bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3939: The effect of DNA glycosylase depletion on the transcriptome and epigenome
Authors: George Jay , Sobol Rob 
Published: February 2011

Abstract
We have developed a panel of human cell lines, each deficient in one of the eleven DNA glycosylase enzymes. To expand background diversity, the same shRNA lentiviruses were also used to develop parallel cell line panels in different tumor backgrounds, including glioma and breast cancer cell lines. Depletion of target mRNA ranged from 67-99% with similar target mRNA depletion across tumor cell backgrounds. Gene expression knockdown was sufficient to functionally diminish enzyme activity, protein levels and mRNA profiling for each exemplified the impact of DNA repair defects on the human transcriptome. As an example of the far reaching potential for a panel of DNA repair deficient cell lines, we show that DNA glycosylase deficiency modulated both the transcriptome and epigenome, implicating some DNA glycosylases in methylation maintenance and genome expression diversity. In addition we demonstrate the impact on DNA repair in glycosylase depleted backgrounds.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3939.
Abstract 394: Development of a fully human immune system in NOD/SCID/IL2Rgamma (NSG) mice for oncology research purpose
Authors: Mirjolet Jean-François , de Boisferon Marc Hillairet , Bichat Francis , Fages Carole , Matyas Robert 
Published: February 2011

Abstract
Background: Humanized mice are a promising translational research model for evaluation of pharmacological compounds efficacy and safety in Oncology. Their use has been enhanced by the development of new stocks of immunodeficient hosts, most notably mouse strain such as NOD-scid/IL2rγ null mice (NSG). As previously described (L. Schultz et al, J. Immunol. 2005) the NSG mice could also be successfully humanized after engraftment of human hematopoietic stem cells (HSC). NSG mice have also been shown to be superior to other immunodeficient mice (BALB/c nu/nu, NOD/Shi-scid) for xenograft of tumour material. These models are particularly needed in preclinical development where there is no appropriate small animal model combining the human immune system and human tumour.
Methods: Freshly collected umbilical cord blood (UCB) samples were provided by the “établissement français du sang, EFS” following the French ethical rules. The UCB were selected for their HSC CD34+ content and T cells depleted before being intracardiacally injected in whole body irradiated newborn NSG mice. The reconstitution of a human immune system within mouse was analyzed in peripheral blood and in primary and secondary lymphoid organs (bone marrow, spleen and thymus) using a 7-color FACS analysis.
The mice were then xenografted with tumour cell lines, fresh primary human solid tumours and haematological malignancies to combine the development of human cancer and human immune system within the same mouse.
Results and conclusions: Fifteen weeks after stem cells injection, the peripheral blood contains about 50% of human leukocytes distributed as followed: about 50% of T lymphocytes, about 40% of B lymphocytes, about few percent of monocytes, macrophages, granulocytes, natural killer cells and platelets. At same time, the central chimerism within lymphoid organs for human leucocytes has represented about 80%, 85% and 95% in bone marrow, spleen and thymus cells, respectively.
This NSG mouse model opens new in vivo perspectives to study the complex relationships between the human immune system and human tumour cells under therapeutic treatments with biologics (antibody-dependent cell-mediated cytotoxicity, antitumour vaccination strategies . . .).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 394.
Abstract 3946: Stem cell protein piwil2 enhances nucleotide excision repair through regulating chromatin remodeling following DNA damage
Authors: Wang Qien , Han Chunhua , Yin De-Tao , Chen Li , Milum Keisha , Yan Qingtao , Wani Gulzar , Ray Alo , Gao Jianxin , Wani Altaf A. 
Published: February 2011

Abstract
The piwi family gene, which are defined by conserved PAZ and Piwi domains, play important roles in stem cell self-renewal, RNA silencing, and translational regulation in various organisms. Three piwi homologs have been identified in the mouse genome. Amongst these, mili (piwil2) protein expression appears to be associated with tumorigenesis as evidenced by the facts that piwil2 stably expresses in pre-cancerous stem cells and also appears at variable levels in different human and animal tumor cell lines. Based on our preliminary data showing that piwil2 is induced in normal cultured human fibroblasts in vitro by physical and chemical genotoxic agents, we hypothesized that piwil2 might function in DNA damage response. Here, we demonstrated that mammalian cells lacking piwil2 are hypersensitive to cisplatin and UV irradiation. In addition, nucleotide excision repair (NER) efficiency is significantly decreased in the absence of piwil2 as assessed by the removal of cisplatin-induced intra-strand cross-links (Pt-GG) and UV-induced cyclobutane pyrimidine dimers (CPDs) from genomic DNA. Although quantitative real-time PCR analysis indicated higher transcript levels of various NER proteins in piwil2 knockout mouse embryo fibroblasts (MEFs), the Western blotting did not show an obvious difference in the NER protein levels between mili+/+ and mili−/− MEFs. Since piwil2 is believed to orchestrate chromatin remodeling, we reasoned that low NER efficiency in mili−/− MEFs may result from disrupted chromatin remodeling in response to UV or cisplatin induced DNA damage. Thus, chromatin relaxation and histone acetylation was analyzed in these MEFs following treatment with UV or cisplatin. MEFs lacking piwil2 showed less sensitivity to micrococcal nuclease (MNase) digestion compared with piwil2-proficient MEFs, indicating a compact chromatin structure in these cells. Moreover, in contrast to mili+/+ MEFs, mili−/− MEFs exhibited decreased acetylated Histone H3 upon both UV and cisplatin treatment. This decrease could be blocked by histone deacetylase (HDAC) inhibition indicating that piwil2 may function in damage-induced chromatin remodeling via inhibiting the HDAC activity. In summary, our data suggests that piwli2 can participate in the NER through regulating chromatin relaxation which could be a pivotal factor in genotoxin-induced tumorigenesis as well as efficacy of cancer therapeutics. (Supported by NIH grants CA93413, ES2388 and ES12991 to AAW).
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3946.
Abstract 3948: Identification of phosphorylated NF45 (T388) as a potential pharmacodynamic biomarker for ARQ 501 (β-lapachone)
Authors: Yu Yi , Gu Xiubin , Zhao Xiaolan , Chang Edward , Cousens Laura , Waghorne Carol G. , Chan Thomas C.K. 
Published: February 2011

Abstract
ARQ 501, a fully synthetic version of β-Lapachone, has demonstrated anti-cancer activity and entered multiple phase II trials. Although the mechanism of the cytotoxic activity of ARQ 501 towards cancer cells is not completely understood, it appears that both DNA damage and DNA checkpoint activation play a role in cell death caused by this compound. We used a proteomic approach to search for pharmacodynamic (PD) biomarkers for ARQ 501 by profiling phosphoproteins. ARQ 501 treatment strongly induced threonine phosphorylation of certain proteins around 45 kD in MIA PaCa2 cells. One of the proteins was identified by mass spectrometry analysis as NF45, also known as ILF2. Immunoprecipitation experiments using a customized antibody against pNF45 confirmed that NF45 is phosphorylated in response to ARQ 501 at threonine 388 in a TQ site (an ATM/ATR phosphorylation motif) near the carboxyl terminus. ARQ 501 increased pNF45 expression in a time- and concentration-dependent manner accompanied by activation of ATM and DNAPK. Inhibition of ATM and DNAPK suppressed ARQ 501-induced pNF45 (T388) elevation. Evidence of ARQ 501-induced DNA damage is supported by the observation of CHK2 phosphorylation and γ-H2AX elevation. We therefore examined the effects of several DNA damaging agents on NF45 phosphorylation and found that only ARQ 501 was able to increase pNF45 (T388) levels, suggesting that induction of pNF45 is not a general response to DNA damage, and that ARQ 501 may inhibit cell proliferation by an alternate mechanism. Immunofluorescent staining using pNF45 (T388) antibody showed there is a significant increase in pNF45 (T388) levels predominantly in nuclei. In order to validate pNF45 (T388) as a PD biomarker, we examined pNF45 (T388) levels in human tumor mouse xenograft models treated with ARQ 501. The ARQ 501 treated tumors treated with ARQ 501 showed increased pNF45 (T388) nuclear staining by immunohistochemistry compared to the vehicle group. Therefore, phosphorylation of NF45 at threonine 388 may serve as a PD biomarker for ARQ 501.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3948.
Abstract 3950: Neuropilin-2, a transmembrane glycoprotein receptor, protects prostate cancer cells from stress
Authors: Zhang Heyu , Wang Enfeng , Tindall Donald J. , Datta Kaustubh 
Published: February 2011

Abstract
Prostate cancer is the most common cancer and the second leading cause of cancer death in men in the United States. Definitive treatment consists of either radical prostatectomy or radiotherapy followed by androgen deprivation. Although majority of the prostate cancers usually responds to these therapies and can be cured, some of them will eventually relapse. It is believed that the relapsed cancers obtained new ability that facilitates their resistance to these therapeutic stresses. Increased expression of VEGF-C and its receptor Neuropilin-2 (NRP-2) in hormone-refractory and metastatic prostate cancers indicates that the VEGF-C/NRP-2 axis could play an important role in the progression of prostate cancer. Indeed, we observed VEGF-C/Neuropilin-2 axis promotes survival of prostate cancer cells during stress induced by hydrogen peroxide or radiation. Detail signaling events downstream of neuropilin-2 for this stress-resistant function have also been determined. Our findings therefore demonstrated a novel and distinct function of NRP-2 in protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3950.
Abstract 3951: EphA10 exhibits anti-apoptotic activity through its dominant-negative role for EphA signaling in cancer cells
Authors: Sato Shuji , Tanaka Hiroshi , Hikichi Yuichi , Sunahara Eiji , Kaieda Isao , Ishii Takafumi , Yoshimura Koji 
Published: February 2011

Abstract
Eph receptors are members of receptor tyrosine kinase family. They are activated by binding of their ligands, ephrins, which regulate numerous physiological responses, including axon guidance, and pattern formation during development. In addition to their important roles during development, several members of the Eph receptor family have been reported to function in carcinogenesis. Recently EphA10 was isolated as the 16th member of the Eph receptor family. EphA10 is expressed in normal testis and binds to ephrin-A. However, biological functions of EphA10 remain unclear. We demonstrate here that EphA10 functions as a dominant-negative receptor for EphA signaling.
Our results show that EphA10 is over-expressed in cancer tissues, especially breast and lung cancer tissues as compared with patient-matched adjacent normal tissues. EphA10 binds to ephrin-A2, 3, 4, and 5. Analysis of the amino acid sequence of EphA10 revealed that EphA10 does not have Lys and Asp in the kinase domain, which are necessary for kinase activity nor two Tyr in the juxtamembrane domain, which are necessary for phosphorylation. As expected from the amino acid sequence, no intrinsic tyrosine kinase activity of EphA10 was detected despite its interaction with ephrin-A. To further investigate the mechanism of EphA10 signaling, we tested the role of EphA10 in modulating ephrin-A4 activity. In our experiment, ephrin-A4 suppressed phosphorylation of ERK1/2 in HEK293 cells. EphA10 over-expression in HEK293 cells reduced the effect of ephrin-A4 on ERK1/2. Conversely, reduction of EphA10 expression by antisense oligonucleotides induced apoptosis in the breast cancer cell line ZR-75-1. In addition to its role in shunting ephrin-A response through binding to ephrin-A directly, we found that EphA10 formed a hetero-complex with functional EphA7, suggesting that EphA10 may block EphA signaling by forming non-functional hetero complexes with other functional EphA receptors.
Our studies demonstrated that EphA10 has anti-apoptotic function in cancer cells by blocking EphA signaling through its dominant-negative activity. Thus, EphA10 potentially plays an important role in cancer cell survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3951.
Abstract 3956: Hedgehog acyltransferase: A key player in Sonic hedgehog signalling in cancer cells
Authors: Jovanovic Biljana , Chang Shu-Chun , Koleva Mirella , Magee Anthony I. 
Published: February 2011

Abstract
Protein acyltransferases (PATs), a group of enzymes that catalyze acylation of a variety of proteins, have recently been shown to play an important part in protein sorting and signalling in the cell. In the Sonic hedgehog (Shh) signalling pathway the PAT Hedgehog acyltransferase (Hhat) is responsible for addition of a palmitic acid (C16) to the N-terminal cysteine residue of Shh. In mice, this modification has been shown to be necessary for proper packaging and release of Shh from the signalling cell as well as for transmitting a potent signal to the receiving cell, rendering Hhat crucial for a functioning Shh signal. Aberrant regulation of the Shh signalling pathway leads to a variety of malignant diseases in adults. Oncogenic activation of the Shh signalling pathway is known to arise from excessive production of the Shh signal or oncogenic mutations in the signal receiving cell. To date, drug therapies targeting the pathway in cancer have been directed at Shh-independent mutations in downstream regulators, Ptch, Smo, and Su(Fu), in the signal-receiving cell. To complement this, we hypothesize that Hhat is a potential drug target in cancers dependent on excessive Shh production for their growth. Here, we validate the potential of Hhat as a therapeutic target in cancer cell lines dependent on Shh for their growth. By knocking down Hhat in established cancer cell lines using siRNA we show that proper distribution and signalling by Shh can be inhibited. We measure the effect of the knock-down on target gene expression of the pathway (Ptch and Gli1), cancer cell growth and invasive properties of the cells. The effect is validated against inhibition of the Shh pathway by the Shh blocking antibody 5E1, and KAAD-cyclopamine, a Smo antagonist.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3956.
Abstract 3963: Wnt-Signaling regulates angiogenesis by regulating Neuropilin-1 expression in osteosarcoma
Authors: Ghaffar Samia , Guo Yi , McQueen Peter , Christ Alex , Tu Khoa , Xie Jun , Zi Xiaolin , Hoang Bang 
Published: February 2011

Abstract
Purpose of Study: To investigate the role of the Neuropilin-1 (NRP-1) in angiogenesis and regulation by Wnt-signaling pathway in osteosarcoma (OS) cell lines.
Methods: In vitro tube formation assay using HUVEC cells to examine the effect of Frzb, WIF1, and DKK3 on angiogenesis. Microarray and real-time PCR to assess the mRNA level of NRP-1 in SaOS-2 cells transfected with Dominant Negative LRP5 (DNLRP5) and PcDNA vector control. Western blots were performed to evaluate the expression of NRP-1 in 8 OS cell lines and normal osteoblast (NHOst), as well as the effect of Wnt inhibitors (DNLPR5, Frzb, WIF-1, DKK3) on NRP-1 expression in OS cell lines (LM7, 143B, and 143.98.2)
Results: In order to develop a new therapeutic target for OS, the most common primary malignant bone tumor, we examined the expression of NRP-1 and vascular endothelial growth factor (VEGF) in 8 established OS cell lines, as well as NHOst. Both VEGF and NRP-1 (a co-receptor of VEGF) were up-regulated in most OS cell lines compared with normal osteoblast, suggesting that VEGF and NRP-1 may be responsible for the excessive blood vessel formation in OS. Given our previous report that Wnt inhibitors Frzb, WIF1, DKK3, and DNLRP5, inhibited tumor growth and metastasis of OS, we hypothesize that one of the potential mechanisms may be through inhibition of tumor angiogenesis. When HUVEC assay was examined, DKK3, Frzb, WIF-1 condition medium significantly inhibited tube formation compared with control, suggesting that these Wnt inhibitors suppressed angiogenesis. Further microarray assay, real time PCR and western blots indicated that these Wnt inhibitors (DKK3, Frzb, WIF-1 and DNLRP5) dramatically down-regulated the expression of NRP-1, but VEGF level remained unchanged. These results show that inhibition of angiogenesis by Wnt signaling may be mediated by down-regulation of NRP-1 instead of VEGF.
Discussion and Conclusions: Our study suggests that the Wnt-signaling reduces tumor growth and metastasis by inhibiting angiogenesis and by down-regulating NRP-1 expression in OS. We are further studying the role of NRP-1 in osteosarcoma by knockdown of NRP1 expression in OS cells to assess tumor proliferation, metastases and angiogenesis. This may represent a novel therapeutic strategy for osteosarcoma.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3963.
Abstract 3965: Geldanamycin-induced heat shock protein 70 negatively regulates TGF-β signaling through interaction with TGF-β receptors
Authors: Lee Ho-Jae , Yoon Sun-Young , Nguyen Thuy Trang , Cho Han-Yang , Kim Tae-Hyun , Jeon Woo-Kwang , Kim Byung-Chul 
Published: February 2011

Abstract
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that plays important roles in a variety of physiological processes including cell proliferation, differentiation, and apoptosis. Dysregulation of TGF-β signaling has been implicated in the pathogenesis of a variety of diseases including cancer; therefore, pharmacological inhibitors that target the TGF-β signaling pathway might be promising drugs for disease therapy. In this study, we investigated the mechanism of inhibition of TGF-β signaling by the Hsp90 inhibitor geldanamycin (GA). Treatment with GA suppressed TGF-β signaling, as evidenced by inhibition of TGF-β-induced phosphorylation and transcriptional activity of Smad3 and decreased induction of target genes. Western blot analysis revealed that GA induced degradation of TGF-β type I and type II receptors through a proteasome-dependent pathway. Hsp70 interacted directly with TGF-β receptors following GA treatment. Notably, induction of Hsp70 by GA correlated with inhibition of TGF-β signaling. Suppression of Hsp70 expression by Hsp70 siRNA or KNK437, an inhibitor of Hsp70 synthesis, blocked the inhibition of TGF-β signaling by GA. Furthermore, down-regulation of endogenous Hsp70 enhanced TGF-β induced transcriptional activity and cell cycle arrest. These results strongly suggest that GA-induced Hsp70 acts as a negative regulator of TGF-β signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3965.
Abstract 3979: In vitro modeling of pharmacodynamics of resveratrol-induced anti-proliferation in breast cancer cells
Authors: Li Hongyu , Melaney Elliot , Lin Sharon , Rubin Noah , Bender Charles , Meng Ran , London David , Tang Heng-Yuan , Lin Hung-Yun 
Published: February 2011

Abstract
We and others have shown that resveratrol, a naturally-occurring stilbene, induces p53-dependent apoptosis in human and animal cancer cell lines. The molecular basis of induction of apoptosis by resveratrol includes activation and nuclear translocation of mitogen-activated protein kinase (MAPK; ERK1/2) and MAPK-mediated Ser-15 phosphorylation of p53 (pSer15-p53). In this study, we used a newly developing perfusion bellows cell culture system to investigate resveratrol-induced apoptosis in the human estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells. The cell culture system is a disposable bioreactor capable of high density cell culture for studies of anti-cancer drugs. Bellows-induced alternate flow of culture medium and air through porous matrices where cells are grown provides a relatively low shear, high aeration, foam-free culture environment. Medium level is raised and lowered to submerge and expose matrices to create a dynamic interface between air and media on the cell surface. Anchorage-dependent cells are grown on plastic flakes in the system; the flakes facilitate harvesting of whole cells for analysis. After 6 days incubation, the IC50 of resveratrol-induced apoptosis was 0.1 μM. Short term incubation with 10 μM resveratrol for 6 days inhibited cell proliferation by 75%. Using an injection system to pump media with different concentrations of resveratrol (0.5 μM to 100 μM), we were able to reproduce the resveratrol-induced anti-proliferation effect in the perfusion bellows culture system. Incubating the cells in either acidic or alkaline condition did not affect anti-proliferation induced by resveratrol. The effect of resveratrol-induced apoptosis is based on increasing transcription of pro-apoptotic p53-dependent genes such as PIG3, c-fos, c-jun and BAD. The aim of the present study is to establish the pharmacodynamics of resveratrol in the suppression or elimination of human breast cancer cells. With the use of the perfusion bellows cell culture system we will provide an efficient, convenient and financially beneficial method for determining optimal regimens for the effective suppression and elimination of these cancer cells.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3979.