bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2198: A literature-based sum score of genetic variants in IGF genes modifies associations between indicators of energy balance and colorectal cancer risk
Authors: Simons Colinda CJM , Schouten Leo J. , Godschalk Roger , Schooten Frederik-Jan van , Brandt Piet A. van den , Weijenberg Matty P. 
Published: May 2015

Abstract
Background: Gene-environment interactions between variants in growth-regulating IGF genes and energy balance in colorectal cancer (CRC) were studied in the Netherlands Cohort Study (NLCS) after 16.3 years follow-up.
Methods: Using a systematic strategy, we selected 25 SNPs and a CA repeat in IGF genes that had repeatedly demonstrated significant associations with CRC risk, energy balance-related exposures or related endpoints in literature, and thus likely modify effects of energy balance on CRC development. Twenty-four SNPs were successfully genotyped in toenail DNA of NLCS subcohort members (n=3,203) and CRC cases (n=2,274) with adequate exposure data. Unfavorable alleles were aggregated into a sum score. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated in case-cohort analyses for linear combinations between tertiles of the genetic sum score and 8 energy balance-related exposures.
Results: Significant and increasingly higher risks were observed for men with more adverse profiles compared to men with the most optimal profile. In particular carrying more unfavorable alleles in combination with a larger adult trouser/skirt size, an increased height or the absence of early life energy restriction during the Dutch Hunger Winter (1944-45) was associated with distal colon cancer [highest vs. lowest linear combinations: HR (95% CI) = 2.03 (1.27-3.24), 2.05 (1.16-3.63) and 1.87 (1.11-3.16), respectively]. A combined effect of IGF polymorphisms and energy balance-related exposures on subsite-specific CRC risk was less convincing in women.
Conclusion: Combined effects of IGF polymorphisms and specific energy balance-related exposures are important in CRC development in men, and less convincingly in women. The availability of extensive environmental data and the aggregation of genetic variants were invaluable for interpreting the joint associations.
Note: This abstract was not presented at the meeting.
Citation Format: Colinda CJM Simons, Leo J. Schouten, Roger Godschalk, Frederik-Jan van Schooten, Piet A. van den Brandt, Matty P. Weijenberg. A literature-based sum score of genetic variants in IGF genes modifies associations between indicators of energy balance and colorectal cancer risk. [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 2198. doi:10.1158/1538-7445.AM2014-2198
Abstract 220: Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features
Authors: Tanaka Shinji , Ogawa Kousuke , Murakata Ayano , Mogushi Kaoru , Matsumura Satoshi , Aihara Arihiro , Ban Daisuke , Ochiai Takanori , Irie Takumi , Kudo Atsushi , Nakamura Noriaki , Tanaka Hiroshi , Arii Shigeki , Tanabe Minoru 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is known to demonstrate a morphological variety of macroscopic appearances, but their pathological and molecular differences remain unclear.
First, the clinicopathologic characteristics as well as genome-wide gene expressions were analyzed in relation to the gross morphology of HCC. Among the patients with nodular type HCC, significantly poor prognosis was recognized in confluent multinodular (CM) type in overall survival as well as recurrence-free survival. Analysis of the genome-wide expression patterns revealed significant deference of CM-type HCC from other types of HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM-type HCC.
Next, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU. Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13, VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13. In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control. Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control.
Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and specific approach for the treatment of HCC with the poor prognostic phenotype.
Citation Format: Shinji Tanaka, Kousuke Ogawa, Ayano Murakata, Kaoru Mogushi, Satoshi Matsumura, Arihiro Aihara, Daisuke Ban, Takanori Ochiai, Takumi Irie, Atsushi Kudo, Noriaki Nakamura, Hiroshi Tanaka, Shigeki Arii, Minoru Tanabe. Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features. [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 220. doi:10.1158/1538-7445.AM2014-220
Abstract 2210: Cumulative risks of gastric cancer by PSCA polymorphism, Helicobacter Pylori infection and smoking history in Japan
Authors: Ito Hidemi , Oze Isao , Hosono Satoyo , Watanabe Miki , Tanaka Hideo , Matsuo Keitaro 
Published: May 2015

Abstract
Appreciating lifetime risk of gastric cancer through established risk factors is one simple way to promote preventive behavior. We have estimated cumulative risks (CRs) of gastric cancer by genetic and environmental risk factors, PSCA-rs2294008 polymorphism, Helicobacter Pylori (HP) infection and smoking, based on a case-control study involving 697 cases and 1372 controls at Aichi Cancer Center. We estimated odds ratio (OR) and 95% confidence interval (CI) for groups by these factors using logistic regression model after adjustment for age, sex, family history of gastric cancer and intake of fruit and vegetable. The ORs were combined with gastric cancer incidence rates in Japan to calculate CRs using the Peto's method. The CRs by age of 75 varied according to the risk groups, from 0.9% (95% CI, 0.3%-3.3%) for never smokers without both HP infection and risk allele of rs2294008 to 13.4% (95% CI, 13.3%-13.4%) for ever smokers with HP infection and 1-2 risk alleles. Among those with 1-2 risk alleles, the CRs were reduced to 2.0% (95% CI, 1.9%-2.0%) in those without both smoking history and HP infection, 3.9% (95% CI, 3.8%-3.9%) for ever smokers without HP infection, 9.4% (95% CI, 9.4%-9.5%) for never smokers with HP infection, although it was 13.4% in those with both smoking history and HP infection. In conclusion, the findings based on genetic and environmental risk factors in this study would be important information for promoting primary and secondary prevention of gastric cancer.
Citation Format: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo. Cumulative risks of gastric cancer by PSCA polymorphism, Helicobacter Pylori infection and smoking history in Japan. [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 2210. doi:10.1158/1538-7445.AM2014-2210
Abstract 2215: Association between single-nucleotide polymorphisms of BRAF and papillary thyroid carcinoma in a Chinese population
Authors: Chen Kexin 
Published: May 2015

Abstract
Background: Papillary thyroid cancer (PTC) is a common malignancy that frequently harbors a high prevalence of somatic mutations in the oncogenic BRAF gene. As a novel prognostic molecular marker, this gene has drawn much attention in recent years for its potential utility in the risk prognosis and management of PTC. However, the contribution of the germline variants in this gene to PTC remains unclear. The study herein was aimed to investigate the potential association between the inherited BRAF variants and PTC based on a case-control study.
Methods: We selected four single-nucleotide polymorphisms (SNPs) and took a systematic step to interrogate whether these SNPs of BRAF are associated with PTC risk by genotyping these SNPs from 368 patients with PTC and 564 healthy controls.
Results: In comparison of cases and controls for the four SNPs, no differences were observed in the genotypic and allelic frequencies, nor was there evidence of an association between BRAF SNPs and overall risk of PTC. After stratification, however, we found a significantly increased risk of PTC attributed to the SNP variants rs17161747, rs1042179, and rs3748093 for those with a family history of cancer, for smokers, and for both those of age &lt;45 years and nondrinkers, respectively. Further, in the PTC cases, those carrying the rs3748093 variant seemed to be less susceptible to developing lymph node metastases, but more likely to suffer from PTC at an earlier age (&lt; 45 years).
Conclusions: These preliminary results may provide evidence for the involvement of the common genetic variants scattered throughout the BRAF oncogene in the prediction of PTC onset and progression. In the future, enlarging the number of samples and performing functional studies in this gene may help to validate whether the association truly exists.
Citation Format: Kexin Chen. Association between single-nucleotide polymorphisms of BRAF and papillary thyroid carcinoma in a 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 2215. doi:10.1158/1538-7445.AM2014-2215
Abstract 2219: STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas
Authors: Spaccarotella Elisa , Pupuleku Aldi , Pellegrino Elisa , Bandini Cecilia , Ferracin Manuela , Cantarella Daniela , Rinaldi Andrea , Provero Paolo , Cunto Ferdinando D. , Medico Enzo , Bertoni Francesco , Inghirami Giorgio , Piva Roberto 
Published: May 2015

Abstract
Anaplastic large cell lymphoma (ALCL) represents a category of T-cell Non-Hodgkin Lymphomas characterized by marked cellular pleomorphism, and expression of CD30. Two systemic forms of ALCL are defined by the presence or absence of chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene at 2p23 locus. Among several pathways triggered by ALK signaling, it has been widely shown that the constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival.
To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we performed gene and miRNA expression profiling experiments in association with functional validation approaches. The transcriptome of STAT3 was analysed in ALK positive ALCL cell lines using a tightly controlled time course experimental condition, in which the STAT3 signalling was abrogated by an inducible short hairpin RNA (shRNA).
Gene expression profiling analysis identified a selected number of genes (1730) specifically modulated by STAT3 silencing. A significant overrepresentation of putative STAT3 binding sites was found in regulatory regions of early down-regulated genes. Functional studies using a shRNA lentiviral library established that Interferon Regulatory Factor-4 (IRF4) targeting specifically affect cell viability of ALK+ ALCL cells. In contrast, forced expression of IRF4 partially rescued STAT3 knock-down sustaining the survival of ALK+ cells.
In a parallel experiment, genome-wide miRNA expression profiling identified 48 miRNAs concordantly modulated by the inducible knock down of ALK and STAT3. Among these, we demonstrated that expression of miR-17∼92 cluster significantly reverted STAT3 deprivation, sustaining both proliferation and survival of ALCL cells.
In conclusion, genes and miRNA expression profiling associated to functional screenings allowed the identification of new biologically relevant targets for ALK+ALCL. We speculate that IRF4 and miR-17∼92 cluster are involved in the lymphomagenesis of STAT3+ ALCL, and that their inhibition might represent an alternative avenue to interfere with ALK signaling in Anaplastic Large Cell Lymphomas.
Citation Format: Elisa Spaccarotella, Aldi Pupuleku, Elisa Pellegrino, Cecilia Bandini, Manuela Ferracin, Daniela Cantarella, Andrea Rinaldi, Paolo Provero, Ferdinando Di Cunto, Enzo Medico, Francesco Bertoni, Giorgio Inghirami, Roberto Piva. STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas. [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 2219. doi:10.1158/1538-7445.AM2014-2219
Abstract 2221: A new promoter of Casp 8 in an esophageal squamous cell carcinoma susceptibility locus
Authors: Lin Zhengwei , Zhao Xiaohang , Xu Yang , Guo Zhimin , Zhao Nan , Sun Yulin 
Published: May 2015

Abstract
Our previous Genome wide associationstudy (GWAS) of esophagealsquamous cell carcinoma (ESCC) identified a susceptibility locus on chromosome 2q33.1 encompassing CASP8 gene. Caspase 8 is an essential initiator in cell apoptosis and is associated with many diseases. CASP8 has varieties of transcripts, which might exert distinct functions. However, the transcriptional determinants, which control CASP8 gene expression remain poorly defined. The present study focused on revealing the mechanism behind the GWAS signal and finding clues for the complex regulation of CASP8.We observed a secondary promoter in CASP8 using a series of luciferase reporter assays, which locates 25kb far away from the previously described CASP8 promoter. The ENCODE ChIP-seq data shows the promoter features at the epigenetic level, including high H3K27Ac, H3K4M3 and low CpG methylation around the novel promoter region. Though people have known lots of transcription factors, little research focuses on which factors exert the transcription function for a certain promoteron earth. To explore the transcription factors that contribute to the secondary promoter of CASP8, we developed an effective strategy based on DNA-protein affinity purification and mass spectrometry. PURα was identified from the eluted protein products that the secondary promoter fragment could bind specific. We validated the mass spectrometry result through western blot analysis and immunoprecipitation assay and confirmed that PURα was involved in the transcription machine and might exert the function by forming a complex together with E2F-1 and Pol II. Remarkably, we observed that if knocking down the expression of PURα, the transcription activity decreased significantly. Although the physiologicrole of the CASP8 secondary promoter and its correspondent transcripts remain unclear, the current data suggest that it could explain the complexity of CASP8's transcription in some degree and expand the GWAS results to the function level. We believe these two promoters have thecapacity to play a role in the very different functions of caspase 8 isoforms.
Note: This abstract was not presented at the meeting.
Citation Format: Zhengwei Lin, Xiaohang Zhao, Yang Xu, Zhimin Guo, Nan Zhao, Yulin Sun. A new promoter of Casp 8 in an esophageal squamous cell carcinoma susceptibility locus. [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 2221. doi:10.1158/1538-7445.AM2014-2221
Abstract 2228: Folate-related genes polymorphism and risk of pediatric acute lymphoplastic leukemia
Authors: Raafat Nermin , Gharib Amal , Elsafy Usama , Hassan Tamer 
Published: May 2015

Abstract
Background: Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children, constituting about 30% of all cancers among children. It constitutes about 75% of pediatric acute leukemia with peak incidence between ages 3 and 4. The assertion that ALL may have a genetic basis has long been pursued through association studies based on candidate genes as folate metabolism. Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia. Increased risk of ALL was observed in reduced folate carrier protein (RFC1) 80GA variant carriers. A 1.4-fold reduction in ALL risk was observed for carriers of the methyl tetrahydrofolate reductase (MTHFR) 677T allele. Objectives: this study was carried out to evaluate the contribution of MTHFR C677T and RFC1 80GA gene polymorphism and susciptability of childhood acute lymphoblastic leukemia. Materials &Methods: DNA was isolated from 200 children, divided into 2 groups, group I included 100 pediatric ALL patients and group II included 100 healthy donors as controls. Genotyping of MTHFR C677T and RFC1 G80A was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using Hinf I and HhaI restriction endonuclease respectively. Results: MTHFR 677T allele carriers were significantly lower in ALL cases (46%) than healthy controls (56%). Reduction in ALL risk was observed for heterozygous (CT) or homozygous (TT) carriers of the MTHFR 677T allele (OR 0.8; 95% CI, 0.9-1.5; P &lt; 0.002). RFC1 80A allelic carriers have an increased susceptibility to ALL. Risk was increased 2.0 times (OR 3.5; 95% CI, 1.5-4.8 ; P .02) for A-allelic carriers. Conclusion: our data suggested that the MTHFR gene variants are associated with decreased ALL rate and risk. the reduced risk associated with the MTHFR C677T polymorphisms may be the result of changed intracellular folate redistribution. the results of our study also supported the suggestion that RFC1 G80A RFC1 G80A single nucleotide polymorphism contributed to increase the susceptibility and the development of pediatric ALL.
Citation Format: Nermin Raafat, Amal Gharib, Usama Elsafy, Tamer Hassan. Folate-related genes polymorphism and risk of pediatric acute lymphoplastic leukemia. [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 2228. doi:10.1158/1538-7445.AM2014-2228
Abstract 223: High-throughput drug discovery against breast cancer stem cells
Authors: McDermott Sean P. , Ndaw Fatou , Fox Alexandra , Roest Steve R. Vander , Larsen Martha J. , Wicha Max S. 
Published: May 2015

Abstract
The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self renewing cell populations that constitute the bulk of the tumor. Clinically, CSCs are predicted to mediate tumor recurrence after chemotherapy and radiotherapy due to the relative inability of these modalities to effectively target CSCs. Therefore, new therapies that target CSC must be developed and combined with standard therapy to achieve a true cure. Targeting breast CSC represents an attractive avenue for developing therapeutics; however, there are multiple pools of breast CSCs utilizing distinct signaling pathways, such as Wnt/β-catenin & NF-κB. These breast CSC pools are identified using flow cytometry as cells with high expression of aldehyde dehydrogenase (ALDH), CD44+CD24-, or CD90+. We have developed a high-throughput flow cytometry based screen against CD90+ breast CSCs. We screened ∼18,500 small molecules for inhibitors of CD90+ frequency and identified 19 compounds. Here, we will present data examining this compounds against ALDH+, and CD44+CD24- breast CSCs. By identifying compounds with that target multiple pools of breast CSCs, these compounds might be exploited in future drug development endeavors.
Citation Format: Sean P. McDermott, Fatou Ndaw, Alexandra Fox, Steve R. Vander Roest, Martha J. Larsen, Max S. Wicha. High-throughput drug discovery against breast cancer stem cells. [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 223. doi:10.1158/1538-7445.AM2014-223
Abstract 2233: Rearrangement of ERG and CHD1 genes in prostate cancer as a marker of tumor heterogeneity
Authors: Tereshchenko Irina V. , Zhong Hua , Chekmareva Marina , Santanam Urmila , Petrosky Whitney , Kane-Goldsmith Noriko , Tischfield Jay A. , DiPaola Robert 
Published: May 2015

Abstract
Efforts to develop targeted therapy based on genomic findings are complicated by the polygenic nature of drug resistance and genetic heterogeneity between separate biopsy cores. These findings have led to the conclusion that analysis of multiple biopsy cores and consideration of multiple targeted agents will be important. Because of our concern that these assessments may be missing an additional layer of heterogeneity within even a single biopsy core, which sequencing alone may not identify, we studied the genetic heterogeneity of cells in focal areas using TMA. Using confocal microscopy, we analyzed the most common and prostate cancer specific gene rearrangement (TMPRSS2-ERG fusion and CHD1 deletion) in neighboring single cells in a tumor focus without changing the stromal microenvironment. We evaluated 56 patients that underwent radical prostatectomy at CINJ with pathological assessment, grading, and ERG rearrangement status. Overall, ERG rearrangements occurred in 24/56 (42.9%) patients. The most frequent mechanism of rearrangements was deletion (58%), while a split event was confirmed in 25% of the ERG-rearranged cases. In 88% of cases the ERG rearrangement was associated with TMPRSS2-ERG gene fusion. A copy number gain of the non-rearranged ERG gene occurred in 10/56 (17.6%) cases. A heterogeneous mix of ERG deletions, translocations, and copy number changes occurred in 8/24 (33%) patients, with a combination of deletions and translocations alone occurring in 3/24 (12.5%) cases. 20/21 (95%) of analyzed cases with ERG-rearrangement were negative for CHD1 gene rearrangement (p&lt; 0.01). Overall, 14/45 (31.1%) of patients had CHD1 deletion, and 13/14 (93%) CHD1- cases correlate with ERG-rearrangement negative status (p&lt; 0.01). 10/45 (22.2%) cases represent CHD1 gene copy number gain. These results support the notion that additional heterogeneity may be present even in a focus of a single biopsy core. These data are extremely important and urgently require further study to understand heterogeneity of genetic changes, because clinical studies have already been launched using genetic changes such as TMPRSS2-ERG fusions found in a single core biopsy to direct a specific therapy, including a trial using ABT-888 only in patients with this fusion now ongoing at CINJ.
Citation Format: Irina V. Tereshchenko, Hua Zhong, Marina Chekmareva, Urmila Santanam, Whitney Petrosky, Noriko Kane-Goldsmith, Jay A. Tischfield, Robert DiPaola. Rearrangement of ERG and CHD1 genes in prostate cancer as a marker of tumor heterogeneity. [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 2233. doi:10.1158/1538-7445.AM2014-2233