bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1780: Potentiating chronic myeloid leukaemia treatment using oligomeric disruption and RNAi
Authors: Woessner David W. , Dixon Andrew S. , Lim Carol S.
Published: August 2014

Exploiting multiple pathways to treat Chronic Myelogenous Leukemia (CML) may improve therapeutic efficacy. CML is caused by expression of the tyrosine kinase oncoprotein, Bcr-Abl, in hematopoietic stem cells resulting in an overproliferative granulocyte cell lineage. Increased circulation of granulocytes or granulocyte progenitors floods the circulatory system resulting in organ failure, infection, hemorrhage and eventually death. Imatinib (Gleevec®) therapy is initially effective in about two-thirds of patients; however resistance to this drug may develop over the course of the disease. Recent reports in the literature have combined imatinib therapy with RNA interference (RNAi) technology in vitro resulting in a more effective induction of apoptosis. An engineered peptide which binds the coiled-coil domain of Bcr-Abl prevents oligomerization and transactivation of the oncogene in K562 cells. This disruption of Bcr-Abl reduces proliferation and blocks downstream oncogenic signaling. To enhance therapeutic efficacy we have integrated short hairpin-mediated RNAi against known disease progression or anti-apoptotic proteins. RNAi targets include autophagy promoting factor ATG7, the aberrant oncoprotein MUC-1, and a leukemic stem cell factor Alox5. Experimental constructs were tested in Bcr-Abl containing K562 cells, a CML blast phase model. Colony forming assays, microscopy and flow cytometry were used to asses proliferation, transformative ability, and apoptosis. When combined with a plasmid encoding the peptide which disrupts Bcr-Abl function, an additive or synergistic enhancement of apoptosis is possible. Targeting CML-causing cells simultaneously through disparate cellular pathways promotes a more complete apoptosis in CML than with currently available TKI therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1780. doi:10.1158/1538-7445.AM2011-1780
Abstract 1782: Recombinant B7-DCIg enhances Bacillus Calmette-Guérin (BCG)-induced Th1 and anti-bladder cancer immune responses in vitro and in vivo
Authors: Henning Jonathan R. , Knudson Matthew J. , Langermann Sol , O'Donnell Michael A. , Liu Linda , Luo Yi
Published: August 2014

Introduction and Objective: B7-DCIg, AMP-224, is a recombinant Fc fusion protein composed of the extracellular domain of B7-DC fused to the hinge and Fc domain of IgG. B7-DCIg interacts with PD-1, reduces the dysfunctional CD8+ T cells, and promotes an effective antitumor response. In vitro M. tuberculosis stimulation of human PBMC upregulates PD-1 expression in T cells. We proposed to test if B7-DCIg could enhance BCG-induced anti-bladder cancer immune responses.

Methods: For in vitro evaluation of B7-DCIg on BCG induction of immune responses, mouse splenocytes were prepared and cultured in the absence or presence of Pasteur strain BCG and/or different doses of B7-DCIg for 3 days, followed by ELISA analysis of interferon gamma (IFN-γ) in culture supernatants. For in vivo evaluation of B7-DCIg on BCG induction of immune responses, mice were treated twice weekly with intravesical (i.b.) PBS plus intraperitoneal (i.p.) PBS, i.b. BCG (0.1 OD/dose) plus i.p. IgG2a (400 μg/dose), or i.b. BCG (0.1 OD/dose) plus i.p. B7-DCIg (400 μg/dose). The bladders were collected after treatments 2, 4 and 6, and analyzed for IFN- γ as well as other mRNAs by RT-PCR. ImageJ software was used to quantify PCR products on agarose gels. To evaluate the effect of B7-DCIg on BCG treatment of bladder cancer, C57BL/6 mice were implanted i.b. with luciferase-expressing MB49 (MB49-Luc) bladder cancer cells at day 0 and treated with i.b. BCG (0.1 OD/dose) plus i.p. B7-DCIg (400 μg/dose) twice weekly starting at day 1 for a total of 6 treatments. Control mice were treated with i.b. PBS plus i.p. PBS or i.b. BCG plus i.p. IgG2a. Bioluminescence was measured with Xenogen IVIS imaging at days 7, 14, and 21. At day 23 mice were euthanized and bladder weights measured.

Results: B7-DCIg enhanced BCG-induced splenocyte IFN- γ production in a dose-dependent manner in vitro. B7-DCIg also enhanced BCG-induced bladder expression of IFN- γ and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) mRNAs in vivo. In the orthotopic tumor model, BCG treatment reduced bladder weight by 53% (p = 0.0503 vs. PBS-treated group). Combination of BCG with B7-DCIg further reduced bladder weight by 5% (p = 0.0257 vs. PBS-treated group). In addition, the combination treatment also led to a delay in tumor growth by bioluminescence compared to BCG-treated group.

Conclusions: B7-DCIg enhanced BCG-induced Th1 and anti-bladder cancer immune responses in mice. B7-DCIg may serve as a potential agent in combination with BCG for the treatment of bladder cancer in humans.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1782. doi:10.1158/1538-7445.AM2011-1782
Abstract 1784: Comparing genetically engineered T cells for chimeric TCR versus CD16 + Herceptin for adoptive immunotherapy against HER2 positive breast carcinomas
Authors: Valsesia-Wittmann Sandrine , Clemenceau Béatrice , Jallas Anne-Catherine , Valladeau Jenny , Rousseau Raphael , Blay Jean-Yves , Caux Christophe , Vie Henri
Published: August 2014

The HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Herceptin, a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, majority of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients relapse after 5 years despite Herceptin-based therapy.

The goal of this project is to develop and compare efficiency of two adoptive immunotherapy approaches by genetically engineered T cells to overcome this resistance. For the first approach, we developed T lymphocytes armed with an anti-HER2 chimaeric TCR (CAR-CTL) to directly kill the HER2 positively cells.

For the second approach, we developed T lymphocytes armed with a high affinity IgG FcR (FcγRIIIα, CD16) linked to its transduction chain FC∈RIγ (CD16/γ). In this latter case, the HER2 antigen is pre-targeted by Herceptin Ab to induce a “two step killing” through Antibodies Dependant Cellular Cytotoxicity (ADCC).

Results obtained in vitro demonstrated the high direct killing efficiency of anti-HER2 chimaeric TCR CTL against HER2 amplified breast carcinoma cells BT474 or SKBR3 (>75%). However, abnormal reactivity of these CTL against cells with low to undetectable HER2 expression was observed (15 to 30% of lysis). This constitutive non specific activation of chimaeric TCR might represent an important limitation point for clinical use.

On the other hand, “two step killing” with CD16/γ-CTL demonstrated a very specific cytotoxicity against HER2 positive cells through ADCC only in the presence of Herceptin. We demonstrated that efficacy of specific lysis is linked to levels of CD16/γ expression and appeared independent of HER2 targeted antigen level.

We are comparing in vivo efficacy of both approaches (“one step” TCR vs “two step”ADCC) to induce regression of HER2 + or – breast carcinoma xenograft in immunodeficient mice model NOD-SCID mβ2-/-. Our last results will be presented. Because the alteration of ADCC mechanisms during Herceptin treatment is one rational explanation for the acquired resistance, improving effectors might represent a safe adjuvant treatment to prevent resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1784. doi:10.1158/1538-7445.AM2011-1784
Abstract 1855: Maternal consumption of long chain omega 3 fatty acids decreases risk for mammary gland cancer in the female C(3)1 TAg mouse
Authors: Ion Gabriela , Akinsete Juliana A. , Witte Theodore R. , Hardman W. Elaine
Published: August 2014

Omega 3 fatty acids have been shown to reduce incidence and slow growth of mammary gland cancer in rodent models. Omega 3 fatty acids in the maternal diet are important for normal fetal brain, eye and nervous system development. Since exposure to dietary components during the critical developmental times of gestation and lactation may alter risk for mammary gland cancer in females, we tested whether exposure to increased levels of long chain omega 3 fatty acids (from fish oils) would be preventive or promotional to mammary gland cancer in the offspring. Normal SV40 female mice were fed AIN 76 diets containing either 10% corn oil (control) or 5% of an omega 3 fatty acid concentrate + 5% canola oil. Females were then mated with C(3)1 TAg transgenic mice. Transgene hemizygous offspring were the experimental mice not the original SV40 female mice. On a normal diet the hemizygous mice are expected to have about 100% tumor incidence by 150 days of age. At weaning (3 weeks) pups were randomized to either the corn oil or the fish oil diet, 15-17 mice per group. At 140 days of age, mice never exposed to fish oil (C/C group) had a significantly higher incidence and multiplicity of mammary gland tumors than mice exposed to fish oil throughout life (F/F group). Mice exposed to fish oil during a portion of life (C/F or F/C) had intermediate incidences and multiplicities. Interestingly, omega 3 in the maternal diet alone decreased tumor multiplicity by 50% compared to no omega 3, even when the mouse received a control diet after weaning. If a mouse, developed a tumor the mean tumor masses were not significantly different though the F/F group had a much smaller mean tumor mass. Adequate omega 3 fatty acids in the maternal diet may reduce risk for mammary gland cancer in the offspring.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1855. doi:10.1158/1538-7445.AM2011-1855
Abstract 1857: Src: A novel target for chemoprevention of early stage ER- breast cancer
Authors: Jain Shalini , Shah Maitri , Li Ping , Wang Qingfei , Zhang Siyuan
Published: August 2014

Selective ER modulators (SERMs) have shown significant efficacy for the prevention of ER-positive breast cancer, however, SERMs are not effective for patients whose tumors do not express ER. Therefore, novel agents are needed for prevention and intervention of high risk ER-breast cancers. The c-Src plays a pivotal role in the progression of EGFR- and HER2-dependent ER negative breast cancer. Thus, targeting Src using agents with minimal toxicity or in combination with other novel agents may prevent/intervene progression of early stage ER- breast cancer. In this study we used Saracatinib (AztraZeneca), a Src inhibitor well-tolerated in phase II clinical trials. We examined the effect of Src inhibition using Saracatinib alone or with other agents for cancer prevention using human mammary epithelial pre-malignant cell lines (MECs) and MMTV-neu mouse model. The MCF10A MECs stably overexpressing ErbB2 (10A.ErbB2 cells) form irregular (grape-like) acini in 3D culture condition. Saracatinib treatment prevents the progression of abnormal 3D acini growth as well reverses the abnormal 3D acini growth of 10A.ErbB2 cells to normal phenotype. Our reverse phase protein array data showed that Saracatinib induces the expression of cell cycle inhibitors and apoptosis related molecules, e.g. P27kip1, RAR beta, and PDCD4. Our 3D acini confocal microscopy experiment showed that it induces luminal apoptosis and suppresses cell proliferation in 10A.ErbB2 cells as detected by activated caspase-3 and ki-67 staining respectively. Next, we used MMTV-neu mouse model which develop ER negative lesions at early stage, to examine correlation between Src activation and ER negative mammary cancer progression. MMTV-neu mice mammary lesions exhibited super-activated Src which were negatively associated with estrogen receptor (ER) expression. Our preliminary data showed that Saracatinib-containing regimen inhibited MMTV-neu mice mammary lesions. Our study demonstrated that targeting Src by Saracatinib may be effective for the chemoprevention of early stage ER negative breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1857. doi:10.1158/1538-7445.AM2011-1857
Abstract 1861: PPAR γ mediated involucrin induction in aerodigestive preneoplasia in vitro
Authors: Rosas Rolando R. , Handley Nathan R. , Gaffney Patrick M. , Wuertz Beverly R. , Ondrey Frank G.
Published: August 2014

Effective prevention and monitoring of head and neck malignancy is a critical component of disease control which is significantly underdeveloped. Currently, no validated biomarkers or therapies for human aerodigestive preneoplasia exist. We have increasing interest in PPARγ mediated therapy for oral leukoplakia reversal based on our preliminary clinical trial results. Involucrin expression is associated with squamous differentiation and we hypothesize involucrin would be involved with PPARγ upregulation in differentiation therapies.

In our present study we examined the use of involucrin as marker of PPARγ activity in response to treatment and effect of bexarotene on pioglitazone mediated PPARγ activation in oral leukoplakia. In an analysis of an Affymetrix database of human head and neck tumors (41 tumors compared to 13 normal oral mucosa samples), we found involucrin is expressed 5.6fold higher in normal versus tumor samples (P<0.0001). We found pioglitazone upregulates PPARγ DNA binding activity and involucrin promoter activity via reporter gene assay. Bexarotene positively effects pioglitazone upregulation of these genes via reporter gene assay and increases protein expression via western blot analysis We conclude the PPARγ activator, pioglitazone, can activate involucrin, which may be useful in upregulating differentiation in oral preneoplasia in clinical trialsin combination with bexarotene. Also involucrin has potential use as a biomarker of disease response to treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1861. doi:10.1158/1538-7445.AM2011-1861
Abstract 1866: (−)-Epigallocatechin gallate suppresses azoxymethane-induced colonic preneoplastic lesions in rats by inhibiting the expression and activation of indoleamine 2,3-dioxygenase
Authors: Ogawa Kengo , Hara Takeshi , Shimizu Masahito , Tsurumi Hisashi , Tanaka Takuji , Moriwaki Hisataka
Published: August 2014

Immune escape is involved in the development and progression of several types of tumors. Indoleamine 2,3-dioxygenase (IDO) plays a critical role in the induction of immune tolerance. (−)-Epigallocatechin gallate (EGCG), the major biologically active component of green tea, exerts cancer chemopreventive and anti-carcinogenic effects in various organs. In the present study, we examined the effects of EGCG and 1-methyl-tryptophan (1-MT), an IDO inhibitor, on the development of azoxymethane (AOM)-induced colonic preneoplastic lesions in F344 rats by focusing on the inhibition of IDO activation. To induce colonic premalignant lesions, male F344 rats were given two weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received drinking water containing 0.1% EGCG or 0.2% 1-MT for 4 weeks, starting 1 week before the first dose of AOM. At sacrifice, drinking water with EGCG and 1-MT significantly decreased the total number of aberrant crypt foci and β-catenin accumulated crypts, which overexpresses IDO protein, compared with the control untreated-rats. Drinking EGCG decreased the expression levels of IDO mRNA on the colonic mucosa of experimental rats. In addition, the enzyme activity of IDO, which was estimated by measuring the serum concentration of kynurenine and tryptophan, was also significantly inhibited by treatment with EGCG and 1-MT. These findings suggest that the up-regulation of IDO is associated with colon carcinogenesis and EGCG prevents this carcinogenesis by inhibiting the expression and activation of IDO. Targeting IDO by using EGCG or IDO inhibitor might be, therefore, a promising strategy for the prevention of colon cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1866. doi:10.1158/1538-7445.AM2011-1866
Abstract 1870: Green tea polyphenol EGCG upregulates mir-210 expression in lung cancer cells by transiently stabilizing HIF1α
Authors: Wang Hong , Bian Shengjie , Yang Chung S.
Published: August 2014

Epigallocatechin-3-gallate (EGCG) has been reported to affect many cellular regulatory pathways. This study aims to determine whether EGCG could target microRNA, one of the mechanisms for cells to achieve subtle change in multiple targets. We found that, in both human and mouse lung cancer cells in culture, EGCG specifically upregulated the expression of mir-210, a major microRNA regulated by HIF1α. Furthermore, we found that overexpression of mir-210 led to reduced cell proliferation rate and anchorage-independent growth as well as reduced sensitivity to EGCG. To explore the mechanisms of mir-210 regulation by EGCG, we demonstrated that the regulation was mediated through hypoxia-response element in mir-210 promoter. Consistently, the upregulation of mir-210 was found to be correlated with the transiently stabilized HIF1α in lung cancer cell lines after EGCG treatment. Such stabilization was further shown by the stabilization of HA-tagged HIF1α, but not the P402A/P564A mutated HIF1α, by EGCG, suggesting that EGCG targets the oxygen-dependent degradation (ODD) domain. Direct evidence was obtained by affinity binding assay showing that EGCG specifically binds HIF1α with a Kd=3.47 μM. This result implies that EGCG binding interferes with the hydroxylation of key Pro residues in the ODD domain, preventing HIF1α from the Pro hydroxylation-induced ubiquitination and subsequent proteosome-mediated degradation. In summary, our results demonstrate the elevation of mir-210 by EGCG and this is mediated by the stabilization of HIF1α. This event may contribute to the anti-cancer activity of EGCG (Supported by NIH grant CA 122474 and CA133021).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1870. doi:10.1158/1538-7445.AM2011-1870
Abstract 1872: A prospective cohort study of shift work and pancreatic cancer risk in Japanese men
Authors: Lin Yingsong , Kikuchi Shogo , Yagyu Kiyoko , Kurosawa Michiko , Tamakoshi Akiko
Published: August 2014

The etiology of pancreatic cancer remains largely unknown. The lack of effective screening tools coupled with the dismal prognosis make it crucial to identify modifiable risk factors that can be incorporated into a prevention strategy for pancreatic cancer. Approximately 15-20% of the working population in industrialized countries engages in night-shift work, drawing considerable interest in the effect of such work patterns on health, including on the formation of cancers. We analyzed data from a large-scale, prospective cohort study of middle-aged and elderly Japanese individuals (the JACC Study) to test the hypothesis that rotating shift work might be associated with an increased risk of pancreatic cancer. Our analysis was restricted to 18,745 men who were 40-60 years of age at baseline (1988-1990) and who reported working full-time or were self-employed. Information on occupation and lifestyle factors was collected using a self-administered questionnaire. Mortality from pancreatic cancer was ascertained from the causes of death recorded on death certificates. The Cox proportional hazards model was used to estimate relative risk (RR) and confidence interval (CI) for the association between shift work and pancreatic cancer risk. A total of 70 pancreatic cancer deaths were observed until Dec 31, 2008. Overall, we found no statistically significant increase in the risk of death from pancreatic cancer associated with rotating shift work. As compared to day-shift workers, the RRs were 0.89 (95%CI: 0.40-1.96) for rotating shift workers and 0.27 (0.04-1.93) for fixed night-shift workers, after adjustment for potential confounding factors. In conclusion, shift work is not associated with the risk of death from pancreatic cancer in this cohort of Japanese men.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1872. doi:10.1158/1538-7445.AM2011-1872
Abstract 1873: Low-dose radiation exposure and the risk of developing acoustic neuroma
Authors: Han Yueh-Ying , Berkowitz Oren , Donovan Maryann , Talbott Evelyn
Published: August 2014

Aside from the rare hereditary syndrome of Neurofibromatosis type 2 or high-dose ionizing radiation exposure, the causes of the vast majority of acoustic neuroma development remain unclear. A hospital-based case-control study was conducted to investigate the roles of exposure to commonly used diagnostic tools and phone technology that emit low dose ionizing and non-ionizing radiation in the etiology of acoustic neuroma.

A total of 353 cases were recruited from a cohort of individuals who underwent Gamma Knife Radiosurgery as primary or adjuvant management of acoustic neuroma between the years 1997-2007 at the Center for Image Guided Neurosurgery, University of Pittsburgh Medical Center (UPMC). Matched by age and gender, 353 controls without brain tumor history were recruited from the Neurosurgery spine and pain clinics at UPMC. Information on demographic characteristics, medical exposure to radiation, use of cell phone, and other potential risk factors of acoustic neuroma were collected via questionnaire by trained interviewers at clinics. Conditional multivariate logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) to assess risk of acoustic neuroma associated with low-dose radiation exposure.

Adjusted for education, smoking, drinking, occupational exposure to noise, previous history of head injury, and family history of cancer, exposure to dental x-ray every 2-3 years and at least once a year was significantly associated with development of acoustic neuroma compared to individuals exposed to dental x-ray less than once every five years (OR=3.57, 95% CI = 1.54-8.23 and OR=2.31, 95% CI=1.06-5.04, respectively). History of full mouth or panorax X-ray exam (OR=1.35, 95% CI=0.76-2.41), CAT or CT scan of head or neck (OR=0.61, 95% CI=0.30-1.23), and other X-ray exam of head or neck (OR=0.77, 95% CI=0.41-1.45) were not found to be related to development of acoustic neuroma. Use of cell phones or cordless phones for more than 10 years was not significantly associated with development of acoustic neuroma (OR=1.30, 95% CI=0.53-3.20 and OR=1.20, 95% CI=0.43-3.37, respectively).

We found that frequent exposure to dental X-rays may contribute the development of acoustic neuroma, although does-response effect was not found. Further epidemiologic studies are necessary to confirm the association of diagnostic dental X-rays exposure and development of acoustic neuroma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1873. doi:10.1158/1538-7445.AM2011-1873
Abstract 1880: Sun exposure and the risk of prostate cancer in an Asian population: The Singapore Prostate Study
Authors: Chia Sin-Eng , Wong Kin Yoke , Lau Weber , Cheng Christopher
Published: August 2014

INTRODUCTION: Recent epidemiological studies have reported an inverse association between sun exposure and prostate cancer which may be related to vitamin D or other factors, but these studies have been conducted almost exclusively in the Western countries, and in temperate locations. The objective of this paper is to study the association of sun exposure and risk of prostate cancer (PC). METHODS: The Singapore Prostate Cancer study is a hospital-based, case-control study conducted in Singapore between April 2007 and May 2009. Singapore residents (ethnic Chinese/Malays/Indians) aged 50 and above formed the study population. Detailed information on outdoor activities under sun (for recreational or occupational purposes) during childhood and in adulthood, skin color and sun sensitivity, and other information on other possible risk factors were collected in personal interviews. A total of 240 incident prostate cancer cases and 268 controls were recruited. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression analysis, adjusted for age, ethnicity, education, family history of any cancers, BMI and skin color. RESULTS: Subjects with black/dark brown eye compared with light brown pigmentation have an adjusted OR of 5.88 (3.17-10.92) of getting PC. The adjusted ORs for skin color “Light Tan” and “Tan/Dark brown/black” subjects when compared with of “very white/white” subjects were 4.43 (2.26-8.69) and 7.62 (3.41-17.03); respectively. Sunburn frequency is associated with increase risk of PC. The adjusted ORs with “Never” sunburn as referent were 1.30 (0.71-2.39) for “Seldom”; 2.27 (0.96-5.35) for “Occasionally”; 4.30 (1.66-11.16) for “Frequently”. This trend was significant (p=0.001). Sun exposure in adulthood (hrs/week) is also associated with increase risk of PC. The adjusted ORs with “0 hrs” sunburn as referent were 1.71 (0.90-3.25) for “0.1-10hrs” and 2.03 (1.09-3.81) for “>10 hrs”. This trend was significant (p=0.017). CONCLUSION: Pigment characteristics (eye and skin color) and sun exposure and possible sensitivity showed association with risk of PC, after adjusting for likely confounders. We observed an overall risk of PC among subjects who reported spending time outdoors regularly.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1880. doi:10.1158/1538-7445.AM2011-1880
Abstract 1922: Ethnic and racial differences in colorectal cancer
Authors: Simon Michael S. , Thomson Cynthia A. , Pettijohn Erin , Kato Ikuko , Rodabough Rebecca , Lane Dorothy , Hubbell F Allan , O'Sullivan Mary Jo , Adams-Campbell Lucille L. , Mouton Charles P. , Abrams Judith , Chlebowski Rowan T.
Published: August 2014

Introduction: The Women's Health Initiative (WHI) provides a robust database to determine whether differences in known colorectal cancer (CRC) risk factors influence ethnic and racial differences in incidence and mortality. Methods: The WHI is a multi-center longitudinal study of postmenopausal women age 50-79 years recruited from 40 centers across the US. Baseline self-administered questionnaires were used to collect self-identified ethnicity or race, other demographics and health status. Cancer screening information was collected annually and cancer diagnoses were centrally adjudicated. Cox proportional hazards regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for invasive CRC by ethnicity/race. Results: The ethnic and racial composition of the sample is 131,481 (84%) White, 14,323 (9%) African American (AA), 6,362 (4%) Hispanic, 694 (<1%) Native American and 4,148 (3%) Asian/Pacific Islander (API). After a mean follow-up of 10.8 years (SD 2.9), CRC incidence was highest among AA (annualized percent 0.14%), followed by Whites and Native Americans (0.12% each), API (0.10%) and Hispanics (0.08%). After adjustment for age and cohort assignment, Hispanics had a lower risk of CRC compared to Whites, HR 0.73 (95% CI: 0.54-0.97) (p=0.03), and AA had a marginally greater risk, HR 1.16 (95% CI: 0.99-1.34), p=0.06. Adjustment for other covariates, eliminated the difference in incidence between AA and Whites (HR 0.99, 95% CI: 0.82-1.20), however the difference in incidence between Hispanics and Whites increased (HR 0.68, 95% CI: 0.48-0.97), p = 0.03. Conclusions: Differences in CRC risk between Hispanics and Whites are not explained by sociodemographic or behavioral factors in the WHI cohort.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1922. doi:10.1158/1538-7445.AM2011-1922
Abstract 1927: Race, health conditions, and endometrial cancer survival
Authors: Olson Sara H. , Atoria Coral L. , Cote Michele L. , Cook Linda S. , Rastogi Radhai M. , Soslow Robert , Brown Carol L. , Elkin Elena
Published: August 2014

Background: Endometrial cancer shows the largest disparity in outcomes between black and white cases of any cancer in the US. Black women have higher prevalence of diabetes and hypertension, conditions that might be associated with poorer survival. Our objectives were to determine whether the presence of diabetes or hypertension was related to disease-specific survival and to investigate whether accounting for these conditions influenced the survival difference for the two racial groups. Methods: Using Surveillance, Epidemiology and End Results cancer registry data linked with Medicare claims, we identified women with diabetes (as defined by Hebert et al, Univ of Minn Rural Health Research Center Working Paper 22, March 1998) and hypertension (defined as 2 claims at least 30 days apart for ICD9 codes 401-404) and investigated the influence of these conditions on survival in black and white women age >=66 diagnosed with endometrial cancer between 2000 and 2005. We used Cox proportional hazards models, adjusted for demographics, tumor characteristics, and treatment, to evaluate whether presence of diabetes or hypertension influenced disease-specific survival and whether adjustment for these factors influenced the difference in outcome between blacks and whites. Results: 22% of whites and 41% of blacks with endometrial cancer met the criteria for diabetes and 52% and 73%, respectively, met the criteria for hypertension. Having diabetes was associated with poorer endometrial cancer specific survival in whites (HR=1.19, 95% CI 1.06-1.35) but not in blacks (HR=0.97, 95% CI 0.73-1.30), after adjustment for variables related to demographics, tumor characteristics, and treatment. Presence of hypertension did not significantly influence survival in either group. As expected, both overall survival and endometrial cancer specific survival were poorer in black women compared to whites, with adjusted hazard ratios for blacks of 1.19 (95% CI 1.08-1.31) for overall survival and 1.30 (95% CI 1.11-1.52) for disease-specific survival. Very little influence was found for diabetes or hypertension for either overall or disease specific survival: after adjustment for these variables the hazard ratios were 1.16 (95% CI 1.05-1.28) for overall survival and 1.27 (95% CI 1.08-1.49) for disease-specific survival. Conclusions: Diabetes influences disease-specific survival only in white women, while hypertension is not associated with disease-specific survival. The racial disparity in survival after a diagnosis of endometrial cancer is not explained by the presence of diabetes or hypertension.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1927. doi:10.1158/1538-7445.AM2011-1927
Abstract 1928: Travel distance and pattern of care for laryngeal cancer in Kentucky
Authors: Huang Bin , Gal Thomas J. , Han Daikwon , Shelton Brent J. , Tucker Thomas C. , Dignan Mark
Published: August 2014

Introduction: Previous studies have found that access to medical care was associated with stage at cancer diagnosis and receipt of treatment. For laryngeal cancer, radiation related treatments are a preferred option in the majority of cases. Travel distance to the radiation facilities may impact patient access to radiation treatment, especially in a rural mountainous state such as Kentucky. The aim of the study is to assess the influence of travel distance to the nearest radiation center and other factors on inclusion of radiation in the first course treatment for laryngeal cancer.

Study Population and Methods: 1995-2006 Kentucky Cancer Registry data were used for this study. A total of 2099 patients age 20 and older at diagnosis with no previous history of cancer and with known TNM stage laryngeal cancer (C32.0-C32.2) were included for the analysis. The road travel distance from their home address to the nearest radiation center was calculated based on road network in GIS. Poverty rate and high school education rate at census tract level were linked with the case data. The SAS procedure GLIMMIX was used to fit random intercept logistic models to predict the association between treatment and other demographic and clinic factors.

Results: About 78% of patients received treatment that included radiation as part of first course treatment. The rate of radiation related treatment increased from 68% to 79% in the study period. The average travel distance was 13.5 miles for the group receiving radiation treatment vs. 13.9 miles for the group not receiving radiation treatment. The multivariate logistic model indicated that the travel distance was not associated with radiation treatment. In addition, patients diagnosed recently (per year) were more likely to have radiation related treatment (OR=1.05, p=0.001), and patients treated in large hospitals were positively associated with radiation treatment (OR=2.72, p=0.002) than patients in small hospitals.

Conclusions: Although longer travel distance has been found as a barrier for cancer patients living in this rural state, we did not find a similar association for laryngeal cancer. The increasing use of radiation related treatment is encouraging and may be associated with increasing availability of radiation centers in this region. Under utilization of radiation treatment for patients treated in smaller hospitals is a serious concern. Further research is needed to investigate the cause of this under utilization.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1928. doi:10.1158/1538-7445.AM2011-1928
Abstract 1935: EBP50 inhibits breast cancer cell proliferation by blocking EGFR phosphorylation
Authors: Zheng Junfang , Yao Wenfang , Feng Duiping , Bian Weihua , Xiong Ying , Yang Xiaomei , Yang Longyan , Zhou Yunying , Zhai Renyou , He Junqi
Published: August 2014

EBP50 (Ezrin-radixin-moesin-binding phosphoprotein-50, also known as NHERF, NHERF1) has been reported to interact with epidermal growth factor receptor (EGFR) and enhance EGFR activity and its downstream ERK signaling in a cervical cancer cell line HeLa. However, our previous results demonstrated that EBP50 could suppress breast cancer cell proliferation, suggesting its inhibitory effect on EGFR signaling in breast cancer cell. So we detected the effect of EBP50 expression on EGF-induced cell proliferation and the activation of EGFR signaling in breast cancer cell lines, MDA-MB-231 and MCF-7. In MDA-MB-231 cells which expressed low level of EBP50, EBP50 over-expression inhibited EGF-induced cell proliferation. In MCF-7 cells which expressed high level of EBP50, EBP50 knockdown promoted EGF-induced cell proliferation. EBP50 was reported to interact with EGFR via its carboxyl terminal regulatory domain, which is adjacent to the autophosphorylation domain of the receptor, so it is possible that the association of EBP50 and EGFR mask the phosphorylation site of EGFR so as to prevent EGFR activation. To test this hypothesis, we detected the phosphorylation status of EGFR in the presence or absence of the EBP50 expression. Over-expression of EBP50 in MDA-MB-231 inhibits EGF-stimulated EGFR phosphorylation, and knockdown of EBP50 in MCF-7 cells led to the enhanced EGF-stimulated EGFR phosphorylation. Meanwhile, the total expression levels of EGFR were not affected by the different expression level of EBP50 during EGF stimulation. In the case of EBP50 expression on the EGFR downstream signaling, EBP50 over-expression inhibited EGF-stimulated ERK activity in MDA-MB-231 cells, and EBP50 knockdown resulted in the enhanced EGF-stimulated ERK activity in MCF-7 cells. These data are consistent with results of MDA-MB-231 and MCF-7 cell lines pretreated with EGFR tyrosine kinase inhibitor-AG1478, that EGF-stimulated ERK activity was inhibited when EGFR phosphorylation was blocked. Taken together, our results demonstrated that EBP50 can suppress EGF-induced proliferation of breast cancer cells by retarding EGFR phosphorylation and blocking EGFR downstream signaling in breast cancer cells. These results provide further insights into the molecular mechanism by which EBP50 regulates the development and progression of breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1935. doi:10.1158/1538-7445.AM2011-1935
Abstract 1936: Notch signaling is switched off and displays properties of a tumor suppressor in Ewing's sarcoma
Authors: Bennani-Baiti Idriss M. , Aryee Dave N.T. , Ban Jozef , Kauer Maximilain , Mühlbacher Karin , Machado Isidro , Amann Gabriele , Llombart-Bosch Antonio , Kovar Heinrich
Published: August 2014

Notch can act as an oncogene or as a tumor suppressor and thus can either promote or inhibit tumor cell growth. To establish Notch status in Ewing's sarcoma family of tumors (ESFT), we investigated the Notch pathway by gene expression profiling meta-analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We find that although Notch receptors were highly expressed, Notch did not appear to be active as evidenced by the absence of Notch receptors in cell nuclei. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch, was also restricted to outside of the nucleus in the majority of tumors, and analysis of HES1 gene targets indicated HES1 to be transcriptionally inactive. Neither forced activation nor pharmacological or genetic blocking of Notch affected HES1 expression in ESFT cells, indicating HES1 expression to be uncoupled from the Notch pathway. Additional functional studies in ESFT cell lines confirmed Notch to be switched off. Finally, unlike experiments in which HES1 expression was modulated, experimental activation of Notch in ESFT cell lines via several means blocked cell proliferation. These indicate that HES1 is uncoupled from Notch in ESFT, that EWS-FLI1-mediated inhibition of Notch contributes to ESFT aggressive cell growth, and supports a role for Notch in ESFT tumor suppression, at least partly through the Notch effector HEY1.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1936. doi:10.1158/1538-7445.AM2011-1936
Abstract 1937: Nemo-like kinase expression is altered during prostate cancer progression
Authors: Brown Lisha G. , Pitts Tiffany EM , Zhang Xiaotun , Vessella Robert L. , Corey Eva
Published: August 2014

MAPKs have been implicated in cancer progression. We have previously shown that Nemo-like kinase (NLK) inhibits androgen receptor signaling and induces apoptosis in prostate cancer cell in vitro. The objective of this study was to investigate NLK expression in clinical samples of primary prostate cancer and in prostate cancer xenografts using immunohistochemistry. TMAs containing primary prostate cancer samples and prostate cancer xenograft tissues were used. Our data show that NLK immunoreactivity is 0.34 higher in primary prostate cancer vs. normal prostate epithelium (p=0.01) but our analysis did not reveal any significant correlations of NLK immunoreactivity with PSA, Gleason score or recurrence of the disease. When we examined NLK immunoreactivity in prostate cancer xenografts our results show that there are signficant differences in cellular localization of NLK between xenografts that respond well to castration vs. those that do not. Xenografts that respond well to castration exhibit lower levels of NLK in nucleoplasm and higher leves of NLK in nucleoli vs. xenografts that do not respons well to castration (t=−4.211, p<.0001, and z=3.994, p<.0001 respectively). Our in vitro studies show that DHT increases localization of NLK in nucleoli of LNCaP. NLK levels in nucleoli negatively correlate with levels of nucleophosmin, a protein involved in regulation of proliferation, in the xenografts and in LNCaP cells in vitro. Interestingly we have also shown that in vitro NLK stimulates wnt signaling in LNCaP cells and this effecst in dependent on expresison of androgen receptor. In summary our data show that NLK expression is altered during prostate cancer progression and that NLK alters androgen receptor and wnt signaling pathways. Further studies to investigate mechanisms of NLK effects and NLK involvement in response to androgen ablation in prostate cancer are ongoing.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2011-1937
Abstract 1940: Reg4 induces the expression of D-type cyclins and associated kinases to induce mitotic division of human colorectal cancer cells
Authors: Bishnupuri Kumar S. , Sainathan Satheesh K. , Luo Qizhi , Dieckgraefe Brian K.
Published: August 2014

Background: Cyclins and cyclin-dependent kinases (CDK) are important component of the cell cycle machinery. D-type cyclins are positive regulators of cell cycle and a known target of Wnt/β-Catenin signaling. Cyclin D1 and cyclin D3 play a prominent role in differentiation and proliferation and is highly upregulated in many cancers. Recent studies also showed frequent upregulation of regenerating (Reg) gene 4 expression in many human gastrointestinal (GI) malignancies including colorectal cancer (CRC). We further observed a Reg4-mediated increase in β-Catenin expression and its subsequent nuclear translocation. Therefore, we tested the hypothesis that Reg4 induces the expression of D-type cyclins and associated kinases to induce the mitotic division of human CRC cells.

Methods: Real time RT-PCR and western blot analyses were performed to determine the effects of Reg4 treatments on the expression of D-type cyclins and associated kinases. Mitotic and MTT assays were performed to determine its association with regulation of mitotic division and proliferation of human CRC cells.

Results: Following real-time RT-PCR and western blot analyses we observed a time-dependent increase in cyclin D1 and D3 expression following the addition of recombinant human Reg4 (rhR4) to the cultures of HCT116 and HT29 human CRC cells. Furthermore, addition of rhR4 to the cell cultures also led to an increased expression of CDK4 and CDK6, the known kinase partners of cyclin D. We previously observed the involvement of Akt kinase, GSK-3β, and β-Catenin activities in mediating Reg4-signaling. Therefore, in the present study we utilized a specific Akt inhibitor as an antagonist and SB216763, an inhibitor of GSK-3β as an agonist of Reg4-signaling and examined their effects on expression of D-type cyclins and mitotic index of human CRC cells. Treatments of specific Akt inhibitor (10 μM) to the human CRC cells significantly inhibited the expression of cyclin D1 and D3, and subsequently inhibited their mitotic index. Furthermore, an addition of rhR4 (200 nM) to the cultures of human CRC cells pretreated with specific Akt inhibitor (10 μM) did not increase the expression of these cyclins, hence the mitotic index of human CRC cells. In addition, the treatments of SB216763 (10 μM) positively modulated the Reg4-signaling and led to significant increases in the expression of D-type cyclins, hence mitotic index of human CRC cells.

Conclusions: These results suggest that Reg4 is a potent regulator of mitotic division of human CRC cells and involves Akt kinase and GSK-3β as important mediators to induce the expression of D-type cyclins.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1940. doi:10.1158/1538-7445.AM2011-1940