bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4066: Early assessment of the XL184 treatment by Diffusion-Weighted MRI in metastatic prostate cancer to the bone murine model
Authors: Brisset Jean-Christophe , Hoff Benjamin , Galban Stefanie , Lemasson Benjamin , Rehemtulla Alnawaz , Galban Craig , Ross Brian Dale 
Published: August 2012

Abstract
Ninety percent of patients with advanced prostate cancer develop metastases to the bone1. At present, there is no definitive means for assessing response to therapy, with RECIST identifying tumors in the bone as “unmeasureable”. Cabozantinib (XL184) is an oral small molecular pan-tyrosine kinase inhibitor of primarily MET and vascular endothelial growth factor receptor 2 (VEGFR2). MET is known to play key roles in cellular proliferation, migration and invasion, which contribute to the survival and metastasis of cancer cells. XL184 is already in Phase 2 trials to evaluate the therapeutic benefit on castration-resistant prostate cancer metastatic to the bone. Diffusion-weighted MRI (DW-MRI) is highly sensitive to microscopic changes in tumor tissue. Our goal was to evaluate DW-MRI for detection and quantification of changes in tumor tissue following one-week XL184 treatment. MR experiments were performed on a 9.4T MRI. Human prostate cancer (PC3) cells were implanted by direct intra-tibial injection into male SCID mice, which serves as a model for prostate bone metastases2. Upon measuring tumor volume of ∼10mm3 on anatomical scans, mice were distributed into 2 groups: XL184 at 30 mg/kg (N=7) and vehicle (N=5). Treatments were delivered by oral gavage once a day for 7 days. DW-MRI was performed at days 0 (pre-treatment), 1, 4, 7, 11, 14 and twice a week after. Apparent diffusion coefficient (ADC) maps were calculated analytically from DW-MR images acquired at b-value 120 and 1200 s/mm2. End point of the study was when tumor volume reached 5x the initial measure. Unpaired Student t-test was performed to compare MRI metrics. XL184 treated mice had smaller tumor volume growth rate than control mice. Significant differences in tumor volume were not observed until 14 days post-treatment initiation (p&lt;0.05). In contrast, significantly higher ADC values (p&lt;0.0.5) for the treated group compared to control were observed at day 7. These results demonstrate the use of DW-MRI as a early biomarker of tumor response to XL184 in a metastatic prostate cancer tumor model. DW-MRI may serve as a surrogate endpoint for assessing patient response to treatment in clinical trials. References: 1. Carlin BI et al. Cancer. 2000;88(12):2989-2994. 2. Lee KC et al. Cancer Res. 2007;67(8):3524-3528.
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 4066. doi:1538-7445.AM2012-4066
Abstract 4069: Determination of single cell surface protein expression using a tagless microfluidic method
Authors: Vellanki Sri HariKrishna , Smith Robin , Kumar Rajan , Wieder Robert 
Published: August 2012

Abstract
Tumors are often inaccessible to biopsy and fine needle aspirates are often the only source of cellular material from tumors either at diagnosis or during therapy for determination of pharmacodynamic response. The few cells that needle aspirates yield are not sufficient for more than visual diagnostic determination of malignancy or potential tumor category. Most processing would result in the loss of these cells and is impractical. A need exists for a different diagnostic tool that can obtain biologically relevant information from cells when only few are available without the need for processing them. We describe a method to detect the expression of a surface protein in single cells without prior labeling or manipulation using a microfluidic device. When the protein is expressed, it undergoes transient bond formation with a ligand immobilized on a patch as the cell is pumped through a microfluidic device, resulting in a specific decrease in the cell's velocity. We sterile sorted LM2 cells, a subline of MDA-MB-231 human breast cancer cells, with a unique lung metastatic capability, into fractions expressing none (P1), medium (P2) and high levels (P3) of interleukin13α2 receptor (IL13Rα2). We used variable chamber heights (25, 50, 75 μm), width 7 mM and 1%, 1.5%, 2.5% glycerol in buffer with variable flow rates. We were able to get specific flow retardation with reduction in mean velocity 15.1 % with shear rate 62.86 (s−1) and shear stress 0.63 (dynes/cm2) in the fraction expressing high levels (P3) of IL13Rα2 receptor compared to controls LM2 (P1), MDA-MB-231, MCF-7 cells. The detection of cells with high expression of the protein (P3) was 100% sensitive and 100% specific. Later we asked the following questions: can cells be reanalyzed after pumping through microfluidic device, can we indentify IL13Rα2 positive cells in mixture and whether specificity of flow retardation is due to antigen and antibody binding. The method is non-destructive and P3 cells can be collected for reanalysis and we got reduction in mean velocities in first and second run 9.7% and 10.0%. The system could identify P3 positive cells with mean velocity reduction 5.5% when mixed with MDA-MB-231 cells in 1:1 ratio and the interaction between the antigen/antibody is highly specific as the mean velocity reduction in P3 cells is 0.2%. Further needle aspirates from mice xenograft were able to detect cells expressing IL13Rα2 receptor. This method will have a potential impact in analyzing cancer cells when only few are available, such as the case with needle aspirates, when labeling and manipulation results in cell loss.
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 4069. doi:1538-7445.AM2012-4069
Abstract 4075: Aerosol azacytidine inhibits the orthotopic lung cancer in mice by its demethylation function but not cytotoxic effect
Authors: Qiu Xuan , Perez-Soler Roman , Zou Yiyu 
Published: August 2012

Abstract
Introduction: Silencing of key tumor suppressor genes by promoter hypermethylation plays an important role in lung cancer carcinogenesis. Reversing the hypermethylation in the early lung cancer cells adjacent to the airway surface may have a potential to inhibit lung cancer development. This study was to explore the therapeutic potential of aerosol administered demethylating agent azacytidine (Aza) for the treatment of bronchial epithelial premalignancy or lung cancer. Methods: The demethylation and gene reactivation functions of Aza administered by aerosol were detected by qPCR methylation array and western blotting assay in the tumor tissues from the orthotopic human non-small cell lung cancer (NSCLC) xenograft models in nude mice. The therapeutic efficacy and toxicity of the aerosol Aza were also evaluate in the same lung cancer models. An intravenous administered Aza with clinical equivalent dose and schedule was used as a control. Results: The aerosol Aza is an appropriate pharmaceutical inhalation formulation with about 80% of droplets size distributing between 0.1 to 5 micron. This aerodynamic size range ensures the aerosol droplets depositing in the lower airway. In animal studies, aerosol administration of Aza significantly prolonged the survival of nude mice with intratracheally inoculated human NSCLC tumors. The %-increased life span was 5- to 10-fold higher than that of a systemic treatment of Aza at a clinical equivalent dose. The aerosol treatment did not cause any detectable lung toxicity or myelosuppression (systemic toxicity of Aza), since the treatment dose was &gt;100-fold lower than the toxic dose. The lung tumors were resected after the aerosol Aza treatment and the methylation levels of the 24 promoters that drive the lung cancer related tumor suppressor genes (TSG) were detected. We found that aerosol Aza significantly reduced the methylation level in 9 of these 24 promoters. The dementhylating aerosol also resulted in the gene reactivation in the protein level of several tested genes. Conclusions: Aerosol administration of Aza has significant therapeutic advantages over the systemic Aza. It can be given at a non-cytotoxic dose, thus its main therapeutic efficacy is the demethylation function of Aza and the TSG reactivation. In our case, the therapeutic index of aerosol Aza is &gt;800-fold higher than that of IV Aza. The clinical trial of aerosol Aza is worth to be conducted. Acknowledgement: Supported by a NIH (NCI) grant 5R01CA154755-02
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 4075. doi:1538-7445.AM2012-4075
Abstract 4089: Identification of a DNA methylation marker to detect the presence of lymph node metastases of gastric cancers
Authors: Shigematsu Yasuyuki , Niwa Tohru , Yamashita Satoshi , Taniguchi Hirokazu , Kushima Ryoji , Katai Hitoshi , Ichinose Masao , Ushijima Toshikazu 
Published: August 2012

Abstract
Accurate detection of the presence of lymph node metastases of gastric cancers (GCs) is clinically important. However, current methods to detect it are unsatisfactory. As a marker, DNA methylation is advantageous because it is biologically and chemically stable and the DNA methylation profile is not disturbed by a small population of cells. Therefore, we focused on aberrant DNA methylation in GCs as a possible marker to detect the presence of lymph node metastases. We first performed genome-wide methylation analyses by Illumina Infinium HumanMethylation450 BeadChip array using three metastatic lymph nodes (MLNs) and three primary GCs without MLNs, and isolated 31 differentially methylated CpG sites. Then, using primary GCs with and without MLNs (screening set; 28 GCs with MLNs and 10 GCs without MLNs), their methylation levels were analyzed by quantitative PCR-based methods. Among the 31 regions, 10 regions showed higher methylation levels in GCs with MLNs than in GCs without MLNs (P &lt; 0.05). In further analysis of the 10 regions using another sample set (validation set; 129 GCs with MLNs and 20 GCs without MLNs), hypermethylation of a region (cg06436185) in GCs with MLNs was validated, and the presence of lymph node metastases was detected with sensitivity of 43% and specificity of 85%. These results indicated that the methylation status of the cg06436185 region is a good marker to detect the presence of lymph node metastases of GCs.
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 4089. doi:1538-7445.AM2012-4089
Abstract 4093: Investigating a role for menin and MLL-AF9 in suppressing C/EBPβ-mediated mixed lineage leukemia cell differentiation
Authors: Thiel Austin T. , Hua Xianxin 
Published: August 2012

Abstract
The Mixed Lineage Leukemia (MLL) gene forms chromosomal translocations with one of multiple partner genes, leading to the expression of MLL fusion proteins (MLL-FPs), which cause acute leukemias with particularly poor prognoses. MLL-FPs contain an N-terminal portion the MLL protein, which is responsible for MLL-FP recruitment to MLL target genes, through interactions with various proteins, including the MEN1 gene product menin. The ability of menin to recruit MLL-FPs to target genes is critical for leukemic transformation. A central hallmark of leukemia is oncogene-mediated suppression of differentiation. Many leukemic oncogenes, including Bcr-Abl and AML-ETO suppress differentiation through inhibiting the C/EBPα transcription factor, a driver of myeloid differentiation. However, a mechanism for MLL-FP-mediated inhibition of C/EBPα has not been reported. We have found that disruption of the MLL-AF9 pathway by acute depletion of its recruiting factor menin causes differentiation of MLL-AF9 leukemia cells in vivo. These results suggest that a major function of menin/MLL-AF9 is to maintain leukemia cells in a de-differentiated state. Further, cDNA microarray analysis of primary MLL-AF9 splenocytes with acute menin depletion showed induction of genes involved in hematopoietic differentiation, including transcriptional targets of C/EBPβ. These results suggest a mechanism for MLL-FP-mediated inhibition of C/EBPα and suppression of leukemic progenitor cell differentiation.
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 4093. doi:1538-7445.AM2012-4093
Abstract 4096: Correction of metabolically sensitive histone epigenetic marks mediates the drug sensitivity of MDA-MB-231 human breast cancer cells
Authors: Simpson Natalie E. , Pogribny Igor P. , Beland Frederick A. 
Published: August 2012

Abstract
Evidence is accumulating that epigenetic alterations are major determinants of breast cancer progression. In a previous study we demonstrated that specific patterns of histone modifications correlated with changes in histone modifying enzymes in human breast cancer cells. More importantly, these changes were metabolically sensitive and differed between cells with epithelial and mesenchymal phenotypes, suggesting that they can be used as diagnostic and prognostic epigenetic biomarkers for breast cancer progression. We have now investigated whether or not metabolic targeting of the epigenome may be used for the treatment of breast cancer. Exposure of breast cancer cells to Compound 968, an allosteric inhibitor of glutaminase (GLS1), which we demonstrated previously to increase global histone H4 lysine 16 acetylation levels in mesenchymal MDA-MB-231 cells versus epithelial T-47D cells, resulted in a marked inhibition of cancer cell growth, with the effects being more prominent in mesenchymal MDA-MB-231 cells than epithelial T-47D cells. The growth inhibitory effect of Compound 968 in MDA-MB-231 breast cancer cells was accompanied by modest changes in H4 lysine 16 acetylation and a decreased level of histone H4 lysine 20 trimethylation at the promoter of tumor suppressor genes (e.g., CDH1), with a concordant rise in expression of the transcriptionally silenced CDH1 gene. Although, Compound 968 did not restore fully CDH1 expression in MDA-MB-231 to the level observed in epithelial T-47D cells, the observed increase in expression may lead to formation of a less aggressive cancer phenotype in MDA-MB-231 cancer cells and increase their sensitivity to chemotherapeutic agents. Indeed, a combined treatment of Compound 968 and the conventional chemotherapeutic drug cisplatin substantially increased the sensitivity of MDA-MB-231 cells to cisplatin. These results indicate that correcting of cancer-related metabolic disturbances may be an effective method for the targeted treatment of the cellular epigenome in aggressive breast cancer and may be useful for improving of the clinical management of breast 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 4096. doi:1538-7445.AM2012-4096
Abstract 4098: COX-2 expression in human pancreatic cancer cells is associated with an epithelial phenotype
Authors: Freitas Gil S. , das Aditi , White Matthew , McConkey David 
Published: August 2012

Abstract
Epithelial to mesenchymal transition is a developmental pathway that has been shown to have a direct role in tumor progression and drug resistance. Increasing evidence suggests that EMT (and MET) leads to global changes in chromatin architecture that modifies expression of numerous genes. Interestingly, reports in the literature indicate a possible association between cyclooxygenase-2 (COX-2) expression and EMT. COX-2 is upregulated in response to inflammation, and is known to be overexpressed in multiple malignancies, including pancreatic cancer. As a critical mediator of prostaglandin production, COX-2 has proangiogenic properties associated with increased tumor growth and invasion, and is also thought to play a role in the carcinogenic process. In this study, we report that COX-2 expression is associated with an epithelial phenotype among a panel of human pancreatic cancer cells. Using chromatin immunoprecipitation (ChIP), we demonstrate increased acetylated H3 at the COX-2 promoter region in the epithelial cell lines versus mesenchymal cell lines. Treatment with a Type-I selective HDAC inhibitor SNDX-275 increased levels of acetylation at the COX-2 promoter region in mesenchymal cell lines and subsequently promoted COX-2 gene expression. Overall, these data point to an epigenetic suppression of COX-2 expression in mesenchymal pancreatic cancer cells that can be reversed by Type-I HDAC inhibitors. Our results suggest that COX2 inhibitors will preferentially target “epithelial” pancreatic cancers and that combinations of Cox2 and HDAC inhibitors may display increased anti-tumor activity.
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 4098. doi:1538-7445.AM2012-4098
Abstract 4099: Utilization of methylation levels across the H19 and IGF2 genes as a predictive marker for various types of cancer
Authors: Poulin Matthew L. , Meyer Ann , Crawford Neil , Lei Shi , Xu Jessica , Yan Liying 
Published: August 2012

Abstract
H19 and IGF2 are reciprocally imprinted genes found on chromosome 11. Epigenetic gene deregulation is increasingly shown to play a role in many types of cancer. Imprinted genes are especially susceptible to epigenetic regulatory changes because of silencing of one allele and the dependence on proper methylation for normal function. One of the goals in cancer research is to identify molecular markers that will predict the onset of specific cancers. The pattern of methylation across the IGF2 and H19 genes can be used to characterize the difference between normal and cancerous tissue as well as the difference between different tumor tissues. By developing methylation assays that can determine the levels of methylation for all of the CpG sites across these two genes, we can establish patterns that could be predictive in detecting the onset of specific cancer types. We have developed numerous methylation assays across the H19 and IGF2 genes and have determined the methylation levels of DNA isolated from breast, cervical, ovarian and colon cancers and their corresponding normal tissue DNAs. We show that there are unique patterns of methylation between normal and cancerous tissues, as well as distinct patterns across different types of cancers. The differences in methylation patterns between DNA isolated from tumor and normal adjacent tissue across four different tumor types in these genes indicates the critical influence of epigenetic regulation in this region on the progression of 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 4099. doi:1538-7445.AM2012-4099
Abstract 4105: Assessment of autophagosome formation in primary cells by lentiviral delivery of fluorescent protein-tagged LC3
Authors: Anderl Janet , Huryn-Selvar Karyn , Liu Haizhen , Su Kevin , Santos Mark , Hsu Matthew , Ma Jun , Kovelman Robert , Armstrong Lucas 
Published: August 2012

Abstract
Assessment of autophagosome formation has been greatly facilitated by monitoring redistribution of LC3-fluorescent protein fusions. The sensitivity of the technique and capability for real-time analysis of autophagosome formation are advantageous over detection of endogenous LC3 redistribution in many experimental settings. However, the necessity for transfection can be an impediment to analysis of autophagosome formation in difficult-to-transfect cells, particularly primary cultures. We have developed lentiviral vectors (employing 3rd generation technology for optimal biosafety) encoding monomeric TagGFP2 and TagRFP fused at the N-termini of wild-type LC3 and LC3G120A as tools for analysis of autophagy in a wide variety of cell types. In immortalized cell lines and in primary cells (HUVEC and human mesenchymal stem cells) transduced with the GFP- and RFP-LC3 lentiviruses, amino acid deprivation in the presence of a lysosome inhibitor induced redistribution of the fluorescence from a diffuse cytoplasmic pattern to a punctate distribution. Minimal background of punctae in fed cells was observed. 3-Methyladenine blocked the starvation-induced redistribution, and the G120A mutant did not undergo detectable redistribution upon amino acid deprivation. In addition, we demonstrate effectiveness of lentiviral GFP-LC3 in HUVECs by flow cytometry, in which the plasma membrane is selectively permeabilized such that free cytosolic fluorescent protein-tagged LC3 is released while autophagosome-bound LC3 fusion protein is retained. We anticipate that these lentiviral autophagy biosensors will facilitate analysis of autophagosome formation in physiologically relevant primary 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 4105. doi:1538-7445.AM2012-4105