bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1744: Hsp27 overexpression enhances the chemosensitivity to MCF7 doxorubicin resistance cells
Authors: Kanagasabai Ragu , Krishnamurthy Karthikeyan , Ilangovan Govindasamy 
Published: July 2012

Abstract
Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy and its inhibition is an effective way to reverse cancer drug resistance. In the present study we report that over expression of HSP27 down-regulated MDR1 expression in MCF7/Doxorubicin (MCF7/DOX), a human breast MDR cancer cell line. In MCF7/Dox cells, mutant p53 was found to be accumulated, whereas Hsp27 level is completely depleted. Since Hsp27 was shown to enhance Akt phosphorylation and G2/M cell cycle arrest, a common pathway of Dox-induced cell death in MCF7 cells, we hypothesized that over expression of Hsp27 in resistant cell will sensitize for chemotherapy. HSP27 over expression significantly inhibited mutant p53 and MDR1 (P-gp) expression and MDR1 mRNA. The suppression of MDR1 was accompanied by partial recovery of intracellular drug accumulation and increased cytotoxicity of Doxorubicin, indicating that HSP27 reversed the MDR phenotype by inhibiting the drug efflux function of MDR1. Moreover, nuclear factor-KB activity and IKB degradation were inhibited by HSP27 over expression through down regulation of mutant p53.
Interestingly, the over expression of HSP27 negatively regulated the cell growth with significant G2/M arrest of cell cycle, and it could up-regulate endogenous p21 in a p53 independent manner leading to enhanced caspase activation to promote intracellular apoptotic signaling for cell death. Taken together, our results suggested that HSP27 is down regulated in MCF7/Dox resistant cells, and when re-expressed, it down regulates MDR1 expression via p53 and NF-KB., which results in growth suppression and higher sensitivity to Doxorubicin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1744. doi:10.1158/1538-7445.AM2011-1744
Abstract 1891: Cigarette smoking and incident colorectal cancer by KRAS mutation status in a population-based cohort of older women
Authors: Samadder Niloy Jewel , Vierkant Robert A. , Wang Alice , Tillmans Lori S. , Lynch Charles F. , Anderson Kristin E. , Haile Robert W. , Harnack Lisa J. , Potter John D. , Slager Susan L. , Smyrk Thomas C. , Thibodeau Stephen N. , Cerhan James R. , Limburg Paul 
Published: July 2012

Abstract
Background: Cigarette smoking (CS) is an established, although relatively modest, colorectal cancer (CRC) risk factor. Emerging data suggest that CS might affect distinct pathways of colorectal carcinogenesis. In this study, we examined CS-associated CRC risks by KRAS mutation status in the population-based Iowa Women's Health Study (IWHS).
Methods: The IIWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 representative CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (current, former), average number of cigarettes per day (1-19, 20-39, &gt; 40) and pack-years (1-19, 20-39, &gt; 40); never smokers were defined as the reference group. KRAS mutation status (wildtype [wt] vs. mutated [mut]) was determined by direct sequence analysis of codons 12 and 13 (exon 2). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).
Results: Of the 732 available CRC cases, 507 (69%) had complete CS and KRAS data. Each of the CS-related variables was more strongly associated with KRAS-wt vs. KRAS-mut tumors (see Table). However, event rates were relatively small in some cells, and tests for heterogeneity between KRAS-defined subtypes were not statistically significant (p &gt; 0.05 for each comparison).
Conclusions: These findings suggest that CS may affect colorectal carcinogenesis through KRAS-independent pathways, but additional data are needed from larger, more diverse study populations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1891. doi:10.1158/1538-7445.AM2011-1891
Abstract 1895: Genetic polymorphisms of an innate immune gene, Toll-Like Receptor 4, and aggressive prostate cancer risk: A systematic review and meta-analysis
Authors: Huang Yi-Ling , Page John H. , Chen Jen-Hau , Lin Yen-Ling , Xu Jianfeng , Koutros Stella , Berndt Sonja , Chanock Stephen J. , Witte John S. , Chen Yen-Ching 
Published: July 2012

Abstract
Toll-like receptor 4 (TLR4) is located on the surface of macrophages and is important for the immune response to several pathogens. Chronic inflammation has been implicated in the pathogenesis of prostate cancer (PCa), and genetic polymorphisms of the innate immune gene TLR4 have been related to the risk of PCa. Six studies have explored the association between TLR4 polymorphisms and the risk of PCa. Five studies mainly included men of European ancestry. We conducted a systematic review of all genetic association studies that evaluated the relationship between TLR4 genotypes and aggressive PCa risk. We found the rs11536889 variant was significantly associated with an increased risk of aggressive PCa under a dominant genetic model [odds ratio (OR) = 1.20, 95% CI = 1.05-1.37]. However, rs1927914, rs2149356, or rs10759932 polymorphisms were not associated with the risk of PCa under any inheritance mode. In conclusion, this study found that the polymorphism TLR4 rs11536889 was significantly associated with the risk of aggressive PCa. Additional large-scale genetic association studies are needed to confirm these findings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1895. doi:10.1158/1538-7445.AM2011-1895
Abstract 190: Targeting ceramide and endoplasmic reticulum-stress in vitamin E induced apoptosis in human breast cancer cells
Authors: Gopalan Archana , Yu Weiping , Sanders Bob , Kline Kimberly 
Published: July 2012

Abstract
Vitamin E consists of eight plant-derived forms classified as tocopherols (α, β, Δ, γ) and tocotrienols (α, β, Δ, γ) which have a chromanol ring and a saturated and unsaturated aliphatic side chain, respectively. The anti-cancer actions of tocopherols and tocotrienols are limited to the gamma and delta forms. Here, we report that both γ-tocopherol (γT) and γ-tocotrienol (γT3) display potent anti-cancer actions with γT3 being more potent. Both forms target similar pro-apoptotic and anti-apoptotic pathways. γT and γT3 induced apoptosis in human breast cancer cells by enhancing death-receptor DR5 mediated activation of caspase-8 and mitochondria dependent caspase-9, as well as by activating ER-stress markers: GADD153/ C/EBP homologous protein (CHOP), GRP-78, ATF-4 and eIF2α. JNK and CHOP are involved in DR5 mediated apoptosis triggered by both vitamin E forms. γT and γT3 decreased protein levels of anti-apoptotic factors c-FLIP, BCl-2 and survivin. Since ceramide is a known upstream inducer of ER-stress and downstream mediator of death receptor apoptotic pathway mediators, treatments with γT and γT3 were conducted in the presence of specific inhibitors of sphingomyelin hydrolysis, de novo ceramide pathways and ER-stress in order to distinguish between the pathways modulated by the vitamin E forms. Data show that both γT and γT3 induced apoptosis via activation of sphingomyelin hydrolysis and the de novo ceramide pathways; however, activation of the ER-stress pathway contributed to apoptosis induced by γT3 only. Taken together, our data suggest that γT3s more potent apoptotic effects in comparison to γT are due to the ability of γT3 to activate ER stress pathways. This better understanding of the anti-cancer properties and mechanistic actions by these two natural occurring agents in vitro provides the necessary impetus to test them in combination with other known anti-cancer agents in pre-clinical xenograft studies to identify novel and safer therapeutic strategies. Research funded by The Clayton Foundation for Research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 190. doi:10.1158/1538-7445.AM2011-190
Abstract 2013: Modulation of cellular uptake and increased therapeutic efficacy of the azacytidine-elaidic acid ester CP-4200 in vitro and in vivo
Authors: Brueckner Bodo , Rius Maria , Markelova Maria Rivera , Fichtner Iduna , Hals Petter-Arnt , Sandvold Marit Liland , Lyko Frank 
Published: July 2012

Abstract
Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependency on variably expressed nucleoside transporters for cellular uptake. To investigate the function of CP-4200, an elaidic acid ester of azacytidine, we performed DNA methyltransferase depletion assays, DNA methylation analysis using capillary electrophoresis and Infinium methylation arrays, transport studies and mouse experiments. We show here that CP-4200 has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, new results show that the uptake mechanisms of colon and leukemic cancer cell lines for CP-4200 and its parent drug azacytidine are fundamentally different, with CP-4200 being substantially less dependent on nucleoside transporters. Correspondingly, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. These results establish a fundamentally novel approach for the delivery of azacytidine to human cancer cells which might have important therapeutic implications.
Reference: Brueckner, B., et al. (2010). Mol. Cancer Ther. 9: 1256-1264.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2013. doi:10.1158/1538-7445.AM2011-2013
Abstract 2015: Effect of valproic acid on fludarabine activity in chronic lymphocytic leukemia patients
Authors: Yoon Ju-Yoon , Szwajcer David , Ganchimeg Ishdorj , Benjaminson Pat , Johnston James , Gibson Spencer 
Published: July 2012

Abstract
Valproic acid (VPA) is a first-generation anti-epileptic drug that has been shown to inhibit proliferation and induce apoptosis in various hematological malignancies, including multiple myeloma and chronic lymphocytic leukemia (CLL). We show here that the mechanism of VPA-induced apoptosis in CLL is associated with activation of the TNF-related apoptosis-inducing ligand (TRAIL) apoptotic pathway in vitro and in vivo. Treatment of leukemic cell lines or primary CLL cells with VPA increased the level of TRAIL receptor 1 (TRAIL-R1), but not TRAIL-R2, and upregulated the TRAIL pathway in vitro, resulting in increased casepase-8 cleavage. Treatment with VPA also induced formation of reactive oxygen species (ROS), and the combined cytotoxicity of VPA and fludarabine was dampened upon co-treatment with a ROS scavenger, N-acetylcysteine. Having shown the effects of VPA in vitro, a phase II clinical trial was initiated at CancerCare Manitoba to determine the activity of VPA in CLL, either when used alone or in combination with fludarabine. Five patients who had received at least one prior therapy with fludarabine have to date been examined. Three out of 5 patients were fludarabine-resistant, as defined as no response to fludarabine or relapse &lt;6 months after completion of treatment with fludarabine. No responses were seen after 28 days using VPA alone. However, in four patients who continued on VPA with fludarabine, 3 patients showed a &gt;50% fall in lymphocyte/lymph node size after receiving 5 cycles of the combination. Peripheral blood samples were obtained prior to each treatment cycle, and mononuclear cells were isolated for analysis by immunoblotting and immunocytochemistry. Levels of both histone 3-acetyl and histone 4-acetyl initially increased and then fluctuated during the course of treatment. TRAIL-R1 levels increased during the course of therapy, while no significant changes in TRAIL-R2 levels were observed. Expression of mRNA levels of genes involved in apoptosis was examined in one patient before and 28 days following VPA. There was a global up-regulation of both pro- and anti-apoptotic genes (as categorized by their gene ontology) which likely explains the effect of VPA on fludarabine sensitivity in CLL. In summary, VPA induces hyper-acetylation of histones in CLL and activates the TRAIL apoptotic pathway. While VPA is ineffective as a single agent in CLL, it can sensitize CLL cells to fludarabine and could be used as an adjuvant in fludarabine-based treatment regimens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2015. doi:10.1158/1538-7445.AM2011-2015
Abstract 2018: Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model
Authors: Li Nan , Grimes Marcie J. , Picchi Maria A. , Mitchell Hugh D. , Stidley Christine A. , Tesfaigzi Yohannes , Channell Meghan M. , Liu Yanbin , Casero Robert A. , Baylin Stephen B. , Reed Mathew D. , Tellez Carmen S. , March Thomas H. , Belinsky Steven A. 
Published: July 2012

Abstract
Epigenetic therapy for solid tumors could benefit from an in vivo model that defines tumor characteristics of responsiveness and resistance to facilitate patient selection. Here we report that combining the histone deacetylase inhibitor entinostat with the demethylating agent vidaza profoundly affected growth of K-ras/p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses. A similar reduction in tumor burden was seen with epigenetic therapy in K-ras or EGFR mutant tumors growing orthotopically. Increased expression of pro-apoptotic genes and the cyclin dependent kinase inhibitor p21 was seen. Hundreds of genes were demethylated highlighted by the re-expression of polycomb-regulated genes coding for transcription factor binding proteins and the p16 gene, a key regulator of the cell cycle. Highly significant gene expression changes were seen in key regulatory pathways involved in cell cycle, DNA damage, apoptosis, and tissue remodeling. These findings demonstrate the promise for epigenetic therapy in cancer management and provide an orthotopic lung cancer model that can assess therapeutic efficacy and reprogramming of the epigenome in tumors harboring different genetic and epigenetic profiles to guide use of these drugs. This study was supported by the Waxman Foundation and by a research grant from NIH (R01 CA095568).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2018. doi:10.1158/1538-7445.AM2011-2018
Abstract 2022: Wnt ligands are overexpressed in murine mammary tumors in BK5.ATF3 transgenic mice
Authors: Yan Leqin , Powell K. Leslie , MacLeod Michael C. 
Published: July 2012

Abstract
The Wnt/β-catenin signaling pathway is up-regulated in mammary tumors that arise with 70% incidence in parous female BK5.ATF3 transgenic mice. Nuclear accumulation of β-catenin is seen in both basal and supra-basal tumor cells in this model, whereas nuclear expression of the transcription factor ATF3 is only seen in the basal cell layer of the tumors. If ATF3 acted as a positive regulator of one or more Wnt ligands in the basal cells, one might expect paracrine upregulation of the Wnt/β-catenin pathway in neighboring supra-basal cells. To test this, we measured mRNA expression levels for 9 Wnt genes in BK5.ATF3 induced mammary tumors and normal mammary glands. The genes for five known positive acting Wnt ligands, Wnt3, Wnt3a, Wnt5a, Wnt7b, and Wnt10b, were significantly upregulated in tumors as compared to transgenic mammary glands. One of these, Wnt3, was significantly down-regulated in non-transgenic glands. In a mouse mammary tumor cell line, EMT6, in which the endogenous Atf3 gene is overexpressed, the only Wnt gene for which expression could be detected by qPCR was Wnt7b. ChIP assays demonstrated binding of both Atf3 and Jun proteins to two putative AP-1 sites upstream of the Wnt7b transcription start site in these cells. ATF3 and JUN are known in other systems to form heterodimers that exhibit positive transactivation through AP-1 sites, and we have identified a physical interaction between ATF3 and JUN in BK5.ATF3-induced tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2022. doi:10.1158/1538-7445.AM2011-2022
Abstract 2033: Transcription factors that regulate MUC16 expression in ovarian cancer
Authors: Thapi Dharmarao , Binder Darcie , Rosales Nestor , Yan Xiu Jun , Lash Alex E. , Spriggs David R. 
Published: July 2012

Abstract
CA125 antigen is found to be elevated in 85% of patients diagnosed with advanced epithelial ovarian cancer. CA125 has a minimal role as a screening modality. The gene which encodes for the CA125 glycoprotein, MUC16, has been previously identified and sequenced. MUC16 has a molecular size of 22,000 bps and consists of cytoplasmic domain, transmembrane region and 9 external domain tandem repeats. The large molecular weight of this gene has made it difficult to study and track. N terminal signal peptide and transcription factor or factors that triggers MUC16 in ovarian cancer is not well demonstrated. The proximal 114 amino acids of MUC16 can transform NIH/3T3 cells and increase soft agar formation and matrigel invasion.
We have designed several constructs from the region about 1000 nucleotides upstream and 300 nucleotides downstream of the MUC16 start Methionine with secretory pMetridia Luciferase Reporter vector (Clonetech, CA). Four constructs of varying lengths had the MUC16 UTR TSS site whereas two did not. Putative binding sites for transcription factors like ER, STAT1, STAT3, CRE-BP1 (ATF2) and NFKB are also present. These constructs were then transfected individually into CA125 negative ovarian cell line, SK-Ov-3, and also into CA125 positive ovarian cell lines, SK-Ov-8 and CAOV3. All cell lines were stably selected with G418 and were used within 10 passages. Western blots confirm the presence of ERalpha, STAT1 and STAT3.
Stably transfected cell lines were cultured in low serum conditions with or without 17β-Estradiol or IL-1β, were used to see the effect of transcription. Clinical CA125 levels were also documented for each construct. Secretory pMetridia Luciferase signals were detected in the supernant of the culture cells. There is no difference between untreated or 17β-Estradiol or IL-1β treated cells. However, gel retardation studies with OVCAR3 and SKOV8 wild type cell lines suggested CREB/ATF (CREBZF) transcription factor involvement and confirmatory reporter gene studies are planned. Currently, we are assessing the putative transcription factor binding sites within the 1300 nucleotides region from which we derived the constructs.
We conclude that these studies will lead us to better understand the biology of MUC16 gene expression and give us an insight about the role of transcription factors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2033. doi:10.1158/1538-7445.AM2011-2033
Abstract 2050: 2-Deoxy-D-Glucose (2-DG) as a glycolytic inhibitor in the treatment of retinoblastoma
Authors: Decatur Christina , Pina Yolanda , Houston Samuel , Cavalcante Ludimila , Shah Nikesh , Murray Timothy 
Published: July 2012

Abstract
Purpose: The aim of the current study is to assess the impact of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on tumor burden and hypoxia in the LHBETATAG retinal tumors.
Methods: Group A: 17-week-old LHBETATAG transgenic mice (n=30) received periocular injections of saline and 2-DG (62.5, 125, 250, and 500mg/kg). Injections were given 2 times a week for 3 weeks. Group B: 4-week-old mice received oral delivery of 2-DG in custom made food pellets and were treated for either 8 or 18 weeks. 17-week-old mice received oral 2-DG for 8 weeks. At the time of enucleation, all eye samples were snap frozen and analyzed for tumor burden and hypoxic regions using immunohistochemistry.
Results: Following injections of 2-DG, tumor control was not different between the control and the lowest two doses (62.5 and 125mg/kg). However, the difference in tumor burden was significant from 250mg/kg dose (p&lt;0.015) and 500mg/kg dose (p&lt;0.001) with 9.7 and 23% tumor burden decrease, respectively. At all doses of periocular 2-DG, the percent hypoxia following drug treatment were lower relative to controls (p&lt;0.001), with a hypoxia decrease in the lowest dose to 2.4% compared to 21% in controls. Following oral delivery of 2-DG, there was a difference between the groups treated with 2-DG and the control groups (p&lt;0.010). A 20% reduction in tumor burden was found in the 8 weeks early treated, a 50% reduction in the 18 weeks early treated, and a 35% reduction in the 8 weeks late treated group. The percent hypoxia was lower relative to controls in the 8 weeks and 18 weeks early treated groups (p&lt;0.001) with a 40% and 50% reduction, respectively. The percent hypoxia did not change following treatment in the treated late group.
Conclusions: This study exhibits the efficacy of focal 2-DG as potential therapy to decrease both intratumoral hypoxia and tumor burden. The current study also shows that the non-invasive oral delivery 2-DG treatment has similar or better effects on the tumor depending on the treatment schedule used. In advanced disease of LHBETATAG retinal tumors, hypoxia is increasingly present. The use of glycolytic inhibitors as a therapeutic strategy has the potential to enhance current retinoblastoma treatments.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2050. doi:10.1158/1538-7445.AM2011-2050