bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-326: Elucidating significant genetic associations between genes and lung cancer
Authors: D'Amelio Anthony M. , Etzel Carol J. 
Published: August 2012

Abstract
Introduction: To further understand and elucidate the genetic risk factors for Lung Cancer (LC) will substantially improve cancer prevention, screening programs, and treatment options for this insidious disease. However, our previous attempts to increase the discriminatory power in an existing risk model with the inclusion of SNPs identified via GWAS have not been very successful. In this analysis, we reassess the increase in discriminatory power by including haplotypes based on existing GWAS-identified SNPs and additional single SNPs. Methods: Cases included 1154 histological-confirmed Caucasian lung cases from MD Anderson Cancer Center in Houston, Texas, and controls included 1137 individuals recruited through the Kelsey-Seybold Clinics in Houston, Texas. Genetic information from both populations was selected for 157 SNPs that exist in the Texas GWAS and were part of the top 200 SNPs as determined by a previously published meta-analysis of 10 different lung cancer GWAS datasets (Landi et al. 2009). Plink and Haploview were used to determine the top SNPs and top haplotype blocks respectively. Then, univariate logistic regression was used to determine the best genetic model for the top SNPs. Joint logistic risk model regression was used to determine haplotype risk for each individual haplotype block. Finally, multivariate logistic regression was used to develop the final extended model that included the original set of risk factors from the Spitz model plus additional haplotypes and SNPs. We evaluated increase in discriminatory power by evaluated change in the area under the receiver-operating characteristic curve and the net reclassification index. Results: The discriminatory power for the original Spitz model was 66.1% (95% CI = 0.638-0.683). With the inclusion of only single SNPs in to the model, the discriminatory power increased by 4.5% to 70.6% (95% CI = 0.684-0.727, p-value = &lt;0.0001). Adding the top 6 haplotypes further increased the discriminatory power to 71.9% (95% CI = 0.697-0.739). The net reclassification index results show that this increase in discriminatory power is evident for both cases (23.47%) and controls (23.43%). Conclusions: Inclusion of genetic variants into an established epidemiologic risk model can substantially increase the discriminatory power; however, selection and modeling of these variants needs to be carefully done.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-326. doi:1538-7445.AM2012-LB-326
Abstract LB-331: Polymorphisms in inflammation pathway genes and endometrial cancer
Authors: Delahanty Ryan J. , Xiang Yong-Bing , Spurdle Amanda , Beeghly-Fadiel Alicia , Long Jirong , Thompson Deborah , Tomlinson Ian , Yu Herbert , Lambrechts Diether , Dörk Thilo , Goodman Marc T. , Salvesen Helga B. , Lu Wei , Cai Qiuyin , Zheng Wei , Shu Xiao Ou 
Published: August 2012

Abstract
Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. To investigate this hypothesis, we carried out a two-stage study to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 830 endometrial cancer cases and 2,322 controls using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P&lt;0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. We then selected one SNP from each of the 24 loci for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in the stage 2 sample, which consisted of eight additional studies including 4,890 endometrial cancer cases and 5,403 controls. Four of the 21 SNPs in or near the FABP1, CXCL3, MSR1, and MMP9 genes were significantly associated with endometrial cancer in the combined data sets. The allelic odds ratios were 0.90 (0.82-0.97) for FABP1, 1.17 (1.05-1.31) for CXCL3, 0.86 (0.78-0.96) for MSR1, and 0.90 (0.85-0.95) for MMP9. The SNPs in CXCL3 and MMP9 were significantly associated with endometrial cancer in both the discovery and replication samples. Of these findings, the association for the MMP9 promoter polymorphism rs3918249 (P=0.00047) remained significant after adjustment for the total number of comparisons. These findings suggest that genetic polymorphisms in the MMP9 gene and possibly in or near the FABP1, CXCL3, and MSR1 genes may contribute to genetic susceptibility to endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-331. doi:1538-7445.AM2012-LB-331
Abstract LB-340: High pain prevalence is reported by patients with head and neck cancer: systematic review
Authors: Macfarlane Tatiana V. , Wirth Tanja , Ranasinghe Sriyani 
Published: August 2012

Abstract
Background: Pain is a major symptom in patients with cancer; however information on head and neck cancer (HNC) related pain is limited. Aim: To investigate the prevalence of pain and associated factors among patients with HNC. Materials and Methods: The systematic review used a wide searching strategy to December 2011. Cancers of the oral mucosa, oropharynx, hypopharynx and larynx were included in this review with pain as main outcome. The review was restricted to full research reports of observational studies published in English. A checklist was used to assess the quality of selected studies. Results: There were 82 studies included in the review and most of them (84%) were conducted in the past ten years. Studies were relatively small, with a median of 80 patients (IQR 44, 154). The quality of reporting was variable, for example only 67% of the articles stated the study design and none of the papers justified sample size. The majority of the papers (84%) did not report efforts that were taken to address potential sources of bias and 35% did not specify the participation rate. Most studies (77%) used self-administered quality of life questionnaires, where pain was a component of the overall scale. Only 32 studies reported pain prevalence in HNC patients (combined estimate from meta-analysis 49%, 95% CI 41% - 57%), in contrast to levels of pain (scale 0-100: mean 55, 95% CI 51 - 59 based on 12 studies). Only 55 studies (67%) considered associated factors, mostly tumour- or treatment-related. Three out of ten studies reported higher levels of pain at older ages and three out of twelve found higher levels in women. There was no consistent evidence of an association with smoking and alcohol. Conclusion: The study has shown high levels of pain prevalence and some factors associated with higher levels of pain. There is a need for higher quality studies in a priority area for the care of patients with HNC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-340. doi:1538-7445.AM2012-LB-340
Abstract LB-343: Defining mechanisms of endocrine resistance in breast cancer using whole exome sequencing
Authors: Chandiramani Natasha , Levano Kelly S. , Peterson Esther A. , Kenny Paraic A. 
Published: August 2012

Abstract
About 70% of breast cancers are estrogen receptor positive (ER+) and current treatments target either ER activity (Tamoxifen and Fulvestrant) or the production of estrogen (aromatase inhibitors). These treatments have led to significant increases in disease-free and overall survival, but after initial response to these agents, many ER+ cancers progress to endocrine resistance. There have been several attempts to understand the molecular mechanisms that lead to acquired resistance, but a clear understanding is still lacking. We hypothesize that endocrine resistant cells in the tumor arise by acquiring compensatory somatic mutations, and that some of these driver mutations responsible for resistance are in oncogenes or tumor suppressor genes. To test this we performed whole exome sequencing on three of MCF7 breast cancer cell sublines that are resistant to either tamoxifen, fulvestrant or exemestane - drugs commonly used in the clinic to treat ER+ breast cancers. An Illumina TruSEQ adaptor-based exonic library was prepared using genomic DNA from the resistant and control cell lines, and multiplexed on an Illumina HiSeq 2000 sequencer (100bp paired-end reads). Reads were aligned to human genome build 19 using BWA, variants were called using SAMTools, somatic mutations in endocrine cell lines were determined with VarScan, and amino acid changes were annotated using ANNOVAR. We have identified several non-synonymous mutations in cancer-relevant genes and are currently working to validate these targets. Studying these genes will increase our understanding of how tumors overcome the requirement for estrogen signaling and ultimately, we hope that comparing tumor profiles of patients with endocrine resistance disease will lead to therapeutics targeted to these secondary mutational lesions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-343. doi:1538-7445.AM2012-LB-343
Abstract LB-347: Identify signaling responses to MEK inhibitor AZD6244 in lung cancer cells with proteomics reverse phase protein array
Authors: Dai Bingbing , Liu Wenbin , Heymach John V. , Byers Lauren A. , Wang Jing , Coombes Kevin R. , Fang Bingliang , Roth Jack A. 
Published: August 2012

Abstract
AZD6244 is small-molecule inhibitor that targets the MAPK pathway, and is currently in phase I/II clinical evaluation. While some efficacy of these agents has been observed in phase I/II clinical trials, one of the hurdles of targeted therapy is the intrinsic and acquired resistance mediated by complex feedback pathways. Identifying downstream effectors required for cellular response to MEK inhibitors will help us understand the mechanism of resistance, possibly leading to the development of direct therapeutic targets. Explore the signaling responses after treatment with MEK inhibitors will also allow us to identify signaling feedback loops and cross talks. We used reverse phase protein array (RPPA) technology to determine which downstream effectors of MEK/ERK pathways critical for cell growth inhibition or apoptosis induced by MEK inhibitors, and to identify which signaling pathways are inhibited or activated when the pathways is blocked. RPPA is a antibody-based quantitative assay used to analyze nanoliter amounts of sample for 200 proteins to determine expression levels and protein modifications such as phosphorylation or cleavage. Experiments were carried out in 5 resistant and 5 sensitive cell lines with the MEK inhibitor, AZD6244. Cells were treated at different time points (0, 6, 12, 24, 48, and 72 hours) and with various dosages (0, 0.3, 1, 3 and 10 µM). Cell lysates were collected and quantified for RPPA assays. The data was analyzed for the presence of clusters based on differential protein expression by using available methods with a statistical software package (StatSoft, Tulsa, OK). Significantly changed proteins were analyzed with Ingenuity Pathway Analysis (IPA). Proteins Data from RPPA was further validated by using Western blotting with the same antibody used in the RPPA assay. The results showed that inhibition of MEK/ERK could activate multiple signaling pathways including AKT, SRC, STAT3 and IGF1R. Activation of those signaling pathway through signaling cross talk and feedbacks may involved in the intrinsic and acquitted resistance to MEK inhibitor. We also indentified a penal of molecules, such as BIM, P27, p53 and JNK were specifically induced only in the sensitive cells. Those molecules might be the mediators of MEK inhibitor induced cell apoptosis. The results will be helpful in understanding of the signaling cross talks and feedbacks and in the exploration of mechanisms of sensitivity and resistance to the treatment with MEK inhibitors in lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-347. doi:1538-7445.AM2012-LB-347
Abstract LB-354: A novel orally-bioavailable small-molecule inhibitor of Stat3 regresses human breast and lung cancer xenografts
Authors: Yue Peibin , Zhang Xiaolei , Page Brent DG , Zhao Wei , Paladino David , Gunning Patrick T. , Turkson James 
Published: August 2012

Abstract
Constitutive activation of STAT3, a member of the Signal Transducer and Activator of Transcription (STAT) family of proteins, occurs with a high frequency in diverse human tumors and is a molecular abnormality promoting carcinogenesis and tumor progression. Although STAT3 has been targeted for anticancer drug development, there is presently no STAT3 drug in the clinic. To identify potent therapeutics for tumors harboring constitutively-active STAT3, the key dimerization step in STAT3 activation was targeted in small-molecule drug development. A novel, orally bio-available small-molecule inhibitor has been identified that binds STAT3 SH2 domain with a KD of 504 nM. BP-1-102 blocks constitutively-active STAT3 signaling and selectively inhibits growth, survival, migration and invasion of diverse STAT3-dependent tumor cells in vitro. BP-1-102-mediated inhibition of aberrantly-active STAT3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and vascular endothelial growth factor (VEGF). Further, treatment with BP-1-102 of breast cancer cells harboring aberrantly-active STAT3 disrupts STAT3-NFκB cross-talk and blocks the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral administration of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts. Data together identify BP-1-102 as a small-molecule STAT3 inhibitor with a great potential for clinical development. The oral bioavailability represents a substantial advancement in the discovery of small-molecule STAT3 inhibitors as novel anticancer drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-354. doi:1538-7445.AM2012-LB-354
Abstract LB-356: Micelle-encapsulated thiostrepton: an effective nanomedicine for inhibiting tumor growth
Authors: Wang Ming , Gartel Andrei 
Published: August 2012

Abstract
The thiazole antiobiotic, thiostrepton, has been found to suppress the expression of FOXM1, the oncogenic forkhead transcription factor overexpressed in cancer cells. Thiostrepton has also been shown to induce cell death in cancer cells through a proteasome inhibitory mechanism. As thiostrepton is highly hydrophobic, encapsulation into nano-sized delivery vehicles not only aides its solubilization but also improves its targeting for tumors in vivo. This is achieved by encapsulating thiostrepton into the interior of an amphiphilic micelle, composed from an assembly of lipid-PEG (polyethylene glycol) conjugates. In this study, we examined the anti-tumor effects of micelle-thiostrepton in both subcutaneous xenograft models (HepG2 liver cancer, Capan-2 pancreatic cancer and MDA-MB-231 breast cancer) and endogenous liver tumor models (DEN/PB-induced adenocarcinomas). In the case of the xenograft tumor-bearing mice, biodistribution studies showed micelle-thiostrepton to accumulate into both the liver (30% of injected dose) and the xenograft tumors (60% of injected dose) from 4 hours post-administration. In the endogenous liver cancer models, micelle-thiostrepton accumulated into the liver only, allowing a high concentration of tumor-associated thiostrepton drug. Continuous administration of micelle-thiostrepton at doses of 40mg/kg, 3 times a week for 30 days retarded the growth rate of all subcutaneous tumors and reduced the occurrence of adenocarinomas in endogenous liver cancer models. Immunoblotting and immunohistochemical staining revealed that treatment with micelle-thiostrepton inhibited the expression of the oncogenic transcription factor FOXM1 in tumors, a reduction of which generally coincides with suppressed cell proliferation and increased cell death. Furthermore, it was found that the reduced tumor growth rate of thiostrepton-treated tumors was indeed related to increased apoptosis, as indicated by the elevated expression of cleaved caspase-3 in such tumors samples. Our data suggest that the thiazole antibiotic/proteasome inhibitor thiostrepton, when formulated into nanoparticles, may be highly suited as a nanomedicine for treating cancer, particularly that of liver cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-356. doi:1538-7445.AM2012-LB-356
Abstract LB-357: Identification of a new inhibitor of the Golgi system, targeting ADP-ribosylation Factor 1 (Arf1) with potential for cancer therapy
Authors: Ohashi Yoshimi , Iijima Hiroshi , Yamaotsu Noriyuki , Yamazaki Kanami , Sato Shigeo , Okamura Mutsumi , Sugimoto Kenji , Dan Shingo , Hirono Shuichi , Yamori Takao 
Published: August 2012

Abstract
[Background] ADP-ribosylation factor 1 (Arf1) plays a major role in mediating vesicular transport. Brefeldin A (BFA), a known inhibitor of the Arf1-guanine nucleotide exchange factor (GEF) interaction, is highly cytotoxic. Therefore, interaction of Arf1 with ArfGEF is an attractive target for cancer treatment. However, BFA and its derivatives have not progressed beyond the pre-clinical stage of drug development because of their poor bioavailability. Here, we aimed to identify novel inhibitors of the Arf1-ArfGEF interaction that display potent antitumor activity in vivo but with a chemical structure distinct from that of BFA. [Results] We exploited a panel of 39 cell lines (termed JFCR39) coupled with a drug sensitivity data base and COMPARE algorithm, resulting in the identification of a possible novel Arf1-ArfGEF inhibitor, (2E,4E)-5-((1S,2S,4aR,6R,7S,8S,8aS)-7-hydroxy-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-2-methyl-N-(pyridin-3-ylmethyl)penta-2,4-dienamide (AMF-26), which differed structurally from BFA. By using a pulldown assay with GGA3-conjugated beads, we demonstrated that AMF-26 inhibited Arf1 activation. Subsequently, AMF-26 induced Golgi disruption, apoptosis, and cell growth inhibition. AMF-26 did not inhibit the phosphorylation of Akt and Erk. Computer modeling/molecular dynamics (MD) simulation suggested that AMF-26 bound to the contact surface of the Arf1-Sec7 domain where BFA bound. AMF-26 affected membrane traffic, including the cis-Golgi and trans-Golgi networks, and the endosomal systems. Furthermore, using AMF-26 and its derivatives, we demonstrated that there was a significant correlation between cell growth inhibition and Golgi disruption. In addition, orally administratedAMF-26(83mg/kgofbodyweight;5 days) induced complete regression of human breast cancer BSY-1 xenografts in vivo. [Conclusion] AMF-26 is a novel anticancer drug lead that inhibits the Golgi system, targeting Arf1 activation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-357. doi:1538-7445.AM2012-LB-357
Abstract LB-358: Heme oxygenase-1 and carbon monoxide arrest tumor growth via modulation of cellular respiration
Authors: Wegiel Barbara , Gallo David , Czismadia Eva , Cunningham Kellie , Seth Pankaj , Persson Jenny , Helczynski Leszek , Otterbein Leo 
Published: August 2012

Abstract
Heme oxygenase-1 (HO-1) and carbon monoxide (CO) are endogenous cytoprotective molecules yet their role in tumor growth, metastasis, cell death and DNA damage has not been elucidated. HO-1 expression was assessed in prostate cancer biopsies from 482 patients and strong nuclear staining, indicative of loss of enzymatic activity was observed in moderately differentiated tumors. Employing prostate cancer (PCa) as our model we treated PCa cells with the chemotherapeutics camptothecin or doxorubicin and observed an increase in cytosolic HO-1 activity that correlated with increased cell death. Overexpression of HO-1 or exogenous pretreatment with CO increased tumor cell sensitivity to chemotherapeutics one thousand fold. In contrast, CO blocked chemotherapeutic-induced cell death of normal prostate epithelial cells. In vivo, CO exposure of mice with established PC3 xenografts resulted in complete growth arrest and sensitization of tumors to doxorubicin with mitotic blockade and enhanced apoptosis of the tumor cells. Exposure to CO showed similar effects in a model of PC3 orthotopic tumors with significant inhibition in markers of invasion. Further, CO blocked development of PIN and prostate tumors in the model of TRAMP mice with concomitant targeting of mitochondria. Further, CO inhibited growth of lung adenocarcinoma in the inducible KRas model of carcinogenesis. Collectively, our data demonstrate the importance of cellular localization of HO-1 in human PCa progression and importantly that CO in part, regulates cellular sensitivity to DNA damaging agents and offers a novel therapeutic adjuvant for the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-358. doi:1538-7445.AM2012-LB-358