bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B32: Role of megalin in uptake of 1α,25(OH)2D in colon cancer cells
Authors: Hibler Elizabeth A. , Jacobs Elizabeth T. , Jurutka Peter W. 
Published: January 2014

Abstract
Vitamin D has been proposed as a chemopreventive agent for colorectal cancer; however, the mechanisms governing the availability of the active form of vitamin D, 1α,25(OH)2D, remain unclear. There is growing evidence that uptake of vitamin D metabolites at the cellular level may involve receptor-mediated endocytosis in certain tissues. Megalin, or low-density lipoprotein 2, has demonstrated effects on uptake of Gc-globulin (GC)-bound vitamin D metabolites in kidney, bone, gallbladder, and mammary gland cells. However, this mode of metabolite uptake has not been tested in the colon. We measured activation of the VDR-RXR heterodimer in the context of a mammalian-2-hybrid (M2H) biological assay system as a marker for uptake of vitamin D metabolites in human HCT-116 colorectal carcinoma cells. Cells were transfected with control versus megalin siRNA or, alternatively, no siRNA but treatment with receptor associated protein (RAP), a ligand for megalin that blocks GC binding. Cells were then treated with ethanol (EtOH) vehicle versus 1x10-8 M, 2.5x10-9 M, or 5x10-10 M 1α,25(OH)2D. The results demonstrate that treatment with either megalin siRNA or RAP induced an overall statistically significant increase in activation of the VDR-RXR heterodimer (ANOVA p&lt; 0.001) compared to control siRNA, after controlling for differences by replicate and 1α,25(OH)2D concentration. Furthermore, stratification by concentration and use of the Tukey HSD test for pairwise comparisons revealed that activation following treatment with megalin siRNA was greater than with RAP, but not statistically significantly different. Activation with megalin siRNA was significantly different from control siRNA at all three 1α,25(OH)2D concentrations compared to EtOH (p&lt; 0.05); however, treatment with RAP only led to the significant increase at 1x10-8 M 1α,25(OH)2D. Further work is ongoing to test uptake of 25(OH)D and an additional assay based upon vitamin D response element binding. These results provide preliminary evidence that colon cells use megalin to regulate uptake of 1α,25(OH)2D and that its presence acts to limit uptake, especially when extracellular concentrations of 1α,25(OH)2D are high. These results identify megalin as a novel target and modulator of vitamin D metabolite delivery at the cellular level that may influence population-level cancer risk. Additional testing of these results under varied cell conditions and in multiple cell lines is necessary to further elucidate the role of megalin in uptake of vitamin D metabolites into cancer cells.
Citation Format: Elizabeth A. Hibler, Elizabeth T. Jacobs, Peter W. Jurutka. Role of megalin in uptake of 1α,25(OH)2D in colon cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B32.
Abstract B37: Antiproliferative effects of pomegranate are associated with downregulation of homologous recombination pathway: Potential use in cancer prevention
Authors: Kovvuru Prasad , Shirode Amit , Reliene Ramune 
Published: January 2014

Abstract
High antioxidant capacity of pomegranate fruit is thought to be responsible for various health benefits, although the link between antioxidant capacity and antiproliferative effects has not been established yet. To better understand this relation we examined growth inhibition by pomegranate extract (PE) in association with antioxidant capacity and analyzed global gene expression changes in breast cancer MCF-7 cells. PE inhibited cell growth by induction of cell cycle arrest in G2/M and the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and regulation of cell proliferation. Of particular interest, both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2 and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs, miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate microRNAs involved in DNA repair processes. Further, PE induced DNA double strand breaks (DSBs) that persisted and cells remained growth-inhibited for at least four days after the removal of PE. These data suggest that PE targets HR sensitizing cells to DSBs, cell cycle arrest and apoptosis. Downregulation of HR by PE is expected to specifically affect transformed and other rapidly growing cells because HR pathway is found to be dispensable for quiescent and post-mitotic tissues. HR not only repairs DSBs and replication-associated lesions but also may result in genome rearrangements and loss of heterozygocity, which drives oncogenic transformation. Hyperactive HR, genetic instability and elevated carcinogenesis has been exemplified in both humans and mice deficient in cell cycle control and DNA damage response genes including TP53 and ATM. Thus, these data suggest that downregulation of HR by PE may retard cell growth and prevent genetic instability and carcinogenesis.
Citation Format: Prasad Kovvuru, Amit Shirode, Ramune Reliene. Antiproliferative effects of pomegranate are associated with downregulation of homologous recombination pathway: Potential use in cancer prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B37.
Abstract B48: Anticancer effect of guava leaves (Psidium guajava L.) in prostate cancer cells
Authors: Yang Woong Mo , Kim Mi Hye , Park Sang-Yoon , Ahn Kwang Seok , Lee Seok-Geun 
Published: January 2014

Abstract
This study was carried out to evaluate the anticancer effects of guava leaf extracts and its fractions. The chemical compositions of the active extracts were also determined. In the present study, we set out to determine whether the anticancer effects of guava leaves are linked with their ability to suppress constitutive AKT/mammalian target of rapamycin (mTOR)/ribosomal p70 S6 kinase (S6K1) and mitogen-activated protein kinase (MAPK) activation pathways in human prostate cancer cells. We found that guava leaf hexane fraction (GHF) was the most potent inducer of cytotoxic and apoptotic effects in PC-3 cells. The molecular mechanism or mechanisms of GHF apoptotic potential were correlated with the suppression of AKT/mTOR/S6K1 and MAPK signaling pathways. This effect of GHF correlated with down-regulation of various proteins that mediate cell proliferation, cell survival, metastasis, and angiogenesis. Analysis of GHF by gas chromatography and gas chromatography-mass spectrometry tentatively identified 60 compounds, including β-eudesmol (11.98%), α-copaene (7.97%), phytol (7.95%), α-patchoulene (3.76%), β-caryophyllene oxide (CPO) (3.63%), caryophylla-3(15),7(14)-dien-6-ol (2.68%), (E)-methyl isoeugenol (1.90%), α-terpineol (1.76%), and octadecane (1.23%). Besides GHF, CPO, but not phytol, also inhibited the AKT/mTOR/S6K1 signaling pathway and induced apoptosis in prostate cancer cells. Overall, these findings suggest that guava leaves can interfere with multiple signaling cascades linked with tumorigenesis and provide a source of potential therapeutic compounds for both the prevention and treatment of cancer.
Citation Format: Woong Mo Yang, Mi Hye Kim, Sang-Yoon Park, Kwang Seok Ahn, Seok-Geun Lee. Anticancer effect of guava leaves (Psidium guajava L.) in prostate cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B48.
Abstract B63: Developing Novel STAT3 Inhibitors for the Treatment and Prevention of Cancer
Authors: Yang Zhengduo , Chen Haijun , Chu Lili , Zhang Yusong , Ding Chunyong , Terry Kristin , Zhou Jia , Shen Qiang 
Published: January 2014

Abstract
Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in the regulation of early embryonic development, immune response, cell proliferation, differentiation, and apoptosis. Particularly, STAT3 regulates lobuloalveolar apoptosis during involution in mammary gland development, and its activation is required for the growth of CD44+CD24- stem cell-like breast cancer cells and the development of multiple cancers including breast cancer. Increased STAT3 transcriptional activity was found to correlate with ER-negative phenotype in breast cancer cell lines and in primary human invasive ductal breast carcinomas. Thus, STAT3 represents a promising target for therapeutic and preventive intervention of breast cancer. Yet current strategies of inhibiting STAT3 activity did not sufficiently block STAT3 activation in cancer cells due to their limited potency, poor solubility or bioavailability. Despite several STAT3 inhibitors have been advanced into early clinical trials, there is an urgent need to develop a more successful strategy targeting STAT3 for cancer therapies, and preventive use in particular. We attempted to identify potent and orally active STAT3 inhibitors for such purposes and have designed, synthesized and screened a series of novel STAT3 inhibitors utilizing fragment-based drug design strategy. A number of small molecules with new scaffolds have been discovered with low-micromolar to nanomolar potency in inhibiting the proliferation of various human breast cancer and pancreatic cancer cells. The identified compound HJC0152 significantly suppresses basal and IL-6-stimulated STAT3 promoter activity and STAT3 phosphorylation, reduces total STAT3 protein expression, induces G2/M cell cycle arrest, and induces early apoptosis. HJC0152 has demonstrated a better potency in suppressing the growth of MDA-MB-231 breast xenograft tumors via intraperitoneal and oral administrative routes, with remarkably improved aqueous solubility (3,300 fold improvement) and less toxicity than the lead compounds. In conclusion, we have developed a new class of orally active STAT3 inhibitors with superior drug-like properties for further preclinical therapeutic and preventive evaluation.
Citation Format: Zhengduo Yang, Haijun Chen, Lili Chu, Yusong Zhang, Chunyong Ding, Kristin Terry, Jia Zhou, Qiang Shen. Developing novel STAT3 inhibitors for the treatment and prevention of cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B63.
Abstract CN05-02: Arsenic carcinogenesis
Authors: Argos Maria 
Published: January 2014

Abstract
Elevated concentrations of arsenic in groundwater pose a public health threat to millions of people worldwide, including severely affected populations in Bangladesh. While arsenic is an established human carcinogen and has been associated with a multitude of health outcomes in epidemiologic studies, a mode of action has yet to be determined for some aspects of arsenic toxicity. In this presentation, we will emphasize the role of recent genetic and molecular epidemiologic investigations of arsenic toxicity. Additionally, we will discuss considerations for the public health impacts of arsenic exposure through drinking water with respect to primary and secondary prevention efforts, including discussion of an on-going chemoprevention trial of selenium and vitamin E supplementation among individuals with manifest arsenic toxicity in Bangladesh.
Citation Format: Maria Argos. Arsenic carcinogenesis. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN05-02.
Abstract CN06-02: Epigenetic Deregulation of MicroRNAs During Tobacco Carcinogen-Induced Transformation of Bronchial Epithelial Cells
Authors: Belinsky Steven A. , Spira Avrum , Tellez Carmen 
Published: January 2014

Abstract
Epigenetic silencing of genes and microRNAs (miRs) via chromatin remodeling and cytosine methylation has emerged as a major mechanism in lung cancer etiology. The reversal of gene and miR silencing using pharmacological agents by affecting cytosine-DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), or histone deacetylases (HDACs) offers new strategies for prevention and intervention for lung cancer. We have developed an in vitro model using hTERT/cdk4 immortalized human bronchial epithelial cell lines (HBECs) that identifies molecular changes driving transformation of preneoplastic lung epithelial cells during exposure to carcinogens found in mainstream and environmental tobacco smoke. Our studies provided a mechanistic link between increased DNMT1 protein, de novo methylation of genes, and reduced DNA repair capacity that together seemed causal for transformation. Our recent studies show that the exposure of HBECs to carcinogens for 4 wk induces a persistent and irreversible, multifaceted dedifferentiation program characterized by the epithelial-to-mesenchymal transition (EMT). EMT induction was epigenetically driven, initially by chromatin remodeling involving H3K27me3 enrichment, with ensuing DNA methylation sustaining the silencing of miR-200b, -200c, and -205 implicated in this developmental program and persisting in malignant tumors. Over expression of these miRs reversed transformation. Next generation sequencing of transformed HBEC lines has identified 25 miRs whose silencing may be regulated through chromatin remodeling and promoter methylation. The impact of specific miRs identified by sequencing on transformation, regulation by chromatin, and their prevalence in lung cancer will be described. (Supported by R01 ES008801 and P50 CA58184).
Citation Format: Steven A. Belinsky, Avrum Spira, Carmen Tellez. Epigenetic deregulation of microRNAs during tobacco carcinogen-induced transformation of bronchial epithelial cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN06-02.
Abstract ED02-03: Animal models for human pancreatic cancer prevention
Authors: Rao Chinthalapally V. 
Published: January 2014

Abstract
Pancreatic cancer has the worst prognosis and is the fourth leading cause of cancer-related deaths in the United States. The five-year survival for this disease is &lt;6% and it is lethal to almost all of the patients diagnosed. As with many epithelial cancers, pre-invasive precursors in the pancreas progress slowly over many years to decades to development of invasive pancreatic cancers in humans. Lack of early detection and effective interventions are major factors contributing to the poor prognosis and dismal survival rates of pancreatic cancer patients for more than sixty years. Detection of pancreatic cancer at an early stage might permit life-saving interventions. Use of tumor xenografts and/or orthotopic models to predict valid targets and for design and development of drugs for pancreatic cancer patients has been disappointing. Animal models with etiological relevance that recapitulate the molecular pathology of human pancreatic intraepithelial neoplasia (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC) are ideal models for establishing pancreatic cancer prevention and treatment strategies. Recent advent in genetically engineered mouse (GEM) models, such as development of transgenic KrasG12D-dependent mouse models of PDAC, that mimic human PDAC offer opportunities to identify putative targets of pancreatic lesion development and targeted drug strategies for PDAC prevention. We will present recent advances on i) selection of optimal Kras mouse models for prevention and early diagnosis, and ii) application of Whole Transcriptome (SOLiD) approaches to identify druggable targets for PanINs and PDAC. Then, iii) we will provide a few examples of development of molecularly targeted chemopreventive drugs using the krasG12D mouse model.
Citation Format: Chinthalapally V. Rao. Animal models for human pancreatic cancer prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED02-03.
Abstract ED02-04: Using mouse models to develop new drugs and strategies for prevention
Authors: Liby Karen T. 
Published: January 2014

Abstract
Numerous high-profile publications have confirmed that an individual tumor contains hundreds of mutations, that a tumor will continue to acquire mutations as it progresses, and that significant tumor heterogeneity exists not only between tumors but also within a tumor. Because of these challenges, prevention of cancer should be more effective than treating end-stage disease. Mouse models are useful tools for developing new drugs and strategies for cancer prevention, and we have used mouse models of breast, pancreas, and lung cancer to ask different types of questions. Our data demonstrate the benefits of early intervention in the process of carcinogenesis. Moreover, multifunctional drugs that target key regulatory nodes are more effective than targeted therapies for prevention, and combining drugs that target different pathways or cell types can enhance the potency and reduce the toxicity of individual drugs.
Citation Format: Karen T. Liby. Using mouse models to develop new drugs and strategies for prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED02-04.
Abstract ED05-03: Building transdisciplinary teams to address cancer health disparities: The Centers for Population Health and Health Disparities (CPHHD) experience
Authors: Paskett Electra D. 
Published: January 2014

Abstract
Cancer health disparities are evident in many underserved and minority populations. Strategies to understand and intervene on these disparities are often complex and occur at multiple levels, and need input from investigators from various disciplines to understand the factors that impact these disparities. In addition, community members, who have the best understanding and knowledge of what is wrong, and how to address disparities in their communities, also need to be involved from the beginning to make relevant and long-lasting differences. The CPHHD initiative, started in 2003, has used 3 main principles to address cancer health disparities in a variety of underserved/minority populations in different regions of the U.S. These principles include: establishing transdisciplinary teams, guided by a theoretical framework developed by the CPHHD initiative to investigate the multi-level factors related to disparate health outcomes, using Community-Based Participatory Research (CBPR). This presentation will describe the multi-level theoretical framework for addressing disparities and how transdisciplinary teams are formed and work together with communities to address disparities in breast, cervical, and prostate cancer among different underserved populations.
Citation Format: Electra D. Paskett. Building transdisciplinary teams to address cancer health disparities: The Centers for Population Health and Health Disparities (CPHHD) experience. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED05-03.
Abstract ED06-02: MicroRNAs and cancer progression
Authors: Croce Carlo M. 
Published: January 2014

Abstract
Since the discovery of miR-15a and miR-16-1 deletions in CLL15, many laboratories around the world have shown miRNA dysregulation in all tumors studied, including the most common, such as lung, breast, prostate and gastrointestinal cancers. Such dysregulation, like the dysregulation of oncogenes and tumor suppressor genes, can be caused by multiple mechanisms, such as deletion, amplification, mutation, transcriptional dysregulation and epigenetic changes.
As miRNAs have multiple targets, their function in tumorigenesis could be due to their regulation of a few specific targets, possibly even one, or many targets. A future challenge will be to identify all of the targets of the miRNAs involved in cancer and establish their contribution to malignant transformation. An additional challenge will be the identification of all of the miRNAs that are dysregulated by pathways that are consistently dysregulated in various types of human cancers. This point is of particular importance, as instead of focusing on specific alterations in protein-coding oncogenes or tumor suppressor genes — which may be difficult to treat — we could focus on their downstream miRNA targets. If these miRNA targets are crucial for the expression of the malignant phenotype and the cancer cells depend on their dysregulation for proliferation and survival, we can expect that the use of miRNAs or anti-miRNAs will result in tumor regression. Genomic analyses for alteration in miRNA genes or for copy number alterations in various human tumors by deep sequencing is in progress but has not been completed. These studies could provide additional information concerning the involvements of miRNAs in cancer and in many other diseases.
Over the past few years, we have observed a shift from conventional chemotherapy to targeted therapies, and miRNAs and anti-miRNAs will contribute extensively to the latter.
Citation Format: Carlo M. Croce. microRNAs and cancer progression. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED06-02.
Abstract ED06-03: Circulating microRNAs as cancer biomarkers
Authors: Tewari Muneesh 
Published: January 2014

Abstract
The discovery of circulating microRNAs (e.g., cell-free microRNAs present in plasma and/or serum) has created new opportunities for improving early detection, prevention and treatment of cancer. My presentation will cover basic mechanisms and clinical applications of circulating microRNA biomarkers, as well as potential pitfalls and key future directions in this nascent but promising research area.
Citation Format: Muneesh Tewari. Circulating microRNAs as cancer biomarkers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED06-03.