and sodium retention play more of a role in chronic CRS. Attention will be given to selected micronutrients which may call for novel assessments and intervention for optimal cardiorenal outcomes.
Design and Rationale of Health-Related Quality of Life and Patient-Reported Outcomes Assessment in the Frequent Hemodialysis Network Trials
Authors: Jhamb Manisha , Tamura Manjula K. , Gassman Jennifer , Garg Amit X. , Lindsay Robert M. , Suri Rita S. , Ting George , Finkelstein Fredric O. , Beach Scott , Kimmel Paul L. , Unruh Mark ,   for the Frequent Hemodialysis Network Trial Group
Published: January 2011

Background: End-stage renal disease patients experience significant impairments in health-related quality of life (HRQOL). Testing various strategies to improve patient HRQOL in multicenter clinical trials, such as the Frequent Hemodialysis Network (FHN) trials is vitally important. Aims: Theaim of this paper is to describe the design and conduct of HRQOL and patient-reported outcomes (PRO) assessment in the FHN trials. Methods: In the FHN trials, HRQOL was examined as a multidimensional concept, and the SF-36 RAND Physical Health Composite score was one of the co-primary outcomes. The instruments completed to assess HRQOL included the Medical Outcomes Study Short Form SF-36, Health Utilities Index 3, Sleep Problems Index, Beck Depression Inventory and feeling thermometer. These instruments have been shown to have high reliability, validity and responsiveness to change in the end-stage renal disease population. Additional items evaluating PRO including sexual function, time to recovery after dialysis and patients’ self-perceived burden to caregiver were also assessed. All questionnaires were administered by trained interviewers using computer-assisted telephone interviewing to ensure blinding and minimizing selection bias. Interim analysis reveals that these instruments can be used to collect a comprehensive set of HRQOL measures with minimal patient burden. Conclusions: Accurate measurement of HRQOL and PRO can help us test whether hemodialysis interventions improve the health and well-being of this compromised patient population. We have shown that a comprehensive set of HRQOL measures can be centrally collected through telephone interviews in a blinded fashion, in a way that is well tolerated with minimum respondent burden.
Current State of Combined Kidney and Pancreas Transplantation
Authors: Richter Anja , Lerner Susan , Schröppel Bernd
Published: January 2011

Glycemic control via the use of exogenous insulin injections in diabetic patients is incomplete, resulting in multiple long-term complications, such as retinopathy, neuropathy, vasculopathy, and nephropathy. The goal of whole-pancreas and kidney transplantation is to achieve long-term insulin independence and correct uremia. The proposed benefits of pancreas and kidney transplantation are improved quality of life, prevention of recurrent diabetic nephropathy, freedom from exogenous insulin, stabilization or improvement in secondary complications, and improved mortality. No other regimen of insulin delivery or renal replacement besides pancreas and kidney transplantation can achieve this level of physiologic regulation.
Prevention of Corneal Neovascularization: Comparison of Different Doses of Subconjunctival Bevacizumab with Its Topical Form in Experimental Rats
Authors: Hashemian Mohammad Naser , Z-Mehrjardi Hadi , Moghimi Sasan , Tahvildari Maryam , Mojazi-Amiri Hoda
Published: January 2011

Background: To compare the effect of different dosages of subconjunctival bevacizumab with its topical administration on preventing the development of corneal neovascularization (CNV) in a rat model of corneal chemical injury. Methods: Neovascularization was induced by pressing a 2-mm diameter alkaline-coated applicator on the central cornea of the right eye of 50 anesthetized male rats. Immediately after cauterization, rats were divided randomly into 5 groups. Groups 1–4 received a subconjunctival injection of 0.02 ml of normal saline (control) or 1, 5 and 25 mg/ml of bevacizumab, respectively. In the fifth group, topical bevacizumab was instilled daily for 7 consecutive days. After 7 days, digital photographs of the cornea were taken and the area of the neovascularized cornea was calculated. Results: Analysis of digital photographs showed that, compared with the controls, a single subconjunctival injection of at least 0.1 mg of bevacizumab (5 mg/ml) – immediately after corneal cauterization – effectively decreased CNV after 7 days. Injection of 25 mg/ml of bevacizumab in the fourth group increased the avascular area more than twofold, compared with the saline-treated group (32.2% compared with 15%, p < 0.001). This difference between groups 4 and 2 was statistically significant (p = 0.04). Although topical delivery of 25 mg/ml bevacizumab was effective to inhibit CNV (p = 0.004), the results were similar to those of the third group. Qualitative microscopic evaluation of the cornea was compatible with the gross findings, as bevacizumab-treated groups had less intense corneal vessel channels and inflammation. Conclusion: Both subconjunctival and topical bevacizumab can prevent CNV in rats.