bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A9: Expression of insulin-like growth factor II and of the type 1 receptor gene in esophageal adenocarcinoma
Authors: Zhao Ronghua , Geyer Ron , Decoteau John , Casson Alan
Published: May 2012

A9

Aim

To explore potential biological mechanisms underlying the association between obesity and esophageal malignancy, we studied the expression of insulin-like growth factor-II (IGF-II) and of the type 1 receptor (IGF-IR) gene in a well characterized series of patients with primary esophageal adenocarcinoma (EADC) and matched histologically normal esophageal epithelia (NE).

Patients and Methods

Banked esophageal tissues (EADC and matched NE, obtained with informed consent) were available from a consecutive series of 52 patients who underwent esophageal resection without preoperative chemoradiation therapy. Following extraction of RNA, expression of IGF-II and IGF-IR mRNA was determined using reverse transcription and real time polymerase chain reaction (RT-PCR). The 2-ΔΔCT (Livak) method was used to quantitate tissue expression of IGF-II and IGF-IR mRNA, which was correlated with measured body mass index (BMI), clinicopathological findings, and outcome.

Results

As expected, significant correlations between tumor stage, differentiation and survival were found for the 49 male and 3 female patients in this series, who ranged in age from 36 to 85 years (median: 60.5 years). A significant association was seen between BMI and IGF-II mRNA expression in NE tissues (rs=0.26, p=0.075). Significantly higher IGF-II mRNA expression was seen in EADC tumors (median 6.45, 95%CI 7.00-13.46) compared to matched NE tissues (median 1.32, 95%CI 1.37-4.31, p<0.01), particularly in poorly differentiated tumors. On multivariate analysis, IGF-II expression was an independent predictor of disease-free survival (p=0.02) and overall survival (p=0.03). Expression levels of IGF-II mRNA correlated significantly with IGF-IR in both EADC (rs=0.47, p<0.01) and NE (rs=0.46, p<0.01). Furthermore, IGF-IR mRNA expression was found to be significantly higher in EADC (median 1.57; 95%CI 1.47-3.86) compared with matched NE (median 0.57; 95%CI 0.50-0.85) (p<0.01), but only in patients with the A variant of the common IGF-IR G3174A polymorphism, which has recently been shown to modulate the obesity risk for EADC.

Conclusions

These studies further implicate perturbations of the IGF axis in the molecular pathogenesis of human EADC, and suggest a plausible mechanistic basis to explain the association between obesity and risk for malignancy. The significant association between IGF-II expression and survival suggests that IGF-II may be a clinically relevant biomarker for prognosis, or molecular target for novel anti-cancer therapies.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A9.
Abstract A90: Anthropometry, cigarette smoking, alcohol consumption, and the risk of thyroid cancer in the U.S. Radiologic Technologists Study
Authors: Meinhold Cari , Ron Elaine , Schonfeld Sara , Alexander Bruce , Freedman D. Michal , Linet Martha , Berrington de Gonzalez Amy
Published: May 2012

A90

Several case-control studies suggest that BMI may increase and cigarette smoking may reduce the risk of thyroid cancer, but results from prospective studies are limited. We investigated the associations between anthropometric factors, cigarette smoking, alcohol consumption and thyroid cancer risk by following a cohort of 67,055 female and 20,557 male radiologic technologists in the United States from 1983 through 2006. Hazards ratios (HRs) and 95% confidence intervals (CIs) were calculated using proportional hazards models adjusted for age, sex, smoking status, and benign thyroid conditions, and where appropriate, height or BMI. After a mean follow-up of 15.8 years, 268 (229 female and 39 male) incident thyroid cancer cases were ascertained. Obesity (BMI ≥30.0 kg/m2) was associated with an increased risk of thyroid cancer (HR for women= 1.74, 95% CI 1.22, 2.49; HR for men= 2.27, 95% CI 1.00, 5.13) compared to BMI in the normal range (18.5-24.9 kg/m2). Compared to never smokers, current but not former smokers had a reduced risk of thyroid cancer (HR for women= 0.52, 95% CI 0.34, 0.79; HR for men= 0.28, 95% CI 0.08, 0.94). Alcohol consumption and smoking duration and intensity were not associated with thyroid cancer after adjustment for current smoking. The results were similar after restricting to confirmed (N=223, 83%) or papillary (N=191, 86%) thyroid cancers. We estimate that obesity may account for 9% of thyroid cancers in this cohort and 22% of incident thyroid cancers in the United States currently. In this prospective study, obesity increases and current cigarette smoking decreases the risk of thyroid cancer in both women and men.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A90.
Abstract A91: Obesity and the TMPRSS2:ERG translocation in prostate cancer
Authors: Mucci Lorelei , Ma Jing , Perner Sven , Stampfer Meir , Kurth Tobias , Rubin Mark , Kantoff Philip
Published: May 2012

A91

Background

The recently identified TMPRSS2:ERG translocation is an early and common somatic event in prostate cancer pathogenesis involving the TMPRSS2 promotor, which is androgen regulated, and ERG, a member of the ETS family of transcriptional factors. Regulation of TMPRSS2 by androgens is intriguing and suggests both a potential mechanism whereby a man’s hormonal milieu could drive the progression of prostate tumor cells and also a mechanism by which androgen deprivation therapy may work. We explored the relationship of obesity, with its known relation with lower circulating testosterone and higher estradiol, on prostate cancer risk according to TMPRSS2:ERG fusion status.

Methods

The study was nested among 29,067 men in the prospective Physicians’ Health Study (PHS) during 1982 to 2008. Information on obesity was collected through structured questionnaires at baseline and follow-up, and included total obesity (weight and body mass index, BMI) and central obesity (waist circumference) measures. We characterized the TMPRSS2:ERG fusion by fluorescence in situ hybridization on archival tumor tissue from 305 men diagnosed with incident prostate cancer during 25 years of follow-up. We applied logistic regression models to compare the association of obesity on relative risk of fusion positive and fusion negative prostate cancer.

Results

Almost half the men in PHS were overweight (BMI 25-26.9 kg/m2) or very overweight/obese (BMI 27 kg/m2 or greater) at the start of follow-up. Prevalence of the TMPRSS2:ERG translocation among the men with prostate cancer was 40.0%, in line with other studies. The association of obesity on prostate cancer risk differed in relation to the translocation. Men with a higher BMI at baseline had a reduced risk of developing fusion positive prostate cancer (7% lower risk per increase in BMI, p for trend ~ 0.0021). Compared to healthy weight men, those who were very overweight/obese had a 60% lower risk of fusion positive prostate cancer (RR=0.43, 95% CI 0.22-0.83). Moreover, men with a larger waist circumference were at lower risk of developing fusion positive cancer (p for trend ~0.0017). In contrast, there was no association between total or central adiposity measures at baseline and risk of fusion-negative prostate cancer.

Discussion

Obesity appears to reduce the risk of prostate tumors that carry the TMPRSS2:ERG fusion, but is unrelated to risk of prostate cancers that occur via fusion-independent mechanisms. These preliminary data provide insight into the link between the hormonal milieu and the heterogeneity of prostate cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A91.
Abstract A95: Genetic variability in energy metabolism and pancreatic cancer risk: A population-based case-control study in Minnesota
Authors: Zhang Jianjun , Dhakal Ishwori , Gross Myron , Lang Nicholas , Kadlubar Fred , Kadlubar Susan , Anderson Kristin
Published: May 2012

A95

Pancreatic cancer is one of the leading causes of cancer death in developed countries. Although the etiology of pancreatic cancer remains elusive, based on epidemiologic studies, obesity and type-2 diabetes appear to increase risk of this fatal disease. Therefore, it is possible that polymorphisms in genes involved in energy metabolism modulate pancreatic cancer risk. We investigated this hypothesis using a case-control study conducted during 1994-1998 in Minnesota. Cases (n=189), aged 20 years or older, were ascertained from all hospitals in the metropolitan area of the Twin Cities and the Mayo Clinic; from the later, only cases residing in the Upper Midwest of the US were recruited. Controls (n=486) were randomly selected from the general population and frequency matched to cases by age (within 5 years) and sex. Polymorphisms in four genes were genotyped: leptin (LEP, -2548G>A, rs7799039), leptin receptor (LEPR, Gln223Arg, rs1137101), and neuropeptide Y (NPY, Leu7Pro, rs16139) (regulating energy intake), and β2-adrenoceptor (ADRB2, Gly16Arg, rs1042713) (regulating energy expenditure). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. After adjustment for age, sex, race, education, cigarette smoking, and alcohol use, a statistically significantly reduced risk of pancreatic cancer was observed in subjects who were heterozygous or homozygous for the NPY7Pro allele as compared with those who were homozygous for the NPY7Leu allele) [OR (95%CI): 0.39 (0.15-0.89)]. The variant allele (16Arg) of ADRB2 was associated with a borderline significantly increased risk [OR (95%CI): 1.47 (0.99-2.21)]. No appreciable effects were detected for the LEP and LEPR sequence variants examined. The genetic associations described above were not markedly modified by physical activity or dietary intake of energy, fat, or fiber. This study offers novel data suggesting that genetic variability in the regulation of energy intake and expenditure influences pancreatic cancer risk.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A95.
Abstract A96: Association of leptin with sex steroid hormones, insulin, and CRP among adult men in NHANES III
Authors: Lai Gabriel , Rohrmann Sabine , Rifai Nader , Platz Elizabeth
Published: May 2012

A96

Objective

We previously observed an inverse association between leptin concentration and risk of prostate cancer, which was contrary to our hypothesis (AACR 2008). It is possible that the association between leptin - a hormone secreted by adipocytes - and prostate cancer or other cancers may be explained by confounding by other hormone and metabolic biomarkers. To address this issue, we evaluated the association of leptin with sex steroid hormones, insulin, and C-reactive protein (CRP) among a nationally representative sample of US men in the Third National Health and Nutrition Survey (NHANES III).

Methods

1149 men aged 20+ years and who attended the morning examination session of Phase I of NHANES III (1988-1991) were included. We measured serum concentrations of testosterone, androstanediol glucuronide (AAG) (a metabolite of dihydrotestosterone), estradiol, and sex hormone binding globulin (SHBG) by immunoassay. Insulin, CRP, and leptin were measured previously. Free hormones were estimated from measured total hormones, albumin, and SHBG. Height, weight and waist circumference were measured. Percent body fat was calculated from bioelectrical impedance and anthropometric data. Data on alcohol, smoking, and physical activity were obtained by interview. Using linear regression, we estimated geometric mean concentrations of hormones, insulin, and CRP by quartiles of leptin, applying sampling weights and adjusting for age, alcohol, smoking, physical activity, waist circumference, percent body fat and race/ethnicity.

Results

Men who had higher leptin concentrations had lower testosterone (Q1: 5.7, Q2: 5.3, Q3: 4.8, Q4: 4.7 ng/mL; p-trend = 0.02). Although the trend was not statistically significant, men who had higher leptin had lower free testosterone (0.109, 0.106, 0.098, 0.096 ng/mL; p-trend = 0.10). Men who had higher leptin had higher estradiol (34.7, 34.8, 36.4, 38.5 pg/mL; p-trend = 0.03), free estradiol (0.86, 0.89, 0.94, 1.01 pg/mL; p-trend = 0.007), and insulin (43.7, 50.1, 56.3, 60.0 pmol/L; p-trend = 0.0006) levels. Men in the lowest quartile of leptin had the highest SHBG; levels were the same in the upper 3 quartiles (37.7, 34.0, 33.1, 32.5 nmol/mL; p-trend = 0.14). Leptin did not appear to be associated with AAG or CRP. These patterns were similar within age strata.

Conclusions

Even after taking into account extent of body fat and other factors, leptin appears to be inversely associated with total and free testosterone but positively associated with estradiol, free estradiol, and insulin. In analysis of the independent association of leptin and prostate and other cancers, whether overall or by stage/grade, in addition to adiposity, adjustment for other hormonal and metabolic correlates of leptin may also be necessary.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A96.
Abstract A98: Cigarette smoking, environmental tobacco smoke exposure, and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition
Authors: Vrieling Alina , Bueno-de-Mesquita H. Bas , Boshuizen Hendriek , the EPIC study group For
Published: May 2012

A98

Cigarette smoking is an established risk factor for pancreatic cancer. However, prospective data for most European countries are lacking, and epidemiologic studies on exposure to environmental tobacco smoke (ETS) in relation to pancreatic cancer risk are scarce.

We examined the association of cigarette smoking (current and lifetime intensity, duration, pack-years, time since quitting) and exposure to ETS with pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). This analysis was based on 465,910 participants, including 524 first incident pancreatic cancer cases diagnosed after a median follow-up of 8.9 years. Estimates of risk were obtained by Cox proportional hazard models and adjusted for weight, height, and history of diabetes mellitus.

Current cigarette smokers had an elevated risk of pancreatic cancer compared to never smokers (hazard ratio (HR) = 1.71, 95% confidence interval (CI): 1.36, 2.15), and risk increased with greater intensity and pack-years. Former cigarette smokers who quit for less than 10 years were also at greater risk of pancreatic cancer (HR = 1.44, 95% CI: 1.06, 1.95), but risk was comparable to never smokers after quitting for 10 years or more. Further, pancreatic cancer risk was increased among never smokers daily exposed to ETS (for many hours) during childhood (HR = 2.60, 95% CI: 0.95, 7.06) and exposed to ETS at home and/or work (HR = 1.54, 95% CI: 1.00, 2.39).

These results from a large European prospective cohort suggest that both active cigarette smoking, as well as exposure to ETS, is associated with increased risk of pancreatic cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A98.
Abstract B10: Development and pilot testing of a brochure to increase awareness of inherited breast cancer in black women
Authors: Vadaparampil Susan , Quinn Gwendolyn , Giyishi Anxhela , Pal Tuya
Published: May 2012

B10

Background

Due to low levels of awareness about hereditary breast cancer and underutilization of genetic counseling and testing services in the Black community, there is an urgent need to provide information about these topics to Black women. Existing genetic education materials have generally been developed by and for White women and thus may have reduced relevance for Black women. Objective: To create a culturally tailored, educationally relevant brochure to increase awareness about hereditary breast cancer within the Black community. Methods: Three focus groups were conducted with female members of Black community based organizations representing a diverse set of sociodemographic (e.g., age, education) and clinical (e.g., breast cancer status) characteristics. Discussions were led using a standardized guide with probes to assess the creative and educational aspects of a mock brochure (n=46). Trained, race-concordant moderators with previous experience discussing preventive health behaviors were used for each focus group. Each focus group was audio-taped and handwritten notes were taken by at least 3 members of the research team. Summaries of each focus group were created using these data sources. Content analysis based on Grounded Theory was conducted using an iterative process, and each summary was independently coded by three members of the research team.

Results

The majority of participants were over age 41 (67%) and married (43%). Thirty-seven percent were college graduates or beyond and 72% had children. The key content areas related to improvement of the brochure were to: (1) Include additional information about aspects of breast cancer specific to Black women; (2) Use the term Black rather than African American or Women of Color; (3) Provide more details about the process of genetic counseling and testing; and (4) Include a color scheme representative of the Black community. Positive aspects of the brochure that were well received included: (1) Using patient photos and personal vignettes; (2) Targeting Black women with the race specific information about risk; and 3) Acknowledgment of common misperceptions about hereditary breast cancer.

Conclusion

Black women in this study expressed a strong desire for culturally relevant information related to genetic counseling and testing for hereditary breast cancer. When provided an opportunity to offer feedback prior to finalizing a brochure, women identified important areas for improvement that are likely to lead to more culturally tailored and acceptable educational materials. By implementing these suggestions, the study team expects the brochure will provide meaningful information about inherited breast cancer that is appropriate for widespread dissemination to Black women.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B10.
Abstract B100: Chemopreventive efficacy of Spirulina in precancerous lesions of cervix.
Authors: Sharma Nidhi , Kumar Ashok
Published: May 2012

B100

Objectives

Gynaecological malignancies represent approximately 13 % of cancers in women and accounts for 9.8% of all cancers deaths. India accounts for one-fifth of the world burden of cervical cancer, which is a good example of disease with a preclinical phase that can be detected in a pre-invasive stage, using Papanicolaou Smear. In the present study attempt has been made to prevent or delay the development of cancer in ostensibly healthy females with specified risk factors or precancerous conditions through chemoprevention. Extensive work has been done on the chemopreventive efficacy of the Spirulina in oral cancer patients, which is a tiny bluish algae and is the highest source of vitamin b12 in addition with iron, vit-A, C, E, zinc and selenium.

Method

78 females above the age of 35, with eroded cervix were identified with precancerous lesions in Zanana Hospital (in between 2002-2005) who were questioned about their habits, habitat, dietary habits, economic status, reproductive history and other related conditions. The female were divided into two groups, the first group with eroded cervix was treated with Monalina (a product of Spirulina)and the other group served as control and both the groups were screened at 4 to 6 month intervals for two years annually thereafter.

Results

The results in the first group demonstrated significantly reduction in the progression of dysplasia incidence, while in some cases the moderate condition was arrested as such without transformation into hyperplasia as compared to the control group.

Conclusions

There is a lot of research potential in analyzing the cervical cancer patients with Spirulina, by screening them with Pap smear, before the onset of invasive cervical carcinoma.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B100.
Abstract B101: Caspase-dependent induction of apoptosis by novel lupane-type pentacyclic triterpenoids
Authors: Koohang Ali , Mar Aye Aye , Szotek Erika , Eiznhamer David , Flavin Michael , Xu Ze-Qi
Published: May 2012

B101

Background

Betulinic acid is a naturally occurring lupane-type pentacyclic triterpenoid with great activity in the treatment and prevention of cancer. As an apoptosis inducer, it inhibits cancer cell growth in human melanoma, glioblastoma, neuroblastoma, leukemia, prostate and ovarian carcinomas. Several studies have linked the anticancer property of betulinic acid to its ability to induce apoptosis in cancer cells by targeting the mitochondrial pathway of apoptosis. We have been interested in the structure -activity studies of modified lupane-type pentacyclic triterpenoids to develop new cancer preventive drugs with enhanced pro-apoptotic activities.

Methods

New compounds were prepared in five to seven synthetic steps. The panel of cell lines used in our investigation included SK-MEL-2 and A-375 from malignant melanoma of the skin, Daoy and LN-229 from cerebellar medulloblastoma, OVCAR-3 from ovarian, HT-29 from colorectal adenocarcinoma and MCF-7 from breast adenocarcenoma clinical samples. Cell growth inhibitory activity was measured by tetrazolium-based MTS assay and reported as IC50 values. Homogeneous caspase activation was quantified by a fluorimetric assay and apoptosis induction was characterized by an annexin-type flow cytometry assay and measured as ratio of early-mid apoptotic to necrotic cells.

Results

The structure -activity relationship analysis reveals that amino group incorporation has significant impact on the cytotoxicty of triterpenes. Mono-amino derivatives inhibited cancer cell growth with potency 2-6 times higher than betulinic acid, whereas bis-amino analogues exhibited inhibitory effect with IC50 values of 10-100 times lower. Further mechanism of action studies revealed that these new amino pentacyclic triterpenoids induced apoptosis and activated caspases. In SK-MEL-2 (melanoma) cells, apoptosis was induced as early as 2 h at 15 μM and a similar amount of apoptosis induction was observed at 16 h in Daoy (glioblastoma) cells.

Conclusions

Our results show that incorporation of amino groups into the structure of lupane-type pentacyclic triterpenoids at various positions markedly improves cytotoxicity of these molecules with unique apoptosis induction ability. Further pharmacological evaluation on this new class of modified natural products is warranted to develop promising agents for cancer treatment and prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B101.
Abstract B102: Fenretinide induces lethal autophagy via a novel ensemble of life and death regulators: dihydroceramide and sphinganine versus sphinganine 1-phosphate
Authors: Sims Kacee , Fluke Katie , Symolon Holly , Zheng Wenjing , Munter Elizabeth , Momin Amin , Pack Carrie , Haynes Chris , Kelly Samuel , Allegood Jeremy , Wang Elaine , Merrill Alfred
Published: May 2012

B102

Fenretinide (4-hydroxyphenylretinamide, 4HPR) is a promising anticancer agent that is being evaluated in human clinical trials. One of the proposed mechanisms of action for 4HPR is to increase the biosynthesis of ceramide, an inducer of apoptosis. Using liquid chromatography, electrospray ionization tandem mass spectrometry (LC ESI MS/MS) for “sphingolipidomic” analysis, we have found (H Wang et al., Mol. Cancer Ther. 7: 2967-2976, 2008) that 4HPR elevates dihydroceramides instead of ceramides due to the inhibition of dihydroceramide desaturase, and also increases the amounts of sphinganine and sphinganine 1-phosphate. In exploring how these metabolites could mediate 4HPR cytotoxicity, we have additionally discovered that dihydroceramides induce autophagy, and whether this is cytotoxic depends on the relative amounts of sphinganine 1-phosphate versus sphinganine--a highly toxic compound due to its effects on multiple signaling pathways as well as being lysosomotrophic. These findings reveal new facets of sphingolipid biology and autophagy, and suggest that the efficacy of 4HPR_and presumably other inhibitors of dihydroceramide desaturase--might be increased by concomitant inhibition of sphingosine kinase. (Acknowledgement: Some of these studies were conducted in collaboration with Dr. Myles Cabot of the John Wayne Cancer Institute, and funded by the Lipid MAPS Consortium grant GM069338.)

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B102.
Abstract B103: Aquaporin 5 (AQP5) is expressed in primary human leukemic cells.
Authors: Chae Young Kwang , Kim Myungshin , Han Kyungja , Jung Chan Kwon , Kim Yonggoo , Sidransky David , Moon Chulso
Published: May 2012

B103

Aquaporins (AQPs) are water channel proteins that facilitate transcellular water movements. H        uman AQPs have previously been associated with increased expression in solid tumors. Recent reports suggest the role of AQP5 in promoting cancer progression,         providing a potential basis for designing a novel therapy targeting AQP5        . However, its expression pattern in hematologic malignancies has not been described yet. Thus, here, we have performed flow cytometry analysis with bone marrow samples of human leukemic patients (n=47). We have found that AQP5 is expressed in human leukemia (57.4%, 27/47) including acute myeloid leukemia (13/22), acute lymphoblastic leukemia (6/10), and chronic myelogenous leukemia (7/14) and chronic lymphocytic leukemia (1/1). However, normal bone marrow samples (n=5) did not show any expression of AQP5. Among 47 samples, cells with only surface expression of AQP5 were 8 (17.0%), cells with only cytoplasmic expression were 12 (25.5%), and cells with both surface and cytoplasmic expression were 7 (14.9%). Of interest, the association between AQP5 expression and resistance in chemotherapy was suggestive (chi square test, p=0.059). 7 out of 8 relapse cases expressed AQP5. Intriguingly, the odds of developing relapse in patients with AQP5 expression (7/20) was 6.7 times that in patients without AQP5 expression (1/19).

In summary, our report demonstrates for the first time that human AQP5 is expressed in all types of primary human leukemic cells. It also provides a basis for pursuing its possible role in the progression of human blood cancers as in solid tumors.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B103.
Abstract B105: Inhibition of angiogenesis by oleanoleic acid-derived triterpenoids: mechanisms of action and potential prostate cancer prevention
Authors: Sogno Ilaria , Tosetti Francesca , Vene Roberta , Cammarota Rosaria , Generoso Luca , Noonan Douglas , Sporn Michael , Albini Adriana
Published: May 2012

B105

Angiogenesis is a limiting step for the switch from a dormant to malignant state in tumor progression. During tumor development tumor cells induce profound changes in the surrounding tissue, leading to the formation of an altered tumor microenvironment that is critical in permitting further tumor growth and tumor progression.. Angiogenesis and inflammation are common targets of many chemopreventive molecules that suppress the antiangiogenic switch in premalignant tumors.We evaluated in vitro and in vivo the antiangiogenic activity of two synthetic oleanoleic acid-derived triterpenoids under study for their chemopreventive and therapeutic potential, CDDO -Me and -Im. In vitro both compounds exhibited a strong inhibitory activity on endothelial cells isolated from umbilical veins (HUVEC). Futher, these compounds inhibited inflammatory cell chemotaxis towards specific chemokine stimului. The triterpenoids interfered with activation of the PI3K/Akt pathway following VEGF stimulation and activation of the NF-kappaB pathway subsequent to TNFalpha stimulation. Moreover CDDO-Me induces cell death in androgen-responsive and unresponsive human prostate cancer cell lines at very low concentrations, by acting agains GS3K pathway (Venè R, Larghero P, Arena G, Sporn MB, Albini A, Tosetti F. Cancer Res. 2008).In vivo CDDO-Im and especially CDDO-Me significantly inhibit neoangiogenesis in the matrigel sponge assay in C57BL mice, reducing both CD31+ cell number and Hb content in the sponges. We tested different schedules of treatment, by administering compounds as prevention before matrigel injection, as therapy after injection and as combination of prevention and therapy. All three protocols reduced angiogenesis when compared to controls the combinationof prevention and intervention was the most effective and at very low dosages. Since currently CDDO-Me is being assessed phase I trials in the US, the potential anti-angiogenic activity of these drugs should be taken into consideration in evaluating efficacy in these trials.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B105.
Abstract B115: Parity alters responses to ionizing radiation in the human mammary gland
Authors: Carter Matthew , Troester Melissa , Johnson Melissa , Jerry D. Joseph , Schneider Sallie
Published: May 2012

B115

Parity is associated with a significant reduction in breast cancer risk. Identification of key pathways, which are altered by parity, will provide important information for the development of chemoprotective agents against breast cancer. Radiation is a potent carcinogen in the mammary gland. It appears to have mutagenic effects through its ability to induce DNA damage, as well as through its ability to induce “bystander effects”. These effects have been shown to be tumor promoting in immortalized cells and involve modulation of various growth factor pathways for stem cell maintenance. We hypothesized that we would be able to obtain important information on parity-induced changes by examining gene expression responses to radiation exposure from the two types of tissue. Methods: Women undergoing elective breast reduction surgery were asked to enroll and donate their excised tissue. Portions of tissue were cultured and then either exposed or not to 5 Gy radiation. The tissue remained in culture for six hours to allow for changes in gene expression. Tissue was fixed for immunohistochemical analysis or RNA was isolated for microarray analysis. Results: A SAM analysis indicated a loose 200 gene signature, which responded to radiation differentially. The breast tissue from nulliparous women showed the most striking changes with increased expression of 80% genes in response to radiation whereas tissue from parous women illustrated no change or decreased expression of these same genes. The other 20% of the genes were strongly down regulated in tissue from nulliparous women in response to radiation, while they were up-regulated or not changed in parous tissue. The major pathways that appeared to be inversely affected in these tissues indicate parity-induced changes in signaling to tissue homeostasis and wound repair, as well as DNA replication and repair.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B115.
Abstract B116: Adjuvant-mediated DNA immunotherapy for cancer
Authors: Yang Ya-Wun , Ma Yi-Fan
Published: May 2012

B116

Cancer immunotherapy invokes immunity against cancerous cells by stimulating the immune response from the host. In an attempt to investigate the effect of adjuvant-mediated therapy, polyethyleneimine (PEI), a nonviral polycationic gene delivery vector, was employed in this study as an adjuvant to investigate the immunostimulatory effect on the murine bone marrow-derived dendritic cells (BMDCs) and in the tumor-bearing animals.

The physicochemical properties of the DNA-PEI complexes was characterized by the size and surface potential measurements. Murine bone-marrow-derived dendritic cells (BMDCs) at day 6 were treated with DNA-PEI complexes at various DNA/PEI ratios, followed by flow cytometric analysis of the expression of costimulatory molecules, including CD40, CD80, and CD86, at 24 h post-treatment. The production of the reactive oxygen species (ROS) after treatment with the PEI in the BMDCs was assessed with 2',7'-dichlorofluorescein diacetate (DCFH-DA) and hydroethidine (HE), followed by flow cytometry. To determine the effect of adjuvant on immunotherapeutic response, approximately 2 x 105 B16F10 melanoma cells were inoculated s.c. on the back of C57BL/6. Control groups were injected with PBS. When the tumor sizes reached 100 mm3 on day 6 after inoculation of B16F10 cells, animals were treated with the PEI-DNA complexes, containing the IL2 or caspase (fusion of caspase-2 prodomain and amino-terminal truncated caspase-3) plasmid DNA. Tumor sizes were measured with a caliper, and the volumes were determined using the formula of (length x width2)/2. Each group contained 4 animals.

Results obtained in this study demonstrated that treatment of BMDCs with PEI or LPS impaired the endocytic activity of BMDCs, and upregulated the expression of the costimulatory molecules, such as CD40 and CD86, suggesting the induction of maturation by PEI on the BMDCs. Treatment of BMDCs with the DNA-PEI complexes also lead to a concentration-dependent production of the reactive oxygen species (ROS), implicating the adjuvant function of PEI on immunostimulation. Injection of the animals with IL-2 or caspase plasmid DNA, complexed with PEI, was able to induce significant inhibition of the growth of tumors in the tumor-bearing animals. These results demonstrated the prevention and therapeutic effect of adjuvant-mediated DNA immunotherapy in the murine melanoma model.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B116.
Abstract B12: Variations in cancer incidence rate sex ratios
Authors: Cook Michael , Dawsey Sanford , Devesa Susan , McGlynn Katherine
Published: May 2012

B12

Cancer epidemiology manuscripts often make passing reference to the fact that cancer rates are often higher among males than females, yet rarely is this theme the subject of investigation. In a hypothesis-generating exercise, we used the Surveillance, Epidemiology, and End Results (SEER) program data to compute age-adjusted (2000 US standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites/histologies for the period 1975-2004. The ten most frequent cancers among males were lung and bronchus (81.6 per 100,000 man-years), colon and rectum (60.2), urinary bladder (31.8), non-Hodgkin lymphoma (18.9), skin excluding basal and squamous (17.0), stomach (12.6), kidney and renal pelvis (12.4), pancreas (12.1), lymphocytic leukemia (7.8) and larynx (7.6). The respective cancers for females were breast (115.1 per 100,000 woman-years), colon and rectum (45.4), lung and bronchus (40.2), non-Hodgkin lymphoma (13.2), skin excluding basal and squamous (12.7), pancreas (9.4), thyroid (8.5), urinary bladder (8.4), kidney and renal pelvis (6.3) and stomach (5.9). The ten cancers with the largest male-to-female IRR during 1975-2004 were Kaposi sarcoma (32.00), lip (7.24), larynx (5.14), mesothelioma (4.64), hypopharynx (4.10), urinary bladder (3.78), esophagus (3.49), tonsil (3.05), oropharynx (2.93), and other oral cavity and pharynx (2.72). Only five cancer sites had a higher incidence in females compared to males: breast (0.01), peritoneum, omentum and mesentery (0.29), thyroid (0.37), gallbladder (0.56), and anus, anal canal and anorectum (0.77). Of the 47 cancers analyzed, 19 had a male-to-female IRR higher than 2. The largest, consistent increases in male-to-female IRR during 1975-2004 were for cancers of the tonsil, oropharynx and esophagus. Cancers for which the male-to-female IRR has been decreasing include: pancreas, gum and other mouth, retroperitoneum, larynx, ureter, lip, nose, nasal cavity and middle ear, Hodgkin lymphoma, cranial nerves and other nervous system, peritoneum, omentum and mesentery, kidney and renal pelvis, thyroid, and lung and bronchus. Male-to-female IRRs may be informative because they are likely not to be subject to artifactual trends attributable to changes in diagnostics, prevention, tumor definitions and coding practices. In addition, male-to-female IRRs may be indicative of differential exposures and/or responses important in the pathogenesis of cancer. Higher levels of tobacco use and alcohol consumption among males have likely contributed to many of the elevated IRRs, but other exposures have also certainly played a role. These observations should serve as a foundation for further studies of sex differences in cancer etiopathogenesis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B12.
Abstract B120: Capturing connection between aging and aging-associated diseases: The case of cancer
Authors: Yashin Anatoli , Akushevich Igor , Arbeev Konstantin , Akushevich Lucy , Kulminski Alexander , Ukraintseva Svetlana
Published: May 2012

B120

Traditional epidemiological studies of cancer often approximate age patterns of the incidence and mortality rates by appropriate parametric functions. Although such formal description is certainly convenient from the demographic point of view it does not allow for biological interpretation of the respective parameters, and, therefore, has limited use beyond demographic applications. The idea to describe cancer hazard rates in terms of biologically interpretable parameters resulted in the development of the research area called the “mathematical modeling of cancer” or “cancer modeling.” These models, however, do not allow for studying either connection between health history events, or links between cancer and aging, detected in a number of recent molecular biological and experimental studies. To take such connections into account, the new models of cancer are needed.

In this paper, we suggest a new approach to modeling health history events associated with cancer and aging. The events include the onset of cancer, death from causes different from cancer, and death of individuals with and without cancer. Besides, this approach allows for taking into account unobservable precancerous changes in tissues, as well as deterioration in individuals’ health associated with the aging related processes. An attractive feature of this model is that all functional forms for the population characteristics can be derived analytically. The model also allows for studying a possible trade-off between two lines of organisms’ defense against a disease. The first is responsible for its vulnerability (robustness) and affects the age of disease onset. The second deals with organism’s resilience, i.e., its ability of coping with disease when it strikes. It affects chances of recovery, as well as duration of staying in an unhealthy state. The model allows for testing hypotheses about possibility of trade-off between these two defense strategies.

The derived model was tested by fitting it to the combined data set consisting of the Surveillance, Epidemiology and End Results (SEER) dataset on cancer incidence and case-fatality data in the U.S. for different types of cancer and the U.S. overall mortality data taken from the Human Mortality Database (HMD). The results of the analyses show that the approach captures non-monotonic age patterns of cancer incidence and case fatality rates. The developed approach is capable of explaining links among health history data and provides useful insights on mechanisms of cancer occurrence, disease progression, other aging related changes, and mortality. The results also indicate that parameters, characterizing individual aging rate, may depend on type of cancer developing in body. Further developments of this approach are discussed.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B120.
Abstract B123: Stopping a silent killer in the underserved Asian community: A novel liver cancer prevention clinic
Authors: Lin Steven , Kang Hyunseung , Aguilar Phillip , Chan Elton , Jeong Monica , Thieu William , Trinh Frank
Published: May 2012

B123

Asian and Pacific Islanders bear a disproportionate burden of liver disease caused by chronic hepatitis B virus (HBV) infection, which is associated with a 25% risk of death from cirrhosis or liver cancer. However, few community based programs exist to tackle this serious public health problem among low income, uninsured Asian and Pacific Islander immigrants. The Hep B Free Clinic is a student-run grassroots organization that focuses on HBV and liver cancer prevention in one of the nation’s largest immigrant communities: San Jose, California. From 2007-2008, we provided free HBV serological screening to 510 patients. For chronically infected patients who elected to undergo follow up monitoring, a series of blood tests were given to evaluate for liver damage (alanine transaminase, ALT), a liver cancer marker (alpha-fetoprotein, AFP), and HBV replication (HBV DNA levels). Of those screened, 17% were chronically infected. Remarkably, one-third (33%) of infected patients were unaware that they were infected. Of those chronically infected, 100% showed signs of active liver damage as measured by elevated ALT, and 9% had elevated AFP tumor markers for hepatocellular carcinoma. Nearly one-quarter (24%) of those chronically infected carried HBV DNA levels that met the criteria for treatment. Patients who were candidates for antiviral therapy were signed up for free drug assistance programs, and those requiring triphasic CT scans for possible liver cancer were referred. Uninfected patients lacking protective HBV antibodies were provided free vaccinations. Our striking findings call for more aggressive liver cancer prevention in this community, including universal screening for HBV.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B123.
Abstract B125: Adipose tissue accumulation of d-limonene with the consumption of a lemonade preparation rich in d-limonene content.
Authors: Miller Jessica , Hakim Iman , Chew Wade , Thompson Patricia , Thomson Cynthia , Chow H-H. Sherry
Published: May 2012

B125

Purpose

d-Limonene is a bioactive food component commonly found in high concentration in citrus peel. It has demonstrated anti-cancer effects in preclinical studies with the most compelling results in mammary carcinogenesis models. Information on the oral bioavailability and tissue disposition of d-limonene in humans is rather limited for extrapolation of preclinical data to human situations. As a fat-soluble compound, d-limonene is more likely to deposit in fatty tissues such as the breast where we hypothesize that biologic activity may be greatest. We conducted a clinical study to determine the systemic and adipose tissue disposition of d-limonene with the consumption of a lemonade preparation rich in d-limonene content.

Methods

Seven healthy adults underwent a one-week washout period during which their diets were void of all citrus. At entry, participants consumed a breakfast that included the freshly prepared lemonade (40 oz containing 0.6 gm d-limonene) in the clinic. Serum and needle fat biopsies of the buttocks were collected 6 hours post-feeding. Participants then consumed 40 oz of freshly prepared lemonade daily for 4 weeks. At completion of the 4-week feeding period, participants repeated the controlled breakfast with high d-limonene lemonade prepared in the clinic followed by repeat serum and fat sampling. Matched pre- and post-intervention fat biopsies (n = 7) and serum samples (n = 6) were analyzed for d-limonene levels using gas chromatography-mass spectrometry.

Results

The d-limonene levels in the initial fat biopsies ranged from non-detectable to 0.79 μM (median = 2.55 μM) concentration. The adipose d-limonene levels increased significantly (p < 0.01) after 4 weeks of intervention with levels ranging from 53.56 to 293 μM (median = 99.68 μM). There was a slight but statistically significant increase (p < 0.05) in serum d-limonene levels after 4 weeks of intervention; initial levels ranged from 0.35 - 0.72 μM (median = 0.46 μM) and post intervention levels ranged from 0.54 - 1.65 μM (median = 1.20 μM). The adipose d-limonene levels were significantly higher than the serum d-limonene levels (p < 0.05).

Conclusions

Oral consumption of high d-limonene lemonade results in d-limonene deposition in adipose tissue in levels much higher than levels in the systemic circulation. Assessing the serum d-limonene levels is not likely to reflect d-limonene exposure in the adipose tissue. In addition, given d-limonene’s anticarcinogenic properties, and because breast tissue is mostly composed of adipose, the data suggests that d-limonene could also accumulate at this site, thus potentially modulating breast cancer risk.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B125.
Abstract B127: Alcohol consumption and risk of testicular germ cell carcinoma
Authors: Biggs Mary , Starr Jacqueline , Doody David , Schwartz Stephen
Published: May 2012

B127

The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy among men aged 20-34, has increased several-fold during the past several decades. The etiology of TGCC is poorly understood and the cause of the increased incidence is unknown. Established risk factors include age, race, personal history of undescended testes, and family history of TGCC, none of which is modifiable.

Alcohol is an established testicular toxicant, causing testicular atrophy, gynecomastia, and disrupted sexual function in alcoholic men. In both alcoholics and non-alcoholic men with moderate intake, alcohol depresses levels of circulating testosterone and luteinizing hormone. We hypothesized that alcohol consumption, particularly during adolescence, increases the risk of TGCC. A single previous epidemiologic analysis of alcohol intake and TGCC found no association.

We conducted a population-based case-control study among 18-44 year-old male residents of three Washington State counties. Cases (n=400) were diagnosed during 1999-2006 with a first, primary TGCC. Controls (n=1,020) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors, including usual consumption of beer, wine, and liquor during the 5 years prior to reference date and during grades 7-12. We used logistic regression models to compute odds ratio (OR) estimates and 95% confidence intervals (CI) for TGCC in men that consumed 1-6, 7-13, and 14+ alcoholic beverages per week compared to those that consumed none, adjusting for age, education, smoking, and current marijuana use.

A higher proportion of cases than controls (73% vs. 66%) reported drinking 1 or more alcoholic beverages per week during the five years prior to reference date, and during grades 9-12 (44% vs. 37%). Consumption of 14+ alcoholic drinks/week was associated with an approximately 60% increased risk of TGCC (OR=1.62; 95% CI: 1.02-2.58) for consumption during the 5 years prior to reference date, and for consumption during grades 9-12 (OR=1.56; 95% CI: 0.99-2.47). The risk of TGCC appeared to be similar for consumption of beer, wine, or liquor, and for consumption of alcoholic beverages during adolescence versus consumption during adulthood. The risk of TGCC associated with 14+ alcoholic drinks/week was higher among men diagnosed with nonseminomas (OR=2.28; 95% CI: 1.08-4.82) than among men diagnosed with seminomas (OR=1.40 95%CI: 0.80-2.42).

Our results indicate that consumption of 14 or more alcoholic beverages per week during adolescence or adulthood may be associated with a doubling of the risk of non-seminomatous TGCC. This is the first study to report an association between alcohol consumption and an increased risk of TGCC. Additional studies are needed to clarify the relationship between alcohol intake and TGCC.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B127.