bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2935: Modulation of immune checkpoint B7-H1/B7-DC/PD-1 interaction in combination with live attenuated Listeria monocytogenes expressing a tumor associated antigen effectively treats hepatic colorectal cancer metastases
Authors: Yoshimura Kiyoshi , Olino Kelly , Edil Barish , Wada Satoshi , Pan Xiaoyu , Meckel Kristen , Pardoll Drew , Schulick Richard 
Published: February 2011

Abstract
Introduction: The successful eradication of tumor deposits by immunotherapy requires the generation of an appropriate primary and memory immune effector immune response as well as the establishment of a tumor micro-environment within that organ to target, traffic and amplify the appropriate immune response. B7-H1 is expressed on dendritic cells (DCs), macrophages, T/B cells and on various cancer cell lines. B7-H1 when bound to its T-cell receptor, programmed death-1 (PD-1) induces a negative regulatory signal inhibiting T cell responses. These are particularly attractive targets of therapy in metastatic colorectal cancer as the cancer and the liver microenvironment express B7H1, while tumor infiltrating CD8+ T cells express PD-1. It appears that cancer is able to exploit the B7H1-PD-1 inhibitory mechanism thus making the blockade of this interaction capable of enhancing our already validated vaccine platform of doubly attenuated Listeria Monocytogenes (LM).
Methods and Results: Isolated hepatic metastases were generated in Balb/c mice and treated with intraperitoneal injections of 0.1 x LD50 of LM on postoperative days 3, 6, 9. In addition, intravenous injection of a mouse anti-mouse B7-H1 blocking antibody was given on days 4,7,10 and compared to mice given vaccine alone, antibody alone, and no treatment. We analyzed immune cell populations in the liver with flow cytometry to define the activity, specificity and kinetics. After blockade of B7-H1 we performed survival analysis and in vitro studies for T cell proliferation of activated T cells.
Results: Mice treated with LM and B7-H1 showed a 60% survival, LM alone showed 30% survival, while antibody alone and untreated mice did not survive (Figure 1). We first demonstrated B7-H1 expression on colon cancer cell line CT26. We then found CD8+ T cells and conventional dendritic cells (cDC) treated with LM, showed an up-regulation of B7-H1. However, these receptors upregulation were both abgrogated when combined with B7H1 blocking antibody. When B7H1 blocking antibody was used alone, there was a decrease in B7H1 expression but an increased expression on PD-1 on CD8+ T cells. T cell proliferation assay in vitro showed sustained T cell activity with B7-H1 blockade even in the presence of tumor.
Conclusion Blockade of B7-H1 is an effective method of overcoming immune evasion and improves the efficacy of LM vaccine in the treatment of metastatic colorectal cancer to the liver.
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 2935.
Abstract 2947: Knockdown of splicing factor SRp20 induces apoptosis in ovarian tumor cells
Authors: He Xiaolong , Arslan Ahmet D. , Ho Tsui-Ting , Beck William T. 
Published: February 2011

Abstract
SRp20 is a member of the serine/arginine-rich (SR) protein family with multiple functions in RNA processing such as alternative splicing and polyadnylation. Our previous studies found that SRp20, together with another splicing factor, polypyrimidine tract-binding protein (PTB), is up-regulated in human ovarian tumors compared to normal ovarian surface epithelia (He, X et al, Clin Cancer Res, 10:4652). In order to determine whether overexpressed SRp20 is required for ovarian tumor cell growth, we studied the effects of SRp20 knockdown in several ovarian cancer cell lines. The knockdown of SRp20 expression was achieved by lentivirus-delivered, doxycycline (Dox)-induced siRNAs. We identified two effective siRNAs against SRp20, SRp20si1 and SRp20si2, which can suppress SRp20 expression by approximately 50% and 90%, respectively. In ovarian cancer cell lines A2780, SKOV3 and IGROV1, knockdown of SRp20 by either SRp20 siRNA caused substantial inhibition of cell growth and colony formation in soft agar. The degree of inhibition correlated with the extent of SRp20 suppression. Massive down-regulation of SRp20 expression by SRp20si2 led to almost complete loss of A2780's capability to form colonies in soft agar. Moreover, Hoechst 33342 staining revealed that the percentage of apoptotic cells was remarkably increased when SRp20 was knocked down ∼90% by SRp20si2. In contrast, moderate suppression (∼50%) of SRp20 by SRp20si1 did not trigger apoptosis. These results suggest that overexpression of SRp20 is required for ovarian cancer cell growth and survival. To determine which apoptotic pathway is activated by SRp20 knockdown, we examined the cleaved fragments of several caspases by immunoblotting and found that caspases 9, 3 and 7 but not caspases 2 and 8were cleaved in cells with SRp20 knocked down by SRp20si2. These results imply that the intrinsic apoptotic pathway is activated by massive SRp20 knockdown. In support of this, we also observed a substantial down-regulation of Bcl-2, a major anti-apoptotic regulator of the intrinsic apoptotic pathway, in the above cells. How SRp20 regulates Bcl-2 expression is unclear at present and currently under investigation. (Supported in part by CA40570 and CA138762 from NCI (to WTB), in part by OCRF (to XH), and in part by UIC).
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 2947.
Abstract 2948: Nicotine-induced expression of MUC4 in pancreatic cancer cells is mediated by E2F1 and STAT-1 upregulation: Relevance to smoking and pancreatic cancer
Authors: Kunigal Sateesh S. , Batra Surinder K. , Chellappan Srikumar P. 
Published: February 2011

Abstract
The membrane-bound mucins belong to an ever-increasing family of O-glycoproteins. Based on their structure and localization at the cell surface they are thought to play important biological roles in cell-cell and cell-matrix interactions and cell signaling. The human mucin gene MUC4 is overexpressed in pancreatic cancer and cancer cell lines, while remaining undetectable in the normal pancreas, indicating its potential role in pancreatic cancer pathogenesis. Smoking has been correlated with pancreatic cancer, even though the underlying molecular mechanisms are unknown. Attempts were made to elucidate the molecular mechanisms involved in the regulation of MUC4 gene expression by nicotine as well as cytokines. In this report, we used pancreatic cancer cell lines CD18 as well as PANC1 stimulated with nicotine to identify the signaling pathways and transcription factors regulating MUC4 expression. Through chromatin immunoprecipiation assay and real-time PCR, we found that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression. Additionally, the effect is abrogated by short interfering RNA (siRNA)-mediated inhibition of E2F1 and STAT-1 expression, supporting pivotal role played by E2F1 and STAT-1 in MUC4 regulation. The same molecules were responsible for MUC4 induction by nicotine in combination with IFN- and RA. Inhibiting the acetylacholinergic receptors with inhibitors reversed the effects of nicotine stimulation. Similarly, the induction was dependent on the PI3 kinase as well as Src signaling pathways. Additionally, nicotine treatment alone and in combination with IFN- and RA activates and relocalizes signal transducer and activator of transcription-1 (STAT-1) via phosphorylating Jak2 at the tyrosine residue to induce MUC4. These results suggest that nicotine alone and also in combination with IFN- and RA, upregulates the MUC4 expression involving JAK-STAT pathway. In conclusion, our findings identify novel mechanisms for MUC4 regulation in pancreatic cancer cells and will be helpful understanding the transcriptional regulation of MUC4 in response to exposure to nicotine and tobacco smoke.
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 2948.
Abstract 2949: The VEGF quadruplex-forming sequence inhibits cell growth of lung cancer
Authors: Thomas Shelia D. , Grant Campbell M. , Clarkson Cortney R. , Miller Donald M. , Sedoris Kara C. 
Published: February 2011

Abstract
Vascular endothelial growth factor (VEGF), commonly overexpressed in a variety of malignancies including lung cancer, is a key regulator of angiogenesis promoting tumor survival, growth, and metastasis. The promoters of several cancer-related genes, including VEGF, contain disproportionate sequences within nuclease hypersensitivity regions capable of forming quadruplex (four-stranded) DNA. The VEGF quadruplex-forming sequence (VEGFq), a polyG/polyC tract located in the proximal promoter region upstream of the transcription initiation site, has been implicated in the regulation of both basal and inducible VEGF expression. However, the biological role of this sequence remains unclear. We hypothesize that treatment of A549 non-small lung cancer cells with VEGFq induces cell death by inhibiting gene expression. To determine the biological role of VEGF on lung cancer cell proliferation, A549 cells were treated with VEGFq or the corresponding mutant sequence (MutVEGF), which lacks runs of two or more guanines. Changes in cell proliferation were compared to levels of VEGF protein expression. Quadruplex formation was confirmed by circular dichroism spectroscopy. Our results demonstrate that VEGFq formed a stable parallel quadruplex structure, while the MutVEGF sequence did not form a quadruplex. Treatment of A549 cells with VEGFq caused a significant dose and time-dependent decrease in cell proliferation after 3 and 6 days (IC50&lt;5µM) as determined by MTT assay. No change in the growth of nontransformed fibroblast cells occurred in response to VEGFq indicating the effect is specific for malignant cells. Confocal and flow cytometry analysis of cells treated with FITC-labeled VEGFq or MutVEGF showed prominent uptake and nuclear localization of VEGFq not MutVEGF after 72 h. Inhibition of cell proliferation corresponded with decreased VEGF protein expression. No specific change in the cell cycle was measured after 72 h. These results demonstrate striking growth inhibition of A549 cells in response to the VEGF quadruplex-forming sequence related to inhibition of VEGF expression and suggest significant therapeutic implications for the treatment of non-small cell lung 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 2949.
Abstract 2957: Characterization of oral tumors by massively parallel ligation sequencing
Authors: Laborde Rebecca R. , Tuch Brian B. , Olsen Kerry D. , Kasperbauer Jan L. , Moore Eric J. , Barker Melissa A. , De La Vega Francisco M. , Smith David I. 
Published: February 2011

Abstract
Cancers of the head and neck rank as the 6th most commonly observed cancers worldwide with an average 5-year survival rate of only 50% for advanced disease. Nearly 95% of head and neck cancers are squamous cell carcinomas (SSC) and these are frequently highly invasive metastatic tumors. The newly developing technologies of Next Generation Sequencing have allowed for the most comprehensive genetic analysis of these cancers to date. We have taken 3 tumor/normal pairs from patients with oral squamous cell carcinoma and performed full transcriptome and mate-pair DNA sequencing analysis using the AB SOLiD system. These runs generated 129-256 million 50bp long sequence reads per sample, with 21 to 56 million reads per sample uniquely aligning to human genome sequence. Analysis of these samples has revealed pathways with aberrant expression in tumor versus normal tissue. Our results show up-regulation of some metalloproteinase genes, HGMA2, which is a prognostic marker for oral carcinoma, and extracellular matrix, adhesion, and motility gene classes in tumors. Our functional analysis also indicates extensive down-regulation, in the tumors, of genes functioning in epidermal development. We were also able to measure allelic specific expression for the 50% most highly expressed genes and detect examples of allelic imbalance linked to pathways with dysregulated gene expression. Additionally, the depth of sequencing that was achieved (5-16X coverage of RefSeq Exons) also allowed us to detect mutations occurring in the transcripts. We have also detected evidence of RNA editing associated with point mutations, which we are validating in a larger group of samples.
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 2957.
Abstract 297: Activating transcription factor 4 negatively regulates the mammalian target of rapamycin via Redd1 expression in response to 2-deoxyglucose
Authors: Jin Hyeon-Ok , Hong Seok-Il , Park In-Chul 
Published: February 2011

Abstract
Aerobic glycolysis is one of major metabolic changes found in cancer cells and is a valid target for cancer therapy. The nonmetabolizable glucose analogue, 2-deoxyglucose (2-DG) interferes with glucose metabolism and enhances chemotherapy/radiotherapy in cancer cells. We have investigated the mechanism of action by which 2-DG inhibits mammalian target of rapamycin (mTOR) activity. We found that 2-DG treatment led to decreased mTOR activity which was regulated by induction of Redd1 protein in both lung cancer cells and cervical cancer cells. We also found 2-DG treatment led to increased ATF4 protein expression and transcriptional activity. Suppression of ATF4 using siRNAs led to decrease of 2-DG induced Redd1 expression. Our data suggested that 2-DG induced Redd1 expression is regulated by the ATF4, leading to mTOR inhibition.
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 297.
Abstract 2973: Poly(ADP)ribose inhibition forces the repair of topoisomerase I cleavage complexes through homologous recombination and non-homologous end joining
Authors: Zhang Yongwei , Regairaz Marie , Seiler Jennifer , Agama Keli , Doroshow James , Pommier Yves 
Published: February 2011

Abstract
Poly(ADP-Ribose) polymerase (PARP) inhibitors represent a promising class of novel anticancer agents. In the present study, we explored the strategy of combining the classical topoisomerase I (Top1) inhibitor camptothecin (CPT) and the novel PARP inhibitor ABT-888 in human cancer cells. ABT-888 potentiated cell killing by CPT. By colony forming assay, the survival ratio of CPT-treated colon cancer HT-29 cells was 52%, while the survival fraction were decreased to 35% when HT-29 cells were co-treated with CPT and ABT-888. By measuring γH2AX, a DNA double-strand break marker, we found that ABT-888 enhanced the γH2AX level induced by CPT. The enhanced γH2AX response in the presence of ABT-888 affected both replication-related γH2AX but also transcription-related γH2AX. In osteosarcoma U2OS cells, ABT-888 also enhanced γH2AX in both EdU (5-ethynyl-2′- deoxyuridine) positive and negative cells. Even in non-replicating human primary lymphocytes, ABT-888 enhanced CPT-induced γH2AX foci (1.3 ± 1.2 vs. 5.1 ± 3.1 γH2AX foci/per cell in the absence and presence of co-treatment with ABT-888, respectively). Proteasome inhibition with MG-132 blocked the γH2AX induction by CPT, and PARP inhibition could not overcome the block, which demonstrates that PARP acts downstream from the proteasome. Neutral Comet assays showed that the enhanced γH2AX response was related to DNA breaks. Alkaline elution assays revealed that ABT-888 increased CPT-induced DNA single-strand breaks (SSBs) but without a corresponding increase in DNA protein crosslinks indicating that ABT-888 was inducing DNA breaks in addition to the Top1-DNA cleavage complexes trapped by CPT. These additional DNA breaks were dependent on XPF/ERCC1 endonuclease. Furthermore, after removing CPT, reversal of γH2AX in the absence or presence of ABT-888 showed the same reversal rate, although there was more γH2AX in the presence of ABT-888, suggesting that PARP inhibition did not affect the repair of double-strand breaks. Moreover, PARP inhibition enhanced DNA-PK and ATM activation with increased formation of Rad51 foci. Therefore, we propose that PARP inhibition forces the cells to activate alternative endonucleolytic and recombination pathways in response to Top1-mediated DNA damage.
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 2973.
Abstract 2976: Array comparative genomic hybridization analysis reveals distinct genetic alterations in African Americans with colon cancer
Authors: Brim Hassan , Lee Edward L. , Smoot Duane T. , Ashktorab Hassan 
Published: February 2011

Abstract
Purpose: Microsatellite Instability (MIN), CpG Island Methylation phenotype (CIMP) and Chromosomal Instability (CIN) are known processes through which colorectal cancer (CRC) can occur. In a given tumor, one or more of these events might be responsible for tumor development. We previously reported the results of our MSI and CIMP analysis of colorectal tumors in African Americans (AA), a group at high risk. Here, we report our array Comparative Genomic Hybridization (aCGH) analysis of 30 AA colorectal tumors and its implication for the understanding of CRC development in this population.
Experimental design: We applied aCGH using a 105k chip to identify copy number aberrations in samples from 30 AA colon cancer patients. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer candidate genes (CAN genes). Bioinformatics analysis was done to calculate the chromosomal imbalance using Agilent Genomic Workbench 5.0.
Results: There was an average of 30 aberrations per patient with all samples displaying some level of chromosomal instability. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to alterations in Caucasians (22 cases).
Conclusions: Prominent chromosome X amplification in male patients and chromosome 4, 8 and 18 deletions were the primary targets in AAs. Most CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. CIN seems to be more prominent in AAs and may play a distinctive role in CRC development in this population.
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 2976.
Abstract 2979: Tumor suppressor ING1b maintains genomic stability through PCNA monoubiquitination and histone H4 acetylation
Authors: Wong Ronald PC , Lin Hanyang , Chen David W. , Li Gang 
Published: February 2011

Abstract
Unrepaired lesion on DNA template blocks replication fork progression and causes replication stress. Prolonged stalling of replication may give rise to serious consequences such as replication collapse, DNA double strand breaks (DSBs), recombination and genomic instability. The lesion bypass pathway, which is regulated by PCNA monoubiquitination, is essential for resolving replication stalling. We demonstrated a novel tumor suppressive function of p33ING1b (ING1b) in preserving genomic stability upon replication stress. We found that ING1b knockdown cells exhibit defects in S phase recovery and enhanced genomic instability due to UV-induced replication blockage. We showed that ING1b is required for PCNA monoubiquitination upon replication stress. Enhanced PCNA monoubiquitination due to overexpression of the E3 ligase Rad18 or knockdown of the deubiquitinating enzyme USP1 is abrogated in ING1b depleted cells. Furthermore, ING1b is required for Rad18 foci formation, localization to chromatin and interaction with PCNA after UV. In addition, ING1b is required for foci formation of Polη, a translesion DNA polymerase, indicating that ING1b is involved in regulation of the lesion bypass mechanism. We found that ING1b depleted cells display hypoacetylation of histone H4 at S phase and treatment with class I and II histone deacetylase inhibitors restores histone H4 acetylation and PCNA monoubiquitination in ING1b knockdown cells. These data suggest that ING1b regulates PCNA monoubiquitination through histone H4 acetylation to facilitate lesion bypass and recovery from replication blockage. This provides insights into a novel mechanism regulating lesion bypass through chromatin remodeling in maintaining genomic stability upon replication stress. It has implications in developing new strategies for cancer prevention and treatment.
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 2979.