bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2897: Profiling lipoxygenase metabolism in specific steps of colorectal tumorigenesis
Authors: Shureiqi Imad , Chen Dongning , Day R. Sue , Zuo Xiangsheng , Ross William , Moy Ofir , Morris Jeffrey Scott , Xiao Lianchun , Newman Robert A. , Yang Peiying , Lippman Scott M. 
Published: February 2011

Abstract
Lipoxygenases (LOXs) are key enzymes for the oxidative metabolism of polyunsaturated fatty acids into products that influence cell signaling, structure, and metabolism. Previous data on comparative levels of various LOX products in human tumorigenesis are limited primarily to retrospectively collected surgical samples from cancer patients. Therefore, we examined LOX product profiles by liquid chromatography/tandem mass spectrometry in the major steps of colorectal tumorigenesis (normal, polyp, and cancer) in a clinical study of 125 subjects (49 with a normal colon, 36 with colorectal polyps, and 40 with colorectal cancer) who underwent prospective colorectal biopsies to control for various potential confounding factors (e.g. diet, medications). Mean 13-hydroxyoctadecadienoic acid (13-HODE) levels were significantly higher in normal colons (mean = 36.11 ng/mg protein, 95% confidence interval [CI]: 31.56-40.67) than in paired colorectal cancer mucosa (mean = 27.01 ng/mg protein, 95% CI: 22.00-32.02; P = 0.0002) and in normal colons (mean = 37.15 ng/mg protein, 95% CI: 31.95-42.34) than in paired colorectal polyp mucosa (mean = 28.07 ng/mg protein, 95% CI: 23.66-32.48; P &lt; 0.001). Mean 13-HODE levels, however, were similar between the left (mean = 37.15 ng/mg protein, 95% CI: 31.95-42.35) and right normal colons (mean = 32.46 ng/mg protein, 95% CI: 27.95-36.98; P = 0.09). No significant differences with regard to 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, or leukotriene B4 (LTB4) levels were detected between normal, polyp and cancer mucosa. Downregulation of 15-LOX-1 expression, the rate limiting enzyme for 13-HODE production, in human colorectal neoplastic mucosa was confirmed by quantitative real time PCR in a subset colorectal cancer patients for whom samples with adequate RNA quality were available. This study establishes that reduced 13-HODE levels are a specific alteration in the LOX product profile associated with human colorectal tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2897.
Abstract 2899: Multiple-dose phase 1 study of 3,3′-diindolylmethane (DIM): Pharmacokinetics and biological effects
Authors: Reed Gregory A. , Sunega Jean M. , Latinis Kevin , Gray John , Crowell James A. , Perloff Marjorie 
Published: February 2011

Abstract
We have completed our examination of the safety, tolerability, pharmacokinetics, and effects of twice daily doses of 100 mg and 200 mg of 3, 3’-diindolylmethane (DIM) for four weeks. Healthy adult subjects self-administered an absorption-enhanced formulation of DIM (BR-DIM). Eight subjects received the low dose, and six subjects received the high dose of BR-DIM. Based on medical histories, physical examinations and a battery of blood and urine tests we concluded that BR-DIM in this dosing regimen was very well tolerated, with no significant adverse effects. The pharmacokinetics of DIM were determined at each dose for both the first dose and last dose of BR-DIM in these subjects. The first dose Cmax and AUC values obtained for the two doses were similar to the results of our previous single ascending dose study of BR-DIM. Surprisingly, after four weeks of twice daily dosing, the mean Cmax of DIM fell by 29% and 73% and the mean AUC fell by 46% and 71% in the low and high dose groups, respectively. Multiple daily dosing with BR-DIM clearly altered expression either of specific transporters or of enzymes that biotransform DIM, resulting in a marked decrease in bioavailability. This decreased systemic exposure, however, must be considered in light of the observed induction of CYP1A2, one of our primary biomarkers of effect. Mean CYP1A2 activity increased by 250% at the low dose and by 181% at the high dose, suggesting that effective concentrations of DIM or an active metabolite were achieved in the liver, and that this resulted in induction of hepatic CYP1A2. No effects of BR-DIM were seen on activities of CYPs 2C9, 2D6, or 3A4. The lack of systemic exposure to DIM could result either from induced hepatic metabolism of DIM or from increased biliary secretion of DIM. This proposal for the altered pharmacokinetics of DIM, allowing hepatic effects but not extrahepatic effects, is consistent with the very modest effects of BR-DIM we observed on peripheral blood lymphocyte GST activity, and suggests that the lymphocyte activity may not be an accurate surrogate for hepatic effects of DIM. The lack of significant change in the 2-hydroxyestrone:16α-hydroxyestrone ratio, judged by us to be a key biomarker of efficacy in our previous trial with the DIM precursor indole-3-carbinol, raises the possibility that the change in that ratio is based to a significant extent on extrahepatic hydroxylation of estrone, rather than modulation of hepatic estrogen metabolism. Supported by NCI N01 CN-35008-38 and P20RR021940.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2899.
Abstract 2900: Risk of recurrence of colorectal neoplasia among type 2 diabetes mellitus patients randomized to placebo in the Polyp Prevention Clinical Trials
Authors: Acevedo Alejandro , Cruz-Correa Marcia R. , Diaz Yaritza , Grau Maria , Baron John 
Published: February 2011

Abstract
Introduction: Diabetes Mellitus (DM) has been reported to be associated with an increased risk of colorectal cancer is several case-control studies. However, very limited data have examined the risk of recurrence of colorectal neoplasia (CRN) among individuals with type 2 DM. This study examined the risk of recurrence of CRN (either adenomas or carcinoma) among individuals with type 2 DM compared to those without type 2 DM.
Methods: Retrospective cohort study evaluated subjects recruited into several randomized clinical trials (RCTs) (Antioxidant Polyp Prevention Study, the Calcium Polyp Prevention study, and the Aspirin/Folate Prevention Study). Diagnosis of type 2 DM was established by previous medical diagnosis and/or anti-diabetic medication use. Participants had to have undergone colonoscopy to the cecum, with removal of all polyps, within three to four months before study entry. Also, they must have had colonoscopies during follow-up study periods (as outlined for each protocol). Logistic regression was employed to estimate the association between type 2 DM and CRN using STATA 10.0.
Results: 2,915 individuals (2068 women; 85.3% White; mean age 59.7 ± 9.3 years) were enrolled into any of the three RCTs. 882 (30.3%) subjects were assigned to placebo vs. 2033 (69.7%) to active drug; mean follow-up time was 35.0 ± 3.9 months from randomization to first colonoscopy. A total of 208 subjects had type 2 DM (mean age 62.9 ± 7.6 yrs, 75.5% females), of which 61(29.3%) were assigned to the placebo arm. Colorectal adenomas developed in 44.5% (27/61) and 55.1% (410/744) of DM and non-DM individuals, respectively (p=0.40) assigned to the placebo arm. While advanced colorectal adenomas (≥ 1 cm in size or advanced histology) developed in 9.8% (9/61) and 9.3% (69/744) of DM and non-DM individuals, respectively (p=0.89). Colorectal cancer developed in 1.64% (1/61) of DM patients vs. 0.4% (3/744) of non-DM patients (p=0.19). There was no statistically significant association between location of CRN, number/size of adenomas, or tumor stage and DM.
Discussion: Recurrence of colorectal adenomas was not increased among patients with DM compared to non-DM patients. Similarly, occurrence of colorectal advanced lesions was not increased in DM patients compared to non-DM patients. A small number of subjects with DM and short follow-up time may have limited the power of the study to detect differences in CRN.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2900.
Abstract 2914: Mice deficient in Smurf2 exhibit increased spontaneous tumorigenesis
Authors: Zhang Hong , Ramkumar Charusheila 
Published: February 2011

Abstract
Smurf2, a HECT family E3 ubiquitin ligase has been shown to ubiquitinate and target for degradation of several proteins that promote tumorigenesis, including TGF-β receptors, Smad2/3, β-catenin, and Mad2. Furthermore, we have previously found that Smurf2 can induce senescence in early passage cells in culture. As senescence has been postulated to act as a tumor suppression mechanism, we hypothesize that Smurf2 functions as a tumor suppressor. To test this hypothesis, we generated a Smurf2-deficienct mouse strain using a gene trapping strategy, in which transcription of Smurf2 is compromised. The homozygous Smurf2-deficient mice were obtained with the expected Mendelian ratio after intercrossing of heterozygous mice, and they exhibited no obvious developmental defects. Analysis of mouse embryonic fibroblasts from these Smurf2-deficient mice revealed that they exhibited delayed senescence entry and consequently had an increased tendency to become immortalized in culture. Cohorts of Smurf2-deficient and wild-type mice were generated and monitored for spontaneous tumor development. In this ongoing study, 37% (13 out of 35) of the Smurf2-deficient mice, but none of the wild-type mice showed signs of morbidity after 14-month of age. The moribund Smurf2-deficient mice were found to have enlarged spleen, pale kidneys and liver, and/or enlarged lymph nodes. Histopathology analysis indicated that most of the tumors are lymphomas. In addition, adenocarcinoma of the small intestine was found in one Smurf2-deficient mouse. Collectively, our data suggest that Smurf2 is a tumor suppressor. Preliminary studies of the underlying molecular mechanism of tumorigenesis in Smurf2-deficient mice will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2914.
Abstract 2919: XBP1 and the unfolded protein response in antiestrogen resistance in breast cancer
Authors: Shajahan Ayesha N. , Riggins Rebecca B. , Zwart Alan , Hickman F. Edward , Clarke Robert 
Published: February 2011

Abstract
Most of the 178,000 newly diagnosed cases of invasive breast cancer in 2010 will be estrogen receptor positive α positive (ER+). For these patients, endocrine therapy, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole (LET), is the least toxic and most effective means to manage their hormone-dependent breast cancer. While 5 years of Tamoxifen (TAM) produces a 26% proportional reduction in mortality, advanced ER+ breast cancer largely remains an incurable disease and resistance to endocrine therapy remains a significant clinical problem. Previously, we have shown that antiestrogen resistant breast cancer cells over-express X-Box Binding Protein 1 (XBP1), a transcription factor that belongs to the basic region/leucine zipper (bZIP) family. XBP1(U) and XBP1(S) variants result from an unconventional splicing of the XBP1 mRNA by IRE1α. High ratio of XBP1(S):XBP1(U) mRNA in breast tumors is associated with poor response to TAM in patients. IRE1α, ATF6 and PERK are endoplasmic reticulum proteins that sense cellular stress in the unfolded protein response (UPR) - an adaptive signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. Initially a compensatory mechanism allowing cells to recover normal endoplasmic reticulum function, prolonged UPR may induce cell death; this is often dependent upon which arm of the UPR predominates. XBP1 is an obligate component in both the IRE1α and ATF6 arms of the UPR. Here we show that antiestrogen resistant breast cancer cells survive by activating pro-survival autophagy through XBP1-mediated UPR. MCF7/LCC9 [Faslodex resistant; TAM cross-resistant; high level of XBP1(S)] cells showed an increase in UPR signaling as detected by increased expression of BiP/GRP78. MCF-7/XBP1 or T47D/XBP1 stable cells that over-express XBP1(S) showed increased level of basal and Faslodex-induced autophagy as measured by cleaved LC3BII protein fragment, GFP-LC3 activity, and reduced expression of p62/SQSTM1. Thus, our results highlight a novel cell fate signaling through the UPR in breast cancer cells that leads to antiestrogen resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2919.
Abstract 2938: A novel OX40 agonist licenses systemic anti-tumor immunity to overcome local immune suppression induced by well-established tumors
Authors: Pardee Angela D. , Epstein Alan L. , Storkus Walter J. 
Published: February 2011

Abstract
Immune modulating reagents that trigger the T cell costimulatory molecules GITR and OX40 are being evaluated as anti-cancer agents in early-stage clinical trials. However, little pre-clinical information is available regarding the efficacy and mechanism(s) of action for these agents in the setting of advanced, well-established disease. To further characterize the molecular, cellular, and treatment-associated consequences of GITR and OX40 engagement, novel agonistic reagents directed against murine GITR and OX40 (ligand-Fc fusion proteins) were recently constructed and characterized in vitro. We now show that the growth of well-established, day 17 sarcomas is significantly inhibited or ablated by a short course of either treatment, with OX40L-Fc demonstrating superior anti-tumor efficacy over GITRL-Fc at comparable doses. Despite diminished frequencies of CD4+Foxp3+ regulatory T cells (Treg) in the tumor microenvironment (TME) 3 days post-treatment, the presence of myeloid-derived suppressor cells (MDSC) and inhibitory cytokines such as IL-10 and TGFβ appears unaltered and effector T cell production of the Type-1 cytokine IFNγ remains low. Treatment with either GITR or OX40 agonists, however, induces a coordinate increase in CCR7+ dendritic cells in the tumor-draining lymph nodes (TDLN), followed approximately 7 days after treatment by profound expansion of effector T cells expressing the Type-1 chemokine receptor CXCR3. By day 10 post-treatment, particularly with the OX40 agonist, T cells displaying a recently-activated effector phenotype accumulate in the tumor microenvironment and secrete high levels of IFNγ. Collectively, these data suggests a model in which the first level effect of costimulatory treatment is to direct CCR7+ dendritic cells from the TME to the draining lymph nodes. A secondary, systemic response reflects the expansion of highly-reactive CXCR3+ Type-1 T cells in the TDLN and their subsequent trafficking into the TME. The therapeutic efficacy demonstrated in this model by OX40L-Fc, and to a lesser extent GITRL-Fc, strongly supports the translation of such modalities into human clinical trials, while the mechanistic insight gained from these studies suggests that successful immunotherapies will license both local, and perhaps more importantly, systemic Type-1 T cell immunity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2938.
Abstract 294: Protein interactions of PTEN and its cancer-associated G20E mutant compared by SILAC-based parallel affinity purification and mass spectrometry
Authors: Gunaratne Jayantha , Goh Mei Xian , Foon Swa Lee , Lee Fen Yee , Sanford Emma , Wong Loke Meng , Hogue Kelly , Blackstock Walter , Okumura Koichi 
Published: February 2011

Abstract
The tumor suppressor PTEN (phosphatase and tensin homologue) negatively regulates the phosphatidyl-inositol-3-kinase (PI3K) pathway through its lipid phosphatase activity and is one of the most commonly lost tumor suppressors in human cancers. Though the tumor suppressive function involves PTEN's lipid phosphatase-dependent and -independent activities, the mechanism leading to the phosphatase independent function of PTEN is poorly understood. Some PTEN mutants have lipid phosphatase activity but fail to suppress cell growth. Here we use a cancer associated mutant, G20E, to gain insight on the phosphatase independent function of PTEN by investigating protein-protein interactions using stable isotope labeling by amino acids in cell culture (SILAC). A strategy named parallel affinity purification (PAP) and mass spectrometry (MS) has been developed to allow prioritizing interactors acquired from SILAC pull-downs and the comparison of the interactions between wild-type and G20E PTEN. Liquid chromatography-MS analysis of tryptic digested SILAC-PAP pull-downs revealed known and new interactors. Hierarchical clustering of the heat map generated from the proteins with elevated SILAC ratios from PAP-MS analysis show three distinct clusters: 1) wild-type specific interactors, 2) those unique to the G20E mutant and 3) proteins common to wild-type and mutant. Pathway analyses indicate that the new interactors can be subdivided into apoptosis, cell migration, polarity and the Ca2+ signaling network. These finding contribute to a better understanding of the novel mechanisms of PTEN's phosphatase dependent and independent functions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 294.
Abstract 2940: Altered hematopoiesis and lymphomagenesis through loss of chromatin-associated protein KIF4
Authors: Mazumdar Manjari 
Published: February 2011

Abstract
Hematopoiesis, the process of blood cell formation is largely dependent on specialized chromatin environment for stem cell self-renewal and multi-lineage differentiation. The kinesin motor protein KIF4 associates with chromatin during interphase, performs essential functions in mitosis and its loss causes hypercondensation of mitotic chromosomes leading to genomic instability. We have demonstrated that KIF4 is a modulator of interphase chromatin architecture. In KIF4-null mouse ES cells, heterochromatin blocks are lost, pericentormeric heterochromatin regions are decondensed in S phase and chromatin is globally decondensed. The global chromatin decondensation has functional consequences as indicated by mis-regulation of significant number of genes detected by microarray expression analysis. To understand the molecular mechanism of KIF4 function in vivo, we have developed KIF4 knockout (KIF4 KO) mouse. Here we show that in the absence of KIF4 animals develop splenomegaly, substantial populations of mice have thymic and splenic hyperplasia and ∼40% of heterozygous female mice developed Follicular B cell lymphoma similar to human Non-Hodgkin lymphoma. Flow sorting (FACS) analysis of young mice indicated that loss of KIF4 causes defects in hematopietic development and differentiation. Lymphocytes from animals lacking KIF4 exhibit chromatin defects, aneuploidy, DNA damage and slow progression of lymphocytes through cell cycle. More importantly, we find that there is an accumulation of mature B cells in the spleen in the absence of KIF4. The increased survival of germinal center B cells in the absence of KIF4 may cause the observed hyperplasia and B cell neoplasm. The mechanism of survival and expansion of lymphocytes in spite of genomic instability could be linked to the defects in chromatin organization and changes in transcriptional potential. We propose KIF4 may act as a modulator of chromatin function to regulate cell fate decision during lymphocyte development and a guardian of genome stability to prevent hematopoietic neoplasm. Hematologic malignancy via deletion of a chromatin-associated molecular motor protein is a novel paradigm both in the fields of molecular motors and cancer biology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2940.
Abstract 2942: The effect of AR expression level on the chromatin binding of the receptor
Authors: Urbanucci Alfonso , Sahu Biswajyoti , Seppälä Janne , Kukkola Saara , Waltering Kati , Lähdesmäki Harri , Jänne Olli , Visakorpi Tapio 
Published: February 2011

Abstract
Treatment of castration resistant prostate cancer remains to be a challenge. Androgen receptor (AR) is overexpressed and still active at this stage of the disease. Our goal is to identify AR downstream genes and to study the effect of AR overexpression on the chromatin binding.
We established, by stable transfection of wtAR into LNCaP cell, two cell lines that over express moderate (LNCaP-ARmo: 2-3 fold) and high (LNCaP-ARhi: 4-5 fold) receptor amounts of protein. We cultured the cell lines in androgen depleted medium for 4 days and subsequently treated them for 2 hours with vehicle or 1nM and 100nM of 5α-dihydrotestosterone (DHT). Subsequently, we used chromosome immunoprecipitation and deep sequencing (ChIP-seq) to identify AR binding. Expression profiling was done by Illumina array. The data analysis is ongoing. We first studied the well known AR target gene PSA. Our data indicated that in depleted medium there is not apparent difference in the loading of the promoter and enhancer of the PSA regulatory region in different cell lines. Instead, the promoter and the enhancer are more loaded in LNCaP-ARmo/−ARhi than in control cell line upon DHT stimulation. Our preliminary data show that there is a positive correlation between AR-levels and whole genome-wide binding upon stimulation with 1 nM DHT. Whereas, in 100 nM DHT, which is a saturating concentration of the ligand, there is a negative correlation. In the 1 nM DHT, AR seems to bind to different genomic loci in LNCaP-ARhi or ARmo than in control cells. In conclusions, the amount of AR has an effect on the chromatin binding of the receptor. Cells overexpressing AR seems to be more androgen-responsive.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2942.