bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3125: Relative distribution of folate species is associated with global DNA methylation in human colorectal mucosa
Authors: Liu Jia , Hesson Luke B. , Meagher Alan P. , Bourke Michael J. , Hawkins Nicholas J. , Rand Keith N. , Molloy Peter L. , Pimanda John E. , Ward Robyn L. 
Published: August 2012

Abstract
Folate, an important cellular methyl donor, exists as functionally diverse species within cells. Folate deficiency is thought to contribute to DNA hypomethylation in colorectal cancer (CRC) however findings on the relationship between total folate concentration and global DNA methylation have been inconsistent. The aim of this study was to determine if global DNA methylation in blood and colorectal mucosa from healthy and CRC patients is related to folate species distribution. Blood and colorectal mucosa was collected from 112 CRC patients, 114 healthy individuals and 82 low folate individuals. Global methylation and folate was determined using liquid chromatography tandem mass spectrometry and repeat element methylation was determined using end-specific polymerase chain reaction. In colorectal mucosa mean global methylation was 8% lower compared to blood while LINE-1 and Alu elements were 3.3-fold and 1.9-fold hypomethylated respectively (P &lt;0.0001). After adjusting for age and smoking, statistically significant but small (2.2%) differences in global but not repeat methylation were found in normal colorectal mucosa from CRC patients compared to healthy individuals. Low folate patients had 18% lower blood 5-methyltetrahydrofolate distribution (P &lt;0.0001) and global (P =0.001) and LINE-1 demethylation (P &lt;0.0001) compared to healthy individuals. The colorectal mucosa from cancer and healthy patients had an altered distribution of folate species (lower 5-methyltetrahydrofolate) similar to the folate distribution found in the blood of low folate individuals. On a background of tissue specific hypomethylation, global methylation of the normal mucosa of CRC patients is similar to healthy individuals. The level of global and repeat element hypomethylation may reflect the underlying distribution of folate species rather than total folate concentration. Future studies on the relationship between methylation and folate should consider folate species distribution, and how genetic or other factors may alter this balance in different tissue types and in neoplasia.
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 3125. doi:1538-7445.AM2012-3125
Abstract 314: The interaction between chronic alcohol consumption and melanoma skews the iNKT cell cytokine profile towards IL-4 dominance
Authors: Zhang Hui , Zhu Zhaohui , Meadows Gary G. 
Published: August 2012

Abstract
Despite the growing evidence that alcohol consumption is associated with the incidence of many different types of cancer, there is little research regarding the effect of continued alcohol consumption on growth, progression and subsequent survival of cancer patients. Using a well-established mouse model we previously found that chronic alcohol consumption impairs the anti-melanoma functions of CD8+T cells and NK cells, and this leads to decreased survival of melanoma-bearing mice. The underlying mechanism for these effects is not known. Herein we examined the relationship of NKT cells to regulation of anti-tumor responses in alcohol consuming mice since NKT cells play important roles in the regulation of the anti-tumor immune response. The phenotype and function of invariant (i)NKT cells were examined in female B16BL6-bearing C57BL6 mice given 20% alcohol for three months. We found that alcohol consumption increased iNKT cells in the liver of mice not inoculated with melanoma, but did not alter iNKT cells in other organs. iNKT cells were dramatically increased in the blood and liver of chronic alcohol consuming, melanoma-bearing mice; however, these cells were not increased in the spleen or draining lymph nodes. Immature NK1.1- iNKT cells decreased 2-4 fold in the blood, spleen and liver of the alcohol-consuming, melanoma-bearing mice, suggesting that alcohol interacting with the melanoma tumors stimulates iNKT cells maturation. Upon activation, fewer iNKT cells produced IFN-gamma in these mice compared to water-drinking, melanoma-bearing mice. The ratio of IL-4:IFN-gamma-producing iNKT cells increased 2-fold as a result of the alcohol/tumor interaction, thus skewing the cytokine profile toward Th2 dominance. The Th2 dominant cytokine profile could negatively regulate the anti-tumor activities of CD8+ T cell and NK cells as well as increase myeloid derived suppressor cells, which we previously reported. Collectively, these data support an important role for iNKT cells in regulation of melanoma progression. (Supported by NIH grants R01AA07293 and K05AA017149, and WSU Alcohol and Drug Abuse Research Program grant 13B-2957-1246).
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 314. doi:1538-7445.AM2012-314
Abstract 3243: Dysfunctional of TGF-β signaling via loss of β2SP activates SOX9 and C-MYC via Notch signaling in Barrett's esophageal adenocarcinoma
Authors: Song Shumei , Maru Dipen M. , Piera-Velazquez Sonsoles , Stroehlein John R. , Davila Marta , Mishra Lopa 
Published: August 2012

Abstract
Background: Esophageal adenocarcinoma (EA) is often considered to arise from a clonal stem like population of cells, potentially responsible for its poor prognosis. TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis. We have demonstrated loss of TGF-β signaling components and activation of Notch signaling in Barrett's esophageal adenocarcinoma; however, their contributions to EA and the mechanisms of their action remain unclear. Methods: Immunoblotting and immunofluorescence were used to evaluate protein expression and localization. Notch targets Hes-1, SOX9 and C-MYC transcription were assayed using their luciferase reporters and Q-PCR. Functional studies were performed in β2SP wild type and mutant MEFs cells and in EA cell lines genetically engineered to express high or low levels of β2SP. Results: Increased levels of Notch signaling Hes1 and Jagged1 occurred in EA tissues and cell lines, compared to normal tissues. Loss of β2SP in MEFs cells increased Hes1 expression by 40 fold. In addition, SOX9, a target gene of Notch signaling and a documented stem cell marker was highly up-regulated in EA tumor cells and tissues. Expression of SOX9 was increased in the absence of β2SP in MEFs cells by 9 fold. Down-regulation of β2SP in SKTG-4, FLO-1 and BE3 EA cells by lentivirus shRNA led to increased SOX9 expression and enhanced nuclear localization of both active intracellular Notch1 domain (ICN1) and SOX9. Reintroducing β2SP into EA cells with knock down β2SP decreased SOX9 promoter activity by 10 fold. Concomitantly, an increased proportion of stem cells in β2SP knock down cells were identified using stem cell marker OCT3/4, indicating expansion of putative cancer stem cells in the absence of β2SP. Most interestingly, we observed a direct interaction between Smad3 and ICN1 via Smad3 MH1 domain by GST-pull down assays and that loss of β2SP increases the binding of Smad3 with ICN1 and induces Notch targets SOX9 and C-MYC transcription. Conclusions: Our findings suggests that loss of TGF-β signaling adaptor β2SP may switch Smad3 function from tumor suppression to tumor promotion by binding intracellular Notch1 domain (ICN1) and activating Notch signaling. Thereby, a potential therapeutic value for targeted therapy in EA is in the setting of loss of β2SP/TGF-β with active Notch signaling.
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 3243. doi:1538-7445.AM2012-3243
Abstract 3245: The Golgi protein GLG1 participates in tumor progression
Authors: Planche Anne , Bacac Marina , Stamenkovic Ivan 
Published: August 2012

Abstract
Increasing evidence suggests that endocytosis and membrane trafficking are deregulated in cancer cells. Because of their dependence on selected signaling pathways, tumor cells may need to rely on accelerated receptor recycling and increased secretion of a variety of molecules such as matrix components, adhesion molecules and growth factors. Mass spectrometry analysis of proteins associated with separase, recently shown to be an important regulator of membrane trafficking, identified the Golgi apparatus protein 1 (GLG1). GLG1 is primarily known as an E-selectin ligand that mediates the initial step of tethering and rolling of leukocytes on vascular endothelium. We therefore addressed the possibility that GLG1 could play a similar role in circulating tumor cells, facilitating arrest and extravasation into adjacent tissues. Consistent with this possibility, tail vein injection of stably GLG1-depleted tumor cells into NOD/SCID mice resulted in reduced numbers of metastatic nodules. Moreover, metastatic tumor growth was almost exclusively intravascular, indicating impaired extravasation of tumor cells. Further investigation, however, showed that, in tumor cells, GLG1 is almost exclusively localized to the Golgi apparatus, challenging the notion that it plays a direct role in mediating tumor cell adhesion to endothelium as in leukocytes. To elucidate the molecular mechanisms by which GLG1 could affect tumor cell migration through interactions at the Golgi level, we conducted experiments using GLG1-depleted human tumor cell lines. Transient silencing of GLG1 by siRNA was observed to modify cell shape (elongated morphology), to markedly alter Golgi architecture, to inhibit migration of a range of tumor cell lines, and to decrease β1 integrin protein level and impair its internalization/recycling. In addition, subsequent experiments led to the identification of BIG1, an Arf-GEF required to initiate membrane vesicle formation by promoting guanine-nucleotide exchange on Arf1 and Arf3, as a new interactor of GLG1. Taken together, our observations provide insight into a novel and specific role of GLG1 in tumor progression by affecting, thanks to its privileged position in the secretory pathway, trafficking of key molecules implicated in cell migration.
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 3245. doi:1538-7445.AM2012-3245
Abstract 3436: Suppression of the epithelial-mesenchymal transition (EMT) by a wound-healing gene, Grainyhead-like-2
Authors: Cieply Benjamin , Riley Philip A. , Ivanov Alexey , Pifer Phillip M. , Addison Joseph B. , Widmeyer Joseph , Denvir James , Frisch Steven M. 
Published: August 2012

Abstract
Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound healing processes and the cancer stem cell-like compartment of tumors, including TGF-β-dependence, we investigated the role of a Grainyhead gene (GRHL2) in oncogenic EMT. Grainyhead was specifically down-regulated in the claudin-low subclass of mammary tumors and in the basal-B subclass of breast cancer cell lines. Functionally, GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis-sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by its suppression of ZEB1 expression, by direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription, and up-regulated mir200b/c as well as the TGF-β receptor antagonist, BMP2. The expression of GRHL2 in the breast cancer cell line MDA-MB-231 triggered a mesenchymal-to-epithelial transition and sensitized the cells to anoikis. These results indicate that GRHL2 is a suppressor of the oncogenic EMT, and provide a novel molecular focus for the wound-healing/oncogenic EMT relationship.
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 3436. doi:1538-7445.AM2012-3436
Abstract 3492: γ-secretase inhibitor PF-03084014 diminishes the tumor-initiating cells and demonstrates synergy with docetaxel in breast cancer xenograft models
Authors: Zhang Cathy C. , Yan Zhengming , Zong Qing , Fang Douglas , Painter Cory , Zhang Qin , Pavlicek Adam , Lira Maruja E , John-Baptiste Annette , Christensen James 
Published: August 2012

Abstract
Notch signaling is known to be a survival pathway for tumor-initiating cells. In this report, we demonstrate that the γ-secretase inhibitor PF-03084014 significantly enhances the antitumor activity of docetaxel in multiple xenograft models of triple-negative breast cancer. Mechanistic evaluation revealed that PF-03084014 perturbs the Notch signaling pathway and suppresses the function of tumor initiating cells (TIC). In MDA-MB-231Luc model, treatment of docetaxel led to a significant increase of CD133+/CD44+ and ALDH+ subpopulations by FACS analysis. In combination with PF-03084014, these two unique cell subpopulations were significantly diminished. Correspondingly, the functional analyses by tumor re-implant and mammosphere-forming efficiency assays revealed that docetaxel-therapy promoted the tumor initiating capability of the remaining cells, in which an increased stem cell property and Notch pathway activation were observed through gene signature changes. In contrast, PF-03084014 co-treatment with docetaxel substantially hampered the self-renewal ability of these cells. Notch target gene analysis demonstrated the biological relevance of PF-03084014-induced activity. To characterize the function of CD133+/CD44+ subpopulation, MDA-MB-231Luc tumors were de-bulked by the treatment with docetaxel. Subsequently, the CD133+/CD44+ and CD133-/CD44- subpopulatons were isolated and re-implanted in SCID-bg mice using a limiting dilution approach. The results showed that CD133+/CD44+ cells gave rise to tumors with a 100 % take rate (10/10), whereas CD133-/CD44- cells were not tumorgenic (0/10). In addition, CD133+/CD44+ cells exhibited much higher tumorigenicity compared with the respective adherent parental cell line. PF-03084014 treatment caused a significant delay of CD133+/CD44+ tumor growth. The ability of PF-03084014 to suppress TICs was also observed in other breast cancer xenografts, including patient derived models. This data suggests that anti-TIC is one of the contributing mechanisms for the synergistic activities of PF-03084014 in combination with docetaxel. Our work provides potential therapeutic opportunities for PF-03084014 to improve conventional cytotoxic therapy by inhibiting Notch signaling in tumor-initiating cells and other bulk tumor 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 3492. doi:1538-7445.AM2012-3492
Abstract 3500: T cells redirected against HER2 for the adoptive immunotherapy for HER2-positive osteosarcoma
Authors: Ahmed Nabil , Brawley Vita , Diouf Oumar , Anderson Peter , Hicks John , Wang Lisa , Dotti Gianpietro , Wels Winfried , Liu Hao , Gee Adrian , Rooney Cliona , Brenner Malcolm , Heslop Helen , Gottschalk Stephen 
Published: August 2012

Abstract
INTRODUCTION: The prognosis for patients with advanced osteosarcoma (OS) has not improved over the last two decades. Hence novel biologically-based therapies, such as immunotherapy, are needed for these patients. We have shown in preclinical studies that T cells, genetically modified with a HER2-specific chimeric antigen receptor (CAR; HER2-CAR T cells), kill HER2+ OS cells ex vivo and induce regression of HER2+ OS xenografts in animal models. Based on these findings we developed a Phase I/II clinical study with HER2-CAR T cells in patients with metastatic and/or recurrent OS. METHODS: The primary objective of this clinical trial is to determine the safety of escalating doses of HER2-CAR T cells in patients with advanced HER2+ OS. The secondary objective is to determine the expansion, persistence and anti-tumor effects of infused HER2-CAR T cells. RESULTS: 43 (78%) out of 55 screened OS patients had HER2+ tumors. Twenty one HER2-CAR T-cell lines have been generated to date by retroviral transduction. Median HER2-CAR expression was 67.4% (range 50.7-85.6%) and HER2-CAR T cells killed HER2+ OS cells in contrast to non-transduced T cells (p &lt;0.0001). The median CD4+:CD8+ T-cell ratio was 1:1.3, and T-cell products contained naïve (CD45RA+; median: 11.8%; range 2.4-33.2%), effector memory (CD45RO+/CCR7-/CD62L-; median: 29.3%; range: 7.8-67.5%), and central memory T cells (CD45RO+/CD62L+; median 55.9%; range: 21.9-87.9%). Nine patients have been infused so far at HER2-CAR T-cell doses between 104/m2 to 1x106/m2. Infusions were well tolerated without systemic side effects, and no increase of proinflammatory cytokines (IL-2, IFN-γ, GM-CSF, TNF-α) was observed in the patients’ plasma post infusion. HER2-CAR T cells were detectable for up to 3 months post infusion. CONCLUSION: HER2-CAR T cells have shown promising antitumor activity in preclinical OS animal models. We are currently evaluating the safety and efficacy of HER2-CAR T cells in a Phase I/II clinical study. Initial safety data at low T-cell dose levels are encouraging, warranting further active exploration of HER2-CAR T-cell based therapies for OS and other HER2+ malignancies.
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 3500. doi:1538-7445.AM2012-3500
Abstract 3539: Anti-CSF-1R antibodies reduce tumor-associated macrophages and inhibit tumor growth in preclinical models
Authors: Doody Jacqueline , Mathew Sneha , Wu Lan , Li Yanxia , Wang Ying , Persaud Kris , Burtrum Douglas , Balderes Paul , Surguladze David , Haurum John , Ludwig Dale 
Published: August 2012

Abstract
In cancer, increased infiltration of macrophages within and surrounding the tumor mass correlates with increased tumor invasiveness and growth. In addition, presence of tumor-associated macrophages (TAMs) has been shown to correlate with poor prognosis, particularly in breast, prostate, ovarian and cervical cancer. TAM proliferation, differentiation and survival is dependent on Colony Stimulating Factor - 1 Receptor (CSF-1R) activation, a type III integral membrane tyrosine kinase receptor selectively expressed on cells of the mononuclear phagocyte lineage. Given that TAMs enhance tumor growth and that activation of the CSF-1R pathway is required for TAM function, an antibody against mouse CSF-1R was generated for proof-of-principle studies. CS7, a monoclonal anti-mouse CSF-1R antibody inhibited both CSF-1 and IL-34 binding to mouse CSF-1R, leading to inactivation of the receptor and downstream signaling molecules. In addition, CS7 prevented monocyte proliferation and macrophage differentiation with IC50s of 0.1 nM and 0.75 nM, respectively. In murine models of breast cancer using CSF-1-secreting MDA-MB-231, Hcc1954, 4T1 or EMT6 tumor cells, CS7 treatment led to a marked reduction in TAMs and an associated decrease in tumor growth. In contrast, breast tumor xenografts with CSF-1 non-secreting breast tumor cell lines JimT1 and MCF-7 had limited or no decrease in tumor volume following CS7 treatment. In prostate models, DU145 tumor cell line xenografts (CSF-1-secreting) but not PC3 (CSF-1 non-secreting) tumor growth was inhibited by CS7, recaptitulating the results seen with breast xenografts. Thus, in breast and prostate preclinical models, CSF-1 secretion by tumor cells is a prerequisite for sensitivity to anti-CSF-1R treatment. Taken together, targeting CSF-1R with a monoclonal antibody inhibits CSF-1R signaling via CSF-1 and IL-34, prevents monocytic to macrophage differentiation, and reduces tumor volume in preclinical models, validating CSF-1R as a target for therapeutic application in 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 3539. doi:1538-7445.AM2012-3539
Abstract 3665: An EMT gene expression diagnostic predicts resistance to EGFR and MEK-targeted therapies in cell lines and patients
Authors: Eddy Sean F. , Williams Paul , Tomilo Mark , Sadis Seth , Wyngaard Peter , Vo Lien , Oades Kahuku , Kim Hyunsoo , Wang Yipeng , Lee Byung-In , Monforte Joseph , Rhodes Daniel 
Published: August 2012

Abstract
The epithelial to mesenchymal transition (EMT) in cancer cells results in the acquisition of metastatic properties and may contribute to chemoresistance. Several studies have shown that transition to a mesenchymal phenotype leads to decreased dependence on EGFR-RAS signaling and insensitivity to EGFR inhibitors. To better understand the importance of EMT as a general predictor of drug response, we defined an EMT gene signature derived from a meta-analysis of differential gene expression signatures representing genes up-regulated following transfection of breast cell lines with various EMT regulators (Taube et al., 2010 Proc Natl Acad Sci USA 107:15449-54). We then determined the expression of the EMT signature across cell line panels and determined whether it predicted sensitivity or resistance to various targeted therapies. Consistent with previous results, expression of EMT signature was significantly associated with resistance to an EGFR inhibitor, lapatinib. Similarly, the EMT signature also predicted resistance to PQIP (IGF1R), GSK1120212 (MEK), GSK690693 (AKT), and perifosine (AKT/PI3K), suggesting that EMT may be a common resistance mechanism to a number of drugs that target growth factor signaling. As more of these targeted agents are entering clinical trials, the ability to characterize the signature may have important implications for drug development. To study the relevance of the EMT signature in clinical tumors, we compared the signature to a collection of tumor co-expression patterns, known as OncoScore modules, which were defined from 40,000+ tumor microarray experiments. Notably, the EMT signature was significantly associated with a major tumor co-expression pattern representing mesenchymal and/or stromal phenotype observed in almost all major solid tumor types. In retrospective microarray scoring analyses of key clinical datasets, the mesenchymal/stromal module predicted resistance to cetuximab. This finding was validated with an independent cohort of colorectal cancer patients treated with cetuximab using the Oncoscore Colon diagnostic. Oncoscore Colon is a qPCR test optimized for formalin-fixed paraffin-embedded tissue that measures the twelve key colon cancer transcriptional modules, including the mesenchymal module. Because the mesenchymal/stromal module monitors a fundamental phenotype of cancer cells important for drug response, this validated qPCR test has broad application to companion diagnostics development and personalized medicine.
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 3665. doi:1538-7445.AM2012-3665