bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract CN13-02: Breast tissue composition and risk of breast cancer
Authors: Boyd Norman , Martin Lisa , Menichouk Olga , Gunasekara Anoma , Selah Ahesha , Yaffe Martin , Chavez Sonia , Bronskill Michael
Published: May 2012

CN13-02

Background

Susceptibility to breast carcinogens is greatest before the age of 20 years. We have used magnetic resonance (MR) to measure the water content of the breast in young women, and have identified factors associated with variations in breast water. Breast water, like mammographic density, reflects fibro-glandular breast tissue, which is strongly associated with breast cancer risk in middle aged and older women.

Methods

We recruited 400 young women aged 15-30 years and their mothers, measured breast water and fat in daughters using (MR), and obtained anthropometric and other data. Mothers provided mammograms (n=365) and a random sample (n=100) also had breast MR.

Results

Percent water by MR in daughters (median=44.8%) was greater than in mothers (median=27.8%) (P<0.0001), and was greater in daughters aged 15-19 years (n=199; median=49%) than in those aged 20-30 years (n=201; median=41%). Percent water in daughters was correlated with both breast water (n=100 pairs; r=0.28; p=0.005), and percent mammographic density in mothers (n=356 pairs; r=0.25, p<0.0001). Percent water in daughters was independently associated with their age (p=0.04) and weight (p<0.0001) (both inversely), and with their height (p<0.0001) and percent density in their mothers’ mammogram (p<0.0001) (both positively).

Conclusions

Percent breast water was greatest at ages when susceptibility to breast carcinogens is also greatest. The distribution of breast water according to age was consistent with a model in which mammographic density in mid-life is in part the result of genetic influences and growth and development in early life that determine initial breast tissue composition.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN13-02.
Abstract CN15-02: Gut microbiota and colorectal adenoma
Authors: Keku Temitope
Published: May 2012

CN15-02

The human body is home to about 10 -100 trillion commensal bacterial organisms, of which about 70% reside in the gut. Growing evidence from animal and human studies suggest that these bacteria may contribute to the etiology of diseases such as colorectal cancer, a leading cause of cancer mortality in the United States. Although epidemiologic studies have implicated genetic factors and diet in the etiology of colorectal cancer, the findings from dietary studies have been inconsistent. It is reasonable that the inconsistencies in these dietary studies are related to the influence of the gut microbiota, a mostly understudied component. We hypothesize that the gut microbiota may contribute to the pathogenesis of colorectal cancer through interactions with diet, changes in community composition, production of toxic substances that lead to DNA damage and inflammation. Recent advances in molecular techniques make it possible to describe the gut bacterial communities and evaluate associations with diseases such as colorectal cancer. The presentation will review evidence for the role of gut bacteria in colorectal cancer, discuss potential mechanisms for the link between the gut bacteria and colorectal cancer and identify areas for future investigations.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN15-02.
Abstract CN15-03: Targeting APC-deficient cells for apoptosis: a therapeutic approach for colorectal cancer prevention
Authors: Wu Xiangwei
Published: May 2012

CN15-03

Cancer prevention is generally perceived as long-term process and inevitably associated with adverse effects. Here we report the development of a procedure that specifically targets premalignant tumor cells for apoptosis, potentially making cancer prevention work like therapy. This procedure is based on our finding that deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of β-catenin leads to repression of cFLIP expression through activation of c-Myc. Independently, retinoid (RA) upregulates tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Combination of TRAIL and RA results in specific killing of APC-deficient cells without harming normal cells. We further show that co-treatment with TRAIL and RA in APC+/Min mice induces apoptosis specifically in intestinal polyps and strongly inhibits tumor growth. Since mutations in the APC tumor suppressor gene are frequently associated with early stages of colorectal cancer (CRC), these results provide a therapeutic approach for chemoprevention of CRC by targeting APC-deficient cells for apoptosis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN15-03.
Abstract ED01-01: Use of natural products as the scaffolds for the design of molecularly targeted agents for cancer treatment and prevention
Authors: Wang Shaomeng
Published: May 2012

ED01-01

Natural products have played a major role in the development of anticancer therapies for both treatment and prevention of human cancers. Approximately 70% of the current anticancer drugs are natural products per se or semi-synthetic analogues of natural products. In addition, natural products can be also used as the inspiration for the design of molecularly targeted anticancer drugs. In this presentation, we describe the use of natural products to design a scaffold for a new class of small-molecule inhibitors to target the MDM2-p53 protein-protein interaction and to activate p53 for both cancer treatment and potentially prevention. We have designed the spiro-oxindole scaffold, which is embedded in a number of diverse natural products to mimic one key binding element in p53 using a computational structure-based design approach. Using the spiro-oxindole scaffold as the starting point, we have obtained a class of highly potent and specific small-molecule inhibitors of the MDM2-p53 interactions. Our lead compound (MI-219) binds to MDM2 with an affinity >1000-times more potent than the natural p53 peptide and demonstrates greater than 100,000-fold selectivity to MDMX, a close homologous protein of MDM2. MI-219 effectively induces p53 activation in both cancer and normal cells with wild-type p53. Activation of p53 leads to cell cycle arrest and apoptosis in cancer cells but only cycle arrest in normal cells. MI-219 achieves an excellent oral bioavailability. MI-219 activates p53 in both normal and tumor tissues. While MI-219 achieves strong antitumor activity in xenograft models of human cancer, it does not cause damage to normal tissues. Our data suggest that MI-219 should be investigated as a novel treatment and prevention agent in the clinic.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED01-01.
Abstract ED01-02: Sphingolipid biodiversity and cancer: an endless source of surprises in cell regulation and novel strategies for cancer chemoprevention and chemotherapy
Authors: Merrill Alfred
Published: May 2012

ED01-02

Sphingolipids are found in essentially all eukaryotes and some prokaryotes and viruses where they influence cell structure, signaling, and interactions with the extracellular environment. The structural diversity of sphingolipids is mind-bogglingly complex due to the combinatorial possibilities for subspecies variation in the lipid backbones (sphingoid base and N-acyl-derivatives, i.e., “ceramides”) and headgroups.

Early comparisons of the glycosphingolipids of normal and transformed cells found differences that prompted speculation that “the structural remodeling of glycolipids and glycoproteins are undoubtedly a key to open a secret box of malignancy” (Hakomori and Murakami,1968). This hypothesis can be reexamined using conventional and “bio-imaging” mass spectrometry, which can be combined with gene expression data for tumors and cancer cell lines to explore the molecular basis for this diversity, and possibly to identify new biomarkers.

The lipid backbones of sphingolipids are additionally interesting because they serve as intracellular and extracellular signals for a wide spectrum of pathways that are important in cancer. This has provided new leads for pharmacologic intervention as well as better understanding of how some chemotherapeutic drugs, and some componsnts of the diet, affect cancer. However, because sphingolipids affect a large number of signaling pathways, it is difficult to interpret and optimize their effects using the typical paradigm of drug discovery (i.e., as agents that are active against a single molecular target). Nonetheless, as an understanding of this complexity has evolved, it has become likely that sphingolipids suppress cancer by modulation of multiple interrelated signaling pathways--in essence, behave like a multi-drug combination. It will probably be necessary to employ the tools of “omics” and systems biology to understand, and capitalize on, the exceptional promise of sphingolipids for cancer detection, chemotherapy and prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED01-02.
Abstract ED03-03: CXC chemokines in cancer
Authors: Strieter Robert
Published: May 2012

ED03-03

The biology of CXC chemokines in cancer has expanded beyond their role in mediating migration of specific subsets of leukocytes. CXC Chemokines have been found to display pleiotropic effects for enhancing immunity to tumor associated antigens, regulating angiogenesis, promoting proliferation/anti-apoptosis of tumor cells; and mediating tumor cell invasion and trafficking in an organ-specific manner that leads to metastases. In this presentation, we will discuss the importance of CXC chemokines in regulating angiogenesis and promoting metastases; and demonstrate why they can be seen as important therapeutic targets for intervention in a variety of cancers.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED03-03.
Abstract ED04-02: The role of genes in protecting against age-related disease in cancer
Authors: Barzilai Nir
Published: May 2012

ED04-02

Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. We have comprehensively characterized over 450 Ashkenazi Jewish families with exceptional longevity (survival in good health to at least age 95) and have identified several biological markers that may be causative in their longevity. These subjects and their offspring have 2-3 fold increases in rates of polymorphism in 3 genes all validated by other in other studies. Two genes are regulating lipoprotein--cholesterol ester transfer protein (CETP) and apolipoprotein C-3 (APOC-3)--and decrease in plasma levels CETP and APOC-3. Another gene is Adiponectin (ADIPOQ) regulating insulin action and inflammation. We have also demonstrated that these genotypes and phenotypes are associated with less hypertension (HTN), cardiovascular disease (CVD) and metabolic syndrome (MS), and improved cognitive function. However, these genes have not been shown yet to protect against cancer.

Modulation of GH/IGF-1 axis is conferring longevity in mamalians and low IGF-1 levels is associated with decreased rates of cancers in humans. We demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan, possibly by protecting against cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED04-02.
Abstract ED05-03: The development of tractable mouse models to study therapeutic response
Authors: Hemann Michael
Published: May 2012

ED05-03

Many human cancers fail to respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. While chemoresistance has been observed since the earliest chemotherapeutic application, relatively little is known about the genetic determinants of drug response. Thus, chemotherapy is commonly administered without regard to the specific constellation of genetic alterations present in a given tumor. This current clinical reality is problematic for a number of reasons. First, patients are frequently given chemotherapies that have little or no chance of success. Second, potential tumor vulnerabilities conferred by specific genetic lesions are rarely considered prior to therapeutic administration, so the “right therapy” is generally not matched with the “right tumor”. Third, combination therapies are currently assembled by random trial and error, rather than through a genuine understanding of the basis for drug synergy in a given tumor. Finally, potentially effective drugs frequently fail in clinical trials due to an inability to genetically define small subsets of tumors in which these drugs have significant efficacy. Thus, new approaches to define patient populations most likely to benefit from a particular drug and to identify potentially effective drug combinations are urgently needed. Our lab combines emerging RNA interference technologies with tractable mammalian cancer models to identify genes that influence the action of conventional and molecularly targeted therapies. Specifically, we have performed highly parallel in vivo genetic screens to identify short hairpin RNAs (shRNAs) capable of enhancing or reducing the sensitivity of cancer cells to select anticancer agents, with the objective of finding potential biomarkers that may be used for patient selection, pathways required for drug action, and strategies for effective combination therapy. Importantly, these screens are carried out in vivo, in mammalian systems that more closely approximate the pharmacokinetic, pharmocodynamic, microenvironmental and immunological setting encountered in the treatment of human cancers. It is our expectation that these approaches will provide powerful preclinical test systems that can be used to identify therapies that circumvent traditional drug resistance mechanisms or test novel ‘targeted’ therapeutics.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED05-03.
Abstract PL03-01: Role of Stat3 in the tumor microenvironment
Authors: Yu Hua
Published: May 2012

PL03-01

An essential role of immune cells as extrinsic tumor suppressor has been demonstrated. However, immune cells in the tumor microenvironment not only fail to mount an effective antitumor immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. We and others have demonstrated that Stat3, a key oncogenic transcription factor constitutively activated in diverse cancer cells and important for tumor cell survival and invasion, is also activated in tumor stromal immune cells and potently immunosuppressive. Constitutively-activated Stat3 inhibits the expression mediators necessary for immune activation against tumor cells. Moreover, Stat3 activity promotes the production of immunosuppressive factors that activate Stat3 in diverse immune cell subsets. Among the immunosuppressive factors regulated by Stat3 are IL-6, IL-23 and IL-17, which are elevated in cancer, promote chronic inflammation, and cancer progression. Many of these immunosuppressive factors are also Stat3 activators. Our recent results further demonstrate that activated Stat3 in tumor myeloid cells, including macrophages and myeloid-derived suppressor cells, is important for mediating tumor angiogenesis. As such, Stat3 propagates several levels of crosstalk between tumor cells and the tumor microenvironment, leading to tumor-induced immunosuppression, tumor survival and tumor angiogenesis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL03-01.
Abstract PL05-01: Mechanistic targets for preventing obesity-related cancers
Authors: Hursting Stephen
Published: May 2012

PL05-01

The prevalence of obesity, an established risk factor for many cancers (1), has risen steadily for the past several decades in the US and many other countries (2). Unfortunately, the mechanisms underlying the obesity and cancer connection are not well understood, and new targets and strategies for offsetting the impact of obesity on cancer risk are urgently needed. Several hormones and growth factors have been implicated as potential mediators of the energy metabolism -carcinogenesis relationship. These include insulin-like growth factor-1 (IGF-1), insulin, several adipokines, and inflammatory/ oxidative stress factors. Calorie restriction (CR), the most commonly recommended dietary strategy for preventing or reversing obesity, has been shown to inhibit spontaneous, transplanted and chemically induced tumors in a variety of animal models (3). In contrast, diet-induced obesity enhances tumorigenesis in many of these same models (3-6). We have also shown in a series of transgenic model systems and microarray studies that the insulin and insulin-like growth factor signaling pathways appear central to many of the anti-cancer effects of CR, as well as the pro-cancer effects of obesity (3). Using AZIP/F1 transgenic mice, which lack white adipose tissue but have high levels of insulin, IGF-1 and inflammatory markers, we have reported that elevated IGF-1 and insulin, as well as increased inflammatory factors (which typically accompany obesity), independent of the adipose tissue per se, appear to be the important dietary targets for disrupting the obesity-cancer link (4). In addition, biochemical and molecular analyses of tissues from lean, overweight and obese mice, as well as IGF-1 deficient mice, established that the Akt and mTOR pathways provide an important target for disrupting the obesity-cancer link via dietary energy balance (5,6).

The other side of the energy balance equation is energy expenditure, which includes the energetics of growth, metabolism, thermoregulation and physical activity (the only truly modulatable aspect of energy expenditure). Epidemiologic studies have established that increased physical activity is associated with reduced risk of colorectal cancer and postmenopausal breast cancer (7). In addition, there is limited but encouraging epidemiologic data suggesting that increased physical activity may be associated with reduced risk of several other cancers as well (7). Physical activity also exerts anticancer effects in several of our transgenic models, but apparently through very different mechanisms than CR (7). For example, the protective effects of exercise appear to be dependent on p53 gene dosage and independent of IGF-1, based on studies in Apc min mice and Wnt-1 transgenic mice (7,8). A better understanding of the mechanisms underlying the energy balance-cancer link will facilitate the development of novel prevention and treatment strategies for offsetting the effects of obesity on cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL05-01.
Abstract PL05-02: Antioxidants and nutritional intervention in aging and age-associated disease
Authors: Meydani Mohsen
Published: May 2012

PL05-02

Aging is a complex and multifactorial biological phenomenon that is commonly manifested by the decline of many physiological functions and is often associated with chronic diseases such as cancer, cardiovascular disease, obesity, diabetes, arthritis, cataract, osteoporosis, neuronal diseases, and infections. Nutrition has been recognized to play an important role in the aging process and age-associated diseases. Changes in bodily functions with aging, together with malnutrition associated with advancing age, also increase the risk of developing a number of age-related diseases. Free radicals and oxidative stress have been recognized as important factors in the biology of aging and many age-associated degenerative diseases. In this regard, the modulation of oxidative stress by calorie restriction in animal models has been suggested to be one mechanism that helps to slow aging and the decline of bodily functions. Our human studies also indicate a reduction of oxidative stress by lowering caloric intake. Experimental and epidemiological data suggest that dietary interventions with micronutrients such as B vitamins, calcium, zinc and antioxidants such as carotenoids, vitamins E and C, selenium as well as specific phytochemical components in grains, fruits, and vegetables contribute to healthy aging through the primary prevention of age-related decline of bodily functions and associated disorders. In summary, nutrition is a critical determinant of the quality of life in the elderly and may have a significant impact on longevity. Supported by USDA-58-1950-7-707

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL05-02.
Abstract PR-10: Poverty, insurance status, and colorectal cancer in Colorado: 1995-2006.
Authors: Palisoc Alma , Byers Tim , Miller Sara , Finch Jack
Published: May 2012

PR-10

Background

Poverty in Colorado is an important factor that lowers the advantages of being diagnosed with colorectal cancer (CRC) at the earlier stage of disease and decreases survival due to CRC. Health insurance status can also lead to disparities in early detection of CRC.

Methods

Data from the Colorado Central Cancer Registry in the Colorado Department of Public Health and Environment and information from the 2000 U.S. census were used to determine the proportions of Colorado residents with CRC residing in areas designated as “less than 10% poverty” or wealthier areas, “10-19% poverty” or middle poverty areas, and “20+% poverty” or poorest areas. Since income was not reported to the cancer registry, the poverty level of the census block group area, obtained through the 2000 U.S. Census, where each cancer case resided was used to assign the poverty level for that case. The analyses presented included CRC cases over a 12-year period, from 1995-2006, in order to compare early stage diagnosis by area poverty level and age (less than 65 vs. 65 and older). Early stage at CRC diagnosis and insurance status by area poverty level for 1998-2006 and five-year cause-specific survival among Colorado CRC cases from 1999-2002 were also analyzed.

Results

Among the 21,212 colorectal cancer cases reported to the cancer registry from 1995-2006, 64.5% resided in wealthier areas, 24.8% were from middle poverty areas, and 10.7 % were from the poorest areas of the state. The proportion of early stage diagnosis was lower among the CRC cases from the poorest areas (42.0%) compared to those from the wealthier areas (44.2%). Among those less than aged 65, there was a substantial decrease in early stage at CRC diagnosis as poverty level increased (42.0% from wealthier areas vs. 37% from poorest areas). This is in contrast to those aged 65 and older (45.5% from wealthier areas vs. 44.4% from the poorest areas). In addition, of those younger than age 65 whose insurance status was available from the cancer registry for 1998-2006 (n=5,288), having no insurance or only Medicaid coverage was a disadvantage for early stage diagnosis compared to those with private insurance in all three poverty groups. More importantly, five-year cause-specific survival decreased as poverty level increased (64.1% from wealthier areas, 58.1% from middle poverty areas, 50.8% from the poorest areas of the state). This association between survival differences and socioeconomic status was apparent in those younger than 65 (67.8%, 66.9%, 48.7%) and in those 65 and older (61.5%, 53.9%, 51.9%).

Conclusions

Poverty and lack of health insurance are disadvantages that lead to disparities in early detection of and survival from colorectal cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-10.
Abstract PR-12: Is the screening-related increase of breast cancer mainly caused by lesions that would undergo spontaneous regression if left untreated?
Authors: Zahl Per-Henrik , M?hlen Jan
Published: May 2012

PR-12

Objective

In Norway mammography screening is associated with a 50% long-term increase of the incidence of invasive breast cancer. Based on an analysis of incidence data from the Norwegian screening program, we have recently argued that the majority of these extra cancers would have undergone spontaneous regression in the absence of screening (Zahl PH, Mæhlen J, Welch HG. The natural history of breast cancer detected by screening mammography. Archives of Internal Medicine 2008; Nov 24th). At mammography a large number of ductal carcinoma in-situ (DCIS) are detected and treated as low grade cancer. The objective of the present study is to repeat this analysis on a data set containing both invasive cancer and DCIS.

Materials and Methods

The data from the Norwegian Cancer Registry include invasive cancer and DCIS from the last 16 years for women of four counties in which the age group 50-69 years (n =166 000) was been invited to biennial mammography screening from 1996. We compared the 6-year cumulative incidence in two age matched and partly overlapping cohorts. The first cohort (the test group) included women born 1932-46 invited biennially during the 6-year observation period 1996-2001. The second cohort (the control group) included women born 1928-42 and invited once at the end of the 6-year observation period 1992-97. Note that for both cohorts the age span was 50-64 years at the start of the respective observation periods.

Results

The 6-year cumulative incidence of invasive cancer and DCIS combined was 28 % higher in the first cohort than in the second cohort. (2206 vs. 1739 per 100 000; RR = 1.27 (95% CI: 1.20 - 1.34). A sensitivity analysis of the potential effect of HRT showed that at most 2% of the 27% difference could be explained by differences in the HRT use. We also tested if low sensitivity could explain the difference - it could not explain the difference (P<0.001).

Conclusion

We have shown that the screening related incidence increase in the first four years of the 6-year observation period in the first cohort is not compensated for by a corresponding incidence increase when the previously un-screened women in the second cohort were invited in year 5-6. Increasing use of HRT and low sensitivity in the screening did not explain the difference. We propose that most of the screening-related incidence increase of invasive cancers and DCIS is due to tumors that in the absence of screening would have undergone spontaneous regression.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-12.
Abstract PR-3: A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress
Authors: Huang Qing , Wu You-Tong , Tan Hui-Ling , Ong Choon-Nam , Shen Han-Ming
Published: May 2012

PR-3

Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here we first show that hydrogen peroxide (H2O2) induces necrotic cell death in Bax-/- Bak -/- mouse embryonic fibroblasts (MEFs) through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H2O2. More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H2O2-induced necrotic cell death as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H2O2-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy via the LKB1-AMPK-mTOR pathway to enhance cell survival in cells under oxidative stress.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-3.
Abstract PR-8: Trichomonas vaginalis infection and prostate cancer incidence and mortality: A prospective study in the Physicians’ Health Study
Authors: Stark Jennifer , Judson Gregory , Alderete John , Sutcliffe Siobhan , Mundodi Vasanthakrishna , Kucknoor Ashwini , Giovannucci Edward , Platz Elizabeth , Fall Katja , Kurth Tobias , Ma Jing , Stampfer Meir , Mucci Lorelei
Published: May 2012

PR-8

Background

Several inflammation-related factors have been implicated in prostate cancer risk and progression, but the origin of inflammation is unclear. Infections are one possible source, but studies of specific infections have been largely inconclusive. A recent prospective study found that antibody seropositivity against Trichomonas vaginalis was positively associated with subsequent incidence of prostate cancer. This parasitic protozoan has received relatively little attention despite being the most common non-viral sexually transmitted infection. We sought to further explore and extend this hypothesis in an independent population, both for prostate cancer incidence as well as progression.

Methods

We conducted a prospective case-control study nested within the Physicians’ Health Study that included 673 prostate cancer cases and 673 individually matched controls. T. vaginalis antibody serostatus was assessed by an ELISA that detects IgG antibodies against purified, recombinant T. vaginalis α-actinin protein. We used conditional logistic regression for analyses of total prostate cancer incidence and Cox proportional hazards models to estimate hazard ratios for lethal prostate cancer (prostate cancer-specific death or development of bony metastases).

Results

The seroprevalence of T. vaginalis infection was 21% in controls and 25% in cases. Among cases, the average time between blood draw and prostate cancer diagnosis was 9.3 years (range 0.3 years - 17.9 years). Though not statistically significant, the magnitude of the association between T. vaginalis seropositivity and overall prostate cancer risk (OR: 1.23; 95% CI: 0.94, 1.61) was similar to the original study, which observed a 43% increased risk. Further, seropositive men had a 2.2-fold increase in risk of extraprostatic disease (95% CI: 1.08, 4.37) and a 2.7-fold greater risk of lethal prostate cancer (95% CI: 1.37, 5.28; 39 cases developed bony metastases or died of prostate cancer). Time-to event analyses included 7,776 person-years of follow-up and showed that, compared to seronegative cases, cases with serologic evidence of infection prior to cancer diagnosis had a 50% greater rate of progression to lethal prostate cancer (95% CI: 1.01, 2.16).

Conclusions

In this large prospective study, we observed a modest association between anti-T. vaginalis antibodies and overall prostate cancer risk and found that T. vaginalis infection was principally associated with clinically relevant, potentially lethal disease. If our findings are confirmed, T. vaginalis infection may represent a common risk factor for which chemoprevention could reduce burden of aggressive prostate cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-8.
Abstract PR-9: Results of surveillance for hereditary pancreatic cancer using MRI(CP)
Authors: Vasen Hans , Wasser Martin , Bonsing Bert , van Mil Anneke , Hommes Daniel , Morreau Hans , de Vos Wouter
Published: May 2012

PR-9

Introduction

Surveillance for pancreatic cancer (PC) in high risk groups may lead to early detection and may improve overall survival. We screened for early pancreatic neoplasia in individuals with a p16- germline mutation or with a strong family history of PC (FPC).

Methods

Since 2000, high risk individuals were offered annual surveillance by Magnetic Resonance Imaging (MRI(CP)). In case of suspected lesions, surgery or additional follow up (FU) was provided. In case of doubt, the examination was repeated within 2-4 months.

Results

A total of 66 (28 M) individuals with an average age of 56 yrs (range: 40-72) were studied (60 from p16, six from FPC families). The median FU was 3.4 yrs (range: 0-7). In 20% of the patients, a (pre)malignant lesion was detected. Ductectasias or IPMN (intraductal papillary mucinous neoplasm) were identified in eight patients (12%). Three patients underwent a prophylactic partial resection of the pancreas; histology showed IPMN in one and PanIn-II lesions in two patients. Five patients (8%) were diagnosed with PC. Three asymptomatic patients underwent partial pancreatectomy. One patient had no evidence for residual disease after surgery. The second patient had positive resection margins and nodes but survived 21 months. The third patient had metastatic carcinoid at surgery (in addition to pancreatic cancer). The remaining two patients did not undergo surgery because of metastatic disease (pulmonary metastases of melanoma, metastatic pancreatic cancer).

Conclusion

(Pre)malignant lesions were identified in a high proportion of patients. Small lesions of a few mm can be detected by MRI(CP). In view of the substantial morbidity of pancreatic surgery, a major challenge is to decide at what stage and to what extent prophylactic surgery should be performed. Close observation of high risk groups provides valuable information on the natural history of neoplastic lesions in the pancreas.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-9.
Abstract SS02-02: Chemoprevention: Poised for Success
Authors: Greenwald Peter
Published: May 2012

SS02-02

AACR Frontiers in Cancer Prevention

Special Session: Achieving the Potential of Chemoprevention

Monday, November 17, 2008; 12:00-1:00pm

Abstract

Chemoprevention: Poised for Success

Peter Greenwald

National Cancer Institute

greenwald@nih.gov

Phase III trials to prevent breast, prostate and colo-rectal cancers demonstrate clearly that reducing cancer risk via chemoprevention is possible and merits major research investment in addition to a balanced approach to public and professional education about the potential benefits for many people. In September 2007, the FDA approved raloxifene to reduce the risk of breast cancer in post-menopausal women at high risk of the disease. Thus, based in large part on the breast cancer prevention trial with tamoxifen and the more recent STAR trial, there are now two drugs approved for the prevention of breast cancer. The Prostate Cancer Prevention Trial showed that men who took 5 mg of finasteride daily for 7 years had a 25% reduced risk of developing prostate cancer compared with men taking placebo. Subsequent studies provide reassurance that the drug was probably not causing high grade cancers in the finasteride group (an earlier concern), but rather finasteride may simply have made it easier to detect high-grade cancers. Seventy percent of colon polyps, including 92 % of advanced adenomas, were prevented by a combination of the investigational compound DFMO and the anti-inflammatory agent sulindac. As a group, these pivotal trials demonstrate that major reductions in risk for common cancers are possible by means of chemoprevention. Expansion of pre-clinical chemoprevention studies, exploratory investigational studies of pharmaceuticals and bioactive food compounds for cancer prevention, and phase I & II trials, together with increased attention to building public-private partnerships and professional and public interest, will help to grow this promising field of cancer prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):SS02-02.
Abstract A10: Insulin resistance's effect on PSA level for prostate cancer screening
Authors: Park Jinho , Cho Belong
Published: May 2012

Introduction: Previous studies showed that BMI decreased serum PSA level. Insulin resistance in obesity is suggested one of reasons. The negative association between BMI and PSA level may be partially due to low testosterone concentration caused by obesity-related hormonal disturbances (decrease of sex-hormone binding globulin and increase of aromatase and IR)

Objective: To examine the effect of homeostasis model assessment of insulin resistance (HOMA) index on PSA level after adjusting prostate volume(PV) effect in a screening population.

Design: We performed multivariate linear regression and ANOVA to assess potential influencing factors in a cross-sectional study of 30- to 80-year-old Korean men who underwent routine checkups from 2004–2008 (n=3,320).

Main Outcome Measures: Associations between factor variables (BMI, HOMA Index, PV) and PSA level assessed by trends tests by multivariate linear regression and/or ANOVA.

Results: PSA level was negatively associated with BMI before (P for trend <.01) and after (P for trend by quartile <.05 for all) PV stratification, but not associated with HOMA index before (P for trend >.05) and after (P for trend by quartile >.05 for all) PV stratification.

Conclusions: BMI has negative effect on PSA level irrespective of PV stratification, but IR had no association. Hemodilutional effect by obesity may be main cause of BMI's negative association on PSA level.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A10.
Abstract A105: Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue, and lung cancer risk
Authors: Lam Tram K. , Rotunno Melissa , Lubin Jay H. , Wacholder Sholom , Consonni Dario , Bertazzi Pier Alberto , Pesatori Angela C. , Chanock Stephen , Burdette Laurie , Goldstein Alisa M. , Tucker Margaret , Caporaso Neil E. , Subar Amy F. , Landi Maria Teresa
Published: May 2012

Background: Quercetin is a flavonol found in fruits (apple, grape) and vegetables (onion, broccoli). Quercetin possesses anticarcinogenic properties that protect against cancer. However, the epidemiological evidence on the association of quercetin-rich food intake with lung cancer risk is inconclusive, and how quercetin affects lung carcinogenesis in humans is largely unknown. Laboratory analyses have shown that quercetin may inhibit Phase I cytochrome P450s enzymes responsible for the activation of tobacco-related procarcinogens, and induce Phase II glutathione S-transferase (GST) enzymes responsible for the removal of activated carcinogens.

Methods: We investigated the role of dietary quercetin and the interaction between quercetin and P450 and GST polymorphisms on lung cancer risk in incident lung cancer cases and matched controls from Environment and Genetics in Lung cancer Etiology (EAGLE), a population-based case-control study including 2100 primary lung cancer cases and 2120 controls. Dietary information and genotype data were available for 1740 cases and 1919 controls. In fresh-frozen non-tumor lung tissue from 38 adenocarcinoma patients, we also assessed the correlation between dietary quercetin intake and mRNA expression of tobacco-related Phase I and Phase II metabolic genes. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific quintile of intake were calculated using unconditional logistic regression, adjusted for putative risk factors. Two sample t-test was used to assess difference in expression by quercetin-rich consumption status.

Results: Frequent intake of quercetin-rich foods was inversely associated with lung cancer risk (ORQ5vsQ1=0.49;95% CI=0.37–0.67; p-trend: <0.001), and did not differ by genotype, gender, or histological subtypes. The association was stronger in subjects who smoked more than 20 cigarettes per day (ORQ5vsQ1=0.35;95% CI=0.19–0.66; p-trend=0.003). The comparison between gene expression and high-versus-low consumption of quercetin-rich foods showed an overall down-regulation of P450 and up-regulation of GST metabolic genes (p-values<0.05) in lung tissue.

Conclusions: Quercetin-rich diet was associated with lower risk of lung cancer and with down-regulation of Phase I P450 genes and up-regulation of Phase II GST genes in lung tissue. These findings suggest a possible mechanism for quercetin-related protection against lung cancer risk through quercetin-induced changes in the expression of genes involved in the metabolism of tobacco-carcinogens. Further studies exploring the interplay between quercetin intake, tobacco smoking, and lung cancer risk are warranted.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A105.
Abstract A107: Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies
Authors: Bao Ying , Ng Kimmie , Wolpin Brian M. , Michaud Dominique S. , Giovannucci Edward , Fuchs Charles S.
Published: May 2012

Background: Experimental data indicate that vitamin D has anticancer properties. However, epidemiologic studies on vitamin D and pancreatic cancer risk have yielded inconsistent results. We previously developed a model to predict long-term plasma 25-hydroxyvitamin D3 [25(OH)D] levels from multiple determinants of vitamin D status (dietary and supplementary vitamin D, skin pigmentation, adiposity, geographic residence, and leisure-time physical activity as a surrogate of sunlight exposure). Here, we examine the association between predicted vitamin D status and pancreatic cancer risk in the Nurses' Health Study and Health Professionals Follow-up Study.

Methods: We prospectively followed 118,597 participants in these two cohorts from 1986–2006. We calculated a 25(OH)D score from six predictors of vitamin D status for each individual using a multiple linear regression model and then examined the predicted 25(OH)D levels in relation to pancreatic cancer risk with Cox proportional hazards models. The multivariate models were adjusted for age, sex, race, height, smoking, and diabetes.

Results: During 20 years of follow-up, we identified 575 incident pancreatic cancer cases. Higher 25(OH)D score was associated with a significant reduction in pancreatic cancer risk; compared with the lowest quintile, participants in the highest quintile of 25(OH)D score had an adjusted RR of 0.65 (95% CI, 0.50–0.86; P for trend = 0.001). The results remained unchanged after further adjusting for BMI and physical activity or after excluding the first 2 years of follow-up. This inverse association was also consistent across gender and strata of other covariates, including age, region, smoking, BMI, and physical activity.

Conclusion: Higher 25(OH)D score was associated with a lower risk of pancreatic cancer in these two prospective cohort studies.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A107.
Abstract A108: Serum retinol and risk of prostate cancer in the alphatocopherol, beta-carotene (ATBC) cancer prevention study
Authors: Mondul Alison M. , Watters Joanne L. , Virtamo Jarmo , Albanes Demetrius
Published: May 2012

Purpose: Retinol (vitamin A) may prevent prostate cancer by promoting cell differentiation and apoptosis, although under some conditions it could stimulate growth and de-differentiation. We examined serum retinol, measured at baseline and three years, in relation to prostate cancer risk in the ATBC Study.

Methods: The ATBC Study is a randomized controlled trial conducted to determine the effects of -tocopherol and s-carotene supplements on cancer incidence. 29,133 Finnish male smokers were recruited from 1985–1988 and were assigned to groups using a 2×2 factorial design: 1) -tocopherol, 2) β-scarotene, 3) both supplements, or 4) placebo. Fasting blood samples were collected at baseline and after 3 years, and as of April 30, 2006, 2,041 prostate cancer cases occurred during 417,532 person-years. Cox proportional hazards models were used to estimate the relative risk (as hazard ratio, HR) of total and aggressive (n=461) prostate cancer by quintile of baseline and 3-year serum retinol concentrations, as well as by change in serum retinol. No confounding by factors associated with either prostate cancer or retinol was observed.

Results: Men in higher quintiles of baseline retinol were more likely to develop prostate cancer compared with men in the lowest quintile (age-adjusted HR, 95%CI vs. Q1; Q2: 1.05, 0.91 – 1.21; Q3: 1.06 0.92 – 1.22; Q4: 1.13, 0.98 – 1.30; Q5: 1.19, 1.03 – 1.36; p-trend = 0.009). The association was similar for aggressive prostate cancer and when the 3-year retinol was used. Compared to men whose retinol did not differ between baseline and 3 years, men with either higher or lower retinol at follow-up were at similar risk of prostate cancer. When we jointly categorized men based on quintiles of baseline and 3-year retinol, we noted that men who were in the highest quintile of retinol at both time points had the greatest increased risk (baseline/3-year Q5/Q5 vs. Q1/Q1 HR: 1.31 95% CI: 1.08 – 1.59). Other joint categories were also at higher risk, particularly among men who did not receive the trial β-carotene supplement. Men randomized to the β-carotene arm had generally higher risk for any baseline/3-year retinol category compared to men in the no β-carotene arm, and those whose serum retinol decreased substantially from baseline Q4 or Q5 appeared to have a lower prostate cancer risk (HR, 95% CI vs. Q1/Q1; Q5 to Q1–3: 0.60, 0.35 – 1.03; Q4 to Q1–2: 0.85, 0.54 – 1.33).

Conclusion: In this largest study to date of serum retinol and prostate cancer that incorporates retinol measured at two time points three years apart, higher serum concentrations were associated with elevated risk, with sustained high exposure conferring the greatest risk. Distinct patterns of change in serum retinol over time may relate to differing risks of developing prostate cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A108.
Abstract A11: Development of minimally invasive techniques for monitoring genome health: A preventative health approach to reducing disease
Authors: O'Callaghan Nathan , Bull Caroline , Fenech Michael
Published: May 2012

It is becoming increasingly evident that risk for developmental and degenerative disease, including cancers, increases with more DNA damage. Importantly, DNA damage is influenced (and can be modified) by nutritional status. Optimal concentrations of nutrients for reduction of genome damage are also dependent on many factors (genetic background, age, nutrient uptake) that vary from individual to individual.

In the genomic health era of personalised nutrition for disease prevention, there is a need to develop minimally invasive methodologies to measure alterations in disease risk biomarkers in an effort to identify at risk individuals early in disease progression. Using qPCR techniques developed by us, we aimed to evaluate the use of buccal cells and saliva as a minimally-invasive approach to measure markers of genome health in a cross-sectional study.

Buccal cells, saliva and blood samples were collected from 91 volunteers. This cohort comprised 18M and 25F in the young group (aged 18–31 years), and 25M and 23F in the older group (65–75yrs). Telomere length was determined in lymphocytes, buccal cells and saliva (by qPCR). Telomere length was negatively correlated with age; the strength of this correlation varied between gender and tissue type.

We report that buccal cells and saliva can be used to measure DNA damage. Further research is required to evaluate the effectiveness of buccal cells and/or saliva as a minimally-invasive biomarker of oxidative DNA damage, genome health and disease risk status.

The development of dietary patterns, functional foods and supplements that are designed to improve genome-health maintenance in an individual with increased disease risk may lead to a preventative health strategy based on the diagnosis and individualised nutritional prevention of genome damage.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A11.