bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3350: Inhibition of breast cancer and cancer stem cells via a novel micheliolide analogue CY-9
Authors: Newman Bryan W. , Zhang Quan , Lu Yaxin , Zhai Jiadai , Ding Yahui , Ma Weiwei , Fan Hongxia , Long Jing , Zhang Haoliang , Wang Miao , Chen Yue , Sun Duxin 
Published: June 2012

Abstract
Natural products that target cancer stem cells (CSCs) have the potential to treat cancers and reduce the occurrence of relapse. The sesquiterpene lactone parthenolide has received much attention for its ability to preferentially target CSCs over their normal equivalents. However, poor pharmacokinetics have severely limited the clinical use of parthenolide, and prompted synthesis of a water soluble analogue, LC-1. Although currently in Phase I trials for disseminated cancers, LC-1 suffers from a short half-life, which could potentially limit its efficacy. In order to identify new sesquiterpene lactones which function similarly to parthenolide and LC-1 but with improved pharmacokinetics, we tested a new micheliolide analogue CY-9 for activity against both breast cancer and CSCs. Using the MTS assay, SUM159 breast cancer cells displayed sensitivity to CY-9 with an IC50 of 5 μM, which is similar to reported inhibitory concentrations of parthenolide. SUM159 cells assayed for Aldefluor expression after a three day treatment with CY-9 (1, 2.5, 5 μM) showed a 27%, 64%, and 83% reduction in their CSC populations, respectively. This CSC depletion was largely reversed in SUM159 cells that were pre-treated with the antioxidant N-Acetyl-Cysteine (NAC) before exposure to CY-9. Inhibition of SUM159 CSC self-renewal after CY-9 treatment was assayed using tumorsphere formation of single SUM159 Aldefluor-positive cells. A seven day treatment of 5 μM CY-9 reduced SUM159 Aldefluor-positive cell tumorsphere formation by 74%. Under drug-free conditions, tumorsphere formation was reduced by 26% in the second passage, but returned to control levels by the third passage. Western blotting also showed that 5 μM CY-9 reduced the levels of nuclear NF-κB. These results demonstrate the effectiveness of our new micheliolide analogue CY-9 at targeting populations of both bulk breast tumor cells and CSCs. The slight reduction in tumorsphere formation under drug-free conditions suggests that inhibition of self-renewal plays a minor role in CY-9's activity against CSCs. Loss of CY-9 activity with cells pre-treated with NAC suggests that the inhibitory effect of CY-9 is partially mediated by its interaction with biologically relevant cysteines and/or ROS generation. Additionally, as NF-κB is vital for defense against cellular stressors such as ROS, depletion of nuclear NF-κB might also explain the observed inhibition with CY-9. Together, these results warrant further study of CY-9 as a potential therapy for breast cancer and CSCs.
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 3350. doi:10.1158/1538-7445.AM2011-3350
Abstract 3374: Effect of Ginsenoside Rg3 on 17β-estradiol-induced epithelial mesenchymal transition through HuR protein in MCF-7 human breast cancer cells
Authors: Lee Chang Ki , Chung Won-Yoon , Kim Jin , Park Kwang-Kyun 
Published: June 2012

Abstract
Epithelial-mesenchymal transition (EMT) is a cellular mechanism long recognized as a central feature of normal development, such as neural crest formation and heart morphogenesis. More recent studies have reported that physiopathological transitions occur during the progression of epithelial tumors, endowing cancer cells with increased motility and invasiveness. EMT implicated that epithelial cells become elongated, lose their polarity and cellular junctions, and show mesenchymal fibroblast-like properties. The role of estrogen and estrogen receptor (ER) in breast cancer cell motility and invasion is controversial. Although ER-positive breast tumors are considered less aggressive and more differentiated, they still undergo metastasis. Human antigen R (HuR) represents one of the best characterised RNA-binding proteins. HuR is involved in mRNA shuttling between nuclear and cytoplasmic compartments and has been shown to increase stability of many mRNA. In recent reports, HuR might serve as a central step in the control of the expression of factors that are involved in tumor growth and angiogenesis, and also plays a critical role in the control of ER mRNA stability. In this study, we investigated whether ginsenoside Rg3 could inhibit the 17β-estradiol (E2)-induced EMT via HuR in MCF-7 human breast cancer cell. Upon E2 stimulation, the levels of epithelial markers, E-cadherin and γ-catenin were strikingly suppressed, whereas those of mesenchymal markers, vimentin, α-SMA, β-catenin and HuR were significantly up-regulated. E2 stimulated the transfer of HuR protein from nucleus into cytoplasm. HuR down-regulated (HuR-DR) MCF-7 cells were established using the HuR shRNA plasmid. Down regulation of HuR did not change the levels of E-cadherin and ER-α, but decreased the levels of β-catenin and vimentin in E2-stimulated MCF-7 cells. Cell proliferation, migration and invasion was not affected by E2 in HuR-DR MCF-7 cells. Rg3 decreased the viability, migration and invasion of MCF-7 cells in the absence or presence of E2. Rg3 treatment inhibited EMT, evidenced by the increased expression of E-cadherin and ER-α, and the decreased expression of β-catenin and vimentin as compared with E2 stimulation. Rg3 inhibited E2-induced expression and cytoplasmic translocalization of HuR protein. In a mouse xenograft model, Rg3 attenuated tumor growth of MCF-7 cells and blocked expressions of EMT marker proteins and HuR, whereas HuR-DR MCF-7 cells did not result in tumor growth. Therefore, Rg3 inhibited E2-stimulated migration, invasion and growth by blocking E2-induced EMT via HuR as well as tumor growth in MCF-7 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 3374. doi:10.1158/1538-7445.AM2011-3374
Abstract 3387: Deletion of NR4A orphan nuclear receptors in adult mice leads to development of acute myeloid leukemia due to disrupted HSC homeostasis
Authors: Ramirez-Herrick Ashley M. , Zhang Shuo , Conneely Orla M. 
Published: June 2012

Abstract
The NR4A subfamily of orphan nuclear receptors (NR4A1, NR4A2, and NR4A3) function as nuclear transcription factors that transduce diverse extracellular and stress signals into altered gene transcription to coordinate apoptosis, proliferation, cell cycle arrest and DNA repair. We previously discovered that two of these receptors, NR4A1 and NR4A3, are potent tumor suppressors of acute myeloid leukemia (AML); they are silenced in human AML and abrogation of both genes in mice results in extremely rapid early postnatal development of AML.
To address the cellular and molecular mechanisms by which NR4As regulate myeloid homeostasis we have generated tamoxifen regulated conditional knockout mice to interrogate the preleukemic effects of NR4A1/3 deletion in hematopoietic cells. We show that deletion of NR4As in adult mice leads to development of transplantable AML disease with a mean survival latency of 15 weeks. Retroviral rescue of NR4A1 or NR4A3 expression after AML development is sufficient to prevent long-term reconstitution of leukemia initiating cells after transplantation into sub-lethally irradiated NOD-SCIDγ mice.
AML development in the conditional knockout mice is associated with loss of hematopoietic stem cell (HSC) homeostasis due to unscheduled HSC proliferation and abnormal skewing of the lineage development program of HSC subpopulations. Skewing of HSC developmental potential leads to a decrease in lymphoid-biased HSCs and relative overproduction of myeloid-biased HSCs, resulting in excessive generation of myeloid progenitor progeny. Our data indicate that NR4As are intrinsic transcriptional regulators of HSC homeostasis that are essential for coordination of lineage development programming of HSCs.
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 3387. doi:10.1158/1538-7445.AM2011-3387
Abstract 3410: Regulation of pluripotency and lineage differentiation in human male germ cell tumors
Authors: Jagadish Nirmala , Kustagi Manjunath , Mendiratta Geetu , Kushwaha Ritu , Bansal Mukesh , Hyunjae Kim R. , Sumazin Pavel , Alvarez Mariano , Lefebvre Celine , Viale Agnes , Korkola James E. , Houldsworth Jane , Bosl George J. , Califano Andrea , Chaganti Raju SK 
Published: June 2012

Abstract
Pluripotent embryonal carcinoma (EC) cells derived from germ cell tumors (GCTs) are an excellent model system to study the interface between malignancy, pluripotency, and lineage differentiation. We previously characterized the gene expression profile (GEP) of a panel of 135 germ cell tumor (GCT) biopsies comprising all described differentiation lineages and 6 normal testes as controls, using the Affymetrix U133A+B arrays (Korkola et al. Cancer Res., 66: 820-7, 2006 and J. Clin. Oncol., 27: 5240-7, 2009). We applied the ARACNE reverse engineering algorithm to this GEP to obtain the first de novo and context-specific transcriptional interactome (GCTNet) comprising 1,310 transcription factors (TFs). GCTnet recapitulated 830 regulatory targets together of POU5F1, NANOG, and SOX2, the core pluripotency TFs. ChIP-seq and ChIP-PCR analysis of NT2/D1 embryonal carcinoma and H9 ES cells provided significant validation of ARACNe-inferred targets, besides providing the first detailed mapping of DNA binding sites of these 3 genes in human cells. Functional validation of ARACNe-inferred targets by stable knockdown of the POU5F1, NANOG and SOX2 in NT2/D1 cells also showed a significant enrichment of ARACNe targets. Analysis of GEP in a time-course of SOX2 knockdown by principal component analysis (PCA) identified 3 orthogonal gene expression programs: (1) genes with monotonic change (PC1), (2) genes showing a strong and focal gene expression at day 5 (PC2), and (3) genes which show oscillatory pattern of expression (PC3). Ingenuity and GO annotation analysis of PCA provided new insights into the pathways regulated by this TF. Our results provide a novel, comprehensive, and accurate regulatory networks responsible for pluripotency and lineage differentiation in GCTs.
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 3410. doi:10.1158/1538-7445.AM2011-3410
Abstract 346: Integrative genomic analysis of sporadic clear cell renal cell carcinoma
Authors: Dondeti Vijay R. , Wubbenhorst Bradley , Lal Priti , Gordan John D. , D'Andrea Kurt , Attiyeh Edward F. , Simon M Celeste , Nathanson Katherine L. 
Published: June 2012

Abstract
Sporadic clear cell Renal Cell Carcinoma (ccRCC) is the most common type of adult kidney cancer. Using high-density copy-number profiling and gene expression profiles, we performed an integrated genomic analysis of 54 sporadic tumor samples. We took a two pronged approach, focusing on 1) all samples and 2) comparing ccRCCs that express both HIF1α and HIF2α (H1H2) and those that express only HIF2α (H2), sub-types of ccRCC that we previously described. For all samples at a frequency over 10%, we identified regions of amplification on 1q, 5q, 7q, 8q, 12p, and 20q, and regions of deletion on 1p, 3p, 6q, 8p, 9p, and 14q, as previously described. We used our integrative analysis to identify target genes that had consistent copy-number and gene expression changes (e.g. amplified and upregulated or deleted and downregulated) within regions on chromosomes 5 and 7. Combining our data with an independent dataset (Beroukhim et al., 2009) and including a literature based analysis, we were able to narrow down to three target genes, which we subsequently validated using a renal cancer cell line. We then compared genomic changes in H1H2 and H2 ccRCCs. Prior data suggested that H2 ccRCCs have increased expression of genes involved in double strand break repair, thus potentially greater genomic stability. Using high-density copy-number data, we have confirmed that H2 tumors have significantly fewer genomic aberrations compared to H1H2 tumors (for amplifications p=0.032 and for deletions p=0.003). In addition, using GISTIC, we found that deletion of chromosome 6 is significantly more common in H1H2 tumors (p&lt;0.001), whereas deletion of chromosome 9 is significantly more common in H2 tumors (p&lt;0.001). Of note, deletion of chromosome 9 previously has been associated with poor prognosis. Thus, correlations between the copy-number data and gene expression profiles indicate that the H1H2 and H2 classes of ccRCC tumors may each have a distinct set of drivers of tumorigenesis; target gene validation for these groups is underway. These experiments provide novel insights into the biology of clear cell Renal Cell Carcinoma (ccRCC).
Beroukhim et al. Patterns of Gene Expression and Copy-Number Alternations in von-Hippel Lindau Disease-Associated and Sporadic Clear Cell Carcinoma of the Kidney. Can Res 2009; 69: (11):4674-81.
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 346. doi:10.1158/1538-7445.AM2011-346
Abstract 3462: PARP inhibition sensitizes high grade childhood brain tumors to radiation
Authors: van Vuurden Dannis G. , Meijer Olga L.M. , Hulleman Esther , Würdinger Thomas , Noske David P. , Kaspers Gertjan L. , Cloos Jacqueline 
Published: June 2012

Abstract
Background: Poly ADP-ribose polymerases (PARPs) are proteins involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy as in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in genes in double strand break repair pathways. Besides this, PARP inhibition enhances sensitivity of tumor cells to DNA damaging agents, such as chemo- and radiotherapy.
Aim of this study is to investigate the expression of PARP1 in normal brain tissues and high grade childhood brain tumors, medulloblastoma, ependymoma and high grade glioma (HGG), and to analyse sensitivity and radiosensitizing properties of PARP inhibitor Olaparib in cell lines of these tumors.
Methods: Expression of PARP1 has been determined in medulloblastoma, ependymoma and HGG patient material and normal brain tissues by in silico analysis of PARP1 mRNA expression arrays, Western blot and immunohistochemistry. In addition, we performed clonogenic and viability assays, combining radiation with PARP inhibition in medulloblastoma, ependymoma and HGG cell lines.
Results: Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Moreover, medulloblastoma gene expression analysis revealed high PARP1 expression to be associated with poor prognosis. Growth inhibition with PARP inhibitor Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.8 to 30 µM in cell lines, irrespective of PARP1 protein expression. HGG cell line SF-188, which harbors a focal deletion of NF1 gene, showed a 15-fold higher sensitivity to Olaparib compared to other HGG cell lines. This high sensitivity may be due to synthetic lethality and warrants further investigation. The combination of subcytotoxic concentrations of Olaparib and radiation showed increased cytotoxicity and reduced clonogenic capacity in medulloblastoma, ependymoma and HGG cell lines.
Conclusion: PARP1 is overexpressed in high grade childhood brain tumors. In medulloblastoma, high PARP expression is correlated with poor prognosis. PARP inhibition sensitizes ependymoma, medulloblastoma and HGG cells to radiation. These results provide a basis for clinical translation, combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors.
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 3462. doi:10.1158/1538-7445.AM2011-3462
Abstract 3466: Tumor pericytes: A novel target for immune therapy in renal cell carcinoma
Authors: Chi Nina , Taylor Jennifer , Maranchie Jodie , Storkus Walter 
Published: June 2012

Abstract
Tumor vasculature is classified by leaky, chaotic blood vessels consisting of several components including vascular endothelial cells (VEC) and mural cells (smooth muscle cells and pericytes), as well as immune regulatory cells, stem cells and vascular progenitors. Irregular tumor vasculature limits immune effector cell access to the tumor, and may in part be responsible for the modest success observed in many current anti-cancer immunotherapies. Certain drugs targeting tyrosine kinase receptors expressed on tumor stromal cells induce a Type-1 proinflammatory skewing of the tumor microenvironment (TME) with a coordinate reduction in the number of immune regulatory cell populations. A transient normalization of the vasculature may also occur in association with enhanced leukocyte recruitment. We have shown that vaccination against tumor-associated stromal antigens leads to the activation of VCAM-1 expression on tumor vascular endothelial cells and the enhanced recruitment of protective Type-1 T cells into the TME. Currently little is known regarding pericyte biology and their behavior in the TME, with no existing treatments specifically targeting pericytes. We hypothesize that pericytes residing in the TME differentially express antigens that distinguish them from pericytes in healthy tissue, and vaccination specifically targeting tumor pericyte antigens will result in vascular normalization and improved delivery of protective Type-1 T cells into the TME. To address these hypotheses, we examined mRNA expression of pericytes and VEC that have been flow-sorted from human renal cell carcinoma (RCC) tumors and patient-matched normal adjacent kidney (NAK) tissue. We have identified antigens that are differentially expressed by pericytes and/or by VEC in the TME versus NAK (such as RGS5). We are currently investigating the therapeutic efficacy of genetic (lentiviral) vaccines encoding tumor-associated stromal antigens in murine tumor models.
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 3466. doi:10.1158/1538-7445.AM2011-3466
Abstract 3477: Radiation impaired cell migration and wound healing after postoperative radiotherapy is mediated through inhibition of Shp2 tyrosine phosphatase
Authors: Natarajan Mohan , Mohan Sumathy , Zheng Xiangpeng , Aravindan Natarajan 
Published: June 2012

Abstract
The influence and mechanism of the postoperative radiotherapy on wound healing process is controversial. Based on the vital role of endothelial cell migration on wound healing, this study investigated the response of endothelial cells to low-dose irradiation and the underlying mechanism. Primary vascular endothelial cells were grown to more than 90% of confluence in complete MCDB-131 medium. A wound was inflicted in the confluent monolayer exposing a cell-free zone on the plate. The cells were then exposed to acute dose of 10 cGy, 2 or 10 Gy at a dose rate of 1.29 Gy/min. The number of cells crossing the wound border and the migration distance in the wounded region were measured. Integrin signaling pathway was examined by the assay of expression of αvβ3 integrins, focal adhesion kinase (FAK) and phosphorylated FAK (tyr397), and actin fibers through immunoblotting. Confocal immunofluorescence was applied to observe the distribution and morphological alteration of FAK tyr397 and actins after radiation exposure. Also RNA samples were extracted from the radiation-treated cells and reverse transcriptase polymerase chain reaction was performed to analyze the transcription level of SHP-2 tyrosine phosphatase, the regulator of FAK. The results revealed a dose-dependent decrease in cell motility in terms of migration distance and the number of migrating cells. The migrating distance in 2 and 10 Gy exposed cells were only 0.5 and 0.1 mm, respectively compared to 3mm seen in mock irradiated control cells. With 10 Gy exposure, the expression of β3 domain of integrins was inhibited compared to the levels in other irradiated groups and the control group while there was no detectable difference in αv domain and α-actin among all groups. Although the level of total FAK was invariable, phosphor-FAK tyr397 was higher in the irradiated groups. RT-PCR analysis of SHP-2 demonstrated a significantly dose-dependent decrease in transcription of SHP-2 mRNA. These results suggested that radiation inhibited endothelial cell migration. Unlike chemical factors inducing chemotaxis through the reaction with integrins receptors and the ensuing signaling cascade, radiation-induced inhibition of cell migration could be attributing to the direct damage to SHP-2 transcription, and the subsequent accumulated phosphor-FAK abrogated the contraction of cytoskeletons.
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 3477. doi:10.1158/1538-7445.AM2011-3477