bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-289: Telomere length, genetic variants and gastroesophageal cancer risk: a case-control study in Chinese population
Authors: Du Jiangbo , Zhu Xun , Zhu Chen , Ma Hongxia , Hu Zhibin , Shen Hongbing , Jin Guangfu 
Published: May 2015

Abstract
Backgrounds
Telomeres are protective DNA-protein repeats structure at the extreme end of linear chromosomes that maintain chromosomal stability and integrity. Short telomere in peripheral blood leukocyte has been associated with an increased risk of multiple cancers. Moreover, heterogeneity of inter-individual telomere length is partly determined by hereditary factor. Recent genome-wide association studies (GWAS) have identified several telomere length related loci at 2p16.2 (ACYP2), 3q26 (TERC), 4q32.2 (NAF1), 5p15.33 (TERT), 10q24.33 (OBFC1), 19p12 (ZNF208) and 20q13.3 (RTEL1), some of which were also implicated with cancer risk. However, these findings were mainly observed in populations of European descent, and were not well demonstrated in other populations, especially for gastroesophageal cancer that is high incident in China but not in western countries.
Design and Methods
We measured relative telomere length (RTL) by quantitative real-time polymerase chain reaction in a Chinese case-control study including 1,136 gastric cancer cases, 1,045 esophageal cancer cases and 1,012 matched controls. Moreover, we performed genotyping by TaqMan assay for genetic variants at 2p16.2 (rs11125529), 3q26 (rs10936599), 4q32.2 (rs7675998), 5p15.33 (rs2736100, rs2736108), 10q24.33 (rs4387287), 19p12 (rs8105767), and 20q13.3 (rs755017).
Results
As compared with individuals in the fourth quintile of telomere length (i.e., moderately long telomeres), those with short telomeres were at an increased risk with ORs (95%CI) being 1.19 (0.92-1.55), 1.53 (1.19-1.98) and 3.00 (2.33-3.85) for the third, second and first quintiles, respectively. More interestingly, a significant elevated risk (OR= 1.54, 95%CI: 1.19-2.00) was also found in those at the fifth quintile with extreme long telomeres. We also confirmed that the G allele of rs2736100 at 5p15.33 exhibited a significant association with longer telomere length (r2= 0.106, P = 0.047), which, however, was not significantly associated with gastroesophageal cancer risk. We did not observe significant association of the other loci with telomere length or gastroesophageal cancer risk.
Conclusions
These findings suggest that either short or extreme long telomere may be risk factor for gastroesophageal cancer while telomere length related variants may be less important in the susceptibility to gastroesophageal cancer in Chinese population.
Citation Format: Jiangbo Du, Xun Zhu, Chen Zhu, Hongxia Ma, Zhibin Hu, Hongbing Shen, Guangfu Jin. Telomere length, genetic variants and gastroesophageal cancer risk: a case-control study in Chinese population. [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 LB-289. doi:10.1158/1538-7445.AM2014-LB-289
Abstract LB-290: The influence of body size and weight gain on global and gene promoter methylation in a population-based breast cancer study
Authors: McCullough Lauren E. , Chen Jia , White Alexandra J. , Xu Xinran , Cho Yoon Hee , Bradshaw Patrick T. , Eng Sybil M. , Teitelbaum Susan L. , Terry Mary Beth , Garbowski Gail , Neugut Alfred I. , Hibshoosh Hanina , Santella Regina M. , Gammon Marilie D. 
Published: May 2015

Abstract
Purpose. Little is known about how modifiable lifestyle factors, influence the epigenome. Elevated body mass index (BMI, weight kg/height m2) and adult weight gain are associated with increased risk of postmenopausal breast cancer, but the underlying mechanisms are not well understood. We hypothesized that these anthropometric factors may modify DNA methylation status by altering sex-steroid hormones levels and inflammatory markers.
Methods. Resources from a population-based study (∼650 postmenopausal cases/∼650 postmenopausal controls) were used to construct logistic regression models. We explored potential modification of the global methylation-breast cancer association by BMI and weight gain using two assays: the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) in white blood cell DNA. Additionally, we estimated associations between anthropometrics and promoter methylation status in a panel of 13 breast cancer-related genes using ∼600 breast tumor tissues.
Results. We observed a multiplicative interaction between LUMA and BMI (p=0.033) in relation to breast cancer. There was a greater than two-fold risk of postmenopausal breast cancer among women in the highest quartile of LUMA for each strata of BMI: age-adjusted odds ratios (95% confidence intervals) were 2.19(1.37, 3.52), 2.91(1.77, 4.80) and 2.51(1.45, 4.33) for women with BMI&lt;25, BMI25-29.9 and BMI≥30, respectively. The observed estimates did not differ, statistically, across BMI categories. Additionally, we found no interactions with LINE-1 and observed no associations between anthropometrics and promoter methylation status in the genes examined.
Conclusions. Our data suggest that the association between BMI, weight gain and postmenopausal breast cancer may arise from mechanisms other than DNA methylation.
Citation Format: Lauren E. McCullough, Jia Chen, Alexandra J. White, Xinran Xu, Yoon Hee Cho, Patrick T. Bradshaw, Sybil M. Eng, Susan L. Teitelbaum, Mary Beth Terry, Gail Garbowski, Alfred I. Neugut, Hanina Hibshoosh, Regina M. Santella, Marilie D. Gammon. The influence of body size and weight gain on global and gene promoter methylation in a population-based breast cancer study. [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 LB-290. doi:10.1158/1538-7445.AM2014-LB-290
Abstract LB-291: Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma
Authors: Yamamoto Hiromasa , Higasa Koichiro , Sakaguchi Masakiyo , Shien Kazuhiko , Soh Junichi , Ichimura Koichi , Furukawa Masashi , Hashida Shinsuke , Tsukuda Kazunori , Takigawa Nagio , Matsuo Keitaro , Kiura Katsuyuki , Miyoshi Sinichiro , Matsuda Fumihiko , Toyooka Shinichi 
Published: May 2015

Abstract
Familial cancers arising from several organs are often reported including breast and colon cancers, although familial lung cancers are few reported. We encountered a family of Japanese descent in which multiple members developed lung adenocarcinomas. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the same transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt, an effector kinase regarding to cell survival. In addition, they activated the other kinase, p38 at a remarkable level, which is thought to promote critically cell proliferation in lung adenocarcinoma. Coupling experiments revealed that mutant HER2 avidly dimerized with EGFR, HER3 and HER4 in the same manner to those with wild type HER2. The formation of mutant HER2 homodimers was also observed, whereas we less detected homodimers of wild type HER2. Our findings strongly suggest that mutations in the transmembrane domain of HER2 are oncogenic, causing hereditary and sporadic lung adenocarcinomas.
Citation Format: Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka. Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma. [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 LB-291. doi:10.1158/1538-7445.AM2014-LB-291
Abstract LB-293: Circulating tumor cells in peripheral and pulmonary venous blood predict poor long-term survival in surgical resected non-small cell lung cancer patients
Authors: Liu Zhidong , Li Yunsong , Su Chongyu , Han Yi , Xu Shaofa 
Published: May 2015

Abstract
Background: We tested the hypothesis that the circulating tumor cells (CTCs) in preoperative peripheral blood (PPB) and intraoperative pulmonary venous blood (IPVB) could predict poor long term survival in surgically resected NSCLC patients.
Methods: CTCs were separated from the blood using magnetic beads coated by antibody against epithelial-cell adhesion molecule (EpCAM) through magnetic activated cell sorting (MACS). The CTCs were quantified with fluorescence labeled antibodies against pan-cytokeratin through flow cytometry. CTCs were prospectively quantified in PPB and IPVB in 23 consecutive stage I-IIIA patients with surgically resected NSCLC. Association between CTCs and prognosis of these patients was evaluated after 5-year follow-up.
Results: In the NSCLC patients, outcomes were assessed according to levels of CTCs at surgery, and compared with CTCs detected in benign pulmonary diseases, and healthy volunteers, where the mean and 95%CI of CTCs counts were all 5 CTCs/15mL in PPB and &gt;50 CTCs/15mL in IPVB. Univariate Cox proportional-hazards regression analysis showed that CTCs count in PPB or IPVB was an independent risk factor for tumor-free and overall survivals. The high risk group of patients had a shorter median tumor-free survival (22 months vs. &gt;60.0 months, P60 months, P&lt;0.0015).
Conclusions: CTCs count in PPB and IPVB was an independent risk factor for tumor-free and overall survival in surgically resected NSCLC patients.
Citation Format: Zhidong Liu, Yunsong Li, Chongyu Su, Yi Han, Shaofa Xu. Circulating tumor cells in peripheral and pulmonary venous blood predict poor long-term survival in surgical resected non-small cell lung cancer patients. [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 LB-293. doi:10.1158/1538-7445.AM2014-LB-293
Abstract LB-301: gp130/Jak/Stat3 inhibition blocks WNT signaling-mediated intestinal tumorigenesis and regeneration
Authors: Ernst Matthias 
Published: May 2015

Abstract
The capacity of crypt stem cells to respond to canonical Wnt signaling enables the adult intestinal epithelium to continuously renew, regenerate after injury and, as a consequence of Apc tumor suppressor mutations, give rise to colon cancers. Likewise, Stat3 signaling is required for stem cell function and therefore also intestinal homeostasis. We previously described that therapeutic inhibition of gp130/Jak/Stat3 signaling suppresses colitis-associated colon cancer in mice [1,2]. We now find that genetic activation of gp130/Jak/Stat3 signaling augments intestinal regeneration and enhances sporadic tumorigenesis in Apc-mutant mice. Conversely, systemic gp130/Jak/Stat3 pathway restriction, or therapeutic Jak inhibition, suppresses regeneration, and also blocks initiation and growth of Apc-mutant mouse tumors, and colon cancer xenografts, without interfering with intestinal homeostasis and despite persisting high Wnt signaling. We identify gp130/Jak/Stat3-dependent induction of Bmi-1 and associated p16/p21 repression as the underlying mechanism. Our findings put in perspective observations that associate complete epithelial Stat3 deletion with reduced crypt stem cell survival and progression of Apc-mutant tumors. We therefore propose that gp130/Jak/Stat3 signaling becomes selectively rate-limiting for Apc-mutant tumor growth by serving as the “rheostat” that links intestinal proliferation to the epithelial wound-healing process hijacked by tumor cells. In turn, our findings provide a rational for therapeutic Jak inhibition in colon cancer.
1 Putoczki et al., Cancer Cell 2013
2 Stuart et al., Mol Cancer Therapy 2014
Citation Format: Matthias Ernst. gp130/Jak/Stat3 inhibition blocks WNT signaling-mediated intestinal tumorigenesis and regeneration. [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 LB-301. doi:10.1158/1538-7445.AM2014-LB-301
Abstract LB-303: A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic ductal adenocarcinoma
Authors: Fujimura Ken , Wright Tracy , Strnadel Jan , Kelber Jonathan , Kaushal Sharmeela , Metildi Cristina , Lowy Andrew , Bouvet Michael , Klemke Richard 
Published: May 2015

Abstract
Deregulation of mRNA translation and protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression. eIF5A1, and its highly related isoform eIF5A2, are critical translation initiation factors implicated in several human malignancies. Interestingly, eIF5A proteins are the only known proteins in nature that are regulated by a distinct posttranslational modification termed hypusination. This unique lysine modification ([N-(4-amino-2-hydroxybutyl)lysine]) involves polyamine biosynthesis and is catalyzed by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The highly selective nature of the hypusine modification and its amenability to pharmacological and genetic inhibition make the eIF5A-hypusine pathway an attractive therapeutic target to combat human cancers. Here, we investigated the role of eIF5A1/A2-hypusine pathway in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Hypusinated eIF5A1/A2 are upregulated in human PDAC tissues and in early stage PanIN tissues isolated from genetically engineered Pdx-Cre:LSL-KRASG12D mice. RNAi-mediated knockdown of eIF5A1/A2 in human PDAC cell lines inhibited cancer cell growth in vitro and inhibited tumor growth orthotopically in mice. In contrast, amplification of eIF5A1/A2 in PDAC cells increased orthotopic growth and tumor formation in mice. The deoxyhypusine hydroxylase inhibitor, CPX, and the deoxyhypusine synthase inhibitor, GC7, inhibited eIF5A1/A2 hypusination, preventing PDAC cell growth. Interestingly, we find that eIF5A1/A2 regulates cancer cell expansion by modulating the expression level of PEAK1, a non-receptor tyrosine kinase essential for PDAC cell growth. Our findings suggest that eIF5A1/A2 utilizes PEAK1 tyrosine kinase as a downstream effector to drive PDAC pathogenesis, and that pharmacological inhibition of the eIF5A1/A2 hypusination-PEAK1 axis may provide a novel therapeutic strategy to combat this deadly disease.
Citation Format: Ken Fujimura, Tracy Wright, Jan Strnadel, Jonathan Kelber, Sharmeela Kaushal, Cristina Metildi, Andrew Lowy, Michael Bouvet, Richard Klemke. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic ductal adenocarcinoma. [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 LB-303. doi:10.1158/1538-7445.AM2014-LB-303
Abstract LB-304: Smad7-Skp2 complex orchestrates c-Myc stability
Authors: Kim Tae-Aug , Kang Jin-Muk , Niderhuber John , Kim Seong-Jin 
Published: May 2015

Abstract
In most of human cancer, the c-Myc proto-oncogene is highly activated. Dysregulation of c-Myc oncoprotein contributes to drive tumorigenesis in numerous tissues and organs. Thus, targeting c-Myc stability can be a critical step for cancer therapy. Here we report Smad7 as a key molecule to regulate c-Myc stability and activity by recruiting F-box protein, Skp2. Ectopic expression of Smad7 down-regulated the protein level of c-Myc without affecting transcription level and significantly repressed its transcriptional activity, leading to inhibition of cell proliferation and tumorigenic activity. Furthermore, Smad7 enhanced ubiquitination of c-Myc through direct interaction with c-Myc and recruitment of Skp2. Ablation of Smad7 resulted in less sensitivity to the growth inhibitory effect of TGF-β by inducing stable c-Myc expression. In conclusion, these findings that Smad7 functions as a transductory role in c-Myc oncoprotein degradation and enhances the cytostatic effect of TGF-β signaling provide new insightful therapeutic approach for cancer treatment.
Citation Format: Tae-Aug Kim, Jin-Muk Kang, John Niderhuber, Seong-Jin Kim. Smad7-Skp2 complex orchestrates c-Myc stability. [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 LB-304. doi:10.1158/1538-7445.AM2014-LB-304
Abstract LB-309: Interplay between E3 ligases modulate Per2 stability
Authors: liu jingjing , Finkielstein Carla V. 
Published: May 2015

Abstract
Circadian oscillation relies on autoregulatory loops generated by sequential phases of transcription/translation, protein modification, and degradation. Interestingly, disruption of the clock gene period2 (per2) in mice is associated with a hyperplasic phenotype and loss of apoptotic response. When irradiated, per2 knockout mice show a significantly higher frequency of tumor development most likely due to loss of normal circadian control of genes concerned with the regulation of the DNA-damage response as well as partial resistance to radiation-induced apoptosis. Although evidence suggests that the per2 gene functions in tumor suppression, no mechanism of Per2 action is known. Our work show direct evidences of crosstalk mechanisms that involve Per2 and the oncogenic E3-ligase Mdm2. Whereas we know much about the role of b-TrCP in modulating the oscillatory levels of Per2 in the cell, the functional relevance of Mdm2 targeting of Per2 has just been uncovered. Bacterial two-hybrid screenings led to the identification of Mdm2 as a new PER2 binding partner, an interaction that was later validated by immunoprecipitation studies from both ectopicaly expressed and endogenous proteins. In vitro experiment show that recombinantly expressed Per2 serves as a substrate for Mdm2 and polyubiquitination takes place shortly after interaction. These results were later confirmed when Mdm2 was overexpressed and ubiquitination of Per2 was detected in immunoprecipitated samples. Interestingly, knock down of either beta-TrCP or Mdm2 dampened PER2 oscillation, although the mechanism by either E3 ligase seems to act relies in the subcellular localization of the substrate., Lastly, there is an interplay between these two ligases as we showed that downregulation of Mdm2 influences the total levels of beta-TrCP and direct interaction between these protein was confirmed by immunoprecipitation. Moreover, experiments carried out with constitutively negative active forms of each ligase show they are each other targeted for ubiquitination and that Per2 exerts a very relevant control on stability of b-TrCP by binding to Mdm2 and inhibiting its E3-ligase activity.
Citation Format: jingjing liu, Carla V. Finkielstein. Interplay between E3 ligases modulate Per2 stability. [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 LB-309. doi:10.1158/1538-7445.AM2014-LB-309
Abstract LB-317: Interactive pipeline for reproducible genomics analyses
Authors: Considine Michael , Parker Hilary S. , Wei Yingying , Xia Xiao X. , Cope Leslie , Ochs Michael F. , Fertig Elana J. 
Published: May 2015

Abstract
Automated Genomics Analysis (AGA) is a program to analyze high-throughput genomic data sets, such as Affymetrix gene expression arrays. The software implements an easy to use, point and click, guided pipeline to combine, define and compare datasets, and customize their outputs. Batch correction techniques are implemented to combine data sets. Options to save plots, tables and data are available throughout the analysis, and log files containing the R script run are also generated to facilitate reproducible analyses.
The software has been applied to gene expression measurements from head and neck squamous cell carcinoma (HNSCC). It has batch corrected several public domain microarray HNSCC datasets, facilitating accurate comparison of subtypes such as HPV status. Moreover, current extensions enable users to interactively perform reproducible genomics analysis using clinical covariates in RNA sequencing data from TCGA.
Citation Format: Michael Considine, Hilary S. Parker, Yingying Wei, Xiao X. Xia, Leslie Cope, Michael F. Ochs, Elana J. Fertig. Interactive pipeline for reproducible genomics analyses. [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 LB-317. doi:10.1158/1538-7445.AM2014-LB-317
Abstract LB-319: Functionally validated shRNA libraries for large-scale RNAi screens
Authors: Sridhar Vaishali , Lai Dan Yu , Sinha Nishi , Premsrirut Prem K. , Fellmann Christof 
Published: May 2015

Abstract
RNA interference (RNAi) has become an indispensable tool for loss-of-function genetics across eukaryotes. By enabling stable and reversible gene silencing, short hairpin RNA (shRNA) triggers of RNAi provide a means to study long term phenotypes, perform pool-based forward genetic screens and examine the consequences of temporary target inhibition in vivo. However, efficient implementation in vertebrate systems has been hindered by our incomplete understanding of the sequence requirements for effective shRNA biogenesis and target suppression. Consequently, single-gene studies still depend on laborious testing of many candidates and pooled shRNA screens contain non-functional sequences that make the interpretation of negative results inconclusive.
To address this limitation, we recently developed a high-throughput “RNAi Sensor assay” that enables functional identification of effective shRNAs at large scale. We showed that this assay allows testing of tens of thousands of candidates in parallel and robustly identifies potent single-copy shRNAs targeting virtually any gene. Here we applied this technology to evaluate 20,000 preselected candidate shRNAs targeting over 330 disease-relevant mouse genes to generate a functionally validated shRNA library for potent single-copy target knockdown. Beyond their use in RNAi transgenic animals, such shRNA libraries will enable comprehensive pooled RNAi screening and open a promising avenue for high-throughput functional genetics in the post-genomic era.
Citation Format: Vaishali Sridhar, Dan Yu Lai, Nishi Sinha, Prem K. Premsrirut, Christof Fellmann. Functionally validated shRNA libraries for large-scale RNAi screens. [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 LB-319. doi:10.1158/1538-7445.AM2014-LB-319