bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2549: Chromosomal instability and DNA repair status during folic acid deficiency in breast cancer cells
Authors: Wyatt Michael D. , Brady Katie , Litvinchuk Alexandra , Noxon Virginia , Wang Xiao-Hong , Sobol Robert W. 
Published: August 2012

Abstract
Folic acid deficiency is thought to be procarcinogenic because it promotes the incorporation of genomic uracil. Base excision repair (BER) normally prevents genomic instability by removing procarcinogenic base lesions. However, BER might paradoxically contribute to folate deficient-carcinogenesis if the pathway is initiated but cannot be completed, resulting in the accumulation of BER intermediates (DNA strand breaks). DNA polymerase ≤ (POLα) performs two key steps in BER and so we utilized human metastatic breast cancer cells in which the expression of POLα has been eliminated or transgenically expressed to determine the influence of POLα on chromosomal stability. We found that folic acid deficiency induced premature chromatin condensation (PCC) and strand breaks in POLα deficient cells, demonstrating that folic acid deficiency and BER deficiency induce chromosomal instability. We also examined the expression and localization of PARP1, a key component of BER and strand break repair. PARP1 was not cleaved during folic acid deficiency, suggesting that apoptosis was not occurring under these conditions. More interestingly, PARP1 was dramatically re-localized within the nucleus in POLα deficient cells. We are currently examining the effect of PARP inhibitors and the activation of PARP under these conditions. Collectively, the data suggests that folic acid deficiency in combination with deficiency in POLα is capable of inducing gross chromosomal instability that invokes DSB repair pathways.
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 2549. doi:1538-7445.AM2012-2549
Abstract 255: Identification of a novel TRAIL sensitizer in TRAIL-resistant cancer cells
Authors: Park So Jung , Jo Yoon Kyung , Ha Ye Jin , Kim Jin Cheon , Cho Dong-Hyung 
Published: August 2012

Abstract
The Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), a TNF-family member is a highly promising agent for cancer therapy as it selectively induces apoptosis in various cancer cells but not in normal cells. However, many primary tumors are resistant to TRAIL-induced apoptosis and the resistant mechanisms are not fully understood. To identify novel TRAIL signaling regulatory molecules, we screened a siRNA library that target 719 whole human protein kinases in TRAIL-resistant lung cancer cell line (A549 cell). As a screening result, we identified a member of NIMA-related kinases as a new regulator of TRAIL-induced cell death. NEK family play key role in controlling mitosis but the role in TRAIL signaling was not elucidated. Down-regulation of NEK by siRNA dramatically increased TRAIL-induced apoptosis in TRAIL resistant cancer cells including A549 cells. However it was not effective on both etoposide and TNF/CHX-mediated apoptosis. In addition, inhibition of NEK highly activated caspase-3 in response to TRAIL. On the other hand, over-expression of NEK reduced TRAIL-induced apoptosis in TRAIL sensitive cells. Our findings suggest that NEK is a novel negative modulator of TRAIL-induced apoptosis in cancer cells.
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 255. doi:1538-7445.AM2012-255
Abstract 2550: Expanded simple tandem repeat (ESTR) mutations in offspring of benzo(a)pyrene exposed DNA repair deficient male mice
Authors: Godschalk Roger , Verhofstad Nicole , Linschooten Joost , Benthem Jan Van , Steeg Harry Van , Yauk Carole , Schooten Frederik-Jan Van 
Published: August 2012

Abstract
Germ line mutations can be transmitted to the offspring and may thus affect an infinite number of generations thereafter. To study germ line mutations, expanded simple tandem repeats (ESTR) can be used as a sensitive tool, because they are known to be highly unstable and therefore exhibit high mutation rates. This facilitates the assessment of germ line mutations in a relatively small number of offspring following exposures that may pose a genetic risk to the germ line. We used two ESTR loci Ms6-hm and Hm-2 in families of benzo(a)pyrene (BaP) exposed and unexposed male mice, proficient or deficient for global genome repair (Xpc-/-). Male mice (C57BL/6) were exposed to BaP during 6 weeks (13 mg/kg bw, 3 times per week) and were crossed with female mice (Balb/C) 6 weeks after the last exposure to obtain offspring and to ensure the analysis of mutations originating from spermatogonial stem cells. The overall ESTR mutation rate at both ESTR loci, irrespective of the DNA repair capacity, was higher in offspring of benzo(a)pyrene exposed mice than in control mice (9.4% vs. 4.5%, P=0.054). This effect was predominantly seen in BaP exposed DNA repair deficient Xpc-/- mice; mutation frequencies were 12.5% in the exposed group (12 out of 96 offspring carried a mutant allele) and 3.4% in the unexposed group (3 out of 87), respectively (P=0.024). In DNA repair proficient mice, BaP was unable to increase the mutation frequency transmitted to the offspring (5.8% vs. 5.5% for offspring of exposed and unexposed fathers). These results indicate that analysis of tandem repetitive sequences is a sensitive method for the detection of germline mutations transmitted to the offspring and that the environmental mutagen BaP is able to induce germ line mutations in DNA repair deficient mice.
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 2550. doi:1538-7445.AM2012-2550
Abstract 2551: New understanding of cancer induction by ionizing radiation
Authors: Burns Fredric J. , Tang Moon-Shong (Eric) , Wu Feng 
Published: August 2012

Abstract
Ionizing radiation is a unique carcinogen that provides an opportunity to vary the location of biological damage within a cell nucleus. For example, electron and x-ray beams deposit dose uniformly and randomly, while energetic heavy ions deposit dose in densely packed straight lines along the ion paths. Cancer yields for these 2 radiations vary as follows: upward curvature with dose rate sparing for random and linearity and no dose rate sparing for heavy ions. Dose rate sparing has long been assumed to be based on biological repair, but it has never been explained why dose responses should differ between these radiation or why repair should be ineffective for heavy ions. To understand this better, consider how the distribution of a typical molecular lesion, DNA double strand breaks (DSBs), varies with the type of radiation. For heavy ions at a specific energy, DSBs are expected to be lined up at random intervals along each track, their number being proportional to average track length in each nucleus, i.e. DSBs per nucleus are proportional to radiation dose (D). Increased charge on the heavy ion causes increased lineal energy transfer (L), i.e. DSBs are also proportional to L. Similarly for heavy ions fusions between DSBs would also be proportional to D and L. The comparable scenario for randomly deposited radiation differs in that the DSBs are distributed randomly with the nuclei. Their number remains proportional to radiation dose, but now fusions would exhibit proportionality to dose-squared as a direct result of the randomness of the DSBs. Moreover randomness eliminates simultaneity. Consequently DSBs can be eliminated before second ones occur close enough to fuse, which automatically gives rise to dose rate sparing. DSB fusion yields based on the above considerations would have the form Yfusions = CfLD + BfD2 with no dose rate sparing for the first term and positive dose rate sparing for the second term. If fusions are the initial lesion of radiation carcinogenesis, then Ycancer = CcaLD + BcaD2. Extensive cancer data in rat skin based on radiations with very different L values (56Fe (L = 150 keV/µ), 40Ar (L = 125 keV/ µ), 29Ne (L = 26 keV/ µ), 1H (L = 0.34 keV/ µ).) and doses are presented that confirm the existence of independent linear and dose-squared terms and that dose rate sparing only applies to the dose-squared term. The data support the proposition that DSB fusions could be the initial lesion of radiation carcinogenesis in the rat skin model.
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 2551. doi:1538-7445.AM2012-2551
Abstract 2556: Stat1 plays a major role in skin tumor promotion by chrysarobin but not TPA
Authors: Bozeman Ronald , DiGiovanni John 
Published: August 2012

Abstract
The cellular and molecular mechanisms that underlie promotion by diverse tumor promoting agents remain to be fully elucidated. Studies using Stat1 knockout (KO) mice have shown that they were highly resistant to two-stage skin carcinogenesis using chrysarobin as the promoter. In contrast, Stat1 KO mice treated with 12-O-tetradecanoylphorbol 13-acetate (TPA) as the tumor promoter exhibited no significant differences in tumor formation. To further investigate mechanism(s) whereby Stat1 mediates skin tumor promotion by chrysarobin Stat1 KO mice and wild-type (WT) controls were treated with the respective tumor promoters and Stat1-dependent signaling pathways were evaluated. Mice deficient in Stat1 displayed an attenuated induction of epidermal Cox-2 mRNA and protein as well as reduced PGE2 levels compared to WT controls following topical application of chrysarobin, whereas, mice treated with TPA exhibited no significant differences in Cox-2 levels or PGE2 levels. Other results also suggest that Stat1 may regulate various cytokine/chemokines involved in the inflammatory response following chrysarobin treatment. Preliminary experiments have also shown that Stat1 KO mice exhibit reduced induction of interferon regulatory factor-1 (IRF-1) following chrysarobin treatment, compared to WT controls. In contrast, treatment with TPA caused no significant differences in expression of IRF-1. Collectively, these findings suggest that chrysarobin may elicit a Stat1-dependent signaling response that is dependent on IRF-1, whereas TPA-mediated tumorigenesis is independent of this signaling pathway. These and other ongoing studies aimed at characterizing the role of Stat1 and IRF-1 signaling in chrysarobin-mediated tumor promotion will be presented.
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 2556. doi:1538-7445.AM2012-2556
Abstract 256: Involvement of ERK and ROS in CLEFMA-induced apoptosis in lung cancer cells
Authors: Yadav Vivek R. , Sahoo Kaustuv K. , Awasthi Vibhudutta 
Published: August 2012

Abstract
CLEFMA (4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid) is novel synthetic molecule with potent growth inhibitory activity in human cancer cells. Our microarray gene expression analysis suggested that it induces oxidative stress in lung adenocarcinoma H441 cells but not in normal lung fibroblasts. That oxidative stress is a triggering mechanism for both apoptotic and autophagic cell death has been supported by several recent reports. Compared to normal cells, the cancer cells are more vulnerable to oxidative stress-induced cell death because of their high metabolic activity, increased likelihood of electron escape during oxidative phosphorylation and overburdened antioxidant system. In this study, we tested our hypothesis that CLEFMA-induced apoptotic cell death was dependent on the accompanying increase in oxidative stress in H441cells. Methods: Inhibition of cell growth by CLEFMA (10 µM) was estimated by MTT or hexosaminidase assay. ROS production, cell cycle and apoptotic cell population were assessed by flow cytometry. The phosphorylation levels of extracellular signal-regulated kinase (ERK1/2), p38 and JNK1/2 were examined by Western blotting. N-acetylcysteine (NAC, 5 mM) and PD98059 (5 mM) were used as ROS scavenger and ERK1/2 inhibitors, respectively. The molecular markers of apoptosis were analyzed by RT-PCR and immunobloting. Results: NCI-DTP program confirmed anticancer activity of CLEFMA in 60 human cancer cell lines. CLEFMA-treated H441 cells showed typical molecular signatures of apoptosis- upregulated pro-apoptotic and downregulated anti-apoptotic genes. There was time-dependent activation of caspases 3/7, PARP cleavage and BAX; the expression of anti-apoptotic XIAP1 and BCL-xL was reduced, whereas pro-apoptotic p53 was increased. Since BID was not activated, it appears that CLEFMA works through intrinsic apoptosis pathway. CLEFMA also induced sustained activation of ERK, p38 and JNK. The pharmacologic inhibition of ERK, but not that of p38 and JNK, resulted in decreased anti-proliferative activity of CLEFMA. ERK inhibition with PD98059 abrogated CLEFMA-induced apoptosis. The sustained ERK activation was found to be associated with the inhibition of dual specificity phosphatase, DUSP6, expression. Treatment with ROS scavenger NAC abrogated CLEFMA-induced cell death, ERK activation and pro-apoptotic biomarkers, and reinstated DUSP6 expression. Conclusion: From the results of this study, we conclude that CLEFMA-induces apoptosis by enhancing oxidative stress in the cancer cells, and that the accompanying prolonged ERK activation is required for CLEFMA-induced H441 cell death.
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 256. doi:1538-7445.AM2012-256
Abstract 2562: Ultra sensitive immuno-array based multiplexed assay capable of profiling RTKs and signaling proteins, heterodimers, and growth factors for routine analysis of clinical samples with limited availability
Authors: Hoe Nicholas , Zhou Jinyao , Kirkland Richard , Nguyen Anthony , Roxas Gio , Kuy Crystal , Mateling Michael , Lee Tani , Magonova Katya , Kim Phillip , Liu Xinjun , Singh Sharat 
Published: August 2012

Abstract
Patient stratification based on target protein expressions or mutations alone has limitations in selecting efficacious therapeutic regimens for solid tumors. Information on the activation status of signaling pathway proteins as determined by their phosphorylation states and the level of expression, profiling of growth factors responsible for its activation, and their dimerization partners, can significantly influence clinical decisions. Herein we report a comprehensive analysis of key receptor tyrosine kinases (HER1, HER2, p95HER2, HER3, cMET, IGF1R, FGFRs, and others) and their downstream signal proteins (PI3K, Shc, AKT, MEK, ERK, PRAS40, RPS6, P70S6K, RSK), and dimerization partners (HER1:HER2, HER2:HER3, HER1:HER3, and others), and secreted growth factors (AREG, EREG, NRG1, HB-EGF, HGF, BTC, EGF, TGF, VEGF, and IGF-1) based on a multiplexed immunoarray CEER (Collaborative Enzyme Enhanced Reactive-immunoassay) platform. CEER platform utilizes the formation of an unique “triple-antibody-enzyme-channeling” immuno-complex. This complex requires co-localization of two detector-antibodies conjugated with corresponding channeling-enzymes once target proteins are bound by the capture antibodies. The immuno-collaboration between two detector enzymes, glucose oxidase (GO, conjugated to anti-target protein antibodies) and horseradish peroxidase (HRP, conjugated to anti-phosphorylated sites within the target) via target-specific, tyramide-mediated signal amplification enables target protein expression /phosphorylation profiling with validated analytical sensitivity between 1 to 10 cells. Using the CEER platform, quantitative modulations of target protein(s) in response to targeted agent(s) and treatment effect on associated downstream and upstream pathway proteins were measured. Due to the extreme sensitivity and specificity, CEER can be utilized in clinical samples with limited availability (e.g., FNA or CTCs). A comprehensive signaling pathway analysis can be a critical guide for selecting effective clinical strategies for targeted drug combinations or sequential therapeutic regimens. In addition, continued signaling pathway profiling after drug administration can monitor drug response and provide valuable information on potential drug resistance mechanisms.
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 2562. doi:1538-7445.AM2012-2562
Abstract 2563: Characterization of a p53 knockout Sprague Dawley rat
Authors: McCoy Aaron M. , Cui Xiaoxia , Weinstein Edward 
Published: August 2012

Abstract
The tumor suppressor protein TP53 plays a crucial role in cancer biology, and the Tp53 gene is the most mutated gene in human cancer. The Tp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of Zinc Finger Nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11 bp deletion in exon 3. This deletion produces a frameshift and premature stop codons in the open reading frame. In cohorts of 30 homozygous, 35 heterozygous and 25 wild type rats, the homozygotes have an average life span of 126 days, and half of heterozygotes died by a year of age. Both heterozygous and homozygous knockouts developed a wide spectrum of tumors, most commonly, sarcomas. However, there is a strikingly high incidence of brain lesions, especially in homozygous animals. In addition, unlike the Tp53 knockout mice, both male and female homozygous Tp53 knockout rats are fertile. We believe this knockout rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development.
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 2563. doi:1538-7445.AM2012-2563
Abstract 2567: DIM regulates anoikis through sonic hedgehog in ovarian cancer cells
Authors: Kandala Prabodh K. , Srivastava Sanjay K. 
Published: August 2012

Abstract
Ovarian cancer is the second leading gynecological cancer with poor prognosis. By the time of detection, it usually metastasizes to peritoneum or organs such as stomach and liver. Detachment of a cell from extracellular matrix (ECM) allows the cells to travel and lodge at metastatic site. Anoikis is an emerging form of cell death that is associated with the apoptosis of cells detached from ECM. Normal or immortal epithelial cells are sensitive to anoikis. However, carcinomas are generally associated with resistance to anoikis. Hence, induction of anoikis is an important step in preventing metastasis. We have recently shown that diindolylmethane (DIM), a compound present in cruciferous vegetables reduces the survival of ovarian cancer cells by inducing apoptosis. Here, we evaluated the effect of DIM in inducing anoikis in ovarian cancer cells. A2780, SKOV-3 and OVCAR-429 cells were grown on low attachment plates and treated with various concentrations of DIM for 24 hours and analyzed. Our results show that DIM treatment resulted in the concentration-dependent anoikis in all the cell lines. For example, anoikis induction was approximately 50-70% in all the cell lines treated with 75µM DIM. Furthermore, Integrin Linked Kinase 1 (ILK-1), an important regulator of anoikis was significantly down-regulated by DIM treatment. Western blotting revealed cleavage of caspase-3 and PARP by DIM treatment, confirming anoikis induction in our model. Few recent studies showed that Sonic Hedgehog (Shh) pathway is activated in ovarian tumors. Shh pathway is also associated with metastasis of various cancers. We therefore next determined whether Shh pathway was involved in anoikis induction by DIM. Our results demonstrated that DIM treatment reduced the expression of Shh and Gli1 in a concentration-dependent manner. Moreover, Shh secretion as well was reduced by DIM treatment in ovarian cancer cells. Importantly, Shh pretreatment significantly inhibited DIM-induced anoikis in A2780 ovarian cancer cells. Treatment of cells with Shh also reduced the cleavage of caspase-3 or PARP induced by DIM treatment indicating the involvement of Shh pathway in anoikis. Taken together, these results suggest that DIM induces anoikis in ovarian cancer cells by regulating sonic hedgehog signaling. Further in-depth mechanistic studies are in progress to establish anoikis induction by DIM and to validate it in an in vivo model. [Supported in part by R01 grants CA 1065953 and CA 129038 awarded to S.K.S by National Cancer Institute, NIH]
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 2567. doi:1538-7445.AM2012-2567