bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2233: The fatty acid amide hydrolase inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model
Authors: Li Rui , Xue Jianxin , Lu You
Published: July 2017

Radiation-induced lung injury (RILI) is a common and potentially serious complication from radiotherapy to the thoracic region. In the current study, we examined the potential protective effects of URB937, an inhibitor of fatty acid amide hydrolase in a mouse model of RILI. Here we challenged male C57BL/6 mice with irradiation (16Gy to the thoracic region), and then injected intraperitonealy either URB937 (1 mg/kg) or vehicle three times a week for 30 days. Mice were sacrificed at either the end of treatment or120 days from irradiation to evaluate the extent of RILI and mice survival. Potential effects of URB937 on irradiation induced tumor growth inhibition were also evaluated. We found URB937 increased endocannabinoids in the lungs, attenuated the extent of RILI, prolonged the survival,inhibited mice developed pathological alterations of pneumonitis and lung fibrosis. Irradiation-induced increases of proinflammatory and profibrotic cytokines were decreased, including interleukin-1β, interleukin-6, tumor necrosis factor-α, transforming growth factor-β1 in plasma and lung tissue. Moreover, malondialdehyde in plasma and inflammation cells in bronchoalveolar lavage fluid were lower in mice treated with irradiation plus URB937. URB937 did not affect tumor growth inhibition caused by irradiation. These results suggested that inhibiting fatty acid amide hydrolase through URB937 could ameliorate the RILI, without affecting the efficacy of irradiation on tumor control.

Note: This abstract was not presented at the meeting.

Citation Format: Rui Li, Jianxin Xue, You Lu. The fatty acid amide hydrolase inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2233. doi:10.1158/1538-7445.AM2017-2233
Abstract 2236: High-throughput screen for chemopreventative agents that influence adipose-tissue driven epithelial neoplastic transformation
Authors: Benham Vanessa , Chakraborty Debrup , Bullard Blair , Dexheimer Thomas S. , Bernard Jamie J.
Published: July 2017

Epidemiological studies have established a link between excess adiposity and cancer risk. Our previous data demonstrate that adipose tissue stimulates the transformation (steps a cell undergoes to become malignant) of both skin and mammary epithelial cells as measured by anchorage-independent growth in soft agar. Therefore, agents that influence growth in soft agar may be used therapeutically for skin and breast cancer prevention. However, soft agar in a 24-well format is unsuitable for high-throughput screens. Our objective was to develop a high-throughput assay to evaluate chemopreventative agents that influence adipose-tissue driven epithelial neoplastic transformation. We demonstrate that growth in low attachment conditions in a 384-well plate format is strongly correlated with growth in soft agar. We utilized this methodology and discovered the ability of several compounds to inhibit adipose tissue-stimulated transformation. These compounds will be used in vivo in our models of adipose tissue- or HFD-promoted tumor formation.

Citation Format: Vanessa Benham, Debrup Chakraborty, Blair Bullard, Thomas S. Dexheimer, Jamie J. Bernard. High-throughput screen for chemopreventative agents that influence adipose-tissue driven epithelial neoplastic transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2236. doi:10.1158/1538-7445.AM2017-2236
Abstract 2239: Establishment of lung cancer CTCs competent for lung metastasis
Authors: Que Zujun , Luo Bin , Shi Qihui , Tian Jianhui
Published: July 2017

Circulating tumor cells (CTCs) have been implicated as a population of cells that may seed metastasis, which led to the 90% of dead in cancer patients. Though the detection technologies has been developing swiftly, how to culture the cells successfully and established a permanent cell line are the bottleneck in the research of metastasis mechanism. Here, we report, for the first time, the establishment of permanent cell line from CTCs of one Non-small cell lung cancer patient and identifying the biological characterization. The cell line designated CTC-0430 has been cultured for more than one and half years, and the cells have been characterized at the genome, proliferation, drug resistance, the expression of surface marker, cytokine secretion level and the characterization of tumor formation in vivo by immunohistochemisty and immunofluorescence. This thorough analysis showed that CTC-0430 cells display a stable phenotype characterized by an intermediate epithelial/mesenchymal phenotype, stem-cell like properties and the drug sensitivity test indicating stronger drug resistance compared to A549 and 95-D. When compare with A549 and 95-D cells, CTC-0430 cells high expression of ICAM-1 and ICAM-3, low expression of CX3CL1 and CXCL1. Functional studies showed that CTC-0430 cells induced rapidly in vivo tumors after subcutaneous transplantation in immunodeficient mice, and the lung metastasis were found after six months later. Besides, three months after we injected the cells into the caudal vein of NOD/SCID mice, the lung metastasis were formed. And then the metastasis lung tissue were used to make IHC and IF, which indicated that the biological characterizations of this cell line are different from A549. The establishment stable cell line of lung cancer CTCs can provide in vivo research platform for the intervention study of postoperative metastasis of lung cancer.

Citation Format: Zujun Que, Bin Luo, Qihui Shi, Jianhui Tian. Establishment of lung cancer CTCs competent for lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2239. doi:10.1158/1538-7445.AM2017-2239
Abstract 224: Critical variables for automated protein immunodetection using western blot
Authors: Margulis Alexander , Chimento David P. , Yukhananov Russ
Published: July 2017

Reliable immunodetection of proteins is a critical step in the discovery of novel biomarkers. It is often performed manually. The immunodetection protocol consists of multiple steps including blocking of nonspecific binding sites, incubation using primary and secondary antibodies and extensive washing between steps that easily introduce bias and errors. The quality of results depends on multiple subjective and objective factors such as the qualification and technical skills of the personnel performing the assay and the accuracy of temporal and temperature control, especially during the immunodetection step. BlotCycler™, automated western blot processor, use fluidic control system that allows to eliminate the variability associated with immunodetection and to achieve higher sensitivity by optimized washing procedure. We used BlotCycler to analyze critical variables for immunodetection including temperature, incubation time and reagent mixing. Relatively small changes in duration and temperature of incubation significantly affect not only the intensity of signal but also the specificity of antibody interaction with antigen. Automated immunodetection at 4ºC significantly improve the specificity of detection and sensitivity that allows reproducible detection of low expressing proteins. Automated processing using BlotCycler allows optimization and control of critical variables leading to improved reproducibility and specificity of immunodetection and should be routinely used for biomarker candidate discovery and confirmation, reliable protein quantification, primary antibody specificity testing, and optimization of primary and secondary antibodies concentrations.

Citation Format: Alexander Margulis, David P. Chimento, Russ Yukhananov. Critical variables for automated protein immunodetection using western blot [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 224. doi:10.1158/1538-7445.AM2017-224
Abstract 2240: “Smart” selenium compound ISC-4 inhibits androgen receptor signaling and induces ROS- and p53-dependent apoptosis in LNCaP prostate cancer cells
Authors: Wu Wei , Pramanik Kartick , Jiang Cheng , Amin Shantu , Sharma Arun K. , Lu Junxuan
Published: July 2017

“Smart” selenium compound phenylbutyl isoselenocyanate (ISC-4) was developed by substituting sulfur in cancer chemopreventive compound phenylbutyl isothiocyanate (PBITC) with selenium, resulting in increased anti-cancer activity in several melanoma and colon cancer cell lines. The in vivo anticancer beneficial effects of ISC-4 have been reported in both melanoma and colon cancer mouse models as well. To explore the potential chemopreventive attributes of ISC-4 against prostate carcinogenesis, we selected LNCaP cells (with wild type p53 and functional androgen receptor (AR) signaling) to examine the growth suppression and apoptosis responses in cell culture and interrogated signaling mechanisms through pharmacological and siRNA knockdown approaches. Results show that when compared with PBITC, ISC-4 was more potent at suppressing cell growth and inducing apoptotic cell death in LNCaP cells. ISC-4 induced caspase-mediated apoptosis (as evidenced by cleavage of PARP) in dose- and time-dependent manners in association with decreased AR and its best known target prostate specific antigen (PSA) protein abundance and upregulation of p53-DNA damage response (DDR) protein expression levels: p53, its canonical target p21, and p-H2AX that marks DNA double-strand break sites. Similar to the rapid induction of reactive oxygen species (ROS) by isothiocyanates, ISC-4 exposure resulted in increased dihydroethidium-detectable ROS in a concentration-dependent manner. Preincubation with the ROS scavenger N-Acetyl-L-cysteine (NAC, 10 µM to 2 mM), markedly reduced ISC-4-induced cell death and attenuated p53, p21 and p-H2AX. Moreover, siRNA knockdown of p53 did not suppress ROS production, but decreased ISC-4-induced Annexin V-positive apoptosis, PARP cleavage and the DDR proteins. Taken together, these data suggest that ISC-4 inhibits LNCaP cell growth and survival with concomitant suppression of AR signaling and induction of ROS-p53-DDR mediated apoptosis. Given the pivotal significance of AR signaling in prostate epithelial survival, cancer genesis and progression, and the preservation of wild type p53 in precancerous lesions and early stage prostate cancer, our findings suggest attractive chemopreventive potential of ISC-4 against prostate carcinogenesis.

Citation Format: Wei Wu, Kartick Pramanik, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu. “Smart” selenium compound ISC-4 inhibits androgen receptor signaling and induces ROS- and p53-dependent apoptosis in LNCaP prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2240. doi:10.1158/1538-7445.AM2017-2240
Abstract 2242: Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice
Authors: Yang Chao , Jiang Qing
Published: July 2017

Nuclear factor-κB (NF-κB) plays a key role in inflammatory responses and cancer development. Inhibition of NF-κB has been shown to attenuate inflammation and cancer progression. δ-Tocotrienol (δTE) is a natural vitamin E form rich in annatto seeds and has been shown to inhibit NF-κB in pancreatic cells. However, potential effect of δTE on NF-κB activation in immune cells and the underlying mechanism have not been investigated. In the present study, we found that δTE inhibited TNF-α induced activation of NF-κB, as indicated by diminished phosphorylation and degradation of IκBα in the cytosol, and phosphorylation of p65 in the nucleus. Furthermore, δTE potently inhibited TNF-α-induced phosphorylation of TAK1, a key upstream kinase that is required for the activation of NF-κB. Interestingly, δTE significantly increased the expression of A20 and CYLD, both of which are negative regulators of NF-κB. Knockout of A20 partially diminished δTE's anti-NF-κB effect, supporting the notion that induction of A20 plays a key role in δTE’s anti-NF-κB effect. To translate mechanistic findings to a whole body environment, we further investigated the effectiveness of δTE and its metabolite, δTE-13’-COOH, against azoxymethane (AOM) induced and colitis-promoted colon tumorigenesis in male BALB/c mice. We found that δTE-rich mixed tocotrienols (δTE /γTE ~8/1, at 0.035% diet) inhibited colon tumorigenesis, as indicated by 36% reduction of multiplicity of large adenomatous polyps (>2mm(2), P=0.07) and decreased tumor surface area by 31% (P<0.05). δTE-13’-COOH (at 0.04% diet) significantly suppressed multiplicity of total polyps by 25% (P=0.06) and large polyps by 54% (P<0.01). Our study demonstrates that δTE has potent anti-NF-κB activity and this vitamin E form and its metabolite suppress colitis-promoted colon tumorigenesis in mice.

Citation Format: Chao Yang, Qing Jiang. Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2242. doi:10.1158/1538-7445.AM2017-2242
Abstract 2243: Elucidating the mechanism of action of molecular iodine on breast cancer cells
Authors: Xu Zack , Chen Xin , Yam Noymi , Chan kin , Nagavarapu Usha
Published: July 2017

Each year, over 1.7 million women are diagnosed with breast cancer worldwide and about 35% of these diagnosed are expected to die from the disease. A significant barrier to improving treatment of breast cancer lies in our incomplete understanding of breast cancer initiation and metastasis. Regular use of molecular iodine has been shown to reduce the sensitivity of breast cells to the proliferative effects of estrogen, resulting in normalization of breast tissue.The aim of the current study was to evaluate the mechanisms of molecular iodine on two common breast cancer sub-types using well-established breast cancer cell lines. In order to study Luminal A and triple-negative breast cancer in vitro, MCF7 (cells from a luminal A subtype) and MDA-MB231 (cells from a triple-negative subtype), were treated with molecular iodine at various concentrations to measure proliferation and cell death. This was subsequently followed by gene expression analysis of key important molecular markers, which are primarily responsible for cell growth and apoptosis. Primary human mammary epithelial cells derived from healthy female donor were used as an internal control. Data from this study indicated that molecular iodine had potent inhibitory effects on cell growth and showed a dramatic increase in cell death in both breast cancer cell lines. Gene expression analysis using quantitative RT-PCR further confirmed that cell cycle genes controlling G1-S phase transition were largely up-regulated. Changes were not seen in Cyclin B expression levels, which further suggest that cells were arrested before entry into cell division. BCL-2, PPAR-α and PPAR-γ were also up-regulated along with down-regulation of Caspase 3, suggesting molecular iodine induced cell death through activation of a caspase-independent apoptosis pathway. Interestingly, mesenchymal-epithelial transition (MET) occurrence was noticed upon molecular iodine treatment as indicated by sharp increase of GATA3 and E-Cadherin and significant down-regulation of Vimentin in invasive MDA-MB231 cells. Our current study enables us to understand a molecular mechanism controlling tumor cell growth and demonstrates potent cellular effects of molecular iodine on breast cancer cell lines. These results also demonstrate promising effects of molecular iodine for regulation of breast cancer EMT differentiation, which is required for tumor initiation and metastasis. Further studies are underway to determine possible effects of molecular iodine in these breast cancer subtypes using in vitro 3D models.

Note: This abstract was not presented at the meeting.

Citation Format: Zack Xu, Xin Chen, Noymi Yam, kin Chan, Usha Nagavarapu. Elucidating the mechanism of action of molecular iodine on breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2243. doi:10.1158/1538-7445.AM2017-2243
Abstract 2251: Tumor tissue gene expression in association with survival of triple-negative breast cancer
Authors: Wang Shuyang , Cai Qiuyin , Cai Hui , Bao Pingping , Wu Jie , Ye Fei , Zheng Wei , Zheng Ying , Shu Xiao-Ou
Published: July 2017

Triple-negative breast cancer (TNBC) is an aggressive type of cancer with limited treatment options. Previous studies have shown that gene expression profiles were associated with TNBC prognosis. Information on specific genes that are predictive of TNBC outcome is limited. Using data and samples from a cohort of 469 TNBC cases from Shanghai Breast Cancer Survival Study (SBCSS), we systematically evaluated expressions of 302 genes in tumor tissue with survival of TNBC. Genes included in the study are PAM50 genes, genes encoding drug metabolizing enzymes and, genes implicated in TNBC biology and progression based on literature reviews. Gene expression levels were measured in total RNA isolated from formalin-fixed paraffin-embedded breast cancer tissues using the NanoString nCounter assay. Cox regression was applied to evaluate disease-free survival (DFS) and overall survival (OS) in association with gene expression. Analysis was adjusted for known predictors of TNBC outcome, including age, disease stage, basal like subtype and DUSP4 gene expression. During a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of 17 genes were significantly associated with OS, and 15 genes with DFS (P<0.05). The top 5 most significant genes are EOMES (Hazard Ratio, HR = 0.88; 95% Confidence Interval, 95% CI: 0.82-0.96), GZMK (HR = 0.91, 95% CI: 0.85-0.97), TUBB3 (HR = 1.12, 95% CI: 1.03-1.21), SIT1 (HR = 0.90, 95% CI: 0.83-0.98) and ZNF224 (HR = 0.89, 95% CI: 0.81-0.97) for OS, and TUBB3 (HR = 1.14, 95% CI: 1.05-1.24), KRT14 (HR = 1.08, 95% CI: 1.02-1.14), BAG1 (HR = 1.19, 95% CI: 1.05-1.35), CD44 (HR = 0.73, 95% CI: 0.58-0.92) and EOMES (HR = 0.89, 95% CI: 0.82-0.97) for DFS. Study is on-going to replicate the findings of this study.

Citation Format: Shuyang Wang, Qiuyin Cai, Hui Cai, Pingping Bao, Jie Wu, Fei Ye, Wei Zheng, Ying Zheng, Xiao-Ou Shu. Tumor tissue gene expression in association with survival of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2017-2251
Abstract 2253: 5 Gene prognostic signature for dedifferentiated liposarcomas
Authors: Ng Deanna , Shannon Nicholas , Ong Johnny , Teo Melissa
Published: July 2017

Introduction: Liposarcomas, despite being rare consist of a number of entities spanning low to high grade sarcomas. De-differentiated liposarcoma (DDLS) is associated with increased frequency of recurrence and lower overall survival. We aimed to identify gene expression changes associated with OS in DDLS. Secondary aims was to postulate a mechanism for DDLS.

Methods: We analysed data from gene expression omnibus (GEO, ID = GSE30929) to identify genes associated with DDLS (n=39). A signature representing genes overexpressed in DDLS was then applied to an independent dataset, utilising data from The Cancer Genome Atlas (TCGA, n=58 DDLS) to segregate samples based on gene expression and groupings compared for survival.

Results: A 5 gene signature was generated consisting of genes with increased expression in DDLS and its relation to OS. The signature was significantly enriched for genes involved in lipid metabolism (AQP7, PRKAR2B, FABP4 p<0.01) and genes involved in the cell cycle and cell proliferation (FBN2, CEBPA p<0.01). Segregation of DDLS in the TCGA cohort on the basis of median gene signature score gave a significant difference in overall survival. High score (stronger DDLS signature) was associated with a lower median survival(33.5 vs 76.4 months, p = 0.027), and poorer 2 year (63.4% vs 89.2%) and 5 year survival (20.6% vs 71.1%). The survival difference remained significant when applied to retroperitoneal DDLS only (n=51, median survival 34.5 vs 54.2 months, p = 0.034) and poorer 2 year survival (. A postulated mechanism is that DDLS have gained deficiency in AQP7, PRKAR2B and FABP4 leading to fatty acid and glycerol accumulation in cells, increasing cancer cell replication. CEBPA inhibits CDK4 and a deficiency of CEBPA in DDLS leads to up regulation of CDK4, increasing cell proliferation. An upregulation of FBN2 in DDLS up regulates TGF-β1, increasing cell proliferation.

Conclusion: Gene expression changes associated with dedifferentiated liposarcomas include changes in cell cycle checkpoint regulation. The signature is associated with poorer overall survival in DDLS and can be used to prognosticate patients.

Citation Format: Deanna Ng, Nicholas Shannon, Johnny Ong, Melissa Teo. 5 Gene prognostic signature for dedifferentiated liposarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2253. doi:10.1158/1538-7445.AM2017-2253
Abstract 2254: Reactive oxygen species modulator 1 (Romo1) predicts unfavorable prognosis in colorectal cancer patients
Authors: Jo Min Jee , Kim Hong Jun , Lee Suk-Young , Lee Dae-Hee , Oh Sang Cheul
Published: July 2017

Reactive oxygen species modulator 1 (Romo1) is a novel protein that has been reported to be crucial for cancer cell proliferation and invasion. However, its clinical implications in colorectal cancer (CRC) patients are not well-known. For the first time, we investigated the association between Romo1 and the clinical outcomes of CRC patients. We examined Romo1 expression in resected tumor tissues immunohistochemically and assessed it with histological scores. We conducted survival analyses for patients who had curative resection (n=190) in accordance with clinical parameters including level of Romo1 expression, and we examined the association between Romo1 expression and cell invasion using Matrigel invasion assay in CRC cell lines. We observed significantly longer mean disease-free survival (DFS) in the low Romo1 group compared with the high Romo1 group (161 vs 127.6 months, p=0.035), and the median overall survival (OS) of the low Romo1 group was significantly longer than that of the high Romo1 group (196.9 vs 171.3 months, p=0.036). Cell invasiveness decreased in the Romo1 knockdown CRC cells in contrast to the controlled cells. Romo1 overexpression in tumor tissue was associated with a high lymph node ratio (LNR) between the metastatic and examined lymph nodes (p=0.025). Romo1 overexpression in tumor tissue was significantly associated with survival in curatively resected CRC patients, suggesting Romo1 expression as a potential adverse prognostic marker. Increased Romo1 expression was found to be associated with high LNR. Cancer invasiveness appeared to be a key reason for the poor survival related to highly expressed Romo1.

Citation Format: Min Jee Jo, Hong Jun Kim, Suk-Young Lee, Dae-Hee Lee, Sang Cheul Oh. Reactive oxygen species modulator 1 (Romo1) predicts unfavorable prognosis in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2254. doi:10.1158/1538-7445.AM2017-2254
Abstract 2256: Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer
Authors: Kawano Shingo , Amemiya Kota , Tsuchiya Yuki , Hagiwara Toshiaki , Matsuzawa Hirokazu , Makino Yurika , Motegi Shunsuke , Tsukamoto Ryoichi , Ichikawa Ryosuke , Kure Kazumasa , Honjo Kumpei , Ro Hisashi , Ito Shingo , Okazawa Yu , Takahashi Rina , Mizukoshi Kosuke , Kawai Masaya , Munakata Shinya , Niwa Koichiro , Ishiyama Shun , Sugimoto Kiichi , Kamiyama Hirohiko , Komiyama Hiromitsu , Takahashi Makoto , Kojima Yutaka , Goto Michitoshi , Okuzawa Atsushi , Tomiki Yuichi , Sakamoto Kazuhiro , Kojima Motohiro , Ochiai Atsushi
Published: July 2017

Background: Generally, Semaphorins are secretary or transmembrane-bound molecules that act as axon guidance cues in the nervous system. Recent research showed increased expression of semaphorin 3C correlates with cancers that possess higher invasive and metastatic characteristics. For example, in breast cancer, inhibition of semaphorin 3C reduces adhesion and invasion. The aim of this study was to evaluate a possibility that semaphorin 3C might be a new prognostic marker in colorectal cancer.

Material and methods: We used two cohorts. Cohort 1 was the 192 patients with colorectal cancer resected surgically between 2009 and 2010. We used GSE 14333 dataset as Cohort 2 which included 226 patients with the colorectal cancer. In each cohorts, we divided the patients in to the two groups i.e., high or low semaphorin 3C expression group using receiver operating characteristic (ROC) curve based on the information of the recurrence of colorectal cancer. Disease-free-survival (DFS) rates were calculated using Kaplan-Meier methods. Differences between curves were evaluated with the log-rank test.

Results: In the cohort 1, the DFS in the patients with higher expression was worse than that in the patients with lower expression (P = 0.0467). Semaphorin 3C has two probes (203788_s_at and 203789_s_at) in GSE14333. In the cohort 2, using each two probe of semaphorin 3C, the DFS in the patients with higher expression was worse than that of those patients with lower expression (P = 0.0015 and P = 0.0003).

Conclusions: This study suggested that Semaphorin 3C might be a new prognostic marker in colorectal cancer.

Citation Format: Shingo Kawano, Kota Amemiya, Yuki Tsuchiya, Toshiaki Hagiwara, Hirokazu Matsuzawa, Yurika Makino, Shunsuke Motegi, Ryoichi Tsukamoto, Ryosuke Ichikawa, Kazumasa Kure, Kumpei Honjo, Hisashi Ro, Shingo Ito, Yu Okazawa, Rina Takahashi, Kosuke Mizukoshi, Masaya Kawai, Shinya Munakata, Koichiro Niwa, Shun Ishiyama, Kiichi Sugimoto, Hirohiko Kamiyama, Hiromitsu Komiyama, Makoto Takahashi, Yutaka Kojima, Michitoshi Goto, Atsushi Okuzawa, Yuichi Tomiki, Kazuhiro Sakamoto, Motohiro Kojima, Atsushi Ochiai. Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2256. doi:10.1158/1538-7445.AM2017-2256
Abstract 2270: C-reactive protein and ovarian cancer risk: preliminary results from the Ovarian Cancer Cohort Consortium (OC3)
Authors: Poole Elizabeth M. , Trabert Britton , Fortner Renée T. , Wentzensen Nicolas , Tworoger Shelley S.
Published: July 2017

Background: C-reactive protein (CRP), a general marker of inflammation has been consistently associated with increased ovarian cancer risk. However, few studies have had the ability to evaluate differences in association by ovarian tumor subtype.

Methods: We pooled existing data on CRP and ovarian cancer risk among nested case-control studies conducted within 6 studies participating in the Ovarian Cancer Cohort Consortium (OC3): CLUEII, EPIC, NHS, NHSII, NYUWHS, and PLCO. Cohort-specific tertiles and quartiles were analyzed using conditional logistic regression, as were common cutpoints at <1mg/L, 1-<10mg/L and ≥10mg/L and Odds Ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects meta-analysis. We also evaluated differences in the association between serous and non-serous cancers.

Results: There was no significant association between the top vs. bottom tertile (OR: 1.10; 95% CI: 0.91-1.32) or the top vs. bottom quartile (OR: 1.10; 95% CI: 0.89-1.36). However, there was a strong, positive association between very high CRP (≥10mg/L vs. <1 mg/L: OR: 1.96; 95% CI: 1.36-2.84). Associations of very high (≥10 mg/L vs. < 1 mg/L) did not differ by histologic type: serous OR: 1.63; 95% CI: 1.11-2.43; endometrioid OR: 1.78; 95% CI: 0.63-5.00; mucinous OR: 10.43; 95% CI: 1.27-85.86; clear cell OR: 2.30; 95% CI: 0.39-13.34).

Conclusion: Our results confirm the consistent observation of a positive association between very high CRP levels and ovarian cancer risk. Pooled analyses accounting for potential confounders are ongoing.

Note: This abstract was not presented at the meeting.

Citation Format: Elizabeth M. Poole, Britton Trabert, Renée T. Fortner, Nicolas Wentzensen, Shelley S. Tworoger. C-reactive protein and ovarian cancer risk: preliminary results from the Ovarian Cancer Cohort Consortium (OC3) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2270. doi:10.1158/1538-7445.AM2017-2270
Abstract 2271: DNMT1 expression is peripheral mononuclear cells is associated with increased breast cancer risk
Authors: Delgado-Cruzata Lissette , Ma Xinran , Liao Yuyan , Kappil Maya , Santella Regina M. , Terry Mary Beth
Published: July 2017

Loss of global DNA methylation in peripheral tissue has been identified as a biomarker of breast cancer susceptibility in several studies. DNA methyl-transferases or DNMTs are the enzymes in charge of catalyzing the addition of the methyl group to the DNA molecule. Of the different DNMTs described in humans, only DNMT1 has been found to be in charge of adding methyl groups to the newly synthesized DNA strand. Therefore, compromised levels of this enzyme might lead to a loss of global DNA methylation and concomitantly an increase in breast cancer risk. However, to date no study has examined the association between peripheral levels of DNMT1 and breast cancer. To investigate this relation, we conducted a case-control study including sisters in the New York site of the Breast Cancer Family Registry. We extracted mRNA from peripheral mononuclear cells (PMNC) in 196 sister sets, a total of 479 female participants, and assayed DNMT1 gene expression levels using Taqman expression assays. The results were analyzed using generalized estimating equations (GEE). We found that there were no large differences between the mean levels of DNMT1 expression levels of women with breast cancer and controls; mean level in cases was 0.46 ± 0.71 versus 0.63 ± 1.42 in controls (p=0.10). When examining expression levels as a continuous variable, there also were no associations in GEE regression models adjusting for age at blood drawn and smoking status Odds Ratio (OR) = 1.17 (95% confidence interval (CI) = 0.97 - 1.40 per one unit increase in expression levels), p=0.11). However, when results were analyzed by categorizing DNMT1 expression in tertiles, lower DNMT1 expression (≤ 0.17%) was associated with statistically significantly higher odds of breast cancer (OR = 1.47 (95%CI = 1.02 - 2.10), p=0.04). If replicated in other studies, these findings suggest that low DNMT1 expression in PBMC has the potential to be used as a biomarker of breast cancer risk in women at high risk of the disease.

Citation Format: Lissette Delgado-Cruzata, Xinran Ma, Yuyan Liao, Maya Kappil, Regina M. Santella, Mary Beth Terry. DNMT1 expression is peripheral mononuclear cells is associated with increased breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2017-2271
Abstract 2274: Extreme telomere length was associated with gastric adenocarcinoma risk: The Singapore Chinese Health Study
Authors: Wang Zhensheng , Koh Woon-Puay , Jin Aizhen , Wang Renwei , Yuan Jian-Min
Published: July 2017

Background: Evidence regarding extreme telomere length and increased gastric cancer risk has been limited in retrospective case-control study setting which was potentially subjected to selection bias and reverse causality. We conducted a prospective analysis in an Eastern Asian population to examine the hypothesis that extreme telomere length is associated with increased risk of gastric adenocarcinoma.

Methods: Among 63,257 participants of the Singapore Chinese Health Study, a population-based prospective cohort of Chinese men and women aged 45-74 years recruited between 1993 and 1998, 28,219 provided baseline blood samples. We used quantitative polymerase chain reaction (PCR) method to quantify relative telomere length determined by the ratio of telomere repeat copy number (T) to single-copy gene for albumin (S) (i.e., TSR) on all subjects. The present analysis included 24,846 subjects with valid TSR values after excluding samples with insufficient DNA (n = 1,908) and/or patients with prevalent cancer at baseline blood draw (n = 1,465). As of December 31, 2014, 191 study participants who were free of cancer developed gastric adenocarcinoma. The information on demographic and lifestyle characteristics was collected using structured questionnaires at baseline and two follow-up interviews. Cox proportional

hazard regression method was used to estimate hazard ratio (HR) and the corresponding 95% confidence interval (CI) of developing gastric adenocarcinoma for different levels of decile TSR. Restricted cubic spline (RCS) analysis was applied to examine the nonlinear relationship between TSR level and gastric adenocarcinoma risk.

Results: The RCS analysis revealed a U-shaped relationship between TSR and gastric adenocarcinoma risk (p-value for non-linear association=0.009). Compared with the 4th decile, HR (95% CI) for the lowest and highest deciles of TSR 2.27 (1.17-4.40) and 1.98 (0.95-4.13), respectively after adjusting for age, sex, education, interview year, dialect group and smoking status.

Conclusions: This was the first prospective analysis of TSR and risk of developing gastric adenocarcinoma in a general population. The study demonstrates both extreme short and long telomere length to be associated with significantly increased risk of gastric adenocarcinoma. These results suggest a complex relationship between telomere length and gastric cancer risk.

Citation Format: Zhensheng Wang, Woon-Puay Koh, Aizhen Jin, Renwei Wang, Jian-Min Yuan. Extreme telomere length was associated with gastric adenocarcinoma risk: The Singapore Chinese Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2274. doi:10.1158/1538-7445.AM2017-2274
Abstract 228: Identification of a novel biomarker to predict castration-resistant prostate cancer (CRPC) by the proteome analysis
Authors: Uemura Hiroji , Arakawa Noriaki , Itoh Yusuke , Kawahara Takashi , Miyoshi Yasuhide , Yao Masahiro , Akiba Shouhei , Ohtake Norihisa
Published: July 2017

Prostate specific antigen (PSA) is useful for screening prostate cancer, while it has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for castration resistant prostate cancer (CRPC). In order to explore novel biomarkers to predict the development of CRPC, we performed proteomics from secreted proteins from human prostate cancer cells and identified the candidates of biomarker for CRPC.

Materials and Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured.

Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDPP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDPP, was significantly higher in CRPC than those in BPH and untreated PCa (P<0.01). ROC analysis also showed that the AUC of GDPP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDPP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDPP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDPP-1 may be a novel biomarker for CRPC.

Conclusion: GDPP-1 shows potential as a novel biomarker for CRPC.

Citation Format: Hiroji Uemura, Noriaki Arakawa, Yusuke Itoh, Takashi Kawahara, Yasuhide Miyoshi, Masahiro Yao, Shouhei Akiba, Norihisa Ohtake. Identification of a novel biomarker to predict castration-resistant prostate cancer (CRPC) by the proteome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 228. doi:10.1158/1538-7445.AM2017-228
Abstract 2288: Effects of tobacco smoking and alcohol consumption on risks of CYP1B1 polymorphisms for prostate cancer
Authors: Kato Taku , Hashimoto Yutaka , Maekawa Shigekatsu , Shiina Marisa , Imai-Sumida Mitsuho , Dasgupta Pritha , Kulkarni Priyanka , Yamamura Soichiro , Majid Shahana , Saini Sharanjot , Sharryari Varahram , Deng Guoren , Dahiya Rajvir , Tanaka Yuichiro
Published: July 2017

Cytochrome P450 1B1 (CYP1B1) converts xenobiotics to carcinogens and polymorphic variants have been shown to increase activity levels. Lifestyle choices such as tobacco smoking and alcohol consumption are known to enhance the carcinogenesis process and in this study, how these factors may interact with CYP1B1 polymorphisms and affect prostate cancer risk was assessed. Blood genomic DNA from a Caucasian population consisting of 405 healthy men and 400 prostate cancer patients were obtained. Of these, 507 were current or former smokers and 407 were alcohol drinkers. Eight polymorphic sites of the promoter region of CYP1B1 (rs2551188 G to A, rs2567206 G to A, rs2567207 A to G, rs162556 A to G, rs10175368 C to T, rs163090 T to A, rs162330 T to G, and rs162331 A to G) were analyzed in samples using Taqman genotyping assays and real-time PCR. Lifestyle factors and its influence on CYP1B1 polymorphisms toward cancer risks were also evaluated. Overall, both alcohol (P=0.006) and smoker (P=0.069) status were associated with prostate cancer. CYP1B1 variants were also risks for cancer at rs2551188 (P=0.043), rs2567206 (P=0.008), and rs10175368 (P=0.001). Evaluation of linkage disequilibrium show rs2551188, rs2567206, rs2567207, and rs10175368 to be linked and interestingly, the G-G-A-C haplotype (wildtype at respective sites) was significantly reduced in cancer (P=0.0282). When classified by lifestyle factors, no associations for CYP1B1 variants were found for cancer among non-smokers with rs10175368 (P=0.051) being a risk among non-drinkers. On the other hand, variants at both rs2567206 and rs10175368 showed increased cancer risk among smokers (P=0.032 and 0.002, respectively) as well as drinkers (P=0.044 and 0.019, respectively). No genotyping differences were observed when analyzing cancers by pathological grades. These results demonstrate smoker and alcoholic drinker status to modify the risks of CYP1B1 polymorphisms for prostate cancer and this is of importance in understanding their role in the pathogenesis of this disease.

Citation Format: Taku Kato, Yutaka Hashimoto, Shigekatsu Maekawa, Marisa Shiina, Mitsuho Imai-Sumida, Pritha Dasgupta, Priyanka Kulkarni, Soichiro Yamamura, Shahana Majid, Sharanjot Saini, Varahram Sharryari, Guoren Deng, Rajvir Dahiya, Yuichiro Tanaka. Effects of tobacco smoking and alcohol consumption on risks of CYP1B1 polymorphisms for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2288. doi:10.1158/1538-7445.AM2017-2288
Abstract 2290: Perceived stressfulness of life events impacts breast cancer risk
Authors: Fischer Avital , Ziogas Argios , Anton-Culver Hoda
Published: July 2017

Background: Breast cancer is the most prevalent malignancy and the second most common cause of cancer mortality among women. Approximately 60% of variability in breast cancer risk remains unexplained. It is imperative to perform further research focusing on identifying preventable risk factors for breast cancer. The relationship between psychological stress and breast cancer risk is unclear. Psychological stress arises when environmental demands are appraised as going beyond one’s coping abilities. Higher perceived stress has been linked to increased cortisol levels and HPA perturbations. The purpose of this study is to understand the relationship between stressfulness appraisal of salient life events and breast cancer risk.

Methods: A case-control design was used and included 664 female cases identified through the Cancer Surveillance Program of Orange County, CA and 203 female population-based controls. Participants completed a risk factor questionnaire that included a life event section. Participants were asked to determine if events occurred and if they were considered to be significantly stressful or not. Multivariate unconditional logistic regression was used to calculate ORs while adjusting for known breast cancer covariates.

Results: Cumulative adverse life events perceived as stressful were associated with increased breast cancer risk in a dose response fashion (OR=1.63, 95% CI=1.00-2.66, Ptrend=0.045). Conversely, cumulative adverse life events not reported as stressful did not have a significant impact on breast cancer risk (OR=2.04, 95% CI=0.77-5.43). History of personal illness was directly related to increased breast cancer risk, when perceived as stressful (OR=2.84, 95% CI=1.96-4.11) or non-stressful (OR=3.47, 95% CI=1.34-8.94). Interestingly, abortion and relocation were observed to have a protective effect on breast cancer risk only when reported as being stressful (OR=0.54, 95% CI=0.32-0.92; OR=0.63, 95% CI=0.43-0.93 respectively).

Conclusions: This study broadens our understanding of the relationship between major life events and breast cancer risk and underscores the importance of stressfulness appraisal. Our results indicate the importance of incorporating assessments of perceived stressfulness in future epidemiological investigations focusing on the assessment of life events and breast cancer risk.

Note: This abstract was not presented at the meeting.

Citation Format: Avital Fischer, Argios Ziogas, Hoda Anton-Culver. Perceived stressfulness of life events impacts breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2290. doi:10.1158/1538-7445.AM2017-2290
Abstract 2296: Metformin reduces colon cancer risk in patients with type 2 diabetes: a retrospective cohort analysis
Authors: Tseng Chin-Hsiao
Published: July 2017

Background: The effect of metformin on colon cancer is rarely investigated in Asian populations.

Methods: This is a retrospective cohort study. Patients with newly diagnosed type 2 diabetes during 1999-2005 were recruited from Taiwan’s National Health Insurance. A 1:1 propensity score matched-pair sample of 16314 ever users and 16314 never users of metformin were followed until December 31, 2011. Cox regression incorporated with the inverse probability of treatment weighting using propensity score was used to estimate hazard ratios.

Results: The incidence of colon cancer was 272.04 and 392.44 per 100,000 person-years, respectively, in ever and never users. The overall hazard ratio (0.691, 95% confidence interval: 0.578-0.826) suggested a significantly lower risk in metformin users. While compared to never users, the hazard ratio (95% confidence interval) for the first (<20.00 months), second (20.00-45.20 months) and third (>45.20 months) tertile of cumulative duration of metformin therapy was 1.455 (1.165-1.816), 0.683 (0.526-0.885) and 0.224 (0.152-0.331), respectively. The protective effect of metformin on colon cancer was not affected by the use of aspirin and statin or the infection of Helicobacter pylori in additional analyses.

Conclusions: Metformin reduces colon cancer risk in patients with type 2 diabetes. The protective effect is more remarkable when the cumulative duration is more than 20 months.

Citation Format: Chin-Hsiao Tseng. Metformin reduces colon cancer risk in patients with type 2 diabetes: a retrospective cohort analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2296. doi:10.1158/1538-7445.AM2017-2296