bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-322: A modified HER2/neu peptide vaccine (2L9V-GP2) demonstrates enhanced CD8+ T cell recognition and stimulation in breast cancer patients at high risk for recurrence
Authors: Patil Ritesh , Clifton Guy T. , Clive Kevin , Tyler Josh , Zacharia Athina , Jama Yusuf , Mursal Mohamed , Ciano Kathy , Holmes Jarrod P. , Mittendorf Elizabeth A. , Peoples George E. , Ponniah Sathibalan 
Published: February 2011

Abstract
Introduction: The affinity between tumor-associated antigens and MHC Class I complexes directly affects the degree of CD8+ T cell (CTL) response. GP2 (IISAVVGIL, p654-662) is a HER2/neu-derived peptide, that has poor binding affinity to HLA-A2 (A2) and HLA-A3 (A3). We conducted a preclinical study to determine if amino acid substitutions in the GP2 peptide, predicted to increase binding affinity to A2 and A3, enhance CTL recognition and stimulation.
Methods: Based on computer modeling algorithms (BIMAS, SYFPEITHI), two GP2 peptide variants were predicted to have higher binding affinity to A2: SPA-12(2L9V-GP2) and SPA-13(2L5L9V-GP2). Freshly isolated PBMCs were obtained from randomly chosen, disease-free, node positive (NP) and high risk node negative (NN) breast cancer (BCa) patients, who had completed standard adjuvant therapy and are enrolled in the E75 vaccine booster trial. Peptide-specific CD8+ T cells were measured by HLA-A2: IgG dimer (A2 pts) and by interferon-γ ELISPOT (A2, A3 pts) assays. Groups were compared by t-test (dimer) and Mann-Whitney U (ELISPOT) tests.
Results: Thirty-five A2 (21 NP, 14 NN) and thirteen A3 (13 NP) samples were included in the study. Among A2 pts, the mean level of SPA-12-specific CTLs was greater than the GP2- (2.8±0.3% vs. 1.7±0.1%, p&lt;0.001) and SPA-13-specific CTLs (2.8±0.3% vs. 1.1±0.1%, p&lt;0.001). The level of SPA-13-specific CTLs was less than GP2-specific CTLs (p&lt;0.001). For both A2 and A3 pts, the median number of IFN- producing cells was greater in response to SPA-12 (144, range 0-799 spots/105 cells) compared to GP2 (88, range 0-432 spots/105 cells, p=0.03) and SPA-13 (0, range 0-344 spots/105 cells, p&lt;0.001). Again, the response to SPA-13 was less than GP2 (p=0.001). In addition, the NP A2 pts demonstrated a more robust CD8+ T cell response to SPA-12 compared to the NNs, both by HLA-A2: IgG dimer (3.2±.5 vs 2.2±0.2, p=0.05) and ELISPOT assay (223, range 0-799 vs 65, range 0-548 p=0.003). Nodal status did not have any significant bearing on the responses to GP2 and SPA-13.
Conclusion: The substituted sequences SPA-12 (2L9V-GP2) and SPA-13 (2L5L9V-GP2), both have higher predicted binding affinity to A2 and A3 than GP2. While SPA-12 showed significantly increased recognition and functional CTL responses compared to GP2, SPA-13 demonstrated lower responses. These data suggest that SPA-12 may be a more effective cancer vaccine than GP2, particularly in NP BCa patients.
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 LB-322.
Abstract LB-326: Synergistic therapeutic effects of cytokine-induced killer (CIK) cell and temozolomide against glioblastoma
Authors: Jin Younggeon , Jin Juyoun , Joo Kyeung Min , Lee Se Jeong , Jo Mi-young , Kim Yonghyun , Nam Do-Hyun 
Published: February 2011

Abstract
The presence of active immunity within the brain supports the possibility of effective immunotherapy for glioblastoma (GBM). To provide a clinically-relevant adoptive immunotherapy for GBM using ex vivo expanded cytokine-induced killer (CIK) cells, the treatment capability of CIK cells, either alone or in combination with temozolomide (TMZ) were evaluated. Human CIK (hCIK) cells were cultured from PBMC using activating anti-CD3 antibody and IL-2, which were 99% CD3+, 91% CD3+CD8+ and 29% CD3+CD56+. In vitro, hCIK cells showed tumor-specific cytotoxicity against U-87MG human GBM cells. When hCIK cells were injected into tail veins of immune-compromised mice bearing U-87MG tumors in their brains, numerous CIK cells infiltrated into the brain tumors. CIK treatments (1 × 105, 1 × 106 or 1 × 107, once a week for four weeks) inhibited the tumor growth significantly in a dose-dependent manner; 44%, 54% and 72% tumor volume reduction, respectively, compared with the control group (P &lt; 0.05). Moreover, hCIK cells (1 × 107, once a week for four weeks) and TMZ (2.5 mg/kg, daily for 5 days) combination treatment further increased tumor cell apoptosis and decreased tumor cell proliferation and vessel density (P &lt; 0.05), creating a more potent therapeutic effect (95% reduction in tumor volume) compared with either hCIK cells or TMZ single therapy (72% for both, P &lt; 0.05). Taken together, CIK cell-immunotherapy and TMZ chemotherapy have synergistic therapeutic effects and could be combined for a successful treatment of GBM.
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 LB-326.
Abstract LB-332: MDM4 transcription is discordantly regulated by common variants of p53
Authors: Bainer Russell , Marioni John , Barriero Luis , Blekhman Ran , Onel Kenan , Gilad Yoav 
Published: February 2011

Abstract
The transcription factor p53 is a central mediator of the DNA damage response programs controlling cell cycle arrest and apoptosis that are critical to the prevention of oncogenesis. Although p53 has been subject to intense study, the functional consequences of the common proline to arginine coding polymorphism at codon 72 have yet to be fully elucidated. We hypothesized that the previously reported difference in apoptotic potential between cells expressing the two common p53 alleles may be due in part to differences in each variant's ability to transcriptionally regulate downstream target genes. To test this, we used a combination of expression profiling and ChIP-on-chip techniques to identify differences in the transcriptional networks regulated by the alternate alleles of p53 in isogenic cell lines. Our results indicate that although the majority of p53 transcriptional targets are equivalently regulated by both allelic variants, a small number of genes are specifically regulated by the respective versions of p53. Surprisingly, among the genes differentially induced by alternate p53 variants is MDM4 (HDMX), a well-characterized regulator of p53 activity. We subsequently used luciferase expression assays to identify a functional site containing a putative p53 binding element within the MDM4 promoter that discordantly interacts with the two p53 variants. These data provide the first evidence that MDM4 transcription is directly mediated by p53, and suggest a mechanism that could contribute to previously-reported differences in apoptotic potential between the common p53 alleles.
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 LB-332.
Abstract LB-333: A CREBZF/Zhangfei isoform activates CHOP and promotes apoptosis during prolonged endoplasmic reticulum stress
Authors: Li Yu , Zhang Yani , Audas Timothy E. , Martyn Amanda C. , Lu Ray 
Published: February 2011

Abstract
The basic leucine zipper transcription factor CREBZF (Zhangfei or ZF) was identified through its interaction with Herpes Simplex Virus-1 related cellular protein HCF-1, and has been implicated in cellular stress responses through its interaction with other proteins, such as CREB3/Luman and ATF4. Here we investigated the production of four CREBZF isoforms, which arise from translational initiation of a downstream AUG at codon 83 and mRNA alternative splicing that adds an IFFFR pentapeptidyl tail to the C-terminus. We found that in addition to transcriptional induction, the short-tailed CREBZF (stZF) isoform was specifically induced by prolonged ER stress treatment and amino acid deprivation. This stZF isoform is a potent transcriptional activator of the pro-apoptotic protein CHOP. Overexpression of stZF activates transcription of CHOP through a CCAAT enhancer binding protein (C/EBP)-ATF site, and promotes apoptosis. We propose that 1) CREBZF is a key component of the integrated stress response; 2) stZF is tightly regulated and induced primarily under prolonged cellular stress, and is essential for the role of CREBZF in inducing CHOP and promoting cell death.
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 LB-333.
Abstract LB-336: A novel pathway for CXCR3-B-mediated growth inhibitory signals in renal cancer
Authors: Datta Dipak , Pal Soumitro 
Published: February 2011

Abstract
Chemokines and their receptors are classically known to be involved in tumor cell migration playing a critical role in tumor metastasis. However, their role in regulating direct tumor growth is under appreciated. Although chemokine receptor CXCR3 and their ligands have tumor inhibitory properties, some recent reports suggest that they may also promote tumor growth. We recently reported that this controversy in the function of CXCR3, in terms of tumor inhibition vs. progression, is in part related to the observation that CXCR3 is alternatively spliced producing two variants called CXCR3-A (promoting cell proliferation) and CXCR3-B (mediating growth inhibition). Previously, we observed that the expression of CXCR3-B is markedly downregulated in human renal cancer and overexpression of CXCR3-B in renal tumor cells inhibited endogenous tumor cell proliferation. We hypothesize that CXCR3-B-mediated growth inhibitory signals are one of the crucial factors for the renal cancer cell proliferative response. To dissect the inhibitory signals mediated by CXCR3-B, we first overexpressed CXCR3-B in renal cancer cells (Caki-1 and 786-O) using an overexpression plasmid, and validated the overexpression of CXCR3-B at both mRNA and protein levels by realtime PCR and FACS analysis. As CXCR3-A is known to mediate its proliferative signals through Akt, we first evaluated the status of phospho-Akt in CXCR3-B overexpressed cells compared to control by western blot analysis. We did not find any significant change in the phospho-Akt level in our CXCR3-B overexpressed cells. However, we observed marked cell death (apoptosis) in these CXCR3-B overexpressed cells especially under stress, like serum deprivation. To further understand the anti-proliferative or pro-apoptotic signals through CXCR3-B, we checked the expression pattern of 24 different genes that are related to either cell death or survival by performing a protein array. We found the selective reduction of cytoprotective hemeoxygenase-1 (HO-1) or Heat Shock Protein-32 (HSP-32) gene expression in CXCR3-B overexpressed cells compared with control cells. We also validated the downregulation of HO-1 protein expression by western blot analysis. HO-2 and some important genes directly related to apoptosis (DR4 and DR5) remained unaltered in these CXCR3-B overexpressed cells. Together, HO-1 is known to promote cell survival under stress-induced responses; in this condition, CXCR3-B overexpression may inhibit renal cancer cell proliferation/survival through downregulation of HO-1 expression. Thus, our study defines a novel mechanism of CXCR3-B mediated cell death in human renal cancer.
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 LB-336.
Abstract LB-352: B-CLL phenotype in Eµ-miR-29 transgenic mice
Authors: Santanam Urmila , Zanesi Nicola , Efanov Alexey , Palamarchuk Alexey , Costinean Stefan , Hagan John , Croce Carlo , Pekarsky Yuri 
Published: February 2011

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the western world. Human B-CLL occurs in two forms: aggressive (showing high ZAP-70 expression and unmutated IgH VH) and indolent (showing low ZAP-70 expression and mutated IgH VH). We found that miR-29a is upregulated in indolent human B-CLL compared to aggressive B-CLL and normal CD19+ B-cells. To study the role of miR-29 in B-CLL, we generated Eµ-miR-29 transgenic mice overexpressing miR-29 in mouse B-cells. Flow cytometric analysis revealed a markedly expanded CD5+ population in the spleen of these mice starting at 2 months of age. Over 80% of miR-29 transgenic mice exhibited an expanded population of CD5+ B-cells, a characteristic of the B-CLL phenotype. An average of 56% of the B-cell population in these transgenics were CD5 positive. At the age of 2 years these mice showed significantly enlarged spleens and an increase in CD5+ B-cell population of up to 100% of B-cells. Over 8% (3/36) of Eµ-miR-29 transgenic mice developed frank leukemia and prematurely died from the disease at the age of 24-26 months. The expanded CD5+ B-cell population was found to be proliferative, with an increased number of cells in the S-phase of the cell cycle, compared to wild type CD19+ B-cells. These results suggest that deregulation of miR-29 can cause, or at least significantly contribute to the pathogenesis of indolent B-CLL.
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 LB-352.
Abstract LB-363: Inhibition of placental growth factor (PlGF) leads to regression of medulloblastoma
Authors: Snuderl Matija , Kirkpatrick Nathaniel D. , Walsh Elisa C. , Chung Euiheon , Kamoun Walid S. , Peterson Teresa E. , Munn Lance L. , Duda Dan G. , Fukumura Dai , Carmeliet Peter , Xu Lei , Jain Rakesh K. 
Published: February 2011

Abstract
Introduction: Medulloblastoma contains a rich and abnormal vascular network offering a potential target for anti-angiogenic treatment. However, in pediatric patients anti-VEGF treatments may have serious adverse effects and other antiangiogenic drugs have not shown efficacy. Placental growth factor (PlGF) is a mediator of post-natal pathological angiogenesis, and its inhibition may not be associated with significant side effects. Here, we examine the role of PlGF in medulloblastoma growth and as a target for therapy in this pediatric brain tumor.
Methods: Tissues collected from 5 pediatric medulloblastomas and 4 adult cerebelli were screened for 96 genes associated with angiogenesis using a commercially available PCR array. Immunohistochemistry was performed on 14 formalin fixed paraffin embedded (FFPE) medulloblastoma samples. D283Med and D341Med human medulloblastoma cells were transfected with Gaussia luciferase cDNA and implanted orthotopically into cerebelli of SCID mice. Tumor growth was followed by whole body imaging and blood Gluc assay. Tumor-derived PlGF was blocked by anti-PlGF antibody (PL5D11D4, ThromboGenics) or silenced by siRNA. WST-1 Cell Proliferation Assay was performed to explore direct effects of anti-PlGF Ab in vitro.
Results: PlGF was not expressed in adult cerebelli and was overexpressed in all medulloblastomas tissues and cell lines by PCR. Twelve of fourteen (85%) FFPE medulloblastomas showed expression of PlGF by immunohistochemistry. Mice with implanted medulloblastoma cells with PlGF silenced by siRNA or blocked by the antibody from the day of implantation showed a significant delay in tumor growth (p &lt; 0.0001) and prolonged survival (p = 0.003) when compared to control IgG-treated mice. Treatment of established tumors with anti-PlGF antibody - started at ∼3 weeks post-implantation - showed stabilization of disease and regression of medulloblastomas (p = 0.017) by Gluc and whole body imaging measurements, and prolongation of survival (p = 0.0009). However, in vitro we found no direct effect of anti-PlGF treatment on tumor cells. Further mechanistic findings will be presented at the meeting.
Conclusion: PlGF is highly expressed in medulloblastomas. Mice bearing orthotopic tumors showed significantly delayed tumor growth and longer survival after PlGF inhibition. Thus, PlGF targeting in these tumors may provide a safe and efficient therapy for pediatric medulloblastoma.
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 LB-363.
Abstract LB-368: III-tubulin knockdown in endothelial cells increases the antivascular activity of chemotherapeutic drugs
Authors: Pasquier Eddy , Sinnappan Snega , Verdier-Pinard Pascal , Braguer Diane , Kavallaris Maria 
Published: February 2011

Abstract
The microtubule cytoskeleton plays a crucial role in tumor angiogenesis, as evidenced by the potent anti-vascular properties of microtubule-targeting anticancer agents (MTAs). Accumulating evidence shows that the expression level of β-tubulin isotypes influences drug response and βIII-tubulin in particular has been involved in cancer cell resistance to MTAs as well as other classes of chemotherapeutic agents (1). However, the role of β-tubulin isotypes in the context of tumor angiogenesis and anti-vascular therapy remains unknown. Comparative western blot analysis revealed that human vascular endothelial cells express relatively high levels of βII- and βIII-tubulin. Using siRNA gene silencing, we effectively suppressed the expression levels of βII-and βIII-tubulin isotypes in vascular endothelial cells, by 90% and 80%, respectively. Functional analysis showed that βII-tubulin expression did not significantly influence either the capacity of endothelial cells to form vascular structures on Matrigel or the anti-vascular properties of MTAs. In contrast, knocking down the expression of βIII-tubulin in endothelial cells significantly inhibited the formation of capillary-like structures on Matrigel by 18 ± 3 % (p&lt;0.001). Furthermore, the anti-angiogenic activity of the microtubule-stabilizing agent, paclitaxel, and the microtubule-depolymerizing agents, vinblastine and 2-methoxyestradiol (2-ME2), was significantly increased between 1.6 and 2.5-fold (p&lt;0.05) in βIII-tubulin knockdown endothelial cells, as compared to control siRNA and βII-tubulin knockdown cells. Similarly, the vascular-disrupting activity of ENMD-1198, a new analog of 2-ME2, was also increased by 2.2-fold (p&lt;0.05) in βIII-tubulin knockdown endothelial cells. More broadly, βIII-tubulin knockdown in endothelial cells also increased the anti-angiogenic activity of other classes of chemotherapeutic drugs, such as topoisomerase inhibitor etoposide (18 ± 1%, p&lt;0.01) and alkylating agent cyclophosphamide (35 ± 5%, p&lt;0.05). Altogether these results strongly suggest that βIII-tubulin may play a role in tumor angiogenesis and influence the anti-vascular activity of chemotherapeutic drugs. Further investigations are currently underway to unravel the underlying mechanisms.
References
1. Gan P., Pasquier E. and Kavallaris M. Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non-small cell lung cancer. Cancer Res. 2007, 67: 9356-9363.
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 LB-368.
Abstract LB-377: Regulation of expression of choline kinase by a conserved HIF1 binding hypoxia-responsive element
Authors: Bansal Aditya , Harris Robert A. , DeGrado Timothy R. 
Published: February 2011

Abstract
Hypoxic microenvironment and overexpression of choline kinase alpha (ChKa) have been associated with tumor malignancy, but the regulation of ChKa expression in hypoxic conditions is poorly understood. In this study, the effects of chronic hypoxia on choline metabolism and ChKa expression were examined in prostate cancer cell line, PC-3. Chronic hypoxia (1% O2, 24h) decreased proliferation rate and intracellular levels of phosphocholine, while intracellular levels of free choline were increased. Choline tracer uptake and washout studies confirmed the decreased rate of choline phosphorylation in hypoxic cells. Overexpression of HIF1a or DMOG exposure in normoxic PC-3 cells decreased both choline uptake and choline kinase activity. RT-PCR analysis showed decreased transcription of ChKa gene in hypoxic PC-3 correlating with decreased enzymatic activity of choline kinase in hypoxic cell extracts. Alignment of nucleotide sequence of the putative promoter region of ChKa from rat, mouse, chimpanzee and human revealed a highly conserved hypoxia responsive element upstream to transcription start site of ChKa. Electrophoretic mobility shift competition/supershift assay and chromatin immunoprecipitation-quantitative PCR assay confirmed binding of native HIF-1α protein to the conserved HRE. To understand the transcription control of ChKa under hypoxia, a putative promoter of ChKa was isolated from PC-3 genomic DNA and cloned into a luciferase (Luc) based reporter vector system. In PC-3, hypoxia decreased the expression of Luc under the control of the ChKa promoter. Mutation of the conserved HRE and subsequent Luc reporter assays demonstrated that this HRE is involved in hypoxia/HIF1α mediated regulation of ChKa. The results suggest that the decreased choline phosphorylation in PC-3 cells in response to hypoxia is mediated in part by the newly-identified conserved HIF1α binding HRE.
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 LB-377.