bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2793: A hypermethylated phenotype in anaplastic oligodendroglial brain tumors is a better predictor of survival than MGMT methylation in the EORTC 26951 study
Authors: van den Bent Martin , Gravendeel Lonneke , Gorlia Thierry , Kros Johan M. , Wesseling Pieter , Teepen Johannes , Idbaih Ahmed , Sanson Marc , French Pim 
Published: June 2012

Abstract
We have performed methylation profiling (Illumina Human Methylation 27 beadchip) on 69 anaplastic oligodendrogliomas (AOD) or anaplastic mixed oligoastrocytomas (MOA) and one non-diseased normal brain. Fifty-two of these samples were treated as part of the EORTC 26951 study, the primary objective of which was to compare the overall survival (OS) of patients with AOD or MOA treated with radiotherapy (59.4 Gy) vs. ± PCV chemotherapy. Remaining samples were also AOD or MOA and received similar treatment paradigms. Unsupervised clustering using hierarchical ordered partitioning and collapsing hybrid (Hopach) was performed using all or the 10,000, 5,000, 2,000, 1,000, 500, 200 or 100 most variably methylated CpG loci. In all analyses, we identified two main clusters that were highly stable (determined by Fuzzy clustering). In general, these clusters could be separated by predominantly methylated vs. unmethylated CpG loci. Survival (as determined from the date of resection) in the “hypermethylated” subgroup was markedly better than the survival of the unmethylated subgroup (5. 62 vs. 1.24 years, P&lt;0.0001). In fact, methylation profiling was able to better separate long vs. short survivors than histology, MGMT promoter methylation status (as determined by MLPA), 1p/19q LOH (as determined by FISH) or IDH1 mutation status. Methylation phenotype remained an independent prognostic marker in a multivariate analysis that includes diagnosis, age, sex, 1p19q LOH and IDH1 mutation status. We validated our results on methylation profiling data from the cancer genome atlas (TCGA) by assigning TCGA samples to one of the molecular clusters identified in our dataset. 14/80 and 66/80 samples of were assigned to the “hypermethylated” and “unmethylated” cluster respectively. Similar to the initial “test” dataset, survival between the hypermethylated and unmethylated subgroups were significantly different (2.87 vs. 1.02 years, P&lt;0.0001).
In conclusion, methylation profiling has identified two main subgroups of oligodendroglial brain tumors. These methylation subgroups correlate better with survival than histology, MGMT promoter methylation, 1p19q LOH and IDH1 mutation status. We are currently integrating methylation data with expression data.
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 2793. doi:10.1158/1538-7445.AM2011-2793
Abstract 28: Resequence-analysis of 166kb KITLG region in eamilial testicular germ cell tumors
Authors: Chung Charles C. , Yeager Meredith , Boland Joseph , Greene Mark , Chanock Stephen , Kratz Christian 
Published: June 2012

Abstract
Recent genome-wide association studies (GWAS) have identified multiple loci associated with testicular germ cell tumor (TGCT) risk, particularly in KITLG on chromosome 12q22, which has the strongest per-allele odds ratio in cancer GWAS to date. KITLG, also known as stem cell factor or Steel, encodes the ligand for the membrane receptor tyrosine kinase, c-KIT. It is notable that mutations in the KIT/KITLG system have been implicated in both testicular cancer development and infertility, both of which are established TGCT risk factors. Therefore, a comprehensive cataloguing of variants around the region is essential for further functional studies. We defined a 166kbps region (chromosome 12: 87371132-87537273) around KITLG, based on linkage disequilibrium patterns and tag analysis using HapMap III CEU and the 1000 genome CEU low-coverage pilot data (July 2010 release). No obvious recombination hotspot was observed within a 1Mb region centered on KITLG. Our study sample set included 10 parent-son trios, of which 6 trios contained 2 familial TGCT cases, 51 familial TGCT cases and 36 sporadic bilateral cases, totaling 117 individuals, all from the National Cancer Institute's Familial Testicular Cancer Study (FTCS). We have catalogued common and rare KITLG variants using deep coverage in next-generation sequencing and also identified haplotypes possibly enriched in familial cases in contrast to normal controls. These study results will facilitate further functional elucidation of TGCT susceptibility loci within this genomic region.
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 28. doi:10.1158/1538-7445.AM2011-28
Abstract 2801: Fueling immunity: The role of Myc in metabolic reprogramming of activated T cells
Authors: Wang Ruoning , Dillon Christopher , Green Douglas 
Published: June 2012

Abstract
One of the fundamental problems in animal cells is the coordination of the metabolic program with cell proliferation-associated bioenergetic demand. Primary T lymphocytes rapidly switch from a quiescent phase to a rapid-proliferation phase one day after antigen stimulation. To meet the bioenergetic and biosynthetic demand for this burst of proliferation, T cells rapidly reprogram their metabolic pathways from fatty acid beta-oxidation and glucose aerobic respiration to glycolysis (converting glucose to lactate) and glutaminolysis (converting glutamine to metabolites of the TCA cycle). This is reminiscent of tumor-associated metabolic reprogramming in many ways. Recent work has indicated that oncogenic signaling can reform tumor metabolic programs by targeting relatively few key metabolic genes. However, we found that global regulation of the metabolic gene transcriptome precedes the switch of T cell metabolic activities. In silico analysis of DNA-binding motifs associated with the metabolic gene expression profile revealed HIF1a, c-Myc and p53 as three of the top-ranked candidate transcription factors responsible for T cell metabolic reprogramming. Consistent with this, HIF1a, c-Myc and p53 are each highly induced in primary T cells upon antigen stimulation and have been implicated in the regulation of tumor metabolism. However, while germline deletion of p53 and acute deletion of HIF1a showed no defects in metabolic reprogramming upon antigen stimulation, acute deletion of c-Myc in mature T lymphocytes profoundly reduced antigen-stimulated glycolysis and glutamine oxidation in primary T cells. In addition, c-Myc deletion significantly compromised T cell growth and T cell proliferation after antigen stimulation. Finally, we found that many of the key metabolic genes involved in glycolysis and glutamine oxidation are regulated in a c-Myc-dependent manner. Our results further suggest a novel c-Myc dependent metabolic pathway linking glutamine oxidation to the biosynthesis of polyamines, which is a group of metabolites essential for cell proliferation. Our studies clearly demonstrate that primary T lymphocytes drive a c-Myc-dependent metabolic reprogramming upon antigen stimulation, which may represent a general mechanism of the metabolic reprogramming under both pathological and physiological conditions.
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 2801. doi:10.1158/1538-7445.AM2011-2801
Abstract 2837: Adiponectin knockout enhances intestinal carcinogenesis in Min and wild-type mice
Authors: Mutoh Michihiro , Teraoka Naoya , Takasu Shinji , Takahashi Mami , Onuma Kunishige , Kubota Naoto , Kadowaki Takashi , Wakabayashi Keiji , Nakagama Hitoshi 
Published: June 2012

Abstract
Obesity-associated cancers, including colon cancer, are increasing in Western countries. It has been demonstrated that increased amounts of visceral fat and decreased levels of plasma adiponectin (APN) are associated with development of human colorectal cancer. Thus, we here investigated the function of APN in intestinal carcinogenesis. Male APN+/+, APN+/- or APN-/- C57BL/6J mice were injected with azoxymethane (AOM) once a week for 6 weeks, which led to the development of intestinal tumors. C57BL/6J mice with each genotype were sacrificed at the age of 55 weeks, and the number and size of colorectal tumors were examined by pathological study. Furthermore, these strains of mice were also crossed with Min mice (C57BL/6J background) to assess the effects of APN on intestinal polyp formation. At the age of 9 and 12 weeks, Min mice each with the APN genotype were sacrificed, and the number and size of intestinal polyps were examined by pathological study. Levels of adipocytokine and phosphorylation of AMPK were also evaluated to clarify the effect of APN on intestinal tumor development. The incidence of AOM-induced tumors was 40% of APN+/+, 50% of APN+/- and 71% (p&lt;0.05) of male APN-/- C57BL/6J mice, respectively. Multiplicities of AOM-induced tumors in each genotype were 0.5±0.7, 0.6±0.7 and 1.1±1.0 (p&lt;0.05), respectively. The total number of intestinal polyps developed in 9-week-old male APN+/- Min and APN-/-Min mice increased 2.4- and 3.2-fold compared with those in APN+/+Min mice, respectively, and was further enhanced at 12 weeks of age, being 3.2- and 3.4-fold, respectively. Studies with female mice gave similar results. Phosphorylation levels of AMPK in intestinal epithelial cells were decreased in APN-/- mice compared with APN+/+ mice. Among serum adipocytokines, levels of serum Pai-1 increased in APN-/- C57BL/6J mice and APN-/-Min mice with AOM injection. Activation of AMPK by metformin treatment suppressed Pai-1 expression in Min mice. AOM-induced colorectal aberrant crypt foci in APN-/- C57BL/6J mice were decreased by a Pai-1 blocker. In conclusion, APN-deficient mice developed more intestinal tumors. Decreased phosphorylation of AMPK and increased levels of Pai-1 were observed in APN-deficient mice compared with wild-type mice. APN and its receptors might be good targets for developing colorectal cancer chemopreventive agents.
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 2837. doi:10.1158/1538-7445.AM2011-2837
Abstract 2855: The codon 72 polymorphism of p53 influences the transcription of genes involved in immunity and inflammation
Authors: Frank Amanda , Hollstein Monica , Murphy Maureen E. 
Published: June 2012

Abstract
A common polymorphism at codon 72 in the p53 tumor suppressor protein encodes either proline (P72) or arginine (R72). Several groups have reported that in engineered cell lines this polymorphism influences p53's transcriptional, growth arrest, and apoptotic functions. However, the impact of this polymorphism within the context of a living organism has never been examined. In efforts to understand the biological consequences of the p53 codon 72 polymorphism in a living organism, we generated P72 and R72 mice in the background of the Humanized p53 knock-in (Hupki) mouse. In Hupki mice that are extensively back-crossed into a C57Bl/6 background, we find that there are consistent tissue-specific differences in apoptotic function between the P72 and R72 variants. Within the thymus, we find that the P72 variant is associated with increased apoptosis following gamma radiation. Micro-array analysis indicates that a small subset of genes show increased transactivation in thymocytes from P72 mice compared to R72. These genes include caspase 4/11, which mediates the processing of caspase 1. Interestingly, several of these genes are also regulated by NF-kB, and play roles in immunity and inflammation. Mechanistically we show that p53 interacts with the p65 Rel A subunit of NF-kB, and further that the P72 variant of p53 interacts significantly better than R72. These data indicate that the codon 72 polymorphism affects the ability of p53 to interact with NF-kB and to cooperate in the transactivation of genes involved in immunity and inflammation.
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 2855. doi:10.1158/1538-7445.AM2011-2855
Abstract 2862: Bioengineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis
Authors: Tazawa Hiroshi , Yano Shuya , Yoshida Ryosuke , Urata Yasuo , Fujiwara Toshiyoshi 
Published: June 2012

Abstract
Autophagy is known to have a cytoprotective role under various cellular stresses, such as deprivation of nutrients, hypoxia and interruption of growth signaling. In contrast, autophagy also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Recent accumulating evidences have suggested the implication of autophagy on the oncolytic adenovirus-mediated cell death in human cancer cells. However, the molecular mechanism underlying oncolytic adenovirus-mediated autophagic cell death remains unclear. We previously generated a genetically engineered oncolytic adenovirus (Telomelysin®: OBP-301) that replicates and induces autophagic cell death against human cancer cells in a telomerase-dependent manner. As microRNA (miRNA), a post-transcriptional regulator of gene expression, has been recently shown to regulate diverse cell fates including autophagy, we hypothesized that OBP-301 infection induces autophagic cell death through miRNA modulation in human cancer cells. In this study, we attempted the role of miRNA on the OBP-301-mediated autophagic cell death in human cancer cells. We used 3 human cancer cell lines (H1299, A549 and T.Tn), that showed different sensitivities to OBP-301. OBP-301 infection upregulated miR-7 expression in OBP-301-sensitive human cancer cell lines (H1299 and A549), but not OBP-301-resistant human cancer cell line (T.Tn). Expression levels of miR-7 upregulated after OBP-301 infection was significantly associated with OBP-301-mediated cytopathic activity and autophagic cell death, which was confirmed by western blot for autophagy-related proteins (LC3-I/II, Atg5 and p62). We also revealed that OBP-301-mediated miR-7 upregulation mainly depended on enhanced expression of the E2F1 protein after OBP-301 infection. Furthermore, ectopic expression of miR-7 in human cancer cell lines suppressed cell viability and subsequently induced autophagy through inhibition of epidermal growth factor receptor (EGFR) expression. OBP-301 infection efficiently suppressed EGFR expression, which was significantly associated with miR-7 upregulation and cytopathic activity, in human cancer cell lines. Our results suggest that oncolytic adenovirus OBP-301 induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy.
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 2862. doi:10.1158/1538-7445.AM2011-2862
Abstract 2866: Targeting autophagy in pancreatic cancer
Authors: Ustach Carolyn V. , Bisanz Kristen , Von Hoff Daniel D. , Xu Eric , Han Haiyong 
Published: June 2012

Abstract
Autophagy is a cell survival pathway that has been shown to be activated in a variety of cancers including pancreatic cancer. It has been suggested that cancer cells activate autophagy to survive microenvironmental stresses such as depletion of nutrients, hypoxia and chemotherapeutic agents. Studies have shown that inhibition of autophagy can sensitize cancer cells to the treatment of therapeutic agents. Chloroquine (CQ) is a well established pharmacological inhibitor of autophagy and has been shown to enhance the sensitivity of cancer cells to treatment of cytotoxic agents. Dexamethasone (DEX), a synthetic gluococorticoid, which has been reported to sensitize pancreatic cancer cells to the treatment of gemcitabine (GEM) and carboplatin, is known to induce autophagy. In addition, activation of glucocorticoid receptor (GR) by DEX inhibits NF-kB and AP-1, two activators of survival pathways in many tumors. Whether DEX increases the cytotoxic effects of GEM through autophagy, NF-kB signaling, or a combo of both is unclear. Our preliminary studies show that DEX dramatically enhances the anti-tumor activity of CQ, indicating that the inhibition of autophagy may increase cell sensitivity to drug treatment. Therefore, we hypothesize that a combination pretreatment with CQ and DEX will significantly enhance the anti-tumor activity of GEM in pancreatic cancer, and that such enhancement in GEM activity is induced by the synergistic inhibition of autophagy by CQ and DEX. In vitro cell growth assay results showed that addition of CQ and DEX significantly increase the antitumor activity of GEM in MIA PaCa-2 and SU.86.86 pancreatic cancer cells. Interestingly, combination treatment of DEX+GEM or CQ+GEM did not show significant synergistic effect. A correlation between autophagy inhibition and cell death was evident when levels of LC3B-II protein, a common indicator of autophagy induction, were compared in cells exposed to single or combination drug treatments. In MIA PaCa-2 cells, CQ+DEX with 100nM GEM reduced LC3B-II levels by at least 50%. Animal studies are underway to determine the efficacy of the triple drug combination in vivo. Our results indicate pancreatic cells use autophagy as a cell survival mechanism in response to gemcitabine, and the drug combination dexamethasone and chloroquine are able to inhibit authophagy, thus rendering the pancreatic cancer cells more sensitive to gemcitabine.
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 2866. doi:10.1158/1538-7445.AM2011-2866
Abstract 2876: A novel multi-parametric assay of cell death pathways: Autophagy, apoptosis, and necrosis
Authors: Shen Dee , Chan Eric , Pande Praveen , Patton Wayne F. 
Published: June 2012

Abstract
Cell death can be classified into a number of types including apoptotic, autophagic, necrotic and others. The hallmarks of apoptotic cell death include exposure of phosphatidyl serine on the extracellular face of the plasma membrane, activation of caspases, disruption of mitochondrial membrane potential, cell shrinkage, DNA fragmentation and DNA condensation. Necrotic cell death is characterized by cell swelling, as well as destruction of the plasma membrane and subcellular organelles, without nuclear fragmentation and condensation. Autophagic cell death is a degradative process involving sequestration of cellular components in double-membrane vesicles that fuse with lysosomes to form the autophagolysosomes. Autophagy is a survival strategy in situations of stress, but can also lead to non-apoptotic cell death. Due to the overall complexity of the cited death pathways, a sensitive assay capable of distinguishing between autophagy, apoptosis and necrosis is fundamental to further understanding of these pathophysiological processes. Thus, a three-parameter cell-based assay was developed utilizing a green-emitting fluorophore to highlight the various vacuolar components of the autophagy pathway, a violet-excitable fluorophore conjugate of annexin V to measure phosphatidyl serine exposure in early stage apoptosis, and a cell-impermeable red fluorescent DNA intercalation dye to measure membrane disintegration in late-stage apoptosis/necrosis. The assay was validated using a range of conditions known to modulate autophagy, apoptosis and necrosis pathways. The assay provides a rapid, information-rich read-out of the various cell death pathways by fluorescence microscopy and flow cytometry and should facilitate better drug activity profiling and clearer kinetic analysis of these fundamental processes in living cells.
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 2876. doi:10.1158/1538-7445.AM2011-2876
Abstract 2878: A sensitive cell signaling assay for low level activation of endogenous receptors – a comparison of AlphaScreen® SureFire® and TR-FRET assays
Authors: Hurt Stephen , Titus David 
Published: June 2012

Abstract
Two closely related proteins, ERK1 and ERK2, belong to a widely conserved family of serine/threonine protein kinases whose activities are regulated by phosphorylation. These kinases are components of signal transduction pathways which control critical cellular processes such as growth, differentiation, metabolism and apoptosis. In addition to normal cellular processes, these pathways have been associated with signaling in many cancers. Phosphorylation of ERK 1/2 has been shown to be mediated by signal transduction pathways which are activated by ligand binding to both receptor tyrosine kinase receptors (RTKs) and G protein-coupled receptors (GPCRs). The focus of cell signaling studies is increasingly shifting to endogenous cell surface receptors rather than recombinant, over-expressed receptors. The hope is that these model systems will have greater biological relevance, more closely reflecting the physiology of the organism studied. In such studies the sensitivity of the assay platform becomes critical for success, especially when the endogenous receptors are activated at low levels. Several technologies have been used to quantitate relative levels of protein phosphorylation, including western blot, time-resolved fluorescence resonance energy transfer (TR-FRET), and AlphaScreen® SureFire® assays. AlphaScreen® SureFire® assays are homogenous, bead-based assays designed to measure endogenous levels of intracellular phosphorylated proteins. Here we describe the performance of the AlphaScreen® SureFire® p-ERK 1/2 assay compared to that of a TR-FRET assay. For this study we used two different cell lines. The first was CHO-K1 cells stably transfected with the human somatostatin sst5 GPCR, which is stimulated by its natural ligand somatostatin-28. The second was wild-type HEK 293 cells, which express endogenous receptors for epidermal growth factor (an RTK), and endogenous GPCRs activated by acetylcholine and ATP. In general, the AlphaScreen® SureFire® assay gave higher S/B ratios than the TR-FRET assay in all conditions tested, which in turn can have a significant impact on the assay robustness. In situations that gave wide response windows, such as stimulation of the CHO over-expressed somatostatin receptor or the HEK 293 endogenous EGF receptor, both assay kits yielded excellent results. However, the HEK 293 endogenous GPCRs for acetylcholine and ATP are coupled to a lower production of p-ERK, and in those cases the AlphaScreen® SureFire® assay proved to be much more robust, with significantly higher overall signal levels and S/B ratios.
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 2878. doi:10.1158/1538-7445.AM2011-2878