bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2804: The thiazolidinedione pioglitazone enhances the cancer preventive activity of the rexinoid LG100268 in Her2/neu induced breast cancer
Authors: Uray Iván P. , Rodenberg Jennifer M. , Zhang Yun , Hill Jamal L. , Brown Powel H. 
Published: August 2015

Abstract
Two major unresolved issues for breast cancer prevention are the lack of effective preventive agents for estrogen receptor (ER)-negative disease and the potential toxicity of long-term pharmacologic treatment. The ability of retinoid X receptor (RXR)-selective retinoids (rexinoids) to inhibit breast cancer formation independently of ER-status was previously demonstrated in various preclinical models. The goal of our study was to identify ideal druggable targets for the synergistic amplification of the cancer preventive effect of synthetic rexinoids and test the efficacy of a low-dose combination treatment in vivo. We identified the nuclear hormone receptors essential for rexinoid-dependent growth suppression by a high throughput siRNA screen of mammary epithelial cells. Knock-down of ELP, COUP-TF II, GR, TR2, VDR and PPARgamma partially reversed the anti-proliferative effect of the rexinoid bexarotene. Conversely, expression profiling showed that the largest fraction of genes up-regulated by the synthetic rexinoid LG100268 represented regulators of lipid metabolism and putative target genes of the RXR partner receptor PPARgamma. Combination dose-response experiments showed that the PPARgamma agonist pioglitazone was synergistic with low doses (100-300 nM) of LG100268. Long-term daily treatment of MMTV-ErbB2 mice with LG100268 (25 mg/kg) or pioglitazone (20 mg/kg), or their combination resulted in a significant delay of tumor formation, while serum triglyceride levels were not significantly elevated by the combination. Suppression of cell proliferation measured by reduced Ki67 staining was enhanced by the addition of pioglitazone, in both lesions and intact mammary epithelium, while pioglitazone also increased the frequency of cells containing cleaved caspase 3. Furthermore, pioglitazone treatment was associated with a marked induction of microvesicle formation in the adipose issue. These data suggest that the combination of LG100268 and pioglitazone, while potentially targeting the same heterodimer, can invoke distinct biological processes resulting in more effective cancer prevention than achieved by either agent alone, and may be an effective strategy for the prevention of ER-negative breast cancer.
Citation Format: Iván P. Uray, Jennifer M. Rodenberg, Yun Zhang, Jamal L. Hill, Powel H. Brown. The thiazolidinedione pioglitazone enhances the cancer preventive activity of the rexinoid LG100268 in Her2/neu induced breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2804. doi:10.1158/1538-7445.AM2015-2804
Abstract 2809: Chemopreventive studies of multiple agents in the methylnitrosourea-induced ER+ mammary cancer model in animals on standard and Western diets
Authors: Grubbs Clinton J. , Miller Mark S. , Steele Vernon E. , Moeinpour Fariba , Seifried Harold , Heckman-Stoddard Brandy M. , Lubet Ronald A. 
Published: August 2015

Abstract
Multiple positive and negative preventive agents [tamoxifen, vorozole (aromatase inhibitor), targretin (RXR agonist), gefitinib (EGFR inhibitor), metformin, and Lipitor] were examined for efficacy in rats given either standard Teklad (4% fat) diet or a modified Western diet [high fat (42%)]. Female Sprague Dawley rats were placed on the high fat or standard diet at 43 days of age, and administered methylnitrosourea (MNU) at 50 days of age. Rats on high fat diet vs standard diet gained approximately 40% more weight, exhibited a 50% increase in cancer multiplicity, and a decrease in cancer latency. The strong preventive agents (tamoxifen, vorozole, targretin, and gefitinib) were highly effective in animals on standard or high fat diets (reducing cancer multiplicity &gt;75% in rats on either diet). It was unclear whether the altered physiology of animals on high fat diet or altered PK of agents in animals with higher fat content might alter activity of these agents. We had previously found that both metformin and Lipitor were ineffective in rats on a standard fat diet, but thought that they might be effective in rats on a high fat diet. Interestingly, neither compound decreased tumorigenesis; but, at least marginally, increased tumor incidence and final tumor weights in rats on both diets. The ability of the various agents to alter proliferation of normal mammary epithelium in MNU-treated rats exposed for 2 weeks to the various agents was determined. It was found that inhibition of proliferation in mammary epithelium corresponded well to the efficacy of these agents in long-term chemopreventive assays. These results demonstrated that: (1) a high fat diet can be employed in this rat model to increase tumor multiplicity; (2) tamoxifen, vorozole, targretin and gefitinib were highly effective in rats on standard or high fat diet; (3) metformin and Lipitor were ineffective with either diet; and (4) there is a correlation between inhibition of proliferation in normal mammary epithelium and long-term preventive efficacy of agents; but this may reflect the homogeneity of the rat mammary cancers. Supported by NCI contract HHSN261201200021I.
Citation Format: Clinton J. Grubbs, Mark S. Miller, Vernon E. Steele, Fariba Moeinpour, Harold Seifried, Brandy M. Heckman-Stoddard, Ronald A. Lubet. Chemopreventive studies of multiple agents in the methylnitrosourea-induced ER+ mammary cancer model in animals on standard and Western diets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2809. doi:10.1158/1538-7445.AM2015-2809
Abstract 281: Virotherapy with a Semliki Forest virus-based vector encoding IL-12 synergizes with PD-1/PD-L1 blockade
Authors: Quetglas José I. , Labiano Sara , Aznar M. Ángela , Bolaños Elixabet , Azpilicueta Arantza , Rodríguez Inmaculada , Casales Erkuden , Rodríguez Alfonso , Smerdou Cristian , Melero Ignacio 
Published: August 2015

Abstract
Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but non-replicative viral vector system based on Semliki Forest virus that encodes IL-12 (SFV-IL-12). Following direct intratumoral injection, infected cells release transgenic IL-12, die and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL-12. In difficult to treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL-12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL-12 + anti-PD-1 mAb treatment only marginally increased the elicited CTL response over SFV-IL-12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL-12 treatment induced expression of PD-L1 on tumor cells in an IFNγ-dependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL-12 + anti-PD-1 mAb combination.
Citation Format: José I. Quetglas, Sara Labiano, M. Ángela Aznar, Elixabet Bolaños, Arantza Azpilicueta, Inmaculada Rodríguez, Erkuden Casales, Alfonso Rodríguez, Cristian Smerdou, Ignacio Melero. Virotherapy with a Semliki Forest virus-based vector encoding IL-12 synergizes with PD-1/PD-L1 blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 281. doi:10.1158/1538-7445.AM2015-281
Abstract 2822: Aspirin and other non-steroidal anti-inflammatory drug prescriptions after diagnosis and upper aerodigestive tract cancer survival
Authors: Macfarlane Tatiana V. 
Published: August 2015

Abstract
Aspirin and other NSAIDs are widely used as analgesics and preventative agents for vascular events. Research evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. Data on the chemo preventative role of these drugs on the mortality in patients with upper aerodigestive tract cancer (UADT) are insufficient.
The aim of this study was to investigate the effect of aspirin and other NSAIDs prescriptions after cancer diagnosis on the survival in UADT cancer patients.
Patients with UADT cancer (oral cavity, oropharynx, hypopharynx, larynx or esophagus) were identified from the Primary Care Clinical Informatics Unit (PCCIU) database which contains information from a sample of general medical practices in Scotland, United Kingdom. Cox regression was used for statistical data analysis.
There were 2,392 cases of UADT cancer diagnosed between 1996 and 2010 from 131 general medical practices. The mean age of patients was 66 years (SD 12), and most were male (63%). Median survival in head and neck cancer (HNC) patients was 94 months, while median survival in oesophageal cancer patients was 10 months.
For HNC, improved survival was observed with aspirin prescription (ever vs never Hazard Ration (HR) = 0.5 95% Confidence Interval (CI) 0.4, 0.7) and other NSAIDs prescription (ever vs never HR = 0.7 95% CI 0.6, 0.9), however there was no association with COX-2 prescriptions. For oesophageal cancer patients, improved survival was observed with aspirin prescriptions (ever vs never HR = 0.5 95% CI 0.5, 0.6), Cox-2 prescriptions (HR = 0.8 95% CI 0.6, 0.9) and other NSAIDs (HR = 0.7 95% CI 0.6, 0.8).
Conclusion: Aspirin and other NSAIDs prescriptions after diagnosis may reduce all-cause mortality in UADT cancer patients.
Citation Format: Tatiana V. Macfarlane. Aspirin and other non-steroidal anti-inflammatory drug prescriptions after diagnosis and upper aerodigestive tract cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2822. doi:10.1158/1538-7445.AM2015-2822
Abstract 2824: Evaluation of Ibuprofen loaded solid lipid nanoparticles and its combination regimens for pancreatic cancer chemoprevention
Authors: Thakkar Arvind , Chenreddy Sushma , Wang Jeffrey , Prabhu Sunil 
Published: August 2015

Abstract
The objective of the present study was to establish the individual and combined chemopreventive potential of a widely used non-steroidal anti-inflammatory drug, ibuprofen (IBU), encapsulated in solid lipid nanoparticles (SLNs) for the chemoprevention of pancreatic cancer. The synergistic effect of combination of IBU with sulforaphane (SFN) was also evaluated. Cell viability studies were conducted followed by colony formation and NF-κB DNA binding assays. The IC50 concentration of free IBU in human pancreatic cancer cells Panc-1 and MIA PaCa-2 were 1.25mM and 1.26 mM, respectively. SLN optimization study of IBU revealed stearic acid (1:2 drug to lipid ratio) formulated with Poloxamer 188 to be the most efficacious in cell viability study. Upon encapsulation in SLNs, IC50 concentration of IBU-SLN was 113.8 μM and 122.6 μM for Panc-1 and MIA PACa-2 cells respectively, reflecting a 10-fold reduction compared to free IBU. Combinations of low doses of free IBU (250 μM) and SFN (5 μM) reduced cell viability by ∼55% (P&lt;0.01), whereas a lower dose of encapsulated IBU-SLN (62.5 μM) and free SFN (5 μM) reduced cell viability by ∼80% (P&lt;0.001) for both Panc-1 and MIA PaCa-2 cells. These results reflect 4-fold reduction in IBU-SLN dose in combination compared to free IBU. Moreover, IBU-SLN and free SFN combination reduced number of colonies by ∼50% (P&lt;0.01). Further, IBU-SLN and SFN combinations showed down-regulation of DNA binding activity of the p50 subunit of NF-κB. In conclusion, these preliminary results demonstrate the potential of IBU as a chemopreventive agent against pancreatic cancer. Furthermore, when encapsulated in nanotechnology-based SLN delivery systems and delivered in combination with SFN provide evidence of a promising approach for pancreatic cancer prevention and therapy.
Citation Format: Arvind Thakkar, Sushma Chenreddy, Jeffrey Wang, Sunil Prabhu. Evaluation of Ibuprofen loaded solid lipid nanoparticles and its combination regimens for pancreatic cancer chemoprevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2824. doi:10.1158/1538-7445.AM2015-2824
Abstract 283: Smac mimetic and radiotherapy synergize to enhance antitumor immunity in lung cancer by targeting immunosuppressive cells
Authors: Tao Zhen , Myers Carey , Wiedemann Norbert , Vuagniaux Gregoire , Harshyne Larry , Dicker Adam , Hooper D. Craig , Lu Bo 
Published: August 2015

Abstract
Purpose
Hypofractionated radiotherapy (RT) directly kills lung cancer cells and stimulates tumor antigen release, the immune response to which can be augmented further by systemic immune-modulating agents. However, local relapses often occur after RT alone, indicating that inhibitory mechanisms may limit the anti-tumor immune responses elicited by apopotic tumor cells. We hypothesized that delivery of Smac mimetic, which sensitizes cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, following RT might lead to prolonged antitumor immunity by promoting the destruction of immunosuppressive myeloid cells.
Experimental Design
Using a murine model of lung cancer, we tested whether combination treatment with radiotherapy and the Smac mimetic Debio1143 would target immunosuppresive myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and enhance the efficacy of cytotoxic T cells.
Results
We demonstrate that administration of Debio1143 enhances the efficacy of RT by inducing LLC and LLC-OVA cells apoptosis in vitro. In addition, we show that combining radiotherapy and Debio1143 in vivo synergistically reduces the local accumulation of tumor-infiltrating MDSCs through a cytotoxic T cell-dependent mechanism. Activation of cytotoxic T cells by combination therapy proved to be mediated through the enhanced release of tumor necrosis factor alpha (TNF-α) in the tumor microenvironment.
Conclusions
These data offer a new paradigm to limit immunosuppresion by targeting MDSC and serve as the foundation for future clinical translation of combination therapy with Smac mimetics and radiotherapy.
Citation Format: Zhen Tao, Carey Myers, Norbert Wiedemann, Gregoire Vuagniaux, Larry Harshyne, Adam Dicker, D. Craig Hooper, Bo Lu. Smac mimetic and radiotherapy synergize to enhance antitumor immunity in lung cancer by targeting immunosuppressive cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 283. doi:10.1158/1538-7445.AM2015-283
Abstract 2839: Specific mutant tumor DNA can be detected in ovarian cystic fluid of an unknown ovarian tumor cyst
Authors: Sundfeldt Karin , Kristjansdottir Björg , Vogelstein Bert 
Published: August 2015

Abstract
Can we detect rare mutations in ovarian cystic fluid of unknown severity in order to develop a molecular genetic test for epithelial ovarian cancer?
Background: Benign and malignant ovarian cysts are difficult to distinguish. Early diagnose is life saving, however 75% of ovarian adenocarcinomas is found in late stage. Approx. one operated ovarian cyst in 7-10 are found to be cancer and potentially life-threatening, subjecting the woman to unnecessary oophorectomy and morbidity. A genetic test of fine needle aspirated cystic fluid has to be very accurate to be able to substitute the histopathologic examination following surgery.
Methods: DNA was purified from 78 ovarian cystic fluids (collected at the time of operation) from serous adenomas/adenocarcinomas and corresponding tumor tissues and subjected to state-of-the-art genetic analysis. We evaluated ∼10,000 bp for subtle mutations (single base substitutions, small insertions, small deletions). Under the conditions used, mutations present in &gt;0.1% of template molecules could be detected. The analyses were carried out in a completely blind fashion. We then evaluated the DNA of the primary tumor.
Results: We detected zero, one, or two mutations per cyst. The same mutations were identified in the corresponding tumor tissue, and no others. This dramatically confirms the specificity of the approach. 91% of the malignant cysts (n = 32) had at least one mutation and 62% of these were in TP53; 17% in low (n = 12) and 90% in high (n = 20) grade serous adenocarcinoma regardless of stage. In low-grade tumors mutations in KRAS dominated over PIK3C and PTEN. 65% of the borderline type (LMP n = 20) tumors had a BRAF V600E mutation. The mutant allelic fraction was much higher in malignant than benign tumors; the DNA concentration was relatively low in 20 benign cysts and no mutations were identified in this group consisting of 10 serous adenoma and 10 simple cysts (healthy controls). Results will be correlated to survival.
Conclusion: Data proofs that we can detect mutant tumor DNA corresponding to the primary ovarian tumor in the ovarian cystic fluid. Data suggest that gene-testing of ovarian cystic fluid could aid in diagnostics and further guide its management.
Citation Format: Karin Sundfeldt, Björg Kristjansdottir, Bert Vogelstein. Specific mutant tumor DNA can be detected in ovarian cystic fluid of an unknown ovarian tumor cyst. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2839. doi:10.1158/1538-7445.AM2015-2839
Abstract 2845: Co-acquisition of T790M and EMT in resistant EGFR mutant non-small cell lung cancer can be overcome by combined irreversible EGFR and BCL-XL inhibition
Authors: Hata Aaron N. , Niederst Matthew J. , Archibald Hannah L. , Mulvey Hillary , Ham Jungoh , Gomez-Caraballo Maria , Kalsy Anuj , Faber Anthony C. , Engelman Jeffrey 
Published: August 2015

Abstract
The development of acquired drug resistance limits the effectiveness of targeted therapies for lung cancer. In 50% of patients with EGFR mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR inhibitors can be attributed to the development of a secondary T790M mutation that prevents drug binding. Third generation irreversible EGFR inhibitors that effectively inhibit EGFR with T790M are currently under clinical development. Using patient-derived EGFR mutant NSCLC models of T790M+ acquired resistance, we observed that the presence of a mesenchymal phenotype was associated with a decreased response to subsequent irreversible EGFR inhibitor therapy. Epithelial-to-mesenchymal transformation (EMT) led to suppression of pro-apoptotic signaling and a blunted apoptotic response to EGFR inhibition. Combination BCL-XL and irreversible EGFR inhibitor therapy restored the apoptotic response and resulted in regressions of T790M+ resistant tumors that exhibited poor response to single agent irreversible EGFR inhibitors. This suggests that combining BCL-XL and irreversible EGFR inhibitors may be an effective treatment strategy for T790M+ resistant EGFR mutant lung cancers with suppressed apoptotic signaling due co-acquisition of a mesenchymal phenotype.
Citation Format: Aaron N. Hata, Matthew J. Niederst, Hannah L. Archibald, Hillary Mulvey, Jungoh Ham, Maria Gomez-Caraballo, Anuj Kalsy, Anthony C. Faber, Jeffrey Engelman. Co-acquisition of T790M and EMT in resistant EGFR mutant non-small cell lung cancer can be overcome by combined irreversible EGFR and BCL-XL inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2845. doi:10.1158/1538-7445.AM2015-2845
Abstract 2862: MBD3 regulates chromatin accessibility at active promoters
Authors: Shimbo Takashi , Lavender Christopher , Grimm Sara A. , Doi Makiko I. , Henriques Telmo , Cannady Kimberly R. , Murphy Kevin J. , Gilchrist Daniel A. , Burkholder Adam , Hayes Jeffrey J. , Adelman Karen , Archer Trevor K. , Zaret Kenneth S. , Wade Paul A. 
Published: August 2015

Abstract
Chromatin structure is tightly regulated in cells and its dysregulation is associated with diseases such as cancer. The Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex is postulated to organize chromatin structure using its nucleosome remodeling and histone deacetylase activities. MBD3 is an integral component of NuRD, which potentially targets the complex to the specific sites of the genome. Recently, we have demonstrated that MBD3/NuRD targets regulatory elements of active genes, a finding diametrically opposed to historical models depicting NuRD as a co-repressor localized to transcriptionally non-permissive chromatin. Moreover, MBD3 co-localized with RNA polymerase II (pol II) at loci where promoter-enhancer loops are formed. Although our previous findings shed light on the role of NuRD in the regulation of active genes, the detailed mechanism of how NuRD is involved in transcriptional regulation is yet not fully understood. To investigate this question, we have developed a next generation, tagmentation based chromatin immunoprecipitation method followed by massively parallel sequencing (ChIP-nexo), which substantially increased the resolution of the MBD3/NuRD mapping. ChIP-nexo defined MBD3/NuRD localization at high resolution, showing accumulation of MBD3 at active promoters with a dip at transcription start site, suggesting an active role of NuRD in modulation of the cell-type specific transcriptional network. To interrogate the detailed functions of NuRD at active promoters, we conducted MNase-seq using conditions which measures both nucleosome positioning and sensitivity, in MBD3 depleted cells. Depletion of MBD3 changed the accessibility of nucleosomes at promoters, while maintaining overall nucleosome positioning. These data indicate an active regulatory function of NuRD in fine tuning the transcriptional network by modulating transcription rates of pol II. We propose that NuRD may be involved in establishing cell type specific gene expression patterns in diverse cell types by organizing promoter nucleoprotein architecture.
Citation Format: Takashi Shimbo, Christopher Lavender, Sara A. Grimm, Makiko I. Doi, Telmo Henriques, Kimberly R. Cannady, Kevin J. Murphy, Daniel A. Gilchrist, Adam Burkholder, Jeffrey J. Hayes, Karen Adelman, Trevor K. Archer, Kenneth S. Zaret, Paul A. Wade. MBD3 regulates chromatin accessibility at active promoters. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2862. doi:10.1158/1538-7445.AM2015-2862