bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 286: Epigenome-wide association study of normal lung tissues identifies hypomethylation of multiple CpG sites associated with cigarette smoking
Authors: Li Wen-Qing , Shi Jianxin , Wheeler William , Caporaso Neil , Laird-Offspringa Ite , Landi Maria Teresa 
Published: May 2015

Abstract
Background: DNA methylation due to tobacco smoking have been reported in studies of blood genomic DNA, indicating a possible role of methylation changes due to smoking in multiple adverse health outcomes. Since DNA methylation is known to be tissue-specific, we profiled methylation in normal human lung tissues and evaluated the association with cigarette smoking based on a large sample size.
Methods: We studied histologically normal lung tissues of 237 lung cancer patients (121 current cigarette smokers and 116 current nonsmokers) from the Environment And Genetics in Lung cancer Etiology study. DNA methylation was assayed using the Illumina Infinium HumanMethylation450 BeadChip arrays and methylation for 338,456 autosomal probes remained after quality control filters. We examined the association of log-transformed methylation with current smoking status, as well as with quantitative measures of smoking, using linear regression models adjusting for covariates. We sought to replicate the findings in The Cancer Genome Atlas normal lung samples (12 current smokers and 50 nonsmokers).
Results: Eight CpG sites were significantly hypomethylated in lung tissues of current smokers after Bonferroni-correction (P&lt;1.48×10-7). Of them, six were associated with smoking duration, pack-years and years from quitting smoking, and were replicated in TCGA samples (P&lt;0.10), including cg17113147 (NXN), cg05575921 (AHRR), cg07992500 (CDC42EP3), cg14120703 (NOTCH1), cg11152412 (EDC3), and cg03224163 (HIPK2). These loci have not been reported in prior studies, except for cg05575921, which was shown to be hypomethylated in smokers in studies of blood DNA.
Conclusions: Our study in lung tissues shows that smoking is associated with alterations in DNA methylation in genes involved in tobacco smoking metabolism or cancer progression. These findings suggest that smoking-associated epigenetic changes may have an important role in lung tumorigenesis.
Citation Format: Wen-Qing Li, Jianxin Shi, William Wheeler, Neil Caporaso, Ite Laird-Offspringa, Maria Teresa Landi. Epigenome-wide association study of normal lung tissues identifies hypomethylation of multiple CpG sites associated with cigarette smoking. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 286. doi:10.1158/1538-7445.AM2014-286
Abstract 2865: High serum transforming growth factor β1 levels associated with poor survivals in patients with advanced hepatocellular carcinoma
Authors: Lin Tzu-Hsuan , Shao Yu-Yun , Chan Soa-Yu , Huang Chung-Yi , Cheng Ann-Lii , Hsu Chih-Hung 
Published: May 2015

Abstract
Background: TGF-β (Transforming growth factor β) signaling pathway plays a significant role in mediating progression, metastasis, and immune evasion of human malignancies. Previous studies have found that serum TGF-β1 levels were elevated in patients with hepatocellular carcinoma (HCC) compared to patients with chronic hepatitis or cirrhosis. However, the prognostic role of serum TGF-β1 levels in patients with advanced HCC is currently unknown.
Patients and Methods: We enrolled patients who had received sorafenib or sorafenib-based combination therapy for advanced HCC, defined as metastatic or locally advanced diseases not amenable to loco-regional therapies, at National Taiwan University Hospital, Taipei, Taiwan, between 2007 and 2012. The baseline blood samples were collected before sorafenib treatment with the consent of the patients. Serum TGF-β1 levels were measured by Human TGF-β1 Instant ELISA (eBioscience, Vienna, Austria), and were correlated with disease control rate (DCR), progression- free survival (PFS), and overall survival (OS) of the patients.
Results: The study enrolled 91 patients (M:F=82:9), with a median age of 56.9 years. Sixty-nine patients (75.8 %) had chronic hepatitis B virus (HBV) infection, 18 (19.7%) had chronic hepatitis C infection, 82 (90.1%) had Barcelona Clinic Liver Cancer stage C disease, 81(89.0%) had either extrahepatic metastasis or macrovascular invasion, and 88 (96.7%) had Eastern Cooperative Oncology Group performance status of ≤ 1. All patients had Child-Puch class A liver function reserve. Patients with high baseline serum TGF-β1 levels (higher than the median level of the whole patient cohort), compared to patients with low serum TGF-β1 levels, had significantly shorter PFS (median, 2.54 vs. 4.27 months, p = 0.022) and OS (median, 5.57 vs. 11.6 months, p = 0.029). The DCRs for patients with high and low TGF-β1 were not statistically different (54.3 % vs. 62.2%, p = 0.4463). High baseline TGF-β1 levels tended to associate with high serum alpha-fetal protein (AFP) levels and high Cancer of the Liver Italian Program (CLIP) scores, although not reaching statistical significance.
Conclusions: High baseline serum TGF-β1 levels were associated with poor PFS and OS in patients with advanced HCC. (This study was supported by grants NRPB-100CAP1020-2, NSC101-2314-B-002-141 & NSC102-2314-B-002 -120).
Citation Format: Tzu-Hsuan Lin, Yu-Yun Shao, Soa-Yu Chan, Chung-Yi Huang, Ann-Lii Cheng, Chih-Hung Hsu. High serum transforming growth factor β1 levels associated with poor survivals in patients with advanced hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2014-2865
Abstract 2879: Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer
Authors: Suzawa Ken , Toyooka Shinichi , Shien Kazuhiko , Tanaka Norimitsu , Watanabe Masami , Soh Junichi , Sakaguchi Masakiyo , Matsuo Keitaro , Yamamoto Hiromasa , Furukawa Masashi , Asano Hiroaki , Tsukuda Kazunori , Nasu Yasutomo , Huh Nam-Ho , Miyoshi Shinichiro , Kumon Hiromi 
Published: May 2015

Abstract
Objectives: REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC).
Materials and Methods: We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines.
Results: Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a non-malignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells.
Conclusion: Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.
Citation Format: Ken Suzawa, Shinichi Toyooka, Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon. Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2879. doi:10.1158/1538-7445.AM2014-2879
Abstract 2887: Molecular farming and molecular engineering of cancer vaccines
Authors: Shukla Sourabh , Steinmetz Nicole F. 
Published: May 2015

Abstract
Human epidermal growth factor receptor 2 (HER2)+ cancers are aggressive, have poor prognoses, high rate of metastasis and relapse. Immunotherapy (e.g. trastuzumab) has shown improvement in outcome for HER2+ patients. Development of drug resistance and short half-lives limiting the duration of the therapy, are barriers in the development of effective therapeutic strategies. Furthermore, while passive immunotherapy provides treatment, it does not reduce the risk of recurrence of the disease. Therefore, we propose a HER2 vaccine to mount an active HER2-specific immune response, with long lasting immunological memory to overcome the limitations of passive immunotherapy and prevent tumor progression, metastasis, and relapse.
We hypothesize that integration of HER2 epitopes on the plant-produced vaccination platform potato virus X (PVX) will overcome immunological tolerance against HER2. We have shown that PVX naturally targets dendritic and B-cells stimulating Th1 biased immunity, important for successful tumor prevention. The carrier acts as an adjuvant, improves stability of epitopes, and increases circulation time, therefore ensuring a sustained stimulus post vaccination and production of HER2-specific antibodies that could act against HER2+ tumors via a variety of effector mechanisms. Immunizations of FBV/N mice resulted in the production of HER2-specific antibodies, as shown by ELISA and confocal microscopy using HER2+ human cancer cell lines. Vaccination studies using animals pre-disposed to HER2+ cancer are currently ongoing. Our long-term goal is to produce the vaccine through molecular farming in edible plant tissue and make it available globally, especially in underdeveloped countries where repeated administration of costly immunotherapies is not affordable or unavailable.
Citation Format: Sourabh Shukla, Nicole F. Steinmetz. Molecular farming and molecular engineering of cancer vaccines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2887. doi:10.1158/1538-7445.AM2014-2887
Abstract 2909: A gene signature composed of 13 p53 target genes predicts for response to NVP-CGM097, a novel p53-Mdm2 inhibitor, in cell lines and in human primary tumor xenograft models
Authors: Jeay Sebastien , Gaulis Swann , Ferretti Stéphane , Albrecht Geneviève , Barys Louise , Guthy Daniel , Halilovic Ensar , Ito Moriko , Murakami Masato , Pornon Astrid , Ruetz Stephan , Venkatesan Kavitha , Yu Jianjun , Jensen Michael , Wiesmann Marion , Wuerthner Jens , Graus-Porta Diana 
Published: May 2015

Abstract
Patient selection biomarkers are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study we have identified a novel patient selection strategy for NVP-CGM097, a p53-Mdm2 inhibitor currently in a Phase I clinical trial (NCT01760525). We have analyzed the sensitivity of over 500 cell lines from the “Cancer Cell Line Encyclopedia” to the p53-Mdm2 inhibitor in cell viability assays, and intersected response data with information on gene expression and genomic alterations. This analysis has led to the identification of a gene signature consisting of 13 genes, as a predictor for sensitivity to NVP-CGM097. Interestingly, these 13 genes are known p53 downstream target genes, supporting the hypothesis that the identified gene signature is reflective of the p53 pathway functionality in sensitive cell lines. We show the performance of the signature as ROC and Precision-Recall curves in cell lines as well as in a number of human primary tumor xenografts, both unselected as well as pre-selected for p53 wild-type status. Work is now ongoing to validate this gene signature using baseline tumor biopsy samples and RECIST-based efficacy readouts in the current Phase I clinical trial.
Citation Format: Sebastien Jeay, Swann Gaulis, Stéphane Ferretti, Geneviève Albrecht, Louise Barys, Daniel Guthy, Ensar Halilovic, Moriko Ito, Masato Murakami, Astrid Pornon, Stephan Ruetz, Kavitha Venkatesan, Jianjun Yu, Michael Jensen, Marion Wiesmann, Jens Wuerthner, Diana Graus-Porta. A gene signature composed of 13 p53 target genes predicts for response to NVP-CGM097, a novel p53-Mdm2 inhibitor, in cell lines and in human primary tumor xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2909. doi:10.1158/1538-7445.AM2014-2909
Abstract 2926: PNA as novel targeted cancer therapy for BRAFV600E mutant melanoma
Authors: Rothman Jeffrey H. , Surriga Oliver , Vasudeva Shyamprasad D. , Ambrosini Grazia , Ouerfelli Ouathek , Schwartz Gary K. 
Published: May 2015

Abstract
Our aim is to target tumor cells specifically by directly suppressing their oncogenes with peptide nucleic acid (PNA) oligonucleotide analogues. PNA oligonucleotides bind to DNA over 1000-fold more avidly than its native complement, are completely resistant to intra and extra cellular enzymatic degradation, show no nonspecific toxicity at therapeutic levels, and when conjugated to delivery peptides can be made nuclear and cell membrane permeable. We have employed these PNA oligomers to target BRAFV600E which is prevalent in cutaneous melanoma in a sequence-specific complementary manner so as to disrupt transcription by strand invasion. For these studies, we have developed a novel delivery peptide conjugated to PNA modified to increase both cellular delivery and PNA stability towards its target. Our results indicate that exposure of the melanoma cell lines to a modified PNA-peptide conjugate selective for BRAFV600E results in a concentration-dependent inhibition of cell growth that is specific for the BRAFV600E mutant melanoma cell lines with an IC50 range of 250 to 500 nM. Moreover, there is no inhibition of BRAFWT cell growth at these concentrations. This is associated with suppression of BRAFV600E protein over time with no effect on BRAFWT protein levels. Furthermore, BRAFV600E protein expression was suppressed for up to 6 days following initial exposure proving the durability of this type of inhibition. Exposure to this modified PNA-peptide down-regulates BRAFV600E mRNA transcription exclusively in the mutant cell lines. Live cell imaging of BRAFV600E mutant cells confirms localization of fluorescein-labeled PNA-delivery peptide specific to BRAFV600E to the nucleus within 3 hours of treatment. Our results indicate that these PNA-peptide derivatives could represent a novel and promising new therapy for patients with BRAFV600E mutant melanoma, and this technology could be applied to a multitude of other cancers either with specific translocations or mutations differing from wild-type cells even by only a single base pair.
Citation Format: Jeffrey H. Rothman, Oliver Surriga, Shyamprasad D. Vasudeva, Grazia Ambrosini, Ouathek Ouerfelli, Gary K. Schwartz. PNA as novel targeted cancer therapy for BRAFV600E mutant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2926. doi:10.1158/1538-7445.AM2014-2926
Abstract 2967: Metformin selectively targets tumor initiating cells in erbb-2 overexpressing breast cancer models
Authors: Zhu Pei , Davis Meghan , Blackwelder Amanda , Bachman Nora , Liu Bolin , Edgerton Susan , Williams Leonard L. , Thor Ann D. , Yang Xiaohe 
Published: May 2015

Abstract
Metformin is an oral biguanide used for type II diabetes. Epidemiologic studies suggest a link between metformin use and reduced risk of breast and other types of cancers. erbB-2 expressing breast cancer is a subgroup of tumors with poor prognosis. Previous studies demonstrated that metformin is a potent inhibitor of erbB-2 overexpressing breast cancer cells; metformin treatment extends the life span and impedes mammary tumor development in ErbB-2 transgenic mice in vivo. However, the mechanisms of metformin associated anti-tumor activity, especially in prevention models, remain unclear. In this study, we investigated the mechanisms of metformin associated prevention/inhibition of ErbB-2 mediated breast cancer development by focusing on the potential effect of metformin on tumor initiating cells (TICs)/cancer stem cells (CSCs) in the MMTV-erbB-2 transgenic mouse model and its context with existing in vitro models. We report here for the first time that systemic administration of metformin (250 mg/kg/day, ip, between 8- and 18-week of age) selectively inhibits CD61high/CD49fhigh subpopulation, a group of TICs of MMTV-ErbB-2 mammary tumors, in preneoplastic mammary glands. Metformin also inhibited CD61high/CD49fhigh subpopulation in MMTV-erbB-2 tumor-derived cells, which was correlated with their compromised tumor initiation/development in a syngeneic tumor graft model. Molecular analysis indicated that metformin induced downregulation of erbB-2 and EGFR expression and inhibited the phosphorylation of erbB family members, IGF1R, Akt, mTOR and Stat3 in vivo. In vitro data indicate that low doses (1 mM) of metformin inhibited the self-renewal/proliferation of CSCs/TICs in ErbB-2-overexpressing breast cancer cells. We further demonstrated that the expression and activation of ErbB-2 were preferentially increased in CSC/TIC-enriched tumorsphere cells, which promoted their self-renewal/proliferation and rendered them more sensitive to metformin. Our results, especially the in vivo data, provide fundamental support for developing metformin-mediated preventive strategies targeting erbB-2-associated carcinogenesis.
Citation Format: Pei Zhu, Meghan Davis, Amanda Blackwelder, Nora Bachman, Bolin Liu, Susan Edgerton, Leonard L. Williams, Ann D. Thor, Xiaohe Yang. Metformin selectively targets tumor initiating cells in erbb-2 overexpressing breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2967. doi:10.1158/1538-7445.AM2014-2967
Abstract 3050: Human rectal carcinoid tumors highly express DCLK1, a putative cancer stem cell marker
Authors: Ikezono Yu , Koga Hironori , Abe Mitsuhiko , Yoshida Takafumi , Nakamura Toru , Akiba Jun , Yano Hirohisa , Tsuruta Osamu , Torimura Takuji , Sata Michio 
Published: May 2015

Abstract
Background and Aim: Doublecortin-like kinase 1 (Dclk1) is known to regulate neuronal differentiation, migration, and neurogenesis (Shu et al., Neuron 2006). Accumulating evidence suggests that the protein is a putative marker for intestinal and pancreatic stem cells, including cancer stem cells (CSCs) of those organs (Gagliardi et al., Pathol Res 2012, Nakanishi et al., Nat Genet 2013, Bailey et al., Gastroenterology 2013). Since carcinoid tumor is defined as a neuroendocrine tumor, we assessed whether or not the Dclk1 protein, a marker of CSC, was expressed in human rectal carcinoid tumor tissues. Patients and Methods: Eighteen patients (9 male, 9 female; mean age, 51) with rectal carcinoid tumors were included in this study. Informed consent was obtained from all of the patients. The tumors were safely resected by endoscopic mucosal resection (EMR) method between 2003 and 2012 in the Kurume University Hospital. Mean diameter of the tumors was 5.4 mm (range, 2.0-8.0 mm). Immunohistochemical staining was performed to examine the Dclk1 protein expression, accompanied by the staining for the commonly-used neuroendocrine markers synaptophysin, chromogranin A, and CD56. The immune-reactivity was evaluated according to the following criteria: the intensity of staining was scored in each specimen on a scale of 0 to 3, in which 0 = negative staining, 1 = weakly positive staining, 2 = moderately positive staining, and 3 = strongly positive staining. The extent to which positive cells were seen in each specimen (‘‘extent of distribution’’ of positive cells) was estimated on a scale of 0 to 2, in which 0 = positive staining in 0% to 20% of cells; 1, in 21% to 60%; and 2, in 61% to 100%. Sum of the scores was calculated for each specimen. Results: The total score for Dclk1, synaptophysin, CD56, and chromogranin A was 87/90, 86/90, 60/90, and 34/90, respectively. Conclusions: Human rectal caricinoid tumor highly expressed Dclk1, and the high expression rate indicated that the protein expression was a novel feature for the neuroendocrine tumor. It is suggested that Dclk1 is a potential marker of not only CSCs but also non-epithelial tumors, such as carcinoid tumor, regulating crucial tumor cell behaviors.
Citation Format: Yu Ikezono, Hironori Koga, Mitsuhiko Abe, Takafumi Yoshida, Toru Nakamura, Jun Akiba, Hirohisa Yano, Osamu Tsuruta, Takuji Torimura, Michio Sata. Human rectal carcinoid tumors highly express DCLK1, a putative cancer stem cell marker. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3050. doi:10.1158/1538-7445.AM2014-3050