bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 261: The novel Akt inhibitor API-1 induces c-FLIP degradation and synergizes with TRAIL to augment apoptosis independent of Akt inhibition
Authors: Li Bo , Rentsch Hui , Yue Ping , Chen Mingwei , Khuri Fadlo R. , Sun Shiyong 
Published: August 2012

Abstract
API-1 is a novel small molecule inhibitor of Akt, which acts by binding to Akt and preventing its membrane translocation, and has promising preclinical antitumor activity. In this study, we reveal a novel function of API-1 in regulation of c-FLIP levels and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, independent of Akt inhibition. API-1 effectively induced apoptosis in tested cancer cell lines including activation of caspase-8 and caspase-9. It reduced the levels of c-FLIP without increasing the expression of DR4 or DR5. Accordingly, it synergized with TRAIL to induce apoptosis. Enforced expression of ectopic c-FLIP did not attenuate API-1-induced apoptosis, but inhibited its ability to enhance TRAIL-induced apoptosis. These data indicate that downregulation of c-FLIP mediates enhancement of TRAIL-induced apoptosis by API-1, but is not sufficient for API-1-induced apoptosis. API-1-induced reduction of c-FLIP could be blocked by the proteasome inhibitor MG132. Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability. These data together suggest that API-1 downregulates c-FLIP by facilitating its ubiquitination and proteasome-mediated degradation. Since other Akt inhibitors including API-2 and MK2206 had minimal effects on reducing c-FLIP and enhancement of TRAIL-induced apoptosis, it is likely that API-1 reduces c-FLIP and enhances TRAIL-induced apoptosis independent of its Akt-inhibitory activity. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award and National Cancer Institute NIH SPORE P50 grant CA128613. F.R.K. and S-Y.S. are Georgia Cancer Coalition Distinguished Cancer Scholars)
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 261. doi:1538-7445.AM2012-261
Abstract 2625: Is familial risk of cancer limited to relatively early onset cases
Authors: Kharazmi Elham , Fallah Mahdi , Janquest Kristina , Hemminki Kari 
Published: August 2012

Abstract
Purpose: It is widely believed that familial cancers are of early onset. We aimed to find out whether familial risk of cancer is limited to relatively early onset cases. Methods and material: Standardized incidence ratios (SIR) were calculated for familial risk in offspring by parental age at diagnosis in the nation-wide Swedish Family-Cancer Database including all Swedes born after 1931 with their biological parents, totaling &gt;12.2 million individuals and including &gt;1.1 million first primary cancer cases. Results: Median parental age at diagnosis in those whose offspring were affected with a concordant cancer was somewhat over 70 years. Some 56-86% of familial cancers in parents occurred at age over 69 years. Even when parents were diagnosed at advanced age (90+), the risk of concordant cancer in offspring was significantly increased for skin (SIR=2.1), colorectal (1.7), breast (1.6), and prostate cancer (1.5). In offspring aged 60 to 76 years whose parents were affected with a concordant cancer, almost none of the cases had a parent affected at &lt;40 years. Conclusion: Despite the common believe that familial cancers are of early onset, the majority of familial cancers occur at advanced ages. Familial cancers may not be early onset in those whose probands were affected at advanced ages, which may suggest concordance of age of onset in familial cancers. We identified reliable familial risks for skin, colorectal, breast, and prostate cancer even when parents were diagnosed at age 90+. The present study provides novel information, important for clinical counseling, cancer genetics and screening guidance.
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 2625. doi:1538-7445.AM2012-2625
Abstract 2626: Apoptosis-related single nucleotide polymorphisms and the risk of non-small cell lung cancer in a case-control study of women
Authors: Pathak Anand , Wenzlaff Angela S. , Cote Michele L. , Keele Greg R. , Land Susan , Schwartz Ann G. 
Published: August 2012

Abstract
Background: Often, lung cancer is diagnosed at later stages, resulting in a 15% 5-year survival rate. Improved survival is seen for those with early stage disease, thus it is crucial to identify genetic markers that can identify those at the highest risk for early disease. In this study, we focused on understanding the risk of developing non-small cell lung cancer (NSCLC) associated with germline single nucleotide polymorphisms (SNPs) in apoptosis related genes among women in the Detroit metropolitan area. Methods: 453 cases of NSCLC and 478 control subjects were examined in a population based case-control study. Since the allele frequency differed significantly in over 74% of the SNPs between whites and African Americans, analysis was stratified by race. Eight SNPs found not to be in HWE were excluded from the study, leaving 97 SNPs in 32 apoptosis related genes examined for association with risk of lung cancer. Odds ratios and 95% confidence intervals were estimated from unconditional logistic regression models using a dominant model, stratified by race, and adjusted for age, pack years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education. Results: Among whites, a polymorphism in APAF-1 (rs1007573) was associated with a 2.86 fold increase in risk of lung cancer among smokers (95% CI: 1.58-5.16). SNPS in CD40 rs3765459 and rs1535045 were associated with a reduced risk of lung cancer among white smokers. After carrying out a backwards elimination procedure, only APAF-1 rs1007573 and CD40 rs1535045 remained as significant predictors of risk. Both of these SNPs were found to be noteworthy, as per the False Discovery Reporting Percentage (FDRP) method. In African Americans, 7 SNPs were found to be significantly associated with NSCLC. After the backwards elimination procedure, only SNPs in ATM rs1801516 (OR=24.15, 95% CI: 3.50-166.55), TNF rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and p63 rs6790167 (OR: 2.85, 95% CI:1.33-6.09) were found to be significant. Testing these SNPs using the FDRP method revealed that only p63 (rs6790167) was noteworthy. Indeed, this locus may represent an important target in NSCLC, as previous SNPs in p63 have been reported to increase the risk of lung cancer in larger GWAS studies. Conclusions: We report two significant SNPs associated with NSCLC risk in whites (APAF-1 rs1007573 and CD40 rs1535045) and one significant SNP in African Americans (p63 rs6790167) as potentially important contributors to NSCLC.
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 2626. doi:1538-7445.AM2012-2626
Abstract 263: Silence of SOX2 induces apoptosis through both mitochondria and death receptor signal pathway by activating the RAS/MAPK signals in human lung cancer cells
Authors: Chen Si , Li Xuefei , Xu Yingxi , Wang Lina , Chen Yanan , Lv Dan , Reisfeld Ralph A. , Li Na , Xiang Rong 
Published: August 2012

Abstract
Previous study showed that the stem cell gene-SOX2 plays an important role in the anti-apoptotic property of tumor cells, but the regulatory mechanism of SOX2 in the apoptosis signals is still elusive. In this study we used lentivirus system to deliver the shRNA to human lung cancer cell line- A549 and H460 and found that silencing of SOX2 gene can effectively induce apoptosis. Proteomic array assay and western blotting showed that down-regulation of SOX2 activates both the mitochondria and death receptor signal pathway, which were marked by the overexpression and phosphorylation of p53, overexpression of Bax and Bad, and activation of caspase 3 and 8 in A549 cells with SOX2 silencing. Real-time RT-PCR showed that down-regulation of SOX2 leads to the activation of Ras/MAPK signal pathway, which activated the transcription of two key inducers for apoptosis signals-TNF-α and p53 and also down-regulates the expression of survivin. In vitro and in vivo experiment further showed that this apoptotic effect of SOX2 silencing was compromised by overexpression of survivin. Immunohistochemistry study of human lung tissues showed that the protein expression level of SOX2 is closely correlated with that of survivin. In addition, SOX2 and survivin double positive patients showed worse prognosis, suggesting these two proteins can be used as dual-diagnosis factors to evaluate the clinical progression and prognosis of lung cancer patient. These findings revealed the important mechanism for SOX2 to regulate the apoptosis signals and demonstrated that survivin is one of vital downstream molecules that contribute to the anti-apoptosis property of SOX2.
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 263. doi:1538-7445.AM2012-263
Abstract 2631: Analysis of PI3K pathway genes in bladder cancer
Authors: Seven Didem , Tigli Hatice , Buyru Nur 
Published: August 2012

Abstract
Bladder cancer is the most common cancer of the urinary tract and is the ninth the most common cancer among men. Its incidence directly increases with age, it rarely occurs before the age of 50 and it is three to four times more common in men compared to women. Although there is now exclusive information on bladder cancer genetics, epigenetics and gene expression, several questions remain unanswered. Global profiling via expression and genomic microarray technologies may provide answers to some of the outstanding questions. Many studies have assessed the status of known oncogenes and tumor suppressor genes and have investigated common chromosomal alterations to identify novel genomic events in bladder cancer. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays critical role in cell growth, proliferation, and apoptosis. As a result of genomic alterations and loss of some tumor suppressor genes signaling through this pathway is commonly altered in many types of cancer including bladder. In the present study, our interest was focused on the expression analysis of some critical genes in this pathway. For this purpose, expression of seven genes (mTOR, KRAS, PIK3CA, TSC1, STK11, Rheb, PTEN and AKT1) acting in this pathway was analyzed in 35 matched bladder tumor and non-cancerous tissue samples by quantitative RT-PCR. Expression of all genes except PIK3CA and PTEN were similar for the normal bladder and tumor tissue. We observed downregulated expression of PTEN and PIK3CA genes in bladder tumors. The median PTEN mRNA levels in non-cancerous and tumor tissue samples were 2.11 and 0.35, respectively and the difference between the two groups was statistically significant (p=0.00). PIK3CA was also downregulated in the tumor tissues. Tumor tissue samples displayed 6.62 fold decrease in PIK3CA expression compared to normal tissue samples (p=0.002). On the other hand, slightly decreased Rheb mRNA expression was also observed in tumor tissue compared to the non-cancerous tissue. However, the difference expression levels of Rheb between two groups was not statistically significant. Our result indicate that, PI3K pathway has an important function in bladder cancer progression with the contribution of more than one gene in this pathway.
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 2631. doi:1538-7445.AM2012-2631
Abstract 2633: Single nucleotide polymorphisms in one carbon metabolism genes are associated with methylation patterns and plasma metabolites in high risk smokers based on gender
Authors: Flores Kristina G. , Stidley Christine A. , Picchi Maria A. , Mackey Amanda J. , Stabler Sally P. , Byers Tim , Berwick Marianne , Belinsky Steven A. , Leng Shuguang 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer related deaths and most lung cancers are detected at a late stage. Gene promoter hypermethylation is now regarded as a promising biomarker to identify early risk and progression of lung cancer. The one carbon metabolism pathway is postulated to affect DNA methylation because it is necessary for the generation of S-adenosyl methionine or (SAM), the methyl donor for cellular DNA methylation reactions, through complex interactions with metabolites including folate, homocysteine, and methionine. This study investigated the association of single nucleotide polymorphisms (SNPs) in one carbon metabolism related genes with DNA promoter hypermethylation in sputum cell DNA from current and former smokers in the Lovelace Smokers Cohort (n=907). The association of SNPs with methylation was analyzed by logistic regression using gender specific high and low methylation cutoffs from a 12 gene methylation panel as the outcome. SNPs in the cystathionine beta-synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were found to be statistically associated with methylation in a gender specific fashion (CBS SNP, OR=4.9; CI: 1.98, 12.2, p=.0006 in males) and (MTRR SNP, OR= 0.57, CI: 0.42, 0.77, p=0.0003 in females). Plasma homocysteine levels and the ratio of homocysteine to cystathionine increased in male samples with heterozygous or homozygous minor alleles of the CBS SNP compared to male samples with homozygous common alleles (n=86). This study suggests that SNPs in the CBS and MTRR genes are associated with methylation patterns in smokers by gender. The CBS SNP may be important in regulating plasma homocysteine and cystathionine levels that could theoretically mediate the aberrant DNA methylation in smokers at high risk to develop lung cancer. Grant Support: This work is supported by K01CA128823 NCI (Flores) and R01CA097356 NCI (Belinsky).
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 2633. doi:1538-7445.AM2012-2633
Abstract 2636: Nonmelanoma skin cancer as a marker of a cancer-prone phenotype: Potential role of DNA repair gene variants
Authors: Ruczinski Ingo , Jorgensen Timothy , Shugart Yin Yao , Berthier-Schaad Yvette , Kessing Bailey , Hoffman-Bolton Judithh , Helzlsouer Kathy , Kao W.H. Linda , Wheless Lee , Francis Lesley , Alani Rhoda , Strickland Paul , Smith Michael , Alberg Anthony J. 
Published: August 2012

Abstract
Purpose: For unknown reasons, nonmelanoma skin cancer (NMSC) is associated with increased risk of other malignancies. This study tested the hypothesis that DNA repair gene variants contribute to the increased cancer risk associated with a personal history of NMSC. Methods: From the parent CLUE II cohort study, established in 1989 in Washington County MD, the study consisted of a cancer-free control group (n=2,296) compared to three mutually exclusive groups of cancer cases ascertained through 2007: 1) Other (non-NMSC) cancer only (n=2,349); 2) NMSC only (n=694); and 3) NMSC plus other cancer (n=577). The frequency of minor alleles in 759 DNA repair single nucleotide polymorphisms (SNPs) was compared in these four groups. Results: Comparing those with both NMSC and other cancer versus those with no cancer, 10 SNPs had additive model p-values&lt;0.01. The two top-ranked SNPs were both within the thymine DNA glycosylase gene (TDG). One was a nonsynonymous coding SNP (rs2888805) (per allele odds ratio (OR) 1.40, 95% confidence interval (CI) 1.16-1.70; p-value=0.0006) and the other was an intronic SNP in high linkage disequilibrium with rs2888805 (rs4135150). Conclusion: The results pinpoint DNA repair genes most likely to contribute to the NMSC cancer-prone phenotype. A promising lead is genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the NMSC-associated increase in overall cancer risk.
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 2636. doi:1538-7445.AM2012-2636
Abstract 2641: Polymorphisms in pattern recognition genes in the innate immunity system and risk of non-Hodgkin lymphoma
Authors: Hu Wei , Xu Jun , Bassig Bryan A. , Zheng Tongzhang , Zhang Yawei , Berndt Sonja I. , Holford Theodore R. , Hosgood H. Dean , Leaderer Brian , Menashe Idan , Boyle Peter , Chanock Stephen , Lan Qing , Rothman Nathaniel 
Published: August 2012

Abstract
The pattern recognition pathway plays an important role in infection recognition and immune responses, and previous studies have suggested an association between genetic variation in innate immunity genes and non-Hodgkin lymphoma (NHL). We evaluated NHL risk associated with the common genetic variation in pattern recognition genes using data from a case-control study of NHL conducted in Connecticut women. Single nucleotide polymorphisms (SNPs) in 27 pattern recognition genes were genotyped in 432 Caucasian incident NHL cases and 494 frequency-matched controls. Unconditional logistic regression was used to compute odds ratios (ORs) for NHL and four major NHL subtypes in relation to individual SNPs and haplotypes. A gene-based analysis that adjusted for the number of tagSNPs genotyped in each gene showed significant association with overall NHL for the MBP gene (p=0.028), with DLBCL subtype for the MASP2 gene (p=0.011), and with FL subtype for the DEFB126 (p=0.041). A SNP-based analysis showed that MBP rs8094402 was associated with decreased risks of overall NHL (allele risk OR=0.72, p-trend=0.0018), DLBCL (allele risk OR=0.72, p-trend=0.036), and FL (allele risk OR=0.67, p-trend=0.021). MASP2 rs12711521 was associated with a decreased risk of DLBCL (allele risk OR=0.57, p-trend=0.0042). We also observed an increased risk of FL for DEFB126 rs6054706 (allele risk OR=1.39, p-trend=0.033). Our results are suggestive of a potential role of the pattern recognition in susceptibility to NHL but require replication in larger studies.
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 2641. doi:1538-7445.AM2012-2641
Abstract 2643: Interactions between polycyclic aromatic hydrocarbon exposure and genetic polymorphisms on benzo(a)pyrene-DNA adducts in a Polish cohort of mothers and newborns
Authors: Iyer Shoba , Xiong Wei , Tang Deliang , Jedrychowski Wieslaw , Chanock Stephen , Wang Shuang , Stigter Laura , Mroz Elzbieta , Perera Frederica 
Published: August 2012

Abstract
Background Polycyclic aromatic hydrocarbons (PAHs) are a class of chemicals common in the environment. Major sources of PAHs include fossil fuel combustion and cigarette smoking. Certain PAHs are carcinogenic, though the degree to which genetic variation influences susceptibility to PAH exposure remains unclear. Benzo(a)pyrene (BaP) is a well-studied PAH that is classified as a probable human carcinogen. Here, we evaluated single nucleotide polymorphism (SNP) frequency in genes related to PAH metabolism and detoxification, and explored the interactions between PAH exposure and SNPs on BaP-DNA adducts, an established cancer risk marker, in umbilical cord white blood cells (WBCs). Methods Maternal and umbilical cord blood were collected at delivery from participants in a longitudinal cohort study of Polish mothers and newborns in Krakow, Poland. WBC DNA was isolated from cord blood, and genetic polymorphisms and BaP-DNA cord adducts were then measured in 503 mothers and 445 newborns. Maternal PAH exposure was measured during pregnancy with a personal air exposure monitor. For this study 7 maternal and newborn genes related to PAH metabolism, detoxification and repair were selected for SNP analyses: CYP1A1, CYP1A2, CYP1B1, GSTM3, GSTT2, NQO1 and XRCC1. SNP x PAH interactions on logarithmic (ln)-transformed BaP-DNA adduct levels were explored. Results We observed a number of significant interactions between high PAH exposure and SNPs in both mothers and newborns on BaP-DNA adducts in cord blood. For example, the interaction between a CYP1A2 SNP (rs2069514) and high PAH exposure on cord BaP-DNA adducts in newborns was significant (α=−1.34, p&lt;0.01). We will present significant interaction results from analyses performed on both maternal and newborn CYP1A1, CYP1A2, GSTM3, GSTT2, NQO1 and XRCC1 SNPs. Discussion It is biologically plausible that an individual's abilities to metabolically activate and detoxify BaP and repair DNA damage play a role in susceptibility to DNA adduct formation following prenatal PAH exposure. Ultimately, this susceptibility could correlate with future risk of cancer development. Our findings of several SNP x PAH exposure interactions on cord BaP-DNA adducts support the hypothesis that genetic variability can contribute to susceptibility and potential cancer risk from prenatal PAH exposures.
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 2643. doi:1538-7445.AM2012-2643