bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 942: Protein kinase CK2 contributes to 1, 25-dihydroxyvitamin D3-mediated CYP24A1 gene expression in prostate cancer cells
Authors: Luo Wei , Karpf Adam R. , Chernov Mikhail Chernov , Johnson Candace , Trump Donald 
Published: June 2012

Abstract
The active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a major role in regulating calcium homeostasis and bone mineralization. 1,25(OH)2D3 also modulates cellular proliferation and differentiation in a variety of cell types through the activation of vitamin D receptor (VDR), by both genomic and nongenomic pathways. 1,25-(OH)2D3 has anti-tumor effects in several tumor models. 24-hydroxylase, encoded by the CYP24A1 gene, plays a key role in degrading 1,25(OH)2D3. Suppression of CYP24A1 function enhances the antitumor activity of vitamin D. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established the prostate cancer cell line PC3 stably transfected with CYP24A1 promoter driving luciferase expression and used this cell line to screen for compounds that inhibit CYP24A1 promoter activity, using a drug library. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz specifically inhibits CYP24A1 promoter activity induced by 1,25(OH)2D3 in prostate cancer DU145 and PC3 cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25(OH)2D3 induced CYP24A1 mRNA expression in PC3 cells. This inhibitory effect on CYP24A1 expression by CK2 siRNA is enhanced by the addition of TBBz. These results suggest that CK2 signaling contributes to 1,25(OH)2D3 mediated induction of CYP24A expression. This study provides among the first line of evidence that CK2 is linked to vitamin D metabolism. Future studies will elucidate the mechanism(s) underlying the mechanism by which CK2 regulates CYP24A1 expression. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25(OH)2D3, and highlight a novel strategy to facilitate the optimization of antitumor therapy of vitamin D.
This study was supported by NIH/NCI grants 5R01CA067267 and 5R01CA095045
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 942. doi:10.1158/1538-7445.AM2011-942
Abstract 98: Differential methylation of promoters in ductal adenocarcinoma and cancers of the ampulla vateri of the pancreas
Authors: Pilarsky Christian , Biewusch Katja , Heyne Marie , Grützmann Robert , Saeger Hans Detlev 
Published: June 2012

Abstract
Background: Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC neither a specific marker for early diagnosis nor a target protein for a new therapeutic approach have been identified so far. Determination of DNA methylation events is a promising technology for the early detection and classification of cancer. We were therefore interested to elucidate the significance of DNA methylation to distinct between ductal adenocarcinoma and cancers of the ampulla vateri (AVT) of the pancreas.
Methods: DNA isolation using the Qiamp mini kit and modification using the Zymo EZ DNA Methylation-Gold system was performed. Primers for methylation specific PCR (MSP) for RELN, ADAMTS8, SFRP1, BNIP3, ID4 and TFPI2 were selected from the literature and tested for their performance on bisulfite modified fully methylated human DNA. After successfully establishing the assays, DNA samples isolated from formalin fixed and paraffin embedded tissue from patients with diagnosed ductal adenocarcinoma (n = 14) and tumors of the ampulla vateri (n=7) were investigated. MSP was performed and the amount of produced fragment was scored semiquantitatively using agarose gelelectrophoresis.
Results: MSP analysis of the bisulfite modified DNA showed methylation differences in RELN (PDAC: 63%, AVT: 37%), ADAMTS8 (PDAC: 37%, AVT: 14%), BNIP3 (PDAC: 85%, AVT: 50%), SFRP1 (PDAC: 84%, AVT: 100%) and ID4 (PDAC: 93%, AVT: 62,5). Interestingly, for TFPI2 both tumors types showed nearly the same incidence of methylation events (PDAC: 86%; AVT: 87%).
Conclusion: Detection of DNA methylation is able to indentify differences between tumors of the pancreas. This might resemble crucial changes during tumor development, which are also reflected in gene expression and histopathologic appearance. For the establishment of a methylation-based discrimination of tumors further samples and promoters have to be tested.
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 98. doi:10.1158/1538-7445.AM2011-98
Abstract LB-106: Expression of stem cell biomarkers in benign breast tissue from patients with triple negative breast cancer
Authors: Atkinson Rachel L. , Yang Wei T. , Landis Melissa D. , Wong Helen , Creighton Chad , Hilsenbeck Susan G. , Lewis Michael T. , Woodward Wendy A. , Brewster Abenaa , Sahin Aysegul A. , Chang Jenny C. 
Published: June 2012

Abstract
Numerous studies suggest that breast cancers contain a subpopulation of cancer stem cells that are thought to maintain the heterogeneity and self-renewing potential of the tumor. In our previously published data, we had described a breast cancer stem cell signature comprised of 493 statistically significant differentially expressed genes, which were present in a tumorigenic subpopulation of cells. Cells from patient samples with the cell surface markers CD44+CD49f+CD133/2+ have been shown to have self-renewal and tumorigenic properties – characteristics of breast cancer stem cells. In this study, we investigated the benign tissue from 42 patients with breast cancer treated with mastectomy to examine the incidence CD44+CD49f+CD133/2+ positive cells. Benign tissue was obtained at a distant site, at least 5 cm from the primary tumor, and examined with hematoxylin-eosin by a breast pathologist (AS), only samples containing normal breast tissue with at least 60% epithelial content were selected. A significant increase in expression of CD44+CD49f+CD133/2+ by immunofluorescence was identified in the benign tissue associated with patients with triple negative (ER negative/PR negative/Her2 negative) disease (8 out of 8), compared with ER positive and Her2 positive tumors combined (5 out of 36), P&lt;0.001, Wilcoxon rank sum test. The definition of a positive score was more then 1% positive staining or negative for less then 1% triple positive cells, scoring approximately 1000 cells per sample. We further examined whether global RNA expression from these benign tissues correlated to our previously published tumorigenic microarray signature. We found that array data from benign tissue from patients with triple negative breast cancer was significantly correlated with our previously published tumorigenic signature (P=.01 two sided t test). Thus, these pathologically defined benign cells bearing cancer stem cell markers may be cells of origin for tumor development in triple negative breast cancer, and their presence in benign tissue (including tissue in some cases from the uninvolved contralateral breast) implies a systemic etiology to triple negative breast cancer. In conclusion, putative cancer stem cell markers are enriched in the benign breast tissue of women who have developed triple negative breast cancer, and their presence may represent a biomarker for increased breast cancer risk.
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 LB-106. doi:10.1158/1538-7445.AM2011-LB-106
Abstract LB-157: Overcoming T-regulatory effects towards developing a more effective immunotherapy targeting multiple myeloma
Authors: Chang Lung-Ji , Han Shuhong , Okada Starlyn , Patel Ekta , Yang Li-jun , Moreb Jan S. , Pircher Hanspeter , Perez Lia E. , Alsina Melissa 
Published: June 2012

Abstract
Recent progress in dendritic cell (DC) and T cell therapies has offered a new avenue in treating multiple myeloma (MM). We have reported that MM patients' DCs cannot effectively present MM antigens and, instead, preferrentially activate T regulatory cells (Tregs). Furthermore, the MM cells actively suppress patients' DC and T cell functions (Han et al. 2008 Mol Ther. 16, 269–279). Therefore, an effective immunotherapy must overcome immune tolerance to the cancer cells and effectively expand functional MM-specific effector cells. To obtain critical data about MM patient's immune status, a longitudinal study of Treg cells before and after treatments of twenty MM patients was conducted. Patients' bone marrow (BM) and peripheral blood (PB) specimens were collected in the first visit and the follow up visits during treatment. Treg cell populations were examined using antibodies against CD4, CD25, CD127 and Foxp3. At the same time, naïve versus memory phenotype was assessed using antibodies against CD45RA, CCR7 and CD27. Besides the above markers, the surface molecule KLRG1 reflecting T cell senescence and longivity was also detected by flow cytometry. Analysis of Tregs at different time points showed a clear trend of gradual increase in Treg population both in the BM and PB of the MM patients; compared with healthy donors, MM patients' Tregs expand more than two to three folds. Surface marker analysis suggests that the expanded Tregs are mostly memory effector cells, which coincides with a decrease in the ratio of naïve Tregs. Analysis of MM-specific T cell responses by examining effector cytokines and cytolytic activities against autologous tumor cells revealed that BM contained more cytotoxic T cells than did PB. Increased expansion of MM-specific immune effector cells in culture was observed when Treg activities were suppressed using various immune modulators. Further understanding of Treg-mediated cancer tolerance will be essential to develop clinically more effective immunotherapy towards improved survival of MM patients.
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 LB-157. doi:10.1158/1538-7445.AM2011-LB-157
Abstract LB-158: MEDI4736: Delivering effective blockade of immunosupression to enhance tumour rejection: Monoclonal antibody discovery and preclinical development
Authors: Stewart Ross A. , Morrow Michelle , Chodorge Matthieu , Marcus Danielle , Boyle Melanie , Mulgrew Kathy , Hammond Scott , Wang Suping , Alimzhanov Marat , Robbins Paul , Lanning Karen , Bedian Vahe , McCourt Matthew , Lo Mathew 
Published: June 2012

Abstract
Cancerous cells emerge within the body following accumulation of deleterious genetic mutations. These mutations alter the phenotype of a cancer cell marking it as distinct from the surrounding host; an immunological state termed “altered self”. These cells, like other non-self entities such as viruses and bacteria, are recognised by the immune system and marked for destruction, a process known as “immune surveillance”. B7-H1 expression by tumour cells is believed to aid tumours in evading detection and elimination by the immune system. B7-H1 functions in this respect via several alternative mechanisms including driving exhaustion and anergy of tumour infiltrating T lymphocytes, stimulating secretion of immune repressive cytokines into the tumour micro-environment, stimulating repressive regulatory T cell function and protecting B7-H1 expressing tumour cells from lysis by tumour cell specific cytotoxic T cells.
Using hybridoma technology and high throughput screening MedImmune has identified a series of fully human antibodies specific for human B7-H1. Further characterisation of these antibodies led to the identification of a single high affinity antibody, MEDI 4736, with the ability to relieve B7-H1 mediated suppression of T cell activation in vitro and to enhance sub-optimal T cell activation in a mixed lymphocyte reaction. In vitro testing shows that MEDI 4736 does not trigger non-specific cytokine release in whole blood, and is only able to activate T cells in the context of an active T cell receptor signal.
A surrogate anti-mouse B7-H1 antibody shows significant anti-tumour activity in a syngeneic model when dosed in combination with chemotherapy. Similarly MEDI 4736 is able to inhibit tumour growth in a novel in vivo xenograft model, via a mechanism that is dependent on the presence of tumour specific human T 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 LB-158. doi:10.1158/1538-7445.AM2011-LB-158
Abstract LB-224: Development of a novel breast cancer segregation panel assay for multiple genetic subtyping based on gene expression modules developed from Oncomine™
Authors: Oades Kahuku , Chattopadhyay Sukla , Kim Hyunsoo , Vo Lien , Telford David , Wang Yipeng , Lee Byung-in , Monforte Joseph , Vansant Gordon , Freshley John , Wyngaard Peter , Rhodes Daniel , Tomlins Scott 
Published: June 2012

Abstract
Breast cancer is a highly heterogeneous disease as evidenced by comprehensive genetic studies which have revealed multiple subtypes using gene expression profiling and cell lineage classifier analyses. Previous studies have characterized different subtypes including normal breast-like, luminal epithelial A, luminal epithelial B, Her 2 over-expression and basal type carcinoma. However, the genetic variation within breast cancer is far more diverse than these core subtypes, and it is necessary to fully characterize this diversity in order to move beyond simple prognosis and to specifically predict drug sensitivity.
In a review of global gene expression and SNP-based cytogenetic data of more than 5,000 breast cancer patients in the Oncomine™ database, we have been able to characterize approximately 30 different genetic variations that are shared by 1% or more of the breast cancer population. These core, independent variables reflect diverse elements of the disease at a molecular level including cell lineage, dysregulated core biological functions, factors of cell growth, and importantly, the tumor microenvironment. Further genetic subtypes are characterized within the various large and focal genomic amplifications, such as Her2 and Myc, as well as focal expression events present subpopulations of patients. In aggregate these genetic variables represent all of the major genetic factors that present within breast cancer.
Currently biomarker/diagnostic approaches have tended to be over-tailored to specific clinical questions and therefore have lacked broad applicability, with every diagnostic test requiring a custom gene set and tailored signature and in some cases, requiring separate validated assays using multiple technologies and consequent splitting of clinical samples. To overcome these limitations, we have developed a single, 96-gene qRT-PCR test for rapid breast cancer companion diagnostics development using FFPE tumor tissue. All 30 of the core variables or “modules” are represented by this test which reports on both gene expression and chromosomal amplification events. We demonstrate in this study that this single test, with its multiple modules, can report on standard histopathological parameters, such as ER, PR and Her2, and reproduce existing prognostic and predictive genomic signatures. Data will be presented on prediction of overall survival, neoadjuvant chemotherapy response, and in-vitro sensitivity to MEK and PI3K inhibitors.
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 LB-224. doi:10.1158/1538-7445.AM2011-LB-224
Abstract LB-236: Identifying novel kinase fusions via targeted DNA capture and next-generation sequencing
Authors: Chmielecki Juliann , Peifer Martin , Viale Agnes , Socci Nicolas , Jia Peilin , Zhao Zhongming , Thomas Roman , Pao William 
Published: June 2012

Abstract
Tyrosine kinase (TK) fusion proteins result from genomic rearrangements that juxtapose TK signaling domains with various upstream partners. Since tumor cells can become dependent upon the resultant constitutive kinase activity for tumorigenesis and survival, TK fusions serve as attractive targets for anti-cancer therapy. In the past, identification of TK fusions in cancers has been hindered by experimental techniques that lack sufficient sensitivity and throughput. To overcome these challenges, we developed a screen to systematically identify TK fusions in tumor DNA based upon observed conservation of genomic fusion breakpoints. The approach involves selective capture of regions upstream of GXGXXG kinase motifs where TK fusion breakpoints are likely to occur followed by next generation sequencing and custom computational analysis. The feasibility of this approach (v1.0) was previously validated using cell line DNA (Chmielecki et al, 2010). We have since developed an improved version of our platform (v2.0) and used it to identify a novel c6orf204-PDGFRbeta fusion using DNA isolated from whole blood of a patient with T-cell acute lymphoblastic leukemia (T-ALL). The patient had an elevated white blood cell count with hypereosinophilia (HES) that was responsive to imatinib therapy. Multiple tumor samples (e.g. EGFR/KRAS/ALK wildtype lung adenocarcinomas, lung squamous cell carcinomas, ‘triple-negative’ breast carcinomas, and head and neck squamous cells carcinomas, etc.) are currently undergoing screening for other novel TK fusions, and candidate fusions are undergoing validation.
This work was supported by an SU2C-AACR Innovative Research Grant to WP.
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 LB-236. doi:10.1158/1538-7445.AM2011-LB-236
Abstract LB-238: Regulation of signaling pathways by endogenous small molecules
Authors: Nachtergaele Sigrid , Mydock Laurel , Krishnan Kathiresan , Covey Douglas , Rohatgi Rajat 
Published: June 2012

Abstract
A major goal in cancer biology is the comprehensive understanding of signals that drive the growth and spread of cancer cells. My long term goal is to develop methods to isolate new small molecules that play a role in cancer signaling and then to identify the proteins that interact with these small molecules. Such small molecule-protein pairs are likely to be particularly good drug targets in oncology. To develop tools for this endeavor, we are focusing on the identification of small molecules that regulate the “Hedgehog” signaling circuit. Damage to this circuit has been shown to drive the development of a large number of adult and childhood cancers. We are taking advantage of the previous observation that molecules related to cholesterol, called oxysterols, can activate the Hedgehog pathway. To understand how these enigmatic molecules work, we are attempting to find the protein targets through which oxysterols function and also generating analogs of these molecules as novel modulators of this important cancer signaling pathway.
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 LB-238. doi:10.1158/1538-7445.AM2011-LB-238
Abstract LB-70: Breaking the Silence
Authors: Hall Shaundra 
Published: June 2012

Abstract
The National Cervical Cancer Coalition (NCCC) is a grassroots organization that exists solely to educate and support patients, caregivers, family members, and communities about cervical cancer and other HPV-related diseases. NCCC is responsible for the development of the nation's first hotline devoted to helping women and family members resolve issues they have related to cervical cancer and HPV. The NCCC also developed the Cervical Cancer/HPV Quilts Project that travels the country to help put a personal face on the disease. The NCCC began the nationally-recognized FREE Pap Test Day held on the second Friday of January to enable disadvantaged women who have not received a Pap test in the past three years. The NCCC runs an award winning cervical cancer website and is currently developing a national network of local state affiliates. The NCCC cosponsored two fundraising conferences on cervical cancer issues in Malawi, Africa, and has held many prevention education fundraisers over the years as well. The coalition is developing a national grassroots effort in all 50 states. Through the efforts of our coalition members, we are addressing issues of cervical cancer/HPV prevention with education about vaccination and regular Pap and HPV testing. The organization always works to reduce the stigma associated with HPV infection and cervical cancer.
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 LB-70. doi:10.1158/1538-7445.AM2011-LB-70
Abstract SY14-03: Inferring causality for oncology drug discovery and development
Authors: Khalil Iya 
Published: June 2012

Abstract
Decisions in drug development are made based upon determinations of cause and effect from experimental observations that span all development phases. Despite major advances in our powers of observation due to the advent of multi-omic technologies, the ability to determine disease mechanisms, biomarkers, and effective combination therapies from large-scale and diverse data sets in the context of ill-defined and complex biological systems continues to be a major bottleneck in the drug development process. Current methods of statistical analysis do not allow for causal inferences, leaving this impossible task to the human mind. This major bottleneck can only be overcome by utilizing automated computational learning methods that identify from compound data the circuits and connections between drug-affected molecular constituents and physiological observables. We will present several case studies in oncology drug development where we employ massively parallel machines to reverse engineer populations of models that predict the ‘gearing’ between drug, genetic, and genomic molecular components with respect to oncology phenotypic outcomes. Since a single topology or model cannot capture the reality of a biological system under investigation, Monte Carlo simulation strategies over the population of models reveal how the drug, genetic, gene expression and clinical variables work together to impact phenotypic outcomes. We will show how the marriage of multi-omic technologies within the network inference approach is helping to fill in the missing insights needed to improve drug development success rates.
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 SY14-03. doi:10.1158/1538-7445.AM2011-SY14-03