bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4769: Growth hormone-releasing hormone (GHRH) antagonist attenuates cell motility of human endometrial cancer by down-regulating Twist and N-Cadherin expression.
Authors: Wu Hsien-Ming , Schally Andrew V. , Leung Peter C.K.
Published: August 2014

Introduction :

More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastases. GHRH is secreted by the hypothalamus and stimulates the synthesis and secretion of GH from the pituitary. The expression of GHRH and its receptors has been demonstrated in peripheral tissues. In recent years, many antagonistic analogs of GHRH were developed. GHRH antagonists have effects on tumor cells, but the underlying molecular mechanism is not well known. Although Twist and N-Cadherin play important roles in cancer cell motility, it is not established whether Twist and N-Cadherin are required for GHRH antagonists-attenuated cell motility on endometrial cancer cells. In the present study, we examined the action of GHRH antagonist-attenuated cell motility and the mechanisms of the action in endometrial cancer.

Methods and Materials :

Endometrial cancer cell line Ishikawa and ECC-1 were derived from an endometrial adenocarcinoma. GHRH antagonist MIA-602 was synthesized by solid phase methods. Cell motility was estimated by invasion and migration assay. Immunoblot analysis and RT-PCR were performed to investigate the expression of GHRH receptor, GHRH, and the effects of GHRH antagonist in Twist and N-Cadherin. Human GHRH receptor siRNA was used to knock down the expression of GHRH receptor for elucidating the mechanisms of GHRH antagonist action.

Results :

The GHRH receptor was expressed in human endometrial cancer cells. The GHRH antagonist attenuated cell motility in a dose-dependent manner. GHRH antagonist-attenuated cell motility was restored in cells pretreated with GHRH receptor siRNA. GHRH antagonist suppressed Twist and N-Cadherin signaling. Knockdown of GHRH receptor with siRNA recovered the expression of Twist and N-Cadherin signaling.

Conclusions

These results demonstrate that the GHRH antagonist suppressed the cell motility of human endometrial cancer through the GHRH receptor and the down-regulation of Twist and N-Cadherin. Our findings represent a new concept regarding the mechanisms of GHRH antagonist-suppressed cell motility in human endometrial cancer, suggesting the possibility of GHRH antagonist as a potential therapeutic intervention for the treatment of human endometrial cancer.

Citation Format: Hsien-Ming Wu, Andrew V. Schally, Peter C.K. Leung. Growth hormone-releasing hormone (GHRH) antagonist attenuates cell motility of human endometrial cancer by down-regulating Twist and N-Cadherin expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4769. doi:10.1158/1538-7445.AM2013-4769

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 477: Long-term protection against B16F1 melanoma upon vaccination with tumor cell lysate combined with LTX-315 as a novel adjuvant.
Authors: Berge Gerd , Camilio Ketil Andre , Rekdal Øystein , Areffard Ali
Published: August 2014

Here, we demonstrate the potency of LTX-315 as a novel adjuvant in combination with B16F1 tumor cell lysate vaccine. LTX-315 is a chemically modified cationic peptide derived from a family of molecules called host defense peptides. Through its cytolytic activity, the main mechanism of LTX-315 is the induction of immunogenic cell death which leads to local inflammation by recruitment and activation of the immune system at the injection site. This is important to obtain strong vaccine-specific immune responses. We have selected the B16F1 melanoma model for this study since this tumor model is poorly immunogenic and have been described for being notoriously difficult to treat. Mice were vaccinated once a week for 4 weeks and challenged with viable B16F1 cells s.c. two weeks after the last vaccination. Tumor protected mice were re-challenged 10 weeks post primary challenge. In contrast to other studies where tumor growth inhibition is observed for this model, our results not only demonstrate complete tumor regression, but also long-term protection against the B16F1 melanoma. In total, 14/18 animals had established long-term protection which indicates induction of immunological memory against B16F1 melanoma. In conclusion, LTX-315 is a novel adjuvant with substantial potency to induce strong and durable immune responses against the poorly immunogenic B16F1 in vivo. The efficacy of vaccinations to further document the potency of LTX-315 as an adjuvant are currently studied in therapeutic and metastatic B16 models and other orthotopic models. The present results indicate the potential of LTX-315 to be a next generation adjuvant for therapeutic vaccines based on tumor-associated antigens (TAA).

Citation Format: Gerd Berge, Ketil Andre Camilio, Øystein Rekdal, Ali Areffard. Long-term protection against B16F1 melanoma upon vaccination with tumor cell lysate combined with LTX-315 as a novel adjuvant. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 477. doi:10.1158/1538-7445.AM2013-477
Abstract 4773: Is upregulation of CYP2R1-, CYP27B1- and CYP24 genes in clear cell renal cell carcinoma tissue involved in carcinogenesis.
Authors: Urbschat Anja E. , Paulus Patrick , von Quernheim Quirine Freiin , Brück Patrick , Ramos-Lopez Elizabeth
Published: August 2014

Renal cell carcinoma (RCC) represent approximately 3-5% of all malignancies reported each year. Among these clear cell renal cell carcinoma (ccRCC) represent the most frequently diagnosed histological classification accounting for 80% of renal cell carcinoma. The incidence has been reported to be higher in countries located at higher latitudes. In this context UVB-light which is essential for the synthesis of vitamin D has been inversely associated with the development of diverse carcinomas including renal cell carcinoma. Further steps of vitamin D synthesis are performed by CYP2R1, CYP27B1 and CYP24.

We therefore investigated the quantitative mRNA expression of the CYP2R1, CYP27B1 and CYP24 genes in patients (n=29) with ccRCC. For this purpose total RNA was isolated from tumor and corresponding adjacent healthy tissues of all patients and integrity was assessed on a denaturing agarose gel stained with ethidium bromide. Intact RNA was transcribed using random hexameric primers and reverse transcriptase. Reverse transcription was performed and amplified by real-time PCR. Statistic association was evaluated by Mann-Whitney-Test and Kruskal-Wallis-Test. A P value less than 0.05 was considered significant.

mRNA of all three genes (CYP2R1, CYP27B1 and CYP24) was expressed in both normal and carcinoma tissue with a significant upregulation in carcinoma tissue compared to normal tissue (p<0.0001). In tumor tissue CYP24 displayed a significantly higher expression than CYP27B1 or CYP2R1. Furthermore CYP27B1 showed a higher expression than CYP2R1 (p<0.0001). No differences in the expression of CYP2R1, CYP27B1 and CYP24 were found in normal renal tissue.

We therefore conclude that differing gene expression of CYP2R1, CYP27B1 and CYP24 in normal- and carcinoma tissue could be involved in the pathogenesis of renal cell carcinoma.

Citation Format: Anja E. Urbschat, Patrick Paulus, Quirine Freiin von Quernheim, Patrick Brück, Elizabeth Ramos-Lopez. Is upregulation of CYP2R1-, CYP27B1- and CYP24 genes in clear cell renal cell carcinoma tissue involved in carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4773. doi:10.1158/1538-7445.AM2013-4773
Abstract 4775: HPV16-E2/E4, -E6 and -E7 genes and HPV-disrupted human genes show large variation in expression levels in OSCC independent of the viral physical status.
Authors: Klussmann Jens P. , Olthof Nadine C. , Huebbers Christian U. , Kolligs Jutta , Ramaekers Frans CS , Preuss Simon , Drebber Uta , Vucic Emily , Lam Wan , Kremer Bernd , Speel Ernst Jan
Published: August 2014

Infection with high-risk human papillomavirus (HPV) type 16 is an independent risk factor for the development of oropharyngeal squamous cell carcinomas (OSCC). However, it is unclear whether viral integration is an essential hallmark in the carcinogenic process of OSCC and whether HPV integration correlates to the level of viral gene transcription and influences the expression of disrupted genes.

HPV16 integration sites were assessed in 75 patients with HPV16-DNA- and p16INK4A-positive OSCC using Detection of Integrated Papillomavirus Sequences (DIPS)- as well as Amplification of Papillomavirus Oncogene Transcripts (APOT)-PCR. Quantitative RT-PCR assays were carried out to determine the viral E2/E4, E6 and E7 gene expression levels. Expression levels of 7 human genes disrupted by the virus were extracted from mRNA expression profiling data of 32 OSCC. Nuclear localization of HPV16 was visualized using Fluorescence In Situ Hybridization (FISH) in 59 OSCC, and corresponding viral copy numbers were assessed by quantitative RT-PCR in 61 tumors.

We identified 37 HPV16-human fusion products indicating viral integration in 29 (39%) OSCC. In the remaining tumors (61%) only episome-derived PCR products were detected. When comparing OSCC with or without an integration-derived fusion product, we neither found significant differences in the mean expression of the viral genes E2/E4, E6 and E7, the nuclear FISH staining patters nor the viral copy numbers per cell. The expression of the HPV-invaded genes also did not significantly differ when comparing the expression in the affected tumor with the expression of that gene in either group of OSCC.

In conclusion, our data do not support the hypothesis that integration affects the levels of viral and/or HPV-disrupted human gene transcripts. Thus constitutive, rather than a high level, of expression of oncogene transcripts appears to be required in HPV-related OSCC.

Citation Format: Jens P. Klussmann, Nadine C. Olthof, Christian U. Huebbers, Jutta Kolligs, Frans CS Ramaekers, Simon Preuss, Uta Drebber, Emily Vucic, Wan Lam, Bernd Kremer, Ernst Jan Speel. HPV16-E2/E4, -E6 and -E7 genes and HPV-disrupted human genes show large variation in expression levels in OSCC independent of the viral physical status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4775. doi:10.1158/1538-7445.AM2013-4775
Abstract 4778: Dissecting the gender disparity of hepatocellular carcinoma: roles of HBV X protein and androgen receptor.
Authors: Chiu Yung Tuen , Ng Irene Oi Lin
Published: August 2014

Hepatocellular carcinoma (HCC) is a leading cancer worldwide and especially prevalent in Southeast Asia, due to prevalent hepatitis B virus (HBV) infection. HBV-associated HCC has a male predominance, with a male-to-female ratio of about 4-5:1. HBV is a partially double-stranded DNA virus containing four overlapping open reading frames. Among them, X gene is most frequently integrated into host genome naturally and plays an important role in hepatocarcinogenesis. In male HBV carriers, the risk of HCC development is significantly increased in those with higher serum androgen and androgen receptor (AR) activity. HBV infection may, therefore, particularly cooperate with male-specific AR signalling to accelerate hepatocarcinogenesis. In this study, we hypothesized that HBx cooperated with male-specific AR signalling to enhance hepatocarcinogenesis, and natural HBx truncated mutants exerted different effects on this AR signalling. Firstly, we demonstrated that the expression of androgen receptor was significantly higher in the HCC cells when compared to the immortalized non-tumorigenic normal liver cell lines (LO2 and MIHA). Moreover, the HCC cell lines with higher metastatic potential (MHCC-97L, MHCC-97M and LM3) had a higher AR protein expression level, suggesting a role of AR in HCC development and progression. In human HBV-associated HCC tissues, we found that the natural COOH-terminal truncated HBx was more frequently detectable in HCC tumors from male than female patients (43% and 11%, respectively). Here, we also showed that the natural COOH-terminal HBx truncated mutants HBx ΔC3 (1-95 a.a) and HBx ΔC4 (1-89a.a) physically interacted with AR, indicating the possibility of HBx ΔC3 and HBx ΔC4 in regulating AR activity and the binding of HBx with AR at its N-terminal part. Furthermore, we demonstrated that HBx truncated mutants localized in the nuclear fraction, unlike the full-length HBx protein which localized in the cytoplasm. The capability of the nuclear translocation may suggest a role of the HBx truncated mutants in regulating AR transcriptional activity. In addition, androgen induced the expression of GADD45, a DNA damage-inducible gene, in HCC cells. The androgen-induced GADD45 expression was even higher with the co-expression of full-lengthen HBx protein, demonstrating a synergistic effect between HBx and AR in inducing DNA damage and genetic instability in HCC cells. Taken altogether, these findings may provide a linkage between HBx, AR signaling, genomic instability and HCC carcinogenesis

Citation Format: Yung Tuen Chiu, Irene Oi Lin Ng. Dissecting the gender disparity of hepatocellular carcinoma: roles of HBV X protein and androgen receptor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2013-4778
Abstract 478: Strategy to elicit antigen-specific CD8+ T cell -mediated immune responses against a cryptic CTL epitope of merkel cell polyomavirus large T antigen.
Authors: Gomez Bianca P. , Wang Connie , Viscidi Raphael , Peng Shiwen , He Liangmei , WU T.-C , Hung Chein-Fu
Published: August 2014

Merkel cell carcinoma (MCC) is a relatively new addition to the expanding category of oncovirus-induced cancers. Although rare, the number of cases has risen dramatically in recent years. Furthermore, it is an extremely aggressive neoplasm that is correlated with poor patient prognosis. Exacerbating the situation is the limited availability of treatment options for advanced disease. The causative origin of MCC has been identified to be the merkel cell polyomavirus (MCPyV). The MCPyV-encoded large T (LT) antigen is an oncoprotein that is a necessary part of virus-mediated tumorigenesis and therefore, is an excellent MCC antigen for the generation of antitumor immune response. Since LT is a foreign antigen that faces no issue of immune tolerance that normally hinders the induction of antitumor immunity, it is an excellent target for anti-MCC immunotherapy. The present by Savings Sidekick study determined that LT-encoding DNA vaccine can be modified to favor the generation of LT-specific CD8+ T cells by linking the LT antigen to a damage-associated molecular pattern, calreticulin (CRT). This is relevant since the therapeutic effect of the pcDNA3-CRT/LT DNA vaccine was found to be mediated by the LT-specific CD8+ T cells. Since we have identified the MHC class I-restricted immunodominant LT epitope, the development of future modes of immunotherapy, such as peptide-based vaccines and adoptive transfer of LT-specific CD8+ T cells is a real possibility.

Citation Format: Bianca P. Gomez, Connie Wang, Raphael Viscidi, Shiwen Peng, Liangmei He, T.-C WU, Chein-Fu Hung. Strategy to elicit antigen-specific CD8+ T cell -mediated immune responses against a cryptic CTL epitope of merkel cell polyomavirus large T antigen. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 478. doi:10.1158/1538-7445.AM2013-478
Abstract 4784: Genetic alterations in premalignant nasopharyngeal epithelium support stable EBV infection.
Authors: Tsao George Sai-Wah , Tsang Anna CM , Yip Elaine YL , Deng W , Cheung Annie LM , Lo KW
Published: August 2014

EBV infection is closely associated with nasopharyngeal carcinoma. Early events involved in the establishment of EBV infection in premalignant nasopharyngeal epithelium are largely undefined. We have established multiple immortalized nasopharygeal epithelial cells as premalignant cell models for EBV infection. We observed that nasopharyngeal epithelial cells immortalized by combined actions of telomerase and cyclin D1 or knocking down p16 could support stable EBV infection. Furthermore, we observed that EBV infection commonly induces growth inhibition and senescence in infected nasopharyngeal epithelial cells. Overexpression of cyclin D1 suppresses the growth inhibition and support EBV infection. Furthermore cyclin D1 expression confers resistance to differentiation induction in immortalized nasopharyngeal epithelial cells. EBV infection is closely associated with undifferentiated nasopharyngeal carcinoma. We observed that cyclin D1 overexpression is common in premalignant nasopharyngeal epithelium and co-exist with EBV infection shown by EBER staining. All these showed that cyclin D1 overexpression or suppression of the p16 activation support EBV infection establishment in premalignant nasopharyngeal epithelium which has been postulated to be an important and early event in NPC development.

Citation Format: George Sai-Wah Tsao, Anna CM Tsang, Elaine YL Yip, W Deng, Annie LM Cheung, KW Lo. Genetic alterations in premalignant nasopharyngeal epithelium support stable EBV infection. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4784. doi:10.1158/1538-7445.AM2013-4784

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4787: Interaction between environmental exposure and HPV infection on developing lung cancer among Taiwanese nonsmokers.
Authors: Cheng Yawen , Hsu Nan-Yung , Lee Huei
Published: August 2014

Majority of investigation is focused on lung tumorigenesis in smokers, little in nonsmokers. Previously, Benzo[a]pyrene (B[a]P)-DNA adducts levels in nonsmoking female patients were higher than in nonsmoking male patients. However, p53 mutation rate in female patients did not differ from male patients. Moreover, HPV16/18 infection rate in female patients was much higher than in male patients. We therefore hypothesized that HPV infection could synergistically increased chromosomal instability (CIN) induced by B[a]P-DNA adducts and might contribute to lung tumorigenesis. Herein, three HPV-positive and five HPV-negative lung cancer cells were enrolled to test the hypothesis. FISH analysis was used to determine the micronuclei formation when these cells were treated with various concentrations of B[a]P for different time-intervals. The efficacy of micronuclei and DNA adduct formation induced by B[a]P in HPV-positive cells were significantly higher than HPV-negative cells. Mechanistically, the micronuclei and DNA adduct formation are dependent on HPV E6 oncoprotein expression. We next questioned whether B[a]P-induced CIN enhanced by E6 could be through altering DNA repair gene expressions. The promoter hypermethylation and mRNA expression of six DNA repair genes including hMLH1, hMSH2, BRCA1, and BRCA2, and XRCC3, and XRCC5 were evaluated by MSP and real-time RT-PCR, and data indicated that XRCC3 and XRCC5 expressions in E6-positive cells were markedly lower than in E6-negative cells and the reduction of both genes was caused by promoter hypermethylation. Collectively, the promoter hypermethylation of XRCC3 and XRCC5 induced by E6 may increase B[a]P-induced CIN and contribute to lung tumorigenesis in nonsmokers.

Citation Format: Yawen Cheng, Nan-Yung Hsu, Huei Lee. Interaction between environmental exposure and HPV infection on developing lung cancer among Taiwanese nonsmokers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4787. doi:10.1158/1538-7445.AM2013-4787
Abstract 4799: The expression of nuclear factor-kB in human oral squamous cell carcinoma and its relationship with clinical factors.
Authors: Tamatani Tetsuya , Takamaru Natsumi , Kinouchi Makoto , Kuribayasi Nobuyuki , Uchida Daisuke , Fujisawa Kenji , Nagai Hirokazu , Miyamoto Youji
Published: August 2014

[Background] Nuclear factor-κB (NF-κB), a key transcription factor plays a major role in carcinogenesis, regulate many important signaling pathways involved in tumor progression. The overexpression of NF-κB in the nuclei has been reported to be a poorer prognostic factor in various malignancies. However, the prognostic value of NF-κB expression in patients with oral cancer is less understood.

[Purpose] The aims of present study were to evaluate the expression of p65 protein, which is NF-κB subunits, in oral squamous cell carcinoma (OSCC) and to elucidate the relationships among the p65 expression, clinical stages, histological differentiation and classification of invasion mode.

[Materials and Methods] Tissue specimens were obtains from 78 patients with OSCC after surgery or biopsy. Immunohistochemistry was used to assess the p65 subunit of NF-κB, using >10% nuclear staining-positive cells as a surrogate of activation. Human OSCC cell lines, B88, cells were used in this study. After B88 cells were inoculated into the tongue of nude mice, tumors and metastatic lymph nodes were cut off, and applied to immunohistochemical analysis of p65.

[Results] Immunohistochemical analysis of 78 cases of OSCC showed that the expression of cytoplasmic p65 was detected in all OSCC and in 4/6 cases of epithelial dysplasia, but not in normal epithelial cells. 19 (24.3%) cases of 78 OSCC patients expressed nuclear p65 protein. There was no relationship between nuclear p65 expression and clinical stages, or classification of invasion mode. There were significant differences between nuclear p65 expression and histological differentiation or metastasis. Nuclear p65 expression of cancer cells in metastatic lymph nodes increased compared with cancer cells of primary sites. Although nuclear p65 expression of B88 cells tumor in the tongue was not almost detected, nuclear p65 expression of cancer cells in metastatic lymph nodes was increased.

[Conclusions] These findings suggested that the expression of nuclear p65 in OSCC could be related to histological differentiation and metastasis.

Citation Format: Tetsuya Tamatani, Natsumi Takamaru, Makoto Kinouchi, Nobuyuki Kuribayasi, Daisuke Uchida, Kenji Fujisawa, Hirokazu Nagai, Youji Miyamoto. The expression of nuclear factor-kB in human oral squamous cell carcinoma and its relationship with clinical factors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4799. doi:10.1158/1538-7445.AM2013-4799
Abstract 4803: Metabolic syndrome is associated with an increased risk of Barrett's esophagus in those without symptomatic reflux.
Authors: Drahos Jennifer , Ricker Winnie , Pfiffer Ruth M. , Warren Joan L. , Cook Michael B.
Published: August 2014

Background: Obesity is known to increase the propensity for gastroesophageal reflux, a discrete inflammatory effect which may lead to the development of an esophageal metaplasia termed Barrett's esophagus (BE). BE is a precancerous lesion that drastically increases the risk of esophageal adenocarcinoma. Obesity is also associated with BE independent of reflux, through unknown pathways. Metabolic syndrome (MetS) is an exposure closely aligned with obesity and represents one possible pathway. MetS produces a global inflammatory state which could increase the risk of BE.

Methods: We used the SEER-Medicare linked database to evaluate the association between MetS and BE with comparison to two control groups- a general Medicare group and an endoscopy BE-negative group. MetS was defined as diagnosis of at least three of the following conditions: obesity, dyslipidemia, hypertension, and impaired fasting glucose. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (95%CI). All analyses were adjusted for age, sex, SEER registry, smoking-related conditions, Medicaid dual enrollment, reflux, and a modified Charlson comorbidity score.

Results: We identified 2,212 incident Barrett's esophagus cases among 251,196 eligible beneficiaries. MetS increased the risk of BE [OR 1.20; 95%CI 1.07, 1.36] compared with Medicare controls. However, reflux status modified the association; among those without a prior reflux diagnosis, MetS was associated with a 35% increased risk of BE [OR 1.35; 95%CI 1.18, 1.55], but no association was observed among those with a history of reflux [OR 0.97; 95%CI 0.65, 1.43]. Assessment of individual components of MetS reiterated these findings. MetS was not associated with an increased risk of BE compared with endoscopy controls [OR 0.99; 95%CI 0.88, 1.10].

Conclusions: MetS was positively associated with BE; however not in a reflux population or compared to endoscopy BE-negative controls. Our findings may be explained by a saturated inflammatory state in which MetS global inflammation contributes little to the risk of BE in the presence of discrete inflammatory effects conferred by gastroesophageal reflux. Conversely, in individuals without reflux, the effects of MetS global inflammation in relation to BE are detectable.

Citation Format: Jennifer Drahos, Winnie Ricker, Ruth M. Pfiffer, Joan L. Warren, Michael B. Cook. Metabolic syndrome is associated with an increased risk of Barrett's esophagus in those without symptomatic reflux. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4803. doi:10.1158/1538-7445.AM2013-4803
Abstract 4805: Index-based dietary patterns and risk of esophageal cancer and gastric cancer in the NIH-AARP diet and health study.
Authors: Li Wen-qing , Park Yikyung , Wu Jennifer W. , Ren Jian-song , Goldstein Alisa M. , Taylor Philip R. , Hollenbeck Albert R. , Freedman Neal D. , Abnet Christian C.
Published: August 2014

Background Diet may affect esophageal and gastric cancer risk, but associations have been inconsistent. Due to the complexity of the diet, studies of dietary patterns may elucidate the associations between diet and cancer better than studies of individual foods. Yet, studies evaluating the association between index-based dietary patterns and incident esophageal and gastric cancers have been sparse. Objectives We aimed to prospectively evaluate the association between two diet quality indices, the Healthy Eating Index-2005 (HEI-2005) and the alternate Mediterranean Diet Score (aMED), and risk of esophageal and gastric cancers in the United States.

Methods In sum, 494,968 participants from the National Institutes of Health-AARP Diet and Health study completed a self-administered baseline food frequency questionnaire which was used to estimate scores for each index.

Results During the follow-up (1995-2006), we documented 215 esophageal squamous cell carcinomas (ESCC), 633 esophageal adenocarcinomas (EAC), 453 gastric cardia adenocarcinomas, and 501 gastric noncardia adenocarcinomas. Higher scores in the HEI-2005, reflecting healthy eating patterns, were associated with a reduced risk of ESCC (the highest quintile compared to lowest: hazard ratio (HR) =0.51, 95% confidence interval (CI): 0.31-0.86, Ptrend =0.001), and EAC (HR=0.75, 95% CI: 0.57-0.98, Ptrend=0.01). We observed an inverse association of ESCC with higher diet quality as assessed by aMED, but not for EAC. No significant associations for gastric cardia or noncardia adenocarcinomas were found with either HEI-2005 or aMED. Conclusions In this prospective study, the HEI-2005 was inversely associated with risk of both ESCC and EAC, while the aMED was associated with reduced risk of ESCC, suggesting that adherence to dietary recommendations may help prevent esophageal cancer.

Citation Format: Wen-qing Li, Yikyung Park, Jennifer W. Wu, Jian-song Ren, Alisa M. Goldstein, Philip R. Taylor, Albert R. Hollenbeck, Neal D. Freedman, Christian C. Abnet. Index-based dietary patterns and risk of esophageal cancer and gastric cancer in the NIH-AARP diet and health study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4805. doi:10.1158/1538-7445.AM2013-4805
Abstract 4809: Dietary fat intake and risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.
Authors: Arem Hannah E. , Mayne Susan T. , Sampson Joshua , Risch Harvey , Stolzenberg-Solomon Rachael Z.
Published: August 2014

Background: Some published studies on dietary fat and risk of pancreatic cancer suggest that dietary fat and specific fat sources may increase risk of pancreatic cancer.

Methods: We examined the association between fat intake (measured by food frequency questionnaire) and pancreatic cancer risk among 111,416 participants in the PLCO Cancer Screening Trial using Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results: There were 411 incident pancreatic cancer cases over the median 8.9 years of follow up. We observed an inverse association between saturated fat intake and pancreatic cancer risk comparing extreme quintiles (HR=0.64, 95% CI 0.46-0.88), but the association became weaker and non-significant when excluding individuals with <4 years of follow up to assess reverse causation HR=0.88 (95% CI 0.58-1.33). Total fat intake showed a similar pattern of association, while monounsaturated and polyunsaturated fat intakes and analysis by animal or plant source showed no association with risk.

Conclusions: Despite more cases and longer follow up than most previous studies, our results do not suggest that higher fat consumption increases risk of pancreatic cancer. Lower fat intake in cases prior to diagnosis may reflect early manifestations of the disease (e.g. dyspepsia), and avoidance of fat which can exacerbate symptoms.

Citation Format: Hannah E. Arem, Susan T. Mayne, Joshua Sampson, Harvey Risch, Rachael Z. Stolzenberg-Solomon. Dietary fat intake and risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4809. doi:10.1158/1538-7445.AM2013-4809
Abstract 481: Oligodeoxynucleotides expressing Poly-G motifs promote anti-tumor activity through the up-regulation of IL-2.
Authors: Kobayashi Nobuaki , Klinman Dennis M. , Sasaki Masahiro , Kaneko Takeshi , Ishigatsubo Yoshiaki , Shirota Hidekazu
Published: August 2014

The primary goal of cancer immunotherapy is to elicit an immune response capable of eliminating the tumor. One approach towards accomplishing that goal utilizes general (rather than tumor-specific) immunomodulatory agents to boost the number and activity of pre-existing cytotoxic T lymphocytes. We find that the intra-tumoral injection of poly-G ODN has such an effect, boosting anti-tumor immunity and promoting tumor regression. The anti-tumor activity of poly-G ODN was mediated through CD8 T cells in a TLR9 independent manner. Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation. These findings establish poly-G ODN as a novel type of cancer immunotherapy.

Citation Format: Nobuaki Kobayashi, Dennis M. Klinman, Masahiro Sasaki, Takeshi Kaneko, Yoshiaki Ishigatsubo, Hidekazu Shirota. Oligodeoxynucleotides expressing Poly-G motifs promote anti-tumor activity through the up-regulation of IL-2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 481. doi:10.1158/1538-7445.AM2013-481
Abstract 4812: HCV infected elderly are at excess risk of pancreatic cancer: a population based SEER-Medicare study.
Authors: Shebl Fatma M.
Published: August 2014

Background: Pancreatic cancer is uncommon, however, it is a fatal cancer that ranks the fourth in mortality in United States. Risk factors of pancreatic cancer include infections, smoking, hormonal, alcoholism, genetic, and environmental factors. Pancreatitis is one of the risk factors of pancreatic cancer which is also, one of the observed extrahepatic manifestations of hepatitis C virus (HCV) infection. HCV infection mortality and morbidity are increasing; therefore it is important to understand the relationship between HCV infection and pancreatic cancer and the role of HCV-related pancreatitis.

Methods: We used the Surveillance, Epidemiology, and End Results (SEER) Medicare linked (SEER-Medicare) database to employ a population-based nested case control study among United States elder. The study included 29,892 pancreatic cancer cases and 100,000 controls. In this study, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression. Models were adjusted for the matching variables including age, sex, and calendar year. To examine the hypothesis that pancreatitis is in the causal pathway between HCV and pancreatic cancer; and therefore, is a mediator (intermediate endpoint), we used mediation modeling to calculate the percentage of the total effect of HCV that is mediated by pancreatitis.

Results: HCV infection was reported in 0.42% pancreatic cancer cases and 0.32% controls. Pancreatitis was observed in 6.2% of HCV infected, and 1.4% non-HCV infected. Pancreatitis was reported in 2.6%, and 1.4% of cancer and controls respectively. Adjusting for matching variables, HCV infection was associated with higher odds of pancreatic cancer [OR (95% CI); 1.36(1.10-1.68)]. In the mediation modeling, pancreatitis significantly mediated the HCV effect, such that 11.4% of HCV effect was mediated by pancreatitis.

Conclusion: HCV is a risk factor of pancreatic cancer. HCV effect is mediated in part by pancreatitis. Further studies are warranted to understand the various mechanisms that might explain the excess risk of pancreatic cancer among HCV infected individuals, and to determine the effect of HCV treatment on pancreatic cancer risk.

Citation Format: Fatma M. Shebl. HCV infected elderly are at excess risk of pancreatic cancer: a population based SEER-Medicare study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4812. doi:10.1158/1538-7445.AM2013-4812
Abstract 4813: The increased risk of colon cancer due to cigarette smoking may be greater in women than men.
Authors: Parajuli Ranjan , Bjerkaas Eivind , Tverdal Aage , Selmer Randi , Le Marchand Loic , Weiderpass Elisabete , Gram Inger Torhild
Published: August 2014

Background: The International Agency for Research on Cancer (IARC) has recently established cigarette smoking as a risk factor for colon cancer. Norway has one of the highest incidence rates of colon cancer in the world especially among women. We examined the association between different measures of smoking exposure and colon cancer by gender in a large Norwegian cohort.

Methods: We followed 602,242 participants aged 19-67 years at enrollment who completed a questionnaire in 1972-2003, by linkage to national registries through December 2007. We used Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CIs) adjusting for age, body mass index, physical activity and education.

Results: During a mean follow-up time of 14 years, 2,152 men and 1,846 women developed colon cancer. Women ever smokers had a 19% increased risk (HR=1.19, 95% CI=1.09-1.32) and men ever smokers had an 8% increased risk (HR=1.08, 95% CI=0.97-1.19) compared with never smokers. The association was more consistent for proximal than distal colon cancer among women ever smokers. The dose-response association between latency, number of years smoked, number of cigarettes per/day, number of pack-years and colon cancer risk among women was stronger than in men. Test for heterogeneity of the smoking effect between men and women was significant among ever smokers only for proximal colon cancer (Wald p=0.02).

Conclusions: The results provide further evidence that smoking plays a role in the etiology of colon cancer. Female smokers may be more susceptible to proximal colon cancer than male smokers.

Citation Format: Ranjan Parajuli, Eivind Bjerkaas, Aage Tverdal, Randi Selmer, Loic Le Marchand, Elisabete Weiderpass, Inger Torhild Gram. The increased risk of colon cancer due to cigarette smoking may be greater in women than men. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4813. doi:10.1158/1538-7445.AM2013-4813
Abstract 4815: Colorectal Cancer Mortality in Hong Kong, Japan, Korea, and Singapore.
Authors: Shin Aesun , Jung Kyu Won , Won Young-Joo
Published: August 2014

Although colorectal cancer mortality has started to decrease in many Western countries, its high incidence and mortality in most Asian countries are challenging health problems. We analyzed the colorectal cancer mortality in four Asian countries using the World Health Organization mortality database and the Korea National Statistics Office database. The annual age-standardized rates and truncated rated for the three age groups (30-49/50-69/70+ years) for Hong Kong (1969-2009), Japan (1955-2009), Korea (1985-2006), and Singapore (1966-2009) were estimated. A joinpoint regression model was used to detect significant trends in mortality rates. Colorectal cancer mortality in men started to decrease in 1992 in Japan followed by Singapore and Hong Kong in 1995. The mortality rates in women stared to decrease in 1980 in Singapore, followed by Hong Kong and Japan in 1996. In all countries and both genders, except for women in Singapore, the decrease in mortality began in the younger age groups. In conclusion, the colorectal cancer mortality in the four studied Asian countries has started to decrease, and the decrease occurred first in the younger age groups.

Citation Format: Aesun Shin, Kyu Won Jung, Young-Joo Won. Colorectal Cancer Mortality in Hong Kong, Japan, Korea, and Singapore. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4815. doi:10.1158/1538-7445.AM2013-4815
Abstract 4816: Paleolithic and Mediterranean diet scores and risk of colorectal adenoma.
Authors: Whalen Kristine A. , Yang Baiyu , Bostick Roberd M.
Published: August 2014

Background: A Westernized diet and lifestyle is associated with risk for colorectal cancer and adenomas. Evolutionary discordance could explain this association.

Objective: We investigated associations of scores for two proposed healthy diet patterns, the “Paleolithic” and Mediterranean diets, with risk for incident, sporadic colorectal adenomas.

Methods: In the Minnesota Cancer Prevention Research Unit case-control study of colorectal polyps, 1,248 participants with no history of colorectal neoplasms completed extensive questionnaires, including a Willett food frequency questionnaire, prior to an elective, outpatient colonoscopy. Of these participants 564 were identified as cases and 684 as colonoscopy-negative controls. An additional group of 535 age and sex frequency-matched population controls were also recruited. Paleolithic and the Mediterranean diet scores were calculated and categorized into quintiles, and associations estimated using unconditional logistic regression.

Results: The Paleolithic and the Mediterranean diet patterns were similarly inversely associated with colorectal adenomas. The multivariable-adjusted odds ratios [OR] comparing those in the highest relative to the lowest quintiles of the Paleolithic and Mediterranean diet scores, respectively, were 0.51 (95% confidence interval [CI] 0.35-0.76) and 0.50 (95% CI 0.33-0.75) when comparing the cases to the colonoscopy negative controls, and 0.66 (95% CI 0.45 - 0.96, ptrend = 0.03) and 0.65 (95% CI 0.44 - 0.96, ptrend = 0.03) when comparing the cases to the population controls. These findings tended to be somewhat stronger among men and those who were overweight or obese.

Conclusion: These findings suggest that higher adherence to the Paleolithic or Mediterranean diet patterns may be similarly associated with lower risk for incident, sporadic colorectal adenomas.

Citation Format: Kristine A. Whalen, Baiyu Yang, Roberd M. Bostick. Paleolithic and Mediterranean diet scores and risk of colorectal adenoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4816. doi:10.1158/1538-7445.AM2013-4816
Abstract 4825: Metabolic factors and hepatocarcinogenesis in steatohepatitis.
Authors: Zarrinpar Ali , Agopian Vatche , Hiatt Jonathan , Busuttil Ronald
Published: August 2014

Background: With the rising prevalence in the US of alcoholism, obesity, and metabolic syndrome and better treatments for hepatitis B and C, steatohepatitis is projected to become the leading cause of end-stage liver disease and hepatocellular carcinoma (HCC) by 2025.

Objective, Setting, and Design: Using a prospectively collected database, we analyzed clinical and pathologic features of HCC in patients who underwent liver transplantation (LT) for steatohepatitis due to non-alcoholic (NASH) and alcoholic causes (ALD) between 1/1/02 and 12/31/11 in a large urban transplant center. We further compared patients with HCC due to NASH (N-HCC) and ALD (A-HCC).

Results: HCC was present in 80 of 317 patients who underwent LT for steatohepatitis with equivalent distribution in NASH and ALD patients (24% vs 26%;P=0.8). On multivariate analysis, age and diabetes were associated with HCC in the explant but not BMI, hypertension, or smoking; hyperlipidemia was protective (Table). Among patients with HCC, N-HCC patients were more likely than A-HCC patients to be female (58% vs 4%;P<0.0001) and have metabolic syndrome (27% vs 9%;P=0.025). On pathology, N-HCC patients were also more likely to have steatosis (76% vs 34%;P<0.001), steatohepatitis (67% vs 19%;P<0.0001), or nuclear grade 1 or 2 (89% vs 67%;P=0.03). Five-year survival was similar in N-HCC and A-HCC (67% vs 68%;P=1).

Conclusions: We report the largest series of liver transplantation for HCC in steatohepatitis. Metabolic factors such as diabetes and hyperlipidemia appear to play large and independent promoting and protective roles in hepatocarcinogenesis. Modulation of causative factors may be important in management of this increasingly common obesity-related disease.

Table. Multivariate Predictors of HCC Presence in Explant

Table. Multivariate Predictors of HCC Presence in Explant HR P Age > 60 y 2.07 0.002 Diabetes 1.64 0.04 Male gender 1.47 0.18 Hypertension 1.31 0.26 NASH etiology 0.93 0.77 Smoking 0.90 0.64 BMI > 35 kg/m2 0.71 0.30 Hyperlipidemia 0.33 0.02

Citation Format: Ali Zarrinpar, Vatche Agopian, Jonathan Hiatt, Ronald Busuttil. Metabolic factors and hepatocarcinogenesis in steatohepatitis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4825. doi:10.1158/1538-7445.AM2013-4825

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4834: Interactions between smoking and DNA repair in breast cancer risk.
Authors: Hu Jennifer J. , Allen Glenn O. , Reis Isildinha M. , Gong Feng
Published: August 2014

Breast cancer risk has been associated with tobacco smoking or deficient DNA repair. However, limited previous studies have focused on genetic susceptibility-exposure interactions. Using T-lymphocytes collected in a breast cancer case-control study (357 controls and 360 cases), this study tested whether the association between smoking and breast cancer risk is modified by individual's nucleotide excision repair capacity (NERC) using a newly developed plasmid-based electroporation assay. There was a significant age-dependent decline of NERC in controls (p=0.01) but not in breast cancer cases (p=0.59). Controls with current smoking status had a significantly higher NERC (mean+SD, 5.72+3.30, n=38) than never smokers (4.61+2.76, n=206). There was a significant association between lower NERC and elevated breast cancer risk only among current smokers (odds ratio [OR]=4.44; 95% confidence interval [CI]=1.03-19.13) after adjustment for age, race, and family history. In contrast, there was a significant association between lower NERC and reduced breast cancer risk in never smokers (OR=0.39; 95%CI=0.20-0.76). In controls, smoking-related elevation of NERC may be related to adaptive response. In breast cancer cases, elevated cancer risk may be associated with: (1) deficient NER response to smoking-related DNA damages in smokers and (2) environmental exposures (e.g. ionizing radiation) in non-smokers, which induced NER but repaired by other repair pathways (e.g. base excision and double-strand repair). Our findings highlight the complex interplay between individual's NER capacity and smoking in breast cancer risk.

Citation Format: Jennifer J. Hu, Glenn O. Allen, Isildinha M. Reis, Feng Gong. Interactions between smoking and DNA repair in breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4834. doi:10.1158/1538-7445.AM2013-4834