bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5368: Increase in viral load, viral integration and gain of telomerase genes during uterine cervical carcinogenesis can be simultaneously assessed by the HPV MLPA-assay
Authors: Speel Ernst-Jan M. , Theelen Wendy , Herfs Michael , Reijans Martin , Simons Guus , Meulemans Els V. , Baldewijns Marcella M. , Ramaekers Frans CS , Somja Joan , Delvenne Philippe , Hopman Anton HN 
Published: February 2011

Abstract
Oncogenic human papillomavirus (HPV) infection is the most important risk factor in cervical carcinogenesis with high viral load, viral integration into the host genome, and gain of the telomerase-related genes TERT and TERC being factors associated with progression to cancer. A recently developed multiparameter HPV MLPA-assay (Theelen et al. Int J Cancer 2009, Epub Aug 26) that allows the simultaneous assessment of these factors was applied to a series of normal and (pre)malignant frozen uterine cervical samples, and tested for its ability to identify high grade cervical lesions with both high sensitivity and specificity.
A total of 67 cervical samples from normal cervix, as well as different (pre)malignant stages was analysed by the MLPA-assay and validated by quantitative PCR, the PapilloCheck, and fluorescence in situ hybridization for the individual parameters.
Only 5 out of 37 (14%) normal samples or low grade cervical lesions (CIN1 and condyloma) showed either a HPV16 viral load higher than 25 copies per cell, viral integration, and/or gain of one of the telomerase related genes, whereas for the high grade cervical lesions (CIN2/3 and squamous cell carcinoma) one or more of these parameters were found in 25 out of 30 cases (83%). As a result, the HPV MLPA-assay combines a sensitivity of 83% with a specificity of 86% in frozen cervical specimens, making it a valuable screening tool for cervical (pre)neoplasia.
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 5368.
Abstract 5408: Exploiting the defective p53/MDM2/p14ARF pathway in neuroblastoma by targeting checkpoint kinase Chk1 with AZD7762
Authors: Xu Hong , Wei Xiao , Cheung Irene Y. , Cheung Nai-Kong V. 
Published: February 2011

Abstract
Introduction: A defective p53/MDM2/p14ARF pathway seems to be the principal mode of checkpoint dysfunction in metastatic neuroblastoma following DNA damage, which probably accounts for chemoresistance after initial treatment response. Checkpoint kinase inhibitor AZD7762 (AstraZeneca, currently in clinical trials) has the potential to enhance the action of DNA-damaging agents in some advanced solid malignancies. In this study, we assessed the potential synergy between AZD7762 and chemotherapeutic agents in the in vitro and in vivo treatment of neuroblastoma cells which harbor aberrations in the p53/MDM2/p14ARF pathway.
Experimental Design: AZD7762 was tested in combination with chemotherapeutic agents both in vitro and in vivo against a representative panel of neuroblastoma cell lines. Ten were p53/MDM2/p14ARF pathway-defective (four with p53 mutations, three with MDM2 amplification, and three with p14ARF deletion) and three were wild type. Using these lines, p53/p21 functional assay, drug induced cytotoxicity, S/G2 checkpoint abrogation, and therapy of xenografts were examined. Synergism with chemotherapy was quantified using combination index (CI). CI&lt;1 indicates synergism, CI=1 additive effects, and CI&gt;1 antagonism.
Results: Based on p53/p21 functional assays, all four p53 mutant lines failed to show endogenous p21 induction after DNA damage (defined as p53 pathway nonfunctional). Similarly, p53 was nonfunctional in two of the three MDM2 amplified and one of the three p14ARF deleted cell lines. In cytotoxicity assays, p53 nonfunctional lines were more resistant to DNA-damaging agents when compared to p53 functional lines. Synergy between AZD7762 and DNA-damaging agents (cisplatin, doxorubicin, etoposide, melphalan, SN38 and topotecan) was strong in all p53 nonfunctional lines (average CI values: 0.44 - 0.63), but not in p53 functional lines (average CI values greater than 1.0). In contrast, gemcitabine showed even stronger synergy with AZD7762 regardless of p53 functional status (CI values: 0.11 - 0.47). AZD7762 treatment resulted in the abrogation of DNA damage-induced S/G2 checkpoint arrest, and in the potentiation of antitumor activity of DNA-damaging agents in four mouse xenograft models.
Conclusions: AZD7762 potentiated both in vitro and in vivo the antitumor effects of DNA-damaging agents against neuroblastoma. These results suggest that the addition of AZD7762 may reverse or prevent drug resistance, especially if a defective p53/MDM2/p14ARF pathway is the underlying mechanism.
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 5408.
Abstract 5413: Maximal Power Design and Analysis of Drug Combination Studies: Applications to Vorinostat with Cytosine Arabinoside and Etoposide and Other Combination Studies
Authors: Fang Hong-Bin , Ross Douglas D. , Edelman Martin J. , Sausville Edward A. , Li Wei , Tan Ming T. 
Published: February 2011

Abstract
Drug combinations are the hallmark of cancer therapy. Preclinical experiments on multi-drug combinations are important steps to bring the therapy to clinic. A statistical approach for evaluating the joint effect of the combination is necessary because even in vitro experiments often demonstrate significant variation in dose-effect. Such variation needs to be accounted for in the experimental design and analysis. Our research has developed a maximal power (MP) design and interaction index surface (IIS) analysis methods for in vitro and in vivo (e.g., xenograft) combination studies so that the joint effect of a combination can be estimated efficiently and the most synergistic combination can be identified. We demonstrate that these statistical methods and software have resulted in the identification of highly synergistic dose combinations that could have been missed with classic methods.
The first study is the combination of vorinostat (suberoylanilide hydroxamic acid) combined with ara-C and with etoposide in leukemia cell lines. The doses in the experiment were generated by the MP design and the data analyzed using the IIS approach so that synergistic, additive and antagonistic interaction dose regions are identified. Cytotoxic antagonism resulted when vorinostat was combined concomitantly with ara-C; however, when vorinostat was given first followed by a drug-free interval before ara-C treatment, this sequential combination was mostly synergistic. Etoposide combined with vorinostat was additive to synergistic, and the synergism became more pronounced when etoposide was given post a drug-free interval after vorinostat. These findings are used in designing the CTEP trial (NCI 6829: Phase I trial of vorinostat in combination with cytarabine and etoposide in patients with advanced acute leukemia and high-risk myelodysplastic syndromes, PI: Gojo/Ross). The interim results on toxicity and response have been consistent with the model.
Another study utilized a novel thiazolidine compound plus Sorafnib where initial experiments using classic methods failed to identify synergistic combinations. Subsequent experiments using the MP methodologies demonstrated significant synergistic drug combinations. The SynStat R program for the design and analysis of drug synergy is available at http://www.umgcc.org/research/biostat_software.htm).
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 5413.
Abstract 542: Inoculated carcinoma associated fibroblasts and hormone independent murine mammary tumor growth
Authors: Sahores Ana , Fabris Victoria , Vanzulli Silvia , Lanari Claudia , Lamb Caroline A. 
Published: February 2011

Abstract
Murine mammary carcinomas from the MPA-murine breast cancer model express estrogen and progesterone receptors and transit through different stages of hormone dependence. Hormone dependent (HD) tumors only grow in the presence of medroxyprogesterone acetate (MPA) and hormone independent (HI) variants are those that grow without hormone supply. In co-culture studies we have demonstrated that carcinoma associated fibroblasts (CAF) from HI tumors (CAF HI) can stimulate epithelial cell proliferation better than those from HD tumors (CAF HD). However, in vivo, CAF-HI inoculated together with purified epithelial cells (EPI) only increased tumor growth of EPI HI and they were not able to replace the hormone requirement of EPI HD. Thus, the aim of this study was to investigate the role of CAF HI enhancing HI tumor growth and to elucidate why CAF HI failed to stimulate HD cells in vivo. For this purpose murine C4-HI tumors were transplanted in BALB/c-wt (wt) or in BALB/c-GFP (GFP) mice. Mice were subcutaneously inoculated with EPI HI alone or co-mingled with CAF HI-wt (in GFP mice) or CAF HI-GFP (in wt mice) and the resulting tumors were excised at different time points. Fluorescence analysis of frozen sections indicated that inoculated CAF HI-GFP were detected 7 days after their inoculum in wt mice whereas they were no longer detected at later time points. To elucidate how CAF HI are able to enhance tumor growth when co-inoculated with EPI HI cells, we quantified polymorphonuclear (hematoxilin and eosin) and mast cells (toluidine blue staining) in the EPI HI + CAF HI group and in the EPI HI group and no significant differences were observed. In similar experiments when cells were inoculated intradermically to evaluate angiogenesis, and animals were sacrificed after different time points, we observed that on day 5, there was a significantly higher number of vessels in the co-inoculated group (Control 1.1±0.1; CAF HI 1.8± 0.8; EPI HI 2.0±0.7; EPI HI + CAF HI 3.3±0.5 p&lt;0.05). In summary, we conclude that the inoculated CAF fail to induce HD growth because they do not persist in the tumor mass, although they may participate during the first stages of tumor growth favoring angiogenesis.
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 542.
Abstract 5425: Characterization of synergistic antiproliferative effects of combined γ-tocotrienol and celecoxib treatment on neoplastic mouse mammary epithelial cells in vitro
Authors: Shirode Amit B. , Sylvester Paul W. 
Published: February 2011

Abstract
In the present study, synergistic antiproliferative effects of combined treatment of γ-tocotrienol and celecoxib on +SA mouse mammary epithelial cells were evaluated and characterized for their mechanism(s) of action. Earlier studies have shown that these effects are mediated partly by inhibition of PGE2, which is a direct indicator of COX-2 activity in cells. Since 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD+-dependent oxidation of 15(S)-hydroxyl group of prostaglandins and has been considered a key enzyme in biological inactivation of prostaglandins, the effects of these drugs on intracellular levels of 15-PGDH were assessed. Consistent with earlier findings, western blot analysis showed increased levels of 15-PGDH by individual treatment of effective doses of both γ-tocotrienol (3.5 μM) and celecoxib (20 μM). Combined treatment with subeffective doses of γ-tocotrienol (0.25 μM) and celecoxib (2.5 μM) showed increased levels of 15-PGDH as compared to the same individual doses when treated alone. These studies indicate that the antiproliferative effects are mediated by inducing the expression of 15-PGDH, which leads to enhanced inactivation of PGE2. Similar to earlier studies which showed that these effects were associated with a suppression of Akt and NFκB activity, the present studies showed that treatment with 3.5 μM γ-tocotrienol alone induced a relatively large decrease in phospho-PDK-1 and phospho-Akt levels, but had no effect on PI3K p85, PTEN and phospho-PTEN levels. In contrast, treatment with 20 μM celecoxib alone was associated with a relatively large decrease in PI3K p85 levels. Combined treatment with subeffective doses of γ-tocotrienol and celecoxib caused a large decrease in PI3K, phospho-PDK-1, phospho-Akt and phospho-GSK-3β levels as compared to vehicle treated controls. In addition, a large decrease in phospho-IKK-α/β, phospho-IκB-α, and phospho-NFκB levels was observed in the combination treatment group relative to the same subeffective doses when given alone. In conclusion, these studies show that synergistic antiproliferative effects of combination treatment of γ-tocotrienol and celecoxib are associated with two different mechanisms; 1) a COX-2-dependent mechanism of induction of 15-PGDH leading to enhanced inactivation of PGE2; and 2) a COX-2-independent mechanism of attenuation of EGF-dependent PI3K/PDK-1/Akt and NFκB mitogenic signaling pathways. Further studies are required to evaluate the role of prostaglandin and EGF receptors in mediating these two independent mechanisms. This study was supported by grants from NIH (CA86833) and First Tech International Ltd.
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 5425.
Abstract 543: Stromal impact on tumor invasiveness and gelatinolytic activity at the invasive front
Authors: Hadler-Olsen Elin , Ravuri Chandra , Ljones Hilde , Rikardsen Oddveig , Steigen Sonja , Svineng Gunbjørg , Winberg Jan-Olof , Uhlin-Hansen Lars 
Published: February 2011

Abstract
The aim of this study was to explore the impact of tumor stroma on invasiveness and expression of gelatinases in xenograft carcinomas.
Xenograft tumors of various human carcinoma cells were established either in the tongue or the skin of BALB/c Nude mice. Cell lines originating from oral and skin SCCs were used, as well as a cell line foreign to both organs. Gelatinolytic activity in the tumors was investigated by a novel in situ zymography technique which enables high image resolution. In vivo and in vitro expression of various proteolytic enzymes were analyzed at transcriptional and protein level using RT-qPCR, immunohistochemistry, Western blotting and SDS-PAGE substrate zymography.
Tongue tumors showed an invasive growth pattern, whereas the skin tumors established from the same cell lines were non-invasive. Although the repertoire of proteolytic enzymes differed between the cell lines, the tongue tumors of all cell lines showed strong gelatinolytic activity, especially at the invasive front. In contrast, the skin tumors showed only weak gelatinolytic activity.
Our results suggest that invasiveness as well as activity of proteolytic enzymes in the tumors is more dependent on the tumor microenvironment than on inherent properties of the 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 543.
Abstract 5430: Epigenetic targeting by histone deacetylase inhibitors reduces viability and induces apoptosis in human embryonal carcinoma cells
Authors: Bhinder Arvinder , Varma Vivek , Abbaoui Besma , Clinton Steven K. , Mortazavi Amir 
Published: February 2011

Abstract
The disruption of the epigenetic regulation, including the acetylation status of nucleosomal histones, impacts gene expression; and has been implicated in the pathogenesis of cancer. Histone deacetylase inhibitors (HDACIs) are being evaluated for anticancer activity based upon their ability to induce differentiation, inhibit cancer cell proliferation, and enhance sensitivity to apoptotic signaling. Although, germ cell tumors (GCT) have a high cure rate, effective agents with less toxicity are desired. Most critically, those with relapsed/refractory disease need new and effective second line agents. Serendipitously, in murine studies of prostate carcinogenesis with a novel HDACI developed at the Ohio State University we observed significant testicular atrophy, with essentially no histopathologic toxicity to other organs [Cancer Res 2008; 68:(10)]. This observation led us to investigate the in vitro effects of HDACIs (our novel HDACI and suberoylanilide hydroxamic acid - SAHA) in the NTERA-2, an embryonal carcinoma cell line derived from a human testicular cancer. We evaluated their dose- and time-dependent effects on cell viability (MTS assay), apoptosis (caspase-3/7 activity, and PARP cleavage); and HDAC inhibition (immunoblotting). Assessment of cell signaling pathways (EGFR, and ErbB2) and anti-apoptotic molecules (Bcl-2) were performed by immunoblotting. Treatment of NTERA-2 cells with HDACIs at 0.1 - 10 µM concentrations showed a time- and dose-dependent reduction in cell viability. The IC50, at 72 hours of treatment, was 0.2 µM for our novel HDACI compared to 1.5 µM for SAHA. Both agents significantly induced apoptosis, but SAHA was less potent. Our novel HDACI significantly down-regulated the expression of EGFR, ErbB2 and Bcl-2 along with increased acetylation of histones H-3 and H-4, in a dose-dependent manner. These effects were more potent than observed with SAHA. In conclusion, HDACIs, especially our novel HDACI, appear to be potent inhibitors of cell viability and inducers of apoptosis in NTERA-2 human embryonal carcinoma cells. Our studies suggest that chromatin hyperacetylation, resulting in a coordinated change in recruitment of epigenetic modulators and transcription factors including tumor suppressor genes may result from targeted HDACI in germ cell cancers. The further preclinical development of HDACIs for the treatment of advanced germ cell tumors is underway.
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 5430.
Abstract 5438: A novel therapeutic combination with synergistic antitumor activity in colon cancer: The dual tyrosine kinase inhibitor lapatinib and the histone deacetylase inhibitor LBH589
Authors: LaBonte Melissa J. , Wilson Peter M. , El-Khoueiry Anthony , Lenz Heinz-Josef , Ladner Robert D. 
Published: February 2011

Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. Effective treatment is hindered by the high incidence of drug resistance and tumor recurrence, resulting in the need to identify and exploit novel therapeutic targets and drug combinations to improve clinical efficacy. The epidermal growth factor receptor (EGFR) has been implicated in colon cancer growth, progression and chemoresistance and inhibition of EGFR has therefore become an efficacious drug target. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER-2 and suppressing oncogenic signaling through the RAS-RAF-MEK-ERK and PI3K/AKT pathways. Histone deacetylase inhibitors (HDACi) are a novel class of agents demonstrating promising activity against colon cancer cells through the hyper-acetylation of histone and non-histone proteins resulting in cell cycle arrest and apoptosis. HDACi are also reported to disrupt HSP90 function, inducing the degradation of EGFR-pathway client proteins (e.g. EGFR, HER-2, BRAF). This study sought to evaluate the therapeutic potential of lapatinib in combination with the HDACi LBH589 (Panobinostat) in a panel of eight colon cancer cell lines with varying EGFR/HER-2 expression and KRAS mutational status. EGFR and HER-2 mRNA and protein expression levels were determined by quantitative PCR and Western blot. Concentration-dependent antiproliferative effects of both lapatinib and LBH589 were observed in vitro (lapatinib range 7.6-15.8 μM; LBH589 range 7.2-30 nM) using the MTS assay. The combination of LBH589 and lapatinib interacted synergistically to inhibit both cell proliferation and colony formation in all colon cancer cell lines tested. Combination treatment resulted in decreased signaling through both the PI3K and MAPK pathways as determined by decreased levels of phospho-AKT and phospho-p44/42 MAPK. Co-treatment with lapatinib and LBH589 also resulted in the rapid induction of apoptosis as early as 18 h post-treatment as determined by flow cytometry and Western blot analysis of apoptotic factors including cleaved caspase-8 and PARP. These in vitro observations were extended to a LoVo colon cancer xenograft model where combination treatment resulted in greater antitumor activity than either lapatinib or LBH589 alone, with no apparent increase in toxicity. Together these data provide scientific rationale warranting further investigation of HDACi in combination with EGFR and HER-2-targeted therapies for the treatment of colorectal cancers.
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 5438.